Microencapsulated Pancreatic Islet Allografts Into Nonimmunosuppressed Patients With Type 1 Diabetes (original) (raw)
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Am J Transplant, 2018
Macroencapsulation devices provide the dual possibility of immunoprotecting transplanted cells while also being retrievable, the latter bearing importance for safety in future trials with stem cell-derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets into patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155 000-180 000 islet equivalents (ie, 1800-4600 islet equivalents per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose-stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited (Clinicaltrials.gov: NCT02064309). K E Y W O R D S cellular biology, clinical research/practice, diabetes: type 1, encapsulation, endocrinology/ diabetology, islet transplantation, islets of Langerhans, translational research/science This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Biocompatibility and function of microencapsulated pancreatic islets
Acta Biomaterialia, 2006
Encapsulation of pancreatic islets in alginate is used to protect against xenogenic rejection in diVerent animal models. In this study, several factors, including diVerences in alginate composition, the presence or absence of xenogenic islet tissue and a transient immunosuppression, were investigated in a model of bovine islet transplantation in rats. A pure alginate with predominantly guluronic acid (Manugel) and an ultrapure low viscosity guluronic acid alginate (UP-LVG) were used. When microcapsules of Manugel or UP-LVG containing 16,000 bovine islet equivalents were transplanted in diabetic rats, we observed normoglycemia for 8.3 § 0.7 (range 6-12 days) and 7.5 § 0.2 days (range 7-8 days) on average, respectively. To ameliorate immunoprotection of alginate microcapsules we repeated the same experiments using transient immunosuppressive therapy. Low doses of cyclosporin A (CyA) administered for 18 days after implantation increased the time in normoglycemia, which averaged 27 § 3 days (range 8-55 days) in Manugel capsules while in UP-LVG capsules it averaged 18 § 8 days (range 3-39 days). The surface of recovered capsules showed less capsules free of overgrowth in Manugel with respect to UP-LVG alginate. These data were comparable with those observed in empty microcapsules similarly implanted, indicating that the capsular overgrowth was not promoted by the presence of xenogenic islet tissue. In recovered Manugel capsules the percentage of capsules without Wbrotic overgrowth was higher than that observed without CyA. The same observation was made in empty capsules. These observations indicate that a combination of a highly puriWed alginate and short-term immunosuppression prolong islet function in a model of xenotransplantation.
Transplantation of islets using microencapsulation: studies in diabetic rodents and dogs
Journal of Molecular Medicine, 1999
Studies involving the transplantation of human islets in Type I diabetics have been of significant value both in documenting the potential importance of islet transplantation as a therapeutic modality, and in defining some of the problems which must be overcome before this approach can be used in large numbers of patients. The currently limited supply of adult human pancreatic glands, and the fact that chronic immunosuppression is required to successfully transplant islets into patients, indicate that techniques must be further developed and refined for alloand xenografting of isolated islets from human and animal sources to diabetic patients. An increasing body of evidence using microencapsulation techniques strongly suggests that this will be achieved during the next few years. Data from our laboratory in rodents and dogs indicate that these systems can function for extended periods of time. In one study, insulin independence was achieved in spontaneously diabetic dogs by islet microencapsulation inside uncoated alginate gel spheres (M r exclusion >600 kD). No synthetic materials or membrane coatings were employed in this study. Spheres containing canine islets were implanted into the peritoneum of 4 diabetic dogs. The animals received low-dose CsA (levels below readable limits by HPLC at 3 weeks). Implantation of these spheres completely supplanted exogenous insulin therapy in the dogs for 60 to >175 days. Blood glucose concentration averaged 122±4 mg/dl for these animals during the first 2 months. The glycosylated hemoglobin (Hb AIC ) levels during this period dropped from 6.7±0.5% to 4.2±0.2% (P<0.001). IVGTT K-values at 1 and 2 months postimplantation were 1.6±0.1 (P<0.002) and 1.9±0.1 (P<0.001), respectively compared with 0.71±0.3 before implantation. In a second group of studies, bovine islets were immobilized inside a new type of selectively permeable "microreactor" (M r exclusion <150 kD) and implanted into the peritoneum of 33 STZ-induced diabetic rats without any immunosuppression. Diabetes was promptly reversed, and normoglycemia maintained for periods of several weeks to months. Immunohistochemical staining of microreactors recovered from these animals revealed well-granulated β-cells consistent with functionally active insulin synthesis and secretion. To test further the secretory function of the islets, some of the explanted microreactors were incubated in media containing either basal or stimulatory concentrations of glucose. The islets responded with an approximately 3-to 5-fold average increase above basal insulin secretion. These results are encouraging, and may have important implications in assessing the potential role of these microencapsulation systems as therapy for human insulin-dependent diabetes.
Clinical application of microencapsulated islets: Actual prospectives on progress and challenges
Advanced Drug Delivery Reviews, 2014
After 25 years of intense pre-clinical work on microencapsulated intraperitoneal islet grafts into nonimmunosuppressed diabetic recipients, the application of this procedure to patients with type 1 diabetes mellitus has been a significant step forward. This result, achieved in a few centers worldwide, underlies the safety of biopolymers used for microencapsulation. Without this advance, no permission for human application of microcapsules would have ever been obtained after years of purification technologies applied to the raw alginates. To improve safety of the encapsulated islet graft system, renewed efforts on the capsules' bioengineering, as well as on insulin-producing cells within the capsular membranes, are in progress. It is hoped that advances in these two critical aspects of the cell encapsulation technology will result in wider human application of this system.
Islet Microencapsulation: Strategies and Clinical Status in Diabetes
Purpose of Review Type 1 diabetes mellitus (T1DM) is an autoimmune disease that results from the destruction of insulin-producing pancreatic β cells in the islets of Langerhans. Islet cell transplantation has become a successful therapy for specific patients with T1DM with hypoglycemic unawareness. The reversal of T1DM by islet transplantation is now performed at many major medical facilities throughout the world. However, many challenges must still be overcome in order to achieve continuous, long-term successful transplant outcomes. Two major obstacles to this therapy are a lack of islet cells for transplantation and the need for lifelong immunosuppressive treatment. Microencapsulation is seen as a technology that can overcome both these limitations of islet cell transplantation. This review depicts the present state of microencapsulated islet transplantation. Recent Findings Microencapsulation can play a significant role in overcoming the need for immunosuppression and lack of donor islet cells. Summary This review focuses on microencapsulation and the clinical status of the technology in combating T1DM.
Microencapsulation of pancreatic islets
Diabetes Research and Clinical Practice, 1986
Hamster pancreatic islets were encapsulated by a biocompatible membrane composed of the molecular sequence of alginate-polylysine-alginate. The encapsulated islets released insulin into the culture medium in response to secretagogues in short-term incubation. In long-term culture, the encapsulated islets maintained their insulin-releasing capacity for 28 days at a level similar to that of the unencapsulated islets. No overgrowth of fibroblastic cells was observed inside the capsule even after 70 days of culture. Further, the encapsulated hamster islets were xenotransplanted to streptozotocin-induced diabetic rats intraperitoneally. Some of the encapsulated islets, which were recovered from a recipient 27 days after transplantation, were found to be viable, although prolonged normalization of fasting plasma glucose levels of the recipients could not been achieved. On the contrary, the unencapsulated islets were replaced by massive connective tissue elements and insulin-positive B cells were hardly detected within the grafts 22 days after transplantation. The results of this study seem to confirm the potential of the application of the encapsulating technique to primary culture of parenchymal cells and to transplantation of pancreatic islets.