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Surgical digest

The huge potential of humanized pig organs


Kentaro Noda, PhD

Department of Cardiothoracic Surgery

Jörg C. Gerlach, MD PhD

Department of Surgery University of Pittsburgh

Pablo G. Sanchez MD, PhD

Department of Surgery, Section of Thoracic Surgery University of Chicago

https://doi.org/10.58974/bjss/azbc044

Recent progress in xenotransplantation using humanized pigs is reported for heart and kidney transplants.1,2 The first xenotransplant of a liver into a living person was also performed in China very recently.3 Advancement in this organ transplant field is remarkable, but the earlier consequences of heart and kidney xenotransplants have hindered public acceptance and trust in xenotransplantation. This highlights the need to address the challenges associated with this novel approach for treating end-stage organ disease. It is important not to forget that many current medical technologies and advanced treatments were established after overcoming similar challenges and conducting rigorous safety trials. These clinical challenges are not a disappointment but are essential for future medical advancements. For instance, Transcatheter Aortic Valve Replacement (TAVR) and Thoracic Endovascular Aortic Repair (TEVAR) have become standard alternatives to traditional cardiac and vascular surgery. These procedures started with elderly, high-risk patients and are still being developed to expand their application to younger patients.

As such, xenotransplantation requires further research to ensure its safe use and reduce risks as a treatment for end-stage organ diseases. Identifying and mitigating the potential causes of patient complications is crucial. While some immunological barriers via carbohydrate antigens have been largely addressed through genetic modifications, additional research is needed in various areas, including microbiology, infection control, endocrinology, and organ interaction. Transplanting xenografts into a deceased recipient may provide a key perspective. In 2021, NYU Langone Health performed xenotransplantation surgery on deceased human donors.4 Also, before the first pig-live human transplant this year, a hepatic graft from a humanized pig were tested in a deceased human donor in China; it lasted for 10 days with no signs of rejection.5 This comprehensive approach will require some time but is necessary for the successful integration of xenotransplantation into clinical practice.

At the same time, humanized organs could be used for other purposes, such as a bridge to transplant or as replacement therapy. Current artificial organs made by artificial material are functional as bio-mimetic, but they do not completely replace full function as an in vivo organ does. Also, biocompatibility should be considered for the clinically successful application of artificial organs for long term support. A biohybrid artificial organ approach, using humanized organs, could enhance functionality, improve biocompatibility, and increase longevity and durability (Figure 1).6

Figure 1: The potential applications of humanized pig organs for biohybrid artificial organs. Organs from genetically engineered pigs may replace current artificial organs, improving biocompatibility and more effectively supporting patients suffering from organ failure.

For example, hollow fibre haemodialysers or filtres for renal replacement therapy or apheresis are fully manufactured from synthetic materials. Patients with chronic kidney dysfunction are typically exposed to these artificial membrane surfaces three times a week, which can activate immune cells, platelets, and complement systems. Replacing hemodialysers with a biohybrid approach using a portable system7 could reduce exposure to artificial materials and the frequency of dialysis, regulate blood pressure, and control anaemia. Similarly, liver grafts from humanized pigs could be used for apheresis. The University of Pennsylvania conducted the “PERFUSE-2” study to demonstrate the feasibility, safety, and effectiveness of using a porcine liver perfusion system, and most recently performed the first 72-hour proof-of-concept procedure of extracorporeal liver cross-circulation in a deceased donor.8 Compared to xenotransplants, biohybrid organs may be easier to access for biopsy, conditioning, treatment, and monitoring organ function. Additionally, integrating techniques to isolate potential risk factors in xenografts could reduce the risk of early organ failure and patient death.

Similar to haemodialysis, ventricular assist devices (VAD) for heart failure and artificial lungs for extracorporeal membrane oxygenation (ECMO) are well-established as bridges to transplantation. These devices, fully made from artificial materials, are exposed to blood for extended periods, often leading to acquired coagulopathy, a major issue during transplantation. Surgical consideration has already been given to transplanting a heart heterotopically using a biological left VAD concept that could support systemic cardiac output.9 For lungs, a xenogeneic cross-circulation approach, initially reported for lung recovery, could be modified for systemic respiratory support. Using humanized hearts, lungs, or heart-lung en-bloc to replace manufactured pumps or oxygenators presents several potential benefits including: 1) reduced anticoagulation, 2) enhanced physiological functionality, and 3) improved post-transplant outcomes. As such, biohybrid VAD and ECMO may also be feasible, offering significant improvements over current artificial devices.

In addition to replacing current artificial organs, genetically humanized swine organs may serve as an excellent cell source for bioreactor systems. A bioreactor system is an engineering perfusion culture technology where cells are viably and actively maintained under controlled conditions, enabling them to function as biohybrid artificial organs. These systems use semi-permeable membrane-separated compartments that allow the free exchange of endocrine and metabolic factors, while preventing the communication of cellular immunological factors. A clinical issue often discussed is the cell source and volume required to provide sufficient function to support a critically ill patient through an extracorporeal bioreactor. For example, hybrid extracorporeal liver support could aid patients with hepatic failure through synthesis, detoxification, and regulation, but requires 400-800 grams of primary hepatocytes from clinically healthy donors, which is 30-50% of a whole liver.10 Therefore, humanized swine organs could be an alternative cell source for bioreactor systems. Beyond the liver, this approach could be applicable to other non-solid transplantable cells such as islet cells, thyroid, and adrenal glands. Indeed, the endocrine function of these swine cells should be thoroughly investigated for clinical use.

In conclusion, genetically modified humanized pigs could help address the donor shortage in organ transplantation and advance clinical xenotransplantation. Research contributions in this field might significantly improve the survival of patients with end-stage organ diseases. Beyond xenotransplantation, humanized pigs could be valuable for other clinical applications, such as bridging therapy or extracorporeal organ support. The biohybrid artificial organ approach may enhance the biocompatibility of current synthetic materials and offer significant benefits over traditional artificial organs. Further research into applications using humanized swine organs could directly translate into improved survival and health outcomes for patients with end-stage organ failure.

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