Islet Encapsulation Research Articles

PROTECTION OF ISLETS OF LANGERHANS FROM INTERLEUKIN-1 TOXICITY BY ARTIFICIAL MEMBRANES

Recently it has been reported that interleukin 1 may play a central role in the immune destruction of islets. Since the mass weight of interleukin-1 is close to that of insulin, destruction of transplanted islets may be possible although they are enclosed in membranes that prevent penetration by immune-competent cells and cyto-toxic antibodies. The present in vitro study showed that the encapsulated rat islets are protected from high doses of IL-1 (1000 ng) inside a hollow fiber membrane with a cutoff of 50,000 D. The function of islets in a free-floating culture, however, was suppressed in a dose-dependent manner (1000 ng/L; 20-30% of controls). Histologically, no damage of the free-floating or encapsulated islets was observed at 1000 ng of IL-1-containing medium. Islets washed out of the devices after 2 days of exposure to IL-1 showed no difference in glucose-stimulated insulin release when compared with islets not exposed that were kept in free-floating culture. It is suggested that an unspecific coating of the membranes by serum proteins (containing physiological IL-1 antagonists) may cause the protective effect.

Microencapsulation of mammalian cells in a HEMA‐MMA copolymer: Effects on capsule morphology and permeability

A new process for preparing uniform microcapsules with a hydroxyethyl methacrylate-methyl methacrylate copolymer (HEMA-MMA) has been devised. Capsule diameters were 900-1000 microns in diameter, (+/- 10-20 microns, +/- SD) depending on the precipitation conditions. The process involved the coextrusion of polymer solution (in PEG 200) and the mammalian cell suspension (here erythrocytes) through a needle assembly which is submerged in a layer of hexadecane which is in turn sitting above a stirred isotonic aqueous solution in a volumetric flask. The needle is repeatedly withdrawn from the hexadecane overlayer shearing a droplet from the needle tip which falls into the water, where the solvent is extracted to precipitate the polymer around the cells to yield the capsules. The morphology of the capsule wall was altered by changing the precipitation bath from phosphate buffered saline (PBS) to 0.3 M glycerol. This resulted in greater macroporosity in the wall, presumably because of the faster precipitation due to the higher solvent/precipitant compatibility with 0.3 M glycerol. The permeability to a series of test solutes (glucose, inulin, albumin, and alcohol dehydrogenase, ADH) increased by a factor of approximately 2, presumably because of the increased macroporosity. Addition of 15% water to the polymer solvent enhanced the macroporosity, presumably by bringing the system closer to the cloud point; however, there was no corresponding increase in permeability. There was a significant decrease in permeability between that of albumin (approximately 69,000 D) and ADH (approximately 150,000 D) suggesting that the molecular weight cut-off of these capsules was on the order of 100,000 D as desired. This process is now being evaluated for the encapsulation of pancreatic islets and other cells of potential clinical interest.

Reversal of Diabetes in BB Rats by Transplantation of Encapsulated Pancreatic Islets

Prolonged survival of pancreatic islet allografts implanted in diabetic BB rats was achieved by encapsulation of individual islets in a protective biocompatible alginate-polylysine-alginate membrane without immunosuppression. Intraperitoneal transplantation of the encapsulated islets reversed the diabetic state of the recipients within 3 days and maintained normoglycemia for 190 days. Normal body weight and urine volume were maintained during this period, and no cataracts were detected in the transplant recipients. In contrast, control rats receiving transplants of unencapsulated islets experienced normoglycemia for less than 2 wk. These results demonstrated that microencapsulation can protect allografted islets from both graft rejection and autoimmune destruction without immunosuppression in an animal model that mimics human insulin-dependent diabetes.

Preliminary report on microencapsulated islet transplantation in experimental diabetes mellitus in China

Pancreatic islets were encapsulated with sodium alginate-polylysine after procurement by collagenase digestion and Ficoll density-gradient-dispersion. The encapsulated islets were intact and during the first week of culture produced insulin 63 +/- 42 microU/d vs 69 +/- 42 microU/d by noncapsulated islets. Seven streptozotocin-induced diabetic rats each received 4.0-4.5 x 10(3) microencapsulated islets intraperitoneally. After transplantation, blood glucose dropped from 350 +/- 29 mg/dl to 142 +/- 12 mg/dl. To date, normoglycemia has been maintained for 222 days. Control animals either died or developed cataracts.

Agarose encapsulation of islets of Langerhans: reduced toxicity in vitro.

The physical and chemical properties of agarose have been exploited for encapsulation of islets of Langerhans. Formation of microcapsules by extrusion of a hydrophilic polymer (agarose) into a hydrophobic solution created an interface to which an immunoprotective membrane could be polymerized. The substances and procedure used were devoid of cellular toxicity. Islet function in vitro was found to be normal.

Encapsulation of rat islets of Langerhans prolongs xenograft survival in diabetic mice.

Rat islets encapsulated in alginate-polylysine membranes were implanted intraperitoneally into nonimmunosuppressed streptozocin-induced diabetic mice. Diabetes was reversed within 3 days, and the animals remained normoglycemic for up to 144 days, with a mean xenograft survival of 80 days. This was significantly greater than nonencapsulated islets, which functioned for less than 14 days. The graft survival rate at 50 days was greater than 80%. Xenografts of rat islets encapsulated in alginate-polyornithine membranes also had a prolonged survival rate. This study demonstrates that encapsulation of pancreatic islets in semipermeable membranes can prolong xenograft survival in the absence of immunosuppression.

Encapsulation of rat islets of Langerhans prolongs xenograft survival in diabetic mice

Encapsulation of rat islets of Langerhans prolongs xenograft survival in diabetic mice

Microencapsulation of pancreatic islets: A technique and its application to culture and transplantation

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.

The Role of Biomaterials in Insulin Delivery Systems

The control of blood glucose levels in diabetes involving devices are critically reviewed, and the role of blood-contacting biomaterial components analyzed. These include mechanical insulin-delivery systems of the closed-loop type that require an electronic glucose sensor and feedback, and open-loop systems that deliver insulin without a sensor and feedback. Whole pancreatic and islet transplantations, islet encapsulation, and the potential role of polymeric sustained drug delivery systems are discussed. The medical and social impacts of diabetes mellitus are of prime public health concern and of even greater magnitude than those of heart disease in the United States. While future advances in device design, miniaturization, and biomaterials technology will significantly add to the arsenal of therapeutic alternatives, devices capable of controlling blood glucose levels ought to be viewed as mere interim phases rather than as final goals of the problem.