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Purpose: 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., Methods: We evaluated the historical attempts of xenotransplantation to humans and also made a summary of the preclinical studies in the field., Results: 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., Conclusion: 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.

Currently, type 1 diabetes requires lifelong insulin injection and careful blood glucose control to prevent secondary complications, but islet transplantation could make a type 1 diabetic patient insulin independent. On the other hand, islet transplantation needs human donors and donor shortage is the most serious issue. To alleviate the donor shortage, non-heart-beating and living donors were used; in addition, the efficacy of islet isolation and transplantation has been improved. However, the donor shortage issue will not be solved as long as human donors are the only source. To solve the donor shortage issue, islet xenotransplantation using porcine islets was initiated in 1994. Islet xenotransplantation has a potential to cure many type 1 diabetic patients, although there is the risk of developing serious or novel infection. Therefore, the World Health Organization has been interested in xenotransplantation, and the International Xenotransplantation Association (IXA) has published consensus statements to initiate xenogeneic islet transplantation. Clinical islet xenotransplantation was conducted under the official regulation, and safety and efficacy data have been accumulated. Currently an efficient method to overcome xenorejection is an important research target. In addition to traditional immunosuppressive drugs and immune isolation methods, the gene modification with CRISPR and blastocyst complementation have been investigated with promising outcomes. Once the xenorejection issue is overcome, islet xenotransplantation should become a curative treatment for type 1 diabetic patients., (© 2020 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

There is a well-known worldwide shortage of deceased human donor organs for clinical transplantation. The transplantation of organs from genetically engineered pigs may prove an alternative solution. In the past 5 years, there have been sequential advances that have significantly increased pig graft survival in nonhuman primates. This progress has been associated with (1) the availability of increasingly sophisticated genetically engineered pigs; (2) the introduction of novel immunosuppressive agents, particularly those that block the second T-cell signal (costimulation blockade); (3) a better understanding of the inflammatory response to pig xenografts; and (4) increasing experience in the management of nonhuman primates with pig organ or cell grafts. The range of investigations required in experimental studies has increased. The standard immunologic assays are still carried out, but increasingly investigations aimed toward other pathobiologic barriers (e.g., coagulation dysregulation and inflammation) have become more important in determining injury to the graft.Now that prolonged graft survival, extending to months or even years, is increasingly being obtained, the function of the grafts can be more reliably assessed. If the source pigs are bred and housed under biosecure isolation conditions, and weaned early from the sow, most microorganisms can be eradicated from the herd. The potential risk of porcine endogenous retrovirus (PERV) infection remains unknown, but is probably small. Attention is being directed toward the selection of patients for the first clinical trials of xenotransplantation.

Study of lung xenografts has proven useful to understand the remaining barriers to successful transplantation of other organ xenografts. In this chapter, the history and current status of lung xenotransplantation will be briefly reviewed, and two different experimental models, the ex vivo porcine-to-human lung perfusion and the in vivo xenogeneic lung transplantation, will be presented. We will focus on the technical details of these lung xenograft models in sufficient detail, list the needed materials, and mention analysis techniques to allow others to adopt them with minimal learning curve.

Xenotransplantation, or the grafting of organs from one species to another, may seem at first a far cry from brain death, but there is rising hope in some quarters of the biomedical community that such transplants may reduce, even obviate, the need to harvest human organs-and hence eliminate the primary reason for needing an unambiguous definition of brain death. As with all research on the frontiers of biomedicine, xenotransplantation raises its own ethical quandaries. One concern that has long occupied ethical thought is the degree to which advances in science and technology should control the boundaries between the human and the nonhuman. Might the dimming of a previously entrenched bright line between species entail negative consequences for concepts, such as human dignity and bodily integrity, that historically anchored the protection of both human and animal subjects in biomedical treatment and research? To date, ethical thinking about xenotransplantation, and about gene editing, has largely been left in the hands of scientists, subject only to loose supervision by institutional review boards and animal welfare committees whose remit may be too narrow to address age-old moral concerns., (© 2018 The Hastings Center.)

Xenotransplantation is an attractive solution to the problem of allograft shortage. However, transplants across discordant species barriers are subject to vigorous immunologic and pathobiologic hurdles, some of which might be overcome with the induction of immunologic tolerance. Several strategies have been designed to induce tolerance to a xenograft at both the central (including induction of mixed chimerism and thymic transplantation) and peripheral (including adoptive transfer of regulatory cells and blocking T cell costimulation) levels. Currently, xenograft tolerance has been well-established in rodent models, but these protocols have not yet achieved similar success in nonhuman primates. This review will discuss the major barriers that impede the establishment of immunological tolerance across xenogeneic barriers and the potential solution to these challenges, and provide a perspective on the future of the development of novel tolerance-inducing strategies.

Objective: To summarize the research progress on the source and selection of donor cells in the field of islet replacement therapy for diabetes mellitus., Methods: Domestic and abroad literature concerning islet replacement therapy for diabetes mellitus, as well as donor source and donor selection was reviewed and analyzed thoroughly., Results: The shortage of donor supply is still a major obstacle for the widely clinical application of pancreatic islet transplantation (PIT). Currently, in addition to the progress on the allogeneic/autologous donor islet supply, some remarkable achievements have been also attained in the application of xenogeneic islet (from pig donor), as well as islet like cells derived from stem cells and islet cell line, potentially enlarging the source of implantable cells., Conclusion: Adequate and suitable donor cell supply is an essential prerequisite for widely clinical application of PIT therapy for type 1 diabetes mellitus (T1DM). Further perfection of organ donation system, together with development of immune-tolerance induction, gene and bioengineering technology etc . will possibly solve the problem of donor cell shortage and provide a basis for clinical application of cellular replacement therapy for T1DM.

Among the innovations for the treatment of type 1 diabetes, islet transplantation is a less invasive method of treatment, although it is still in development. One of the greatest barriers to this technique is the low number of pancreas donors and the low number of pancreases that are available for transplantation. Rodent models have been chosen in most studies of islet rejection and type 1 diabetes prevention to evaluate the quality and function of isolated human islets and to identify alternative solutions to the problem of islet scarcity. The purpose of this study is to conduct a review of islet xenotransplantation experiments from humans to rodents, to organize and analyze the parameters of these experiments, to describe trends in experimental modeling and to assess the viability of this procedure. In this study, we reviewed recently published research regarding islet xenotransplantation from humans to rodents, and we summarized the findings and organized the relevant data. The included studies were recent reports that involved xenotransplantation using human islets in a rodent model. We excluded the studies that related to isotransplantation, autotransplantation and allotransplantation. A total of 34 studies that related to xenotransplantation were selected for review based on their relevance and current data. Advances in the use of different graft sites may overcome autoimmunity and rejection after transplantation, which may solve the problem of the scarcity of islet donors in patients with type 1 diabetes.

The domestic pig shares many genetic, anatomical and physiological similarities to humans and is thus considered to be a suitable organ donor for xenotransplantation. However, prior to clinical application of porcine xenografts, three major hurdles have to be overcome: (1) various immunological rejection responses, (2) physiological incompatibilities between the porcine organ and the human recipient and (3) the risk of transmitting zoonotic pathogens from pig to humans. With the introduction of genetically engineered pigs expressing high levels of human complement regulatory proteins or lacking expression of α-Gal epitopes, the HAR can be consistently overcome. However, none of the transgenic porcine organs available to date was fully protected against the binding of anti-non-Gal xenoreactive natural antibodies. The present view is that long-term survival of xenografts after transplantation into primates requires additional modifications of the porcine genome and a specifically tailored immunosuppression regimen compliant with current clinical standards. This requires the production and characterization of multi-transgenic pigs to control HAR, AVR and DXR. The recent emergence of new sophisticated molecular tools such as Zinc-Finger nucleases, Transcription-activator like endonucleases, and the CRISPR/Cas9 system has significantly increased efficiency and precision of the production of genetically modified pigs for xenotransplantation. Several candidate genes, incl. hTM, hHO-1, hA20, CTLA4Ig, have been explored in their ability to improve long-term survival of porcine xenografts after transplantation into non-human primates. This review provides an update on the current status in the production of multi-transgenic pigs for xenotransplantation which could bring porcine xenografts closer to clinical application.

The past decade's rapid progress in human pluripotent stem cell (hPSC) research has generated hope for meeting the rising demand of organ donation, which remains the only effective cure for end-stage organ failure, a major cause of death worldwide. Despite the potential, generation of transplantable organs from hPSCs using in vitro differentiation is far-fetched. An in vivo interspecies chimeric complementation strategy relying on chimeric-competent hPSCs and zygote genome editing provides an auspicious alternative for providing unlimited organ source for transplantation.

Preclinical research in gynecologic malignancies has largely relied upon cloned cancer-derived cell lines and tumor xenografts derived from these cell lines. Unfortunately, the use of cell lines for translational research has disadvantages because genetic and phenotypic alterations from serial passaging have resulted in expression profiles that are different from the original patient tumors. The patient-derived xenograft (PDX) model derived from human tumor not previously cultured has shown better representation of the heterogeneity of gynecologic malignancies and the human tumor microenvironment with preservation of cytogenetics, cellular complexity, and vascular and stromal tumor architecture. Studies have shown promise with these models to analyze tumor development and adaptation, test drug efficacy, and predict clinical outcomes. Their ultimate value may be seen with preclinical drug screening including novel targeted therapies, biomarker identification, and the development of individualized treatment plans. This article reviews PDX model development, current studies testing chemotherapeutics and targeted therapies, and limitations of the PDX model in gynecologic malignancies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Islet transplantation is a treatment modality for diabetes mellitus that can maintain insulin levels within a physiologically appropriate range. However, wider clinical application is limited by insufficient donor numbers and a need for lifelong immunosuppression. Despite various clinical and preclinical trials, there is no single standard immunosuppressive regimen that can suppress acute and chronic immune reactions with lower toxicity to grafted islets. One of the strategies for overcoming lifelong immunosuppression is the incorporation of encapsulation technology, which can provide a physical immune barrier by keeping out high molecular weight immune system components, while still allowing low molecular weight oxygen, insulin and nutrients to pass through. Encapsulated islet transplantation approaches that have been studied so far include macroencapsulation, microencapsulation, conformal coating and nanoencapsulation. Herein we will review the basic concepts of islet encapsulation technique, earlier works to recent progress related to clinical studies and corporate investigations on encapsulated islet transplantation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hepatocyte transplantation (Tx) is a potential therapy for certain diseases of the liver, including hepatic failure. However, there is a limited supply of human livers as a source of cells and, after isolation, human hepatocytes can be difficult to expand in culture, limiting the number available for Tx. Hepatocytes from other species, for example, the pig, have therefore emerged as a potential alternative source. We searched the literature through the end of 2014 to assess the current status of experimental research into hepatocyte xenoTx. The literature search identified 51 reports of in vivo cross-species Tx of hepatocytes in a variety of experimental models. Most studies investigated the Tx of human (n = 23) or pig (n = 19) hepatocytes. No studies explored hepatocytes from genetically engineered pigs. The spleen was the most common site of Tx (n = 23), followed by the liver (through the portal vein [n = 6]) and peritoneal cavity (n = 19). In 47 studies (92%), there was evidence of hepatocyte engraftment and function across a species barrier. The data provided by this literature search strengthen the hypothesis that xenoTx of hepatocytes is feasible and potentially successful as a clinical therapy for certain liver diseases, including hepatic failure. By excluding vascular structures, hepatocytes isolated from genetically engineered pig livers may address some of the immunological problems of xenoTx., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pigs as a source of grafts for xenotransplantation can help to overcome the rapidly growing shortage of human donors. However, in the case of pig-to-human transplantation, the antibody-xenoantigen complexes lead to the complement activation and immediate hyperacute rejection. Methods eliminating hyperacute rejection (HAR) include α1,3-galactosyltransferase (GGTA1) inactivation, regulation of the complement system and modification of the oligosaccharide structure of surface proteins. The humoral immune response control and reduction of the risk of coagulation disorders are the priority tasks in attempts to overcome acute humoral xenograft rejection that may occur after the elimination of HAR. The primary targets for research are connected with the identification of obstacles and development of strategies to tackle them. Because of the magnitude of factors involved in the immune, genetic engineers face a serious problem of producing multitransgenic animals in the shortest possible time.

Organ transplantation represents a unique method of treatment to cure people with end-stage organ failure. Since the first successful organ transplant in 1954, the field of transplantation has made great strides forward. However, despite the ability to transform and save lives, transplant surgery is still faced with a fundamental problem the number of people requiring organ transplants is simply higher than the number of organs available. To put this in stark perspective, because of this critical organ shortage 18 people every day in the United States alone die on a transplant waiting list (U.S. Department of Health & Human Services, http://organdonor.gov/about/data.html). To address this problem, attempts have been made to increase the organ supply through xenotransplantation and more recently, bioengineering. Here we trace the development of both fields, discuss their current status and highlight limitations going forward. Ultimately, lessons learned in each field may prove widely applicable and lead to the successful development of xenografts, bioengineered constructs, and bioengineered xeno-organs, thereby increasing the supply of organs for transplantation., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

This paper situates the public debate over the use of living animal organs and tissue for human therapies within the history of experimental islet transplantation. Specifically, the paper compares and contrasts the Canadian and Australian responses on xenotransplantation to consider what lessons can be learnt about the regulation of a complex and controversial biotechnology. Sobbrio and Jorqui described public engagement on xenotransplantation in these countries as 'important forms of experimental democracy.' While Canada experimented with a novel nation-wide public consultation, Australia sought public input within the context of a national inquiry. In both instances, the outcome was a temporary moratorium on all forms of clinical xenotransplantation comparable to the policies adopted in some European countries. In addition, the Australian xenotransplantation ban coincided with a temporary global ban on experimental islet allotransplantation in 2007. Through historical and comparative research, this paper investigates how public controversies over organ and tissue transplantation can inform our understanding of the mediation of interspeciality and the regulation of a highly contested technoscience. It offers an alternative perspective on the xenotransplantation controversy by exploring the ways in which coinciding moratoriums on islet allograft and xenograft challenge, complicate and confound our assumptions regarding the relationships between human and animal, between routine surgery and clinical experimentation, between biomedical science and social science, and between disease risks and material contagion.

This review will discuss the history and development of the field of genetic modification, up to the most recent scientific discoveries, and will also consider the current uses of genetic therapy., (© 2014 Wiley Periodicals, Inc.)

Objective: To summarize the advances of preclinical research in xenogeneic (porcine) cell transplantation in recent years., Methods: The literature about the preclinical research in xenogeneic (porcine) cell transplantation was analyzed and summarized., Results: With the application of new immunosuppressive agents and the generation of transgenic pigs, great progress has been achieved in xenogeneic transplantation of pig-derived nerve cells, islet cells, liver cells, and various types of stem cells. The survival time of xenogeneic cell (porcine) significantly prolonged, but there is still a long way to go before clinical application., Conclusion: The source ofxenogeneic (porcine) cells is abundant and the experiments are reproducible. However, how to effectively prevent rejection and prolong the survival time in the host, and avoid the spread of virus between species are still need to be solved in the future research.

Background: Over time, the notion of public has evolved. While the concept of public was initially conceived of as a single undifferentiated entity, the common understanding is now that a variety of differentiated, multifaceted and multiple public(s) can be constructed for different purposes. This is equally true in xenotransplantation; the literature shows how different kind of publics can be introduced as relevant. The paper explores the notion of public and the contemporary participatory procedures as participatory rights for citizens in decisions concerning technoscience and society. Its perspective, thus, is normative; namely, it aims at understanding how the political role of citizens is changing in democratic societies where matters of innovation are concerned. It is focused on xenotransplantation whose connections with public discourse and practices are quite paradigmatic among new emerging biomedical technologies, due to its peculiar risks., Methods and Results: The paper reviews the historical background of risk communication and public involvement in science-based decision-making and provides an overview of the current roles and meanings of deliberative procedures in xenotransplantation. After a short discussion of the history of the social implementation of xenotransplantation, the construction of the different publics dealing with this biomedical technology is briefly analysed. Publics have been firstly conceived of as objects of research, which has looked at them to quantify people's positive and negative attitudes towards xenotransplantation. Further developments have led to the notion of the public as composed of citizens, empowered as subjects of decisions. In both Canadian and Australian consultations, citizens were engaged in a complex learning process aimed at committing them to a decision. Despite the fact both public consultations represented important forms of experimental democracy, they were still focused on seeking consensus and assessing compliance from citizens. New Zealand is the most recent example of public consultation in xenotransplantation. Likewise, several public consultations have recently been launched by the European Commission on Advanced Therapies. Unlike in the Canadian and Australian cases, the latter initiatives aimed to reach only certain parts of the population, and the overall consultations were prepared to seek approval., Conclusions: Several categories of individuals may be interesting and interested publics in xenotransplantation. This is a field in which the importance of the potential risks that xenotransplants pose to society has been widely discussed. The point is that publics should not only be educated about the risk but should be given an opportunity to participate actively in the decision about whether and under what conditions they are exposed to the risk. Likewise, the boundaries between surveys, consultations and collection of advice may be blurred in actual practices. The hope remains that all different instruments either to collect or disseminate knowledge, and to explore new tools of governance may help connect science and policy to society in deeper and more complex ways. The next step points to a different meaning of public participation. It is shifting from participation as mere consensus and risk acceptance, to public engagement as a form of shared responsibility for risk control and regulatory decision-making., (© 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.)

Islet transplantation is an attractive treatment of type 1 diabetes mellitus. Xenotransplantation, using the pig as a donor, offers the possibility of an unlimited supply of islet grafts. Published studies demonstrated that pig islets could function in diabetic primates for a long time (>6 months). However, pig-islet xenotransplantation must overcome the selection of an optimal pig donor to obtain an adequate supply of islets with high-quality, to reduce xeno-antigenicity of islet and prolong xenograft survival, and to translate experimental findings into clinical application. This review discusses the suitable pig donor for islet xenotransplantation in terms of pig age, strain, structure/function of islet, and genetically modified pig.

Since the discovery of the "nude" mouse more than 40 years ago, investigators have attempted to model human tumor growth in immunodeficient mice. Here, we summarize how the field has advanced over the ensuing years owing to improvements in the murine recipients of human tumors. These improvements include the discovery of the scid mutation and development of targeted mutations in the recombination-activating genes 1 and 2 (Rag1(null), Rag2(null)) that severely cripple the adaptive immune response of the murine host. More recently, mice deficient in adaptive immunity have been crossed with mice bearing targeted mutations designed to weaken the innate immune system, ultimately leading to the development of immunodeficient mice bearing a targeted mutation in the gene encoding the interleukin 2 (IL2) receptor common γ chain (IL2rg(null), also known in humans as cytokine receptor common subunit γ). The IL2rg(null) mutation has been used to develop several immunodeficient strains of mice, including the NOD-scid IL2rg(null) (NSG) strain. Using NSG mice as human xenograft recipients, it is now possible to grow almost all types of primary human tumors in vivo, including most solid tumors and hematological malignancies that maintain characteristics of the primary tumor in the patient. Programs to optimize patient-specific therapy using patient-derived xenograft tumor growth in NSG mice have been established at several institutions, including The Jackson Laboratory. Moreover, NSG mice can be engrafted with functional human immune systems, permitting for the first time the potential to study primary human tumors in vivo in the presence of a human immune system., (© 2014 Cold Spring Harbor Laboratory Press.)

Strategies to facilitate repair or generate new nephrons are exciting prospects for acute and chronic human renal disease. Repair of kidney injury involves not just local mechanisms but also mobilisation of progenitor/stem cells from intrarenal niches, including papillary, tubular and glomerular locations. Diverse markers characterise these unique cells, often including CD24 and CD133. Extrarenal stem cells may also contribute to repair, with proposed roles in secreting growth factors, transfer of microvesicles and exosomes and immune modulation. Creating new nephrons from stem cells is beginning to look feasible in mice in which kidneys can be dissociated into single cells and will then generate mature renal structures when recombined. The next step is to identify the correct human markers for progenitor cells from the fetus or mature kidney with similar potential to form new kidneys. Intriguingly, development can continue in vivo: whole foetal kidneys and recombined organs engraft, develop a blood supply and grow when xenotransplanted, and there are new advances in decellularised scaffolds to promote differentiation. This is an exciting time for human kidney repair and regeneration. Many of the approaches and techniques are in their infancy and based on animal rather than human work, but there is a rapid pace of discovery, and we predict that therapies based on advances in this field will come into clinical practice in the next decade.

Approximately 39 million people are blind worldwide, with an estimated 285 million visually impaired. The developing world shoulders 90% of the world's blindness, with 80% of causative diseases being preventable or treatable. Blindness has a major detrimental impact on the patient, community, and healthcare spending. Corneal diseases are significant causes of blindness, affecting at least 4 million people worldwide. The prevalence of corneal disease varies between parts of the world. Trachoma, for instance, is the second leading cause of blindness in Africa, after cataracts, but is rarely found today in developed nations. When preventive strategies have failed, corneal transplantation is the most effective treatment for advanced corneal disease. The major surgical techniques for corneal transplantation include penetrating keratoplasty (PK), anterior lamellar keratoplasty, and endothelial keratoplasty (EK). Indications for corneal transplantation vary between countries, with Fuchs' dystrophy being the leading indication in the USA and keratoconus in Australia. With the exception of the USA, where EK will soon overtake PK as the most common surgical procedure, PK is the overwhelming procedure of choice. Success using corneal grafts in developing nations, such as Nepal, demonstrates the feasibility of corneal transplantation on a global scale. The number of suitable corneas from deceased human donors that becomes available will never be sufficient, and so research into various alternatives, for example stem cells, amniotic membrane transplantation, synthetic and biosynthetic corneas, and xenotransplantation, is progressing. While each of these has potential, we suggest that xenotransplantation holds the greatest potential for a corneal replacement. With the increasing availability of genetically engineered pigs, pig corneas may alleviate the global shortage of corneas in the near future., (© 2014 John Wiley & Sons A/S.)

Over the last decade, improvements in islet isolation techniques have made islet transplantation an option for a certain subset of patients with long-standing diabetes. Although islet transplants have shown improved graft function, adequate function beyond the second year has not yet been demonstrated, and patients still require immunosuppression to prevent rejection. Since allogeneic islet transplants have experienced some success, the next step is to improve graft function while eliminating the need for systemic immunosuppressive therapy. Biomaterial encapsulation offers a strategy to avoid the need for toxic immunosuppression while increasing the chances of graft function and survival. Encapsulation entails coating cells or tissue in a semipermeable biocompatible material that allows for the passage of nutrients, oxygen, and hormones while blocking immune cells and regulatory substances from recognizing and destroying the cell, thus avoiding the need for systemic immunosuppressive therapy. Despite advances in encapsulation technology, these developments have not yet been meaningfully translated into clinical islet transplantation, for which several factors are to blame, including graft hypoxia, host inflammatory response, fibrosis, improper choice of biomaterial type, lack of standard guidelines, and post-transplantation device failure. Several new approaches, such as the use of porcine islets, stem cells, development of prevascularized implants, islet nanocoating, and multilayer encapsulation, continue to generate intense scientific interest in this rapidly expanding field. This review provides a comprehensive update on islet and stem cell encapsulation as a treatment modality in type 1 diabetes, including a historical outlook as well as current and future research avenues.

The aim of xenotransplantation is to allow the transplantation of animal organs or cells to humans. This approach would immediately eliminate the human organ shortage that is responsible for a significant mortality of patients on the waiting list for transplantation of organs. The immune differences between pig and human induce an immediate rejection of porcine tissues by humans. This rejection has recently been partially controlled by genetic engineering of pigs, the use of new immunosuppressive drugs and encapsulation of isolated cells. However, due to the risk of transmission of animal infectious agents to humans, the WHO recommends that clinical application of xenotransplantation only takes place if adequate regulations are in place.

Barriers to successful lung xenotransplantation appear to be even greater than for other organs. This difficulty may be related to several macro anatomic factors, such as the uniquely fragile lung parenchyma and associated blood supply that results in heightened vulnerability of graft function to segmental or lobar airway flooding caused by loss of vascular integrity (also applicable to allotransplants). There are also micro-anatomic considerations, such as the presence of large numbers of resident inflammatory cells, such as pulmonary intravascular macrophages and natural killer (NK) T cells, and the high levels of von Willebrand factor (vWF) associated with the microvasculature. We have considered what developments would be necessary to allow successful clinical lung xenotransplantation. We suggest this will only be achieved by multiple genetic modifications of the organ-source pig, in particular to render the vasculature resistant to thrombosis. The major problems that require to be overcome are multiple and include (i) the innate immune response (antibody, complement, donor pulmonary and recipient macrophages, monocytes, neutrophils, and NK cells), (ii) the adaptive immune response (T and B cells), (iii) coagulation dysregulation, and (iv) an inflammatory response (e.g., TNF-α, IL-6, HMGB1, C-reactive protein). We propose that the genetic manipulation required to provide normal thromboregulation alone may include the introduction of genes for human thrombomodulin/endothelial protein C-receptor, and/or tissue factor pathway inhibitor, and/or CD39/CD73; the problem of pig vWF may also need to be addressed. It would appear that exploration of every available therapeutic path will be required if lung xenotransplantation is to be successful. To initiate a clinical trial of lung xenotransplantation, even as a bridge to allotransplantation (with a realistic possibility of survival long enough for a human lung allograft to be obtained), significant advances and much experimental work will be required. Nevertheless, with the steadily increasing developments in techniques of genetic engineering of pigs, we are optimistic that the goal of successful clinical lung xenotransplantation can be achieved within the foreseeable future. The optimistic view would be that if experimental pig lung xenotransplantation could be successfully managed, it is likely that clinical application of this and all other forms of xenotransplantation would become more feasible., (© 2012 John Wiley & Sons A/S.)

Objectives: 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., Materials and Methods: 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., Results: 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., Conclusions: 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.

The histocompatibility system is responsible for the rejection of allografts. The system exists to counter the explosive speed of viral replication by directing the defensive immune attack by cytotoxic T cells on to histocompatibility antigens on the infected cell's surface. This enables destruction of the virus factories before the cytotoxic T cells are swamped by the myriad numbers of new virions, a thousand coming from each infected cell every 10 h. The immunity system mistakes alloantigens for virus-infected host cells that need swift destruction. For transplantation, Sykes has improved Kaplan's technique by adding recipient bone marrow cells to the donor ones injected for reconstitution of the recipient after immune ablation. This technique should enable the use of xenografts from pigs.

Although corneal transplantation (Tx) is readily available in the United States and certain other regions of the developed world, the need for human donor corneas worldwide far exceeds supply. There is currently renewed interest in the possibility of using corneas from other species, especially pigs, for Tx into humans (xeno-Tx). The biomechanical properties of human and pig corneas are similar. Studies in animal models of corneal xeno-Tx have documented both humoral and cellular immune responses that play roles in xenograft rejection. The results obtained from the Tx of corneas from wild-type (ie, genetically unmodified) pigs into nonhuman primates have been surprisingly good and encouraging. Recent progress in the genetic manipulation of pigs has led to the prospect that the remaining immunological barriers will be overcome. There is every reason for optimism that corneal xeno-Tx will become a clinical reality within the next few years.

Xenotransplantation of solid organs will only ever become a clinical reality with genetic modification of the pig, which is now widely accepted as the most likely donor species for humans. The understanding of the barriers to xenotransplantation has required advances in genetic technologies to resolve these problems. Hyperacute rejection has been overcome by overexpression of complement regulatory proteins or targeted disruption of the enzyme associated with the major carbohydrate xenoantigen. The subsequent barriers of disordered coagulation, induced antibody, and cell-mediated rejection remain challenging. The mechanisms for these incompatibilities are being deciphered, and multiple genetic manipulations to resolve these issues are currently in progress. Moreover, new technologies offer help to producing sizeable numbers of modified pigs in a timely manner. This article retraces the basis and foreshadows progress of the genetically modified pig for xenotransplantation as it advances toward the clinic., (Copyright © 2011 Elsevier Inc. All rights reserved.)