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: 10592297
• 负责人: Alisa White
• 金额: $ 2.39万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592297
• 关键词: Address; Affect; Alginates; American; Antioxidants; Artificial Endocrine Pancreas; Autoimmune Diseases; Beta Cell; Bilirubin; Biocompatible Materials; Biomimetics; Blood; Blood Glucose; Cell Aggregation; 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; Injections; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Label; Laboratories; Malignant - descriptor; Manuals; Mediating; Methods; Microcapsules drug delivery system; Microfluidics; Monitor; Morbidity - disease rate; Mus; Nutrient; Operative Surgical Procedures; Organ; Organoids; Ovarian Follicle; Pancreas; Pancreas Transplantation; Patients; Periodicals; Physiological; Procedures; Production; Quality of life; Research; Rest; Risk; Sampling; Solubility; Sorting; Stromal Cells; Structure; System; T-Lymphocyte; Testing; Time; Transplantation; Water; capsule; clinical translation; compliance behavior; deep learning; design; detection method; diabetic patient; effective therapy; immune cell infiltrate; 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.

项目摘要 据估计，目前有160万美国人患有1型糖尿病。的最常见方法 治疗1型糖尿病是通过每日血液监测和胰岛素注射，这可能会影响生活质量 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 但涉及可导致并发症的侵入性手术，具有高发病率， 终生服用免疫抑制剂，这对健康非常有害。的一种方法 已经成为有希望的选择和许多研究焦点的糖尿病治疗是胰岛移植， 这是一种侵入性小得多的方法，但仍然需要患者服用免疫抑制剂， 移植排斥反应防止移植后需要免疫抑制剂的一种方法是通过 将胰岛包封在生物材料中，该生物材料可以允许营养交换，同时通过以下方式减轻免疫排斥： 防止免疫细胞浸润。微囊化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，这可以使用工程和 生物材料在这个项目中提出。目标1将集中于开发新的微胶囊化方法， 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， vivo.胰岛的微流体包封提供了对微胶囊组成和配置的更大控制 其他封装方法。使用这种方法，仿生封装，模仿的结构， 胰腺和使用核壳设计的材料。实现无标签深度 学习检测方法，从芯片上的空胶囊中选择性地挑选装载胰岛的微胶囊， 用于移植的高纯度载胰岛微囊样品，可以大大提高效率， 与使用繁琐的手动分选方法相比，最大限度地减少污染（和相关的免疫反应） 在过去的日子里此外，胰岛将与胰腺基质细胞共包封，以产生仿生的 微环境（即，胰腺类器官）。微囊化的胰岛将被严格表征， 通过监测小鼠的血糖水平在糖尿病小鼠模型中进行体外和体内测试。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 小岛生理量的抗氧化剂显示移植后胰岛存活率提高。封装 纳米颗粒中的抗氧化剂可以提高摄入并允许在胰岛移植期间持续释放。 将在体外测试负载抗氧化剂的纳米颗粒对胰岛存活和胰岛素产生的影响， 然后在体内测试它们对血糖水平的影响。通过结合深度学习， 选择性提取、核-壳水凝胶微囊化和纳米颗粒介质和抗氧化剂递送， 可以解决胰岛移植所面临的主要挑战。这种新颖的多尺度工程策略 具有广泛用于治疗1型糖尿病的临床转化的巨大潜力。