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

利用两性离子改性藻酸盐设计胰岛丝，用于治疗 1 型糖尿病

• 批准号: 10402773
• 负责人: Minglin Ma
• 金额: $ 38.91万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402773
• 关键词: Affect; Alginates; Area; Beta Cell; C57BL/6 Mouse; Canis familiaris; Cell Survival; Cell Transplantation; Cell physiology; Cells; Chemistry; Clinical; Development; Devices; Diabetic mouse; Diffusion; Donor person; Encapsulated; Engineering; Event; Failure; Family suidae; Fiber; Fibrosis; Forcep; Glucose; Goals; Human; Hydrogels; Immune; Immune system; Immunocompetent; Infusion procedures; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans Transplantation; Laparoscopic Surgical Procedures; Mechanics; Metabolic; Microcapsules drug delivery system; Mus; Nanoporous; Neonatal; Nutrient; Outcome; Oxygen; Pain; Patients; Persons; Polymers; Procedures; Property; Rattus; Reporting; Reproducibility; Research; Retrieval; Risk; SCID Beige Mouse; Safety; Scientist; Source; Streptozocin; Structure; Support System; Surface; Surgeon; Surgical sutures; System; Testing; Therapeutic Effect; Thinness; Time; Transplantation; Vertebral column; Work; base; biomaterial compatibility; canine model; cell replacement therapy; clinical application; clinically relevant; clinically translatable; design; diabetic; experience; experimental study; human embryonic stem cell; human stem cells; implantation; innovation; interest; islet; islet stem cells; medical complication; minimally invasive; mouse model; novel; scale up; stem; stem cells; translational potential; transplant model; wasting

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.

该项目的目的是开发一个高级，临床上适用的胰岛/干细胞 1型糖尿病（T1D）的封装系统。细胞封装和移植 治疗T1D的巨大潜力。 Allo或Xeno起源或干细胞衍生的Beta细胞的胰岛是 封装在保护细胞免受宿主免疫排斥的材料或设备中，而 允许便捷的传质保持其生存和功能。许多研究小组 全球取得了重要的进步，但是细胞包封的临床应用已有 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）必须易于处理，使用和 移植以使得封装不会对细胞造成任何损害，并且移植最少 入侵（2）它必须具有足够的生物相容性（即最小或没有纤维化的形成）， 强大的机械稳定性和易于质量传递（例如大的表面积，短扩散 距离和可控制的允许率），以便移植可以长时间起作用，在 至少几个月； （3）检索必须方便，以便可以将其删除或更换 如果发生移植失败或医疗并发症； （4）它必须是可扩展的，以便可以 提供足够的细胞肿块以产生治疗作用。为了满足这些需求，我们建议 开发一种新颖的，临床翻译的流量（胰岛的螺纹增强藻酸盐纤维 T1D的新开发的非纤维化zwitterion-Alginates的封装系统 治疗。关键创新既包括结构设计（即结合薄，但 沿其轴的水凝胶纤维中心的坚硬聚合物线和水凝胶 化学（即Z连锁修饰的藻酸盐）。内部聚合物线授予机械 稳健性并启用易于处理，植入和检索 藻酸盐水凝胶纤维提供了必要的生物相容性和易于质量的传质。我们的目标 使用大鼠胰岛和干细胞衍生的糖尿病小鼠长期治疗（> 6个月） 通过优化设备的生物相容性和传质特性来通过优化β细胞。我们将 还要扩展设备并证明其在狗中的可辨认性和功能。这 这项拟议的研究的预期结果将是新细胞的发展 可以翻译为T1D患者的封装系统。

项目成果

Engineered immunomodulatory accessory cells improve experimental allogeneic islet transplantation without immunosuppression.

• DOI: 10.1126/sciadv.abn0071
• 发表时间: 2022-07-22
• 期刊: Science advances
• 影响因子: 13.6

A Safe, Fibrosis-Mitigating, and Scalable Encapsulation Device Supports Long-Term Function of Insulin-Producing Cells.

• DOI: 10.1002/smll.202104899
• 发表时间: 2022-03
• 期刊: Small (Weinheim an der Bergstrasse, Germany)
• 作者: Liu W;Flanders JA;Wang LH;Liu Q;Bowers DT;Wang K;Chiu A;Wang X;Ernst AU;Shariati K;Caserto JS;Parker B;Gao D;Plesser MD;Grunnet LG;Rescan C;Pimentel Carletto R;Winkel L;Melero-Martin JM;Ma M
• 通讯作者: Ma M

Specialty Tough Hydrogels and Their Biomedical Applications.

• DOI: 10.1002/adhm.201901396
• 发表时间: 2020-01
• 期刊: Advanced healthcare materials
• 影响因子: 10
• 作者: Fuchs S;Shariati K;Ma M
• 通讯作者: Ma M

A predictive computational platform for optimizing the design of bioartificial pancreas devices.

• DOI: 10.1038/s41467-022-33760-5
• 发表时间: 2022-10-13
• 期刊: Nature communications
• 影响因子: 16.6

An Adhesive Hydrogel with "Load-Sharing" Effect as Tissue Bandages for Drug and Cell Delivery.

• DOI: 10.1002/adma.202001628
• 发表时间: 2020-10
• 期刊: Advanced materials (Deerfield Beach, Fla.)
• 作者: Chen J;Wang D;Wang LH;Liu W;Chiu A;Shariati K;Liu Q;Wang X;Zhong Z;Webb J;Schwartz RE;Bouklas N;Ma M
• 通讯作者: Ma M