research paper 55

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Patent Protection for Plants: Legal Options for Developing Countries

The paper examines, first, the exclusion of patent protection for plants, including plant varieties, biological materials, and essentially biological processes for the production of plants. The legal implications of the right – recognized under the TRIPS Agreement – to exclude plants from patent protection are briefly discussed, as well as how the exclusion allowed by article 27.3(b) of said Agreement has been implemented at the national level and, particularly, whether it can be extended to parts and components of plants.

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How To Write A Research Paper

Step-By-Step Tutorial With Examples + FREE Template

By: Derek Jansen (MBA) | Expert Reviewer: Dr Eunice Rautenbach | March 2024

For many students, crafting a strong research paper from scratch can feel like a daunting task – and rightly so! In this post, we’ll unpack what a research paper is, what it needs to do , and how to write one – in three easy steps. 🙂 

Overview: Writing A Research Paper

What (exactly) is a research paper.

• How to write a research paper
• Stage 1 : Topic & literature search
• Stage 2 : Structure & outline
• Stage 3 : Iterative writing
• Key takeaways

Let’s start by asking the most important question, “ What is a research paper? ”.

Simply put, a research paper is a scholarly written work where the writer (that’s you!) answers a specific question (this is called a research question ) through evidence-based arguments . Evidence-based is the keyword here. In other words, a research paper is different from an essay or other writing assignments that draw from the writer’s personal opinions or experiences. With a research paper, it’s all about building your arguments based on evidence (we’ll talk more about that evidence a little later).

Now, it’s worth noting that there are many different types of research papers , including analytical papers (the type I just described), argumentative papers, and interpretative papers. Here, we’ll focus on analytical papers , as these are some of the most common – but if you’re keen to learn about other types of research papers, be sure to check out the rest of the blog .

With that basic foundation laid, let’s get down to business and look at how to write a research paper .

Overview: The 3-Stage Process

While there are, of course, many potential approaches you can take to write a research paper, there are typically three stages to the writing process. So, in this tutorial, we’ll present a straightforward three-step process that we use when working with students at Grad Coach.

These three steps are:

• Finding a research topic and reviewing the existing literature
• Developing a provisional structure and outline for your paper, and
• Writing up your initial draft and then refining it iteratively

Let’s dig into each of these.

Need a helping hand?

Step 1: Find a topic and review the literature

As we mentioned earlier, in a research paper, you, as the researcher, will try to answer a question . More specifically, that’s called a research question , and it sets the direction of your entire paper. What’s important to understand though is that you’ll need to answer that research question with the help of high-quality sources – for example, journal articles, government reports, case studies, and so on. We’ll circle back to this in a minute.

The first stage of the research process is deciding on what your research question will be and then reviewing the existing literature (in other words, past studies and papers) to see what they say about that specific research question. In some cases, your professor may provide you with a predetermined research question (or set of questions). However, in many cases, you’ll need to find your own research question within a certain topic area.

Finding a strong research question hinges on identifying a meaningful research gap – in other words, an area that’s lacking in existing research. There’s a lot to unpack here, so if you wanna learn more, check out the plain-language explainer video below.

Once you’ve figured out which question (or questions) you’ll attempt to answer in your research paper, you’ll need to do a deep dive into the existing literature – this is called a “ literature search ”. Again, there are many ways to go about this, but your most likely starting point will be Google Scholar .

If you’re new to Google Scholar, think of it as Google for the academic world. You can start by simply entering a few different keywords that are relevant to your research question and it will then present a host of articles for you to review. What you want to pay close attention to here is the number of citations for each paper – the more citations a paper has, the more credible it is (generally speaking – there are some exceptions, of course).

Ideally, what you’re looking for are well-cited papers that are highly relevant to your topic. That said, keep in mind that citations are a cumulative metric , so older papers will often have more citations than newer papers – just because they’ve been around for longer. So, don’t fixate on this metric in isolation – relevance and recency are also very important.

Beyond Google Scholar, you’ll also definitely want to check out academic databases and aggregators such as Science Direct, PubMed, JStor and so on. These will often overlap with the results that you find in Google Scholar, but they can also reveal some hidden gems – so, be sure to check them out.

Once you’ve worked your way through all the literature, you’ll want to catalogue all this information in some sort of spreadsheet so that you can easily recall who said what, when and within what context. If you’d like, we’ve got a free literature spreadsheet that helps you do exactly that.

Step 2: Develop a structure and outline

With your research question pinned down and your literature digested and catalogued, it’s time to move on to planning your actual research paper .

It might sound obvious, but it’s really important to have some sort of rough outline in place before you start writing your paper. So often, we see students eagerly rushing into the writing phase, only to land up with a disjointed research paper that rambles on in multiple

Now, the secret here is to not get caught up in the fine details . Realistically, all you need at this stage is a bullet-point list that describes (in broad strokes) what you’ll discuss and in what order. It’s also useful to remember that you’re not glued to this outline – in all likelihood, you’ll chop and change some sections once you start writing, and that’s perfectly okay. What’s important is that you have some sort of roadmap in place from the start.

At this stage you might be wondering, “ But how should I structure my research paper? ”. Well, there’s no one-size-fits-all solution here, but in general, a research paper will consist of a few relatively standardised components:

• Introduction
• Literature review
• Methodology

Let’s take a look at each of these.

First up is the introduction section . As the name suggests, the purpose of the introduction is to set the scene for your research paper. There are usually (at least) four ingredients that go into this section – these are the background to the topic, the research problem and resultant research question , and the justification or rationale. If you’re interested, the video below unpacks the introduction section in more detail. 

The next section of your research paper will typically be your literature review . Remember all that literature you worked through earlier? Well, this is where you’ll present your interpretation of all that content . You’ll do this by writing about recent trends, developments, and arguments within the literature – but more specifically, those that are relevant to your research question . The literature review can oftentimes seem a little daunting, even to seasoned researchers, so be sure to check out our extensive collection of literature review content here .

With the introduction and lit review out of the way, the next section of your paper is the research methodology . In a nutshell, the methodology section should describe to your reader what you did (beyond just reviewing the existing literature) to answer your research question. For example, what data did you collect, how did you collect that data, how did you analyse that data and so on? For each choice, you’ll also need to justify why you chose to do it that way, and what the strengths and weaknesses of your approach were.

Now, it’s worth mentioning that for some research papers, this aspect of the project may be a lot simpler . For example, you may only need to draw on secondary sources (in other words, existing data sets). In some cases, you may just be asked to draw your conclusions from the literature search itself (in other words, there may be no data analysis at all). But, if you are required to collect and analyse data, you’ll need to pay a lot of attention to the methodology section. The video below provides an example of what the methodology section might look like.

By this stage of your paper, you will have explained what your research question is, what the existing literature has to say about that question, and how you analysed additional data to try to answer your question. So, the natural next step is to present your analysis of that data . This section is usually called the “results” or “analysis” section and this is where you’ll showcase your findings.

Depending on your school’s requirements, you may need to present and interpret the data in one section – or you might split the presentation and the interpretation into two sections. In the latter case, your “results” section will just describe the data, and the “discussion” is where you’ll interpret that data and explicitly link your analysis back to your research question. If you’re not sure which approach to take, check in with your professor or take a look at past papers to see what the norms are for your programme.

Alright – once you’ve presented and discussed your results, it’s time to wrap it up . This usually takes the form of the “ conclusion ” section. In the conclusion, you’ll need to highlight the key takeaways from your study and close the loop by explicitly answering your research question. Again, the exact requirements here will vary depending on your programme (and you may not even need a conclusion section at all) – so be sure to check with your professor if you’re unsure.

Step 3: Write and refine

Finally, it’s time to get writing. All too often though, students hit a brick wall right about here… So, how do you avoid this happening to you?

Well, there’s a lot to be said when it comes to writing a research paper (or any sort of academic piece), but we’ll share three practical tips to help you get started.

First and foremost , it’s essential to approach your writing as an iterative process. In other words, you need to start with a really messy first draft and then polish it over multiple rounds of editing. Don’t waste your time trying to write a perfect research paper in one go. Instead, take the pressure off yourself by adopting an iterative approach.

Secondly , it’s important to always lean towards critical writing , rather than descriptive writing. What does this mean? Well, at the simplest level, descriptive writing focuses on the “ what ”, while critical writing digs into the “ so what ” – in other words, the implications . If you’re not familiar with these two types of writing, don’t worry! You can find a plain-language explanation here.

Last but not least, you’ll need to get your referencing right. Specifically, you’ll need to provide credible, correctly formatted citations for the statements you make. We see students making referencing mistakes all the time and it costs them dearly. The good news is that you can easily avoid this by using a simple reference manager . If you don’t have one, check out our video about Mendeley, an easy (and free) reference management tool that you can start using today.

Recap: Key Takeaways

We’ve covered a lot of ground here. To recap, the three steps to writing a high-quality research paper are:

• To choose a research question and review the literature
• To plan your paper structure and draft an outline
• To take an iterative approach to writing, focusing on critical writing and strong referencing

Remember, this is just a b ig-picture overview of the research paper development process and there’s a lot more nuance to unpack. So, be sure to grab a copy of our free research paper template to learn more about how to write a research paper.

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55 Page Essay & Research Paper Examples

What does a 55 page essay look like? Find the answer below!

55 page essays are 13700 to 13750 words long (double-spaced 12 pt). They contain 137 to 183 paragraphs. A paper of such a length is rarely an essay. You’ll more likely be assigned a 55 page research paper or term paper at the graduate level.

How long does it take to write a 55 page essay? Such a long piece should be properly planned. If you need to perform research and add references, you’ll need at least 55 hours. Trying to complete such a serious task in one day is not a good idea.

If you’re searching for 55 page paper examples, look at the collection below. Get inspired to write your own piece with the samples we’ve prepared!

55-page Essay Examples: 25 Samples

Improved work environment for employees working at a production plant.

• Subjects: Business Management
• Words: 15428

Internationalization Process in China

• Subjects: Economics Globalization
• Words: 18058

Apple and Brand-Customer Relationship

• Subjects: Business Marketing
• Words: 14240

Real Estate Text Marketing in China

• Subjects: Economics Housing
• Words: 16003

Mergers: Cisco Systems Incorporation and Bay Networks

• Subjects: Business Company Analysis
• Words: 19381

Chronic Kidney Disease: Body Mass Index and Haemoglobin

• Subjects: Gastroenterology Health & Medicine
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“The War of the Worlds” a Novel by Herbert Wells

• Subjects: British Literature Literature
• Words: 15302

The Management of Police and Development of Law

• Subjects: Politics & Government Public Policies
• Words: 15158

Office Politics in a Multi-Cultural Setting

• Subjects: Business Corporate Culture
• Words: 15144

Strategies for Non-Profit Organisations

• Subjects: Business Strategic Management
• Words: 15174

Tourism Satisfaction and Loyalty: From UK to Shanghai

• Subjects: Effects of Tourism Tourism
• Words: 15090

Agricultural Policies in the EU vs. the US

• Subjects: Agriculture Sciences
• Words: 14960

Energy and Water Projects in the Middle East and North Africa

• Subjects: Economic Development Economics
• Words: 15234

Corporate Governance Practice: Nike in Vietnam

• Subjects: Business Corporate Governance
• Words: 11113

Tourists’ Attitude to Technology in China’s Heritage Tourism

• Subjects: Tourism Tourist Attractions
• Words: 15096

After-Sales Services and Innovative Approaches

• Words: 12584

Real Estate Situation in Manhattan and American Crisis

• Subjects: Big Economic Issues Economics
• Words: 14946

Innovations in Mobile Communication Devices

• Subjects: Phones Tech & Engineering
• Words: 14365

Diagnosing the Renal Artery Stenosis in Children

• Subjects: Health & Medicine Pediatrics
• Words: 15055

Marketing Communications: Expanding Apple’s Loyal Customer Base

• Subjects: Business Marketing Communication
• Words: 15159

Car Brands as Perceived in the UK and Worldwide

• Subjects: Business Industry
• Words: 14935

The Effect of Sleep Quality and IQ on Memory

• Subjects: Cognition and Perception Psychology
• Words: 12777

Oversight and the Expansion of the Five Eyes

• Subjects: Homeland Security Law
• Words: 15155

New Enterprise Start-up Plan: On-Demand Courier Service to Deliver Medicine

• Subjects: Business Entrepreneurship
• Words: 15616

Factors Leading Veterans to Homelessness

• Subjects: Society's Imperfections Sociology
• Words: 15009

Writing a Research Paper

This page lists some of the stages involved in writing a library-based research paper.

Although this list suggests that there is a simple, linear process to writing such a paper, the actual process of writing a research paper is often a messy and recursive one, so please use this outline as a flexible guide.

Discovering, Narrowing, and Focusing a Researchable Topic

• Try to find a topic that truly interests you
• Try writing your way to a topic
• Talk with your course instructor and classmates about your topic
• Pose your topic as a question to be answered or a problem to be solved

Finding, Selecting, and Reading Sources

You will need to look at the following types of sources:

• library catalog, periodical indexes, bibliographies, suggestions from your instructor
• primary vs. secondary sources
• journals, books, other documents

Grouping, Sequencing, and Documenting Information

The following systems will help keep you organized:

• a system for noting sources on bibliography cards
• a system for organizing material according to its relative importance
• a system for taking notes

Writing an Outline and a Prospectus for Yourself

Consider the following questions:

• What is the topic?
• Why is it significant?
• What background material is relevant?
• What is my thesis or purpose statement?
• What organizational plan will best support my purpose?

Writing the Introduction

In the introduction you will need to do the following things:

• present relevant background or contextual material
• define terms or concepts when necessary
• explain the focus of the paper and your specific purpose
• reveal your plan of organization

Writing the Body

• Use your outline and prospectus as flexible guides
• Build your essay around points you want to make (i.e., don’t let your sources organize your paper)
• Integrate your sources into your discussion
• Summarize, analyze, explain, and evaluate published work rather than merely reporting it
• Move up and down the “ladder of abstraction” from generalization to varying levels of detail back to generalization

Writing the Conclusion

• If the argument or point of your paper is complex, you may need to summarize the argument for your reader.
• If prior to your conclusion you have not yet explained the significance of your findings or if you are proceeding inductively, use the end of your paper to add your points up, to explain their significance.
• Move from a detailed to a general level of consideration that returns the topic to the context provided by the introduction.
• Perhaps suggest what about this topic needs further research.

Revising the Final Draft

• Check overall organization : logical flow of introduction, coherence and depth of discussion in body, effectiveness of conclusion.
• Paragraph level concerns : topic sentences, sequence of ideas within paragraphs, use of details to support generalizations, summary sentences where necessary, use of transitions within and between paragraphs.
• Sentence level concerns: sentence structure, word choices, punctuation, spelling.
• Documentation: consistent use of one system, citation of all material not considered common knowledge, appropriate use of endnotes or footnotes, accuracy of list of works cited.

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Home / Guides / Writing Guides / Paper Types / How to Write a Research Paper

How to Write a Research Paper

Research papers are a requirement for most college courses, so knowing how to write a research paper is important. These in-depth pieces of academic writing can seem pretty daunting, but there’s no need to panic. When broken down into its key components, writing your paper should be a manageable and, dare we say it, enjoyable task.

We’re going to look at the required elements of a paper in detail, and you might also find this webpage to be a  useful reference .

Guide Overview

• What is a research paper?
• How to start a research paper
• Get clear instructions
• Brainstorm ideas
• Choose a topic
• Outline your outline
• Make friends with your librarian
• Find quality sources
• Understand your topic
• A detailed outline
• Keep it factual
• Finalize your thesis statement
• Think about format
• Cite, cite and cite
• The editing process
• Final checks

What is a Research Paper?

A research paper is more than just an extra long essay or encyclopedic regurgitation of facts and figures. The aim of this task is to combine in-depth study of a particular topic with critical thinking and evaluation by the student—that’s you!

There are two main types of research paper: argumentative and analytical.

Argumentative  — takes a stance on a particular topic right from the start, with the aim of persuading the reader of the validity of the argument. These are best suited to topics that are debatable or controversial.

Analytical  — takes no firm stance on a topic initially. Instead it asks a question and should come to an answer through the evaluation of source material. As its name suggests, the aim is to analyze the source material and offer a fresh perspective on the results.

If you wish to further your understanding, you can  learn more here .

A required word count (think thousands!) can make writing that paper seem like an insurmountable task. Don’t worry! Our step-by-step guide will help you write that killer paper with confidence.

How to Start a Research Paper

Don’t rush ahead. Taking care during the planning and preparation stage will save time and hassle later.

Get Clear Instructions

Your lecturer or professor is your biggest ally—after all, they want you to do well. Make sure you get clear guidance from them on both the required format and preferred topics. In some cases, your tutor will assign a topic, or give you a set list to choose from. Often, however, you’ll be expected to select a suitable topic for yourself.

Having a research paper example to look at can also be useful for first-timers, so ask your tutor to supply you with one.

Brainstorm Ideas

Brainstorming research paper ideas is the first step to selecting a topic—and there are various methods you can use to brainstorm, including clustering (also known as mind mapping). Think about the research paper topics that interest you, and identify topics you have a strong opinion on.

Choose a Topic

Once you have a list of potential research paper topics, narrow them down by considering your academic strengths and ‘gaps in the market,’ e.g., don’t choose a common topic that’s been written about many times before. While you want your topic to be fresh and interesting, you also need to ensure there’s enough material available for you to work with. Similarly, while you shouldn’t go for easy research paper topics just for the sake of giving yourself less work, you do need to choose a topic that you feel confident you can do justice to.

Outline Your Outline

It might not be possible to form a full research paper outline until you’ve done some information gathering, but you can think about your overall aim; basically what you want to show and how you’re going to show it. Now’s also a good time to consider your thesis statement, although this might change as you delve into your source material deeper.

Researching the Research

Now it’s time to knuckle down and dig out all the information that’s relevant to your topic. Here are some tips.

Make Friends With Your Librarian

While lots of information gathering can be carried out online from anywhere, there’s still a place for old-fashioned study sessions in the library. A good librarian can help you to locate sources quickly and easily, and might even make suggestions that you hadn’t thought of. They’re great at helping you study and research, but probably can’t save you the best desk by the window.

Find Quality Sources

Not all sources are created equal, so make sure that you’re referring to reputable, reliable information. Examples of sources could include books, magazine articles, scholarly articles, reputable websites, databases and journals. Keywords relating to your topic can help you in your search.

As you search, you should begin to compile a list of references. This will make it much easier later when you are ready to build your paper’s bibliography. Keeping clear notes detailing any sources that you use will help you to avoid accidentally plagiarizing someone else’s work or ideas.

Understand Your Topic

Simply regurgitating facts and figures won’t make for an interesting paper. It’s essential that you fully understand your topic so you can come across as an authority on the subject and present your own ideas on it. You should read around your topic as widely as you can, before narrowing your area of interest for your paper, and critically analyzing your findings.

A Detailed Outline

Once you’ve got a firm grip on your subject and the source material available to you, formulate a detailed outline, including your thesis statement and how you are going to support it. The structure of your paper will depend on the subject type—ask a tutor for a research paper outline example if you’re unsure.

Get Writing!

If you’ve fully understood your topic and gathered quality source materials, bringing it all together should actually be the easy part!

Keep it Factual

There’s no place for sloppy writing in this kind of academic task, so keep your language simple and clear, and your points critical and succinct. The creative part is finding innovative angles and new insights on the topic to make your paper interesting.

Don’t forget about our  verb ,  preposition , and  adverb  pages. You may find useful information to help with your writing!

Finalize Your Thesis Statement

You should now be in a position to finalize your thesis statement, showing clearly what your paper will show, answer or prove. This should usually be a one or two sentence statement; however, it’s the core idea of your paper, and every insight that you include should be relevant to it. Remember, a thesis statement is not merely a summary of your findings. It should present an argument or perspective that the rest of your paper aims to support.

Think About Format

The required style of your research paper format will usually depend on your subject area. For example,  APA format  is normally used for social science subjects, while MLA style is most commonly used for liberal arts and humanities. Still, there are thousands of  more styles . Your tutor should be able to give you clear guidance on how to format your paper, how to structure it, and what elements it should include. Make sure that you follow their instruction. If possible, ask to see a sample research paper in the required format.

Cite, Cite and Cite

As all research paper topics invariably involve referring to other people’s work, it’s vital that you know how to properly cite your sources to avoid unintentional plagiarism. Whether you’re paraphrasing (putting someone else’s ideas into your own words) or directly quoting, the original source needs to be referenced. What style of citation formatting you use will depend on the requirements of your instructor, with common styles including APA and  MLA format , which consist of in-text citations (short citations within the text, enclosed with parentheses) and a reference/works cited list.

The Editing Process

It’s likely that your paper will go through several drafts before you arrive at the very best version. The editing process is your chance to fix any weak points in your paper before submission. You might find that it needs a better balance of both primary and secondary sources (click through to find  more info  on the difference), that an  adjective  could use tweaking, or that you’ve included sources that aren’t relevant or credible. You might even feel that you need to be clearer in your argument, more thorough in your critical analysis, or more balanced in your evaluation.

From a stylistic point of view, you want to ensure that your writing is clear, simple and concise, with no long, rambling sentences or paragraphs. Keeping within the required word count parameters is also important, and another thing to keep in mind is the inclusion of gender-neutral language, to avoid the reinforcement of tired stereotypes.

Don’t forget about our other pages! If you are looking for help with other grammar-related topics, check out our  noun ,  pronoun , and  conjunction  pages.

Final Checks

Once you’re happy with the depth and balance of the arguments and points presented, you can turn your attention to the finer details, such as formatting, spelling, punctuation, grammar and ensuring that your citations are all present and correct. The EasyBib Plus  plagiarism checker  is a handy tool for making sure that your sources are all cited. An EasyBib Plus subscription also comes with access to citation tools that can help you create citations in your choice of format.

Also, double-check your deadline date and the submissions guidelines to avoid any last-minute issues. Take a peek at our other grammar pages while you’re at it. We’ve included numerous links on this page, but we also have an  interjection  page and  determiner  page.

So you’ve done your final checks and handed in your paper according to the submissions guidelines and preferably before deadline day. Congratulations! If your schedule permits, now would be a great time to take a break from your studies. Maybe plan a fun activity with friends or just take the opportunity to rest and relax. A well-earned break from the books will ensure that you return to class refreshed and ready for your next stage of learning—and the next  research paper  requirement your tutor sets!

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Impact of COVID-19 pandemic on mental health in the general population: A systematic review

Jiaqi xiong.

a Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON

Orly Lipsitz

c Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario

Flora Nasri

Leanna m.w. lui, hartej gill, david chen-li, michelle iacobucci.

e Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

f Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore

Amna Majeed

Roger s. mcintyre.

b Department of Psychiatry, University of Toronto, Toronto, Ontario

d Brain and Cognition Discovery Foundation, Toronto, ON

Associated Data

As a major virus outbreak in the 21st century, the Coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented hazards to mental health globally. While psychological support is being provided to patients and healthcare workers, the general public's mental health requires significant attention as well. This systematic review aims to synthesize extant literature that reports on the effects of COVID-19 on psychological outcomes of the general population and its associated risk factors.

A systematic search was conducted on PubMed, Embase, Medline, Web of Science, and Scopus from inception to 17 May 2020 following the PRISMA guidelines. A manual search on Google Scholar was performed to identify additional relevant studies. Articles were selected based on the predetermined eligibility criteria.

Results: Relatively high rates of symptoms of anxiety (6.33% to 50.9%), depression (14.6% to 48.3%), post-traumatic stress disorder (7% to 53.8%), psychological distress (34.43% to 38%), and stress (8.1% to 81.9%) are reported in the general population during the COVID-19 pandemic in China, Spain, Italy, Iran, the US, Turkey, Nepal, and Denmark. Risk factors associated with distress measures include female gender, younger age group (≤40 years), presence of chronic/psychiatric illnesses, unemployment, student status, and frequent exposure to social media/news concerning COVID-19.

Limitations

A significant degree of heterogeneity was noted across studies.

Conclusions

The COVID-19 pandemic is associated with highly significant levels of psychological distress that, in many cases, would meet the threshold for clinical relevance. Mitigating the hazardous effects of COVID-19 on mental health is an international public health priority.

1. Introduction

In December 2019, a cluster of atypical cases of pneumonia was reported in Wuhan, China, which was later designated as Coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO) on 11 Feb 2020 ( Anand et al., 2020 ). The causative virus, SARS-CoV-2, was identified as a novel strain of coronaviruses that shares 79% genetic similarity with SARS-CoV from the 2003 SARS outbreak ( Anand et al., 2020 ). On 11 Mar 2020, the WHO declared the outbreak a global pandemic ( Anand et al., 2020 ).

The rapidly evolving situation has drastically altered people's lives, as well as multiple aspects of the global, public, and private economy. Declines in tourism, aviation, agriculture, and the finance industry owing to the COVID-19 outbreak are reported as massive reductions in both supply and demand aspects of the economy were mandated by governments internationally ( Nicola et al., 2020 ). The uncertainties and fears associated with the virus outbreak, along with mass lockdowns and economic recession are predicted to lead to increases in suicide as well as mental disorders associated with suicide. For example, McIntyre and Lee (2020b) have reported a projected increase in suicide from 418 to 2114 in Canadian suicide cases associated with joblessness. The foregoing result (i.e., rising trajectory of suicide) was also reported in the USA, Pakistan, India, France, Germany, and Italy ( Mamun and Ullah, 2020 ; Thakur and Jain, 2020 ). Separate lines of research have also reported an increase in psychological distress in the general population, persons with pre-existing mental disorders, as well as in healthcare workers ( Hao et al., 2020 ; Tan et al., 2020 ; Wang et al., 2020b ). Taken together, there is an urgent call for more attention given to public mental health and policies to assist people through this challenging time.

The objective of this systematic review is to summarize extant literature that reported on the prevalence of symptoms of depression, anxiety, PTSD, and other forms of psychological distress in the general population during the COVID-19 pandemic. An additional objective was to identify factors that are associated with psychological distress.

Methods and results were formated based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ( Moher et al., 2010 ).

2.1. Search strategy

A systematic search following the PRISMA 2009 flow diagram ( Fig. 1 ) was conducted on PubMed, Medline, Embase, Scopus, and Web of Science from inception to 17 May 2020. A manual search on Google Scholar was performed to identify additional relevant studies. The search terms that were used were: (COVID-19 OR SARS-CoV-2 OR Severe acute respiratory syndrome coronavirus 2 OR 2019nCoV OR HCoV-19) AND (Mental health OR Psychological health OR Depression OR Anxiety OR PTSD OR PTSS OR Post-traumatic stress disorder OR Post-traumatic stress symptoms) AND (General population OR general public OR Public OR community). An example of search procedure was included as a supplementary file.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) study selection flow diagram. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

2.2. Study selection and eligibility criteria

Titles and abstracts of each publication were screened for relevance. Full-text articles were accessed for eligibility after the initial screening. Studies were eligible for inclusion if they: 1) followed cross-sectional study design; 2) assessed the mental health status of the general population/public during the COVID-19 pandemic and its associated risk factors; 3) utilized standardized and validated scales for measurement. Studies were excluded if they: 1) were not written in English or Chinese; 2) focused on particular subgroups of the population (e.g., healthcare workers, college students, or pregnant women); 3) were not peer-reviewed; 4) did not have full-text availability.

2.3. Data extraction

A data extraction form was used to include relevant data: (1) Lead author and year of publication, (2) Country/region of the population studied, (3) Study design, (4) Sample size, (5) Sample characteristics, (6) Assessment tools, (7) Prevalence of symptoms of depression/anxiety/ PTSD/psychological distress/stress, (8) Associated risk factors.

2.4 Quality appraisal

The Newcastle-Ottawa Scale (NOS) adapted for cross-sectional studies was used for study quality appraisal, which was modified accordingly from the scale used in Epstein et al. (2018) . The scale consists of three dimensions: Selection, Comparability, and Outcome. There are seven categories in total, which assess the representativeness of the sample, sample size justification, comparability between respondents and non-respondents, ascertainments of exposure, comparability based on study design or analysis, assessment of the outcome, and appropriateness of statistical analysis. A list of specific questions was attached as a supplementary file. A total of nine stars can be awarded if the study meets certain criteria, with a maximum of four stars assigned for the selection dimension, a maximum of two stars assigned for the comparability dimension, and a maximum of three stars assigned for the outcome dimension.

3.1. Search results

In total, 648 publications were identified. Of those, 264 were removed after initial screening due to duplication. 343 articles were excluded based on the screening of titles and abstracts. 41 full-text articles were assessed for eligibility. There were 12 articles excluded for studying specific subgroups of the population, five articles excluded for not having a standardized/ appropriate measure, three articles excluded for being review papers, and two articles excluded for being duplicates. Following the full-text screening, 19 studies met the inclusion criteria.

3.2. Study characteristics

Study characteristics and primary study findings are summarized in Table 1 . The sample size of the 19 studies ranged from 263 to 52,730 participants, with a total of 93,569 participants. A majority of study participants were over 18 years old. Female participants ( n  = 60,006) made up 64.1% of the total sample. All studies followed a cross-sectional study design. The 19 studies were conducted in eight different countries, including China ( n  = 10), Spain ( n  = 2), Italy ( n  = 2), Iran ( n  = 1), the US ( n  = 1), Turkey ( n  = 1), Nepal ( n  = 1), and Denmark ( n  = 1). The primary outcomes chosen in the included studies varied across studies. Twelve studies included measures of depressive symptoms while eleven studies included measures of anxiety. Symptoms of PTSD/psychological impact of events were evaluated in four studies while three studies assessed psychological distress. It was additionally observed that four studies contained general measures of stress. Three studies did not explicitly report the overall prevalence rates of symptoms; notwithstanding the associated risk factors were identified and discussed.

Summary of study sample characteristics, study design, assessment tools used, prevalence rates and associated risk factors.

3.3. Quality appraisal

The result of the study quality appraisal is presented in Table 2 . The overall quality of the included studies is moderate, with total stars awarded varying from four to eight. There were two studies with four stars, two studies with five stars, seven studies with six stars, seven studies with seven stars, and one study with eight stars.

Results of study quality appraisal of the included studies.

3.4. Measurement tools

A variety of scales were used in the studies ( n  = 19) for assessing different adverse psychological outcomes. The Beck Depression Inventory-II (BDI-II), Patient Health Questionnaire-9/2 (PHQ-9/2), Self-rating Depression Scales (SDS), The World Health Organization-Five Well-Being Index (WHO-5), and Center for Epidemiologic Studies Depression Scale (CES-D) were used for measuring depressive symptoms. The Beck Anxiety Inventory (BAI), Generalized Anxiety Disorder 7/2-item (GAD-7/2), and Self-rating Anxiety Scale (SAS) were used to evaluate symptoms of anxiety. The Depression, Anxiety, and Stress Scale- 21 items (DASS-21) was used for the evaluation of depression, anxiety, and stress symptoms. The Hospital Anxiety and Depression Scale (HADS) was used for assessing anxiety and depressive symptoms. Psychological distress was measured by The Peritraumatic Distress Inventory (CPDI) and the Kessler Psychological Distress Scale (K6/10). Symptoms of PTSD were assessed by The Impact of Event Scale-(Revised) (IES(-R)), PTSD Checklist (PCL-(C)-2/5). Chinese Perceived Stress Scale (CPSS-10) was used in one study to evaluate symptoms of stress.

3.5. Symptoms of depression and associated risk factors

Symptoms of depression were assessed in 12 out of the 19 studies ( Ahmed et al., 2020 ; Gao et al., 2020 ; González-Sanguino et al., 2020 ; Huang and Zhao, 2020 ; Lei et al., 2020 ; Mazza et al., 2020 ; Olagoke et al., 2020 ; Ozamiz-Etxebarria et al., 2020 ; Özdin and S.B. Özdin, 2020 ; Sønderskov et al., 2020 ; Wang et al., 2020a ; Wang et al., 2020b ). The prevalence of depressive symptoms ranged from 14.6% to 48.3%. Although the reported rates are higher than previously estimated one-year prevalence (3.6% and 7.2%) of depression among the population prior to the pandemic ( Huang et al., 2019 ; Lim et al., 2018 ), it is important to note that presence of depressive symptoms does not reflect a clinical diagnosis of depression.

Many risk factors were identified to be associated with symptoms of depression amongst the COVID-19 pandemic. Females were reported as are generally more likely to develop depressive symptoms when compared to their male counterparts ( Lei et al., 2020 ; Mazza et al., 2020 ; Sønderskov et al., 2020 ; Wang et al., 2020a ). Participants from the younger age group (≤40 years) presented with more depressive symptoms ( Ahmed et al., 2020 ; Gao et al., 2020 ; Huang and Zhao, 2020 ; Lei et al., 2020 ; Olagoke et al., 2020 ; Ozamiz-Etxebarria et al., 2020 ;). Student status was also found to be a significant risk factor for developing more depressive symptoms as compared to other occupational statuses (i.e. employment or retirement) ( González et al., 2020 ; Lei et al., 2020 ; Olagoke et al., 2020 ). Four studies also identified lower education levels as an associated factor with greater depressive symptoms ( Gao et al., 2020 ; Mazza et al., 2020 ; Olagoke et al., 2020 ; Wang et al., 2020a ). A single study by Wang et al., 2020b reported that people with higher education and professional jobs exhibited more depressive symptoms in comparison to less educated individuals and those in service or enterprise industries.

Other predictive factors for symptoms of depression included living in urban areas, poor self-rated health, high loneliness, being divorced/widowed, being single, lower household income, quarantine status, worry about being infected, property damage, unemployment, not having a child, a past history of mental stress or medical problems, having an acquaintance infected with COVID-19, perceived risks of unemployment, exposure to COVID-19 related news, higher perceived vulnerability, lower self-efficacy to protect themselves, the presence of chronic diseases, and the presence of specific physical symptoms ( Gao et al., 2020 ; González-Sanguino et al., 2020 ; Lei et al., 2020 ; Mazza et al., 2020 ; Olagoke et al., 2020 ; Ozamiz-Etxebarria et al., 2020 ; Özdin and Özdin, 2020 ; Wang et al., 2020a ).

3.6. Symptoms of anxiety and associated risk factors

Anxiety symptoms were assessed in 11 out of the 19 studies, with a noticeable variation in the prevalence of anxiety symptoms ranging from 6.33% to 50.9% ( Ahmed et al., 2020 ; Gao et al., 2020 ; González-Sanguino et al., 2020 ; Huang and Zhao, 2020 ; Lei et al., 2020 ; Mazza et al., 2020 ; Moghanibashi-Mansourieh, 2020 ; Ozamiz-Etxebarria et al., 2020 ; Özdin and Özdin, 2020 ; Wang et al., 2020a ; Wang et al., 2020b ).

Anxiety is often comorbid with depression ( Choi et al., 2020 ). Some predictive factors for depressive symptoms also apply to symptoms of anxiety, including a younger age group (≤40 years), lower education levels, poor self-rated health, high loneliness, female gender, divorced/widowed status, quarantine status, worry about being infected, property damage, history of mental health issue/medical problems, presence of chronic illness, living in urban areas, and the presence of specific physical symptoms ( Ahmed et al., 2020 ; Gao et al., 2020 ; González-Sanguino et al., 2020 ; Huang and Zhao, 2020 ; Lei et al., 2020 ; Mazza et al., 2020 ;  Moghanibashi-Mansourieh, 2020 ; Ozamiz-Etxebarria et al., 2020 ; Ozamiz-Etxebarria et al., 2020 ; Wang et al., 2020a ; Wang et al., 2020b ).

Additionally, social media exposure or frequent exposure to news/information concerning COVID-19 was positively associated with symptoms of anxiety ( Gao et al., 2020 ; Moghanibashi-Mansourieh, 2020 ). With respect to marital status, one study reported that married participants had higher levels of anxiety when compared to unmarried participants ( Gao et al., 2020 ). On the other hand, Lei et al. (2020) found that divorced/widowed participants developed more anxiety symptoms than single or married individuals. A prolonged period of quarantine was also correlated with higher risks of anxiety symptoms. Intuitively, contact history with COVID-positive patients or objects may lead to more anxiety symptoms, which is noted in one study ( Moghanibashi-Mansourieh, 2020 ).

3.7. Symptoms of PTSD/ psychological distress/stress and associated risk factors

With respect to PTSD symptoms, similar prevalence rates were reported by Zhang and Ma (2020) and N. Liu et al. (2020) at 7.6% and 7%, respectively. Despite using the same measurement scale as Zhang and Ma (2020) (i.e., IES), Wang et al. (2020a) noted a remarkably different result, with 53.8% of the participants reporting moderate-to-severe psychological impact. González et al. ( González-Sanguino et al., 2020 ) noted 15.8% of participants with PTSD symptoms. Three out of the four studies that measured the traumatic effects of COVID-19 reported that the female gender was more susceptible to develop symptoms of PTSD. In contrast, the research conducted by Zhang and Ma (2020) found no significant difference in IES scores between females and males. Other risk factors included loneliness, individuals currently residing in Wuhan or those who have been to Wuhan in the past several weeks (the hardest-hit city in China), individuals with higher susceptibility to the virus, poor sleep quality, student status, poor self-rated health, and the presence of specific physical symptoms. Besides sex, Zhang and Ma (2020) found that age, BMI, and education levels are also not correlated with IES-scores.

Non-specific psychological distress was also assessed in three studies. One study reported a prevalence rate of symptoms of psychological distress at 38% ( Moccia et al., 2020 ), while another study from Qiu et al. (2020) reported a prevalence of 34.43%. The study from Wang et al. (2020) did not explicitly state the prevalence rates, but the associated risk factors for higher psychological distress symptoms were reported (i.e., younger age groups and female gender are more likely to develop psychological distress) ( Qiu et al., 2020 ; Wang et al., 2020 ). Other predictive factors included being migrant workers, profound regional severity of the outbreak, unmarried status, the history of visiting Wuhan in the past month, higher self-perceived impacts of the epidemic ( Qiu et al., 2020 ; Wang et al., 2020 ). Interestingly, researchers have identified personality traits to be predictive of psychological distresses. For example, persons with negative coping styles, cyclothymic, depressive, and anxious temperaments exhibit greater susceptibility to psychological outcomes ( Wang et al., 2020 ; Moccia et al., 2020 ).

The intensity of overall stress was evaluated and reported in four studies. The prevalence of overall stress was variably reported between 8.1% to over 81.9% ( Wang et al., 2020a ; Samadarshi et al., 2020 ; Mazza et al., 2020 ). Females and the younger age group are often associated with higher stress levels as compared to males and the elderly. Other predictive factors of higher stress levels include student status, a higher number of lockdown days, unemployment, having to go out to work, having an acquaintance infected with the virus, presence of chronic illnesses, poor self-rated health, and presence of specific physical symptoms ( Wang et al., 2020a ; Samadarshi et al., 2020 ; Mazza et al., 2020 ).

3.8. A separate analysis of negative psychological outcomes

Out of the nineteen included studies, five studies appeared to be more representative of the general population based on the results of study quality appraisal ( Table 1 ). A separate analysis was conducted for a more generalizable conclusion. According to the results of these studies, the rates of negative psychological outcomes were moderate but higher than usual, with anxiety symptoms ranging from 6.33% to 18.7%, depressive symptoms ranging from 14.6% to 32.8%, stress symptoms being 27.2%, and symptoms of PTSD being approximately 7% ( Lei et al., 2020 ; Liu et al., 2020 ; Mazza et al., 2020 ; Wang et al., 2020b ; Zhang et al., 2020 ). In these studies, female gender, younger age group (≤40 years), and student population were repetitively reported to exhibit more adverse psychiatric symptoms.

3.9. Protective factors against symptoms of mental disorders

In addition to associated risk factors, a few studies also identified factors that protect individuals against symptoms of psychological illnesses during the pandemic. Timely dissemination of updated and accurate COVID-19 related health information from authorities was found to be associated with lower levels of anxiety, stress, and depressive symptoms in the general public ( Wang et al., 2020a ). Additionally, actively carrying out precautionary measures that lower the risk of infection, such as frequent handwashing, mask-wearing, and less contact with people also predicted lower psychological distress levels during the pandemic ( Wang et al., 2020a ). Some personality traits were shown to correlate with positive psychological outcomes. Individuals with positive coping styles, secure and avoidant attachment styles usually presented fewer symptoms of anxiety and stress ( Wang et al., 2020 ; Moccia et al., 2020 ). ( Zhang et al. 2020 ) also found that participants with more social support and time to rest during the pandemic exhibited lower stress levels.

4. Discussion

Our review explored the mental health status of the general population and its predictive factors amid the COVID-19 pandemic. Generally, there is a higher prevalence of symptoms of adverse psychiatric outcomes among the public when compared to the prevalence before the pandemic ( Huang et al., 2019 ; Lim et al., 2018 ). Variations in prevalence rates across studies were noticed, which could have resulted from various measurement scales, differential reporting patterns, and possibly international/cultural differences. For example, some studies reported any participants with scores above the cut-off point (mild-to-severe symptoms), while others only included participants with moderate-to-severe symptoms ( Moghanibashi-Mansourieh, 2020 ; Wang et al., 2020a ). Regional differences existed with respect to the general public's psychological health during a massive disease outbreak due to varying degrees of outbreak severity, national economy, government preparedness, availability of medical supplies/ facilities, and proper dissemination of COVID-related information. Additionally, the stage of the outbreak in each region also affected the psychological responses of the public. Symptoms of adverse psychological outcomes were more commonly seen at the beginning of the outbreak when individuals were challenged by mandatory quarantine, unexpected unemployment, and uncertainty associated with the outbreak ( Ho et al., 2020 ). When evaluating the psychological impacts incurred by the coronavirus outbreak, the duration of psychiatric symptoms should also be taken into consideration since acute psychological responses to stressful or traumatic events are sometimes protective and of evolutionary importance ( Yaribeygi et al., 2017 ; Brosschot et al., 2016 ; Gilbert, 2006 ). Being anxious and stressed about the outbreak mobilizes people and forces them to implement preventative measures to protect themselves. Follow-up studies after the pandemic may be needed to assess the long-term psychological impacts of the COVID-19 pandemic.

4.1. Populations with greater susceptibility

Several predictive factors were identified from the studies. For example, females tended to be more vulnerable to develop the symptoms of various forms of mental disorders during the pandemic, including depression, anxiety, PTSD, and stress, as reported in our included studies ( Ahmed et al., 2020 ; Gao et al., 2020 ; Lei et al., 2020 ). Greater psychological distress arose in women partially because they represent a higher percentage of the workforce that may be negatively affected by COVID-19, such as retail, service industry, and healthcare. In addition to the disproportionate effects that disruption in the employment sector has had on women, several lines of research also indicate that women exhibit differential neurobiological responses when exposed to stressors, perhaps providing the basis for the overall higher rate of select mental disorders in women ( Goel et al., 2014 ; Eid et al., 2019 ).

Individuals under 40 years old also exhibited more adverse psychological symptoms during the pandemic ( Ahmed et al., 2020 ; Gao et al., 2020 ; Huang and Zhao, 2020 ). This finding may in part be due to their caregiving role in families (i.e., especially women), who provide financial and emotional support to children or the elderly. Job loss and unpredictability caused by the COVID-19 pandemic among this age group could be particularly stressful. Also, a large proportion of individuals under 40 years old consists of students who may also experience more emotional distress due to school closures, cancelation of social events, lower study efficiency with remote online courses, and postponements of exams ( Cao et al., 2020 ). This is consistent with our findings that student status was associated with higher levels of depressive symptoms and PTSD symptoms during the COVID-19 outbreak ( Lei et al., 2020 ; Olagoke et al., 2020 , Wang et al., 2020a ; Samadarshi et al., 2020 ).

People with chronic diseases and a history of medical/ psychiatric illnesses showed more symptoms of anxiety and stress ( Mazza et al., 2020 ; Ozamiz-Etxebarria et al., 2020 ; Özdin and Özdin, 2020 ). The anxiety and distress of chronic disease sufferers towards the coronavirus infection partly stem from their compromised immunity caused by pre-existing conditions, which renders them susceptible to the infection and a higher risk of mortality, such as those with systemic lupus erythematosus ( Sawalha et al., 2020 ). Several reports also suggested that a substantially higher death rate was noted in patients with diabetes, hypertension and other coronary heart diseases, yet the exact causes remain unknown ( Guo et al., 2020 ; Emami et al., 2020 ), leaving those with these common chronic conditions in fear and uncertainty. Additionally, another practical aspect of concern for patients with pre-existing conditions would be postponement and inaccessibility to medical services and treatment as a result of the COVID-19 pandemic. For example, as a rapidly growing number of COVID-19 patients were utilizing hospital and medical resources, primary, secondary, and tertiary prevention of other diseases may have unintentionally been affected. Individuals with a history of mental disorders or current diagnoses of psychiatric illnesses are also generally more sensitive to external stressors, such as social isolation associated with the pandemic ( Ho et al., 2020 ).

4.2. COVID-19 related psychological stressors

Several studies identified frequent exposure to social media/news relating to COVID-19 as a cause of anxiety and stress symptoms ( Gao et al., 2020 ; Moghanibashi-Mansourieh, 2020 ). Frequent social media use exposes oneself to potential fake news/reports/disinformation and the possibility for amplified anxiety. With the unpredictable situation and a lot of unknowns about the novel coronavirus, misinformation and fake news are being easily spread via social media platforms ( Erku et al., 2020 ), creating unnecessary fears and anxiety. Sadness and anxious feelings could also arise when constantly seeing members of the community suffering from the pandemic via social media platforms or news reports ( Li et al., 2020 ).

Reports also suggested that poor economic status, lower education level, and unemployment are significant risk factors for developing symptoms of mental disorders, especially depressive symptoms during the pandemic period ( Gao et al., 2020 ; Lei et al., 2020 ; Mazza et al., 2020 ; Olagoke et al., 2020 ;). The coronavirus outbreak has led to strictly imposed stay-home-order and a decrease in demands for services and goods ( Nicola et al., 2020 ), which has adversely influenced local businesses and industries worldwide. Surges in unemployment rates were noted in many countries ( Statistics Canada, 2020 ; Statista, 2020 ). A decrease in quality of life and uncertainty as a result of financial hardship can put individuals into greater risks for developing adverse psychological symptoms ( Ng et al., 2013 ).

4.3. Efforts to reduce symptoms of mental disorders

4.3.1. policymaking.

The associated risk and protective factors shed light on policy enactment in an attempt to relieve the psychological impacts of the COVID-19 pandemic on the general public. Firstly, more attention and assistance should be prioritized to the aforementioned vulnerable groups of the population, such as the female gender, people from age group ≤40, college students, and those suffering from chronic/psychiatric illnesses. Secondly, governments must ensure the proper and timely dissemination of COVID-19 related information. For example, validation of news/reports concerning the pandemic is essential to prevent panic from rumours and false information. Information about preventative measures should also be continuously updated by health authorities to reassure those who are afraid of being infected ( Tran, et al., 2020a ). Thirdly, easily accessible mental health services are critical during the period of prolonged quarantine, especially for those who are in urgent need of psychological support and individuals who reside in rural areas ( Tran et al., 2020b ). Since in-person health services are limited and delayed as a result of COVID-19 pandemic, remote mental health services can be delivered in the form of online consultation and hotlines ( Liu et al., 2020 ; Pisciotta et al., 2019 ). Last but not least, monetary support (e.g. beneficial funds, wage subsidy) and new employment opportunities could be provided to people who are experiencing financial hardship or loss of jobs owing to the pandemic. Government intervention in the form of financial provisions, housing support, access to psychiatric first aid, and encouragement at the individual level of healthy lifestyle behavior has been shown effective in alleviating suicide cases associated with economic recession ( McIntyre and Lee, 2020a ). For instance, declines in suicide incidence were observed to be associated with government expenses in Japan during the 2008 economic depression ( McIntyre and Lee, 2020a ).

4.3.2. Individual efforts

Individuals can also take initiatives to relieve their symptoms of psychological distress. For instance, exercising regularly and maintaining a healthy diet pattern have been demonstrated to effectively ease and prevent symptoms of depression or stress ( Carek et al., 2011 ; Molendijk et al., 2018 ; Lassale et al., 2019 ). With respect to pandemic-induced symptoms of anxiety, it is also recommended to distract oneself from checking COVID-19 related news to avoid potential false reports and contagious negativity. It is also essential to obtain COVID-19 related information from authorized news agencies and organizations and to seek medical advice only from properly trained healthcare professionals. Keeping in touch with friends and family by phone calls or video calls during quarantine can ease the distress from social isolation ( Hwang et al., 2020 ).

4.4. Strengths

Our paper is the first systematic review that examines and summarizes existing literature with relevance to the psychological health of the general population during the COVID-19 outbreak and highlights important associated risk factors to provide suggestions for addressing the mental health crisis amid the global pandemic.

4.5. Limitations

Certain limitations apply to this review. Firstly, the description of the study findings was qualitative and narrative. A more objective systematic review could not be conducted to examine the prevalence of each psychological outcome due to a high heterogeneity across studies in the assessment tools used and primary outcomes measured. Secondly, all included studies followed a cross-sectional study design and, as such, causal inferences could not be made. Additionally, all studies were conducted via online questionnaires independently by the study participants, which raises two concerns: 1] Individual responses in self-assessment vary in objectivity when supervision from a professional psychiatrist/ interviewer is absent, 2] People with poor internet accessibility were likely not included in the study, creating a selection bias in the population studied. Another concern is the over-representation of females in most studies. Selection bias and over-representation of particular groups indicate that most studies may not be representative of the true population. Importantly, studies in inclusion were conducted in a limited number of countries. Thus generalizations of mental health among the general population at a global level should be made cautiously.

5. Conclusion

This systematic review examined the psychological status of the general public during the COVID-19 pandemic and stressed the associated risk factors. A high prevalence of adverse psychiatric symptoms was reported in most studies. The COVID-19 pandemic represents an unprecedented threat to mental health in high, middle, and low-income countries. In addition to flattening the curve of viral transmission, priority needs to be given to the prevention of mental disorders (e.g. major depressive disorder, PTSD, as well as suicide). A combination of government policy that integrates viral risk mitigation with provisions to alleviate hazards to mental health is urgently needed.

Authorship contribution statement

JX contributed to the overall design, article selection , review, and manuscript preparation. LL and JX contributed to study quality appraisal. All other authors contributed to review, editing, and submission.

Declaration of Competing Interest

Acknowledgements.

RSM has received research grant support from the Stanley Medical Research Institute and the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/National Natural Science Foundation of China and speaker/consultation fees from Lundbeck, Janssen, Shire, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, and Minerva.

Supplementary material associated with this article can be found, in the online version, at doi: 10.1016/j.jad.2020.08.001 .

Appendix. Supplementary materials

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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.

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The Research Paper

There will come a time in most students' careers when they are assigned a research paper. Such an assignment often creates a great deal of unneeded anxiety in the student, which may result in procrastination and a feeling of confusion and inadequacy. This anxiety frequently stems from the fact that many students are unfamiliar and inexperienced with this genre of writing. Never fear—inexperience and unfamiliarity are situations you can change through practice! Writing a research paper is an essential aspect of academics and should not be avoided on account of one's anxiety. In fact, the process of writing a research paper can be one of the more rewarding experiences one may encounter in academics. What is more, many students will continue to do research throughout their careers, which is one of the reasons this topic is so important.

Becoming an experienced researcher and writer in any field or discipline takes a great deal of practice. There are few individuals for whom this process comes naturally. Remember, even the most seasoned academic veterans have had to learn how to write a research paper at some point in their career. Therefore, with diligence, organization, practice, a willingness to learn (and to make mistakes!), and, perhaps most important of all, patience, students will find that they can achieve great things through their research and writing.

The pages in this section cover the following topic areas related to the process of writing a research paper:

• Genre - This section will provide an overview for understanding the difference between an analytical and argumentative research paper.
• Choosing a Topic - This section will guide the student through the process of choosing topics, whether the topic be one that is assigned or one that the student chooses themselves.
• Identifying an Audience - This section will help the student understand the often times confusing topic of audience by offering some basic guidelines for the process.
• Where Do I Begin - This section concludes the handout by offering several links to resources at Purdue, and also provides an overview of the final stages of writing a research paper.

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Trends and Developments in Mindfulness Research over 55 Years: A Bibliometric Analysis of Publications Indexed in Web of Science

• Published: 16 July 2021
• Volume 12 , pages 2099–2116, ( 2021 )

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• Anuradha Baminiwatta   ORCID: orcid.org/0000-0002-5495-2029 1 &
• Indrajith Solangaarachchi 2  

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This study aimed to identify historical developments, active research areas, and emerging trends within scientific literature on mindfulness published so far, using bibliometric methods. We also aimed to identify prominent journals, authors, organizations, and countries in the field of mindfulness.

Articles or reviews which mention mindfulness in the title, abstract, or keywords were identified using the Web of Science. A descriptive summary of the literature was obtained from the Web of Science Analysis tool. Country collaboration, co-authorship, and keyword co-occurrence networks were visualized using VOSviewer. CiteSpace, which uses document co-citation analysis, was used to identify emerging trends and transient patterns in the literature.

From 1966 to 2021, 16,581 publications on mindfulness were identified. There has been an exponential growth of publications since 2006. Almost half (47%) of the publications were in psychology and about one-fifth (20.8%) in psychiatry. The most prolific journal was Mindfulness (contributing 7% of all publications) and the most prolific author was Eric L. Garland. The vast majority of publications originated from Western countries but representation from Asian countries has increased. The most frequently co-occurring keywords were meditation , depression , stress , and anxiety. Co-citation analysis of the early period (1966–2015) revealed how scholarly work on spiritual themes has inspired early mindfulness research. Recent trends (2016–2021) revealed a rising interest in mechanisms and moderators, long-term meditation, neuroscientific studies, and smartphone/online delivery of interventions.

Conclusions

This comprehensive bibliometric study summarized and visualized 55 years of mindfulness research, revealing pivotal points, active research areas, and emerging trends.

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Mindfulness, which originates from Buddhist contemplative practices dating back more than 25 centuries, has recently enjoyed a surge of popularity in the Western hemisphere, pervading a variety of disciplines (Shapiro & Weisbaum, 2020 ). Adaptation of Buddhist mindfulness techniques into a secular therapeutic intervention in the 1980s in the United States, namely the mindfulness-based stress reduction (MBSR) programme, probably sparked the interest of researchers from myriad disciplines to scientifically and systematically study these meditative practices (Kabat-Zinn, 1982 ; Shapiro & Weisbaum, 2020 ). Since then, a large body of research evidence has accrued in support of the beneficial effects of mindfulness on diverse mental and physical health attributes (Creswell, 2017 ; Khoury et al., 2013 ).

A rapid growth of literature on mindfulness since the turn of the century was recognized earlier (Pagnini & Philips, 2015 ; Van Dam et al., 2018 ). A few studies have previously attempted to identify trends within mindfulness research. An analysis of 1056 articles published in the journal Mindfulness during 2010–2019 showed a few salient trends: increased diversification of the topics being explored as shown by the greater variety of recurring keywords and an increase in the proportion of articles from Asia were noted (Toniolo–Barrios et al., 2020 ). An analysis of trends in systematic reviews on mindfulness revealed an average increase of 19% per year in the number of reviews published from 2003 to 2015 (Chiesa et al., 2017 ). A study by Valerio ( 2016 ) demonstrated how mindfulness literature has become “disembedded” from Buddhist contexts over time: The ratio of literature on Buddhism to that on mindfulness flipped from 4.6:1 before 2008 to 1:1.8 over the following 5 years, and the meditation-to-mindfulness publication ratio dropped from 12.9:1 in 1993–1997 to approximately 1:1 around 2010.

With the explosive growth in the production of research literature, new approaches are required to review and analyze trends within knowledge domains (Chen, 2006 ; van Eck & Waltman, 2010 ). Bibliometrics, defined originally by Pritchard ( 1969 ) as “the application of mathematical and statistical methods to books and other media of communication,” is now widely used to study trends within a body of literature (Thompson & Walker, 2015 ). Application of bibliometrics to study mindfulness literature has so far been limited to the scope of a single journal and short time frame (Toniolo–Barrios et al., 2020 ), a single type of publication (Chiesa et al., 2017 ), or a narrow research question (Valerio, 2016 ). Therefore, we aimed to perform a broader and comprehensive bibliometric analysis of the mindfulness literature, in order to elucidate historical developments, emerging trends, and active research areas within this rapidly expanding domain of scientific knowledge.

Source of Data

Bibliographic data for the analyses were extracted from the Web of Science (WoS) Core Collection. WoS contains over 21,100 peer-reviewed, scholarly journals published worldwide in over 250 disciplines within sciences, social sciences, and arts & humanities. The availability of citation data makes WoS data suitable for bibliometric analyses including co-citation analysis.

Search Strategy and Data Retrieval

A search was performed on WoS for all documents with “mindfulness” as a topic; this identifies all documents with the word “mindfulness” in the title, abstract, or keywords. Only the documents of the article or review type were included; other document types such as meeting proceedings , book reviews , and letters were excluded. Bibliographic data were exported as “full records with cited references.”

Data Analysis and Visualization

Analysis and visualization of the bibliometric data were performed using three analytical tools — the WoS Analysis tool; VOSviewer (version 1.6.16), and CiteSpace (version 5.7.R2). Additionally, ArcGIS 10.8.1 was used to draw a world map of country trends.

Web of Science Analysis

Descriptive analyses summarizing information about the most prominent authors, countries, organizations, journals, and publication years were tabulated or graphically presented using the WoS Analysis tool.

VOSviewer is a software for creating and visualizing maps based on network data (van Eck & Waltman, 2010 ). Country collaboration, co-authorship, and keyword co-occurrence networks within the mindfulness literature were visualized using VOSviewer. In VOSviewer terminology, a cluster is a set of items closely associated with one another in a map (items can be authors, countries, keywords, etc.). One item may belong to only one cluster. In the visualization of a map, items with greater importance (e.g., total link strength) are shown with larger labels and larger circles. For some items, the label may not be displayed in order to avoid overlapping labels. The color of an item is determined by the cluster to which it belongs. A link is a connection between two items. Examples of links are co-authorship links between authors and countries and co-occurrence links between keywords. Each link has a strength , with a numerical value assigned. For example, the strength of a co-authorship link indicates the number of publications two researchers have co-authored, whereas a co-occurrence link indicates the number of publications in which two keywords occur together. The thickness of the lines connecting items indicates the link strength . For a given item, total link strength indicates the total strength of the links it has with other items, e.g., in the case of co-authorship links between authors, the total link strength indicates the total strength of the co-authorship links of a given author with other authors.

CiteSpace is a Java application developed for visualizing emerging trends and transient patterns in a knowledge domain using document co-citation analysis (Chen, 2006 ). Co-citation refers to the frequency of two documents being cited together; the more co-citations two documents receive, the more likely they are semantically related. CiteSpace has drawn from earlier concepts introduced by Small ( 1973 ) to identify underlying intellectual structures. WoS data on mindfulness were split into two arbitrary periods in order to visualize earlier (1966–2015) and recent (2016–2021) trends in mindfulness research. Even though the earlier period was much longer, the number of publications in this period was about half of that in the recent period. Each period was separately visualized to explore historical developments, major research areas, and trends. CiteSpace uses computer algorithms to label co-citation clusters automatically; the log-likelihood ratio method is generally preferred. CiteSpace provides metrics of structural and temporal properties of the network, clusters, and nodes. Structural metrics include betweenness centrality , modularity , and silhouette index . The betweenness centrality (or centrality ), based on concepts of Freeman ( 1978 ), measures the extent to which a node is in the middle of a path that connects other nodes in the network: High centrality values identify potentially revolutionary scientific publications (Chen, 2006 ). Temporal metrics include citation burstness , derived from Kleinberg’s ( 2002 ) burst detection algorithm. CiteSpace allows detection of citation bursts for any type of node (publications, countries, keywords, etc.) over the period studied. Citation bursts indicate sudden surges in interest within the research community towards a particular node during a particular period of time. Sigma is a combined indicator of both structural and temporal properties of a node.

Number of Publications over Time

From 1966 to 2021, 16,581 publications (14,682 articles and 1899 reviews) referring to mindfulness in the title, abstract, or keywords were identified on the WoS. The first publication was “Mindfulness of sensation” published in 1966 in by W. Pe in Psychologia , a Japanese journal. The next two articles were published in 1979 (a theoretical paper on “Empathy and Mindfulness” by R. Schuster) and 1982 (Kabat-Zinn’s preliminary study introducing an outpatient program of mindfulness for chronic pain), respectively.

The number of publication remained less than 100 per year until 2006, and since then, there has been an exponential growth in publications on mindfulness, reaching 2808 publications in 2020 (Fig.  1 ). The number of publications increased by an average of 23.5% per year from 2010 to 2020. The number of reviews has also increased similarly, reaching a peak of 405 in 2019. Two-thirds of all publications (n = 11,164, 67%) were in the period of 2016–2021.

Number of publications on mindfulness indexed in Web of Science 1966–2020

Research Areas

Based on research areas as categorized on WoS, almost half (47%) of the publications on mindfulness were in psychology, and about one-fifth (20.8%) were in psychiatry. Table 1 lists and compares the 25 most prominent research areas in the periods of 1966–2015 and 2015–2021, in order to illustrate changing trends. Publications in psychology have dropped from 50.5 to 45.2% whereas a slight increase from 19.7 to 21.4% is seen for psychiatry. Of note, there is a recent increase in publications in public environmental occupational health (from 3.3 to 5.2%) and general internal medicine (2.2 to 3.5%) and a decline in publications in the area of religion (from 3.2 to 1.7%).

Most Cited Publications

Out of the 10 most cited publications on mindfulness, 7 were review articles. The two most cited publications were empirical research articles; these two articles validated the Mindful Awareness and Attention Scale (MAAS) and the five facet mindfulness questionnaire (FFMQ), respectively (Baer et al., 2006 ; Brown & Ryan, 2003 ). The former had the highest average citations per year. Also included among the 10 most cited empirical articles were two other studies investigating the validity of mindfulness measures (Baer et al., 2004 ; Baer et al., 2008 ); pioneering studies which introduced MBSR for chronic pain (Kabat-Zinn, 1982 ) and anxiety (Kabat-Zinn et al., 1992 ) and MBCT for depressive relapse prevention (Teasdale et al., 2000 ), and one of the first studies on effects of mindfulness on brain function and immunity (Davidson et al., 2003 ). Table 2 lists the most cited empirical articles and reviews on mindfulness.

The most cited review article provided an operational definition of mindfulness (Bishop et al., 2004 ). Other highly cited reviews included a few meta-analyses of the efficacy of mindfulness on health conditions, several theoretical papers on mindfulness and related concepts, and two reviews exploring mechanisms of action of mindfulness. All of the 10 most cited research and review articles were published in or before 2011. Among publications produced after 2011, a review on neuroscience of mindfulness meditation by Tang et al. ( 2015 ) had received the highest citations per year (109 citations/year).

Most Prolific Journals

WoS listed 3644 journals with at least one publication on mindfulness. There were 338 journals with at least 10 publications (accounting for 59% of all publications). Table 3 lists the 25 journals with the highest number of publications related to mindfulness. Mindfulness , published by Springer, had by far the largest number of publications (n = 1169, 7.05%) on mindfulness. The top 10 journals contributed to 15.7% of the publications, whereas the top 25 journals contributed to 22%.

Most Prolific Authors

Authors with the highest number of publications on mindfulness indexed in WoS are listed in Table 4 . The author with the highest number of citations for his publications on mindfulness was Zindel Segal (9469 citations for 44 publications), who played an integral role in introducing MBCT.

Collaborations Among Authors

Figure  2 shows the networks among the top 100 authors based on co-authorship links; 11 author clusters were delineated using VOS viewer. The three authors with the most links with other authors were Javier Garcia-Campayo (total link strength = 175), Nirbhay Singh (total link strength = 136), and Joaquim Soler (total link strength = 126).

Co-authorship networks among the top 100 authors with strongest co-authorship links

Most Prolific Organizations

Table 5 lists the 25 most prolific organizations in terms of mindfulness research output. Out of the top 25, 22 organizations were located in the United States, 2 in the United Kingdom, and 1 in Canada.

Most Prolific Countries

Among 119 countries listed as contributing to the mindfulness literature on WoS, USA had the highest research output (46.7%) overall; however, the proportion of USA publications dropped from 52 in the early period (1966–2015) to 43.4% in the recent period (2016–2021). Contributions from different countries across the two periods are compared in a world map in Fig.  3 . Of note, a few Asian countries showed recent increases in publication output: Contributions from China increased from 2.7 to 5.9%; Iran, from 0.6 to 2.1%, and India, from 0.7 to 1.8%. In terms of rankings, Iran rose from 28 to 10th position, and India rose from 24 to 12th position.

Contributions (%) by countries to mindfulness research in the early (1966–2015) and recent (2016–2021) periods

Collaborations Between Countries

Collaborations between countries were visualized using VOSviewer based on co-authorship data (Fig.  4 ). USA had the greatest amount of links with other countries (total link strength = 2070), followed by England (total link strength = 1165) and Australia (total link strength = 718). Co-authorship among countries formed six clusters. The most prominent cluster consisted of USA, Canada, Germany, and Switzerland (shown in blue in Fig.  4 ). The three strongest links between countries pairwise were seen for USA-Canada (link strength = 317), USA-England (link strength = 195), and USA-Australia (link strength = 183).

Collaboration networks among countries producing mindfulness research. The size of circles represents the total link strength of each country and the thickness of lines indicates the link strength between countries

Country Citation Bursts

Top 10 countries with the strongest citation bursts (indicating sudden increases in interest within the scientific community towards articles from a certain country) as illustrated using CiteSpace revealed currently active citation bursts for Turkey, China, Peru, Vietnam, and Pakistan (Fig.  5 ). The strongest citation burst overall is for China, commencing in 2020.

Top 10 strongest citation bursts for countries 1966–2021. The duration of burst is indicated by the red line along the timeline

Major Research Areas During 1966–2015 (Document Co-citation Analysis)

CiteSpace uses document co-citation analysis to reveal the structure and dynamics within a knowledge domain and provides insight about the major areas of research (in the form of clusters) and how they are inter-connected. Co-citation analysis of 5501 publications in the period of 1966–2015, shown in Fig.  6a , revealed 19 co-citation clusters, labelled using a log-likelihood algorithm based on index terms used by citers. There was good quality of clustering configurations (weighted mean silhouette value of the clusters = 0.87) and satisfactory clarity of decomposition of the network (modularity Q = 0.73).

Major research areas (co-citation clusters) in mindfulness literature during 1966–2015. a Cluster view shows 19 co-citation clusters (in different colors), labelled by an algorithm. b Timeline view shows the temporal progression of activity in each cluster

The largest cluster during 1966–2015 was using mindfulness-based therapeutic intervention (cluster #0), consisting of 179 articles. The most active citer to this cluster was a review of empirical studies on the effects of mindfulness on psychological health (Keng et al., 2011 ). One of the articles in this cluster had the highest centrality value of all nodes in this period; the article by Teasdale et al. ( 1995 ) titled “How does cognitive therapy prevent depressive relapse and why should attentional control (mindfulness) training help” had a centrality of 0.3 (centrality is an indicator of the pivotal role played by an article in paths connecting different clusters). This cluster also included the publication with the highest sigma value (= 327) in the 1966–2015 period, viz. the landmark publication detailing the MBCT programme (Segal et al., 2002 ) (sigma is an indicator of the combined strength of structural and temporal properties of an article within a network).

The next two largest clusters were named meditation practitioner (177 cited articles) and commitment therapy (155 cited articles), respectively. Figure  6a shows the other major research areas within mindfulness literature between 1966 and 2015. Most of the labels provide a reasonable idea about the topics covered in each domain. A closer look at the oddly labelled “Turkish university student” cluster revealed a series of publications on self-compassion conducted among Turkish university students.

Co-citation analysis may also provide insight about the flow of knowledge over time within a knowledge domain. The three oldest clusters (shown on the right side of Fig.  6a ), namely outpatient program (cluster #13, mean year = 1978), reflective practice (cluster #14, mean year = 1984), and transcendental meditation (cluster #5, mean year = 1987), appear to be connected to the more recent body of literature through a cluster named “ breast-prostate cancer ” (cluster #10, mean year = 1991). The article with the highest centrality value within this pivotal cluster (cluster #10) was Kabat-Zinn’s (1992) study on effectiveness of MBSR for anxiety disorders (centrality = 0.26). This cluster #10 had 7 articles with centrality > 0.1, the most for any cluster; two other articles by Kabat-Zinn were also included among them. While the log-likelihood ratio method identified “breast prostate cancer” as the top term in this cluster, the next two top terms in the cluster were “spiritual health” and “intervention strategy,” reflecting the semantic heterogeneity within the cluster.

An article titled “Values and religious issues in psychotherapy and mental health” (Bergin, 1991 ) in the transcendental meditation cluster had the second highest centrality value (= 0.28) in the 1966–2015 period, reflecting its role in connecting the older reflective practice and outpatient program clusters to the breast prostate cancer cluster. The timeline view (Fig.  6b ) shows the progress of research activity in the different clusters through time.

Major Research Areas During 2016–2021

Document co-citation analysis of 11,164 publications in the 2016–2021 period revealed a network divided into 14 co-citation clusters (Fig.  7a ). There was good quality of clustering configurations (weighted mean silhouette value of the clusters = 0.86) and satisfactory clarity of decomposition of the network (modularity Q = 0.7).

Major research areas (co-citation clusters) in mindfulness literature during 1966–2015. a Cluster view shows 14 co-citation clusters (in different colors), labelled by an algorithm. b Timeline view shows the temporal progression of activity in each cluster

The largest cluster (#0) had 152 articles and was labelled as moderating role . The publication with the highest sigma value within this cluster was a meta-analysis of mindfulness-based interventions for reducing stress among healthcare professionals (Burton et al., 2017 ) and the most active citer to this cluster was a meta-analysis of randomized controlled trials evaluating mindfulness-based programs in the workplace (Vonderlin et al., 2020 ). No publications during this period had centrality values > 0.1; no pivotal points could be observed visually as well.

The second largest cluster was long-term meditator , and the publication with the highest sigma value in this cluster was a study that investigated the effects of mindful-attention and compassion meditation training on amygdala response to emotional stimuli in an ordinary, non-meditative state (Desbordes et al., 2012 ).

The article with the highest sigma value (= 4.5) in this period overall was a critical evaluation of research on mindfulness (Van Dam et al., 2018 ) included within the third largest cluster, i.e., mindfulness-based cognitive therapy .

The most recent cluster within the network was covid-19 outbreak (Fig.  7b ). A closer look at the composition of this cluster revealed that publications on mindfulness apps and online mindfulness interventions were also included within it. Studies on acceptance and commitment therapy seemed to cluster within the chronic pain cluster. The cluster which was named by the algorithm as bipolar disorder also included studies on mindfulness interventions for psychotic disorders and at-risk mental states.

Publications with Strongest Citation Bursts (1966–2021)

Top 25 citation bursts detected and visualized using CiteSpace for articles in the period of 1966 to 2021 are illustrated in Fig.  8 . The strongest citation burst (lasting from 2003 to 2011) was observed for the article that validated the MAAS (Brown & Ryan, 2003 ). Four articles show currently active citation bursts: a review on neuroscience of mindfulness meditation (Tang et al., 2015 ); a review of mechanisms of action for MBSR (Gu et al., 2015 ); a critical evaluation of research on mindfulness and meditation (Dam et al., 2018 ), and a review of randomized controlled trials employing mindfulness interventions (Creswell, 2017 ).

Top 25 publications with the strongest citations bursts (1966–2021). The duration of burst is indicated by the red line along the timeline

2.11 Keywords

1 keyword co-occurrence.

Keywords co-occurring in the publications on mindfulness were visualized using VOSviewer (Fig.  9 ): Five clusters of keywords were identified. The most prominent cluster (red) included keywords such as mindfulness , meditation , emotion regulation , attention , and validation . The second cluster (green) included keywords such as depression , anxiety , cognitive therapy , acceptance , and commitment therapy . Third cluster (blue) consisted of keywords such as stress , health , wellbeing , burnout , satisfaction , compassion , empathy , and resilience . Keywords in the fourth cluster (yellow) included stress reduction , intervention , and therapy . The smallest and fifth cluster (purple) comprised the keywords adolescents and children .

Keywords co-occurrence clusters in mindfulness literature. Five clusters are shown in different colors. The size of circles indicates the total link strength of each keyword

The 10 keywords which co-occurred most frequently with mindfulness were meditation (link strength = 2306), depression (link strength = 1996), stress (link strength = 1510), anxiety (link strength = 1445), stress reduction (link strength = 1294), intervention (link strength = 1015), health (link strength = 985), acceptance (link strength = 910), validation (link strength = 890), and emotion regulation (link strength = 838).

Keyword Bursts

Top 50 keywords with the strongest citation bursts during 1966–2021 are illustrated in Fig.  10 using CiteSpace. The three keywords with the strongest citation bursts were mindfulness meditation (1992 to 2011), mood (2004 to 2013), and prevention (2003 to 2012). Currently active bursts are observed for the keywords resource , loneliness , psychological intervention , and gratitude . Other keywords which attracted interest during the last decade include long term meditation , compassion meditation , alcohol dependence , immune , and integrative medicine .

Top 50 keywords with the strongest citation bursts. The duration of burst is indicated by the red line along the timeline

We conducted a bibliometric analysis of 55 years of scientific literature on mindfulness in order to gauge the progress that has been made so far and to detect emerging trends. The number of publications has risen exponentially since the turn of the century, and two-thirds of the total body of literature was produced over the last 5 years. As of 2020, the annual rate of publication exceeded 2800 publications per year, and this rate is likely to keep rising along its exponential trend. Almost half of these publications were within the discipline of psychology; however, this proportion has dropped by a reasonable degree in 2016–2021 compared to 1966–2015. Among the less prominent disciplines, notable recent increases in representation were noted for public environmental occupational health and general internal medicine. Also of note was the decline in the proportion of publications in the subject of religion: This is consistent with Valerio’s ( 2016 ) observation that mindfulness literature has become “disembedded” from Buddhism over the years. Similarly, although mindfulness originated from the Eastern part of the world, the great majority of mindfulness literature came from Western countries. All the top 25 authors and top 25 organizations were also from Western countries. However, a trend of increasing contributions to the mindfulness literature base by Asian countries such as China, Iran, and India was noteworthy. The most prominent surge of interest within the scientific community towards scholarly work from any single country was for China, which is currently in effect.

Historical Developments

Using computer algorithms based on bibliometric principles, we were able to visually depict the landscape of mindfulness research in the early (1966–2015) and recent (2016–2021) periods. Co-citations clusters and their temporal progression in the early period provided insight about the early development of scientific interest into mindfulness and meditation: A cluster of scholarly work on transcendental meditation, reflective practices, and Kabat-Zinn’s pioneering work on mindfulness for chronic pain, appearing in the 1970s and 1980s, seem to have laid the foundation for mindfulness research. Another landmark publication by Kabat-Zinn in 1992 on the effectiveness of MBSR for anxiety disorders, and a cluster of knowledge surrounding this, served as a pivotal point connecting this older knowledge base to a new and rich network of knowledge. The most revolutionary publication of all, in terms of structural properties within the whole network, came out in 1995; this publication by Teasdale et al. provided an information processing analysis of mindfulness and proposed a mechanism by which mindfulness meditation may prevent depressive relapses. This theoretical paper preceded the formal introduction of MBCT by several years. It was part of the largest network of knowledge in this period titled “ using mindfulness based therapeutic intervention .” Several other distinct clusters representing the major mindfulness-based therapeutic interventions were connected to this largest network, namely, MBSR, MBCT, Acceptance and Commitment Therapy, Mindful yoga, and Self-compassion-based therapies.

Recent Trends

The co-citation clusters in the recent period (2016–2021) revealed the currently active research areas in mindfulness (see Fig.  7 ). The knowledge clusters during this period were highly inter-connected and structurally overlapping, without notable pivotal points. The largest cluster being named as moderating role by the algorithm is consistent with the earlier observations of a recent rise in interest towards mechanisms and moderators underlying mindfulness interventions (Chiesa et al., 2017 ). A meta-analytic review of mediation studies (Gu et al., 2015 ) showing a currently active citation burst also confirms this trend. Tang et al.’s review of neuroscience of mindfulness meditation ( 2015 ) has also been garnering attention from the scientific community, indicating the ongoing interest in the neurobiological basis of mindfulness. This review shed light on the neural mechanisms of mindfulness by reviewing the evidence for structural and functional brain changes associated with mindfulness practice. Tang et al. ( 2015 ) recommended that further research should use rigorous research designs and larger sample sizes “to advance the understanding of the mechanisms of mindfulness meditation in regard to the interactions of complex brain networks, and to connect neuroscientific findings with behavioural data.”

Although most secular mindfulness interventions were designed for short-term implementation (e.g., lasting 8 weeks), there may be added benefits of long-term meditation; this seems to be a topic of recent interest since the second largest cluster of this period was labelled as long-term meditator . A citation burst for the keyword long term meditation was also observed from 2012 to 2015.

The most recent co-citation cluster is related to the covid-19 outbreak. The pandemic seems to have created a surge of interest in online interventions and smartphone apps for mindfulness, probably owing to the restrictions on physical gatherings.

The applications of mindfulness in managing several clinical conditions such as eating disorders ( mindful eating ), addiction ( smoking cessation ), and bipolar/psychotic disorders have also gained prominence in recent years. Investigations into the preventive capabilities of mindfulness are reflected by the cluster named school-based mindfulness intervention .

Keywords which have received recent citation bursts also illuminate some emerging trends. Gratitude , which has been called one of the “sisters of mindfulness” (Rosenzweig, 2013 ), seems to have attracted renewed interest within mindfulness literature (Sawyer et al., 2021 ; Swickert et al., 2019 ). The ability of mindfulness to reduce loneliness also appears to have gained recognition; this probably reflects the ongoing need for interventions to combat loneliness in the context of the COVID-19 pandemic (Teoh et al., 2021 ).

Uses and Implications of the Findings

Our study provides insight about the historical developments over 55 years and recent trends in mindfulness research, which will be useful for new researchers, students, and academics in various disciplines, particularly in psychology and psychiatry. Pointers towards important sources of information such as the most cited publications, revolutionary articles, most prolific journals, and authors will be useful for anyone interested in reading scientific literature on mindfulness. This study also provides some foresight into future directions in mindfulness research, as reflected by current trends.

Limitations

This study used all publications on WoS with the term “mindfulness” in the title, abstract, or keywords as articles on mindfulness. Since over 16,000 articles were identified, the authors did not attempt to peruse each article to check whether mindfulness was an important focus of each article. Authors noted that most of the individual articles which were identified algorithmically as important during the analysis included mindfulness as an important component. However, some articles included mindfulness as a minor component only, e.g., one of the 10 most cited reviews — Deci and Ryan ( 2008 ) — discussed mindfulness as only a correlate of motivation.

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We are grateful to Hasindu Gamaarachchi for helping us in data retrieval and to Buddhika Madurapperuma for assisting us with GIS mapping.

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Baminiwatta, A., Solangaarachchi, I. Trends and Developments in Mindfulness Research over 55 Years: A Bibliometric Analysis of Publications Indexed in Web of Science. Mindfulness 12 , 2099–2116 (2021). https://doi.org/10.1007/s12671-021-01681-x

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The Simple Macroeconomics of AI

This paper evaluates claims about large macroeconomic implications of new advances in AI. It starts from a task-based model of AI’s effects, working through automation and task complementarities. So long as AI’s microeconomic effects are driven by cost savings/productivity improvements at the task level, its macroeconomic consequences will be given by a version of Hulten’s theorem: GDP and aggregate productivity gains can be estimated by what fraction of tasks are impacted and average task-level cost savings. Using existing estimates on exposure to AI and productivity improvements at the task level, these macroeconomic effects appear nontrivial but modest—no more than a 0.66% increase in total factor productivity (TFP) over 10 years. The paper then argues that even these estimates could be exaggerated, because early evidence is from easy-to-learn tasks, whereas some of the future effects will come from hard-to-learn tasks, where there are many context-dependent factors affecting decision-making and no objective outcome measures from which to learn successful performance. Consequently, predicted TFP gains over the next 10 years are even more modest and are predicted to be less than 0.53%. I also explore AI’s wage and inequality effects. I show theoretically that even when AI improves the productivity of low-skill workers in certain tasks (without creating new tasks for them), this may increase rather than reduce inequality. Empirically, I find that AI advances are unlikely to increase inequality as much as previous automation technologies because their impact is more equally distributed across demographic groups, but there is also no evidence that AI will reduce labor income inequality. Instead, AI is predicted to widen the gap between capital and labor income. Finally, some of the new tasks created by AI may have negative social value (such as design of algorithms for online manipulation), and I discuss how to incorporate the macroeconomic effects of new tasks that may have negative social value.

Paper prepared for Economic Policy. I am grateful to Can Yeşildere for phenomenal research assistance, and to Leonardo Bursztyn, Mert Demirer, Lauren Fahey, Roberto Galbiati, Isabelle Méjean, Shakked Noy, Sida Peng, Julia Regier, and Whitney Zhang as well as participants in the MIT Solow Memorial conference and the Economic Policy conference for useful comments. I am especially grateful to my discussants, David Hémous and Benoît Coeuré, for insightful comments and suggestions. I thank Pamela Mishkin and Daniel Rock for generously sharing their data on AI exposure. I am also heavily indebted to my collaborators on several projects related to these topics, David Autor, Simon Johnson and Pascual Restrepo, from whom I learned a great deal and who have also given me very useful comments on the current draft. Financial support from the Hewlett Foundation is gratefully acknowledged. All remaining errors are mine. The views expressed herein are those of the author and do not necessarily reflect the views of the National Bureau of Economic Research.

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• Published: 13 May 2024

Single-site iron-anchored amyloid hydrogels as catalytic platforms for alcohol detoxification

• Jiaqi Su   ORCID: orcid.org/0000-0003-2010-8388 1 , 2   na1 ,
• Pengjie Wang   ORCID: orcid.org/0000-0001-9975-6737 3   na1 ,
• Wei Zhou 4 ,
• Mohammad Peydayesh   ORCID: orcid.org/0000-0002-6265-3811 1 ,
• Jiangtao Zhou   ORCID: orcid.org/0000-0003-4248-2207 1 ,
• Tonghui Jin 1 ,
• Felix Donat   ORCID: orcid.org/0000-0002-3940-9183 5 ,
• Cuiyuan Jin 6 ,
• Lu Xia   ORCID: orcid.org/0000-0002-2726-5389 7 ,
• Kaiwen Wang   ORCID: orcid.org/0000-0002-1046-4525 7 ,
• Fazheng Ren   ORCID: orcid.org/0000-0001-6250-0754 3 ,
• Paul Van der Meeren   ORCID: orcid.org/0000-0001-5405-4256 2 ,
• F. Pelayo García de Arquer   ORCID: orcid.org/0000-0003-2422-6234 7 &
• Raffaele Mezzenga   ORCID: orcid.org/0000-0002-5739-2610 1 , 8  

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Constructing effective antidotes to reduce global health impacts induced by alcohol prevalence is a challenging topic. Despite the positive effects observed with intravenous applications of natural enzyme complexes, their insufficient activities and complicated usage often result in the accumulation of toxic acetaldehyde, which raises important clinical concerns, highlighting the pressing need for stable oral strategies. Here we present an effective solution for alcohol detoxification by employing a biomimetic-nanozyme amyloid hydrogel as an orally administered catalytic platform. We exploit amyloid fibrils derived from β-lactoglobulin, a readily accessible milk protein that is rich in coordinable nitrogen atoms, as a nanocarrier to stabilize atomically dispersed iron (ferrous-dominated). By emulating the coordination structure of the horseradish peroxidase enzyme, the single-site iron nanozyme demonstrates the capability to selectively catalyse alcohol oxidation into acetic acid, as opposed to the more toxic acetaldehyde. Administering the gelatinous nanozyme to mice suffering from alcohol intoxication significantly reduced their blood-alcohol levels (decreased by 55.8% 300 min post-alcohol intake) without causing additional acetaldehyde build-up. Our hydrogel further demonstrates a protective effect on the liver, while simultaneously mitigating intestinal damage and dysbiosis associated with chronic alcohol consumption, introducing a promising strategy in effective alcohol detoxification.

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Although widely enjoyed for its social and relaxing effects (Supplementary Fig. 1 ), alcohol consumption consistently poses significant risks to public health. In fact, in 2016 alone, harmful alcohol consumption resulted in nearly three million deaths and 132.6 million disability-adjusted life years 1 , 2 , 3 , 4 . Existing therapies, mainly relying on endogenous enzymes 5 , 6 , 7 , offer only temporary relief from symptoms, such as nausea and headaches, but fail to address other underlying issues, such as drowsiness, exhaustion and chronic alcoholism. Nanocomplexes with multiple complementary hepatic enzymes have emerged as an effective approach for accelerating human alcohol metabolism 8 , 9 . Although promising, a significant obstacle arises from the insufficient activity of commercially available enzymes, leading to the accumulation of a more hazardous intermediate, acetaldehyde, and possibly damage to human organs. Furthermore, natural enzymes possess major disadvantages, such as high cost, poor physicochemical stability and challenging storage, which have so far impeded the practical application of these complexes for alcohol detoxification purposes.

Over the past decades, advances in nanotechnology have facilitated the evolution of artificial enzymes into nanomaterials, that is, nanozymes, which have ignited enormous scientific interest across diverse fields, ranging from in vitro biosensing and detection to in vivo therapeutics 10 , 11 , 12 , 13 . Inspired by natural enzyme frameworks, researchers have predominantly focused on atomically distributed metal catalysts, in which the catalytic centre of natural enzymes is replicated at the atomic level 14 , 15 , 16 . These single-site catalysts, designed with well-defined electronic and geometric architectures, possess excellent catalytic capabilities, holding great potential as viable substitutes for natural enzymes. Given these promising prospects, attempts have been made to develop biomimetic nanozymes for alcohol detoxification by using, for example, natural enzymes on exogenous supports such as graphene oxide quantum dots or metal-organic framework nanozymes 17 , 18 . However, these approaches still either rely on natural enzymes or offer indirect effects, underscoring the potential for substantial design enhancements. The critical, yet challenging, aspect is the design of efficient single-site catalysts that are capable of converting ethanol into less-toxic acetic acid, or further into carbon dioxide and water, while minimizing the generation of acetaldehyde. Additionally, the task also lies in developing an orally administerable nanozyme that can withstand the gastrointestinal environment and which features no additional toxicity.

In this article, we report a biomimetic-nanozyme amyloid hydrogel to alleviate the deleterious effects of alcohol consumption via oral administration. Within this platform, single-site iron-anchored amyloid fibrils, an original kind of atomic-level engineered nanozyme featuring a similar coordination structure to horseradish peroxidase and with remarkable peroxidase-like activity, are used to efficiently catalyse alcohol oxidation. Specifically, the resultant nanozyme exhibits excellent selectivity in favour of acetic acid production. The catalytic activity of the gelatinous nanozyme could largely tolerate the digestive process, leading to a substantial decrease in blood alcohol levels in alcoholic mice, while avoiding the additional build-up of acetaldehyde. We finally demonstrate that this hydrogel also achieves heightened liver protection and substantial alleviation of intestinal damage and dysbiosis, thereby underscoring its potential as an improved therapeutic approach for alcohol-related conditions. By employing atomic-level design and harnessing the capabilities of nanozymes, our study offers promising insights into the development of efficient and targeted alcohol antidotes, with potential benefits for both liver protection and gastrointestinal health.

Synthesis of single-site iron-anchored β-lactoglobulin fibrils

Diverging from conventional methods that use inorganic carriers, in the current work, we sought to utilize a readily available protein material, β-lactoglobulin (BLG) amyloid fibrils, as the supportive framework for atomically dispersed iron. In addition to their intrinsic binding affinity to various metal ions 19 , including iron, the large aspect ratio of protein filaments (Supplementary Fig. 2a ) and tacked-up β-sheet units also enhance the accessibility of potential binding sites, thereby facilitating the high-density loading of iron atoms. Moreover, BLG fibrils can be easily derived from native BLG, a readily available milk protein, and have very recently been demonstrated safe nutrition ingredients by a comprehensive in vitro and in vivo assessment 20 , meeting the requirements for potential oral administration 21 . Moreover, the exceptional gelling property of BLG fibrils allows for the easy production of hydrogels 22 , which anticipates a delayed digestion process and a prolonged action time within the gastrointestinal tract due to their high viscoelasticity 23 , 24 .

The single-site iron-anchored BLG fibrils (Fe SA @FibBLG) catalyst was synthesized by a straightforward wetness impregnation procedure (Fig. 1a ), which involved exposing a dispersion of BLG fibrils in a mixture of ethanol and polyethylene glycol 200 (PEG200) to a Fe(NO 3 ) 3 PEG200 solution. During this process, the natural occurrence of nitrogen in BLG fibrils coordinated with iron ions to form functional Fe–N–C active sites. The resulting precipitate was lyophilized and collected after multiple rounds of centrifugation and washing.

a , Illustration of the synthesis process of Fe SA @FibBLG. b – d , TEM image ( b ), HAADF-STEM image ( c ) and the corresponding EDS mapping images ( d ) of Fe SA @FibBLG. e – g , AFM images of Fe SA @FibBLG ( e, f (I) ) and FibBLG ( f (II) ) on the mica surface and ( g ) the corresponding height profiles of the white auxiliary lines. h , Representative HAADF-STEM image of Fe SA @FibBLG. The images presented in b – f , h are representative of six technical replicates ( n  = 6), each yielding similar results.

Source data

Having synthesized Fe SA @FibBLG, we then performed a comprehensive characterization of the material using multiple analytical techniques. The morphology of Fe SA @FibBLG, which retains a nanometre-scale diameter consistent with pure BLG fibrils (Supplementary Fig. 2b ), suggests minimal structural impact from the integration of iron (Fig. 1b and Supplementary Fig. 2b ). The iron was homogeneously dispersed across the BLG fibril framework, as evidenced by a significant overlap of the Fe K-edge profile with the elemental composition of the BLG fibrils (Fig. 1c,d and Supplementary Fig. 2c ). Atomic force microscopy (AFM) images confirmed a consistent height of approximately 3 nm both before and after iron integration, verifying the negligible presence of crystalline iron or oxide species (Fig. 1e,f,g ). As shown in Fig. 1h and Supplementary Fig. 2d–f , the presence of individual bright dots with a size below 0.2 nm clearly demonstrated the atomic dispersion of single iron atoms over Fe SA FibBLG, indicating that iron, upon participating in the synthetic procedure described above, is present exclusively in single-site form on the BLG fibrils.

Structural analysis of Fe SA @FibBLG

The coordination environment of iron within Fe SA @FibBLG was elucidated by X-ray absorption fine structure (XAFS) spectroscopy 25 . Figure 2a shows that the pre-edge position for Fe SA @FibBLG resided between the positions of iron foil (metallic iron) and Fe 2 O 3 . The white line area located at higher binding energy demonstrates a lower oxidation state and different coordination environments compared with Fe 2 O 3 (ref. 26 ). X-ray absorption near-edge spectroscopy (XANES) features are valuable for discerning site symmetry around iron in macromolecular complexes 27 . A distinct prominent pre-edge feature below 7,120 eV indicates the ferrous iron (Fe 2+ ) square-planar coordination in iron(II) phthalocyanine (FePc), whereas in Fe SA @FibBLG this feature is slightly reduced due to deviations from ideal square-planarity 28 . The XANES spectrum of Fe SA @FibBLG (Fig. 2a , inset) closely resembles that of FePc, implying a positively charged ionic state of iron within Fe SA @FibBLG (Fe δ + , where the average δ is close to 2). Further insights were obtained from extended X-ray absorption fine structure (EXAFS) spectra in R -space (Fig. 2b ), which revealed a single peak at approximately 1.4 Å. From comparison with reference materials this peak was attributable to the backscattering between iron and lighter atoms, primarily nitrogen (Fig. 2b ), supporting the atomic dispersion of iron sites within Fe SA @FibBLG. Wavelet transform analysis differentiated the sample from the iron foil reference by showing a single maximum intensity at approximately 4 Å −1 and 1.4 Å, suggesting significant Fe–N contributions (Fig. 2c and Supplementary Fig. 3 ), with the coordination number of iron estimated to be 4.5 (Fig. 2d and Supplementary Table 1 ). However, given the challenge in distinguishing Fe–N from Fe–O coordination compared to references such as FePc and Fe 2 O 3 , it is crucial to emphasize the potential existence of Fe–O bonds. Collectively, these findings confirmed that iron in Fe SA @FibBLG exists as single-site iron, devoid of any crystalline or oxide iron metal structure and mainly coordinates with nitrogen atoms. X-ray photoelectron spectroscopy (XPS) analysis of Fe SA @FibBLG further identified distinct binding states of carbon, nitrogen, oxygen and iron, demonstrating a majority of single-site iron in the Fe 2+ state and the existence of Fe–N coordination (Supplementary Figs. 4 and 5 ) 29 , 30 , 31 .

a , Normalized XANES spectra at the Fe K-edge of Fe SA @FibBLG along with reference samples. b , Fourier-transformed (FT) magnitudes of the experimental Fe K-edge EXAFS signals of Fe SA @FibBLG along with reference samples. c , Wavelet transform analysis of Fe K-edge EXAFS data. d , Fitting curves of the EXAFS of FeSA@FibBLG in the R -space and k -space (inset). Fitting results are summarized in Supplementary Table 1 . e , Representative snapshots of the assembly structure of 102 amyloid-forming fragments (LACQCL) from BLG in the process of AAMD simulation using the Gromacs54A force field at 10 ns. f , The 3D gradient isosurfaces and corresponding 2D scatter diagram of δg versus sign( λ 2 )ρ for possible non-covalent interactions between a single iron atom and dimer intercepted from BLG fibril segments in e through DFT simulation. δg is a quantitative measure derived from comparing electron density gradients in the presence and absence of interference, highlighting the penetration of electron density from one Bader atom to its neighbor; sign(λ 2 ) ρ is a scalar field value used to describe the product of the sign of the second eigenvalue (λ 2 ) of the Hessian matrix of a scalar field and the scalar field’s density ( ρ ).

Next, we performed a density functional theory (DFT) calculation for the process of anchoring a ferric ion onto the BLG fibril structure. Since the formation of BLG fibrils involved the participation of multiple peptides assembling in a random manner, here a model nanofibre structure was generated in silico based on repetitive amyloid-forming fragments (LACQCL) from BLG, using an all-atom molecular dynamics (AAMD) simulation (Fig. 2e ) 19 . An evident periodic nanofibril was formed at 10 ns containing 102 repetitive fragments, where a peptide dimer with verified thermodynamic stability was intercepted for DFT calculation (Supplementary Fig. 6 ). As shown in Fig. 2f , the blue isosurface observed between the iron atom and surrounding nitrogen atoms corresponds to strong attractive interactions between iron and nitrogen, potentially arising from the sharing of electron pairs between the iron and nitrogen atoms (Supplementary Fig. 7 ). This was further verified by the existence of the prominent peak at approximately −0.03 in the scatter plot (Fig. 2f ). These results clearly demonstrate that the BLG fibrils possessed effective binding sites that were capable of capturing iron atoms through Fe–N coordination, enabling the formation of active iron centres in Fe SA @FibBLG.

Peroxidase-like activity of Fe SA @FibBLG

The coordination structure of the catalytic sites in our Fe SA @FibBLG was similar to that of the horseradish peroxidase enzyme (Supplementary Fig. 8a ) 32 . Inspired by this similarity, we characterized the peroxidase-like activities of Fe SA @FibBLG by studying the facilitated chromogenic reactions through catalysing artificial substrates of peroxidase (for example, 3,3′,5,5′-tetramethylbenzidine (TMB), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) or o -phenylenediamine) in the presence of H 2 O 2 (Supplementary Fig. 8b ). By using the general method described in the current work, two comparison catalysts, namely, single-site iron-anchored BLG (Fe SA @BLG), and iron-nanoparticle-anchored BLG fibrils (FeNP@FibBLG), were synthesized and then used to characterize the enzymatic activity (Supplementary Figs. 9 and 10 and Supplementary Table 2 ). Using TMB as a substrate, the specific activity (SA) values (U mg −1 ) of these nanozymes were measured: the SA of Fe SA @FibBLG was markedly superior, at 95.0 U mg −1 , approximately 1.7 and 10.1 times higher than the SAs of Fe SA @BLG (57.3 U mg −1 ) and FeNP@FibBLG (9.38 U mg −1 ), respectively (Fig. 3a ). Steady-state kinetic assays revealed that Fe SA @FibBLG exhibited superior catalytic performance among the tested nanozymes in oxidizing TMB, with remarkable kinetic parameters including maximum reaction rate ( V max  = 0.788 μM s −1 ), turnover number ( K cat  = 21.9 min −1 ), catalytic efficiency ( K cat / K m  = 5.47 × 10 8  M −1  min −1 ) and selectivity ( K m  = 4.00 × 10 –2  mM) (Fig. 3b and Supplementary Table 3 ). We also determined the kinetic parameters for the H 2 O 2 substrate, which further substantiated the exceptional catalytic performance of Fe SA @FibBLG (Supplementary Table 4 ).

a – f , Typical Michaelis–Menten curves of Fe SA @FibBLG, Fe SA @BLG and FeNP@FibBLG by varying the TMB ( a ), ethanol ( c ) and acetaldehyde ( e ) concentrations in the presence of H 2 O 2 . Comparison of the SAs (U mg −1 ) of Fe SA @FibBLG, Fe SA @BLG and FeNP@FibBLG on TMB ( b ), ethanol ( d ) and acetaldehyde ( f ) oxidation in the presence of H 2 O 2 . One nanozyme activity unit (U) is defined as the amount of nanozyme that catalyses 1 µmol of product per minute. The SAs (U mg −1 ) were determined by plotting the nanozyme activities against their weight and measuring the gradients of the fitting curves. 1 H NMR spectrum of the reaction products of Fe SA @FibBLG-catalysed ethanol (inset d ) and acetaldehyde (inset f ) oxidation. Data are presented as the mean ± s.d. from n  = 3 independent experiments. g , EPR spectra of 5,5-dimethyl-pyrroline- N -oxide/H 2 O 2 solution upon the addition of nanozymes. h , Schematic illustration of the peroxidase-like activities of Fe SA @FibBLG when exposed to various substrates.

Interestingly, Fe SA @FibBLG also exhibited a notable capacity for catalytically oxidizing ethanol and acetaldehyde in the presence of H 2 O 2 (Fig. 3c–f ). The SA of Fe SA @FibBLG achieved a value of 7.90 U mg −1 when ethanol was used as the substrate, remarkably surpassing the other two reference catalysts. The superior catalytic efficacy of Fe SA @FibBLG with respect to ethanol was further confirmed by determining its kinetic parameters, which indicate it achieves a catalytic efficiency ( K cat / K m  = 4.11 × 10 5  M −1  min −1 ) that exceeds that of Fe SA @BLG ( K cat / K m  = 8.66 × 10 4  M −1  min −1 ) by 4.7 times and FeNP@FibBLG ( K cat / K m  = 9.25 × 10 3  M −1  min −1 ) by 44.4 times (Supplementary Table 5 ). Fe SA @FibBLG also manifested the lowest K m value when ethanol was the substrate, signifying its excellent affinity towards ethanol. It is important to note that Fe SA @FibBLG could directly oxidize ethanol to acetic acid, yielding formic acid as the only by-product, without generating any detectable acetaldehyde intermediate, as evidenced by 1 H NMR (Fig. 3d , inset).

To explain this, we performed a steady-state kinetic analysis of Fe SA @FibBLG participating in acetaldehyde oxidation. We found Fe SA @FibBLG to have the lowest K m value of the evaluated nanozymes, signifying its superior substrate affinity towards acetaldehyde. The K cat / K m for this reaction (3.89 × 10 5  M −1  min −1 ) was very close to that for ethanol oxidation (4.11 × 10 5  M −1  min −1 ) (Supplementary Tables 5 and 6 ). Upon the reaction between these nanozymes and H 2 O 2 , the electron paramagnetic resonance (EPR) spectrum exhibited characteristic peaks associated with 5,5-dimethyl-pyrroline- N -oxide–OH · , with Fe SA @FibBLG displaying the strongest EPR signal, indicating the highest production of OH · (Fig. 3g ). The same characteristic peaks were observed in the EPR spectrum of the Fe SA @FibBLG/H 2 O 2 /ethanol reaction system (Supplementary Fig. 17 ), confirming the existence of OH · in ethanol oxidation—a finding that agrees with numerous studies demonstrating the efficacy of OH · in oxidizing diverse organic compounds, including ethanol and acetaldehyde 33 , 34 . Nevertheless, it is essential to emphasize that our investigation serves as a preliminary exploration of the free radicals involved in this reaction; a more comprehensive mechanistic investigation is required for an in-depth understanding of the catalytic process.

Additionally, the catalytic stability of Fe SA @FibBLG was assessed by high-resolution transmission electron microscopy (TEM), high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM), energy-dispersive spectroscopy elemental analysis, X-ray diffraction and XPS (Supplementary Figs. 18 and 19 ). Fe SA @FibBLG did not exhibit substantial morphological or oxidation state alterations and effectively preserved the high atomic dispersion of iron active sites throughout the catalysis. It is also worth mentioning that Fe SA @FibBLG retained at least 95.2% and 84.1% of its activity after undergoing 3 h of digestion in simulated gastric and intestinal fluids, respectively (Supplementary Fig. 20 ). The robust stability observed in Fe SA @FibBLG may be due to the reduction effects of BLG fibril support 21 .

Protective potential on acute alcohol intoxication

Even a single new onset of blood alcohol that exceeds the detoxifying capability of the hepatic system can induce individual symptoms of acute alcohol intoxication, such as hepatocyte destruction, stress response and cognitive deficits 35 , 36 . To mitigate potential damage to the human digestive tract from direct H 2 O 2 ingestion, a biomimetic cascade catalysis system was designed by integrating gold nanoparticles (AuNPs) for onsite and sustainable H 2 O 2 generation 37 , 38 , 39 . AuNPs have demonstrated exceptionally efficient and enduring catalytic activity similar to glucose oxidase, which allows the conversion of glucose into gluconic acid, accompanied by the production of adequate H 2 O 2 (Supplementary Fig. 21 ). Because protein fibrils transiently remained and were mostly digested (generally within 4 h) in the gastrointestinal tract 20 , where the majority of alcohol was absorbed, a salt-induced technique 40 ( Methods ) was followed to fabricate the AuNP-attached Fe SA @FibBLG amyloid hydrogel (Fe SA @AH) (Supplementary Fig. 22 ) to achieve prolonged retention within the gastrointestinal tract, and, thereby, an enhanced overall capacity for ethanol oxidation. The resultant Fe SA @AH showed typical self-standing ability, obvious nanofibril structures (exceptional birefringence under polarized light) and good syringability (Fig. 4a ). We then labelled Fe SA @AH with [ 18 F]fluoro-2-deoxyglucose ([ 18 F]FDG) and visualized its transportation in C57BL/6 mice by using micro positron emission tomography (PET)–computed tomography (CT) scanning. The metabolism of Fe SA @AH took more than 6 h in the upper gastrointestinal tract after gavage, which indicated an extended retention time in vivo due to the hydrogel nature of the compound 20 .

a , Visualization (1) and microstructures (2) of Fe SA @AH under polarized light, and injectability test (3). b , Time-series images of gastrointestinal translocation of [ 18 F]FDG-loaded Fe SA @AH in mice (0–6 h). c , Schematic of acute alcohol intoxication model construction ( Methods ). Created with BioRender.com. d , Effect of different treatment (PBS, AH and Fe SA @AH) on alcohol tolerance time and sobering-up time in C57BL/6 mice. e , Representative trajectory of search strategies of mice with different treatments. f , g , Escape latencies ( f ) and path length ( g ) of four groups of mice. h , i , Mean concentrations of blood alcohol ( h ) and acetaldehyde ( i ) in alcohol-intoxicated mice treated with PBS, AH and Fe SA @AH. j , Serum levels of ALT and AST enzyme levels in four groups of mice. Data are obtained for n  = 8 independent biological replicates, mean ± s.e.m. P values in d , f , g , h , j were tested by one-way analysis of variance followed by Tukey–Kramer test. * P  < 0.05, ** P  < 0.01, *** P  < 0.001, **** P  < 0.0001.

The prophylactic benefits of Fe SA @AH administration were assessed in an alcohol-treated murine model 41 (Fig. 4c ). A group of ethanol-free, but PBS-gavaged mice served as a negative control; all the ethanol-gavaged mice were asleep for alcohol intoxication. Although they tolerated alcohol intake for a longer period of time ( ∼ 40 min), the Fe SA @AH mice were awoken significantly earlier ( ∼ 2 h) than other intoxicated groups (Fig. 4d ). We then conducted the Morris water maze (MWM) test 6 h post-alcohol intake to quantitatively assess murine spatial reference memory (Fig. 4e ). Grouped mean swimming speeds of alcohol-exposed mice were comparable to those of the blank group, indicating recovery of fundamental activities (Supplementary Fig. 25a ). However, PBS- and AH-treated mice showed increased search time and distance to locate the hidden platform, whereas the mice given Fe SA @AH demonstrated markedly improved navigational efficiency (Fig. 4f,g ). Additionally, distinct search strategies were observed, with PBS and AH groups favouring less efficient patterns, in contrast to the strategic approaches of the Fe SA @AH and control groups (Supplementary Fig. 25b ).

Aetiologically, behavioural abnormalities were attributed to alcohol and its in vivo intermediate metabolite, acetaldehyde 42 , and the liver played a core role in ethanolic metabolism. Prophylactic Fe SA @AH immediately and persistently reduced the mice blood alcohol (BA) concentration by a significant amount (Fig. 4h ). The BA in Fe SA @AH mice decreased by 41.3%, 40.4%, 42.0%, 46.6% and 55.8%, respectively, 30, 60, 120, 180 and 300 min post-gavaging. Importantly, the above-mentioned process induced no additional acetaldehyde (BAce) accumulation in blood (Fig. 4i ), which plays a crucial role in safeguarding the liver, as the build-up of acetaldehyde is known to be a catalyst for liver cirrhosis and hepatocellular carcinoma. Stress responses of liver were definitely mitigated, which was revealed by the significantly decreased blood alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA) and glutathione (GSH) levels in the Fe SA @AH group (Fig. 4j and Supplementary Fig. 26a,b ).

Prophylactic effect on chronic alcohol intoxication

The NIAAA model (mouse model of chronic and binge ethanol feeding) was conducted to confirm the long-term beneficial effects of Fe SA @AH 43 . After model constructions (Fig. 5a and Methods ), the PBS mice showed a significantly decreased body weight, increased liver injury (ballooning degeneration and multifocal inflammatory cell infiltration) and hepatic lipid accumulation compared with the blank (Fig. 5b,c ). Notably, Fe SA @AH-rescued mice showed a significantly decreased loss in body weight, less liver damage and re-regulated hepatic lipid metabolism (Fig. 5b,c ) from intoxication. Moreover, mice treated with Fe SA @AH had lower BA than those with PBS and AH (Supplementary Fig. 27a ). It is worth noting, however, that Fe SA @AH also decreased the BAce concentration (Supplementary Fig. 27b ), indicating its dominant competitive role in ethanol elimination to endogenous ADH. Significant lower blood ALT and AST levels further confirmed the inflammation alleviation effect of Fe SA @AH on the liver (Fig. 5d ). Additionally, administration of Fe SA @AH also significantly suppressed triglyceride and total cholesterol accumulation in ethanol-fed mice (Supplementary Fig. 28e–j ).

a , Schematic of the chronic alcohol intoxication model construction ( Methods ). Created with BioRender.com. b , Body weight changes in the four groups of mice during the feeding period. c , Representative H&E-stained images of liver in the four groups. d , Serum ALT and AST levels in mice. e , H&E images of colon (left part) and its assessed scores (right histogram) in different groups of mice. f , Immunofluorescence staining of the tight junction proteins in the colon (left part, 30× magnification). The tight junction proteins (Claudin-1, occludin and ZO-1) were stained green whereas the 4,6-diamidino-2-phenylindole (DAPI) was blue. The histograms (right) show the mean density of the normalized levels of occludin and ZO-1. IOD, integrated optical density. g , Taxonomic and phylogenetic tree of the top 21 most affected genera (genus with >10% mean abundance change in at least one group compared to others) by different treatments generated by GraPhlAn 4.0. Outer circles show the grouped mean relative abundance of each genus. h , Metabolic processes of alcohol to acetate and further in mice. The left colour blocks indicate the endogenous organs, liver, intestine and gut microbiota involved in alcohol decomposition, and the right shows the path in which Fe SA @AH participated. The box-plot shows the relative levels of ko00770 pantothenate and CoA biosynthesis among groups (minimum–maximum). The heatmap shows 83 significantly changed pathways compared with those in the PBS group. Source data are provided as a Source Data file. i , LPS concentrations of mice in the four groups. Data are shown in the form of mean ± s.e.m. from n  = 8 biological replicates. In c , e , f , the images displayed are representative of three independent biological replicates ( n  = 3), each producing consistent results. For histopathological, physiological and biochemical indexes ( c – f , i ), P values were tested by one-way analysis of variance followed by Tukey–Kramer test whereas the pairwise Wilcoxon test with Bonferroni–Holm correction was used for microbial taxa ( h , i ). * P  < 0.05, ** P  < 0.01, *** P  < 0.001.

The gut and its symbionts (the microbiota) are important, but usually overlooked, alcohol-metabolizing organs 44 , 45 , 46 . Chronic alcohol consumption caused histopathological changes in the colon, destroyed epithelial cells, atrophied goblet cells and resulted in inflammatory cell infiltration (Fig. 5e ), and also weakened permeability (Fig. 5f ), which may cause more microbial components to enter the bloodstream 47 . Alcohol also induced significant compositional shifts (β-diversity) in the gut microbiota of mice (Supplementary Fig. 29a ), but showed limited effects on the Shannon index and percentage of Gram-negative bacteria (Supplementary Fig. 29b,c ). Consistently 48 , the mean abundance of Bacteroidota increased in all alcohol-treated groups. Another dominant phylum, Firmicutes , decreased significantly in the PBS group compared with the blank group (Supplementary Fig. 29d ). Interestingly, a significant loss of functional murine-mucoprotein-degrading bacteria, Akkermansia ( verrucomicrobiota ), and transitions of Ileibacterium and Allobaculum (blank) to Bacteroides and Prevotellaceae_UCG-001 (PBS), were identified (Fig. 5g ).

In terms of functional profiles, we found no significant intergroup gut microbial function changes due to ethanol-related processes (Supplementary Table 10 ). In accordance with previous research 47 , gut microbiota were determined to be indirectly involved in ethanol metabolism, especially acetate-induced microbial anaerobic respiration, such as the glycolysis/gluconeogenesis (ko00010) and pentose phosphate pathway (ko00030) (Supplementary Table 10 ). Alcohol consumption also induced significantly overexpressed pantothenate. Moreover, CoA biosynthesis (ko00770) and the citrate cycle (TCA) (ko00020) constituted important carbon unit donors for further processes (Fig. 5h ), such as lipopolysaccharide (LPS) biosynthesis (ko00540)—LPS is widely recognized as an endotoxin that can induce hepatic inflammation 49 . This epithelial pathophysiological damage and intraluminal dysbiosis were significantly mitigated by Fe SA @AH compared with other AHs (Fig. 5e–h ). Furthermore, as one of the final beneficial outputs, the concentration of blood LPS was significantly decreased in Fe SA @AH-treated mice (Fig. 5i ).

In aggregate, we have demonstrated the design of a single-site iron-anchored amyloid hydrogel with remarkable catalytic oxidation capacity for alcohol as a highly efficient catalytic platform for in vivo alcohol metabolism. This work provides compelling evidence for the viability of a biomimetic-nanozyme-based hydrogel as an orally applied antidote for alcohol intoxication. Fe SA @AH demonstrates exceptional preference for acetic acid production, enabling a rapid decrease in blood alcohol levels while simultaneously mitigating the risk of excessive acetaldehyde accumulation, and markedly surpasses the effectiveness of existing alcohol intoxication antidotes that rely on a combination of natural enzymes. Unlike the predominantly liver-centric human intrinsic alcohol metabolism, orally administered Fe SA @AH directs this process towards the gastrointestinal tract, providing increased safety for the liver. In addition, despite this shift in the site of alcohol metabolism, there is no manifestation of additional adverse gastrointestinal symptoms; in fact, Fe SA @AH shows a remarkable alleviation of intestinal damage and dysbiosis induced by alcohol consumption, further demonstrating its potential for clinical translation.

The findings from our study outline a general and efficient strategy for synthesizing a diverse group of orally applied biomimetic nanozymes, and establish the foundation for future investigations aimed at maximizing the potential of artificial enzyme design in different therapeutic applications.

Synthesis of catalysts

BLG (>98%) was purchased from Davisco Foods International and purified using a previously reported protocol 50 . For a detailed description of BLG fibril preparation, see ref. 51 . For the synthesis of Fe SA @FibBLG, 100 mg lyophilized BLG fibril powder was dispersed in a mixture of 8.0 ml ethanol and 1.9 ml PEG200. The dispersion was then subjected to argon bubbling for 30 min to remove the dissolved oxygen, followed by irradiation under a xenon lamp with an ultraviolet filter (250–380 nm, 27.9 mW cm −2 , PLS-SXE300CUV) for 10 min to generate free radicals. Subsequently, 0.1 ml of 108.21 mg ml −1 Fe(NO 3 ) 3 ·9H 2 O EDTA solution was added dropwise to the dispersion of BLG fibrils under magnetic stirring for 12 h at 25 °C. Fe SA @BLG was prepared by the same synthesis procedure as for Fe SA @FibBLG, except that the BLG fibril powder was replaced by an equal amount of BLG powder. For the synthesis of FeNP@FibBLG, the as-obtained Fe SA @FibBLG dispersion was further ultraviolet-irradiated for 18 min under anaerobic conditions to reduce the iron ions. Finally, samples were collected by centrifugation at 4 °C, 11,100 g for 10 min, washed by ethanol (10.0 ml × 6) and resuspended in 5.0 ml deionized water (pH 2). The powdered Fe SA @FibBLG, Fe SA @BLG and FeNP@FibBLG were obtained by lyophilization and stored at 4 °C.

Characterizations

The high-resolution TEM images and elemental mappings were recorded with an FEI Talos F200X microscope at accelerating voltages of 80 kV and 200 kV, respectively. AFM images were obtained using a Bruker Multimode 8 scanning probe microscope. HAADF-STEM images were captured using an FEI Titan Themis G2 microscope equipped with a probe spherical aberration corrector and operated at 300 keV. The crystalline structure and phase purity were detected by a powder diffractometer (Siemens D500 with Cu Kα radiation (λ = 1.5406 Å)). The iron loadings on catalysts were analysed by inductively coupled plasma mass spectrometry (Elan DRC-e, Perkin Elmer). The X-ray absorption structure spectra (Fe K-edge) were collected at beamline BL44B2 of the SPring-8 synchrotron (Japan), operated at 8.0 GeV with a maximum current of 250 mA. Data were collected in transmission mode using a Si(111) double-crystal monochromator. The EXAFS data were analysed using the ATHENA module implemented in IFEFFIT software (CARS). XPS measurements were performed using a multipurpose spectrometer (Sigma Probe, Thermo VG Scientific) with a monochromatic Al Kα X-ray source. EPR spectra were acquired using a Bruker X-band (9.4 GHz) EMXplus 10/12 spectrometer equipped with an Oxford Instruments ESR-910 liquid helium cryostat. All spectra were collected under ambient conditions. Solution 1 H NMR spectra were collected on a Bruker DRX 300 spectrometer (7.05 T; Larmor frequency, 300 MHz ( 1 H)) in deuterated water (D 2 O) at room temperature.

MD simulations

All of the AAMD simulations were performed on a GROMACS 2018 package using a gromacs54A force field 52 . The box size of the initial model was 12 × 12 × 30 nm 3 , including an SPC/E water model and 102 peptide chains (sequence, LACQCL) 19 under three-dimensional periodic boundary conditions. A spherical cut-off of 1.0 nm was used for the summation of van der Waals interactions and short-range Coulomb interactions, and the particle-mesh Ewald method 53 . The temperature and pressure of the system were controlled by means of a velocity rescaling thermal thermostat and a Berendsen barostat. At first, the energy of the system was minimized in small steps to balance the initial velocity of the molecules. Then, the NPT ensemble using a leapfrog integrator with a time step of 1.0 fs was used to simulate the system for 8 ns at 300 K, which is sufficient for the balance of the system. Dynamic snapshot images were generated in Visual Molecular Dynamics 1.9.3 54 .

DFT calculations

To investigate the interaction between iron ions and the system, one iron ion was inserted into the peptide dimer, and the structure was optimized by DFT using the CP2K software package 55 . The Perdew–Burke-Ernzerhof generalized gradient approximation functional was adopted to describe the electronic exchange and correlation, in conjunction with the DZVP-MOLOPT-SR-GTH basis set for all atoms (C, H, O, N, Fe). The structure was optimized with the spin multiplicity to treat the doublet spin state and the charge of the iron ion was set to +2 e . The convergence criterion for the absolute value of the maximum force was set to 4.5 × 10 −4  a.u. and the r.m.s. of all forces to 3 × 10 −4  a.u. Grimme’s DFT-D3 method was adopted for correcting van der Waals interactions 56 .The interaction of the system was characterized by the independent gradient model method, and the based isosurface maps were rendered by Visual Molecular Dynamics from the cube files exported from Multiwfn 3.8 (ref. 57 ).

Peroxidase-like activity

The peroxidase-like activities of nanozymes were assessed at 37 °C using 350 μl of HAc–NaAc buffer (0.1 M, pH 4.0) with varied nanozyme concentrations, using TMB as the substrate. Following the addition of 20 μl of TMB solution (20 mM in dimethylsulfoxide) and 20 μl of H 2 O 2 solution (2 M), 10 μl of nanozymes with varying concentrations was introduced into the system. The catalytic oxidation of TMB (oxTMB) was quantified by measuring the absorbance at 652 nm via an ultraviolet–visible spectrometer. The steady-state kinetics analysis was executed by modifying the concentrations of TMB and H 2 O 2 . To derive the Michaelis–Menten constant, we performed Lineweaver–Burk plot analysis using the double reciprocal of the Michaelis–Menten equation, ν  =  ν max  × [ S ]/( K m  + [S]), where ν denotes the initial velocity, ν max represents the maximum reaction velocity, [ S ] indicates the substrate concentration and K m is the Michaelis constant. Additionally, the catalytic rate constant ( k cat ) was computed as k cat = ν max /[ E ], where [ E ] signifies the molar concentration of metal within the nanozymes. By employing diverse pH buffer solutions, we explored the pH dependency of the peroxidase-like activity of nanozymes, spanning a range from pH 2 to 9. Similarly, we investigated its temperature sensitivity by observing its activity at various temperatures, progressively increasing from 20 °C to 60 °C.

Catalytic oxidation activity on alcohol and acetaldehyde

The catalytic oxidation activities of nanozymes on both alcohol and acetaldehyde were carried out at 37 °C in 350 μl of HAc–NaAc buffer (0.1 M, pH 4.0), with varying nanozyme concentrations (10 μl). Subsequent to adding 20 μl of H 2 O 2 solution (2 M), 20 μl of ethanol or acetaldehyde solution (2 mM) was introduced into separate tubes containing the reaction mixture. Quantification of the catalytic oxidation of ethanol or acetaldehyde was performed using the Ethanol Assay Kit (ab65343) and Acetaldehyde Assay Kit (ab308327) from Abcam Biotechnology. Through altering the concentrations of ethanol or acetaldehyde, steady-state kinetics analysis was carried out, and the Michaelis–Menten constant was determined by analysing Lineweaver–Burk plots involving the double reciprocal of the Michaelis–Menten equation. Additionally, the identification of the reaction products was confirmed by 1 H NMR spectrometry.

Catalytic activity assessment of nanozymes during in vitro simulation of the digestion process

We adhered to the INFOGEST standard protocol for nanozyme digestion to replicate the physiological human gastrointestinal digestion process 58 . In this methodology, stock solutions of simulated gastric fluid and simulated intestinal fluid were prepared and equilibrated at 37 °C prior to use. For gastric digestion, 2 ml of the nanozyme (1 mg ml −1 ) was mixed with 2 ml of simulated gastric fluid stock solution, and porcine pepsin solution was added to achieve a final enzyme activity of 500 U per mg of protein. CaCl 2 (H 2 O) 2 was then introduced into the mixture to reach a final concentration of 0.15 mM prior to adjusting the pH to 3 using 5 M HCl. The mixture was transferred to a water bath shaker (VWR 462-0493) at 37 °C and sampled at 30 and 60 min, after which NaOH solution was used to deactivate the enzyme. Following the gastric digestion, pancreatin (0.1 mg ml −1 ) was dissolved in simulated intestinal fluid containing 0.6 mM CaCl 2 and added to the gastric digests in a 1:1 (v/v) ratio to initiate intestinal digestion, which lasted for 120 min at 37 °C with regular sampling every 30 min. The samples were freeze-dried immediately after collection for enzyme activity evaluation experiments using TMB as a substrate, in which the amount of nanozyme after digestion was normalized.

Hydrogel formation

Gelation of Fe SA @FibBLG dispersion containing AuNPs (Fe SA @AH) was achieved following our previously reported procedure with some modifications 40 . For the synthesis of AuNPs, all glassware was cleaned with freshly prepared aqua regia (HCl:HNO 3  = 3:1 vol/vol) and then thoroughly rinsed with water. A 2 ml solution of BLG fibrils (2.0 wt%, pH 2.0) was mixed with a 40 mM HAuCl 4 solution to reach a final protein:gold mass ratio of 14.7:1. The mixture underwent a chemical reduction through the dropwise addition of a NaBH 4 solution (0.8 ml) under a nitrogen atmosphere. The resulting solution was then dialysed to remove any remaining NaBH 4 and concentrated to 2 ml with a dialysis membrane (Spectra/Por, molecular weight cut-off, 6–8 kDa, Spectrum Laboratories) against a 6 wt% PEG solution ( M r  ≈ 35,000, Sigma-Aldrich) at pH 2.0. TEM imaging of AuNPs stabilized by BLG fibrils revealed three-dimensional particles with an average size of 1.32 nm (Supplementary Fig. 21a ), determined by analysing six TEM images using ImageJ software v.1.8.0. For the preparation of Fe SA @AH, 2 g of Fe SA @FibBLG powder was dissolved in the resulting AuNP-attached BLG fibril solution (2 ml). The mixture was then transferred into a plastic syringe, the top part of which had been previously cut. The plastic syringe was covered with a section of a dialysis tube (Spectra/Por, molecular weight cut-off, 6–8 kDa), and the head of the syringe was positioned in direct contact with an excess of 300 mM NaCl solution at pH 7.4 for at least 16 h in a 4 °C cold room to facilitate gelation. The resulting hydrogel sample was kept under 4 °C. The working hydrogel was freshly prepared by mixing the aforementioned hydrogel with 0.1 ml of a glucose solution (8.0 M) immediately before further characterization or detoxification use. A BLG fibril hydrogel was obtained using the same procedure, except that the Fe SA @FibBLG was replaced with an equal amount of BLG fibril dispersion.

Murine models

Male wild-type C57BL/6 mice, 20–25 g and 8–10 weeks old, were purchased from Beijing Vital River Laboratory Animal Technology. All of the murine experiments in the current study were approved by the Regulations of Beijing Laboratory Animal Management (approval number AW40803202-5-1) and conducted according to the guidelines set forth in the Institutional Animal Care and Use Committee of China Agricultural University.

Acute model

Thirty-two male C57BL/6 mice were randomly divided into four groups after 12 h fasting. Mice were orally gavaged with AH and Fe SA @AH (at doses of 10 ml per kg (body weight)), and two groups of mice received the same volume of PBS (as controls, the blank and the PBS groups), respectively. After 20 min of adaptation, mice from the AH, Fe SA @AH, and PBS groups were orally administered an alcohol liquid diet (10 g per kg (body weight)), while the same volume of PBS was administered for the blank group. All the mice were killed 6 h later.

Chronic model

A mouse model of chronic and binge ethanol feeding (NIAAA model) was conducted following the protocol proposed by Bertola et al. 43 . In brief, after 5 days of ad libitum Lieber–DeCarli diet adaptation, 32 mice were randomly divided into four groups: (1) a control group (Con) of mice were pair-fed with the control diet; (2) an ethanol diet group (EtOH); (3) an ethanol diet group with additional 10 ml per kg (body weight) AH; and (4) an ethanol diet group with additional 10 ml per kg (body weight) Fe SA @AH. The ethanol-fed groups were granted unrestricted access to the ethanol Lieber–DeCarli diet containing 5% (vol/vol) ethanol for 10 days, and additionally received daily morning (9:00) gavage of PBS, AH or Fe SA @AH, respectively. The control group was pair-fed with an isocaloric control diet and daily control-liquid gavage. All animals were maintained in specific pathogen-free conditions, at a temperature of 23 ± 1 °C and 50–60% humidity, under a 12 h light/dark cycle, with access to autoclaved water. On day 16, both the ethanol-fed and pair-fed mice were orally administered a single dose of ethanol (5 g per kg (body weight)) or isocaloric maltose dextrin at 9:20, respectively, and killed 6 h later. The body weight of mice was recorded every 2 days.

After overnight fasting, mice were gavaged with 0.1 ml [ 18 F]FDG-labelled Fe SA @AH. Then, mice were anaesthetized with oxygen containing 2% isoflurane, and placed in and fixed in a prone position in an imaging chamber. Time-series images were obtained with an Inveon microPET/CT scanner (Siemens); the scanner parameters were a 15 min CT scan (80 kVp, 500 μA, 1,100 ms exposure time) followed by a 10 min PET acquisition. Quantification of images was performed by AMIDE software 3.0.

Alcohol tolerance test

Approximately 10 µl of blood was collected from the submandibular vein at 30, 60, 90, 120, 180 and 300 min after alcohol exposure. In the chronic model, sampling was conducted after the binge ethanol feeding. Blood alcohol concentration (BAC) was determined using a test kit from Abcam Biotechnology (ab65343). BACs were normalized to mice body weights as previously described 8 . Normalized BAC, BAC nor , was calculated using the equation: BAC nor  = BAC i  × (BWT i /BWT ave ), where BAC i and BWT i denote the blood alcohol level and body weight of mice, respectively, and BWT ave represents the average weight of all mice in each set of experiments. The quantification of the BAce concentration was carried out using a test kit obtained from Abcam Biotechnology (ab308327), and the normalization process was conducted using the same method as for the BAC.

Alcohol tolerance time was the duration between alcohol administration and the absence of righting reflex, while the duration of the absence of righting reflex was recorded as the sobering-up time. Mice that became ataxic were considered to have lost their righting reflex, and were then placed face up. The time point at which the mice returned to their normal upright position signified they had regained their righting reflex.

An MWM test 59 was conducted by Anhui Zhenghua Biologic Apparatus Facilities, as described previously. Specifically, the MWM apparatus comprised a large circular pool (120 cm diameter and 40 cm height) which was filled with TiO 2 -dyed, 25 °C thermostatic water, and a 10-cm-diameter platform was positioned and fixed 2 cm below the water surface. Before acute ethanol exposure, mice received four rounds of daily training for 6 days. Each trial was limited to 60 s, and the time that it took for the mice to successfully locate the platform was recorded. On day 7, mice were retested (no platform condition) 5 h after ethanol feeding (the time point by which all mice regained their consciousness and mobility). The tested items included trajectory, path length, escape latency and swimming speed (MWM animal behaviour video tracking system, Morris v.2.0).

Biochemical assays

Blood samples were collected through cardiac puncture from anaesthetized mice 6 h after alcohol gavage. Prior to testing, samples were maintained at ambient temperature for 4 h, and then centrifuged (864.9 g , 4 °C) for 20 min. Supernatants were suctioned and stored at −80 °C for further analysis. Serum ALT, AST, triglycerides and total cholesterol were measured by a Hitachi Biochemistry Analyzer 7120 (Hitachi High-Tech).

Weighed liver tissues were collected and immersed immediately in 10% neutral buffered formaldehyde. After overnight fixation, tissues were embedded in paraffin and cut into 5 μm sections for further haematoxylin and eosin (H&E) and oil red O (Sigma) staining. Images were captured by a Nikon Eclipse TI-SR fluorescence microscope. Fresh liver was homogenized in chilled normal saline and centrifuged (1,500 g , 4 °C) for 15 min. GSH and MDA levels of the resultant supernatant were detected using the GSH assay kit (ab65322) and the lipid peroxidation (MDA) assay kit (ab118970), respectively. Hepatic and cellular lipid content was isolated using the chloroform/methanol-based method 60 , and quantified by using the triglyceride assay kit (ab65336) and the mouse total cholesterol ELISA kit (ab285242, SSUF-C), respectively.

Colon histology and immunohistochemistry

Colon length, caecum to anus, was measured, and the distal colon was washed with saline, with one-half being fixed with 4% paraformaldehyde, and the other half stored at −80 °C. Histological measurements of the colon were the same as those for the liver.

For immunofluorescence, colon tissues were treated with EDTA buffer and boiled to expose the antigens. Tissues were then incubated overnight at 4 °C with primary antibody and washed three times for 5 min each with PBS. Subsequently, colon tissues were covered with secondary antibody and incubated at room temperature in the dark for 50 min, followed by another set of three 5 min washes with PBS. The resultant sections were mounted with a mounting medium and stained with 4,6-diamidino-2-phenylindole. Slides were then covered, and the images were captured using a Nikon Eclipse Ti inverted fluorescence microscope.

Microbiota changes

Faecal samples were collected within 5 min after defecation into a sterile tube and stored at −80 °C. Microbial genome DNA was extracted from faeces by using the DNeasy PowerSoil Pro Kit (QIAGEN) according to the manufacturer’s instructions, and the variable 3–4 (V4-v4) region of the 16S rRNA gene was PCR-amplified using barcoded 338F-806R primers (forward primer, 5′-ACTCCTACGGGAGGCAGCAG-3′; reverse primer, 5′-GGACTACHVGGGTWTCTAAT-3′). PCR components contained 25 μl of Phusion High-Fidelity PCR Master Mix, 3 μl (10 μM) of each forward and reverse primer, 10 μl of the DNA template, 3 μl of DMSO and 6 μl of double-distilled H2O. The following cycling conditions were used: initial denaturation at 98 °C for 30 s, followed by 25 cycles of denaturation at 98 °C for 15 s, annealing at 58 °C for 15 s, and extension at 72 °C for 15 s, and a final extension of 1 min at 72 °C. PCR amplicons were purified using Agencourt AMPure XP Beads (Beckman Coulter) and quantified using a PicoGreen dsDNA Assay Kit (Invitrogen). After quantification, amplicons were pooled in equal amounts, and 2 × 150 bp paired-end sequencing was performed using the Illumina Miseq PE300 platform at GUHE Info Technology. Amplicon sequence variants (ASVs) were denoised and clustered by the UNOISE algorithm. Taxa bar plots, and α- and β-diversity analysis, were performed with QIIME 2 v.2020.6 and the R package v.3.6.3. Metabolic function was predicted using PICRUSt2, and the output file was further analysed using the STAMP software package (v.2.1.3).

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Data availability

All the data that validates the outcomes of this study are included in the Article and its Supplementary Information files. For any other relevant source data, interested parties can obtain them from the corresponding authors upon reasonable request. Source data are provided with this paper.

Code availability

Simulation files and code used for modelling iron-anchored BLG fibril segments can be accessed via Zenodo at: https://doi.org/10.5281/zenodo.10819612 (ref. 61 ).

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Acknowledgements

The authors thank I. Kutzli for the purification of BLG, W. Wang for 1 H NMR measurements, and M. Wörle for X-ray diffraction experiments. Bruna F. G. L. is gratefully acknowledged for the help in analysing XAFS data. Appreciation is also extended to C. Zeder for the inductively coupled plasma mass spectrometry measurements. Support from R. Schäublin during electron microscopy observations is gratefully acknowledged. J.S. acknowledges financial support from the Special Research Fund of Ghent University (BOF.PDO.2021.0050.01) and the Research Foundation–Flanders (FWO V420422N). ICFO authors thank CEX2019-000910-S (MCIN/AEI/10.13039/501100011033), Fundació Cellex, Fundació Mir-Puig, Generalitat de Catalunya through CERCA and the La Caixa Foundation (100010434, EU Horizon 2020 Marie Skłodowska-Curie grant agreement 847648).

Open access funding provided by Swiss Federal Institute of Technology Zurich.

Author information

These authors contributed equally: Jiaqi Su, Pengjie Wang.

Authors and Affiliations

Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland

Jiaqi Su, Mohammad Peydayesh, Jiangtao Zhou, Tonghui Jin & Raffaele Mezzenga

Particle and Interfacial Technology Group, Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium

Jiaqi Su & Paul Van der Meeren

Department of Nutrition and Health, Beijing Higher Institution Engineering Research Center of Animal Products, China Agricultural University, Beijing, China

Pengjie Wang & Fazheng Ren

Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland

Institute of Energy and Process Engineering, Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland

Felix Donat

Institute of Translational Medicine, Zhejiang Shuren University, Zhejiang, China

Cuiyuan Jin

ICFO–Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, Barcelona, Spain

Lu Xia, Kaiwen Wang & F. Pelayo García de Arquer

Department of Materials, ETH Zurich, Zurich, Switzerland

Raffaele Mezzenga

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Contributions

R.M. and J.S. conceived the idea, designed the experiments, co-wrote the manuscript and coordinated the overall research project. J.S. developed the fabrication procedure of protein-fibril-based single-atom nanozymes, characterized the enzymatic activities of nanozymes, collected and analysed the data, and performed the computational analysis. L.X. and K.W. performed the XAFS measurements of samples and analysed the data. T.J and M.P. assisted in the analysis of enzyme kinetics data. W.Z. performed XPS and 1 H NMR measurements of samples and analysed the data. J.Z. coordinated the AFM characterization of samples. P.W. and F.R. designed the in vitro and in vivo experiments on cells and animals. P.W. and J.S. carried out cell and animal studies. C.J. contributed to the microbiota test and data analysis. P.V.d.M., F.P.G.d.A. and F.D. contributed to interpreting the data and revised the manuscript. All the authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Jiaqi Su or Raffaele Mezzenga .

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J.S. and R.M. are the inventors of a patent filed jointly by Ghent University and ETH Zurich (EP24153321).

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Supplementary Methods, Discussion, Figs. 1–29, Tables 1–10, Gating strategy for flow cytometry and References.

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Su, J., Wang, P., Zhou, W. et al. Single-site iron-anchored amyloid hydrogels as catalytic platforms for alcohol detoxification. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01657-7

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DOI : https://doi.org/10.1038/s41565-024-01657-7

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Adhesive coatings can prevent scarring around medical implants

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When medical devices such as pacemakers are implanted in the body, they usually provoke an immune response that leads to buildup of scar tissue around the implant. This scarring, known as fibrosis, can interfere with the devices’ function and may require them to be removed.

In an advance that could prevent that kind of device failure, MIT engineers have found a simple and general way to eliminate fibrosis by coating devices with a hydrogel adhesive. This adhesive binds the devices to tissue and prevents the immune system from attacking it.

“The dream of many research groups and companies is to implant something into the body that over the long term the body will not see, and the device can provide therapeutic or diagnostic functionality. Now we have such an ‘invisibility cloak,’ and this is very general: There’s no need for a drug, no need for a special polymer,” says Xuanhe Zhao, an MIT professor of mechanical engineering and of civil and environmental engineering.

The adhesive that the researchers used in this study is made from cross-linked polymers called hydrogels, and is similar to a surgical tape they previously developed to help seal internal wounds. Other types of hydrogel adhesives can also protect against fibrosis, the researchers found, and they believe this approach could be used for not only pacemakers but also sensors or devices that deliver drugs or therapeutic cells.

Zhao and Hyunwoo Yuk SM ’16, PhD ’21, a former MIT research scientist who is now the chief technology officer at SanaHeal, are the senior authors of the study, which appears today in Nature . MIT postdoc Jingjing Wu is the lead author of the paper.

Preventing fibrosis

In recent years, Zhao’s lab has developed adhesives for a variety of medical applications, including double-sided and single-sided tapes that could be used to heal surgical incisions or internal injuries. These adhesives work by rapidly absorbing water from wet tissues, using polyacrylic acid, an absorbent material used in diapers. Once the water is cleared, chemical groups called NHS esters embedded in the polyacrylic acid form strong bonds with proteins at the tissue surface. This process takes about five seconds.

Several years ago, Zhao and Yuk began exploring whether this kind of adhesive could also help keep medical implants in place and prevent fibrosis from occurring.

To test this idea, Wu coated polyurethane devices with their adhesive and implanted them on the abdominal wall, colon, stomach, lung, or heart of rats. Weeks later, they removed the device and found that there was no visible scar tissue. Additional tests with other animal models showed the same thing: Wherever the adhesive-coated devices were implanted, fibrosis did not occur, for up to three months.

“This work really has identified a very general strategy, not only for one animal model, one organ, or one application,” Wu says. “Across all of these animal models, we have consistent, reproducible results without any observable fibrotic capsule.”

Using bulk RNA sequencing and fluorescent imaging, the researchers analyzed the animals’ immune response and found that when devices with adhesive coatings were first implanted, immune cells such as neutrophils began to infiltrate the area. However, the attacks quickly quenched out before any scar tissue could form.

“For the adhered devices, there is an acute inflammatory response because it is a foreign material,” Yuk says. “However, very quickly that inflammatory response decayed, and then from that point you do not have this fibrosis formation.”

One application for this adhesive could be coatings for epicardial pacemakers — devices that are placed on the heart to help control the heart rate. The wires that contact the heart often become fibrotic, but the MIT team found that when they implanted adhesive-coated wires in rats, they remained functional for at least three months, with no scar tissue formation.

“The formation of fibrotic tissue at the interface between implanted medical devices and the target tissue is a longstanding problem that routinely causes failure of the device. The demonstration that robust adhesion between the device and the tissue obviates fibrotic tissue formation is an important observation that has many potential applications in the medical device space,” says David Mooney, a professor of bioengineering at Harvard University, who was not involved in the study.

Mechanical cues

The researchers also tested a hydrogel adhesive that includes chitosan, a naturally occurring polysaccharide, and found that this adhesive also eliminated fibrosis in animal studies. However, two commercially available tissue adhesives that they tested did not show this antifibrotic effect because the commercially available adhesives eventually detached from the tissue and allowed the immune system to attack.

In another experiment, the researchers coated implants in hydrogel adhesives but then soaked them in a solution that removed the polymers’ adhesive properties, while keeping their overall chemical structure the same. After being implanted in the body, where they were held in place by sutures, fibrotic scarring occurred. This suggests that there is something about the mechanical interaction between the adhesive and the tissue that prevents the immune system from attacking, the researchers say.

“Previous research in immunology has been focused on chemistry and biochemistry, but mechanics and physics may play equivalent roles, and we should pay attention to those mechanical and physical cues in immunological responses,” says Zhao, who now plans to further investigate how those mechanical cues affect the immune system.

Yuk, Zhao, and others have started a company called SanaHeal, which is now working on further developing tissue adhesives for medical applications.

“As a team, we are interested in reporting this to the community and sparking speculation and imagination as to where this can go,” Yuk says. “There are so many scenarios in which people want to interface with foreign or manmade material in the body, like implantable devices, drug depots, or cell depots.”

The research was funded by the National Institutes of Health and the National Science Foundation.

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• Xuanhe Zhao
• Hyunwoo Yuk
• Jingjing Wu
• Department of Mechanical Engineering
• Department of Civil and Environmental Engineering

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• Mechanical engineering
• Civil and environmental engineering
• Biomedical engineering
• Medical devices
• National Institutes of Health (NIH)
• National Science Foundation (NSF)

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The world’s benchmark climate monitoring station passes a major milestone

• May 20, 2024
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On May 17, 1974, staff of the new National Oceanographic and Atmospheric Administration’s Geophysical Monitoring for Climatic Change program took their first atmospheric measurements for what would become one of the most scientifically significant records of humanity’s impact on Earth’s climate.

Since then, NOAA’s Global Monitoring Laboratory’s continuous measurements of atmospheric carbon dioxide (CO 2 ) at the Mauna Loa Observatory have contributed to the longest modern datasets of this important greenhouse gas. NOAA’s daily measurements provide independent observations that complement measurements taken by the University of California San Diego’s Scripps Institution of Oceanography, which started sampling in 1958. The sustained, collaborative effort has helped educate scientists and the public about the relentless rise of CO 2 caused primarily by fossil fuel pollution. 

The concentration of carbon dioxide, or CO 2 , in that first sample was 333.46 parts per million (ppm). This month, as the annual CO 2 cycle peaks, concentrations have been averaging 427 ppm, more than 90 ppm above the 1974 level.  

“The long-term measurements at Mauna Loa have given us an accurate and unmistakable record of humans’ impact on the only atmosphere we have,” said Vanda Grubišić, director of the Global Monitoring Laboratory (GML).

This graph shows the full record of monthly mean carbon dioxide measured at Mauna Loa Observatory, Hawaii, by NOAA and the Scripps Institution of Oceanography. Credit: NOAA Global Monitoring Laboratory

Perched high on the barren slopes of the Mauna Loa volcano in the middle of the Pacific Ocean, the observatory protrudes through the strong marine boundary layer temperature inversion that separates the more polluted lower portions of the atmosphere from the much cleaner free troposphere. The 11,135-foot elevation above sea level is ideal for sampling well-mixed air undisturbed by the influence of local pollution sources or vegetation, producing measurements that represent the average state of the atmosphere in the northern hemisphere. 

The characteristics that make the site ideal for measuring CO 2 also provide ideal conditions for a wide variety of other atmospheric research efforts. The observatory’s 10 buildings house instruments that collected up to 250 climatological measurements for NOAA and partner agency scientists and engineers every day before the eruption of the volcano cut off access to the site in November 2022. 

In the beginning

The Mauna Loa Observatory was established by the U.S. Weather Bureau , the precursor to NOAA’s National Weather Service, on June 28th, 1956, but not to monitor climate. Instead, scientists made routine weather observations and studied atmospheric circulation. They also made observations of solar radiation, cosmic radiation, fallout from atomic tests, snow crystals, meteors, the Sun’s corona, even the atmosphere of Mars. 

Charles David Keeling was the first to observe that CO 2 levels rose and fell every year in concert with the seasons, a dynamic which is now known as the Keeling Curve . The highest monthly mean CO 2 value of the year occurs in May, just before plants in the northern hemisphere start to remove large amounts of CO 2 from the atmosphere during the growing season. In the northern fall, winter, and early spring, plants and soils give off CO 2, causing levels to rise through May. 

Keeling was also the first to recognize that despite the seasonal fluctuation, average CO 2 levels were increasing every year. Not only has that trend continued, but the rate of the annual increase has also risen – sharply – in recent decades. (Keeling’s son, geochemist Ralph Keeling, runs the Scripps program at Mauna Loa.)

This aerial photograph shows the dominant fissure erupting on the Northeast Rift Zone of Mauna Loa, taken at approximately 8 a.m. Hawaii Standard Time on November 29, 2022. Lava fountains were up to 25 m (82 ft) that morning as the vent was feeding the main lava flow to the northeast. Credit: M. Patrick/USGS photo

The volcano awakes

On Nov. 27, 2022, lava flows from the erupting Mauna Loa volcano buried more than a mile of the access road and destroyed power poles, temporarily interrupting all scientific activity at the observatory. NOAA and Scripps scientists were able to quickly set up alternative sampling sites for some measurements, including CO 2 , at Maunakea. 

In 2023, MLO staff visiting the site once a week via helicopter restored limited power to four key observatory buildings by augmenting existing solar generation and adding battery systems. Approximately 33 percent of the atmospheric measurements on the mountain site have been restored, including consistent measurements for greenhouse gases, halocarbons and trace gases, ozone, aerosols and global radiation. Reconstruction of the access road to the observatory is anticipated in 2025.

The Mauna Loa Observatory is one of four NOAA atmospheric baseline observatories strategically situated from the Arctic to the South Pole, each of which collects numerous daily in situ and remote atmospheric and solar measurements. Continuous measurements of atmospheric CO 2 at the Barrow Observatory near the ​​village of Utqiaġvik, Alaska began in July 1973, at the South Pole Atmospheric Research Observatory in January 1975, and at the American Samoa Atmospheric Baseline Observatory in January 1976.

To explore more information about the CO 2 record at Mauna Loa Observatory, visit the GML website’s Trends in CO2 page. 

For more information, contact Theo Stein, NOAA Communications: [email protected] .

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