Vascular network-mimetic oxygen-transporting mesh for islet graft

项目总结/摘要： 1型糖尿病（T1 D）患者受益于使用产胰岛素胰岛的细胞替代疗法 这些细胞通常来自已故的捐赠者。为了克服现有的尸体胰岛短缺， 干细胞衍生的β细胞作为一种有前景的替代来源正在迅速出现。然而，干细胞衍生的 β细胞需要密切监测和回收;迄今为止，皮下（SC）组织是唯一的部位 以满足这些要求。然而，SC站点在实现 充足的氧气（O2）供应。缺乏合适的SC移植平台，由于未能克服 缺氧阻碍了干细胞衍生的β细胞的研究进展和临床转化。不实现 如果在SC部位没有有效的植入，β细胞替代疗法的总体策略将不会成功。 与人类胰岛研究网络（HIRN）NIDDK联盟的使命一致， 保护或替代T1 D患者功能性β细胞群的策略，我的团队建议将 缺氧SC网站到一个氧合网站使用一个创新的微型设备。整个器件是一个薄（25 µm- 厚）和柔性的氧气输送3D网。我们的微型设备与其他现有的氧合设备不同 在几个创新方面：1）它使用合成微毛细管的仿生血管网络状结构， 输送和扩散O2，2）由于使用了经临床验证的聚对二甲苯材料，因此具有高度生物相容性 由于其灵活的网状结构，以及3）它是一个自我维持的系统，通过 扩散电位这些特征将为移植物提供生理氧气环境，并确保安全性， 临床应用。我们的微器件可以作为：1）使用股骨柄进行体内表征研究的平台 细胞衍生的β细胞，以及2）用于将β细胞替代疗法从当前肝脏转移的临床平台 进入SC网站。为了提供概念验证，我们将完成以下目标： 在糖尿病大鼠模型中使用大鼠胰岛的微型装置（Aim 1）和使用尸体胰岛的微型装置的验证 免疫缺陷小鼠模型中的人胰岛（Aim 2）。在目的1中，使用良好建立的同系大鼠SC-100。 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/异种移植免疫反应偏倚。在目标2中，验证SC中的微型器械 使用来自尸体供体的人类胰岛的免疫缺陷小鼠的网站将使我们能够连接到随后的未来 测试人类干细胞衍生的β细胞。我们的建议与HIRN联盟的目标完全一致 将β细胞和干细胞生物学的进展与组织工程联合收割机 开发微型设备的技术。我们希望成功完成拟议的项目，以产生一个新的 这是一种微型设备，最终将改善T1 D患者的细胞替代疗法。

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.