Human islet encapsulation provides the opportunity to protect implanted human islets from both auto-immune recurrence in Type 1 Diabetes recipients and rejection of islet allografts in all diabetic recipients without the requirement for immunosuppression following islet transplantation. There has been a long history of islet encapsulation research with hundreds of publications that define four approaches: a) micro-capsules, b) macro-capsules, c) mini-micro-capsules, and d) conformal coatings. Each of these approaches has its own set of complications and restrictions leaving the field without any current candidate likely to be successful in the near future as a clinical product. This Phase 1 SBIR application introduces a novel islet encapsulation technology utilizing a thermal reversible polymer or gel (RTG) produced from carbohydrate chemistry that can be precisely controlled in terms of cross linking and biodegradable characteristics. Through several precise changes in the polymer, the temperature of cross linking, gel hardness, and permselectivity can be predictably controlled as required to encapsulate living cells successfully. Due to its origin from carbohydrate chemistry, it is naturally very biocompatible in rodents and can be caused to biodegrade over a very broad range of time from a few days to several years. Up to this moment, RTG has been a candidate for research as a drug delivery vehicle that can be injected into the body, gelling due to the heat of the body at the time of injection and then slowly releasing its drug into the body. This application requests funding for the first research using this novel RTG system for cell encapsulation, more specifically islet encapsulation for the potential treatment of diabetes. The first Specific Aim in the study is to optimize this RTG for islet encapsulation performing a number of standardizing encapsulations under controlled conditions using human islets from cadaver organ donors for research. The second and third Specific Aims begin testing both the RTG alone and RTG containing human islets implanted into different sites in normal and diabetic mice. One approach is the direct injection of the islets in a cooled gel into the body which causes rapid gelling to take place during the injection, encapsulating and protecting the functional islets. The second approach is to perform the encapsulated islet gel outside the body and simply inject the encapsulated islets in different sites in the body. The results of these studies will prepare for the Phase 2 study that will be focused on adapting this novel gel system for large animal use in preparation for potential clinical trials in patients with diabetes. The last Specific Aim of this application is to explore much longer times of TRG remaining intact in the body before degradation, since predominantly short terms were studied for the drug release studies. This new RTG has a number of potential advantages over current islet encapsulation systems and is the target of these studies to determine if it can be developed into a clinically applicable approach for encapsulated human islet transplantation that would not require immunosuppression.
SBIR Grant Narrative While islet encapsulation has been studied for many years to develop a method of protecting the islets after implantation from immune destruction without the use of immunosuppression, not one of the current methods appears close to the clinic. This Phase 1 SBIR application focuses on an entirely new thermal reversible polymer or gel that has been studied in controlled drug release. This novel gel comes from natural carbohydrate chemistry and is very biocompatible in the body and readily controlled in terms of temperature of cross linking or cell encapsulation. Its pore size can also be controlled as well as its natural degradation time in the body over days to years. It appears to be an excellent new candidate that has promise to overcome many of the current obstacles preventing the older encapsulation methods from advancing out of research. This application is designed to optimize the gel for encapsulating functional human islets that can be tested in diabetic rodents. The next phase of this study will be to advance these studies onto large diabetic animals to determine what would be required to take this novel new encapsulating gel into a clinical product for patients with diabetes.
