How could COVID-19 impact allograft safety?

It is well known that viruses can sequester in organs and tissues, creating the possibility of transmission during transplant. Until more is known about COVID-19 transmission and sequestration, it’s best to presume that there could be potential risks to patients receiving allografts. Therefore, implementation of guidelines which restrict tissue donation are necessary to preserve the safety of the nation’s allograft supply.

Fortunately, the Physician’s Council of the American Association of Tissue Banks has issued guidance on this matter to the US tissue banking community. Per Dr. Roman Hitchev of the Association, here is a summary of those guidelines:

  • Travel within the last 28 days prior to donation to an area designated by the CDC as Alert Level 2 or Warning Level 3 may constitute grounds for exclusion of a deceased donor regardless of symptoms, or deferral of a living donor for as much time is necessary to ensure at least 28 consecutive days without symptoms1 following the last travel date to the designated area.
  • Fever with severe acute lower respiratory illness (e.g., pneumonia, ARDS) requiring hospitalization without alternative explanatory diagnosis (e.g., influenza) and without a negative SARS-CoV-2 diagnostic test, may constitute grounds for exclusion of a deceased donor, or deferral of a living donor for as much time is necessary to ensure at least 28 consecutive days without these syndromic symptoms.
  • Close contact3 within the last 28 days prior to donation with a person who has confirmed COVID-19 infection or with a Person under Investigation2 (PUI) as defined by the CDC may constitute grounds for exclusion of a deceased donor, or a deferral of a living donor for as much time is necessary to ensure at least 28 consecutive days without symptoms1 following the contact.
  • Confirmed infection or designation of a Person under Investigation2(PUI) as defined by the CDC within the last 28 days prior to donation may constitute grounds for exclusion of a deceased donor or deferral of a living donor for as much time is necessary to ensure at least 28 consecutive days without symptoms after the PUI status is lifted.  


  1. Symptoms: Refer to the CDC website –
  2. Person under Investigation(PUI): Refer to CDC Criteria to Guide Evaluation of PUI for COVID-19 –
  3. Close Contact: Refer to the CDC website –


Due to the dynamically changing outbreak geography, medical directors are advised to refer to the CDC on countries at risk for transmission and community spread and the latest travel advisories.

Our country’s tissue banking community is committed to patient safety. The Association and member banks are engaged in research to answer key questions about the new coronavirus and its effects on donated tissues. will be providing updates to the surgical community on the scientific knowledge base as it evolves.

Organs are Allografts, Too!

Did you know that organs are also a type of allograft? We usually think of skin, tendons, bone, and heart valves as allografts, but solid organs are also allografts, which are defined as “a tissue or organ obtained from one member of a species and grafted to a genetically dissimilar member of the same species.”1

Deceased organ donors can donate two kidneys, one liver, two lungs, one heart, one pancreas, and their intestines. Living organ donors can donate one kidney, one lung, or a portion of their liver, pancreas, or intestine.2 Approximately 115,000 people, including children, await organ transplants in the United States right now. 82% of individuals waiting are waiting for a kidney. There are 8,000 deaths each year in the U.S. because donated organs are not procured in time. 683,000 transplants have taken place in the U.S. since 1988.3

To qualify as an organ donor, blood flow and oxygen must have not been interrupted to organs before tissue recovery, to ensure organ viability. As a result, organ donation requires an individual die under circumstances resulting in a fatal brain injury; usually a massive trauma to the head results in bleeding, swelling, or lack of oxygen to the brain which leads to a lack of brain or brainstem activity and brain death. After all efforts to save the patient’s life have been exhausted, a search is conducted to determine if the patient has personally authorized donation or, if not found on the registry, the next of kin or authorized representative is contacted to be offered the opportunity to authorize donation. Once authorization is obtained, medical and social history is collected from the family. Donation and transplantation professionals determine, based on this information, which organs can be donated and match those organs to patients on the national transplant waiting list.4

In 2014, hands and faces were added to the organ transplant list to be collected from deceased donors.2 The first modern hand transplant was performed in France in 1998. The first hand transplant in the United States occurred one year later, in 1999 in Louisville.5 Less than 100 people have received hand transplants in the world, and less than 30 have received hand transplants in the U.S., largely because of concerns about the risk of rejection, the risks of long-term immunosuppression, and the high level of function that can be obtained with modern prosthetics.6  Hand transplants are still considered experimental by most insurance companies because of a lack of evidence as to their effectiveness; the first hand transplant recipient in France stopped taking his immunosuppressants within two years and requested his transplanted hand be removed, while the first American with a double hand transplant complains that he “can do absolutely nothing” with his transplanted hands, and explored the possibility of getting them removed.5,6

A face transplant is a procedure that replaces all or part of a patient’s face with that of a donor. This is usually performed on individuals who have suffered extreme disfigurement to the face such as through burns, trauma, birth defects, or diseases. Those with severe disfigurement are often ostracized by society for not looking “normal,” and, as the tissue is delicate, they may also have issues with eating and talking. The first face transplant was performed in France in 2005. In 2007, the first full-face transplant was conducted, also in France. The first near-total face transplant was performed in the United States in 2008 at the Cleveland Clinic, which was also the first face transplant to be conducted in the U.S.7 Faces are at higher risk for rejection than solid-organ transplants, since they involve so many different kinds of tissue including muscles, nerves, blood vessels, bones, and skin. Preventing rejection requires a lifetime of taking high doses of immunosuppressive drugs, which makes the patient vulnerable to infections and diseases, especially lymphomas and other cancers.8 The first face transplant recipient, Isabelle Dinoire, developed two types of cancer as a result of prolonged use of immunosuppressants and anti-rejection drugs, eventually leading to her death in 2016.9 Because of concerns about the risks to the procedure, and its relative newness, it is still considered an experimental procedure. Face transplants have also been conducted in several other countries, including Spain, Turkey, China, and Poland.9

A newer, amazing application of allografts are penis transplants, which show incredible promise for restoring urinary function as well as, hopefully, sexual functioning. South Africa has successfully conducted two penis transplants from deceased donors.10 In 2016, Massachusetts General Hospital conducted the first penis transplant in the United States utilizing a genitourinary vascularized composite allograft (GUVCA)—which means it included arteries, veins, nerves, urethra, and skin graft pedicle to properly restore appearance and eventual function.11 Johns Hopkins School of Medicine in Baltimore conducted the first total penis and scrotum transplant in the world in 2018. Utilizing tissue from a deceased donor, they transplanted skin, muscles and tendons, nerves, bone, and blood vessels to repair an injury the patient received serving as a soldier in Afghanistan from an IED.12

As transplant medicine progresses, we may see more successful outcomes with these more complex and challenging types of transplants, which promise to improve the quality of life of many more people.


  1. Random House. (2018). Allograft. Retrieved from
  2. U.S. Department of Health & Human Services. (2018). What can be donated. Retrieved from
  3. Donate Life America. (2018). Organ, eye and tissue donation statistics. Retrieved from
  4. Donate Life America. (2018). Deceased donation. Retrieved from
  5. Skelly, L. M. (2011, March 28). Rare hand transplant surgery successfully performed at Emory University Hospital. Emory University. Retrieved from
  6. Duke Health. (n.d.). Hand transplant: Vascular composite allotransplantation. Retrieved from
  7. NYU Langone Health. (n.d.). Facial transplant: Eye of the beholder? High School Bioethics. Retrieved from
  8. Connors, J. (2018, September). How a transplanted face transformed Katie Stubblefield’s life. National Geographic. Retrieved from
  9. BBC. (2016, September 6). First face transplant patient Isabelle Dinoire dies in France. BBC News. Retrieved from
  10. Akwei, I. (2017, May 23). World’s third penis transplant successfully done in South Africa. Africa News. Retrieved from
  11. Brown, N. (2016, May 16). First Genitourinary Vascularized Composite Allograft (penile) transplant in the nation performed at Massachusetts General Hospital. Massachusetts General Hospital. Retrieved from
  12. Kooser, A. (2018, April 23). Wounded US soldier gets first penis and scrotum transplant. CNET. Retrieved from


FDA Revises Screening Guidelines for Zika Virus Based on Study Data

The Food and Drug Administration (FDA) has revised their guidance for screening donated whole blood and blood components for Zika virus, replacing the guidance put in place during the height of the Zika outbreak in August 2016. The revised guidance allows blood establishments to utilize pooled testing of donations, instead of testing each donation individually. Testing of individual donations is still required if there is an increased risk of mosquito-borne transmission of Zika. At this time, Zika has local transmission in Puerto Rico and the U.S. Virgin Islands, which would require testing of individual donations, but this revised guidance excludes all 50 incorporated states since they do not currently have mosquito-borne transmission of the virus.1 The FDA’s decision to use pooled testing brings Zika screening in line with the way blood donations are screened for other diseases, including HIV, West Nile, and hepatitis B.2

Zika first emerged in Brazil in late 2015, and was quickly detected in the United States in travellers originating from Brazil and, as the epidemic spread, surrounding countries. As 2016 progressed, local transmission of the Zika virus was detected in both Florida and Texas, though such mosquito-borne transmission is believed to have been eliminated by the summer of 2017. The epidemic both domestically and internationally has dramatically dwindled since then, due to a combination of factors including mosquito control, prevention measures, and decreased host susceptibility due to the high initial incidence of the disease.3 In the U.S., there have been no cases of mosquito-borne transmission of Zika virus in 2018, and only 41 cases in travellers.4

The association of Zika virus with severe birth defects, its persistence in whole blood, and four cases of possible transmission of Zika by blood transfusion in Brazil all raised significant questions about the safety of the blood supply.5 In February 2016, the FDA recommended screening blood where the outbreak was active, which at the time was only U.S. territories;6 within six weeks, all blood donations were being screened in Puerto Rico, where the outbreak was, and remains, much more severe than the rest of the United States.5 On August 26, 2016, in response to the widespread nature of the outbreak, the risks posed by infection, and the large proportion of asymptomatic cases, the FDA issued revised recommendations directing that all whole blood donations and blood components in the U.S. be screened for Zika virus.7

The American Red Cross supplies roughly 40% of the blood and blood products in the United States and its territories.8 Starting June 20, 2016, the Red Cross began screening all of its whole blood donations and blood components in the U.S. for Zika RNA using the Procleix Zika Virus Assay manufactured by Grifols Diagnostic Solutions, under a special emergency use authorization as an investigational new drug for Zika virus applications.9,10

Between June 2016 and September 2017, 4,325,889 donations were screened by the Red Cross in the United States; 160 were initially reactive for Zika and 9 were confirmed positive. Of these, 4 were IgM negative, meaning they were likely not infective, and one was the recipient of an experimental vaccine.9

Researchers estimated that each RNA-positive donor cost $5.3 million per year to detect using individual donation screening, regardless of whether they were infectious or not, when testing is done by this type of transcription-mediated amplification (TMA) assay. Testing for Zika within the pooled blood supply remains expensive, but the pooled testing method will lower costs compared to the individual assay by an average of $4 per donation.9

Data collected during the 15-month trial period showed that pooled testing of samples were equally effective as the individual assay at detecting confirmed positive samples, but the pooled testing had a better positive predictive value and specificity than the individual assay (5.6% and 99.997%, respectively).9


  1. (2018, July 6). FDA announces revised guidance on the testing of donated blood and blood components for Zika virus. U.S. Food & Drug Administration. Retrieved from
  2. Branswell, H. (2018, May 9). Testing for Zika virus in blood donors finds few infections — at a cost of about $5.3 million each. STAT. Retrieved from
  3. Bunch, C. (2018). Hot topics: Zika virus and allografts, part 1. com. Retrieved from
  4. (2018, September 5). Zika case counts in the US. Reporting and Surveillance. Retrieved from
  5. Saa, P., Proctor, M., Foster, G., Krysztof, D., Winton, C., Linnen, J. M., … Stramer, S. L. (2018, May 10). Investigational testing for Zika virus among U.S. blood donors. New England Journal of Medicine, 378: 1778-1788. doi:1056/NEJMoa1714977
  6. (2016, February 16). FDA issues recommendations to reduce the risk for Zika virus blood transmission in the United States. U.S. Food & Drug Administration. Retrieved from
  7. (2016, August 26). FDA advises testing for Zika virus in all donated blood and blood components in the US. U.S. Food & Drug Administration. Retrieved from
  8. American Red Cross. (2018). Blood supply statistics. Retrieved from
  9. Bloch, E. M., Ness, P. M., Tobian, A. A. R., & Sugarman, J. (2018, May 10). Revisiting blood safety practices given emerging data about Zika virus. New England Journal of Medicine, 378: 1937-1841. doi:1056/NEJMsb1704752
  10. (2018, August 3). Emergency Use Authorizations. Medical Devices. Retrieved from
  11. Photo Credit: Jefferies, P. (2009, 25 September). Units of blood collected during the 69th ADA Blood Drive at the Robertson Blood Center at Fort Hood, Texas on September 18, 2009. United States Army. Retrieved from

What is CRISPR? A Primer

CRISPR is known as a cutting-edge tool for gene editing. Would you be surprised to learn that  that CRISPR originally evolved within single-celled organisms such as bacteria, as their own immune response to viruses? When viruses attack a bacterial cell, they inject their genome—their own viral DNA—into the cell. The bacterial cell, in turn, responds by deploying CRISPR: a scissor-like enzyme called CRISPR-associated protein, or Cas, hooked to a strand of RNA.3 The RNA recognizes the viral DNA, and Cas completely inactivates the targeted gene by making a precise cut in the gene, disabling the viral attack.1

CRISPR is an acronym for “clustered regularly interspaced short palindromic repeats,” which refers to the unique gene organization of bacteria and other microorganisms with short, partially palindromic repeated DNA sequences.2  Since its discovery in bacteria in 2012, scientists have been working in the lab to reproduce the CRISPR method to target plant or animal DNA, rather than viral DNA. CRISPR has the potential to “knock out” specific, targeted genes in plant, animal, or even human cells and, if a strand of DNA coding for a new gene is added, CRISPR can potentially provide a patch in the new gene between the severed ends. If it works, it would actually be fairly simple to design—all a researcher needs is a piece of RNA that can lock on to the targeted gene, attach it to a Cas enzyme, like Cas9, and you have a precision DNA editing tool.1

CRISPR editing technology has the greatest medical potential in humans in utero, to edit genes before birth and prevent the transmission of deadly genetic diseases like Tay-Sachs. Once a person is born with a disease like Tay-Sachs or Huntington’s disease, it’s much more difficult to use CRISPR to treat it.3 Gene editing is also being tested to treat conditions like cancer, blindness, sickle cell, thalassemia, and liver disease—among others.3,4

CRISPR has potentially broad applications that could impact allografts and human tissue engineering. It’s already being used to edit the genomes of mosquitoes, in the hopes of being able to prevent their ability to carry infectious diseases like Zika.3 And CRISPR/Cas is being applied directly within the field of tissue engineering, where it has been used to modify the expression of bone morphogenetic proteins (BMP) improve the osteogenic potential of adipose-derived stem cells (ASC).5

Another application of CRISPR is to edit induced pluripotent stem cell (iPSC) genomes to create special cell lines for use in tissue engineering.5 As techniques are developed to aid in homing and differentiation of stem cells, these customized iPSCs  may allow for the creation of multi-layered tissue scaffolds; cardiovascular grafts, whole organs, and other complex tissues could then be created.

For now, however, medical applications are confined to laboratories.1 Two recent studies have raised concerns that edited cells, designed to treat disease, might trigger cancer, demonstrating the need for further research and refinement before the technique is deployed. Experts describe the cancer risk as “plausible,” but not a “deal-breaker.”4  Considering the potential benefits to humankind, we’ll be staying tuned as the research evolves.


[1] Richter, V. (2016, 18 April). What is CRISPR and what does it mean for genetics? COSMOS: The science of everything. Retrieved from:

[2] Pak, E. (2014). CRISPR: A game-changing genetic engineering technique. Harvard: Science in the News. Retrieved from:

[3] Delviscio, J. (2018, April 4). How CRISPR works, explained in two minutes. STAT. Retrieved from:

[4] Begley, Sharon. (2018, June 12). CRISPR-Edited cells linked to cancer risk in 2 studies. Scientific American. Retrieved from:

[5] Pulgarin, D. A. V., Nyber, W. A., Espiinosa, A. (2017, July). CRISPR/Cas systems in tissue engineering: A succinct overview of current use and future opportunities. Current Trends in Biomedical Engineering and Biosciences, 5(4), 001-004. doi:10.19080/CTBEB.2017.05.555670

Allografts and Storage: What are the Temperature Requirements?

Allografts are produced in different formats. The temperature and method of storage is dependent on the type of tissue, its method of preservation, and its intended use. Methods of cold storage for tissue include refrigerated, frozen, or frozen-cryopreserved techniques, while simple ambient room temperature is appropriate for lyophilized, dehydrated, or desiccated tissues. 1

Standards have been set for cold storage of tissues which identify acceptable temperature ranges and their impact on shelf life. Tissues that can be kept refrigerated (above freezing, 0°C to 10°C) most commonly include placental tissues, cellular tissues, and osteoarticular or osteochondral grafts. The shelf life will vary based on the tissue and processing method. Placental tissue storage temperatures are currently established by the processing tissue bank. 1

Frozen and cryopreserved allografts must be stored at ultra-low temperatures to maintain their viability. Ultra-low freezer temperatures of -20°C to -39°C generally allow a shelf life of 6 months, whereas -40°C to -86°C allow longer terms up to 5 years. For example, tendons, skin, and osteoarticular grafts can be stored at -20°C to -39°C for 6 months or less, and at -40°C to -86°C (or colder) for up to 5 years. 1

Frozen and cryopreserved tissues are not the same. Cryopreserved tissues are specially preserved with a solution containing a cryoprotectant, such as glycerol or dimethylsulfoxide. 1 The purpose is to prevent cell death during freezing and thawing. Cryopreserved grafts are frozen slowly at a controlled rate and are used in procedures requiring viable cells such as chondrocytes.

Cardiac and vascular tissues are cryopreserved and can only be stored at -100°C or colder. 1 Reproductive tissues such as semen and ova must be stored in liquid nitrogen, in either the liquid or vapor phase. Cellular and birth tissues have no FDA-established standards, and as such the temperatures are established by the tissue bank. 1

Lyophilized tissue, commonly referred to as “freeze dried tissue,” is tissue that has been dehydrated for storage by converting the water to gas under a vacuum that extracts moisture. 1 Dehydrated and dessicated tissues are created by removing the water from the tissue, accomplished through chemical means such as alcohol soaks, critical/supercritical drying, simple air drying, or drying in a desiccator. 1 Lyophilized, dehydrated, and dessicated tissues can be stored at ambient room temperature. 1

A temperature monitoring system is required for both refrigerated and frozen systems, which must be utilized to document temperatures and to alert staff with audible and/or visual alarms when temperatures stray outside of set acceptable limits. 1 Many modern freezers and refrigerators also have alarms for power outages, low battery, door opening, filter blockages, or system failures.

Standards of procedure require operational protocols to be in place for reviewing temperature logs, and documenting the review. When storage methods utilize liquid nitrogen cooling, monitoring of either temperature or liquid nitrogen levels is necessary, and documentation is required at regular intervals. 1

1. American Association of Tissue Banks. (2016). Standards for Tissue Banking (14th ed.). J. C. Osborne, K. G. Norman, T. Maye, P. Malone, S. A. Brubaker, et al. (Eds.). Bethesda: Naval Medical Research and Development Command. Available from:

First Commercial Induced Pluripotent Stem Cell Plant Opens in Japan

The first commercial facility to produce induced pluripotent stem cells (iPSCs) opened on March 22, 2018. The $340 million, 30,000 square foot facility was built by Sumitomo Dainippon Pharma and is designed to produce stem cells for therapeutic applications.1  Sumitomo Dainippon is currently involved in using iPSCs to create treatments for conditions including macular degeneration, Parkinson’s disease, retinitis pigmentosa, and spinal cord injuries. The plant’s function, initially, will be to produce stem cells for use in clinical trials and early-stage commercial production.2 The more than 30,000 square feet of floor space is divided in three autonomous zones, each producing different types of stem cells. The iPS cell lines come from those produced by Kyoto University’s Center for iPS Cell Research and Application (CiRA).1

The Sumitomo Dainippon Manufacturing Plant for Regenerative Medicine & Cell Therapy is the only facility designed for commercial purposes that exists worldwide. Existing facilities, including the National Institutes of Health’s Center for Regenerative Medicine and the UK Stem Cell Bank, have made stem cells available to researchers, but to date no facility has provided stem cells for commercial purposes. This demonstrates what Masayo Tada, the president of Sumitomo Dainippon, claims is an “overwhelming advantage in the market of medical and pharmaceutical products” that will help the company “occupy a definite position in the field of regenerative medicine.” Sumitomo Dainippon intends to make regenerative medicine one of its core business strategies, and has plans for significant market growth in the coming decade.1


  1. Daley, J. (2018, March 23). World’s first commercial iPSC cell plant opens in Japan. The Scientist. Retrieved from:
  2. Sumitomo Dainippon Pharma. (2018, March 1). Sumitomo Dainippon Pharma completes manufacturing plant for regenerative medicine and cell therapy. IR News. Retrieved from:
  3. Photo: Immunocytochemistry of Kindey Tubular Epithelial Cells derived from induced pluripotent stem cells. By Ugnezija7, from Wikimedia Commons


Understanding Stem Cells Part 2: Ready for the Clinic?

With advances in research and technology, using stem cells for their regenerative potential has become a reality. But many stem cell treatments on the market have been marketed to the public and applied clinically without scientific evidence of efficacy. Worse, some treatments with stem cells have caused serious adverse events.

Provided that cell and tissue products fall into the “minimally manipulated” classification established by the Food and Drug Administration (FDA) under Title 21 of the Code of Federal Regulations Part 1271, studies to prove efficacy and safety are not required. This makes it possible to promote stem cell treatments for any use, without scientific or medical evidence that they work. Medical practitioners and patients alike must be aware that stem cell treatments are generally not “FDA approved.”

Draft guidance for industry was issued by FDA in 2017, proposing guidelines for evaluating and approving regenerative therapies which have demonstrated safe and efficacious use in serious conditions. These products could achieve a designation of “Regenerative Medicine Advanced Therapy” or “RMAT” in several ways. While the actual policy is still being formulated, this guidance initiated discussion with industry stakeholders and signaled increasing attention by FDA to regulating products touted as “regenerative,” including stem cells.

Cells for stem cell treatments are often autologous, extracted from the patient through bone marrow aspiration, a blood draw and centrifuge process, or liposuction (for adipose stem cells). There are also stem cell products available commercially that are allografts (cells or tissue from a human donor), including umbilical cord blood stem cells, allograft fat, and cell-based bone grafts. The number and type of stem cell varies based on the tissue of origin and the processing of the product, and both of these factors can be expected to affect outcomes.

Stem cell clinics often charge very high prices for stem cell treatments, from $1,500 for a joint injection to $25,000 for a systemic treatment. Insurance typically does not cover these treatments because they are considered experimental. Patients range from injured athletes and weekend warriors who want to avoid surgery, to desperate and terminally ill patients who are struggling with incurable conditions.

One unfortunate example of stem cell treatment gone wrong occurred at a Florida clinic. Three elderly women received stem cell injections to treat age-related macular degeneration and were blinded by the procedure. One of the women was apparently misled into believing that she was taking part in a clinical trial. The clinic which performed the injections, Bioheart Inc., had not conducted any pre-clinical or clinical trials. Today, Bioheart Inc. is doing business as US Stem Cell, which received a warning letter from FDA in August 2017, citing a multitude of deviations from current good manufacturing processes as well as inappropriate marketing claims and clinical uses. Read about it here.

Yet, there are many reasons to be excited about stem cells which are produced, processed, and applied appropriately. The California Institute for Regenerative Medicine (CIRM) has pioneered stem cell treatments to cure children afflicted with Severe Combined Immunodeficiency Disease (SCID), and they are now entering Phase 2 clinical trials for this clinical application. CIRM has over 40 trials running at this time, all targeting devastating medical problems.

In more common clinical scenarios, studies have shown that stem cell injections can improve osteoarthritis symptoms, and many sports medicine and orthopedic specialists are using them to help patients avoid surgery.

Future cardiac applications may become possible, too. In an article published in Nature Communications by Shadrin and colleagues (2017), scientific work investigated the development of a scaffold composed of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which are heart cells derived from adult human stem cells. The scientists developed a “cardiopatch”, essentially a network of organized heart cell tissue, and conducted experiments in a rodent model. The cardiopatches became vascularized, showed specific characteristics of adult heart tissue, and conducted the heart’s electrical charge. The researchers believe that their 4x4cm cardiopatches could eventually be scaled to create larger sections of functioning tissue for myocardial repair.

Validated treatments using stem cells have the potential to improve countless lives. But, for most conditions, we are years away from establishing proper protocols and doses. It’s appropriate for practitioner and patient alike to weigh the risks and benefits of any treatment, including (and, perhaps, especially) those promising stunning disease reversals and health advancements. Meanwhile, research continues to bring the promise of stem cells closer into focus and, step by step, safely into the clinic.



Begley, Sharon. (2017, March 15). Three patients blinded by stem cell procedure, physicians say. STAT. Retrieved from

Doheny, Kathleen. (2017, April 14). Stem cells for knees: promising treatment or hoax? WebMD. Retrieved from

GEN News Highlights. (2018, January 29). Stem cells: On your mark, get set, don’t go. Genetic Engineering & Biotechnology News. Retrieved from

McFarling, Usha Lee. (2016, February 8). FDA moves to crack down on unproven stem cell therapies. STAT. Retrieved from

Shadrin, Ilya Y., Allen, Brian W., Qian, Ying, Jackman, Christopher P., Carlson, Aaron L., Juhas, Mark E., & Bursac, Nenad. (2017, November 28). Cardiopatch platform enables maturation and scale-up of human pluripotent stem cell-derived engineered heart tissues. Nature Communications, 8: 1825. doi:10.1038/s41467-017-01946-x

Uygur, Aysu, & Lee, Richard T. (2016, February 22). Mechanisms of cardiac regeneration. Developmental Cell, 36: 362-374.


Understanding Stem Cells, Part 1: Stem Cells 101

Stem cells are a promising regenerative medicine tool and treatment. So much information on stem cell research exists that sorting through the facts and the hype can be daunting. This post will focus on explaining stem cell basics: What are stem cells, and what are the different types? Here, we will focus on adult stem cells, also known as somatic stem cells, since these are most relevant to medical research and clinical use today.

Nearly every cell in the body has a specific purpose. When a fetus begins to develop, cells become specialized (or differentiated), developing structure and characteristics specific to carrying out a special function in the body.1 For example, heart muscle cells generate movement (i.e., heartbeat), and red blood cells contain hemoglobin so that they can transport oxygen throughout the bloodstream. Stem cells, on the other hand, are unspecialized (undifferentiated); they have the potential to become any type of cell.

There are different categories of stem cells. Most current research focuses on these stem cell types:

  • Totipotent—can form all cell types in the body. During embryonic development, totipotent stem cells differentiate into all of the different cell types in order to form a whole organism. Researchers have been able to take differentiated cells and return them to a state of totipotency. More work is needed to make totipotent cells clinically useful.
  • Pluripotent—are descended from totipotent stem cells and can form into almost all cell types. Pluripotent stem cells can form any type of cell derived from the three germ layers: endoderm (forms the inside lining of stomach, digestive tract, and lungs), mesoderm (forms blood, muscle, and bone), and ectoderm (forms the skin and nervous system.) Pluripotent stem cells naturally exist in the embryo.
  • Multipotent—more specialized than totipotent and pluripotent stem cells, multipotent cells can develop into several different somatic cell types. Multipotent stem cells give rise to various tissues and organs during development, and some of these stem cells remain in a state of dormancy (“quiescence”) within their specific tissue niches of the adult human body. Types of multipotent stem cells include:
    • Hematopoietic stem cells—form the components of the blood.
    • Mesenchymal stem cells—form bone, cartilage, muscle, and fat cells.
    • Neural stem cells—form the nervous system.
    • Epithelial stem cells—form cells in the digestive tract lining.
  • Oligopotent—can form a few different cell types. They are derived from multipotent stem cells, descending from hematopoietic stem cells. Examples:
    • Lymphoid cells—form several types of immune cells, such as B cells and T cells.
    • Myeloid cells—form red blood cells and white blood cells, among others.

As mentioned above, stem cells are found in the adult body within tissues such as blood, bone, skin, heart, and gut, as multipotent cells. It’s believed that the cells are located in a stem cell niche, or a specific area of each tissue. The number of niche-dwelling stem cells is relatively small. These cells may remain quiescent (undifferentiated) for a long time, until disease, injury, or normal body processes cause the need for differentiation.

Three main sources of these adult somatic stem cells are bone marrow, blood, and adipose, tissue. Research is being conducted on ways to grow larger numbers of adult stem cells outside the body. When experimental conditions in the laboratory are right, stem cells can be induced to become specialized cells that perform specific functions. This has important implications for regenerative medicine.

Inducing cells from a patient’s own body to grow into the specific tissue they need to receive could lead to tremendous medical advances, someday eliminating the need for allografts and organ transplants. In the lab, researchers have been able to manipulate adult somatic stem cells to become induced pluripotent stem cells, or iPSCs. Through forced expression of specific genes, transcription factors, and epigenetic factors, differentiated somatic cells can be de-differentiated or induced to return to a pluripotent state. Advances have been made in scientific research on therapeutic implications of iPSCs.

Another source of pluripotent stem cells is umbilical cord blood. Stem cells from umbilical cord blood can be saved just after birth, cryopreserved for later use, and stored in an umbilical cord blood bank.2 There are now commercialized injectable therapies using umbilical cord blood stem cells.

There are many exciting possible applications of the stem cell research now being performed in laboratories worldwide. One example of this involves limbal stem cells, or LSCs. LSCs are found in the limbus, the part of the eye where the cornea meets the sclera. Normally, these cells are used to regenerate the cornea, which has a very fast turnover rate of 1-2 weeks in the human body. If a person’s LSCs deteriorate or they do not have enough LSCs, their corneas degenerate and they will go blind. However, research suggests that if LSCs were transplanted into such an eye, the entire cornea would regenerate.3 Researchers have studied LSCs using experiments with mice, and were able to restore the cornea of mice with experimental blindness. These results are promising for regenerative medicine in humans. For more information about the applications of stem cell research, check out Part 2.


Stem Cell Basics (2016). National Institutes of Health. Retrieved from

Jawdat, Dunia (2016). Banking of Human Umbilical Cord Blood Stem Cells and Their Clinical Applications. In Abdelalim E. (ed.) Recent Advances in Stem Cells. Humana Press. Retrieved from

Limbal Stem Cells for Treatment of Corneal Blindness (2017). Advanced Science News. Retrieved from


3D Printed Tissues From Bench to Bedside

3D bioprinting has the potential to provide significant medical advances. For example, 3D printing of functional tissues and organs could someday alleviate shortages in organ availability and the problem of organ incompatibility. But where does the field stand today?

A look at the research benches of top labs can give us an idea. In this post we’ll take a look at CELLINK’s innovative inks and printers, ORGANOVO’s functional bioprinted tissues, Dr. Anthony Atala’s Wake Forest Institute for Regenerative Medicine, and the 3D printed cortical fibers line by Xtant Medical, 3Demin®.

CELLINK is the world’s first bioink company. A Swedish company founded in 2016, CELLINK solved problems for the tissue engineering community by commercializing hydrogel bioinks which can be used to 3D print cartilage, bone, skin, or muscle. CELLINK is also a top provider of bioprinters. It’s likely to be one of CELLINK’s printers in a researcher’s lab being used to create 3D printed allografts during experiments, as was the case of the 3D printed cartilage mentioned in the prior post. With the right raw materials, it’s possible to create multiple biologics scaffolds and structures, and CELLINK is at the forefront of bioink development.1

ORGANOVO creates functional, responsive bioprinted human tissue models for preclinical testing and drug discovery research. Their 3D bioprinted tissues remain viable and dynamic for more than 28 days in vitro.2 Their key architectural and functional features mimic natural function and provide important information for scientists.

Pharmaceutical companies conducting research can examine the effects of new compounds on ORGANOVO’s ExVive™ 3D bioprinted human tissues. This allows tissue-specific data to be collected to better predict human outcomes, lower total development time, and reduce costs.

For example, liver and kidney tissues can be used to evaluate drug exposure for both acute and chronic toxicity and metabolism studies.2 ORGANOVO is also working on developing functional, 3D tissues for implantation or delivery into the human body, with the intention of creating these tissue for use for repair or replacement of damaged or diseased tissues.3

The Wake Forest Institute for Regenerative Medicine is one of the nation’s top research labs working to translate scientific discoveries in 3D printing into clinical therapies. Led by Dr. Anthony Atala, a pioneer in medical tissue engineering, this interdisciplinary team is engineering more than 30 different replacement tissues and organs to develop curative cell therapies.4 Wake Forest was the first institution to successfully engineer laboratory-grown organs and implant them into humans: these were engineered bladders grown from the patient’s own cells.5

The fact is, all living tissues are composed of many different cell types arranged in a specific order that is essential to function. Therefore, when using 3D printing to create a tissue, precision is critical.6 Researchers at Wake Forest have designed their own inkjet bioprinter that can print kidney cells, and the binders to hold the cells together, into a 3D kidney prototype. This bioprinter could potentially be used to create a custom organ based on a CT scan and patient data. Their bioprinter is also being tested in the creation of other structured tissue, such as the ear.7

While 3D bioprinting of living, functional, clinically applicable tissues and organs remains the Holy Grail, there are much simpler examples of the technology already commercialized and in use today.  Bacterin’s 3Demin® line of demineralized cortical bone fibers is bioprinted into different shapes and sizes designed for specific surgical applications. The bioprinting process creates a porous, interconnected allograft that contains BMPs and other growth factors necessary to promote new bone formation. It is an osteoconductive demineralized cortical fiber matrix with osteoinductive potential that can be used as a stand-alone graft, or in combination with autologous bone, bone marrow, DBM putty, and other products.8

Bacterin’s production of customized bone implants using 3D printing technology was applied clinically during a mission sponsored by the World Craniofacial Foundation. In Zambia, a child named Grace Kabelenga was born with the most severe facial cleft in 40 years (Tessier 0-14), and a total absence of the bones separating her brain from her oral cavity.9 3D printed plastic prototypes allowed the team to simulate surgery and to create molds for custom bone implants. Bacterin’s 3Demin® bone allograft material was used to create custom 3D printed bone to serve as a “bandeau” to define the superior orbital rims above her eyes.10 This was combined with other Bacterin allografts and rhBMP2 to reconstruct missing parts of Grace’s skull.

Multiple surgeries have allowed Grace to function as a normal child would. members can view a video about the WCF mission on our portal. A slide deck is also available here.

3D printing for tissue engineering has the potential to provide incredible benefits to humankind if the technology can be developed to its full potential for medical applications.

If you missed it, you can read more about the history and applications of bioprinting here: 3D Printing in Tissue Engineering.


1 CELLINK. (2017). BioX Printer. Retrieved from

2 ORGANOVO. (2017). 3D human liver tissue testing services. Retrieved from

3 ORGANOVO. (2017). About ORGANOVO. Retrieved from

4 Wake Forest School of Medicine. (n.d.). Wake Forest Institute for Regenerative Medicine. Retrieved from

5 Wake Forest Baptist Medical Center. (2006). Wake Forest physician reports first human recipients of laboratory-grown organs. Retrieved from

6 Wake Forest School of Medicine. (2017, September 6). Using 3D printing technology to print organs and tissue. Retrieved from

7 Wake Forest School of Medicine. (2016, August 8). Replacement organs and tissues: Engineering a kidney. Retrieved from

8 Bacterin. (2015). 3Demin Benefits. Retrieved from:

9 3D Systems. (2016). Delivering the gift of a normal life. Retrieved from:

10 3D Systems. (2017). Delivering the gift of a normal life with 3D systems healthcare solutions. Retrieved from 3D Systems. Delivering the gift of a normal life with 3D systems healthcare solutions. Retrieved from