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

胰岛移植治疗1型糖尿病（T1 D）的临床成功率越来越高，但其适用性仍有待进一步研究。 目前受慢性免疫抑制需要、每个受体所需的胰岛数量和 移植部位封装可以解决许多缺点，但到目前为止，传统的1000 µm 直径的胶囊没有显示出有效性。最有可能的是，这是因为大胶囊限制营养 运输导致功能丧失，并最终导致胰岛移植物死亡。最近，我们开发了一种 封装技术，允许用生物材料的薄层（高达10 μm）“包裹”单个胰岛， 产生“符合”胰岛大小和形状的胶囊。通过将扩散距离减小10倍， 保形涂层（CC）增加了营养物向包封的胰岛的转运。通过减少移植物体积 从约500 mL到约3 mL，CC还允许在血管化部位移植-不限于腹膜内 腔-进一步最大化营养运输。我们的计算模型预测，与传统的 微囊，CC移植物在血管化部位防止由于缺氧引起的中央坏死， 葡萄糖刺激的胰岛素释放。在小鼠中，我们发现T1 D迅速逆转， 移植完全MHC不匹配的CC移植物而不进行免疫抑制。因此，我们假设 我们独特的CC技术可以在T1 D临床前模型中实现胰岛移植的长期功能 而不需要免疫抑制。此外，我们假设，通过最小化囊厚度和 增加营养运输，同时保护移植物，我们可以最大限度地减少逆转所需的胰岛剂量， T1D在目标1中，我们将完成基础CC平台的临床前评价，并确定 与移植成功相关的机制。我们将确定CC胶囊在维持长期- 在同种异体和自身免疫情况下，无免疫抑制的术语功能（目的1.1）。我们还将建立 在临床前模型中CC包封人胰岛的功效（目的1.2）。在目标2中，我们将 通过设计最小化CC剂量的功能，增强CC平台的转化潜力 T1 D逆转所需的胰岛。我们将实现营养物质运输和 通过使CC厚度最小化并掺入免疫调节分子的纳米载体的免疫隔离 (Aim 2.1）。我们还将增加CC移植物血运重建，以改善入站和出站运输， 使用临床上可转化的促血管生成支架（目标2.2）。最后，我们将增加氧气扩散率， CC通过掺入氧纳米载体来增强胰岛功能。这项必要的临床前工作将定位 CC技术的翻译和应用在未来的非人类灵长类动物和临床试验。如果成功， 这项技术可以通过提高移植物存活率、胰岛移植的成功率、 移植还减少了对胰岛和免疫抑制的需要。

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.