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

基本信息

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
项目类别：
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

项目摘要

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.

该项目的目标是开发一种先进的、临床适用的胰岛/干细胞用于 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。同种异体或异种来源的胰岛或干细胞衍生的β细胞封装在材料或装置中，保护细胞免受宿主免疫排斥，同时允许轻松的质量转移以维持其生存和功能。众多研究小组全球范围内已取得重要进展，但细胞封装的临床应用仍然难以捉摸，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，使封装不会对细胞造成伤害，并且移植量最小侵入性； (2) 必须具有足够的生物相容性（即极少形成或不形成纤维化），强大的机械稳定性和轻松的传质（例如大表面积、短扩散距离和可控的通透选择性），使移植物能够长时间发挥作用，至少几个月； (3)必须方便取回，以便拆卸或更换如果发生移植失败或医疗并发症； (4) 必须具有可扩展性输送足够的细胞量以产生治疗效果。为了满足这些需求，我们建议开发一种新型的、临床可转化的 TRAFFIC（用于胰岛的螺纹增强海藻酸盐纤维） enCapsulation）系统，来自我们新开发的用于 T1D 的非纤维化两性离子海藻酸盐治疗。关键的创新包括结构设计（即结合一个薄但坚韧的聚合物沿其轴线进入水凝胶纤维的中心）和水凝胶化学（即两性离子改性藻酸盐）。内部聚合物螺纹赋予机械性能坚固耐用，易于处理、植入和取出，而外部两性离子- 海藻酸盐水凝胶纤维提供必要的生物相容性和轻松的传质。我们的目标是使用大鼠胰岛和干细胞来源实现糖尿病小鼠的长期（>6 个月）治愈通过优化设备的生物相容性和传质特性来优化β细胞。我们将还扩大了该设备的规模，并在狗身上展示了它的可回收性和功能。这这项拟议研究的预期结果将是开发一种新细胞可用于 T1D 患者的封装系统。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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)
影响因子：
0
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

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