Organs are Allografts, Too!

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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.

References

  1. Random House. (2018). Allograft. Dictionary.com. Retrieved from https://www.dictionary.com/browse/allograft
  2. U.S. Department of Health & Human Services. (2018). What can be donated. Organdonor.gov. Retrieved from https://www.organdonor.gov/about/what.html
  3. Donate Life America. (2018). Organ, eye and tissue donation statistics. Retrieved from https://www.donatelife.net/statistics/
  4. Donate Life America. (2018). Deceased donation. Retrieved from https://www.donatelife.net/types-of-donation/deceased-donation/
  5. Skelly, L. M. (2011, March 28). Rare hand transplant surgery successfully performed at Emory University Hospital. Emory University. Retrieved from http://shared.web.emory.edu/whsc/news/releases/2011/03/rare-hand-transplant-surgery.html
  6. Duke Health. (n.d.). Hand transplant: Vascular composite allotransplantation. Retrieved from https://www.dukehealth.org/treatments/transplant-program/hand-transplant
  7. NYU Langone Health. (n.d.). Facial transplant: Eye of the beholder? High School Bioethics. Retrieved from https://med.nyu.edu/highschoolbioethics/briefs/facial-transplantation-eye-beholder
  8. Connors, J. (2018, September). How a transplanted face transformed Katie Stubblefield’s life. National Geographic. Retrieved from https://www.nationalgeographic.com/magazine/2018/09/face-transplant-katie-stubblefield-story-identity-surgery-science/
  9. BBC. (2016, September 6). First face transplant patient Isabelle Dinoire dies in France. BBC News. Retrieved from https://www.bbc.com/news/world-europe-37290986
  10. Akwei, I. (2017, May 23). World’s third penis transplant successfully done in South Africa. Africa News. Retrieved from http://www.africanews.com/2017/05/23/world-s-third-penis-transplant-successfully-done-in-south-africa/
  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 https://www.massgeneral.org/News/pressrelease.aspx?id=1937
  12. Kooser, A. (2018, April 23). Wounded US soldier gets first penis and scrotum transplant. CNET. Retrieved from https://www.cnet.com/news/soldier-gets-first-penis-and-scrotum-transplant-johns-hopkins/

 

Understanding Stem Cells Part 2: Ready for the Clinic?

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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.

 

References

Begley, Sharon. (2017, March 15). Three patients blinded by stem cell procedure, physicians say. STAT. Retrieved from https://www.statnews.com/2017/03/15/stem-cell-patients-blind-macular-degeneration/.

Doheny, Kathleen. (2017, April 14). Stem cells for knees: promising treatment or hoax? WebMD. Retrieved from https://www.webmd.com/osteoarthritis/news/20170407/stem-cells-for-knees-promising-treatment-or-hoax#1.

GEN News Highlights. (2018, January 29). Stem cells: On your mark, get set, don’t go. Genetic Engineering & Biotechnology News. Retrieved from https://www.genengnews.com/gen-news-highlights/stem-cells-on-your-mark-get-set-dont-go/81255432.

McFarling, Usha Lee. (2016, February 8). FDA moves to crack down on unproven stem cell therapies. STAT. Retrieved from https://www.statnews.com/2016/02/08/fda-crackdown-stem-cell-clinics/.

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. https://doi.org/10.1016/j.devcel.2016.01.018

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Understanding Stem Cells, Part 1: Stem Cells 101

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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.

References:

Stem Cell Basics (2016). National Institutes of Health. Retrieved from https://stemcells.nih.gov/info/basics.htm.

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 https://link.springer.com/chapter/10.1007/978-3-319-33270-3_8.

Limbal Stem Cells for Treatment of Corneal Blindness (2017). Advanced Science News. Retrieved from http://www.advancedsciencenews.com/limbal-stem-cells-treatment-corneal-blindness/.

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Introduction to Allografts

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What is an Allograft?

An allograft is a tissue transplant between genetically dissimilar members of the same species1. An allograft is different from an autograft, which utilizes tissue from the same individual’s body and is therefore genetically identical. Examples of human allografts include: anterior tibialis tendon, frozen femoral head, freeze dried bone chips, DBM putty, acellular dermis, and amniotic membrane.

What are the Sources of Allografts?

Allografts are made possible through the generous gift of tissue donation after death by individual donors and through family consent. They are obtained after the donor’s death by procurement teams with specialized training in anatomy and surgical techniques to ensure viable soft tissue and bone grafts.

How are they Regulated?

Human tissue products are regulated by the FDA. Most allografts are regulated as Human Cell and Tissue Products (361 HCT/P’s). To qualify as 361 HCT/P, allografts must be considered “minimally manipulated” according to specific criteria under Part 21 CFR 1271.10(a) of the Public Services Health Act.

Allografts that qualify as minimally manipulated human cells and tissues are not required to undergo the same regulatory approval processes as those allografts that are considered medical devices. Examples of 361 HCT/P allografts include the tendon, femoral head, bone chips, dermis, and amniotic membrane mentioned above, but not the DBM putty.

When a tissue product is combined with a carrier, filler, polymer, or other non-human or synthetic ingredient, the combined product is considered more than minimally manipulated by the FDA. These products must obtain FDA 510K Clearance and premarket approval (PMA) like other medical devices. This approval process requires a preclinical study (using animal models) to demonstrate the safety, effectiveness, and equivalence to a similar product already on the market. Examples of allografts that are regulated as medical devices are DBM putties, which combine demineralized bone matrix with bovine or porcine material, or with non-tissue carriers such as carboxymethylcellulose, glycerol, or hyaluronic acid.

What are the Surgical Uses of Allografts?

Allografts are used for the repair, reconstruction, supplementation, or replacement of a recipient’s cells and tissues. For allografts to qualify as 361 HCT/P’s according to the FDA, the human cell or tissue product must perform the same basic function or set of functions in the recipient as in the donor, also known as “homologous use.” For example, tendons used for ACL reconstruction act as a connector in the recipient, as they did in the donor; connecting muscles to bones in the case of tendons is homologous to the function of connecting two bones, as ligaments do. In the same way, acellular dermis used for breast reconstruction acts as a soft tissue replacement, maintaining the same basic function as the original donor tissue.

Each year there are more than 1.75 million allografts performed in the United States from more than 30,000 donors.2  Since allografts were adopted into modern medicine 150 years ago, they have found increasing and widespread usage in a variety of medical fields, improving surgical outcomes and the quality of life of patients.

Tissue Banks

Tissue banks play a vital role, making it possible to perform life-saving, function-preserving medical transplants. Charged with qualifying donors and preparing and processing tissues for transplant, tissue banks must operate in a way that ensures the quality and safety of allografts.

But how do you know if you are working with a quality tissue bank? How can you tell if your tissue bank is adhering to the industry’s highest standards? What are some of those standards?

Get the answers in this post: Tissue Banks: Standards and Accreditation

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Understanding Tissue Sterilization, Part 2: Radiation Roundup

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In Part 1, we reviewed the differences between aseptic processing and terminal sterilization. In this post, we explore two validated methods of tissue sterilization: gamma radiation and E-beam radiation.

Safety in tissue transplants is of critical importance. All potential donors are first subject to physical assessment, medical and social screening, and serological testing as the first line of defense against infectious disease transmission. To learn more about these standards of practice (SOPs), look at this post. Current Good Tissue Practice SOPs are established as recommendations by the FDA and are required as part of the accreditation process for tissue banks regardless of the processing and/or sterilization methods to be used.

Once donor tissue is accepted, it is aseptically processed and tested for intrinsic bioburden, which is the population of microorganisms existing on the tissue before sterilization. Unfortunately, there have been incidents of infections transmitted to patients by aseptically processed allografts in the past, including Clostridium species (an anaerobic and spore-forming toxin), viral hepatitis, and the HIV virus. Because of this, the Centers for Disease Control and Prevention requires the use of sterilization technologies proven to kill sporicidal organisms for a tissue to be declared sterile.2

Both gamma and E-beam radiation are delivered in quantifiable doses validated to kill or inactivate specific harmful microorganisms including bacteria, viruses, and fungi. However, there are some differences between the two methods.

Gamma radiation is the exposure of tissue to continuous gamma rays, electromagnetic radiation similar to X-rays that are extremely high frequency. The radiation is delivered to a large number of grafts at once. The dose applied to the tissue is measured in kilograys (kGy). When gamma radiation first began to be used in the late 1950s, radiation doses between 30 and 50 kGy were most often used. Clinical outcomes suffered, and early studies showed that these high doses of radiation had negative effects on tissues by altering biomechanical properties of the collagen through the breakdown of the protein.

Modernized methods are now able to validate lower dose ranges (15 to 20 kGy) to achieve terminal sterilization.1 Techniques to prevent collagen damage are typically used during radiation protocols today, including delivering radiation to grafts while they are in a lyophilized state, irradiating tissues while they are kept frozen at ultra-low temperature, or using radioprotectant anti-oxidants.

Electron beam radiation, also called E-beam radiation, is another form of radiation used to sterilize allografts. With E-beam, tissue is irradiated using a beam of accelerated (high energy) electrons. E-beam irradiation is delivered as tissues pass in front of the beam on a conveyor belt.

As with gamma radiation, early studies using high doses of radiation found unwanted negative side effects on the sterilized tissue. However, modern sterilization utilizes low doses of radiation; E-beam sterilization of allografts at doses of 9-21 kGy has been shown to achieve a sterility assurance level (SAL) of 10-6, the highest level of terminal sterilization.

E-beam is more powerful irradiation than gamma radiation, so tissues are exposed to E-beam radiation for a shorter time (on the scale of minutes instead of hours) to achieve sterilization. However, E-beam radiation does not penetrate as deeply and delivers a less uniform dose than gamma radiation. E-beam radiation is well-suited to smaller items that are less densely packed, and it allows faster turnaround of the final product. In addition, E-beam irradiation can also be used on plastic packaging, allowing for sterilization of a final manufactured product.

Both gamma and E-beam radiation are extremely safe sterilization methods; neither method results in any lingering radioactivity in the sterilized allograft. Sterilization through irradiation is considered to be a clean and efficient process. It prevents the need to use harsh chemicals that can damage the collagen in allografts, and it leaves no solvent residue on the tissue. Also, tissues sterilized by irradiation need no quarantine period after terminal sterilization.

Modern irradiation methods have minimal effects on the biomechanical properties of allografts. In fact, studies have shown that most tissues sterilized with low-dose gamma or E-beam radiation are biomechanically similar those that don’t undergo irradiation. Additionally, a substantial amount of research has helped the tissue industry determine how to mitigate negative effects of radiation.

In summary, both E-beam and gamma radiation are efficient, safe, and result in terminal sterilization of tissue with minimal negative effects on structure and function.

References

Singh, Rita; Singh, Durgeshwer; and Singh, Antaryami. (2016). Radiation sterilization of tissue allografts: A review. World Journal of Radiology 8(4): 355-369. 10.4329/wjr.v8.i4.355