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

本项目的目标是开发一种先进的、临床上可应用的胰岛/干细胞 1型糖尿病（T1 D）的治疗。细胞包封和移植保持 治疗T1 D的巨大潜力。同种或异种来源的胰岛或干细胞衍生的β细胞是 包封在保护细胞免受宿主免疫排斥的材料或装置中， 允许容易的质量转移以维持它们的存活和功能。众多研究小组 在世界范围内取得了重要进展，但细胞包封的临床应用 仍然难以捉摸，这在很大程度上是由于缺乏一个可翻译的封装系统， 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，使得包封不会对细胞造成伤害，并且移植是最低限度的， 侵入性;（2）它必须具有足够的生物相容性（即最小或无纤维化形成）， 坚固的机械稳定性和容易的质量传递（例如，大表面积、短扩散 距离和可控的选择性渗透），使得移植物可以长时间地起作用， 至少几个月;（3）必须便于取回，以便拆除或更换 在移植失败或医疗并发症的情况下;（4）它必须是可扩展的，以便它可以 递送足够的细胞质量以产生治疗效果。为了满足这些需求，我们建议 开发一种新型的、临床上可转化的TRAFFIC（用于胰岛的螺纹增强藻酸盐纤维 enCapsulation）系统，从我们新开发的非纤维化两性离子藻酸盐用于T1 D 治疗关键的创新包括结构设计（即结合薄但 沿着其轴进入水凝胶纤维中心的坚韧聚合物线）和水凝胶 化学（即两性离子修饰的藻酸盐）。内部聚合物螺纹赋予机械 坚固耐用，易于操作、植入和取出，而外部的两性离子- 藻酸盐水凝胶纤维提供必要的生物相容性和容易的质量转移。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（>6个月）治愈 通过优化装置的生物相容性和质量传递特性，我们将 还可放大器械并证明其在犬中的可回收性和功能性。的 这项研究的预期成果将是开发一种新的细胞， 这是一种可为T1 D患者翻译的封装系统。

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.