Hydrogels for human beta cell survival, function and evasion of immune rejection

项目摘要 1型糖尿病（T1 D）是一种自身免疫性疾病，其中胰腺的胰岛素产生β细胞被破坏， 摧毁. T1 D影响美国300万儿童和成人，医疗费用超过150亿美元。 使用外源性胰岛素的标准治疗是繁重的，与低血糖的显著危险相关， 并且在预防长期并发症方面仅部分有效。同种异体胰岛移植 最近已经证明，尸体供体与慢性免疫抑制剂联合使用， 在临床试验中恢复Euclidin。然而，T1 D细胞替代疗法的长期未来需要 一种可靠的和易消化的β细胞来源，并且消除了对慢性免疫抑制的需要。β细胞 来源于人类多能干细胞（SC-β细胞）的胰岛素是一种变革性的、无限的胰岛素来源， 产生用于治疗T1 D的细胞。尽管工程化功能性胰岛素产生SC-β 细胞，与长期植入和功能相关的显著屏障，无慢性免疫抑制 阻碍了这些有前途的细胞的临床转化。此外，使用封装装置来保护 由于纤维化反应和缺乏直接的免疫反应，移植细胞在大型动物模型中尚未成功。 血管化我们的目标是设计先进的生物材料输送技术，以（i）提高 （ii）保护SC-β细胞免受免疫系统的排斥 而不需要封装或慢性免疫抑制。我们假设， 血管生成和免疫调节信号的受控呈现将提供可注射的递送载体 指导SC-β细胞存活、植入和功能，而无慢性免疫抑制或包封。 目的1：设计可注射的VEGF递送水凝胶以促进SC-1的血管形成、存活和功能。 将β细胞移植到糖尿病免疫功能低下小鼠的皮下空间中。目标2：评估SA- FasL-微凝胶技术促进糖尿病患者SC-β细胞的免疫接受和功能， 没有慢性免疫抑制的人源化小鼠。目的3：检测VEGF/SA-FasL在肿瘤细胞中的表达能力 水凝胶增强糖尿病非人灵长类动物中SC-β细胞的存活和功能， 免疫抑制试验。这一具有重大意义的创新战略， 从该领域正在进行的工作中，工程先进的可注射生物材料，促进SC-β细胞 血管化、局部免疫接受、存活和功能，无器械或系统性包囊 免疫抑制此外，对人源化鼠和非人灵长类动物模型的关注将有助于 加速开发有效和广泛适用的T1 D治疗方法。

PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β-cells of the pancreas are destroyed. T1D affects 3 million children and adults in the US with healthcare costs exceeding $15 billion. Standard therapy with exogenous insulin is burdensome, associated with a significant danger of hypoglycemia, and only partially efficacious in preventing long-term complications. Transplantation of allogeneic islets from cadaveric donors in conjunction with chronic immunosuppression has been recently shown to be effective in restoring euglycemia in clinical trials. However, the long-term future of cell replacement therapy for T1D requires a reliable and replenishable β-cell source and elimination of the need for chronic immunosuppression. β-cells derived from human pluripotent stem cells (SC-β cells) represent a transformative, unlimited source of insulin- producing cells for the treatment of T1D. Despite advances in engineering functional insulin-producing SC-β cells, significant barriers related to long-term engraftment and function without chronic immunosuppression hinder the clinical translation of these promising cells. Furthermore, the use of encapsulation devices to protect transplanted cells has not been successful in large animal models due to fibrotic responses and lack of direct vascularization. Our objective is to engineer advanced biomaterial delivery technologies to (i) enhance vascularization, survival, and engraftment of SC-β cells and (ii) protect them from rejection by the immune system without the need for encapsulation or chronic immunosuppression. We hypothesize that synthetic hydrogels with controlled presentation of vasculogenic and immunomodulatory signals will provide an injectable delivery vehicle that directs SC-β cell survival, engraftment, and function without chronic immunosuppression or encapsulation. Aim 1: Engineer injectable VEGF-delivering hydrogels to promote vascularization, survival, and function of SC- β cells transplanted in the subcutaneous space of diabetic, immunocompromised mice. Aim 2: Evaluate our SA- FasL-microgel technology to promote SC-β cell immune acceptance and function in diabetic, immunocompetent humanized mice without chronic immunosuppression. Aim 3: Examine the ability of VEGF/SA-FasL hydrogels to enhance SC-β cell survival and function in diabetic nonhuman primates with no or reduced chronic immunosuppression in a pilot study. This highly significant and innovative strategy is fundamentally different from ongoing work in the field in terms of engineering advanced injectable biomaterials that promote SC-β cell vascularization, local immune acceptance, survival, and function without encapsulation in devices or systemic immunosuppression. Furthermore, the focus on humanized murine and nonhuman primate models will accelerate the development of an effective and broadly applicable cure for T1D.