Liver transplantation represents a pivotal intervention in the management of end-stage liver disease, offering a lifeline to countless patients. Despite significant strides in surgical techniques and organ procurement, ethical dilemmas and debates continue to underscore this life-saving procedure. Navigating the ethical terrain surrounding this complex procedure is hence paramount. Dissecting the nuances of ethical principles of justice, autonomy and beneficence that underpin transplant protocols worldwide, we explore the modern challenges that plaques the world of liver transplantation. We investigate the ethical dimensions of organ transplantation, focusing on allocation, emerging technologies, and decision-making processes. PubMed, Scopus, Web of Science, Embase and Central were searched from database inception to February 29, 2024 using the following keywords: "liver transplant", "transplantation", "liver donation", "liver recipient", "organ donation" and "ethics". Information from relevant articles surrounding ethical discussions in the realm of liver transplantation, especially with regards to organ recipients and allocation, organ donation, transplant tourism, new age technologies and developments, were extracted. From the definition of death to the long term follow up of organ recipients, liver transplantation has many ethical quandaries. With new transplant techniques, societal acceptance and perceptions also play a pivotal role. Cultural, religious and regional factors including but not limited to beliefs, wealth and accessibility are extremely influential in public attitudes towards donation, xenotransplantation, stem cell research, and adopting artificial intelligence. Understanding and addressing these perspectives whilst upholding bioethical principles is essential to ensure just distribution and fair allocation of resources. Robust regulatory oversight for ethical sourcing of organs, ensuring good patient selection and transplant techniques, and high-quality long-term surveillance to mitigate risks is essential. Efforts to promote equitable access to transplantation as well as prioritizing patients with true needs are essential to address disparities. In conclusion, liver transplantation is often the beacon of hope for individuals suffering from end-stage liver disease and improves quality of life. The ethics related to transplantation are complex and multifaceted, considering not just the donor and the recipient, but also the society as a whole.

Liver transplantation is the most important achievement in the twentieth and twenty-first century. It is the gold standard treatment for hepatocellular carcinoma. However, it provides the best results when performed under strict selection criteria. Nevertheless, organ supply is overwhelmed by the number of patients on the waiting list. There are certain strategies to expand the donor pool such as split liver transplantation, use of extended criteria donors, and living donor liver transplantation. Xenotransplantation can also be a strategy in decreasing the organ shortage. We reviewed the current status of xenotransplantation.

We evaluated the historical attempts of xenotransplantation to humans and also made a summary of the preclinical studies in the field.

Molecular biology and genetic engineering are developing with an incredible speed. There are great achievements made in cell therapy, 3D bioprinting of the organs, and ultimately xenotransplantation. There is a vast amount of problems to be handled before evaluating the efficacy of xenotransplantation in the treatment of hepatocellular carcinoma. Major problems include antibody-mediated rejection to antigens such as galactose ⍺1-3 galactose, N- glycolylneuraminic acid, β1,4-N-acetylgalactosaminyltransferase, lethal thrombocytopenia, and erythrocyte sequestration. Antibody mediated rejection to these specific antigens are addressed using gene editing technology including CRISPR Cas9, TALEN and other recombination methods. Although hyperacute rejection is reduced, long-term survival could not be achieved in experimental models.

The future is yet to come, there are developments made in the field of genetic editing, immunosuppressive medication, and pretransplant desensitization techniques. Therefore, we believe that xenotransplantation will be in clinical practice, at least for treatment of critically ill patients.

Heart transplantation is the only curative treatment option for end-stage heart failure. However, a shortage of donor organs is a major limitation of this approach. Regenerative medicine targets the goal of increasing the number of available hearts for transplantation. In this review, we highlight the state of the art of building a bioartificial heart. We summarize the components needed, the hurdles, and likely translational steps to make the dream of transplanting a totally functional bioartificial heart a possibility.

The therapies being developed in regenerative medicine aim not only to repair, but also to regenerate or replace failing tissues and organs. The engineering of bioartificial hearts utilizing patient-derived cells could theoretically solve the two main complications of heart transplantations: graft rejection and lifelong immunosuppression. Although many hurdles remain, scientists have reached a point in which some of these hurdles have been overcome. Decellularized heart scaffolds have emerged over the past decade as one of the most promising biofabrications. Two possible options for organ scaffolds exist: nontransplantable human hearts and porcine hearts. The use of these scaffolds could lead to the availability of an unlimited number of transplantable organs. The current challenge remains improving processes required for recellularization - including those for cells, bioreactors, and physiologic conditioning. Researchers should focus to solve these hurdles and pave the way toward the dream of in-vivo bioengineered heart maturation.

Regenerative medicine has emerged as one of the most promising fields of translational research and has the potential to both minimize the need for donor organs and increase their availability. Meeting the challenge of implanting a totally functional bioengineered heart lies in solving multiple issues simultaneously. Dwarfing the technical hurdles, cost is the largest barrier to success. The scientific hurdles mainly involve scaling up and scaling out of laboratory cell processes, building bioreactors, and delivering cells into every needed region of an organ scaffold. Maintaining sterility and quantifying readiness of the nascent organs are also critical for success.

Xenotransplantation is a potential solution for the high mortality of patients on the waiting list for multivisceral transplantation; nevertheless, hyperacute rejection (HAR) hampers this practice and motivates innovative research. In this report, we describe a model of multivisceral xenotransplantation in which we observed immunoglobulin G (IgG) involvement in HAR.

We recovered en bloc multivisceral grafts (distal esophagus, stomach, small intestine, colon, liver, pancreas, and kidneys) from rabbits (n = 20) and implanted them in the swine (n = 15) or rabbits (n = 5, control). Three hours after graft reperfusion, we collected samples from all graft organs for histological study and to assess IgG fixation by immunofluorescence. Histopathologic findings were graded according to previously described methods.

No histopathological features of rejection were seen in the rabbit allografts. In the swine-to-rabbit grafts, features of HAR were moderate in the liver and severe in esophagus, stomach, intestines, spleen, pancreas, and kidney. Xenograft vessels were the central target of HAR. The main lesions included edema, hemorrhage, thrombosis, myosites, fibrinoid degeneration, and necrosis. IgG deposition was intense on cell membranes, mainly in the vascular endothelium.

Rabbit-to-swine multivisceral xenotransplants undergo moderate HAR in the liver and severe HAR in the other organs. Moderate HAR in the liver suggests a degree of resistance to the humoral immune response in this organ. Strong IgG fixation in cell membranes, including vascular endothelium, confirms HAR characterized by a primary humoral immune response. This model allows appraisal of HAR in multiple organs and investigation of the liver's relative resistance to this immune response.

Owing to an imbalance between demand and supply, which is more prominent in pediatric transplant, every year more patients lose their lives on waiting lists. In addition to the use of deceased-donor split and living-donor organs, xenotransplant could provide a solution if associated problems, such as immunologic and physiologic ones, are solved. This study sought to analyze the surgical aspects for liver xenotransplant in a porcine model.

Landrace pigs (n=22, 23 to 37 kg) underwent a laparotomy under general anesthesia. The hepatic hilum was prepared and the common bile ducts, common hepatic artery, portal vein, supra- and infrahepatic inferior vena cava were identified. The length and diameter of each vessel and bile duct and the weight of the liver were measured.

Pearson tests showed a clear correlation between the increase of the pigs' weight and the livers' weight, and the length of the vessels and the bile ducts. We did not find a clear correlation between the increase of the pigs' liver weight and the diameters of the vessels and the bile duct.

As the first reporting, this study on xenotransplants from the surgical point of view, we postulate that it could be possible to estimate the size of the liver and the proper length of its vessels and bile duct by weighing only the pigs. It was not feasible to match the diameter of mentioned structures by the livers' weight. However, the weight of pig's liver as well as vascular anatomy of pigs appeared to be suitable alternative for the human liver.

This overview traces the history of regenerative medicine pertinent to organ transplantation, illustrates potential clinical applications reported to date, and highlights progress achieved in the field of complex modular organ engineering. Regenerative medicine can now produce relatively simple tissues such as skin, bladders, vessels, urethras, and upper airways, whereas engineering or generation of complex modular organs remains a major challenge. Ex vivo organ engineering may benefit from complementary investigations in the fields of developmental biology and stem cells and transplantation before its full potential can be realized.

In order to provide morphological data and theoretical basis for pig-to-human hepatic xenotransplantation, the difference in morphological parameters and vessel wall structural factors between human and porcine hepatic portal vein was studied. From human subjects and pigs of varying ages, hepatic portal veins were collected, paraffin-embedded and cut into sections. The histological structures were stained with HE, and elastin, collagen and smooth muscles were stained with Weigert, Aniline blue and orange G, respectively. Morphological parameters and relative contents of structural components were determined under microscopy and by computer image analysis system, respectively. The results showed that histological structures of human and porcine hepatic portal vein wall were similar. Caliber, wall thickness, lumen and wall area in pigs increased with age, all in linear correlation to months. Morphological parameters of 6- month-old pigs were similar to those of human. In pigs, collagen content increased gradually with months, elastin content remained relatively stable, smooth muscle content reached the peak at the 3rd month, and collagen/elastin (C/E) rose gradually. The contents of collagen and elastin in porcine hepatic portal vein wall were lower, while the content of smooth muscle was higher than in human, and C/E at the 5th and 6th month was similar to that in human. It is concluded that morphological parameters and contents of structural components of porcine hepatic portal vein vary with age. At the 6 month, its caliber, wall thickness, lumen and wall area are similar to those of human. There are differences in contents of structural components between human and pigs. However, in terms of C/E, mechanic properties of pigs at the 5th and 6th month mimic those of human, hence inosculation is viable in xenotrans-plantation between pigs and human.

Acute liver failure is characterized by a dynamic clinical course associated with high mortality. The main prognostic determinant is the development of extrahepatic complications. Close monitoring is mandatory, and prophylactic measures to avoid complications should be initiated. In case of complications, early and aggressive treatment is indicated. To date, artificial liver support devices are still in the experimental phase. Liver transplantation should be considered in patients with predictors of a poor spontaneous prognosis. Therefore, a transplant center should be contacted in every case of acute liver failure.

Liver transplantation is now accepted as effective therapy in the treatment of acute and chronic hepatic failure. Improvements in surgical techniques and immune suppression have led to 5-year survival rates that exceed 70% in most centers. The success of transplantation has led to a dramatic increase in the number of candidates to over 14,000 places on the national waiting list. While the number of patients in need of transplantation increases, there has been little growth in the supply of available cadaveric organs, resulting in an organ shortage crisis. With waiting times often exceeding 1 to 2 years, the waiting list mortality now exceeds 10% in most regions. Several novel approaches have been developed to address the growing disparity between the limited supply and excessive demand for suitable organs.

Little is known about the effect of ischemia/reperfusion with xenogenic blood on function and gene expression of CYP3A4, the enzyme largely responsible for the metabolism of the immunosuppressants Cyclosporin A (CsA) and Tacrolimus.

In a pig liver perfusion model, we have compared the effect of perfusion (3 h) after 20 h cold storage, with either pig or human blood on CsA metabolism and CYP3A4-mRNA expression. mCYP3A4-mRNA was quantified by RT-PCR, CsA and its major metabolites AM1, AM9, AM4N by RP-HPLC. IL-6 served as inflammation marker, GLDH and ALT to estimate tissue damage.

Inflammatory response and tissue damage were more extensive during xenoperfusion. CYP3A4 expression decreased similarly during xenogenic and allogenic perfusion. CsA conversion to its metabolites was also comparable during xeno- and alloperfusion.

There is no evidence that during the early reperfusion period pig liver CYP3A4 is severely affected if the organ is xenoperfused with human blood in comparison with alloperfusion.

Successful liver transplantation in a child is often a hard-won victory, requiring all the combined expertise of a dedicated pediatric transplant team. This article outlines the considerable challenges still facing pediatric liver transplant physicians and surgeons. In looking to the future, where should priorities lie to enhance the success already achieved? First, solutions to the donor shortage must be sought aggressively by increasing the use of from split-liver transplants, judicious application of living-donor programs, and increasing the donation rate, perhaps by innovative means. The major immunologic barriers, to successful xenotransplantation make it unlikely that this option will be tenable in the near future. Second, current immunosuppression is nonspecific, toxic, and unable to be individually adjusted to the patient's immune response. The goal of achieving donor-specific tolerance will require new consideration of induction protocols. Developing a clinically applicable method to measure the recipient's immunoreactivity is of paramount importance, for future studies of new immunosuppressive strategies and to address the immediate concern of long-term over-immunosuppression. The inclusion of pediatric patients in new protocols will require the ongoing insistence of pediatric transplant investigators. Third, the current immunosuppressive drugs have a long-term morbidity and mortality of their own. These long-term effects are particularly important in children who may well have decades of exposure to these therapies. There is now some understanding of their long-term renal toxicity and the risk of malignancy. New drugs may obviate renal toxicity, whereas the risk of malignancy is inherent in any nonspecific immunosuppressive regimen. Although progress is being made in preventing and recognizing PTLD, this entity remains an important ongoing concern. The global effect of long-term immunosuppression on the child's growth, development, and intellectual potential is unknown. Of particular concern is the potential for neurotoxicity from the calcineurin inhibitors. Fourth, recurrent disease and new diseases, perhaps potentiated by immunosuppressive drugs, must be considered. Already the recurrence of autoimmune disease and cryptogenic cirrhosis have been documented in pediatric patients. Now, a new lesion, a nonspecific hepatitis, sometimes with positive autoimmune markers, that may progress to cirrhosis has been recognized. It is not known whether this entity is an unusual form of rejection, an unrecognized viral infection, or a response to immunosuppressive drugs themselves. Finally, pediatric transplant recipients, like any other children, must be protected and nourished physically and mentally if they are to fulfill their potential. After liver transplantation the child's growth, intellectual functioning, and psychologic adaptation may all require special attention from parents, teachers, and physicians alike. There is limited understanding of how the enormous physical intervention of a liver transplantation affects a child's cognitive and psychologic function as the child progresses through life. The persons caring for these children have the difficult responsibility of providing services to evaluate these essential measures of children's health over the long term and to intervene if necessary. Part of the transplant physician's our duty to protect and advocate for children is to fight for equal access to health care. In most of the developing world, economic pressures make it impossible to consider liver transplantation a health care priority. In the United States and in other countries with the medical infrastructure to support liver transplantation, however, health care professionals must strive to be sure that the policies governing candidacy for transplantation and allocation of organs are applied justly and uniformly to all children whose lives are threatened by liver disease. In the current regulatory climate that increasingly takes medical decisions out of the hands of physicians, pediatricians must be even more prepared to protect the unique and often complicated needs of children both before and after transplantation. Only in this way can the challenges of the present and the future be met.

Xenotransplantation of the liver, in its broadest conception, might involve the transplantation of an intact organ or xenogeneic hepatocytes, or the use of an intact xenogeneic liver or cells as an ex vivo "device." The indications for xenotransplantation include not only hepatic failure but also, potentially, the treatment of metabolic diseases. The hurdles to xenotransplantation include immune, physiologic, and infectious complications. New information and progress in experimental systems are bringing xenotransplantation closer to clinical application.

Since the first human liver transplant done in 1963, the procedure has become a routine procedure with an excellent outcome in terms both of quality and of length of survival. The development and introduction into clinical practice of a variety of immunosuppressive agents has given the clinician a bewildering array of therapeutic options but with a lack of evidence on which to select for optimal immunosuppression. Tolerance can be reliably achieved in some animal transplants but remains to be achieved in humans. One of the major challenges facing the transplant community is the shortage of donor organs: imaginative approaches to overcome this problem include more effective use of marginal donor livers, splitting livers and development of living related transplants. While advances have been made in the field of xenotransplantation, there remain many hurdles to be overcome before this approach can be introduced into human transplantation. In the meanwhile, there are difficulties in determining the optimal criteria for listing patients for transplantation and for treating some of the complications arising after transplantation such as recurrence of disease and complications of immunosuppression, e.g. renal failure, malignancy and vascular disease.

Hepatocytes can be successfully transplanted into highly vascular sites such as the spleen, liver, and lungs. Subcutaneous sites lack adequate vascularization to nutritionally support transplanted hepatocytes. We recently reported that matrix-immobilized angiogenic growth factors, e.g., endothelial cell growth factor (ECGF), can induce a high degree of neovascularization. Using this technique, we explored the possibility of transplanting isolated fetal porcine hepatocytes to create liver tissue organoids at a specific subcutaneous site. We evaluated chitosan as a scaffold biomaterial because of its structural similarity to glycosaminoglycans; glycosaminoglycans play a critical role in cell attachment, differentiation, and morphogenesis. Freshly isolated fetal porcine hepatocytes (FPH) (viability greater than 97%) were cultured on modified chitosan scaffolds and transplanted into rat groin fat pads with or without ECGF-induced neovascularization. Cell density and attachment kinetics on chitosan were examined by scanning electron microscopy (SEM) and quantified using a flavianic acid binding assay. Hepatocyte viability and liver organoid formation were examined immunohistochemically. FPH transplanted without prior neovascularization died within 1 day post-transplantation. When transplanted after ECGF-induced neovascularization, FPH thrived for at least 2 weeks and formed liver tissue like structures. Immunohistochemical analysis revealed the presence of hepatocyte-specific cytokeratin staining as well as the presence of alpha-fetoprotein. Light microscopy and SEM revealed that FPH did not change their morphology after attachment to the chitosan surfaces. Thus, chitosan-based biomaterial surfaces have good hepatocyte attachment properties. However, extensive neovascularization is essential for hepatocyte survival and organoid formation. In the future, chitosan-based biomaterials may be useful as scaffolds for creating liver tissue organoids.