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

胰岛移植（ITX）正在经历越来越多的临床成功，但其适用于1型糖尿病， (T1D)目前受到终身慢性免疫抑制（IS）和大量胰岛的限制 从已故的器官捐献者身上提取的样本来逆转T1 D胰岛包裹是减少或消除 慢性IS，但到目前为止，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。最有可能的是，这是因为大而无血管 胶囊限制营养转运并延迟葡萄糖刺激的胰岛素释放（GSIR），导致移植物损失 功能.最近，我们开发了一种封装技术，可以“包裹”每个单独的胰岛 用均匀的薄（> 15 µm）生物材料层，产生“符合"大小和形状的胶囊， 而不是将它们封闭在固定直径的传统胶囊中。通过减少扩散距离 10倍，这种保形涂层（CC）允许增加营养运输。通过减少移植物的总体积 超过100倍（从~500到~3 mL），CC也使血管化良好的移植成为可能。 局限部位，包括预血管化装置，并且不再限于腹腔，进一步 最大限度地提高养分运输。与传统微胶囊中的胰岛相反，CC胰岛显示出没有延迟。 GSIR，我们的计算模型预测，CC移植物放置在有限的网站将提供生理 血运重建后胰岛素释放（GSIR）。我们能够确认长期的健康状况， 在没有免疫抑制的情况下，在糖尿病小鼠中移植完全MHC错配的CC移植物。解决 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 与来自干细胞（SC-b）的基本上无限的胰岛素分泌细胞来源一起使用。因此我们 假设我们独特CC技术可以使原代胰岛和SC-b细胞移植物长期发挥功能 而不需要使用临床上可应用的包被水凝胶进行免疫抑制（目的1）。我们还 假设通过使用创新的纳米材料，我们可以提供局部免疫调节， 在移植后即刻，CC移植部位的氧张力使细胞数量最小化 需要逆转T1 D和最大化长期移植功能（目标2）。在临床前小鼠模型中的工作 在我们可以在灵长类动物中测试我们的基础和纳米材料精制的CC平台之前， 然后是人类。

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.