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

胰岛移植(ITX)的临床成功越来越多，但它对1型糖尿病的适用性 (T1D)目前受到终生慢性免疫抑制(IS)的需要和大量胰岛的限制 来自需要逆转T1D的已故器官捐赠者。胰岛封装是一种减少或消除的可能性 慢性IS，但是，到目前为止，传统的1000微米固定直径胶囊植入腹膜腔未能 提供足够有效和持久的结果。很可能，这是因为大的和无血管的 胶囊限制营养物质的转运并延迟葡萄糖刺激的胰岛素释放(GSIR)导致移植物丢失 功能性。最近，我们开发了一种封装技术，可以‘包裹’每个单独的胰岛 用一层均匀薄(约15微米)的生物材料制成的胶囊大小和形状与 而不是将它们包裹在固定直径的传统胶囊中。通过减小扩散距离 10倍，这种保形涂层(CC)允许增加营养物质的运输。通过减少移植物的总体积 超过100倍(从~500到~3毫升)，CC还使血运良好的移植成为可能 受限部位，包括血管预置装置，不再局限于腹膜腔，进一步 最大限度地促进养分的运输。与传统微囊中的胰岛相反，CC胰岛在 GSIR，我们的计算模型预测，放置在受限部位的CC移植物将提供生理性 血运重建后胰岛素释放(GSIR)。我们能够确认长期的正常血糖在 完全MHC不相合CC移植物在无免疫抑制的糖尿病小鼠中的移植。致信地址 目前ITX协议的另一个主要缺点是，我们最近发现我们的CC平台也适用于 与来自干细胞(SC-b)的基本上无限制的胰岛素分泌细胞来源一起使用。因此，我们 假设我们独特的CC技术可以允许初级胰岛和SC-b细胞移植的长期功能 无需使用临床适用的涂层水凝胶进行免疫抑制(目标1)。此外，我们 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和更高的 移植后即刻CC移植物部位的氧分压使细胞数量最小化 需要逆转T1D和最大化长期移植物功能(目标2)。临床前小鼠模型的研究进展 在我们可以测试我们的基础和纳米材料精炼的CC平台在灵长类动物和 然后在人类身上。

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.