BIOMATERIALS FOR STEM CELL DERIVED BETA CELL TRANSPLANTATION

项目总结 1型糖尿病(T1D)是一种自身免疫性疾病，可在儿童时期开始产生胰岛素 胰腺中的细胞被破坏。极高血糖后服用T1D的一些不良反应 水平是心脏病、慢性伤口和中风。患有T1D的个人需要仔细监测 并每天控制血糖水平以求生存，而最常见的方法就是注射外源性 胰岛素。虽然这种方法确实将胰岛素输送到体内并保持血糖水平，但需要 日常注射可能很难跟上，生理血糖动力学没有完全恢复，以及 胰岛素过多有低血糖的风险。过去最有希望的疗法之一 十年来，来自身体捐赠者的同种异体胰岛移植。而这个方法 已经使多名患者外源性胰岛素非依赖性，这只持续了大约5年后- 由于大多数胰岛植入性差，患者必须接受慢性移植。 免疫抑制，而且供体供应有限。一种为患者提供终身供应的战略 胰岛素产生细胞将成功植入，并防止需要慢性 免疫抑制将是通过水凝胶载体运送干细胞来源的胰岛素产生细胞。研究 到目前为止，使用这种策略已经能够成功地将这些干细胞来源的细胞封装在 天然聚合物水凝胶，如海藻酸盐，但这些细胞不能与宿主完全结合，最终形成 被拒绝，并且使用天然聚合物增加了批次之间的可变性的风险，以及低可调性和 再现性。相比之下，合成聚合物水凝胶具有很高的可调性和重复性，理想情况下可以 作为干细胞培养和分化的细胞载体和平台。本补充资料的目的是 该项目是设计一种具有固定生物活性信号的合成聚合物水凝胶，既可以引导 干细胞来源的胰岛的分化，以及将这些细胞输送给糖尿病患者。目标 1：设计合成水凝胶，在体外促进人类干细胞的3D存活、增殖和分化- 将胰腺祖细胞分化为分泌胰岛素的未成熟β细胞。目标2：评估工作人员的能力 携带新型水凝胶的工程化β细胞可恢复免疫受损糖尿病患者的正常血糖 老鼠。

PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease that can begin in childhood where the insulin-producing cells in the pancreas are destroyed. Some of the adverse effects of T1D that follow very high blood glucose levels are heart diseases, chronic wounds, and strokes. Individuals who suffer from T1D need to carefully monitor and control their blood glucose levels daily to survive, and the most common method is the injection of exogenous insulin. While this method does deliver insulin into the body and maintains blood glucose levels, the need for daily injections can be difficult to keep up with, physiological glucose dynamics are not completely restored, and there is a risk of hypoglycemia due to an excess of insulin. One of the most promising therapies in the past decade has been the transplantation of allogeneic pancreatic islets from cadaveric donors. While this method has made multiple patients be exogenous insulin-independent, this only lasts for about 5 years post- transplantation because most of the islets have poor engraftment, patients must undergo chronic immunosuppression, and there is limited donor supply. A strategy to provide a patient with a lifetime supply of insulin-producing cells that will have successful engraftment and prevent the need for chronic immunosuppression would be to deliver stem cell-derived insulin-producing cells in hydrogel carriers. Studies using this strategy so far have been able to successfully deliver these stem cell-derived cells encapsulated in natural polymer hydrogels such as alginate, but these cells do not fully integrate with the host, end up being rejected, and the use of natural polymers adds the risk of batch-to-batch variability, and low tunability and reproducibility. Synthetic polymer hydrogels, in contrast, have high tunability and reproducibility, and could ideally be used as a cell carrier and platform to culture and differentiate stem cells. The objective of this supplemental project is to engineer a synthetic polymer hydrogel with immobilized bioactive signals that can both direct the differentiation of pancreatic islets derived from stem cells, as well as deliver these cells to diabetic subjects. Aim 1: Engineer synthetic hydrogels that promote in vitro 3D survival, proliferation, differentiation of human stem cell- derived pancreatic progenitors into insulin-secreting immature β cells. Aim 2: Evaluate the ability of the engineered β cells delivered with novel hydrogels to restore normoglycemia in immunocompromised, diabetic mice.