Vascularized Islet transplantation NICHE with local immunosuppression for the treatment of type 1 diabetes

细胞封装技术有望改进传统的胰岛移植，以更有效地 管理I型糖尿病。目前，终生全身免疫抑制是为了避免免疫 排斥移植，尽管有相关的危及生命的不良反应。临床研究显示， 由于缺乏营养、氧气供应和宿主免疫的血管支持，移植最终失败 拒绝。为了解决所有这些关键需求，并得到初步研究的支持，我们提出了利基市场，以及 创新的皮下血管包裹系统，局部洗脱免疫抑制剂以保护 来自免疫排斥反应的移植细胞。这个壁龛提供了两个经皮肤可再灌装的储液罐， 药物和细胞分别由纳米孔膜隔开。局部免疫抑制剂的给药限制 药物到发生免疫攻击的移植物部位，最大限度地减少对身体其他部位的接触，从而避免 全身性免疫抑制及相关不良反应。壁龛细胞储存库被充分的血管化为 功能血管，重塑有利于维持长期生存的理想生理环境 和移植细胞的功能。我们假设这个壁龛将提供一个有血管的环境 局部应用免疫抑制剂治疗长期胰岛移植成功恢复正常血糖 在糖尿病宿主中。在目标1中，我们将研究间充质干细胞诱导血管生成的能力。 利基以及调节利基免疫微环境，有利于胰岛移植 在糖尿病大鼠身上。在目标2之后，将对局部洗脱的免疫抑制剂进行生物分布分析。 并对糖尿病大鼠的免疫调节和药代动力学进行了评价。在目标3中， 为胰岛移植成功恢复正常血糖提供适宜环境的利基效应 糖尿病大鼠将在一年多的时间内接受评估，同时进行生态位微环境的纵向研究 改建。建议的研究是基于我们团队在植入性药物和细胞方面的广泛专业知识 递送系统、组织工程学、研究和临床移植、移植免疫学、1型 糖尿病，以及支持性的初步数据和以前发表的工作。重要的是，利基市场是 设计优先考虑疗效、安全性和用户可接受性的临床因素。经皮细胞和 药物补充允许在需要时容易地进行药物补充，从而延长植入物的寿命 病人的生命周期。此外，壁龛的薄而紧凑的大小，比封装小 植入物在临床研究中，有利于使用者的接受性。圆满完成拟议中的 工作将提供一种广泛适用的具有局部免疫抑制剂长时间给药的胶囊系统。 移植胰岛的长期保护，以及最大限度地减少与免疫抑制相关的不良反应 毒品。这可能转化为在胰岛以外部署细胞疗法的临床突破，包括 干细胞来源的β细胞，用于治疗糖尿病和其他疾病。

Cell encapsulation technologies are poised to improve conventional islet transplantation to more effectively manage type I diabetes. Currently, lifelong whole-body immunosuppression is administered to avoid immune rejection of the transplant, despite the associated life-threatening adverse effects. Clinical studies reveal that transplants eventually fail due to lack of vascular support for nutrients and oxygen supply and host immune rejection. To address all these critical needs and supported by preliminary studies, we propose the NICHE, an innovative subcutaneous vascularized encapsulation system with local elution of immunosuppressants to protect transplanted cells from immune rejection. The NICHE presents dual transcutaneously refillable reservoirs, for drug and cells, respectively, separated by a nanoporous membrane. Local immunosuppressant delivery confines drugs to the graft site where immune attack occurs, minimizing exposure to the rest of the body, thus avoiding systemic immunosuppression and associated adverse effects. The NICHE cell reservoir is fully vascularized with functional vessels, recreating an ideal physiological environment conducive for maintaining long-term viability and function of transplanted cells. We hypothesize that the NICHE will provide a vascularized environment with local immunosuppressant delivery for successful long-term islet engraftment to restore euglycemia in diabetic hosts. In aim 1, we will study the ability of mesenchymal stem cells to induce vascularization within the NICHE as well as modulate the NICHE immune microenvironment to be conducive for islet transplantation in diabetic rats. This will be followed in aim 2 by the biodistribution analysis of immunosuppressants locally eluted in the NICHE and the assessment of immunomodulation and pharmacokinetics in diabetic rats. In aim 3, the NICHE efficacy in providing a suitable environment for successful islet engraftment to restore euglycemia in diabetic rats will be assessed over 1 year, in parallel to a longitudinal study of NICHE microenvironment remodeling. The proposed studies are based on our team’s extensive expertise in implantable drug and cell delivery systems, tissue engineering, research and clinical transplantation, transplant immunology, type 1 diabetes, as well as supportive preliminary data and previously published work. Importantly, the NICHE is designed prioritizing clinical considerations of efficacy, safety and user acceptability. Transcutaneous cell and drug refilling allow for ease of drug replenishment when needed, thus extending implant lifespan potentially for the lifetime of patients. Further, the thin and compact size of the NICHE, which is smaller than the encapsulation implants under clinical investigation, is favorable for user acceptability. Successful completion of the proposed work will provide a broadly applicable encapsulation system with localized immunosuppressant delivery for long- term protection of transplanted islets, as well as minimize adverse effects associated with immunosuppressive drugs. This could translate to a clinical breakthrough for deployment of cell therapies beyond islets, including stem cell-derived β cells, to treat diabetes as well as other diseases.