The Role of Capsule Composition and Biologic Responses In the Function of Transplanted Microencapsulated Islets of Langerhans1 (original) (raw)
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Factors Influencing Functional Survival of Microencapsulated Islet Grafts
Cell Transplantation, 2004
Graft function of encapsulated islets is restricted in spite of the fact that inflammatory responses against capsules are limited to a portion less than 10%. It has been shown that dysfunction is accompanied by a gradual decrease in the glucose-induced insulin response (GIIR), a hyperproliferation of islet cells, and gradual necrosis. Also, limited survival is associated with the presence of macrophages in the overgrowth. In the present study, we investigate whether macrophages are the inducers of dysfunction of encapsulated grafts. Four weeks after successful transplantation of microencapsulated rat allografts we determined the GIIR, the rate of islet cell replication, and islet cell death. Also, we quantified the number of macrophages on the overgrown capsules. This assessment was applied to set up an in vitro coculture system of macrophages and encapsulated islets. We retrieved 93 ± 6.2% of the capsules of which 9.2 ± 0.3% was overgrown. The GIIR of the retrieved nonovergrown isl...
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.
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.
Storage and Microencapsulation of Islets for Transplantation
Cell Transplantation, 2000
Microencapsulation is an effective means of immunoisolation for pancreatic islet transplants. However, the process of isolating, purifying, encapsulating, and transplanting islets in a single day is labor intensive and difficult for routine use. There is an apparent need for reliable methods of islet storage, and cryopreservation has emerged as an attractive system of islet banking. While studies have shown that cryopreserved islets are viable when tested unencapsulated after thawing, it is not clear if the combination of freezing and encapsulation would affect islet function. The purpose of the present study was to determine the in vitro function of cryopreserved islets following thawing and microencapsulation. Islets were isolated from the pancreata of Sprague-Dawley rats and cryopreserved under liquid nitrogen for either 1 week or 1 month, following an overnight culture at 37CC. Upon thawing, the islets were tested either unencapsulated or after encapsulation in polylysine–algina...
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.
Transplantation of micro- and macroencapsulated piglet islets into mice and monkeys
Transplantation proceedings
Neonatal porcine islets within alginate microcapsules transplanted intraperitoneally (IP) or within semi-permeable macrocapsules (TheraCyte) and transplanted subcutaneously (SC) survive and reverse diabetes for up to 16 weeks in diabetic autoimmune nonobese diabetic (NOD) mice. The islets in microcapsules transplanted IP into nondiabetic cynomolgus monkeys survived for 8 weeks. Similar results were shown with islets transplanted in TheraCytes. Neither species showed adverse effects or evidence of infection with porcine endogenous retroviruses or other endemic pig viruses. Proof of principle is illustrated for successful xenotransplantation in humans.
Microencapsulated islet grafts in the BB/E rat: a possible role for cytokines in graft failure
Diabetologia, 1992
Alginate-polylysine microencapsulation has been proposed as a method of protecting transplanted pancreatic islets against immunological attack. Using this technique, prolonged graft survival has been reported in some diabetic animals. However, in the spontaneously diabetic insulindependent BB/E rat we found that intraperitoneal implantation of microencapsulated islets had only a short-lived effect on hyperglycaemia. Recovered microcapsules (both those implanted empty and containing islets) were surrounded by a foreign body type cellular overgrowth and, although many capsules remained intact, encapsulated islets were observed to be disintegrating. Loss of Beta cells was confirmed by immunohistology. Various polymer materials used in artificial membranes have been shown to activate macrophages involved in foreign body reactions and induce synthesis of in-terleukin-lfl, a known Beta-cell toxin. Reduced secretion of insulin and progressive islet damage (indicated by a significant reduction in residual islet insulin and DNA content) were demonstrated when microencapsulated islets were incubated with interleukin-lflin vitro for 9 days. Similar effects were seen following exposure to a combination of gamma interferon and alpha tumour necrosis factor. Successful use of microencapsulation in islet transplantation depends upon the development of biocompatible membranes. The exclusion of smaller molecules, such as cytokines, which may be involved in foreign body mediated damage and microencapsulated islet graft rejection, could also be important.
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.
Advances in Medicine, 2014
Encapsulation of pancreatic islets has been proposed and investigated for over three decades to improve islet transplantation outcomes and to eliminate the side effects of immunosuppressive medications. Of the numerous encapsulation systems developed in the past, microencapsulation have been studied most extensively so far. A wide variety of materials has been tested for microencapsulation in various animal models (including nonhuman primates or NHPs) and some materials were shown to induce immunoprotection to islet grafts without the need for chronic immunosuppression. Despite the initial success of microcapsules in NHP models, the combined use of islet transplantation (allograft) and microencapsulation has not yet been successful in clinical trials. This review consists of three sections: introduction to islet transplantation, transplantation of encapsulated pancreatic islets as a treatment for patients with type 1 diabetes mellitus (T1DM), and present challenges and future perspe...