Restoring normal islet mass and function in type 1 diabetes through regenerative medicine and tissue engineering.

Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic ß-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost ß-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring ß-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived ß-like cells to restore ß-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of ß-cell replacement therapies.

Systematic review of islet cryopreservation.

Pancreatic islet transplantation is being extensively researched as an alternative treatment for type 1 diabetic patients. This treatment is currently limited by temporal mismatch, between the availability of pancreas and isolated islets from deceased organ donor, and the recipient's need for freshly isolated islets. To solve this issue, cryopreservation of islets may offer the potential to bank islets for transplant on demand. Cryopreservation, however, introduces an overwhelmingly harsh environment to the ever-so-fragile islets. After exposure to the freezing and thawing, islets are usually either apoptotic, non-functional, or non-viable. Several studies have proposed various techniques that could lead to increased cell survival and function following a deep freeze. The purpose of this article is to critically review the techniques of islet cryopreservation, with the goal of highlighting optimization parameters that can lead to the most viable and functional islet upon recovery and/or transplant.

El arte de la cirugía pancreática. Pasado, presente y future / The art of pancreatic surgery. Past, present and future. The history of pancreatic surgery

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Enzyme Development for Human Islet Isolation: Five Decades of Progress or Stagnation?

In comparison to procedures used for the separation of individual cell types from other organs, the process of human pancreatic islet isolation aims to digest the pancreatic exocrine matrix completely without dispersing the individual cells within the endocrine cell cluster. This objective is unique within the field of tissue separation, and outlines the challenge of islet isolation to balance two opposing priorities. Although significant progress has been made in the characterization and production of enzyme blends for islet isolation, there are still numerous areas which require improvement. The ultimate goal of enzyme production, namely the routine production of a consistent and standardized enzyme blend, has still not been realized. This seems to be mainly the result of a lack of detailed knowledge regarding the structure of the pancreatic extracellular matrix and the synergistic interplay between collagenase and different supplementary proteases during the degradation of the extracellular matrix. Furthermore, the activation of intrinsic proteolytic enzymes produced by the pancreatic acinar cells, also impacts on the chance of a successful outcome of human islet isolation. This overview discusses the challenges of pancreatic enzymatic digestion during human islet isolation, and outlines the developments in this field over the past 5 decades.

Evolution of Islet Transplantation for the Last 30 Years.

In this article, we will review the changes that have occurred in islet transplantation at the birth of Pancreas 30 years ago. The first attempts at ß-cell replacement in humans, pancreas and islet transplantation, were performed in the 1960s and 1970s. Although pancreas transplantation has been an accepted treatment for severe labile diabetes predating the emergence of the journal, allogeneic islet transplantation remains experimental. Current investigations within islet transplantation focus to improve islet function after transplantation. Improving islet viability during isolation, exploring ways to increase engraftment, and protection from the host immune system are some of the goals of these investigative efforts. The major barriers to clinical islet transplantation are shortage of human pancreas, the need for immunosuppression, and the inadequacy of the islet isolation process. It is generally accepted that islet encapsulation is an immunoisolation tool with good potential to address the first 2 of those barriers. We have therefore devoted a major part of this review to the critical factors needed to make it a clinical reality. With improved islet isolation techniques and determination of the best site of engraftment as well as improved encapsulation techniques, we hope that islet transplantation could someday achieve routine clinical use.

Pancreatic islet cell transplantation: an update for interventional radiologists.

Pancreatic islet cell transplantation is a promising cellular-based therapy for type 1 diabetes mellitus. This procedure involves portal venous injection of islet cells and affords 1-year insulin independence in as many as 80% of recipients. Although transplant surgeons represent historical drivers of islet therapy, requirement for image guidance and transcatheter techniques has fostered collaboration with interventional radiologists, who are positioned to play a significant role in clinical performance of islet transplantation and in basic science research in this field. This review article aims to familiarize interventional radiologists with islet cell transplantation patient selection, procedure technique, clinical outcomes, and future clinical and research avenues.

The isolated pancreatic islet as a micro-organ and its transplantation to cure diabetes: celebrating the legacy of Paul Lacy.

Over the past three decades the pancreatic islet of Langerhans has taken center stage as an endocrine micro-organ whose glucoregulatory function is highly explicable on the basis of the increasingly well understood activities of three highly interactive secretory cells. Islet dysfunction underlies both type 1 and type 2 diabetes mellitus (DM); its protection from immune attack and gluco-and lipo-toxicity may prevent the development of DM; and its replacement by non-surgical transplantation may be curative of DM. During a career marked by vision, focus and tenacity, Paul Lacy contributed substantially to the development of each of these concepts. In this review we focus on Lacy's contribution to the development of the concept of the islet as a micro-organ, how this foreshadowed our current detailed understanding of single cell function and cell-cell interactions and how this led to a reduced model of islet function encouraging islet transplantation. Next, we examine how clinical allotransplantation, first undertaken by Lacy, has contributed to a more complex view of the interaction of islet endocrine cells with its circulation and neighboring tissues, both "in situ" and after transplantation. Lastly, we consider recent developments in some alternative approaches to treatment of DM that Lacy could glimpse on the horizon but did not have the chance to participate in.

Islet transplantation: lessons learned since the Edmonton breakthrough.

This work sought to summarize the main issues of the last decade in the field of clinical islet transplantation. Ten years ago in Edmonton, a new protocol initiated for islet transplantation brought a breakthrough to the field. The earlier, rather poor results were in a sharp contrast to the first published results of 100% insulin freedom at 1 year. However, later it became clear that the promising initial results decline with time; at around 5 years, only about 10% of the patients maintain freedom from external insulin. Despite that fact, a milestone was set and intensive research started worldwide. New hopes were raised for patients. Modifications of the original protocol have been implemented to improve clinical results; however, islet transplantation remains an experimental procedure to date.

Pancreas vs. islet transplantation: a call on the future.

PURPOSE OF REVIEW: The aim of this article is to review recent reports on whole pancreas and islet cell transplantation. It focuses on 'what the call to the future looks like' for both therapies as treatment options for those type 1 diabetes patients who do not respond well to conventional therapy. RECENT FINDINGS: The major benefit of pancreas transplantation is the reversal of diabetes improvement of diabetes complications. Although the procedure requires major surgery and life-long immunosuppression, it remains the gold standard for a specific population of patients who suffer from type 1 diabetes and who do not respond to conventional therapy. Allogeneic islet transplantation is a promising alternative to pancreas transplantation, but patient outcomes remain less than optimal and significant progress is required in order for this procedure to be considered a reliable therapy. CONCLUSION: Several factors have to be taken into consideration before making the decision of which of these procedures would better suit a patient with type 1 diabetes.

History of islet transplantation.

Patients with a diagnosis of type 1 diabetes mellitus endure stringent life-long medical therapy through the use of insulin to prevent end organ complications and maintain normoglycemia. However, some patients still suffer from hypoglycemic unawareness, even under intensive therapy. Within the past decade, noble efforts have been attempted to provide normoglycemia through cadaveric islet of Langerhans transplantation in order to reach a physiologic response. This effort, which has evolved for more than a century, actually predates the discovery of insulin.

Islet transplantation: the quest for an ideal source.

The progress of islet transplantation as a new therapy for patients with diabetes mellitus depends directly upon the development of efficient and practical immunoisolation methods for the supply of sufficient quantities of islet cells. Without these methods, large scale clinical application of this therapy would be impossible. Two eras of advances can be identified in the development of islet transplantation. The first was an era of experimental animal and human research that centered on islet isolation procedures and transplantation in different species as evidence that transplanted islets have the capability to reverse diabetes. The second was the era of the Edmonton protocol, when the focus became the standardization of isolation procedures and introduction of new immunosuppressive drugs to maintain human allograft transplantation. The quest for an alternative source for islets (xenographs, stem cells and cell cultures) to overcome the shortage of human islets was an important issue during these eras. This paper reviews the history of islet transplantation and the current procedures in human allotransplantation, as well as different types of immunoisolation methods. It explores novel approaches to enhancing transplantation site vascularity and islet cell function, whereby future immunoisolation technology could offer additional therapeutic advantages to human islet allotransplantation.

Islet cell transplantation today.

INTRODUCTION: Long-term studies strongly suggest that tight control of blood glucose can prevent the development and retard the progression of chronic complications of type 1 diabetes mellitus. In contrast to conventional insulin treatment, replacement of a patient's islets of Langerhans either by pancreas organ transplantation or by isolated islet transplantation is the only treatment to achieve a constant normoglycemic state and avoiding hypoglycemic episodes, a typical adverse event of multiple daily insulin injections. However, the cost of this benefit is still the need for immunosuppressive treatment of the recipient with all its potential risks. MATERIALS AND METHODS: Islet cell transplantation offers the advantage of being performed as a minimally invasive procedure in which islets can be perfused percutaneously into the liver via the portal vein. Between January 1990 and December 2004, 458 pancreatic islet transplants worldwide have been reported to the International Islet Transplant Registry (ITR) at our Third Medical Department, University of Giessen/Germany. RESULTS: Data analysis of islet cell transplants performed in the last 5 years (1999-2004) shows at 1 year after adult islet transplantation a patient survival rate of 97%, a functioning islet graft in 82% of the cases, whereas insulin independence was meanwhile achieved in 43% of the cases. However, using a novel protocol established by the Edmonton Center/Canada, the insulin independence rates have improved significantly reaching meanwhile a 50-80% level. CONCLUSION: Finally, the concept of islet cell or stem cell transplantation is most attractive, as it offers many perspectives: islet cell availability could become unlimited and islet or stem cells my be transplanted without life-long immunosuppressive treatment of the recipient, just to mention two of them.

Current status of clinical islet cell transplantation.

Clinical outcomes of pancreas transplantation were superior to that of islet transplantation until the introduction of the Edmonton protocol. Significant advances in islet isolation and purification technology, novel immunosuppression and tolerance strategies, and effective antiviral prophylaxis have renewed interest in clinical islet transplantation for the treatment of diabetes mellitus. The introduction of a steroid-free antirejection protocol and islets prepared from two donors led to high rates of insulin independence. The Edmonton protocol has been successfully replicated by other centers in an international multicenter trial. A number of key refinements in pancreas transportation, islet preparation, and newer immunological conditioning and induction therapies have led to continued advancement through extensive collaboration between key centers. This chapter provides an overview of the history of islet transplantation followed by a discussion of the state of the art of clinical islet transplantation. The challenges facing the clinician-scientist in the 21st century are also presented in this review.

Pancreatic islet and stem cell transplantation: new strategies in cell therapy of diabetes mellitus.

Long-term studies strongly suggest that tight control of blood glucose can prevent the development and retard the progression of chronic complications of type 1 diabetes mellitus. In contrast to conventional insulin treatment, replacement of a patient's islets of Langerhans either by pancreas organ transplantation of by isolated islet transplantation is the only treatment to achieve a constant normoglycemic state and avoiding hypoglycemic episodes, a typical adverse event of multiple daily insulin injections. However, the expense of this benefit is still the need for immunosuppressive treatment of the recipient with all its potential risks. Islet cell transplantation offers the advantage of being performed as a minimally invasive procedure, in which islets can be perfused percutaneously into the liver via the portal vein. As of June 2003, 705 pancreatic islet transplants worldwide have been reported to the International Islet Transplant Registry (ITR) at our Third Medical Department, University of Giessen/Germany. Data analysis shows at 1 year after adult islet transplantation a patient survival rate of 97%, a functioning islet graft in 54% of the cases, whereas insulin independence was meanwhile achieved in 20% of the cases. However, using a novel protocol established by the Edmonton Center/Canada, the insulin independence rates have improved significantly reaching meanwhile a 50-80% level. Finally, the concept of islet cell or stem cell transplantation is most attractive since it offers many perspectives: islet cell availability could become unlimited and islet or stem cells my be transplanted without life-long immunosuppressive treatment of the recipient, just to mention 2 of them.