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Aims/hypothesis: Islet transplantation has been studied in small cohorts of recipients with type 1 diabetes complicated by severe hypoglycaemic events (SHEs). We determined factors associated with favourable outcomes in a large cohort of recipients reported to the Collaborative Islet Transplant Registry (CITR). Methods: In 398 non-uraemic islet transplant alone (ITA) recipients with type 1 diabetes and SHEs, transplanted between 1999 and 2015 and with at least 1 year follow-up, we analysed specified favourable outcomes against each of all available characteristics of pancreas donors, islet grafts, recipients and immunosuppressive regimens, as well as immunosuppression and procedure-related serious adverse events (SAEs). Results: Four factors were associated with the highest rates of favourable outcomes: recipient age ≥35 years; total infused islets ≥325,000 islet equivalents; induction immunosuppression with T cell depletion and/or TNF-α inhibition; and maintenance with both mechanistic target of rapamycin (mTOR) and calcineurin inhibitors. At 5 years after the last islet infusion, of the recipients meeting these four common favourable factors (4CFF; N=126), 95% were free of SHEs, 76% had HbA1c <53 mmol/mol (7.0%), 73% had HbA1c <53 mmol/mol (7.0%) and absence of SHEs, and 53% were insulin independent, significantly higher rates than in the remaining recipients (<4CFF; N=272). The incidence of procedural and immunosuppression-related SAEs per recipient that resulted in sequelae, disability or death was low in both the 4CFF (0.056 per person) and <4CFF (0.074 per person) groups. Conclusions/interpretation: In recipients with type 1 diabetes complicated by SHEs, islet transplantation meeting 4CFF protected 95% from SHEs at 5 years after the last islet infusion and exerted a large and significant benefit on glycaemic control, with an acceptable safety profile for this subgroup of type 1 diabetes. [ABSTRACT FROM AUTHOR]

In this study using a discordant, xenogeneic, transplant model we demonstrate the functionality and safety of the first stent-based bioartificial pancreas (BAP) device implanted endovascularly into an artery, harnessing the high oxygen content in blood to support islet viability. The device is a self-expanding nitinol stent that is coated with a bilayer of polytetrafluoroethylene that forms channels to hold islets embedded in a hydrogel. We completed a 1-month study in the nondiabetic swine model (N = 3) to test the safety of the device and to assess islet functionality after device recovery. The luminal diameter of the devices from 3 animals on day 0 and day 30 was 10.01 ± 0.408 mm and 10.05 ± 0.25 mm, respectively. The stimulation index of the control and endovascular BAP devices explanted at day 30 were 3.35 ± 0.97 and 4.83 ±1.20, respectively, and the islets stained positively for insulin and glucagon after 30 days in vivo. This pilot study shows that BAP implantation into a peripheral artery is safe and supports islet functionality over 30 days, providing the groundwork for future work assessing the in vivo function of the device in diabetic swine., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Autologous human islet transplantation to mitigate or prevent surgically induced diabetes after total pancreatectomy for the relief of chronic pancreatitisinduced pain was pioneered in the late 1970s. Islet allotransplantation using islets from human donors to treat type 1 diabetes was first reported several years later. Over the last 40 years, methods for clinical islet transplantation have been methodically standardized to become the methods used today. Human islets are also isolated from donors with pathologies with the aim to conduct a broad range of investigational studies. Human islet isolation undertaken for research can provide the opportunity to further optimize and develop methods that may be helpful in the clinic. The variability of conditions associated with donor and pancreas makes consistent success in isolating islets a challenge, thus, we should re-evaluate the effectiveness of our methods of islet isolation. In order to do this, we must first consider that the intended outcomes for clinical islet transplantation and experimental investigations involving islet isolation are, in fact, quite different and that these differences impact the status and future considerations of islet isolation procedures.

Milestones in the history of diabetes therapy include the discovery of insulin and successful methods of beta cell replacement including whole pancreas and islet cell transplantation options. While pancreas transplantation remains the gold standard for patients who have difficulty controlling their symptoms with exogenous insulin, islet allotransplantation is now able to provide similar results with some advantages that make it an attractive potential alternative. The Edmonton Protocol, which incorporated a large dose of islets from multiple donors with steroid-free immunosuppression helped to establish the modern era of islet transplantation almost 20 years ago. While islet allotransplantation is recognized around the world as a powerful clinical therapy for type 1 diabetes it is not yet recognized by the Federal Drug Administration of the United States. Large-scale clinical trials administered by the Clinical Islet Transplantation Consortium have recently demonstrated that the well-regulated manufacture of a human islet product transplanted into patients with difficult to control type 1 diabetes and with a history of severe hyperglycemic episodes can safely and efficaciously maintain glycemic balance and eliminate the most severe complications associated with diabetes. The results of these clinical trials have established a strong basis for licensure of clinical islet allotransplantation in the US. Recognition by the Federal Drug Administration would likely lead to third party reimbursement for islet allotransplantation as a therapeutic option in the United States and would make the treatment available to many more patients. The high costs of rampant diabetes justify the expense of the treatment, which is in-line with the costs of clinical pancreas transplantation. While much enthusiasm and hope is raised toward the development and optimization of stem cell therapy, the islet transplantation community should push toward licensure, if that means broader access of this procedure to patients who may benefit from it. Even as we prepare to take the first steps in that direction, we must acknowledge the new challenges that a shift from the experimental to clinical will bring. Clinical islet allotransplantation in the United States would be a game-changing event in the treatment of type 1 diabetes and also generate enthusiasm for continued research.

Recently, initiatives have been undertaken to establish an islet transplantation program in Athens, Greece. A major hurdle is the high cost associated with the establishment and maintenance of a clinical-grade islet manufacturing center. A collaboration was established with the University Hospitals of Geneva, Switzerland, to enable remote islet cell manufacturing with an established and validated fully operational team. However, remote islet manufacturing requires shipment of the pancreas from the procurement to the islet manufacturing site (in this case from anywhere in Greece to Geneva) and then shipment of the islets from the manufacturing site to the transplant site (from Geneva to Athens). To address challenges related to cold ischemia time of the pancreas and shipment time of islets, a collaboration was initiated with the University of Arizona, Tucson, USA. An international workshop was held in Athens, December 2011, to mark the start of this collaborative project. Experts in the field presented in three main sessions: (i) islet transplantation: state-of-the-art and the 'network approach'; (ii) technical aspects of clinical islet transplantation and outcomes; and (iii) islet manufacturing - from the donated pancreas to the islet product. This manuscript presents a summary of the workshop. [ABSTRACT FROM AUTHOR]

Clinical islet transplantation has transitioned from curiosity to realistic therapy over the past decade. An estimated 750 patients have undergone intraportal islet-alone transplantation over this period, and a smaller subset received combined islet-kidney transplants. The primary benefit of successful islet transplantation has been to eliminate severe, recurrent hypoglycemia, a problem that has been hard to eliminate by other means in 15% of those with type 1 diabetes. The secondary benefit of independence from insulin has attracted patients, but has had limited sustainability previously, especially with a single-donor graft, but recent results from four independent centers suggest marked improvement in long-term outcome, with 5-year results now approximating solitary pancreas transplantation. Emerging data confirm that islet transplantation can stabilize and reverse several secondary diabetic complications similar to whole pancreas transplantation, but larger, head-to-head trials are needed to compare islet transplantation with best medical therapies. Current goals are to extend durability, and to make islet transplantation more widely available for patients in need. Governmental and health insurance providers in several countries now reimburse islet transplantation as part of clinical care. As the safety of the procedure and of adjunctive immunosuppressive therapies improve, and benefit accrues over potential risk, islet transplantation will be offered earlier in the course of the disease, including newly diagnosed children. The role of islet transplantation in type 2 diabetes has yet to be defined. We review the current status of islet transplantation, and discuss current and future immunosuppressive protocols that will pave the way to more broad application of cellular replacement in diabetes. [ABSTRACT FROM AUTHOR]

The clinical success rate of islet transplantation, namely independence from insulin injections, is limited by factors that lead to graft failure, including inflammation, acute ischemia, acute phase response, and insufficient vascularization. The ischemia and insufficient vascularization both lead to high levels of oxidative stress, which are further aggravated by islet encapsulation, inflammation, and undesirable cell-biomaterial interactions. To identify biomaterials that would not further increase damaging oxidative stress levels and that are also suitable for manufacturing a beta cell encapsulation device, we studied five clinically approved polymers for their effect on oxidative stress and islet (alpha and beta cell) function. We found that 300 poly(ethylene oxide terephthalate) 55/poly(butylene terephthalate) 45 (PEOT/PBT300) was more resistant to breakage and more elastic than other biomaterials, which is important for its immunoprotective function. In addition, it did not induce oxidative stress or reduce viability in the MIN6 beta cell line, and even promoted protective endogenous antioxidant expression over 7 days. Importantly, PEOT/PBT300 is one of the biomaterials we studied that did not interfere with insulin secretion in human islets. • PEOT/PBT300 does not induce oxidative stress in pancreatic alpha and beta cells. • PET and PVDF induce oxidative stress in alpha cells, but not in beta cells. • Beta cells can protect themselves against oxidative stress induced by certain biomaterials. [ABSTRACT FROM AUTHOR]

Milestones in the history of diabetes therapy include the discovery of insulin and successful methods of beta cell replacement including whole pancreas and islet cell transplantation options. While pancreas transplantation remains the gold standard for patients who have difficulty controlling their symptoms with exogenous insulin, islet allotransplantation is now able to provide similar results with some advantages that make it an attractive potential alternative. The Edmonton Protocol, which incorporated a large dose of islets from multiple donors with steroid-free immunosuppression helped to establish the modern era of islet transplantation almost 20 years ago. While islet allotransplantation is recognized around the world as a powerful clinical therapy for type 1 diabetes it is not yet recognized by the Federal Drug Administration of the United States. Large-scale clinical trials administered by the Clinical Islet Transplantation Consortium have recently demonstrated that the well-regulated manufacture of a human islet product transplanted into patients with difficult to control type 1 diabetes and with a history of severe hyperglycemic episodes can safely and efficaciously maintain glycemic balance and eliminate the most severe complications associated with diabetes. The results of these clinical trials have established a strong basis for licensure of clinical islet allotransplantation in the US. Recognition by the Federal Drug Administration would likely lead to third party reimbursement for islet allotransplantation as a therapeutic option in the United States and would make the treatment available to many more patients. The high costs of rampant diabetes justify the expense of the treatment, which is in-line with the costs of clinical pancreas transplantation. While much enthusiasm and hope is raised toward the development and optimization of stem cell therapy, the islet transplantation community should push toward licensure, if that means broader access of this procedure to patients who may benefit from it. Even as we prepare to take the first steps in that direction, we must acknowledge the new challenges that a shift from the experimental to clinical will bring. Clinical islet allotransplantation in the United States would be a game-changing event in the treatment of type 1 diabetes and also generate enthusiasm for continued research.

Background: Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential because they synergize with collagenase for effective pancreatic digestion. The activity of these enzymes is critically dependent on the presence of Ca 2+ ions at a concentration of 5-10 mM. The present study aimed to determine the Ca 2+ concentration during human islet isolation and to ascertain whether the addition of supplementary Ca 2+ is required to maintain an optimal Ca 2+ concentration during the various phases of the islet isolation process., Methods: Human islets were isolated according to standard methods and isolation parameters. Islet quality control and the number of isolations fulfilling standard transplantation criteria were evaluated. Ca 2+ was determined by using standard clinical chemistry routines. Islet isolation was performed with or without addition of supplementary Ca 2+ to reach a Ca 2+ of 5 mM., Results: Ca 2+ concentration was markedly reduced in bicarbonate-based buffers, especially if additional bicarbonate was used to adjust the pH as recommended by the Clinical Islet Transplantation Consortium. A major reduction in Ca 2+ concentration was also observed during pancreatic enzyme perfusion, digestion, and harvest. Additional Ca 2+ supplementation of media used for dissolving the enzymes and during digestion, perfusion, and harvest was necessary in order to obtain the concentration recommended for optimal enzyme activity and efficient liberation of a large number of islets from the human pancreas., Conclusions: Ca 2+ is to a large extent consumed during clinical islet isolation, and in the absence of supplementation, the concentration fell below that recommended for optimal enzyme activity. Ca 2+ supplementation of the media used during human pancreas digestion is necessary to maintain the concentration recommended for optimal enzyme activity. Addition of Ca 2+ to the enzyme blend has been implemented in the standard isolation protocols in the Nordic Network for Clinical Islet Transplantation.