research paper layout

Want to create or adapt books like this? Learn more about how Pressbooks supports open publishing practices.

13.1 Formatting a Research Paper

Learning objectives.

• Identify the major components of a research paper written using American Psychological Association (APA) style.
• Apply general APA style and formatting conventions in a research paper.

In this chapter, you will learn how to use APA style , the documentation and formatting style followed by the American Psychological Association, as well as MLA style , from the Modern Language Association. There are a few major formatting styles used in academic texts, including AMA, Chicago, and Turabian:

• AMA (American Medical Association) for medicine, health, and biological sciences
• APA (American Psychological Association) for education, psychology, and the social sciences
• Chicago—a common style used in everyday publications like magazines, newspapers, and books
• MLA (Modern Language Association) for English, literature, arts, and humanities
• Turabian—another common style designed for its universal application across all subjects and disciplines

While all the formatting and citation styles have their own use and applications, in this chapter we focus our attention on the two styles you are most likely to use in your academic studies: APA and MLA.

If you find that the rules of proper source documentation are difficult to keep straight, you are not alone. Writing a good research paper is, in and of itself, a major intellectual challenge. Having to follow detailed citation and formatting guidelines as well may seem like just one more task to add to an already-too-long list of requirements.

Following these guidelines, however, serves several important purposes. First, it signals to your readers that your paper should be taken seriously as a student’s contribution to a given academic or professional field; it is the literary equivalent of wearing a tailored suit to a job interview. Second, it shows that you respect other people’s work enough to give them proper credit for it. Finally, it helps your reader find additional materials if he or she wishes to learn more about your topic.

Furthermore, producing a letter-perfect APA-style paper need not be burdensome. Yes, it requires careful attention to detail. However, you can simplify the process if you keep these broad guidelines in mind:

• Work ahead whenever you can. Chapter 11 “Writing from Research: What Will I Learn?” includes tips for keeping track of your sources early in the research process, which will save time later on.
• Get it right the first time. Apply APA guidelines as you write, so you will not have much to correct during the editing stage. Again, putting in a little extra time early on can save time later.
• Use the resources available to you. In addition to the guidelines provided in this chapter, you may wish to consult the APA website at http://www.apa.org or the Purdue University Online Writing lab at http://owl.english.purdue.edu , which regularly updates its online style guidelines.

General Formatting Guidelines

This chapter provides detailed guidelines for using the citation and formatting conventions developed by the American Psychological Association, or APA. Writers in disciplines as diverse as astrophysics, biology, psychology, and education follow APA style. The major components of a paper written in APA style are listed in the following box.

These are the major components of an APA-style paper:

Body, which includes the following:

• Headings and, if necessary, subheadings to organize the content
• In-text citations of research sources
• References page

All these components must be saved in one document, not as separate documents.

The title page of your paper includes the following information:

• Title of the paper
• Author’s name
• Name of the institution with which the author is affiliated
• Header at the top of the page with the paper title (in capital letters) and the page number (If the title is lengthy, you may use a shortened form of it in the header.)

List the first three elements in the order given in the previous list, centered about one third of the way down from the top of the page. Use the headers and footers tool of your word-processing program to add the header, with the title text at the left and the page number in the upper-right corner. Your title page should look like the following example.

The next page of your paper provides an abstract , or brief summary of your findings. An abstract does not need to be provided in every paper, but an abstract should be used in papers that include a hypothesis. A good abstract is concise—about one hundred fifty to two hundred fifty words—and is written in an objective, impersonal style. Your writing voice will not be as apparent here as in the body of your paper. When writing the abstract, take a just-the-facts approach, and summarize your research question and your findings in a few sentences.

In Chapter 12 “Writing a Research Paper” , you read a paper written by a student named Jorge, who researched the effectiveness of low-carbohydrate diets. Read Jorge’s abstract. Note how it sums up the major ideas in his paper without going into excessive detail.

Write an abstract summarizing your paper. Briefly introduce the topic, state your findings, and sum up what conclusions you can draw from your research. Use the word count feature of your word-processing program to make sure your abstract does not exceed one hundred fifty words.

Depending on your field of study, you may sometimes write research papers that present extensive primary research, such as your own experiment or survey. In your abstract, summarize your research question and your findings, and briefly indicate how your study relates to prior research in the field.

Margins, Pagination, and Headings

APA style requirements also address specific formatting concerns, such as margins, pagination, and heading styles, within the body of the paper. Review the following APA guidelines.

Use these general guidelines to format the paper:

• Set the top, bottom, and side margins of your paper at 1 inch.
• Use double-spaced text throughout your paper.
• Use a standard font, such as Times New Roman or Arial, in a legible size (10- to 12-point).
• Use continuous pagination throughout the paper, including the title page and the references section. Page numbers appear flush right within your header.
• Section headings and subsection headings within the body of your paper use different types of formatting depending on the level of information you are presenting. Additional details from Jorge’s paper are provided.

Begin formatting the final draft of your paper according to APA guidelines. You may work with an existing document or set up a new document if you choose. Include the following:

• Your title page
• The abstract you created in Note 13.8 “Exercise 1”
• Correct headers and page numbers for your title page and abstract

APA style uses section headings to organize information, making it easy for the reader to follow the writer’s train of thought and to know immediately what major topics are covered. Depending on the length and complexity of the paper, its major sections may also be divided into subsections, sub-subsections, and so on. These smaller sections, in turn, use different heading styles to indicate different levels of information. In essence, you are using headings to create a hierarchy of information.

The following heading styles used in APA formatting are listed in order of greatest to least importance:

• Section headings use centered, boldface type. Headings use title case, with important words in the heading capitalized.
• Subsection headings use left-aligned, boldface type. Headings use title case.
• The third level uses left-aligned, indented, boldface type. Headings use a capital letter only for the first word, and they end in a period.
• The fourth level follows the same style used for the previous level, but the headings are boldfaced and italicized.
• The fifth level follows the same style used for the previous level, but the headings are italicized and not boldfaced.

Visually, the hierarchy of information is organized as indicated in Table 13.1 “Section Headings” .

Table 13.1 Section Headings

A college research paper may not use all the heading levels shown in Table 13.1 “Section Headings” , but you are likely to encounter them in academic journal articles that use APA style. For a brief paper, you may find that level 1 headings suffice. Longer or more complex papers may need level 2 headings or other lower-level headings to organize information clearly. Use your outline to craft your major section headings and determine whether any subtopics are substantial enough to require additional levels of headings.

Working with the document you developed in Note 13.11 “Exercise 2” , begin setting up the heading structure of the final draft of your research paper according to APA guidelines. Include your title and at least two to three major section headings, and follow the formatting guidelines provided above. If your major sections should be broken into subsections, add those headings as well. Use your outline to help you.

Because Jorge used only level 1 headings, his Exercise 3 would look like the following:

Citation Guidelines

In-text citations.

Throughout the body of your paper, include a citation whenever you quote or paraphrase material from your research sources. As you learned in Chapter 11 “Writing from Research: What Will I Learn?” , the purpose of citations is twofold: to give credit to others for their ideas and to allow your reader to follow up and learn more about the topic if desired. Your in-text citations provide basic information about your source; each source you cite will have a longer entry in the references section that provides more detailed information.

In-text citations must provide the name of the author or authors and the year the source was published. (When a given source does not list an individual author, you may provide the source title or the name of the organization that published the material instead.) When directly quoting a source, it is also required that you include the page number where the quote appears in your citation.

This information may be included within the sentence or in a parenthetical reference at the end of the sentence, as in these examples.

Epstein (2010) points out that “junk food cannot be considered addictive in the same way that we think of psychoactive drugs as addictive” (p. 137).

Here, the writer names the source author when introducing the quote and provides the publication date in parentheses after the author’s name. The page number appears in parentheses after the closing quotation marks and before the period that ends the sentence.

Addiction researchers caution that “junk food cannot be considered addictive in the same way that we think of psychoactive drugs as addictive” (Epstein, 2010, p. 137).

Here, the writer provides a parenthetical citation at the end of the sentence that includes the author’s name, the year of publication, and the page number separated by commas. Again, the parenthetical citation is placed after the closing quotation marks and before the period at the end of the sentence.

As noted in the book Junk Food, Junk Science (Epstein, 2010, p. 137), “junk food cannot be considered addictive in the same way that we think of psychoactive drugs as addictive.”

Here, the writer chose to mention the source title in the sentence (an optional piece of information to include) and followed the title with a parenthetical citation. Note that the parenthetical citation is placed before the comma that signals the end of the introductory phrase.

David Epstein’s book Junk Food, Junk Science (2010) pointed out that “junk food cannot be considered addictive in the same way that we think of psychoactive drugs as addictive” (p. 137).

Another variation is to introduce the author and the source title in your sentence and include the publication date and page number in parentheses within the sentence or at the end of the sentence. As long as you have included the essential information, you can choose the option that works best for that particular sentence and source.

Citing a book with a single author is usually a straightforward task. Of course, your research may require that you cite many other types of sources, such as books or articles with more than one author or sources with no individual author listed. You may also need to cite sources available in both print and online and nonprint sources, such as websites and personal interviews. Chapter 13 “APA and MLA Documentation and Formatting” , Section 13.2 “Citing and Referencing Techniques” and Section 13.3 “Creating a References Section” provide extensive guidelines for citing a variety of source types.

Writing at Work

APA is just one of several different styles with its own guidelines for documentation, formatting, and language usage. Depending on your field of interest, you may be exposed to additional styles, such as the following:

• MLA style. Determined by the Modern Languages Association and used for papers in literature, languages, and other disciplines in the humanities.
• Chicago style. Outlined in the Chicago Manual of Style and sometimes used for papers in the humanities and the sciences; many professional organizations use this style for publications as well.
• Associated Press (AP) style. Used by professional journalists.

References List

The brief citations included in the body of your paper correspond to the more detailed citations provided at the end of the paper in the references section. In-text citations provide basic information—the author’s name, the publication date, and the page number if necessary—while the references section provides more extensive bibliographical information. Again, this information allows your reader to follow up on the sources you cited and do additional reading about the topic if desired.

The specific format of entries in the list of references varies slightly for different source types, but the entries generally include the following information:

• The name(s) of the author(s) or institution that wrote the source
• The year of publication and, where applicable, the exact date of publication
• The full title of the source
• For books, the city of publication
• For articles or essays, the name of the periodical or book in which the article or essay appears
• For magazine and journal articles, the volume number, issue number, and pages where the article appears
• For sources on the web, the URL where the source is located

The references page is double spaced and lists entries in alphabetical order by the author’s last name. If an entry continues for more than one line, the second line and each subsequent line are indented five spaces. Review the following example. ( Chapter 13 “APA and MLA Documentation and Formatting” , Section 13.3 “Creating a References Section” provides extensive guidelines for formatting reference entries for different types of sources.)

In APA style, book and article titles are formatted in sentence case, not title case. Sentence case means that only the first word is capitalized, along with any proper nouns.

Key Takeaways

• Following proper citation and formatting guidelines helps writers ensure that their work will be taken seriously, give proper credit to other authors for their work, and provide valuable information to readers.
• Working ahead and taking care to cite sources correctly the first time are ways writers can save time during the editing stage of writing a research paper.
• APA papers usually include an abstract that concisely summarizes the paper.
• APA papers use a specific headings structure to provide a clear hierarchy of information.
• In APA papers, in-text citations usually include the name(s) of the author(s) and the year of publication.
• In-text citations correspond to entries in the references section, which provide detailed bibliographical information about a source.

Writing for Success Copyright © 2015 by University of Minnesota is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License , except where otherwise noted.

How to format a research paper

Last updated

7 February 2023

Reviewed by

Miroslav Damyanov

Writing a research paper can be daunting if you’re not experienced with the process. Getting the proper format is one of the most challenging aspects of the task. Reviewers will immediately dismiss a paper that doesn't comply with standard formatting, regardless of the valuable content it contains. 

In this article, we'll delve into the essential characteristics of a research paper, including the proper formatting.

Make research less tedious

Dovetail streamlines research to help you uncover and share actionable insights

• What is a research paper?

A research paper is a document that provides a thorough analysis of a topic , usually for an academic institution or professional organization. A research paper may be of any length, but they are typically 2,000–10,000 words. 

Unlike less formal papers, such as articles or essays, empirical evidence and data are key to research papers. In addition to students handing in papers, scientists, attorneys, medical researchers, and independent scholars may need to produce research papers.

People typically write research papers to prove a particular point or make an argument. This could support or disprove a theoretical point, legal case, scientific theory, or an existing piece of research on any topic. 

One of the distinguishing characteristics of research papers is that they contain citations to prior research. Citing sources using the correct format is essential for creating a legitimate research paper. 

• Top considerations for writing a research paper

To write a research paper, you must consider several factors. Fields such as the sciences, humanities, and technical professions have certain criteria for writing research papers. 

You’ll write a research paper using one of several types of formatting. These include APA, MLA, and CMOS styles, which we’ll cover in detail to guide you on citations and other formatting rules. 

Specific requirements of the assignment

If the paper is for a college, university, or any specific organization, they’ll give you certain requirements, such as the range of topics, length, and formatting requirements.

You should study the specifics of the assignment carefully, as these will override more general guidelines you may find elsewhere. If you're writing for a particular professor, they may ask for single or double spacing or a certain citation style. 

• Components of a research paper

Here are the basic steps to writing a quality research paper, assuming you've chosen your topic and considered the requirements of the paper. Depending on the specific conditions of the paper you're writing, you may need the following elements:

Thesis statement

The thesis statement provides a blueprint for the paper. It conveys the theme and purpose of the paper. It also informs you and readers what your paper will argue and the type of research it will contain. As you write the paper, you can refer to the thesis statement to help you decide whether or not to include certain items.

Most research papers require an abstract as well as a thesis. While the thesis is a short (usually a single sentence) summary of the work, an abstract contains more detail. Many papers use the IMRaD structure for the abstract, especially in scientific fields. This consists of four elements:

Introduction : Summarize the purpose of the paper

Methods : Describe the research methods (e.g., collecting data , interviews , field research)

Results: Summarize your conclusions.  

Discussion: Discuss the implications of your research. Mention any significant limitations to your approach and suggest areas for further research.

The thesis and abstract come at the beginning of a paper, but you should write them after completing the paper. This approach ensures a clear idea of your main topic and argument, which can evolve as you write the paper.

Table of contents

Like most nonfiction books, a research paper usually includes a table of contents. 

Tables, charts, and illustrations

If your paper contains multiple tables, charts, illustrations, or other graphics, you can create a list of these. 

Works cited or reference page

This page lists all the works you cited in your paper. For MLA and APA styles, you will use in-text citations in the body of the paper. For Chicago (CMOS) style, you'll use footnotes. 

Bibliography

While you use a reference page to note all cited papers, a bibliography lists all the works you consulted in your research, even if you don't specifically cite them. 

While references are essential, a bibliography is optional but usually advisable to demonstrate the breadth of your research.

Dedication and acknowledgments

You may include a dedication or acknowledgments at the beginning of the paper directly after the title page and before the abstract.

• Steps for writing a research paper

These are the most critical steps for researching, writing, and formatting a research paper:

Create an outline

The outline is not part of the published paper; it’s for your use. An outline makes it easier to structure the paper, ensuring you include all necessary points and research. 

Here you can list all topics and subtopics that will support your argument. When doing your research, you can refer to the outline to ensure you include everything. 

Gather research

Solid research is the hallmark of a research paper. In addition to accumulating research, you need to present it clearly. However, gathering research is one of the first tasks. If you compile each piece of research correctly, it will be easier to format the paper correctly. You want to avoid having to go back and look up information constantly.

Start by skimming potentially useful sources and putting them aside for later use. Reading each source thoroughly at this stage will be time-consuming and slow your progress. You can thoroughly review the sources to decide what to include and discard later. At this stage, note essential information such as names, dates, page numbers, and website links. Citing sources will be easier when you’ve written all the information down.

Be aware of the quality of your sources. A research paper should reference scholarly, academic, or scientific journals. It’s vital to understand the difference between primary and secondary sources. 

A primary source is an original, firsthand account of a topic. A secondary source is someone else covering the topic, as in a popular article or interview. While you may include secondary sources, your paper should also include primary research . Online research can be convenient, but you need to be extra careful when assessing the quality of your sources.

Write the first draft

Create a first draft where you put together all your research and address the topic described in your thesis and abstract. 

Edit and format the paper

Proofread, edit, and make any necessary adjustments and improvements to the first draft. List your citations as described below. Ensure your thesis and abstract describe your research accurately. 

• Formatting a research paper: MLA, APA, and CMOS styles

There are several popular formats for research papers: MLA (Modern Language Association) and APA (American Psychological Association). Certain academic papers use CMOS (Chicago Manual of Style). Other formats may apply to particular fields. 

For example, medical research may use AMA (American Medical Association) formatting and IEEE (Institute of Electrical and Electronics Engineers) for particular technical papers. The following are the guidelines and examples of the most popular formats:

The humanities typically use MLA format, including literature, history, and culture. Look over examples of papers created in MLA format . Here are the main rules to keep in mind:

Double-spaced lines.

Indent new paragraphs 1/2 inch.

Title case for headings, where all major words are capitalized, as in "How to Write a Research Paper." 

Use a popular font such as Times New Roman. This applies to all formatting styles.

Use one-inch margins on all sides. 

Number sections of the paper using Arabic numerals (1, 2, 3, etc.). 

Use a running head for each page on the upper right-hand corner, which consists of your last name and the page number.

Use an in-text citation within the text, using the author's last name followed by the page number: "Anything worth dying for is certainly worth living for" (Heller 155).  

On the citations page, list the full name, book or periodical, and other information. For MLA, you will not need footnotes, only in-text citations.

List citations in alphabetical order on a separate page at the end of the paper entitled “Works Cited.” 

Continuing with the above example from Heller, the listing would be: Heller, Joseph. Catch-22, Simon & Schuster, 1961.

For a periodical, the format is "Thompson, Hunter S. "The Kentucky Derby is Decadent and Depraved" Scanlon's, June 1970."

Use title case for source titles, as in "On the Origin of Species."

The sciences typically use APA format, including physical sciences such as physics and social sciences such as psychology. Simply Psychology provides examples of APA formatting . The following are the most important rules of the APA format.

Begin the paper with a title page, which is not required for MLA.

Use double-line spacing.

Use a running head for each page in the upper right-hand corner, which consists of the paper's title in capital letters followed by the page number.

The citations page at the end should be titled "References."

In-text citations should include the publication date: (Smith, 1999, p. 50). Note also that there's a "p" for "page," whereas in MLA, you write the page number without a "p."

As with MLA, use title case for headings, as in "Most Popular Treatments for Cognitive Disorders."

Use sentence case for titles of sources, as in "History of the decline and fall of the Roman empire." Note "Roman" starts with a capital because it's a proper noun.  

When citing in-text references, use the author's last name and the first and middle initials. 

Always use the Oxford comma. This comma goes before the words "or" and "and" in a list. For example, "At the store, I bought oranges, paper towels, and pasta."

CMOS formatting

Book publishers and many academic papers use CMOS formatting based on the Chicago Manual of Style. CMOS is also called Turabian, named after Kate L. Turabian, who wrote the first manual for this style. Here are examples of CMOS style formatting and citations.

Include an unnumbered title page.

Place page numbers on the upper right-hand corner of the page. Do not list your name or the paper's title as you would for MLA or APA styles.

Use title case for both headings and sources (same as MLA).

Unlike MLA and APA, the Chicago style uses footnotes for citations. Use a superscript for footnotes: "Smith argues against Jones' theory¹.” Footnotes may appear at the bottom of the page or the end of the document.  

CMOS supports both short notes and full notes. In most cases, you'll use the full note: "Michael Pollan, The Omnivore's Dilemma: A Natural History of Four Meals (New York: Penguin, 2006), 76." For further references to the same source, use a short note: " Pollan, Omnivore's Dilemma, 45." The requirements of some papers may specify using only short notes for all footnotes.

• General guidelines for writing and formatting research papers

Keep these guidelines in mind for all types of research papers:

Initial formatting

As you create your first draft, don't worry about formatting. If you try to format it perfectly as you write the paper, it will be difficult to progress and develop a flow of thought. With the first draft, you don't have to be concerned about ordering the sections. You can rearrange headings and sections later. 

Citation tools

Use automation tools for citations . Some useful tools make citations easier by automatically generating a citation list and bibliography. Many work with APA, MLA, and CMOS styles.

Check for plagiarism

Use a plagiarism detector to make sure your paper isn't unintentionally plagiarizing. There are many free and paid plagiarism checkers online, such as Grammarly. 

Proofread your work

Do several rounds of editing and proofreading. Editing is necessary for any type of writing, but you’ll need to revisit several distinct areas with a research paper:

Check for spelling and grammatical errors.

Read the paper to make sure it's well-argued and that you’ve organized it properly. 

Check that you’ve correctly formatted citations. It's easy to make errors, such as incorrect numbering of footnotes (e.g., Chicago style) or forgetting to include a source on your citations page.

Get started today

Go from raw data to valuable insights with a flexible research platform

Editor’s picks

Last updated: 21 December 2023

Last updated: 16 December 2023

Last updated: 6 October 2023

Last updated: 25 November 2023

Last updated: 12 May 2023

Last updated: 15 February 2024

Last updated: 11 March 2024

Last updated: 12 December 2023

Last updated: 18 May 2023

Last updated: 6 March 2024

Last updated: 10 April 2023

Last updated: 20 December 2023

Latest articles

Related topics, log in or sign up.

Get started for free

APA Style (7th ed.)

• Cite: Why? When?
• Book, eBook, Dissertation
• Article or Report
• Business Sources
• Artificial Intelligence (AI) Tools
• In-Text Citation
• Format Your Paper

Format Your Paper

Download and use the editable templates for student papers below: .

• APA 7th ed. Template Document This is an APA format template document in Google Docs. Click on the link -- it will ask for you to make a new copy of the document, which you can save in your own Google Drive with your preferred privacy settings.
• APA 7th ed. Template Document A Microsoft Word document formatted correctly according to APA 7th edition.
• APA 7th ed. Annotated Bibliography template A Microsoft Word document formatted correctly for an annotated bibliography.

Or, view the directions for specific sections below:

Order of sections (section 2.17).

• Title page including Title, Author, University and Department, Class, Instructor, and Date
• Body (including introduction, literature review or background, discussion, and conclusion)
• Appendices (including tables & figures)

Margins & Page Numbers (sections 2.22-2.24)

• 1 inch at top, bottom, and both sides
• Left aligned paragraphs and leave the right edge ragged (not "right justified")
• Indent first line of each paragraph 1/2 inch from left margin
• Use page numbers, including on the title page, 1/2 inch from top and flush with right margin

Text Format (section 2.19)

• Times New Roman, 12 point
• Calibri, 11 point
• Arial, 11 point
• Lucinda Sans Unicode, 10 point
• Georgia, 11 point
• Double-space and align text to the left
• Use active voice
• Don't overuse technical jargon
• No periods after a web address or DOI in the References list.

Tables and Figures In-Text (chapter 7)

• Label tables and figures numerically (ex. Table 1)
• Give each table column a heading and use separating lines only when necessary
• Design the table and figure so that it can be understood on its own, i.e. it does not require reference to the surrounding text to understand it
• Notes go below tables and figures

Title Page (section 2.3)

• Include the title, your name,  the class name , and  the college's name
• Title should be 12 words or less and summarize the paper's main idea
• No periods or abbreviations
• Do not italicize or underline
• No quotation marks, all capital letters, or bold
• Center horizontally in upper half of the page

Body (section 2.11)

• Align the text to the left with a 1/2-inch left indent on the first line
• Double-space
• As long as there is no Abstract, at the top of the first page, type the title of the paper, centered, in bold , and in Sentence Case Capitalization
• Usually, include sections like these:  introduction, literature review or background,  discussion, and conclusion -- but the specific organization will depend on the paper type
• Spell out long organization names and add the abbreviation in parenthesis, then just use the abbreviation
• Spell out numbers one through nine and use a number for 10 or more
• Use a number for units of measurement, in tables, to represent statistical or math functions, and dates or times

Headings (section 2.26-2.27)

• Level 1: Center, bold , Title Case 
• Level 2: Align left, bold , Title Case
• Level 3: Alight left, bold italics , Title Case
• Level 4: Indented 1/2", bold , Title Case, end with a period. Follow with text. 
• Level 5: Indented 1/2", bold italics , Title Case, end with a period. Follow with text. 

Quotations (sections 8.26-8.33)

• Include short quotations (40 words or less) in-text with quotation marks
• For quotes more than 40 words, indent the entire quote a half inch from the left margin and double-space it with no quotation marks
• When quoting two or more paragraphs from an original source, indent the first line of each paragraph a half inch from the left margin
• Use ellipsis (...) when omitting sections from a quote and use four periods (....) if omitting the end section of a quote

References (section 2.12)

Begins on a new page following the text of your paper and includes complete citations for the resources you've used in your writing.

• References should be centered and bolded at the top of a new page
• Double-space and use hanging indents (where the first line is on the left margin and the following lines are indented a half inch from the left)
• List authors' last name first followed by the first and middle initials (ex. Skinner, B. F.)
• Alphabetize the list by the first author's last name of of each citation (see sections 9.44-9.49)
• Capitalize only the first word, the first after a colon or em dash, and proper nouns
• Don't capitalize the second word of a hyphenated compound
• No quotation marks around titles of articles

Appendices with Tables, Figures, & Illustrations (section 2.14, and chapter 7)

• Include appendices only to help the reader understand, evaluate, or replicate the study or argument
• Put each appendix on a separate page and align left
• For text, do not indent the first paragraph, but do indent the rest
• If you have only one appendix, label it "Appendix"
• If you have two or more appendices, label them "Appendix A", "Appendix B" and so forth as they appear in the body of your paper
• Label tables and figures numerically (ex. Table 1, or Table B1 and Table B2 if Appendix B has two tables) and describe them within the text of the appendix
• Notes go below tables and figures (see samples on p. 210-226)

Annotated Bibliography

Double-space the entire bibliography. give each entry a hanging indent. in the following annotation, indent the entire paragraph a half inch from the left margin and give the first line of each paragraph a half inch indent. see the template document at the top of this page..

• Check with your professor for the length of the annotation and which elements you should evaluate.

These elements are optional, if your professor or field requires them, but they are  not required for student papers: 

Abstract (section 2.9).

• Abstract gets its own page
• Center "Abstract" heading and do not indent the first line of the text
• Summarize the main points and purpose of the paper in 150-250 words maximum
• Define abbreviations and acronyms used in the paper

Running Head (section 2.8 )

• Shorten title to 50 characters or less (counting spaces and punctuation) for the running head
• In the top margin, the running head is aligned left, with the page number aligned on the right
• On every page, put (without the brackets): [SHORTENED TITLE OF YOUR PAPER IN ALL CAPS] [page number] 

More questions? Check out the authoritative source: APA style blog

• << Previous: In-Text Citation
• Last Updated: Apr 16, 2024 3:02 PM
• URL: https://libguides.uww.edu/apa

What’s Included: Research Paper Template

If you’re preparing to write an academic research paper, our free research paper template is the perfect starting point. In the template, we cover every section step by step, with clear, straightforward explanations and examples .

The template’s structure is based on the tried and trusted best-practice format for formal academic research papers. The template structure reflects the overall research process, ensuring your paper will have a smooth, logical flow from chapter to chapter.

The research paper template covers the following core sections:

• The title page/cover page
• Abstract (sometimes also called the executive summary)
• Section 1: Introduction 
• Section 2: Literature review 
• Section 3: Methodology
• Section 4: Findings /results
• Section 5: Discussion
• Section 6: Conclusion
• Reference list

Each section is explained in plain, straightforward language , followed by an overview of the key elements that you need to cover within each section. We’ve also included links to free resources to help you understand how to write each section.

The cleanly formatted Google Doc can be downloaded as a fully editable MS Word Document (DOCX format), so you can use it as-is or convert it to LaTeX.

FAQs: Research Paper Template

What format is the template (doc, pdf, ppt, etc.).

The research paper template is provided as a Google Doc. You can download it in MS Word format or make a copy to your Google Drive. You’re also welcome to convert it to whatever format works best for you, such as LaTeX or PDF.

What types of research papers can this template be used for?

The template follows the standard best-practice structure for formal academic research papers, so it is suitable for the vast majority of degrees, particularly those within the sciences.

Some universities may have some additional requirements, but these are typically minor, with the core structure remaining the same. Therefore, it’s always a good idea to double-check your university’s requirements before you finalise your structure.

Is this template for an undergrad, Masters or PhD-level research paper?

This template can be used for a research paper at any level of study. It may be slight overkill for an undergraduate-level study, but it certainly won’t be missing anything.

How long should my research paper be?

This depends entirely on your university’s specific requirements, so it’s best to check with them. We include generic word count ranges for each section within the template, but these are purely indicative. 

What about the research proposal?

If you’re still working on your research proposal, we’ve got a template for that here .

We’ve also got loads of proposal-related guides and videos over on the Grad Coach blog .

How do I write a literature review?

We have a wealth of free resources on the Grad Coach Blog that unpack how to write a literature review from scratch. You can check out the literature review section of the blog here.

How do I create a research methodology?

We have a wealth of free resources on the Grad Coach Blog that unpack research methodology, both qualitative and quantitative. You can check out the methodology section of the blog here.

Can I share this research paper template with my friends/colleagues?

Yes, you’re welcome to share this template. If you want to post about it on your blog or social media, all we ask is that you reference this page as your source.

Can Grad Coach help me with my research paper?

Within the template, you’ll find plain-language explanations of each section, which should give you a fair amount of guidance. However, you’re also welcome to consider our private coaching services .

Reference management. Clean and simple.

Getting started with your research paper outline

Levels of organization for a research paper outline

First level of organization, second level of organization, third level of organization, fourth level of organization, tips for writing a research paper outline, research paper outline template, my research paper outline is complete: what are the next steps, frequently asked questions about a research paper outline, related articles.

The outline is the skeleton of your research paper. Simply start by writing down your thesis and the main ideas you wish to present. This will likely change as your research progresses; therefore, do not worry about being too specific in the early stages of writing your outline.

A research paper outline typically contains between two and four layers of organization. The first two layers are the most generalized. Each layer thereafter will contain the research you complete and presents more and more detailed information.

The levels are typically represented by a combination of Roman numerals, Arabic numerals, uppercase letters, lowercase letters but may include other symbols. Refer to the guidelines provided by your institution, as formatting is not universal and differs between universities, fields, and subjects. If you are writing the outline for yourself, you may choose any combination you prefer.

This is the most generalized level of information. Begin by numbering the introduction, each idea you will present, and the conclusion. The main ideas contain the bulk of your research paper 's information. Depending on your research, it may be chapters of a book for a literature review , a series of dates for a historical research paper, or the methods and results of a scientific paper.

I. Introduction

II. Main idea

III. Main idea

IV. Main idea

V. Conclusion

The second level consists of topics which support the introduction, main ideas, and the conclusion. Each main idea should have at least two supporting topics listed in the outline.

If your main idea does not have enough support, you should consider presenting another main idea in its place. This is where you should stop outlining if this is your first draft. Continue your research before adding to the next levels of organization.

• A. Background information
• B. Hypothesis or thesis
• A. Supporting topic
• B. Supporting topic

The third level of organization contains supporting information for the topics previously listed. By now, you should have completed enough research to add support for your ideas.

The Introduction and Main Ideas may contain information you discovered about the author, timeframe, or contents of a book for a literature review; the historical events leading up to the research topic for a historical research paper, or an explanation of the problem a scientific research paper intends to address.

• 1. Relevant history
• 2. Relevant history
• 1. The hypothesis or thesis clearly stated
• 1. A brief description of supporting information
• 2. A brief description of supporting information

The fourth level of organization contains the most detailed information such as quotes, references, observations, or specific data needed to support the main idea. It is not typical to have further levels of organization because the information contained here is the most specific.

• a) Quotes or references to another piece of literature
• b) Quotes or references to another piece of literature

Tip: The key to creating a useful outline is to be consistent in your headings, organization, and levels of specificity.

• Be Consistent : ensure every heading has a similar tone. State the topic or write short sentences for each heading but avoid doing both.
• Organize Information : Higher levels of organization are more generally stated and each supporting level becomes more specific. The introduction and conclusion will never be lower than the first level of organization.
• Build Support : Each main idea should have two or more supporting topics. If your research does not have enough information to support the main idea you are presenting, you should, in general, complete additional research or revise the outline.

By now, you should know the basic requirements to create an outline for your paper. With a content framework in place, you can now start writing your paper . To help you start right away, you can use one of our templates and adjust it to suit your needs.

After completing your outline, you should:

• Title your research paper . This is an iterative process and may change when you delve deeper into the topic.
• Begin writing your research paper draft . Continue researching to further build your outline and provide more information to support your hypothesis or thesis.
• Format your draft appropriately . MLA 8 and APA 7 formats have differences between their bibliography page, in-text citations, line spacing, and title.
• Finalize your citations and bibliography . Use a reference manager like Paperpile to organize and cite your research.
• Write the abstract, if required . An abstract will briefly state the information contained within the paper, results of the research, and the conclusion.

An outline is used to organize written ideas about a topic into a logical order. Outlines help us organize major topics, subtopics, and supporting details. Researchers benefit greatly from outlines while writing by addressing which topic to cover in what order.

The most basic outline format consists of: an introduction, a minimum of three topic paragraphs, and a conclusion.

You should make an outline before starting to write your research paper. This will help you organize the main ideas and arguments you want to present in your topic.

• Consistency: ensure every heading has a similar tone. State the topic or write short sentences for each heading but avoid doing both.
• Organization : Higher levels of organization are more generally stated and each supporting level becomes more specific. The introduction and conclusion will never be lower than the first level of organization.
• Support : Each main idea should have two or more supporting topics. If your research does not have enough information to support the main idea you are presenting, you should, in general, complete additional research or revise the outline.

• Privacy Policy

Home » Research Paper Outline – Types, Example, Template

Research Paper Outline – Types, Example, Template

Table of Contents

By creating a well-structured research paper outline, writers can easily organize their thoughts and ideas and ensure that their final paper is clear, concise, and effective. In this article, we will explore the essential components of a research paper outline and provide some tips and tricks for creating a successful one.

Research Paper Outline

Research paper outline is a plan or a structural framework that organizes the main ideas , arguments, and supporting evidence in a logical sequence. It serves as a blueprint or a roadmap for the writer to follow while drafting the actual research paper .

Typically, an outline consists of the following elements:

• Introduction : This section presents the topic, research question , and thesis statement of the paper. It also provides a brief overview of the literature review and the methodology used.
• Literature Review: This section provides a comprehensive review of the relevant literature, theories, and concepts related to the research topic. It analyzes the existing research and identifies the research gaps and research questions.
• Methodology: This section explains the research design, data collection methods, data analysis, and ethical considerations of the study.
• Results: This section presents the findings of the study, using tables, graphs, and statistics to illustrate the data.
• Discussion : This section interprets the results of the study, and discusses their implications, significance, and limitations. It also suggests future research directions.
• Conclusion : This section summarizes the main findings of the study and restates the thesis statement.
• References: This section lists all the sources cited in the paper using the appropriate citation style.

Research Paper Outline Types

There are several types of outlines that can be used for research papers, including:

Alphanumeric Outline

This is a traditional outline format that uses Roman numerals, capital letters, Arabic numerals, and lowercase letters to organize the main ideas and supporting details of a research paper. It is commonly used for longer, more complex research papers.

I. Introduction

• A. Background information
• B. Thesis statement
• 1 1. Supporting detail
• 1 2. Supporting detail 2
• 2 1. Supporting detail

III. Conclusion

• A. Restate thesis
• B. Summarize main points

Decimal Outline

This outline format uses numbers to organize the main ideas and supporting details of a research paper. It is similar to the alphanumeric outline, but it uses only numbers and decimals to indicate the hierarchy of the ideas.

• 1.1 Background information
• 1.2 Thesis statement
• 1 2.1.1 Supporting detail
• 1 2.1.2 Supporting detail
• 2 2.2.1 Supporting detail
• 1 2.2.2 Supporting detail
• 3.1 Restate thesis
• 3.2 Summarize main points

Full Sentence Outline

This type of outline uses complete sentences to describe the main ideas and supporting details of a research paper. It is useful for those who prefer to see the entire paper outlined in complete sentences.

• Provide background information on the topic
• State the thesis statement
• Explain main idea 1 and provide supporting details
• Discuss main idea 2 and provide supporting details
• Restate the thesis statement
• Summarize the main points of the paper

Topic Outline

This type of outline uses short phrases or words to describe the main ideas and supporting details of a research paper. It is useful for those who prefer to see a more concise overview of the paper.

• Background information
• Thesis statement
• Supporting detail 1
• Supporting detail 2
• Restate thesis
• Summarize main points

Reverse Outline

This is an outline that is created after the paper has been written. It involves going back through the paper and summarizing each paragraph or section in one sentence. This can be useful for identifying gaps in the paper or areas that need further development.

• Introduction : Provides background information and states the thesis statement.
• Paragraph 1: Discusses main idea 1 and provides supporting details.
• Paragraph 2: Discusses main idea 2 and provides supporting details.
• Paragraph 3: Addresses potential counterarguments.
• Conclusion : Restates thesis and summarizes main points.

Mind Map Outline

This type of outline involves creating a visual representation of the main ideas and supporting details of a research paper. It can be useful for those who prefer a more creative and visual approach to outlining.

• Supporting detail 1: Lack of funding for public schools.
• Supporting detail 2: Decrease in government support for education.
• Supporting detail 1: Increase in income inequality.
• Supporting detail 2: Decrease in social mobility.

Research Paper Outline Example

Research Paper Outline Example on Cyber Security:

A. Overview of Cybersecurity

• B. Importance of Cybersecurity
• C. Purpose of the paper

II. Cyber Threats

A. Definition of Cyber Threats

• B. Types of Cyber Threats
• C. Examples of Cyber Threats

III. Cybersecurity Measures

A. Prevention measures

• Anti-virus software
• Encryption B. Detection measures
• Intrusion Detection System (IDS)
• Security Information and Event Management (SIEM)
• Security Operations Center (SOC) C. Response measures
• Incident Response Plan
• Business Continuity Plan
• Disaster Recovery Plan

IV. Cybersecurity in the Business World

A. Overview of Cybersecurity in the Business World

B. Cybersecurity Risk Assessment

C. Best Practices for Cybersecurity in Business

V. Cybersecurity in Government Organizations

A. Overview of Cybersecurity in Government Organizations

C. Best Practices for Cybersecurity in Government Organizations

VI. Cybersecurity Ethics

A. Definition of Cybersecurity Ethics

B. Importance of Cybersecurity Ethics

C. Examples of Cybersecurity Ethics

VII. Future of Cybersecurity

A. Overview of the Future of Cybersecurity

B. Emerging Cybersecurity Threats

C. Advancements in Cybersecurity Technology

VIII. Conclusion

A. Summary of the paper

B. Recommendations for Cybersecurity

• C. Conclusion.

IX. References

A. List of sources cited in the paper

B. Bibliography of additional resources

Introduction

Cybersecurity refers to the protection of computer systems, networks, and sensitive data from unauthorized access, theft, damage, or any other form of cyber attack. B. Importance of Cybersecurity The increasing reliance on technology and the growing number of cyber threats make cybersecurity an essential aspect of modern society. Cybersecurity breaches can result in financial losses, reputational damage, and legal liabilities. C. Purpose of the paper This paper aims to provide an overview of cybersecurity, cyber threats, cybersecurity measures, cybersecurity in the business and government sectors, cybersecurity ethics, and the future of cybersecurity.

A cyber threat is any malicious act or event that attempts to compromise or disrupt computer systems, networks, or sensitive data. B. Types of Cyber Threats Common types of cyber threats include malware, phishing, social engineering, ransomware, DDoS attacks, and advanced persistent threats (APTs). C. Examples of Cyber Threats Recent cyber threats include the SolarWinds supply chain attack, the Colonial Pipeline ransomware attack, and the Microsoft Exchange Server hack.

Prevention measures aim to minimize the risk of cyber attacks by implementing security controls, such as firewalls, anti-virus software, and encryption.

• Firewalls Firewalls act as a barrier between a computer network and the internet, filtering incoming and outgoing traffic to prevent unauthorized access.
• Anti-virus software Anti-virus software detects, prevents, and removes malware from computer systems.
• Encryption Encryption involves the use of mathematical algorithms to transform sensitive data into a code that can only be accessed by authorized individuals. B. Detection measures Detection measures aim to identify and respond to cyber attacks as quickly as possible, such as intrusion detection systems (IDS), security information and event management (SIEM), and security operations centers (SOCs).
• Intrusion Detection System (IDS) IDS monitors network traffic for signs of unauthorized access, such as unusual patterns or anomalies.
• Security Information and Event Management (SIEM) SIEM combines security information management and security event management to provide real-time monitoring and analysis of security alerts.
• Security Operations Center (SOC) SOC is a dedicated team responsible for monitoring, analyzing, and responding to cyber threats. C. Response measures Response measures aim to mitigate the impact of a cyber attack and restore normal operations, such as incident response plans (IRPs), business continuity plans (BCPs), and disaster recovery plans (DRPs).
• Incident Response Plan IRPs outline the procedures and protocols to follow in the event of a cyber attack, including communication protocols, roles and responsibilities, and recovery processes.
• Business Continuity Plan BCPs ensure that critical business functions can continue in the event of a cyber attack or other disruption.
• Disaster Recovery Plan DRPs outline the procedures to recover from a catastrophic event, such as a natural disaster or cyber attack.

Cybersecurity is crucial for businesses of all sizes and industries, as they handle sensitive data, financial transactions, and intellectual property that are attractive targets for cyber criminals.

Risk assessment is a critical step in developing a cybersecurity strategy, which involves identifying potential threats, vulnerabilities, and consequences to determine the level of risk and prioritize security measures.

Best practices for cybersecurity in business include implementing strong passwords and multi-factor authentication, regularly updating software and hardware, training employees on cybersecurity awareness, and regularly backing up data.

Government organizations face unique cybersecurity challenges, as they handle sensitive information related to national security, defense, and critical infrastructure.

Risk assessment in government organizations involves identifying and assessing potential threats and vulnerabilities, conducting regular audits, and complying with relevant regulations and standards.

Best practices for cybersecurity in government organizations include implementing secure communication protocols, regularly updating and patching software, and conducting regular cybersecurity training and awareness programs for employees.

Cybersecurity ethics refers to the ethical considerations involved in cybersecurity, such as privacy, data protection, and the responsible use of technology.

Cybersecurity ethics are crucial for maintaining trust in technology, protecting privacy and data, and promoting responsible behavior in the digital world.

Examples of cybersecurity ethics include protecting the privacy of user data, ensuring data accuracy and integrity, and implementing fair and unbiased algorithms.

The future of cybersecurity will involve a shift towards more advanced technologies, such as artificial intelligence (AI), machine learning, and quantum computing.

Emerging cybersecurity threats include AI-powered cyber attacks, the use of deepfakes and synthetic media, and the potential for quantum computing to break current encryption methods.

Advancements in cybersecurity technology include the development of AI and machine learning-based security tools, the use of blockchain for secure data storage and sharing, and the development of post-quantum encryption methods.

This paper has provided an overview of cybersecurity, cyber threats, cybersecurity measures, cybersecurity in the business and government sectors, cybersecurity ethics, and the future of cybersecurity.

To enhance cybersecurity, organizations should prioritize risk assessment and implement a comprehensive cybersecurity strategy that includes prevention, detection, and response measures. Additionally, organizations should prioritize cybersecurity ethics to promote responsible behavior in the digital world.

C. Conclusion

Cybersecurity is an essential aspect of modern society, and organizations must prioritize cybersecurity to protect sensitive data and maintain trust in technology.

for further reading

X. Appendices

A. Glossary of key terms

B. Cybersecurity checklist for organizations

C. Sample cybersecurity policy for businesses

D. Sample cybersecurity incident response plan

E. Cybersecurity training and awareness resources

Note : The content and organization of the paper may vary depending on the specific requirements of the assignment or target audience. This outline serves as a general guide for writing a research paper on cybersecurity. Do not use this in your assingmets.

Research Paper Outline Template

• Background information and context of the research topic
• Research problem and questions
• Purpose and objectives of the research
• Scope and limitations

II. Literature Review

• Overview of existing research on the topic
• Key concepts and theories related to the research problem
• Identification of gaps in the literature
• Summary of relevant studies and their findings

III. Methodology

• Research design and approach
• Data collection methods and procedures
• Data analysis techniques
• Validity and reliability considerations
• Ethical considerations

IV. Results

• Presentation of research findings
• Analysis and interpretation of data
• Explanation of significant results
• Discussion of unexpected results

V. Discussion

• Comparison of research findings with existing literature
• Implications of results for theory and practice
• Limitations and future directions for research
• Conclusion and recommendations

VI. Conclusion

• Summary of research problem, purpose, and objectives
• Discussion of significant findings
• Contribution to the field of study
• Implications for practice
• Suggestions for future research

VII. References

• List of sources cited in the research paper using appropriate citation style.

Note : This is just an template, and depending on the requirements of your assignment or the specific research topic, you may need to modify or adjust the sections or headings accordingly.

Research Paper Outline Writing Guide

Here’s a guide to help you create an effective research paper outline:

• Choose a topic : Select a topic that is interesting, relevant, and meaningful to you.
• Conduct research: Gather information on the topic from a variety of sources, such as books, articles, journals, and websites.
• Organize your ideas: Organize your ideas and information into logical groups and subgroups. This will help you to create a clear and concise outline.
• Create an outline: Begin your outline with an introduction that includes your thesis statement. Then, organize your ideas into main points and subpoints. Each main point should be supported by evidence and examples.
• Introduction: The introduction of your research paper should include the thesis statement, background information, and the purpose of the research paper.
• Body : The body of your research paper should include the main points and subpoints. Each point should be supported by evidence and examples.
• Conclusion : The conclusion of your research paper should summarize the main points and restate the thesis statement.
• Reference List: Include a reference list at the end of your research paper. Make sure to properly cite all sources used in the paper.
• Proofreading : Proofread your research paper to ensure that it is free of errors and grammatical mistakes.
• Finalizing : Finalize your research paper by reviewing the outline and making any necessary changes.

When to Write Research Paper Outline

It’s a good idea to write a research paper outline before you begin drafting your paper. The outline will help you organize your thoughts and ideas, and it can serve as a roadmap for your writing process.

Here are a few situations when you might want to consider writing an outline:

• When you’re starting a new research project: If you’re beginning a new research project, an outline can help you get organized from the very beginning. You can use your outline to brainstorm ideas, map out your research goals, and identify potential sources of information.
• When you’re struggling to organize your thoughts: If you find yourself struggling to organize your thoughts or make sense of your research, an outline can be a helpful tool. It can help you see the big picture of your project and break it down into manageable parts.
• When you’re working with a tight deadline : If you have a deadline for your research paper, an outline can help you stay on track and ensure that you cover all the necessary points. By mapping out your paper in advance, you can work more efficiently and avoid getting stuck or overwhelmed.

Purpose of Research Paper Outline

The purpose of a research paper outline is to provide a structured and organized plan for the writer to follow while conducting research and writing the paper. An outline is essentially a roadmap that guides the writer through the entire research process, from the initial research and analysis of the topic to the final writing and editing of the paper.

A well-constructed outline can help the writer to:

• Organize their thoughts and ideas on the topic, and ensure that all relevant information is included.
• Identify any gaps in their research or argument, and address them before starting to write the paper.
• Ensure that the paper follows a logical and coherent structure, with clear transitions between different sections.
• Save time and effort by providing a clear plan for the writer to follow, rather than starting from scratch and having to revise the paper multiple times.

Advantages of Research Paper Outline

Some of the key advantages of a research paper outline include:

• Helps to organize thoughts and ideas : An outline helps to organize all the different ideas and information that you want to include in your paper. By creating an outline, you can ensure that all the points you want to make are covered and in a logical order.
• Saves time and effort : An outline saves time and effort because it helps you to focus on the key points of your paper. It also helps you to identify any gaps or areas where more research may be needed.
• Makes the writing process easier : With an outline, you have a clear roadmap of what you want to write, and this makes the writing process much easier. You can simply follow your outline and fill in the details as you go.
• Improves the quality of your paper : By having a clear outline, you can ensure that all the important points are covered and in a logical order. This makes your paper more coherent and easier to read, which ultimately improves its overall quality.
• Facilitates collaboration: If you are working on a research paper with others, an outline can help to facilitate collaboration. By sharing your outline, you can ensure that everyone is on the same page and working towards the same goals.

About the author

Muhammad Hassan

Researcher, Academic Writer, Web developer

You may also like

How to Cite Research Paper – All Formats and...

Delimitations in Research – Types, Examples and...

Research Paper Format – Types, Examples and...

Research Design – Types, Methods and Examples

Research Paper Title – Writing Guide and Example

Research Paper Introduction – Writing Guide and...

• USC Libraries
• Research Guides

Organizing Your Social Sciences Research Paper

• Types of Research Designs
• Purpose of Guide
• Design Flaws to Avoid
• Independent and Dependent Variables
• Glossary of Research Terms
• Reading Research Effectively
• Narrowing a Topic Idea
• Broadening a Topic Idea
• Extending the Timeliness of a Topic Idea
• Academic Writing Style
• Applying Critical Thinking
• Choosing a Title
• Making an Outline
• Paragraph Development
• Research Process Video Series
• Executive Summary
• The C.A.R.S. Model
• Background Information
• The Research Problem/Question
• Theoretical Framework
• Citation Tracking
• Content Alert Services
• Evaluating Sources
• Primary Sources
• Secondary Sources
• Tiertiary Sources
• Scholarly vs. Popular Publications
• Qualitative Methods
• Quantitative Methods
• Insiderness
• Using Non-Textual Elements
• Limitations of the Study
• Common Grammar Mistakes
• Writing Concisely
• Avoiding Plagiarism
• Footnotes or Endnotes?
• Further Readings
• Generative AI and Writing
• USC Libraries Tutorials and Other Guides
• Bibliography

Introduction

Before beginning your paper, you need to decide how you plan to design the study .

The research design refers to the overall strategy and analytical approach that you have chosen in order to integrate, in a coherent and logical way, the different components of the study, thus ensuring that the research problem will be thoroughly investigated. It constitutes the blueprint for the collection, measurement, and interpretation of information and data. Note that the research problem determines the type of design you choose, not the other way around!

De Vaus, D. A. Research Design in Social Research . London: SAGE, 2001; Trochim, William M.K. Research Methods Knowledge Base. 2006.

General Structure and Writing Style

The function of a research design is to ensure that the evidence obtained enables you to effectively address the research problem logically and as unambiguously as possible . In social sciences research, obtaining information relevant to the research problem generally entails specifying the type of evidence needed to test the underlying assumptions of a theory, to evaluate a program, or to accurately describe and assess meaning related to an observable phenomenon.

With this in mind, a common mistake made by researchers is that they begin their investigations before they have thought critically about what information is required to address the research problem. Without attending to these design issues beforehand, the overall research problem will not be adequately addressed and any conclusions drawn will run the risk of being weak and unconvincing. As a consequence, the overall validity of the study will be undermined.

The length and complexity of describing the research design in your paper can vary considerably, but any well-developed description will achieve the following :

• Identify the research problem clearly and justify its selection, particularly in relation to any valid alternative designs that could have been used,
• Review and synthesize previously published literature associated with the research problem,
• Clearly and explicitly specify hypotheses [i.e., research questions] central to the problem,
• Effectively describe the information and/or data which will be necessary for an adequate testing of the hypotheses and explain how such information and/or data will be obtained, and
• Describe the methods of analysis to be applied to the data in determining whether or not the hypotheses are true or false.

The research design is usually incorporated into the introduction of your paper . You can obtain an overall sense of what to do by reviewing studies that have utilized the same research design [e.g., using a case study approach]. This can help you develop an outline to follow for your own paper.

NOTE : Use the SAGE Research Methods Online and Cases and the SAGE Research Methods Videos databases to search for scholarly resources on how to apply specific research designs and methods . The Research Methods Online database contains links to more than 175,000 pages of SAGE publisher's book, journal, and reference content on quantitative, qualitative, and mixed research methodologies. Also included is a collection of case studies of social research projects that can be used to help you better understand abstract or complex methodological concepts. The Research Methods Videos database contains hours of tutorials, interviews, video case studies, and mini-documentaries covering the entire research process.

Creswell, John W. and J. David Creswell. Research Design: Qualitative, Quantitative, and Mixed Methods Approaches . 5th edition. Thousand Oaks, CA: Sage, 2018; De Vaus, D. A. Research Design in Social Research . London: SAGE, 2001; Gorard, Stephen. Research Design: Creating Robust Approaches for the Social Sciences . Thousand Oaks, CA: Sage, 2013; Leedy, Paul D. and Jeanne Ellis Ormrod. Practical Research: Planning and Design . Tenth edition. Boston, MA: Pearson, 2013; Vogt, W. Paul, Dianna C. Gardner, and Lynne M. Haeffele. When to Use What Research Design . New York: Guilford, 2012.

Action Research Design

Definition and Purpose

The essentials of action research design follow a characteristic cycle whereby initially an exploratory stance is adopted, where an understanding of a problem is developed and plans are made for some form of interventionary strategy. Then the intervention is carried out [the "action" in action research] during which time, pertinent observations are collected in various forms. The new interventional strategies are carried out, and this cyclic process repeats, continuing until a sufficient understanding of [or a valid implementation solution for] the problem is achieved. The protocol is iterative or cyclical in nature and is intended to foster deeper understanding of a given situation, starting with conceptualizing and particularizing the problem and moving through several interventions and evaluations.

What do these studies tell you ?

• This is a collaborative and adaptive research design that lends itself to use in work or community situations.
• Design focuses on pragmatic and solution-driven research outcomes rather than testing theories.
• When practitioners use action research, it has the potential to increase the amount they learn consciously from their experience; the action research cycle can be regarded as a learning cycle.
• Action research studies often have direct and obvious relevance to improving practice and advocating for change.
• There are no hidden controls or preemption of direction by the researcher.

What these studies don't tell you ?

• It is harder to do than conducting conventional research because the researcher takes on responsibilities of advocating for change as well as for researching the topic.
• Action research is much harder to write up because it is less likely that you can use a standard format to report your findings effectively [i.e., data is often in the form of stories or observation].
• Personal over-involvement of the researcher may bias research results.
• The cyclic nature of action research to achieve its twin outcomes of action [e.g. change] and research [e.g. understanding] is time-consuming and complex to conduct.
• Advocating for change usually requires buy-in from study participants.

Coghlan, David and Mary Brydon-Miller. The Sage Encyclopedia of Action Research . Thousand Oaks, CA:  Sage, 2014; Efron, Sara Efrat and Ruth Ravid. Action Research in Education: A Practical Guide . New York: Guilford, 2013; Gall, Meredith. Educational Research: An Introduction . Chapter 18, Action Research. 8th ed. Boston, MA: Pearson/Allyn and Bacon, 2007; Gorard, Stephen. Research Design: Creating Robust Approaches for the Social Sciences . Thousand Oaks, CA: Sage, 2013; Kemmis, Stephen and Robin McTaggart. “Participatory Action Research.” In Handbook of Qualitative Research . Norman Denzin and Yvonna S. Lincoln, eds. 2nd ed. (Thousand Oaks, CA: SAGE, 2000), pp. 567-605; McNiff, Jean. Writing and Doing Action Research . London: Sage, 2014; Reason, Peter and Hilary Bradbury. Handbook of Action Research: Participative Inquiry and Practice . Thousand Oaks, CA: SAGE, 2001.

Case Study Design

A case study is an in-depth study of a particular research problem rather than a sweeping statistical survey or comprehensive comparative inquiry. It is often used to narrow down a very broad field of research into one or a few easily researchable examples. The case study research design is also useful for testing whether a specific theory and model actually applies to phenomena in the real world. It is a useful design when not much is known about an issue or phenomenon.

• Approach excels at bringing us to an understanding of a complex issue through detailed contextual analysis of a limited number of events or conditions and their relationships.
• A researcher using a case study design can apply a variety of methodologies and rely on a variety of sources to investigate a research problem.
• Design can extend experience or add strength to what is already known through previous research.
• Social scientists, in particular, make wide use of this research design to examine contemporary real-life situations and provide the basis for the application of concepts and theories and the extension of methodologies.
• The design can provide detailed descriptions of specific and rare cases.
• A single or small number of cases offers little basis for establishing reliability or to generalize the findings to a wider population of people, places, or things.
• Intense exposure to the study of a case may bias a researcher's interpretation of the findings.
• Design does not facilitate assessment of cause and effect relationships.
• Vital information may be missing, making the case hard to interpret.
• The case may not be representative or typical of the larger problem being investigated.
• If the criteria for selecting a case is because it represents a very unusual or unique phenomenon or problem for study, then your interpretation of the findings can only apply to that particular case.

Case Studies. Writing@CSU. Colorado State University; Anastas, Jeane W. Research Design for Social Work and the Human Services . Chapter 4, Flexible Methods: Case Study Design. 2nd ed. New York: Columbia University Press, 1999; Gerring, John. “What Is a Case Study and What Is It Good for?” American Political Science Review 98 (May 2004): 341-354; Greenhalgh, Trisha, editor. Case Study Evaluation: Past, Present and Future Challenges . Bingley, UK: Emerald Group Publishing, 2015; Mills, Albert J. , Gabrielle Durepos, and Eiden Wiebe, editors. Encyclopedia of Case Study Research . Thousand Oaks, CA: SAGE Publications, 2010; Stake, Robert E. The Art of Case Study Research . Thousand Oaks, CA: SAGE, 1995; Yin, Robert K. Case Study Research: Design and Theory . Applied Social Research Methods Series, no. 5. 3rd ed. Thousand Oaks, CA: SAGE, 2003.

Causal Design

Causality studies may be thought of as understanding a phenomenon in terms of conditional statements in the form, “If X, then Y.” This type of research is used to measure what impact a specific change will have on existing norms and assumptions. Most social scientists seek causal explanations that reflect tests of hypotheses. Causal effect (nomothetic perspective) occurs when variation in one phenomenon, an independent variable, leads to or results, on average, in variation in another phenomenon, the dependent variable.

Conditions necessary for determining causality:

• Empirical association -- a valid conclusion is based on finding an association between the independent variable and the dependent variable.
• Appropriate time order -- to conclude that causation was involved, one must see that cases were exposed to variation in the independent variable before variation in the dependent variable.
• Nonspuriousness -- a relationship between two variables that is not due to variation in a third variable.
• Causality research designs assist researchers in understanding why the world works the way it does through the process of proving a causal link between variables and by the process of eliminating other possibilities.
• Replication is possible.
• There is greater confidence the study has internal validity due to the systematic subject selection and equity of groups being compared.
• Not all relationships are causal! The possibility always exists that, by sheer coincidence, two unrelated events appear to be related [e.g., Punxatawney Phil could accurately predict the duration of Winter for five consecutive years but, the fact remains, he's just a big, furry rodent].
• Conclusions about causal relationships are difficult to determine due to a variety of extraneous and confounding variables that exist in a social environment. This means causality can only be inferred, never proven.
• If two variables are correlated, the cause must come before the effect. However, even though two variables might be causally related, it can sometimes be difficult to determine which variable comes first and, therefore, to establish which variable is the actual cause and which is the  actual effect.

Beach, Derek and Rasmus Brun Pedersen. Causal Case Study Methods: Foundations and Guidelines for Comparing, Matching, and Tracing . Ann Arbor, MI: University of Michigan Press, 2016; Bachman, Ronet. The Practice of Research in Criminology and Criminal Justice . Chapter 5, Causation and Research Designs. 3rd ed. Thousand Oaks, CA: Pine Forge Press, 2007; Brewer, Ernest W. and Jennifer Kubn. “Causal-Comparative Design.” In Encyclopedia of Research Design . Neil J. Salkind, editor. (Thousand Oaks, CA: Sage, 2010), pp. 125-132; Causal Research Design: Experimentation. Anonymous SlideShare Presentation; Gall, Meredith. Educational Research: An Introduction . Chapter 11, Nonexperimental Research: Correlational Designs. 8th ed. Boston, MA: Pearson/Allyn and Bacon, 2007; Trochim, William M.K. Research Methods Knowledge Base. 2006.

Cohort Design

Often used in the medical sciences, but also found in the applied social sciences, a cohort study generally refers to a study conducted over a period of time involving members of a population which the subject or representative member comes from, and who are united by some commonality or similarity. Using a quantitative framework, a cohort study makes note of statistical occurrence within a specialized subgroup, united by same or similar characteristics that are relevant to the research problem being investigated, rather than studying statistical occurrence within the general population. Using a qualitative framework, cohort studies generally gather data using methods of observation. Cohorts can be either "open" or "closed."

• Open Cohort Studies [dynamic populations, such as the population of Los Angeles] involve a population that is defined just by the state of being a part of the study in question (and being monitored for the outcome). Date of entry and exit from the study is individually defined, therefore, the size of the study population is not constant. In open cohort studies, researchers can only calculate rate based data, such as, incidence rates and variants thereof.
• Closed Cohort Studies [static populations, such as patients entered into a clinical trial] involve participants who enter into the study at one defining point in time and where it is presumed that no new participants can enter the cohort. Given this, the number of study participants remains constant (or can only decrease).
• The use of cohorts is often mandatory because a randomized control study may be unethical. For example, you cannot deliberately expose people to asbestos, you can only study its effects on those who have already been exposed. Research that measures risk factors often relies upon cohort designs.
• Because cohort studies measure potential causes before the outcome has occurred, they can demonstrate that these “causes” preceded the outcome, thereby avoiding the debate as to which is the cause and which is the effect.
• Cohort analysis is highly flexible and can provide insight into effects over time and related to a variety of different types of changes [e.g., social, cultural, political, economic, etc.].
• Either original data or secondary data can be used in this design.
• In cases where a comparative analysis of two cohorts is made [e.g., studying the effects of one group exposed to asbestos and one that has not], a researcher cannot control for all other factors that might differ between the two groups. These factors are known as confounding variables.
• Cohort studies can end up taking a long time to complete if the researcher must wait for the conditions of interest to develop within the group. This also increases the chance that key variables change during the course of the study, potentially impacting the validity of the findings.
• Due to the lack of randominization in the cohort design, its external validity is lower than that of study designs where the researcher randomly assigns participants.

Healy P, Devane D. “Methodological Considerations in Cohort Study Designs.” Nurse Researcher 18 (2011): 32-36; Glenn, Norval D, editor. Cohort Analysis . 2nd edition. Thousand Oaks, CA: Sage, 2005; Levin, Kate Ann. Study Design IV: Cohort Studies. Evidence-Based Dentistry 7 (2003): 51–52; Payne, Geoff. “Cohort Study.” In The SAGE Dictionary of Social Research Methods . Victor Jupp, editor. (Thousand Oaks, CA: Sage, 2006), pp. 31-33; Study Design 101. Himmelfarb Health Sciences Library. George Washington University, November 2011; Cohort Study. Wikipedia.

Cross-Sectional Design

Cross-sectional research designs have three distinctive features: no time dimension; a reliance on existing differences rather than change following intervention; and, groups are selected based on existing differences rather than random allocation. The cross-sectional design can only measure differences between or from among a variety of people, subjects, or phenomena rather than a process of change. As such, researchers using this design can only employ a relatively passive approach to making causal inferences based on findings.

• Cross-sectional studies provide a clear 'snapshot' of the outcome and the characteristics associated with it, at a specific point in time.
• Unlike an experimental design, where there is an active intervention by the researcher to produce and measure change or to create differences, cross-sectional designs focus on studying and drawing inferences from existing differences between people, subjects, or phenomena.
• Entails collecting data at and concerning one point in time. While longitudinal studies involve taking multiple measures over an extended period of time, cross-sectional research is focused on finding relationships between variables at one moment in time.
• Groups identified for study are purposely selected based upon existing differences in the sample rather than seeking random sampling.
• Cross-section studies are capable of using data from a large number of subjects and, unlike observational studies, is not geographically bound.
• Can estimate prevalence of an outcome of interest because the sample is usually taken from the whole population.
• Because cross-sectional designs generally use survey techniques to gather data, they are relatively inexpensive and take up little time to conduct.
• Finding people, subjects, or phenomena to study that are very similar except in one specific variable can be difficult.
• Results are static and time bound and, therefore, give no indication of a sequence of events or reveal historical or temporal contexts.
• Studies cannot be utilized to establish cause and effect relationships.
• This design only provides a snapshot of analysis so there is always the possibility that a study could have differing results if another time-frame had been chosen.
• There is no follow up to the findings.

Bethlehem, Jelke. "7: Cross-sectional Research." In Research Methodology in the Social, Behavioural and Life Sciences . Herman J Adèr and Gideon J Mellenbergh, editors. (London, England: Sage, 1999), pp. 110-43; Bourque, Linda B. “Cross-Sectional Design.” In  The SAGE Encyclopedia of Social Science Research Methods . Michael S. Lewis-Beck, Alan Bryman, and Tim Futing Liao. (Thousand Oaks, CA: 2004), pp. 230-231; Hall, John. “Cross-Sectional Survey Design.” In Encyclopedia of Survey Research Methods . Paul J. Lavrakas, ed. (Thousand Oaks, CA: Sage, 2008), pp. 173-174; Helen Barratt, Maria Kirwan. Cross-Sectional Studies: Design Application, Strengths and Weaknesses of Cross-Sectional Studies. Healthknowledge, 2009. Cross-Sectional Study. Wikipedia.

Descriptive Design

Descriptive research designs help provide answers to the questions of who, what, when, where, and how associated with a particular research problem; a descriptive study cannot conclusively ascertain answers to why. Descriptive research is used to obtain information concerning the current status of the phenomena and to describe "what exists" with respect to variables or conditions in a situation.

• The subject is being observed in a completely natural and unchanged natural environment. True experiments, whilst giving analyzable data, often adversely influence the normal behavior of the subject [a.k.a., the Heisenberg effect whereby measurements of certain systems cannot be made without affecting the systems].
• Descriptive research is often used as a pre-cursor to more quantitative research designs with the general overview giving some valuable pointers as to what variables are worth testing quantitatively.
• If the limitations are understood, they can be a useful tool in developing a more focused study.
• Descriptive studies can yield rich data that lead to important recommendations in practice.
• Appoach collects a large amount of data for detailed analysis.
• The results from a descriptive research cannot be used to discover a definitive answer or to disprove a hypothesis.
• Because descriptive designs often utilize observational methods [as opposed to quantitative methods], the results cannot be replicated.
• The descriptive function of research is heavily dependent on instrumentation for measurement and observation.

Anastas, Jeane W. Research Design for Social Work and the Human Services . Chapter 5, Flexible Methods: Descriptive Research. 2nd ed. New York: Columbia University Press, 1999; Given, Lisa M. "Descriptive Research." In Encyclopedia of Measurement and Statistics . Neil J. Salkind and Kristin Rasmussen, editors. (Thousand Oaks, CA: Sage, 2007), pp. 251-254; McNabb, Connie. Descriptive Research Methodologies. Powerpoint Presentation; Shuttleworth, Martyn. Descriptive Research Design, September 26, 2008; Erickson, G. Scott. "Descriptive Research Design." In New Methods of Market Research and Analysis . (Northampton, MA: Edward Elgar Publishing, 2017), pp. 51-77; Sahin, Sagufta, and Jayanta Mete. "A Brief Study on Descriptive Research: Its Nature and Application in Social Science." International Journal of Research and Analysis in Humanities 1 (2021): 11; K. Swatzell and P. Jennings. “Descriptive Research: The Nuts and Bolts.” Journal of the American Academy of Physician Assistants 20 (2007), pp. 55-56; Kane, E. Doing Your Own Research: Basic Descriptive Research in the Social Sciences and Humanities . London: Marion Boyars, 1985.

Experimental Design

A blueprint of the procedure that enables the researcher to maintain control over all factors that may affect the result of an experiment. In doing this, the researcher attempts to determine or predict what may occur. Experimental research is often used where there is time priority in a causal relationship (cause precedes effect), there is consistency in a causal relationship (a cause will always lead to the same effect), and the magnitude of the correlation is great. The classic experimental design specifies an experimental group and a control group. The independent variable is administered to the experimental group and not to the control group, and both groups are measured on the same dependent variable. Subsequent experimental designs have used more groups and more measurements over longer periods. True experiments must have control, randomization, and manipulation.

• Experimental research allows the researcher to control the situation. In so doing, it allows researchers to answer the question, “What causes something to occur?”
• Permits the researcher to identify cause and effect relationships between variables and to distinguish placebo effects from treatment effects.
• Experimental research designs support the ability to limit alternative explanations and to infer direct causal relationships in the study.
• Approach provides the highest level of evidence for single studies.
• The design is artificial, and results may not generalize well to the real world.
• The artificial settings of experiments may alter the behaviors or responses of participants.
• Experimental designs can be costly if special equipment or facilities are needed.
• Some research problems cannot be studied using an experiment because of ethical or technical reasons.
• Difficult to apply ethnographic and other qualitative methods to experimentally designed studies.

Anastas, Jeane W. Research Design for Social Work and the Human Services . Chapter 7, Flexible Methods: Experimental Research. 2nd ed. New York: Columbia University Press, 1999; Chapter 2: Research Design, Experimental Designs. School of Psychology, University of New England, 2000; Chow, Siu L. "Experimental Design." In Encyclopedia of Research Design . Neil J. Salkind, editor. (Thousand Oaks, CA: Sage, 2010), pp. 448-453; "Experimental Design." In Social Research Methods . Nicholas Walliman, editor. (London, England: Sage, 2006), pp, 101-110; Experimental Research. Research Methods by Dummies. Department of Psychology. California State University, Fresno, 2006; Kirk, Roger E. Experimental Design: Procedures for the Behavioral Sciences . 4th edition. Thousand Oaks, CA: Sage, 2013; Trochim, William M.K. Experimental Design. Research Methods Knowledge Base. 2006; Rasool, Shafqat. Experimental Research. Slideshare presentation.

Exploratory Design

An exploratory design is conducted about a research problem when there are few or no earlier studies to refer to or rely upon to predict an outcome . The focus is on gaining insights and familiarity for later investigation or undertaken when research problems are in a preliminary stage of investigation. Exploratory designs are often used to establish an understanding of how best to proceed in studying an issue or what methodology would effectively apply to gathering information about the issue.

The goals of exploratory research are intended to produce the following possible insights:

• Familiarity with basic details, settings, and concerns.
• Well grounded picture of the situation being developed.
• Generation of new ideas and assumptions.
• Development of tentative theories or hypotheses.
• Determination about whether a study is feasible in the future.
• Issues get refined for more systematic investigation and formulation of new research questions.
• Direction for future research and techniques get developed.
• Design is a useful approach for gaining background information on a particular topic.
• Exploratory research is flexible and can address research questions of all types (what, why, how).
• Provides an opportunity to define new terms and clarify existing concepts.
• Exploratory research is often used to generate formal hypotheses and develop more precise research problems.
• In the policy arena or applied to practice, exploratory studies help establish research priorities and where resources should be allocated.
• Exploratory research generally utilizes small sample sizes and, thus, findings are typically not generalizable to the population at large.
• The exploratory nature of the research inhibits an ability to make definitive conclusions about the findings. They provide insight but not definitive conclusions.
• The research process underpinning exploratory studies is flexible but often unstructured, leading to only tentative results that have limited value to decision-makers.
• Design lacks rigorous standards applied to methods of data gathering and analysis because one of the areas for exploration could be to determine what method or methodologies could best fit the research problem.

Cuthill, Michael. “Exploratory Research: Citizen Participation, Local Government, and Sustainable Development in Australia.” Sustainable Development 10 (2002): 79-89; Streb, Christoph K. "Exploratory Case Study." In Encyclopedia of Case Study Research . Albert J. Mills, Gabrielle Durepos and Eiden Wiebe, editors. (Thousand Oaks, CA: Sage, 2010), pp. 372-374; Taylor, P. J., G. Catalano, and D.R.F. Walker. “Exploratory Analysis of the World City Network.” Urban Studies 39 (December 2002): 2377-2394; Exploratory Research. Wikipedia.

Field Research Design

Sometimes referred to as ethnography or participant observation, designs around field research encompass a variety of interpretative procedures [e.g., observation and interviews] rooted in qualitative approaches to studying people individually or in groups while inhabiting their natural environment as opposed to using survey instruments or other forms of impersonal methods of data gathering. Information acquired from observational research takes the form of “ field notes ” that involves documenting what the researcher actually sees and hears while in the field. Findings do not consist of conclusive statements derived from numbers and statistics because field research involves analysis of words and observations of behavior. Conclusions, therefore, are developed from an interpretation of findings that reveal overriding themes, concepts, and ideas. More information can be found HERE .

• Field research is often necessary to fill gaps in understanding the research problem applied to local conditions or to specific groups of people that cannot be ascertained from existing data.
• The research helps contextualize already known information about a research problem, thereby facilitating ways to assess the origins, scope, and scale of a problem and to gage the causes, consequences, and means to resolve an issue based on deliberate interaction with people in their natural inhabited spaces.
• Enables the researcher to corroborate or confirm data by gathering additional information that supports or refutes findings reported in prior studies of the topic.
• Because the researcher in embedded in the field, they are better able to make observations or ask questions that reflect the specific cultural context of the setting being investigated.
• Observing the local reality offers the opportunity to gain new perspectives or obtain unique data that challenges existing theoretical propositions or long-standing assumptions found in the literature.

What these studies don't tell you

• A field research study requires extensive time and resources to carry out the multiple steps involved with preparing for the gathering of information, including for example, examining background information about the study site, obtaining permission to access the study site, and building trust and rapport with subjects.
• Requires a commitment to staying engaged in the field to ensure that you can adequately document events and behaviors as they unfold.
• The unpredictable nature of fieldwork means that researchers can never fully control the process of data gathering. They must maintain a flexible approach to studying the setting because events and circumstances can change quickly or unexpectedly.
• Findings can be difficult to interpret and verify without access to documents and other source materials that help to enhance the credibility of information obtained from the field  [i.e., the act of triangulating the data].
• Linking the research problem to the selection of study participants inhabiting their natural environment is critical. However, this specificity limits the ability to generalize findings to different situations or in other contexts or to infer courses of action applied to other settings or groups of people.
• The reporting of findings must take into account how the researcher themselves may have inadvertently affected respondents and their behaviors.

Historical Design

The purpose of a historical research design is to collect, verify, and synthesize evidence from the past to establish facts that defend or refute a hypothesis. It uses secondary sources and a variety of primary documentary evidence, such as, diaries, official records, reports, archives, and non-textual information [maps, pictures, audio and visual recordings]. The limitation is that the sources must be both authentic and valid.

• The historical research design is unobtrusive; the act of research does not affect the results of the study.
• The historical approach is well suited for trend analysis.
• Historical records can add important contextual background required to more fully understand and interpret a research problem.
• There is often no possibility of researcher-subject interaction that could affect the findings.
• Historical sources can be used over and over to study different research problems or to replicate a previous study.
• The ability to fulfill the aims of your research are directly related to the amount and quality of documentation available to understand the research problem.
• Since historical research relies on data from the past, there is no way to manipulate it to control for contemporary contexts.
• Interpreting historical sources can be very time consuming.
• The sources of historical materials must be archived consistently to ensure access. This may especially challenging for digital or online-only sources.
• Original authors bring their own perspectives and biases to the interpretation of past events and these biases are more difficult to ascertain in historical resources.
• Due to the lack of control over external variables, historical research is very weak with regard to the demands of internal validity.
• It is rare that the entirety of historical documentation needed to fully address a research problem is available for interpretation, therefore, gaps need to be acknowledged.

Howell, Martha C. and Walter Prevenier. From Reliable Sources: An Introduction to Historical Methods . Ithaca, NY: Cornell University Press, 2001; Lundy, Karen Saucier. "Historical Research." In The Sage Encyclopedia of Qualitative Research Methods . Lisa M. Given, editor. (Thousand Oaks, CA: Sage, 2008), pp. 396-400; Marius, Richard. and Melvin E. Page. A Short Guide to Writing about History . 9th edition. Boston, MA: Pearson, 2015; Savitt, Ronald. “Historical Research in Marketing.” Journal of Marketing 44 (Autumn, 1980): 52-58;  Gall, Meredith. Educational Research: An Introduction . Chapter 16, Historical Research. 8th ed. Boston, MA: Pearson/Allyn and Bacon, 2007.

Longitudinal Design

A longitudinal study follows the same sample over time and makes repeated observations. For example, with longitudinal surveys, the same group of people is interviewed at regular intervals, enabling researchers to track changes over time and to relate them to variables that might explain why the changes occur. Longitudinal research designs describe patterns of change and help establish the direction and magnitude of causal relationships. Measurements are taken on each variable over two or more distinct time periods. This allows the researcher to measure change in variables over time. It is a type of observational study sometimes referred to as a panel study.

• Longitudinal data facilitate the analysis of the duration of a particular phenomenon.
• Enables survey researchers to get close to the kinds of causal explanations usually attainable only with experiments.
• The design permits the measurement of differences or change in a variable from one period to another [i.e., the description of patterns of change over time].
• Longitudinal studies facilitate the prediction of future outcomes based upon earlier factors.
• The data collection method may change over time.
• Maintaining the integrity of the original sample can be difficult over an extended period of time.
• It can be difficult to show more than one variable at a time.
• This design often needs qualitative research data to explain fluctuations in the results.
• A longitudinal research design assumes present trends will continue unchanged.
• It can take a long period of time to gather results.
• There is a need to have a large sample size and accurate sampling to reach representativness.

Anastas, Jeane W. Research Design for Social Work and the Human Services . Chapter 6, Flexible Methods: Relational and Longitudinal Research. 2nd ed. New York: Columbia University Press, 1999; Forgues, Bernard, and Isabelle Vandangeon-Derumez. "Longitudinal Analyses." In Doing Management Research . Raymond-Alain Thiétart and Samantha Wauchope, editors. (London, England: Sage, 2001), pp. 332-351; Kalaian, Sema A. and Rafa M. Kasim. "Longitudinal Studies." In Encyclopedia of Survey Research Methods . Paul J. Lavrakas, ed. (Thousand Oaks, CA: Sage, 2008), pp. 440-441; Menard, Scott, editor. Longitudinal Research . Thousand Oaks, CA: Sage, 2002; Ployhart, Robert E. and Robert J. Vandenberg. "Longitudinal Research: The Theory, Design, and Analysis of Change.” Journal of Management 36 (January 2010): 94-120; Longitudinal Study. Wikipedia.

Meta-Analysis Design

Meta-analysis is an analytical methodology designed to systematically evaluate and summarize the results from a number of individual studies, thereby, increasing the overall sample size and the ability of the researcher to study effects of interest. The purpose is to not simply summarize existing knowledge, but to develop a new understanding of a research problem using synoptic reasoning. The main objectives of meta-analysis include analyzing differences in the results among studies and increasing the precision by which effects are estimated. A well-designed meta-analysis depends upon strict adherence to the criteria used for selecting studies and the availability of information in each study to properly analyze their findings. Lack of information can severely limit the type of analyzes and conclusions that can be reached. In addition, the more dissimilarity there is in the results among individual studies [heterogeneity], the more difficult it is to justify interpretations that govern a valid synopsis of results. A meta-analysis needs to fulfill the following requirements to ensure the validity of your findings:

• Clearly defined description of objectives, including precise definitions of the variables and outcomes that are being evaluated;
• A well-reasoned and well-documented justification for identification and selection of the studies;
• Assessment and explicit acknowledgment of any researcher bias in the identification and selection of those studies;
• Description and evaluation of the degree of heterogeneity among the sample size of studies reviewed; and,
• Justification of the techniques used to evaluate the studies.
• Can be an effective strategy for determining gaps in the literature.
• Provides a means of reviewing research published about a particular topic over an extended period of time and from a variety of sources.
• Is useful in clarifying what policy or programmatic actions can be justified on the basis of analyzing research results from multiple studies.
• Provides a method for overcoming small sample sizes in individual studies that previously may have had little relationship to each other.
• Can be used to generate new hypotheses or highlight research problems for future studies.
• Small violations in defining the criteria used for content analysis can lead to difficult to interpret and/or meaningless findings.
• A large sample size can yield reliable, but not necessarily valid, results.
• A lack of uniformity regarding, for example, the type of literature reviewed, how methods are applied, and how findings are measured within the sample of studies you are analyzing, can make the process of synthesis difficult to perform.
• Depending on the sample size, the process of reviewing and synthesizing multiple studies can be very time consuming.

Beck, Lewis W. "The Synoptic Method." The Journal of Philosophy 36 (1939): 337-345; Cooper, Harris, Larry V. Hedges, and Jeffrey C. Valentine, eds. The Handbook of Research Synthesis and Meta-Analysis . 2nd edition. New York: Russell Sage Foundation, 2009; Guzzo, Richard A., Susan E. Jackson and Raymond A. Katzell. “Meta-Analysis Analysis.” In Research in Organizational Behavior , Volume 9. (Greenwich, CT: JAI Press, 1987), pp 407-442; Lipsey, Mark W. and David B. Wilson. Practical Meta-Analysis . Thousand Oaks, CA: Sage Publications, 2001; Study Design 101. Meta-Analysis. The Himmelfarb Health Sciences Library, George Washington University; Timulak, Ladislav. “Qualitative Meta-Analysis.” In The SAGE Handbook of Qualitative Data Analysis . Uwe Flick, editor. (Los Angeles, CA: Sage, 2013), pp. 481-495; Walker, Esteban, Adrian V. Hernandez, and Micheal W. Kattan. "Meta-Analysis: It's Strengths and Limitations." Cleveland Clinic Journal of Medicine 75 (June 2008): 431-439.

Mixed-Method Design

• Narrative and non-textual information can add meaning to numeric data, while numeric data can add precision to narrative and non-textual information.
• Can utilize existing data while at the same time generating and testing a grounded theory approach to describe and explain the phenomenon under study.
• A broader, more complex research problem can be investigated because the researcher is not constrained by using only one method.
• The strengths of one method can be used to overcome the inherent weaknesses of another method.
• Can provide stronger, more robust evidence to support a conclusion or set of recommendations.
• May generate new knowledge new insights or uncover hidden insights, patterns, or relationships that a single methodological approach might not reveal.
• Produces more complete knowledge and understanding of the research problem that can be used to increase the generalizability of findings applied to theory or practice.
• A researcher must be proficient in understanding how to apply multiple methods to investigating a research problem as well as be proficient in optimizing how to design a study that coherently melds them together.
• Can increase the likelihood of conflicting results or ambiguous findings that inhibit drawing a valid conclusion or setting forth a recommended course of action [e.g., sample interview responses do not support existing statistical data].
• Because the research design can be very complex, reporting the findings requires a well-organized narrative, clear writing style, and precise word choice.
• Design invites collaboration among experts. However, merging different investigative approaches and writing styles requires more attention to the overall research process than studies conducted using only one methodological paradigm.
• Concurrent merging of quantitative and qualitative research requires greater attention to having adequate sample sizes, using comparable samples, and applying a consistent unit of analysis. For sequential designs where one phase of qualitative research builds on the quantitative phase or vice versa, decisions about what results from the first phase to use in the next phase, the choice of samples and estimating reasonable sample sizes for both phases, and the interpretation of results from both phases can be difficult.
• Due to multiple forms of data being collected and analyzed, this design requires extensive time and resources to carry out the multiple steps involved in data gathering and interpretation.

Burch, Patricia and Carolyn J. Heinrich. Mixed Methods for Policy Research and Program Evaluation . Thousand Oaks, CA: Sage, 2016; Creswell, John w. et al. Best Practices for Mixed Methods Research in the Health Sciences . Bethesda, MD: Office of Behavioral and Social Sciences Research, National Institutes of Health, 2010Creswell, John W. Research Design: Qualitative, Quantitative, and Mixed Methods Approaches . 4th edition. Thousand Oaks, CA: Sage Publications, 2014; Domínguez, Silvia, editor. Mixed Methods Social Networks Research . Cambridge, UK: Cambridge University Press, 2014; Hesse-Biber, Sharlene Nagy. Mixed Methods Research: Merging Theory with Practice . New York: Guilford Press, 2010; Niglas, Katrin. “How the Novice Researcher Can Make Sense of Mixed Methods Designs.” International Journal of Multiple Research Approaches 3 (2009): 34-46; Onwuegbuzie, Anthony J. and Nancy L. Leech. “Linking Research Questions to Mixed Methods Data Analysis Procedures.” The Qualitative Report 11 (September 2006): 474-498; Tashakorri, Abbas and John W. Creswell. “The New Era of Mixed Methods.” Journal of Mixed Methods Research 1 (January 2007): 3-7; Zhanga, Wanqing. “Mixed Methods Application in Health Intervention Research: A Multiple Case Study.” International Journal of Multiple Research Approaches 8 (2014): 24-35 .

Observational Design

This type of research design draws a conclusion by comparing subjects against a control group, in cases where the researcher has no control over the experiment. There are two general types of observational designs. In direct observations, people know that you are watching them. Unobtrusive measures involve any method for studying behavior where individuals do not know they are being observed. An observational study allows a useful insight into a phenomenon and avoids the ethical and practical difficulties of setting up a large and cumbersome research project.

• Observational studies are usually flexible and do not necessarily need to be structured around a hypothesis about what you expect to observe [data is emergent rather than pre-existing].
• The researcher is able to collect in-depth information about a particular behavior.
• Can reveal interrelationships among multifaceted dimensions of group interactions.
• You can generalize your results to real life situations.
• Observational research is useful for discovering what variables may be important before applying other methods like experiments.
• Observation research designs account for the complexity of group behaviors.
• Reliability of data is low because seeing behaviors occur over and over again may be a time consuming task and are difficult to replicate.
• In observational research, findings may only reflect a unique sample population and, thus, cannot be generalized to other groups.
• There can be problems with bias as the researcher may only "see what they want to see."
• There is no possibility to determine "cause and effect" relationships since nothing is manipulated.
• Sources or subjects may not all be equally credible.
• Any group that is knowingly studied is altered to some degree by the presence of the researcher, therefore, potentially skewing any data collected.

Atkinson, Paul and Martyn Hammersley. “Ethnography and Participant Observation.” In Handbook of Qualitative Research . Norman K. Denzin and Yvonna S. Lincoln, eds. (Thousand Oaks, CA: Sage, 1994), pp. 248-261; Observational Research. Research Methods by Dummies. Department of Psychology. California State University, Fresno, 2006; Patton Michael Quinn. Qualitiative Research and Evaluation Methods . Chapter 6, Fieldwork Strategies and Observational Methods. 3rd ed. Thousand Oaks, CA: Sage, 2002; Payne, Geoff and Judy Payne. "Observation." In Key Concepts in Social Research . The SAGE Key Concepts series. (London, England: Sage, 2004), pp. 158-162; Rosenbaum, Paul R. Design of Observational Studies . New York: Springer, 2010;Williams, J. Patrick. "Nonparticipant Observation." In The Sage Encyclopedia of Qualitative Research Methods . Lisa M. Given, editor.(Thousand Oaks, CA: Sage, 2008), pp. 562-563.

Philosophical Design

Understood more as an broad approach to examining a research problem than a methodological design, philosophical analysis and argumentation is intended to challenge deeply embedded, often intractable, assumptions underpinning an area of study. This approach uses the tools of argumentation derived from philosophical traditions, concepts, models, and theories to critically explore and challenge, for example, the relevance of logic and evidence in academic debates, to analyze arguments about fundamental issues, or to discuss the root of existing discourse about a research problem. These overarching tools of analysis can be framed in three ways:

• Ontology -- the study that describes the nature of reality; for example, what is real and what is not, what is fundamental and what is derivative?
• Epistemology -- the study that explores the nature of knowledge; for example, by what means does knowledge and understanding depend upon and how can we be certain of what we know?
• Axiology -- the study of values; for example, what values does an individual or group hold and why? How are values related to interest, desire, will, experience, and means-to-end? And, what is the difference between a matter of fact and a matter of value?
• Can provide a basis for applying ethical decision-making to practice.
• Functions as a means of gaining greater self-understanding and self-knowledge about the purposes of research.
• Brings clarity to general guiding practices and principles of an individual or group.
• Philosophy informs methodology.
• Refine concepts and theories that are invoked in relatively unreflective modes of thought and discourse.
• Beyond methodology, philosophy also informs critical thinking about epistemology and the structure of reality (metaphysics).
• Offers clarity and definition to the practical and theoretical uses of terms, concepts, and ideas.
• Limited application to specific research problems [answering the "So What?" question in social science research].
• Analysis can be abstract, argumentative, and limited in its practical application to real-life issues.
• While a philosophical analysis may render problematic that which was once simple or taken-for-granted, the writing can be dense and subject to unnecessary jargon, overstatement, and/or excessive quotation and documentation.
• There are limitations in the use of metaphor as a vehicle of philosophical analysis.
• There can be analytical difficulties in moving from philosophy to advocacy and between abstract thought and application to the phenomenal world.

Burton, Dawn. "Part I, Philosophy of the Social Sciences." In Research Training for Social Scientists . (London, England: Sage, 2000), pp. 1-5; Chapter 4, Research Methodology and Design. Unisa Institutional Repository (UnisaIR), University of South Africa; Jarvie, Ian C., and Jesús Zamora-Bonilla, editors. The SAGE Handbook of the Philosophy of Social Sciences . London: Sage, 2011; Labaree, Robert V. and Ross Scimeca. “The Philosophical Problem of Truth in Librarianship.” The Library Quarterly 78 (January 2008): 43-70; Maykut, Pamela S. Beginning Qualitative Research: A Philosophic and Practical Guide . Washington, DC: Falmer Press, 1994; McLaughlin, Hugh. "The Philosophy of Social Research." In Understanding Social Work Research . 2nd edition. (London: SAGE Publications Ltd., 2012), pp. 24-47; Stanford Encyclopedia of Philosophy . Metaphysics Research Lab, CSLI, Stanford University, 2013.

Sequential Design

• The researcher has a limitless option when it comes to sample size and the sampling schedule.
• Due to the repetitive nature of this research design, minor changes and adjustments can be done during the initial parts of the study to correct and hone the research method.
• This is a useful design for exploratory studies.
• There is very little effort on the part of the researcher when performing this technique. It is generally not expensive, time consuming, or workforce intensive.
• Because the study is conducted serially, the results of one sample are known before the next sample is taken and analyzed. This provides opportunities for continuous improvement of sampling and methods of analysis.
• The sampling method is not representative of the entire population. The only possibility of approaching representativeness is when the researcher chooses to use a very large sample size significant enough to represent a significant portion of the entire population. In this case, moving on to study a second or more specific sample can be difficult.
• The design cannot be used to create conclusions and interpretations that pertain to an entire population because the sampling technique is not randomized. Generalizability from findings is, therefore, limited.
• Difficult to account for and interpret variation from one sample to another over time, particularly when using qualitative methods of data collection.

Betensky, Rebecca. Harvard University, Course Lecture Note slides; Bovaird, James A. and Kevin A. Kupzyk. "Sequential Design." In Encyclopedia of Research Design . Neil J. Salkind, editor. (Thousand Oaks, CA: Sage, 2010), pp. 1347-1352; Cresswell, John W. Et al. “Advanced Mixed-Methods Research Designs.” In Handbook of Mixed Methods in Social and Behavioral Research . Abbas Tashakkori and Charles Teddle, eds. (Thousand Oaks, CA: Sage, 2003), pp. 209-240; Henry, Gary T. "Sequential Sampling." In The SAGE Encyclopedia of Social Science Research Methods . Michael S. Lewis-Beck, Alan Bryman and Tim Futing Liao, editors. (Thousand Oaks, CA: Sage, 2004), pp. 1027-1028; Nataliya V. Ivankova. “Using Mixed-Methods Sequential Explanatory Design: From Theory to Practice.” Field Methods 18 (February 2006): 3-20; Bovaird, James A. and Kevin A. Kupzyk. “Sequential Design.” In Encyclopedia of Research Design . Neil J. Salkind, ed. Thousand Oaks, CA: Sage, 2010; Sequential Analysis. Wikipedia.

Reference List: Textual Sources

Welcome to the Purdue OWL

This page is brought to you by the OWL at Purdue University. When printing this page, you must include the entire legal notice.

Copyright ©1995-2018 by The Writing Lab & The OWL at Purdue and Purdue University. All rights reserved. This material may not be published, reproduced, broadcast, rewritten, or redistributed without permission. Use of this site constitutes acceptance of our terms and conditions of fair use.

Basic Format for Books

Edited book, no author, edited book with an author or authors, a translation.

Note : When you cite a republished work, like the one above, in your text, it should appear with both dates: Plato (385-378/1989)

Edition Other Than the First

Article or chapter in an edited book.

Note : When you list the pages of the chapter or essay in parentheses after the book title, use "pp." before the numbers: (pp. 1-21). This abbreviation, however, does not appear before the page numbers in periodical references, except for newspapers. List any edition number in the same set of parentheses as the page numbers, separated by a comma: (2nd ed., pp. 66-72).

Multivolume Work

Articles in periodicals.

APA style dictates that authors are named with their last name followed by their initials; publication year goes between parentheses, followed by a period. The title of the article is in sentence-case, meaning only the first word and proper nouns in the title are capitalized. The periodical title is run in title case, and is followed by the volume number which, with the title, is also italicized. If a DOI has been assigned to the article that you are using, you should include this after the page numbers for the article. If no DOI has been assigned and you are accessing the periodical online, use the URL of the website from which you are retrieving the periodical.

Article in Print Journal

Note: APA 7 advises writers to include a DOI (if available), even when using the print source. The example above assumes no DOI is available.

Article in Electronic Journal

Note :  This content also appears on Reference List: Online Media .

As noted above, when citing an article in an electronic journal, include a DOI if one is associated with the article.

DOIs may not always be available. In these cases, use a URL. Many academic journals provide stable URLs that function similarly to DOIs. These are preferable to ordinary URLs copied and pasted from the browser's address bar.

Article in a Magazine

Article in a newspaper.

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• My Account Login
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Open access
• Published: 23 April 2024

Efficacy and safety of human umbilical cord-derived mesenchymal stem cells in the treatment of refractory immune thrombocytopenia: a prospective, single arm, phase I trial

• Yunfei Chen   ORCID: orcid.org/0000-0001-7309-8545 1 , 2   na1 ,
• Yanmei Xu   ORCID: orcid.org/0000-0003-4607-9781 1 , 2   na1 ,
• Ying Chi 1 , 2   na1 ,
• Ting Sun 1 , 2   na1 ,
• Yuchen Gao   ORCID: orcid.org/0000-0002-0619-1595 1 , 2   na1 ,
• Xueqing Dou 3 ,
• Zhibo Han 1 , 4 ,
• Feng Xue 1 , 2 ,
• Huiyuan Li 1 , 2 ,
• Wei Liu 1 , 2 ,
• Xiaofan Liu 1 , 2 ,
• Huan Dong 1 , 2 ,
• Rongfeng Fu 1 , 2 ,
• Mankai Ju 1 , 2 ,
• Xinyue Dai 1 , 2 ,
• Wentian Wang 1 , 2 ,
• Yueshen Ma 1 , 2 ,
• Zhen Song 1 , 2 ,
• Jundong Gu 4 ,
• Wei Gong 4 ,
• Renchi Yang 1 , 2 &
• Lei Zhang   ORCID: orcid.org/0000-0001-7769-7377 1 , 2 , 5  

Signal Transduction and Targeted Therapy volume  9 , Article number:  102 ( 2024 ) Cite this article

228 Accesses

7 Altmetric

Metrics details

• Immunological disorders
• Mesenchymal stem cells

Patients with refractory immune thrombocytopenia (ITP) frequently encounter substantial bleeding risks and demonstrate limited responsiveness to existing therapies. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) present a promising alternative, capitalizing on their low immunogenicity and potent immunomodulatory effects for treating diverse autoimmune disorders. This prospective phase I trial enrolled eighteen eligible patients to explore the safety and efficacy of UC-MSCs in treating refractory ITP. The research design included administering UC-MSCs at escalating doses of 0.5 × 10 6 cells/kg, 1.0 × 10 6 cells/kg, and 2.0 × 10 6 cells/kg weekly for four consecutive weeks across three cohorts during the dose-escalation phase, followed by a dose of 2.0 × 10 6 cells/kg weekly for the dose-expansion phase. Adverse events, platelet counts, and changes in peripheral blood immunity were monitored and recorded throughout the administration and follow-up period. Ultimately, 12 (with an addition of three patients in the 2.0 × 10 6 cells/kg group due to dose-limiting toxicity) and six patients were enrolled in the dose-escalation and dose-expansion phase, respectively. Thirteen patients (13/18, 72.2%) experienced one or more treatment emergent adverse events. Serious adverse events occurred in four patients (4/18, 22.2%), including gastrointestinal hemorrhage (2/4), profuse menstruation (1/4), and acute myocardial infarction (1/4). The response rates were 41.7% in the dose-escalation phase (5/12, two received 1.0 × 10 6 cells/kg per week, and three received 2.0 × 10 6 cells/kg per week) and 50.0% (3/6) in the dose-expansion phase. The overall response rate was 44.4% (8/18) among all enrolled patients. To sum up, UC-MSCs are effective and well tolerated in treating refractory ITP (ClinicalTrials.gov ID: NCT04014166).

Similar content being viewed by others

Effects of donor-specific antibodies on engraftment and long-term survival after allogeneic hematopoietic stem cell transplantation—A systematic review and meta-analysis

Comparable survival outcomes with haploidentical stem cell transplantation and cord blood transplantation

Outcome of human umbilical cord blood stem cell transplantation (CBT) for acute myeloid leukemia in patients achieving first complete remission after one versus two induction courses: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Introduction.

Immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease characterized by isolated thrombocytopenia, resulting from an imbalance of immune tolerance that leads to accelerated platelet destruction and impaired platelet production. 1 , 2 , 3 The most common clinical manifestations of ITP include the arrest in megakaryocyte maturation and reduction in platelet count. Treatments for adult patients with ITP include glucocorticoids, intravenous immunoglobulin, TPO receptor agonist (TPO-RA), rituximab, splenectomy, and immunosuppressants. 4 , 5 Refractory ITP refers to patients who have failed multiple therapies (including TPO-RA and rituximab) and/or have not responded or relapsed after splenectomy. 6 , 7 These patients often have aggravated bleeding symptoms, a severe decline in quality of life, and increased mortality. 6 , 7 However, the regimens recommended by the current guidelines have limited effectiveness in alleviating the situation, and patients with refractory ITP are in urgent need of novel therapies to overcome this dilemma. 8 , 9

Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, are pluripotent progenitor cells with regenerative and immunomodulatory properties. 10 Since Hillard Lazarus’s first report in 1995 on treating hematologic malignancies with autologous bone marrow-derived progenitor stromal cells, the application of MSCs has gradually increased. 11 Many preclinical and clinical studies have confirmed that MSCs can influence both innate and adaptive immune responses through paracrine or cell-to-cell contact mechanisms. 12 , 13 Current data show that 10 mesenchymal stem cell products have been approved for marketing worldwide and are mainly used for immunoregulation and injury repair in graft-versus-host disease (GVHD), Crohn’s disease, myocardial infarction, osteoarthritis and other diseases. 14 , 15 We and other researchers have previously found that MSCs from ITP patients showed defective haematopoietic support function, impaired proliferative capacity, and reduced suppression of activated T cells. Meanwhile, we compared and analyzed the characteristics of MSCs from different tissue sources through single-cell transcriptomic and proteomic sequencing, and found that perinatal mesenchymal stem cells had stronger immunosuppressive ability than bone marrow-derived and adipose-derived MSCs. 16 Therefore, correcting the impaired autologous MSCs by drugs or infusion of exogenous umbilical cord-derived MSCs (UC-MSCs) may partly reshape the immune microenvironment in patients with ITP. 17 , 18

In the past decade, several researchers have attempted small-sample studies on the treatment of ITP using UC-MSCs and achieved the expected results. In 2012, we first reported that two patients with chronic ITP showed effective improvement in platelet count and bleeding symptoms after the administration of UC-MSCs (4.0 × 10 5 cells/kg). 19 Five years later, Wang reported that four chronic ITP patients who received UC-MSC infusion with a total cell count ranging between 5.0 × 10 7 and 1.0 × 10 8 achieved complete remission, and three relapsed within one year. 20 Although the effectiveness of UC-MSCs in treating ITP has been recognized to some extent, there is no consensus on the dosage of infusion, and there is a lack of support from standardized clinical trial research evidence. 21

Given the limited research results on the clinical efficacy, optimal treatment timing and regimen of MSCs for treating patients with refractory ITP, we conducted a prospective clinical study to evaluate the safety and efficacy of UC-MSCs for treating refractory ITP patients and explored the appropriate dose of UC-MSC therapy.

Patient characteristics

Between November 2019 and August 2022, 18 refractory ITP patients hospitalized in our center were successfully screened and enrolled in the study, including 12 patients in the dose escalation and 6 patients in the dose expansion phase (Fig. 1 ). The demographics and baseline characteristics of all eligible patients are shown in Table 1 and Supplementary Table S1 . The median age of the patients was 44 years old (range: 30–50), and 15/18 patients (83.3%) were female. All of the participants were chronic ITP patients with a median duration of 73 months (range: 15–360). A total of 15/18 patients (83.3%) had 5 or more unique prior therapies (Supplementary Table S2 ). A total of 10/18 patients (55.6%) and 13/18 patients (72.2%) had previously received splenectomy and rituximab, respectively. Platelet glycoprotein (GP) autoantibodies were detected by a commercial kit (PakAutoassay, Immucor GTI Diagnostics, USA), and 11/18 patients (61.1%) showed positive results, including anti-GP Ib/IX single positive (2/18, 11.1%), anti-GP IIb/IIIa single positive (6/18, 33.3%), and anti-GP IIb/IIIa and GP Ia/IIa double positive (3/18, 16.7%).

Flow diagram of the study. Twenty-two patients were screened for eligibility, 3 patients were excluded based on the eligibility criteria, and one patient withdrew informed consent. Finally, 18 patients were enrolled in the study. In the dose-escalation phase, 12 patients were enrolled and assigned to the 3-dose group, and 6 patients were subsequently enrolled in the dose-expansion phase

Safety and tolerability

During the dose-escalation phase, three patients were sequentially enrolled in each of the three predetermined dose groups and received UC-MSC treatment according to the protocol. Unfortunately, one patient in 2.0 × 10 6 cells/kg group experienced a grade 3 treatment-related adverse event (acute myocardial infarction) 10 days after the fourth infusion of UC-MSCs, and it was determined by experts from the academic and ethics committee as a dose-limiting toxicity event (DLT) (Supplementary Fig. S1 ). Therefore, we added three more patients to the 2.0 × 10 6 cells/kg group, and no DLT was reported in these patients. Based on this, we determined 2.0 × 10 6 cells/kg as the dosage for the subsequent dose-expansion phase.

All 18 patients enrolled in the study successfully finished the full course (four times) of UC-MSC infusion. Within the 28-week UC-MSC treatment and follow-up period, 13 patients (13/18, 72.2%) had one or more treatment emergent adverse events (TEAEs), most of which were grade 1 or 2, and all of them recovered spontaneously or after short-term intervention. The detailed adverse events (AEs) are presented in Table 2 . Briefly, the most common TEAEs were fatigue (5/18, 27.8%), blood bilirubin elevation (4/18, 22.2%) and uric acid elevation (3/18, 16.7%). Three patients reported treatment-related adverse events (TRAEs), including two cases of infusion-related reaction and one case of acute myocardial infarction that occurred ten days after the fourth infusion (with platelet count <30 × 10 9 /L at onset), which was considered possibly related to the infusion of UC-MSCs. Two patients (2/18, 11.1%) in 1.0 × 10 6 cells/kg group experienced chest tightness that was spontaneously relieved during the first UC-MSC infusion.

Serious adverse events (SAEs) occurred in four patients (4/18, 22.2%), including patient 006 in 1.0 × 10 6 cells/kg group, patients 007 and 009 in 2.0 × 10 6 cells/kg group, and patient 014 in the expansion cohort. Patients 006 and 014 experienced grade 3 gastrointestinal hemorrhage, and patient 009 had profuse menstruation during UC-MSC treatment, these were all thought to be associated with thrombocytopenia. Patient 007 experienced the DLT event mentioned above. To date, all patients enrolled and treated with UC-MSCs have not reported any AEs of malignant neoplasms.

The efficacy of UC-MSCs was analyzed separately for the dose-escalation phase and the dose-expansion phase (Supplementary Table S3 ). Excluding the influence of rescue therapy, the platelet response (R, defined as platelet count ≥30 × 10 9 /L, with at least 2-fold increase from the baseline count and the absence of bleeding) was achieved by 5 patients (41.7%, 5/12) in the dose-escalation phase, and 3 patients (50.0%, 3/6) in the dose-expansion phase. The overall response rate was 44.4% (8/18), with a median cumulative response duration of 6.5 weeks (range 3–27). The median time to the first platelet count ≥50 × 10 9 /L was 21 days (range: 7–42) (Supplementary Fig. S2 ).

Amone the 5 patients who achieved a response in the dose-escalation phase, 2 belonged to the 1.0 × 10 6 cells/kg group, and 3 belonged to the 2.0 × 10 6 cells/kg group. Therefore, the efficacy rate was 0.0% (0/3) for the 0.5 × 10 6 cells/kg group, 66.7% (2/3) for the 1.0 × 10 6 cells/kg group, and 50.0% (3/6) for the 2.0 × 10 6 cells/kg group. The median cumulative response duration among responding patients was 4.5 weeks (range: 3–6) in the 1.0 × 10 6 cells/kg group and 27 weeks (range: 7–27) in the 2.0 × 10 6 cells/kg group, respectively. The proportions of patients with platelet counts ≥50 × 10 9 /L at least once were 0.0% (0/3) in the 0.5 × 10 6 cells/kg group, 66.7% (2/3) in the 1.0 × 10 6 cells/kg group, and 50.0% (3/6) in the 2.0 × 10 6 cells/kg group. The proportions of patients with platelet counts ≥100 × 10 9 /L at least once were 0.0% (0/3), 66.7% (2/3), and 33.3% (2/6), respectively.

In the dose-expansion phase, three patients met a response, resulting in an efficacy rate of 50.0% (3/6). All three responding patients achieved platelet counts ≥50 × 10 9 /L at least once, with a median cumulative response duration of 6 weeks (range: 3–8). The proportions of patients with platelet counts ≥100 × 10 9 /L at least once was 50.0% (3/6).

After four weeks of UC-MSC treatment, patients in each group showed an improvement in the bleeding symptoms (Supplementary Table S4 ). Six patients (6/12, 50.0%) and five patients (5/6, 83.3%) were treated with rescue therapy in the dose-escalation phase and dose-expansion phase, respectively (Supplementary Table S5 ). Nine patients (9/18, 50.0%) had concomitant medications in the study (Supplementary Table S6 ). Each patient’s concomitant medications, response and rescue therapy are shown as a bar chart in Fig. 2a . The mean platelet counts with standard errors from baseline to week 28 in all patients are shown in Fig. 2b .

Treatment response, outcomes and platelet counts over time in all patients. a The best responses, concomitant medications, and rescue therapy of all 18 patients with different infusion doses (0.5 × 10 6 cells/kg, 1.0 × 10 6 cells/kg, and 2.0 × 10 6 cells/kg) are shown in the swimmer plot. GC glucocorticoids, TPO-RA thrombopoietin receptor agonist, R response. b The mean platelet counts of all enrolled patients from baseline to 24 weeks after the completion of UC-MSC administration. Data are the mean ± s.e.m., and different colors represent different infusion doses of UC-MSCs

Patient 008 relapsed 30 weeks after the first UC-MSC infusion, and patient 010 did not experience recurrence after one year of follow-up with eltrombopag 25 mg/day (the maintenance dose for three months before enrollment was 75 mg/day). Patient 007 relapsed 13 weeks after the first UC-MSC infusion, but the patient was no longer bleeding, and the platelet count was consistently >30 × 10 9 /L for 16 months of follow-up thereafter.

Compassionate use of UC-MSCs

In total, we infused 19 courses of UC-MSCs in this study. Patient 008 received another course of UC-MSC (2.0 × 10 6 cells/kg) treatment after relapse and reached treatment response again. However, the maximum platelet count after redosing was lower than that in the first course (61 × 10 9 /L vs. 89 × 10 9 /L), and the cumulative response time was also decreased (8 weeks vs. 30 weeks). TRAEs did not occur during the next 28 weeks.

Pharmacokinetics of UC-MSCs

A total of eight patients underwent pharmacokinetics assays with informed consent (Supplementary Table S7 ). The SRY gene started to be detectable in the peripheral blood of all patients at 30 min and could last for 4 h in most patients. There was no detectable human-specific sequence in the blood 8 h after injection (except patient 005). Collectively, the longest peripheral blood residence time for MSCs administered via intravenous infusion in this study was 8 h.

Humoral immunogenicity

Anti-drug antibodies (ADA) were analyzed pre-cell (−1 h ~ 0 h) and after-cell (48 h after the 4th MSC infusion) infusion in 12 patients (Supplementary Table S8 ). No ADA was detected at any time point, which demonstrated that there was no occurrence of ADA in patients after UC-MSC infusion.

Immunological changes in the peripheral blood after UC-MSC treatment

Differences in the peripheral immune environment of ITP patients before and after infusion were assessed through flow cytometry analysis (Fig. 3 and Supplementary Figs. S3 – S8 ). Due to the impact of COVID-19, some follow-up data of the enrolled patients were missing. Consequently, for the evaluation of peripheral immune alterations, we consolidated observations at 16 weeks and 24 weeks, presenting them as ≥16 weeks.

The peripheral immune monitoring plan of enrolled patients and the dynamic changes in peripheral blood immune cells after receiving UC-MSC infusion. a Blood samples were collected from all enrolled patients for platelet count and peripheral blood immune subpopulation monitoring at baseline and 2, 4, 8, 12, 16 and 24 weeks after the first infusion (peripheral blood samples at the baseline and 2 week observation points were collected within 2 h before the UC-MSC infusion). b , c Changes in the proportion of CD8+ T cells in peripheral lymphocytes after UC-MSC infusion ( n  = 8 in the response group, n  = 8 in the no response group). d , e Changes in the proportion of suppressor T cells (Tregs, CD8 + CD28 − T cells) after UC-MSC infusion ( n  = 8 in the response group, n  = 10 in the no response group). f , g Dynamic changes in the counts and percentages of CD19 + B cells in peripheral blood after UC-MSC infusion ( n  = 8 in the response group, n  = 9 in the no response group). Due to the impact of COVID-19, some follow-up data of enrolled patients were missing. Consequently, for the evaluation of peripheral immune alterations, we consolidated observations at 16 weeks and 24 weeks, presenting them as ≥16 weeks. Data are the mean ± s.e.m., and different colors represent different infusion doses of UC-MSCs in the scatterplots: purple = 0.5 × 10 6 cells/kg, green = 1.0 × 10 6 cells/kg, red = 2.0 × 10 6 cells/kg. Statistical analysis was conducted using independent samples t -tests or Wilcoxon signed-rank test, with a significance level set at p  < 0.05. W weeks, R response, NR no response

Comparing baseline immune profiles between responsive and non-responsive patients, we found that responders displayed slightly higher percentages and absolute counts of T lymphocytes, whereas B cell metrics displayed the opposite trend. However, these variances lacked statistical significance (Supplementary Fig. S3 ). The infusion period of UC-MSCs was characterized by a transient reduction in both the proportion and absolute count of peripheral T lymphocytes. In the subsequent follow-up period, these metrics exhibited a gradual upward trend, especially in the proportion of CD8 + T cells, with this increase being slightly more evident in the response group compared to the no response group, though not reaching statistical significance (Fig. 3b, c and Supplementary Fig. S4a–g ). Notably, a significant gradual increase in the proportion of CD8 + CD28 − T cells was observed in the response group. Conversely, the proportion of T regulatory cells (Tregs, CD4 + CD25 + CD127 dim/− ) significantly rose in the no response group. The absolute counts of CD8 + CD28 − T cells and Tregs demonstrated a similar pattern throughout the study period in both groups (Fig. 3d, e and Supplementary Figs. S5 and S6 ). Additionally, marginal decreases in the percentages of naïve (CD45RA + CCR7 + T cells) and central memory (CD45RA − CCR7 + T cells) T lymphocytes were observed in responsive patients (Supplementary Fig. S7 ). B cell monitoring revealed similar outcomes to T cells, though baseline B cell proportions were higher in non-responsive patients than in responsive patients (Fig. 3f, g and Supplementary Fig. S4h ), with no significant difference in the suppressor B-cell subset (CD19 + CD38 hi CD24 hi ) between two groups (Supplementary Fig. S8 ).

Quantitative analysis of plasma cytokine concentrations before and after UC-MSC infusion (0, 2, 4 weeks) in patients revealed that there were no statistically significant differences in baseline cytokine levels between the response and no response groups. However, patients in the no response group showed a significant increase in plasma levels of various inflammatory cytokines, including IL-1β, IL-2, IL-6, and IL-17, after receiving UC-MSC infusion, whereas such changes were not observed in the response group (Fig. 4 ).

Quantitative analysis of plasma cytokine concentrations before and after UC-MSC infusion. The concentrations of 12 kinds of cytokines were measured before (0), during UC-MSC infusion (2 weeks), and after UC-MSC infusion (4 weeks) in the response and no response group, respectively ( n  = 8 in the response group, n  = 10 in the no response group). The levels of plasma IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17A, IFN-α, and TNF-α had significantly increased after the infusion of UC-MSC (all p  < 0.05). No significant changes were observed in the response group before and after the UC-MSC infusion. Data are the mean ± s.e.m., circle represents response group, square represents no response group. And different colors represent different infusion doses of UC-MSCs in the scatterplots: purple = 0.5 × 10 6 cells/kg, green = 1.0 × 10 6 cells/kg, red = 2.0 × 10 6 cells/kg. Statistical analysis was conducted using paired t -test or Wilcoxon signed-rank test, with a significance level set at p  < 0.05. W weeks, R response, NR no response

To our knowledge, this is the first prospective, open-label study that evaluated the safety and efficacy of UC-MSC infusion in refractory ITP and was first successfully documented by the China Medicinal Biotechnology Association. Although previous case reports and small sample studies have suggested that allogeneic MSC infusion may reshape immune homeostasis, improve platelet counts and alleviate bleeding symptoms in ITP patients, the sources of MSCs used in these studies vary greatly, and there are significant differences in the infusion doses used in different studies. 18 , 21 In the dose-escalation phase of this study, we compared and analyzed the safety and efficacy of UC-MSC therapy for refractory ITP under three different doses and established 2.0 × 10 6 cells/kg as the infusion dose for the dose-expansion phase.

As the most important study endpoint of this research, 72.2% of the enrolled patients experienced TEAEs after treatment, most of which were grade 1–2. Grade 3 bleeding manifestations (gastrointestinal hemorrhage, profuse menstruation) occurred in three patients, which may be attributable to the fact that all subjects in this study were refractory ITP patients with bleeding tendency and the limited efficacy of UC-MSCs. The DLT in this study was acute myocardial infarction, which was reported in one patient in the 2.0 × 10 6 cells/kg group. Although there is no previous report that MSC infusion can induce thrombotic events, the platelet count on set was low, and there was no previous history of cardiovascular disease or risk factors, so UC-MSC infusion could not be ruled out. 22 Notably, 22.2% of the subjects reported elevated liver transaminase (all incidents were Grade 1 AEs) during the observation period, which were considered related to the long-term use of concomitant drugs (danazol or TPO-RAs).

All 18 patients included in the study completed the UC-MSC treatment successfully, with an overall effective rate of 44.4% (8/18), and four patients (4/18, 22.2%) reached complete response after treatment. However, the 2.0 × 10 6 cells/kg dosage did not show the expected advantage compared to the 1.0 × 10 6 cells/kg dosage in achieving long-term remission (≥6 months, data not shown) after the infusion of UC-MSCs. Results in the dose-escalation phase reveal a dose-dependent trend in the efficacy of UC-MSCs in the dose range of 0.5–2.0 × 10 6 cells/kg, but this tendency is less pronounced when analyzing data from both phases together. UC-MSC therapy is also effective in patients who have failed or relapsed after undergoing splenectomy or rituximab. The response rates among patients who had previously undergone splenectomy or rituximab were 40.0% (4/10) and 46.2% (6/13), respectively. Patients who had received both splenectomy and rituximab previously showed a similar response rate (40.0%, 2/5). In addition, our results indicated that bleeding symptoms can be completely relieved in 60.0%–75.0% of patients after treatment, supporting the feasibility of mesenchymal stem cells as an auxiliary or emergency treatment option.

In this study, we provided some insights into the circulation dynamics of UC-MSCs by detecting the SRY gene in peripheral blood. This approach minimizes patient discomfort and is ethically acceptable. However, it cannot provide information about the distribution and metabolism of UC-MSCs in organ tissues, which is a limitation of our research. We anticipate the development of more advanced methods in the future that can simultaneously monitor the distribution and metabolism of UC-MSCs in both peripheral blood and tissues. Such advancements will contribute to a more comprehensive understanding of the potential mechanisms underlying UC-MSC treatment for refractory ITP and variations in treatment efficacy among individuals.

Previous in vitro and in vivo studies have shown that mesenchymal stem cells exert immunomodulatory effects mainly through paracrine or direct cell contact, and the main target cells are T cells. 23 , 24 In this study, we monitored peripheral blood immune cell subsets before and after UC-MSC infusion. Our findings indicate a temporary decrease in T cell percentages during the infusion of UC-MSCs, followed by a gradual increase in the proportion of CD8 + CD28 − suppressive T cell subsets. These observations would lend further support to the notion that the immunosuppressive actions of MSCs in vivo are predominantly directed at T cells, particularly in attenuating the activation of CD8 + T cells. Nonetheless, given the limited sample size and variability in dosage among patients, these results warrant confirmation through larger-scale, randomized controlled trials. In addition, we also observed a decrease in the proportion of B cells after infusion, which was considered to be associated with the inhibition of T cells by UC-MSCs indirectly affecting the activation of B cells. 25 The immunomodulatory capacity of MSCs is plastic and is believed to depend upon the kinds and concentration of inflammatory medicators as well as the intensity of the immune microenvironment activation. 26 Quantitative analysis of peripheral blood plasma cytokines revealed a predominant elevation in proinflammation cytokines in the no response group, which implied that the failure of UC-MSC treatment might be partly associated with the intricate state of the inflammation microenvironment.

This study has several limitations. Firstly, it is a single-arm, non-randomized controlled trial with a small sample size. Additionally, the total duration of follow-up was relatively short, and the COVID-19 pandemic resulted in missing data at certain follow-up points for some participants. Moreover, the limited sample size precluded the possibility of conducting subgroup analyses, including those pertinent to changes in peripheral blood immune status post-UC-MSC infusion. Therefore, the results pertaining to safety and efficacy reported in this study should be validated through future large-scale, randomized, multicentre clinical trials.

Overall, UC-MSC infusion achieved a 44.4% overall response rate in patients with refractory ITP and mild adverse events. The related mechanism may involve inhibiting T-cell activation and inducing the production of suppressor CD8+ T cells. However, given the limited sample size and expansion dosage of this study, the results need to be further verified by clinical trials with larger sample sizes and higher infusion doses.

Study design

This prospective, open-label, phase I study consisted of two parts: a dose-escalation phase for exploring the safety and efficacy of three different dosage groups according to the traditional 3 + 3 protocol and a dose-expansion phase for further verifying the optimal UC-MSC dosage (Fig. 1 ). 27 , 28 The study protocol was approved by the Ethics Committees of the Institute of Hematology and Blood Diseases Hospital, and informed consent was obtained from each participant according to the Declaration of Helsinki (ClinicalTrials.gov ID: NCT04014166).

UC-MSC product preparation

Off-the-shelf GMP-grade male infant-derived UC-MSCs were provided by Tianjin Amcellgene Co. Ltd., which has been approved by the China National Medical Products Administration (NMPA) with agreements to start clinical trials for GVHD and acute chronic liver failure (ACLF). This cryopreserved product is a mixture containing 2.0 × 10 7 UC-MSCs, 10% DMSO, and 5% human serum albumin, which needs to be thawed in a 37 °C water bath and diluted with multiple electrolyte injections (20 ml) before infusion into patients.

Patients and treatments

Patients diagnosed with refractory ITP according to the international consensus on the identifying and treating of refractory immune thrombocytopenia were screened for the study. 7 , 29 The major inclusion criteria included age 18 to 60 years, ITP duration lasting for more than 6 months, platelet count <30 × 10 9 /L and concomitant bleeding manifestations at enrollment. Patients were allowed to have concomitant treatments (TPO-RAs, glucocorticoids, danazol), but the doses must have been stable at the time of enrollment. Patients who had thrombosis, malignant tumors or severe dysfunction of vital organs (liver, kidney, lung, heart) were excluded from the study (see Supplementary Methods for details).

In the dose escalation phase, eligible patients were divided into three different dose groups sequentially. The UC-MSCs were administered once a week for a total of four times (0.5 × 10 6 cells/kg group; 1.0 × 10 6 cells/kg group; 2.0 × 10 6 cells/kg group). Subsequently, the investigator determined an optimal dose to expand the sample size by referring to the results of the dose escalation phase. In addition, during the UC-MSC infusion and follow-up period, the dosage of concomitant medications should be kept stable or gradually tapered. If the participants had sustained thrombocytopenia (platelet count <30 × 10 9 /L) or severe bleeding manifestations during the follow-up period, the investigators should propose appropriate rescue therapy or advise the patient to withdraw from the study. Moreover, if the patient did not respond well to all of the current ITP regimens and was willing to have UC-MSCs administered again, a course of UC-MSC treatment could be given again 16 weeks after the first infusion.

Patients needed to visit every week from day 1 to day 112 and every month for three months thereafter to collect data on safety and efficacy outcomes, pharmacokinetic data of UC-MSCs, incidence of UC-MSC antibodies and changes in immune status.

Pharmacokinetic study

An exploratory pharmacokinetic study was conducted to clarify the retention time of UC-MSCs in peripheral blood after injection. Briefly, the blood samples of female subjects who had never gave birth to a male infant were collected before (−1 h～0 h) and after (30 min, 1, 2, 4, 8, 16, 24, 48, 72, and 96 h) UC-MSCs infusion. Then, total DNA was extracted for PCR assays to detect the specific human DNA sequence as the SRY gene according to the manufacturer’s instructions. The operation range of the standard curve should have covered 4.00 × 10 1 –1.00 × 10 7 copies/reaction.

Anti-MSC antibody detection assay

The GMP-grade UC-MSCs were dissociated into single cells by 0.25% Trypsin-EDTA (Gibco), incubated with ADA samples for up to 30 min, and then labeled with conjugated antibodies against protein L-PE (Sino Biological) for 15 min in the dark. After washing with PBS twice, the cells were analyzed by FACS Canto II (BD Biosciences, USA) according to the instructions.

Cell staining and flow cytometry

To monitor the influence of UC-MSC infusion on peripheral immune cells, blood samples were collected from patients at various monitoring points (Fig. 3a ) and stained with antibodies (Supplementary Methods). Then, the samples were lysed with lysis buffer (BD Biosciences, USA) and washed twice with PBS. Stained cells were analyzed by FACS Canto II cytometry (BD Biosciences, USA). Quantitatively analyzed the concentrations of 12 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-17, IFN-γ, IFN-α, and TNF-α) in peripheral blood plasma using flow cytometry bead-based assay (ABplex Human Chemokine 12-Plex Assay Kit, ABclonal).

The primary endpoints were the safety and tolerability of UC-MSCs, which were reflected by the DLT. The National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 was used as the principle for grading and recording AEs throughout the study. The main evaluation indexes consist of physical examination, laboratory tests (liver function, renal function, electrocardiography, and virological examination) and infusion-related reactions. DLT was defined as any grade ≥3 TRAEs that occurred during the first administration to 1 month post completion of UC-MSCs and could not be relieved to grade 1 within 72 h after treatment with drugs or other interventions. The correlation between treatment and AEs was determined by the principal investigator. The secondary endpoints were the efficacy, pharmacokinetic and immunological data of UC-MSCs. Clinical response was evaluated according to the efficacy criteria of ITP, as outlined in the Supplementary Methods. 30 Response (R) was defined as platelet count ≥30 × 10 9 /L, with at least 2-fold increase from the baseline count and the absence of bleeding. No response (NR) was defined as platelet count <30 × 10 9 /L or less than 2-fold increase from the baseline platelet count or the presence of bleeding. Relapse was defined as a platelet count <30 × 10 9 /L, or less than a doubling of the baseline count, or bleeding, which occurring after the achievement of a response. The efficacy endpoint was the proportion of patients with platelet count ≥30 × 10 9 /L at least doubling of the baseline count, ≥50 × 10 9 /L, and ≥100 × 10 9 /L at least once after receiving UC-MSCs. Changes in WHO bleeding score after treatment were assessed based on the World Health Organization’s Bleeding Scale. 31

Statistical analysis

All statistical analyses were mainly descriptive and conducted using SPSS v26.0 and GraphPad Prism 9.0 software. Quantitative data are presented as medians (minimum and maximum), and qualitative data are presented as n (%). Statistical differences in the immunological changes between the effective and ineffective groups were calculated using independent sample t -test, paired t -test or Wilcoxon signed-rank test, with p values less than 0.05 considered statistically significant. Summary tables for AEs had to include all AEs that occurred in the whole period of study.

Data availability

Eligible researchers can request data sets, including unidentified individual subject data. Data may be available on request from the corresponding author from 12 to 36 months after trial completion.

Audia, S. et al. Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia. Blood 124 , 2858–2866 (2014).

Article   CAS   PubMed   Google Scholar  

Liu, Y. et al. Deciphering transcriptome alterations in bone marrow hematopoiesis at single-cell resolution in immune thrombocytopenia. Signal Transduct. Target. Ther. 7 , 347 (2022).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Cooper, N. & Ghanima, W. Immune thrombocytopenia. N. Engl. J. Med. 381 , 945–955 (2019).

Article   PubMed   Google Scholar  

Neunert, C. et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 3 , 3829–3866 (2019).

Provan, D. et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 3 , 3780–3817 (2019).

Article   PubMed   PubMed Central   Google Scholar  

Miltiadous, O., Hou, M. & Bussel, J. B. Identifying and treating refractory ITP: difficulty in diagnosis and role of combination treatment. Blood 135 , 472–490 (2020).

Cuker, A. & Neunert, C. E. How I treat refractory immune thrombocytopenia. Blood 128 , 1547–1554 (2016).

Mahevas, M. et al. Characteristics, outcome, and response to therapy of multirefractory chronic immune thrombocytopenia. Blood 128 , 1625–1630 (2016).

Arnold, D. M. et al. Combination immunosuppressant therapy for patients with chronic refractory immune thrombocytopenic purpura. Blood 115 , 29–31 (2010).

Zhao, K. et al. Mesenchymal stromal cells plus basiliximab, calcineurin inhibitor as treatment of steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3, open-label trial. J. Hematol. Oncol . 15 , 22 (2022).

Lazarus, H. M., Haynesworth, S. E., Gerson, S. L., Rosenthal, N. S. & Caplan, A. I. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 16 , 557–564 (1995).

CAS   PubMed   Google Scholar  

Ren, G. et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2 , 141–150 (2008).

Augello, A. et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur. J. Immunol. 35 , 1482–1490 (2005).

Wang, L. L. et al. Cell therapies in the clinic. Bioeng. Transl. Med. 6 , e10214 (2021).

Cheng, L. et al. Human umbilical cord mesenchymal stem cells for psoriasis: a phase 1/2a, single-arm study. Signal Transduct. Target. Ther. 7 , 263 (2022).

Gao, Y. et al. Multi-omics analysis of human mesenchymal stem cells shows cell aging that alters immunomodulatory activity through the downregulation of PD-L1. Nat. Commun. 14 , 4373 (2023).

Di Paola, A. et al. Eltrombopag in paediatric immune thrombocytopenia: iron metabolism modulation in mesenchymal stromal cells. Br. J. Haematol. 197 , 110–119 (2022).

Li, H. et al. Role of bone marrow-derived mesenchymal stem cell defects in CD8(+) CD28(−) suppressor T-lymphocyte induction in patients with immune thrombocytopenia and associated mechanisms. Br. J. Haematol. 191 , 852–862 (2020).

Ma, L. et al. Immunosuppressive function of mesenchymal stem cells from human umbilical cord matrix in immune thrombocytopenia patients. Thromb. Haemost. 107 , 937 (2012).

Wang, X. et al. Intravenous infusion umbilical cord-derived mesenchymal stem cell in primary immune thrombocytopenia: a two-year follow-up. Exp. Ther. Med. 13 , 2255–2258 (2017).

Wu, F. et al. Therapeutic potential of MSCs and MSC-derived extracellular vesicles in immune thrombocytopenia. Stem Cell Res. Ther 14 , 79 (2023).

Lalu, M. M. et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS ONE 7 , e47559 (2012).

Di Nicola, M. et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99 , 3838–3843 (2002).

Ghannam, S., Pene, J., Moquet-Torcy, G., Jorgensen, C. & Yssel, H. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J. Immunol. 185 , 302–312 (2010).

Ruterbusch, M., Pruner, K. B., Shehata, L. & Pepper, M. In vivo CD4(+) T cell differentiation and function: revisiting the Th1/Th2 paradigm. Annu. Rev. Immunol. 38 , 705–725 (2020).

Wang, Y., Chen, X., Cao, W. & Shi, Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat. Immunol. 15 , 1009–1016 (2014).

Storer, B. E. Design and analysis of phase I clinical trials. Biometrics 45 , 925–937 (1989).

Le Tourneau, C., Lee, J. J. & Siu, L. L. Dose escalation methods in phase I cancer clinical trials. J. Natl. Cancer Inst. 101 , 708–720 (2009).

Provan, D. et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 115 , 168–186 (2010).

Rodeghiero, F. et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113 , 2386–2393 (2009).

Fogarty, P. F., Tarantino, M. D., Brainsky, A., Signorovitch, J. & Grotzinger, K. M. Selective validation of the WHO Bleeding Scale in patients with chronic immune thrombocytopenia. Curr. Med. Res. Opin. 28 , 79–87 (2012).

Download references

Acknowledgements

This project was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS) (grant numbers 2020-I2M-C&T-B-086, 2022-I2M-2-003, and 2021-I2M-1-073), the National Key Research and Development Program of China (grant numbers 2021YFA1101603, 2023YFC2507802), and the National Natural Science Foundation of China (grant numbers 82270152, 81970121, 82070125, 82170127, and 82100151). The authors would like to acknowledge Xuan Liang from Yiducloud (Beijing) Technology Ltd. for his assistance in the data analysis. The authors appreciate all the patients for participating in this study.

Author information

These authors contributed equally: Yunfei Chen, Yanmei Xu, Ying Chi, Ting Sun, Yuchen Gao

Authors and Affiliations

State Key Laboratory of Experimental Hematology, National Clinical Research Centre for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China

Yunfei Chen, Yanmei Xu, Ying Chi, Ting Sun, Yuchen Gao, Zhibo Han, Feng Xue, Huiyuan Li, Wei Liu, Xiaofan Liu, Huan Dong, Rongfeng Fu, Mankai Ju, Xinyue Dai, Wentian Wang, Yueshen Ma, Zhen Song, Renchi Yang & Lei Zhang

Tianjin Institutes of Health Science, Tianjin, 301600, China

Yunfei Chen, Yanmei Xu, Ying Chi, Ting Sun, Yuchen Gao, Feng Xue, Huiyuan Li, Wei Liu, Xiaofan Liu, Huan Dong, Rongfeng Fu, Mankai Ju, Xinyue Dai, Wentian Wang, Yueshen Ma, Zhen Song, Renchi Yang & Lei Zhang

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

Xueqing Dou

National Engineering Research Centre of Cell Products, Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, AmCellGene Engineering Co., Ltd, Tianjin, 300457, China

Zhibo Han, Jundong Gu & Wei Gong

School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China

You can also search for this author in PubMed   Google Scholar

Contributions

L. Z. designed the clinical trial. Y. C., Y. X., Y. G., Y. C., and T. S. executed the study, collected the data, and drafted the manuscript. X. D., F. X., W. L., X. L., H. D., R. F., M. J., X. D., H. L., W. W., and R. Y. contributed to the patient follow-up and data collection. Z. H., J. G., and W. G. were responsible for conducting the anti-drug antibody and pharmacokinetic assays. Y. M. and Z. S. contributed to the statistical analysis of the data and for editing the manuscript. Y. X. and Y. G. were responsible for the design of figures in manuscript and Supplementary Appendix. All authors reviewed and approved the final version of this manuscript.

Corresponding author

Correspondence to Lei Zhang .

Ethics declarations

Competing interests.

The authors declare no competing interests.

Supplementary information

Supplementary information, rights and permissions.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Cite this article.

Chen, Y., Xu, Y., Chi, Y. et al. Efficacy and safety of human umbilical cord-derived mesenchymal stem cells in the treatment of refractory immune thrombocytopenia: a prospective, single arm, phase I trial. Sig Transduct Target Ther 9 , 102 (2024). https://doi.org/10.1038/s41392-024-01793-5

Download citation

Received : 07 August 2023

Revised : 18 February 2024

Accepted : 02 March 2024

Published : 23 April 2024

DOI : https://doi.org/10.1038/s41392-024-01793-5

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies