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: 10062501
• 负责人: Alice Tomei
• 金额: $ 46.48万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-11 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062501
• 关键词: Address; Adult; Anti-Inflammatory Agents; Antigens; Autoimmune; Beta Cell; Biocompatible Materials; Blood Vessels; Caliber; Cells; Child; Chronic; Clinical; Computer Models; Devices; Diabetic mouse; Diffuse; Diffusion; Dose; Engraftment; Equilibrium; Ethylenes; Extrahepatic; Glucose; Graft Survival; Greater sac of peritoneum; Human; Hydrogels; Immunomodulators; Immunophenotyping; Immunosuppression; Implant; In Vitro; Inbred NOD Mice; Individual; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Laboratories; Lead; Mechanics; Mediating; Microcapsules drug delivery system; Modeling; Mus; NOD/SCID mouse; Nutrient; Oligonucleotides; Organ Donor; Outcome; Oxygen; Patients; Permeability; Pharmaceutical Preparations; Physiological; Pre-Clinical Model; Primates; Procedures; Protocols documentation; Shapes; Site; Source; Sulfides; T-Cell Activation; Technology; Testing; Thinness; Time; Translations; Transplantation; Work; amphiphilicity; autoreactive T cell; base; capsule; clinical application; diabetic; euglycemia; experience; graft function; human stem cells; immune activation; immunoregulation; implantation; in silico; in vivo Model; innovation; insulin secretion; intraperitoneal; islet; islet stem cells; macrophage; mouse model; nanofilament; nanomaterials; nanomedicine; nonhuman primate; novel; post-transplant; pre-clinical; predictive modeling; response; stem cells; success

Islet transplantation (ITX) is experiencing increasing clinical success, but its applicability for type 1 diabetes (T1D) is currently limited by the need for lifelong chronic immunosuppression (IS) and the high number of islets from deceased organ donors needed to reverse T1D. Islet encapsulation is a possibility to reduce or eliminate chronic IS, but, so far, traditional 1000 µm fixed-diameter capsules implanted in the peritoneal cavity failed to provide sufficiently effective and long-lasting outcomes. Most likely, this is because large and avascular capsules limit nutrient transport and delay glucose-stimulated insulin release (GSIR) causing loss of graft functionality. Recently, we developed an encapsulation technology that allows ‘wrapping’ each individual islet with a uniformly thin (»15 µm) layer of biomaterial, generating capsules that ‘conform’ to the size and shape of the islet rather than enclosing them in fixed-diameter traditional capsules. By reducing the diffusion distance 10-fold, this conformal coating (CC) allows increased nutrient transport. By reducing the overall graft volume more than 100-fold (from ~500 to ~3 mL), CC also makes possible transplantation in well vascularized confined sites, including pre-vascularized devices, and is no longer limited to the intraperitoneal cavity, further maximizing nutrient transport. Contrary to islets in traditional microcapsules, CC islets display no delay in GSIR, and our computational model predicts that CC grafts placed in confined sites will provide physiological insulin release (GSIR) after revascularization. We were able to confirm long-term euglycemia after transplantation of fully MHC-mismatched CC grafts in diabetic mice without immunosuppression. To address another main shortcoming of current ITX protocols, we recently found that our CC platform is also suitable for use with essentially unlimited insulin-secreting cell sources derived from stem cells (SC-b). Accordingly, we hypothesize that our unique CC technology can allow long-term function of primary islets and SC-b cell grafts without the need for immunosuppression using clinically applicable coating hydrogels (aim 1). Further, we hypothesize that by using innovative nanomaterials, we can provide local immunomodulation and higher oxygen tension at the CC graft site in the immediate post-transplant period minimizing the number of cells needed to reverse T1D and maximizing long-term graft function (aim 2). The work in preclinical mouse models proposed here is needed before we can test our base and nanomaterial-refined CC platform in primates and then in humans.

胰岛移植 (ITX) 的临床成功率越来越高，但其对 1 型糖尿病的适用性 (T1D) 目前因需要终生慢性免疫抑制 (IS) 和大量胰岛而受到限制 逆转 T1D 所需的已故器官捐献者的胰岛封装是减少或消除的一种可能性。 慢性 IS，但迄今为止，植入腹膜腔的传统 1000 µm 固定直径胶囊未能 提供足够有效和持久的结果很可能是因为大且无血管。 胶囊限制营养物质运输并延迟葡萄糖刺激的胰岛素释放（GSIR），导致移植物损失 最近，我们开发了一种封装技术，可以“包裹”每个单独的胰岛。 具有均匀薄（»15 µm）的生物材料层，生成“符合”尺寸和形状的胶囊 通过减少扩散距离，将其封闭在胰岛中，而不是将其封闭在固定直径的传统胶囊中。 这种保形涂层 (CC) 通过减少移植物的整体体积，可以增加 10 倍的营养输送。 超过 100 倍（从约 500 至约 3 mL），CC 还使得血管化良好的移植成为可能 受限部位，包括预血管化装置，并且不再限于腹膜内腔，进一步 与传统微胶囊中的胰岛相反，CC 胰岛没有延迟。 GSIR 和我们的计算模型预测，放置在受限部位的 CC 移植物将提供生理功能 血运重建后的胰岛素释放（GSIR）我们能够确认术后长期血糖正常。 在没有免疫抑制的情况下，在糖尿病小鼠中移植完全 MHC 不匹配的 CC 移植物。 当前ITX协​​议的另一个主要缺点，我们最近发现我们的CC平台也适用于 与基本上无限的干细胞来源的胰岛素分泌细胞（SC-b）一起使用。 我们独特的 CC 技术可以让原代胰岛和 SC-b 细胞移植物长期发挥功能 无需使用临床适用的涂层水凝胶进行免疫抑制（目标 1）。 培养了通过使用创新纳米材料，我们可以提供局部免疫调节和更高的 移植后立即 CC 移植部位的张力可最大限度地减少细胞数量 逆转 T1D 并最大化长期移植物功能所需（目标 2）。 在我们可以在灵长类动物和动物中测试我们的基础和纳米材料精制 CC 平台之前，需要这里提出的 然后在人类中。