the function of literature review

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Literature reviews, what is a literature review, learning more about how to do a literature review.

• Planning the Review
• The Research Question
• Choosing Where to Search
• Organizing the Review
• Writing the Review

A literature review is a review and synthesis of existing research on a topic or research question. A literature review is meant to analyze the scholarly literature, make connections across writings and identify strengths, weaknesses, trends, and missing conversations. A literature review should address different aspects of a topic as it relates to your research question. A literature review goes beyond a description or summary of the literature you have read. 

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Writing a Literature Review

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A literature review is a document or section of a document that collects key sources on a topic and discusses those sources in conversation with each other (also called synthesis ). The lit review is an important genre in many disciplines, not just literature (i.e., the study of works of literature such as novels and plays). When we say “literature review” or refer to “the literature,” we are talking about the research ( scholarship ) in a given field. You will often see the terms “the research,” “the scholarship,” and “the literature” used mostly interchangeably.

Where, when, and why would I write a lit review?

There are a number of different situations where you might write a literature review, each with slightly different expectations; different disciplines, too, have field-specific expectations for what a literature review is and does. For instance, in the humanities, authors might include more overt argumentation and interpretation of source material in their literature reviews, whereas in the sciences, authors are more likely to report study designs and results in their literature reviews; these differences reflect these disciplines’ purposes and conventions in scholarship. You should always look at examples from your own discipline and talk to professors or mentors in your field to be sure you understand your discipline’s conventions, for literature reviews as well as for any other genre.

A literature review can be a part of a research paper or scholarly article, usually falling after the introduction and before the research methods sections. In these cases, the lit review just needs to cover scholarship that is important to the issue you are writing about; sometimes it will also cover key sources that informed your research methodology.

Lit reviews can also be standalone pieces, either as assignments in a class or as publications. In a class, a lit review may be assigned to help students familiarize themselves with a topic and with scholarship in their field, get an idea of the other researchers working on the topic they’re interested in, find gaps in existing research in order to propose new projects, and/or develop a theoretical framework and methodology for later research. As a publication, a lit review usually is meant to help make other scholars’ lives easier by collecting and summarizing, synthesizing, and analyzing existing research on a topic. This can be especially helpful for students or scholars getting into a new research area, or for directing an entire community of scholars toward questions that have not yet been answered.

What are the parts of a lit review?

Most lit reviews use a basic introduction-body-conclusion structure; if your lit review is part of a larger paper, the introduction and conclusion pieces may be just a few sentences while you focus most of your attention on the body. If your lit review is a standalone piece, the introduction and conclusion take up more space and give you a place to discuss your goals, research methods, and conclusions separately from where you discuss the literature itself.

Introduction:

• An introductory paragraph that explains what your working topic and thesis is
• A forecast of key topics or texts that will appear in the review
• Potentially, a description of how you found sources and how you analyzed them for inclusion and discussion in the review (more often found in published, standalone literature reviews than in lit review sections in an article or research paper)
• Summarize and synthesize: Give an overview of the main points of each source and combine them into a coherent whole
• Analyze and interpret: Don’t just paraphrase other researchers – add your own interpretations where possible, discussing the significance of findings in relation to the literature as a whole
• Critically Evaluate: Mention the strengths and weaknesses of your sources
• Write in well-structured paragraphs: Use transition words and topic sentence to draw connections, comparisons, and contrasts.

Conclusion:

• Summarize the key findings you have taken from the literature and emphasize their significance
• Connect it back to your primary research question

How should I organize my lit review?

Lit reviews can take many different organizational patterns depending on what you are trying to accomplish with the review. Here are some examples:

• Chronological : The simplest approach is to trace the development of the topic over time, which helps familiarize the audience with the topic (for instance if you are introducing something that is not commonly known in your field). If you choose this strategy, be careful to avoid simply listing and summarizing sources in order. Try to analyze the patterns, turning points, and key debates that have shaped the direction of the field. Give your interpretation of how and why certain developments occurred (as mentioned previously, this may not be appropriate in your discipline — check with a teacher or mentor if you’re unsure).
• Thematic : If you have found some recurring central themes that you will continue working with throughout your piece, you can organize your literature review into subsections that address different aspects of the topic. For example, if you are reviewing literature about women and religion, key themes can include the role of women in churches and the religious attitude towards women.
• Qualitative versus quantitative research
• Empirical versus theoretical scholarship
• Divide the research by sociological, historical, or cultural sources
• Theoretical : In many humanities articles, the literature review is the foundation for the theoretical framework. You can use it to discuss various theories, models, and definitions of key concepts. You can argue for the relevance of a specific theoretical approach or combine various theorical concepts to create a framework for your research.

What are some strategies or tips I can use while writing my lit review?

Any lit review is only as good as the research it discusses; make sure your sources are well-chosen and your research is thorough. Don’t be afraid to do more research if you discover a new thread as you’re writing. More info on the research process is available in our "Conducting Research" resources .

As you’re doing your research, create an annotated bibliography ( see our page on the this type of document ). Much of the information used in an annotated bibliography can be used also in a literature review, so you’ll be not only partially drafting your lit review as you research, but also developing your sense of the larger conversation going on among scholars, professionals, and any other stakeholders in your topic.

Usually you will need to synthesize research rather than just summarizing it. This means drawing connections between sources to create a picture of the scholarly conversation on a topic over time. Many student writers struggle to synthesize because they feel they don’t have anything to add to the scholars they are citing; here are some strategies to help you:

• It often helps to remember that the point of these kinds of syntheses is to show your readers how you understand your research, to help them read the rest of your paper.
• Writing teachers often say synthesis is like hosting a dinner party: imagine all your sources are together in a room, discussing your topic. What are they saying to each other?
• Look at the in-text citations in each paragraph. Are you citing just one source for each paragraph? This usually indicates summary only. When you have multiple sources cited in a paragraph, you are more likely to be synthesizing them (not always, but often
• Read more about synthesis here.

The most interesting literature reviews are often written as arguments (again, as mentioned at the beginning of the page, this is discipline-specific and doesn’t work for all situations). Often, the literature review is where you can establish your research as filling a particular gap or as relevant in a particular way. You have some chance to do this in your introduction in an article, but the literature review section gives a more extended opportunity to establish the conversation in the way you would like your readers to see it. You can choose the intellectual lineage you would like to be part of and whose definitions matter most to your thinking (mostly humanities-specific, but this goes for sciences as well). In addressing these points, you argue for your place in the conversation, which tends to make the lit review more compelling than a simple reporting of other sources.

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A literature review surveys prior research published in books, scholarly articles, and any other sources relevant to a particular issue, area of research, or theory, and by so doing, provides a description, summary, and critical evaluation of these works in relation to the research problem being investigated. Literature reviews are designed to provide an overview of sources you have used in researching a particular topic and to demonstrate to your readers how your research fits within existing scholarship about the topic.

Fink, Arlene. Conducting Research Literature Reviews: From the Internet to Paper . Fourth edition. Thousand Oaks, CA: SAGE, 2014.

Importance of a Good Literature Review

A literature review may consist of simply a summary of key sources, but in the social sciences, a literature review usually has an organizational pattern and combines both summary and synthesis, often within specific conceptual categories . A summary is a recap of the important information of the source, but a synthesis is a re-organization, or a reshuffling, of that information in a way that informs how you are planning to investigate a research problem. The analytical features of a literature review might:

• Give a new interpretation of old material or combine new with old interpretations,
• Trace the intellectual progression of the field, including major debates,
• Depending on the situation, evaluate the sources and advise the reader on the most pertinent or relevant research, or
• Usually in the conclusion of a literature review, identify where gaps exist in how a problem has been researched to date.

Given this, the purpose of a literature review is to:

• Place each work in the context of its contribution to understanding the research problem being studied.
• Describe the relationship of each work to the others under consideration.
• Identify new ways to interpret prior research.
• Reveal any gaps that exist in the literature.
• Resolve conflicts amongst seemingly contradictory previous studies.
• Identify areas of prior scholarship to prevent duplication of effort.
• Point the way in fulfilling a need for additional research.
• Locate your own research within the context of existing literature [very important].

Fink, Arlene. Conducting Research Literature Reviews: From the Internet to Paper. 2nd ed. Thousand Oaks, CA: Sage, 2005; Hart, Chris. Doing a Literature Review: Releasing the Social Science Research Imagination . Thousand Oaks, CA: Sage Publications, 1998; Jesson, Jill. Doing Your Literature Review: Traditional and Systematic Techniques . Los Angeles, CA: SAGE, 2011; Knopf, Jeffrey W. "Doing a Literature Review." PS: Political Science and Politics 39 (January 2006): 127-132; Ridley, Diana. The Literature Review: A Step-by-Step Guide for Students . 2nd ed. Los Angeles, CA: SAGE, 2012.

Types of Literature Reviews

It is important to think of knowledge in a given field as consisting of three layers. First, there are the primary studies that researchers conduct and publish. Second are the reviews of those studies that summarize and offer new interpretations built from and often extending beyond the primary studies. Third, there are the perceptions, conclusions, opinion, and interpretations that are shared informally among scholars that become part of the body of epistemological traditions within the field.

In composing a literature review, it is important to note that it is often this third layer of knowledge that is cited as "true" even though it often has only a loose relationship to the primary studies and secondary literature reviews. Given this, while literature reviews are designed to provide an overview and synthesis of pertinent sources you have explored, there are a number of approaches you could adopt depending upon the type of analysis underpinning your study.

Argumentative Review This form examines literature selectively in order to support or refute an argument, deeply embedded assumption, or philosophical problem already established in the literature. The purpose is to develop a body of literature that establishes a contrarian viewpoint. Given the value-laden nature of some social science research [e.g., educational reform; immigration control], argumentative approaches to analyzing the literature can be a legitimate and important form of discourse. However, note that they can also introduce problems of bias when they are used to make summary claims of the sort found in systematic reviews [see below].

Integrative Review Considered a form of research that reviews, critiques, and synthesizes representative literature on a topic in an integrated way such that new frameworks and perspectives on the topic are generated. The body of literature includes all studies that address related or identical hypotheses or research problems. A well-done integrative review meets the same standards as primary research in regard to clarity, rigor, and replication. This is the most common form of review in the social sciences.

Historical Review Few things rest in isolation from historical precedent. Historical literature reviews focus on examining research throughout a period of time, often starting with the first time an issue, concept, theory, phenomena emerged in the literature, then tracing its evolution within the scholarship of a discipline. The purpose is to place research in a historical context to show familiarity with state-of-the-art developments and to identify the likely directions for future research.

Methodological Review A review does not always focus on what someone said [findings], but how they came about saying what they say [method of analysis]. Reviewing methods of analysis provides a framework of understanding at different levels [i.e. those of theory, substantive fields, research approaches, and data collection and analysis techniques], how researchers draw upon a wide variety of knowledge ranging from the conceptual level to practical documents for use in fieldwork in the areas of ontological and epistemological consideration, quantitative and qualitative integration, sampling, interviewing, data collection, and data analysis. This approach helps highlight ethical issues which you should be aware of and consider as you go through your own study.

Systematic Review This form consists of an overview of existing evidence pertinent to a clearly formulated research question, which uses pre-specified and standardized methods to identify and critically appraise relevant research, and to collect, report, and analyze data from the studies that are included in the review. The goal is to deliberately document, critically evaluate, and summarize scientifically all of the research about a clearly defined research problem . Typically it focuses on a very specific empirical question, often posed in a cause-and-effect form, such as "To what extent does A contribute to B?" This type of literature review is primarily applied to examining prior research studies in clinical medicine and allied health fields, but it is increasingly being used in the social sciences.

Theoretical Review The purpose of this form is to examine the corpus of theory that has accumulated in regard to an issue, concept, theory, phenomena. The theoretical literature review helps to establish what theories already exist, the relationships between them, to what degree the existing theories have been investigated, and to develop new hypotheses to be tested. Often this form is used to help establish a lack of appropriate theories or reveal that current theories are inadequate for explaining new or emerging research problems. The unit of analysis can focus on a theoretical concept or a whole theory or framework.

NOTE : Most often the literature review will incorporate some combination of types. For example, a review that examines literature supporting or refuting an argument, assumption, or philosophical problem related to the research problem will also need to include writing supported by sources that establish the history of these arguments in the literature.

Baumeister, Roy F. and Mark R. Leary. "Writing Narrative Literature Reviews."  Review of General Psychology 1 (September 1997): 311-320; Mark R. Fink, Arlene. Conducting Research Literature Reviews: From the Internet to Paper . 2nd ed. Thousand Oaks, CA: Sage, 2005; Hart, Chris. Doing a Literature Review: Releasing the Social Science Research Imagination . Thousand Oaks, CA: Sage Publications, 1998; Kennedy, Mary M. "Defining a Literature." Educational Researcher 36 (April 2007): 139-147; Petticrew, Mark and Helen Roberts. Systematic Reviews in the Social Sciences: A Practical Guide . Malden, MA: Blackwell Publishers, 2006; Torracro, Richard. "Writing Integrative Literature Reviews: Guidelines and Examples." Human Resource Development Review 4 (September 2005): 356-367; Rocco, Tonette S. and Maria S. Plakhotnik. "Literature Reviews, Conceptual Frameworks, and Theoretical Frameworks: Terms, Functions, and Distinctions." Human Ressource Development Review 8 (March 2008): 120-130; Sutton, Anthea. Systematic Approaches to a Successful Literature Review . Los Angeles, CA: Sage Publications, 2016.

Structure and Writing Style

I.  Thinking About Your Literature Review

The structure of a literature review should include the following in support of understanding the research problem :

• An overview of the subject, issue, or theory under consideration, along with the objectives of the literature review,
• Division of works under review into themes or categories [e.g. works that support a particular position, those against, and those offering alternative approaches entirely],
• An explanation of how each work is similar to and how it varies from the others,
• Conclusions as to which pieces are best considered in their argument, are most convincing of their opinions, and make the greatest contribution to the understanding and development of their area of research.

The critical evaluation of each work should consider :

• Provenance -- what are the author's credentials? Are the author's arguments supported by evidence [e.g. primary historical material, case studies, narratives, statistics, recent scientific findings]?
• Methodology -- were the techniques used to identify, gather, and analyze the data appropriate to addressing the research problem? Was the sample size appropriate? Were the results effectively interpreted and reported?
• Objectivity -- is the author's perspective even-handed or prejudicial? Is contrary data considered or is certain pertinent information ignored to prove the author's point?
• Persuasiveness -- which of the author's theses are most convincing or least convincing?
• Validity -- are the author's arguments and conclusions convincing? Does the work ultimately contribute in any significant way to an understanding of the subject?

II.  Development of the Literature Review

Four Basic Stages of Writing 1.  Problem formulation -- which topic or field is being examined and what are its component issues? 2.  Literature search -- finding materials relevant to the subject being explored. 3.  Data evaluation -- determining which literature makes a significant contribution to the understanding of the topic. 4.  Analysis and interpretation -- discussing the findings and conclusions of pertinent literature.

Consider the following issues before writing the literature review: Clarify If your assignment is not specific about what form your literature review should take, seek clarification from your professor by asking these questions: 1.  Roughly how many sources would be appropriate to include? 2.  What types of sources should I review (books, journal articles, websites; scholarly versus popular sources)? 3.  Should I summarize, synthesize, or critique sources by discussing a common theme or issue? 4.  Should I evaluate the sources in any way beyond evaluating how they relate to understanding the research problem? 5.  Should I provide subheadings and other background information, such as definitions and/or a history? Find Models Use the exercise of reviewing the literature to examine how authors in your discipline or area of interest have composed their literature review sections. Read them to get a sense of the types of themes you might want to look for in your own research or to identify ways to organize your final review. The bibliography or reference section of sources you've already read, such as required readings in the course syllabus, are also excellent entry points into your own research. Narrow the Topic The narrower your topic, the easier it will be to limit the number of sources you need to read in order to obtain a good survey of relevant resources. Your professor will probably not expect you to read everything that's available about the topic, but you'll make the act of reviewing easier if you first limit scope of the research problem. A good strategy is to begin by searching the USC Libraries Catalog for recent books about the topic and review the table of contents for chapters that focuses on specific issues. You can also review the indexes of books to find references to specific issues that can serve as the focus of your research. For example, a book surveying the history of the Israeli-Palestinian conflict may include a chapter on the role Egypt has played in mediating the conflict, or look in the index for the pages where Egypt is mentioned in the text. Consider Whether Your Sources are Current Some disciplines require that you use information that is as current as possible. This is particularly true in disciplines in medicine and the sciences where research conducted becomes obsolete very quickly as new discoveries are made. However, when writing a review in the social sciences, a survey of the history of the literature may be required. In other words, a complete understanding the research problem requires you to deliberately examine how knowledge and perspectives have changed over time. Sort through other current bibliographies or literature reviews in the field to get a sense of what your discipline expects. You can also use this method to explore what is considered by scholars to be a "hot topic" and what is not.

III.  Ways to Organize Your Literature Review

Chronology of Events If your review follows the chronological method, you could write about the materials according to when they were published. This approach should only be followed if a clear path of research building on previous research can be identified and that these trends follow a clear chronological order of development. For example, a literature review that focuses on continuing research about the emergence of German economic power after the fall of the Soviet Union. By Publication Order your sources by publication chronology, then, only if the order demonstrates a more important trend. For instance, you could order a review of literature on environmental studies of brown fields if the progression revealed, for example, a change in the soil collection practices of the researchers who wrote and/or conducted the studies. Thematic [“conceptual categories”] A thematic literature review is the most common approach to summarizing prior research in the social and behavioral sciences. Thematic reviews are organized around a topic or issue, rather than the progression of time, although the progression of time may still be incorporated into a thematic review. For example, a review of the Internet’s impact on American presidential politics could focus on the development of online political satire. While the study focuses on one topic, the Internet’s impact on American presidential politics, it would still be organized chronologically reflecting technological developments in media. The difference in this example between a "chronological" and a "thematic" approach is what is emphasized the most: themes related to the role of the Internet in presidential politics. Note that more authentic thematic reviews tend to break away from chronological order. A review organized in this manner would shift between time periods within each section according to the point being made. Methodological A methodological approach focuses on the methods utilized by the researcher. For the Internet in American presidential politics project, one methodological approach would be to look at cultural differences between the portrayal of American presidents on American, British, and French websites. Or the review might focus on the fundraising impact of the Internet on a particular political party. A methodological scope will influence either the types of documents in the review or the way in which these documents are discussed.

Other Sections of Your Literature Review Once you've decided on the organizational method for your literature review, the sections you need to include in the paper should be easy to figure out because they arise from your organizational strategy. In other words, a chronological review would have subsections for each vital time period; a thematic review would have subtopics based upon factors that relate to the theme or issue. However, sometimes you may need to add additional sections that are necessary for your study, but do not fit in the organizational strategy of the body. What other sections you include in the body is up to you. However, only include what is necessary for the reader to locate your study within the larger scholarship about the research problem.

Here are examples of other sections, usually in the form of a single paragraph, you may need to include depending on the type of review you write:

• Current Situation : Information necessary to understand the current topic or focus of the literature review.
• Sources Used : Describes the methods and resources [e.g., databases] you used to identify the literature you reviewed.
• History : The chronological progression of the field, the research literature, or an idea that is necessary to understand the literature review, if the body of the literature review is not already a chronology.
• Selection Methods : Criteria you used to select (and perhaps exclude) sources in your literature review. For instance, you might explain that your review includes only peer-reviewed [i.e., scholarly] sources.
• Standards : Description of the way in which you present your information.
• Questions for Further Research : What questions about the field has the review sparked? How will you further your research as a result of the review?

IV.  Writing Your Literature Review

Once you've settled on how to organize your literature review, you're ready to write each section. When writing your review, keep in mind these issues.

Use Evidence A literature review section is, in this sense, just like any other academic research paper. Your interpretation of the available sources must be backed up with evidence [citations] that demonstrates that what you are saying is valid. Be Selective Select only the most important points in each source to highlight in the review. The type of information you choose to mention should relate directly to the research problem, whether it is thematic, methodological, or chronological. Related items that provide additional information, but that are not key to understanding the research problem, can be included in a list of further readings . Use Quotes Sparingly Some short quotes are appropriate if you want to emphasize a point, or if what an author stated cannot be easily paraphrased. Sometimes you may need to quote certain terminology that was coined by the author, is not common knowledge, or taken directly from the study. Do not use extensive quotes as a substitute for using your own words in reviewing the literature. Summarize and Synthesize Remember to summarize and synthesize your sources within each thematic paragraph as well as throughout the review. Recapitulate important features of a research study, but then synthesize it by rephrasing the study's significance and relating it to your own work and the work of others. Keep Your Own Voice While the literature review presents others' ideas, your voice [the writer's] should remain front and center. For example, weave references to other sources into what you are writing but maintain your own voice by starting and ending the paragraph with your own ideas and wording. Use Caution When Paraphrasing When paraphrasing a source that is not your own, be sure to represent the author's information or opinions accurately and in your own words. Even when paraphrasing an author’s work, you still must provide a citation to that work.

V.  Common Mistakes to Avoid

These are the most common mistakes made in reviewing social science research literature.

• Sources in your literature review do not clearly relate to the research problem;
• You do not take sufficient time to define and identify the most relevant sources to use in the literature review related to the research problem;
• Relies exclusively on secondary analytical sources rather than including relevant primary research studies or data;
• Uncritically accepts another researcher's findings and interpretations as valid, rather than examining critically all aspects of the research design and analysis;
• Does not describe the search procedures that were used in identifying the literature to review;
• Reports isolated statistical results rather than synthesizing them in chi-squared or meta-analytic methods; and,
• Only includes research that validates assumptions and does not consider contrary findings and alternative interpretations found in the literature.

Cook, Kathleen E. and Elise Murowchick. “Do Literature Review Skills Transfer from One Course to Another?” Psychology Learning and Teaching 13 (March 2014): 3-11; Fink, Arlene. Conducting Research Literature Reviews: From the Internet to Paper . 2nd ed. Thousand Oaks, CA: Sage, 2005; Hart, Chris. Doing a Literature Review: Releasing the Social Science Research Imagination . Thousand Oaks, CA: Sage Publications, 1998; Jesson, Jill. Doing Your Literature Review: Traditional and Systematic Techniques . London: SAGE, 2011; Literature Review Handout. Online Writing Center. Liberty University; Literature Reviews. The Writing Center. University of North Carolina; Onwuegbuzie, Anthony J. and Rebecca Frels. Seven Steps to a Comprehensive Literature Review: A Multimodal and Cultural Approach . Los Angeles, CA: SAGE, 2016; Ridley, Diana. The Literature Review: A Step-by-Step Guide for Students . 2nd ed. Los Angeles, CA: SAGE, 2012; Randolph, Justus J. “A Guide to Writing the Dissertation Literature Review." Practical Assessment, Research, and Evaluation. vol. 14, June 2009; Sutton, Anthea. Systematic Approaches to a Successful Literature Review . Los Angeles, CA: Sage Publications, 2016; Taylor, Dena. The Literature Review: A Few Tips On Conducting It. University College Writing Centre. University of Toronto; Writing a Literature Review. Academic Skills Centre. University of Canberra.

Writing Tip

Break Out of Your Disciplinary Box!

Thinking interdisciplinarily about a research problem can be a rewarding exercise in applying new ideas, theories, or concepts to an old problem. For example, what might cultural anthropologists say about the continuing conflict in the Middle East? In what ways might geographers view the need for better distribution of social service agencies in large cities than how social workers might study the issue? You don’t want to substitute a thorough review of core research literature in your discipline for studies conducted in other fields of study. However, particularly in the social sciences, thinking about research problems from multiple vectors is a key strategy for finding new solutions to a problem or gaining a new perspective. Consult with a librarian about identifying research databases in other disciplines; almost every field of study has at least one comprehensive database devoted to indexing its research literature.

Frodeman, Robert. The Oxford Handbook of Interdisciplinarity . New York: Oxford University Press, 2010.

Another Writing Tip

Don't Just Review for Content!

While conducting a review of the literature, maximize the time you devote to writing this part of your paper by thinking broadly about what you should be looking for and evaluating. Review not just what scholars are saying, but how are they saying it. Some questions to ask:

• How are they organizing their ideas?
• What methods have they used to study the problem?
• What theories have been used to explain, predict, or understand their research problem?
• What sources have they cited to support their conclusions?
• How have they used non-textual elements [e.g., charts, graphs, figures, etc.] to illustrate key points?

When you begin to write your literature review section, you'll be glad you dug deeper into how the research was designed and constructed because it establishes a means for developing more substantial analysis and interpretation of the research problem.

Hart, Chris. Doing a Literature Review: Releasing the Social Science Research Imagination . Thousand Oaks, CA: Sage Publications, 1 998.

Yet Another Writing Tip

When Do I Know I Can Stop Looking and Move On?

Here are several strategies you can utilize to assess whether you've thoroughly reviewed the literature:

• Look for repeating patterns in the research findings . If the same thing is being said, just by different people, then this likely demonstrates that the research problem has hit a conceptual dead end. At this point consider: Does your study extend current research?  Does it forge a new path? Or, does is merely add more of the same thing being said?
• Look at sources the authors cite to in their work . If you begin to see the same researchers cited again and again, then this is often an indication that no new ideas have been generated to address the research problem.
• Search Google Scholar to identify who has subsequently cited leading scholars already identified in your literature review [see next sub-tab]. This is called citation tracking and there are a number of sources that can help you identify who has cited whom, particularly scholars from outside of your discipline. Here again, if the same authors are being cited again and again, this may indicate no new literature has been written on the topic.

Onwuegbuzie, Anthony J. and Rebecca Frels. Seven Steps to a Comprehensive Literature Review: A Multimodal and Cultural Approach . Los Angeles, CA: Sage, 2016; Sutton, Anthea. Systematic Approaches to a Successful Literature Review . Los Angeles, CA: Sage Publications, 2016.

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What is a literature review?

A literature review is a critical analysis of the literature related to your research topic. It evaluates and critiques the literature to establish a theoretical framework for your research topic and/or identify a gap in the existing research that your research will address.

A literature review is not a summary of the literature. You need to engage deeply and critically with the literature. Your literature review should show your understanding of the literature related to your research topic and lead to presenting a rationale for your research.

A literature review focuses on:

• the context of the topic
• key concepts, ideas, theories and methodologies
• key researchers, texts and seminal works
• major issues and debates
• identifying conflicting evidence
• the main questions that have been asked around the topic
• the organisation of knowledge on the topic
• definitions, particularly those that are contested
• showing how your research will advance scholarly knowledge (generally referred to as identifying the ‘gap’).

This module will guide you through the functions of a literature review; the typical process of conducting a literature review (including searching for literature and taking notes); structuring your literature review within your thesis and organising its internal ideas; and styling the language of your literature review.

The purposes of a literature review

A literature review serves two main purposes:

1) To show awareness of the present state of knowledge in a particular field, including:

• seminal authors
• the main empirical research
• theoretical positions
• controversies
• breakthroughs as well as links to other related areas of knowledge.

2) To provide a foundation for the author’s research. To do that, the literature review needs to:

• help the researcher define a hypothesis or a research question, and how answering the question will contribute to the body of knowledge;
• provide a rationale for investigating the problem and the selected methodology;
• provide a particular theoretical lens, support the argument, or identify gaps.

Before you engage further with this module, try the quiz below to see how much you already know about literature reviews.

Research and Writing Skills for Academic and Graduate Researchers Copyright © 2022 by RMIT University is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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What is a Literature Review?

So, what is a literature review .

"A literature review is an account of what has been published on a topic by accredited scholars and researchers. In writing the literature review, your purpose is to convey to your reader what knowledge and ideas have been established on a topic, and what their strengths and weaknesses are. As a piece of writing, the literature review must be defined by a guiding concept (e.g., your research objective, the problem or issue you are discussing, or your argumentative thesis). It is not just a descriptive list of the material available or a set of summaries." - Quote from Taylor, D. (n.d)."The Literature Review: A Few Tips on Conducting it".

• Citation: "The Literature Review: A Few Tips on Conducting it"

What kinds of literature reviews are written?

Each field has a particular way to do reviews for academic research literature. In the social sciences and humanities the most common are:

• Narrative Reviews: The purpose of this type of review is to describe the current state of the research on a specific research topic and to offer a critical analysis of the literature reviewed. Studies are grouped by research/theoretical categories, and themes and trends, strengths and weaknesses, and gaps are identified. The review ends with a conclusion section that summarizes the findings regarding the state of the research of the specific study, the gaps identify and if applicable, explains how the author's research will address gaps identify in the review and expand the knowledge on the topic reviewed.
• Book review essays/ Historiographical review essays : A type of literature review typical in History and related fields, e.g., Latin American studies. For example, the Latin American Research Review explains that the purpose of this type of review is to “(1) to familiarize readers with the subject, approach, arguments, and conclusions found in a group of books whose common focus is a historical period; a country or region within Latin America; or a practice, development, or issue of interest to specialists and others; (2) to locate these books within current scholarship, critical methodologies, and approaches; and (3) to probe the relation of these new books to previous work on the subject, especially canonical texts. Unlike individual book reviews, the cluster reviews found in LARR seek to address the state of the field or discipline and not solely the works at issue.” - LARR

What are the Goals of Creating a Literature Review?

• To develop a theory or evaluate an existing theory
• To summarize the historical or existing state of a research topic
• Identify a problem in a field of research 
• Baumeister, R.F. & Leary, M.R. (1997). "Writing narrative literature reviews," Review of General Psychology , 1(3), 311-320.

When do you need to write a Literature Review?

• When writing a prospectus or a thesis/dissertation
• When writing a research paper
• When writing a grant proposal

In all these cases you need to dedicate a chapter in these works to showcase what has been written about your research topic and to point out how your own research will shed new light into a body of scholarship.

Where I can find examples of Literature Reviews?

Note:  In the humanities, even if they don't use the term "literature review", they may have a dedicated  chapter that reviewed the "critical bibliography" or they incorporated that review in the introduction or first chapter of the dissertation, book, or article.

• UCSB electronic theses and dissertations In partnership with the Graduate Division, the UC Santa Barbara Library is making available theses and dissertations produced by UCSB students. Currently included in ADRL are theses and dissertations that were originally filed electronically, starting in 2011. In future phases of ADRL, all theses and dissertations created by UCSB students may be digitized and made available.

Where to Find Standalone Literature Reviews

Literature reviews are also written as standalone articles as a way to survey a particular research topic in-depth. This type of literature review looks at a topic from a historical perspective to see how the understanding of the topic has changed over time. 

• Find e-Journals for Standalone Literature Reviews The best way to get familiar with and to learn how to write literature reviews is by reading them. You can use our Journal Search option to find journals that specialize in publishing literature reviews from major disciplines like anthropology, sociology, etc. Usually these titles are called, "Annual Review of [discipline name] OR [Discipline name] Review. This option works best if you know the title of the publication you are looking for. Below are some examples of these journals! more... less... Journal Search can be found by hovering over the link for Research on the library website.

Social Sciences

• Annual Review of Anthropology
• Annual Review of Political Science
• Annual Review of Sociology
• Ethnic Studies Review

Hard science and health sciences:

• Annual Review of Biomedical Data Science
• Annual Review of Materials Science
• Systematic Review From journal site: "The journal Systematic Reviews encompasses all aspects of the design, conduct, and reporting of systematic reviews" in the health sciences.
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In This Article Expand or collapse the "in this article" section Literature Reviews

Introduction, what is a literature review.

• Literature Reviews for Thesis or Dissertation
• Stand-alone and Systemic Reviews
• Purposes of a Literature Review
• Texts on Conducting a Literature Review
• Identifying the Research Topic
• The Persuasive Argument
• Searching the Literature
• Creating a Synthesis
• Critiquing the Literature
• Building the Case for the Literature Review Document
• Presenting the Literature Review

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• Meta-Analysis and Research Synthesis in Education
• Methodologies for Conducting Education Research
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Literature Reviews by Lawrence A. Machi , Brenda T. McEvoy LAST REVIEWED: 27 October 2016 LAST MODIFIED: 27 October 2016 DOI: 10.1093/obo/9780199756810-0169

Literature reviews play a foundational role in the development and execution of a research project. They provide access to the academic conversation surrounding the topic of the proposed study. By engaging in this scholarly exercise, the researcher is able to learn and to share knowledge about the topic. The literature review acts as the springboard for new research, in that it lays out a logically argued case, founded on a comprehensive understanding of the current state of knowledge about the topic. The case produced provides the justification for the research question or problem of a proposed study, and the methodological scheme best suited to conduct the research. It can also be a research project in itself, arguing policy or practice implementation, based on a comprehensive analysis of the research in a field. The term literature review can refer to the output or the product of a review. It can also refer to the process of Conducting a Literature Review . Novice researchers, when attempting their first research projects, tend to ask two questions: What is a Literature Review? How do you do one? While this annotated bibliography is neither definitive nor exhaustive in its treatment of the subject, it is designed to provide a beginning researcher, who is pursuing an academic degree, an entry point for answering the two previous questions. The article is divided into two parts. The first four sections of the article provide a general overview of the topic. They address definitions, types, purposes, and processes for doing a literature review. The second part presents the process and procedures for doing a literature review. Arranged in a sequential fashion, the remaining eight sections provide references addressing each step of the literature review process. References included in this article were selected based on their ability to assist the beginning researcher. Additionally, the authors attempted to include texts from various disciplines in social science to present various points of view on the subject.

Novice researchers often have a misguided perception of how to do a literature review and what the document should contain. Literature reviews are not narrative annotated bibliographies nor book reports (see Bruce 1994 ). Their form, function, and outcomes vary, due to how they depend on the research question, the standards and criteria of the academic discipline, and the orthodoxies of the research community charged with the research. The term literature review can refer to the process of doing a review as well as the product resulting from conducting a review. The product resulting from reviewing the literature is the concern of this section. Literature reviews for research studies at the master’s and doctoral levels have various definitions. Machi and McEvoy 2016 presents a general definition of a literature review. Lambert 2012 defines a literature review as a critical analysis of what is known about the study topic, the themes related to it, and the various perspectives expressed regarding the topic. Fink 2010 defines a literature review as a systematic review of existing body of data that identifies, evaluates, and synthesizes for explicit presentation. Jesson, et al. 2011 defines the literature review as a critical description and appraisal of a topic. Hart 1998 sees the literature review as producing two products: the presentation of information, ideas, data, and evidence to express viewpoints on the nature of the topic, as well as how it is to be investigated. When considering literature reviews beyond the novice level, Ridley 2012 defines and differentiates the systematic review from literature reviews associated with primary research conducted in academic degree programs of study, including stand-alone literature reviews. Cooper 1998 states the product of literature review is dependent on the research study’s goal and focus, and defines synthesis reviews as literature reviews that seek to summarize and draw conclusions from past empirical research to determine what issues have yet to be resolved. Theoretical reviews compare and contrast the predictive ability of theories that explain the phenomenon, arguing which theory holds the most validity in describing the nature of that phenomenon. Grant and Booth 2009 identified fourteen types of reviews used in both degree granting and advanced research projects, describing their attributes and methodologies.

Bruce, Christine Susan. 1994. Research students’ early experiences of the dissertation literature review. Studies in Higher Education 19.2: 217–229.

DOI: 10.1080/03075079412331382057

A phenomenological analysis was conducted with forty-one neophyte research scholars. The responses to the questions, “What do you mean when you use the words literature review?” and “What is the meaning of a literature review for your research?” identified six concepts. The results conclude that doing a literature review is a problem area for students.

Cooper, Harris. 1998. Synthesizing research . Vol. 2. 3d ed. Thousand Oaks, CA: SAGE.

The introductory chapter of this text provides a cogent explanation of Cooper’s understanding of literature reviews. Chapter 4 presents a comprehensive discussion of the synthesis review. Chapter 5 discusses meta-analysis and depth.

Fink, Arlene. 2010. Conducting research literature reviews: From the Internet to paper . 3d ed. Los Angeles: SAGE.

The first chapter of this text (pp. 1–16) provides a short but clear discussion of what a literature review is in reference to its application to a broad range of social sciences disciplines and their related professions.

Grant, Maria J., and Andrew Booth. 2009. A typology of reviews: An analysis of 14 review types and associated methodologies. Health Information & Libraries Journal 26.2: 91–108. Print.

DOI: 10.1111/j.1471-1842.2009.00848.x

This article reports a scoping review that was conducted using the “Search, Appraisal, Synthesis, and Analysis” (SALSA) framework. Fourteen literature review types and associated methodology make up the resulting typology. Each type is described by its key characteristics and analyzed for its strengths and weaknesses.

Hart, Chris. 1998. Doing a literature review: Releasing the social science research imagination . London: SAGE.

Chapter 1 of this text explains Hart’s definition of a literature review. Additionally, it describes the roles of the literature review, the skills of a literature reviewer, and the research context for a literature review. Of note is Hart’s discussion of the literature review requirements for master’s degree and doctoral degree work.

Jesson, Jill, Lydia Matheson, and Fiona M. Lacey. 2011. Doing your literature review: Traditional and systematic techniques . Los Angeles: SAGE.

Chapter 1: “Preliminaries” provides definitions of traditional and systematic reviews. It discusses the differences between them. Chapter 5 is dedicated to explaining the traditional review, while Chapter 7 explains the systematic review. Chapter 8 provides a detailed description of meta-analysis.

Lambert, Mike. 2012. A beginner’s guide to doing your education research project . Los Angeles: SAGE.

Chapter 6 (pp. 79–100) presents a thumbnail sketch for doing a literature review.

Machi, Lawrence A., and Brenda T. McEvoy. 2016. The literature review: Six steps to success . 3d ed. Thousand Oaks, CA: Corwin.

The introduction of this text differentiates between a simple and an advanced review and concisely defines a literature review.

Ridley, Diana. 2012. The literature review: A step-by-step guide for students . 2d ed. Sage Study Skills. London: SAGE.

In the introductory chapter, Ridley reviews many definitions of the literature review, literature reviews at the master’s and doctoral level, and placement of literature reviews within the thesis or dissertation document. She also defines and differentiates literature reviews produced for degree-affiliated research from the more advanced systematic review projects.

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• Academic Skills
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• Literature reviews

Writing a literature review

Find out how to write a lit review.

What is a literature review ?

A literature review explores and evaluates the literature on a specific topic or question. It synthesises the contributions of the different authors, often to identify areas that need further exploration.

You may be required to write a literature review as a standalone document or part of a larger body of research, such as a thesis.

• The point of a standalone literature review is to demonstrate that you have read widely in your field and you understand the main arguments.
• As part of a thesis or research paper, the literature review defines your project by establishing how your work will extend or differ from previous work and what contribution it will make.

What are markers looking for?

In the best literature reviews, the writer:

• Has a clear understanding of key concepts within the topic.
• Clarifies important definitions and terminology.
• Covers the breadth of the specific topic.
• Critically discusses the ideas in the literature and evaluates how authors present them.
• Clearly indicates a research gap for future enquiry.

How do I write a literature review?

This video outlines a step by step approach to help you evaluate readings, organise ideas and write critically. It provides examples of how to connect, interpret and critique ideas to make sure your voice comes through strongly.

Tips for research, reading and writing

You may be given a specific question to research or broad topics which must be refined to a question that can be reasonably addressed in the time and word limit available.

Use your early reading to help you determine and refine your topic.

• Too much literature? You probably need to narrow your scope. Try to identify a more specific issue of interest.
• Not enough literature? Your topic may be too specific and needs to be broader.

Start with readings suggested by your lecturers or supervisors. Then, do your own research - the best place to go is the Library Website .

You can also use the Library Guides or speak to a librarian to identify the most useful databases for you and to learn how to search for sources effectively and efficiently.

Cover the field

Make sure your literature search covers a broad range of views and information relevant to your topic. Focussing on a narrow selection of sources may result in a lack of depth. You are not expected to cover all research and scholarly opinions on your topic, but you need to identify and include important viewpoints. A quality literature review examines and evaluates different viewpoints based on the evidence presented, rather than providing only material that reinforces a bias.

Use reading strategies

Survey, skim and scan to find the most relevant articles, and the most relevant parts of those articles. These can be re-read more closely later when you have acquired an overview of your topic.

Take notes as you read

This helps to organise and develop your thoughts. Record your own reactions to the text in your notes, perhaps in a separate column. These notes can form the basis of your critical evaluation of the text. Record any facts, opinions or direct quotes that are likely to be useful to your review, noting the page numbers, author and year.

Stop reading when you have enough

This depends on the word count required of this literature review. A review of one thousand words can only cover the major ideas and probably less than ten references. Longer reviews that form part of a large research paper will include more than fifty. Your tutor or supervisor should be able to suggest a suitable number.

As you read, ask yourself these questions:

• Have I answered my question without any obvious gaps?
• Have I read this before? Are there any new related issues coming up as I search the literature?
• Have I found multiple references which cover the same material or just enough to prove agreement?

There are many possible ways to organise the material. For example:

• chronologically
• by theoretical perspective
• from most to least important
• by issue or theme

It is important to remember that you are not merely cataloguing or describing the literature you read. Therefore, you need to choose an organisation that will enable you to compare the various authors' treatment of ideas. This is often best achieved by organising thematically, or grouping ideas into sets of common issues tackled in the various texts. These themes will form the basis of the different threads that are the focus of your study.

A standalone literature review

A standalone literature review is structured much like an academic essay.

• Introduction - establish the context for your topic and outline your main contentions about the literature
• Main body - explain and support these inferences in the main body
• Conclusion - summarise your main points and restate the contention.

The main difference between an essay and this kind of literature review is that an essay focuses on a topic and uses the literature as a support for the arguments. In a standalone literature review, the literature itself is the topic of discussion and evaluation. This means you evaluate and discuss not only the informational content but the quality of the author’s handling of the content.

A literature review as part of a larger research paper?

As part of a larger research paper, the literature review may take many forms, depending on your discipline, your topic and the logic of your research. Traditionally, in empirical research, the literature review is included in the introduction, or a standalone chapter immediately following the introduction. For other forms of research, you may need to engage more extensively with the literature and thus, the literature review may spread over more than one chapter, or even be distributed throughout the thesis.

Start writing early. Writing will clarify your thinking on the topic and reveal any gaps in information and logic. If your ideas change, sections and paragraphs can be reworked to change your contentions or include extra information.

Similarly, draft an overall plan for your review as soon as you are ready, but be prepared to rework sections of it to reflect your developing argument.

The most important thing to remember is that you are writing a review . That means you must move past describing what other authors have written by connecting, interpreting and critiquing their ideas and presenting your own analysis and interpretation.

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The objective of a literature review

Questions to Consider

B. In some fields or contexts, a literature review is referred to as the introduction or the background; why is this true, and does it matter?

The elements of a literature review • The first step in scholarly research is determining the “state of the art” on a topic. This is accomplished by gathering academic research and making sense of it. • The academic literature can be found in scholarly books and journals; the goal is to discover recurring themes, find the latest data, and identify any missing pieces. • The resulting literature review organizes the research in such a way that tells a story about the topic or issue.

The literature review tells a story in which one well-paraphrased summary from a relevant source contributes to and connects with the next in a logical manner, developing and fulfilling the message of the author. It includes analysis of the arguments from the literature, as well as revealing consistent and inconsistent findings. How do varying author insights differ from or conform to previous arguments?

Language in Action

A. How are the terms “critique” and “review” used in everyday life? How are they used in an academic context?

In terms of content, a literature review is intended to:

• Set up a theoretical framework for further research • Show a clear understanding of the key concepts/studies/models related to the topic • Demonstrate knowledge about the history of the research area and any related controversies • Clarify significant definitions and terminology • Develop a space in the existing work for new research

The literature consists of the published works that document a scholarly conversation or progression on a problem or topic in a field of study. Among these are documents that explain the background and show the loose ends in the established research on which a proposed project is based. Although a literature review focuses on primary, peer -reviewed resources, it may begin with background subject information generally found in secondary and tertiary sources such as books and encyclopedias. Following that essential overview, the seminal literature of the field is explored. As a result, while a literature review may consist of research articles tightly focused on a topic with secondary and tertiary sources used more sparingly, all three types of information (primary, secondary, tertiary) are critical.

The literature review, often referred to as the Background or Introduction to a research paper that presents methods, materials, results and discussion, exists in every field and serves many functions in research writing.

Adapted from Frederiksen, L., & Phelps, S. F. (2017). Literature Reviews for Education and Nursing Graduate Students. Open Textbook Library

Review and Reinforce

Two common approaches are simply outlined here. Which seems more common? Which more productive? Why? A. Forward exploration 1. Sources on a topic or problem are gathered. 2. Salient themes are discovered. 3. Research gaps are considered for future research. B. Backward exploration 1. Sources pertaining to an existing research project are gathered. 2. The justification of the research project’s methods or materials are explained and supported based on previously documented research.

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Sourcing, summarizing, and synthesizing:  Skills for effective research writing  Copyright © 2023 by Wendy L. McBride is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License , except where otherwise noted.

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How To Structure Your Literature Review

3 options to help structure your chapter.

By: Amy Rommelspacher (PhD) | Reviewer: Dr Eunice Rautenbach | November 2020 (Updated May 2023)

Writing the literature review chapter can seem pretty daunting when you’re piecing together your dissertation or thesis. As  we’ve discussed before , a good literature review needs to achieve a few very important objectives – it should:

• Demonstrate your knowledge of the research topic
• Identify the gaps in the literature and show how your research links to these
• Provide the foundation for your conceptual framework (if you have one)
• Inform your own  methodology and research design

To achieve this, your literature review needs a well-thought-out structure . Get the structure of your literature review chapter wrong and you’ll struggle to achieve these objectives. Don’t worry though – in this post, we’ll look at how to structure your literature review for maximum impact (and marks!).

But wait – is this the right time?

Deciding on the structure of your literature review should come towards the end of the literature review process – after you have collected and digested the literature, but before you start writing the chapter. 

In other words, you need to first develop a rich understanding of the literature before you even attempt to map out a structure. There’s no use trying to develop a structure before you’ve fully wrapped your head around the existing research.

Equally importantly, you need to have a structure in place before you start writing , or your literature review will most likely end up a rambling, disjointed mess. 

Importantly, don’t feel that once you’ve defined a structure you can’t iterate on it. It’s perfectly natural to adjust as you engage in the writing process. As we’ve discussed before , writing is a way of developing your thinking, so it’s quite common for your thinking to change – and therefore, for your chapter structure to change – as you write. 

Need a helping hand?

Like any other chapter in your thesis or dissertation, your literature review needs to have a clear, logical structure. At a minimum, it should have three essential components – an  introduction , a  body   and a  conclusion . 

Let’s take a closer look at each of these.

1: The Introduction Section

Just like any good introduction, the introduction section of your literature review should introduce the purpose and layout (organisation) of the chapter. In other words, your introduction needs to give the reader a taste of what’s to come, and how you’re going to lay that out. Essentially, you should provide the reader with a high-level roadmap of your chapter to give them a taste of the journey that lies ahead.

Here’s an example of the layout visualised in a literature review introduction:

Your introduction should also outline your topic (including any tricky terminology or jargon) and provide an explanation of the scope of your literature review – in other words, what you  will   and  won’t   be covering (the delimitations ). This helps ringfence your review and achieve a clear focus . The clearer and narrower your focus, the deeper you can dive into the topic (which is typically where the magic lies). 

Depending on the nature of your project, you could also present your stance or point of view at this stage. In other words, after grappling with the literature you’ll have an opinion about what the trends and concerns are in the field as well as what’s lacking. The introduction section can then present these ideas so that it is clear to examiners that you’re aware of how your research connects with existing knowledge .

2: The Body Section

The body of your literature review is the centre of your work. This is where you’ll present, analyse, evaluate and synthesise the existing research. In other words, this is where you’re going to earn (or lose) the most marks. Therefore, it’s important to carefully think about how you will organise your discussion to present it in a clear way. 

The body of your literature review should do just as the description of this chapter suggests. It should “review” the literature – in other words, identify, analyse, and synthesise it. So, when thinking about structuring your literature review, you need to think about which structural approach will provide the best “review” for your specific type of research and objectives (we’ll get to this shortly).

There are (broadly speaking)  three options  for organising your literature review.

Option 1: Chronological (according to date)

Organising the literature chronologically is one of the simplest ways to structure your literature review. You start with what was published first and work your way through the literature until you reach the work published most recently. Pretty straightforward.

The benefit of this option is that it makes it easy to discuss the developments and debates in the field as they emerged over time. Organising your literature chronologically also allows you to highlight how specific articles or pieces of work might have changed the course of the field – in other words, which research has had the most impact . Therefore, this approach is very useful when your research is aimed at understanding how the topic has unfolded over time and is often used by scholars in the field of history. That said, this approach can be utilised by anyone that wants to explore change over time .

For example , if a student of politics is investigating how the understanding of democracy has evolved over time, they could use the chronological approach to provide a narrative that demonstrates how this understanding has changed through the ages.

Here are some questions you can ask yourself to help you structure your literature review chronologically.

• What is the earliest literature published relating to this topic?
• How has the field changed over time? Why?
• What are the most recent discoveries/theories?

In some ways, chronology plays a part whichever way you decide to structure your literature review, because you will always, to a certain extent, be analysing how the literature has developed. However, with the chronological approach, the emphasis is very firmly on how the discussion has evolved over time , as opposed to how all the literature links together (which we’ll discuss next ).

Option 2: Thematic (grouped by theme)

The thematic approach to structuring a literature review means organising your literature by theme or category – for example, by independent variables (i.e. factors that have an impact on a specific outcome).

As you’ve been collecting and synthesising literature , you’ll likely have started seeing some themes or patterns emerging. You can then use these themes or patterns as a structure for your body discussion. The thematic approach is the most common approach and is useful for structuring literature reviews in most fields.

For example, if you were researching which factors contributed towards people trusting an organisation, you might find themes such as consumers’ perceptions of an organisation’s competence, benevolence and integrity. Structuring your literature review thematically would mean structuring your literature review’s body section to discuss each of these themes, one section at a time.

Here are some questions to ask yourself when structuring your literature review by themes:

• Are there any patterns that have come to light in the literature?
• What are the central themes and categories used by the researchers?
• Do I have enough evidence of these themes?

PS – you can see an example of a thematically structured literature review in our literature review sample walkthrough video here.

Option 3: Methodological

The methodological option is a way of structuring your literature review by the research methodologies used . In other words, organising your discussion based on the angle from which each piece of research was approached – for example, qualitative , quantitative or mixed  methodologies.

Structuring your literature review by methodology can be useful if you are drawing research from a variety of disciplines and are critiquing different methodologies. The point of this approach is to question  how  existing research has been conducted, as opposed to  what  the conclusions and/or findings the research were.

For example, a sociologist might centre their research around critiquing specific fieldwork practices. Their literature review will then be a summary of the fieldwork methodologies used by different studies.

Here are some questions you can ask yourself when structuring your literature review according to methodology:

• Which methodologies have been utilised in this field?
• Which methodology is the most popular (and why)?
• What are the strengths and weaknesses of the various methodologies?
• How can the existing methodologies inform my own methodology?

3: The Conclusion Section

Once you’ve completed the body section of your literature review using one of the structural approaches we discussed above, you’ll need to “wrap up” your literature review and pull all the pieces together to set the direction for the rest of your dissertation or thesis.

The conclusion is where you’ll present the key findings of your literature review. In this section, you should emphasise the research that is especially important to your research questions and highlight the gaps that exist in the literature. Based on this, you need to make it clear what you will add to the literature – in other words, justify your own research by showing how it will help fill one or more of the gaps you just identified.

Last but not least, if it’s your intention to develop a conceptual framework for your dissertation or thesis, the conclusion section is a good place to present this.

Example: Thematically Structured Review

In the video below, we unpack a literature review chapter so that you can see an example of a thematically structure review in practice.

Let’s Recap

In this article, we’ve  discussed how to structure your literature review for maximum impact. Here’s a quick recap of what  you need to keep in mind when deciding on your literature review structure:

• Just like other chapters, your literature review needs a clear introduction , body and conclusion .
• The introduction section should provide an overview of what you will discuss in your literature review.
• The body section of your literature review can be organised by chronology , theme or methodology . The right structural approach depends on what you’re trying to achieve with your research.
• The conclusion section should draw together the key findings of your literature review and link them to your research questions.

If you’re ready to get started, be sure to download our free literature review template to fast-track your chapter outline.

Psst… there’s more!

This post is an extract from our bestselling short course, Literature Review Bootcamp . If you want to work smart, you don't want to miss this .

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27 Comments

Great work. This is exactly what I was looking for and helps a lot together with your previous post on literature review. One last thing is missing: a link to a great literature chapter of an journal article (maybe with comments of the different sections in this review chapter). Do you know any great literature review chapters?

I agree with you Marin… A great piece

I agree with Marin. This would be quite helpful if you annotate a nicely structured literature from previously published research articles.

Awesome article for my research.

I thank you immensely for this wonderful guide

It is indeed thought and supportive work for the futurist researcher and students

Very educative and good time to get guide. Thank you

Great work, very insightful. Thank you.

Thanks for this wonderful presentation. My question is that do I put all the variables into a single conceptual framework or each hypothesis will have it own conceptual framework?

Thank you very much, very helpful

This is very educative and precise . Thank you very much for dropping this kind of write up .

Pheeww, so damn helpful, thank you for this informative piece.

I’m doing a research project topic ; stool analysis for parasitic worm (enteric) worm, how do I structure it, thanks.

comprehensive explanation. Help us by pasting the URL of some good “literature review” for better understanding.

great piece. thanks for the awesome explanation. it is really worth sharing. I have a little question, if anyone can help me out, which of the options in the body of literature can be best fit if you are writing an architectural thesis that deals with design?

I am doing a research on nanofluids how can l structure it?

Beautifully clear.nThank you!

Lucid! Thankyou!

Brilliant work, well understood, many thanks

I like how this was so clear with simple language 😊😊 thank you so much 😊 for these information 😊

Insightful. I was struggling to come up with a sensible literature review but this has been really helpful. Thank you!

You have given thought-provoking information about the review of the literature.

Thank you. It has made my own research better and to impart your work to students I teach

I learnt a lot from this teaching. It’s a great piece.

I am doing research on EFL teacher motivation for his/her job. How Can I structure it? Is there any detailed template, additional to this?

You are so cool! I do not think I’ve read through something like this before. So nice to find somebody with some genuine thoughts on this issue. Seriously.. thank you for starting this up. This site is one thing that is required on the internet, someone with a little originality!

I’m asked to do conceptual, theoretical and empirical literature, and i just don’t know how to structure it

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Why is it important to do a literature review in research?

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 “A substantive, thorough, sophisticated literature review is a precondition for doing substantive, thorough, sophisticated research”. Boote and Baile 2005

Authors of manuscripts treat writing a literature review as a routine work or a mere formality. But a seasoned one knows the purpose and importance of a well-written literature review.  Since it is one of the basic needs for researches at any level, they have to be done vigilantly. Only then the reader will know that the basics of research have not been neglected.

The aim of any literature review is to summarize and synthesize the arguments and ideas of existing knowledge in a particular field without adding any new contributions.   Being built on existing knowledge they help the researcher to even turn the wheels of the topic of research.  It is possible only with profound knowledge of what is wrong in the existing findings in detail to overpower them.  For other researches, the literature review gives the direction to be headed for its success. 

The common perception of literature review and reality:

As per the common belief, literature reviews are only a summary of the sources related to the research. And many authors of scientific manuscripts believe that they are only surveys of what are the researches are done on the chosen topic.  But on the contrary, it uses published information from pertinent and relevant sources like

• Scholarly books
• Scientific papers
• Latest studies in the field
• Established school of thoughts
• Relevant articles from renowned scientific journals

and many more for a field of study or theory or a particular problem to do the following:

• Summarize into a brief account of all information
• Synthesize the information by restructuring and reorganizing
• Critical evaluation of a concept or a school of thought or ideas
• Familiarize the authors to the extent of knowledge in the particular field
• Encapsulate
• Compare & contrast

By doing the above on the relevant information, it provides the reader of the scientific manuscript with the following for a better understanding of it:

• It establishes the authors’  in-depth understanding and knowledge of their field subject
• It gives the background of the research
• Portrays the scientific manuscript plan of examining the research result
• Illuminates on how the knowledge has changed within the field
• Highlights what has already been done in a particular field
• Information of the generally accepted facts, emerging and current state of the topic of research
• Identifies the research gap that is still unexplored or under-researched fields
• Demonstrates how the research fits within a larger field of study
• Provides an overview of the sources explored during the research of a particular topic

Importance of literature review in research:

The importance of literature review in scientific manuscripts can be condensed into an analytical feature to enable the multifold reach of its significance.  It adds value to the legitimacy of the research in many ways:

• Provides the interpretation of existing literature in light of updated developments in the field to help in establishing the consistency in knowledge and relevancy of existing materials
• It helps in calculating the impact of the latest information in the field by mapping their progress of knowledge.
• It brings out the dialects of contradictions between various thoughts within the field to establish facts
• The research gaps scrutinized initially are further explored to establish the latest facts of theories to add value to the field
• Indicates the current research place in the schema of a particular field
• Provides information for relevancy and coherency to check the research
• Apart from elucidating the continuance of knowledge, it also points out areas that require further investigation and thus aid as a starting point of any future research
• Justifies the research and sets up the research question
• Sets up a theoretical framework comprising the concepts and theories of the research upon which its success can be judged
• Helps to adopt a more appropriate methodology for the research by examining the strengths and weaknesses of existing research in the same field
• Increases the significance of the results by comparing it with the existing literature
• Provides a point of reference by writing the findings in the scientific manuscript
• Helps to get the due credit from the audience for having done the fact-finding and fact-checking mission in the scientific manuscripts
• The more the reference of relevant sources of it could increase more of its trustworthiness with the readers
• Helps to prevent plagiarism by tailoring and uniquely tweaking the scientific manuscript not to repeat other’s original idea
• By preventing plagiarism , it saves the scientific manuscript from rejection and thus also saves a lot of time and money
• Helps to evaluate, condense and synthesize gist in the author’s own words to sharpen the research focus
• Helps to compare and contrast to  show the originality and uniqueness of the research than that of the existing other researches
• Rationalizes the need for conducting the particular research in a specified field
• Helps to collect data accurately for allowing any new methodology of research than the existing ones
• Enables the readers of the manuscript to answer the following questions of its readers for its better chances for publication
• What do the researchers know?
• What do they not know?
• Is the scientific manuscript reliable and trustworthy?
• What are the knowledge gaps of the researcher?

22. It helps the readers to identify the following for further reading of the scientific manuscript:

• What has been already established, discredited and accepted in the particular field of research
• Areas of controversy and conflicts among different schools of thought
• Unsolved problems and issues in the connected field of research
• The emerging trends and approaches
• How the research extends, builds upon and leaves behind from the previous research

A profound literature review with many relevant sources of reference will enhance the chances of the scientific manuscript publication in renowned and reputed scientific journals .

References:

http://www.math.montana.edu/jobo/phdprep/phd6.pdf

journal Publishing services  |  Scientific Editing Services  |  Medical Writing Services  |  scientific research writing service  |  Scientific communication services

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What Are the Functions of Literature?

The functions of Literature range from entertainment, language learning and usage, character training, social progress, cognitive development and psychology to motivation for personal growth.

Are you searching for the most important functions of Literature? Then you are in the right place. In this post, I will show you the major functions of Literature as they apply to you as an individual, to education and to society as a whole.

What is Literature all about?

Literature is about life. Thus, Literature is about people, be they individuals or groups of individuals.

Literature is all about the places and environments in which people live, work and interact with one another. Literature is about the actions of real people like you and me. In fact, literature is about the motives behind those actions. Literature is about time and moments in time.

As you can see, Literature is a product of the way we live as social human beings.

Literature comes in many forms. Check out just a few here.

• stories or fiction or narrative prose
• poetry and music
• films or movies
• different works of art

So what are the functions of literature? Here are six functions of literature for you.

1. Literature entertains.

One of the most important functions of Literature is that it is a source of entertainment and leisure. Literature, be it comedy or tragedy, has the power to excite and make people feel refreshed.

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2. Literature forces us to use all our senses.

Literature thus has the abiding effect of making us remain active and conscious beings.

3. Literature teaches us valuable lessons about human nature.

Another function of Literature is that it instils in us a spirit of tolerance and understanding. Literature enables us to live harmoniously with one another.

Here are some popular Literature books to enjoy:

• INVISIBLE MAN
• HARVEST OF CORRUPTION
• THE GREAT GATSBY
• LOOK BACK IN ANGER
• THE LORD OF THE RINGS
• SECOND CLASS CITIZEN
• A RAISIN IN THE SUN

4. Literature has a moral effect on society.

Satirical and didactic literary works, for example, are known to have played a positive role in changing the behaviour of individuals and the way societies are organized.

In fact, literature is a powerful tool for effecting behavioural and social change.

5. Literature improves and enriches our use of language.

This is borne out of the fact that the main medium of literary expression is language. The home of idioms, figures of speech and other stylistic expressions is Literature.

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6. Literature inspires.

Stories, movies, plays, speeches, and poems have since time immemorial inspired people to do great things.

Are you encouraged by the benefits you can derive from studying Literature? There is a host of resources available on the web you can access to learn more about Literature at your own convenience.

Just take a quick look at these inspiring works of literature.

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• 15 Uplifting movies you can watch on Netflix
• 10 Novels that changed the world

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4 thoughts on “what are the functions of literature”.

Thank you for providing a comprehensive list of the functions of literature! As a reader and literature enthusiast, I wholeheartedly agree that literature has the power to shape our perspectives, evoke emotions, and foster empathy. The idea that literature can be used as a tool for social and political commentary is particularly insightful. I will definitely be sharing this post with my friends and fellow book lovers. Great job!

Not complete 🔻🤬😤

Thank you so much.

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Article Contents

Introduction, materials and methods, the benefits of moderate selenium, toxicity of excessive selenium, the effect of form of selenium on zebrafish, conclusions and future research directions, acknowledgments, author contributions.

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The beneficial and toxic effects of selenium on zebrafish. A systematic review of the literature

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Yuanshan Lin, Liyun Hu, Xinhang Li, Jie Ma, Qipeng Li, Xiaofan Yuan, Yuan Zhang, The beneficial and toxic effects of selenium on zebrafish. A systematic review of the literature, Toxicology Research , Volume 13, Issue 2, April 2024, tfae062, https://doi.org/10.1093/toxres/tfae062

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Selenium is an important and essential trace element in organisms, but its effects on organisms are also a “double-edged sword”. Selenium deficiency or excess can endanger the health of humans and animals. In order to thoroughly understand the nutritional value and toxicity hazards of selenium, researchers have conducted many studies on the model animal zebrafish. However, there is a lack of induction and summary of relevant research on which selenium acts on zebrafish. This paper provides a review of the reported studies. Firstly, this article summarizes the benefits of selenium on zebrafish from three aspects: Promoting growth, Enhancing immune function and anti-tumor ability, Antagonizing some pollutants, such as mercury. Then, three aspects of selenium toxicity to zebrafish are introduced: nervous system and behavior, reproductive system and growth, and damage to some organs. This article also describes how different forms of selenium compounds have different effects on zebrafish health. Finally, prospects for future research directions are presented.

Selenium is an important biologically essential trace element, and its value for human and animal health has been recognized. Selenium participates in the various basic life processes of organisms in the form of the selenoaminoacid incorporated in selenoproteins. 1 The impact of selenium on humans and animals is characterized by a typical “U” shape, and long-term insufficient intake can cause many serious health problems. 2 Selenium deficiency is clearly related to the occurrence of cardiovascular diseases, with a typical example being Keshan disease discovered in selenium deficient areas. It has been proven that oral selenium can reverse selenium deficiency and improve Keshan disease. 3 Severe selenium deficiency can also cause diseases like Kashin-beck disease and other joint diseases. 4 Meanwhile, selenium is also an essential element for maintaining thyroid function, and selenium deficiency is closely related to immune thyroid disease. 5 , 6 Insufficient selenium intake can also lead to liver dysfunction, increased cancer risk, increased mortality rate and so on. 7 However, the excessive addition of selenium to livestock feed by humans indirectly causes selenium poisoning in humans and animals, leading to severe anemia, skeletal stiffness, hair loss, blindness, and more. 8 Current research shows that moderate and high selenium exposure increases the risk of type 2 diabetes and the incidence of cardiovascular disease. 9–11 It is worth noting that selenium slightly above the nutritional level can exhibit severe neurotoxicity, not only damaging various neurotransmitters, key proteins, and even affecting signaling molecules involved in behavior and cognitive function. 12 The safe nutritional range of selenium is relatively narrow, and it is easy for humans and animals to experience deficiency or excess. Just as selenium has an impact on the nervous system, the deficiency of selenoprotein highly affects the function of the central nervous system, 10 but excessive exposure to selenium at similar nutritional levels can produce neurotoxicity. 13 Therefore, researchers need to conduct extensive research to determine the required amount and toxicity.

Fish are sensitive models for detecting the exposure of various toxic substances in the ecological environment, 14 based on the fact that most toxins enter the aquatic environment naturally or unnaturally, and fish living in the aquatic environment easily produce various perceptible toxic reactions to these toxins. 15 Selenium compounds naturally exist in the ecological environment, but they cause harm to fish due to various human interventions flowing into the aquatic environment. 16 The model animal zebrafish is known as the “lab rats in the water” due to its high homology of 87% with human genes, transparent embryos and larvae, rapid reproduction and development, and low breeding costs; it has a wide range of applications in drug toxicology. 17 For this reason, researchers have conducted many studies on selenium using zebrafish models. This article reviews the current reported studies on the beneficial and toxic effects of selenium on zebrafish, providing reference for the research of selenium in Fish and zebrafish.

This review retrieves articles published in English from Pubmed, Web of Science, and Google Scholar databases. Search using the following keywords: “zebrafish”, “selenium”, “selenoprotein”, “selenomethionine”, “selenocysteine”, “sodium selenite”, “selenate”, “selenium nanoparticles”. The retrieval strategy is to use "zebrafish" to search one by one with other keywords in an “and” manner, and exclude duplicate articles. The inclusion criteria include relevant studies on the effects of selenium on zebrafish, and exclude papers unrelated to the toxicity and benefits of selenium. Further read qualified papers to determine the requirements that meet the topic. When reading qualified literature, pay attention to articles that are similar to the topic, and judge whether the content can be used as evidence to support the opinion on the topic.

Selenoprotein promotes growth

The normal growth and various physiological and biochemical functions of fish are inseparable from selenium. Inorganic or organic compounds containing selenium are absorbed by fish and used to synthesize selenoprotein, participating in physiological metabolism. Activating appropriate amounts of selenoenzyme and selenoprotein is important in protecting fish from oxidative damage, promoting fish growth, enhancing fish immunity, and other metabolic regulation. 18 Currently, 14 types of selenoproteins have been detected in zebrafish, of which 11 are highly homologous to human selenoproteins. 19 Most selenoproteins have antioxidant properties, and it has been confirmed that selenoproteins with antioxidant capacity include glutathione peroxidase, thioredoxin reductase, and thyroxine deiodinase, which play an important role in eliminating oxidative stress. 20 Glutathione peroxidase catalyzes the conversion of reduced glutathione to oxidized glutathione. During the catalytic transformation, reduced glutathione converts toxic peroxides or oxygen radicals into non-toxic alcohols or water. 7 Thioredoxin reductase catalyzes the reaction of oxidized thioredoxin with the reducing agent and consumes the electrons provided by NADPH, thereby achieving the purpose of scavenging oxygen free radicals. 21 At the same time, thyroxine deiodinase also regulates the process of thyroxine production, and the physiological metabolism of many tissues and organs is affected by thyroid hormone. 5 Although other selenium proteins’ functions are unclear, they also have antioxidant potential and participate in other important metabolic processes. 22 Selenoprotein P is a plasma selenium transporter protein that plays an important role in maintaining stable selenium levels and antioxidant balance in the brain, reproductive, and other systems. 23 Selenoprotein H is a recently discovered nucleolar oxidoreductase inhibiting tumor activity and regulating redox balance, inflammatory response, and DNA damage during zebrafish embryonic development. Selenoprotein H deficiency in zebrafish disrupts redox balance and causes inflammation, thereby accelerating the development of gastrointestinal tumors. 24 Selenoprotein N is present in the muscle tissue of zebrafish and is highly expressed during the early development of zebrafish somatic cells and notochord. During the development of zebrafish muscles, the lack of selenoprotein N causes a decrease in slow muscle fiber production and abnormal myofibrils, leading to muscular dystrophy. It also leads to impaired Ryanodine receptor/calcium release channel activity in zebrafish muscles. 25

Fish in areas close to human industrial activities or selenium mines can easily ingest selenium to maintain basic life needs due to their proximity to selenium sources. 26 But artificially farmed fish require the addition of selenium-enriched yeast to their feed to maintain selenium balance. 18 Moderate selenium intake can support the expression of various Selenoproteins in important organs and enhance the antioxidant activity of selenium proteases to keep the body’s redox balance and increase the growth rate of fish. 27 Long-term selenium deficiency leads to the continuous accumulation of reactive oxygen species (ROS) in physiological metabolism, leading to oxidative stress and affecting the growth of zebrafish. Through dietary experiments with selenium-enriched yeast added from low to high, it was concluded that adding 0.34 mg/kg selenium to feed is the most suitable for the hypertrophy and growth of zebrafish skeletal muscles while maintaining high antioxidant activity. At this concentration, the protein synthesis rate in zebrafish muscle is the highest, and the degradation rate is the lowest. In contrast, low or high selenium reduces the protein synthesis rate and increases the decomposition rate. 28

Selenium enhances immune function and anti-tumor ability

The importance of selenium in immune function has been confirmed in animal experiments and cell model experiments. 29 Selenium deficiency leads to weakened immunity and increases the probability of tumor occurrence. Selenoprotein expression is limited in low selenium conditions, which affects the differentiation, development, and maturation of immune cells and hinders the activation and function of mature immune cells. 30 Generally speaking, antioxidants also have anti-inflammatory effects. During the inflammatory process, NADPH oxidase is influenced by pro-inflammatory factors and promotes synthesis, which can catalyze the production of a large amount of reactive oxygen species. Reactive oxygen species kill invading microorganisms, but excessive accumulation of reactive oxygen species can also damage normal cells, including immune cells. 31 In selenium deficiency, the redox equilibrium is imbalanced, and the ROS produced by immune cells cannot be removed in time, which affects immune function. Therefore, appropriate selenium supplementation can improve the function of the immune system, thereby reducing the susceptibility to pathogenic microbial infections and cancer. With the rise of nanotechnology, the potential of nanoparticles in medical applications has been gradually explored, especially in cancer treatment. Selenium nanoparticles can be synthesized through chemical, physical, and biological methods, all committed to reducing the cost of synthesis, environmental pollution, toxicity, and improving bioavailability. 32 Compared with ordinary selenium, selenium nanoparticles have higher bioavailability, biological activity, and controllable release, and their antioxidant, immune, and anti-cancer effects are stronger than ordinary selenium. 32 A study 33 comparing the growth, immunity, and oxidation status of tilapia after 65 days of feeding diets containing different forms of selenium found that organic selenium and selenium nanoparticles had the best growth promotion effect, and selenium nanoparticles had the strongest effect on immunity, immune gene expression, and antioxidant capacity. Unfortunately, similar studies have not yet been conducted on zebrafish. Combining inulin fructan with moderate anti-tumor ability and selenium to form selenium nanoparticles has been confirmed to enhance the anti-tumor ability of in vitro experiments and zebrafish tumor xenotransplantation experiments. 34 These research results fully demonstrate the potential of selenium nanoparticles in immune and anti-tumor fields.

Selenium can antagonize mercury and other pollutants poisoning

Mercury is one of the most common toxic elements in aquatic organisms and humans. As a result of human overexploitation of natural resources and industrial pollution, the mercury contents in polluted marine environments increase and are converted by microorganisms into methylmercury, which fish more easily absorb. Methylmercury has strong neurotoxicity and can penetrate the blood–brain barrier to damage nerve cells, causing sensory and behavioral disorders. 35 The interaction between selenium and mercury is relatively complex, and selenium can serve as an antagonist to methylmercury poisoning. Some studies suggest that the neurotoxicity caused by methylmercury may be due to selenium deficiency caused by methylmercury. Methylmercury can chelate with selenium to form a nonbioavailable form, and this selenium deficiency state can be prevented by supplementing selenium. 36 Dietary experiments with selenomethionine and methylmercury in zebrafish have confirmed that increasing dietary selenium can reduce the accumulation of methylmercury in zebrafish muscles and enhance zebrafish’s ability to eliminate methylmercury. 37 When exposed to mercury, methylmercury absorbed by zebrafish preferentially binds to selenoaminoacid in the active center of selenoprotein, thereby affecting the function of selenoprotein and causing redox imbalance. Experiments have shown that methylmercury inhibits the antioxidant selenoproteinase activity and gene expression in zebrafish, and supplementing selenium can partially rescue the inhibitory effect caused by methylmercury. 38

Common pollutants in the aquatic environment include heavy metals, pesticides, etc., which are highly toxic, and most of them can promote oxidation, causing oxidative stress to marine organisms and damaging their health. 39 As an antioxidant, selenium can effectively combat oxidative stress caused by environmental pollutants. Exposure studies of paraquat, a highly toxic quaternary ammonium herbicide, have demonstrated that dietary pretreatment with sodium selenite in zebrafish prevented the increased levels of carbonylated protein, reactive oxygen species, and nitrites/nitrates, and the decrease in non-protein thiols levels caused by paraquat, thereby improving the behavioral and biochemical abnormalities associated with paraquat exposure. 40 In another experiment, 41 zebrafish embryos were exposed to fluoride, which led to oxidative damage and apoptosis, resulting in developmental toxicity and inflammation. Selenomethionine treatment not only alleviates the adverse effects caused by fluoride but also gradually eliminates fluorine-induced oxidative stress and inflammatory responses and relieves fluorine-induced liver and intestinal damage. Recently, it has been reported that selenium selenite can alleviate the inhibitory effects of perfluorooctane sulfonic acid and cadmium on antioxidant enzymes in zebrafish liver and reduce toxicity to zebrafish liver. 42 These studies have demonstrated that selenium can reduce the toxic effects caused by environmental pollutants.

Although selenium was already known to have certain toxic effects before it was recognized as a necessary trace element, humans initially did not pay attention to its adverse effects on natural ecosystems. Selenium in nature is mainly found in carbonate rocks, volcanic soils, and sedimentary soils. However, 40% of selenium in the atmosphere and aquatic environment is caused by the intervention of various industrial activities such as mining and mineral refining. 43 Selenium pollution poses a serious health hazard to marine organisms. The most typical example is the selenium pollution of Lake Belus due to the discharge of wastewater from coal-fired power plants. The fish community in this lake continued to suffer chronic selenium poisoning, causing multi-system and multi-organ damage as well as obvious malformations. 44 Lower selenium concentrations have an antioxidant effect, but high selenium levels produce a prooxidant effect. In the state of high selenium, selenium can directly form intramolecular disulfide bonds, selenium trisulfide bonds, and selenium sulfur bonds with essential thiol groups or cysteine residues in the active center of the enzyme protein to inactivate enzyme protein activity. Selenium can replace sulfur during protein synthesis, causing protein folding errors. In addition, selenium can also consume glutathione to produce superoxide anions, causing accumulation of ROS, leading to a decrease in intracellular reduction status and cell damage. 45 A study on zebrafish embryos exposed to selenium showed that when the concentration of selenomethionine reached 100 ug/L, the mortality and deformity rates of embryos significantly increased. The glutathione level significantly decreased at 400 ug/L, and the TGSH: GSSG ratio decrease indicates that the embryo was under oxidative stress. The addition of antioxidant N-acetylcysteine significantly improved mortality and deformity rates and alleviated low levels of glutathione. 46

The effects of selenium on the nervous system and ethology of zebrafish

Most environmental pollutants have neurotoxic effects on zebrafish, affecting the development of the central nervous system, synthesis and release of neurotransmitters, etc. 47 Excessive selenium also has neurotoxic effects and involves behavioral changes in zebrafish. Regardless of the exposure method, the basic toxic mechanism of excessive selenium is through the induction of oxidative stress. Zebrafish embryos exposed to selenomethionine to 96 h post fertilization (hpf) showed that the number of brain cells decreased significantly and the number of apoptotic cells increased. Mitochondria in brain cells are reduced and destroyed, and the nuclear membrane structure is loosely folded. The inflammatory response of brain tissue is enhanced. 48 In addition, embryos exposed to sodium selenite to 48 hpf through immunofluorescence detection of acetylation α-tubulin found that tubulin in axons was absent or abnormally arranged, resulting in abnormal development of neural tubes and neurons in the trunk and tail. 49 Under selenium exposure, oxidative damage occurs within neuronal cells, disrupting the stability of the mitochondrial inner membrane, producing more ROS, and further damaging other organelles, including the endoplasmic reticulum, impairing protein synthesis function. This may be the reason for the blockage of the synthesis of many neurotransmitters in the brain. The experiment also confirmed that related markers and gene transcription of dopamine, serotonin, γ-aminobutyric acid, acetylcholine, and histamine were affected. 50 Under the influence of this series of pathological changes, zebrafish also have adverse consequences in ethology. Behavioral analysis of zebrafish exposed to selenium revealed that its basic movement ability was impaired. 49 Its locomotor activity weakens with increasing exposure concentration, and touch experiments show that larvae exposed to high concentrations have slower reactions and poorer escape ability. 48 The maze experiment of more complex visual stimuli and food rewards reflects the severe impairment of associative learning behavior in adults exposed to high selenium. 50 , 51

Moreover, the neurological and behavioral effects of selenium exposure can even affect offspring through intra-ovo accumulation. Embryos born from long-term selenium-exposed mothers are no longer exposed to selenium since fertilization. Still, the embryos exhibit the same diminished clustering, decreased social learning ability, and dysregulated neurotransmitter transmission as their mother in adulthood. 52 Peroxisome proliferator-activated receptor (PPAR) is a nonsteroidal nuclear receptor involved in the development and functioning of the nervous system. Activating PPAR can alleviate neurological dysfunction and improve exercise capacity. 53 A study reported that KEGG analysis of zebrafish with neurobehavioral disorders after selenium exposure revealed significant downregulation of PPAR signaling pathway-related genes, confirmed on qPCR. However, using PPAR agonists can only improve the downregulation of related genes but not behavioral defects. 48 The PPAR signaling pathway is involved in the neurotoxic process of selenium exposure, but it may not be the main damage mechanism. The specific mechanism of the nervous system and behavioral changes in zebrafish damaged by high selenium concentrations is still not fully understood.

The effects of selenium on reproduction and growth of zebrafish

Long-term exposure to selenium contamination can lead to the continuous accumulation of selenium levels in fish organs, mostly in the liver, skeletal muscle, heart, and ovary. Although the ovaries are not the most severe selenium residual organs, the reproductive toxicity induced by selenium poses the most harm to the continuation of fish populations. 44 According to reports, under high concentration selenium stress, the primary oocytes of female zebrafish delay maturation and partially undergo apoptosis due to oxidative stress, resulting in a decrease in zebrafish egg production. Due to the biological enrichment of selenium, the hatching rate decreases, and the mortality rate increases in offspring. 44 , 54 The maturation of oocytes is also regulated by hormones in the hypothalamic–pituitary gonadal axis. However, high selenium exposure reduces the expression of this axis hormone in zebrafish through endoplasmic reticulum stress, especially estradiol, which is involved in inhibiting oocyte maturation. 55 Long-term selenium exposure inhibits the growth of parent zebrafish and limits offspring development due to selenium stress transmitted by parents through fertilized eggs. Studies have shown that gene expression and content of the thyroid hormone axis and somatotropin axis are significantly inhibited in both selenium-exposed parents and their offspring born but not exposed to selenium. 56 Moreover, the deformity rate of offspring is considerably higher than that of parents; the degree and types of malformations are also diverse, including craniofacial malformations, eye malformations, pigment loss, pericardial and abdominal edema, spinal cord malformations, spleen and gallbladder lesions, etc. 57

The behavior of fish is crucial in their growth, especially their swimming ability. Excess selenium negatively affects fish behavior through neurotoxicity and can interfere with fish energy metabolism and impair fish swimming ability. Experiments have shown that zebrafish fed excessive organic selenium have a lower critical swimming speed and impaired swimming ability. In maintaining the same regular exercise and balance, the high-selenium group needs to consume more energy and oxygen, i.e. the metabolic rate increases. Biochemical tests showed that zebrafish’s blood sugar and triglyceride levels in the high selenium group increased. 58 The changes in blood sugar and triglycerides have been explained in the latest report: excessive selenium inhibits the expression of genes related to fat breakdown but has no significant effect on genes related to fat synthesis. 59 Excessive selenium also inhibits the glycolytic pathway and tricarboxylic acid cycle and overactivates the gluconeogenesis pathway. The report also found that excessive selenium damaged pancreatic function, inhibited insulin secretion, and ultimately disrupted glycometabolism in zebrafish. 59 In addition, excessive selenium in the endoplasmic reticulum causes protein folding errors and hinders some protein synthesis. 60 Abnormal metabolism of the three major nutrients is bound to have adverse consequences for the growth of zebrafish.

Toxic effects of selenium on other organs

Whether it is environmental or dietary exposure when the selenium concentration exceeds the nutritional range, the fish’s liver is one of the organs with a severe accumulation of selenium. 18 It is also the most sensitive organ to changes in the antioxidant enzyme system. 59 After acute selenium exposure in zebrafish, histopathological observations showed a decrease in liver volume, slow development, and impaired liver function 59 ; Focal necrosis, hemorrhage, and interstitial edema in liver tissue; Hepatocytes have irregular shapes, swelling, nuclear pyknosis, and the formation of fat large vacuoles. 61 Moderate lipid vacuolar degeneration, macrophage aggregation, and glycogen depletion were also observed in the chronic dietary selenium sublethal exposure of Pogonichthys macrolepidotus . 62 Unfortunately, the report did not detect changes in blood glucose levels in P. macrolepidotus . Both reports 59 , 61 tested the antioxidant enzyme system in zebrafish liver and confirmed that the mechanism of liver damage caused by excessive selenium is still driven by oxidative damage. The production of a large number of ROS inhibits the autophagy function of hepatocytes so that hepatocytes cannot remove harmful substances in time, resulting in hepatocyte damage. The autophagy inducer rapamycin restored the autophagic function of hepatocytes and saved some liver function and developmental malformations in zebrafish embryos. 59

The protective effect of selenium on cardiovascular diseases has been studied to a certain extent. It is negatively correlated with the occurrence of cardiovascular diseases in the range of nutrient concentrations. Selenoprotein plays an important role in the heart’s development and the myocardium’s protection from oxidative damage. 63 However, exceeding the nutritional range of selenium poses a serious burden on the cardiovascular system, which has been confirmed in zebrafish. Zebrafish embryos exposed to sodium selenite at 4 to 120 hpf, abnormal cardiac development, and pericardial edema can be seen. Atrioventricular staining shows atrial and ventricular cavity hypoplasia and is smaller than the normal group. 49 Specific fluorescent expression genes labeled myocardial cells in transgenic zebrafish embryos were used to observe cardiac development. After exposure to selenomethionine, smaller ventricles and larger atria were observed, with a significant increase in atrioventricular area ratio. HE staining showed loose myocardial cells. 64 Embryos exposed to more toxic selenium nanoparticles can even see crookedly circular and linear chambers and the ventricles in front of the atrium. 65 Selenium, in either form, caused a statistically significant decrease in the heart rate of zebrafish embryos. 49 , 64 , 65 The oxidative stress caused by excessive selenium leading to cell apoptosis is the fundamental mechanism of cardiac developmental abnormalities, and the antioxidant folic acid can prevent heart defects caused by sodium selenite. 49 Research has found that after exposure to selenomethionine, the expression of the heart development-related gene lrp2b in zebrafish is downregulated. After silencing the lrp 2b gene, zebrafish exhibited similar characteristics to selenomethionine exposure; Overexpression of the lrp 2b gene protects embryos exposed to selenomethionine. 64 The abnormal expression of genes related to cardiac development may be due to selenium interference with DNA methylation in the early developmental genome. 49 Still, it has not been confirmed whether the inhibition of DNA methylation affects the expression of lrp 2b.

One of the little-known symptoms of selenium poisoning in fish is the occurrence of visual impairment, which may be due to the accumulation of selenium in the eyes and damage to the development and function of the eyes. 66 Research has found that excessive selenium exposure leads to incomplete and delayed eye development, smaller eye radius, and abnormal expression of genes related to the eyes and optic nerve in zebrafish. 67 The study also found that oxidative stress caused by high selenium induces apoptosis and ferroptosis. Salvage experiments were conducted using antioxidant, ferroptosis inhibitors, and apoptosis and ferroptosis activator cisplatin. The results showed that antioxidants could not completely antagonize selenium-induced eye defects, while low-dose cisplatin can improve. 67 In addition, confocal X-ray fluorescence imaging technology was used to observe embryos produced by female fish fed a high selenium diet. It was found that selenium preferentially accumulates in the lens of embryos through parental transmission, ultimately leading to lens opacities or cataracts in zebrafish. 68

The different forms of selenium have varying degrees of beneficial and toxic effects on zebrafish, which may be related to the utilization rates of the various forms of selenium in zebrafish. 69 One study treated zebrafish embryos with different forms of selenium and analyzed their accumulation levels, which found the dosage of organic selenium was much lower than that of inorganic selenium. Still, the accumulation concentration of organic selenium in juvenile zebrafish was higher, 70 indicating that organic selenium has greater toxicity and higher bioavailability to fish. So, dietary exposure experiments most commonly use selenomethionine as the source of selenium intake. The inorganic selenium used in the embryo exposure experiment is sodium selenite, with an exposure concentration of 10 umol/L, 49 while the commonly used organic selenium is selenomethionine, with an exposure concentration of 0.5 umol/L. 48 , 59 , 67 The increase in exposure concentration leads to an increase in the embryonic mortality rate and a decrease in the embryonic hatching rate, which affects the experimental results. Lower concentrations must be used for long-term chronic exposure to reduce mortality rates. In addition, the form of selenium also includes simple selenium nanoparticles (SeNPs) synthesized through biological or chemical methods and composite selenium nanoparticles combined with other substances. Embryo exposure experiments have shown that chemically synthesized SeNPs’ antioxidant capacity is stronger than sodium selenite at the same dose. 71 Still, its toxicity is greater than sodium selenite. 65 The toxicity of biosynthetic SeNPs is several times lower than that of sodium selenate, and it has more stable dissolution kinetics and characterization than chemically synthesized SeNPs. 72 However, there has been no study comparing the toxicity of SeNPs with organic selenium. Composite SeNPs cannot be reached in toxicity with other forms of selenium due to their combination with other substances. Still, their significant advantage is that they greatly enhance selenium’s beneficial effects. For example, a composite SeNPs diet composed of chitosan, which also has immune-enhancing properties, can significantly improve the immune function of zebrafish compared to a diet consisting solely of chitosan and sodium selenite. After intraabdominal injection of Aeromonas hydrophila , the survival rate of zebrafish fed with composite SeNPs was significantly higher than that of other groups. 73 Inulin fructan and selenium, which both have anti-tumor effects composed of SeNPs, are also the same. 34

Selenium is an essential trace element for animals; we must truly understand the nutritional value and toxicity to provide a reference for fish to supplement selenium reasonably. An appropriate amount of selenium can provide fish with necessary beneficial effects, such as participating in important physiological processes, promoting growth, enhancing antioxidant effects, enhancing immune response, and preventing related diseases. However, it is also necessary to be cautious of excessive intake, which can cause neurotoxicity and damage to internal organs. Although some achievements have been made in studying selenium on zebrafish, further research is still needed. The following aspects may provide ideas for further research on the benefits and toxicity of selenium to zebrafish: (1) At present, most of the selenoproteins in humans and zebrafish have been identified, but some of the identified selenoproteins have not fully understood their functions and roles in physiological processes. (2) The safe nutritional range of zebrafish selenium is narrow and has a "double-edged sword" characteristic. An authoritative, safe concentration range should be explored, and this range should vary with the chemical form of selenium and different stages of zebrafish development. (3) Selenides and SeNPs can be used as potential therapeutic drugs for some diseases, such as diabetes, 74 cancer, etc., and zebrafish can be used to establish disease models to explore the therapeutic effects of selenium-containing drugs. (4) Excessive selenium can cause body axis deformities in zebrafish, such as lordosis, kyphosis, and scoliosis. Is body axis deformity related to abnormal gene expression or myogenic? There is currently a lack of relevant research in this area. The only study on Japanese medaka has shown that skeletal abnormalities caused by selenium in craniofacial and caudal fin deformity are associated with abnormal gene expression related to cartilage and bone formation. 75 (5) After selenium poisoning, fish can exhibit multiple organ damage, and further research on the pathological changes and damage mechanisms of other organs such as gills, kidneys, and pancreas can be carried out on zebrafish. (6) Most research on organ damage remains focused on the abnormal expression of related genes caused by oxidative stress, and the specific mechanisms of damage or related pathways activated through ROS still need to be further explored.

Yuan Zhang and Yuanshan Lin contributed to the study conception and design. Data collection and analysis were performed by Liyun Hu, Xinhang Li and Jie Ma. The first draft of the manuscript was written by Yuanshan Lin. The manuscript was reviewed and corrected by Qipeng Li and Xiaofan Yuan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

This work was funded by the National Natural Science Foundation of China (grant number 81560366) and the Major Science and Technology Project of Yunnan Provincial Department of Science and Technology, Yunnan Provincial Orthopedic and Sports Rehabilitation Clinical Medicine Research Center (grant number 202102AA310068).

Conflict of interest statement . The authors declare that they have no financial interests.

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• Published: 23 December 2022

Role of miRNAs interference on ovarian functions and premature ovarian failure

• Narjes Nouri 1 , 2 , 3 ,
• Olduz Shareghi-Oskoue 2 , 3 ,
• Leili Aghebati-Maleki 4 ,
• Shahla Danaii 5 ,
• Javad Ahmadian Heris 6 ,
• Mohammad Sadegh Soltani-Zangbar 2 , 3 ,
• Amin Kamrani 2 , 3 &
• Mehdi Yousefi 2 , 3 , 7  

Cell Communication and Signaling volume  20 , Article number:  198 ( 2022 ) Cite this article

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Premature ovarian failure is a to some extent unknown and intricate problem with diverse causes and clinical manifestations. The lack of ovarian sex hormones presumably is effective in the occurrence of ovarian failure. Our progress in this field has been very little despite undertaken scientific research endeavors; scholars still are trying to understand the explanation of this dilemmatic medical condition. In contrast, the practice of clinical medicine has made meaningful strides in providing assurance to the women with premature ovarian insufficiency that their quality of life as well as long-term health can be optimized through timely intervention. Very recently Scientists have investigated the regulating effects of small RNA molecules on steroidogenesis apoptosis, ovulation, gonadal, and corpus luteum development of ovaries. In this literature review, we tried to talk over the mechanisms of miRNAs in regulating gene expression after transcription in the ovary.

Video abstract

Introduction

MicroRNAs (miRNAs) are a class of small non-systematize RNAs that function in gene regulation accompanying a main role in cell activity, proliferation, and development [ 1 ]. The supervisory part of these small RNA molecules has currently surveyed in ovarian cells, uncovering their influence on steroidogenesis, gonadal development, ovulation, apoptosis, and corpus luteum development. Herein, we reviewed the current understanding of miRNA biogenesis, mechanism, and the act that miRNAs play in gene expression regulation following transcription, as well the current evidence of miRNAs practice in ovarian development and function [ 2 ]. Ovulation and oocyte growth happens inside the ovaries. Ovaries granulosa cells provide estrogen for ovaries itself and also endocrine signals to other organs and tissues [ 3 ]. Ovarian somatic cells work for the growth and maturation of the oocyte very near to the rise of luteinizing hormone (LH), creating a physiological reaction above ovulation. This answer involves, encouraging steroidogenesis, meiosis, follicular maturation, cumulus cells development, progesterone secretion, and luteinizing, eventually oocyte maturation [ 4 , 5 ]. It has been discovered that Dicer (ribonuclease III) knockout, which is in charge of pre-small RNA processing into functional small RNAs caused disruption in the several biological events inside the ovary including folliculogenesis, oocyte development, ovulation leading to infertility [ 6 , 7 , 8 , 9 , 10 ]. siRNAs, miRNAs, and piRNAs are the principal small RNAs work for the healthy functioning of the ovary. PiRNAs mainly pay to the heathy functioning of the germ cell [ 11 ]. With regard to complicated miRNAs play during fetal development, fetal gonadal steroidogenesis includes many genes linked expression [ 12 ].

Premature ovarian failure is a intricate disease with prevalence of 1 in 250 women below the age 35 and 1 in 100 women below 40 [ 13 , 14 , 15 ]. POF characteristics consist of increased estrogen level, decreased gonadotropin hormone level, lack of menstruation that pay to female infertility and medical condition prior to the menopause [ 16 ]. Additionally there is some adverse outcomes to POF including heightened probability of cardiovascular diseases, weakened sexual function and fragile bones [ 16 ]. Three categories of cells are found in Ovarian follicles: oocytes, granulosa and theca cells. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) affect granulosa and theca cells through specific receptors, which are vital for the follicles growth and development and this normal folliculogenesis process is changed in POF [ 17 , 18 ].

Scientific investigations have identified the role of gene defects like X chromosome and autosomes abnormalities in the POF emergence, particularly structural differences and X chromosome translocation with autosomes trisomy of X, Turner syndrome, pre-mutations and mutations of X associated genes and also aberrations of autosomal associated genes have been detected in POF cases [ 18 , 19 ].

In addition to genetic and chromosomal parameters interfering in the appearance of POF, other determinants are including autoimmunity, enzymes, and environmental factors [ 18 , 20 ].

Profile of effective miRNAs in the ovary

miRNAs are expressed in the ovary function for the managing of mammalian reproduction. miRNA expression profiles have recognized in various species containing human, mouse, bovine, sheep, chicken, fish, swine and equine species [ 21 ]. miRNA expression in each organ is closely related to organ function. The expression and function of miRNAs depend on the cell types is different. The ovary contains oocytes and many somatic cell types such as granulosa cells, theca cells, and cumulus cells. In total, 58 miRNAs were mainly expressed in bovine fetal ovary compared to somatic tissue. Eight miRNAs bta-miR-10b, bta-miR-99a, bta-miR-199a-5p, bta-miR-199a-3p, bta-miR-100, bta-miR-424, bta-miR-214and bta-miR-455) expression were 10 times higher in fetal bovine ovaries than in the pool of somatic tissues. Additional examination indicated that bta-miR-10b together with bta-miR-424 were extremely amplified in oocytes germinal vesicle (GV)[ 22 ]. Analogous expression arrays proposed to the maternal inheritance of these miRNAs and might possibly stay engaged in transcription throughput zygote gene activation. Numerous miRNAs function in maturation of oocyte, like miR-7, miR-2, miR-100, miR-184, miR-9b, let-7, miR-133, miR-79, miR-252 and miR-275 indicating different miRNA expression in several stages of the egg [ 23 , 24 , 25 ]. miR-133 and miR-2 are meaningfully amplified in metaphase I (MI) compared to GV stage, and both prevent cyclin B translation through abridging the 3′-UTRs of the crab cyclin B gene [ 24 ]. Several miRNAs, like the let-7 family, showed a species-independent housekeeping character in the ovary [ 26 , 27 ]. Granulosa cells express miRNA differentially during luteal and follicular stages. miR-503 expression decreased in both the luteinization and FSH-reactive follicular growth stages however increased in the following pre-ovulatory stage [ 6 ].

Xu et al. characterized the cumulus granulosa cells of human (CGCs miRNA profile), and introduced let-7 family as the profusely amplified miRNA in cumulus granulosa cells of both women with healthy cycling and women with polycystic ovarian syndrome (PCOS) [ 27 ]. Comparing to the women with heathy cycling, the expression of miR-1307-3p, miR-10a-5p, miR-1273g-3p, miR-423-5p, miR-185-5p, miR-199a-3p, and miR-483-5p intensely boosted in the GC cells of women with PCOS. miR-483-5p expression overpowers both mitogen-activated protein kinase 3 (MAPK3) and Notch3 with decreasing expression in CGCs through direct bounding to MAPK3 and Notch3 mRNAs 3′-UTRs [ 27 ]. Bioinformatics and Gene regulation studies have discovered the effective sequences of pronouncedly expressed miRNAs in the ovary which contributing in the cellular events including cell proliferation, cell cycle, and apoptosis affecting ovaries functioning; and endocrine arrangement [ 28 ]. Moreover, recently it has been revealed that miR-143 prevents early follicle development through decreasing cyclin-dependent kinases (CDKs) 4 and 6 as well B1, D2,and E2 cyclins expression in early granulosa cells [ 29 ]. Additionally, miR-181a prevents the mice ovaries granulosa cells growth through direct impacting of activin IIA receptor [ 30 ]. miR-26b impedes the ataxia telangiectasia gene mutation (ATM) and in follicular ovaries granulosa cells promotes apoptosis [ 31 ]. In conclusion, miR-212 and miR-132 do some touches on ovulation and luteinization through endocrine system regulation [ 32 ].

miRNAs and ovarian function

Mirnas impact on ovarian follicle development.

Depending on the species, the oocyte can remain suspended in the primordial follicle in the prophase of meiosis 1 for months and years. Follicle growth is initiated by cyclic signals with unknown origin. At this stage, the egg creates a thick extracellular matrix that forms the zona pellucida, which leads to the relative separation of the egg from the pre-granulosa cell layer. At this stage, pre-granulosa cells are differentiated into cubic granulosa cells and begin to multiply. Follicle growth continues with successive growth of oocyte and granulosa cells. The granulosa cells fluid-filled antrum is created among the granulosa cells layers (antral follicle). At the same time that granulosa cell and oocyte growth carry on, the granulosa cells excrete follicular liquid, leading to the creation of the antral hollow in the widening follicle. This vital liquid contains of proteins and other molecules providing nutrition as well signaling molecules among dissimilar cells inside of the follicle. The antrum formation encouraged granulosa cells departure and differentiation into cumulus cells. The cumulus granulosa cell layer is the oocyte nearby layer, maintaining straight interaction with oocyte by means of trans-zonal reactions spreading from cumulus cells in order to contact the oocyte surface in the porous zona pellucida. Cumulus cells and the oocytes impact each other through autocrine elements, gap junctions, and probably with transference of tiny extracellular vesicles (exosomes/micro-vesicles), sharing molecules among the granulosa cells and the oocytes seems indispensable for the follicle’s maturation, since either oocyte or the granulosa cells could not last by their own. Since these cells are dependent to each other, the gene expression regulation in both cells is vital for emerging the healthy babies. Numerous research work has confirmed the differential expression of miRNAs in diverse sections and time points inside the ovary, including oocyte development, luteal action and follicle maturation [ 33 ].

During different phases of follicle development, diverse growth elements indicate dissimilar properties on phase-specific purposes in disparate cell categories [ 2 , 34 ]. As well miRNAs critically function in the different phases of follicle development, covering tiny follicles (1.5–3.5 mm), average follicles (4.0–5.5 mm), pre-ovulatory follicles, early corpora lutea, late corpora lutea, and corpus albicans. The utmost profusely expressed miRNAs through the different stages of development are miR-125b, miR-21, let-7a, let-7b and follicular stage over-expressed miRNAs are miR-145, miR-199a-3p and miR-31 with noticeable reduction in the follicular-luteal transformation. In the contrary, miR-21, miR-142-3p, and miR-503 are expressed at minor quantities in the follicular periods with marked rises in luteinized tissues [ 35 ]. Based on a study, miR-181a expression decreased in mice pre-antral and antral follicles relative to mature follicles similarly miR-181a inhibited activin receptor IIA expression (acvr2a) as well reduced the phosphorylation of intracellular signal transducer activin and Suppressor of Mothers against decapentaplegic homologue 2 (Smad2) in rat granulosa cells, affecting the granulosa cell proliferation and ovaries development [ 30 ]. Folliculogenesis starts with collapsing clusters of germ cells and primary follicles formation. Zhang et al. with in situ hybridization presented that pre-granulosa cells express miR-143 and miR-143 which hinders primordial follicles formation through pre-granulosa cell proliferation suppression and declining cell cycle-specific genes expression, like cyclin D2, CDK6, and CDK4 [ 29 ]. Since, across folliculogenesis, above 99% of ovarian follicles turn into atresia, miRNAs function in the follicle growth and atresia have lately been recognized. Since, disparate miRNAs expression is designed for healthy, pre-atretic and more atretic follicles [ 31 ] For this reason, P-miR-1281, Hsa-miR-936, mmu-miR-1224, hsa-miR-26b, P-miR-466g-b, hsa-miR-10b, P-miR-1275, R-miR-26b, hsa-miR-574-5p, hsa-miR-1275, hsa-miR-149*, and hsa-miR-99a a miRNAs expression increased, while hsa-let-7i, R-let-7a, hsa-miR-92a, hsa-miR-92b, P-miR-923, R-miR-739, hsa-miR-1979, hsa-miR-1826, hsa-miR-1308, P-miR-1826, and ssc-miR-184 expression decreased in follicles. Increased miR-26b expression, in follicular atresia, promotes DNA breaks and increases apoptosis in granulosa cells by direct objecting ATM and follicles trigger atresia through granulosa cells apoptosis [ 36 , 37 ]. Considering miRNAs function in the trigger of apoptosis in granulosa cell, miR-34s initiates cell apoptosis and stops growth by p53 activation as well p21 cyclin-dependent kinase inhibitor [ 38 , 39 ].

Tu et al. stated in a study on pig ovarian follicles that miR-34a encouraged apoptosis in granulosa cells through targeting beta B (INHBB) gene inhibition [ 40 ]. Carletti et al. stated that luteinizing hormone (LH) caused higher expression of miR-21 in rat granulosa cells and miR-21 silencing in vitro triggered apoptosis in granulosa cells [ 41 ]. Based on very advanced research findings miRNAs play key role in the oocyte maturation and the eggs move in to the meiosis stage at the initiation of DNA synthesis and stays in the MI stage till meiosis continues. Prior to ovulation, oocytes turn in to secondary oocytes following the first meiosis and are stopped in meiosis metaphase II (MII) up to fertilization [ 7 , 25 ]. Xiao et al. stated that transgelin 2 (TAGLN2), with encoding an actin protein, contributes to ovaries growth and maturation. Furthermore, miR-133b controls oocyte development with targeting TAGLN2 at both mRNA and protein producing levels [ 25 ]. Dicer as a ribonuclease works in the synthesis and production of functional mature miRNAs in both granulosa cells and oocytes of the mice ovaries follicles [ 35 ].

Similarly, Dicer work in pre-ovulation follicles development has been clarified. Lei et al. stated that temporary inactivating of Dicer1 in follicular granulosa cells caused augmented supply in the pool of primordial follicles, hastened early recruitment of follicles and an upsurge in corrupt follicles in ovaries with temporary Dicer knockout (cKO) [ 6 ].

miR-503 is an ovary-specific miRNA, Dicer1 affects follicle maturation by knockdown of miRNA and miR-503 sequences. Inactivating Dicer1 in female rats led to atypical follicles formation and infertility [ 6 , 7 , 42 ].

Based on research studies Dicer functions importantly in follicle growth and oocyte maturation. Number of elements like members of TGF-β superfamily [ 43 , 44 ], Ligand stimulating of type I activin receptor-like kinases (ALKs) and Smads [ 45 , 46 , 47 ] are regulated by miRNAs impacting follicle development. Recently in a study has been revealed that miR-224 expression regulates TGF-β/Smad signaling, miR-224 overexpression promotes TGF-β1-mediated granulosa cell proliferation together with Smad4, whereas miR-224 suppression partly overpowers TGF-β1-mediated granulosa cell proliferation, representing critical work of miR-224 in folliculogenesis [ 48 ].

Secondary and early antral follicles miRNA content

Because of the need for isolation of small follicles out of pure populations and inadequate available procedures for ex vivo studying of folliculogenesis, a few investigations have been advocated for studying miRNAs role in tiny and developing follicles, moreover, even though there are range of molecular protocols for optional silencing of miRNA genes in early follicles development, most of the trials are intricate and often subject to fail also due to the miRNA progressive regulatory abilities, certain knockout could not abolish the preceding synthesized miRISC, thus fail to change function. Consequently, large part of ongoing research inspecting miRNA properties in folliculogenesis could be introductory in vitro inferences, clarifying some of the inconsistent data driven from the studies presenting proof of miRNA in vitro expression contribution in variable facets of granulosa cell function [ 34 , 49 , 50 , 51 ]. Majority of the ovarian investigations largely depend on the cultivated granulosa cells or immortal granulosa cell lines, even though lack of in vivo functional studies always has been felt. Findings of in vitro experimentations without specific linking to studied in vivo effects cannot either specify the endogenous in vivo position, or justify the miRNAs properties and require precise validation and confirmation in order to be adequately comprehended. Early scientists’ inferences could provide to some extent the outline for upcoming research and medical practice either with confirming or discrediting the impact of these small RNA molecules in ovarian biology. Since, it is of a highly importance to verify many facets of inter- and intracellular complex signaling, in this way, in vitro experiments can be major implements to aid deciphering the codes of cellular communications. One example can be the constant study of transforming growth factor (TGF) regulation mediated miRNAs signaling pathway. TGF-β1 superfamily Proteins function critically in follicles’ maturation, and related miRNAs regulate this complex signaling pathway. Yao et al. revealed that miR-224 expression affected 16 TGF-β1 reactive miRNAs detected in cultured granulosa cells of pre-antral murine [ 48 ]. Based on bioinformatics studies, smad4, a TGF-β1 signaling intracellular effector [ 52 ], previously recognized as a miR-224 potential target. Increased expression of miR-224 declined the protein amounts of smad4 in cultivated granulosa cells, though it indicated a slight influence on mRNAs expression [ 48 , 53 ]. Regarding GABRE as a TGF-β1 reactive gene, p53 and p65 are tumor suppressor genes regulate GABRE and miR-224 and p53 and/or p65 Knockdown leads to boosted amounts of miR-224 as well higher granulosa cell proliferation through TGF-β1 signaling [ 54 ]. A current study verified that miR-224 connects to the pentraxin 3 (ptx3) from 3'UTR head, a gene which is vital for cumulus cells growth [ 55 ]. It is assumed that after LH stimulation miR-224 expression should be reduced however the findings of these studies displayed irrelevant alterations in miR-224 level. This research claimed that TGF-β1 instigated a cut in miR-224 level, accordingly the amplitude in ptx3 and LH/hCG treated cumulus cells growth is inevitable [ 55 ]. Strangely, this finding opposes earlier findings indicating miR-224 rise responding to TGF-β1 in immature mice pre-antral granulosa cells [ 48 ].

Antral follicles miRNA content

During development of primary antral follicles, luteinizing hormone receptor (LHCGR) level in granulosa cells is elevated through estradiol and follicle-stimulating hormone. The LH rise results in ovulation; therefore, this stimulation is indispensable for opting of the main follicle(s) and for ensuing LH-reactive molecular events within granulosa cells. The LH upsurge stimulates key modifications in genes function in pre-ovulation granulosa cells, resulted in modifications in several pathways inside the cells, comprising miRNAs, transcription factors, and matrix renovation factors [ 56 , 57 ]. Alterations in miRNA expression after LH upsurge redirect general variations in gene expression [ 32 ].

Using a bioinformatics approach, Troppmann et al. analyzed the 3′UTR sequences of the LHCGR gene in search of miRNAs that might regulate its expression [ 58 , 59 , 60 ] Their analysis identified miR-513a-3p as a potential regulator of LHCGR. This miRNA was detectable in whole ovarian lysates in addition to human granulosa cells collected from large antral follicles of women undergoing assisted reproduction. Further test of the gene sequence for miR-513a-3p identified it as an X-linked gene appeared only in animals. To decide either there is a connection between the expression levels of miR-513a-3p and LHCGR, scientists measured the levels of both gene collected yields of human luteinized granulosa cells during oocyte retrieval in assisted reproductive technologies (ART) all along cultivation earlier calculated in lab environments [ 60 ].

During sample gathering, dropped LHCGR and heightened miR-513a-3p expression was observed. By time pass, levels of miR-513a-3p increased as LHCGR levels decreased. Thus, they demonstrated an inverse association between expression of LHCGR and miR-513a-3p, supporting the role of miR-513a-3p in affecting expression of LH receptor in granulosa cells [ 60 ].

miR-212 and miR-132 placed in 11700016P03Rik gene intron number 1 and thus both are contributed in the transcript of pri-mRNA. LH signaling causes cAMP-regulatory element-binding protein (creb) activation and Creb in neurons regulate miR-212 and miR-132 expression, therefore this could enlighten the reason of rise in miR-212 and miR-132 expression after LH activation [ 32 , 61 ]. Bioinformatics survey has been performed with the aim of finding miR-132/212 miRNAs from the 3′UTR of ovarian mRNA databank and 77 sequences detected and recognized indicating ctbp1 as of a particular attention. Ctbp1 (carboxy-terminal binding protein 1) act together with steroidogenic factor 1 (sf-1), thus modulate promoter activity and regulate steroidogenesis in adrenal cells [ 62 ]. A comparable character however has not been confirmed yet suggesting for miR-132/212 in affecting steroidogenesis in granulosa cell. Granulosa cells stimulation by LH/hCG indicated no change in ctbp1 mRNA amounts, though meaningfully reduced ctbp1 protein amounts suggesting an activity for miRNA following transcription [ 32 ]. Recent data in bovine oocytes proposes that miR-212 regulates the oocyte-specific FIGLA expression [ 63 ]. Therefore, further studies are needed for miR-132/212 function evaluation in the ovary. The role of miRNA-21 in carcinogenesis has been studied, it has been found that miRNA-21 expression is raised in most of tumor. In the ovary tissues miR-21 is controlled after in vivo hCG/LH activation, intensely expressed in human granulosa cells affecting granulosa cells growth and maturation [ 32 , 41 , 64 ]. Granulosa cells apoptosis happens by the omission of miR-21 through particular inhibitors; therefore miR-21 acts for granulosa cells maintenance in the follicles prior to the ovulation [ 41 ]. Notably, in vivo miR-21 action blockade through using blocking oligonucleotide into the ovarian bursa stopped ovulation [ 9 , 41 ]. Also In vivo inhibition of miR-224 can lead to impaired ovulation [ 55 ]. Similar studies demonstrated inactivation of specific associated miRNAs can imitate the Dicer-knockout phenotype in ovaries, implicating miRNAs critical functions in ovulation. Lately, miR-125b has been recognized as a downstream influencer of the androgen receptor in mouse granulosa cells [ 65 ]. Androgens upregulate miR-125b expression in granulosa cells, and blocks apoptotic pathways leading to increased granulosa cell maintenance [ 65 , 66 ].

Corpus luteum miRNA

The corpus luteum (CL) is made following ovulation and on account of the differentiation of mural granulosa cells. The corpus luteum is an endocrine gland works as hormonal provision for primary pregnancy and therefore is reduced in the lack of pregnancy, and also nearly prior to the beginning of the subsequent menstrual cycle. Lately, one research has pointed to the query of miRNA interference in luteal function, though many further research has recognized a number of significant miRNAs comprising miR-17-5p, let-7b, miR-125, miR-378, and miR-122 inside luteal tissues at disparate physiological phases (CL development, pregnancy, and regression). Through line of investigations miRNAs interfering regulatory mechanisms in the CL practice has been perceived. Since thorough lack of Dicer is lethal to embryos, therefore the scientists produced a Dicer hypomorphic mouse (dicerhypo) produces lower amounts of Dicer and lives up to adulthood. The lack of CL in Female dicer hypo mice leads to infertility, a disorder with frequent abortions in females [ 8 ].

Researchers suggest that the luteal tissue vascularization absence originates from the lack of some miRNAs (like miR-17-5p and let-7b) that affect the anti-angiogenic elements, tissue inhibitor of metalloproteinase-1 (timp1) miR-17-5p and let-7b replacement by straight transfection into the pregnant dicerhypo mice bursa may somewhat save the mice by enhancing vascularity and raising progesterone amounts. Though, one dose administration could not be able to keep pregnancy, the interference of other factors is possible [ 8 ]. Also, a group of researchers applied a bovine model to investigate miRNA expression alterations affecting CL function in periods of higher levels of progesterone compared to the time that CL bears regression, noticeable changes in miRNA production were perceived [ 67 ]. Since miRNA-378 cause the CL up-regulation with no recession further studies need to be conducted so as to recognize the likely character of this miRNA in CL up-keep. Based on preceding investigations, miRNA-378 acting in apoptosis through dropping the expression of interferon gamma 1 receptor (IFNGR1) gene. Consequently, Quantitative RT-PCR experimentations proved the link between higher levels of IFNGR1 mRNA and miR-378 with CL in the mid and late phases of CL upkeep, though minor levels of miR-378 in CL regression. Increased protein expression supported the possibility of post-transcriptional regulation of IFNGR1, however no change in IFNGR1 mRNA amounts within luteal regression has been seen [ 67 ]. CYP19, recognized as an estrogen-synthesizing aromatase enzyme, expressed nearly prior to ovulation and beginning of CL production. miR-378 can lead to CYP19 downregulation in porcine granulosa cells [ 68 ]. As well, a hairpin pre-miRNA inside the intron number 1 of the peroxisome proliferator-activated coactivator γ-1β (PGC-1β) gene produces miR-378 and miR-378 [ 69 ]. Although we found no reports of PGC-1β activity in ovarian cells, genetic alterations of the gene PGC-1α recognized in women with PCO [ 70 , 71 ]. Therefore, in vivo studies are essential for confirming the biological activity of this miRNA because most cases of miR-378 in ovarian function have been reported by in vitro experiments.

miRNA in the oocyte

With oocyte growth in the follicle, maternal mRNA and proteins are collected, relied on even fertilization and the embryonic genome activation. miRNA biogenesis pathway involved genes expression status in the mammalian oocytes and cleavage time embryos was examined through PREGER databank [ 72 , 73 ]. Revealed by research, Drosha, DGCR8 and Dicer mRNA levels, as vital compartments of the miRNA pathway, upsurge throughout mammalian oocyte development. Most of oocytes and early embryos expressing miRNAs biogenesis pathways are unresponsive to α-amanitin, an RNA polymerase enzyme, leads to chiefly raised miRNAs expression in cleavage-time embryos [ 73 ]. Owing to the finding of distinctive alterations in miRNA biogenesis in the oocyte, our comprehension of oocyte biology has been impacted, herein we tried to discuss miRNA expression alterations and their significance in the human oocyte understanding. Typically, mouse oocytes, are studied for oocyte miRNA research, which above full-length Dicer expression, as well generates a particular oocyte figure that is not indicated in other species [ 74 ]. The mice and rats dicer gene consists of an MT-C retrotransposon promoter inside intron 6, which resulted in the yield of a short amino-terminal isoform of dicero (Dicero), specifically essential in the endogenous siRNA production for mouse oocyte function [ 74 ]. Therefore, it is predicted that the bulk of RNA species created in the mouse oocyte are consist of siRNAs and miRNAs. Dicer/AGO2 pathway produce double-stranded siRNAs, however dissimilar to miRNAs, siRNAs are not relied on DGCR8. Dicer Omission bases infertility in females and atypical metaphase spindles in mouse oocyte development, like parent AGO2-zp3-cKO and Dicer-zp3-cKO mice, therefore approving preceding research [ 7 , 74 , 75 ]. Conversely, DGCR8-zp3-cKO oocytes develop and fertilize with no obvious aberrations [ 76 ]. These preceding investigations confirmed the necessity of ago2 and dicer signaling communications for mouse oocyte development but not dgcr8. The origin of metaphase failure through maturing is unidentified, it might because of particular cytoskeletal regulation and cell cycle progression interfered genes directing endogenous siRNAs [ 42 , 74 , 77 ]. Majority of oocyte-related miRNA investigations have been conducted in rodent species expressing a shortened form of dicer with no expression in other species. Consequently, it is worth to inspect the siRNA and miRNAs corresponding functions in further species. Line of research led on bovine oocytes and as well other species, showing that miRNAs perform practically in oocytes developments [ 78 , 79 ]. Similar investigation studied the function of miR-212 in the FIGLA regulation. FIGLA is an oocyte-related transcription factor that is necessary for follicle maturation and the synchronized expression of the zona pellucida proteins, ZP2, ZP3, and ZP1 [ 80 ]. According to number of research investigating the influence of miRNAs in the FIGLA expression regulation, studying the possible connection spots in the 3′UTR of bovine FIGLA mRNA by means of MicroInspecto software. This examination recognized miR-212 as a controller of FIGLA expression in bovine germinal cells. miR-212 and miR-132 expressions in tandem are co-regulated in granulosa cells after LH-rise in follicles [ 32 ].

Examining the expression outline of miR-212 of bovine tissues presented that it is pronouncedly expressed in the oocytes germinal vesicle with an inclination to escalation in the cleavage time of the embryo till the eight-cell stage, when the cow embryo experiences this transmission from the mother zygotic gene regulation. This expression outline is in consistence with other miRNAs expected to regulate transcript throughput in maternal-zygote transmission, consisting Zebrafish miR-430 [ 78 ], Xenopus miR-427[ 79 ], and mouse miR-290 [ 81 ]. The miR-212 expression in embryo and oocyte is counter-correlated with the expression of FIGLA, representing a possible miR-212 negative controlling function [ 63 ]. By means of FIGLA in miR-212 transfected cell culture models it has been displayed that miR-212 connects to the FIGLA mRNA 3′UTR head. miR-212 transfection simulates declining in FIGLA protein expression in the stage of eight-cells bovine embryos, representing the function of miR-212 in the control of FIGLA transcription factor [ 63 ]. Comparable research has merged miR-181a and miR-196a in the regulation of maternal oocyte related NPM2 and NOBOX genes [ 82 , 83 ].

Up to the present time, some investigations have been accomplished concerning miRNA expression changes in human oocytes. In research, human MII oocytes genes expression was studied compared to human blastocysts [ 84 ]. By means of "Genome Survey Microarray", oocytes biosynthetic genes miRNA amounts and blastocysts were comparatively examined. Candidate genes narrow down was made, together with "housekeeping" genes as well human embryonic stem cells genes identified. A category of miRNAs has been derived from the nonhuman primate PREGER gene expression databank [ 73 ]. Similarly, non-human mammals, Drosha and Dicer gene yields were identified in human oocytes as well blastocysts. It has been found that, three nucleotides repeat gene 6B (TNRC6B), is a piece of the RISC complex, has been mainly expressed in oocytes. Exportin 5 (XPO5), responsible for transferring pre-miRNAs to the cytoplasm, was pronouncedly expressed in the blastocyst. Dicer, Drosha, Gem (nuclear organelle)-associated protein 5 (GEMIN5), and TNRC6B elevation in the oocyte have been comparable to what identified between mouse oocytes and blastocysts [ 72 , 73 , 85 ]. MOV10 mRNA, involved in human oocytes RISC complex [ 86 ] was untraceable in non-human primates however markedly increased in the human blastocyst [ 84 ]. PIWIL1 miRNA, part of the RISC assembly, affects germinal stem cell upkeep in Drosophila, nevertheless has not been discovered neither in human samples nor non-human primates [ 73 , 84 ].

miRNAs and urogenital disorders

Lately several groups of researchers have stated that disparate expression and disarray of miRNAs are attributed to ovarian diseases, like POF, PCOS and ovarian cancer [ 87 , 88 ].

miRNAs and POF

POF is ovary related disorder caused by various factors and is mostly reported as the incidence of amenorrhea, hypergonadotropism and hypoestrogenism in women below the age of 40 [ 89 ]. Investigations conducted on ovarian tissue and plasma recognized interfered miRNAs in the creation of POF condition. Dong et al. found that the miR-22-3p plasma level was declined in Han Chinese patients POF group in comparison to the control group. It was identified that miR-22-3p expression was associated with decreased ovarian maintenance [ 90 ]. Based on preceding research, different miRNAs in plasma of women with POF and women with healthy cycling are presented, with different roles in affecting signaling pathways [ 87 ]. In addition, Kuang et al. recognized 63 increased and 20 decreased miRNAs in ovarian biopsies of 4-vinylcyclohexene diepoxide (VCD)-prompted mice POF mockups in comparison to the biopsies of healthy mice [ 16 ]. Advanced studies proved that the miR-29a and miR-144 downregulation in POF samples and their potential function in prostaglandin synthesis regulation through directing PLA2G4A, however increased expression in variety of miRNAs, including, miR-151, miR-672, miR-190 and miR-27b, affects the hormonal stimulating and apoptosis [ 16 ]. Recently studies specify that single-nucleotide polymorphisms (SNPs) miRNA are connected with vulnerability degree of disease. In A study regarding miRNA polymorphism the connection between joint genotypes and haplotypes of miR-146aC > G, miR-196a2T > C, and miR-499A > G in Korean women with POF has been recognized; based on their findings the miR-146a and miR-196a2 transcriptional aberration persuaded by SNPs miRNA with potential function in POF development [ 91 ]. Effective miRs in immunopathology of POF are inclouding.

Since both TRERNA1 and miR-23a expression are varied in POF, probably TRERNA1 and miR-23a cooperatively act to control granulosa cell apoptosis [ 92 ]. Since, Granulosa cells are in charge of producing steroids and LH receptors to protect and ensure the ovaries healthy work, and profuse granulosa cell apoptosis pay to the creation of POF through decreased ovarian healthy function [ 93 ]. Overexpression of TRERNA1 can lead to decreased apoptosis rate in KGN cells. Thus, TRERNA1 probably pay to POF by stopping apoptosis in granulosa cells, and increasing its expression can be effective in the treatment of POF. Irregular and differential expression of miRNAs could be considered as possible biosignals for variety of diseases [ 94 ]. For instance, miR-21 overpowers the ovaries granulosa cells proliferation through directing SNHG7 in early ovarian insufficiency coupled with PCO (polycystic ovary syndrome) [ 94 ]. Also miR-23a can encourage apoptosis in granulosa cells, representing its contribution in POF [ 95 ]. miR-23a overexpression inhibits the SIRT1 expression, decline in the SIRT1 expression, hinders the p-ERK1/2 expression which leads to rise in apoptosis of GCs, TRERNA1 can suppress the miR-23a which is promoting KGN cell apoptosis [ 96 , 97 ].

miR-146b-5p

Based on conducted research, miR-146b-5p indicate an encouraging influence on early ovarian failure in mice. miR-146b-5p cooperates with lncRNA DLEU1, a significant key in ovarian cancer development, consequently heightened DLEU1 expression and lowered miR-146b-5p expression in POF. DLEU1 cooperates with MiR-146b-5p which presented in both KGN cells nuclei as well cytoplasm samples. Though, DLEU1 encouraged cell apoptosis and abridged the miR-146b-5p preventive properties on cell apoptosis [ 98 ]. Granulosa cells (GCs) as follicular somatic cells are in charge for excreting steroid derivatives and supplementing vital nutrients for follicles generation [ 93 , 99 ]. Accordingly, GC unhealthy function and risen apoptosis results in POF progression. Based on research, DLEU1 pronouncedly expressed in POF patients, caused GC apoptosis. Since, DLEU1 heightened expression in POF can support syndrome development through intensifying cell apoptosis, therefore DLEU1 suppression could probably benefit in POF treatment. MiR-146b-5p has been stated to contribute in mouse POF through overpowering γH2A phosphorylation and disabling Dab2ip/Ask1/ p38-Mapk pathway [ 100 ]. miR-146b-5p overexpression causes reduction in G cells apoptosis. Thus, miR-146b-5p performs a protecting role in POF through stopping cell apoptosis therefore might control the miR-146b-5p expression, and might be worked in the clinic for POF treatment. DLEU1 can cooperate with miR-146b-5p, also DLEU1 is detectable in GCs nucleus and cytoplasm samples and more remarkably, DLEU1 and miR-146b-5p are not affected by the expression of each other, however DLEU1 repressed the miR-146b-5p apoptotic effect. The lncRNAs are responsible for sponging miRNAs to stop their work nevertheless not affect expression status, DLEU1 with sponging miR-146b-5p could promote apoptosis in GCs, in so doing encouraging POF [ 98 ].

miR-144-5p expression allegedly has been utilized as a predictive bio-signal for many cancers including breast esophagus [ 101 ], gastric [ 102 ]. Contrary to mentioned findings, one research stated that decrease in expression of miR-144-3p and miR-144-5p recurrently detected in bladder cancer cells and silencing miR-144-5p stopped tumor cell growth through encouraging cell cycle arrest [ 103 ]. These miRNAs function intricately in a range of biological practices so as to uphold body [ 104 ]. Likewise, exosome miR-144-5p in BMSCs is capable to object PTEN, CTX-damaged GCs apoptosis involved protein. PTEN adversely influences the PI3K/AKT signaling inducing apoptosis or cell cycle arrest at the G1 phase [ 105 ] granulosa cells apoptosis ultimately resulted in premature ovarian failure (POF) then infertility.

miR-15a Overexpression results in growth prevention of and aging mouse ovary granulosa cells [ 106 ]. In a research on mice POI, it was discovered that miR-15b heightened expression causes POI and endogenous α-Klotho mRNA suppression together with instigating the function of lower hand transforming growth factor β1 (TGFβ1)/SMAD pathway [ 107 ]. As well, in cultivated mice granulosa cells treated with elevating dosages of cisplatin, it has been revealed that miR-125a-5p triggered granulosa cells apoptosis through dropping signal transducer and activator of transcription 3 (STAT3). Since STAT3 is worked in several reproductive purposes through transducing signs responding to growth factors and cytokines, this discovery delivers different visions toward POI comprehension [ 108 ].

Interleukin (IL)-1 receptor-attributed kinase (IRAK1) and tumor necrosis receptor-associated factor 6 (TRAF6), are two important scaffold/ adaptor/proteins in the IL-1 and Toll-like receptor (TLR) signaling pathway, identified as positive regulators for nuclear factor (NF)-κB function, expressed by IκBα and IRAK1 and TRAF6 phosphorylation are assumed to be directed by miR-146a as a part of the NF-κB-prompted negative feedback [ 109 , 110 ]. NF-κB has been confirmed to be engaged in the other biological processes [ 111 ], immune reactions, apoptosis and inflammation. The caspase signaling cascade is an imperative pathway for apoptosis, and caspase-8 and caspase-9 activation leads to cell apoptosis, with cleaving the cell apoptosis executor caspase-3 to degrades the substrate poly (ADP-ribose) polymerase (PARP) [ 112 ]. Consequently, it was presumed that miR-146a pays to the ovarian granulosa cells apoptosis through caspase cascade by directly targeting IRAK1 and TRAF6 [ 113 ] (Fig.  1 and Table 1 ).

According to the figure, several miRs induce apoptosis in granulosa cells by targeting different molecules and signaling pathways. miR-146a activates apoptosis by targeting TRAF 6. Downstream signaling of TRAF6 leads to the production of anti-apoptotic molecules such as survivin, XIAP, and cIAPs which are inhibitors of caspase 3 and 7. In another way, miR-146b can induce apoptosis by inhibiting DIAB2 expression. Mir23a by targeting SIRT1 leads to the activation of caspase 3 and apoptosis. miR-144 by targeting PTEN leads to the activation of MDM2 and FOXO, and apoptosis occurs. miR-15 leads to apoptosis by inhibiting SMAD4

Conclusions

POF is a prevalent medical condition accompanying intricate molecular mechanisms. Herein we tried to review miRNAs as a group of critical regulatory elements after transcription in the development of POF. With regard to ability of an individual single miRNA in repressing expression of numerous genes, and probability of a single gene expression adjustment by several miRNAs, copious miRNAs are expressed in GC interfere in the maintenance and healthy practice of ovarian follicles, including ovulation, atresia, and ovarian steroidogenesis through directing certain molecules and manipulating variety of signaling pathways, like TGFB. Furthermore, miRNAs interfere decisively in female reproductive diseases, like POF, GCT, and PCOS, by influencing GC.

Prospects and clinical applications of miRNAs in the treatment of premature ovarian failure

Due to the advances made in genomic and proteomic sciences, more comprehensive information about more miRNAs and their role in human health, diseases and also treatment has been provided. miRNAs have always had important effects in important cellular activities including transcription, gene translation and epigenetics. In this article, we have presented several reports on the effect of microRNAs on the important pathological processes of premature ovarian failure. Knowing the role of each of these miRNAs in the ovary can help in the early diagnosis of the disease and choosing the best treatment for the patient. As a result, conducting other specific researches on the types of effective miRNAs and their mechanism of action in the ovary, can help in timely diagnosis and treatment of the ovarian disease including premature ovarian failure.

Availability of data and materials

Not applicable.

Abbreviations

Interleukins

Natural killer cells

• Premature ovarian failure

Small mothers against decapentaplegic

Transforming growth factor-beta

Phosphatase and tensin homolog

Polycystic ovary syndrome

Tumor necrosis factor receptor associated factor 6

Interleukin-1 receptor associated kinase 1

Small interfering RNA

Assisted reproductive technologies

Activin receptor-like kinases

Luteinizing hormone receptor

Luteinizing hormone

Cumulus granulosa cells

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Acknowledgements

This work is financially supported by Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran [Grant No. 70649].

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MY contributed to the conception and design of the study. NN contributed to write the manuscript and references gathering, LA-M and SD contributed to references gathering. NN and OS-O contributed to figure designing. AK contributed to table designing. MSS-Z and JAH contributed to the final editing of the manuscript. All authors reviewed the manuscript.

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Nouri, N., Shareghi-Oskoue, O., Aghebati-Maleki, L. et al. Role of miRNAs interference on ovarian functions and premature ovarian failure. Cell Commun Signal 20 , 198 (2022). https://doi.org/10.1186/s12964-022-00992-3

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Soft robotics and functional electrical stimulation advances for restoring hand function in people with SCI: a narrative review, clinical guidelines and future directions

• Lucas R. L. Cardoso   ORCID: orcid.org/0000-0001-9723-1582 1 ,
• Vanesa Bochkezanian 2 ,
• Arturo Forner-Cordero 3 ,
• Alejandro Melendez-Calderon 1 , 4 , 5 &
• Antonio P. L. Bo 1  

Journal of NeuroEngineering and Rehabilitation volume  19 , Article number:  66 ( 2022 ) Cite this article

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Recovery of hand function is crucial for the independence of people with spinal cord injury (SCI). Wearable devices based on soft robotics (SR) or functional electrical stimulation (FES) have been employed to assist the recovery of hand function both during activities of daily living (ADLs) and during therapy. However, the implementation of these wearable devices has not been compiled in a review focusing on the functional outcomes they can activate/elicit/stimulate/potentiate. This narrative review aims at providing a guide both for engineers to help in the development of new technologies and for clinicians to serve as clinical guidelines based on the available technology in order to assist and/or recover hand function in people with SCI.

A literature search was performed in Scopus, Pubmed and IEEE Xplore for articles involving SR devices or FES systems designed for hand therapy or assistance, published since 2010. Only studies that reported functional outcomes from individuals with SCI were selected. The final collections of both groups (SR and FES) were analysed based on the technical aspects and reported functional outcomes.

A total of 37 out of 1101 articles were selected, 12 regarding SR and 25 involving FES devices. Most studies were limited to research prototypes, designed either for assistance or therapy. From an engineering perspective, technological improvements for home-based use such as portability, donning/doffing and the time spent with calibration were identified. From the clinician point of view, the most suitable technical features (e.g., user intent detection) and assessment tools should be determined according to the particular patient condition. A wide range of functional assessment tests were adopted, moreover, most studies used non-standardized tests.

SR and FES wearable devices are promising technologies to support hand function recovery in subjects with SCI. Technical improvements in aspects such as the user intent detection, portability or calibration as well as consistent assessment of functional outcomes were the main identified limitations. These limitations seem to be be preventing the translation into clinical practice of these technological devices created in the laboratory.

Spinal cord injury (SCI) often leads to motor and sensory deficits, in addition to other complications, such as autonomic dysfunction, respiratory problems and urinary incontinence [ 1 ]. Among these complications, one of the major therapeutic priorities of people with tetraplegia is the recovery of arm and hand function since they are essential to independently perform most of the activities of daily living (ADLs) [ 2 , 3 , 4 ].

The rehabilitation of arm, hand and finger-related functional abilities after SCI can follow different approaches. One of them is through invasive procedures, like nerve and tendon transfer, in which preserved working nerves (tendons) are surgically re-directed to proximal non-functioning motor pathways [ 5 ]. Although this technique has the potential to produce relevant functional outcomes, it may demand long training time for adaptation post-surgery [ 5 ].

Another alternative to recover hand function after SCI are activity-based therapies. These comprise several training protocols and techniques, usually delivered under the supervision of physical or occupational therapist, and have the potential to increase range of motion, decrease pain and spasticity or recover lost functional movements, relying on the principles of neuroplasticity [ 6 ]. When the patient’s limb is activated, combining volitional control and external assistance, sensory afferent input is produced, which triggers a series of neurorestoration processes (e.g., synapse formation, remyelination, neural reorganization and repair), either in supraspinal or in spinal structures [ 6 , 7 , 8 ]. However, due to the high number of repetitions required to enhance neuroplastic adaptations, this type of intervention can be time-consuming and costly [ 7 , 9 , 10 ]. To potentially reduce treatment cost and time, and improve functional outcomes, activity-based therapies can be supported by technological hand neuroprostheses. In addition to therapeutical purposes, these engineering features have been employed as assistive devices, increasing the user’s independence and augmenting the overall practicing time.

Functional electrical stimulation (FES) is one of the technologies used to build neuroprostheses to support activity-based training after SCI. During a conventional FES therapy, subjects are encouraged to voluntary activate their muscles to perform a certain task while the FES system stimulates the muscles using superficial or implanted electrodes [ 11 , 12 ]. According to this approach, purposeful movements are produced in parallel to a combination of cortical activation (due to the voluntary attempt) and peripheral stimulation. The FES produces additional afferent information thus enhancing the practice-induced brain and spinal plasticity [ 13 , 14 , 15 ]. A common method used to trigger electrical stimulation is through a push-button. However, a more intuitive system detects user intent via physiological signals, e.g., electroencephalography (EEG) or electromyography (EMG), which increases usability and learning outcomes, by pairing stimulation with movement intention [ 16 ]. Despite promising results as a therapeutical tool [ 17 ], FES devices are limited in generating high accuracy control and muscle selectivity [ 18 ]. In this respect, implanted systems [ 19 ] or superficial multi-pad electrode matrices [ 20 , 21 ] can yield better outcomes but they still have many obstacles, such as the limitations of its use in case of lower motor neuron damage [ 22 , 23 ] or in people with cervical injury without any volitional control of the hand. [ 14 ].

Robotic systems are also employed to support activity-based therapy for hands after SCI. Typically, these are non-portable devices that are able to assist end-user’s hand in a clinical setting, throughout repeatable and predictable movement patterns [ 24 ]. However, most of these devices are bulky and are built using rigid links, which hampers the biomimetics of the human hand [ 25 ], and possibly limits the potential outcomes of the therapy [ 26 ]. In this sense, neuroprostheses based on Soft Robotics (SR) devices have emerged as a specific category of robotic rehabilitation systems, relying on soft actuators (usually back-drivable) and flexible links, increasing comfort and flexibility to adjust to the contours of the human body [ 25 , 27 , 28 , 29 ]. SR devices developed for hand function are also intended to be lightweight and portable, possibly for home-rehabilitation use, which is important to increase end-user adherence to treatment and also to meet assistance needs in ADLs. The underlying neuroplastic process associated to the use of SR tools is the same as observed in conventional activity-based therapies, since they also provide mechanical assistance for the movement execution. However, they are intended to increase the user engagement (by supporting activities in a daily basis) and consequently increase the number of repetitions (practice time), for a more affordable cost compared to the constant supervision of a physiatrist [ 28 ].

Noticeably, FES and SR have complementary features which encourages protocols combining both technologies. In a recent review, Dunkelberger and colleagues described a hybrid muscle stimulation and robotic assistance that was used for upper limb movement in people with SCI [ 30 ]. Even if the review did not focus on hand function or in SR, the authors concluded that the combination of FES and SR was promising, but argued that technological advances (e.g., improve tunability, reduce size and weight or detect user intent in an intuitive and unobtrusive way), both in FES and robotics, should be achieved to be fully integrated in an efficient hybrid system [ 30 ].

The present narrative review aims to identify the effects of FES, SR and their combination in the recovery of hand function in people with SCI. Therefore, this review summarizes the most recent research articles that presented any hand functional outcomes in people with SCI, using neuroprostheses based on FES and/or SR, either for assistance or therapy purposes. Results from this review will inform engineers on the next steps to develop these technologies and will allow clinicians to use this information as easy-to-use clinical guidelines.

Related reviews

There are four aspects from previous reviews on this topic that are worth discussing: the intervention aim, target population, affected function and assessment approach. Table 1 presents some of the related study reviews from the last 5 years.

Intervention aim Devices can be designed to meet therapeutic or assistive needs. One key difference between these types is that assistive devices are usually worn continuously or, at least, during ADLs. On the other hand, the use of therapeutic devices is restricted to short periods of time, such as the duration of each therapy session. However, the main underlying processes involved in the positive outcomes of therapeutic interventions are associated to practice-induced neural plasticity [ 14 , 33 ]. Therefore, it is worth considering the benefits of hybrid systems that integrate therapeutic and assistance tasks in a single device [ 27 ]. Interestingly, according to Table 1 , current reviews in SR aimed for both tasks, whereas FES studies usually focus on a single intervention aim. For the purposes of providing guidelines for both clinicians and engineers, this review will focus on studies with both interventions.

Target population Although different neurological conditions share similar physical deficits, the mechanisms involved in their rehabilitative process may differ significantly [ 33 ]. In particular, people with SCI present specific voluntary muscle activation limitations after injury that require specialized task-oriented rehabilitation [ 37 ]. Although SR or FES assistive devices may attend the needs of diverse clinical populations, their everyday performance and long-term improvements in functional outcomes can significantly vary based on level, severity and type of clinical condition [ 28 ]. Thus, results from different target population are not strictly interchangeable. To date, as shown in Table 1 , there is no literature on SR devices designed for hand function recovery exclusively for people with SCI. There are some studies that include people with SCI together with other conditions [ 28 , 31 , 33 ], but those studies did not present functional outcomes separately, which limits the interpretation of the results and hampers the translation to clinical practice, specifically for people with spinal cord injury.

Affected function Some literature reviews were very broad and covered studies with a great variety of functional outcomes, from limbs strength to bladder control (see [ 35 ] for a comprehensive review on FES treatment after SCI), while others were more specific including only one therapeutic aim (Table 1 ). For people with tetraplegia, recovery of arm and hand movements is usually ranked as one of the highest priorities, because these functions have a high potential to restore their daily independence [ 2 , 3 , 4 ]. However, although most ADLs depend on arms and hands, the neuroprostheses developed for each of these functions have distinct characteristics and are at different stages of technological development. Specific investigations are required to understand the potential of SR and FES for reaching (e.g., arms and shoulders) or grasping (e.g., hand and fingers) and, according to Table 1 , there is not current literature review on FES devices exclusively investigating hand function in people with SCI.

Assessment approach Some reviews focused on studies evaluating the technical features of the device, but did not consider the end-user needs or functional outcomes. On the other hand, some studies present and discuss their results in terms of functional outcomes using standard Clinical Outcome Assessments (COA) [ 38 ]. Studies with the first approach may be referred as system-centric whereas the second have a user-centric point-of-view [ 30 ]. User-centric studies are particularly important for clinicians who want to use SR and FES devices based on end-user’s individual characteristics.

This work includes the analysis of functional outcomes of FES, SR and their combination in the recovery of the hand function of people with SCI. In this context, the present study aims at providing a guide for engineers to help in the development of new FES- or SR-based hand neuroprostheses, and for clinicians to serve as clinical guidelines in order to assist and/or recover hand function in people with SCI. We intend to fill the gap in the literature identified in Table 1 , by focusing on the intersection highlighted in the Venn diagram of Fig. 1 .

The focus of the present narrative review. Report of functional outcomes is key to determine the role of FES and SR-based neuroprostheses in the hand function recovery after SCI

FES and SR-based neuroprostheses for hand function after SCI

Selection process.

The selection process of this review was based on the PRISMA method (preferred reporting items for systematic reviews and meta-analyses) [ 39 ] and included the following steps:

Identification: collection of all records identified through the search parameters, in all considered databases. Duplicate studies were removed;

Screening: first, papers were screened based on the following inclusion criteria: (i) published in English (ii) published since 2010 and (iii) article, journal or conference paper. Reviews of any kind (literature, narrative or systematic) or book chapters were excluded. In the next step, full-texts were screened in terms of the eligibility criteria specified below;

Inclusion: final collection of studies, including documents that did not appeared in the initial identification.

It is worth noting that this process was repeated twice, first for the SR and then for the FES studies following the searching criteria specified for each of them.

Eligibility criteria

The inclusion and exclusion criteria used to narrow the literature search is as follows:

Inclusion criteria:

Either therapeutic or assistive devices;

Only subjects with SCI;

Either therapy or assistance of hands and fingers;

Novel device or experimental findings using a previously studied system device;

Functional outcomes—using standardized or non-standardized tests.

Exclusion criteria:

Studies that included combined therapies—with drugs (e.g., BOTOX), surgery, blood flow restriction, Transcranial Magnetic Stimulation were excluded, except when combined with conventional occupational therapy;

Other clinical conditions, such as stroke;

Wrist function only;

Articles that only report impairment improvements (e.g., range of motion or muscle strength).

Search strategy

The literature search was carried out in the following databases: IEEE Xplore, Pubmed and Scopus. The search queries were composed by three basic groups. The first group specified the technology, thus it varied when searching for SR devices (“robotic”, “robot”, “soft”, “wearable”, “exoskeleton”) or FES systems (“electrical stimulation”, “FES”, “NMES”). The other group for both SR and FES was related to the function (“hand”, “finger”, “thumb”, “glove”) and to the clinical condition (“sci”, “spinal cord injury”, “tetraplegia”, “quadriplegia”, “paralysis”, “hand impairment”).

Summary overview

The final search for this review was completed in March 2022. After removing duplicate records, a total of 276 and 825 articles, were identified from the SR and FES searches, respectively. In terms of the SR studies, the first part of screening process excluded 54 records and the second part of the screening process (full-text screening) resulted in the exclusion of an additional 211 articles. Regarding FES studies, both procedures excluded 469 and 332 papers, respectively. One additional document from SR [ 40 ] and another from FES [ 41 ], that did not appear in the first screening phase, were added in the inclusion phase. Thus, the final selection was 12 SR and 25 FES documents. Figure 2 shows a summary of the article selection process.

Summary results of the literature search process

Several documents were excluded due to the lack of evidence on functional outcomes. In some cases, the article reported outcomes in terms of the user’s range of motion (ROM) or muscle strength [ 42 , 43 , 44 , 45 ]. These types of measurements represented assessments of impairment, instead of assessment of functional outcomes, thus the documents were excluded from the final selection. Two articles reported the results of the same experiment [ 11 , 46 ], thus they were analysed as a single study. One [ 47 ] was a retrospective study that included the same results reported by [ 46 ] and [ 11 ], therefore it was excluded. One paper used a device that combined FES and robotic assistance for the fingers [ 48 ]. Additionally, one paper combined a FES neuroprostheses and a motorized hand orthosis in the same rehabilitation protocol [ 49 ].

The articles included in this review presented and validated FES or SR systems by focusing on a certain intervention aim, either therapeutic or assistive modes. From the 12 articles selected for the SR group, only 1 described a therapeutic protocol [ 50 ]. On the other hand, from FES articles, 9 out of 25 presented therapeutic applications.

Interestingly, a few research groups have published three or more articles that were included in this review, often reporting results obtained using different versions of the same device. For example, from the SR collection, three documents [ 51 , 52 , 53 ] were from the same laboratory at Harvard University. Three studies [ 40 , 54 , 55 ] were part of to the same laboratory at Seoul National University. In terms of the FES collection, five research studies [ 20 , 21 , 56 , 57 , 58 ] had the same origin (Ohio State University) and shared many of their authors. Other examples were the Case Western Reserve University and the Toronto Rehabilitation Institute (University of Toronto), which were two other research groups with four [ 19 , 59 , 60 , 61 ] and three articles each [ 11 , 62 , 63 ]. Together, these five research groups were involved in 18 research articles, representing nearly a half of the entire collection.

Technical aspects

Tables 2 and 3 , presented the main technical characteristics of the devices that were used or developed by each study included in the SR and FES collections, respectively.

The columns Active Fingers, Assisted Motions and Grasp Patterns are associated to the active support provided by the device to the user. In this paper, the words “active” or “passive” always refer to the device, not to the end-user. Thus, an active system necessarily has an actuator, while passive component may represent springs, wires or rigid and sliding structures.

The tables also include the Home-based category, that evaluates whether the device is prepared to be used at home. The devices were classified according to characteristics like portability, ease to don and doff, and weight, as being either “Ready” (R) for in-home use/therapy or “Potentially” (P) prepared (e.g., the device is portable and lightweight, but it was not tested outside the laboratory). In some cases, not enough evidence was presented to determine the classification (“Unclear”, or U).

1) Actuation type

Soft robotics. The final SR collection included three types of actuation, namely, pneumatic, cable driven and based on a three-layered sliding spring (TLSS) mechanism. Pneumatic systems [ 51 , 52 , 53 ] uses pressurized air to inflate air-tight bladders that form a glove with attachment points. As the fabric compresses or expands it induces finger flexion or extension.

Seven, out of the twelve papers, presented or tested a device actuated by cables [ 40 , 50 , 54 , 55 , 66 , 67 , 68 ]. Cable driven is a bioinspired actuation system that mimics the tendon mechanism of a human finger. This system drives finger flexion or extension by tensing cables (typically, using Bowden cables) guided throughout the fingers and attached to the distal phalanges using fabric straps.

In the Exo-Glove Poly [ 40 ] and in the Exo-Glove Poly II [ 55 ]—the second and third generation of In and colleagues’ work [ 54 ]—straps material was replaced by waterproof polymer, aiming to increase hygiene and comfort aspects. The hand orthosis presented by Yoo and colleagues [ 67 ] was designed to enhance tenodesis grip, and it was based on 3D-printed components in order to become more affordable and customizable. Different from the other systems driven by cables, the “mano” device [ 68 ] uses Bowden cables in a dual manner: as artificial tendons and as structural elements. In this device, with Bowden cable sheaths attached only to the dorsal side of the hand and finger phalanges, the palm and fingertips were left fully uncovered, increasing the users’ opportunity to experience any sensation on their hands.

Two studies [ 64 , 65 ] presented devices based on a three-layered sliding spring mechanism, adapted from the concept originally presented in [ 79 ]. In TLSS, two spring blades are layered, with rigid elements connecting them. By moving one sliding spring and fixing the other, the relative length of the springs changes, bending the springs in specific locations, mimetizing the human finger. In [ 64 ], the sliding springs are actuated by Bowden-cables, that transmit the torque of electric motors storage in a backpack. In [ 65 ], the electric motors are directly attached to the TLSS. Both hand exoskeletons based on TLSS are mounted on the dorsal side of the hand, which is advantageous for somatosensation aspects.

The “mano” device and the SEM Glove (Bioservo Technologies AB), tested by Osuagwu and colleagues [ 50 ], are the only systems that are currently commercially available.

FES. Two main modes to delivery stimulation were identified, either by using superficial [ 11 , 20 , 21 , 41 , 48 , 49 , 56 , 57 , 58 , 62 , 63 , 70 , 71 , 72 , 74 , 75 , 76 , 77 , 78 ] or implanted [ 19 , 59 , 60 , 61 , 69 , 73 ] electrodes.

Six out of twenty five articles described experiments using implanted electrodes for FES, and four of them came from the same research laboratory [ 19 , 59 , 60 , 61 ]. The FreeHand system [ 61 ] and its latest version, the IST-12 [ 19 , 59 ], were fully implantable, while Ajiboye and colleagues [ 60 ] used another system with percutaneous (“readily removable”, according to the authors) electrodes. In [ 69 ], the authors used a pair of multi-contact cuff electrodes, which is intended to increase the selectivity during functional movements.

All the implanted FES systems used an electrical current with a biphasic waveform. Only two studies reported on the frequency (up to 25 Hz) and pulse width (maximum 255 \(\mu s\) ).

Among studies involving superficial stimulation, the number of channels (and electrodes) varied from a single channel [ 74 , 75 ] to multi-pad systems, using an array of multiple electrodes [ 20 , 21 , 56 , 57 , 58 ]. The strap-based matrix system composed by 130 electrodes was employed by five studies, all of them from the same research laboratory [ 20 , 21 , 56 , 57 , 58 ]. One study designed a stimulation setup combining two channels with a pair of electrodes (for finger extension and thumb/finger flexion) and one array with 30 pads (for thumb extensor/opposition) [ 41 ]. In [ 72 ] a multi-pad system was also used, but the authors did not mention the number of electrodes.

The stimulation parameters of the superficial systems included pulse frequencies ranging from 16 to 50 Hz and amplitudes up to 63 mA. The strap-based matrix system was the only with a monophasic current waveform.

2) User intent detection

Soft robotics. Six different methods for user intent detection were identified in the final SR collection. The most frequent method employed is the push button, representing 4 out of 12 papers (33 \(\%\) ) [ 51 , 53 , 55 , 64 ]. This mechanism is very simple: when the button is pressed, actuators close or open the hand. The “mano” device [ 68 ] uses a similar approach, with a user interface (smartphone app) in which the subject (or the therapist) is able to individually adjust the angle of each finger.

Pressure (or force) sensors were used by other two devices [ 50 , 52 ]: in Zhou’s work [ 52 ], a state machine controller determined the hand pose based on the signals of pressure sensors placed on the palm and fingertips; and in the SEM Glove [ 50 ] proportional pulling force in the flexion direction is applied according to what is sensed from fingertips’ pressure sensors. Within the final SR collection, other user intent detection methods were identified: wrist extension, based on the signals of a bending sensor positioned on the dorsal side of the wrist [ 54 ]; myoelectric (EMG) signals, recorded from either the ipsilateral biceps or the upper trapezius muscle [ 67 ], or other muscles [ 64 , 65 ]; voice command, in which the user is able to combine keywords to determine the action to be performed, creating a customized dictionary [ 66 ]. In [ 40 ], Kim and colleagues used a first-person-view camera to record spatial/temporal information and used it to detect user intent. The camera approach is particularly interesting because it detects user’s intention without requiring any previous calibration or initialization.

FES. Three studies used a push button to trigger electrical stimulation [ 11 , 62 , 77 ]. The ReGrasp (Rehabtronics) [ 76 , 78 ] and the system presented by [ 73 ] have a “behind-the-ear bluetooth device” that senses the user’s tooth click, through which stimulation is activated. Compared to the push button method, the tooth click has the benefit of letting both hands free, thus it is more suitable for assistive devices.

Other studies employed EMG signals to detect muscular activity, using either superficial [ 74 ] or implanted electrodes [ 19 , 59 , 61 , 69 ]. Fattal and colleagues also tested the detection of movements through the user’s shoulder position using a inertial measurement unit (IMU) [ 69 ]. Shoulder control was also implemented by other studies [ 41 , 70 , 71 ].

Another approach for user intent detection is through the direct communication between the brain and the stimulation system, which is called Brain Machine Interface (BMI). Trincado-Alonso and colleagues [ 75 ] developed a non-invasive BMI based on superficial EEG recordings. Their therapeutic platform classifies the EEG signals and triggers the FES when motor attempt is detected. The user interacts with a visual interface. In [ 63 ] the BMI is also superficial, but the authors used a single EEG channel per hand. Differently, the BMI developed by the Ohio State University group [ 20 , 21 , 56 , 57 , 58 ] or presented by [ 60 ] consists of a microelectrode array implanted in the brain motor cortex of a subject. Instead of intracortical but still implanted, Cajigas and colleagues recorded electrocorticographic (ECoG) signals from the brain surface [ 49 ].

There are some systems that do not rely on any method to detect user intent [ 48 , 78 ]. These were therapeutic devices that cyclically delivered electrical stimulation during a predetermined period, together with physical and occupational therapy [ 78 ] or repetitive task with robotic assistance [ 48 ]. The MUNDUS project, the system presented in [ 72 ], can detect user intention of movement through multiple ways, but none of them were tested with people with SCI to control the hand neuroprostheses.

3) Active support

Soft robotics. In terms of the assisted motion, most devices actively support flexion and extension (i.e., hand opening), except the SEM Glove [ 50 ] and the Yoo’s [ 67 ] device that are restricted to flexion. The FLEXotendon Glove-II [ 66 ] produces finger flexion and thumb abduction actively, but the hand opening movement (finger extension and thumb adduction) is passively actuated using a flexible wire attached to the dorsal side of the hand. The ETHZ RELab tenoexo [ 64 ] also uses a passive structure to produce thumb abduction and adduction.

Regarding finger assistance, the pneumatic gloves [ 51 , 52 , 53 ] and the devices based on TLSS mechanism [ 64 , 65 ], actuate all the four fingers and thumb, although the three-fingered grasp was the most frequent configuration observed in the final collection. The combination of thumb, index and middle fingers is used by four devices [ 40 , 54 , 66 , 67 ], while the configuration of thumb, middle and ring fingers is adopted by the SEM Glove, [ 50 ]. The “mano” device [ 68 ] is reported in the study as being able to actively assist the four fingers and the thumb, however, during the described experimental setup, the three-fingered configuration was used. The Exo-Glove Poly II [ 55 ] is the one with less finger support (only the index and middle fingers), because a passive structure is used for the thumb (i.e., without an actuator). This structure keeps the thumb in opposed position (adduction), which helps with manipulation of objects.

Most devices are prepared to produce a 3-point grasp type (with different finger configuration) a precision grasp according to Cutkosky’s taxonomy [ 80 ]. In the pneumatic gloves [ 51 , 52 , 53 ] and in the devices based on TLSS mechanism [ 64 , 65 ] a power grasp (according to Cutkosky’s taxonomy) can be generated too since all fingers are actuated. However, in [ 64 ] and [ 65 ], the fingers are unable to move independently. Based on the description provided in Randazo’s study [ 68 ], “mano” system is not prepared to support specific hand positions, but the angles of the fingers can be individually adjusted as per the user’s needs. The same characteristic was observed in FLEXotendon Glove-II [ 66 ], in which the voice commands can be customized by the user to produce specific grasp patterns or sequence of movements.

FES. The grasp patterns produced by a FES system depend on the number of electrodes, because with more channels the device is able to stimulate more muscles, thus eliciting more hand positions. With the 1-channel devices [ 74 , 75 ], hand closing was the only possible hand movement, and there was no information about the grasping type. However, in [ 20 , 21 , 56 , 57 , 58 ] a multi-pad system was reported, reaching higher resolution and producing up to seven grasp patterns that could be grouped in precision grasps of thumb plus 2 or 3 fingers, and power grasps, like palmar and lateral key. In general, most devices were programmed to generate two hand positions, which were, palmar and lateral grasps. In [ 48 ], the device was not able to produce a functional grasp, but can reproduce repetitive finger movements. The system presented by Gan and colleagues is described by generating hand opening and closing, but the authors did not mention a specific grasp pattern [ 73 ].

4) Home-based use

Soft robotics. The use of lightweight systems (including the orthotic component and the control box) is important to provide users with at-home assistance or therapeutic activities for prolonged periods of time. In this respect, devices range from 50g [ 68 ] to 228g [ 65 ], when considered only the part that is attached to the hand. The FLEXotendon Glove-II [ 66 ] is the heaviest system if the motors (attached to the forearm) are considered (69g of the orthotic components plus 228g of the actuators). Cappello and colleagues [ 51 ] presented a 5 kg-control box (that some users reported to be noisy), designed to be mounted on a wheelchair or placed on a table. The “mano” device [ 68 ] includes a chest-pack that weights 930g and hosts the actuators, energy storage and control units. SEM Glove [ 50 ] and ETHZ RELab tenoexo [ 64 ] are two systems reported as being fully portable.

Another desirable feature for at-home therapy is the ease to independently don and doff the device. In most studies, the authors did not mention whether the subjects were able to don and doff the system without help. Osuagwu and colleagues [ 50 ] informed that the majority of participants were able to independently don the glove, although the participants with more severe hand impairment required a carer’s assistance. In [ 64 ], the unique subject that experienced the system could don (spent 3.5 minutes) and doff (less than 30 seconds) the ETHZ RELab tenoexo without any help, but the authors did not mention whether he was familiar with the device before the test.

Although all devices of the final SR collection were reported as being portable, only in one part of the studies the experimental setup was carried at the participant’s home. This fact is the only evidence that shows the system is most likely prepared to be taken away from the laboratory. That was the reason why the studies of [ 51 , 67 , 68 ] [ 65 ] and [ 64 ] were classified as “potentially” prepared for home-based use or therapy. The articles [ 53 ] and [ 52 ] fell in the same classification because they tested the latest version of Cappello’s [ 51 ]. Osuagwu’s study [ 50 ] was the only one classified as “ready”, because it focused on home-based therapy, describing a self-administered protocol specifically designed for this purpose.

FES. Most FES studies used commercially available portable devices, such as, the implanted FreeHand [ 61 ] or the IST-12 [ 19 , 59 ], the Compex Motion [ 11 , 62 ], the MeCFES [ 74 ], the Empi 300 PV [ 77 ] and the ReGrasp [ 76 , 78 ]. However, only a small part of these studies performed experiments at the end-user’s home, like in [ 41 , 59 ] and particularly in [ 78 ], in which home tele-rehabilitation was tested. Other studies were not clear about the system portability [ 48 , 63 , 69 , 70 , 72 , 75 ].

In regards to the FES system with an invasive BMI, the authors in [ 20 , 21 , 56 , 57 , 58 ] mentioned the portability as a limitation, thus preventing it to be promptly tested at home. In [ 49 ], although some trials were performed in the subject’s home, only a motorized hand orthosis was tested in this environment and no functional assessments were done in home setting (due to the COVID-19 pandemic).

In terms of ease to don and doff, most superficial systems depend on placing self-adhesive electrode pads on the skin, which is time consuming and usually require support [ 11 , 62 , 71 , 74 , 75 , 77 , 78 ]. The ReGrasp device, used by [ 76 , 78 ], incorporated the electrodes into a custom-made garment [ 76 , 78 ] that facilitated donning and doffing and ensure repetitive electrodes placement. The implanted systems had the advantage of not requiring an additional set-up.

Functional outcomes

Eleven different standardized functional assessment tools were identified from the SR and FES collections. Furthermore, most studies also evaluated end-users using non-standardized tests [ 21 , 40 , 54 , 55 , 56 , 59 , 60 , 65 , 68 , 71 , 72 , 73 ].

Table 4 shows, for each study, details about the population (sample size, lesion completeness and time since injury), and the assessment tools adopted by each one. The arrows were used to indicate positive or negative outcomes, only when statistical analysis was presented.

Toronto Rehabilitation Institute-Hand Function Test (TRI-HFT) [ 81 ] is an evaluation tool used to assess improvement in unilateral gross motor hand function. The TRI-HFT consists of 3 components: the first evaluates the power grasp, the lateral pinch, and precision grip, through the manipulation of 10 ADLs objects (max. 7 points per object); the second component uses 9 wooden blocks of various masses and surface finishes (maximum of 7 points per object) to evaluate the strength of both power and lateral grasps; the third part is not validated, thus it will not be considered in the following discussion.

Assistance. Comparing the baseline and assisted condition, without any training time, participants in Cappello’s study [ 51 ] improved \(33\%\) (relative to the maximal test score) in the first component of the test, and \(37\%\) in the second. Yoo’s paper [ 67 ] reported similar relative improvements, of \(22\%\) and \(29\%\) , for the first and second components. All the results of these two research studies that used soft robots are statistically significant. However, both agreed that their device designs did not allow for manipulation of small objects, such as pencils.

Therapy. In an uncontrolled study, Osuagwu and colleagues [ 50 ] described a protocol in which the participants were encouraged to practice a set task and perform their usual ADLs using the robotic glove, for a minimum of 4 hours per day, for 12 weeks. A significant effect was observed only for the power grasp component after 6 weeks, participants improved \(12\%\) relative to the maximal test score. In a randomized control trial, Popovic and colleagues [ 11 ] (or [ 46 ]) combined 40h of conventional occupational therapy with 40h of functional electrical stimulation therapy. The intervention group significatively improved \(23\%\) and \(21\%\) , for the power and lateral grasps TRI-HFT components (the control group received 80h of conventional occupational therapy). A similar protocol was reported in [ 62 ] but they did not present any statistical analysis due to the small sample size. Although they used different technology, it is worth noting that Osuagwu’s work [ 50 ] involved chronic population while Popovic’s study [ 11 ] recruited subjects with sub-acute SCI. Furthermore, the first study employed a more intense therapy (mean glove usage of about 120h, at week 6), whereas the second was moderate (80h, after 8 weeks). In a more recent study of the same research group as [ 11 ] and [ 62 ], Jovanovic and colleagues tested a bilateral rehabilitation protocol using non-invasive BMI controlling a superficial FES system, during (on average) 30 1-hour therapy sessions [ 63 ]. The authors used TRI-HFT to assess separately the left and right upper extremities. For the left and right upper extremities, the mean change score on the Object Manipulation component was \(38\%\) and \(16\%\) (relative to the maximal test score), respectively, comparing baseline to discharge.

The Jebsen-Taylor Hand Function Test (JTHFT) [ 82 ] is a standardized 7-item test designed to evaluate fine and gross motor hand function using simulated ADLs (writing, simulated page-turning, lifting small objects, simulated feeding, stacking, and lifting large, lightweight, and heavy objects). Time of performance is recorded for each task, thus, shorter times indicate better performance.

Assistance. Tran and colleagues [ 66 ] reported that JTHFT performance was worse when the subject wore the exoskeleton. These results were attributed to the delays of the voice control system and motors. Zhou’s study [ 52 ] showed (without any statistical analysis) lower average times for some participants when using the device, however there was a high variability in these responses and some participants took longer when using the device. Correia and colleagues [ 53 ] did not find any statistically significant changes in mean completion time when using their device. Both [ 53 ] and [ 52 ] hypothesized that the low performance was due to lack of participant’s training and adaptation time. Correia and colleagues [ 53 ] also measured completion rate, which was calculated by the ratio between the items completed by the participant and the total number of items in a certain JTHFT subtest. In this case they found that participants improved from a median completion rate lower than \(30\%\) at baseline, to \(76\%\) , with the active glove. Controlled by a ECoG device implantation and actuated by superficial electrical stimulation, the subject in [ 49 ] significantly improved performance when lifting small objects, lifting light cans and lifting heavy cans. The authors also reported increase in the handwriting clarity while wearing the device.

Therapy. In a prospective case series, Martin and colleagues [ 77 ] administered JTHFT at baseline, immediately after the first session and after 24h of the eight sessions of intervention. For two weeks, participants attended eight 30-min sessions in which electrical stimulation was used to assist a grasp and release task. End-users significantly improved their performance (reducing task time) in \(33\%\) (immediately after the first session) and \(53\%\) (after 24h of the eighth sessions), both compared to the time spent at baseline.

The Functional Independence Measure (FIM) [ 83 ] assesses functional ability in 6 areas (self-care, sphincter management, transfers, locomotion, communication, and social cognition). As the present review focused on the hand function, only the self-care subscale was considered. This subscale is composed by 6 items (eating, grooming, bathing, dressing upper body, dressing lower body and toileting), each one is graded from 0 to 7.

Assistance. The participants that used the device introduced by Yoo and colleagues [ 67 ] showed a significant increase in FIM score of \(18\%\) . However, the only significant increase was found in the eating category.

Therapy. In the randomized control trial of Popovic and colleagues [ 11 ] (or [ 46 ]), the combination of conventional occupational therapy (40h) with FES therapy (40h) resulted in \(71\%\) significant increase in the FIM self-care subscale, when compared to baseline. Furthermore, after 8 weeks, the self-care subscore of the intervention group was \(58\%\) greater than the control (which received 80h of conventional occupational therapy). In [ 62 ], a similar randomized control trial compared the FIM self-care scores of two groups that received 39h of therapy, one with FES (intervention) and the other 39h of conventional occupational therapy (control). The authors did not present any statistical analysis but, the control group got a lower subscore when compared to the intervention group. In a more recent study of the same research group, Jovanovic and colleagues reported a significative increase of about \(98\%\) in the mean score on the FIM self-care sub-component at discharge, when compared to baseline [ 63 ]. In this study, the patients attended on average to 30 1-hour sessions of treatment.

In [ 48 ], after a 6-week intervention using their device the authors reported that “no worsening of FIM score was noted”.

The Spinal Cord Independence Measure (SCIM) [ 84 ] addresses three groups of functions in people with spinal cord injuries (SCI): self-care (feeding, grooming, bathing, and dressing), respiration and sphincter management, and a subject’s mobility abilities (bed and transfers and indoors/outdoors). SCIM III is the newest version, created to consider intercultural differences of subjects. In this review, only the self-care subscale was considered (of either SCIM or SCIM III), which score ranges from 0 to 20.

Assistance. In Yoo and colleagues’ study [ 67 ], no significant increase was observed in any scores of each individual ADLs task. However, the total score significantly increased \(32\%\) , comparing the assisted and the unassisted conditions. In [ 49 ] there was no change in the SCIM score compared to the baseline.

Therapy. In Popovic and colleagues [ 11 ] (or [ 46 ]), following the protocol described before, the study reported that, after eight weeks of treatment, the SCIM self-care subscale score of the first group was \(89\%\) superior to the second group. The results obtained by Harvey and colleagues [ 76 ] indicate that the addition of a hand training program involving FES to a combination of usual care plus three 15-minute sessions per week of one-to-one hand therapy, did not improve hand function in terms of the SCIM (self-care subscale). Both studies only recruited people living with sub-acute SCI, but Harvey’s sample size was considerably larger. Harvey and colleagues argued that their results may have been associated with the sessions of individualised one-to-one hand therapy and usual care that both groups received. According to them, these treatments may have hindered the effect of FES-based hand training that the experimental group received.

In [ 63 ]—a more recent study from the same research group as [ 11 ]—the authors reported that three, out of five patients significantly improved in SCIM self-care subscores, exceeding the minimal clinically important difference, after about 30 1-hour sessions of treatment.

Other two studies, [ 62 ] and [ 75 ], reported SCIM scores, both without any statistical analysis due to a very small sample size. In [ 62 ], a randomized control trial was performed comparing the performance of two groups: with 39h of conventional occupational therapy or 39h of FES therapy. After 13 to 16 weeks of treatment, the SCIM self-care subscore of the intervention group (FES therapy) was \(46\%\) higher than the one obtained by the control group (conventional occupational therapy). However, the study did not present any statistical analysis. In [ 75 ], the effect of FES system was assessed after five sessions of one hour each. However, the results were inconclusive: one subject improved his score, one got worse and the other two obtained the same scores before and after the intervention.

The Box and Block Test (BBT) [ 85 ] is a quick, simple and inexpensive assessment tool that measures unilateral gross hand function. It requires the participant to move wooden blocks, one by one, across a partition in the middle of a wooden box. The score is based on the number of blocks moved in 60 seconds. Each hand is evaluated separately.

Assistance. In Zhou and colleagues [ 52 ], two of three participants scored higher in BBT when supported by the robotic glove without previous training. Comparing the best active condition trial to baseline, one participant improved from 0 to 4 and the other from 7 to 9 blocks. No statistical analysis was presented. Tran and colleagues [ 66 ] compared the BBT performance of one subject, with and without a robotic glove. Due to the time delays introduced by the voice control system and motors, the user was able to transfer two times more blocks without the device support. Bockbrader and colleagues [ 20 ] used the BBT to test the performance of one subject controlling a surface FES system through an implanted BMI. They concluded that the participant reached a higher rate at baseline using his residual hand function (12 blocks/min) than when he was supported by the BMI-FES (9 blocks/min). In [ 70 ], the authors were not clear about the results of BBT they obtained.

Therapy. In the prospective case series reported by Martin and colleagues [ 77 ], three participants attended, for two weeks, eight 30-min electrical stimulation sessions to assist a grasp and release task. The motor function was assessed with BBT at baseline, after the first session and 24h after the eighth session of intervention. There was only a significant difference between the baseline (mean of 18 blocks) and the post-8 session (mean of 24.67 blocks), but not immediately after the first session.

The Grasp and Release Test (GRT) [ 86 ] is designed to evaluate neuroprosthetics performance in individuals living with SCI. Using palmar or lateral grasp, the participant is required to pick up, move and release six objects of different sizes, weights and textures (peg, block, video tape, fork, can and paperweight). The aim is to release the objects in the target region as many times as possible in 30 seconds. Successful transfers are recorded.

Assistance. In [ 20 , 58 ] and [ 57 ] the same system (BCI-FES) was tested with the same subject, but at different times. Accordingly, they presented similar results in terms of GRT assessment. In [ 58 ] and [ 20 ], the BCI-FES significantly improved median success rates for all the objects, except the block—which usually, required tip-to-tip grasp type. Results in [ 57 ] also indicated improvements using the BCI-FES although they only tested three objects (peg, fork, can). Testing an implanted FES system, Kilgore and colleagues [ 19 ] reported that, prior to surgery, the majority of participants could manipulate at least two, out of the six GRT objects. After the surgery, with the system turned on, this number increased to five. The heaviest objects resulted in more failures to manipulate the object. Heald and colleagues [ 61 ] tested a similar implanted system, but controlled by a different method, with only one subject. The authors only reported successful trials, instead of the number of blocks transferred within the test time. At baseline (without any supporting system), the subject could only transfer the peg and the block, but with the FES system, all the six objects could be successfully manipulated. In [ 70 ], the authors did not compare the GRT scores with and without wearing the FES system, but assessed the participants once week during a 12-week long clinical study, always using the device, to test their ability to learn how to use the neuroprostheses. The two participants increased their GRT scores in 80 \(\%\) and 142 \(\%\) , after 4 and 6 weeks, respectively. In Rohm and colleagues’ study [ 71 ], although the GRT was mentioned (with the same main reference), they only described the transfer of “single blocks”, “double blocks” and pegs. They reported that the subject succeeded in manipulating these objects in 17 out of 26 trials. Similarly, in [ 41 ] the authors only included three objects in the test (namely, paperweight, videotape and cylinder) and both patients performed better when wearing the system compared to their baseline condition.

Therapy. None of the included papers used the GRT to evaluate the therapeutic effect of a SR or FES device.

The Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) [ 87 ] is a standardized test developed to assess three major domains of hand function: strength (max. 50 points), gross grasping ability (qualitative prehension, with max. of 12 points), prehensile skills (quantitative prehension, with max. of 30 points) and sensibility. Due to the focus of this paper, the sensibility domain will not be considered.

Assistance. In [ 56 ] and [ 20 ], the same FES system was tested with the same subject, reporting similar results. The authors normalized the GRASSP domain scores to benchmarks of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and the American Spinal Injury Association Impairment Scale (ASIA) [ 88 ]. Thus, Bouton and colleagues [ 56 ] reported that when the participant used the implanted BMI, his strength improved from C6 to C7-C8 level, his gross grasping ability improved from C7-C8 to C8-T1 level, and his prehensile skills improved from C5 to C6 level.

Therapy. Without showing any statistical analysis, Kapadia and colleagues [ 62 ] reported that, after 13 to 16 weeks, all GRASSP components in the treatment group (39h of superficial FES therapy) showed a greater increase (from baseline to post-treatment) when compared to the control group (39h of conventional occupational therapy). In a more recent study of the same research group as [ 62 ], Jovanovic and colleagues reported significative increase in the strength components in the three participants that completed discharge, after completing 30 1-hour sessions (average) [ 63 ].In [ 75 ], Trincado-Alonso and colleagues also did not present any statistical analysis but, in this case, they reported inconclusive results based on GRASSP scores.

The Action Research Arm Test (ARAT) [ 89 ] is an assessment tool of upper extremity performance, composed of 19 items, categorized as grasp, grip, pinch, and gross movement. Functional tasks are, for example, lifting and moving blocks of various sizes, pouring water, picking up, and placing small objects. Task performance is rated on a 4-point scale, thus the total score varies from 0 to 57. A positive score change exceeding 5.7 is considered clinically relevant.

Assistance. Bockbrader and colleagues [ 20 ] used an invasive BMI to control a superficial FES and tested it with one subject. With the system turned on, the total ARAT score significantly increased from 18 to 30 ( \(32\%\) to \(53\%\) of maximum ARAT score). Thorsen and colleagues [ 74 ] tested a superficial FES system controlled by EMG and analysed immediate and therapeutic effects. In terms of immediate effects (measured at baseline, comparing the ARAT performance between the conditions with and without the system support), in average, subjects significantly increased only 2 points in ARAT score. Although the authors did not present any statistical analysis, in [ 64 ] the ARAT scores also exceeded clinically relevant improvement when the subject was assisted by the ETHZ RELab tenoexo.

Therapy. Thorsen and colleagues [ 74 ] measured the therapeutic effects of an FES system, assessing ARAT scores without the system at baseline and after 12 2h-sessions of training. Only \(11\%\) of the end-users exceeded the clinically relevant change of 5.7 points. The combined effect (i.e., measured without the system, at baseline and, with the system, after the training intervention) showed that \(30\%\) of participants exceeded the clinical relevance threshold. With a greater sample size, Harvey and colleagues [ 76 ] suggested that the addition of a hand training program involving FES to a combination of usual care plus three 15-minute sessions per week of one-to-one hand therapy, did not significantly improve ARAT score. According to the authors, the sessions of individualised hand therapy and usual care may have hidden the effects of FES-based hand training. In [ 78 ] two different exercise therapies were compared, both including FES and delivered by in-home tele-therapy. One of the exercise therapies was referred as being conventional and the other used a specific workstation for the exercises and a modern FES device. The conventional therapy did not increase the ARAT score above the clinically relevant threshold, while the other reached 7.41 points of significant improvement.

The Capabilities of Upper Extremity (CUE) [ 90 ] assessment comprises thirty-two activities (categorized by, reaching and lifting, pushing and pulling, wrist actions, hand and finger actions) that are scored based on participant self-report and physical or occupational therapist observation, from 0 to 4 (unable, severe difficulty, moderate difficulty, mild difficulty, no difficulty). The maximum unilateral (arm + hand) converted score is 60.

Assistance. Only one study used CUE-T assessment. Bockbrader and colleagues [ 20 ] reported that the unilateral total score increased from 27 to 49 ( \(45\%\) to \(82\%\) of maximum CUE-T score) when comparing assisted and unassisted conditions. The system could not improve reaching and lifting or pushing and pulling scores.

Therapy. None of the included papers used the CUE test to evaluate the therapeutic effect of a SR or FES device.

The Quadriplegia Index of Function-Short Form (QIF-SF) [ 91 ] is based on a self-rating interview and assesses the independence level of people with SCI according to 6 self-care tasks.

Assistance. Only Bockbrader and colleagues [ 20 ] used the QIF-SF assessment. The authors compared the actual functional independence rated at the participant’s home and his expected level of function to use the system at home. The user reported expected to gain “independence with assistive device” for grooming, feeding, and patient-lift transfers, which were not mentioned to being done before trying the system.

Therapy. None of the included papers used the QIF-SF test to evaluate the therapeutic effect of a SR or FES device.

The Motor Capacities Scale (MCS) [ 92 ] is an evaluation tool that was specifically designed and validated to assess arm and hand function of people with SCI that underwent a tendon transfer surgical procedure. The assessment has three sub-categories (A, B, C and D), but only MCS-C and D were considered in this review because they are related to the hands (C, right hand, and D, left hand). The patient needs to perform three steps (grab, hold, and release) with different ADL objects. A score is given to each step using a four-point scale (maximum 72).

Assistance. The work of Fattal and colleagues [ 69 ] was the only study to use the MCS. The authors presented a system with invasive electrodes controlled by the user’s shoulder position. According to the article, with the system turned off, hand opening and closing was not possible in both subjects that participated in the study. With the stimulation, MCS-C score rose from 18 to 39 and from 18 to 37 in patients 1 and 2, respectively, after 27 days using the device.

Therapy. None of the included papers used the MSC test to evaluate the therapeutic effect of a SR or FES device.

12) Non-standardized test

In 12 out of the 37 documents (32 \(\%\) ) of the final collection, the authors used non-standardized tests to evaluate the end-user’s performance wearing a FES system or a robotic glove for assistance or their therapeutic effects. In some studies, the non-standardized test consisted of a grasp and release task, picking up and releasing ADLs objects of various shapes, like a plastic bottle, a banana or a baseball [ 54 , 55 ]. Other authors asked the subjects to execute other ADLs, like eating, writing, drinking a cup of coffee [ 59 , 60 , 68 , 71 ] or simulating a real activity [ 56 ]. In addition, in one study [ 21 ] they designed a very specific activity involving hand supination and pronation. In [ 73 ], functional tests were not described but the authors reported that the subject of the study used the implanted device for 37 months to support ADLs. In [ 72 ] a non-standardized 3-level score evaluation was performed by three experts. Finally, some authors used only non-standardized tests [ 21 , 40 , 54 , 60 , 65 , 68 , 72 , 73 ], others combined it with an assessment of impairment (e.g., range of motion or strength measurements) [ 55 , 59 ], and others mixed up with standardized functional assessment tools, such as GRT [ 71 ] and GRASSP [ 56 ].

The recovery of arm and hand function is one of the main therapeutical priorities of people with tetraplegia [ 2 , 3 , 4 ]. Soft Robotics (SR) and Functional Electrical Stimulation (FES) are two technologies that may either assist movements during daily tasks or accompany the conventional intervention in protocols for hand function therapy. Although devices based on SR or FES are not novel, they still demand technological development to be fully integrated into the end-user’s routine and, most importantly, they need to be clinically validated with a view to represent a safe, reliable and effective treatment for hand function after SCI. To this extent, the present review compiled the available articles that reported functional outcomes obtained through the use of SR or FES devices (including their combination), assisting or treating hand function of people living with SCI.

The final collection included a total of 37 articles, 12 SR and 25 FES studies. They focused on different clinical goals, tested devices with various technical features and employed multiple assessment tools to evaluate functional outcomes. Figure 3 connects the selected studies with each of these domains.

Different domains (clinical goals, technical features and assessment tools) and their connections to the studies of the final collection

Following, key-points and recommendations are listed together with the discussion of each point.

Key-point 1: Most studies have a system-centric approach and are limited to research prototypes.

Recommendations: Increase the focus on functional outcomes. We suggest the use of other commercially available devices designed for different clinical populations, such as stroke.

Most studies about restoring hand function in people with SCI, using SR or FES technology, have a system-centric point-of-view, which means the articles usually evaluate the performance of the engineered system but fall short in evaluating the clinical added value and testing with end-users. As a result, there are scarce evidence about functional outcomes produced by this sort of devices, with this specific population. Indeed, 18 out of the 37 studies included in our final collection were published by only five research groups. Additionally, most of the reported systems are still research prototypes, which usually have limited feasibility in terms of clinical testing. This is a limitation of the present review, as it only included published articles from year 2010 onwards, which may represent a very short time for research to get translated into clinical practice. FES devices have been extensively used in clinical settings for the last two decades and commercial devices are currently available. Even though, most studies combined commercial stimulators with customized setups (e.g., to change the system to detect user intention), which makes the entire system as experimental as any laboratory prototype. In terms of SR, although its use as rehabilitation tool is relatively new, there are products originally designed for other clinical conditions (e.g., stroke) that could be tested for people with SCI. According to the present review, only one study reported functional outcomes following this approach. We believe that similar studies should be pursued in a way to validate devices that could have a prompt clinical application for people with SCI.

Key-point 2: Certain technological components of FES and SR related to portability and easy-to-use capabilities must be improved. The resources should be better prescribed to match end-user’ needs.

Recommendations: From an engineering perspective, further work is needed to produce an easy-to-use, intuitive and fast-response user intent detection method. Portability, donning/doffing and the time spent with calibration are other major technological challenges. Innovative devices should embrace a feedback system (either visual or haptic) and a system for continuous control the movements. For clinicians, the ideal selectivity level, active support and even the user intent detection method should be determined according to the individual situation of each end-user. Further investigation is necessary to match these features to different subject’s conditions.

The fact that most devices described in this study were at an early stage of development translates to technological and usability issues that need further investigation. For example, there is not a consensus regarding the ideal user intent detection method for a given user level of impairment. Some devices use buttons to control the state of the glove or to trigger the stimulation, which is a reliable and robust method to detect user intent, but this system does not provide the user with intuitive interaction and requires the support of the contralateral hand, which may restricts the usage in the target population of people with SCI and limited hand function bilaterally. Other studies use an intuitive and unobtrusive method to operate the system, such as, the brain machine interfaces (BMI), either via non-invasive EEG electrodes or brain implantation. In [ 60 ], for example, the intracortical implant was used to control the FES stimulation and the subject reported to make movements without the need to concentrate hard at the task. At the cost of a surgical procedure, the invasive system provides more accurate data when compared to the superficial one, thus it allows to recognize and select between different grasp patterns and could also control continuous movements [ 93 ]. Other studies have proposed alternative methods to detect user intent, such as voice control, superficial EMG, force sensors, but their successful applicability depends on specific condition of the user. To resolve this discrepancy, this matter requires a user-centered approach to identify the most appropriate detection method based on the users’ individual residual function and needs. The study of Predrocchi and colleagues [ 72 ] was the only one in our collection that used a user-centered approach to determine the best configuration of the system to match the patient’s needs, varying the intention detection method (between button, eye tracking or BCI) and the actuation system (either FES or a robotic orthosis).

Other technological challenges identified among the selected devices were the time delay introduced by the control systems, the frequent calibration to recognize user intent and the difficulty to independently don and doff the glove or place the surface electrodes without assistance. Additionally, interactive and constant feedback should be considered in order to enhance the practice-induced brain and spinal plasticity [ 14 , 94 ] and increase usability features. None of the studies reported a feedback system, except a visual interface used to support the training time. In terms of challenges from the FES selected studies, all devices, except one, were reported to use a biphasic waveform, and most of them did not vary the pulse amplitude or the frequency. In a recent study with people with stroke, authors reported different outcomes for neuromuscular electrical stimulation of varied frequency [ 95 ].

Related to the SR collection, there is a need to improve the physical structure of some robotic gloves or hand orthotics. Due to their size and design, part of the fingertips and palm are covered, which hinders the natural user’s somatosensation. People with incomplete SCI may have preserved some sense of touch, thus for those individuals it would be relevant to sense the external objects and tools during manipulation. When the device uses a glove interface [ 51 , 52 , 53 , 54 ] the entire hand is covered, but other designs preserve the full area of fingertips [ 67 ] or have no obstructions on palms and fingertips [ 64 , 65 , 68 ]. Interestingly, either a glove with absent somatosensation [ 51 ] or a hand orthosis with no obstruction at the fingertips [ 67 ], can present difficulties for end-users to manipulate small objects (like pencils), which represent another issue that should be addressed.

In terms of the active support provided by SR or FES devices, some of them only consider finger flexion, thus the manipulated objects are released when the system is not activated (relax state) [ 50 , 67 , 74 , 75 ]. This method may be useful, for example, to enhance tenodesis grip [ 67 , 74 ], and considerably reduces system complexity, which means less actuators or few number of electrodes, as well as smaller size and lighter weight. Although a stable and secure finger flexion may be enough to match some end-users’ needs, it is worth expanding the potential active support of SR and FES devices since most ADLs rely on an extensive grasp taxonomy [ 80 , 96 , 97 ]. In this respect, among FES articles, the studies involving a BMI interface and a multi-pad stimulation system, presented the widest range of grasping types, including precision and power grasps [ 20 , 21 , 56 , 57 , 58 ]. The use of a matrix with multiple electrodes seems to be a promising way to balance between precision of movement and invasiveness. In the SR collection, it is plain that a broader set of hand patterns is possible with more active fingers and multiple assisted motions (e.g., the lateral key depends on thumb adduction and abduction), even if some motions are assisted passively [ 64 ].

The user intent detection method also plays a crucial role in the grasping performance. For example, the system presented by [ 20 , 21 , 49 , 56 , 57 , 58 ] used superficial stimulation and invasive cortical electrodes to detect user intention of movement, whereas studies [ 19 , 59 , 61 ] employed implanted electrodes to stimulate nerves and muscles, and implanted EMG for the user intent detection. Although invasive stimulation is known to have higher resolution, which means it is suitable to produce complex hand poses, the studies in [ 19 , 59 , 61 ] presented inferior performance in terms of grasping types when compared to the system presented by [ 20 , 21 , 56 , 57 , 58 ]. In this case, the intracortical implant seemed to be more appropriate to recognize and select different hand poses than the EMG technique. Hence, the system described by [ 60 ] was potentially the most powerful among our collection since it combined percutaneous electrical stimulation and intracortical signals. Unfortunately, the authors did not elaborate at the grasp taxonomy, as much as the studies in [ 58 ] or [ 20 ] did. Still, in terms of innovative user intent detection, it would be useful to expand a new paradigm of continuous control interface, instead of the current situation in which a variety of hand patterns options is offered to the user. This would allow the end-user to combine familiar movements to compose novel hand functions, following a process similar to the generalization, which is typical in human motor learning.

A semi-custom approach—off-the-shelf items that best fit user’s needs combined with customizable protocols, assisted and monitored by the wearable devices—may be suitable in order to ensure the right fit for different subject’s conditions and the available SR and FES technological resources.

Key-point 3: Devices are designed and tested with a specific purpose, either assistance or therapy, but not both.

Recommendations: Design and test devices for both assistive and therapeutic purposes.

In a research involving elderly, subjects with stroke and healthcare professionals, Radder and colleagues pointed that the end-users prefer to have wearable robotic devices not only for assistance during ADLs, but also for therapeutic goals [ 98 ]. This suggestion of unified systems has been identified in a recent literature review about SR for hands [ 27 ] and has also already been tested for other neurological conditions, such as stroke [ 10 ]. Almost all devices we identified were described by the authors as either assistive or therapeutic tools for people with SCI, although most of them could be utilised in both ways after minor or any changes. Among the studies of our collection, only one SR [ 50 ], and two FES studies [ 76 , 78 ], assessed the therapeutic effects of a device originally designed for assistance. Particularly, in [ 74 ], Thorsen and colleagues evaluated both the therapeutic and the assistance effects of a myoelectrically controlled functional electrical stimulator. As expected, the greater clinical relevance was observed for the combination of training and assistive effects.

This characterization between either assistive or therapeutic goals, may be partially motivated by the differences in the validation process and clinical testing of both systems. The former usually undergoes an observational study, comparing the same hand function tasks with and without assistance, whereas the therapeutic effects are commonly investigated with longitudinal studies, assessing the same motor functions, without wearing the system, before and after a certain training time. In studies in which the user acceptance is assessed, different aspects are evaluated, such as the subject’s perception after wearing a device for a full day or by using the device during clinical sessions. Additionally, assistive devices prioritise the individual aspect and the cost affordability, whereas the therapeutic tools prioritises the shared use of the device by different users. In despite of these differences, SR and FES systems should be designed and validated for assistive and therapeutic purposes in order to accomplish integral recovery of hand function and integrate it back to the end-user’s routine. A system with unified goals may help increases device usage time as being supported during ADLs, and consequently the therapeutic outcomes are enhanced due to the increased dosage (according to the practice-induced neural plasticity mechanism [ 14 , 33 ]). Additionally, systems combining assistance and therapeutic aims could lead to customizable and adaptative rehabilitation programs, supported and monitored by SR and FES wearable devices.

Nevertheless, to be integrated to the daily basis, a system must be portable and allow the user to independently don and doff, among other desirable features. To date, few studies of our collection described devices ready to be used at home [ 19 , 41 , 49 , 50 , 59 , 73 , 76 , 78 ].

Key-point 4: There is a great variety of assessments used by studies and frequently no standardized tests are adopted.

Recommendations: Combine assessments to evaluate functional outcomes in terms of effectiveness and efficiency and focus on the performance of the hands and fingers instead of the entire upper limbs function.

There is no consensus about the preferred functional assessment used to report user’s performance, which limits the comparison between different studies. Our selection identified up to eleven different types of tests, while the SR articles focused on six of them. In terms of the metrics adopted by these assessments, both efficiency or effectiveness can be measured. Efficiency is interpreted as a measure of the efforts expended with the intention of achieving a certain goal and it typically involves timed tasks (e.g., counting the number of successful transfers of wooden blocks within a certain time period). Within our collection of assessments, JTHFT, BBT and GRT fall into this category. On the other hand, effectiveness is associated to the accuracy of the motor execution, thus scores are commonly used to quantify the performance, either based on participant self-report or physiatrist observation. Examples of tests that assesses effectiveness are, TRI-HFT, GRASSP, FIM, SCIM, ARAT, CUE-T, QIF-SF and MCS. Both approaches are interrelated and should be used in a complementary fashion for a comprehensive assessment. Nevertheless, only two studies of our full collection measured the functional outcomes combining both assessment types [ 20 , 49 ].

Analysing the set of functions each test comprises, it is noticeable that part of them is specifically designed to evaluate hand function (TRI-HFT, GRASSP and JTHFT), while others focus on the performance of ADLs or other tasks that usually involves shoulder and arm function (this is the case of BBT, GRT, FIM, SCIM, ARAT, CUE-T, MCS and QIF-SF). From a user-centric point-of-view, we believe that assessing hand function performance contextualized to the subject’s routine is important, which emphasizes the value of this type of assessment.

However, when isolated, this approach may not represent the current hand function and its improvements could not be perceived due to the low performance of the unsupported limbs. In our collection, eight studies Footnote 1 (all regarding FES) solely used assessments that involve the performance of functions beyond the hands (e.g., arms and shoulders), even testing a neuroprostheses that only acts on the fingers and wrist [ 19 , 48 , 57 , 58 , 61 , 71 , 76 , 78 ]. This type of assessment may not be appropriate for people with cervical and complete SCI. Thus, we believe that the assessment tool should be based on the current level of function of each patient.

Besides the variability of functional assessment, other factors also limited our examination of functional outcomes. One of them was the use of non-standardized tests to evaluate user’s performance, which happened in almost a third part of the entire collection—with eight studies using no other functional assessment tool [ 21 , 40 , 54 , 60 , 65 , 68 , 72 , 73 ]. Another limitation we found was the small sample size of most articles, usually designed as case studies or case series. In the case of invasive devices, this may be justified for the low number of eligible participants, but other authors justified their small sample size by a proof-of-concept design. Furthermore, the lack of statistical analysis of some studies also limited the comparison between studies. Considering the twenty-five articles that have used at least one standardized test, eleven of them did not present statistical analysis, and it cannot be directly associated to a limited sample size.

In addition, regarding the details of the analysed population (sample size, lesion completeness and time since injury), our review showed low heterogeneity among studies. The population of most articles was constituted by people with chronic and complete SCI, a small part of papers included subjects with sub-acute SCI [ 11 , 51 , 53 , 63 , 75 , 76 ] and notably none of them considered the acute condition. More importantly, many documents did not describe the participant’s lesion completeness. This is a significant limitation as lesion completeness and level are crucial to determine the most appropriate functional assessment for a certain patient. Additionally, the particular condition description can have an important impact on functional outcomes using these therapeutic or assistive devices [ 33 ]. A recent publication involving people with chronic stroke showed that in order to maximize the therapeutic effect of a neurorehabilitation, the treatment program must be in accordance with the severity of each patient’s clinical condition [ 99 ]. In this sense, standardized neurological examination may also help to provide context to the observed functional outcomes.

Major functional outcomes of each study were presented to serve as a guideline for clinicians and engineers who are interested in the application and continuing development of these SR and FES technologies, so people with SCI can have access to these technologies and improve their hand function in the clinical and home settings.

Rehabilitation of hand function plays a crucial role in the independence of people with SCI. SR and FES wearable devices are two promising technologies that can either assist daily tasks or support hand therapy. From an engineering perspective, technological improvements are needed before these devices can be extensively prescribed in clinical setting or for home-based use. For instance, portability, donning/doffing and the time spent with calibration were identified as important limitations of most devices. In addition, an easy-to-use, intuitive and fast-response user intent detection method should be explored further. From a clinician’s point of view, studies should match technological features to end-user’s conditions. Consistent assessment of functional outcomes between studies is another limitation of the studies.

We are confident that SR and FES wearable devices have a huge potential to support hand rehabilitation after SCI. The present narrative review helps engineers providing information on the next steps to develop these technologies and serve as clinical guidelines for clinicians to better prescribe these devices for assistance and therapy of people with SCI.

Availability of data and materials

Not applicable.

Although the study [ 69 ] only used the MCS test to evaluate functional improvement, the authors solely assessed MCS sub-categories C and D, that are focused on the hands.

Abbreviations

• Soft robotics
• Functional electrical stimulation
• Spinal cord injury

Activities of daily living

Implanted and surface brain machine interface

Implanted and surface electromyography

Three-layered sliding spring mechanism

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Cardoso, L.R.L., Bochkezanian, V., Forner-Cordero, A. et al. Soft robotics and functional electrical stimulation advances for restoring hand function in people with SCI: a narrative review, clinical guidelines and future directions. J NeuroEngineering Rehabil 19 , 66 (2022). https://doi.org/10.1186/s12984-022-01043-1

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Literature Reviews, Theoretical Frameworks, and Conceptual Frameworks: An Introduction for New Biology Education Researchers

Julie a. luft.

† Department of Mathematics, Social Studies, and Science Education, Mary Frances Early College of Education, University of Georgia, Athens, GA 30602-7124

Sophia Jeong

‡ Department of Teaching & Learning, College of Education & Human Ecology, Ohio State University, Columbus, OH 43210

Robert Idsardi

§ Department of Biology, Eastern Washington University, Cheney, WA 99004

Grant Gardner

∥ Department of Biology, Middle Tennessee State University, Murfreesboro, TN 37132

Associated Data

To frame their work, biology education researchers need to consider the role of literature reviews, theoretical frameworks, and conceptual frameworks as critical elements of the research and writing process. However, these elements can be confusing for scholars new to education research. This Research Methods article is designed to provide an overview of each of these elements and delineate the purpose of each in the educational research process. We describe what biology education researchers should consider as they conduct literature reviews, identify theoretical frameworks, and construct conceptual frameworks. Clarifying these different components of educational research studies can be helpful to new biology education researchers and the biology education research community at large in situating their work in the broader scholarly literature.

INTRODUCTION

Discipline-based education research (DBER) involves the purposeful and situated study of teaching and learning in specific disciplinary areas ( Singer et al. , 2012 ). Studies in DBER are guided by research questions that reflect disciplines’ priorities and worldviews. Researchers can use quantitative data, qualitative data, or both to answer these research questions through a variety of methodological traditions. Across all methodologies, there are different methods associated with planning and conducting educational research studies that include the use of surveys, interviews, observations, artifacts, or instruments. Ensuring the coherence of these elements to the discipline’s perspective also involves situating the work in the broader scholarly literature. The tools for doing this include literature reviews, theoretical frameworks, and conceptual frameworks. However, the purpose and function of each of these elements is often confusing to new education researchers. The goal of this article is to introduce new biology education researchers to these three important elements important in DBER scholarship and the broader educational literature.

The first element we discuss is a review of research (literature reviews), which highlights the need for a specific research question, study problem, or topic of investigation. Literature reviews situate the relevance of the study within a topic and a field. The process may seem familiar to science researchers entering DBER fields, but new researchers may still struggle in conducting the review. Booth et al. (2016b) highlight some of the challenges novice education researchers face when conducting a review of literature. They point out that novice researchers struggle in deciding how to focus the review, determining the scope of articles needed in the review, and knowing how to be critical of the articles in the review. Overcoming these challenges (and others) can help novice researchers construct a sound literature review that can inform the design of the study and help ensure the work makes a contribution to the field.

The second and third highlighted elements are theoretical and conceptual frameworks. These guide biology education research (BER) studies, and may be less familiar to science researchers. These elements are important in shaping the construction of new knowledge. Theoretical frameworks offer a way to explain and interpret the studied phenomenon, while conceptual frameworks clarify assumptions about the studied phenomenon. Despite the importance of these constructs in educational research, biology educational researchers have noted the limited use of theoretical or conceptual frameworks in published work ( DeHaan, 2011 ; Dirks, 2011 ; Lo et al. , 2019 ). In reviewing articles published in CBE—Life Sciences Education ( LSE ) between 2015 and 2019, we found that fewer than 25% of the research articles had a theoretical or conceptual framework (see the Supplemental Information), and at times there was an inconsistent use of theoretical and conceptual frameworks. Clearly, these frameworks are challenging for published biology education researchers, which suggests the importance of providing some initial guidance to new biology education researchers.

Fortunately, educational researchers have increased their explicit use of these frameworks over time, and this is influencing educational research in science, technology, engineering, and mathematics (STEM) fields. For instance, a quick search for theoretical or conceptual frameworks in the abstracts of articles in Educational Research Complete (a common database for educational research) in STEM fields demonstrates a dramatic change over the last 20 years: from only 778 articles published between 2000 and 2010 to 5703 articles published between 2010 and 2020, a more than sevenfold increase. Greater recognition of the importance of these frameworks is contributing to DBER authors being more explicit about such frameworks in their studies.

Collectively, literature reviews, theoretical frameworks, and conceptual frameworks work to guide methodological decisions and the elucidation of important findings. Each offers a different perspective on the problem of study and is an essential element in all forms of educational research. As new researchers seek to learn about these elements, they will find different resources, a variety of perspectives, and many suggestions about the construction and use of these elements. The wide range of available information can overwhelm the new researcher who just wants to learn the distinction between these elements or how to craft them adequately.

Our goal in writing this paper is not to offer specific advice about how to write these sections in scholarly work. Instead, we wanted to introduce these elements to those who are new to BER and who are interested in better distinguishing one from the other. In this paper, we share the purpose of each element in BER scholarship, along with important points on its construction. We also provide references for additional resources that may be beneficial to better understanding each element. Table 1 summarizes the key distinctions among these elements.

Comparison of literature reviews, theoretical frameworks, and conceptual reviews

This article is written for the new biology education researcher who is just learning about these different elements or for scientists looking to become more involved in BER. It is a result of our own work as science education and biology education researchers, whether as graduate students and postdoctoral scholars or newly hired and established faculty members. This is the article we wish had been available as we started to learn about these elements or discussed them with new educational researchers in biology.

LITERATURE REVIEWS

Purpose of a literature review.

A literature review is foundational to any research study in education or science. In education, a well-conceptualized and well-executed review provides a summary of the research that has already been done on a specific topic and identifies questions that remain to be answered, thus illustrating the current research project’s potential contribution to the field and the reasoning behind the methodological approach selected for the study ( Maxwell, 2012 ). BER is an evolving disciplinary area that is redefining areas of conceptual emphasis as well as orientations toward teaching and learning (e.g., Labov et al. , 2010 ; American Association for the Advancement of Science, 2011 ; Nehm, 2019 ). As a result, building comprehensive, critical, purposeful, and concise literature reviews can be a challenge for new biology education researchers.

Building Literature Reviews

There are different ways to approach and construct a literature review. Booth et al. (2016a) provide an overview that includes, for example, scoping reviews, which are focused only on notable studies and use a basic method of analysis, and integrative reviews, which are the result of exhaustive literature searches across different genres. Underlying each of these different review processes are attention to the s earch process, a ppraisa l of articles, s ynthesis of the literature, and a nalysis: SALSA ( Booth et al. , 2016a ). This useful acronym can help the researcher focus on the process while building a specific type of review.

However, new educational researchers often have questions about literature reviews that are foundational to SALSA or other approaches. Common questions concern determining which literature pertains to the topic of study or the role of the literature review in the design of the study. This section addresses such questions broadly while providing general guidance for writing a narrative literature review that evaluates the most pertinent studies.

The literature review process should begin before the research is conducted. As Boote and Beile (2005 , p. 3) suggested, researchers should be “scholars before researchers.” They point out that having a good working knowledge of the proposed topic helps illuminate avenues of study. Some subject areas have a deep body of work to read and reflect upon, providing a strong foundation for developing the research question(s). For instance, the teaching and learning of evolution is an area of long-standing interest in the BER community, generating many studies (e.g., Perry et al. , 2008 ; Barnes and Brownell, 2016 ) and reviews of research (e.g., Sickel and Friedrichsen, 2013 ; Ziadie and Andrews, 2018 ). Emerging areas of BER include the affective domain, issues of transfer, and metacognition ( Singer et al. , 2012 ). Many studies in these areas are transdisciplinary and not always specific to biology education (e.g., Rodrigo-Peiris et al. , 2018 ; Kolpikova et al. , 2019 ). These newer areas may require reading outside BER; fortunately, summaries of some of these topics can be found in the Current Insights section of the LSE website.

In focusing on a specific problem within a broader research strand, a new researcher will likely need to examine research outside BER. Depending upon the area of study, the expanded reading list might involve a mix of BER, DBER, and educational research studies. Determining the scope of the reading is not always straightforward. A simple way to focus one’s reading is to create a “summary phrase” or “research nugget,” which is a very brief descriptive statement about the study. It should focus on the essence of the study, for example, “first-year nonmajor students’ understanding of evolution,” “metacognitive prompts to enhance learning during biochemistry,” or “instructors’ inquiry-based instructional practices after professional development programming.” This type of phrase should help a new researcher identify two or more areas to review that pertain to the study. Focusing on recent research in the last 5 years is a good first step. Additional studies can be identified by reading relevant works referenced in those articles. It is also important to read seminal studies that are more than 5 years old. Reading a range of studies should give the researcher the necessary command of the subject in order to suggest a research question.

Given that the research question(s) arise from the literature review, the review should also substantiate the selected methodological approach. The review and research question(s) guide the researcher in determining how to collect and analyze data. Often the methodological approach used in a study is selected to contribute knowledge that expands upon what has been published previously about the topic (see Institute of Education Sciences and National Science Foundation, 2013 ). An emerging topic of study may need an exploratory approach that allows for a description of the phenomenon and development of a potential theory. This could, but not necessarily, require a methodological approach that uses interviews, observations, surveys, or other instruments. An extensively studied topic may call for the additional understanding of specific factors or variables; this type of study would be well suited to a verification or a causal research design. These could entail a methodological approach that uses valid and reliable instruments, observations, or interviews to determine an effect in the studied event. In either of these examples, the researcher(s) may use a qualitative, quantitative, or mixed methods methodological approach.

Even with a good research question, there is still more reading to be done. The complexity and focus of the research question dictates the depth and breadth of the literature to be examined. Questions that connect multiple topics can require broad literature reviews. For instance, a study that explores the impact of a biology faculty learning community on the inquiry instruction of faculty could have the following review areas: learning communities among biology faculty, inquiry instruction among biology faculty, and inquiry instruction among biology faculty as a result of professional learning. Biology education researchers need to consider whether their literature review requires studies from different disciplines within or outside DBER. For the example given, it would be fruitful to look at research focused on learning communities with faculty in STEM fields or in general education fields that result in instructional change. It is important not to be too narrow or too broad when reading. When the conclusions of articles start to sound similar or no new insights are gained, the researcher likely has a good foundation for a literature review. This level of reading should allow the researcher to demonstrate a mastery in understanding the researched topic, explain the suitability of the proposed research approach, and point to the need for the refined research question(s).

The literature review should include the researcher’s evaluation and critique of the selected studies. A researcher may have a large collection of studies, but not all of the studies will follow standards important in the reporting of empirical work in the social sciences. The American Educational Research Association ( Duran et al. , 2006 ), for example, offers a general discussion about standards for such work: an adequate review of research informing the study, the existence of sound and appropriate data collection and analysis methods, and appropriate conclusions that do not overstep or underexplore the analyzed data. The Institute of Education Sciences and National Science Foundation (2013) also offer Common Guidelines for Education Research and Development that can be used to evaluate collected studies.

Because not all journals adhere to such standards, it is important that a researcher review each study to determine the quality of published research, per the guidelines suggested earlier. In some instances, the research may be fatally flawed. Examples of such flaws include data that do not pertain to the question, a lack of discussion about the data collection, poorly constructed instruments, or an inadequate analysis. These types of errors result in studies that are incomplete, error-laden, or inaccurate and should be excluded from the review. Most studies have limitations, and the author(s) often make them explicit. For instance, there may be an instructor effect, recognized bias in the analysis, or issues with the sample population. Limitations are usually addressed by the research team in some way to ensure a sound and acceptable research process. Occasionally, the limitations associated with the study can be significant and not addressed adequately, which leaves a consequential decision in the hands of the researcher. Providing critiques of studies in the literature review process gives the reader confidence that the researcher has carefully examined relevant work in preparation for the study and, ultimately, the manuscript.

A solid literature review clearly anchors the proposed study in the field and connects the research question(s), the methodological approach, and the discussion. Reviewing extant research leads to research questions that will contribute to what is known in the field. By summarizing what is known, the literature review points to what needs to be known, which in turn guides decisions about methodology. Finally, notable findings of the new study are discussed in reference to those described in the literature review.

Within published BER studies, literature reviews can be placed in different locations in an article. When included in the introductory section of the study, the first few paragraphs of the manuscript set the stage, with the literature review following the opening paragraphs. Cooper et al. (2019) illustrate this approach in their study of course-based undergraduate research experiences (CUREs). An introduction discussing the potential of CURES is followed by an analysis of the existing literature relevant to the design of CUREs that allows for novel student discoveries. Within this review, the authors point out contradictory findings among research on novel student discoveries. This clarifies the need for their study, which is described and highlighted through specific research aims.

A literature reviews can also make up a separate section in a paper. For example, the introduction to Todd et al. (2019) illustrates the need for their research topic by highlighting the potential of learning progressions (LPs) and suggesting that LPs may help mitigate learning loss in genetics. At the end of the introduction, the authors state their specific research questions. The review of literature following this opening section comprises two subsections. One focuses on learning loss in general and examines a variety of studies and meta-analyses from the disciplines of medical education, mathematics, and reading. The second section focuses specifically on LPs in genetics and highlights student learning in the midst of LPs. These separate reviews provide insights into the stated research question.

Suggestions and Advice

A well-conceptualized, comprehensive, and critical literature review reveals the understanding of the topic that the researcher brings to the study. Literature reviews should not be so big that there is no clear area of focus; nor should they be so narrow that no real research question arises. The task for a researcher is to craft an efficient literature review that offers a critical analysis of published work, articulates the need for the study, guides the methodological approach to the topic of study, and provides an adequate foundation for the discussion of the findings.

In our own writing of literature reviews, there are often many drafts. An early draft may seem well suited to the study because the need for and approach to the study are well described. However, as the results of the study are analyzed and findings begin to emerge, the existing literature review may be inadequate and need revision. The need for an expanded discussion about the research area can result in the inclusion of new studies that support the explanation of a potential finding. The literature review may also prove to be too broad. Refocusing on a specific area allows for more contemplation of a finding.

It should be noted that there are different types of literature reviews, and many books and articles have been written about the different ways to embark on these types of reviews. Among these different resources, the following may be helpful in considering how to refine the review process for scholarly journals:

• Booth, A., Sutton, A., & Papaioannou, D. (2016a). Systemic approaches to a successful literature review (2nd ed.). Los Angeles, CA: Sage. This book addresses different types of literature reviews and offers important suggestions pertaining to defining the scope of the literature review and assessing extant studies.
• Booth, W. C., Colomb, G. G., Williams, J. M., Bizup, J., & Fitzgerald, W. T. (2016b). The craft of research (4th ed.). Chicago: University of Chicago Press. This book can help the novice consider how to make the case for an area of study. While this book is not specifically about literature reviews, it offers suggestions about making the case for your study.
• Galvan, J. L., & Galvan, M. C. (2017). Writing literature reviews: A guide for students of the social and behavioral sciences (7th ed.). Routledge. This book offers guidance on writing different types of literature reviews. For the novice researcher, there are useful suggestions for creating coherent literature reviews.

THEORETICAL FRAMEWORKS

Purpose of theoretical frameworks.

As new education researchers may be less familiar with theoretical frameworks than with literature reviews, this discussion begins with an analogy. Envision a biologist, chemist, and physicist examining together the dramatic effect of a fog tsunami over the ocean. A biologist gazing at this phenomenon may be concerned with the effect of fog on various species. A chemist may be interested in the chemical composition of the fog as water vapor condenses around bits of salt. A physicist may be focused on the refraction of light to make fog appear to be “sitting” above the ocean. While observing the same “objective event,” the scientists are operating under different theoretical frameworks that provide a particular perspective or “lens” for the interpretation of the phenomenon. Each of these scientists brings specialized knowledge, experiences, and values to this phenomenon, and these influence the interpretation of the phenomenon. The scientists’ theoretical frameworks influence how they design and carry out their studies and interpret their data.

Within an educational study, a theoretical framework helps to explain a phenomenon through a particular lens and challenges and extends existing knowledge within the limitations of that lens. Theoretical frameworks are explicitly stated by an educational researcher in the paper’s framework, theory, or relevant literature section. The framework shapes the types of questions asked, guides the method by which data are collected and analyzed, and informs the discussion of the results of the study. It also reveals the researcher’s subjectivities, for example, values, social experience, and viewpoint ( Allen, 2017 ). It is essential that a novice researcher learn to explicitly state a theoretical framework, because all research questions are being asked from the researcher’s implicit or explicit assumptions of a phenomenon of interest ( Schwandt, 2000 ).

Selecting Theoretical Frameworks

Theoretical frameworks are one of the most contemplated elements in our work in educational research. In this section, we share three important considerations for new scholars selecting a theoretical framework.

The first step in identifying a theoretical framework involves reflecting on the phenomenon within the study and the assumptions aligned with the phenomenon. The phenomenon involves the studied event. There are many possibilities, for example, student learning, instructional approach, or group organization. A researcher holds assumptions about how the phenomenon will be effected, influenced, changed, or portrayed. It is ultimately the researcher’s assumption(s) about the phenomenon that aligns with a theoretical framework. An example can help illustrate how a researcher’s reflection on the phenomenon and acknowledgment of assumptions can result in the identification of a theoretical framework.

In our example, a biology education researcher may be interested in exploring how students’ learning of difficult biological concepts can be supported by the interactions of group members. The phenomenon of interest is the interactions among the peers, and the researcher assumes that more knowledgeable students are important in supporting the learning of the group. As a result, the researcher may draw on Vygotsky’s (1978) sociocultural theory of learning and development that is focused on the phenomenon of student learning in a social setting. This theory posits the critical nature of interactions among students and between students and teachers in the process of building knowledge. A researcher drawing upon this framework holds the assumption that learning is a dynamic social process involving questions and explanations among students in the classroom and that more knowledgeable peers play an important part in the process of building conceptual knowledge.

It is important to state at this point that there are many different theoretical frameworks. Some frameworks focus on learning and knowing, while other theoretical frameworks focus on equity, empowerment, or discourse. Some frameworks are well articulated, and others are still being refined. For a new researcher, it can be challenging to find a theoretical framework. Two of the best ways to look for theoretical frameworks is through published works that highlight different frameworks.

When a theoretical framework is selected, it should clearly connect to all parts of the study. The framework should augment the study by adding a perspective that provides greater insights into the phenomenon. It should clearly align with the studies described in the literature review. For instance, a framework focused on learning would correspond to research that reported different learning outcomes for similar studies. The methods for data collection and analysis should also correspond to the framework. For instance, a study about instructional interventions could use a theoretical framework concerned with learning and could collect data about the effect of the intervention on what is learned. When the data are analyzed, the theoretical framework should provide added meaning to the findings, and the findings should align with the theoretical framework.

A study by Jensen and Lawson (2011) provides an example of how a theoretical framework connects different parts of the study. They compared undergraduate biology students in heterogeneous and homogeneous groups over the course of a semester. Jensen and Lawson (2011) assumed that learning involved collaboration and more knowledgeable peers, which made Vygotsky’s (1978) theory a good fit for their study. They predicted that students in heterogeneous groups would experience greater improvement in their reasoning abilities and science achievements with much of the learning guided by the more knowledgeable peers.

In the enactment of the study, they collected data about the instruction in traditional and inquiry-oriented classes, while the students worked in homogeneous or heterogeneous groups. To determine the effect of working in groups, the authors also measured students’ reasoning abilities and achievement. Each data-collection and analysis decision connected to understanding the influence of collaborative work.

Their findings highlighted aspects of Vygotsky’s (1978) theory of learning. One finding, for instance, posited that inquiry instruction, as a whole, resulted in reasoning and achievement gains. This links to Vygotsky (1978) , because inquiry instruction involves interactions among group members. A more nuanced finding was that group composition had a conditional effect. Heterogeneous groups performed better with more traditional and didactic instruction, regardless of the reasoning ability of the group members. Homogeneous groups worked better during interaction-rich activities for students with low reasoning ability. The authors attributed the variation to the different types of helping behaviors of students. High-performing students provided the answers, while students with low reasoning ability had to work collectively through the material. In terms of Vygotsky (1978) , this finding provided new insights into the learning context in which productive interactions can occur for students.

Another consideration in the selection and use of a theoretical framework pertains to its orientation to the study. This can result in the theoretical framework prioritizing individuals, institutions, and/or policies ( Anfara and Mertz, 2014 ). Frameworks that connect to individuals, for instance, could contribute to understanding their actions, learning, or knowledge. Institutional frameworks, on the other hand, offer insights into how institutions, organizations, or groups can influence individuals or materials. Policy theories provide ways to understand how national or local policies can dictate an emphasis on outcomes or instructional design. These different types of frameworks highlight different aspects in an educational setting, which influences the design of the study and the collection of data. In addition, these different frameworks offer a way to make sense of the data. Aligning the data collection and analysis with the framework ensures that a study is coherent and can contribute to the field.

New understandings emerge when different theoretical frameworks are used. For instance, Ebert-May et al. (2015) prioritized the individual level within conceptual change theory (see Posner et al. , 1982 ). In this theory, an individual’s knowledge changes when it no longer fits the phenomenon. Ebert-May et al. (2015) designed a professional development program challenging biology postdoctoral scholars’ existing conceptions of teaching. The authors reported that the biology postdoctoral scholars’ teaching practices became more student-centered as they were challenged to explain their instructional decision making. According to the theory, the biology postdoctoral scholars’ dissatisfaction in their descriptions of teaching and learning initiated change in their knowledge and instruction. These results reveal how conceptual change theory can explain the learning of participants and guide the design of professional development programming.

The communities of practice (CoP) theoretical framework ( Lave, 1988 ; Wenger, 1998 ) prioritizes the institutional level , suggesting that learning occurs when individuals learn from and contribute to the communities in which they reside. Grounded in the assumption of community learning, the literature on CoP suggests that, as individuals interact regularly with the other members of their group, they learn about the rules, roles, and goals of the community ( Allee, 2000 ). A study conducted by Gehrke and Kezar (2017) used the CoP framework to understand organizational change by examining the involvement of individual faculty engaged in a cross-institutional CoP focused on changing the instructional practice of faculty at each institution. In the CoP, faculty members were involved in enhancing instructional materials within their department, which aligned with an overarching goal of instituting instruction that embraced active learning. Not surprisingly, Gehrke and Kezar (2017) revealed that faculty who perceived the community culture as important in their work cultivated institutional change. Furthermore, they found that institutional change was sustained when key leaders served as mentors and provided support for faculty, and as faculty themselves developed into leaders. This study reveals the complexity of individual roles in a COP in order to support institutional instructional change.

It is important to explicitly state the theoretical framework used in a study, but elucidating a theoretical framework can be challenging for a new educational researcher. The literature review can help to identify an applicable theoretical framework. Focal areas of the review or central terms often connect to assumptions and assertions associated with the framework that pertain to the phenomenon of interest. Another way to identify a theoretical framework is self-reflection by the researcher on personal beliefs and understandings about the nature of knowledge the researcher brings to the study ( Lysaght, 2011 ). In stating one’s beliefs and understandings related to the study (e.g., students construct their knowledge, instructional materials support learning), an orientation becomes evident that will suggest a particular theoretical framework. Theoretical frameworks are not arbitrary , but purposefully selected.

With experience, a researcher may find expanded roles for theoretical frameworks. Researchers may revise an existing framework that has limited explanatory power, or they may decide there is a need to develop a new theoretical framework. These frameworks can emerge from a current study or the need to explain a phenomenon in a new way. Researchers may also find that multiple theoretical frameworks are necessary to frame and explore a problem, as different frameworks can provide different insights into a problem.

Finally, it is important to recognize that choosing “x” theoretical framework does not necessarily mean a researcher chooses “y” methodology and so on, nor is there a clear-cut, linear process in selecting a theoretical framework for one’s study. In part, the nonlinear process of identifying a theoretical framework is what makes understanding and using theoretical frameworks challenging. For the novice scholar, contemplating and understanding theoretical frameworks is essential. Fortunately, there are articles and books that can help:

• Creswell, J. W. (2018). Research design: Qualitative, quantitative, and mixed methods approaches (5th ed.). Los Angeles, CA: Sage. This book provides an overview of theoretical frameworks in general educational research.
• Ding, L. (2019). Theoretical perspectives of quantitative physics education research. Physical Review Physics Education Research , 15 (2), 020101-1–020101-13. This paper illustrates how a DBER field can use theoretical frameworks.
• Nehm, R. (2019). Biology education research: Building integrative frameworks for teaching and learning about living systems. Disciplinary and Interdisciplinary Science Education Research , 1 , ar15. https://doi.org/10.1186/s43031-019-0017-6 . This paper articulates the need for studies in BER to explicitly state theoretical frameworks and provides examples of potential studies.
• Patton, M. Q. (2015). Qualitative research & evaluation methods: Integrating theory and practice . Sage. This book also provides an overview of theoretical frameworks, but for both research and evaluation.

CONCEPTUAL FRAMEWORKS

Purpose of a conceptual framework.

A conceptual framework is a description of the way a researcher understands the factors and/or variables that are involved in the study and their relationships to one another. The purpose of a conceptual framework is to articulate the concepts under study using relevant literature ( Rocco and Plakhotnik, 2009 ) and to clarify the presumed relationships among those concepts ( Rocco and Plakhotnik, 2009 ; Anfara and Mertz, 2014 ). Conceptual frameworks are different from theoretical frameworks in both their breadth and grounding in established findings. Whereas a theoretical framework articulates the lens through which a researcher views the work, the conceptual framework is often more mechanistic and malleable.

Conceptual frameworks are broader, encompassing both established theories (i.e., theoretical frameworks) and the researchers’ own emergent ideas. Emergent ideas, for example, may be rooted in informal and/or unpublished observations from experience. These emergent ideas would not be considered a “theory” if they are not yet tested, supported by systematically collected evidence, and peer reviewed. However, they do still play an important role in the way researchers approach their studies. The conceptual framework allows authors to clearly describe their emergent ideas so that connections among ideas in the study and the significance of the study are apparent to readers.

Constructing Conceptual Frameworks

Including a conceptual framework in a research study is important, but researchers often opt to include either a conceptual or a theoretical framework. Either may be adequate, but both provide greater insight into the research approach. For instance, a research team plans to test a novel component of an existing theory. In their study, they describe the existing theoretical framework that informs their work and then present their own conceptual framework. Within this conceptual framework, specific topics portray emergent ideas that are related to the theory. Describing both frameworks allows readers to better understand the researchers’ assumptions, orientations, and understanding of concepts being investigated. For example, Connolly et al. (2018) included a conceptual framework that described how they applied a theoretical framework of social cognitive career theory (SCCT) to their study on teaching programs for doctoral students. In their conceptual framework, the authors described SCCT, explained how it applied to the investigation, and drew upon results from previous studies to justify the proposed connections between the theory and their emergent ideas.

In some cases, authors may be able to sufficiently describe their conceptualization of the phenomenon under study in an introduction alone, without a separate conceptual framework section. However, incomplete descriptions of how the researchers conceptualize the components of the study may limit the significance of the study by making the research less intelligible to readers. This is especially problematic when studying topics in which researchers use the same terms for different constructs or different terms for similar and overlapping constructs (e.g., inquiry, teacher beliefs, pedagogical content knowledge, or active learning). Authors must describe their conceptualization of a construct if the research is to be understandable and useful.

There are some key areas to consider regarding the inclusion of a conceptual framework in a study. To begin with, it is important to recognize that conceptual frameworks are constructed by the researchers conducting the study ( Rocco and Plakhotnik, 2009 ; Maxwell, 2012 ). This is different from theoretical frameworks that are often taken from established literature. Researchers should bring together ideas from the literature, but they may be influenced by their own experiences as a student and/or instructor, the shared experiences of others, or thought experiments as they construct a description, model, or representation of their understanding of the phenomenon under study. This is an exercise in intellectual organization and clarity that often considers what is learned, known, and experienced. The conceptual framework makes these constructs explicitly visible to readers, who may have different understandings of the phenomenon based on their prior knowledge and experience. There is no single method to go about this intellectual work.

Reeves et al. (2016) is an example of an article that proposed a conceptual framework about graduate teaching assistant professional development evaluation and research. The authors used existing literature to create a novel framework that filled a gap in current research and practice related to the training of graduate teaching assistants. This conceptual framework can guide the systematic collection of data by other researchers because the framework describes the relationships among various factors that influence teaching and learning. The Reeves et al. (2016) conceptual framework may be modified as additional data are collected and analyzed by other researchers. This is not uncommon, as conceptual frameworks can serve as catalysts for concerted research efforts that systematically explore a phenomenon (e.g., Reynolds et al. , 2012 ; Brownell and Kloser, 2015 ).

Sabel et al. (2017) used a conceptual framework in their exploration of how scaffolds, an external factor, interact with internal factors to support student learning. Their conceptual framework integrated principles from two theoretical frameworks, self-regulated learning and metacognition, to illustrate how the research team conceptualized students’ use of scaffolds in their learning ( Figure 1 ). Sabel et al. (2017) created this model using their interpretations of these two frameworks in the context of their teaching.

Conceptual framework from Sabel et al. (2017) .

A conceptual framework should describe the relationship among components of the investigation ( Anfara and Mertz, 2014 ). These relationships should guide the researcher’s methods of approaching the study ( Miles et al. , 2014 ) and inform both the data to be collected and how those data should be analyzed. Explicitly describing the connections among the ideas allows the researcher to justify the importance of the study and the rigor of the research design. Just as importantly, these frameworks help readers understand why certain components of a system were not explored in the study. This is a challenge in education research, which is rooted in complex environments with many variables that are difficult to control.

For example, Sabel et al. (2017) stated: “Scaffolds, such as enhanced answer keys and reflection questions, can help students and instructors bridge the external and internal factors and support learning” (p. 3). They connected the scaffolds in the study to the three dimensions of metacognition and the eventual transformation of existing ideas into new or revised ideas. Their framework provides a rationale for focusing on how students use two different scaffolds, and not on other factors that may influence a student’s success (self-efficacy, use of active learning, exam format, etc.).

In constructing conceptual frameworks, researchers should address needed areas of study and/or contradictions discovered in literature reviews. By attending to these areas, researchers can strengthen their arguments for the importance of a study. For instance, conceptual frameworks can address how the current study will fill gaps in the research, resolve contradictions in existing literature, or suggest a new area of study. While a literature review describes what is known and not known about the phenomenon, the conceptual framework leverages these gaps in describing the current study ( Maxwell, 2012 ). In the example of Sabel et al. (2017) , the authors indicated there was a gap in the literature regarding how scaffolds engage students in metacognition to promote learning in large classes. Their study helps fill that gap by describing how scaffolds can support students in the three dimensions of metacognition: intelligibility, plausibility, and wide applicability. In another example, Lane (2016) integrated research from science identity, the ethic of care, the sense of belonging, and an expertise model of student success to form a conceptual framework that addressed the critiques of other frameworks. In a more recent example, Sbeglia et al. (2021) illustrated how a conceptual framework influences the methodological choices and inferences in studies by educational researchers.

Sometimes researchers draw upon the conceptual frameworks of other researchers. When a researcher’s conceptual framework closely aligns with an existing framework, the discussion may be brief. For example, Ghee et al. (2016) referred to portions of SCCT as their conceptual framework to explain the significance of their work on students’ self-efficacy and career interests. Because the authors’ conceptualization of this phenomenon aligned with a previously described framework, they briefly mentioned the conceptual framework and provided additional citations that provided more detail for the readers.

Within both the BER and the broader DBER communities, conceptual frameworks have been used to describe different constructs. For example, some researchers have used the term “conceptual framework” to describe students’ conceptual understandings of a biological phenomenon. This is distinct from a researcher’s conceptual framework of the educational phenomenon under investigation, which may also need to be explicitly described in the article. Other studies have presented a research logic model or flowchart of the research design as a conceptual framework. These constructions can be quite valuable in helping readers understand the data-collection and analysis process. However, a model depicting the study design does not serve the same role as a conceptual framework. Researchers need to avoid conflating these constructs by differentiating the researchers’ conceptual framework that guides the study from the research design, when applicable.

Explicitly describing conceptual frameworks is essential in depicting the focus of the study. We have found that being explicit in a conceptual framework means using accepted terminology, referencing prior work, and clearly noting connections between terms. This description can also highlight gaps in the literature or suggest potential contributions to the field of study. A well-elucidated conceptual framework can suggest additional studies that may be warranted. This can also spur other researchers to consider how they would approach the examination of a phenomenon and could result in a revised conceptual framework.

It can be challenging to create conceptual frameworks, but they are important. Below are two resources that could be helpful in constructing and presenting conceptual frameworks in educational research:

• Maxwell, J. A. (2012). Qualitative research design: An interactive approach (3rd ed.). Los Angeles, CA: Sage. Chapter 3 in this book describes how to construct conceptual frameworks.
• Ravitch, S. M., & Riggan, M. (2016). Reason & rigor: How conceptual frameworks guide research . Los Angeles, CA: Sage. This book explains how conceptual frameworks guide the research questions, data collection, data analyses, and interpretation of results.

CONCLUDING THOUGHTS

Literature reviews, theoretical frameworks, and conceptual frameworks are all important in DBER and BER. Robust literature reviews reinforce the importance of a study. Theoretical frameworks connect the study to the base of knowledge in educational theory and specify the researcher’s assumptions. Conceptual frameworks allow researchers to explicitly describe their conceptualization of the relationships among the components of the phenomenon under study. Table 1 provides a general overview of these components in order to assist biology education researchers in thinking about these elements.

It is important to emphasize that these different elements are intertwined. When these elements are aligned and complement one another, the study is coherent, and the study findings contribute to knowledge in the field. When literature reviews, theoretical frameworks, and conceptual frameworks are disconnected from one another, the study suffers. The point of the study is lost, suggested findings are unsupported, or important conclusions are invisible to the researcher. In addition, this misalignment may be costly in terms of time and money.

Conducting a literature review, selecting a theoretical framework, and building a conceptual framework are some of the most difficult elements of a research study. It takes time to understand the relevant research, identify a theoretical framework that provides important insights into the study, and formulate a conceptual framework that organizes the finding. In the research process, there is often a constant back and forth among these elements as the study evolves. With an ongoing refinement of the review of literature, clarification of the theoretical framework, and articulation of a conceptual framework, a sound study can emerge that makes a contribution to the field. This is the goal of BER and education research.

Supplementary Material

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Case report

• Open access
• Published: 23 April 2024

Surgical management of renal cell carcinoma with subhepatic inferior vena cava tumor thrombus: a case report and review of the literature

• Bekim Ademi 1 ,
• Luan Jaha 1 ,
• Isa Haxhiu 2 ,
• Xhevdet Çuni 2 ,
• Afrim Tahiri 3 ,
• Jetmir Gashi 1 ,
• Adhurim Koshi 1 &
• Art Jaha 1  

Journal of Medical Case Reports volume  18 , Article number:  201 ( 2024 ) Cite this article

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Renal cell carcinomas are the most common form of kidney cancer in adults. In addition to metastasizing in lungs, soft tissues, bones, and the liver, it also spreads locally. In 2–10% of patients, it causes a thrombus in the renal or inferior vena cava vein; in 1% of patients thrombus reaches the right atrium. Surgery is the only curative option, particularly for locally advanced disease. Despite the advancements in laparoscopic, robotic and endovascular techniques, for this group of patients, open surgery continues to be among the best options.

Here we present a case of successful tumor thrombectomy from the infrahepatic inferior vena cava combined with renal vein amputation and nephrectomy. Our patient, a 58 year old Albanian woman presented to the doctors office with flank pain, weight loss, fever, high blood pressure, night sweats, and malaise. After a comprehensive assessment, which included urine analysis, complete blood count, electrolytes, renal and hepatic function tests, as well as ultrasonography and computed tomography, she was diagnosed with left kidney renal cell carcinoma involving the left renal vein and subhepatic inferior vena cava. After obtaining informed consent from the patient we scheduled her for surgery, which went well and without complications. She was discharged one week after to continue treatment with radiotherapy, chemotherapy, and immunotherapy.

Open surgery is a safe and efficient way to treat renal cell carcinoma involving the renal vein and inferior vena cava. It is superior to other therapeutic modalities. When properly done it provides acceptable long time survival and good quality of life to patients.

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Renal cell carcinomas (RCCs) in adults account for around 85% of kidney neoplasms [ 1 , 2 ] and may be linked to various risk factors, such as genetics, smoking, obesity, and exposure to certain chemicals. Other potential risk factors include hypertension, exposure during work to trichloroethylene, benzene or herbicides, the use of nonsteroidal anti-inflammatory drugs, dialysis, hepatitis C infection, and kidney stones [ 3 , 4 ].

RCC can remain clinically undetected throughout much of its progression. In around 90% of cases, RCC does not present with the hallmark symptoms of flank mass, hematuria, and flank pain until the disease has progressed significantly. Other signs and symptoms are weight loss, malaise, fever, night sweats, hypercalcemia, and hypertension. Male patients may also experience varicoceles on their left side as a result of obstruction of the testicular vein. However, almost one third of patients show no symptoms and end up discovering the carcinoma incidentally [ 5 ].

Around one third of RCC patients develop metastatic disease, with metastases being present either at the time of diagnosis or, in up to half of cases, later after a nephrectomy. The most common sites for metastatic disease are the lungs, soft tissues, bones, and liver, although the skin and central nervous system are also frequently affected [ 6 ].

A comprehensive diagnostic approach typically involves urinalysis, blood tests, renal and hepatic profiles, and imaging techniques, such as PET scans and angiotomography. Percutaneous core biopsy may also be performed to determine malignancy status.

RCC is staged using tumor, node, metastasis (TNM) classification and the American Joint Committee on Cancer (AJCC) staging system. Higher grade tumors are associated with poorer prognosis; inferior cava vein involvement is classified as stage III within these staging systems [ 6 ].

Surgical intervention is currently the only effective treatment for localized RCC, although it may also be utilized to relieve symptoms in cases of metastatic disease. The specific surgical approach depends on the location of the tumor thrombus. Several surgical staging systems have been proposed, including the Neves, Novick, and Hinman systems. In the Novick system, which we have used in this case report, a tumor thrombus found in the renal vein that extends less than 2 cm within the inferior vena cava (IVC) is classified as a level I thrombus. An infrahepatic thrombus is classified as a level II thrombus. A level III classification is given to an intrahepatic IVC thrombus below the diaphragm, while a level IV classification is reserved for an IVC tumor thrombus that extends above the diaphragm, as illustrated in Fig.  1 [ 7 , 8 , 9 ].

Preoperative computed tomography angiography, coronary view

We are pleased to present a successful tumor thrombectomy from the infrahepatic inferior vena cava (class II) in patients with renal cell carcinoma. Our patient was a 58-year-old Albanian housewife who presented at the doctors office with a range of symptoms, including flank pain, hematuria, weight loss, fever, hypertension, night sweats, and malaise.

Despite these symptoms, she remained well-oriented to person, place, and time. Her vital signs were slightly altered, with a blood pressure of 150/95 mmHg, heart rate of 90 beats per minute, respiratory rate of 20 breaths per minute, and temperature of 38 °C. The skin appeared reddened, warm, and moist, without any lesions or rashes observed. The head was normocephalic and the neck was supple with no masses or lymphadenopathy. No visual deficits, ptosis, or facial asymmetry indicating cranial nerve pathology were noted. Muscle strength was 5/5 bilaterally, and sensations were intact to light touch and pinprick throughout. Reflexes were 2 and symmetric in all extremities, with no pathological reflexes present. Gait was steady and coordinated, without any observed abnormalities. Palpation over the left flank elicited tenderness, pain, and guarding, as did percussion. No abnormalities were heard on auscultation of the abdomen.

After a comprehensive assessment, which included urine analysis, complete blood count, electrolytes, renal and hepatic function tests, as well as ultrasonography and computed tomography, she was diagnosed with left kidney renal cell carcinoma involving the left renal vein and subhepatic inferior vena cava (Figs.  1 , 2 ). All tests came back normal, except for microhematuria and slight hypoalbuminemia. A minor increase in C-reactive protein was also noted (Table  1 ).

Preoperative computed tomography angiography, sagittal view

Apart from for a beta blocker (carvedilol 6.25 mg, twice a day orally) that she was taking for hypertension, she was on no other medications. The patient was a nonsmoker and did not consume alcohol. There was no history of kidney or other malignancy in the family.

The cancer extension into the left renal vein and subhepatic inferior vena cava corresponded to Neves II stage disease. After careful consideration, we decided to perform a nephrectomy, renal vein amputation and thrombectomy of the subhepatic vena cava.

A team composed of vascular surgeons, urologists, a hepatobiliary surgeon, and an anesthesiologist came together to form a multidisciplinary team. Adequate amounts of blood products, such as packed red blood cells, platelets, cryoprecipitate, fresh frozen plasma, and clotting factors, were made available for surgery. The surgical procedure was carried out under general endotracheal anesthesia. To monitor and resuscitate the patient during surgery, a large bore central venous catheter, a 15 F catheter in the right internal jugular vein, and a right radial arterial catheter were inserted.

A midline incision was made to approach the abdomen as it was thought to provide optimal exposure of the inferior vena cava and contralateral kidney, enable thorough metastatic evaluation, and minimize postoperative pain. Since we decided to remove the kidney first and cancer thrombus after, we mobilized the colon medially, brought the kidney outside of Gerota’s fascia, and tied the ureter. After tying the renal artery and leaving the kidney attached only by the renal vein, the kidney was removed (Fig.  3 ).

Nephrectomy

Afterwards, liver was separated from its connections and tourniquets were positioned around the suprahepatic IVC, which was then mobilized together with the contralateral renal vein. To manage and identify lumbar veins, vascular clamps were placed above and below the tumor thrombus (Fig.  4 ). Patient response was monitored with a 1 minute test clamp, during which no hemodynamic changes were observed, allowing the clamps to remain in place as we performed cavotomy. A precise incision was created around the ostium of the renal vein into the IVC, followed by placement of a Fogarty catheter to facilitate thrombus removal (Fig.  5 ). The tumor itself was successfully removed without any issues and the cavotomy incision was closed using a 3–0 polypropylene suture (Figs.  6 , 7 ). After ensuring meticulous hemostasis, the abdominal cavity was closed using multiple layers.

Vascular control of the inferior vena cava, right renal vein, and ovarian vein

Tumor thrombus removal

Suturing of the inferior vena cava

Overall, the patient received 10 units of packed red blood cells, 10 units of fresh frozen plasma, 10 units of platelets, and 10 units of cryoprecipitate. The surgery proceeded without complications. The patient was then referred for further treatment in the ICU, where she stayed for a day for postoperative care. She received an additional two units of red blood cells and one unit of plasma to achieve a hematocrit value of 38% and hemoglobin level of 115 g/L. Blood urea nitrogen (BUN) and creatinine levels were within the normal range, as were the electrolyte levels. Liver enzyme levels were also normal. Hemodynamically, she remained stable, and her oxygen saturation consistently stayed above 98%. At 6 hours later, she was successfully extubated. On the second day after surgery, she was transferred to the ward, and 1 week later, she was discharged to continue treatment with radiotherapy, chemotherapy, and immunotherapy. During her ward stay, she received intravenous antibiotics (1 g of ceftriaxone twice daily and metronidazole 500 mg three times daily), subcutaneous low molecular weight heparin (enoxaparin 4000 IU/day), intravenous proton pump inhibitor (pantoprazole 40 mg once daily), and analgesics (diclofenac 50 mg intravenously twice daily for the first two days and as needed for pain thereafter). No additional blood transfusions were required (Fig. 8 ).

Postoperative computed tomography

The ICV is free of thrombus, but there are already developed regional and liver metastases.

On the follow-up computed tomography (CT) scan performed one month after surgery, the inferior vena cava was free of tumor, but unfortunately, the tumor had already spread to the liver and retroperitoneum (Fig.  7 ). The patient’s condition deteriorated 3 months after surgery and despite aggressive chemotherapy, she passed away 6 months later. Owing to religious reasons, no autopsy was performed.

In the midst of the ongoing debate concerning the role of open surgery in the treatment of renal cell carcinoma involving the renal vein and inferior vena cava, especially when compared with less invasive surgical approaches, our case presentation aims to align with those who consider open surgical thrombectomy from the infrahepatic inferior vena cava combined with renal vein amputation and the removal of the affected kidney, a viable treatment option.

However, it requires extensive preoperative management, a multidisciplinary team, precise technical expertise during the procedure, exceptional anesthesia management, and diligent postoperative care. The surgical team must be well-prepared for any unexpected situations that may arise during the procedure while also having a clear understanding of the procedure at hand. When dealing with cases above the liver, the team should include vascular, urology, hepatobiliary, and cardiac surgeons. Additionally, strategies, such as kidney immobilization and tyrosine inhibitors, are recommended to decrease the size of the tumor before surgery.

The first routine preoperative arterial embolization of the kidney to decrease the tumor size and facilitated the surgical procedure was advocated by Pouliot and coworkers [ 10 ], but was found to have no significant advantage over no embolization. Preoperative arterial embolization of the kidney has not shown significant advantages and is only recommended in specific situations, as it is associated with complications, such as angioinfarction syndrome and inflammation around the kidney and surgical field [ 11 ]. The usefulness of tyrosine kinase inhibitors is still debated and remains to be confirmed through randomized trials despite its effectiveness in treating metastatic RCC [ 12 , 13 , 14 ].

There have been reports of surgeons placing IVC Greenfield Filters during surgery to prevent pulmonary embolism, but studies have found this practice to be ineffective and potentially dangerous. The filter may become clogged with thrombus, requiring complete removal and IVC reconstruction [ 15 ].

When dealing with a patient with RCC and IVC tumor thrombus, the surgical approach must be personalized on the basis of the level of the thrombus and characteristics of the tumor. Precise preoperative imaging plays a critical role in effective planning [ 16 ]. It is imperative to ascertain the location of the tumor thrombus—whether it is infrahepatic, intrahepatic, or suprahepatic—as this will dictate the appropriate surgical approach, methodology for controlling the inferior vena cava, and potential requirement for vascular bypass [ 6 ].

In patients with RCC and IVC tumor thrombus, general endotracheal anesthesia is favored over regional epidural anesthesia owing to the risk of significant blood loss and coagulopathy, which increases the potential for epidural hematomas.

Various modes of surgical treatment have been described for patients with RCC involving renal vein and IVC, including laparoscopic, robotic, and endovascular surgery [ 17 , 18 , 19 , 20 ]. In certain exceptional situations of renal cell carcinoma (RCC) and tumor thrombus in level I of the inferior vena cava (IVC), a laparoscopic method might be feasible. However, recorded cases have indicated an elevated possibility of intraoperative complications with minimal proof regarding its cancer-fighting efficacy and safety. Moreover, robotic radical nephrectomy has proven to be effective in certain instances of low-level thrombi, but thorough research remains inadequate, and these minimally invasive procedures are not commonly recommended [ 6 ].

Open surgery, specifically nephrectomy and IVC thrombectomy, remains the preferred option and has shown usefulness even in metastatic disease, provided the patient is a candidate for surgery and has local symptoms [ 21 ]. In patients with metastatic RCC, the most reliable indicators of their prognosis are their response to systemic therapy and the burden of their metastatic disease [ 22 , 23 , 24 ].

The factors that could affect the survival of patients in this cohort are related to pathological TNM stage, nuclear grade, histological tumor subtype, regional lymph node status, and perinephritic fat invasion. It is worth noting, however, that there is little or no correlation between the level of IVC tumor thrombus and overall survival (OS). According to a recent study, the recurrence rate might be influenced by the extent of IVC tumor thrombus, however, there does not seem to be any correlation with OS [ 25 ]. Additionally, research on the results of surgery in patients with RCC who underwent nephrectomy and IVC thrombectomy revealed that the existence of fragile venous thrombus could augment the probability of synchronous nodal or distant metastases [41]. According to reports, the 5-year OS rate following surgical approach ranges from 32 to 69% in patients with IVC tumor thrombus wall invasion [ 25 , 26 , 27 , 28 ].

As for the procedure itself, radical nephrectomy with concomitant IVC thrombectomy has a reported perioperative mortality rate of 5–10%. However, it has been associated with significant morbidity, resulting in an overall complication rate of 38% [50]. As such complex surgeries require extensive vascular, hepatobiliary, cardiothoracic, and anesthesia support, it is recommended that only centers of excellence with the necessary resources undertake these procedures. Specifically, they should be reserved for patients with more advanced level III and IV IVC tumor thrombi [ 29 , 30 , 31 , 32 ].

The effective management of renal cell carcinoma and inferior vena cava tumor thrombus relies heavily on a skilled multidisciplinary surgical team. Adequate preoperative imaging is crucial for the planning and facilitation of surgical procedures for such cases. The surgical strategy should be customized to suit the specific characteristics and extent of the tumor thrombus situated in the inferior vena cava. While minimally invasive surgical techniques (including robotics) may have a role in this matter, their use should be limited to specific cases, particularly level I IVC tumor thrombus cases with favorable anatomic and tumor characteristics. For smaller lesions in patients who are not candidates for surgery, thermal ablation may provide a viable alternative. Metastatic disease in RCC can be treated with targeted therapy and immunotherapy, whereas chemotherapy and hormonal therapy have generally been unsuccessful.

Availability of data and materials

The data are available under consideration of the corresponding author upon reasonable request.

Abbreviations

• Renal cell carcinoma

Inferior vena cava

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Bekim Ademi, Luan Jaha, Jetmir Gashi, Adhurim Koshi & Art Jaha

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The surgical procedure was carried out by BA, LJ, IH, XC, AK, and AT. LJ and AJ conducted extensive research on medical literature, gathered relevant data, and were the main contributors to writing the manuscript. All authors read and approved final manuscript.

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Correspondence to Luan Jaha .

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Ademi, B., Jaha, L., Haxhiu, I. et al. Surgical management of renal cell carcinoma with subhepatic inferior vena cava tumor thrombus: a case report and review of the literature. J Med Case Reports 18 , 201 (2024). https://doi.org/10.1186/s13256-024-04517-z

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Received : 05 September 2023

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Published : 23 April 2024

DOI : https://doi.org/10.1186/s13256-024-04517-z

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A loss-of-function AGTR1 variant in a critically-ill infant with renal tubular dysgenesis: case presentation and literature review

Affiliations.

• 1 Laboratory of Genomic Medicine, Sidra Medicine, P.O. Box 26999, Doha, Qatar.
• 2 Department of Human Genetics-Precision Medicine in Diabetes Prevention, Sidra Medicine, P.O. Box 26999, Doha, Qatar.
• 3 Neonatology Division, Sidra Medicine, P.O. Box 26999, Doha, Qatar.
• 4 Genetic Pathology, Sidra Medicine, P.O. Box 26999, Doha, Qatar.
• 5 Anatomical Pathology, Sidra Medicine, P.O. Box 26999, Doha, Qatar.
• 6 Laboratory of Genomic Medicine, Sidra Medicine, P.O. Box 26999, Doha, Qatar. [email protected].
• 7 Department of Human Genetics-Precision Medicine in Diabetes Prevention, Sidra Medicine, P.O. Box 26999, Doha, Qatar. [email protected].
• 8 College of Health and Life Sciences, Hamad Bin Khalifa University, P.O. Box 34110, Doha, Qatar. [email protected].
• 9 Department of Genetic Medicine, Weill Cornell Medical College, P.O. Box 24144, Doha, Qatar. [email protected].
• PMID: 38649831
• PMCID: PMC11034062
• DOI: 10.1186/s12882-024-03569-z

Background: Renal tubular dysgenesis (RTD) is a severe disorder with poor prognosis significantly impacting the proximal tubules of the kidney while maintaining an anatomically normal gross structure. The genetic origin of RTD, involving variants in the ACE, REN, AGT, and AGTR1 genes, affects various enzymes or receptors within the Renin angiotensin system (RAS). This condition manifests prenatally with oligohydramninos and postnatally with persistent anuria, severe refractory hypotension, and defects in skull ossification.

Case presentation: In this report, we describe a case of a female patient who, despite receiving multi vasopressor treatment, experienced persistent hypotension, ultimately resulting in early death at five days of age. While there was a history of parental consanguinity, no reported family history of renal disease existed. Blood samples from the parents and the remaining DNA sample of the patient underwent Whole Genome Sequencing (WGS). The genetic analysis revealed a rare homozygous loss of function variant (NM_000685.5; c.415C > T; p.Arg139*) in the Angiotensin II Receptor Type 1 (AGTR1) gene.

Conclusion: This case highlights the consequence of loss-of-function variants in AGTR1 gene leading to RTD, which is characterized by high mortality rate at birth or during the neonatal period. Furthermore, we provide a comprehensive review of previously reported variants in the AGTR1 gene, which is the least encountered genetic cause of RTD, along with their associated clinical features.

Keywords: AGTR1; Middle East; Rare Mendelian disease; Renal tubular dysgenesis; Whole genome sequencing.

© 2024. The Author(s).

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• NPRP11S-0110-180250/Qatar National Research Fund