Engineering Ultrathin Immunomodulatory Coatings for Islet Encapsulation

用于胰岛封装的超薄免疫调节涂层工程

• 批准号: 9054112
• 负责人: Cherie L Stabler
• 金额: $ 44.03万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054112
• 关键词: Allogenic; Autoimmunity; Biocompatible Materials; Biological; Cell Surface Proteins; Cell surface; Cells; Chemicals; Chronic; Clinical; Development; Diabetes Mellitus; Diffusion; Digestive System Disorders; Disease Management; Encapsulated; Engineering; Engraftment; Environment; Failure; Figs - dietary; Functional disorder; Glucose; Health; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; Implant; In Vitro; Inflammatory; Infusion procedures; Institutes; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans Transplantation; Kidney Diseases; Lead; Link; Liver; Masks; Membrane Proteins; Microencapsulations; Mission; Nutrient; Nutritional; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Polymers; Process; Proteins; Public Health; Quality of life; Recurrence; Regimen; Replacement Therapy; Structure; Surface; Surface Antigens; Techniques; Testing; Therapeutic; Therapeutic immunosuppression; Thick; Tissues; Translations; Transplantation; adaptive immunity; allograft rejection; base; biocompatible polymer; blood glucose regulation; capsule; design; diabetic; glucose transport; hypoglycemia unawareness; immune activation; implantation; improved; in vivo; islet; loss of function; mouse model; nano; nanometer; nanoscale; novel; response; therapy development

DESCRIPTION (provided by applicant): Clinical islet transplantation (CIT), the infusion of allogeneic islets into the liver, has shown significant promise in the long-term treatment of Type diabetes by providing a cell-based means to mimic the normal physiological response to glucose. While promising, it is dampened by the impaired function and loss of islets following implantation. This loss is attributed to strong inflammatory and immunological responses to the transplant, primarily instigated by cell surface proteins and antigens. In this application, we see to minimize detrimental host responses that lead to islet engraftment failure by encapsulating the islets in novel ultrathin polymeric layers. Ultrathin coatings are generated through the covalent layer-by-layer assembly of biomaterials functionalized with bioorthogonal chemical handles. Through the controlled, covalent linking of polymers layers on the islet cell cluster surface, resulting stable capsules are on the order of 500-fold smaller than standard practices; thus, void volumes are dramatically reduced and nutritional transport and glucose sensing are unaffected. Further, the composition, structure, thickness, and function of these layers can be intricately controlled on the nanometer scale. Once fabricated, these ultrathin layers serve as ideal platforms for cell surface engineering, whereby bioactive motifs capable of dynamically interacting with implant-host interface can be tethered. As such, the inert biomaterial layer can be converted to a bioactive surface capable of actively altering the localized implant environment. We hypothesize that covalently stabilized, ultrathin coatings, generated via covalent layer-by-layer assembly, will enhance islet engraftment and functional duration by masking host recognition of surface antigens and proteins, without imparting limitations on nutrient or insulin diffusion. In addition, the tethering of bioactive agents capable of instructin immune responses will further enhance long-term survival of the transplanted islets. To test this hypothesis, biostable, covalently-linked, ultrathin coatings will be generated on the islet surface using biocompatible polymers capable of masking surface antigens and inflammatory proteins (Aim 1). Additionally, the surface of ultrathin coatings will be functionalized with immunomodulatory agents capable of directing host innate and adaptive immune responses at the transplant interface (Aim 2). Aims will be evaluated both in vitro and in diabetic murine models. The design of effective strategies to build tailored nano-thin layers on the islet surface capable of expressing active immunomodulatory agents could significantly improve the efficacy and long-term stability of islet transplants in the absence of chronic, systemic immunosuppression.

描述（由申请人提供）：临床胰岛移植（CIT），将同种异体胰岛输注到肝脏中，通过提供基于细胞的糖尿病的长期治疗中的长期治疗中有很大的希望，可以模仿基于细胞的糖尿病方法，以模仿正常的生理反应对葡萄糖。在有希望的同时，植入后的功能受损和胰岛丢失会抑制它。这种损失归因于对移植的强烈炎症和免疫学反应，主要是由细胞表面蛋白和抗原促进的。在此应用中，我们认为，通过将胰岛封装在新型超薄聚合物层中，从而最大程度地减少了有害的宿主反应，从而导致胰岛植入失败。超薄涂层是通过生物材料化学柄官能化的生物材料的共价层组装产生的。通过在胰岛细胞簇表面的受控，共价链接的共价链接，稳定的胶囊的稳定胶囊比标准实践小500倍。因此，空隙体积大大减少，营养转运，葡萄糖感应不受影响。此外，这些层的组成，结构，厚度和功能可以在纳米尺度上精心控制。一旦制造，这些超薄层就可以作为细胞表面工程的理想平台，从而可以将能够与植入物宿主接口动态相互作用的生物活性图案束缚。因此，惰性生物材料层可以转化为能够主动改变局部植入环境的生物活性表面。我们假设通过逐层组装产生的共价稳定，超薄涂层将通过掩盖宿主识别表面抗原和蛋白质的识别，而不会对养分或胰岛素扩散的限制，从而增强了胰岛植入和功能持续时间。此外，能够教学免疫反应的生物活性剂的束缚将进一步增强移植胰岛的长期存活。为了检验该假设，将在胰岛表面生成可生物固定的，共价连接的超薄涂层 使用能够掩盖表面抗原和炎性蛋白的生物相容性聚合物（AIM 1）。此外，超薄涂层的表面将用能够指导宿主先天和适应性免疫反应在移植界面处的免疫调节剂进行功能化（AIM 2）。目标将在体外和糖尿病鼠模型中评估。在没有慢性，全身免疫抑制的情况下，在能够表达活跃的免疫调节剂的胰岛表面上建立量身定制的纳米薄层的策略的设计可以显着提高胰岛移植物的疗效和长期稳定性。