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Engineering Biomaterials to Exert Molecular Control of Immune Cell Function

工程生物材料对免疫细胞功能进行分子控制

基本信息

批准号：
8358630
负责人：
Wendy Liu
金额：
$ 230.25万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8358630
关键词：
Affect Animals Autoimmune Process Beta Cell Biocompatible Coated Materials Biocompatible Materials Cell Therapy Cell physiology Cells Clinic Clinical Diabetes Mellitus Drug Formulations Encapsulated Engineering Evaluation Failure Fibrosis Image Immune Immune response Inflammation Inflammatory Inflammatory Response Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Life Materials Testing Medical Device Modality Modeling Molecular Molecular Weight Patients Peptides Phage Display Proteins Receptor Cell Signal Transduction Surface Technology Testing Time Tissue Donors Translations Transplantation United States Work Xenograft procedure abstracting beta cell replacement biomaterial compatibility combinatorial density design implantation in vivo innovation islet islet xenograft novel strategies prevent public health relevance receptor response success

项目摘要

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.

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，促进长期植入囊化胰岛治疗糖尿病。I型糖尿病是由胰岛内产生胰岛素的β细胞受到自身免疫攻击而引起的，在美国有近300万患者受到影响。虽然用健康的供体组织替代β细胞是一种经过验证的治疗方式，但广泛的临床成功受到产生胰岛素的β细胞的充足可获得性的限制。微囊化异种胰岛移植仍然是一种有前景的方法，但移植到临床上仍然难以实现，这主要是由于微囊化的生物材料未能在很长一段时间内保持无纤维化状态。这项工作的目的是开发抑制局部免疫细胞的生物材料，以防止微囊化细胞疗法引起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，在生物材料设计中，材料上装饰着免疫调节分子，这些分子积极地向局部免疫细胞传递耐受信号。我假设，用免疫调节分子包覆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，以生理相关的密度展示免疫调节蛋白模型。此外，我将使用噬菌体展示屏幕针对已知的免疫细胞受体或直接与免疫细胞识别免疫调节小分子多肽。识别出的多肽将用于修饰包裹材料，并在高通量活体成像模型中以组合方式进行测试，该模型允许实时评估材料在活体动物中的生物相容性。已确定的多肽配方将作为包衣材料在异种移植模型中进行进一步测试。这项研究将探索一种生物材料设计的创新策略，其中表面被设计为展示免疫调节分子，以减轻宿主的反应。这种方法不仅有利于细胞封装技术，而且对医疗器械生物材料的设计也有广泛的影响。公共卫生相关性：囊化胰岛移植治疗I型糖尿病仍然是一种很有前途的治疗方式，但会受到宿主对包膜材料的炎症反应的阻碍。该项目将探索一种新的生物材料设计方法，其中材料被量身定做，以与免疫细胞上表达的特定受体相互作用，并抑制其激活，从而减轻宿主对包裹的胰岛治疗糖尿病的反应。