NOVEL THERMAL REVERSIBLE POLYMER (TRG) FOR HUMAN ISLET ENCAPSULATION AND IMPLANTA

描述（由申请人提供）：人类胰岛包埋提供了保护移植的人类胰岛免受1型糖尿病受体自身免疫复发和所有糖尿病受体异体胰岛移植排斥的机会，而无需在胰岛移植后进行免疫抑制。胰岛胶囊研究已经有很长的历史，数百种出版物定义了四种方法：a)微胶囊，b)大胶囊，c)微型微胶囊和d)保形涂层。每种方法都有自己的一套并发症和限制，使得该领域目前没有任何可能在不久的将来作为临床产品成功的候选产品。第一阶段的SBIR应用引入了一种新的胰岛封装技术，该技术利用由碳水化合物化学产生的热可逆聚合物或凝胶（RTG），可以在交联和可生物降解特性方面进行精确控制。通过对聚合物进行几次精确的改变，交联温度、凝胶硬度和透性选择性可以根据需要进行可预测的控制，从而成功地封装活细胞。由于其来源于碳水化合物化学，它在啮齿类动物中具有天然的生物相容性，并且可以在几天到几年的很长时间内进行生物降解。到目前为止，RTG一直是研究的候选药物递送载体，它可以注射到体内，在注射时由于身体的热量而凝胶化，然后缓慢地将其药物释放到体内。本申请申请为首次使用这种新型RTG系统进行细胞包封的研究提供资金，更具体地说是胰岛包封，用于潜在的糖尿病治疗。本研究的第一个具体目标是优化该RTG用于胰岛封装，使用来自尸体器官供体的人类胰岛在受控条件下进行许多标准化封装。第二个和第三个特定目标开始测试单独的RTG和含有RTG的人类胰岛植入正常和糖尿病小鼠的不同部位。一种方法是将冷却凝胶中的胰岛直接注射到体内，在注射过程中迅速凝胶化，包裹和保护功能的胰岛。第二种方法是在体外进行封装的胰岛凝胶，并简单地将封装的胰岛注射到身体的不同部位。这些研究的结果将为第二阶段的研究做准备，该阶段的研究重点是将这种新型凝胶系统用于大型动物试验，为糖尿病患者的潜在临床试验做准备。本应用程序的最后一个特定目的是探索在降解之前TRG在体内保持完整的更长的时间，因为药物释放研究主要研究的是短期。与目前的胰岛包封系统相比，这种新的RTG具有许多潜在的优势，是这些研究的目标，以确定它是否可以发展成一种临床适用的方法，用于不需要免疫抑制的人胰岛包封移植。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.