Engineering Biomaterials to Exert Molecular Control of Immune Cell Function

描述（由申请人提供） 摘要：该项目旨在开发生物材料，通过设计直接调节局部免疫细胞功能的表面，促进囊化胰岛的长期植入，以治疗糖尿病。I型糖尿病是由对胰岛内产生胰岛素的β细胞的自身免疫攻击引起的，并且在美国影响近300万患者。虽然用健康供体组织替代β细胞是一种经证实的治疗方式，但广泛的临床成功受到产生胰岛素的β细胞的充足可用性的限制。包封的异种移植胰岛的移植仍然是一种有前途的方法，但转化到临床仍然是难以捉摸的，主要是由于包封生物材料在长时间内不能保持无纤维化。这项工作的目的是开发抑制局部免疫细胞的生物材料，以防止对包封细胞疗法的炎症和随后的纤维化反应。我试图通过使用一种新的生物材料设计方法来减轻免疫反应，其中材料用免疫调节分子装饰，这些分子主动向局部免疫细胞传递耐受信号。我假设，具有免疫调节分子的涂层材料将抑制局部炎症，从而减少生物材料植入引起的宿主反应。为了验证这一假设，我将设计表面，以生理相关密度显示模型免疫调节蛋白。此外，我将确定免疫调节小分子量肽使用噬菌体展示屏幕对已知的免疫细胞受体或直接免疫细胞。鉴定的肽将用于修饰包封材料，并在高通量体内成像模型中以组合方式进行测试，该模型允许实时评价活动物体内的材料生物相容性。将进一步测试鉴定的肽制剂作为异种移植物移植模型中包封材料的涂层。这项研究将探讨一种创新的战略，生物材料的设计，表面工程显示免疫调节分子，减轻宿主的反应。这种方法不仅有利于细胞包封技术，而且还广泛影响医疗器械生物材料的设计。 公共卫生相关性：移植包囊胰岛治疗I型糖尿病仍然是一种有前途的治疗方式，但受到宿主对包囊材料的炎症反应的阻碍。该项目将探索生物材料设计的新方法，其中材料被定制为与免疫细胞上表达的特定受体相互作用并抑制其激活，从而减轻宿主对胶囊化胰岛的反应以治疗糖尿病。

DESCRIPTION (Provided by the applicant) Abstract: This project aims to develop biomaterials that will promote the long term implantation of encapsulated islets for treatment of diabetes by designing surfaces that directly modulate the function of local immune cells. Type I diabetes is caused by autoimmune attack on insulin- producing beta-cells within pancreatic islets, and affects nearly 3 million patients in the United States. While replacement of beta-cells with healthy donor tissue is a proven treatment modality, widespread clinical success has been limited by the sufficient availability of insulin- producing beta-cells. Transplantation of encapsulated xenograft islets remains a promising approach, but translation to the clinic has remained elusive primarily due to the failure of the encapsulating biomaterial to remain free of fibrosis over long periods of time. The objective of this work is to develop biomaterials that inhibit local immune cells, in order to prevent the inflammatory and ensuing fibrotic response to encapsulated cell therapies. I seek to mitigate the immune response by using a new approach to biomaterial design, where materials are decorated with immunomodulatory molecules that actively deliver tolerizing signals to local immune cells. I hypothesize that coating materials with immunomodulatory molecules will inhibit local inflammation and therefore reduce the host response that results from biomaterial implantation. To test this hypothesis, I will engineer surfaces to display a model immunomodulatory protein at physiologically relevant densities. In addition, I will identify immunomodulatory small molecular weight peptides using phage display screens against known immune cell receptors or directly to immune cells. Identified peptides will be used to modify encapsulation materials and tested in a combinatorial manner within a high throughput in vivo imaging model that allows the real-time evaluation of material biocompatibility within live animals. Identified peptide formulations will be further tested as coatings for encapsulation materials in a xenograft transplant model. This study will investigate an innovative strategy to biomaterial design, where surfaces are engineered to display immunomodulatory molecules that mitigate the host response. This approach may not only benefit cell encapsulation technologies, but also broadly impact the design of biomaterials for medical devices. Public Health Relevance: Transplantation of encapsulation pancreatic islets to treat type I diabetes remains a promising treatment modality, but is hindered by the host inflammatory response to the encapsulating material. This project will explore a new approach to biomaterial design, where materials are tailored to interact with specific receptors expressed on immune cells and inhibit their activation, therefore mitigating the host response to encapsulated islets fr treatment of diabetes.