Optimizing encapsulation to treat Type 1 diabetes mellitus: the role of oxygenation, antigen shedding and innate immune response in graft success

优化封装治疗 1 型糖尿病：氧合、抗原脱落和先天免疫反应在移植成功中的作用

• 批准号: 10349470
• 负责人: Christopher Alan Fraker
• 金额: $ 40.22万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349470
• 关键词: Address; Affect; Alginates; Anoxia; Antigens; Apical; Apoptosis; Attention; Autoimmune; Biocompatible Materials; Blood Vessels; Cell Death; Cell Survival; Cell physiology; Cells; Chemicals; Clinical; Coculture Techniques; Computer Models; Data; Devices; Diabetes Mellitus; Diffuse; Diffusion; Disease; Encapsulated; Engraftment; Environment; Epidemiology; Equilibrium; Fluorocarbons; Gases; Geometry; Glucose; Goals; Healthcare Systems; Hour; Hypoxia; Immune; Immunocompetent; Immunosuppression; Impairment; Implant; In Vitro; Inbred BALB C Mice; Incidence; Individual; Inflammatory; Inflammatory Response; Innate Immune Response; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Investigation; Islets of Langerhans Transplantation; Longevity; Metabolic; Methodology; Methods; Microcapsules drug delivery system; Mus; Nutrient; Oxygen; Particle Size; Pathway interactions; Patients; Performance; Permeability; Polyethylene Glycols; Procedures; Production; Public Health; Research; Research Priority; Role; Streptozocin; Structure; Study models; Surface; System; Technology; Testing; Time; Tissue Transplantation; Tissues; Translations; Transplantation; Work; base; capsule; cell capsule; clinical translation; clinically relevant; comorbidity; cost; crosslink; density; experience; functional disability; improved; in vivo; islet; loss of function; macrophage; monomer; mouse model; nanoemulsion; oxygen transport; prevent; response; restoration; success

PROJECT SUMMARY The past fifty years have seen substantial advances in the field of encapsulation of insulin producing tissues for the treatment of Type 1 Diabetes Mellitus. Persistent obstacles and limitations of the current technologies have prevented translation of these results to the clinical realm. Multiple groups are now poised for clinical translation, but still lack adequate, easily retrievable delivery devices. One major obstacle is the limitation of tissue loading in conventional encapsulation that results from the high metabolic demand of native islets/SC-β and the concomitant mass transport limitations of most encapsulation materials. Importantly, native islets experience oxygen and nutrient deficit in loading densities greater than 1.5 to 2% v/v in standard alginate microcapsules. In smaller capsules of alternate materials, mass transfer is impaired due to monomer structure and cross-linking strategies. This adversely affects the benefit afforded by the smaller diffusive distance. Fundamental aspects of cell encapsulation must be reexamined. Research efforts have been focused on the in vivo application where reduction in device geometry is crucial to clinical success through the reduction of oxygen transfer distances and overall biomaterial/graft volume. There has been little study of pre-transplant culture where hypoxia and loss of viability/function are the result of cell proximity to the plastic basal surface. This causes cell death and results in antigen shedding. In vivo, the opposite holds true where larger geometry results in increased chance of hypoxia at clinically relevant loading densities. The central hypothesis of this proposal is that impaired oxygen mass transfer results in increased hypoxia/anoxia, loss of function, apoptosis and antigen shedding. This proposal seeks to address these obstacles through the following specific aims: 1.) we will determine the effect of capsule geometry and pre-implant culture methods on encapsulated islet/SC-β viability, function, antigen shedding and in-vitro inflammatory response from co-culture with macrophages. 2.) we will employ oxygen carrying perfluorocarbon nanoemulsions in islet encapsulation devices in immune-deficient, immune competent and autoimmune mouse models (BALB/C, C57BL/6, NOD-SCID, NOD) with chemical induction (STZ) of diabetes to ascertain the additive effect of each on engraftment and restoration of normoglycemia. !

项目总结 在过去的五十年里，在胶囊领域取得了实质性的进展 用于治疗1型糖尿病的胰岛素产生组织。持久化 当前技术的障碍和限制阻碍了这些内容的翻译 结果推广到临床领域。多个小组现在已经准备好进行临床翻译，但 仍然缺乏足够的、容易取回的递送设备。一个主要的障碍是 组织负载在传统包埋中的限制是由于高 天然胰岛/SC-β的代谢需求和伴随的质量运输限制 在大多数封装材料中。重要的是，当地的小岛会经历氧气和 在标准藻酸盐中，装载密度大于1.5%至2%v/v时的营养亏缺 微胶囊。在由替代材料制成的较小胶囊中，由于 到单体结构和交联剂策略。这对收益产生了不利影响 由较小的扩散距离提供。 必须重新检查信元封装的基本方面。研究 人们的努力主要集中在体内应用上，在体内应用中，设备几何形状的减少 是临床成功的关键，通过减少氧转移距离和 生物材料/移植物的总体积。关于移植前培养的研究很少。 缺氧和丧失活力/功能是细胞接近塑料的结果 基面。这会导致细胞死亡，并导致抗原脱落。在活体内， 相反，几何形状越大，缺氧的几率就越大 临床相关的负荷密度。这项提议的中心假设是 氧质传递障碍会导致缺氧/缺氧增加， 功能、细胞凋亡和抗原脱落。这项提案旨在解决这些问题 通过以下具体目标设置障碍：1.我们将测定胶囊的作用。 囊化胰岛/SC-β的几何构型和植入前培养方法 与巨噬细胞共培养的抗原脱落和体外炎症反应。 2.)我们将使用载氧全氟碳纳米乳剂进行胰岛封装。 免疫缺陷、免疫活性和自身免疫小鼠模型中的装置 (BALB/C，C57BL/6，NOD-SCID，NOD)与化学诱导(STZ)糖尿病 确定每种药物对植入和恢复正常血糖的相加作用。 好了！