new research on xenotransplantation

• Alzheimer's disease & dementia
• Arthritis & Rheumatism
• Attention deficit disorders
• Autism spectrum disorders
• Biomedical technology
• Diseases, Conditions, Syndromes
• Endocrinology & Metabolism
• Gastroenterology
• Gerontology & Geriatrics
• Health informatics
• Inflammatory disorders
• Medical economics
• Medical research
• Medications
• Neuroscience
• Obstetrics & gynaecology
• Oncology & Cancer
• Ophthalmology
• Overweight & Obesity
• Parkinson's & Movement disorders
• Psychology & Psychiatry
• Radiology & Imaging
• Sleep disorders
• Sports medicine & Kinesiology
• Vaccination
• Breast cancer
• Cardiovascular disease
• Chronic obstructive pulmonary disease
• Colon cancer
• Coronary artery disease
• Heart attack
• Heart disease
• High blood pressure
• Kidney disease
• Lung cancer
• Multiple sclerosis
• Myocardial infarction
• Ovarian cancer
• Post traumatic stress disorder
• Rheumatoid arthritis
• Schizophrenia
• Skin cancer
• Type 2 diabetes
• Full List »

share this!

October 21, 2021

Progress in xenotransplantation opens door to new supply of critically needed organs

by NYU Langone Health

The first investigational transplantation of a genetically engineered, nonhuman kidney to a human body was recently completed at NYU Langone Health—marking a major step forward in potentially utilizing an alternative supply of organs for people facing life-threatening disease.

Known as xenotransplantation, the surgery was performed on Saturday, September 25, 2021, at NYU Langone's campus in Manhattan. Robert Montgomery, MD, DPhil, the H. Leon Pachter, MD, Professor and chair of the Department of Surgery at NYU Langone and director of its Transplant Institute, led a surgical team during the two-hour operation. The kidney was obtained from a genetically engineered pig hundreds of miles away and transplanted into a deceased donor who was maintained on a ventilator, with the consent of the family, for 54 hours while the function and acceptance of the new kidney was studied.

The gene that encodes the glycan known as alpha-gal—which is responsible for a rapid antibody-mediated rejection of porcine organs by humans—was "knocked out" in the donor pig.  Additionally, the pig's thymus gland, which is responsible for "educating" the immune system, was transplanted with the kidney to stave off novel immune responses to the pig kidney.

The surgery was part of a larger study approved by a specially designated research ethics oversight board at NYU Langone. It is the latest step in a research protocol that calls for additional and similar procedures to be performed. Whole body donation after death for the purpose of breakthrough studies represents a new pathway that allows an individual's altruism to be realized after brain death declaration in circumstances in which their organs or tissues are not suitable for transplantation.

The kidney was attached to the blood vessels in the upper leg, outside the abdomen, and covered with a protective shield for observation and kidney tissue sampling over the 54-hour period of study. Urine production and creatinine levels—key indicators of a properly functioning kidney—were normal and equivalent to what is seen from a human kidney transplant. Throughout the procedure and subsequent observation period, no signs of rejection were detected. The results of the study will be presented for peer review and subsequent publication.

Critical Shortage of Transplantable Organs

The number of usable, donated organs available for transplantation has not grown sufficiently over the past half century, while the need for organs has soared. According to data compiled by the Organ Procurement and Transplantation Network of the U.S. Department of Health and Human Services, there are more than 90,000 people awaiting a life-saving kidney transplant in the U.S. and more than 32,000 people have been added to the national kidney wait list year to date.

"This is a transformative moment in organ transplantation," Montgomery says. "The medical and scientific communities have been working toward xenotransplantation to sustain human life for more than 50 years. There have been many hurdles along the way, but our most recent procedure significantly moves these endeavors forward. This research provides new hope for an unlimited supply of organs, a potential game-changer for the field of transplantation and those now dying for want of an organ."

The kidney used in this procedure was procured from a pig in which the alpha-gal biomolecule—principally responsible for the hyperacute rejection of pig-to-human xenografts—has been removed. Known as a GalSafe pig, the animal was engineered by Revivicor, Inc., a subsidiary of United Therapeutics Corporation. In December 2020, the U.S. Food and Drug Administration approved the GalSafe pig for use as a potential source for human therapeutics.

A Gracious Donor

While the research and surgical practices for xenotransplantation have been in development for years at NYU Langone's Transplant Institute, actual application could not progress without a human donor. After months of waiting for the appropriate donor, the opportunity to move forward came on the afternoon of Friday, September 24—setting in motion the historic procedure.

"It was the family's wish for the decedent to be an organ donor, but due to mitigating factors the decedent's organs were not suitable for donation," says Montgomery, who himself is the recipient of a donated heart. "Instead, the family graciously approved donation of their loved one's body for this procedure. That extraordinary generosity paved the way for this major step forward in creating a sustainable supply of life-saving organs and hopefully ending the current paradigm that someone has to die for someone to live."

LiveOnNY, the nonprofit organization that facilitates organ and tissue donation in the greater New York City area, was a critical partner in the effort to obtain consent from the donor family and the prompt retrieval of the porcine organ.

"I applaud Dr. Montgomery and the entire NYU Langone transplant team for this incredible scientific achievement," says Chad Ezzell, chief clinical officer of LiveOnNY. "We are entering a new era for our field and this will give new hope to those on our wait list as this important research moves forward. It is important to remember that none of this would be possible without the extraordinary donor and their family. We can never thank our families enough for the courage they show in saying yes to donation."

The Future of Organ Transplantation

A world-renowned surgeon and researcher, Montgomery helped pioneer a laparoscopic technique for procuring a kidney for live donation that is now common practice. He also developed "domino paired kidney donations" which is when two or more donors and recipients are paired in a kidney swap. This latest milestone in xenotransplantation—albeit part of a longer research process—could signal another exciting chapter in advancing transplantation medicine.

"The potential here is incredible," Montgomery says. "If the science and experimentation continue to move ahead positively, we could be close to kidney xenotransplantation into a living human being. And the future of this work is not limited to kidneys. Transplanting hearts from a genetically engineered pig may be the next big milestone. This is an extraordinary moment that should be celebrated—not as the end of the road, but the beginning. There is more work to do to make xenotransplantation an everyday reality."

Explore further

Feedback to editors

Engineers use bioprinted blood vessels to model deadly brain tumors

17 minutes ago

Team introduces a noninvasive method to monitor postprandial cardiovascular health

24 minutes ago

Stem cells map reveals molecular choreography behind individual variation in human development

Researchers establish largest stem cell repository focused on centenarians

Pigs may be transmission route of rat hepatitis E to humans

2 hours ago

Community resources linked with better teen mental health

Digital biomarkers shed light on seasonality in mood disorders

Q&A: Study identifies potential new treatment for liver fibrosis

Study provides new insights into development of ovarian follicles and previously unknown variations

How developmental signals can contribute to genomic mosaicism

Related stories.

Pig kidney works in human patient in 'potential miracle'

Oct 21, 2021

Pig-to-human transplants come a step closer with new test

Oct 20, 2021

'Missing self' contributes to organ rejection after transplantation

Jul 22, 2021

Asian donor and black recipient kidney transplants more likely to fail sooner compared with white counterparts

Aug 30, 2021

Living donors may benefit transplant patients

Feb 1, 2019

Expert alert: Five things to know about being a living liver donor

Nov 12, 2020

Recommended for you

New models quantify how 'nociception' could help improve management of surgical pain

Sep 23, 2024

New prostate biopsy technique lowers infection risk

Sep 19, 2024

Long-term outcomes good for face transplant recipients, study finds

Sep 18, 2024

Study finds two common surgeries equally effective for treating blinding condition of the eyelid

Sep 17, 2024

Scientists discover key features of language sites that could help preserve function after brain surgery

Sep 16, 2024

Mucin gel may help disk herniation patients after surgery

Let us know if there is a problem with our content.

Use this form if you have come across a typo, inaccuracy or would like to send an edit request for the content on this page. For general inquiries, please use our contact form . For general feedback, use the public comments section below (please adhere to guidelines ).

Please select the most appropriate category to facilitate processing of your request

Thank you for taking time to provide your feedback to the editors.

Your feedback is important to us. However, we do not guarantee individual replies due to the high volume of messages.

E-mail the story

Your email address is used only to let the recipient know who sent the email. Neither your address nor the recipient's address will be used for any other purpose. The information you enter will appear in your e-mail message and is not retained by Medical Xpress in any form.

Newsletter sign up

Get weekly and/or daily updates delivered to your inbox. You can unsubscribe at any time and we'll never share your details to third parties.

More information Privacy policy

Donate and enjoy an ad-free experience

We keep our content available to everyone. Consider supporting Science X's mission by getting a premium account.

E-mail newsletter

• ACS Foundation
• Inclusive Excellence
• ACS Archives
• Careers at ACS
• Federal Legislation
• State Legislation
• Regulatory Issues
• Get Involved
• SurgeonsPAC
• About ACS Quality Programs
• Accreditation & Verification Programs
• Data & Registries
• Standards & Staging
• Membership & Community
• Practice Management
• Professional Growth
• News & Publications
• Information for Patients and Family
• Preparing for Your Surgery
• Recovering from Your Surgery
• Jobs for Surgeons
• Become a Member
• Media Center

Our top priority is providing value to members. Your Member Services team is here to ensure you maximize your ACS member benefits, participate in College activities, and engage with your ACS colleagues. It's all here.

• Membership Benefits
• Find a Surgeon
• Find a Hospital or Facility
• Quality Programs
• Education Programs
• Member Benefits
• February 2024 | Volume 109...
• Xenotransplantation Bridge...

Xenotransplantation Bridges Past and Present, Revolutionizes Field of Transplantation

Brendan P. Lovasik, MD, Joshua M. Rosenblum, MD, PhD, FACS, Jahnavi K. Srinivasan, MD, FACS, and David Vega, MD, FACS

February 7, 2024

The prospect of clinical xenotransplantation recently has been invigorated by two pioneering cardiac xenotransplant cases performed at the University of Maryland in 2022 and 2023.

However, there are several renowned surgeons who embarked upon early attempts at cardiac xenotransplantation, including James D. Hardy, MD (1964), Donald Ross, MD, FACS (1967), Denton A. Cooley, MD, FACS (1968), and Leonard Lee Bailey, MD (1984), who performed the first infant heart transplant on “Baby Fae” at Loma Linda University Medical Center in California—a case that captured news headlines around the world.

This historical retrospective traces the history of cardiac xenotransplantation and the controversies associated with previous attempts at human trials, while providing insight into new opportunities for this revolutionary and potentially lifesaving therapy.

The Greek myth  Daedalus and  Icarus is one of the first recorded instances of xenotransplantation.

From Ancient Greece to the 20th Century

Xenotransplantation, from the Greek “xénos” (foreign, guest, strange), refers to the transplantation of tissues across species barriers. The first successful clinical xenotransplant in ancient legend was performed by Daedalus, who grafted bird feathers onto his arms to escape by flight from Crete to Athens. The first xenograft failure was noted in Daedalus’s son Icarus, who developed hyperacute graft rejection due to a thermolabile reaction. 1

Later attempts at clinical xenotransplantation began in the early 20th century, when advances in the understanding of physiology led to new interest in renal xenografts. In 1906, Mathieu Jaboulay, a professor of clinical surgery in Lyon, France, attempted two heterotopic renal xenografts from a sheep and goat; both grafts failed due to hyperacute rejection with vascular thrombosis.

In 1910, Ernst Unger, a German physician and surgeon, performed a renal xenotransplant from a nonhuman primate to human, which similarly failed after 32 hours due to vascular thrombosis. 1 In 1923, Harold Neuhof, a pioneer of thoracic surgery, performed a renal sheep-to-human xenotransplant at Mt. Sinai Hospital in New York City. This xenograft survived for 9 days and represented a leap forward in xenograft survival.

Dr. Neuhof later wrote: “[This case] proves, however, that a heterografted kidney in a human being does not necessarily become gangrenous and the procedure is, therefore, not necessarily a dangerous one, as had been supposed. It also demonstrates that thrombosis or hemorrhage at the anastomosis is not inevitable. I believe that this case report should turn attention anew.” 2 Dr. Neuhof was a founding member of the American Board of Surgery in 1937.

The next attempts at renal xenotransplantation followed the development of renal replacement therapy by hemodialysis in the 1940s and 50s. While hemodialysis treatment showed exciting promise at sustaining life, the relative shortage of dialysis machines led to new innovations in renal replacement. In 1964, Keith Reemtsma, MD, a surgeon at Tulane University in New Orleans, Louisiana, published reports of 13 chimpanzee-to-human xenotransplants. While most grafts survived 4-to-6 weeks, one of these xenografts survived for more than 9 months and allowed its recipient to return to activities of daily life, including work as a schoolteacher. 3

Also in 1964, Thomas E. Starzl, MD, PhD, FACS, published a report of six baboon-to-human renal xenotransplants with varying success, as well as heterotopic auxiliary liver xenografts. 4,5 Dr. Starzl would pioneer human liver transplantation in 1967, and later the use of cyclosporine and tacrolimus.

Dr. James Hardy

From First to Fae (1964–1984)

“We should solve the problem [of organ transplantation] by using heterografts [xenografts] one day if we try hard enough, and maybe in less than 15 years.” —Sir Peter Medawar, Nobel Prize-winning immunologist, 1969 1

The first human heart transplant was a xenotransplant using a chimpanzee heart performed on 68-year-old Boyd Rush on January 23, 1964, by Dr. Hardy at the University of Mississippi in Jackson. After completing his medical education at the University of Pennsylvania in 1942, Dr. Hardy was later recruited to become the inaugural chair of surgery at the University of Mississippi in 1955. There, he focused the department’s efforts on organ transplantation. This was a reasonably attainable goal, as this area was still an emerging field and the new department could readily compete with more established surgical departments. He also was able to use expertise from Dr. Reemtsma’s transplant laboratory in nearby New Orleans. 

Just a few days before the xenotransplant, Rush experienced a presumed myocardial infarction and was transferred to the University of Mississippi. Over the subsequent days, Rush developed progressive cardiac failure.

At the time, Dr. Hardy was considering performing a human-to-human heart transplant, using the heart of a neurologically devastated trauma patient who was in Mississippi’s intensive care unit, but the potential donor’s heart was still beating (in an era before clinical brain death).

Rush developed fulminant cardiac failure on the night of January 23 and was taken emergently to the OR for cardiopulmonary bypass as salvage therapy. Rush’s sister signed an informed consent form that stated “any heart transplant would represent the initial transplant in man,” though it did not state the heart to be used was from a nonhuman primate. The orthotopic chimpanzee heart functioned for 60-90 minutes following transplant, but Rush was unable to be weaned from bypass and died.

The University of Mississippi’s director of public information released a guarded statement on the priority of this first human heart transplant that included the vague phrase "the dimensions of the only available donor heart" and did not disclose that the donor heart came from a chimpanzee. The Associated Press widely distributed a story that began with, "Surgeons took the heart from a dead man, revived it, and transplanted it into the chest of a man dying of heart failure today," failing to recognize the use of a nonhuman primate as the donor. Dr. Hardy would publish this case report in The Journal of the American Medical Association ( JAMA ) later that same year. 6

Dr. Hardy’s career as a pioneering cardiothoracic transplant surgeon is remarkable, as he also performed the first human lung transplant in 1963, using a human donor. Dr. Hardy served as the President of the ACS from 1980 to 1981.

In 1968, Dr. Ross performed a heterotopic pig-to-human cardiac xenotransplant at the National Heart Hospital in London. This xenograft survived less than 5 minutes due to hyperacute rejection. Dr. Ross is best known for developing the pulmonary valve autograft to replace a failing aortic valve in 1967, now known as the eponymous Ross procedure, as well as performing the UK’s first human cardiac allotransplant in 1968.

Also in 1968, Dr. Cooley performed an orthotopic sheep-to-human cardiac xenotransplant at the Texas Heart Institute in Houston. 7 This xenograft also survived only a few minutes due to hyperacute rejection.

Dr. Cooley is perhaps the most famous American cardiac surgeon to date, with a long list of accolades and “firsts” in cardiac surgery. As a resident, he assisted Alfred Blalock, MD, FACS, in his first subclavian-pulmonary arterial shunt in 1944 (now the eponymous Blalock-Thomas-Taussig shunt). He founded the Texas Heart Institute in 1962 and was the first to implant a total artificial heart in 1969.

In 1977, Christiaan Barnard, a surgeon in South Africa, performed two clinical xenotransplant procedures using hearts from nonhuman primates at the University of Cape Town. 8 These procedures were unique, as they were heterotopic xenotransplants that were used as a ventricular-support bridge to supplement circulation in two patients who were unable to be weaned from cardiopulmonary bypass. The two xenografts were taken from a chimpanzee and baboon, which functioned for 5 hours and 4 days, respectively. Dr. Barnard is best known for performing the first successful human cardiac allotransplant in 1967.

The next attempt at cardiac xenotransplantation would not come for several years. In 1984, Dr. Bailey performed a baboon-to-human orthotopic heart transplant into an infant at Loma Linda Medical Center. The patient, Stephanie Fae Beauclair, was born prematurely with hypoplastic left heart syndrome.

At the time, there had never been an attempt at heart transplantation of any kind in an infant. Intended as a bridge to allotransplant, “Baby Fae” underwent this procedure on October 26, 1984, at 12 days old due to progressive instability and fulminant cardiac failure with her native heart.

The xenotransplant was performed using cyclosporine immunosuppression across an ABO-incompatible immune barrier using an AB-type baboon donor into the O-type recipient (as the O blood type is nonexistent in baboons).

This procedure and its potential for success captivated the nation, even making the cover of Time magazine in an article “Baby Fae Stuns the World.” 9 Baby Fae lived for 20 days post-transplant before dying from complications of acute graft rejection.

The Time article revealed some of the sharp divisions regarding xenotransplantation within the surgical community. In the article, John Najarian, MD—chair of surgery at the University of Minnesota and pioneer in the use of antithymocyte globulin for use in transplantation—remarked: “There has never been a successful cross-species transplantation. To try it now is merely to prolong the dying process. I think Baby Fae is going to reject her heart.” 9

John J. Collins Jr., MD, chief of the Division of Cardiac Surgery from 1970 to 1987 at Brigham and Women’s Hospital in Boston, Massachusetts, said: “It’s easy to sit back and be negative when a new treatment is announced. If we all were afraid to attempt the untried, we would have no new treatments.” 9 The transplant also sparked new questions regarding the ethics of laboratory animals used for medical research.

Thirteen months after the transplant, JAMA published three articles on the Baby Fae xenotransplant. The first was a detailed scientific paper authored by Dr. Bailey “describing the first case of cardiac xenotransplantation in a neonate.” 10 The second, “Informed Consent and Baby Fae” noted “there has been great public concern about the ethical problems involved in the highly experimental surgery” and ethics of parents deciding experimental cures for their children. The third was an editorial and medical review, which concluded that the transplantation was doomed to fail and that hopes for a successful transplant by Dr. Bailey were “wishful thinking.”

Despite the controversies surrounding Baby Fae’s transplant, Dr. Bailey persisted and would perform the first human cardiac allotransplant in an infant the following year.

Modern Cardiac Xenotransplant and the “Holy Grail”

Xenotransplantation “is just around the corner, but it   may be a very long corner.”   — Sir Roy Calne, organ transplantation pioneer, 1995

Following the Baby Fae xenograft, it would be nearly 40 years before the next attempt at clinical xenotransplantation. On January 7, 2022, Bartley P. Griffith, MD, FACS, and colleagues at the University of Maryland (UM) in Baltimore, performed a life-sustaining orthotopic pig-to-human cardiac xenotransplant into a 57-year-old man using a genetically modified pig donor and novel immunosuppression medications. 11-13 This graft sustained function for 60 days before failing due to diffuse endothelial injury and immune activation. 14 Dr. Griffith and his team then performed a second orthotopic cardiac xenotransplant into a 58-year-old man on September 20, 2023, using a similar protocol. The second transplant functioned for 40 days until it failed due to xenograft rejection. 15 Both xenotransplant recipients were unable to receive clinically available advanced heart failure therapies due to other comorbidities.

Several preclinical breakthroughs have paved the way for the use of xenografts in clinical application. Novel immunosuppressive medications developed to target the costimulation pathway CD40-CD40L have been established in preclinical studies to be superior to clinically available immunosuppression agents like tacrolimus.

Advances in genetic engineering have allowed modification of the porcine donor using transcription activator—like effector nucleases and somatic cell transfer using CRISPR/Cas9 to prevent xenograft rejection. This genetically modified pig included deletion of porcine-specific cell-surface carbohydrates (alpha-1,3-Gal, Beta-4-Gal, and Neu5Gc), deletion of intrinsic growth factor (GHR) and the addition of several human genes that modulate complement regulation (CD46, CD55), anticoagulation (EPCR, thrombomodulin), and innate anti-inflammatory (CD47, HO-1) signaling. 12 Along with improvements in cardiac intensive care and extracorporeal circulatory support to mitigate perioperative early heart dysfunction, these new innovations have re-invigorated the interest in cardiac xenotransplantation.

Cardiac Xenotransplant: Ready for Primetime?

“Xenotransplantation is the future of transplantation, and always will be.” —Norman E. Shumway, MD, PhD, a cardiac surgeon who performed first heart transplant in US 1

Several barriers still exist before xenotransplantation can be considered a clinically available therapy for patients with end-stage heart failure. Overcoming the remaining immunologic, physiologic, infectious, social, ethical, and regulatory hurdles to xenotransplantation while ensuring foremost patient safety and patient outcomes remains paramount. 7

Lingering questions include the optimal organ for xenotransplantation trials, recipient functional status, xeno donor, and immunosuppressive regimen to best support the patient post-transplantation. Looking further into the future, advances in tissue engineering and biomechanical engineering may allow for a more tolerogenic or even autologous synthetic organ.

The history of cardiac xenotransplantation is rich with immunologic and technical innovations, as well as courageous patients and compassionate surgeons. Many of the preeminent cardiac surgeons, including Drs. Hardy, Ross, Barnard, Bailey, and Griffith, have built upon years of knowledge and study to pioneer this revolutionary therapy to improve patient care.

Dr. Brendan Lovasik is a clinical fellow in transplant surgery at Washington University in St. Louis, Missouri.

• Cooper DKC, Ekser B, Tector AJ. A brief history of clinical xenotransplantation. Int J Surg. 2015;23(Pt B):205-210.
• Neuhof H. The Transplantation of Tissues. Appleton and Company; 1923:297.
• Reemtsma K, McCracken BH, Schlegel JU, et al. Renal heterotransplantation in man. Ann Surg. 1964;160(3):384-410.
• Starzl TE, Marchioro TL, Faris TD, McCardle RJ, et al Avenues of future research in homotransplantation of the liver with particular reference to hepatic supportive procedures, antilymphocyte serum, and tissue typing. Am J Surg. Sep 1966;112(3):391-400.

Starzl TE, Marchioro TL, Peters GN, et al. Renal heterotransplantation from baboon to man: Experience with 6 cases. Transplantation . 1964;2:752-776.

Hardy JD, Kurrus FD, Chavez CM, et al. Heart transplantation in man. Developmental studies and report of a case. JAMA . 1964;188(13):1132-1140.

• Boulet J, Cunningham JW, Mehra MR. Cardiac xenotransplantation: Challenges, evolution, and advances. JACC Basic Transl Sci. 2022;7(7):716-729.
• Barnard CN, Wolpowitz A, Losman JG. Heterotopic cardiac transplantation with a xenograft for assistance of the left heart in cardiogenic shock after cardiopulmonary bypass. S Afr Med J. 1977;52(26):1035-1038.

Wallis C, Holmes S. Baby Fae stuns the world. Time . Nov 12, 1984;124(20):70-72.

Bailey LL, Nehlsen-Cannarella SL, Concepcion W, Jolley WB. Baboon-to-human cardiac xenotransplantation in a neonate. JAMA . 1985;254(23):3321-3329.

• American College of Surgeons. ACS Fellow performs first successful pig-to-human heart transplant. Bull Am Coll Surg. February 4, 2022. Available at: https://bulletin.facs.org/2022/02/acs-fellow-performs-first-successful-pig-to-human-heart-transplant/. Accessed January 4, 2024.
• Griffith BP, Goerlich CE, Singh AK, et al. Genetically modified porcine-to-human cardiac xenotransplantation. N Engl J Med. 2022;387(1):35-44.
• Peregrin T. Dr. Bartley P. Griffith discusses landmark pig heart transplant. American College of Surgeons. Bull Am Coll Surg. June 2022. Available at: https://www.facs.org/for-medical-professionals/news-publications/news-and-articles/bulletin/june-2022-volume-107-number-6/dr-bartley-p-griffith-discusses-landmark-pig-heart-transplant/. Accessed January 4, 2024.

Mohiuddin MM, Singh AK, Scobie L, et al. Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report. Lancet . 2023;402(10399):397-410.

• Rabin RC. Second Maryland man to receive altered pig’s heart dies. New York Times. October 31, 2023. Available at: https://www.nytimes.com/2023/10/31/health/pig-heart-transplant-faucette.html. Accessed January 4, 2024.

Related Pages

In the House of Surgery, Pediatrics Is in Every Room

Learn more about the ACS’s commitment to improving pediatric surgical care, and opportunities for pediatric surgeons to engage with the College.

Surgeons Are Humanizing the Esophagectomy

Discover how technical adaptations to the esophagectomy and a team approach to perioperative care improve outcomes and reduce complications.

Understanding the Pandemic's Long-Term Effects on Cancer Care

Gain insights into new research demonstrating how the pandemic disrupted cancer care and data reporting.

Grave Robbing, Cadaver Acquisition Evolve from Cemetery to Classroom

Learn how an increased focus on human anatomy in the 19th century led to a greater demand for cadavers, sometimes obtained via grave robbers.

For Surgeons, Music Augments Relaxation, Improvisation, and Flow

Hear from four surgeon-musicians on how music can affect work conducted both in and out of the OR.

Women Build Bonds and Break Ceilings to Redefine Leadership in Cardiothoracic Surgery

Learn how current surgeon leaders can support women surgeons in the future through mentorship, leadership training, and more.

"Blood Deserts" Face the Burden of Global Blood Deficits

Learn how creative, community-based solutions are meeting the challenges presented by the global blood deficit.

Visionary Gift Supports UR Chief Residents’ Attendance at Clinical Congress

Get inspired by Dr. Peacock’s goal of supporting future UR chief residents’ educational and networking opportunities at Clinical Congress.

ACS Toolkit Provides Must-Have Surgical Patient Education Content

Learn about the ACS Patient Education Toolkit, a digital point-of-care surgical education resource that comes in two editions: provider and hospital.

Top 10 Most Read Bulletin Articles in 2023

Discover which articles published in the ACS Bulletin were the most popular with your surgeon colleagues in 2023.

Top JACS Articles in 2023 Unveil Pulse of Surgical Progress

Click on the most cited and most read articles published in 2023 by the Journal of the American College of Surgeons.

Member News, February 2024

Learn more about ACS members who have been recognized for noteworthy achievements.

Subscribe or Renew

Create an E-mail Alert for This Article

Genetically modified porcine-to-human cardiac xenotransplantation, permissions, information & authors, metrics & citations, view options.

Expanded-Access Investigational New Drug Application and Ethics Approvals

Genetically engineered pig source animal, immunosuppression and monitoring, xenozoonosis mitigation strategies and surveillance, viral screening, early postoperative period.

Peritonitis and Feeding Issues

Immunosuppression and infection prophylaxis, endomyocardial biopsy.

Evidence of Infection

Failure of the xenograft, supplementary material, information, published in, translation.

• Cardiology General
• Ethical and Legal Issues
• Gene Editing
• Genetics General
• Heart Transplantation
• Infectious Disease General
• Research Ethics
• Transplantation

Affiliations

Export citation.

Select the format you want to export the citation of this publication.

• Hina Jhelum,
• Vasileios Papatsiros,
• Georgios Papakonstantinou,
• Ludwig Krabben,
• Benedikt Kaufer,
• Joachim Denner,
• Uwe Fiebig,
• Luise Krüger,
• Nikolaos Chrysakis,
• Dimitrios E. Magouliotis,
• Kyriakos Spiliopoulos,
• Thanos Athanasiou,
• Alexandros Briasoulis,
• Filippos Triposkiadis,
• John Skoularigis,
• Andrew Xanthopoulos,
• Rachel L. Washburn,
• David K. C. Cooper,
• Emanuele Cozzi,
• Wayne J. Hawthorne,
• Daniel L. Eisenson,
• Hayato Iwase,
• Weili Chen,
• Yu Hisadome,
• Wanxing Cui,
• Michelle R. Santillan,
• Alexander C. Schulick,
• Amanda Maxwell,
• Kristy Koenig,
• Zhaoli Sun,
• Daniel Warren,
• Kazuhiko Yamada,
• Mengyu Gao,
• XingLong Zhu,
• WanLiu Peng,
• YanYan Zhou,
• Guangneng Liao,
• Jiayin Yang,
• Guang Yang,
• Atsushi Harada,
• Naoto Matsumoto,
• Yoshitaka Kinoshita,
• Kenji Matsu,
• Yuka Inage,
• Keita Morimoto,
• Shuichiro Yamanaka,
• Masashi Kurobe,
• Takashi Yokoo,
• Haruki Kume,
• Takao Ohki,
• Eiji Kobayashi,
• Clésio Gomes Mariano Junior,
• Vanessa Cristina de Oliveira,
• Carlos Eduardo Ambrósio,

View options

Content link.

Copying failed.

PREVIOUS ARTICLE

Next article, more from vol. 387 no. 1.

• Original Article
• Jul 07, 2022

Effects of Previous Infection and Vaccination on Symptomatic Omicron Infections

Trastuzumab deruxtecan in previously treated her2-low advanced breast cancer.

• Review Article

The Vaccine-Hesitant Moment

Masks Strongly Recommended but Not Required in Maryland

Respiratory viruses continue to circulate in Maryland, so masking remains strongly recommended when you visit Johns Hopkins Medicine clinical locations in Maryland. To protect your loved one, please do not visit if you are sick or have a COVID-19 positive test result. Get more resources on masking and COVID-19 precautions .

• Vaccines  
• Masking Guidelines
• Visitor Guidelines  

Johns Hopkins Medicine to Receive $21.4 Million to Advance Viability of Animal Organs for Transplants and Enable Human Clinical Trials

Goal of $21.4 M in research funding to @HopkinsMedicine @hopkinssurgery: preclinical studies needed to advance to successful #xenotransplantation (animal organs into humans) & reduce transplant organ shortages. #DrKazuhikoYamada @AndrewMCameron ›

As part of the worldwide effort to facilitate a research and clinical pathway toward successful xenotransplantation — the transplantation of living cells, tissues and organs from one species to another — two Johns Hopkins Medicine surgeons, Kazuhiko Yamada, M.D., Ph.D. , and Andrew Cameron, M.D., Ph.D. , will receive a total of $21.4 million in funding over the next two years under two sponsored research agreements with biotechnology company United Therapeutics Corporation. The company focuses on developing novel pharmaceutical therapies and technologies that expand the availability of transplantable organs.

The agreements announced today will support preclinical studies (animal and laboratory), conducted in collaboration with United Therapeutics, to advance the use of genetically modified pigs — whose kidneys are more compatible for transplantation into humans than non-modified animals — enabling a reduced risk of immune system attack, better avoidance of organ rejection and failure, and increased chances for a recipient’s long-term survival with the xenograft.

“We are tremendously excited about what we will learn through this new research endeavor at Johns Hopkins Medicine,” says Cameron, surgeon-in-chief and director of the Department of Surgery at the Johns Hopkins University School of Medicine. “Although we have a highly successful kidney transplant program, we’ve been limited — like other medical institutions — by the shortage of available human donor organs. Hopefully, xenotransplantation will soon be able to join other strong efforts at Johns Hopkins to address this challenge, such as our nondirected [altruistic] and directed [designated recipient] living donor programs.”

End-stage kidney disease, a condition that without treatment results in kidney failure and death, can only be remedied by dialysis (mechanically filtering wastes from the blood when the kidneys cannot) or transplantation of a working organ from either a deceased or living donor. Unfortunately, according to the federal government’s Organ Procurement and Transplantation Network , the number of people needing a kidney far exceeds the number of available organs. For example, the website states that in 2022, there were some 96,000 patients on waiting lists for a kidney, but only about 25,500 transplants were performed.

Annually in the United States, the number of usable organs for transplantation remains extremely low, and according to the federal organdonor.gov website, 17 people die each day simply because they cannot get a transplantable human organ.

Researchers worldwide have investigated the use of pig organs — primarily hearts and kidneys — for decades as potential options for xenotransplantation in humans because of similarities between the two species in how their organs function. The U.S. Food and Drug Administration (FDA) has not yet approved such transplants for clinical use, but has on rare occasions permitted “compassionate use” exceptions.

“Over the next two years, our research team hopes to improve the strategies and techniques that have made genetically modified pig kidneys for transplantation so promising to this point, and then take them to the level where human clinical trials can begin,” says Yamada, professor of surgery at the Johns Hopkins University

School of Medicine. “Then, hopefully, we can finally realize that promise.”

Yamada, recruited in August 2022 to lead Johns Hopkins Medicine’s growing xenotransplantation research program, is considered a pioneer in the field. In 2003, he performed the first pig-to-primate kidney xenotransplant using genetically modified alpha-gal knockout (or GaIT-KO) pig kidneys.

Alpha-gal sugar is a compound on cell surfaces that stimulates the immune system, and it is believed to be a trigger of transplant rejection in humans. GalT-KO pigs are modified so that they lack the gene that produces alpha-gal sugar. This modification — known as a gene “knockout” — makes their tissues and organs more likely to be accepted.

“Under the new research agreements,” Yamada says, “we will study the impact on xenotransplantation of knockouts, as well as ‘knocking in’ [adding] human genes that could help prevent rejection.”

A second approach to be studied under the new agreements is to “teach” the human immune system to recognize the donated pig organ as “self.” This involves a technique pioneered by Yamada — concurrently transplanting a pig kidney with thymus tissue from the same animal donor.

“By transplanting pig thymus tissue along with the donor kidney, the immune response of the recipient is reduced, prolonging the viability of the organ, and with less need for medical immunosuppression,” says Yamada.

• Health Tech
• Health Insurance
• Medical Devices
• Gene Therapy
• Neuroscience
• H5N1 Bird Flu
• Health Disparities
• Infectious Disease
• Mental Health
• Cardiovascular Disease
• Chronic Disease
• Alzheimer's
• Coercive Care
• The Obesity Revolution
• The War on Recovery
• Adam Feuerstein
• Matthew Herper
• Jennifer Adaeze Okwerekwu
• Ed Silverman
• CRISPR Tracker
• Breakthrough Device Tracker
• Generative AI Tracker
• Obesity Drug Tracker
• 2024 STAT Summit
• All Summits
• STATUS List
• STAT Madness
• STAT Brand Studio

Don't miss out

Subscribe to STAT+ today, for the best life sciences journalism in the industry

After a flurry of firsts, xenotransplantation is suddenly back in the spotlight

By Megan Molteni Jan. 20, 2022

I n his more than 30 years as a surgeon, Robert Montgomery has transplanted hundreds of kidneys. But at four in the morning September 25, the director of NYU Langone’s Transplant Institute performed one unlike any he’d ever done before. The kidney — six inches long, bean-shaped, and pale pink — was excised overnight from a genetically engineered pig, and flown into New York by private plane and helicopter from hundreds of miles away. The “patient,” lying face-up on the operating table, had died the day before. Machines now kept her body in a state of suspended animation, long enough to undergo the two-hour procedure to attach the organ to blood vessels in the woman’s leg, and to study what happened after.

It was the first of a flurry of firsts over the last few months that have suddenly drawn attention to the niche field of xenotransplantation and its potential to solve the shortage of donated human organs.

advertisement

Five days later, Jayme Locke, a surgeon who had trained under Montgomery, went one step further. Her team at the University of Alabama at Birmingham put two kidneys from a different herd of designer pigs into a man who had recently passed away. This time, they swapped his organs for the porcine ones, took off the clamps, and held their breaths. The man’s brain-dead body could still mount an immune attack. And if it did, blue splotches would begin to appear on the kidneys as clots would cripple it from the inside out, turning it to a hard black mass within minutes.

Instead, they turned pink. Within 20 minutes, one of them was peeing. “It was exhilarating to say the least,” Locke told STAT this week.

The world first learned of the NYU operation last October, when it was reported by USA Today . Locke’s team waited for a peer-review of their own experiment, the results of which were published Thursday in the American Journal of Transplantation. In the meantime, Montgomery’s team performed a second kidney attachment to a brain-dead human, and a third team at the University of Maryland Medical Center transplanted a genetically engineered pig heart into a living patient . The 57-year-old man is recovering and doing well nearly two weeks out from the groundbreaking procedure, one of his doctors said.

Xenotransplantation — putting animal organs into humans — is a centuries’ old idea that has been revived at multiple times throughout history as technological advances offer new hope of overcoming what has seemed like a never-ending parade of scientific hurdles. Norman Shumway, the pioneering Stanford surgeon considered the father of heart transplantation famously said that “xenotransplantation is the future, and always will be.”

For decades, that has certainly seemed to be the case. The field has long been stuck in the preclinical stage — testing organs in baboons and chimpanzees. But the gap is closing. And while it’s still too early to say exactly what new scientific knowledge has been gained, these recent experiments are generating new excitement for the possibility of an unlimited supply of organs that could relieve a supply shortage that leads to about 6,000 deaths each year in the U.S. alone. Now the race is on to build the sorts of biosecure facilities regulators are requiring for the pig organs to be tested in humans.

M illions of years of divergent evolution have made the human body a pretty inhospitable place for an organ grown inside a pig. When you transplant one into the other, a cascade of defensive maneuvers ensues. Anyone wishing to succeed at xenotransplantation has to come up with strategies for blocking or sidestepping them.

The first and most dangerous hurdle is hyperacute rejection. Within the first minutes to the first hours, human antibodies swarm over the new organ, glomming onto foreign sugars and other cell-surface proteins and triggering inflammation. This summons platelets, a type of blood cell that begins to form clots, hindering blood flow to the organ. Pig heart valves, which have become a stopgap in recent years, avoid these problems through a chemical processing step that removes immunogenic pig proteins (but also renders the tissue rigid, making it not suitable for whole organs).

The modern era of xenotransplantation dates back to the early 1960s, when surgeons at Tulane University transplanted 13 chimpanzee kidneys into humans and another team at the University of Colorado tried the procedure six times with baboon kidneys. Back then, the main tool available to these doctors were primitive immunosuppressive drugs. Only one patient survived for more than a few months; the others died either of rejection or infections.

Sign up for Daily Recap

A roundup of STAT's top stories of the day.

It became clear that more nuanced methods were needed. They arrived in the ‘90s with the first generation of genetic engineering tools. Money and interest flowed into the field. One company even received approval from the Food and Drug Administration for clinical trials of pig livers altered to carry a handful of human genes. Then, a hiccup.

Pigs carry a number of viruses believed at the time to only transmit between members of their own species. These porcine endogenous retroviruses, or PERVs, embed copies of themselves in the DNA of pig cells, making them impossible to eradicate. In 1997, researchers in London discovered that PERVs could jump into human cells in culture. Later that year, the FDA put a halt on all xenotransplantation trials until researchers could prove that they had developed procedures for preventing PERV infection in human subjects. Although the moratorium was lifted the following year, the agency remained skittish, and commercial efforts sputtered out.

In the early 2000s, David Ayares, then COO of a Scottish company called PPL Therapeutics, used recombinant DNA technology and cloning to create pigs as a source of solid organs. The company had made one very important change to its animals’ DNA, disrupting a gene that made a cell-surface sugar called alpha-Gal.

The same sugar studs the cells of bacteria that live in the human gut. So our immune systems have evolved strong defenses for keeping them there, and not allowing infections to spread into our blood. These defenses are so strong, scientists realized, that almost 1% of all the antibodies we make are meant to recognize alpha-Gal — an order of magnitude greater than any other immune target. PPL Therapeutics spun out Revivicor as a standalone company to pursue xenotransplantation.

Related: First transplant of a genetically altered pig heart into a person sparks ethics questions

And for almost a decade, Revivicor was the only commercial outfit in the hunt. Then came the invention of even more precise gene editing tools like CRISPR. Paired with knowledge gleaned over decades from scientists studying the mechanisms the immune system uses to detect foreign invaders, these tools could be used to hoodwink it into regarding the pig as something more akin to a friendly tourist.

They could also be used to deal with that other pesky problem: PERVs. In 2015, Harvard University biologist George Church and members of his lab used CRISPR to snip out all traces of the viruses and make PERV-free piglets . They founded a company called eGenesis to further develop the technology. Organs from their animals are now being tested in monkeys at Duke University and Massachusetts General Hospital.

“When I first started, I thought I’d arrived just late enough for it not to be exciting,” said Joseph Tector, a clinical transplant surgeon at the University of Miami who for three decades has been pursuing xenotransplantation. “Then I thought, not only are we going to be there, but we might be there by ourselves. Now, all of a sudden it’s a race.”

In 2015, while at Indiana University, the surgeon-scientist made a triple-knockout pig that removed not just alpha-Gal, but two other immune-inflaming pig antigens. The changes made it possible to keep primates alive a year after receiving the modified kidneys. A company he co-founded called Makana, and which merged with genome engineering firm Recombinetics in 2020, is now working to test kidneys from those animals in humans.

Makana’s flashier competitors are betting that more editing will yield even better results. In 2020, scientists at eGenesis reported creating pigs carrying the triple knockout plus nine human genes that code for immune-dampening molecules. Revivicor has added six such transgenes and an additional knockout in a porcine growth hormone receptor gene, aimed at preventing organs from getting too big for their human recipients. It’s this “ten-gene” pig that Locke’s team in Alabama used in its kidney experiment and the Maryland group used for its heart transplant.

But there’s still  debate over how many changes are really necessary to achieve long-lasting xenotransplants. And some researchers say overengineering the animals can make it harder to produce consistent organs, which is something regulators are likely to consider when deciding what to greenlight for human testing. “The science of adding genes isn’t as advanced as the science of deleting things,” said Tector.

Montgomery told STAT that’s one reason he’s taking a “less is more” approach, using Revivicor’s original single-edit pig. Trademarked under the name “GalSafe,” these pigs were approved by the FDA for consumption and some biomedical research in late 2020.

Scientists won’t know which approach works best in humans until, well, they try xenotransplantation in humans. But according to Montgomery, momentum toward starting clinical trials, has picked up in recent months. “For a long time, t here was a lack of forward inertia. Now we have it,” he said. “Even the skeptics are coming around.”

X enotransplantation requires expertise from across many fields. You need genetic engineers to design pigs whose cells won’t trip a human’s immune’s system; animal scientists who understand the peculiarities of livestock species to raise them; immunologists to build tests that can predict if a patient will reject a pig organ and develop drugs to prevent that from happening over the long term; infectious disease experts to minimize the risks of pig viruses spilling over into human patients; and finally, a surgical team to do all the actual slicing and clipping and stitching. And one more thing: a decidedly non-sty-like home for the pigs.

“The hurdle now facing every group is building facilities to produce a pig that’s suitable for clinical transplantation,” Megan Sykes, a surgeon and immunologist at Columbia University told STAT. She was referring to a designated pathogen-free pig facility — a hermetically sealed building ventilated and pressurized to keep out bacteria, viruses, and fungi — the kind of place in which the FDA says any pigs destined to be human organ donors must be raised. “It’s a major undertaking,” said Sykes.

The University of Alabama at Birmingham began building theirs back in 2016, as part of a large grant it received from United Therapeutics, the pharmaceutical firm that acquired Revivicor in 2011. According to financial filings, the facility was federally certified in March of last year, and when Locke performed the kidney xenotransplant into a deceased individual last September, the organs came from an animal raised right there on the campus. “We wanted to make sure that we had documentation of that pig’s disease status throughout the course of its life,” said Locke. “And we were able to show that the transplant recipient did not have PERV-C, which is the one that people worry about being able to cause disease in humans. Those were important milestones for us as we think about how we are going to scale this up.”

STAT+: Exclusive analysis of biopharma, health policy, and the life sciences.

Locke said her UAB team is now working on breeding pigs so that they can build up the herd to support a clinical trial, which she’s hopeful they could start as soon as the end of this year. “If everything goes off without a hitch and we can start Phase 1 later this year, then in theory the earliest we could be ready to offer this to the masses would be five years from now.”

Their first effort had mixed results. The kidneys weren’t immediately rejected. But they also didn’t work very well. The one that produced urine didn’t successfully filter out creatinine — a critical waste product. And the other one didn’t produce urine at all. Locke said she suspected it had to do with the fact that the recipient had been brain-dead for five days before the procedure.

“Brain death causes all sorts of pathological conditions in the body,” said David Cooper, a xenotransplantation researcher at Harvard Medical School’s Center for Transplant Sciences. “By day three this person was bleeding to death, essentially, as a consequence of an inflammatory response. We don’t know if that was because of the brain-death or the pig graft, so the results are very difficult to interpret.”

On the other hand, at least there’s data to analyze. The results from the two xenotransplants performed at NYU Langone have not yet been published. Montgomery told STAT they are currently going through peer review. As his group waits for publication, he’s planning another study, also with recently deceased individuals. It will also be with kidneys from Revivicor GalSafe pigs, but this time they intend to keep the bodies on life support longer to try to understand what happens two to four weeks post-transplantation.

Related: Creating Pig3.0, the world’s most CRISPR’d animal, raises hopes of transplantable organs

“We know from the primate work that this is a critical time,” said Montgomery. In studies of monkeys, about half of the animals do just fine and half start to have problems, often fatal ones, he said. “Right now, no one fully understands that, so we think the additional information we might be able to get out of longer studies of the recently deceased would be very convincing to the regulators that this is ready for prime time.”

Sykes isn’t so sure there’s much to be gained from putting pig organs in brain-dead people. “I would describe them as small steps,” she said of the NYU Langone and University of Alabama at Birmingham experiments. Scientifically, they merely confirm what many studies in monkeys would have predicted, she said. Where their impact may have far wider implications is in making cross-species organ donation go mainstream. “The bigger impact is that it’s gotten the world accustomed to the notion that xenotransplantation is a real thing that’s going to be tried soon, and I think that’s a very positive outcome.”

She’s more excited about the transplant performed at the University of Maryland Medical Center earlier this month, in which a man received a heart from a “10-gene” pig. That effort was led by Muhammad Mohiuddin, who is best known for pioneering a 2016 trial in which his team kept baboons with transplanted pig hearts alive for over a year with a unique cocktail of immunosuppressants. One lived 945 days, a record. The next year he moved from the National Institutes of Health to start a cardiac xenotransplantation program there in Maryland as part of another United Therapeutics-funded project.

He told STAT this week that his team had approached the FDA about starting a human trial last year, and they were told they needed to show more consistently that they could keep a large group of primates alive for at least six months. They are in the process of running that study now. But in the meantime, they sought and received a one-time permission to try the procedure in a critically ill patient who wasn’t eligible for a human organ.

“I’ve been in this field for 30 years and I could not have imagined that this would happen in my lifetime,” said Mohiuddin. “Every time we’ve come close we’ve seen another problem pop up, like peeling the layer off an onion. “But now it’s like a dream-come-true moment.”

For now, both the Maryland and NYU teams have been getting their organs from Revivicor, which has a farm in Blacksburg, Va, and a herd of GalSafe pigs at a facility in Iowa. Mohiuddin told STAT that the company is building its own pathogen-free facility to supply organs for clinical trials.

Montgomery read about the Maryland team’s success with a particularly personal jolt of joy. He inherited a progressive genetic heart disorder, one that killed his father and an older brother. In 2018, he received a heart transplant of his own. “My stake in this is a little different,” he told STAT. “I really want to see this move forward so that my family has different options than I had and 6,000 people don’t have to die every year waiting for an organ.”

Cooper, who is an advisor to eGenesis, told STAT that the company not having a pathogen-free facility was holding up efforts to move forward into human testing. “I think we have reached the end of the road as far as animals go; we’ve done almost as much as we can possibly do,” he said. “We have the right pigs, very potent immunosuppressive drugs, and if we choose the right patient I think we have every chance of success. The one thing we need … is this clean facility.”

After this story published, a spokesperson for eGenesis told STAT via email that the company has secured an established biosecure animal facility in the Midwest from which it intends to supply pig organs—likely starting with the kidney—for human trials.

This story has been updated to include comment from eGenesis.

About the Author Reprints

Megan molteni.

Science Writer

Megan Molteni reports on discoveries from the frontiers of genomic medicine, neuroscience, and reproductive tech. She joined STAT in 2021 after covering health and science at WIRED.

To submit a correction request, please visit our Contact Us page .

Recommended

Recommended Stories

STAT Plus: Amgen scores late-stage trial success for eczema and myasthenia gravis treatments, but faces stiff competition

STAT Plus: Baltimore claims Biogen ‘bribed’ PBMs to favor its pricey MS drug over generics

STAT Plus: Q&A: How scientists aim to kill cancers by starving them

STAT Plus: Electronic health records giant Epic Systems sued over alleged monopolistic practices

STAT Plus: Genentech, a biotech with a storied past, confronts new turbulence in the present

Pig Kidneys in Humans? Xenotransplantation Explained

June 14, 2022

We dedicate this to the Parson Family, who made the selfless decision to delay their grieving and allow the doctors at the University of Alabama to maintain Jim Parsons' body functioning on a ventilator so this scientific and medical breakthrough could be possible.

Science has come a long way in extending life for kidney patients. Is transplantation between humans and animals the next step? In this episode of Hot Topics, Jayme Locke, MD, MPH, the lead doctor and surgeon behind the first successful transplant of a human receiving a pig kidney, answers this question and more.

What is xenotransplantation?

If you were to picture a kidney transplant, you'd probably imagine one person donating their kidney to another. This is known as allotransplantation or transplantation within the same species. 

Xenotransplantation is the same concept, however, it uses an organ from one species and transfers it to another. In this case, researchers are transplanting a pig's kidney into a human. 

Why we need xenotransplantation

There are 37 million Americans with chronic kidney disease, 660,000 people living with kidney failure, and 100,000 people on the transplant list. 

Unfortunately, there are not enough organs available for everyone.

"We have an organ shortage, not just in the U.S., but in the world." said Dr. Locke, "It's sort of an unmitigated crisis, and it's really challenging for me as a transplant surgeon…to know that even those individuals on the waitlist are going to really struggle to find an organ." 

Sadly, many people looking for a kidney don’t know they are at risk until it’s too late.  The best way to avoid this is through early detection and controlling risk factors like diabetes and high blood pressure. 

Start by taking this one-minute quiz to determine if you are at risk . Then take these results to your healthcare provider to get your kidney health conversation started.

What's unique about pig kidneys?

The internal structure of a pig kidney is extremely similar to humans. 1 Dr. Locke explained they:

● have similar blood flow to a human ● can balance fluids and electrolytes  ● can handle the foods humans eat ● have eGFRs similar to humans

With the potential of the pig kidney identified, Dr. Locke started working to make sure the transplant worked in a living person. "This is the result of 30 years worth of work and certainly not all my work. I'm the person who's trying to figure out how to make it work in a living person. It's a testament to our scientists who have been at this for a very long time, and I hope this gives people hope and knowledge that they are not forgotten."

Immune systems and transplantation

Even in human-to-human transplants, doctors perform compatibility tests to lower the risk of rejection. After the surgery, recipients take immunosuppressants to protect the new kidney from their immune system.

So, if the body attacks another human's kidney, imagine how it would react to a pig's kidney: It would immediately reject it. 

How did the team overcome this barrier? They created the UKidney™ , a genetically modified pig kidney designed to work in humans. A lab removed three genes from the pig DNA, one being the growth hormone receptor which would have caused the kidney to outgrow the human body, and added six human genes to help regulate the immune and blood clotting system.

The preclinical trial human model study

While the changes made to the pig kidney seemed scientifically sound in theory, there is only one way to determine if it would work in the human body–  performing a transplant.

Due to the inherent risk of a new procedure, researchers wanted to first perform the xenotransplant on an individual who had been declared brain dead and could not donate their organs for transplantation. That’s when Jim Parson was identified and, with his family on board, the surgery was scheduled. 

"I think you could have heard a pin drop in the room. We didn't want it to not work." said Dr. Locke, "When we took the clamps off and restored blood flow–that kidney turned pink, and it stayed pink. Then 20 minutes later, it made urine. I don't even know how to characterize it, but it was just remarkable."

After 77 hours, the study succeeded; the kidney worked the whole time despite the complications of brain death, like fluctuating blood pressure.

Keep learning about  xenotransplantation .

What's next?

This was a huge step in the right direction, however, it may be a while before you see pig kidneys xenotransplanted into humans. The team proved their preclinical trial model but moving to a living human clinical trial requires U.S. Food and Drug Administration approval to use genetically modified pig kidneys in humans. Afterward, the clinical trial proposal will need to pass the UAB’s Institutional Review Board for Human Use review. 

“We anticipate getting additional guidance from the FDA about what they think is appropriate soon,” Dr. Locke said . “It is quite possible that they may want us to do additional studies in the human brain-dead model. We plan to move this model forward, and look to perform additional transplants in this model to continue to collect and compile data to make the case that we are ready to do this in living people.”

As they move forward, however, they'll never forget the sacrifice of the Parson family, who made this possible. 

"I do want to make sure I thank the Parsons family; we have named this the Parsons model in his honor." said Dr. Locke, "I think their gift is truly extraordinary and has really helped us advance the field in a meaningful way, and I think is going to help us make a difference in hundreds of thousands of people's lives to the patients out there."

Learn more about the xenotransplantation study .

Looking for the latest in kidney research, care, and treatment?

Join us as we highlight the latest in kidney research, dispel myths, bring you up-to-date news in kidney care, and answer questions from patients to help them live well with kidney disease or a transplant.  Subscribe to Hot Topics in Kidney Health . 

Related Kidney Topics

Fluid overload in a dialysis patient, choosing a treatment for kidney failure, five drugs you may need to avoid or adjust if you have kidney disease, bk virus: what transplant patients need to know, hemodialysis access, kidney stone treatment: shock wave lithotripsy, acid reflux and proton pump inhibitors, percutaneous nephrolithotomy / nephrolithotripsy, related news and stories.

September 17, 2024

Affordable Medications for All: Save Up to 80% with NKF’s BuzzRx® Card

July 25, 2024

The Future of Artificial Kidneys

December 12, 2018

Modern Family Star Opens Up About Her Kidney Disease and Transplants

June 18, 2024

A Son’s Gift. A Wife’s Promise: Fighting for Living Kidney Donors

June 04, 2024

Unfiltered Story: Losing a Transplant

May 31, 2024

Breaking Ground in Transplantation: A New Era with Xenotransplantation

April 24, 2024

Unfiltered Story: Anthony Tuggle

April 02, 2024

Matilda's Miracle: From Dialysis to Kidney Transplant

March 26, 2024

Making the Case for Home Dialysis

REVIEW article

Xenotransplantation: a new era.

• 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
• 2 Department of Vascular Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
• 3 Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
• 4 Faculty of Science and Medicine, Section of Medicine, University of Fribourg, Fribourg, Switzerland

Organ allotransplantation has now reached an impassable ceiling inherent to the limited supply of human donor organs. In the United States, there are currently over 100,000 individuals on the national transplant waiting list awaiting a kidney, heart, and/or liver transplant. This is in contrast with only a fraction of them receiving a living or deceased donor allograft. Given the morbidity, mortality, costs, or absence of supportive treatments, xenotransplant has the potential to address the critical shortage in organ grafts. Last decade research efforts focused on creation of donor organs from pigs with various genes edited out using CRISPR technologies and utilizing non-human primates for trial. Three groups in the United States have recently moved forward with trials in human subjects and obtained initial successful results with pig-to-human heart and kidney xenotransplantation. This review serves as a brief discussion of the recent progress in xenotransplantation research, particularly as it concerns utilization of porcine heart, renal, and liver xenografts in clinical practice.

Introduction

The limited supply of donor organs and tissues remains the greatest barrier for expanding transplantation, despite many advances in the field over the past several decades. In the United States, there are currently over 100,000 individuals on the national transplant waiting list. Greater than 91,000 of these individuals – approximately 83% – is awaiting a kidney transplant, 3% awaiting a heart transplant, and 10% awaiting a liver transplant ( 1 ). This is in contrast with the 22,817 kidney transplants, 3,658 heart transplants, and 8,906 liver transplants performed in 2020 utilizing both living and deceased donor allografts. Worldwide, in 2020 over 129,000 organs were transplanted, which was actually a decrease of 17.6% from the previous year ( 2 ). Less than a quarter of these were from living donors. Kidneys and livers donated from living donors represented approximately 28% of the total worldwide organ transplants in 2020. Given the morbidity and mortality of hemodialysis (40-50% survival rate at five years), the generally poor prognosis of patients with end-stage heart or liver failure, and the overall significant cost to the healthcare system that sustaining a patient with end-stage organ failure represents, any advancement that could shorten international wait list times would significantly improve patient health, lifespan, and system expenditures ( 3 ). This problem is particularly pronounced in the developing world, where access to hemodialysis or ventricular assist devices (VAD) is often cost-prohibitive and limited, leading to high mortality rates from kidney and heart diseases ( 4 ). Artificial liver replacement does not yet exist, and the lack of liver grafts is a global problem.

Xenotransplantation has the potential for reducing the shortage of access to critically needed organ grafts. Animal donor organs and tissue have been subjects of study since the 1960s, and some xenotransplant tissues, particularly heart valves, have been commonly utilized in clinical practice. However, these structures are frequently decellularized extracellular products and therefore do not trigger a robust immune response ( 5 ). Until very recently, most research efforts in xenotransplantation focused on creation of donor organs from pigs with various genes edited out using CRISPR technologies and transgenes edited in and utilizing non-human primates for trial. Three groups in the US – University of Maryland, Baltimore (UMB) ( 6 ), New York University Langone Health (NYU) ( 7 ), University of Alabama at Birmingham (UAB) ( 8 , 9 ) – have recently moved forward with trials in human subjects. These include one life-sustaining heart xenotransplant in a patient with end-stage heart failure (UMB) ( 6 ), and two institutions who have performed kidney xenotransplants in brain-dead subjects (NYU ( 7 ) and UAB ( 8 , 9 )). Lessons learned so far from these initial clinical xenotransplants will be discussed in this review. Further trials for longer periods of time may be justified in patients for whom dialysis or VAD is either cost-prohibitive or unavailable, or who may not be appropriate candidates for a human allograft ( 3 ). This review serves as a brief discussion of the recent progress in xenotransplantation research, particularly as it concerns utilization of porcine heart, renal, and liver xenografts in clinical practice.

The Development of Suitable Porcine Xenografts

Early research efforts in xenotransplantation focused on utilizing donor organs from non-human primates (NHPs). Despite their close phylogenic relationship with humans, NHPs were found to not be suitable for a number of reasons, including ethical concerns, costs, difficulties in generating genetic modifications, and biosafety ( 5 ). Since the 1990s, utilization of donor xenografts from pigs has been the main focus of study. Xenotransplantation utilizing pig xenografts could provide a theoretically endless supply of alternative allografts ( 10 ); however, a number of barriers exist for the use of porcine xenografts in clinical practice.

The use of knockout pigs as a source for xenografts has several distinct advantages. Pigs are comparatively straightforward to raise, mature quickly, and will have organs similar in size to a human adult in approximately six months ( 5 , 11 , 12 ). Pigs also reach reproductive maturity rather quickly for large mammals, have relatively large litter sizes, and have physiologic and anatomical similarity to humans ( 3 , 5 ). For these reasons, pigs were identified as a possible source of renal xenografts and research efforts have focused on transplanting porcine kidneys into NHPs for pre-clinical evaluation of efficacy and suitability. However, the use of NHPs for pre-clinical evaluation of porcine xenografts into human subjects is challenging despite being the standard model for pre-clinical testing of the primate immune response to porcine xenografts and the effects of new immunosuppression regimens ( 5 ). NHPs, particularly old-word monkeys (OWMs), often carry naturally occurring specific preformed antibodies to pig cells that are not always present in human serum ( 13 , 14 ). NHPs, like pigs, express N-glycolylneuraminic acid (Neu5Gc), but when this is knocked out of TKO pigs at least one new antigen, called the “fourth xenoantigen” is exposed which can lead to a robust immune response that does not adequately mimic a TKO pig-to-human model ( 15 ). Also, the use of NHP models is considered ethically complex due to their phylogenetic closeness to humans and they take a significant amount of time to physiologically mature. Additionally, NHPs are a very expensive experimental model system to set up and maintain. However, most researchers agree that results in porcine xenograft-NHP models are a necessary step prior to clinical application ( 5 ).

Advanced Immunosuppression Protocols for Xenotransplant Trials

Recent advancements in the gene-editing techniques and immunosuppressive protocols have made clinical xenotransplantation more applicable. Like allotransplant, a major challenge in successful xenotransplantation is to alleviate the risks of immune rejection of the xenotransplant. Following the transplant, three types of rejection may occur- (i) hyperacute rejection, (ii) acute humoral rejection, and (iii) acute cellular rejection.

Hyperacute rejection (HAR) is a type of humoral rejection which occurs within minutes to few hours of transplant due to preformed antibodies in recipient’s blood ( 16 ). These preformed antibodies can recognize the α-Gal (galactose-α1,3-galactose) antigen expressed on porcine endothelial cells of organ, which triggers a chain of complement protein activation resulting in the demolition of graft vasculature and finally graft rejection ( 17 ). If the graft survives beyond 24 hours, acute humoral xenograft rejection (AHXR) can destroy the transplanted organ. AHXR occurs due to humoral as well as cellular immune responses and is a common cause of xenograft loss seen amongst multiple trials ( 18 ). Two non-Gal antigens, Neu5Gc (N-glycolylneuraminic acid) and SDa blood group, are known to be responsible for AHXR ( 19 – 21 ). In the present immunotherapy protocols, HAR and AHXR can be avoided using plasmapheresis and use of pigs genetically modified for the deletion of α-Gal and the two non-Gal antigens (triple knockout or TKO) ( 5 , 22 , 23 ). Acute cellular xenograft rejection (ACXR), which involves NK cells, macrophages, neutrophils, T-cells and B-Cells, also remains major hurdle in long-term xenograft survival ( 5 ). Activation of T-cells is one of the main causes of ACXR ( 5 , 24 ) and alleviation of the T-cell immune responses is critical in the xenotransplantation. Although deletion of α-Gal antigens and expression of human CRPs in donor pigs have been shown to be associated with reduced T-cells responses, this alone is not sufficient for successful long-term survival of xenotransplants ( 25 , 26 ).

A successful immunosuppression protocol should involve the combination of agents that can increase the length of transplant and have the least side effects on the recipient. Current immunosuppression therapies consist of (i) plasmapheresis to remove the preformed antibodies against the donor, (ii) targeting T-cells and B-cells to keep them low and less active to avoid immune rejection of transplant, (iii) complement protein inhibitors, (iv) anticoagulants, and (v) anti-inflammatory agents to avoid local trafficking of immune cells to the transplant. Various types of transgenic pigs are available to study xenotransplantation. They have been genetically engineered to prevent the humoral and cellular immune responses, coagulation, and complement mediated rejection ( 27 ). Of note, not all classes of immunosuppression can be used together, as concurrent use of certain classes together, particularly calcineurin inhibitors and costimulatory blockers, have been shown to have adverse effects ( 28 ). Additionally, intravenous immunoglobulin, which is frequently used in the treatment or prevention of rejection, may possibly infuse xeno-antigen antibodies, and its use should be avoided in clinical trials ( 29 ).

Most of the immunosuppressive therapies that are being tested in pig to NHP xenotransplants block co-stimulatory signals CD40-CD154 and the CD28/CTLA4-CD80/86 interaction, which are required for T-cell activation ( 30 – 33 ). Initial trials with anti-CD154 monoclonal antibodies (mAb) showed promising results in attenuating T-cell response in pig to NHP models ( 34 ), but further research showed that anti-CD154mAb had thrombogenic effects and has been discontinued in clinical use ( 35 ). Recently, anti-CD40mAb has been shown to be equally effective in blocking the CD40-CD154 interaction. In 2016, Mohiuddin et al. demonstrated that the use of anti-CD40 mAb enhanced the survival of cardiac xenografts up to 945 days in GTKO.hCD46.hTBM pig xenografts in NHPs ( 33 ). anti-CD40 mAb also suppress B-cell function by blocking the co-stimulation pathway. In a recent trial of pig to human heart transplant conducted in the University of Maryland, Baltimore, anti-CD40 mAb was used as a part of immunosuppressive regimen along with other immunosuppressants including rituximab (anti-CD20 mAb) and RATG ( 36 , 37 ). The patient expired 61 days after his cardiac xenotransplant mainly due to non-cardiac causes. The most important lesson learned with this unique case is that the genetically modified pig heart was not subject to hyperacute rejection and functioned appropriately in a human body for about two months. Importantly, these major advances were possible thanks to over two decades of pre-clinical work in large animal models ( 33 , 38 – 43 ). This represents the longest survival of a life sustaining pig organ in a human and revived historical xenotransplantation trials, initiated many decades ago using primate organs ( Figure 1 ).

Figure 1 Longest survival of xenotransplanted organs or tissues in human. WT, wild type.

In addition to T-cells and B-cells, natural killer (NK) cells also play important role in xenograft rejection ( 44 ). Use of genetically modified pigs GalT-KO and HLA-E/human β2 macroglobulin may possibly prevent NK cell-mediated rejection ( 27 , 45 ). In the past few years, use of regulatory T-cells (Tregs) as immunosuppressive therapy in xenotransplantation has become area of interest. Xenoantigen-specific recipient Tregs can induce donor-specific tolerance by suppressing effector T-cell responses ( 46 , 47 ). In 2018, one report demonstrated xenograft rejection was correlated with low number of Tregs in peripheral blood lymphocytes in pig to NHPs cardiac xenograft models ( 48 ). Wu et al. found that Tregs play an important role in the maintenance of donor-specific tolerance in rodent models of pig neonatal islet xenotransplantation ( 49 ). Huang et al. demonstrated that adoptive transfer of ex vivo expanded baboon CD39+ Tregs could prevent the porcine islet xenotransplant rejection in primatized NOD-SCID IL-2rγ-/- mice for more than 100 days ( 50 ). In addition to regulatory T-cells, Bregs play significant role in transplantation. Bregs can prevent the graft rejection by various mechanisms such as suppressing effector T-cells, activating Tregs, suppressing antigen presentation by dendritic cells and macrophages ( 51 ). Another class of regulatory immune cells is tolerogenic dendritic cells (DCs), which can induce central and peripheral tolerance via clonal deletion, activating Tregs and suppressing memory T-cell responses ( 52 ). Madelon et al. proved that co-transplantation of autologous IL-10 treated murine tolerogenic DCs enhanced the rat islet xenograft survival in diabetic mice ( 53 ). One group in 2018 demonstrated that NHP derived tolerogenic DCs could induce the porcine-specific Tregs ( 54 ).

Though an approach combining genetically modified pigs with advanced immunosuppression protocols in NHPs has made the clinical use of pig to human xenotransplant possible in near future, a better understanding of cellular immune responses due to other cells such as NK cells, dendritic cells, and innate cells is required to design an effective immunosuppression protocol.

Functional and Metabolic Capacities of Pig Xenografts

Though most functions are similar between human allografts and their xenograft counterparts, there are some notable differences in functional and metabolic capabilities that must be accounted for. Though Leo Loeb’s theory regarding protein differences produced by genetically distinct species accounting for graft failure failed to recognize rejection as the ultimate etiology of xenograft failure, it did raise questions about how physiologic differences between species, including their genetic protein structures and subsequent functions, could lead to graft incompatibility ( Table 1 ) ( 55 ). Porcine lung, kidney, heart, and pancreas allografts have been shown to sustain life in NHPs while porcine liver xenografts have frequently encountered life-threatening complications, implying that these physiologic differences may vary between organs. One important physiologic change triggered by xenografts appears to be thrombotic microangiopathy and systemic consumptive coagulopathy ( 36 ), which can be overcome by utilizing pigs that overexpress human coagulation regulation proteins ( 5 ).

Table 1 Potential physiologic incompatibility between xenograft and recipient.

In both humans and pigs, kidneys must clear creatinine and other waste products, regulate volume, and accommodate similar volumes of blood flow ( 56 , 57 ). Pigs tend to maintain somewhat higher levels of potassium, phosphorus, and calcium than do humans and NHPs, whereas albumin and total protein levels are lower. Iwase et al. noted dehydration and hypovolemia with transient increases in serum creatinine in multiple NHP recipients of porcine allografts ( 56 ). The recipient NHPs did not exhibit behaviors consistent with dehydration such as changes in oral intake, urine output, body weight, or mental status though other signs of hypovolemia, such as low central venous pressure and visibly dehydrated skin and tissues were present ( 56 ). This may be due to molecular differences between porcine and human/NHP renin, as porcine renin has failed to cleave human or NHP angiotensinogen in in-vitro models ( 58 , 59 ). It is suspected that an alternative mechanism for fluid regulation must exist given the maintenance of body weight and overall fluid balance in NHP recipients in prior studies.

Severe proteinuria and hypoalbuminemia were noted in early porcine-NHP xenotransplants, necessitating frequent administration of intravenous albumin to maintain protein balance in an appropriate range ( 56 , 58 ). The level of proteinuria in these studies was consistent with nephrotic syndrome. However, with recent genetic modifications of donor pigs and improved pharmacological intervention, more recent studies have frequently shown only minimal or modest proteinuria as well as prolonged graft survival, implying that this protein wasting may be a sign of chronic rejection and increased glomerular permeability secondary to podocyte effacement. Proteinuria does not appear to be a normal finding in healthy pigs, though it has been posited as a means by which the porcine kidney lowers albumin levels to those typically found in a pig, which is much lower than that of humans and NHPs ( 10 ). Similar to human allograft recipients, immunosuppression regimens including rituximab delay the development of proteinuria in xenotransplant models ( 58 , 60 – 62 ).

Porcine hematologic parameters are quite different as well. Pig red blood cell (RBC), white blood cell (WBC), and platelet counts are higher than those of NHPs or humans ( 56 , 57 ), though overall hemoglobin levels are lower. There is amino acid variability between the erythropoietin produced by pig and NHP/human kidneys, which may contribute to the gradual development of normocytic anemia in NHPs that receive life-sustaining porcine allografts ( 56 ) as a molecular incompatibility between porcine erythropoietin and the NHP erythropoietin receptor exists. Repeated blood draws and drug-induced myelosuppression may also contribute to this observation. The administration of recombinant human erythropoietin maintains stable hematocrit levels in NHPs that receive porcine allografts. For potential human xenograft recipients, either the routine administration of recombinant erythropoietin or engineering pigs that produce human erythropoietin may solve this issue.

Cardiac xenotransplants have a different set of physiologic challenges compared to kidneys. First, unaltered cardiac xenografts will undergo maladaptive hypertrophy, leading to diastolic heart failure early after transplantation ( 63 , 64 ). Utilization of an immunosuppression protocol including temsirolimus and afterload reducing agents can reduce this growth, as this massive cardiac hypertrophy appears to be associated with increased expression of mTOR in cardiac xenografts ( 64 , 65 ) and the higher blood pressures in primates, including NHPs and humans, can stimulate detrimental cardiac growth for a porcine xenograft ( 66 ). This growth can also be eliminated with the use of growth hormone receptor (GHR) knockout xenografts, eliminating the need for medications to overcome the problem ( 64 ). An additional change that has been shown to improve survival for porcine xenografts in NHPs has been utilization of non-ischemic heart preservation ( 5 ). A similar preservation mechanism was used with the first life sustaining cardiac xenotransplant in a human, performed in January 2022 at the University of Maryland ( 6 ).

The significant blood pressure differences between pigs and primates must be addressed as well, even when utilizing knockout xenografts ( 3 ). NHPs and humans have systemic vascular resistance (SVR) and mean arterial pressures (MAP) significantly higher than that of age-matched pigs ( 63 ), which can provide an extrinsic cause for xenograft hypertrophy. Recipients of porcine xenografts will likely need strict blood pressure control to reduce this extrinsic pressure on the graft that would ultimately lead to failure.

Possible liver xenografts represent a more complex problem. Given the wide and complex array of functions of the liver – including synthesis of most circulating proteins, conjugation and excretion of bilirubin, and detoxification and modification of many incoming chemicals and molecules – the number of potential physiologic incompatibilities between porcine and human/NHP models is very high. Notably, previous hepatic xenotransplant models have been limited by the development of severe thrombocytopenia, coagulopathy, and TMA ( 5 , 67 ). The addition of exogenous coagulation factors to a co-stimulation blockade in conjunction with the use of α-Gal knockout donor xenografts has allowed for improved success in pig-to-primate liver xenotransplant models, leading to survival times approaching one month in trials ( 10 , 67 ) with spontaneous platelet recovery and prevention of protein dysregulation. Esker et al. also noted that differences in the amount and activity of various proteins produced by the porcine liver and biliary system – including alkaline phosphatase, lactate dehydrogenase, albumin, and coagulation factors – may also reflect their native species in a xenotransplant and would benefit from genetic alteration to achieve function closer to that of humans.

Recipient Selection

Of all organs with the potential for clinical xenotransplant trials, the kidney represents the most straightforward, as it can be easily removed and immunosuppression withdrawn with return to dialysis should the recipient require it ( 3 , 68 , 69 ). The current median wait time for a deceased donor renal transplant is over four years, but approaching ten years in some areas ( 70 ); additionally, many patients on the wait list are older than 60, and patients over age 70 are not considered for transplant at some institutions ( 3 ). Potential candidates for a xenotransplantation have not been conclusively defined, but general principles regarding good candidates for early xenotransplantation trials have been suggested. Patients for whom their anticipated wait list time is much longer than their life expectancy and who have no identified living donor have been proposed as potential candidates for renal xenotransplantation ( 3 ). Those who have renal diseases that are likely to recur in an allograft are also good candidates for xenograft trials as well as those who have exhausted vascular access for hemodialysis but are not candidates for human renal allografts ( 71 ). An additional group that may benefit from a xenotransplant would be highly sensitized patients with high titers of anti-human leukocyte antigen (HLA) antibodies where only a limited number of donors can provide a match; anti-HLA antibodies may not react strongly with swine leukocyte antigens (SLA) and therefore not stimulate a significant effect on T-cell and B-cell response ( 71 , 72 ). Approximately one third to one half of patients on the ESRD waiting list have been shown to have negative crossmatch results when using TKO pigs, implying that those who are difficult to match may benefit from a xenotransplantation trial ( 15 , 73 ). Alternatively, considering the xenogeneic human TCR repertoire ( 74 ), one could consider use of SLA-I knockout pigs in the future ( 75 , 76 ). However, use of SLA-I depleted organs and cells in transplant raises the concerns about NK cell-mediated injury due to missing self-antigens. This could potentially be avoided by using the transgenic pigs with modified SLA amino acids to prevent the binding of cross-reactive anti-HLA antibodies ( 77 ). Patients declined for transplant because of a history of non-compliance might be a category to consider since the risk of wasting a human organ is absent. Society and the medical community might grant an easier access to xenotransplantation in this context. Those for whom deceased human organ donation is culturally taboo may also benefit from a xenotransplant if culturally permissible ( 78 ). Kidney xenotransplantation could also be considered in an emergency basis for patients whose life expectancy is short (regardless of the reason) and in whom the continuous need of renal replacement therapy leads to a dramatically decreased quality of life. In summary, potential candidates for a kidney xenotransplantation fall into six main categories: 1) Older age, 2) Sensitized, 3) Lack of dialysis access, 4) Cultural barriers, 5) Non-compliance 6) Short life expectancy with low quality of life ( Figure 2 ).

Figure 2 Potential candidates for heart, kidney, and liver xenotransplantation.

Regarding cardiac xenograft candidates, in addition to the six categories here-above (except for dialysis access), potential candidates could include those who need a re-transplantation, as well as those with contraindications to or who are inadequately supported by the implantation of a ventricular assist device ( 79 ). The ideal candidates for liver xenotransplantation could match any of the categories mentioned here above (except for dialysis and VAD access). In addition, the liver has a unique situation since its function cannot be artificially replaced. Consequently, for patients with fulminant, acute, and acute on chronic liver failure, decisions on transplant candidacy need to be made quickly. Thus, acutely ill patients declined for allotransplant unfortunately die within a few days.

Because many patients who are not acceptable candidates for an allogeneic transplantation may be candidates for xenotransplant trials, it will be important to avoid direct comparison of the outcomes between both approaches ( 3 ). A fairer comparison will be to initially assess the results of xenotransplantation against the recipient’s anticipated morbidity and mortality without transplantation. Comparison between recipients of xenografts and allografts may still be considered as the science progresses further.

Recent Xenograft Clinical Trials

On January 7, 2022, University of Maryland, Baltimore reported on the first life-sustaining, 10G-pig xenoheart ( 80 ) transplant ever performed in a living human ( 6 ). He received a modified immunosuppression protocol including co-stimulation blockade (anti-CD40) maintenance. This transplant was conducted under the umbrella of an emergency New Drug Application (eIND) by the Food and Drug Administration (FDA). This authorization was granted in the setting of an absence of an alternative therapeutic option as the patient was not eligible for an allotransplant nor for a Ventricular Assist Device implantation. Following transplant, the xenograft functioned immediately and ECMO was severed after a few days. The patient was able to be extubated and started the recovery process from his severe deconditioning; the patient had spent several weeks in the hospital prior to transplant. Early results released indicated that the heart was performing extremely well in the absence of rejection. Until day 45-50, he was doing well, despite intermittent infectious episodes. However, in the 8 th week post-transplant, his status started to decline, and he unfortunately passed away from multiorgan failure just after reaching the 2-months post-transplant mark. A detailed scientific report of this achievement is currently underwriting, and the lessons learned from this xenotransplant are yet to come. Nonetheless, it clearly appears that hyperacute rejection was defeated and that the xenograft was able to prolong the life of this patient who had no other options. To gain perspective, it is worth noting that the first ever heart allotransplant recipient died 18 days post-transplant of a pneumonia ( 81 ). It is also interesting to note that, similarly to the Maryland first heart xenotransplant, the history of the first human heart transplant was also presented to the public long before any scientific publication.

Whether the regulatory process used here, namely an EIND, could be used for a xenogeneic kidney transplant remains to be determined. By definition, the need to urgently replace a kidney is relative as compared to the heart. On the other hand, the kidney presents the advantage of being removed at any time with potentially less severe consequences.

Following this intention to not place a patient under the stress of undergoing a transplant which could immediately fail, it was thought to conduct the initial kidney trial in a human decedent model. On Friday, September 24, 2021, The New York Times reported the results of an experimental pig to human xenotransplantation at New York University led by Dr. Robert Montgomery ( 7 ). With consent from the participant’s family, a kidney from an alpha 1,3-galactosyltransferase gene-knockout pig was implanted onto the femoral vessels of a first-person consent organ donor who had progressed into brain death but whose organs were not appropriate for donation. Porcine thymic tissue was implanted under the renal capsule 2 months before the procurement. Over the course of 54 hours, the organ was closely monitored and noted to make urine, clear creatinine, and show no overt signs of rejection ( 7 , 82 ). A similar procedure was also performed on another brain-dead patient at NYU in late 2021 ( 83 ). Several major aspects of the trial, such as the subject’s native renal function, have recently been made available and detailed information about the experiment has just been published in the New England Journal of Medicine (see reference here below). Additionally, there is now data available on inflammatory marker levels, biopsies, and what the patient’s immune response was, and though graft function appears to have been preserved for the duration of the experiment. The experiment also did not utilize a TKO donor kidney, but instead one with a single-gene knockout (⍺-Gal) provided by Revivicor.

On January 20, 2022, the results of a very similar trial performed at UAB were published, using a TKO pig kidney with seven additional genetic modifications (ten genetic modifications or 10G-pigs) transplanted in a brain-dead patient ( 8 , 9 ). The UAB team noted unequivocally the absence of HAR and documented this with negative flow crossmatches before and after transplant (until 74 hours when the trial was ended) ( 9 ). Of note, they used standard immunosuppression with the addition of rituximab, i.e. methylprednisolone taper, anti-thymocyte globulin for a total of 6 mg/kg, and anti-CD20, as well as maintenance consisting of mycophenolate mofetil, tacrolimus, and prednisone. The key learning points from this very initial experience were: 1) no hyper acute rejection, 2) biopsy revealing TMA, 3) urine production but no creatinine clearance. It is unclear if the TMA seen on this patient’s biopsies was secondary to antibody-mediated rejection (AMR) as the subject had some evidence of a hypercoagulable state and inflammation due to their TBI ( 36 ). This initial report revealed some limitations inherent to the nature of the recipient, whose physiological state was certainly very distant from a living recipient. The recipient used was a brain-dead donor after bilateral native nephrectomy, and over the course of the study developed multi-organ failure consistent with brain death, including shock liver, disseminated intravascular coagulation, acidemia, and hemorrhagic shock after planned surgical exploration to obtain xenotransplant biopsies on day 3. The pro-inflammatory cytokine storm and hemodynamic instability from these events might have prevented any kidney to function and further enhanced TMA, which was likely preexisting and presumably attributable to the inflammatory-hypercoagulable state caused by traumatic brain injury rather than AMR ( 36 ). Other limitations included procurement injuries to the kidneys (a vein injury that required significant clamp time) and the use of a standard immunosuppression in the recipient which might have been insufficient. Other similar trials ( 7 ) which will be likely soon reported in a scientific form soon, along with extensive experiments in NHPs ( 84 , 85 ), seem to indicate that in more stable situations, pig kidney xenografts can clear creatinine. In particular, TMA was avoided in NHPs and long-term xenograft survival was achieved when using the most advanced immunosuppression protocols including co-stimulation blockade ( 86 ). For these reasons, leading authors in the filed suggest the next step should be to transplant genetically-engineered pig kidneys into dialysis-dependent patient with no hope of an allotransplant ( 36 ).

These recent trials clearly contribute to a significant advance in the field, but also raise a number of new scientific questions. As they were reported in news media, they did have the distinct advantage of drawing public attention to the potential of utilizing xenotransplantation to solve a critical organ shortage ( 82 ). The fact that those trials were reported in popular media first reflect the importance, sensitive nature, and fascination generated by xenotransplantation. Due to a concern that the public would see the trials as “unusual” or “unnatural,” there has previously been reticence to report trials involving xenotransplant grafts to media. Public knowledge of this trial and other porcine xenograft trials that have been published in the last several decades will hopefully spark more conversation, research, and public interest ( 87 ). On the other hand, the eagerness of the scientific community to see detailed reports of these trials is palpable.

Ethical Concerns

The use of pigs engineered to grow organs with a low likelihood of rejection raises a number of ethical concerns. Transplant teams utilizing xenografts as a source of donor organs should be prepared to discuss these issues as the regular use of xenografts moves forward in “daily” clinical practice. There are many social benefits that xenotransplantation can help realize, namely relief of the long wait times for a suitable allograft, reduction in dialysis complications, and, especially in some parts of the world, elimination of coercion and financial compensation for organs ( 71 ). However, a number of ethical and psychosocial issues exist around xenotransplantation that do not necessarily apply to the use of traditional human allografts.

In some cultures, the use of porcine-based products is considered taboo, though some scholars from these groups will allow for transplants from pigs if the patient would die from organ failure without it ( 12 ). There are additionally those who eschew the use of animals and/or animal products as a source of food or dry goods for either religious or animal welfare concerns, and these individuals may take issue with utilization of xenografts as a resource for reducing the transplant wait list ( 88 ). There are others still that take issue with raising animals with the exclusive intent of utilizing their organs for xenotransplantation, though the anticipated number of animals needed for this purpose is significantly smaller than the more than 100 million animals killed for food each year in the US alone ( 82 , 88 ). Keeping in mind the perspective of balancing risks and benefits between use and needs, it is worth mentioning that 240 patients on dialysis die every day in the United States ( 89 ).

Pigs raised as a source of xenografts would likely require confinement to reduce the risk of infection and subsequent transmission of an infection to the future recipient of the xenograft. Animals raised under such conditions would not be in an environment in which they would be able to freely roam and interact with other animals like some of their farm-raised counterparts ( 12 , 88 ). This leads to a conflict among those with animal welfare concerns because the need to raise a xenograft-donor pig in a sterile environment to protect the recipient is in direct conflict with the pig’s natural instincts and needs. The degree of influence of both sides of this conflict has not yet been defined and warrants further exploration involving all stakeholders.

An additional source of ethical concern would be exposing the immunosuppressed patient to the possibility of zoonotic disease transmission. There are some viruses carried by pigs, particularly porcine endogenous retroviruses (PERVs) and Nipah virus that are carried harmlessly by pigs but able to cause significant human disease as human cellular receptors for these viruses exist ( 88 , 90 ). A PERV is suspected to be the virus responsible for a 2009 epidemic of swine flu that led to the loss of over 250,000 human lives. The risk associated with zoonotic viruses would be amplified by post-transplant immunosuppression ( 3 ). There are also some bacteria that may potentially be transmitted by a xenograft that risk horizontal transmission across the community. This is in addition to already an increased infection risk burden that is taken on by transplant recipients because of induction and maintenance immunosuppression. This risk is substantially reduced with raising a pig intended as a xenograft donor in a dedicated sterile, biosecure environment, addressing biosafety concerns but raising the aforementioned ethical issues with regards animal welfare. Specialized molecular assays for viruses may also further reduce this risk ( 90 ). Utilizing CRISPR technology, a pig has been produced that has had all PERVs inactivated, reducing the risk of infection with PERVs that could occur with xenotransplantation and allaying this source of ethical quandary ( 71 , 90 , 91 ).

Lastly, public perception of scientific breakthroughs and advancement in the field of xenotransplantation raises both fascination and ethical concerns. There should be general societal involvement in the development of xenotransplant policy, but in the United States public understanding of scientific knowledge and the scientific method is lacking ( 88 ). The field of ethics is often considered “outside” of the scope of science, creating a divide between the scientific community and general public on issues of ethics that makes genuine and rational discussion of ethical issues in xenotransplantation challenging. Resolution to this divide would require the integration of both ethical issues and social responsibility into scientific education as well as improvement of science education and understanding in society at large – both of which are noble and challenging goals to achieve.

Utilization of porcine organs as a source of xenografts has the potential to drastically reduce the long waitlist for transplant and expand eligibility for transplant to those who might otherwise not be candidates. The science behind these trials has advanced considerably and more human clinical trials utilizing porcine xenografts are quickly approaching. However, utilization of xenografts is not without its challenges, and addressing these is critical to both clinical success and public acceptable of early porcine-to-human xenograft trials. Recent media attention around the first clinical trials has cast attention on the field, and this will hopefully continue to stimulate a conversation about the ethical and social concerns regarding the use of porcine xenografts as initial trials are developed, conducted, and reported in a scientific format ( 92 ). Ideally, these trials would focus on determining appropriate recipient selection criteria and the identification of an appropriate immunosuppression regimen for xenograft recipients as these are currently substantial unknowns that require further investigation in order for xenotransplants to be integrated into standard clinical practice.

Author Contributions

AC, AV, MM, MP, YM, AL, CB, LB, DM, and RM designed the study, collected the data, interpreted the data, and wrote the manuscript. AC, AV, MM, MP, YM, AL, CB, LB, DM, and RM had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Abbreviations

AHXR, Acute humoral xenograft rejection; AMR, Antibody-mediated rejection; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; eIND, Emergency New Drug Application; FD, Food and Drug Administration; GHR, Growth hormone receptor; HLA, Human leukocyte antigen; HAR, Hyperacute rejection; mTOR, Mammalian target of rapamycin; MAP, Mean arterial pressures; mAb, Monoclonal antibodies; NYU, New York University Langone Health; NHPs, Non-human primates; OWMs, Old-word monkeys; PERVs, Porcine endogenous retroviruses; RBC, Red blood cell; SLA, Swine leukocyte antigens; SVR, Systemic vascular resistance; TMA, Thrombotic microangiopathy; TKO, Triple knockout or; UAB, University of Alabama at Birmingham; UMB, University of Maryland, Baltimore; VAD, Ventricular assist devices; WBC, White blood cell.

1. Organ Donation Statistics (2021). Available at: https://www.organdonor.gov/learn/organ-donation-statistics (Accessed December 1, 2021).

Google Scholar

2. Global Observatory on Donation. International Report on Organ Donation and Transplant Activities . Madrid, Spain:WHO-ONT (2021).

3. Meier RPH, Longchamp A, Mohiuddin M, Manuel O, Vrakas G, Maluf DG, et al. Recent Progress and Remaining Hurdles Toward Clinical Xenotransplantation. Xenotransplantation (2021) 28(3):e12681. doi: 10.1111/xen.12681

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Mushi L, Marschall P, Fleba S. The Cost of Dialysis in Low and Middle-Income Countries: A Systematic Review. BMC Health Serv Res (2015) 15:506. doi: 10.1186/s12913-015-1166-8

5. Lu T, Yang B, Wang R, Qin C. Xenotransplantation: Current Status in Preclinical Research. Front Immunol (2020) 10. doi: 10.3389/fimmu.2019.03060

6. Rabin RC. In a First, Man Receives a Heart From a Genetically Altered Pig. In: The New York Times . New York, NY:: The New York Times Company. (2022).

7. Rabin RC. In a First, Surgeons Attached a Pig Kidney to a Human, and It Worked. In: The New York Times . New York, NY: The New York Times Company (2021).

8. Rabin RC. Kidneys From A Genetically Altered Pig Are Implanted in a Brain-Dead Patient. In: The New York Times . New York, NY: The New York Times Company. (2022).

9. Porrett PM, Orandi BJ, Kumar V, Houp J, Anderson D, Killian AC, et al. First Clinical-Grade Porcine Kidney Xenotransplant Using a Human Decedent Model. Am J Transplant (2022) 22(4):1037–53. doi: 10.1111/ajt.16930

10. Esker B, Ezzelarab M, Hara H, van der Windt DJ, Wijkstrom M, Bottino R, et al. Clinical Xenotransplantation: The Next Medical Revolution? Lancet (2012) 379(9816):672–83. doi: 10.1016/S0140-6736(11)61091-X

11. Cooper DKC, Gaston R, Eckhoff DE, Ladowski J, Yamamoto T, Wang L, et al. Xenotransplantation — the Current Status and Prospects. Br Med Bull (2018) 125(1):5–14. doi: 10.1093/bmb/ldx043

12. Loike JD, Kadish A. Ethical Rejections of Xenotransplantation? The Potential and Challenges of Using Human-Pig Chimeras to Create Organs for Transplantation. EMBO Rep (2018) 19(8):e46337. doi: 10.15252/embr.201846337

13. Yamamoto T, Iwase H, Patel D, Jagdale A, Ayares D, Anderson D, et al. Old World Monkeys are Less Ideal Transplantation Models for Testing Pig Organs Lacking Three Carbohydrate Antigens (Triple-Knockout). Sci Rep (2020) 10(1):9771. doi: 10.1038/s41598-020-66311-3

14. Cooper DKC, Hara H, Iwase H, Yamamoto T, Jagdale A, Kumar V, et al. Clinical Pig Kidney Xenotransplantation: How Close Are We? J Am Soc Nephrol (2020) 31(1):12–21. doi: 10.1681/ASN.2019070651

15. Cui Y, Yamamoto T, Raza SS, Morsi M, Nguyen HQ, Ayares D, et al. Evidence for GTKO/β4galnt2ko Pigs as the Preferred Organ-Source for Old World Nonhuman Primates as a Preclinical Model of Xenotransplantation. Transplant Direct (2020) 6(8):e590. doi: 10.1097/TXD.0000000000001038

16. Moreau A, Varey E, Anegon I, Cuturi MC. Effector Mechanisms of Rejection. Cold Spring Harb Perspect Med (2013) 3(11):a015461. doi: 10.1101/cshperspect.a015461

17. Grafals M, Thurman JM. The Role of Complement in Organ Transplantation. Front Immunol (2019) 10. doi: 10.3389/fimmu.2019.02380

18. Firl DJ, Markmann JF. Measuring Success in Pig to Non-Human-Primate Renal Xenotransplantation: Systematic Review and Comparative Outcomes Analysis of 1051 Life-Sustaining NHP Renal Allo- and Xeno-Transplants. Am J Transplant (2022) 00:1–10. doi: 10.1111/ajt.16994

CrossRef Full Text | Google Scholar

19. Byrne G, Ahmad-Villiers S, Du Z, McGregor C. B4GALNT2 and Xenotransplantation: A Newly Appreciated Xenogeneic Antigen. Xenotransplantation (2018) 25(5):e12394. doi: 10.1111/xen.12394

20. Shimizu A, Hisashi Y, Kuwaki K, Tseng YL, Dor FJ, Houser SL, et al. Thrombotic Microangiopathy Associated With Humoral Rejection of Cardiac Xenografts From Alpha1,3-Galactosyltransferase Gene-Knockout Pigs in Baboons. Am J Pathol (2008) 172(6):1471–81. doi: 10.2353/ajpath.2008.070672

21. Song K-H, Kang Y-J, Jin U-H, Park Y-I, Kim S-M, Seong H-H, et al. Cloning and Functional Characterization of Pig CMP-N-Acetylneuraminic Acid Hydroxylase for the Synthesis of N-Glycolylneuraminic Acid as the Xenoantigenic Determinant in Pig–Human Xenotransplantation. Biochem J (2010) 427(1):179–88. doi: 10.1042/BJ20090835

22. Kobayashi T, Yokoyama I, Nagasaka T, Namii Y, Hayashi S, Liu D, et al. Efficacy of Double Filtration Plasmapheresis Pretreatment in Clinical ABO-Incompatible Transplantation and Experimental Pig-to-Baboon Xenotransplantation. Transplant Proc (2000) 32(1):57. doi: 10.1016/S0041-1345(99)00875-1

23. Lee YT, Chu CH, Sue SH, Chen IC, Wei J. Efficacy of Double Filtration Plasmapheresis in Removing Xenoantibodies and Prolonging Xenograft Survival in an Ex Vivo Swine Perfusion Model. Transplant Proc (2012) 44(4):1143–5. doi: 10.1016/j.transproceed.2012.02.012

24. Scalea J, Hanecamp I, Robson SC, Yamada K. T-Cell-Mediated Immunological Barriers to Xenotransplantation. Xenotransplantation (2012) 19(1):23–30. doi: 10.1111/j.1399-3089.2011.00687.x

25. Ezzelarab MB, Ayares D, Cooper DK. Transgenic Expression of Human CD46: Does it Reduce the Primate T-Cell Response to Pig Endothelial Cells? Xenotransplantation (2015) 22(6):487–9. doi: 10.1111/xen.12209

26. Wilhite T, Ezzelarab C, Hara H, Long C, Ayares D, Cooper DK, et al. The Effect of Gal Expression on Pig Cells on the Human T-Cell Xenoresponse. Xenotransplantation (2012) 19(1):56–63. doi: 10.1111/j.1399-3089.2011.00691.x

27. Meier RPH, Muller YD, Balaphas A, Morel P, Pascual M, Seebach JD, et al. Xenotransplantation: Back to the Future? Transpl Int (2018) 31(5):465–77. doi: 10.1111/tri.13104

28. Izawa A, Sayegh MH, Chandraker A. The Antagonism of Calcineurin Inhibitors and Costimulatory Blockers: Fact or Fiction? Transplant Proc (2004) 36(2 Suppl):570s–3s. doi: 10.1016/j.transproceed.2004.01.020

29. Yamamoto T, Cui Y, Patel D, Jagdale A, Iwase H, Ayares D, et al. Effect of Intravenous Immunoglobulin (IVIg) on Primate Complement-Dependent Cytotoxicity of Genetically Engineered Pig Cells: Relevance to Clinical Xenotransplantation. Sci Rep (2020) 10(1):11747. doi: 10.1038/s41598-020-68505-1

30. Mohiuddin MM, Singh AK, Corcoran PC, Hoyt RF, Thomas ML3, Lewis BG, et al. Role of Anti-CD40 Antibody-Mediated Costimulation Blockade on non-Gal Antibody Production and Heterotopic Cardiac Xenograft Survival in a GTKO.hCD46Tg Pig-to-Baboon Model. Xenotransplantation (2014) 21(1):35–45. doi: 10.1111/xen.12066

31. Samy KP, Butler JR, Li P, Cooper DKC, Ekser B. The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation. J Immunol Res 2017 (2017) 2017:8415205. doi: 10.1155/2017/8415205

32. Vanhove B, Poirier N, Soulillou JP, Blancho G. Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation. Transplantation (2019) 103(9):1783–9. doi: 10.1097/TP.0000000000002740

33. Mohiuddin MM, Singh AK, Corcoran PC, Thomas ML3, Clark T, Lewis BG, et al. Chimeric 2C10R4 Anti-CD40 Antibody Therapy is Critical for Long-Term Survival of GTKO.hCD46.hTBM Pig-to-Primate Cardiac Xenograft. Nat Commun (2016) 7:11138. doi: 10.1038/ncomms11138

34. Higginbotham L, Mathews D, Breeden CA, Song M, Farris AB, Larsen CP, et al. Pre-Transplant Antibody Screening and Anti-CD154 Costimulation Blockade Promote Long-Term Xenograft Survival in a Pig-to-Primate Kidney Transplant Model. Xenotransplantation (2015) 22(3):221–30. doi: 10.1111/xen.12166

35. Bottino R, Knoll MF, Graeme-Wilson J, Klein EC, Ayares D, Trucco M, et al. Safe Use of Anti-CD154 Monoclonal Antibody in Pig Islet Xenotransplantation in Monkeys. Xenotransplantation (2017) 24(1):e12283. doi: 10.1111/xen.12283

36. Riella LV, Markmann JF, Madsen JC, Rosales IA, Colvin RB, Kawai T, et al. Kidney Xenotransplantation in a Brain-Dead Donor: Glass Half-Full or Half-Empty? Am J Transplant (2022) 00:1–2. doi: 10.1111/ajt.17011

37. Mohuiddin M. Personal Communication (2022). Baltimore, Maryland:University of Maryland Baltimore

38. Azimzadeh AM, Kelishadi SS, Ezzelarab MB, Singh AK, Stoddard T, Iwase H, et al. Early Graft Failure of GalTKO Pig Organs in Baboons is Reduced by Expression of a Human Complement Pathway-Regulatory Protein. Xenotransplantation (2015) 22(4):310–6. doi: 10.1111/xen.12176

39. Chan JL, Miller JG, Singh AK, Horvath KA, Corcoran PC, Mohiuddin MM. Consideration of Appropriate Clinical Applications for Cardiac Xenotransplantation. Clin Transplant (2018) 32(8):e13330. doi: 10.1111/ctr.13330

40. Goerlich CE, Kaczorowski D, Singh A, Abdullah M, Lewis B, Zhang T, et al. Human Thrombomodulin Transgene Expression Prevents Intracardiac Thrombus in Life Supporting Pig-To-Baboon Cardiac Xenotransplantation. J Heart Lung Transplant (2020) 39(4):S145–5. doi: 10.1016/j.healun.2020.01.1069

41. Mohiuddin M, Kline G, Shen Z, Ruggiero V, Rostami S, Disesa VJ. Experiments in Cardiac Xenotransplantation - Response to Intrathymic Xenogeneic Cells and Intravenous Cobra Venom Factor. J Thorac Cardiovasc Surg (1993) 106(4):632–5. doi: 10.1016/S0022-5223(19)33704-3

42. Mohiuddin MM, DiChiacchio L, Singh AK, Griffith BP. Xenotransplantation: A Step Closer to Clinical Reality? Transplantation (2019) 103(3):453–4. doi: 10.1097/TP.0000000000002608

43. Mohiuddin MM, Reichart B, Byrne GW, McGregor CGA. Current Status of Pig Heart Xenotransplantation. Int J Surg (2015) 23(Pt B):234–9. doi: 10.1016/j.ijsu.2015.08.038

44. Inverardi L, Clissi B, Stolzer AL, Bender JR, Sandrin MS, Pardi R. Human Natural Killer Lymphocytes Directly Recognize Evolutionarily Conserved Oligosaccharide Ligands Expressed by Xenogeneic Tissues. Transplantation (1997) 63(9):1318–30. doi: 10.1097/00007890-199705150-00021

45. Forte P, Baumann BC, Weiss EH, Seebach JD. HLA-E Expression on Porcine Cells: Protection From Human NK Cytotoxicity Depends on Peptide Loading. Am J Transplant (2005) 5(9):2085–93. doi: 10.1111/j.1600-6143.2005.00987.x

46. Muller YD, Golshayan D, Ehirchiou D, Wekerle T, Seebach JD, Bühler LH. T Regulatory Cells in Xenotransplantation. Xenotransplantation (2009) 16(3):121–8. doi: 10.1111/j.1399-3089.2009.00531.x

47. Lin YJ, Hara H, Tai HC, Long C, Tokita D, Yeh P, et al. Suppressive Efficacy and Proliferative Capacity of Human Regulatory T Cells in Allogeneic and Xenogeneic Responses. Transplantation (2008) 86(10):1452–62. doi: 10.1097/TP.0b013e318188acb0

48. Singh AK, Chan JL, Seavey CN, Corcoran PC, Hoyt RF Jr, Lewis BGT, et al. CD4+CD25(Hi) FoxP3+ Regulatory T Cells in Long-Term Cardiac Xenotransplantation. Xenotransplantation (2018) 25(2):e12379. doi: 10.1111/xen.12379

49. Wu J, Hu M, Qian YW, Hawthorne WJ, Burns H, Liuwantara D, et al. In Vivo Costimulation Blockade-Induced Regulatory T Cells Demonstrate Dominant and Specific Tolerance to Porcine Islet Xenografts. Transplantation (2017) 101(7):1587–99. doi: 10.1097/TP.0000000000001482

50. Huang D, Wang Y, Hawthorne WJ, Hu M, Hawkes J, Burns H, et al. Ex Vivo -Expanded Baboon CD39 + Regulatory T Cells Prevent Rejection of Porcine Islet Xenografts in NOD-SCID IL-2rγ(-/-) Mice Reconstituted With Baboon Peripheral Blood Mononuclear Cells. Xenotransplantation (2017) 24(6):e12344. doi: 10.1111/xen.12344

51. Schmitz R, Fitch ZW, Schroder PM, Choi AY, Jackson AM, Knechtle SJ, et al. B Cells in Transplant Tolerance and Rejection: Friends or Foes? Transpl Int (2020) 33(1):30–40. doi: 10.1111/tri.13549

52. Ezzelarab M, Thomson AW. Tolerogenic Dendritic Cells and Their Role in Transplantation. Semin Immunol (2011) 23(4):252–63. doi: 10.1016/j.smim.2011.06.007

53. Madelon N, Montanari E, Gruaz L, Pimenta J, Muller YD, Bühler LH, et al. Prolongation of Rat-to-Mouse Islets Xenograft Survival by Co-Transplantation of Autologous IL-10 Differentiated Murine Tolerogenic Dendritic Cells. Xenotransplantation (2020) 27(4):e12584. doi: 10.1111/xen.12584

54. Li M, Eckl J, Abicht JM, Mayr T, Reichart B, Schendel DJ, et al. Induction of Porcine-Specific Regulatory T Cells With High Specificity and Expression of IL-10 and TGF-β1 Using Baboon-Derived Tolerogenic Dendritic Cells. Xenotransplantation (2018) 25(1):e12355. doi: 10.1111/xen.12355

55. Platt JL, Cascalho M, Piedrahita JA. Xenotrasnplantation: Progress Along Paths Uncertain From Models to Application. ILAR J (2018) 59(3):286–308. doi: 10.1093/ilar/ily015

56. Iwase H, Klein EC, Cooper DKC. Physiologic Aspects of Pig Kidney Transplantation in Nonhuman Primates. Comp Med (2018) 68(5):3332–340. doi: 10.30802/AALAS-CM-17-000117

57. Ekser B, Bianchi J, Ball S, Iwase H, Walters A, Ezzelerab M, et al. Comparison of Hematologic, Biochemical, and Coagulation Parameters in α1,3-Galactosyltransferase Gene-Knockout Pigs, Wild-Type Pigs, and 4 Primate Species. Xenotransplantation (2012) 19(6):342–54. doi: 10.1111/xen.12007

58. Iwase H, Kobayashi T. Current Status of Pig Kidney Xenogtransplantation. Int J Surg (2015) 23:229–33. doi: 10.1016/j.ijsu.2015.07.721

59. Soin B, Smith KG, Zaidi A, Cozzi E, Bradley JR, Ostlie DJ, et al. Physiological Aspects of Pig-to-Primate Renal Xenotransplantation. Kidney Int (2001) 60(4):1592–7. doi: 10.1046/j.1523-1755.2001.00973.x

60. Reiser J, Fornoni A. Rituximab: A Boot to Protect the Foot. J Am Soc Nephrol (2014) 25(4):647–8. doi: 10.1681/ASN.2013121331

61. Tasaki M, Shimizu A, Hanekamp I, Torabi R, Villani V, Yamada K. Rituximab Treatment Prevents the Early Development of Proteinuria Following Pig-to-Baboon Xeno-Kidney Transplantation. J Am Soc Nephrol (2014) 25(4):737–44. doi: 10.1681/ASN.2013040363

62. Muller YD, Ghaleb N, Rotman S, Vionnet J, Halfon M, Catana E, et al. Rituximab as Monotherapy for the Treatment of Chronic Active Antibody-Mediated Rejection After Kidney Transplantation. Transpl Int (2018) 31(4):451–5. doi: 10.1111/tri.13111

63. Goerlich CE, Sing A, Treffalls JA, Griffith B, Ayares D, Mohiuddin MM. An Intrinsic Link to an Extrinsic Cause of Cardiac Xenograft Growth After Xenotransplantation. Xenotransplantation (2022) 29(1):e12724. doi: 10.1111/xen.12724

64. Goerlich CE, Griffith B, Hanna P, Hong SN, Ayares D, Sing AK, et al. The Growth of Xenotranspkanted Hearts can be Reduced With Growth Hormone Receptor Knockout Pig Donors. J Thorac Cardiovasc Surg (2021) 21:1261–7. doi: 10.1016/j.jtcvs.2021.07.051

65. Pierson RN III, Fisherman JA, Lewis GD, D’Alessandro DA, Connoly MR, Burdorf L, et al. Progress Toward Cardiac Xenotransplantation. Circulation (2020) 142:1389–98. doi: 10.1161/CIRCULATIONAHA.120.048186

66. Fernandez-Ruiz I. Breakthrough in Heart Xenotransplantation. Nat Rev Cardiol (2019) 16:69. doi: 10.1038/s41569-018-0151-4

67. Shah JA, Patel MS, Elias N, Navarro-Alvarez N, Rosales I, Wilkinson RA, et al. Prolonged Survival Following Pig-To-Primate Liver Xenotransplantation Utilizing Exogenous Coagulation Factors and Co-Stimulation Blockade. Am J Transplant (2017) 17(8):2178–85. doi: 10.1111/ajt.14341

68. Meier RPH, Muller YD, Balaphas A, Morel P, Pascual M, Seebach JD, et al. Xenotransplantation: Back to the Future? Transplant Int (2017) 31(5):465–77. doi: 10.1111/tri.13104

69. Cowan PJ, Cooper DKC, d’Apice AJF. Kidney Xenotransplantation. Kidney Int (2014) 85(2):265–75. doi: 10.1038/ki.2013.381

70. United States Renal Data System Annual Data Report: Epidemiology of Kidney Disease in the United States, U.S.R.D. System. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases (2021).

71. Wijkstrom M, Iwase H, Paris W, Hara H, Ezzelarab M, Cooper DKC. Renal Xenotransplantation: Experimental Progress and Clinical Prospects. Kidney Int (2016) 91(4):790–6. doi: 10.1016/j.kint.2016.08.035

72. Zhang Z, Hara H, Long C, Hayato I, Qi H, Macedo C, et al. Immune Responses of HLA-Highly-Sensitized and Nonsensitized Patients to Genetically-Engineered Pig Cells. Transplantation (2018) 102(5):e195–204. doi: 10.1097/TP.0000000000002060

73. Adams AB, Kim SC, Martens GR, Ladowski JM, Estrada JL, Reyes LM, et al. Xenoantigen Deletion and Chemical Immunosuppression Can Prolong Renal Xenograft Survival. Ann Surg (2018) 268(4):564–73. doi: 10.1097/SLA.0000000000002977

74. Brouard S, Vanhove B, Gagne K, Neumann A, Douillard P, Moreau A, et al. T Cell Repertoire Alterations of Vascularized Xenografts. J Immunol (1999) 162(6):3367–77. doi: 10.1016/s0041-1345(00)01038-1

75. Fischer K, Rieblinger B, Hein R, Sfriso R, Zuber J, Fischer A, et al. Viable Pigs After Simultaneous Inactivation of Porcine MHC Class I and Three Xenoreactive Antigen Genes GGTA1, CMAH and B4GALNT2. Xenotransplantation (2020) 27(1):e12560. doi: 10.1111/xen.12560

76. Reyes LM, Estrada JL, Wang ZY, Blosser RJ, Smith RF, Sidner RA, et al. Creating Class I MHC-Null Pigs Using Guide RNA and the Cas9 Endonuclease. J Immunol (2014) 193(11):5751–7. doi: 10.4049/jimmunol.1402059

77. Ladowski JM, Hara H, Cooper DKC. The Role of SLAs in Xenotransplantation. Transplantation (2021) 105(2):300–7. doi: 10.1097/TP.0000000000003303

78. Da Silva IRF, Frontera JA. Worldwide Barriers to Organ Donation. JAMA Neurlogy (2015) 72(1):112–8. doi: 10.1001/jamaneurol.2014.3083

79. Pierson RN, Burdorf L, Madsen JC, Lewis GD, D’Alessandro DA. Pig-To-Human Heart Transplantation: Who Goes First? Am J Transplant (2020) 20(10):2669–74. doi: 10.1111/ajt.15916

80. Rothblatt M. Commentary on Achievement of First Life-Saving Xenoheart Transplant. Xenotransplantation (2022):e12746. doi: 10.1111/xen.12746

81. Christiaan Barnard, in: Encyclopaedia Britannica . Available at: https://www.britannica.com/biography/Christiaan-Barnard (Accessed March 19, 2022).

82. Cooper D. Genetically Engineered Pig Kidney Transplantation in a Brain-Dead Subject. Xenotransplantation (2021) 28(6):e12718. doi: 10.1111/xen.12718

83. DeVries C. NYU Langone Health Performs Second Successful Xenotransplantation Surgery . New York, New York: NYU Langone (2021).

84. Kim SC, Mathews DV, Breeden CP, Higginbotham LB, Ladowski J, Martens G, et al. Long-Term Survival of Pig-to-Rhesus Macaque Renal Xenografts is Dependent on CD4 T Cell Depletion. Am J Transplant (2019) 19(8):2174–85. doi: 10.1111/ajt.15329

85. Ma D, Hirose T, Lassiter G, Sasaki H, Rosales I, Coe TM, et al. Kidney Transplantation From Triple-Knockout Pigs Expressing Multiple Human Proteins in Cynomolgus Macaques. Am J Transplant (2022) 22(1):46–57. doi: 10.1111/ajt.16780

86. Hirose T, Ma D, Lassiter G, Sasaki H, Rosales I, Coe T, et al. Successful Long-Term TMA- and Rejection-Free Survival of a Kidney Xenograft With Triple Xenoantigen Knockout Plus Insertion of Multiple Human Transgenes. Am J Transplant (2021) 21(s4):477–7. doi: 10.1111/ajt.16847

87. Hu X, Geng Z, Gonelle C, Hawthrone WJ, Deng S, Buhler L. International Human Xenotransplantation Inventory: A 10-Y Follow-Up. Transplantation (2022). doi: 10.1097/TP.0000000000004016

88. Rollin BE. Ethical and Societal Issues Occasioned by Xenotransplantation. Anim (Basel) (2020) 10(9):1965. doi: 10.3390/ani10091695

89. Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States: 2019. Atlanta, GA: US Department of Health and Human Services (2019).

90. Fishman JA. Infectious Disease Risks in Xenotransplantation. Am J Transplant (2018) 18:1857–64. doi: 10.1111/ajt.14725

91. Yang L, Guell M, Niu D, George H, Lesha E, Grishin D, et al. Genome-Wide Inactivation of Porcine Endogenous Retroviruses (PERVs). Science (2015) 350(6264):1101–4. doi: 10.1126/science.aad1191

92. Montgomery RA, Stern JM, Lonze BE, Tatapudi VS, Mangiola M, Wu M, et al. Results of Two Cases of Pig-to-Human Kidney Xenotransplantation. N Engl J of Med (2022) 386(20):1889–98. doi: 10.1056/NEJMoa2120238

Keywords: xenotransplantation, kidney, heart, rejection, clinical trial, pig, xenograft

Citation: Carrier AN, Verma A, Mohiuddin M, Pascual M, Muller YD, Longchamp A, Bhati C, Buhler LH, Maluf DG and Meier RPH (2022) Xenotransplantation: A New Era . Front. Immunol. 13:900594. doi: 10.3389/fimmu.2022.900594

Received: 20 March 2022; Accepted: 02 May 2022; Published: 09 June 2022.

Reviewed by:

Copyright © 2022 Carrier, Verma, Mohiuddin, Pascual, Muller, Longchamp, Bhati, Buhler, Maluf and Meier. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Raphael P. H. Meier, [email protected] ; orcid.org/0000-0001-9050-0436

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

• U.S. Department of Health & Human Services

• Virtual Tour
• Staff Directory
• En Español

You are here

Nih research matters.

September 24, 2024

Mapping a brain network involved in depression

At a glance.

• Researchers found differences in brain network organization that are associated with depression.
• The findings suggest mechanisms underlying depression and could lead to new ways to diagnose, prevent, and treat depression.

The mechanisms that lead to depression are poorly understood. Depression symptoms aren’t constant, but often come and go, making them difficult to study. Previous brain imaging studies have shown only modest differences between people with and without depression. Yet few imaging studies have tracked individuals with depression over time.

A brain imaging technique called precision functional mapping uses functional magnetic resonance imaging (fMRI) to analyze the connectivity or activation of different brain areas. This has revealed variations in the size, shape, and location of brain areas and networks across healthy people.

A research team led by Drs. Charles Lynch and Conor Liston at Weill Cornell Medicine used precision functional mapping to analyze brain networks in people with depression and healthy controls. Some of the people with depression were scanned dozens of times over several months. This allowed the researchers to observe changes over time associated with mood shifts. Results appeared in Nature on September 4, 2024.

The team began by mapping networks over time in six people with major depression and 37 healthy controls. They found that the salience network, which includes brain regions in the frontal cortex and striatum, was almost twice as large on average in people with depression. This network is involved in reward processing and determining what to pay attention to. The size of the salience network did not change over time in people with or without depression. Nor did it relate to depression symptoms in people with depression.

To confirm that a larger salience network is associated with depression, the team mapped brain networks in 135 more people. In this larger group, the salience network was significantly larger than in healthy controls. The enlarged salience network led to a decrease in the size of neighboring networks.

These results suggested that an enlarged salience network might be associated with the risk of developing depression. To find out, the researchers analyzed data from the Adolescent Brain Cognitive Development study. Fifty-seven children in this study didn’t have depression symptoms initially but developed them by age 13 or 14. The team found that children who later developed depression had larger salience networks than those who never developed depression.

Further study showed that the strength of connectivity between certain parts of the salience network changed over time. These changes correlated with the timing of depressive symptoms. In one person, connectivity changes preceded depressive symptoms by up to a week.

The results suggest that expansion of the salience network may predispose people to depression. They also suggest that changes in functional connectivity within this network may drive mood changes in people with depression.

However, challenges remain for using this information to predict depression. “For years, many investigators assumed that brain networks look the same in everybody,” Lynch says. “But the findings in this work build on a growing body of research indicating that there are fundamental differences between individuals.”

Future work will be needed to assess whether the patterns seen in this study are specific for depression or shared with other psychological disorders. Analysis of the salience network may have potential value in the clinic. The knowledge gained in this study might also help guide the development of novel prevention and treatment strategies.

—by Brian Doctrow, Ph.D.

Related Links

• Research in Context: Treating Depression
• New Insights into the Brain’s Motor Cortex
• Factors That Affect Depression Risk
• Neural Signature Predicts Antidepressant Response
• How Ketamine Relieves Symptoms of Depression
• Depression Screening and Treatment in Adults
• An Expanded Map of The Human Brain
• Mapping Brain Circuits Involved in Attention
• Shake it Off: Boosting Your Mood
• Brain Basics: Know Your Brain
• Magnetic Resonance Imaging (MRI)

References:  Frontostriatal salience network expansion in individuals in depression. Lynch CJ, Elbau IG, Ng T, Ayaz A, Zhu S, Wolk D, Manfredi N, Johnson M, Chang M, Chou J, Summerville I, Ho C, Lueckel M, Bukhari H, Buchanan D, Victoria LW, Solomonov N, Goldwaser E, Moia S, Caballero-Gaudes C, Downar J, Vila-Rodriguez F, Daskalakis ZJ, Blumberger DM, Kay K, Aloysi A, Gordon EM, Bhati MT, Williams N, Power JD, Zebley B, Grosenick L, Gunning FM, Liston C. Nature . 2024 Sep;633(8030):624-633. doi: 10.1038/s41586-024-07805-2. Epub 2024 Sep 4. PMID: 39232159.

Funding:  NIH’s National Institute of Mental Health (NIMH) and National Institute on Drug Abuse (NIDA); Hope for Depression Research Foundation; Foundation for OCD Research; Wellcome Leap; Deutsche Forschungsgemeinschaft.

Connect with Us

• More Social Media from NIH

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

The PMC website is updating on October 15, 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• HHS Author Manuscripts

XENOTRANSPLANTATION: PAST, PRESENT, AND FUTURE

Burcin ekser.

1 Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

David K.C. Cooper

2 Xenotransplantation Program, Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA

Purpose of review

To review the progress in the field of xenotransplantation with special attention to most recent encouraging findings which will eventually bring xenotransplantation to the clinic in the near future.

Recent findings

Starting from early 2000, with the introduction of Gal-knockout pigs, prolonged survival especially in heart and kidney xenotransplantation was recorded. However, remaining antibody barriers to nonGal antigens continue to be the hurdle to overcome. The production of genetically-engineered pigs was difficult requiring prolonged time. However, advances in gene editing, such as zinc finger nucleases, transcription activator-like effector nucleases, and most recently CRISPR technology made the production of genetically-engineered pigs easier and available to more researchers. Today, the survival of pig-to-nonhuman primate heterotopic heart, kidney, and islet xenotransplantation reached >900 days, >400 days, and >600 day, respectively. The availability of multiple-gene pigs (5 or 6 genetic modifications) and/or newer costimulation blockade agents significantly contributed to this success. Now, the field is getting ready for clinical trials with an international consensus.

Clinical trials in cellular or solid organ xenotransplantation are getting closer with convincing preclinical data from many centers. The next decade will show us new achievements and additional barriers in clinical xenotransplantation.

Introduction

Outcomes of organ and cell allotransplantation continue to improve. However, the shortage of transplantable organs remains as the major hurdle in the field of transplantation despite the use of marginal deceased donors and living donors [ 1 ]. Xenotransplantation (i.e., cross-species transplantation between pig and humans) could offer an unlimited and prompt supply of transplantable organs, when needed [ 2 ]. In addition to organ transplantation, many disorders could be treated by xenotransplantation ( Figure 1 ).

* Reproduced with permission from Ekser et al [ 2 ].

In this review, we (i) briefly mention the past experience with xenotransplantation (mainly by referring to seminal review articles), (ii) provide a review of the most recent (within the last 24 months) advances in the field ( present ), and suggest future applications in the clinic ( future ).

The concept of xenotransplantation is not new, and there have been numerous clinical attempts during the past 300 years or more [ 3 ]. Clinical blood xenotransfusion was attempted in the 17 th century by Jean Baptiste Denis, corneal xenotransplantation from pig-to-human followed in the early 19 th century, and attempts were made at nonhuman primate (NHP) kidney xenotransplantation in the 1960s by Reemtsma [ 3 , 4 ] and others [ 5 ]. The world experience in pig-to-NHP models of xenotransplantation (until 1997) was reviewed by Lambrigts et al. [ 6 ], and a comprehensive review regarding progress in pig-to-NHP since then (1998–2013) was published in 2014 [ 7 ].

Xenotransplantation research was stimulated by the production of pigs in which the important antigen, galactose-α1,3-galactose (Gal), had been deleted by gene-knockout (GTKO pigs) in 2003 [ 8 ]. More recently, the identification of other xenoantigens has also been important.

Techniques for making genetically-engineered pigs have become easier and faster. Rapid improvement in the results of preclinical studies has made the field more hopeful of the initiation of clinical trials [ 8 – 11 ]. Recent papers have discussed the selection of patients for initial clinical trials for solid organ xenotransplantation [ 12 ] and islet xenotransplantation. We here briefly review progress in pig-to-NHP models.

Heart xenotransplantation

Mohiuddin et al [ 13 ] demonstrated that long-term survival of genetically-engineered pig heterotopic heart grafts could be achieved in NHPs. Genetic modifications in the pig (GTKO.hCD46.hThrombomodulin) combined with a successful treatment regimen based on a chimeric anti-CD40 monoclonal antibody (mAb), consistently prevented humoral rejection and systemic coagulation pathway dysregulation, sustaining cardiac xenograft survival in one case beyond 900 days ( Figure 2 ) [ 13 ].

Microencapsulated pancreatic xeno-islets survived for 804 days with retransplantation, but 250 days without retransplantation. Neuronal xeno-cells survived for 521 days. Pancreatic xeno-islets survived for >603 days. Corneal (deep-lamellar) xenografts survived for >389 days. Xeno-hepatocytes survived for 243 days with retransplantation, but 80 days without retransplantation. Heterotopic xeno-heart survived for >900 days. Kidney xenograft (life-supporting) survived for 405 days. Orthotopic xeno-heart survived for 57 days. Liver xenograft survived for 29 days. Lung xenograft survived for 5 days.

Iwase et al. tested three different costimulation blockade-based immunosuppressive regimens in the pig-to-baboon heterotopic heart xenotransplantation model, and demonstrated that the combination of anti-CD40mAb+belatacept proved effective in preventing a T cell response [ 14 ]. Despite significant progress on the survival of heterotopic pig heart xenotransplantation, orthotopic heart xenotransplantation experiments were limited and the longest survival recorded to date was <60 days. Murthy et al recently reviewed the historical background, experimental progress, and clinical prospects in heart xenotransplantation [ 15 ].

Kidney xenotransplantation

The last 2 years have shown us that we are close to clinical trials of genetically-engineered pig kidney xenotransplantation. Two groups separately showed prolonged survival of life-supporting renal xenografts compared with historical 90-day survival [ 2 , 6 ] in different pig-to-NHP models [ 16 , 17 ]. The Emory group performed pre-transplant antibody screening in recipient monkeys and showed that the combination of low titer antibody and anti-CD154mAb costimulation blockade promoted long-term renal xenograft survival [ 16 ]. The Pittsburgh group showed that specific genetic modifications of the pig are important in achieving prolonged survival [ 17 ]. Most recently, Kim et al reported the longest survival (405 days) of a life-supporting pig kidney xenograft in a preclinical model, emphasizing the importance of CD4 + T cell depletion ( Figure 2 ) [ 18 ].

Tanabe et al. studied the role of intrinsic (graft) versus extrinsic (host) factors in the growth of renal xenografts in GTKO pig-to-baboon model and identified that not only the size-mismatch (extrinsic – host factors), but also the intrinsic (graft) factors are responsible for growth of donor organs with a threshold for renal xenograft volume of 25cm 3 /kg of recipient body weight at which cortical ischemia was induced [ 19 ]. Iwase et al reported the immunological and physiological observations in baboons with life-supporting genetically-engineered pig kidney grafts with particular attention to the use of multiple-gene pigs, an effective costimulation blockade-based immunosuppressive regimen, and anti-inflammatory therapy in preventing immune injury [ 20 ]. In a recent review, Wijkstrom et al discussed the experimental progress and clinical prospects in renal xenotransplantation [ 21 ].

Lung xenotransplantation

Most recently, only the Maryland group has been active in exploring lung xenotransplantation. Burdorf et al. showed that platelet sequestration and activation during GTKO.hCD46 pig lung perfusion by human blood was primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor [ 22 ]. Laird et al showed that transgenic expression of human leukocyte antigen (HLA)-E attenuates GTKO.hCD46 pig lung xenograft injury [ 23 ]. A recent review from the same group concluded that genetic modification of pigs coupled with drugs targeting complement activation, coagulation, and inflammation have significantly increased duration of pig lung function in ex vivo human blood perfusion models, and life-supporting lung xenograft survival in vivo [ 24 ]. However, lung xenotransplantation is still measured in days rather than weeks or months.

Liver xenotransplantation

Although limited, fairly consistent 7–9 days’ survival has been reported by different groups using GTKO and GTKO.hCD46 pig liver xenografts in NHPs after orthotopic pig liver xenotransplantation [ 25 ]. The Boston group increased survival to 29 days by the exogenous administration of human coagulation factors using the same model [ 26 ]. They reported two GTKO pig liver xenografts that survived >25 days (longest 29 days) ( Figure 2 ), with immunosuppressive therapy consisting of anti-CD40mAb or belatacept [ 27 ]. Although there remain problems with this regimen, clinical trials of bridging to allotransplantation with a pig liver graft might become a possibility [ 28 ].

Islet xenotransplantation

In 2016, the International Xenotransplantation Association (IXA) published the first update on its consensus statement on conditions for undertaking clinical trials of porcine islet products in patients with type 1 diabetes [ 29 – 36 ]. This comprehensive report included (i) an update on national regulatory frameworks pertinent to clinical islet xenotransplantation [ 30 ], (ii) evaluation of the source of pigs in order to prevent xenozoonoses [ 31 ], (iii) genetically-modified pigs as the source of islets [ 32 ], (iv) production and manufacturing of porcine islets [ 33 ], (v) requirement and efficacy of the pre-clinical data to justify a clinical trial [ 34 ], (vi) recipient monitoring and response plan for preventing disease transmission [ 35 ], and, finally, (vii) patient selection for pilot clinical trials of pig islet xenotransplantation [ 36 ].

Matsumoto et al published a clinical trial using encapsulated neonatal wild-type pig islets in patients with type 1 diabetes [ 37 ]. Their study showed that there was a clinical benefit of islet xenotransplantation with improved HbA1c, especially when a greater number of islets was transplanted [ 37 ]. Although recipients did not become normoglycemic, the study provided some hope for future clinical trials [ 38 ].

While progress of encapsulation (micro or macro) is still under investigation [ 39 ], studies have recently been published on the use of different materials, such as agarose encapsulation, the microbiological safety of porcine islets [ 40 ], and the anti-fibrotic effect of rapamycin-containing polyethylene glycol-coated alginate microcapsules [ 41 ]. New drugs, such as cell-penetrating tat-metallothionein for immunomodulation have been studied, together with xeno-islet encapsulation [ 42 , 43 ].

Although a recent pre-clinical study by Shin et al showed long-term control of diabetes in NHPs by the transplantation of wild-type adult porcine islets [ 44 ], a study by Kang et al showed that higher D-dimer levels negatively correlated with survival of porcine islet xenografts [ 45 ]. Despite more data becoming available on pig islet xenotransplantation in NHPs, the streptozotocin-induced diabetes model in NHP is still under debate [ 46 ].

The field is being advanced by the use of newly-available genetically-modified pigs and newer costimulation blockade agents. Lee et al used pig islets overexpressing human hemeoxygenase-1 and soluble tumor necrosis factor-alpha receptor type 1 with human IgG1 Fc in order to suppress early apoptosis during engraftment of xeno-islets [ 47 ]. Arefanian et al showed that porcine islet-specific tolerance induced by the combination of anti-lymphocyte function-associated antigen-1 and anti-CD154mAb is dependent on PD-1 (programmed cell death protein-1) [ 48 ]. Two recent reviews by Hawthorne et al [ 49 ] on genetic strategies to bring islet xenotransplantation to the clinic, and Bottino et al [ 50 ] on the safe use of anti-CD154mab underline the importance of genetic engineering and costimulation blockade in islet xenotransplantation. Recently, a seminal review was published by Liu et al on the past, present, and future of pig-to-primate islet xenotransplantation [ 51 ].

Tissue (cornea, heart valve, skin) xenotransplantation

Porcine corneal xenotransplantation shows promising application in the clinic. Lee et al studied the impact of the expression of N-glycolylneuraminic acid on pig corneas, concluding that the absence of N-glycolylneuraminic acid expression on GTKO pig corneas may not prove an advantage over GTKO pig corneas [ 52 , 53 ]. Dong et al recently published their initial results of GTKO.hCD46 pig full-thickness corneal xenografts in NHPs, which were comparable to the survival of wild-type pig corneas [ 54 ]. Lee et al provided evidence that the limiting factor of survival of pig corneas was the development of a retrocorneal membrane [ 55 ]. The Seoul group recently reported prolonged survival (>389 days) of porcine deep-lamellar corneal xenografts in NHPs under immunosuppressive therapy with anti-CD40mAb ( Figure 2 ) [ 56 ]. The same group also published the biophysico-functional compatibility of their miniature pig corneas as grafts in clinical trials [ 57 ].

Reuven et al [ 58 ] and Lee et al [ 59 ] studied the impact of N-glycolylneuraminic acid expression in bioprosthetic pig heart valves on human antibody recognition and structural deterioration.

Tena et al demonstrated that pig cells expressing human CD47 are associated with an immune-modulating effect, which leads to markedly-prolonged survival of pig skin grafts in NHPs [ 60 ].

Cellular (hepatocyte, neuronal cell) xenotransplantation

Machaidze et al tested porcine hepatocytes in alginate-poly-l-lysine microspheres transplanted intraperitoneally immediately after hepatectomy in a model of fulminant liver failure in baboons [ 61 ]. The microencapsulated porcine hepatocytes provided temporary functional support [ 61 ]. Mahou et al. reviewed the contribution of polymeric materials in the xenotransplantation of microencapsulated cells (mainly hepatocytes and islets), and addressed the state-of-the-art in cell microencapsulation with special focus on the choice of materials, and the design and fabrication of the microspheres [ 62 ]. Iwase et al. transplanted genetically-engineered pig hepatocytes directly into the spleen and other sites in immunosuppressed baboons, and reported very early graft failure [ 63 ].

The European Consortium (Xenome Project) studied the feasibility of pig neuronal cell xenotransplantation in NHPs to cure Parkinson’s disease [ 64 ]. Parkinsonian NHPs received wild-type or CTLA4-Ig-transgenic porcine xenografts and different durations of exogenous immunosuppressive therapy to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in the NHPs that received systemic plus local immunosuppression for 6 months, which was also associated with restoration of dopaminergic activity [ 64 ]. However, some recipients developed post-transplant lymphoproliferative disease, probably due to over-immunosuppression [ 65 ].

Inflammation and coagulation

Further attention was directed to inflammation in xenotransplantation. Ezzelarab et al. showed that systemic inflammation in xenograft recipients precedes activation of coagulation [ 66 ]. Iwase et al. measured serum free triiodothyronine (thyroid hormone) as a marker of inflammation in healthy naïve baboons, healthy naïve monkeys, and after pig-to-baboon heterotopic heart xenotransplantation, orthotopic liver xenotransplantation, artery patch xenotransplantation, and in monkey heterotopic heart allotransplantation [ 67 ]. They showed that there is a dramatic fall in serum thyroid hormone levels following operative procedures. A persistent low level of thyroid hormone after pig heart and liver xenotransplantation may be associated with a continuing inflammatory state, which might be corrected with extraneous replacement of thyroid hormone [ 67 ]. Other inflammatory states and markers, particularly of extracellular histones, have been discussed with their potential therapeutic regulation in xenotransplantation [ 68 , 69 ].

The potential for the transmission of infection from animal-to-human has always been of concern. Therefore, several porcine viruses have been studied in regard to xenotransplantation. Denner et al. published seminal reviews on virological safety in xenotransplantation [ 70 , 71 ]. Particular attention has been directed to porcine endogenous retroviruses (PERV) [ 72 ], their susceptibility to retroviral inhibitors [ 73 ], and their genome-wide inactivation by genetic technology [ 74 ]. Morozov et al. showed that there was no PERV transmission during a clinical trial of pig islet xenotransplantation [ 75 ]. Similarly, no PERV transmission was shown by Choi et al. in pig-to-NHP corneal xenotransplantation [ 76 ]. Morozov et al. also published an extended characterization of porcine cytomegalovirus and other viruses in specially-bred pigs [ 77 ].

Porcine circoviruses (both type 1 and 2) were recently studied [ 78 ]. Whereas type 1 is not pathogenic in pigs, type 2 may induce severe disease. Although there is evidence that type 2 porcine circovirus does not infect (at least immunocompetent) humans, the recommendation is that pigs that will be sources of xenografts should be screened using sensitive methods to ensure virus elimination [ 78 ].

Ethics and regulatory aspects

As initial clinical trials draw closer, ethics [ 79 ], acceptance of xenotransplantation by hospital personnel [ 80 ], and by the general population with different cultural and religious backgrounds [ 81 – 83 ], are topics of importance. Schuurman has recently comprehensively reviewed regulatory aspects of xenotransplantation in Europe and in the United States in his seminal papers [ 84 – 85 ].

Genetic engineering

The introduction of CRISPR (clustered regularly interspaced short palindromic repeats) technology in xenotransplantation has increased the speed in which genetic manipulations can be achieved in pigs. In the early years, genetic engineering of pigs was performed by homologous recombination, which might take longer than 2 years from cell work to pregnancy [ 86 ]. Table 1 summarizes the timeline of the evolving genetic engineering techniques in xenotransplantation. Today, research groups can produce multiple gene knock-out or knock-in pigs using CRISPR technology [ 87 – 94 ], which can also be used to delete PERV expression [ 74 , 95 ]. Genetically-modified pigs using CRIPSR technology have been used in several important studies relating to antibody binding [ 96 – 98 ] and coagulation dysfunction [ 99 , 100 ]. There are now more than 26 genetically-engineered pigs for xenotransplantation research ( Table 2 ). Cooper recently published a review on carbohydrate antigen targets on pig cells [ 101 ]. Cowan et al also published a commentary on the importance of modifying the glycome in pigs for xenotransplantation [ 102 ].

Timeline for application of evolving techniques for genetic engineering of pigs employed in xenotransplantation.

CRISPR/Cas9, clustered randomly interspaced short palindromic repeats and the associated protein 9. (Table adopted from Cooper et al.) [ 8 ]

Selected genetically-modified pigs currently available for xenotransplantation research *

Future of xenotransplantation

With our accumulated experience [ 2 , 103 ] and recent achievements [ 13 , 18 , 86 ] in xenotransplantation, the stage may now be set for the first-in-human exploration [ 11 ]. Although a small clinical trial of microencapsulated wild-type pig islet xenotransplantation is currently underway [ 37 , 38 ], the future is set for well-controlled trials of genetically-engineered pig islet xenotransplantation. The xenotransplantation research community needs to decide (i) whether successful orthotopic heart transplantation in the pig-to-NHP model is required before proceeding to a clinical trial [ 104 ], and (ii) whether the preclinical threshold for a clinical renal xenotransplantation trial can be reduced [ 105 ].

The resurgence of xenotransplantation is now obvious [ 9 , 10 , 106 ], with prolonged survival of cellular and solid organ xenografts ( Figure 2 ) associated with the administration of newer costimulation blockade agents [ 107 , 108 ] and access to genetically-engineered pigs. Our increasing knowledge of the pig genome [ 109 ] will almost certainly lead to further genetic manipulations. The future of xenotransplantation is vibrant.

• In the last 24 months, prolonged survivals were achieved in heart, kidney, liver, islet, and corneal xenotransplantation with the use of genetically-engineered pigs and/or newer costimulation blockade agents.
• Thanks to the CRISPR technology, the production of multiple-gene pigs is easier and faster and more genetically-engineered pigs are now available for xenotransplantation research.
• The International Xenotransplantation Association has recently published the first update of the consensus statement on conditions for undertaking clinical trials of porcine islet products.
• First-in-man explorations (in some organs), and/or clinical (solid organ, islet, or tissue) xenotransplantation trials might start sooner than expected.

Acknowledgments

Work on xenotransplantation in the Xenotransplantation Research Laboratory at Indiana University has been supported by internal funds of the Department of Surgery. Work on xenotransplantation at the University of Alabama at Birmingham is supported in part by NIH NIAID U19 grant AI090959.

Abbreviations

Conflict of interest

The authors declare no conflict of interest.

References and Recommended Reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

* of special interest

** of outstanding interest

Surging AI demand could cause the world's next chip shortage, research says

A surge in demand for artificial intelligence-focused semiconductors and AI-enabled smartphones and laptops could lead to the next global chip shortage, according to a report released Wednesday by consultancy Bain & Co.

The last major semiconductor shortage happened during the Covid-19 pandemic amid supply chain disruption and a rise in demand for consumer electronics as people were forced to stay and work at home.

Technology giants have been snapping up graphics processing units, or GPUs, mainly from  Nvidia . These GPUs which are housed in data centers are critical for the training of huge AI models which underpin applications like OpenAI’s ChatGPT.

Meanwhile, companies like  Qualcomm  are designing chips that go into smartphones and personal computers and allow those devices to  run AI applications locally  rather than via an internet connection in the cloud. These are often referred to as AI-enabled devices and companies from Samsung to  Microsoft  have released such products.

Bain said demand for GPUs and AI consumer electronics could be the cause of a chip shortage.

“Surging demand for graphics processing units (GPUs) has caused shortages in specific elements of the semiconductor value chain,” Anne Hoecker, head of the technology practice in the Americas at Bain, told CNBC by email.

“If we combine the growth in demand for GPUs alongside a wave of AI-enabled devices, which could accelerate PC product refresh cycles, there could be more widespread constraints on semiconductor supply.”

However, it’s  unclear at this point  how much demand such AI-enabled gadgets will have, given what appears to be a cautious approach to them from consumers so far.

Bain noted that the semiconductor supply chain is “incredibly complex, and a demand increase of about 20% or more has a high likelihood of upsetting the equilibrium and causing a chip shortage.”

“The AI explosion across the confluence of the large end markets could easily surpass that threshold, creating vulnerable chokepoints throughout the supply chain,” the report added.

The semiconductor supply chain is spread across multiple companies. For example, while Nvidia might design its GPUs, they are made by Taiwan Semiconductor Manufacturing Co., or  TSMC , in Taiwan. TSMC  relies on chipmaking tools  from countries around the world, such as the Netherlands. Furthermore, the most cutting-edge chips  can only be made at a large scale by TSMC and Samsung Electronics .

Geopolitics could also be a factor prompting a chip shortage. Semiconductors are seen by governments around the world as strategic technology. The U.S. has been on a campaign,  via export restrictions and other sanctions , of trying to restrict China’s access to the most advanced chips. Meanwhile, Washington has sought to shore up its own domestic capacity to produce semiconductors.

“Geopolitical tensions, trade restrictions, and multinational tech companies’ decoupling of their supply chains from China continue to pose serious risks to semiconductor supply. Delays in factory construction, materials shortages, and other unpredictable factors could also create pinch points,” Bain said.

More from CNBC:

• FTX fraudster Caroline Ellison sentenced to 2 years in prison, ordered to forfeit $11 billion
• How birria took over restaurant menus across the country
• Southwest Airlines to cut service and staffing in Atlanta to slash costs

Arjun Kharpal is a senior correspondent for CNBC in London.

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

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Review Article
• Published: 24 September 2024

Encapsulated islet transplantation

• Sophie S. Liu   ORCID: orcid.org/0000-0002-6616-1339 1 ,
• Surim Shim 2 ,
• Yoshimasa Kudo 1 ,
• Cherie L. Stabler 3 , 4 ,
• Eoin D. O’Cearbhaill   ORCID: orcid.org/0000-0002-4666-5863 5 , 6 ,
• Jeffrey M. Karp   ORCID: orcid.org/0000-0002-4752-7374 1 , 7 , 8 , 9 , 10 &
• Kisuk Yang   ORCID: orcid.org/0000-0002-2724-5222 2 , 11  

Nature Reviews Bioengineering ( 2024 ) Cite this article

8 Altmetric

Metrics details

• Biomedical materials
• Cell delivery
• Type 1 diabetes

Islet transplantation may provide a prospective treatment for type 1 diabetes. To enable islet transplantation and restore autonomous glucose monitoring and insulin secretion, islets or β cells can be encapsulated in immuno-protective, polymeric micro- or macroscale coatings that allow the selective exchange of nutrients and small proteins while preventing the infiltration of immune mediators that cause immunorecognition. However, several challenges remain to be addressed before islet-encapsulation technologies can be used in human patients. In this Review, we highlight different islet-encapsulation designs, examining how these can be optimized to improve material biocompatibility, oxygen supply and revascularization at transplant sites and to reduce excessive fibrotic responses. We also discuss how islet-encapsulation approaches can be combined with immunotherapy and gene editing, highlighting regulatory hurdles that will need to be addressed to enable translation to the clinic.

The transplantation of pancreatic islets may restore autonomous insulin function in patients with type 1 diabetes.

Encapsulation technologies based on microcapsules or macroencapsulation devices aim to protect transplanted islets from immune responses and to prolong their survival.

The transplantation of encapsulated islets is often limited by insufficient nutrient transfer, lack of revascularization and excessive fibrosis.

Encapsulation technologies may be combined with immunomodulatory and gene-editing strategies to bypass challenges associated with host immune responses.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 digital issues and online access to articles

111,21 € per year

only 9,27 € per issue

Buy this article

• Purchase on SpringerLink
• Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead

Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes

Finishing the odyssey to a stem cell cure for type 1 diabetes

Foster, N. C. et al. State of type 1 diabetes management and outcomes from the T1D exchange in 2016–2018. Diabetes Technol. Ther. 21 , 66–72 (2019).

Article   Google Scholar  

Atkinson, M. A., Eisenbarth, G. S. & Michels, A. W. Type 1 diabetes. Lancet 383 , 69–82 (2014).

Shapiro, A. M. J. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343 , 230–238 (2000).

Ryan, E. A. et al. Five-year follow-up after clinical islet transplantation. Diabetes 54 , 2060–2069 (2005).

Berney, T. et al. A worldwide survey of activities and practices in clinical islet of Langerhans transplantation. Transpl. Int. 35 , 10507 (2022).

Stabler, C. L. & Russ, H. A. Regulatory approval of islet transplantation for treatment of type 1 diabetes: implications and what is on the horizon. Mol. Ther. 31 , 3107–3108 (2023).

Cnop, M. et al. Longevity of human islet α- and β-cells. Diabetes Obes. Metab. 13 , 39–46 (2011).

Carlsson, P.-O. et al. Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus. Am. J. Transplant. 18 , 1735–1744 (2018).

Shapiro, A. M. J. et al. Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Rep. Med. 2 , 100466 (2021).

Basta, G. et al. Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts. Diabetes Care 34 , 2406–2409 (2011).

Li, Y. et al. In vitro platform establishes antigen-specific CD8 + T cell cytotoxicity to encapsulated cells via indirect antigen recognition. Biomaterials 256 , 120182 (2020).

Jones, K. S., Sefton, M. V. & Gorczynski, R. M. In vivo recognition by the host adaptive immune system of microencapsulated xenogeneic cells. Transplantation 78 , 1454–1462 (2004).

Kobayashi, T. et al. Immune mechanisms associated with the rejection of encapsulated neonatal porcine islet xenografts. Xenotransplantation 13 , 547–559 (2006).

Duvivier-Kali, V. F., Omer, A., Lopez-Avalos, M. D., O’Neil, J. J. & Weir, G. C. Survival of microencapsulated adult pig islets in mice in spite of an antibody response. Am. J. Transplant. 4 , 1991–2000 (2004).

Kharbikar, B. N., Chendke, G. S. & Desai, T. A. Modulating the foreign body response of implants for diabetes treatment. Adv. Drug. Deliv. Rev. 174 , 87–113 (2021).

Veiseh, O. et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat. Mater. 14 , 643–651 (2015).

Chang, T. M. S. Semipermeable microcapsules. Science 146 , 524–525 (1964).

Lim, F. & Sun Anthony, M. Microencapsulated islets as bioartificial endocrine pancreas. Science 210 , 908–910 (1980).

Lee, S. J., Lee, J. B., Park, Y.-W. & Lee, D. Y. In Biomimetic Medical Materials: from Nanotechnology to 3D Bioprinting (ed. Noh, I.) 355–374 (Springer Singapore, 2018).

Kizilel, S., Garfinkel, M. & Opara, E. The bioartificial pancreas: progress and challenges. Diabetes Technol. Ther. 7 , 968–985 (2005).

Sakata, N. et al. MRI assessment of ischemic liver after intraportal islet transplantation. Transplantation 87 , 825–830 (2009).

Chen, C. et al. Improved intraportal islet transplantation outcome by systemic IKK-β inhibition: NF-κB activity in pancreatic islets depends on oxygen availability. Am. J. Transplant. 11 , 215–224 (2011).

Olsson, R., Olerud, J., Pettersson, U. & Carlsson, P. O. Increased numbers of low-oxygenated pancreatic islets after intraportal islet transplantation. Diabetes 60 , 2350–2353 (2011).

Shapiro, A. M. J., Pokrywczynska, M. & Ricordi, C. Clinical pancreatic islet transplantation. Nat. Rev. Endocrinol. 13 , 268–277 (2017).

Qi, M. et al. A recommended laparoscopic procedure for implantation of microcapsules in the peritoneal cavity of non-human primates. J. Surg. Res. 168 , e117–e123 (2011).

Bochenek, M. A. et al. Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques. Nat. Biomed. Eng. 2 , 810–821 (2018).

Damyar, K., Farahmand, V., Whaley, D., Alexander, M. & Lakey, J. R. T. An overview of current advancements in pancreatic islet transplantation into the omentum. Islets 13 , 115–120 (2021).

Berman, D. M. et al. Long-term survival of nonhuman primate islets implanted in an omental pouch on a biodegradable scaffold. Am. J. Transplant. 9 , 91–104 (2008).

Carlsson, P.-O., Palm, F., Andersson, A. & Liss, P. Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site. Diabetes 50 , 489–495 (2001).

Cao, R., Avgoustiniatos, E., Papas, K., Vos, P. & Lakey, J. R. T. Mathematical predictions of oxygen availability in micro‐ and macro‐encapsulated human and porcine pancreatic islets. J. Biomed. Mater. Res. B 108 , 343–352 (2019).

Korsgren, O. Islet encapsulation: physiological possibilities and limitations. Diabetes 66 , 1748–1754 (2017).

Gilla, R. G. Antigen presentation pathways for immunity to islet transplants: relevance to immunoisolation. Ann. NY Acad. Sci. 875 , 255–260 (1999).

Gray, D. W. R. An overview of the immune system with specific reference to membrane encapsulation and islet transplantation. Ann. NY Acad. Sci. 944 , 226–239 (2001).

Brauker, J., Martinson, L. A., Young, S. K. & Johnson, R. C. Local inflammatory response around diffusion chambers containing xenografts. Transplantation 61 , 1671–1677 (1996).

Kumagai-Braesch, M. et al. The TheraCyte™ device protects against islet allograft rejection in immunized hosts. Cell Transpl. 22 , 1137–1146 (2013).

Loudovaris, T., Mandel, T. E. & Charlton, B. Cd4 + T cell mediated destruction of xenografts within cell-impermeable membranes in the absence of Cd8 + T cells and B cells. Transplantation 61 , 1678–1684 (1996).

Rayat, G. R. et al. The degree of phylogenetic disparity of islet grafts dictates the reliance on indirect CD4 T-cell antigen recognition for rejection. Diabetes 52 , 1433–1440 (2003).

Gray, D. W. R. Encapsulated islet cells: the role of direct and indirect presentation and the relevance to xenotransplantation and autoimmune recurrence. Br. Med. Bull. 53 , 777–788 (1997).

O’Shea, G. M., Goosen, M. F. A. & Sun, A. M. Prolonged survival of transplanted islets of Langerhans encapsulated in a biocompatible membrane. Biochim. Biophys. Acta 804 , 133–136 (1984).

Kollmer, M., Appel, A. A., Somo, S. I. & Brey, E. M. Long-term function of alginate-encapsulated islets. Tissue Eng. B 22 , 34–46 (2016).

Ching, S. H., Bansal, N. & Bhandari, B. Alginate gel particles — a review of production techniques and physical properties. Crit. Rev. Food Sci. Nutr. 57 , 1133–1152 (2015).

Dhamecha, D., Movsas, R., Sano, U. & Menon, J. U. Applications of alginate microspheres in therapeutics delivery and cell culture: past, present and future. Int. J. Pharm. 569 , 118627 (2019).

King, A., Lau, J., Nordin, A., Sandler, S. & Andersson, A. The effect of capsule composition in the reversal of hyperglycemia in diabetic mice transplanted with microencapsulated allogeneic islets. Diabetes Technol. Ther. 5 , 653–663 (2003).

Clayton, H. A., London, N. J. M., Colloby, P. S., Bell, P. R. F. & James, R. F. L. The effect of capsule composition on the biocompatibility of alginate-poly-1-lysine capsules. J. Microencapsul. 8 , 221–233 (2008).

King, A., Sandler, S. & Andersson, A. The effect of host factors and capsule composition on the cellular overgrowth on implanted alginate capsules. J. Biomed. Mater. Res. 57 , 374–383 (2001).

Thu, B. et al. Alginate polycation microcapsules. Biomaterials 17 , 1031–1040 (1996).

Strand, B. L. et al. Poly- l -lysine induces fibrosis on alginate microcapsules via the induction of cytokines. Cell Transpl. 10 , 263–275 (2017).

Sawhney, A. S., Pathak, C. P. & Hubbell, J. A. Modification of islet of Langerhans surfaces with immunoprotective poly(ethylene glycol) coatings via interfacial photopolymerization. Biotechnol. Bioeng. 44 , 383–386 (1994).

Cruise, G. M., Hegre, O. D., Scharp, D. S. & Hubbell, J. A. A sensitivity study of the key parameters in the interfacial photopolymerization of poly(ethylene glycol) diacrylate upon porcine islets. Biotechnol. Bioeng. 57 , 655–665 (1998).

Scharp, D. W. & Marchetti, P. Encapsulated islets for diabetes therapy: history, current progress, and critical issues requiring solution. Adv. Drug. Del. Rev. 67-–68 , 35–73 (2014).

Teramura, Y. & Iwata, H. Bioartificial pancreas: microencapsulation and conformal coating of islet of Langerhans. Adv. Drug. Del. Rev. 62 , 827–840 (2010).

Zhi, Z.-L., Liu, B., Jones, P. M. & Pickup, J. C. Polysaccharide multilayer nanoencapsulation of insulin-producing β-cells grown as pseudoislets for potential cellular delivery of insulin. Biomacromolecules 11 , 610–616 (2010).

Zhi, Z. L., Kerby, A., King, A. J. F., Jones, P. M. & Pickup, J. C. Nano-scale encapsulation enhances allograft survival and function of islets transplanted in a mouse model of diabetes. Diabetologia 55 , 1081–1090 (2012).

Bhaiji, T., Zhi, Z.-L. & Pickup, J. C. Improving cellular function and immune protection via layer-by-layer nanocoating of pancreatic islet β-cell spheroids cocultured with mesenchymal stem cells. J. Biomed. Mater. Res. A 100A , 1628–1636 (2012).

Fischer, D., Li, Y., Ahlemeyer, B., Krieglstein, J. & Kissel, T. In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis. Biomaterials 24 , 1121–1131 (2003).

Chanana, M. et al. Interaction of polyelectrolytes and their composites with living cells. Nano Lett. 5 , 2605–2612 (2005).

Teramura, Y. & Iwata, H. Cell surface modification with polymers for biomedical studies. Soft Matter. 6 , 1081–1091 (2010).

Song, S. & Roy, S. Progress and challenges in macroencapsulation approaches for type 1 diabetes (T1D) treatment: cells, biomaterials, and devices. Biotechnol. Bioeng. 113 , 1381–1402 (2016).

Brauker, J. H. et al. Neovascularization of synthetic membranes directed by membrane microarchitecture. J. Biomed. Mater. Res. 29 , 1517–1524 (1995).

Faleo, G., Lee, K., Nguyen, V. & Tang, Q. Assessment of immune isolation of allogeneic mouse pancreatic progenitor cells by a macroencapsulation device. Transplantation 100 , 1211–1218 (2016).

Agulnick, A. D. et al. Insulin-producing endocrine cells differentiated in vitro from human embryonic stem cells function in macroencapsulation devices in vivo. Stem Cell Transl. Med. 4 , 1214–1222 (2015).

Pullen, L. C. Stem cell-derived pancreatic progenitor cells have now been transplanted into patients: report from IPITA 2018. Am. J. Transplant. 18 , 1581–1582 (2018).

Henry, R. R. et al. Initial clinical evaluation of VC-01TM combination product — a stem cell-derived islet replacement for type 1 diabetes (T1D). Diabetes 67 (Suppl. 1), 138-OR (2018).

ClinicalTrials.gov A safety, tolerability, and efficacy study of VC-01™ combination product in subjects with type I diabetes mellitus. US National Library of Medicine https://clinicaltrials.gov/ct2/show/results/NCT02239354 (2022).

ClinicalTrials.gov A study to evaluate safety, engraftment, and efficacy of VC-01 in subjects with T1 diabetes mellitus (VC01-103) . US National Library of Medicine https://classic.clinicaltrials.gov/ct2/show/NCT04678557 (2019).

Maki, T. et al. Successful treatment of diabetes with the biohybrid artificial pancreas in dogs. Transplantation 51 , 43–50 (1991).

Sullivan, S. et al. Biohybrid artificial pancreas: long-term implantation studies in diabetic, pancreatectomized dogs. Science 252 , 718–721 (1991).

Maki, T. et al. Treatment of diabetes by xenogeneic islets without immunosuppression: use of a vascularized bioartificial pancreas. Diabetes 45 , 342–347 (1996).

Yang, K. et al. A therapeutic convection-enhanced macroencapsulation device for enhancing β cell viability and insulin secretion. Proc. Natl Acad. Sci. USA 118 , e2101258118 (2021).

Oppler, S. H. et al. A bioengineered artificial interstitium supports long-term islet xenograft survival in nonhuman primates without immunosuppression. Sci. Adv. 10 , eadi4919 (2024).

Hilburger, C. E., Rosenwasser, M. J. & Delcassian, D. The type 1 diabetes immune niche: immunomodulatory biomaterial design considerations for beta cell transplant therapies. J. Immunol. Regen. Med. 17 , 100063 (2022).

Google Scholar  

Gibly, R. F. et al. Advancing islet transplantation: from engraftment to the immune response. Diabetologia 54 , 2494–2505 (2011).

Chandorkar, Y., Ravikumar, K. & Basu, B. The foreign body response demystified. ACS Biomater. Sci. Eng. 5 , 19–44 (2018).

Mariani, E., Lisignoli, G., Borzì, R. M. & Pulsatelli, L. Biomaterials: foreign bodies or tuners for the immune response? Int. J. Mol. Sci. 20 , 636 (2019).

Rafael, E., Wernerson, A., Arner, P., Wu, G. S. & Tibell, A. In vivo evaluation of glucose permeability of an immunoisolation device intended for islet transplantation: a novel application of the microdialysis technique. Cell Transpl. 8 , 317–326 (1999).

Matsumoto, S. et al. Clinical porcine islet xenotransplantation under comprehensive regulation. Transplant. Proc. 46 , 1992–1995 (2014).

Matsumoto, S., Abalovich, A., Wechsler, C., Wynyard, S. & Elliott, R. B. Clinical benefit of islet xenotransplantation for the treatment of type 1 diabetes. eBioMedicine 12 , 255–262 (2016).

Morozov, V. A. et al. No PERV transmission during a clinical trial of pig islet cell transplantation. Virus Res. 227 , 34–40 (2017).

Elliott, R. B. et al. Transplantation of micro- and macroencapsulated piglet islets into mice and monkeys. Transplant. Proc. 37 , 466–469 (2005).

Elliott, R. B. et al. Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant. Proc. 37 , 3505–3508 (2005).

Doloff, J. C. et al. Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates. Nat. Mater. 16 , 671–680 (2017).

Dondossola, E. et al. Examination of the foreign body response to biomaterials by nonlinear intravital microscopy. Nat. Biomed. Eng. 1 , 0007 (2016).

Vegas, A. J. et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat. Biotechnol. 34 , 345–352 (2016).

Vegas, A. J. et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived β cells in immune-competent mice. Nat. Med. 22 , 306–311 (2016).

Bose, S. et al. A retrievable implant for the long-term encapsulation and survival of therapeutic xenogeneic cells. Nat. Biomed. Eng. 4 , 814–826 (2020).

Liu, Q. et al. Zwitterionically modified alginates mitigate cellular overgrowth for cell encapsulation. Nat. Commun. 10 , 5262 (2019).

Liu, W. et al. A safe, fibrosis-mitigating, and scalable encapsulation device supports long-term function of insulin-producing cells. Small 18 , e2104899 (2022).

Liu, Q. et al. A zwitterionic polyurethane nanoporous device with low foreign‐body response for islet encapsulation. Adv. Mater. 33 , e2102852 (2021).

Chen, T. et al. Alginate encapsulant incorporating CXCL12 supports long-term allo- and xenoislet transplantation without systemic immune suppression. Am. J. Transplant. 15 , 618–627 (2015).

Alagpulinsa, D. A. et al. Alginate‐microencapsulation of human stem cell-derived β cells with CXCL12 prolongs their survival and function in immunocompetent mice without systemic immunosuppression. Am. J. Transplant. 197 , 1930–1940 (2019).

Sremac, M. et al. Preliminary studies of the impact of CXCL12 on the foreign body reaction to pancreatic islets microencapsulated in alginate in nonhuman primates. Transplant. Direct 5 , e447 (2019).

Su, J., Hu, B.-H., Lowe, W. L., Kaufman, D. B. & Messersmith, P. B. Anti-inflammatory peptide-functionalized hydrogels for insulin-secreting cell encapsulation. Biomaterials 31 , 308–314 (2010).

Lin, C.-C., Metters, A. T. & Anseth, K. S. Functional PEG–peptide hydrogels to modulate local inflammation induced by the pro-inflammatory cytokine TNFα. Biomaterials 30 , 4907–4914 (2009).

Kuppan, P. et al. Co‐localized immune protection using dexamethasone‐eluting micelles in a murine islet allograft model. Am. J. Transplant. 20 , 714–725 (2019).

Bünger, C. M. et al. Deletion of the tissue response against alginate-PLL capsules by temporary release of co-encapsulated steroids. Biomaterials 26 , 2353–2360 (2005).

Jiang, K. et al. Local release of dexamethasone from macroporous scaffolds accelerates islet transplant engraftment by promotion of anti-inflammatory M2 macrophages. Biomaterials 114 , 71–81 (2017).

Weaver, J. D. et al. Controlled release of dexamethasone from organosilicone constructs for local modulation of inflammation in islet transplantation. Tissue Eng. A 21 , 2250–2261 (2015).

Primavera, R. et al. Enhancing islet transplantation using a biocompatible collagen-PDMS bioscaffold enriched with dexamethasone-microplates. Biofabrication 13 , 035011 (2021).

Veiseh, O. & Vegas, A. J. Domesticating the foreign body response: recent advances and applications. Adv. Drug. Del. Rev. 144 , 148–161 (2019).

Ranta, F. et al. Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes 55 , 1380–1390 (2006).

Bocca, N. et al. Soft corticosteroids for local immunosuppression: exploring the possibility for the use of loteprednol etabonate for islet transplantation. Pharmazie 63 , 226–232 (2008).

Patil, S. D., Papadmitrakopoulos, F. & Burgess, D. J. Concurrent delivery of dexamethasone and VEGF for localized inflammation control and angiogenesis. J. Control. Rel. 117 , 68–79 (2007).

Vaithilingam, V. et al. Co-encapsulation and co-transplantation of mesenchymal stem cells reduces pericapsular fibrosis and improves encapsulated islet survival and function when allografted. Sci. Rep . 7 , 10059 (2017).

Jacobson, S., Kumagai-Braesch, M., Tibell, A., Svensson, M. & Flodström-Tullberg, M. Co-transplantation of stromal cells interferes with the rejection of allogeneic islet grafts. Ann. NY Acad. Sci. 1150 , 213–216 (2008).

Prud’homme, G. J. Pathobiology of transforming growth factor β in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab. Invest. 87 , 1077–1091 (2007).

Ding, Y. et al. Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 58 , 1797–1806 (2009).

Wu, H., Wen, D. & Mahato, R. I. Third-party mesenchymal stem cells improved human islet transplantation in a humanized diabetic mouse model. Mol. Ther. 21 , 1778–1786 (2013).

Berman, D. M. et al. Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. Diabetes 59 , 2558–2568 (2010).

Wang, X. et al. Engineered immunomodulatory accessory cells improve experimental allogeneic islet transplantation without immunosuppression. Sci. Adv. 8 , eabn0071 (2022).

An, D. et al. Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes. Proc. Natl Acad. Sci. USA 115 , E263–E272 (2018).

An, D. et al. An atmosphere‐breathing refillable biphasic device for cell replacement therapy. Adv. Mater. 31 , e1905135 (2019).

Ramzy, A. et al. Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 28 , 2047–2061 e2045 (2021).

Keymeulen, B. et al. Encapsulated stem cell-derived β cells exert glucose control in patients with type 1 diabetes. Nat. Biotechnol. 10.1038/s41587-023-02055-5 (2023).

Pepper, A. R. et al. Diabetes is reversed in a murine model by marginal mass syngeneic islet transplantation using a subcutaneous cell pouch device. Transplantation 99 , 2294–2300 (2015).

Bachul, P. et al. 307.5: Modified approach allowed for improved islet allotransplantation into pre-vascularized Sernova Cell Pouch™ device — preliminary results of the phase I/II clinical trial at University of Chicago. Transplantation 105 (12S1), S2 (2021).

Paez-Mayorga, J. et al. Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats. Nat. Commun. 13 , 7951 (2022).

Deuse, T. et al. Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat. Biotechnol. 37 , 252–258 (2019).

ClinicalTrials.gov An open-label, FIH study evaluating the safety, tolerability, and efficacy of VCTX211 combination product in subjects with T1D. US National Library of Medicine https://classic.clinicaltrials.gov/ct2/show/NCT05565248 (2022).

Reichman, T. W. et al. 836-P: glucose-dependent insulin production and insulin-independence in type 1 diabetes from stem cell-derived, fully differentiated islet cells — updated data from the VX-880 clinical trial. Diabetes 72 , 836–83 (2023).

Hogrebe, N. J., Ishahak, M. & Millman, J. R. Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes. Cell Stem Cell 30 , 530–548 (2023).

ClinicalTrials.gov A safety, tolerability, and efficacy study of VX-264 in participants with type 1 diabetes. US National Library of Medicine https://classic.clinicaltrials.gov/ct2/show/NCT05791201 (2023).

Cai, E. P. et al. Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes. Nat. Metab. 2 , 934–945 (2020).

Lim, D. et al. Engineering designer beta cells with a CRISPR-Cas9 conjugation platform. Nat. Commun. 11 , 4043 (2020).

Gerace, D. et al. Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance. Cell Rep. Med. 4 , 100879 (2023).

Yoshihara, E. et al. Immune-evasive human islet-like organoids ameliorate diabetes. Nature 586 , 606–611 (2020).

Davies, B. The technical risks of human gene editing. Hum. Reprod. 34 , 2104–2111 (2019).

Safley, S. A. et al. Inhibition of cellular immune responses to encapsulated porcine islet xenografts by simultaneous blockade of two different costimulatory pathways. Transplantation 79 , 409–418 (2005).

Cui, H. et al. Long-term metabolic control of autoimmune diabetes in spontaneously diabetic nonobese diabetic mice by nonvascularized microencapsulated adult porcine islets. Transplantation 88 , 160–169 (2009).

Lei, J. et al. FasL microgels induce immune acceptance of islet allografts in nonhuman primates. Sci. Adv. 8 , eabm9881 (2022).

Headen, D. M. et al. Local immunomodulation Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance. Nat. Mater. 17 , 732–739 (2018).

Shrestha, P. et al. Immune checkpoint CD47 molecule engineered islets mitigate instant blood‐mediated inflammatory reaction and show improved engraftment following intraportal transplantation. Am. J. Transplant. 20 , 2703–2714 (2020).

Batra, L. et al. Localized immunomodulation with PD-L1 results in sustained survival and function of allogeneic islets without chronic immunosuppression. J. Immunol. 204 , 2840–2851 (2020).

Wu, D. C. et al. Ex vivo expanded human regulatory T cells can prolong survival of a human islet allograft in a humanized mouse model. Transplantation 96 , 707–716 (2013).

Yi, S. et al. Adoptive transfer with in vitro expanded human regulatory t cells protects against porcine islet xenograft rejection via interleukin-10 in humanized mice. Diabetes 61 , 1180–1191 (2012).

Putnam, A. L. et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 58 , 652–662 (2009).

Krzystyniak, A., Gołąb, K., Witkowski, P. & Trzonkowski, P. Islet cell transplant and the incorporation of T reg s. Curr. Opin. Organ. Transplant. 19 , 610–615 (2014).

Liu, C. et al. B lymphocyte–directed immunotherapy promotes long-term islet allograft survival in nonhuman primates. Nat. Med. 13 , 1295–1298 (2007).

Oura, T. et al. Kidney versus islet allograft survival after induction of mixed chimerism with combined donor bone marrow transplantation. Cell Transpl. 25 , 1331–1341 (2016).

Singh, A. et al. Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes. Nat. Commun. 10 , 3495 (2019).

Jansson, L. & Carlsson, P. O. Graft vascular function after transplantation of pancreatic islets. Diabetologia 45 , 749–763 (2002).

Jansson, L. et al. Pancreatic islet blood flow and its measurement. Upsala J. Med. Sci. 121 , 81–95 (2016).

Davalli, A. M. et al. Vulnerability of islets in the immediate posttransplantation period: dynamic changes in structure and function. Diabetes 45 , 1161–1167 (1996).

Bowers, D. T., Song, W., Wang, L. H. & Ma, M. Engineering the vasculature for islet transplantation. Acta Biomater. 95 , 131–151 (2019).

De Vos, P. et al. Why do microencapsulated islet grafts fail in the absence of fibrotic overgrowth? Diabetes 48 , 1381–1388 (1999).

Citro, A. et al. Directed self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes. Nat. Commun. 14 , 878 (2023).

Citro, A. et al. Biofabrication of a vascularized islet organ for type 1 diabetes. Biomaterials 199 , 40–51 (2019).

Wassmer, C. H. et al. Bio-engineering of pre-vascularized islet organoids for the treatment of type 1 diabetes. Transpl. Int. 35 , 10214 (2021).

Nalbach, L. et al. Improvement of islet transplantation by the fusion of islet cells with functional blood vessels. EMBO Mol. Med. 13 , e12616 (2021).

Chao, X. et al. Comparative study of two common in vitro models for the pancreatic islet with MIN6. Tissue Eng. Regen. Med. 20 , 127–141 (2023).

Padera, R. F. & Colton, C. K. Time course of membrane microarchitecture-driven neovascularization. Biomaterials 17 , 277–284 (1996).

Sörenby, A., Rafael, E., Tibell, A. & Wernerson, A. Improved histological evaluation of vascularity around an immunoisolation device by correlating number of vascular profiles to glucose exchange. Cell Transpl. 13 , 713–720 (2017).

rafael, e, wernerson, a, arner, P. & Tibell, A. In vivo studies on insulin permeability of an immunoisolation device intended for islet transplantation using the microdialysis technique. Eur. Surg. Res. 31 , 249–258 (1999).

Rafael, E., Gazelius, B., Wu, G. S. & Tibell, A. Longitudinal studies on the microcirculation around the TheraCyte™ immunoisolation device, using the laser Doppler technique. Cell Transpl. 9 , 107–113 (2000).

Rafael, E., Wu, G. S., Hultenby, K., Tibell, A. & Wernerson, A. Improved survival of macroencapsulated islets of Langerhans by preimplantation of the immunoisolating device: a morphometric study. Cell Transpl. 12 , 407–412 (2003).

Sörenby, A. K. et al. Preimplantation of an immunoprotective device can lower the curative dose of islets to that of free islet transplantation — studies in a rodent model. Transplantation 86 , 364–366 (2008).

Magisson, J. et al. Safety and function of a new pre-vascularized bioartificial pancreas in an allogeneic rat model. J. Tissue Eng. 11 , 2041731420924818 (2020).

Pepper, A. R. et al. A prevascularized subcutaneous device-less site for islet and cellular transplantation. Nat. Biotechnol. 33 , 518–523 (2015).

Levey, R. E. et al. Assessing the effects of VEGF releasing microspheres on the angiogenic and foreign body response to a 3D printed silicone-based macroencapsulation device. Pharmaceutics 13 , 2077 (2021).

Weaver, J. D. et al. Design of a vascularized synthetic poly(ethylene glycol) macroencapsulation device for islet transplantation. Biomaterials 172 , 54–65 (2018).

Weaver, J. D. et al. Vasculogenic hydrogel enhances islet survival, engraftment, and function in leading extrahepatic sites. Sci. Adv. 3 , e1700184 (2017).

Kakkar, A. et al. Current status of stem cell treatment for type I diabetes mellitus. Tissue. Eng. Regen. Med. 15 , 699–709 (2018).

Figliuzzi, M. et al. Bone marrow-derived mesenchymal stem cells improve islet graft function in diabetic rats. Transplant. Proc. 41 , 1797–1800 (2009).

Ito, T. et al. Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function. Transplantation 89 , 1438–1445 (2010).

Rackham, C. L. et al. Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice. Diabetologia 54 , 1127–1135 (2011).

Park, K.-S. et al. Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation. Transplantation 89 , 509–517 (2010).

Rackham, C. L., Dhadda, P. K., Le Lay, A. M., King, A. J. F. & Jones, P. M. Preculturing islets with adipose-derived mesenchymal stromal cells is an effective strategy for improving transplantation efficiency at the clinically preferred intraportal site. Cell Med. 7 , 37–47 (2014).

de Souza, B. M. et al. Effect of co-culture of mesenchymal stem/stromal cells with pancreatic islets on viability and function outcomes: a systematic review and meta-analysis. Islets 9 , 30–42 (2017).

Rackham, C. L. et al. Pre-culturing islets with mesenchymal stromal cells using a direct contact configuration is beneficial for transplantation outcome in diabetic mice. Cytotherapy 15 , 449–459 (2013).

Sakata, N., Chan, N. K., Chrisler, J., Obenaus, A. & Hathout, E. Bone marrow cell cotransplantation with islets improves their vascularization and function. Transplantation 89 , 686–693 (2010).

McGuigan, A. P. & Sefton, M. V. Vascularized organoid engineered by modular assembly enables blood perfusion. Proc. Natl Acad. Sci. USA 103 , 11461–11466 (2006).

Vlahos, A. E., Cober, N. & Sefton, M. V. Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets. Proc. Natl Acad. Sci. USA 114 , 9337–9342 (2017).

Song, W. et al. Engineering transferrable microvascular meshes for subcutaneous islet transplantation. Nat. Commun. 10 , 4602 (2019).

Komatsu, H., Kandeel, F. & Mullen, Y. Impact of oxygen on pancreatic islet survival. Pancreas 47 , 533–543 (2018).

Carlsson, P. O., Liss, P., Andersson, A. & Jansson, L. Measurements of oxygen tension in native and transplanted rat pancreatic islets. Diabetes 47 , 1027–1032 (1998).

Vériter, S., Gianello, P. & Dufrane, D. Bioengineered sites for islet cell transplantation. Curr. Diab. Rep. 13 , 745–755 (2013).

Papas, K. K., De Leon, H., Suszynski, T. M. & Johnson, R. C. Oxygenation strategies for encapsulated islet and beta cell transplants. Adv. Drug. Del. Rev. 139 , 139–156 (2019).

Rodriguez-Brotons, A. et al. Impact of pancreatic rat islet density on cell survival during hypoxia. J. Diabetes Res. 2016 , 3615286 (2016).

Paredes-Juarez, G. A. et al. DAMP production by human islets under low oxygen and nutrients in the presence or absence of an immunoisolating-capsule and necrostatin-1. Sci. Rep. 5 , 14623 (2015).

Ludwig, B. et al. A novel device for islet transplantation providing immune protection and oxygen supply. Horm. Metab. Res. 42 , 918–922 (2010).

Neufeld, T. et al. The efficacy of an immunoisolating membrane system for islet xenotransplantation in minipigs. PLoS ONE 8 , e70150 (2013).

Ludwig, B. et al. Favorable outcome of experimental islet xenotransplantation without immunosuppression in a nonhuman primate model of diabetes. Proc. Natl Acad. Sci. USA 114 , 11745–11750 (2017).

Ludwig, B. et al. Transplantation of human islets without immunosuppression. Proc. Natl Acad. Sci. USA 110 , 19054–19058 (2013).

Krishnan, S. R. et al. A wireless, battery-free device enables oxygen generation and immune protection of therapeutic xenotransplants in vivo. Proc. Natl Acad. Sci. USA 120 , e2311707120 (2023).

Razavi, M. et al. A collagen based cryogel bioscaffold that generates oxygen for islet transplantation. Adv. Funct. Mater. 30 , 1902463 (2020).

Pedraza, E., Coronel, M. M., Fraker, C. A., Ricordi, C. & Stabler, C. L. Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials. Proc. Natl Acad. Sci. USA 109 , 4245–4250 (2012).

Coronel, M. M., Geusz, R. & Stabler, C. L. Mitigating hypoxic stress on pancreatic islets via in situ oxygen generating biomaterial. Biomaterials 129 , 139–151 (2017).

Liang, J. P. et al. Engineering a macroporous oxygen-generating scaffold for enhancing islet cell transplantation within an extrahepatic site. Acta Biomater. 130 , 268–280 (2021).

Wang, L. H. et al. An inverse-breathing encapsulation system for cell delivery. Sci. Adv. 7 , eabd5835 (2021).

Wang, L.-H. et al. A bioinspired scaffold for rapid oxygenation of cell encapsulation systems. Nat. Commun. 12 , 5846 (2021).

Korsgren, O. et al. Current status of clinical islet transplantation. Transplantation 79 , 1289–1293 (2005).

Ricordi, C. & Strom, T. B. Clinical islet transplantation: advances and immunological challenges. Nat. Rev. Immunol. 4 , 259–268 (2004).

Owyang, S., Jastrzebska-Perfect, P., Scott, M. & Traverso, G. Re-considering quantity requirements in islet transplantation. Nat. Rev. Bioeng. 1 , 382–384 (2023).

Brennan, D. C. et al. Long-term follow-up of the Edmonton protocol of islet transplantation in the United States. Am. J. Transplant. 16 , 509–517 (2016).

D’Amour, K. A. et al. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat. Biotechnol. 23 , 1534–1541 (2005).

D’Amour, K. A. et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24 , 1392–1401 (2006).

Kroon, E. et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat. Biotechnol. 26 , 443–452 (2008).

Rezania, A. et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat. Biotechnol. 32 , 1121–1133 (2014).

Shapiro, A. M. J. & Verhoeff, K. A spectacular year for islet and stem cell transplantation. Nat. Rev. Endocrinol. 19 , 68–69 (2023).

Gala-Lopez, B. L. et al. Subcutaneous clinical islet transplantation in a prevascularized subcutaneous pouch — preliminary experience. CellR4 4 , e2132 (2016).

Tang, L., Jennings, T. A. & Eaton, J. W. Mast cells mediate acute inflammatory responses to implanted biomaterials. Proc. Natl Acad. Sci. USA 95 , 8841–8846 (1998).

Anderson, J. M., Rodriguez, A. & Chang, D. T. Foreign body reaction to biomaterials. Semin. Immunol. 20 , 86–100 (2008).

Noskovicova, N., Hinz, B. & Pakshir, P. Implant fibrosis and the underappreciated role of myofibroblasts in the foreign body reaction. Cells 10 , 1794 (2021).

Iglesias-Lopez, C., Agusti, A., Obach, M. & Vallano, A. Regulatory framework for advanced therapy medicinal products in Europe and United States. Front. Pharmacol. 10 , 921 (2019).

Piemonti, L. et al. US food and drug administration (FDA) panel endorses islet cell treatment for type 1 diabetes: a pyrrhic victory? Transpl. Int. 34 , 1182–1186 (2021).

Iglesias-Lopez, C., Obach, M., Vallano, A. & Agusti, A. Comparison of regulatory pathways for the approval of advanced therapies in the European Union and the United States. Cytotherapy 23 , 261–274 (2021).

Hering, B. J. et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care 39 , 1230–1240 (2016).

Ricordi, C. & Japour, A. Transplanting islet cells can fix brittle diabetes. Why isn’t it available in the U.S.? CellR4 7 , e2768 (2019).

Weir, G. C. & Bonner-Weir, S. Why pancreatic islets should be regarded and regulated like organs. CellR4 9 , e3083 (2021).

Witkowski, P. et al. The demise of islet allotransplantation in the United States: a call for an urgent regulatory update. Am. J. Transplant. 21 , 1365–1375 (2021).

Witkowski, P. et al. Arguments against the requirement of a biological license application for human pancreatic islets: the position statement of the islets for US collaborative presented during the FDA advisory committee meeting. J. Clin. Med. 10 , 2878 (2021).

Download references

Acknowledgements

This work was supported by the Ministry of Science and ICT of Korea (NRF-2022R1C1C1008610) and the Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korean government (Code: KFRM 22A0105L1-11 and 24A0105L1).

Author information

Authors and affiliations.

Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Sophie S. Liu, Yoshimasa Kudo & Jeffrey M. Karp

Division of Bioengineering, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Republic of Korea

Surim Shim & Kisuk Yang

Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA

Cherie L. Stabler

University of Florida Diabetes Institute, Gainesville, FL, USA

UCD Centre for Biomedical Engineering, School of Mechanical and Materials Engineering, University College Dublin, Dublin, Ireland

Eoin D. O’Cearbhaill

Advanced Manufacturing Research Centre, School of Mechanical and Manufacturing Engineering, Dublin City University, Dublin, Ireland

Harvard Medical School, Boston, MA, USA

Jeffrey M. Karp

Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA

Broad Institute, Cambridge, MA, USA

Harvard Stem Cell Institute, Boston, MA, USA

Research Center for Bio Materials & Process Development, Incheon National University, Incheon, Republic of Korea

You can also search for this author in PubMed   Google Scholar

Contributions

S.S.L., S.S., Y.K. and K.Y. conducted the literature review, prepared the manuscript and figures. C.L.S., E.D.O’C., J.M.K. and K.Y. reviewed and commented on the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Eoin D. O’Cearbhaill , Jeffrey M. Karp or Kisuk Yang .

Ethics declarations

Competing interests.

J.M.K. has been a paid consultant and or equity holder for multiple companies; these include Alivio Therapeutics, Abercrombie and Fitch, Cobro Ventures, Altrix Bio, Stempeutics, Sanofi, Celltex, LifeVaultBio, Tissium, Takeda, Skintifique, Corner Therapeutics, Ligandal, Lumicell, Guidepoint Global, Biomodels, One Fun Company, Katharos Labs, Triton Systems, Edge Immune, W. L. Gore, Camden Partners, Stemgent, Gyro Gear, Mirakel Labs, Janssen Research & Development, Biogen, Pancryos, IP Asset Ventures, Enlight Biosciences, Mesoblast, SRU Biosystems, New Frontier Bio, Clear Nanosystems, Bullseye Therapeutics, Schick Manufacturing Inc, Biolacuna, Oakley, Element Biosciences, Frequency Therapeutics, Molecular Infusions, Quthero and Vyome. J.M.K. holds equity in several companies that have licensed intellectual property generated by him that may benefit financially if the intellectual property is further validated. The interests of J.M.K. were reviewed and are subject to a management plan overseen by his institutions in accordance with its conflict-of-interest policies. E.D.O’C. has been a paid consultant for Pancryos. S.S.L., Y.K., S.S., C.L.S. and K.Y. declare no competing interests.

Peer review

Peer review information.

Nature Reviews Bioengineering thanks Alessandro Grattoni, who co-reviewed with Jocelyn Campa-Carranza, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Allogeneic islet cell therapy: https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes

Combination of microencapsulated islets within the Cell Pouch device: https://www.sernova.com/technology/#Cell_Pouch_System

Diabetes Atlas: https://diabetesatlas.org/data/en/world/

Encapsulated allogeneic islet product: https://www.ema.europa.eu/en/documents/report/scientific-recommendation-classification-advanced-therapy-medicinal-products-allogeneic-pancreatic-islets-encapsulated-elastin-recombinamers_en.pdf

Fast Track Designation: https://www.biospace.com/vertex-presents-positive-updated-vx-880-results-from-ongoing-phase-1-2-study-in-type-1-diabetes-at-the-european-association-for-the-study-of-diabetes-59th-annual-meeting

Lantidra: https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes

Licensing agreement with CRISPR Therapeutics: https://crisprtx.gcs-web.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-licensing-agreement

PEC211 cell line: https://ir.crisprtx.com/static-files/5c256eb5-4982-4e47-b463-79eff954e622

PRIME designation: https://investors.vrtx.com/news-releases/news-release-details/vertex-presents-positive-vx-880-results-ongoing-phase-12-study

Regulatory barrier: https://www.adameetingnews.org/regulatory-barriers-put-u-s-behind-in-adoption-of-islet-transplantation-for-type-1-diabetes/

VCTX210 pipeline: https://crisprtx.com/about-us/press-releases-and-presentations/crispr-therapeutics-and-viacyte-inc-announce-first-patient-dosed-in-phase-1-clinical-trial-of-novel-gene-edited-cell-replacement-therapy-for-treatment-of-type-1-diabetes-t1d

VX-880 pipeline: https://crisprtx.gcs-web.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-licensing-agreement

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Cite this article.

Liu, S.S., Shim, S., Kudo, Y. et al. Encapsulated islet transplantation. Nat Rev Bioeng (2024). https://doi.org/10.1038/s44222-024-00238-6

Download citation

Accepted : 05 August 2024

Published : 24 September 2024

DOI : https://doi.org/10.1038/s44222-024-00238-6

Share this article

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

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

Provided by the Springer Nature SharedIt content-sharing initiative

Quick links

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

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

UC Davis’ Historic Expect Greater Campaign Raises $2.25 Billion

Over 93% of the 448,000 gifts were $1,000 or less.

• by Courtney Tompkins
• September 24, 2024

The University of California, Davis, is celebrating its most successful fundraising campaign — Expect Greater: From UC Davis, for the World — a multi-year effort that raised over $2.25 billion for student support, health research and care, sustainability, innovation and more.

Gifts to the campaign have empowered first-generation students to achieve their dreams, funded groundbreaking research across disciplines, and expanded resources that contribute to the university’s vibrant culture and academic excellence.

“Expect Greater has proven that when we come together, our community can achieve extraordinary things,” said Shaun B. Keister, vice chancellor for Development and Alumni Relations. “Its success demonstrates the profound trust our donors place in us to educate, innovate and lead. We are immensely grateful for their support and partnership.”

From July 2016 through June 2024, over 133,000 donors worldwide gave $2,255,625,098 in more than 448,000 gifts and pledges to support UC Davis’ efforts to advance solutions to the planet’s most pressing problems and build a brighter future for California and beyond.

UC Davis exceeded its $2 billion campaign goal 10 months ahead of schedule, in August 2023, which is a remarkable achievement considering the campaign launched publicly in 2020 amid a worldwide pandemic that closed schools and exacerbated economic uncertainty.

Legacy of impact

Of the total campaign gifts and pledges, donors gave $822 million — or more than one-third of all funds raised — to support research and identify solutions to society’s most pressing challenges, like food security, health equity and climate change. These funds also bolster UC Davis’ interdisciplinary approach to making transformative discoveries, together.

Other funding highlights: 

• $469 million in department and faculty support . This includes over 70 new endowed chairs and professorships, as well as new graduate student fellowships, classroom and laboratory resources, and other funding to support faculty and foster academic growth.
• $323 million in student support. This includes 1,573 new scholarships, funds for student emergencies, basic needs and research opportunities, as well as awards for experiential learning and professional development.
• $267 million for construction and renovation. This includes new, state-of-the-art spaces at UC Davis and UC Davis Health in Sacramento, such as the Edwards Family Athletics Center, Advanced Veterinary Surgery Center, Ernest E. Tschannen Eye Institute Building, Diane Bryant Engineering Student Design Center, and the UC Davis Coffee Center, the nation’s first academic research and teaching facility dedicated entirely to the study of coffee.

Every gift fuels a brighter tomorrow

More than 93% of gifts to UC Davis were $1,000 or less, and with a median gift amount of $25, the Expect Greater campaign demonstrated the collective power of community support and the key role that every donation plays in creating lasting change.

“We are deeply grateful to all who have given so generously throughout this campaign,” said Chancellor Gary S. May. “On behalf of our students, faculty and the entire UC Davis community, thank you for believing in our mission and strengthening our impact at home and around the world.”

From an 11-year-old’s $20 gift to the Bodega Marine Laboratory to grateful patient Ernest E. Tschannen’s $38.5 million commitment to vision science, private support is vital because it drives innovation and accelerates discovery. Thirteen gifts were $10 million or more.

Lynda and Stewart Resnick, co-owners of The Wonderful Company, were the top individual donors with $50 million to the College of Agricultural and Environmental Sciences. The Resnicks’ gift is helping build a world-class agricultural innovation center and funding competitive research grants for projects focused on agricultural sustainability.

UC Davis Foundation Chair Deborah J. Neff ’76 expressed appreciation to the university’s volunteer community for their pivotal role in the campaign’s success.

“We owe our deepest thanks to our incredible volunteers who generously gave their time and energy to support this campaign,” Neff said. “Their leadership and dedication have truly made a difference for UC Davis.”

A momentous final year

The final year of the Expect Greater campaign was the second-best fundraising year in UC Davis history. In fiscal year 2023-24, UC Davis raised over $290 million, or about $55 million more than its annual fundraising goal.

Noteworthy gifts include:

• $20+ million from philanthropist Maria Manetti Shrem to establish the Maria Manetti Shrem Arts Renaissance in the College of Letters and Science, funding programming plus endowed chairs in arts, arts history and sustainable design
• $8 million estate gift from Victor and Phela Vesci to the UC Davis Children’s Hospital to help create a new Neonatal Intensive Care Unit and establish endowments for pediatric intensive care, lung and gastrointestinal programs
• $4.1 million from more than 4,700 donors on the eighth annual Give Day, “Reaching Greater Heights,” which set a university giving-day record

To learn more about the historic Expect Greater campaign, visit giving.ucdavis.edu .

FOR THE WORLD

With funding from Expect Greater donors, UC Davis is advancing life-changing research and innovations.

• A man paralyzed by ALS spoke to his family for the first time in years. Read his story .
• A new stem-cell therapy treated spina bifida in bulldogs and was adapted to treat human babies in utero. Watch the video here .
• When the COVID-19 pandemic hit, Healthy Davis Together set a national model for keeping communities safe. See how we did it .
• The UC Davis arts scene is thriving like never before. Explore the arts renaissance underway.
• The next generation of nutritious, planet-friendly foods is on the menu. Get a taste here.

About UC Davis

UC Davis is a top-ranked, public research university recognized for its leadership in addressing global challenges through innovative research and education. With more than 40,000 students enrolled across undergraduate, graduate and professional programs, UC Davis offers a diverse and inclusive academic environment.

The university consistently ranks among the top 10 public universities in the United States – today, it’s No. 3 in a Wall Street Journal/College Pulse ranking – and is a global leader in the fields of veterinary medicine, agriculture and environmental science, health care and sustainability.

Located in California’s Central Valley, UC Davis drives groundbreaking research and fosters a culture of hands-on learning, collaboration and public service that seeks to benefit humans, animals and the planet. 

Media Resources

Media Contact:

• Betsy Towner Levine, Development and Alumni Relations, 530-752-9693, [email protected]

Primary Category