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

描述（由申请人提供）：人胰岛包封提供了保护植入的人胰岛免受1型糖尿病接受者中自身免疫复发和所有糖尿病接受者中胰岛同种异体移植物排斥的机会，而不需要在胰岛移植后进行免疫抑制。胰岛包封研究已经有很长的历史，有数百篇出版物定义了四种方法：a）微胶囊，B）大胶囊，c）迷你微胶囊和d）保形涂层。这些方法中的每一种都有其自身的一组并发症和限制，使得该领域目前没有任何候选产品可能在不久的将来作为临床产品获得成功。该第1阶段SBIR应用介绍了一种新型胰岛封装技术，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），可以在交联和生物降解特性方面进行精确控制。通过在聚合物中的几个精确的变化，交联的温度，凝胶硬度和选择渗透性可以根据需要可预测地控制成功地封装活细胞。由于其来源于碳水化合物化学，它在啮齿动物中具有天然的生物相容性，并且可以在几天到几年的非常广泛的时间范围内进行生物降解。到目前为止，RTG一直是研究的候选药物输送载体，可以注射到体内，由于注射时身体的热量而凝胶化，然后缓慢地将其药物释放到体内。该申请要求为使用这种新型RTG系统进行细胞封装的第一项研究提供资金，更具体地说，胰岛封装用于糖尿病的潜在治疗。本研究的第一个具体目标是优化该RTG用于胰岛包封，在受控条件下使用来自尸体器官供体的人胰岛进行许多标准化包封用于研究。第二个和第三个特定目标开始测试单独的RTG和植入正常和糖尿病小鼠不同部位的含RTG的人胰岛。一种方法是将冷却的凝胶中的胰岛直接注射到体内，这在注射期间引起快速胶凝，封装和保护功能性胰岛。第二种方法是在体外进行包封的胰岛凝胶，并简单地将包封的胰岛注射到体内的不同部位。这些研究的结果将为II期研究做准备，该研究将重点关注这种新型凝胶系统在大型动物中的应用，为糖尿病患者的潜在临床试验做准备。本申请的最后一个特定目的是探索降解前TRG在体内保持完整的更长时间，因为药物释放研究主要是短期研究。这种新的RTG与目前的胰岛包封系统相比具有许多潜在的优势，并且是这些研究的目标，以确定它是否可以发展成为一种临床适用的方法，用于不需要免疫抑制的包封人胰岛移植。 公共卫生相关性：SBIR格兰特叙述虽然胰岛封装已经研究了多年，以开发一种在不使用免疫抑制剂的情况下保护植入后的胰岛免受免疫破坏的方法，但目前的方法中没有一种接近临床。这一阶段1 SBIR应用的重点是一个全新的热可逆聚合物或凝胶，已在控制药物释放的研究。这种新型凝胶来自天然碳水化合物化学，在体内具有非常好的生物相容性，并且在交联或细胞包封的温度方面易于控制。它的孔径大小也可以控制，以及它在体内的自然降解时间在几天到几年。它似乎是一个很好的新候选人，有望克服许多目前的障碍，阻止旧的封装方法从研究中前进。该应用程序旨在优化凝胶，用于封装可在糖尿病啮齿动物中进行测试的功能性人类胰岛。这项研究的下一阶段将是将这些研究推进到大型糖尿病动物身上，以确定将这种新型胶囊凝胶用于糖尿病患者的临床产品需要什么。

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.