Deep Learning-reinforced Engineering of Pancreatic Organoids with Micro-nano Biomaterials for Type 1 Diabetes Treatment

利用微纳米生物材料深度学习强化胰腺类器官工程治疗 1 型糖尿病

• 批准号: 10389894
• 负责人: Alisa White
• 金额: $ 3.42万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389894
• 关键词: Address; Affect; Alginates; American; Antioxidants; Artificial Endocrine Pancreas; Autoimmune Diseases; Beta Cell; Bilirubin; Biocompatible Materials; Biomimetics; Blood; Blood Glucose; Cell Death; Cell Separation; Cell Survival; Cells; Cessation of life; Chronic; Coculture Techniques; Detection; Diabetes Mellitus; Diabetic mouse; Dimethyl Sulfoxide; Disease; Encapsulated; Engineering; Face; Glucose; Goals; Graft Rejection; Health; Housing; Human; Hydrogels; Hyperglycemia; Hypoxia; Immune; Immune response; Immune system; Immunosuppressive Agents; In Vitro; Infection; Infiltration; Injections; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Label; Lead; Malignant - descriptor; Manuals; Mediating; Methods; Microcapsules drug delivery system; Microencapsulations; Microfluidics; Monitor; Morbidity - disease rate; Mus; Nutrient; Operative Surgical Procedures; Organ; Organoids; Ovarian Follicle; Pancreas; Pancreas Transplantation; Patients; Periodicity; Physiological; Procedures; Production; Quality of life; Research; Rest; Risk; Sampling; Solubility; Sorting - Cell Movement; Stromal Cells; Structure; System; T-Lymphocyte; Testing; Time; Transplantation; Water; base; capsule; clinical translation; compliance behavior; deep learning; design; detection method; diabetic patient; effective therapy; implantation; improved; in vitro testing; in vivo; in vivo evaluation; islet; learning strategy; mortality; mouse model; nano; nanoparticle; nanoparticle delivery; novel; post-transplant; prevent; stem; uptake

PROJECT SUMMARY An estimated 1.6 million Americans are currently living with type 1 diabetes. The most common method of treating type 1 diabetes is through daily blood monitoring and insulin injections, which can affect quality of life and may result in severe health issues. Full pancreatic transplantations are a more permanent treatment option but involve invasive surgery that can lead to complications, has a high morbidity rate, and patients are required to take immunosuppressants for the rest of their lives which can be very detrimental to health. One method for diabetes treatment that has become a promising option and focus of a lot of research is islet transplantation, which is a much less invasive method but still requires patients to take immunosuppressants or risk transplantation rejection. A way to prevent the need for immunosuppressants post-transplantation is through encapsulating the islets in biomaterials which can allow nutrient exchange while mitigating immune rejection by preventing immune cell infiltration. Encapsulated islet transplantation still faces many problems including immune responses and poor islet viability post-transplantation, which may be addressed using engineering and biomaterials as proposed in this project. Aim 1 will focus on developing novel microencapsulation methods, which we hypothesize will result in lower islet cell death and lower post-transplantation immune responses in vivo. Microfluidic encapsulation of islets gives greater control over microcapsule composition and configuration than other encapsulation methods. Using this method, a biomimetic encapsulation that mimics the structure of the pancreas and uses materials in a core-and-shell design can be achieved. Implementing a label-free deep learning detection method to selectively pick islet-laden microcapsules from empty capsules on-chip to obtain a highly pure sample of islet-laden microcapsules for transplantation, may greatly improve the efficiency and minimize contamination (and associated immune response), compared to tedious manual sorting methods used in the past. Furthermore, the islets will be co-encapsulated with pancreatic stromal cells to create a biomimetic microenvironment (i.e., pancreatic organoid). The microencapsulated islets will be rigorously characterized in vitro and tested in vivo in a diabetic mouse model by monitoring blood glucose levels of the mice. Aim 2 will focus on developing a nanoparticle-based strategy for further improving the survival of the microencapsulated islets. Physiological amounts of antioxidants show enhanced islet survival post-transplantation. Encapsulating antioxidants in nanoparticles can improve the uptake and allow for sustained release during islet transplantation. Effect of the antioxidant-laden nanoparticles on islet survival and insulin production will be tested in vitro and then their effects on blood glucose levels tested in vivo. Through a combination of deep learning-enabled selective extraction, core-shell hydrogel microencapsulation, and nanoparticle-mediatexd antioxidants delivery, major challenges facing islet transplantation may be addressed. This novel multiscale engineering strategy has great potential for clinical translation to be widely used for treating type 1 diabetes.

项目概要 据估计，目前有 160 万美国人患有 1 型糖尿病。最常见的方法是 治疗 1 型糖尿病是通过日常血液监测和胰岛素注射来治疗，这会影响生活质量 并可能导致严重的健康问题。全胰腺移植是一种更持久的治疗选择 但涉及侵入性手术，可能导致并发症，发病率高，需要患者 终生服用免疫抑制剂，这对健康非常不利。一种方法用于 糖尿病治疗已成为一种有前途的选择，并且许多研究的焦点是胰岛移植， 这是一种侵入性较小的方法，但仍需要患者服用免疫抑制剂或有风险 移植排斥反应。防止移植后需要免疫抑制剂的一种方法是 将胰岛封装在生物材料中，可以进行营养交换，同时减轻免疫排斥 防止免疫细胞浸润。封装胰岛移植仍面临免疫等诸多问题 反应和移植后胰岛活力差，可以通过工程和技术来解决 本项目中提出的生物材料。目标 1 将重点开发新型微胶囊方法， 我们假设这将导致较低的胰岛细胞死亡和较低的移植后免疫反应 体内。胰岛的微流体封装可以更好地控制微胶囊的组成和结构 与其他封装方法相比。使用这种方法，模仿结构的仿生封装 胰腺并使用核壳设计的材料可以实现。实施无标签深度 学习检测方法从芯片上的空胶囊中选择性地挑选载有胰岛的微胶囊以获得 高纯度的载有胰岛的微胶囊样本用于移植，可以大大提高效率和 与使用的繁琐的手动分选方法相比，最大限度地减少污染（以及相关的免疫反应） 在过去。此外，胰岛将与胰腺基质细胞共同封装，以创建仿生细胞 微环境（即胰腺类器官）。微囊化胰岛将被严格表征 体外并通过监测小鼠的血糖水平在糖尿病小鼠模型中进行体内测试。目标2将 专注于开发基于纳米颗粒的策略，以进一步提高微胶囊的存活率 胰岛。生理量的抗氧化剂显示出移植后胰岛存活率的提高。封装 纳米颗粒中的抗氧化剂可以提高胰岛移植过程中的吸收并持续释放。 载有抗氧化剂的纳米粒子对胰岛存活和胰岛素产生的影响将在体外进行测试 然后在体内测试它们对血糖水平的影响。通过深度学习的结合 选择性提取、核壳水凝胶微胶囊化和纳米粒子介导的抗氧化剂递送， 胰岛移植面临的主要挑战可能会得到解决。这种新颖的多尺度工程策略 临床转化广泛用于治疗1型糖尿病的巨大潜力。