Engineering an Islet Thread from zwitterionically modified alginates for type 1 diabetes

该项目的目标是开发一种先进的、临床适用的胰岛/干细胞。 1型糖尿病(T1D)胶囊系统。细胞封装和移植成立 治疗T1D的巨大潜力。异体或异种来源的胰岛或干细胞来源的β细胞是 被封装在保护细胞免受宿主免疫排斥的材料或装置中，同时 允许方便的传质以维持它们的生存和功能。众多研究小组 在世界范围内都取得了重要的进展，但细胞包埋的临床应用 仍然难以捉摸，这在很大程度上是由于缺乏可翻译的封装系统 满足以下基本但关键的临床需求：(1)必须易于操作、使用和 移植，使包裹不会对细胞造成伤害，移植是最小限度的 侵入性；(2)必须具有足够的生物相容性(即最小或没有形成纤维化)， 坚固的机械稳定性和易于传质(如大表面积、短扩散 距离和可控的渗透选择性)，以便移植可以长时间工作 至少几个月；(3)必须便于取回，以便拆卸或更换 在移植失败或医疗并发症的情况下；(4)它必须是可扩展的，以便能够 提供足够的细胞团以产生治疗效果。为满足这些需要，我们建议 开发一种新型的、临床可翻译的交通(用于胰岛的螺纹增强海藻酸纤维 我们新开发的用于T1D的非纤维化两性离子海藻酸盐)系统 治疗。关键的创新包括结构设计(即结合薄但 沿着水凝胶纤维的轴线进入水凝胶纤维中心的韧性聚合物)和水凝胶 化学(即两性离子改性的海藻酸盐)。内聚合物螺纹赋予机械性能 坚固耐用，易于操作、植入和取出，而外层的两性离子- 海藻酸盐水凝胶纤维具有良好的生物相容性和良好的传质性能。我们的目标是 使用大鼠胰岛和干细胞来源的干细胞实现糖尿病小鼠的长期(&gt；6个月)治愈 通过优化该设备的生物兼容性和传质性能，实现了对BETA电池性能的优化。我们会 此外，还可以放大该设备，并在狗身上展示其可检索性和功能。这个 这项拟议研究的预期结果将是开发一种新的细胞 T1D患者可翻译的封装系统。

The objective of this project is to develop an advanced, clinically applicable islet/stem cell encapsulation system for type 1 diabetes (T1D). Cell encapsulation and transplantation holds enormous potential to treat T1D. Islets of allo or xeno origin or stem cell-derived beta cells are encapsulated in a material or device that protects the cells from host immune rejection while allowing facile mass transfer to maintain their survival and function. Numerous research groups worldwide have made important progress, but clinical application of cell encapsulation has remained elusive, due in a large part to the lack of a translatable encapsulation system that meets the following basic but critical clinical needs: (1) It must be easy to handle, use and transplant so that the encapsulation causes no harm to cells and the transplantation is minimally invasive; (2) It must have sufficient biocompatibility (i.e. minimal or no formation of fibrosis), robust mechanical stability and facile mass transfer (e.g. large surface area, short diffusion distance and controllable permselectivity) so that the transplant can function for a long time, at least several months; (3) It must be convenient to retrieve so that it can be removed or replaced in the event of transplant failure or medical complications; (4) It must be scalable so that it can deliver sufficient cell mass to produce a therapeutic effect. To meet these needs, we propose to develop a novel, clinically translatable, TRAFFIC (Thread-Reinforced Alginate Fiber For Islet enCapsulation) system from our newly developed, non-fibrotic zwitterionic-alginates for T1D treatment. The critical innovations include both the structure design (i.e. incorporation a thin but tough polymer thread into the center of a hydrogel fiber along its axis) and the hydrogel chemistry (i.e. zwitterionically modified alginates). The inner polymer thread imparts mechanical robustness and enables easy handling, implantation and retrieval, while the outer zwitterionic- alginate hydrogel fiber provides necessary biocompatibility and facile mass transfer. We aim to achieve long-term (>6 months) cures of diabetic mice using both rat islets and stem cell-derived beta cells by optimizing the biocompatibility and mass transfer properties of the device. We will also scale up the device and demonstrate its retrievability and functionality in dogs. The anticipated outcome of this proposed research will be the development of a new cell encapsulation system that is translatable for T1D patients.