Vascular network-mimetic oxygen-transporting mesh for islet graft

用于胰岛移植的血管网络模拟输氧网

• 批准号: 10295653
• 负责人: HIROTAKE KOMATSU
• 金额: $ 18.6万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-04 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295653
• 关键词: 3-Dimensional; Adult; Air; Allogenic; Beta Cell; Biomimetic Devices; Biomimetics; Blood Vessels; Cadaver; Cell Transplantation; Cessation of life; Child; Chronic; Clinical; Data; Development; Devices; Diffuse; Diffusion; Engineering; Engraftment; Ensure; Environment; Evaluation; Exposure to; Extrahepatic; Face; Failure; Fibrosis; Fostering; Future; Goals; Gold; Graft Survival; Human; Hypoxia; Immunodeficient Mouse; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Liver; Mission; Modeling; Monitor; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Organ; Oxygen; Patients; Physiological; Play; Process; Public Health; Quality of life; Rattus; Reaction; Research; Rest; Safety; Silicones; Site; Skin; Source; Stem cell transplant; Structure; Subcutaneous Tissue; System; Technology; Testing; Thick; Thinness; Tissue Engineering; Tissues; Transplantation; United States; Validation; base; beta cell replacement; biomaterial compatibility; capsule; cell replacement therapy; chemical reaction; clinical application; clinical translation; design; diabetic; diabetic rat; efficacy validation; flexibility; human stem cells; immunodeficient mouse model; immunoreaction; implantable device; improved; in vivo; in vivo evaluation; innovation; islet; islet stem cells; microdevice; mimetics; minimally invasive; novel; oxygen transport; parylene; post-transplant; prevent; prototype; scaffold; stem cell biology; stem cells; subcutaneous; success; transplant model

PROJECT SUMMARY/ABSTRACT: Patients with type 1 diabetes (T1D) benefit from cell replacement therapy using insulin-producing pancreatic islet cells, which are typically sourced from deceased donors. To overcome an existing shortage of cadaveric islets, stem cell-derived beta cells are rapidly emerging as a promising alternative source. However, stem cell-derived beta cells require close monitoring and retrievability; to date, the subcutaneous (SC) tissue is the only site available to accommodate these requirements. However, the SC site faces a major challenge in achieving an adequate oxygen (O2) supply. Lack of an appropriate SC transplantation platform, due to the failure to overcome hypoxia, hinders both research progress and clinical translation of stem cell-derived beta cells. Without achieving effective engraftment in the SC site, the overall strategy of beta cell replacement therapy will not be successful. In alignment with the mission of the Human Islet Research Network (HIRN) NIDDK consortium to find innovative strategies to protect or replace functional beta cell mass in people with T1D, my group proposes to transform the hypoxic SC site into an oxygenated site using an innovative microdevice. The overall device is a thin (25 µm- thick) and flexible O2-transporting 3D mesh. Our microdevice is distinct from other existing oxygenation devices in several innovative aspects: 1) it uses a biomimetic, vascular network-like structure of synthetic microcapillaries to transport and diffuse O2, 2) it is highly biocompatible due to use of clinically proven Parylene material as well as its flexible mesh structure, and 3) it is a self-sustaining system that transports O2 from the ambient air via diffusion potential. These features will provide a physiological O2 environment for the graft and ensure safety in clinical applications. Our microdevice may serve as: 1) a platform for in vivo characterization studies using stem cell-derived beta cells, and 2) a clinical platform for shifting beta-cell replacement therapy from the current liver site into the SC site. To provide proof of concept, we will complete the following Aims: Optimization of the microdevice using rat islets in a diabetic rat model (Aim 1) and Validation of the microdevice using cadaveric human islets in an immunodeficient mouse model (Aim 2). In Aim 1, use of a well-established syngeneic rat SC- islet transplantation model will allow us to focus on the fabrication and oxygenation aspects of the device without immunoreaction bias in allogeneic/xenogeneic transplantations. In Aim 2, validating the microdevice in the SC site of immunodeficient mice using human islets from cadaveric donors will allow us bridge to subsequent future testing of human stem cell-derived beta cells. Our proposal is well-aligned with the goal of the HIRN Consortium on Human Islet Biomimetics to combine advances in beta cell and stem cell biology with tissue engineering technologies to develop microdevices. We expect successful completion of the proposed project to yield a novel microdevice that will ultimately improve cell replacement therapy for patients with T1D.

项目摘要/摘要： 1型糖尿病（T1D）的患者使用产生胰岛素的胰岛受益于细胞替代疗法 细胞，通常来自已故供体。要克服现有的尸体胰岛短缺， 干细胞来源的β细胞迅速成为有望的替代来源。但是，干细胞来源 Beta细胞需要密切监视和可检索性；迄今为止，皮下（SC）组织是唯一的部位 可用于满足这些要求。但是，SC网站在实现A和 足够的氧气（O2）供应。由于未能克服，缺乏适当的SC移植平台 缺氧，阻碍了干细胞衍生β细胞的研究进度和临床翻译。没有实现 在SC地点有效植入，β细胞替代疗法的总体策略将无法成功。 与人类胰岛研究网络（HIRN）NIDDK财团的任务保持一致 我的小组提出的转换的策略是保护或替代具有T1D的人的功能性β细胞量的策略 低氧SC位点使用创新的微电位进入氧化位点。整个设备是薄的（25 µm- 厚）和灵活的O2传输3D网眼。我们的微电位与其他现有的氧合设备不同 在几个创新方面：1）它使用合成微毛细血管的仿生，血管网络状结构 运输和扩散的O2，2）由于使用临床经过验证的Parylene材料，它具有高度生物相容性 作为其灵活的网格结构，3）它是一个自我维持的系统，可通过环境空气传输O2 扩散潜力。这些功能将为移植物提供物理O2环境，并确保安全 临床应用。我们的微电位可以用作：1）使用Stem进行体内表征研究的平台 细胞来源的β细胞和2）从当前肝脏转移β细胞替代疗法的临床平台 站点进入SC站点。为了提供概念证明，我们将完成以下目的：优化 使用糖尿病大鼠模型中的大鼠胰岛（AIM 1）和使用Cadaveric验证的微电视 免疫缺陷小鼠模型中的人类胰岛（AIM 2）。在AIM 1中，使用公认的合成大鼠sc- 胰岛移植模型将使我们能够专注于设备的制造和氧合方面 同种异体/异种移植中的免疫反应偏差。在AIM 2中，验证SC中的微电位 使用尸体供体的人类胰岛的免疫缺陷小鼠部位将使我们桥梁到后来的未来 测试人类干细胞衍生的β细胞。我们的提议与HIRN财团的目标非常合适 关于人类胰岛的仿生学，将β细胞和干细胞生物学的进步与组织工程结合起来 开发微型发行的技术。我们预计拟议项目的成功完成将产生小说 微电位最终将改善T1D患者的细胞替代疗法。