BIOMATERIALS FOR STEM CELL DERIVED BETA CELL TRANSPLANTATION

用于干细胞衍生的 β 细胞移植的生物材料

• 批准号: 10517827
• 负责人: Andres J Garcia
• 金额: $ 1.98万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517827
• 关键词: 3-Dimensional; Adhesives; Adverse effects; Alginates; Autoimmune Diseases; Beta Cell; Biocompatible Materials; Blood Glucose; Cadaver; Cell Transplantation; Cells; Childhood; Chronic; Diabetic mouse; Encapsulated; Engineering; Engraftment; Glucose; Goals; Heart Diseases; Homologous Transplantation; Hydrogels; Hypoglycemia; Immobilization; Immunocompromised Host; Immunosuppression; In Vitro; Individual; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Maleimides; Methods; Monitor; Pancreas; Patients; Peptides; Physiological; Polymers; Reproducibility; Risk; Signal Transduction; Stroke; Testing; Vascular Endothelial Growth Factors; base; chronic wound; density; diabetic; directed differentiation; human stem cells; islet; matrigel; mechanical properties; novel; post-transplant; prevent; progenitor; stem cell differentiation; stem cells

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.

项目摘要 1型糖尿病（T1 D）是一种自身免疫性疾病，可开始于儿童时期， 胰腺中的细胞被破坏。T1 D的一些副作用是伴随着非常高的血糖 水平是心脏病，慢性创伤和中风。患有T1 D的人需要仔细监测 并控制其血糖水平，每天生存，最常见的方法是注射外源性 胰岛素虽然这种方法确实将胰岛素输送到体内并维持血糖水平，但对胰岛素的需求仍然存在。 每日注射可能难以跟上，生理葡萄糖动力学没有完全恢复， 由于过量的胰岛素存在低血糖的风险。过去最有前途的疗法之一 从尸体供体移植同种异体胰岛已经有十年了。虽然该方法 已经使多个患者成为外源性胰岛素非依赖性，这仅持续约5年后， 由于大多数胰岛移植效果不佳，患者必须接受慢性移植， 免疫抑制，并且供体供应有限。为患者提供终身供应的策略 产生胰岛素的细胞，将有成功的植入，并防止需要慢性 免疫抑制将是在水凝胶载体中递送干细胞衍生的胰岛素产生细胞。研究 使用这种策略，迄今为止已经能够成功地将这些干细胞衍生的细胞包裹在 天然聚合物水凝胶，如藻酸盐，但这些细胞不完全与宿主整合，最终被 拒绝，并且使用天然聚合物增加了批次间可变性和低可调性的风险， 再现性相比之下，合成聚合物水凝胶具有高的可调性和再现性，并且可以理想地 可作为干细胞培养和分化的细胞载体和平台。本补充的目的 一个项目是设计一种合成聚合物水凝胶，它具有固定的生物活性信号， 本发明的目的是提供用于分化源自干细胞的胰岛的方法，以及将这些细胞递送至糖尿病受试者。目的 1：设计合成水凝胶，促进体外3D生存，增殖，人类干细胞分化- 将胰腺祖细胞衍生为分泌胰岛素的未成熟β细胞。目标2：评估 用新型水凝胶递送的工程化β细胞在免疫功能低下的糖尿病患者中恢复正常血糖 小鼠