Conformal islet encapsulation for transplantation at vascularized sites to allow physiological insulin secretion

适形胰岛封装，用于在血管化部位移植，以允许生理性胰岛素分泌

• 批准号: 9293659
• 负责人: Alice Tomei
• 金额: $ 22.83万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-05 至 2017-12-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9293659
• 关键词: Acute; Address; Affect; American; Antigens; Autoimmune Diseases; Beta Cell; Biocompatible Materials; Caliber; Cessation of life; Chronic; Clinical; Clinical Trials; Computer Simulation; Diffusion; Dose; Encapsulated; Engineering; Engraftment; Equilibrium; Ethylenes; Failure; Fibrin; Fluorocarbons; Future; Gel; Glucose; Graft Survival; Human; Hydrogels; Hypoxia; Immune; Immunosuppression; In Vitro; Inbred NOD Mice; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Life; Lung; Measures; Mechanics; Microcapsules drug delivery system; Modeling; Mus; Necrosis; Nutrient; Oligonucleotides; Organ Donor; Outcome; Oxygen; Patients; Permeability; Pharmaceutical Preparations; Physiological; Positioning Attribute; Pre-Clinical Model; Shapes; Site; Sulfides; Technology; Testing; Thick; Time; Translations; Transplantation; Work; blood glucose regulation; capsule; diabetic; experience; improved; innovation; insulin secretion; intraperitoneal; islet; mouse model; nanocarrier; nanofiber; nonhuman primate; novel; oxygen transport; pre-clinical; preclinical evaluation; prevent; response; scaffold; success; transplantation typing

Islet transplantation for type 1 diabetes (T1D) is experiencing increasing clinical success, but its applicability is currently limited by the need for chronic immunosuppression the amount of islets needed per recipient and the transplantation site. Encapsulation may allow addressing many shortcomings but so far traditional 1000 µm diameter capsules have not been shown effective. Most likely, this is because large capsules limit nutrient transport leading to loss of functionality and, ultimately, death of the islet graft. Recently, we developed an encapsulation technology that allows `wrapping' single islets with a thin (up to 10 µm) layer of biomaterial, generating capsules that `conform' to the islet size and shape. By reducing the diffusion distance 10-fold, conformal coating (CC) increases nutrient transport to the encapsulated islets. By reducing the graft volume from ~500 mL to ~3 mL, CC also allows transplantation in vascularized sites - not limited to the intraperitoneal cavity - further maximizing nutrient transport. Our computational models predict that, contrary to traditional microcapsules, CC grafts at vascularized sites prevent central necrosis due to hypoxia, and allow physiological glucose-stimulated insulin release. In mice, we showed prompt T1D reversal and long-term euglycemia after transplantation of fully MHC-mismatched CC grafts without immunosuppression. Accordingly, we hypothesize that our unique CC technology can allow long-term function of islet transplantation in preclinical models of T1D without the need for immunosuppression. Further, we hypothesize that by minimizing capsule thickness and increasing nutrient transport yet protecting the graft, we can minimize the dose of islets required to reverse T1D. In Aim 1, we will complete the preclinical evaluation of the basic CC platform and determine the mechanisms associated with graft success. We will establish the efficacy of CC capsules in maintaining long- term function without immunosuppression in allo and auto-immune settings (Aim 1.1). We will also establish the efficacy of CC encapsulation of human islets in preclinical models (Aim 1.2). In parallel, in Aim 2, we will enhance the translational potential of the CC platform by engineering features that minimize the dose of CC islets required for T1D reversal. We will achieve the ideal balance between nutrient transport and immunoisolation by minimizing CC thickness and incorporating nanocarriers of immunomodulatory molecules (Aim 2.1). We will also increase CC graft revascularization to improve inbound and outbound transport by using clinically translatable pro-angiogenic scaffolds (Aim 2.2). Finally, we will increase oxygen diffusivity in CC to enhance islet function by incorporating oxygen nanocarriers. This necessary preclinical work will position the CC technology for translation and application in future nonhuman primate and clinical trials. If successful, this technology can significantly impact the field by promoting graft survival, the success rate of islet transplantation yet reducing the need for islets and immunosuppression.

1型糖尿病（T1D）的胰岛移植正经历临床成功的增加，但适用性是 目前，由于需要慢性免疫选择的需要，每个受体和接收者所需的胰岛数量。 移植地点可能有许多缺点，但到目前为止 直径胶囊尚未显示有效。 运输导致功能丧失，并最终导致胰岛移植物的死亡。 封装技术允许“包装”单胰岛，具有薄（最高10 µm）的生物局部， 通过减小10倍的扩散距离生成“符合胰岛和形状”的胶囊。 共形涂层（CC）通过减少移植体积来增加养分的养分。 从〜500 mL到〜3 mL，CC还允许在血管化位点移植 - 不限于核内 腔 - 最大化营养转运。 微胶囊，脉管化部位的CC移植物可预防缺氧引起的中枢坏死，并允许生理。 葡萄糖刺激的胰岛素释放。 我们假设对完全MHC匹配的CC移植物的移植 我们独特的CC技术可以在T1D的临床前胰岛推理的长期功能 没有下一步 增加养分的运输却保护移植物，我们可以最大程度地减少逆转所需的胰岛剂量 T1D。在AIM 1中，我们将强制对基本CC平台的临床前评估 与移植成功相关的机制。 在Allo和自动免疫设置中具有免疫培训的术语功能（AIM 1.1）。 临床前模型中人类胰岛的CC封装的功效（AIM 1.2）。 通过工程增强CC平台的转化潜力，特征是CC的剂量 T1D逆转所需的胰岛。 通过最小化CC厚度并掺入免疫调节分子的纳米载体来免疫分散 （AIM 2.1）。 使用临床上可翻译的促启动支架（AIM 2.2）。 CC通过掺入氧气纳米载体来增强胰岛功能。 在未来的非人类灵长类动物和临床试验中进行翻译和应用的CC技术。 技术可以通过促进移植生存，伊斯莱特的成功率来显着影响该领域 移植但减少了对胰岛和免疫选择的需求。