Vascular network-mimetic oxygen-transporting mesh for islet graft

项目摘要/摘要： 1型糖尿病(T1D)患者受益于使用产生胰岛素的胰岛的细胞替代疗法 细胞，这些细胞通常来自已故捐赠者。为了解决现有的身体小岛短缺问题， 干细胞来源的贝塔细胞正在迅速崛起，成为一种有希望的替代来源。然而，干细胞来源的 β细胞需要密切监测和检索；到目前为止，皮下(SC)组织是唯一的部位 可满足这些要求。然而，SC站点在实现 氧气(O2)供应充足。缺乏适当的干细胞移植平台，由于未能克服 低氧阻碍了干细胞来源的β细胞的研究进展和临床转化。在没有实现 在SC部位进行有效的植入，整体的β细胞替代治疗策略将不会成功。 根据人类岛屿研究网络(HIRN)的使命，NIDDK财团将寻找创新的 保护或替换T1D患者功能性β细胞团的策略，我的团队建议将 利用一种创新的微型设备，将缺氧的SC部位转变为有氧部位。整个器件是薄的(25微米- 厚)和灵活的氧气传输三维网格。我们的微型设备有别于其他现有的充氧设备 在几个创新方面：1)它使用了一种仿生的、血管网状的人造微毛细血管结构 运输和扩散氧气，2)由于使用了经过临床验证的对二甲苯材料，它具有高度的生物相容性 作为其灵活的网状结构，以及3)它是一个自给自足的系统，通过 扩散势。这些特点将为移植物提供生理氧气环境，并确保安全 临床应用。我们的微设备可以作为：1)使用STEM进行活体表征研究的平台 细胞来源的β细胞，以及2)从目前的肝脏转移β细胞替代疗法的临床平台 站点到SC站点。为了提供概念证明，我们将完成以下目标：优化 糖尿病大鼠模型中使用大鼠胰岛的微型装置(目标1)及身体对该装置的验证 免疫缺陷小鼠模型中的人胰岛(目标2)。在目标1中，使用成熟的同基因大鼠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，而不需要 异基因/异种移植中的免疫反应偏向。在目标2中，验证SC中的微器件 使用身体捐赠者的人胰岛的免疫缺陷小鼠的位置将使我们能够连接到未来 人类干细胞来源的贝塔细胞的测试。我们的建议与Hirn财团的目标非常一致 将β细胞和干细胞生物学的进展与组织工程相结合的人胰岛仿生学 开发微型设备的技术。我们预计拟议项目的成功完成将产生一个新颖的 最终将改善T1D患者细胞替代疗法的微型设备。

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.