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（T1D）是一种自身免疫性疾病，可以从童年开始产生胰岛素 胰腺中的细胞被破坏。 T1D的某些不良反应遵循非常高血糖 水平是心脏病，慢性伤口和中风。患有T1D的人需要仔细监视 并每天控制其血糖水平以生存，最常见的方法是注射外源性 胰岛素。虽然该方法确实将胰岛素输送到体内并保持血糖水平，但需要 每天的注射可能很难跟上，物理葡萄糖动态尚未完全恢复，并且 由于过量的胰岛素过量，患有低血糖的风险。过去最有前途的疗法之一 十年是从尸体供体中移植同种异体胰岛。而这个方法 已经使多名患者是外源胰岛素独立的，这仅持续约5年 移植是因为大多数胰岛的植入不良，因此患者必须经历慢性 免疫抑制，供体供应有限。一种为患者提供终生供应的策略 产生胰岛素的细胞，这些细胞将成功植入并防止需要慢性 免疫抑制是在水凝胶载体中输送干细胞衍生的产生胰岛素的细胞。研究 到目前为止，使用此策略已经能够成功地传递封装在 天然聚合物水凝胶，例如藻酸盐，但这些细胞并未与宿主完全集成，最终是 被拒绝，使用天然聚合物的使用增加了批处理变异性的风险，可密可线性较低和 相比之下，合成聚合物水凝胶具有高的可密鼠性和可重复性，理想情况下可以 用作培养和区分干细胞的细胞载体和平台。这种补充的目的 项目是用固定的生物活性信号来设计合成聚合物水凝胶，既可以指导 源自干细胞的胰岛的分化，并将这些细胞传递到糖尿病患者中。目的 1：促进体外3D存活，增殖，人类干细胞分化的工程师合成水凝胶 将胰腺祖细胞衍生成胰岛素分泌未成熟的β细胞。目标2：评估 用新型水凝胶传递的工程β细胞以恢复免疫功能低下的糖尿病 老鼠。