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Structure of Scholarly Articles and Peer Review: Structure of a Biomedical Research Article

Created by health science librarians.

Title, Authors, Sources of Support and Acknowledgments

Structured abstract, introduction, results and discussion, international committee of medical journal editors (icmje).

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Medical research articles tend to be structured in similar ways. This standard structure helps assure that research is reported with the information readers need to critically appraise the research process and results.

This guide to the structure of a biomedical research article was informed by the description of standard manuscript sections found in the International Committee of Medical Journal Editors (ICMJE) Recommendations chapter on Manuscript Preparation: Preparing for Submission .

If you are writing an article for submisson to a particular journal be sure to obtain that journal's instructions for authors for specific guidelines.

Example Article: Lyons EJ, Tate DF, Ward DS, Wang X. Energy intake and expenditure during sedentary screen time and motion-controlled video gaming. Am J Clin Nutr. 2012 Aug;96(2):234-9. doi: 10.3945/ajcn.111.028423. Epub 2012 Jul 3. PubMed PMID: 22760571; PubMed Central PMCID: PMC3396440. (Free full text available)

Article title:  Should provide a succinct description of the purpose of the article using words that will help it be accurately retrieved by search engines. 

Author information:  Includes the author names and the institution(s) where each author was affiliated at the time the research was conducted. Full contact information is provided for the corresponding author. 

Source(s) of support: Specific information about grant funding or source of equipment, drugs, etc. obtained to support the research. 

Acknowledgments:  This section may found at the end of the article and is used to name people who contributed to the paper, but not fully enough to be named as an author. It may also include more information about the authors' specific roles.

The structure of quantitative research articles is derived from the scientifc process and includes sections covering introduction, methods, results, and discussion (IMRaD). The actual labels for the various parts may vary between journals.

Abstract:  A structured abstract reports a summary of each of the IMRaD sections. Enough information should be included to provide the purpose of the research; an outline of methods used; results with data; and conclusions that highlight the findings. 

The introduction provides background information about what is known from previous related research, citing the relevant studies, and points out the gap in previous research that is being addressed by the new study. Often, many of the references cited in a paper are in the introduction. The purpose of the research should be clearly stated in this section.

The sample paper's introduction links television watching to increased energy intake and obesity, notes that several studies have shown a similar link with video gaming, and states no study was identified that compared television and video gaming. Eighteen of the thirty-one references used in the paper are cited in the introduction. The final paragraph of the introduction has two sentences that clearly state the purpose and the hypothesized expected outcome of the study.

The methods section clearly explains how the study was conducted. The ICMJE recommends that this section include information about how participants were selected, detailed demographics about who the participants were, and explanations of why any particular populations were included or excluded from the study. The details of how the study was conducted should be described with enough detail that the study could be replicated. Selected statistical methods should be reported in enough detail that readers can evaluate their appropriateness to the data being gathered.

The sample paper’s methods section includes subsections covering:  recruitment; procedures used for each study subgroup (TV, VG, motion-controlled VG); what snacks and beverages were used and how they were made available; how energy intake and energy expenditure were measured; how the data was analyzed and the specific statistical analysis and secondary analysis that was used.

The results section reports the data gathered and the statistical analysis of the data. Tables and / or graphs are often used to clearly and compactly present the data.

The results section of the sample paper  has two subsections and two tables. One subsection and related table shows the analysis of participant characteristics, The other subsection and table covers the analysis of energy intake, expenditure, and surplus.

In order to critically appraise the quality of the study you need to be able to understand the statistical analysis of the data. Two articles that help with this task are:

• Greenhalgh Trisha.  How to read a paper: Statistics for the non-statistician. I: Different types of data need different statistical tests  BMJ 1997; 315:364
• Greenhalgh Trisha.  How to read a paper: Statistics for the non-statistician. II: “Significant” relations and their pitfalls  BMJ 1997; 315:422

Another aid to critically reading a paper is to see if it has been included and evaluated in a systematic review. Try searching for the article you are reading in Google Scholar and seeing if the cited references include a systematic review. The sample paper was critically reviewed in:

• Marsh S, Ni Mhurchu C, Maddison R. The non-advertising effects of screen-based sedentary activities on acute eating behaviours in children, adolescents, and young adults. A systematic review. Appetite. 2013 Dec;71:259-73. doi: 10.1016/j.appet.2013.08.017. Epub 2013 Aug 31. PubMed Abstract . Full-text for UNC-CH .

The  discussion section  clearly states the primary findings of the study, poses explanations for the findings and any conclusions that can be drawn from them. It may also include the author’s assessment of limitations in the research as conducted and suggestions for further research that is needed.

The structure of biomedical research articles has been standardized across different journals at least in part due to the work of the International Committee of Medical Journal Editors. This group first published the  Uniform Requirements for Manuscripts Submitted to Biomedical Journals  in 1978.

The  Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in Medical Journals  (2013) is the most recent update of ICMJE's work. 

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• Last Updated: May 14, 2024 12:50 PM
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A Conclusion to My Time as a Biomedical Student

By Ekpreet Sahota

Welcome to the last edition of A Day in the Life of a Biomedical Student!

In this blog I will be summarising my time as a Biomedical student. I will discuss what I have learned and my plans for the future, plus I’ll share some tips on what you can do during your degree to help you prepare for life after you graduate.

What transferable skills have I learned? 

Transferable skills are skills which can be applied to a variety of different jobs and roles. This means that the skills I have learned throughout my biomedical degree have not only prepared me for a career in the biomedical field but elsewhere too. These are some of the transferable skills I learned throughout my degree and what you could expect to develop too:

• Research and report writing – I was able to develop this skill through all the coursework I was given; it is a skill required in almost any career. Every single piece of work required us to research appropriate biomedical papers, analyse them, and include them in our reports or presentations.
• Effective Communication – communication was very important during my lab project as half of our group would go in one day and the other half another day. We had to learn to regularly communicate with each other so that our whole group were on the same page and understood what tasks had to be done. I learned that communication becomes even more effective when you can use as few words as possible to convey an important image, making it easier for the person you are communicating with to understand.
• Leadership & Responsibility – You can develop leadership skills from group projects, but also from taking on important roles in societies. You can also expect to gain a strong sense of responsibility, whether it’s responsibility for a group or for yourself. At university you realise that you are responsible for keeping on top of your own work, and unlike school, teachers will not be watching you all the time and pick up on whether you might be falling behind.
• Planning – University can be quite hectic. You will be juggling a lot of responsibilities and you will need to find time to take notes, consolidate your notes, do your coursework, socialise and many more things. I learned how to plan my week ahead which made everything seem less crazy!

Career Options for a Biomedical Graduate

Typically, a biomedicine degree prepares you for a career as a biomedical scientist. This may involve academic research in a wide range of fields, from cancer biology to stem cell research. Researchers in these types of fields mainly aim to investigate how our biology behaves in certain diseases in hopes to create appropriate treatment down the line. Becoming a researcher doesn’t limit you to investigating human biology – you can also apply the same skills to work for companies which make or test certain products. For example, at a careers event I saw a company which sold women’s cosmetics wanting biomedical graduates to to work in their ‘research & development’ department! However, as mentioned before, the skills you learn will be transferable and so you are not limited to a career as a researcher. Many jobs require you to have a degree, but a lot of jobs don’t necessarily require you to have a specific degree – just relevant skills and work experience. You might want to become a science communicator (what we do here at Centre of the Cell!), a sales representative or even an accountant.

Here are some things you can do while at university to give you a head start in thinking about your future career:

• Go to career fairs (very important!)

• Apply to internships to gain some work experience (these usually take place in the summer of your 1 st or 2 nd year). It’s never too early to start researching what kind of work experience you want. Whether you’re in college, or just started university, start developing a list of companies who offer the type of work experience you want – so when the time comes you won’t waste any time and you can can get to applying!
• Volunteer or get a part-time job, so that you can experience different environments and gain lots of valuable skills. It’s important to experience different things to know what you want to do next.
• Speak to students in the years above you to see what they have planned

This February we will be launching our YMS Virtual Work Experience where you can gain an insight into the types of careers available to you as a science graduate. Sign up to the YMS and keep an eye out for further details soon!

What is my career goal? 

From a very young age I’ve always wanted to be a teacher. Nonetheless, when I got to university, I was quite open-minded as to what possible career paths I could choose. I realised over the years at university that working as a researcher in a laboratory was something that I did not want to do. I found it a little difficult to think of alternative career paths since teachers would generally only talk about careers as a researcher – this is why it’s very important to have a one-on-one with your tutor to get some personalised advice!

I went to a careers fair at the beginning of my second year and, although there were many research-based companies, there were also many companies from a variety of backgrounds. I came across the Teach First stall, where I was introduced to their STEM internship which involved learning about the theory of teaching and about educational inequality in the UK. Since I was interested in becoming a teacher, I applied. I received an offer and in July 2020 I took part in the internship and gained a wealth of knowledge and skills I knew would help me in becoming a teacher. The internship definitely put me on the right track towards becoming a teacher.

My next steps…

Now that I’m in my final year everything is moving quite fast! My time here at Centre of the Cell finishes at the beginning of February, and after that I’m back to online lectures and assessments. Luckily this year is all coursework and no exams! Whilst at Centre of Cell, I have been applying to various graduate schemes. These schemes are specifically designed for those who have just graduated where they train you at an entry-level, and there is usually a cohort of graduates they take on for the scheme. I’ve applied to a wide variety of graduate schemes – some associated with health communication, some with marketing and one teaching scheme. If I get accepted onto a graduate scheme, then I should start working in September 2021. There are also companies which do not have graduate schemes, but general entry-level roles which I have also been applying to.

How to make the most of your time at university:

Here are a few things you can do to really make your time at university an experience to remember – some of these things I wish I did when I started 3 years ago!

• If you’re new to the area, take some time to explore it
• Join as many societies as you can – this is a great way to pursue your hobby, try something new and meet new people
• Become a student representative for your class – you will act as a liaison between students and teachers. You will formally discuss with teachers any issues with the course raised by your peers. You will also become a trusted member of your class and get to know pretty much everyone!
• Expand your knowledge – guest speakers often come to universities to discuss ground-breaking research and other fascinating topics. By attending these talks, you can learn about something new or even deepen your knowledge of your field of study.
• Work on your CV – engaging with different opportunities that come your way, or even creating opportunities for yourself, will help build your CV. This might include internships, tutoring and taking on leadership roles in societies.

That’s the end!

I hope you enjoyed reading this blog series and have learned things which may encourage you to apply for a biomedical degree or help you prepare for your course!

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• Open access
• Published: 26 February 2019

Stem cells: past, present, and future

• Wojciech Zakrzewski 1 ,
• Maciej Dobrzyński 2 ,
• Maria Szymonowicz 1 &
• Zbigniew Rybak 1  

Stem Cell Research & Therapy volume  10 , Article number:  68 ( 2019 ) Cite this article

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In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Stem cell classification

Stem cells are unspecialized cells of the human body. They are able to differentiate into any cell of an organism and have the ability of self-renewal. Stem cells exist both in embryos and adult cells. There are several steps of specialization. Developmental potency is reduced with each step, which means that a unipotent stem cell is not able to differentiate into as many types of cells as a pluripotent one. This chapter will focus on stem cell classification to make it easier for the reader to comprehend the following chapters.

Totipotent stem cells are able to divide and differentiate into cells of the whole organism. Totipotency has the highest differentiation potential and allows cells to form both embryo and extra-embryonic structures. One example of a totipotent cell is a zygote, which is formed after a sperm fertilizes an egg. These cells can later develop either into any of the three germ layers or form a placenta. After approximately 4 days, the blastocyst’s inner cell mass becomes pluripotent. This structure is the source of pluripotent cells.

Pluripotent stem cells (PSCs) form cells of all germ layers but not extraembryonic structures, such as the placenta. Embryonic stem cells (ESCs) are an example. ESCs are derived from the inner cell mass of preimplantation embryos. Another example is induced pluripotent stem cells (iPSCs) derived from the epiblast layer of implanted embryos. Their pluripotency is a continuum, starting from completely pluripotent cells such as ESCs and iPSCs and ending on representatives with less potency—multi-, oligo- or unipotent cells. One of the methods to assess their activity and spectrum is the teratoma formation assay. iPSCs are artificially generated from somatic cells, and they function similarly to PSCs. Their culturing and utilization are very promising for present and future regenerative medicine.

Multipotent stem cells have a narrower spectrum of differentiation than PSCs, but they can specialize in discrete cells of specific cell lineages. One example is a haematopoietic stem cell, which can develop into several types of blood cells. After differentiation, a haematopoietic stem cell becomes an oligopotent cell. Its differentiation abilities are then restricted to cells of its lineage. However, some multipotent cells are capable of conversion into unrelated cell types, which suggests naming them pluripotent cells.

Oligopotent stem cells can differentiate into several cell types. A myeloid stem cell is an example that can divide into white blood cells but not red blood cells.

Unipotent stem cells are characterized by the narrowest differentiation capabilities and a special property of dividing repeatedly. Their latter feature makes them a promising candidate for therapeutic use in regenerative medicine. These cells are only able to form one cell type, e.g. dermatocytes.

Stem cell biology

A blastocyst is formed after the fusion of sperm and ovum fertilization. Its inner wall is lined with short-lived stem cells, namely, embryonic stem cells. Blastocysts are composed of two distinct cell types: the inner cell mass (ICM), which develops into epiblasts and induces the development of a foetus, and the trophectoderm (TE). Blastocysts are responsible for the regulation of the ICM microenvironment. The TE continues to develop and forms the extraembryonic support structures needed for the successful origin of the embryo, such as the placenta. As the TE begins to form a specialized support structure, the ICM cells remain undifferentiated, fully pluripotent and proliferative [ 1 ]. The pluripotency of stem cells allows them to form any cell of the organism. Human embryonic stem cells (hESCs) are derived from the ICM. During the process of embryogenesis, cells form aggregations called germ layers: endoderm, mesoderm and ectoderm (Fig.  1 ), each eventually giving rise to differentiated cells and tissues of the foetus and, later on, the adult organism [ 2 ]. After hESCs differentiate into one of the germ layers, they become multipotent stem cells, whose potency is limited to only the cells of the germ layer. This process is short in human development. After that, pluripotent stem cells occur all over the organism as undifferentiated cells, and their key abilities are proliferation by the formation of the next generation of stem cells and differentiation into specialized cells under certain physiological conditions.

Oocyte development and formation of stem cells: the blastocoel, which is formed from oocytes, consists of embryonic stem cells that later differentiate into mesodermal, ectodermal, or endodermal cells. Blastocoel develops into the gastrula

Signals that influence the stem cell specialization process can be divided into external, such as physical contact between cells or chemical secretion by surrounding tissue, and internal, which are signals controlled by genes in DNA.

Stem cells also act as internal repair systems of the body. The replenishment and formation of new cells are unlimited as long as an organism is alive. Stem cell activity depends on the organ in which they are in; for example, in bone marrow, their division is constant, although in organs such as the pancreas, division only occurs under special physiological conditions.

Stem cell functional division

Whole-body development.

During division, the presence of different stem cells depends on organism development. Somatic stem cell ESCs can be distinguished. Although the derivation of ESCs without separation from the TE is possible, such a combination has growth limits. Because proliferating actions are limited, co-culture of these is usually avoided.

ESCs are derived from the inner cell mass of the blastocyst, which is a stage of pre-implantation embryo ca. 4 days after fertilization. After that, these cells are placed in a culture dish filled with culture medium. Passage is an inefficient but popular process of sub-culturing cells to other dishes. These cells can be described as pluripotent because they are able to eventually differentiate into every cell type in the organism. Since the beginning of their studies, there have been ethical restrictions connected to the medical use of ESCs in therapies. Most embryonic stem cells are developed from eggs that have been fertilized in an in vitro clinic, not from eggs fertilized in vivo.

Somatic or adult stem cells are undifferentiated and found among differentiated cells in the whole body after development. The function of these cells is to enable the healing, growth, and replacement of cells that are lost each day. These cells have a restricted range of differentiation options. Among many types, there are the following:

Mesenchymal stem cells are present in many tissues. In bone marrow, these cells differentiate mainly into the bone, cartilage, and fat cells. As stem cells, they are an exception because they act pluripotently and can specialize in the cells of any germ layer.

Neural cells give rise to nerve cells and their supporting cells—oligodendrocytes and astrocytes.

Haematopoietic stem cells form all kinds of blood cells: red, white, and platelets.

Skin stem cells form, for example, keratinocytes, which form a protective layer of skin.

The proliferation time of somatic stem cells is longer than that of ESCs. It is possible to reprogram adult stem cells back to their pluripotent state. This can be performed by transferring the adult nucleus into the cytoplasm of an oocyte or by fusion with the pluripotent cell. The same technique was used during cloning of the famous Dolly sheep.

hESCs are involved in whole-body development. They can differentiate into pluripotent, totipotent, multipotent, and unipotent cells (Fig.  2 ) [ 2 ].

Changes in the potency of stem cells in human body development. Potency ranges from pluripotent cells of the blastocyst to unipotent cells of a specific tissue in a human body such as the skin, CNS, or bone marrow. Reversed pluripotency can be achieved by the formation of induced pluripotent stem cells using either octamer-binding transcription factor (Oct4), sex-determining region Y (Sox2), Kruppel-like factor 4 (Klf4), or the Myc gene

Pluripotent cells can be named totipotent if they can additionally form extraembryonic tissues of the embryo. Multipotent cells are restricted in differentiating to each cell type of given tissue. When tissue contains only one lineage of cells, stem cells that form them are called either called oligo- or unipotent.

iPSC quality control and recognition by morphological differences

The comparability of stem cell lines from different individuals is needed for iPSC lines to be used in therapeutics [ 3 ]. Among critical quality procedures, the following can be distinguished:

Short tandem repeat analysis—This is the comparison of specific loci on the DNA of the samples. It is used in measuring an exact number of repeating units. One unit consists of 2 to 13 nucleotides repeating many times on the DNA strand. A polymerase chain reaction is used to check the lengths of short tandem repeats. The genotyping procedure of source tissue, cells, and iPSC seed and master cell banks is recommended.

Identity analysis—The unintentional switching of lines, resulting in other stem cell line contamination, requires rigorous assay for cell line identification.

Residual vector testing—An appearance of reprogramming vectors integrated into the host genome is hazardous, and testing their presence is a mandatory procedure. It is a commonly used procedure for generating high-quality iPSC lines. An acceptable threshold in high-quality research-grade iPSC line collections is ≤ 1 plasmid copies per 100 cells. During the procedure, 2 different regions, common to all plasmids, should be used as specific targets, such as EBNA and CAG sequences [ 3 ]. To accurately represent the test reactions, a standard curve needs to be prepared in a carrier of gDNA from a well-characterized hPSC line. For calculations of plasmid copies per cell, it is crucial to incorporate internal reference gDNA sequences to allow the quantification of, for example, ribonuclease P (RNaseP) or human telomerase reverse transcriptase (hTERT).

Karyotype—A long-term culture of hESCs can accumulate culture-driven mutations [ 4 ]. Because of that, it is crucial to pay additional attention to genomic integrity. Karyotype tests can be performed by resuscitating representative aliquots and culturing them for 48–72 h before harvesting cells for karyotypic analysis. If abnormalities are found within the first 20 karyotypes, the analysis must be repeated on a fresh sample. When this situation is repeated, the line is evaluated as abnormal. Repeated abnormalities must be recorded. Although karyology is a crucial procedure in stem cell quality control, the single nucleotide polymorphism (SNP) array, discussed later, has approximately 50 times higher resolution.

Viral testing—When assessing the quality of stem cells, all tests for harmful human adventitious agents must be performed (e.g. hepatitis C or human immunodeficiency virus). This procedure must be performed in the case of non-xeno-free culture agents.

Bacteriology—Bacterial or fungal sterility tests can be divided into culture- or broth-based tests. All the procedures must be recommended by pharmacopoeia for the jurisdiction in which the work is performed.

Single nucleotide polymorphism arrays—This procedure is a type of DNA microarray that detects population polymorphisms by enabling the detection of subchromosomal changes and the copy-neutral loss of heterozygosity, as well as an indication of cellular transformation. The SNP assay consists of three components. The first is labelling fragmented nucleic acid sequences with fluorescent dyes. The second is an array that contains immobilized allele-specific oligonucleotide (ASO) probes. The last component detects, records, and eventually interprets the signal.

Flow cytometry—This is a technique that utilizes light to count and profile cells in a heterogeneous fluid mixture. It allows researchers to accurately and rapidly collect data from heterogeneous fluid mixtures with live cells. Cells are passed through a narrow channel one by one. During light illumination, sensors detect light emitted or refracted from the cells. The last step is data analysis, compilation and integration into a comprehensive picture of the sample.

Phenotypic pluripotency assays—Recognizing undifferentiated cells is crucial in successful stem cell therapy. Among other characteristics, stem cells appear to have a distinct morphology with a high nucleus to cytoplasm ratio and a prominent nucleolus. Cells appear to be flat with defined borders, in contrast to differentiating colonies, which appear as loosely located cells with rough borders [ 5 ]. It is important that images of ideal and poor quality colonies for each cell line are kept in laboratories, so whenever there is doubt about the quality of culture, it can always be checked according to the representative image. Embryoid body formation or directed differentiation of monolayer cultures to produce cell types representative of all three embryonic germ layers must be performed. It is important to note that colonies cultured under different conditions may have different morphologies [ 6 ].

Histone modification and DNA methylation—Quality control can be achieved by using epigenetic analysis tools such as histone modification or DNA methylation. When stem cells differentiate, the methylation process silences pluripotency genes, which reduces differentiation potential, although other genes may undergo demethylation to become expressed [ 7 ]. It is important to emphasize that stem cell identity, together with its morphological characteristics, is also related to its epigenetic profile [ 8 , 9 ]. According to Brindley [ 10 ], there is a relationship between epigenetic changes, pluripotency, and cell expansion conditions, which emphasizes that unmethylated regions appear to be serum-dependent.

hESC derivation and media

hESCs can be derived using a variety of methods, from classic culturing to laser-assisted methodologies or microsurgery [ 11 ]. hESC differentiation must be specified to avoid teratoma formation (see Fig.  3 ).

Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There is a different result, however, when commitment signals (in forms of soluble factors and culture conditions) are applied and enable the selection of progenitor cells

hESCs spontaneously differentiate into embryonic bodies (EBs) [ 12 ]. EBs can be studied instead of embryos or animals to predict their effects on early human development. There are many different methods for acquiring EBs, such as bioreactor culture [ 13 ], hanging drop culture [ 12 ], or microwell technology [ 14 , 15 ]. These methods allow specific precursors to form in vitro [ 16 ].

The essential part of these culturing procedures is a separation of inner cell mass to culture future hESCs (Fig.  4 ) [ 17 ]. Rosowski et al. [ 18 ] emphasizes that particular attention must be taken in controlling spontaneous differentiation. When the colony reaches the appropriate size, cells must be separated. The occurrence of pluripotent cells lasts for 1–2 days. Because the classical utilization of hESCs caused ethical concerns about gastrulas used during procedures, Chung et al. [ 19 ] found out that it is also possible to obtain hESCs from four cell embryos, leaving a higher probability of embryo survival. Additionally, Zhang et al. [ 20 ] used only in vitro fertilization growth-arrested cells.

Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells are formed. Blastocysts with ICM are formed on the sixth day after fertilization. Pluripotent stem cells from ICM can then be successfully transmitted on a dish

Cell passaging is used to form smaller clusters of cells on a new culture surface [ 21 ]. There are four important passaging procedures.

Enzymatic dissociation is a cutting action of enzymes on proteins and adhesion domains that bind the colony. It is a gentler method than the manual passage. It is crucial to not leave hESCs alone after passaging. Solitary cells are more sensitive and can easily undergo cell death; collagenase type IV is an example [ 22 , 23 ].

Manual passage , on the other hand, focuses on using cell scratchers. The selection of certain cells is not necessary. This should be done in the early stages of cell line derivation [ 24 ].

Trypsin utilization allows a healthy, automated hESC passage. Good Manufacturing Practice (GMP)-grade recombinant trypsin is widely available in this procedure [ 24 ]. However, there is a risk of decreasing the pluripotency and viability of stem cells [ 25 ]. Trypsin utilization can be halted with an inhibitor of the protein rho-associated protein kinase (ROCK) [ 26 ].

Ethylenediaminetetraacetic acid ( EDTA ) indirectly suppresses cell-to-cell connections by chelating divalent cations. Their suppression promotes cell dissociation [ 27 ].

Stem cells require a mixture of growth factors and nutrients to differentiate and develop. The medium should be changed each day.

Traditional culture methods used for hESCs are mouse embryonic fibroblasts (MEFs) as a feeder layer and bovine serum [ 28 ] as a medium. Martin et al. [ 29 ] demonstrated that hESCs cultured in the presence of animal products express the non-human sialic acid, N -glycolylneuraminic acid (NeuGc). Feeder layers prevent uncontrolled proliferation with factors such as leukaemia inhibitory factor (LIF) [ 30 ].

First feeder layer-free culture can be supplemented with serum replacement, combined with laminin [ 31 ]. This causes stable karyotypes of stem cells and pluripotency lasting for over a year.

Initial culturing media can be serum (e.g. foetal calf serum FCS), artificial replacement such as synthetic serum substitute (SSS), knockout serum replacement (KOSR), or StemPro [ 32 ]. The simplest culture medium contains only eight essential elements: DMEM/F12 medium, selenium, NaHCO 3, l -ascorbic acid, transferrin, insulin, TGFβ1, and FGF2 [ 33 ]. It is not yet fully known whether culture systems developed for hESCs can be allowed without adaptation in iPSC cultures.

Turning point in stem cell therapy

The turning point in stem cell therapy appeared in 2006, when scientists Shinya Yamanaka, together with Kazutoshi Takahashi, discovered that it is possible to reprogram multipotent adult stem cells to the pluripotent state. This process avoided endangering the foetus’ life in the process. Retrovirus-mediated transduction of mouse fibroblasts with four transcription factors (Oct-3/4, Sox2, KLF4, and c-Myc) [ 34 ] that are mainly expressed in embryonic stem cells could induce the fibroblasts to become pluripotent (Fig.  5 ) [ 35 ]. This new form of stem cells was named iPSCs. One year later, the experiment also succeeded with human cells [ 36 ]. After this success, the method opened a new field in stem cell research with a generation of iPSC lines that can be customized and biocompatible with the patient. Recently, studies have focused on reducing carcinogenesis and improving the conduction system.

Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their role as somatic cells and, once again, become pluripotent and can differentiate into any cell type of human body

The turning point was influenced by former discoveries that happened in 1962 and 1987.

The former discovery was about scientist John Gurdon successfully cloning frogs by transferring a nucleus from a frog’s somatic cells into an oocyte. This caused a complete reversion of somatic cell development [ 37 ]. The results of his experiment became an immense discovery since it was previously believed that cell differentiation is a one-way street only, but his experiment suggested the opposite and demonstrated that it is even possible for a somatic cell to again acquire pluripotency [ 38 ].

The latter was a discovery made by Davis R.L. that focused on fibroblast DNA subtraction. Three genes were found that originally appeared in myoblasts. The enforced expression of only one of the genes, named myogenic differentiation 1 (Myod1), caused the conversion of fibroblasts into myoblasts, showing that reprogramming cells is possible, and it can even be used to transform cells from one lineage to another [ 39 ].

Although pluripotency can occur naturally only in embryonic stem cells, it is possible to induce terminally differentiated cells to become pluripotent again. The process of direct reprogramming converts differentiated somatic cells into iPSC lines that can form all cell types of an organism. Reprogramming focuses on the expression of oncogenes such as Myc and Klf4 (Kruppel-like factor 4). This process is enhanced by a downregulation of genes promoting genome stability, such as p53. Additionally, cell reprogramming involves histone alteration. All these processes can cause potential mutagenic risk and later lead to an increased number of mutations. Quinlan et al. [ 40 ] checked fully pluripotent mouse iPSCs using whole genome DNA sequencing and structural variation (SV) detection algorithms. Based on those studies, it was confirmed that although there were single mutations in the non-genetic region, there were non-retrotransposon insertions. This led to the conclusion that current reprogramming methods can produce fully pluripotent iPSCs without severe genomic alterations.

During the course of development from pluripotent hESCs to differentiated somatic cells, crucial changes appear in the epigenetic structure of these cells. There is a restriction or permission of the transcription of genes relevant to each cell type. When somatic cells are being reprogrammed using transcription factors, all the epigenetic architecture has to be reconditioned to achieve iPSCs with pluripotency [ 41 ]. However, cells of each tissue undergo specific somatic genomic methylation. This influences transcription, which can further cause alterations in induced pluripotency [ 42 ].

Source of iPSCs

Because pluripotent cells can propagate indefinitely and differentiate into any kind of cell, they can be an unlimited source, either for replacing lost or diseased tissues. iPSCs bypass the need for embryos in stem cell therapy. Because they are made from the patient’s own cells, they are autologous and no longer generate any risk of immune rejection.

At first, fibroblasts were used as a source of iPSCs. Because a biopsy was needed to achieve these types of cells, the technique underwent further research. Researchers investigated whether more accessible cells could be used in the method. Further, other cells were used in the process: peripheral blood cells, keratinocytes, and renal epithelial cells found in urine. An alternative strategy to stem cell transplantation can be stimulating a patient’s endogenous stem cells to divide or differentiate, occurring naturally when skin wounds are healing. In 2008, pancreatic exocrine cells were shown to be reprogrammed to functional, insulin-producing beta cells [ 43 ].

The best stem cell source appears to be the fibroblasts, which is more tempting in the case of logistics since its stimulation can be fast and better controlled [ 44 ].

• Teratoma formation assay

The self-renewal and differentiation capabilities of iPSCs have gained significant interest and attention in regenerative medicine sciences. To study their abilities, a quality-control assay is needed, of which one of the most important is the teratoma formation assay. Teratomas are benign tumours. Teratomas are capable of rapid growth in vivo and are characteristic because of their ability to develop into tissues of all three germ layers simultaneously. Because of the high pluripotency of teratomas, this formation assay is considered an assessment of iPSC’s abilities [ 45 ].

Teratoma formation rate, for instance, was observed to be elevated in human iPSCs compared to that in hESCs [ 46 ]. This difference may be connected to different differentiation methods and cell origins. Most commonly, the teratoma assay involves an injection of examined iPSCs subcutaneously or under the testis or kidney capsule in mice, which are immune-deficient [ 47 ]. After injection, an immature but recognizable tissue can be observed, such as the kidney tubules, bone, cartilage, or neuroepithelium [ 30 ]. The injection site may have an impact on the efficiency of teratoma formation [ 48 ].

There are three groups of markers used in this assay to differentiate the cells of germ layers. For endodermal tissue, there is insulin/C-peptide and alpha-1 antitrypsin [ 49 ]. For the mesoderm, derivatives can be used, e.g. cartilage matrix protein for the bone and alcian blue for the cartilage. As ectodermal markers, class III B botulin or keratin can be used for keratinocytes.

Teratoma formation assays are considered the gold standard for demonstrating the pluripotency of human iPSCs, demonstrating their possibilities under physiological conditions. Due to their actual tissue formation, they could be used for the characterization of many cell lineages [ 50 ].

Directed differentiation

To be useful in therapy, stem cells must be converted into desired cell types as necessary or else the whole regenerative medicine process will be pointless. Differentiation of ESCs is crucial because undifferentiated ESCs can cause teratoma formation in vivo. Understanding and using signalling pathways for differentiation is an important method in successful regenerative medicine. In directed differentiation, it is likely to mimic signals that are received by cells when they undergo successive stages of development [ 51 ]. The extracellular microenvironment plays a significant role in controlling cell behaviour. By manipulating the culture conditions, it is possible to restrict specific differentiation pathways and generate cultures that are enriched in certain precursors in vitro. However, achieving a similar effect in vivo is challenging. It is crucial to develop culture conditions that will allow the promotion of homogenous and enhanced differentiation of ESCs into functional and desired tissues.

Regarding the self-renewal of embryonic stem cells, Hwang et al. [ 52 ] noted that the ideal culture method for hESC-based cell and tissue therapy would be a defined culture free of either the feeder layer or animal components. This is because cell and tissue therapy requires the maintenance of large quantities of undifferentiated hESCs, which does not make feeder cells suitable for such tasks.

Most directed differentiation protocols are formed to mimic the development of an inner cell mass during gastrulation. During this process, pluripotent stem cells differentiate into ectodermal, mesodermal, or endodermal progenitors. Mall molecules or growth factors induce the conversion of stem cells into appropriate progenitor cells, which will later give rise to the desired cell type. There is a variety of signal intensities and molecular families that may affect the establishment of germ layers in vivo, such as fibroblast growth factors (FGFs) [ 53 ]; the Wnt family [ 54 ] or superfamily of transforming growth factors—β(TGFβ); and bone morphogenic proteins (BMP) [ 55 ]. Each candidate factor must be tested on various concentrations and additionally applied to various durations because the precise concentrations and times during which developing cells in embryos are influenced during differentiation are unknown. For instance, molecular antagonists of endogenous BMP and Wnt signalling can be used for ESC formation of ectoderm [ 56 ]. However, transient Wnt and lower concentrations of the TGFβ family trigger mesodermal differentiation [ 57 ]. Regarding endoderm formation, a higher activin A concentration may be required [ 58 , 59 ].

There are numerous protocols about the methods of forming progenitors of cells of each of germ layers, such as cardiomyocytes [ 60 ], hepatocytes [ 61 ], renal cells [ 62 ], lung cells [ 63 , 64 ], motor neurons [ 65 ], intestinal cells [ 66 ], or chondrocytes [ 67 ].

Directed differentiation of either iPSCs or ESCs into, e.g. hepatocytes, could influence and develop the study of the molecular mechanisms in human liver development. In addition, it could also provide the possibility to form exogenous hepatocytes for drug toxicity testing [ 68 ].

Levels of concentration and duration of action with a specific signalling molecule can cause a variety of factors. Unfortunately, for now, a high cost of recombinant factors is likely to limit their use on a larger scale in medicine. The more promising technique focuses on the use of small molecules. These can be used for either activating or deactivating specific signalling pathways. They enhance reprogramming efficiency by creating cells that are compatible with the desired type of tissue. It is a cheaper and non-immunogenic method.

One of the successful examples of small-molecule cell therapies is antagonists and agonists of the Hedgehog pathway. They show to be very useful in motor neuron regeneration [ 69 ]. Endogenous small molecules with their function in embryonic development can also be used in in vitro methods to induce the differentiation of cells; for example, retinoic acid, which is responsible for patterning the nervous system in vivo [ 70 ], surprisingly induced retinal cell formation when the laboratory procedure involved hESCs [ 71 ].

The efficacy of differentiation factors depends on functional maturity, efficiency, and, finally, introducing produced cells to their in vivo equivalent. Topography, shear stress, and substrate rigidity are factors influencing the phenotype of future cells [ 72 ].

The control of biophysical and biochemical signals, the biophysical environment, and a proper guide of hESC differentiation are important factors in appropriately cultured stem cells.

Stem cell utilization and their manufacturing standards and culture systems

The European Medicines Agency and the Food and Drug Administration have set Good Manufacturing Practice (GMP) guidelines for safe and appropriate stem cell transplantation. In the past, protocols used for stem cell transplantation required animal-derived products [ 73 ].

The risk of introducing animal antigens or pathogens caused a restriction in their use. Due to such limitations, the technique required an obvious update [ 74 ]. Now, it is essential to use xeno-free equivalents when establishing cell lines that are derived from fresh embryos and cultured from human feeder cell lines [ 75 ]. In this method, it is crucial to replace any non-human materials with xeno-free equivalents [ 76 ].

NutriStem with LN-511, TeSR2 with human recombinant laminin (LN-511), and RegES with human foreskin fibroblasts (HFFs) are commonly used xeno-free culture systems [ 33 ]. There are many organizations and international initiatives, such as the National Stem Cell Bank, that provide stem cell lines for treatment or medical research [ 77 ].

Stem cell use in medicine

Stem cells have great potential to become one of the most important aspects of medicine. In addition to the fact that they play a large role in developing restorative medicine, their study reveals much information about the complex events that happen during human development.

The difference between a stem cell and a differentiated cell is reflected in the cells’ DNA. In the former cell, DNA is arranged loosely with working genes. When signals enter the cell and the differentiation process begins, genes that are no longer needed are shut down, but genes required for the specialized function will remain active. This process can be reversed, and it is known that such pluripotency can be achieved by interaction in gene sequences. Takahashi and Yamanaka [ 78 ] and Loh et al. [ 79 ] discovered that octamer-binding transcription factor 3 and 4 (Oct3/4), sex determining region Y (SRY)-box 2 and Nanog genes function as core transcription factors in maintaining pluripotency. Among them, Oct3/4 and Sox2 are essential for the generation of iPSCs.

Many serious medical conditions, such as birth defects or cancer, are caused by improper differentiation or cell division. Currently, several stem cell therapies are possible, among which are treatments for spinal cord injury, heart failure [ 80 ], retinal and macular degeneration [ 81 ], tendon ruptures, and diabetes type 1 [ 82 ]. Stem cell research can further help in better understanding stem cell physiology. This may result in finding new ways of treating currently incurable diseases.

Haematopoietic stem cell transplantation

Haematopoietic stem cells are important because they are by far the most thoroughly characterized tissue-specific stem cell; after all, they have been experimentally studied for more than 50 years. These stem cells appear to provide an accurate paradigm model system to study tissue-specific stem cells, and they have potential in regenerative medicine.

Multipotent haematopoietic stem cell (HSC) transplantation is currently the most popular stem cell therapy. Target cells are usually derived from the bone marrow, peripheral blood, or umbilical cord blood [ 83 ]. The procedure can be autologous (when the patient’s own cells are used), allogenic (when the stem cell comes from a donor), or syngeneic (from an identical twin). HSCs are responsible for the generation of all functional haematopoietic lineages in blood, including erythrocytes, leukocytes, and platelets. HSC transplantation solves problems that are caused by inappropriate functioning of the haematopoietic system, which includes diseases such as leukaemia and anaemia. However, when conventional sources of HSC are taken into consideration, there are some important limitations. First, there is a limited number of transplantable cells, and an efficient way of gathering them has not yet been found. There is also a problem with finding a fitting antigen-matched donor for transplantation, and viral contamination or any immunoreactions also cause a reduction in efficiency in conventional HSC transplantations. Haematopoietic transplantation should be reserved for patients with life-threatening diseases because it has a multifactorial character and can be a dangerous procedure. iPSC use is crucial in this procedure. The use of a patient’s own unspecialized somatic cells as stem cells provides the greatest immunological compatibility and significantly increases the success of the procedure.

Stem cells as a target for pharmacological testing

Stem cells can be used in new drug tests. Each experiment on living tissue can be performed safely on specific differentiated cells from pluripotent cells. If any undesirable effect appears, drug formulas can be changed until they reach a sufficient level of effectiveness. The drug can enter the pharmacological market without harming any live testers. However, to test the drugs properly, the conditions must be equal when comparing the effects of two drugs. To achieve this goal, researchers need to gain full control of the differentiation process to generate pure populations of differentiated cells.

Stem cells as an alternative for arthroplasty

One of the biggest fears of professional sportsmen is getting an injury, which most often signifies the end of their professional career. This applies especially to tendon injuries, which, due to current treatment options focusing either on conservative or surgical treatment, often do not provide acceptable outcomes. Problems with the tendons start with their regeneration capabilities. Instead of functionally regenerating after an injury, tendons merely heal by forming scar tissues that lack the functionality of healthy tissues. Factors that may cause this failed healing response include hypervascularization, deposition of calcific materials, pain, or swelling [ 84 ].

Additionally, in addition to problems with tendons, there is a high probability of acquiring a pathological condition of joints called osteoarthritis (OA) [ 85 ]. OA is common due to the avascular nature of articular cartilage and its low regenerative capabilities [ 86 ]. Although arthroplasty is currently a common procedure in treating OA, it is not ideal for younger patients because they can outlive the implant and will require several surgical procedures in the future. These are situations where stem cell therapy can help by stopping the onset of OA [ 87 ]. However, these procedures are not well developed, and the long-term maintenance of hyaline cartilage requires further research.

Osteonecrosis of the femoral hip (ONFH) is a refractory disease associated with the collapse of the femoral head and risk of hip arthroplasty in younger populations [ 88 ]. Although total hip arthroplasty (THA) is clinically successful, it is not ideal for young patients, mostly due to the limited lifetime of the prosthesis. An increasing number of clinical studies have evaluated the therapeutic effect of stem cells on ONFH. Most of the authors demonstrated positive outcomes, with reduced pain, improved function, or avoidance of THA [ 89 , 90 , 91 ].

Rejuvenation by cell programming

Ageing is a reversible epigenetic process. The first cell rejuvenation study was published in 2011 [ 92 ]. Cells from aged individuals have different transcriptional signatures, high levels of oxidative stress, dysfunctional mitochondria, and shorter telomeres than in young cells [ 93 ]. There is a hypothesis that when human or mouse adult somatic cells are reprogrammed to iPSCs, their epigenetic age is virtually reset to zero [ 94 ]. This was based on an epigenetic model, which explains that at the time of fertilization, all marks of parenteral ageing are erased from the zygote’s genome and its ageing clock is reset to zero [ 95 ].

In their study, Ocampo et al. [ 96 ] used Oct4, Sox2, Klf4, and C-myc genes (OSKM genes) and affected pancreas and skeletal muscle cells, which have poor regenerative capacity. Their procedure revealed that these genes can also be used for effective regenerative treatment [ 97 ]. The main challenge of their method was the need to employ an approach that does not use transgenic animals and does not require an indefinitely long application. The first clinical approach would be preventive, focused on stopping or slowing the ageing rate. Later, progressive rejuvenation of old individuals can be attempted. In the future, this method may raise some ethical issues, such as overpopulation, leading to lower availability of food and energy.

For now, it is important to learn how to implement cell reprogramming technology in non-transgenic elder animals and humans to erase marks of ageing without removing the epigenetic marks of cell identity.

Cell-based therapies

Stem cells can be induced to become a specific cell type that is required to repair damaged or destroyed tissues (Fig.  6 ). Currently, when the need for transplantable tissues and organs outweighs the possible supply, stem cells appear to be a perfect solution for the problem. The most common conditions that benefit from such therapy are macular degenerations [ 98 ], strokes [ 99 ], osteoarthritis [ 89 , 90 ], neurodegenerative diseases, and diabetes [ 100 ]. Due to this technique, it can become possible to generate healthy heart muscle cells and later transplant them to patients with heart disease.

Stem cell experiments on animals. These experiments are one of the many procedures that proved stem cells to be a crucial factor in future regenerative medicine

In the case of type 1 diabetes, insulin-producing cells in the pancreas are destroyed due to an autoimmunological reaction. As an alternative to transplantation therapy, it can be possible to induce stem cells to differentiate into insulin-producing cells [ 101 ].

Stem cells and tissue banks

iPS cells with their theoretically unlimited propagation and differentiation abilities are attractive for the present and future sciences. They can be stored in a tissue bank to be an essential source of human tissue used for medical examination. The problem with conventional differentiated tissue cells held in the laboratory is that their propagation features diminish after time. This does not occur in iPSCs.

The umbilical cord is known to be rich in mesenchymal stem cells. Due to its cryopreservation immediately after birth, its stem cells can be successfully stored and used in therapies to prevent the future life-threatening diseases of a given patient.

Stem cells of human exfoliated deciduous teeth (SHED) found in exfoliated deciduous teeth has the ability to develop into more types of body tissues than other stem cells [ 102 ] (Table  1 ). Techniques of their collection, isolation, and storage are simple and non-invasive. Among the advantages of banking, SHED cells are:

Guaranteed donor-match autologous transplant that causes no immune reaction and rejection of cells [ 103 ]

Simple and painless for both child and parent

Less than one third of the cost of cord blood storage

Not subject to the same ethical concerns as embryonic stem cells [ 104 ]

In contrast to cord blood stem cells, SHED cells are able to regenerate into solid tissues such as connective, neural, dental, or bone tissue [ 105 , 106 ]

SHED can be useful for close relatives of the donor

Fertility diseases

In 2011, two researchers, Katsuhiko Hayashi et al. [ 107 ], showed in an experiment on mice that it is possible to form sperm from iPSCs. They succeeded in delivering healthy and fertile pups in infertile mice. The experiment was also successful for female mice, where iPSCs formed fully functional eggs .

Young adults at risk of losing their spermatogonial stem cells (SSC), mostly cancer patients, are the main target group that can benefit from testicular tissue cryopreservation and autotransplantation. Effective freezing methods for adult and pre-pubertal testicular tissue are available [ 108 ].

Qiuwan et al. [ 109 ] provided important evidence that human amniotic epithelial cell (hAEC) transplantation could effectively improve ovarian function by inhibiting cell apoptosis and reducing inflammation in injured ovarian tissue of mice, and it could be a promising strategy for the management of premature ovarian failure or insufficiency in female cancer survivors.

For now, reaching successful infertility treatments in humans appears to be only a matter of time, but there are several challenges to overcome. First, the process needs to have high efficiency; second, the chances of forming tumours instead of eggs or sperm must be maximally reduced. The last barrier is how to mature human sperm and eggs in the lab without transplanting them to in vivo conditions, which could cause either a tumour risk or an invasive procedure.

Therapy for incurable neurodegenerative diseases

Thanks to stem cell therapy, it is possible not only to delay the progression of incurable neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease (AD), and Huntington disease, but also, most importantly, to remove the source of the problem. In neuroscience, the discovery of neural stem cells (NSCs) has nullified the previous idea that adult CNS were not capable of neurogenesis [ 110 , 111 ]. Neural stem cells are capable of improving cognitive function in preclinical rodent models of AD [ 112 , 113 , 114 ]. Awe et al. [ 115 ] clinically derived relevant human iPSCs from skin punch biopsies to develop a neural stem cell-based approach for treating AD. Neuronal degeneration in Parkinson’s disease (PD) is focal, and dopaminergic neurons can be efficiently generated from hESCs. PD is an ideal disease for iPSC-based cell therapy [ 116 ]. However, this therapy is still in an experimental phase ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539501 /). Brain tissue from aborted foetuses was used on patients with Parkinson’s disease [ 117 ]. Although the results were not uniform, they showed that therapies with pure stem cells are an important and achievable therapy.

Stem cell use in dentistry

Teeth represent a very challenging material for regenerative medicine. They are difficult to recreate because of their function in aspects such as articulation, mastication, or aesthetics due to their complicated structure. Currently, there is a chance for stem cells to become more widely used than synthetic materials. Teeth have a large advantage of being the most natural and non-invasive source of stem cells.

For now, without the use of stem cells, the most common periodontological treatments are either growth factors, grafts, or surgery. For example, there are stem cells in periodontal ligament [ 118 , 119 ], which are capable of differentiating into osteoblasts or cementoblasts, and their functions were also assessed in neural cells [ 120 ]. Tissue engineering is a successful method for treating periodontal diseases. Stem cells of the root apical areas are able to recreate periodontal ligament. One of the possible methods of tissue engineering in periodontology is gene therapy performed using adenoviruses-containing growth factors [ 121 ].

As a result of animal studies, dentin regeneration is an effective process that results in the formation of dentin bridges [ 122 ].

Enamel is more difficult to regenerate than dentin. After the differentiation of ameloblastoma cells into the enamel, the former is destroyed, and reparation is impossible. Medical studies have succeeded in differentiating bone marrow stem cells into ameloblastoma [ 123 ].

Healthy dental tissue has a high amount of regular stem cells, although this number is reduced when tissue is either traumatized or inflamed [ 124 ]. There are several dental stem cell groups that can be isolated (Fig.  7 ).

Localization of stem cells in dental tissues. Dental pulp stem cells (DPSCs) and human deciduous teeth stem cells (SHED) are located in the dental pulp. Periodontal ligaments stem cells are located in the periodontal ligament. Apical papilla consists of stem cells from the apical papilla (SCAP)

Dental pulp stem cell (DPSC)

These were the first dental stem cells isolated from the human dental pulp, which were [ 125 ] located inside dental pulp (Table  2 ). They have osteogenic and chondrogenic potential. Mesenchymal stem cells (MSCs) of the dental pulp, when isolated, appear highly clonogenic; they can be isolated from adult tissue (e.g. bone marrow, adipose tissue) and foetal (e.g. umbilical cord) [ 126 ] tissue, and they are able to differentiate densely [ 127 ]. MSCs differentiate into odontoblast-like cells and osteoblasts to form dentin and bone. Their best source locations are the third molars [ 125 ]. DPSCs are the most useful dental source of tissue engineering due to their easy surgical accessibility, cryopreservation possibility, increased production of dentin tissues compared to non-dental stem cells, and their anti-inflammatory abilities. These cells have the potential to be a source for maxillofacial and orthopaedic reconstructions or reconstructions even beyond the oral cavity. DPSCs are able to generate all structures of the developed tooth [ 128 ]. In particular, beneficial results in the use of DPSCs may be achieved when combined with other new therapies, such as periodontal tissue photobiomodulation (laser stimulation), which is an efficient technique in the stimulation of proliferation and differentiation into distinct cell types [ 129 ]. DPSCs can be induced to form neural cells to help treat neurological deficits.

Stem cells of human exfoliated deciduous teeth (SHED) have a faster rate of proliferation than DPSCs and differentiate into an even greater number of cells, e.g. other mesenchymal and non-mesenchymal stem cell derivatives, such as neural cells [ 130 ]. These cells possess one major disadvantage: they form a non-complete dentin/pulp-like complex in vivo. SHED do not undergo the same ethical concerns as embryonic stem cells. Both DPSCs and SHED are able to form bone-like tissues in vivo [ 131 ] and can be used for periodontal, dentin, or pulp regeneration. DPSCs and SHED can be used in treating, for example, neural deficits [ 132 ]. DPSCs alone were tested and successfully applied for alveolar bone and mandible reconstruction [ 133 ].

Periodontal ligament stem cells (PDLSCs)

These cells are used in periodontal ligament or cementum tissue regeneration. They can differentiate into mesenchymal cell lineages to produce collagen-forming cells, adipocytes, cementum tissue, Sharpey’s fibres, and osteoblast-like cells in vitro. PDLSCs exist both on the root and alveolar bone surfaces; however, on the latter, these cells have better differentiation abilities than on the former [ 134 ]. PDLSCs have become the first treatment for periodontal regeneration therapy because of their safety and efficiency [ 135 , 136 ].

Stem cells from apical papilla (SCAP)

These cells are mesenchymal structures located within immature roots. They are isolated from human immature permanent apical papilla. SCAP are the source of odontoblasts and cause apexogenesis. These stem cells can be induced in vitro to form odontoblast-like cells, neuron-like cells, or adipocytes. SCAP have a higher capacity of proliferation than DPSCs, which makes them a better choice for tissue regeneration [ 137 , 138 ].

Dental follicle stem cells (DFCs)

These cells are loose connective tissues surrounding the developing tooth germ. DFCs contain cells that can differentiate into cementoblasts, osteoblasts, and periodontal ligament cells [ 139 , 140 ]. Additionally, these cells proliferate after even more than 30 passages [ 141 ]. DFCs are most commonly extracted from the sac of a third molar. When DFCs are combined with a treated dentin matrix, they can form a root-like tissue with a pulp-dentin complex and eventually form tooth roots [ 141 ]. When DFC sheets are induced by Hertwig’s epithelial root sheath cells, they can produce periodontal tissue; thus, DFCs represent a very promising material for tooth regeneration [ 142 ].

Pulp regeneration in endodontics

Dental pulp stem cells can differentiate into odontoblasts. There are few methods that enable the regeneration of the pulp.

The first is an ex vivo method. Proper stem cells are grown on a scaffold before they are implanted into the root channel [ 143 ].

The second is an in vivo method. This method focuses on injecting stem cells into disinfected root channels after the opening of the in vivo apex. Additionally, the use of a scaffold is necessary to prevent the movement of cells towards other tissues. For now, only pulp-like structures have been created successfully.

Methods of placing stem cells into the root channel constitute are either soft scaffolding [ 144 ] or the application of stem cells in apexogenesis or apexification. Immature teeth are the best source [ 145 ]. Nerve and blood vessel network regeneration are extremely vital to keep pulp tissue healthy.

The potential of dental stem cells is mainly regarding the regeneration of damaged dentin and pulp or the repair of any perforations; in the future, it appears to be even possible to generate the whole tooth. Such an immense success would lead to the gradual replacement of implant treatments. Mandibulary and maxillary defects can be one of the most complicated dental problems for stem cells to address.

Acquiring non-dental tissue cells by dental stem cell differentiation

In 2013, it was reported that it is possible to grow teeth from stem cells obtained extra-orally, e.g. from urine [ 146 ]. Pluripotent stem cells derived from human urine were induced and generated tooth-like structures. The physical properties of the structures were similar to natural ones except for hardness [ 127 ]. Nonetheless, it appears to be a very promising technique because it is non-invasive and relatively low-cost, and somatic cells can be used instead of embryonic cells. More importantly, stem cells derived from urine did not form any tumours, and the use of autologous cells reduces the chances of rejection [ 147 ].

Use of graphene in stem cell therapy

Over recent years, graphene and its derivatives have been increasingly used as scaffold materials to mediate stem cell growth and differentiation [ 148 ]. Both graphene and graphene oxide (GO) represent high in-plane stiffness [ 149 ]. Because graphene has carbon and aromatic network, it works either covalently or non-covalently with biomolecules; in addition to its superior mechanical properties, graphene offers versatile chemistry. Graphene exhibits biocompatibility with cells and their proper adhesion. It also tested positively for enhancing the proliferation or differentiation of stem cells [ 148 ]. After positive experiments, graphene revealed great potential as a scaffold and guide for specific lineages of stem cell differentiation [ 150 ]. Graphene has been successfully used in the transplantation of hMSCs and their guided differentiation to specific cells. The acceleration skills of graphene differentiation and division were also investigated. It was discovered that graphene can serve as a platform with increased adhesion for both growth factors and differentiation chemicals. It was also discovered that π-π binding was responsible for increased adhesion and played a crucial role in inducing hMSC differentiation [ 150 ].

Therapeutic potential of extracellular vesicle-based therapies

Extracellular vesicles (EVs) can be released by virtually every cell of an organism, including stem cells [ 151 ], and are involved in intercellular communication through the delivery of their mRNAs, lipids, and proteins. As Oh et al. [ 152 ] prove, stem cells, together with their paracrine factors—exosomes—can become potential therapeutics in the treatment of, e.g. skin ageing. Exosomes are small membrane vesicles secreted by most cells (30–120 nm in diameter) [ 153 ]. When endosomes fuse with the plasma membrane, they become exosomes that have messenger RNAs (mRNAs) and microRNAs (miRNAs), some classes of non-coding RNAs (IncRNAs) and several proteins that originate from the host cell [ 154 ]. IncRNAs can bind to specific loci and create epigenetic regulators, which leads to the formation of epigenetic modifications in recipient cells. Because of this feature, exosomes are believed to be implicated in cell-to-cell communication and the progression of diseases such as cancer [ 155 ]. Recently, many studies have also shown the therapeutic use of exosomes derived from stem cells, e.g. skin damage and renal or lung injuries [ 156 ].

In skin ageing, the most important factor is exposure to UV light, called “photoageing” [ 157 ], which causes extrinsic skin damage, characterized by dryness, roughness, irregular pigmentation, lesions, and skin cancers. In intrinsic skin ageing, on the other hand, the loss of elasticity is a characteristic feature. The skin dermis consists of fibroblasts, which are responsible for the synthesis of crucial skin elements, such as procollagen or elastic fibres. These elements form either basic framework extracellular matrix constituents of the skin dermis or play a major role in tissue elasticity. Fibroblast efficiency and abundance decrease with ageing [ 158 ]. Stem cells can promote the proliferation of dermal fibroblasts by secreting cytokines such as platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), and basic fibroblast growth factor. Huh et al. [ 159 ] mentioned that a medium of human amniotic fluid-derived stem cells (hAFSC) positively affected skin regeneration after longwave UV-induced (UVA, 315–400 nm) photoageing by increasing the proliferation and migration of dermal fibroblasts. It was discovered that, in addition to the induction of fibroblast physiology, hAFSC transplantation also improved diseases in cases of renal pathology, various cancers, or stroke [ 160 , 161 ].

Oh [ 162 ] also presented another option for the treatment of skin wounds, either caused by physical damage or due to diabetic ulcers. Induced pluripotent stem cell-conditioned medium (iPSC-CM) without any animal-derived components induced dermal fibroblast proliferation and migration.

Natural cutaneous wound healing is divided into three steps: haemostasis/inflammation, proliferation, and remodelling. During the crucial step of proliferation, fibroblasts migrate and increase in number, indicating that it is a critical step in skin repair, and factors such as iPSC-CM that impact it can improve the whole cutaneous wound healing process. Paracrine actions performed by iPSCs are also important for this therapeutic effect [ 163 ]. These actions result in the secretion of cytokines such as TGF-β, interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and basic fibroblast growth factor (bFGF). Bae et al. [ 164 ] mentioned that TGF-β induced the migration of keratinocytes. It was also demonstrated that iPSC factors can enhance skin wound healing in vivo and in vitro when Zhou et al. [ 165 ] enhanced wound healing, even after carbon dioxide laser resurfacing in an in vivo study.

Peng et al. [ 166 ] investigated the effects of EVs derived from hESCs on in vitro cultured retinal glial, progenitor Müller cells, which are known to differentiate into retinal neurons. EVs appear heterogeneous in size and can be internalized by cultured Müller cells, and their proteins are involved in the induction and maintenance of stem cell pluripotency. These stem cell-derived vesicles were responsible for the neuronal trans-differentiation of cultured Müller cells exposed to them. However, the research article points out that the procedure was accomplished only on in vitro acquired retina.

Challenges concerning stem cell therapy

Although stem cells appear to be an ideal solution for medicine, there are still many obstacles that need to be overcome in the future. One of the first problems is ethical concern.

The most common pluripotent stem cells are ESCs. Therapies concerning their use at the beginning were, and still are, the source of ethical conflicts. The reason behind it started when, in 1998, scientists discovered the possibility of removing ESCs from human embryos. Stem cell therapy appeared to be very effective in treating many, even previously incurable, diseases. The problem was that when scientists isolated ESCs in the lab, the embryo, which had potential for becoming a human, was destroyed (Fig.  8 ). Because of this, scientists, seeing a large potential in this treatment method, focused their efforts on making it possible to isolate stem cells without endangering their source—the embryo.

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate into desired cell types

For now, while hESCs still remain an ethically debatable source of cells, they are potentially powerful tools to be used for therapeutic applications of tissue regeneration. Because of the complexity of stem cell control systems, there is still much to be learned through observations in vitro. For stem cells to become a popular and widely accessible procedure, tumour risk must be assessed. The second problem is to achieve successful immunological tolerance between stem cells and the patient’s body. For now, one of the best ideas is to use the patient’s own cells and devolve them into their pluripotent stage of development.

New cells need to have the ability to fully replace lost or malfunctioning natural cells. Additionally, there is a concern about the possibility of obtaining stem cells without the risk of morbidity or pain for either the patient or the donor. Uncontrolled proliferation and differentiation of cells after implementation must also be assessed before its use in a wide variety of regenerative procedures on living patients [ 167 ].

One of the arguments that limit the use of iPSCs is their infamous role in tumourigenicity. There is a risk that the expression of oncogenes may increase when cells are being reprogrammed. In 2008, a technique was discovered that allowed scientists to remove oncogenes after a cell achieved pluripotency, although it is not efficient yet and takes a longer amount of time. The process of reprogramming may be enhanced by deletion of the tumour suppressor gene p53, but this gene also acts as a key regulator of cancer, which makes it impossible to remove in order to avoid more mutations in the reprogrammed cell. The low efficiency of the process is another problem, which is progressively becoming reduced with each year. At first, the rate of somatic cell reprogramming in Yamanaka’s study was up to 0.1%. The use of transcription factors creates a risk of genomic insertion and further mutation of the target cell genome. For now, the only ethically acceptable operation is an injection of hESCs into mouse embryos in the case of pluripotency evaluation [ 168 ].

Stem cell obstacles in the future

Pioneering scientific and medical advances always have to be carefully policed in order to make sure they are both ethical and safe. Because stem cell therapy already has a large impact on many aspects of life, it should not be treated differently.

Currently, there are several challenges concerning stem cells. First, the most important one is about fully understanding the mechanism by which stem cells function first in animal models. This step cannot be avoided. For the widespread, global acceptance of the procedure, fear of the unknown is the greatest challenge to overcome.

The efficiency of stem cell-directed differentiation must be improved to make stem cells more reliable and trustworthy for a regular patient. The scale of the procedure is another challenge. Future stem cell therapies may be a significant obstacle. Transplanting new, fully functional organs made by stem cell therapy would require the creation of millions of working and biologically accurate cooperating cells. Bringing such complicated procedures into general, widespread regenerative medicine will require interdisciplinary and international collaboration.

The identification and proper isolation of stem cells from a patient’s tissues is another challenge. Immunological rejection is a major barrier to successful stem cell transplantation. With certain types of stem cells and procedures, the immune system may recognize transplanted cells as foreign bodies, triggering an immune reaction resulting in transplant or cell rejection.

One of the ideas that can make stem cells a “failsafe” is about implementing a self-destruct option if they become dangerous. Further development and versatility of stem cells may cause reduction of treatment costs for people suffering from currently incurable diseases. When facing certain organ failure, instead of undergoing extraordinarily expensive drug treatment, the patient would be able to utilize stem cell therapy. The effect of a successful operation would be immediate, and the patient would avoid chronic pharmacological treatment and its inevitable side effects.

Although these challenges facing stem cell science can be overwhelming, the field is making great advances each day. Stem cell therapy is already available for treating several diseases and conditions. Their impact on future medicine appears to be significant.

After several decades of experiments, stem cell therapy is becoming a magnificent game changer for medicine. With each experiment, the capabilities of stem cells are growing, although there are still many obstacles to overcome. Regardless, the influence of stem cells in regenerative medicine and transplantology is immense. Currently, untreatable neurodegenerative diseases have the possibility of becoming treatable with stem cell therapy. Induced pluripotency enables the use of a patient’s own cells. Tissue banks are becoming increasingly popular, as they gather cells that are the source of regenerative medicine in a struggle against present and future diseases. With stem cell therapy and all its regenerative benefits, we are better able to prolong human life than at any time in history.

Abbreviations

Basic fibroblast growth factor

Bone morphogenic proteins

Dental follicle stem cells

Dental pulp stem cells

Embryonic bodies

Embryonic stem cells

Fibroblast growth factors

Good Manufacturing Practice

Graphene oxide

Human amniotic fluid-derived stem cells

Human embryonic stem cells

Human foreskin fibroblasts

Inner cell mass

Non-coding RNA

Induced pluripotent stem cells

In vitro fertilization

Knockout serum replacement

Leukaemia inhibitory factor

Monocyte chemotactic protein-1

Fibroblasts

Messenger RNA

Mesenchymal stem cells of dental pulp

Myogenic differentiation

Osteoarthritis

Octamer-binding transcription factor 3 and 4

Platelet-derived growth factor

Platelet-derived growth factor-AA

Periodontal ligament stem cells

Rho-associated protein kinase

Stem cells from apical papilla

Stem cells of human exfoliated deciduous teeth

Synthetic Serum Substitute

Trophectoderm

Vascular endothelial growth factor

Transforming growth factors

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Zakrzewski, W., Dobrzyński, M., Szymonowicz, M. et al. Stem cells: past, present, and future. Stem Cell Res Ther 10 , 68 (2019). https://doi.org/10.1186/s13287-019-1165-5

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Biomedical Research Leads Science’s 2021 Breakthroughs

Posted on January 4th, 2022 by Lawrence Tabak, D.D.S., Ph.D.

Hi everyone, I’m Larry Tabak. I’ve served as NIH’s Principal Deputy Director for over 11 years, and I will be the acting NIH director until a new permanent director is named. In my new role, my day-to-day responsibilities will certainly increase, but I promise to carve out time to blog about some of the latest research progress on COVID-19 and any other areas of science that catch my eye.

I’ve also invited the directors of NIH’s Institutes and Centers (ICs) to join me in the blogosphere and write about some of the cool science in their research portfolios. I will publish a couple of posts to start, then turn the blog over to our first IC director. From there, I envision alternating between posts from me and from various IC directors. That way, we’ll cover a broad array of NIH science and the tremendous opportunities now being pursued in biomedical research.

Since I’m up first, let’s start where the NIH Director’s Blog usually begins each year: by taking a look back at Science ’s Breakthroughs of 2021. The breakthroughs were formally announced in December near the height of the holiday bustle. In case you missed the announcement, the biomedical sciences accounted for six of the journal Science ’s 10 breakthroughs. Here, I’ll focus on four biomedical breakthroughs, the ones that NIH has played some role in advancing, starting with Science ’s editorial and People’s Choice top-prize winner:

Breakthrough of the Year: AI-Powered Predictions of Protein Structure

The biochemist Christian Anfinsen, who had a distinguished career at NIH, shared the 1972 Nobel Prize in Chemistry, for work suggesting that the biochemical interactions among the amino acid building blocks of proteins were responsible for pulling them into the final shapes that are essential to their functions. In his Nobel acceptance speech, Anfinsen also made a bold prediction: one day it would be possible to determine the three-dimensional structure of any protein based on its amino acid sequence alone. Now, with advances in applying artificial intelligence to solve biological problems—Anfinsen’s bold prediction has been realized.

But getting there wasn’t easy. Every two years since 1994, research teams from around the world have gathered to compete against each other in developing computational methods for predicting protein structures from sequences alone. A score of 90 or above means that a predicted structure is extremely close to what’s known from more time-consuming work in the lab. In the early days, teams more often finished under 60.

In 2020, a London-based company called DeepMind made a leap with their entry called AlphaFold. Their deep learning approach—which took advantage of 170,000 proteins with known structures—most often scored above 90, meaning it could solve most protein structures about as well as more time-consuming and costly experimental protein-mapping techniques. (AlphaFold was one of Science ’s runner-up breakthroughs last year.)

This year, the NIH-funded lab of David Baker and Minkyung Baek, University of Washington, Seattle, Institute for Protein Design, published that their artificial intelligence approach , dubbed RoseTTAFold, could accurately predict 3D protein structures from amino acid sequences with only a fraction of the computational processing power and time that AlphaFold required [1]. They immediately applied it to solve hundreds of new protein structures, including many poorly known human proteins with important implications for human health.

The DeepMind and RoseTTAFold scientists continue to solve more and more proteins [1,2], both alone and in complex with other proteins. The code is now freely available for use by researchers anywhere in the world. In one timely example, AlphaFold helped to predict the structural changes in spike proteins of SARS-CoV-2 variants Delta and Omicron [3]. This ability to predict protein structures, first envisioned all those years ago, now promises to speed fundamental new discoveries and the development of new ways to treat and prevent any number of diseases, making it this year’s Breakthrough of the Year.

Anti-Viral Pills for COVID-19

The development of the first vaccines to protect against COVID-19 topped Science ’s 2020 breakthroughs. This year, we’ve also seen important progress in treating COVID-19, including the development of anti-viral pills .

First, there was the announcement in October of interim data from Merck, Kenilworth, NJ, and Ridgeback Biotherapeutics, Miami, FL, of a significant reduction in hospitalizations for those taking the anti-viral drug molnupiravir [4] (originally developed with an NIH grant to Emory University, Atlanta). Soon after came reports of a Pfizer anti-viral pill that might target SARS-CoV-2, the novel coronavirus that causes COVID-19, even more effectively. Trial results show that, when taken within three days of developing COVID-19 symptoms, the pill reduced the risk of hospitalization or death in adults at high risk of progressing to severe illness by 89 percent [5].

On December 22, the Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for Pfizer’s Paxlovid to treat mild-to-moderate COVID-19 in people age 12 and up at high risk for progressing to severe illness, making it the first available pill to treat COVID-19 [6]. The following day, the FDA granted an EUA for Merck’s molnupiravir to treat mild-to-moderate COVID-19 in unvaccinated, high-risk adults for whom other treatment options aren’t accessible or recommended, based on a final analysis showing a 30 percent reduction in hospitalization or death [7].

Additional promising anti-viral pills for COVID-19 are currently in development. For example, a recent NIH-funded preclinical study suggests that a drug related to molnupiravir, known as 4’-fluorouridine, might serve as a broad spectrum anti-viral with potential to treat infections with SARS-CoV-2 as well as respiratory syncytial virus (RSV) [8].

Artificial Antibody Therapies

Before anti-viral pills came on the scene, there’d been progress in treating COVID-19, including the development of monoclonal antibody infusions . Three monoclonal antibodies now have received an EUA for treating mild-to-moderate COVID-19, though not all are effective against the Omicron variant [9]. This is also an area in which NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV ) public-private partnership has made big contributions.

Monoclonal antibodies are artificially produced versions of the most powerful antibodies found in animal or human immune systems, made in large quantities for therapeutic use in the lab. Until recently, this approach had primarily been put to work in the fight against conditions including cancer, asthma, and autoimmune diseases. That changed in 2021 with success using monoclonal antibodies against infections with SARS-CoV-2 as well as respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), and other infectious diseases. This earned them a prominent spot among Science ’s breakthroughs of 2021.

Monoclonal antibodies delivered via intravenous infusions continue to play an important role in saving lives during the pandemic. But, there’s still room for improvement, including new formulations highlighted on the blog last year that might be much easier to deliver.

CRISPR Fixes Genes Inside the Body

One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions. This year has certainly been no exception.

CRISPR is a highly precise gene-editing system that uses guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct disease-causing misspellings. Science highlights a small study reported in The New England Journal of Medicine by researchers at Intellia Therapeutics, Cambridge, MA, and Regeneron Pharmaceuticals, Tarrytown, NY, in which six people with hereditary transthyretin (TTR) amyloidosis , a condition in which TTR proteins build up and damage the heart and nerves, received an infusion of guide RNA and CRISPR RNA encased in tiny balls of fat [10]. The goal was for the liver to take them up, allowing Cas9 to cut and disable the TTR gene. Four weeks later, blood levels of TTR had dropped by at least half.

In another study not yet published, researchers at Editas Medicine, Cambridge, MA, injected a benign virus carrying a CRISPR gene-editing system into the eyes of six people with an inherited vision disorder called Leber congenital amaurosis 10. The goal was to remove extra DNA responsible for disrupting a critical gene expressed in the eye. A few months later, two of the six patients could sense more light, enabling one of them to navigate a dimly lit obstacle course [11]. This work builds on earlier gene transfer studies begun more than a decade ago at NIH’s National Eye Institute.

Last year, in a research collaboration that included former NIH Director Francis Collins’s lab at the National Human Genome Research Institute (NHGRI), we also saw encouraging early evidence in mice that another type of gene editing, called DNA base editing, might one day correct Hutchinson-Gilford Progeria Syndrome, a rare genetic condition that causes rapid premature aging. Preclinical work has even suggested that gene-editing tools might help deliver long-lasting pain relief . The technology keeps getting better , too. This isn’t the first time that gene-editing advances have landed on Science ’s annual Breakthrough of the Year list, and it surely won’t be the last.

The year 2021 was a difficult one as the pandemic continued in the U.S. and across the globe, taking far too many lives far too soon. But through it all, science has been relentless in seeking and finding life-saving answers, from the rapid development of highly effective COVID-19 vaccines to the breakthroughs highlighted above.

As this list also attests, the search for answers has progressed impressively in other research areas during these difficult times. These groundbreaking discoveries are something in which we can all take pride—even as they encourage us to look forward to even bigger breakthroughs in 2022. Happy New Year!

References :

[1] Accurate prediction of protein structures and interactions using a three-track neural network . Baek M, DiMaio F, Anishchenko I, Dauparas J, Grishin NV, Adams PD, Read RJ, Baker D., et al. Science. 2021 Jul 15:eabj8754.

[2] Highly accurate protein structure prediction with AlphaFold . Jumper J, Evans R, Pritzel A, Green T, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D. et al. Nature. 2021 Jul 15.

[3] Structural insights of SARS-CoV-2 spike protein from Delta and Omicron variants . Sadek A, Zaha D, Ahmed MS. preprint bioRxiv. 2021 Dec 9.

[4] Merck and Ridgeback’s investigational oral antiviral molnupiravir reduced the risk of hospitalization or death by approximately 50 Percent compared to placebo for patients with mild or moderate COVID-19 in positive interim analysis of phase 3 study . Merck. 1 Oct 2021.

[5] Pfizer’s novel COVID-19 oral antiviral treatment candidate reduced risk of hospitalization or death by 89% in interim analysis of phase 2/3 EPIC-HR Study . Pfizer. 5 November 52021.

[6] Coronavirus (COVID-19) Update: FDA authorizes first oral antiviral for treatment of COVID-19 . Food and Drug Administration. 22 Dec 2021.

[7] Coronavirus (COVID-19) Update: FDA authorizes additional oral antiviral for treatment of COVID-19 in certain adults . Food and Drug Administration. 23 Dec 2021.

[8] 4′-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication . Sourimant J, Lieber CM, Aggarwal M, Cox RM, Wolf JD, Yoon JJ, Toots M, Ye C, Sticher Z, Kolykhalov AA, Martinez-Sobrido L, Bluemling GR, Natchus MG, Painter GR, Plemper RK. Science. 2021 Dec 2.

[9] Anti-SARS-CoV-2 monoclonal antibodies . NIH COVID-19 Treatment Guidelines. 16 Dec 2021.

[10] CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis . Gillmore JD, Gane E, Taubel J, Kao J, Fontana M, Maitland ML, Seitzer J, O’Connell D, Walsh KR, Wood K, Phillips J, Xu Y, Amaral A, Boyd AP, Cehelsky JE, McKee MD, Schiermeier A, Harari O, Murphy A, Kyratsous CA, Zambrowicz B, Soltys R, Gutstein DE, Leonard J, Sepp-Lorenzino L, Lebwohl D. N Engl J Med. 2021 Aug 5;385(6):493-502.

[11] Editas Medicine announces positive initial clinical data from ongoing phase 1/2 BRILLIANCE clinical trial of EDIT-101 For LCA10 . Editas Medicine. 29 Sept 2021.

Structural Biology (National Institute of General Medical Sciences/NIH)

The Structures of Life (NIGMS)

COVID-19 Research (NIH)

2021 Science Breakthrough of the Year (American Association for the Advancement of Science, Washington, D.C)

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Tags: 4'-fluorouridine , Accelerating COVID-19 Therapeutic Interventions and Vaccines , ACTIV , AI , AlphaFold , amino acids , artificial antibodies , artificial intelligence , biochemistry , Christian Anfinsen , Chronic Pain , computational biology , coronavirus , COVID pill , COVID-19 , CRISPR , CRISPR/Cas9 , DeepMind , Delta variant , Editas Medicine , EUA , gene editing , hereditary transthyretin amyloidosis , Hutchinson-Gilford progeria syndrome , Intellia Therapeutics , Leber congenital amaurosis , Merck , molnupiravir , monoclonal antibodies , Omicron variant , pandemic , Pfizer , progeria , protein structure , rare disease , Regeneron , RoseTTAFold , SARS-CoV-2 , Science Breakthrough of the Year , Science Breakthroughs of 2021 , structural biology

14 Comments

It would be remiss not to celebrate another NIH milestone in 2021: on March 1, 2021, the NIH finally took a stand against structural racism in biomedical research ( https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-stands-against-structural-racism-biomedical-research ) — and given the rampant health inequities exposed by COVID-19 and also the profound issues of structural racism and economic adversity affecting the health and well-being of the US population, it is essential that this NIH breakthrough be celebrated, institutionalized, and supported with ample funding and leadership.

Biology is a fascinating thing. It’s amazing to think what a few nucleotides can do and how epigenetics can dictate very different outcomes. Something that is toxic in one species can be fairly benign in another. As the pandemic becomes endemic and there are other host animals (such as what is being seen with deer and certain zoo animals), one does have to ask about the evolutionary advantage of codon optimization and the value of pseudo-uridine. Perhaps there are lessons that can be gleaned from Gleevac?

Thank you for carrying on this important communication that I continue to share throughout my own circle. It is vital in combatting “qanonense” and more in our time.

Happy New Year Dr. Tabak, Congratulations on your important work in the NIH and thank you for this special explanation on medical advances being studied.

These goals deeply affect medical problems that are still difficult to manage, such as diseases of genetic origin. Even though they are sometimes rare diseases, we have to think that behind that statistical number is a face, a person, who begs for our help as doctors. I still remember today a young patient (visited decades ago) suffering from Leber’s congenital amaurosis who explained his tragedy to me: at the time I couldn’t find words to help him.

Looking at future treatments for chronic pain that is sometimes devastating to the affected person, it is encouraging to know that the CRISPR gene editing tool could help these patients. https://directorsblog.nih.gov/2021/04/01/could-crispr-gene-editing-technology-be-an-answer-to-chronic-pain/

Just yesterday, a patient who has been suffering from spinal damage for years, writes to me: he periodically updates me on the operations he is undergoing, unfortunately with poor results. Last planned, implantation of a medullary electro-stimulator. But the stress resulting from this situation also causes recurrent central serous chorioretinopathies, a source of serious fear for his sight.

I read tons of scientific ‘stuff’, mostly related to geo-hydromorphological, ecological and botanical, so reading outside these areas challenges my patience. I have to say, this presentation of accomplishments engages to most weary readers. So much of our science has become inaccessible from unnecessary jargon. Larry shows us how to reach out with clear, concise and understandable descriptions. It was a pleasure read! Thank you!

It’s delightful to read, and be reminded of the incredible work that’s been done over the past 2 years, with so much promise in the years soon to come.

Excellent, Dr. Tabak and colleagues….look forward to tracking this blog in the years ahead. Thank you from a colleague in the national and economic security world…

Science is a complicated thing to parlay to lay people without adequate training. The CDC serves to communicate public health concerns to the general public whereas the FDA serves as a regulatory body. Those with the background and training to make informed choices may make decisions that are different from the lay public. However with any of these organizations there needs to be a forum to communicate dissent without repercussion. If a non-majority voice is squashed either by intimidation or other measures, it hardly serves the purpose behind science. The difficult part lays in communicating the message to the majority of the “intended” population while respecting individual informed choices. Not an enviable position to be, and everyone should realize that. It’s like being given the job of a real time translator where nuances may have very different outcomes.

Welcome Larry Tabak. Best wishes for you & the NIH team.

I’m a hereditary TTR patient currently taking Tafamidis daily. My son is genetically positive. Good to read about advances. Need test subjects?

Biology is a fascinating thing. It’s amazing to think what a few nucleotides can do and how epigenetics can dictate very different outcomes.

Some solid-state metrology advances would improve medical equipment tools. I’ve been treating improving antenna design as replacing as much of its metal construction with solid-state lattice building processes, as is efficient. Before medical equipment, there is a need for metrology to improve. Solid-state mechanical reactions have no ground truth. X-ray diffraction, Raman Spectroscopy, NMR, XANES, manometry and thermometry, may all improve solid state manufacturing if improved. They can be improved themselves by solid state advances. This virtuous cycle will lead to soft medicine and now-metal equipment both being better prototyped by the above tools developed initially for solid state metrology. Seeing how many milli-seconds a ball bearing heats a mill surface will lead to the equipment will be quieter using more lattices than metals.

Sorry, I do not understand what the second sentence to stating. Please explain, restate. Thanks

My app was radar dishes and coils, improving them with better materials. The principle also works for say, a microscope. The eyepiece wheel on a Bruker Optics microscope is made of metal. Heavy enough to deaden some vibrations. Precision ground and buffed to have balance. Massive enough to take handling and minimize elastic forces handling wear as well as accidental impacts. But replace the metal with sapphire and 3/4 of the material properties improve with 1/4 being worse. Namely, a lighter microscope made in the shape of a hollow cell membrane will outperform CNC lasered metal or extruded plastic parts. Bigger lenses would throw the existing microscope off balance in months. Already I suggest making such equipment out of planetary mill constituents. I had a 1930s X-ray in 2007 and the machine took up 1/4 the room; consider how small baggage X-rays are now.

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Science, Medicine, and Animals (1991)

Chapter: conclusion.

People clearly want the benefits that derive from animal research. They also want animals to be well-treated and to undergo a minimum of pain and distress. These desires result from our values, from the importance we ascribe to both human and animal life.

But decisions about the use of animals should be based both on reason and values. It makes no sense to sacrifice future human health and well being by not using animals in research today. In fact, it would be immoral and selfish not to use animals in research today, given the harm that could accrue to future generations if such research were halted.

The promise that animal research holds for generations of humans remains undiminished

The majority of Americans agree that animal research must continue. But legislators rarely hear from this majority, whereas they are bombarded by appeals from the small minority who wish to stop or severely curtail such research. Many scientific, medical, and patient groups have come out strongly in favor of humanely conducted animal research. The National Academy of Sciences and Institute of Medicine would like to add their voices to the chorus of support for animal research.

We owe our good health to past investigators and the animals they studied. As we decide on the future of animal research, we should keep in mind the future generations who will look back at us and ask if we acted wisely.

The necessity for animal use in biomedical research is a hotly debated topic in classrooms throughout the country. Frequently teachers and students do not have access to balanced, factual material to foster an informed discussion on the topic. This colorful, 50-page booklet is designed to educate teenagers about the role of animal research in combating disease, past and present; the perspective of animal use within the whole spectrum of biomedical research; the regulations and oversight that govern animal research; and the continuing efforts to use animals more efficiently and humanely.

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What does a biomedical scientist do?

Would you make a good biomedical scientist? Take our career test and find your match with over 800 careers.

What is a Biomedical Scientist?

Biomedical scientists uses scientific methods to investigate biological processes and diseases that affect humans and animals. They conduct experiments, analyze data, and interpret findings to improve our understanding of diseases and develop new treatments and cures. They also ensure the safety and efficacy of drugs and medical devices through clinical trials and regulatory processes.

The work of biomedical scientists covers a wide range of areas, including genetics, microbiology, immunology, and biochemistry. Various tools and techniques are used to study living organisms at the molecular and cellular levels, such as microscopy, DNA sequencing, and protein analysis. Biomedical scientists often collaborate with other healthcare professionals, such as physicians and nurses, to develop new diagnostics and treatments for diseases.

What does a Biomedical Scientist do?

The work of biomedical scientists has a profound impact on human health and has contributed to the development of numerous life-saving medical advances.

Duties and Responsibilities The duties and responsibilities of a biomedical scientist vary depending on their area of specialization and the specific role they play within their organization. However, some common responsibilities of biomedical scientists include:

• Conducting Research: Biomedical scientists design and conduct experiments to investigate biological processes and diseases. They use various laboratory techniques, including microscopy, DNA sequencing, and protein analysis, to study living organisms at the molecular and cellular levels. They collect and analyze data, interpret findings, and communicate results to other scientists and healthcare professionals.
• Developing New Treatments: Biomedical scientists work to develop new drugs, therapies, and medical devices to treat diseases. They conduct preclinical studies to test the safety and efficacy of new treatments, and they work with clinicians to design and conduct clinical trials to evaluate the effectiveness of new treatments in humans.
• Analyzing Samples: Biomedical scientists analyze biological samples, such as blood, tissue, and urine, to diagnose diseases and monitor treatment. They use laboratory techniques to detect and quantify biomarkers, such as proteins and DNA, that are associated with specific diseases.
• Ensuring Quality Control: Biomedical scientists are responsible for ensuring the quality and accuracy of laboratory tests and procedures. They follow established protocols and standard operating procedures, maintain laboratory equipment, and monitor laboratory safety to ensure compliance with regulatory requirements.
• Managing Laboratory Operations: Biomedical scientists may be responsible for managing laboratory operations, including supervising staff, developing and implementing laboratory policies and procedures, and ensuring that laboratory equipment is properly maintained and calibrated.
• Collaborating with Other Healthcare Professionals: Biomedical scientists collaborate with other healthcare professionals, including physicians, nurses, and pharmacists, to develop and implement treatment plans for patients. They communicate laboratory results and provide expert advice on the interpretation of test results.
• Teaching and Mentoring: Biomedical scientists may be responsible for teaching and mentoring students and junior researchers. They may develop and deliver lectures, supervise laboratory activities, and provide guidance and mentorship to students and trainees.

Types of Biomedical Scientists There are several different types of biomedical scientists, each with their own area of specialization and focus. Here are some examples of different types of biomedical scientists and what they do:

• Microbiologists : Microbiologists study microorganisms, including bacteria, viruses, and fungi. They investigate how these organisms cause disease, develop new treatments to combat infections, and develop new diagnostic tests to identify infectious agents.
• Immunologists : Immunologists study the immune system and its role in fighting disease. They investigate how the immune system responds to infectious agents, cancer cells, and other foreign substances, and they develop new treatments that harness the immune system to fight disease.
• Geneticists : Geneticists study genes and their role in disease. They investigate the genetic basis of diseases, such as cancer, and develop new diagnostic tests and treatments that target specific genetic mutations.
• Biochemists : Biochemists study the chemical processes that occur in living organisms. They investigate how cells and tissues produce and use energy, and they develop new drugs and therapies that target specific metabolic pathways.
• Toxicologists : Toxicologists study the effects of toxic substances on the body. They investigate how chemicals, pollutants, and other environmental factors can cause disease, and they develop strategies to prevent and mitigate the harmful effects of toxic exposures.
• Pharmacologists: Pharmacologists study the effects of drugs on the body. They investigate how drugs interact with cells and tissues, and they develop new drugs and therapies to treat disease.
• Medical Laboratory Scientists: Medical laboratory scientists, also known as clinical laboratory scientists, perform laboratory tests on patient samples to diagnose diseases and monitor treatment. They analyze blood, urine, tissue, and other samples using various laboratory techniques and instruments.

What is the workplace of a Biomedical Scientist like?

Biomedical scientists work in diverse settings, contributing to advancements in medical research, healthcare, and the understanding of diseases. The workplace of a biomedical scientist can vary based on their specific role, specialization, and the nature of their work.

Academic and Research Institutions: Many biomedical scientists are employed in universities, medical schools, and research institutions. In these settings, they conduct cutting-edge research, lead laboratory teams, and contribute to scientific discoveries. Academic biomedical scientists often split their time between conducting research, teaching students, and publishing their findings in scientific journals.

Hospitals and Healthcare Settings: Biomedical scientists play a crucial role in healthcare, especially in clinical laboratories and diagnostic facilities. They may be involved in analyzing patient samples, conducting medical tests, and interpreting results to assist in the diagnosis and treatment of diseases. Biomedical scientists working in hospitals collaborate with clinicians and healthcare professionals to ensure accurate and timely diagnostic information.

Biotechnology and Pharmaceutical Companies: The biotechnology and pharmaceutical industries employ biomedical scientists to drive innovation in drug discovery, development, and testing. In these settings, scientists work on designing experiments, conducting preclinical and clinical trials, and developing new therapeutic interventions. Biomedical scientists may also be involved in quality control, ensuring the safety and efficacy of pharmaceutical products.

Government Agencies and Public Health Organizations: Biomedical scientists can work for government agencies such as the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), or the Food and Drug Administration (FDA). In these roles, they contribute to public health research, policy development, and the regulation of healthcare products.

Nonprofit Research Organizations: Nonprofit organizations dedicated to medical research and public health also employ biomedical scientists. These organizations focus on specific diseases or health issues and work towards finding solutions, advancing knowledge, and advocating for improved healthcare practices.

Private Research Foundations: Biomedical scientists may work for private research foundations that fund and conduct medical research. These foundations often collaborate with academic institutions and industry partners to support innovative research projects with the potential to impact human health.

Collaborative and Interdisciplinary Teams: Biomedical scientists frequently collaborate with professionals from various disciplines, including bioinformaticians, clinicians, engineers, and statisticians. Interdisciplinary collaboration is common, especially in research projects that require a multifaceted approach to address complex health challenges.

Frequently Asked Questions

Biology related careers and degrees.

• Animal Scientist
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Relationship between funding source and conclusion among nutrition-related scientific articles

Affiliation.

• 1 Department of Medicine, Children's Hospital, Boston, Massachusetts, United States of America. [email protected]
• PMID: 17214504
• PMCID: PMC1764435
• DOI: 10.1371/journal.pmed.0040005

Background: Industrial support of biomedical research may bias scientific conclusions, as demonstrated by recent analyses of pharmaceutical studies. However, this issue has not been systematically examined in the area of nutrition research. The purpose of this study is to characterize financial sponsorship of scientific articles addressing the health effects of three commonly consumed beverages, and to determine how sponsorship affects published conclusions.

Methods and findings: Medline searches of worldwide literature were used to identify three article types (interventional studies, observational studies, and scientific reviews) about soft drinks, juice, and milk published between 1 January, 1999 and 31 December, 2003. Financial sponsorship and article conclusions were classified by independent groups of coinvestigators. The relationship between sponsorship and conclusions was explored by exact tests and regression analyses, controlling for covariates. 206 articles were included in the study, of which 111 declared financial sponsorship. Of these, 22% had all industry funding, 47% had no industry funding, and 32% had mixed funding. Funding source was significantly related to conclusions when considering all article types (p = 0.037). For interventional studies, the proportion with unfavorable conclusions was 0% for all industry funding versus 37% for no industry funding (p = 0.009). The odds ratio of a favorable versus unfavorable conclusion was 7.61 (95% confidence interval 1.27 to 45.73), comparing articles with all industry funding to no industry funding.

Conclusions: Industry funding of nutrition-related scientific articles may bias conclusions in favor of sponsors' products, with potentially significant implications for public health.

Publication types

• Research Support, Non-U.S. Gov't
• Beverages / adverse effects
• Beverages / economics
• Carbonated Beverages / adverse effects
• Carbonated Beverages / economics
• Food Industry / economics*
• Food Industry / ethics*
• Milk / economics
• Nutritional Sciences / economics*
• Nutritional Sciences / ethics*
• Peer Review, Research / ethics*
• Peer Review, Research / standards*
• Public Health
• Research Support as Topic / economics*

Grants and funding

• P30 DK040561/DK/NIDDK NIH HHS/United States
• P30 DK040561-11/DK/NIDDK NIH HHS/United States

OpenSAFELY: Effectiveness of COVID-19 vaccination in children and adolescents

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Background Children and adolescents in England were offered BNT162b2 as part of the national COVID-19 vaccine roll out from September 2021. We assessed the safety and effectiveness of first and second dose BNT162b2 COVID-19 vaccination in children and adolescents in England.

Methods With the approval of NHS England, we conducted an observational study in the OpenSAFELY-TPP database, including a) adolescents aged 12-15 years, and b) children aged 5-11 years and comparing individuals receiving i) first vaccination with unvaccinated controls and ii) second vaccination to single-vaccinated controls. We matched vaccinated individuals with controls on age, sex, region, and other important characteristics. Outcomes were positive SARS-CoV-2 test (adolescents only); COVID-19 A&E attendance; COVID-19 hospitalisation; COVID-19 critical care admission; COVID-19 death, with non-COVID-19 death and fractures as negative control outcomes and A&E attendance, unplanned hospitalisation, pericarditis, and myocarditis as safety outcomes.

Results Amongst 820,926 previously unvaccinated adolescents, the incidence rate ratio (IRR) for positive SARS-CoV-2 test comparing vaccination with no vaccination was 0.74 (95% CI 0.72-0.75), although the 20-week risks were similar. The IRRs were 0.60 (0.37-0.97) for COVID-19 A&E attendance, 0.58 (0.38-0.89) for COVID-19 hospitalisation, 0.99 (0.93-1.06) for fractures, 0.89 (0.87-0.91) for A&E attendances and 0.88 (0.81-0.95) for unplanned hospitalisation. Amongst 441,858 adolescents who had received first vaccination IRRs comparing second dose with first dose only were 0.67 (0.65-0.69) for positive SARS-CoV-2 test, 1.00 (0.20-4.96) for COVID-19 A&E attendance, 0.60 (0.26-1.37) for COVID-19 hospitalisation, 0.94 (0.84-1.05) for fractures, 0.93 (0.89-0.98) for A&E attendance and 0.99 (0.86-1.13) for unplanned hospitalisation. Amongst 283,422 previously unvaccinated children and 132,462 children who had received a first vaccine dose, COVID-19-related outcomes were too rare to allow IRRs to be estimated precisely. A&E attendance and unplanned hospitalisation were slightly higher after first vaccination (IRRs versus no vaccination 1.05 (1.01-1.10) and 1.10 (0.95-1.26) respectively) but slightly lower after second vaccination (IRRs versus first dose 0.95 (0.86-1.05) and 0.78 (0.56-1.08) respectively). There were no COVID-19-related deaths in any group. Fewer than seven (exact number redacted) COVID-19-related critical care admissions occurred in the adolescent first dose vs unvaccinated cohort. Among both adolescents and children, myocarditis and pericarditis were documented only in the vaccinated groups, with rates of 27 and 10 cases/million after first and second doses respectively.

Conclusion BNT162b2 vaccination in adolescents reduced COVID-19 A&E attendance and hospitalisation, although these outcomes were rare. Protection against positive SARS-CoV-2 tests was transient.

Competing Interest Statement

BG has received research funding from the Laura and John Arnold Foundation, the NHS National Institute for Health Research (NIHR), the NIHR School of Primary Care Research, NHS England, the NIHR Oxford Biomedical Research Centre, the Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, the Wellcome Trust, the Good Thinking Foundation, Health Data Research UK, the Health Foundation, the World Health Organisation, UKRI MRC, Asthma UK, the British Lung Foundation, and the Longitudinal Health and Wellbeing strand of the National Core Studies programme; he is a Non-Executive Director at NHS Digital; he also receives personal income from speaking and writing for lay audiences on the misuse of science. BMK is also employed by NHS England working on medicines policy and clinical lead for primary care medicines data. IJD has received unrestricted research grants and holds shares in GlaxoSmithKline (GSK).

Funding Statement

The OpenSAFELY Platform is supported by grants from the Wellcome Trust (222097/Z/20/Z); MRC (MR/V015757/1, MC_PC-20059, MR/W016729/1); NIHR (NIHR135559, COV-LT2-0073), and Health Data Research UK (HDRUK2021.000, 2021.0157). In addition, this research used data assets made available as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20058). BG has also received funding from: the Bennett Foundation, the Wellcome Trust, NIHR Oxford Biomedical Research Centre, NIHR Applied Research Collaboration Oxford and Thames Valley, the Mohn-Westlake Foundation; all Bennett Institute staff are supported by BG's grants on this work. The views expressed are those of the authors and not necessarily those of the NIHR, NHS England, UK Health Security Agency (UKHSA) or the Department of Health and Social Care.

Funders had no role in the study design, collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Health Research Authority (REC reference 20/LO/0651) and by the London School of Hygeine and Tropical Medicine Ethics Board (reference 21863).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Data Availability

All data were linked, stored and analysed securely using the OpenSAFELY platform, https://www.opensafely.org/ , as part of the NHS England OpenSAFELY COVID-19 service. Data include pseudonymised data such as coded diagnoses, medications and physiological parameters. No free text data was included. All code is shared openly for review and re-use under MIT open license [ https://github.com/opensafely/vaccine-effectiveness-in-kids ]. Detailed pseudonymised patient data is potentially re-identifiable and therefore not shared. Primary care records managed by the GP software provider, TPP were linked to ONS death data and the Index of Multiple Deprivation through OpenSAFELY.

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• 31 May 2024

Biomedical paper retractions have quadrupled in 20 years — why?

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Retraction rates in European biomedical science papers have quadrupled since 2000. Credit: bagi1998/Getty

The retraction rate for European biomedical-science papers increased fourfold between 2000 and 2021, a study of thousands of retractions has found.

Two-thirds of these papers were withdrawn for reasons relating to research misconduct, such as data and image manipulation or authorship fraud . These factors accounted for an increasing proportion of retractions over the roughly 20-year period, the analysis suggests.

“Our findings indicate that research misconduct has become more prevalent in Europe over the last two decades,” write the authors, led by Alberto Ruano‐Ravina, a public-health researcher at the University of Santiago de Compostela in Spain.

Other research-integrity specialists point out that retractions could be on the rise because researchers and publishers are getting better at investigating and identifying potential misconduct. There are more people working to spot errors and new digital tools to screen publications for suspicious text or data.

Rising retractions

Scholarly publishers have faced increased pressure to clear up the literature in recent years as sleuths have exposed cases of research fraud , identified when peer review has been compromised and uncovered the buying and selling of research articles . Last year saw a record 10,000 papers retracted . Although misconduct is a leading cause of retractions, it is not always responsible: some papers are retracted when authors discover honest errors in their work.

More than 10,000 research papers were retracted in 2023 — a new record

The latest research, published on 4 May in Scientometrics 1 , looked at more than 2,000 biomedical papers that had a corresponding author based at a European institution and were retracted between 2000 and mid-2021. The data included original articles, reviews, case reports and letters published in English, Spanish or Portuguese. They were listed in a database collated by the media organization Retraction Watch, which records why papers are retracted.

The authors found that overall retraction rates quadrupled during the study period — from around 11 retractions per 100,000 papers in 2000 to almost 45 per 100,000 in 2020. Of all the retracted papers, nearly 67% were withdrawn owing to misconduct and around 16% for honest errors. The remaining retractions did not give a reason.

Looking at the papers retracted for misconduct specifically, Ruano‐Ravina and his colleagues found that the major causes have changed over time. In 2000, the highest proportions of retractions were attributed to ethical and legal problems, authorship issues — including dubious or false authorships, objections to authorship by institutions and lack of author approval — and duplication of images , data or large passages of text. By 2020, duplication was still one of the top reasons for retraction, but a similar proportion of papers was retracted owing to ‘unreliable data’ (see ‘Misconduct retractions’).

Source: Ref 1

‘Unreliable data’ refers to studies that cannot be trusted for reasons including original data not being provided and problems with bias or lack of balance. The authors suggest that the rise in retractions attributable to this cause could be related to an increase in the number of papers suspected to be produced by paper mills , businesses that generate fake or poor-quality papers to order.

Authorship problems fell to the joint fifth reason for retractions in 2020. This is “possibly due to the implementation of authorship control systems and increased researcher awareness”, write Ruano‐Ravina and his colleagues.

International variation

The study also identified the four European countries that had the highest number of retracted biomedical science papers: Germany, the United Kingdom, Italy and Spain. Each had distinct ‘profiles’ of misconduct-related retractions. In the United Kingdom, for example, falsification was the top reason given for retractions in most years, but the proportion of papers withdrawn because of duplication fell between 2000 and 2020. Meanwhile, Spain and Italy both saw huge rises in the proportion of papers retracted because of duplication.

Arturo Casadevall, a microbiologist at Johns Hopkins University in Baltimore, Maryland, contributed to work that in 2012 found similar rates of paper withdrawal for misconduct 2 . “To me, this argues that the underlying problems in science have not changed appreciably in the past 12 years,” he says.

But the overall increase in retraction rates could reflect the fact that authors, institutions and journals are increasingly using retractions to correct the literature, he adds.

Science’s fake-paper problem: high-profile effort will tackle paper mills

Sholto David, a biologist and research-integrity specialist based in Wales, UK, points out that methods for detecting errors in research improved during the 20-year study period. An increasing number of people now scan the literature and point out flaws, which could help to explain increasing retraction rates, he says. In particular, the launch of the post-publication peer-review website PubPeer in 2012 has offered sleuths the opportunity to scrutinize papers en masse, he adds, and it has become much more common for researchers to send whistle-blowing e-mails to journals.

Ivan Oransky, Retraction Watch’s co-founder who is based in New York City, suggests that the routine use of plagiarism-detection software by publishers during the past decade might have contributed to the rising rates of retraction because of plagiarism and duplication. It remains to be seen how more recent digital tools, such as those that detect image manipulation, could affect paper withdrawal rates in the coming years, he adds.

doi: https://doi.org/10.1038/d41586-024-01609-0

Freijedo-Farinas, F., Ruano-Ravina, A., Pérez-Ríos, M., Ross, J. & Candal-Pedreira, C. Scientometrics 129 , 2867–2882 (2024).

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Fang, F. C., Steen, R. G. & Casadevall, A. Proc. Natl Acad. Sci. USA 109 , 17028–17033 (2012).

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How consistent are the key recommendations, and what is the quality of guidelines and expert consensus regarding paediatric cow’s milk protein allergy?

• Published: 29 May 2024

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• Tengfei Li 1 , 2   na1 ,
• Qingyong Zheng 2   na1 ,
• Mingyue Zhang 2 ,
• Yiyi Li 1 ,
• Yongjia Zhou 1 ,
• Caihua Xu 2 ,
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The objective of this study was to assess the quality and consistency of recommendations in clinical practice guidelines (CPGs) and expert consensus on paediatric cow’s milk protein allergy (CMPA) to serve as a foundation for future revisions and enhancements of clinical guidelines and consensus documents. We conducted a comprehensive literature search across several databases, including the Chinese Biomedical Literature Database (CBM), PubMed, Embase, Web of Science, UpToDate, ClinicalKey, DynaMed Plus and BMJ Best Practice. We spanned the search period from the inception of each database through October 1, 2023. We integrated subject headings (MeSH/Emtree) and keywords into the search strategy, used the search methodologies of existing literature and developed it in collaboration with a librarian. Two trained researchers independently conducted the literature screening and data extraction. We evaluated methodological quality and recommendations by using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) and AGREE-Recommendations for Excellence (AGREE-REX) tools. Moreover, we compared and summarized key recommendations from high-quality CPGs. Our study included 27 CPGs and expert consensus documents on CMPA. Only four CPGs (14.8%) achieved a high-quality AGREE II rating. The four high-quality CPGs consistently provided recommendations for CMPA. The highest scoring domains for AGREE II were ‘scope and purpose’ (77 ± 12%) and ‘clarity of presentation’ (75 ± 22%). The lowest scoring domains were ‘stakeholder involvement’ (49 ± 21%), ‘rigor of development’ (34 ± 20%) and ‘applicability’ (12 ± 20%). Evaluation with AGREE-REX generally demonstrated low scores across its domains.

   Conclusion : Recommendations within high-quality CPGs for the paediatric CMPA showed fundamental consistency. Nevertheless, the methodology and recommendation content of CPGs and the expert consensus exhibited low quality, thus indicating a substantial scope for enhancement. Guideline developers should rigorously follow the AGREE II and AGREE-REX standards in creating CPGs or expert consensuses to guarantee their clinical efficacy in managing paediatric CMPA.

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Abbreviations

The Appraisal of Guidelines for Research & Evaluation II

The AGREE-Recommendation for Excellence

Clinical practice guidelines

• Cow’s milk protein allergy

China Biomedical Literature Database

The Grading of Recommendations Assessment, Development, and Evaluation

Intraclass correlation coefficient

Immunoglobulin E

Oral food challenge

Oral immunotherapy

Preferred Reporting Items for Systematic Reviews and Meta-analyses

Skin prick test

Scottish Intercollegiate Guidelines Network

World Allergy Organization

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Acknowledgements

We extend our deepest gratitude to the dedicated individuals who developed the guidelines, the insightful reviewers for their invaluable feedback, our research team for their unwavering support and collaboration throughout this study, and express our sincere appreciation for the support provided by the Natural Science Foundation of Gansu Province. This work was supported by the Natural Science Foundation of Gansu Province (21JR11RA178).

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Tengfei Li and Qingyong Zheng contributed equally to this work and should be considered as co-first authors.

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School of Nursing, Gansu University of Chinese Medicine, Lanzhou, China

Tengfei Li, Yiyi Li, Yongjia Zhou & Bowa Zhang

Evidence-Based Medicine Centre, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China

Tengfei Li, Qingyong Zheng, Mingyue Zhang, Caihua Xu & Jinhui Tian

First Clinical College of Medicine, Lanzhou University, Lanzhou, China

Department of Gastroenterology, Gansu Province Maternity and Child Health Hospital (Gansu Province Central Hospital), Lanzhou, China

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Tengfei Li and Jinhui Tian conceived the manuscript. Tengfei Li and Qingyong Zheng drafted the manuscript. Mingyue Zhang, Yiyi Li, and Yongjia Zhou filtered the articles. Mingyue Zhang, Yiyi Li, Yongjia Zhou, Caihua Xu, Bowa Zhang, and Zeiwei Wang analysed the data and constructed the graphs. Jinhui Tian and Li Zhou provided a critical version of the manuscript. All authors contributed to the revision of the manuscript and approved the final manuscript.

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Li, T., Zheng, Q., Zhang, M. et al. How consistent are the key recommendations, and what is the quality of guidelines and expert consensus regarding paediatric cow’s milk protein allergy?. Eur J Pediatr (2024). https://doi.org/10.1007/s00431-024-05622-3

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UB Awards 320 Biomedical Science Degrees; 35 Earn PhDs

Commencement 2024.

Lauryn Alexandria Scott, a biomedical sciences undergraduate student, is all smiles as she walks across the stage during the May 19 biomedical sciences commencement ceremony.

By Dirk Hoffman

Published May 29, 2024

Thirty-five doctoral, 76 master’s and 209 baccalaureate candidates were eligible to receive degrees in biomedical science fields during the May commencement ceremony.

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Six graduate students and nine senior undergraduates were singled out for special honors, including four graduates who received a Chancellor’s Award, the highest State University of New York undergraduate honor.

Graduates completed work in 14 departments or programs of the Jacobs School of Medicine and Biomedical Sciences :

• biochemistry
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Graduates also completed the following programs offered in alliance with the  Roswell Park Comprehensive Cancer Center Graduate Division : cancer pathology and prevention, cancer sciences, immunology, and molecular pharmacology and cancer therapeutics.

Fifteen of the doctoral degrees and eight of the master’s degrees were awarded in Roswell Park’s programs.

Allison Brashear, MD, MBA, UB’s vice president for health sciences and dean of the Jacobs School, congratulates the Class of 2024.

Lessons Learned From Recent Solar Eclipse

Allison Brashear, MD, MBA , UB’s vice president for health sciences and dean of the Jacobs School, welcomed attendees to the May 19 event at UB’s Center for the Arts and addressed the graduates.

“It fills my heart with immense joy to see all of you gathered here today,” she said.

“In the face of the challenges that have beset us in recent times, these bright scholars and scientists have exhibited extraordinary resilience, determination and perseverance in their academic endeavors. I am confident that these qualities will serve as guiding lights as they embark upon their journeys in their respective fields.”

She noted that biomedical science is one of the broadest areas of medical science and underpins much of modern medicine.

“Biomedical scientists are at the heart of multidisciplinary teams in health care. Biomedical research looks at ways to prevent and treat disease,” Brashear said. “Your innovative approaches and unwavering dedication will continue to push the boundaries of scientific discoveries and technology, leading to a brighter and healthier future for all of us.”

In his address, UB President Satish K. Tripathi, PhD, told the graduates they could learn a lot from the recent solar eclipse that generated excitement in Western New York in early April.

“Allow me to share three tips of advice gathered from the path of totality,” he quipped.

“Reconnect with the natural world, as often as possible. Instead of taking selfies, take time for self-reflection,” he said. “When you give wide berth to the stressors of modern life, you allow yourself space to find both your place in the world and your responsibility to it.”

“Do not regret circumstances beyond your control,” Tripathi added, noting the sunny days leading up to the eclipse, but the extreme cloudiness that persisted over much of WNY on April 8, the day of the event. “Notwithstanding the uncooperative weather, we all experienced a breathtaking moment. Magnify your disappointments and you miss occasions for learning, enrichment and wonder.”

“Lastly, use your expertise for the greater good. When you apply what you have learned for others’ benefit, you put your UB education to its highest purpose,” he said.

Doctoral graduate Haley Victoria Hobble won two separate graduate awards for her research and dissertation. She is flanked by Mark R. O’Brian, PhD, left, and John C. Panepinto, PhD.

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Biochemistry graduate student research achievement award.

Doctoral graduate Haley Victoria Hobble was honored for research that received national or international recognition and for being selected to give an oral presentation at a major national or international meeting.

Dissertation: “Intrafamily Heterooligomerization of the N-Terminal Methyltransferase METTL11A”

Mentor: Christine E. Schaner-Tooley, PhD , associate professor of biochemistry

Roswell Park Graduate Division Award for Excellence in Research

Doctoral graduate Abigail Cornwell was the recipient of this award for outstanding research for her dissertation titled “Impact of Benzodiazepines on the Pancreatic Ductal Adenocarcinoma Tumor Microenvironment”

Mentor: Michael Feigin, PhD, associate professor of oncology, Roswell Park Comprehensive Cancer Center

The Dean’s Award for Outstanding Dissertation Research

Doctoral graduate Haley Victoria Hobble was the winner of this award that recognizes demonstrated excellence in research.

She was honored for her dissertation: “Intrafamily Heterooligomerization of the N-Terminal Methyltransferase METTL11A”

Mentor:  Christine E. Schaner-Tooley, PhD , associate professor of  biochemistry

The Microbiology and Immunology Award for Excellence in Dissertation Research in Memory of Dr. Murray W. Stinson

Doctoral graduate Katherine Shannon Wackowski was honored for her dissertation “Cooperation of RESC Proteins in Trypanosome RNA Editing and Holoenzyme Dynamics”

Mentor: Laurie K. Read, PhD , professor of microbiology and immunology

Dennis Higgins Award for PhD Dissertation Research in Pharmacology and Toxicology

Doctoral graduate Shirley Xu was honored for her dissertation “Troponin-Mediated Autoimmune Mechanisms of Immune Checkpoint Inhibitor-Induced Myocarditis”

Mentor: Umesh Sharma, MD, PhD , associate professor of medicine

Bishop Neuroscience Thesis Award

Doctoral graduate Richard Adam Seidman was honored for his dissertation “Oscillatory Calcium Mediated Regulation of Human Oligodendrocyte Progenitor Cells”

Mentor: Fraser J. Sim, PhD , professor of pharmacology and toxicology

The Structural Biology Award for Excellence in Dissertation Research in Memory of Dr. Robert H. Blessing

Doctoral graduate Nicholas David Clark was honored for his dissertation “Structure/Function Studies of Virulence Factors from Periodontal Pathogens and Membrane Sphingolipid Hydroxylases”

Mentor: Michael G. Malkowski, PhD , professor and chair of structural biology

The four undergraduate SUNY Chancellor’s Award winners, from left, Bryan R. Renzoni, Lea Kyle, Rachel Esther Sanyu and Sarah Bukhari, along with Jennifer A. Surtees, PhD.

SUNY Chancellor’s Award for Student Excellence

Sarah Bukhari, Lea Kyle, Bryan R. Renzoni and Rachel Esther Sanyu were recognized with the SUNY Chancellor’s Award. It recognizes students for their integration of academic excellence with other aspects of their lives that may include leadership, athletics, community service, creative and performing arts, entrepreneurship or career achievement.

Bukhari graduates with a bachelor’s degrees in biochemistry. She is an undergraduate researcher in the lab of  Jennifer A. Surtees, PhD , professor of  biochemistry . Bukhari secured funding from the Experiential Learning Network and a Mentored Research micro-credential.

Beyond academics, the Grand Island, New York, native is deeply involved in community engagement, serving as both the volunteer coordinator and vice president of the largest student-run pre-health organization, the Association of Pre-Medical Students, and was awarded a Community Engagement micro-credential and gathering 500+ volunteer hours.

With dual roles as dance coach and social media coordinator for the Pakistani Student Association, she fosters a network of communities to embrace diversity and celebrate traditions.

A native of Martville, New York, Kyle is a University Honors College Scholar who graduates with a Bachelor of Science degree in biochemistry with minors in both physics and public health.

She has been a Student Association, Recreation Department, Student Engagement and TASS Center employee. She also is the current president of UB Rotaract, a volunteering club on campus.

Kyle is also a student researcher in the  Department of Microbiology and Immunology ,  Elizabeth A. Wohlfert, PhD , associate professor of microbiology and immunology, focusing on the effects of chronic inflammation on muscle function due to chronic infection..

Renzoni, of East Amherst, New York, graduates with a Bachelor of Science degree in biochemistry. He is a University Honors College Presidential Scholar and Honors College Ambassador.

A BioXFEL Scholar, he has received multiple research internship positions and worked in two different laboratories, contributing to work on the development of novel organic and organometallic compounds with applications as cancer therapies.

Renzoni has also served as a co-chair of the G14 Leadership Summit, president and executive adviser of UB ChemClub, and both assistant music director and music director of The Enchords, UB’s all-gender a cappella group.

Sanyu, an international student from Uganda, graduates with a bachelor’s degree in pharmacology and toxicology.

She is an Honors College Scholar who conducted oncology research within the lab of Wendy Huss, PhD, at Roswell Park Comprehensive Cancer Center and at Johnson & Johnson, where she earned the 2023 Inspire Spotlight Award.

Sanyu has also worked as a student assistant in the Office of Interprofessional Education and an honors peer mentor. 

She is a founder of a health care app and is involved with the community through her work with Suubi Cancer Relief and Hillside Family of Agencies.

Sanyu also loves to dance and was a member of the UBMystique and 8-Count dance teams.

Undergraduate Outstanding Senior Awards

The following awards honor high academic performance and involvement in the campus community and external organizations:

Biochemistry Sarah Bukhari

Biomedical Sciences Alexis Krayevsky

Biotechnology Tanvi Dixit

Medical Technology Eva Wisniewski

Neuroscience Leah Heiler

Nuclear Medicine Technology Kelly Mahan

Pharmacology and Toxicology Rachel Esther Sanyu

Commencement speaker Styliani-Anna (Stella) E. Tsirka, PhD, tells the graduates to never lose sight of the wonder and awe that first drew them to the biomedical sciences.

Keynote Theme One of Compassion, Resilience

Commencement speaker Styliani-Anna (Stella) E. Tsirka, PhD, the Miriam and David Donoho Distinguished Professor of pharmacological sciences and vice dean for faculty affairs at the Renaissance School of Medicine at Stony Brook University, spoke about empathy and persistence.

“Beyond the technical skills and academic achievements that you have earned and will continue to earn, what will set you apart is your capacity for empathy, for compassion, your ethical responsibility,” she said.

“In the pursuit of scientific advancement, try not to lose sight of the human element and the living organisms whose lives may be impacted by our work.”

Tsirka noted that biomedical scientists have a serious duty to use their expertise to make society better, alleviate suffering and to promote the health and well-being of all people, regardless of race, gender or socioeconomic status.

“If you decide to further pursue scientific inquiry, do remember that you will need persistence and resilience,” she said. “Experimental science is not for the faint of heart.”

She remarked that her lab members often talk about the fact that it is called “research” instead of just “search.”

“The majority of our experiments will not be successful, but the ones that provide that ‘eureka moment’ will last a lifetime,” Tsirka assured the graduates. “Remember that setbacks are valuable lessons that shape the way for future success.”

Tsirka encouraged the graduates to embrace the idea of lifelong learning.

“To remain at the forefront of your field, you must remain curious and receptive of new ideas,” she said.

“Importantly, science is also delicate. Continue to approach it with integrity and rigor.”

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Biomedical Waste Management and Its Importance: A Systematic Review

Himani s bansod.

1 Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND

Prasad Deshmukh

2 Head and Neck Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND

The waste generated in various hospitals and healthcare facilities, including the waste of industries, can be grouped under biomedical waste (BMW). The constituents of this type of waste are various infectious and hazardous materials. This waste is then identified, segregated, and treated scientifically. There is an inevitable need for healthcare professionals to have adequate knowledge and a proper attitude towards BMW and its management. BMW generated can either be solid or liquid waste comprising infectious or potentially infectious materials, such as medical, research, or laboratory waste. There is a high possibility that inappropriate management of BMW can cause infections to healthcare workers, the patients visiting the facilities, and the surrounding environment and community. BMW can also be classified into general, pathological, radioactive, chemical, infectious, sharps, pharmaceuticals, or pressurized wastes. India has well-established rules for the proper handling and management of BMW. Biomedical Waste Management Rules, 2016 (BMWM Rules, 2016) specify that every healthcare facility shall take all necessary steps to ensure that BMW is handled without any adverse effect on human and environmental health. This document contains six schedules, including the category of BMW, the color coding and type of containers, and labels for BMW containers or bags, which should be non-washable and visible. A label for the transportation of BMW containers, the standard for treatment and disposal, and the schedule for waste treatment facilities such as incinerators and autoclaves are included in the schedule. The new rules established in India are meant to improve the segregation, transportation, disposal methods, and treatment of BMW. This proper management is intended to decrease environmental pollution because, if not managed properly, BMW can cause air, water, and land pollution. Collective teamwork with committed government support in finance and infrastructure development is a very important requirement for the effective disposal of BMW. Devoted healthcare workers and facilities are also significant. Further, the proper and continuous monitoring of BMW is a vital necessity. Therefore, developing environmentally friendly methods and the right plan and protocols for the disposal of BMW is very important to achieve a goal of a green and clean environment. The aim of this review article is to provide systematic evidence-based information along with a comprehensive study of BMW in an organized manner.

Introduction and background

The amount of daily biomedical waste (BMW) produced in India is enormous [ 1 ]. People from all segments of society, regardless of age, sex, ethnicity, or religion, visit hospitals, which results in the production of BMW, which is becoming increasingly copious and heterogeneous [ 2 ]. BMW produced in India is about 1.5-2 kg/bed/day [ 3 ]. BMW include anatomical waste, sharps, laboratory waste, and others and, if not carefully segregated, can be fatal. Additionally, inappropriate segregation of dirty plastic, a cytotoxic and recyclable material, might harm our ecosystem [ 4 ]. Earlier, BMW was not considered a threat to humans and the environment. In the 1980s and 1990s, fears about contact with infectious microorganisms such as human immunodeficiency virus (HIV) and hepatitis B virus (HBV) prompted people to consider the potential risks of BMW [ 5 ]. BMW is hazardous in nature as it consists of potential viruses or other disease-causing microbial particles; it may be present in human samples, blood bags, needles, cotton swabs, dressing material, beddings, and others. Therefore, the mismanagement of BMW is a community health problem. The general public must also take specific actions to mitigate the rising environmental degradation brought on by negligent BMW management. On July 20, 1998, BMW (Management and Handling) Rules were framed. On March 28, 2016, under the Environment (Protection) Act, 1986, the Ministry of Environment and Forest (MoEF) implemented the new BMW Rules (2016) and replaced the earlier one (1988). BMW produced goes through a new protocol or approach that helps in its appropriate management in terms of its characterization, quantification, segregation, storage, transport, and treatment.

According to Chapter 2 of the Medical Waste Management and Processing Rules, 2016, “The BMW could not be mixed with other wastes at any stage while producing inside hospitals, while collecting from hospitals, while transporting, and should be processed separately based on classification.” The COVID-19 pandemic has now transformed healthy societies worldwide into diseased ones, resulting in a very high number of deaths. It also created one significant problem: improper handling of the medical waste produced in the testing and treatment of the disease [ 6 ]. In India, BMW generated due to COVID-19 contributed to about 126 tonnes per day out of the 710 tonnes of waste produced daily [ 7 ]. 

The basic principle of the management of BMW is Reduce, Reuse, and Recycle-the 3Rs. Out of the total amount of BMW generated, 85% is general (non-hazardous) waste, and the remaining 15% is hazardous. As BMW contains sharps and syringes, the pathogens can enter the human body through cuts, abrasions, puncture wounds, and other ways. There might also be chances of ingestion and inhalation of BMW, which can lead to infections. Some examples of infections are Salmonella, Shigella, Mycobacterium tuberculosis, Streptococcus pneumonia, acquired immunodeficiency syndrome (AIDS), hepatitis A, B, and C, and helminthic infections [ 8 ]. This systematic review is conducted to obtain essential, up-to-date information on BMW for the practical application of its management. The highlight of the management of BMW is that the “success of BMW management depends on segregation at the point of generation” [ 9 ].

The findings have been reported following the principles and criteria of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). The systematic review has been conducted according to these standards and principles.

Search Sources/Search Strategy

We used the MeSH strategy to obtain articles from PubMed and ResearchGate employing the following terms: (“Biomedical/waste” [Majr] OR “Biomedical Waste/source” [Majr] OR “Biomedical Waste/hazards” [Majr] OR “Biomedical Waste/segregation” [Majr] OR “Biomedical Waste/rules” [Majr] OR “Biomedical Waste/laws” [Majr] OR “Biomedical Waste/environment” [Majr]). Specifically, for management-related studies, the search terms (“Management/steps” [Majr] OR “Management/handling” [Majr] OR “Management/coding” [Majr] OR “Color coding/segregation” [Majr] OR “Treatment/method” [Majr] OR “Autoclaving/waste” [Majr] OR “Incineration/waste” [Majr]) were used. We obtained the most pertinent research papers and used them in different arrangements using the Boolean operators “AND” and “OR.”

Inclusion and exclusion criteria

We focused on papers written in the English language, published within the last decade, relevant to the central questions of this review article, and that are systematic reviews such as randomized clinical trials and observational studies. We, however, excluded papers published in languages other than English, irrelevant to the questions, and related to topics other than BMW.

Search outcomes

After the initial screening, we narrowed the search results down to 264 papers. A total of 42 duplicate papers were removed. Subsequently, publications were refined by the title/abstract, and we eliminated a few studies due to the lack of full text and/or related articles. Finally, after assessing 27 items for eligibility, we included 11 papers in our review. Figure ​ Figure1 1 is the flow chart for article selection formulated on PRISMA.

PRISMA: Preferred Reporting Items for Systematic Review and Meta-analysis, PMC: PubMed Central

Need for BMW management in hospitals

BMW threatens the health of medical staff, hospital-visiting patients, and people in the nearby community. Improper disposal leads to severe hospital-acquired diseases along with an increased risk of air and water pollution. Due to open-space waste disposal practices, animals and scavengers might get infected, leading to the scattering of waste and the spreading of infections. In countering such activities, four major principle functions of BMW management are applicable: the placement of bins at the source of generation of BMW, segregation of BMW, removal or mutilation of the recyclable waste, and disinfection of the waste [ 10 ]. BMW management methods aim predominantly to avoid the generation of waste and, if generated, then recover as much as possible [ 11 ].

BMW management rules in India

On March 28, 2016, under the Environment (Protection) Act, 1986, the MoEF notified the new BMW Rules, 2016 and replaced the earlier Rules (1988). BMW produced goes through a new protocol or approach which helps in the appropriate management of waste, i.e., its characterization, quantification, segregation, storage, transport, and treatment, all of which aim to decrease environmental pollution [ 12 ]. Problems with the improper management of BMW also shed light on the scavengers who, for recycling, segregate the potentially hazardous BMW without using gloves or masks. Strict rules have been implemented to ensure that there is no stealing of recyclable materials or spillage by some humans or animals and that it is transported to the common BMW treatment facility [ 10 ]. The first solution to stop the spread of hazardous and toxic waste was incineration. Incineration is required in all hospitals and healthcare facilities that produce BMW. However, due to the absence of services that provide certified incinerators in a few countries, BMW has to be sent to landfills, which leads to land contamination and harms the environment [ 13 ]. Incinerators used for disposal might also lead to environmental pollution. Numerous toxins are formed during incineration, which are the products of incomplete combustion. Thus, some new standards have been issued to resolve this problem and safeguard the environment and public health [ 14 ].

Steps in the management of BMW

BMW management needs to be organized, as even a single mistake can cause harm to the people in charge. There are six steps in the management of BMW [ 15 ]: surveying the waste produced; segregating, collecting, and categorizing the waste; storing, transporting, and treating the waste. Segregation is the separation of different types of waste generated, which helps reduce the risks resulting from the improper management of BMW. When the waste is simply disposed of, there is an increased risk of the mixture of waste such as sharps with general waste. These sharps can be infectious to the handler of the waste. Further, if not segregated properly, there is a huge chance of syringes and needles disposed of in the hospitals being reused. Segregation prevents this and helps in achieving the goal of recycling the plastic and metal waste generated [ 16 ]. According to Schedule 2, waste must be segregated into containers at the source of its generation, and according to Schedule 3, the container used must be labeled. The schedules of BMW (Management and Handling) Rules, 1998, which were initially ten in number, have now been reduced to four [ 17 ]. The collection of BMW involves the use of different colors of bins for waste disposal. The color is an important indicator for the segregation and identification of different categories of waste into suitable-colored containers. They must be labeled properly based on the place they have been generated, such as hospital wards, rooms, and operation theatres. It is also very important to remember that the waste must be stored for less than 8-10 hours in hospitals with around 250 beds and 24 hours in nursing homes. The storage bag or area must be marked with a sign [ 16 ]. 

Figure ​ Figure1 1 shows the biohazard signs that symbolize the nature of waste to the general public.

Biohazards are substances that threaten all living things on earth. The biohazard symbol presented in Figure ​ Figure1 1 was remarked as an important public sign, signaling the harms and hazards of entering the specified zone or room [ 18 ]. Along with the biohazard sign, the room door must have a label saying “AUTHORISED PERSONNEL ONLY.” The temporary storage room must always be locked and away from the general public's reach. The waste is then collected by the vehicles daily. A ramp must be present for easy transportation. The waste collected is then taken for treatment. The loading of wastes should not be done manually. It is very vital to properly close or tie the bag or the container to avoid any spillage and harm to the handlers, the public, and the environment. The transport vehicle or trolley must be properly covered, and the route used must be the one with less traffic flow [ 19 ].

BMW handling staff should be provided with personal protective equipment (PPE), gloves, masks, and boots. BMW retrievers must be provided with rubber gloves that should be bright yellow. After usage, the importance of disinfecting or washing the gloves twice should be highlighted. The staff working in or near the incinerator chamber must be provided with a non-inflammable kit. This kit consists of a gas mask that should cover the nose and mouth of the staff member. The boots should cover the leg up to the ankle to protect from splashes and must be anti-skid [ 16 ]. According to the revised BMW management rules, 2016, it is mandatory to provide proper training to healthcare facility staff members on handling BMW. The training should be mandatorily conducted annually. Along with the management step of the color coding for segregation, it is also important for the staff to be trained in record keeping. This practice of record-keeping helps track the total amount of waste generated and the problems that occurred during the management process, thus helping improve segregation, treatment, and disposal [ 20 ].

Color coding for segregation of BMW

Color coding is the first step of BMW management. Different wastes are classified into different types, and therefore, they must be handled and disposed of according to their classification. The bins used for waste disposal in all healthcare facilities worldwide are always color-coded. Based on the rule of universality, bins are assigned a specific color, according to which the waste is segregated. This step helps avoid the chaos that occurs when all types of waste are jumbled, which can lead to improper handling and disposal and further result in the contraction of several diseases [ 21 ]. The different kinds of categories of waste include sharp waste such as scalpels, blades, needles, and objects that can cause a puncture wound, anatomical waste, recyclable contaminated waste, chemicals, laboratory waste such as specimens, blood bags, vaccines, and medicines that are discarded. All the above-mentioned wastes are segregated in different colored bins and sent for treatment [ 22 ]. Yellow bins collect anatomical waste, infectious waste, chemical waste, laboratory waste, and pharmaceutical waste, covering almost all types of BMW. Different bins and various types of sterilization methods are used depending on how hazardous the waste is. The best tools for sterilization are autoclaves. Red bins collect recyclable contaminated wastes, and non-chlorinated plastic bags are used for BMW collection. Blue containers collect hospital glassware waste such as vials and ampoules. White bins are translucent where discarded and contaminated sharps are disposed of. Sharp wastes must always be disposed of in puncture-proof containers to avoid accidents leading to handlers contracting diseases [ 23 , 24 ]. 

Figure ​ Figure3 3 illustrates the different colored bins used for the segregation of BMW.

BMW management refers to completely removing all the hazardous and infectious waste generated from hospital settings. The importance of waste treatment is to remove all the pathogenic organisms by decontaminating the waste generated. This helps in the prevention of many severe health-related issues that can be caused because of the infective waste. It is a method used to prevent all environmental hazards [ 25 ].

Methods for the treatment of BMW

There are many methods that are used for the treatment of BMW. One of the most economical ways of waste treatment is incineration, which is just not some simple “burning” but the burning of waste at very high temperatures ranging from 1800℉ to 2000℉ to decrease the total mass of decontaminated waste by converting it into ash and gases, which is then further disposed of in landfills [ 25 , 26 ]. Important instructions associated with the use of incinerators are as follows: chlorinated plastic bags must not be put inside the incinerators as they can produce dioxin [ 26 ]. Metals should not be destroyed in an incinerator. The metals present in BMW are made of polyvinyl chloride. When these metals are burned, they produce a huge amount of dioxin. Dioxins are very toxic chlorinated chemical compounds, as dioxins, when released into the environment, can lead to environmental pollution and a higher incidence of cancer and respiratory manifestations [ 14 ].

Autoclaving is an alternate method of incineration. The mechanism of this process involved sterilization using steam and moisture. Operating temperatures and time of autoclaving is 121℃ for 20-30 minutes. The steam destroys pathogenic agents present in the waste and also sterilizes the equipment used in the healthcare facility [ 25 ]. Autoclaving has no health impacts and is very cost-friendly. It is recommended for the treatment of disposables and sharps, but the anatomical, radioactive, and chemical wastes must not be treated in an autoclave [ 27 ]. Chemical methods are the commonest methods that include chemicals such as chlorine, hydrogen peroxide, and Fenton’s reagent. They are used to kill the microorganisms present in the waste and are mainly used for liquid waste, such as blood, urine, and stool. They can also be used to treat solid waste and disinfect the equipment used in hospital settings and surfaces such as floors and walls [ 28 ]. Thermal inactivation is a method that uses high temperatures to kill the microorganisms present in the waste and reduce the waste generated in larger volumes. The temperature differs according to the type of pathogen present in the waste. After the treatment is done, the contents are then discarded into sewers [ 29 ].

Very serious environmental and health hazards can be triggered if hospital waste is mixed with normal garbage, which can lead to poor health and incurable diseases such as AIDS [ 30 ]. The needle sticks can be highly infectious if discarded inappropriately. Injury by these contaminated needles can lead to a high risk of active infection of HBV or HIV [ 31 ]. The groups at increased risk of getting infected accidentally are the medical waste handlers and scavengers. Sharps must properly be disposed of in a translucent thin-walled white bin. If sharps are discarded in a thin plastic bag, there is a high chance that the sharps might puncture the bag and injure the waste handler [ 32 ]. It can also be the main cause of severe air, water, and land pollution. Air pollutants in BMW can remain in the air as spores. These are known as biological air pollutants. Chemical air pollutants are released because of incinerators and open burning. Another type of threat is water pollutants. BMW containing heavy metals when disposed of in water bodies results in severe water contamination. The landfills where the disposal takes place must be constructed properly, or the waste inside might contaminate the nearby water bodies, thus contaminating the drinking water. Land pollution is caused due to open dumping [ 33 ]. BMW must also be kept away from the reach of rodents such as black rats and house mice, which can spread the pathogens to the people living nearby [ 34 ].

Many promising steps were taken to minimize the volume of waste discarded from the source, its treatment, and disposal. The 3R system encourages the waste generators to reuse, reduce, and recycle. Everyone must be aware of the 3Rs because this approach can help achieve a better and cleaner environment [ 35 ]. Unfortunately, most economically developing countries cannot correctly manage BMW. Very few staff members of healthcare facilities are educated about proper waste management. The waste handlers are also poorly educated about the hazards of waste [ 36 ]. Every member helping in the waste management process must be made aware of the dangers of BMW to avoid accidents that harm the environment and living beings [ 37 ].

Conclusions

BMW is generated by healthcare facilities and can be hazardous and infectious. Improper handling can lead to health hazards. Collection, segregation, transportation, treatment, and disposal of BMW are important steps in its management. The color coding of bins, the use of technologies such as incineration and autoclaving, and attention to environmental impacts are also highly crucial. BMW management aims to reduce waste volume and ensure proper disposal. All those involved should strive to make the environment safer.

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The authors have declared that no competing interests exist.