Abstract

This month's installment of “The AJT Report” discusses the first successful transplant of a bioengineered whole organ and the potential future of this technology to save human lives. We also report on a new transplant program designed to address the needs of Black Americans.

Despite considerable challenges, the first human clinical trial of bioengineered liver transplantation is slated to take place as early as 2022

Key Points Miromatrix has announced the first successful transplant of a bioengineered whole organ in a large animal. The success of bioengineered liver transplantation must still meet the challenge of replacing bile duct function. Bioengineered kidneys may be able to rescue the lives of the many patients who would otherwise die on dialysis. A future with implantable bioengineered organs will have a marked impact on transplant centers and surgeons.

In October 2021, Miromatrix Medical Inc. of Eden Prairie, Minnesota, announced the first successful transplant of a bioengineered whole organ in a large animal. The preclinical study of a liver transplant had advanced their decellularization/recellularization approach toward clinical trials.1 The study, performed at the Mayo Clinic in Rochester, Minnesota, evaluated the transplantation and functionality of a bioengineered liver in an acute liver failure model. In a press release, Miromatrix CEO Jeff Ross, PhD, said, “Now that we have demonstrated our technology in a large animal model, we are targeting our initial human clinical trial with an external liver in the second half of 2022 for acute liver failure, bringing us closer to our goal of eliminating the organ transplant waitlist.” Miromatrix had its initial public offering in June 2021 and raised 43 million dollars.

The people at Miromatrix believe that their patented perfusion decellularization and recellularization technology is poised to offer new options for transplantation for the 114 000 people in the US waiting for a life-saving organ transplant. Scott Nyberg, MD, PhD, a professor of surgery and biomedical engineering at the Mayo Clinic and head of its Liver Regeneration Program, performed the Miromatrix study. It included five pigs, three of which were implanted with a liver scaffold seeded with human vascular cells and porcine hepatocytes. The bioengineered livers slowed ammonia accumulation during in vivo perfusion in pigs with surgically induced acute liver failure.

MULTIPLE EFFORTS UNDERWAY

Noting that bioengineered organs are probably years away from replacing traditional solid organs, Dr. Nyberg describes the stages necessary to realize a functioning bioengineered liver transplant. The first, he says, is having the ability to achieve a transplant without clotting, a milestone that has now been reached without blood thinners by recellularizing the graft's vessels with endothelial cells. The second stage is production of a functional graft, and this challenge has been realized with the addition of hepatocytes. The milestone that remains, Dr. Nyberg explains, is the replacement of bile duct function.

According to Miromatrix's website, they intend to initiate a phase I clinical trial of its external assist liver for the treatment of acute liver failure in the second half of 2022. Phase I clinical trials for miroLiver and miroKidney, is expected to start in the second half of 2023/first half of 2024. Additional products in the pipeline include the miroHeart, miroLung and miroPancreas.

While Miromatrix closes in on commercializing bioengineered organs, others are also working toward this goal. Dr. Nyberg has developed the spheroid reservoir bio-artificial (SRBAL) extracorporeal liver. He and his team have demonstrated that the SRBAL can facilitate the survival of pigs 90 h after hepatectomy, and he has formed the Minnesota-based company Liver Cell Technologies to commercialize the bioengineered organ.2 He acknowledges, however, that the clinical trials are expensive and that there are still multiple barriers standing between the laboratory and the patient.

On the West Coast, Shuvo Roy, PhD, professor of bioengineering at University of California, San Francisco, is building an implantable bioartificial kidney.3 Dr. Roy and his team, in collaboration with William H. Fissell, MD, associate professor of medicine at Vanderbilt University Medical Center in Nashville, have developed an implantable artificial kidney that will, in effect, provide continuous dialysis. The device contains a high-efficiency membrane for hemofiltration combined with a bioreactor of kidney tubule cells for electrolyte balance. The team has demonstrated that the compact cartridge can be implanted in the abdomen of a healthy Yucatan minipig without complications. Over the course of three, 3-hour sessions over 3 days, the device resulted in creatinine clearance ranging from 11 to 42 ml/min/m2 and urea clearance ranging from 26 to 74 ml/min/m2. The team continues to engineer the device so that it will work like a native kidney.

PATIENTS DIE WAITING

According to the National Institute of Diabetes and Digestive and Kidney Diseases, approximately 800 000 individuals in the US have end-stage kidney disease, and 70% of them are on dialysis. Dr. Roy describes with urgency the problem of kidney failure, highlighting that many individuals receive little advance notice of their deteriorating condition; instead, they are given the diagnosis of kidney failure along with an immediate referral to dialysis. This is especially the case for individuals who do not receive regular checkups.

"This is a highly underserved population despite how many people there are," says Dr. Roy, noting that individuals at the lower end of the socioeconomic scale, who have limited access to medical care, are over-represented in patients with kidney failure. The Social Security Amendments of 1972 extended Medicare coverage to individuals with end-stage renal disease who require either dialysis or transplantation to maintain life. Dialysis now costs Medicare approximately 50 billion dollars. "No other disease has that level of financial feedback," says Dr. Roy, reporting that Medicare spends "about $90 000 per dialysis patient per year."

Moreover, despite the high price tag, dialysis outcomes are poor. Only half of individuals survive for 5 years on dialysis, says Dr. Roy, adding that this mortality rate is worse than that of most cancers. He concludes that dialysis is not a long-term solution for kidney failure but rather a form of palliative care that places patients on a glide path to death. Transplants, conversely, save money and lives. Unfortunately, of the approximately 100 000 people on the transplant list waiting for a kidney, only 20 000 actually receive a kidney transplant each year, meaning that patients on dialysis are more likely to die than to receive a transplant. Hence the need for bioengineered organs.

“NOT A HOPELESS CAUSE”

Dr. Roy acknowledges that many people still regard bioengineered organs as belonging in the realm of science fiction. “Some of the clinical people are jaded,” he says, adding, “This is real.” He wants the transplant community to understand that the process of creating a bioengineered organ is fundamentally different from the process of drug discovery and compares the bioengineering process to that used to build the Mars Rover. “Yes, it's still challenging,” he says. “It requires meticulous planning and meticulous work…. This is an engineering effort, not a discovery science effort… We have shown this to work.”

Dr. Roy explains that he and his team are in the process of scaling up the bioengineered kidney, but that the process is expensive and funding for such translational work is scarce. And, although he counts every year of delay in bringing a bioengineered kidney to market in the number of lives lost, he wants the transplant community to know that these patients “are not a hopeless cause.” Research indicates that if patients are given dialysis 6 days per week instead of the standard 3, they can recover their health, he says, emphasizing, “The phenotype is rescuable.”4

According to Dr. Roy, it is not a matter of if, but rather when, bioengineered organs will play an everyday role in the treatment of kidney failure, thus solving an expensive and painful problem. He notes that as this transformation is implemented, it will reverberate throughout transplant centers, explaining that “somebody has got to put this stuff in,” and that “it won't be a nephrologist…. Bioengineered organs will give transplant surgeons more work.”

REFERENCES REFERENCES 1Anderson BD, Nelson ED, Joo DongJin, et al. Functional characterization of a bioengineered liver after heterotopic implantation in pigs. Commun Biol. 2021; 4: 1157. 2Chen HS, Joo DJ, Shaheen M, et al. Randomized trial of spheroid reservoir bioartificial liver in porcine model of posthepatectomy liver failure. Hepatol. 2019; 69: 329- 342. 3Hois N, Fissell WH, Roy S. Ambulatory hemodialysis-technology landscape and potential for patient-centered treatment. Clin J Am Soc Nephrol. 2020; 15: 152- 159. 4Daugirdas JT, Greene T, Rocco MV, et al. Effect of frequent hemodialysis on residual kidney function. Kidney Int. 2013; 83: 949- 958. NORTHWESTERN LAUNCHES AFRICAN AMERICAN ACCESS TRANSPLANT PROGRAM

Northwestern Memorial Hospital in Chicago has recruited Dinee Simpson, MD, the first and only Black female transplant surgeon in Illinois and one of only 11 in the US, to develop the nation's first African American Transplant Access Program (AATAP). The aim of the program is to address the needs of Black Americans in underserved communities. As Dr. Simpson explains in a recent article published in Northwestern Medicine, many individuals in Black communities harbor a distrust of the healthcare system stemming from the system's long history of mistreating Black patients.1 Unfortunately, this suspicion constitutes a barrier for the medical community in delivering much needed care for kidney disease, a leading cause of death among Black Americans.

The creation of the AATAP reflects Northwestern Medicine's focus on health equity in diseases of the liver and the kidney. The program prioritizes patient-centered communication and has recently hired a dedicated social worker. In addition, the hospital's new satellite clinic in Oak Lawn, a suburb located in the predominantly Black South Side of Chicago, is helping to ease the travel and cost constraints associated with commuting to the downtown hospital.

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