Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy

用于细胞替代疗法的蛋白质释放微孔支架

• 批准号: 7889716
• 负责人: William L Lowe
• 金额: $ 32.96万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7889716
• 关键词: Address; Affect; Angiogenic Factor; Apoptosis; Architecture; Autoimmune Process; Beta Cell; Blood; Blood Circulation; Brain; Calcineurin inhibitor; Cell Death; Cell Survival; Cell Therapy; Cell Transplants; Cell physiology; Cells; Chronic Disease; Development; Diabetes Mellitus; Engraftment; Environment; Exhibits; Exposure to; Extracellular Matrix; Failure; Fatty acid glycerol esters; Fibroblast Growth Factor 2; Glycolic-Lactic Acid Polyester; Growth Factor; Heart; Hepatic; Hormones; Hyperglycemia; Hypoxia; Immune system; Immunosuppressive Agents; Infiltration; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor I; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Left; Liver; Mediating; Metabolic; Modeling; Morphology; Mus; Nutrient; Organ; Pancreas; Peptides; Peritoneal; Pharmaceutical Preparations; Polymers; Porosity; Process; Prolactin; Proteins; Reaction; Replacement Therapy; Risk; Secondary to; Sirolimus; Source; Stress; Supporting Cell; Testing; Time; Tissues; Toxic effect; Toxin; Transplant Recipients; Transplantation; Vascular Endothelial Growth Factors; Vascularization; Waste Products; angiogenesis; cell growth; conditioning; exenatide; improved; in vivo; interest; islet; liver transplantation; macrophage; novel strategies; prevent; public health relevance; scaffold; success

DESCRIPTION (provided by applicant): Cell-based therapies provide a novel approach to treating chronic diseases. Recapitulating a damaged organ's function by secreting hormones or other factors is dependent upon successful engraftment of transplanted cells. Engraftment of the transplanted cells requires that cells survive the initial hypoxic environment following transplantation, connect with the host vasculature for exchange of nutrients and waste products and also deliver secreted factors into the circulation. Doing this requires creating an environment that promotes long term function of the transplanted cells. If the cell supply is limited, approaches to expand the transplant graft in vivo may also be important. We propose to address the hypothesis that micro-porous polymer scaffolds capable of delivering biologically active peptides can create a microenvironment to promote cell engraftment, survival and proliferation. A classic paradigm for cell-based therapy is islet transplantation for treatment of type 1 diabetes in which destruction of insulin-secreting beta cells in the pancreas results in hyperglycemia and its complications. Recent trials have provided proof of concept that islet transplantation can be efficacious, yet problems remain. To address these problems, we are proposing to transplant islets on microporous scaffolds capable of releasing proteins that can influence the host tissue (e.g., vascularization) or enhance the functionality of the transplanted islets. These factors will condition the microenvironment to promote islet engraftment, survival, and function. We have recently shown that microporous scaffolds can serve as a platform for islet transplantation. The Specific Aims are as follows. (i) 1) To investigate the hypothesis that the scaffold architecture, as defined by porosity, pore size, and stability, will influence islet engraftment and function. (ii) To address the hypothesis that use of a polymer scaffold to deliver angiogenic factors will improve islet survival and function post-transplantation in a murine model of diabetes. (iii) To test the hypothesis that polymer scaffolds delivering factors that inhibit islet cell death and/or increase islet cell mass post-transplantation will enhance islet engraftment and function. (iv) To determine whether delivering a combination of growth factors that affect different processes (e.g., angiogenesis and islet cell survival and/or proliferation) is more efficacious than delivering a single factor. These studies have the potential to substantially advance cell therapies for islet transplantation. PUBLIC HEALTH RELEVANCE: Transplantation of islets or, ultimately, insulin-secreting cells from other sources represents a potential cure for diabetes, which results from destruction of insulin-secreting cells by the immune system. To enhance cell replacement therapy for diabetes, we are developing scaffolds for transplantation of islets or insulin-secreting cells into peritoneal fat. These scaffolds provide a support for cell growth and can deliver proteins which will be to enhance cell survival and function following islet transplantation.

描述（由申请人提供）：基于细胞的疗法提供了治疗慢性疾病的新方法。通过分泌激素或其他因子来恢复受损器官的功能取决于移植细胞的成功植入。移植细胞的植入需要细胞在移植后的初始缺氧环境中存活，与宿主脉管系统连接以交换营养物和废物，并且还将分泌的因子递送到循环中。这样做需要创造一个促进移植细胞长期功能的环境。如果细胞供应有限，体内扩增移植物的方法也可能很重要。我们建议解决的假设，微孔聚合物支架能够提供生物活性肽可以创建一个微环境，以促进细胞植入，存活和增殖。基于细胞的治疗的经典范例是用于治疗1型糖尿病的胰岛移植，其中胰腺中分泌胰岛素的β细胞的破坏导致高血糖症及其并发症。最近的试验提供了概念证据，证明胰岛移植可以有效，但问题仍然存在。为了解决这些问题，我们建议将胰岛移植到能够释放可以影响宿主组织的蛋白质（例如，血管化）或增强移植胰岛的功能。这些因素将调节微环境以促进胰岛植入、存活和功能。我们最近发现微孔支架可以作为胰岛移植的平台。具体目标如下。(i)1）研究由孔隙率、孔径和稳定性定义的支架结构将影响胰岛移植和功能的假设。(ii)在糖尿病小鼠模型中，使用聚合物支架递送血管生成因子将改善移植后胰岛的存活和功能。(iii)为了测试以下假设：聚合物支架递送抑制胰岛细胞死亡和/或增加移植后胰岛细胞质量的因子将增强胰岛植入和功能。(iv)为了确定是否递送影响不同过程的生长因子的组合（例如，血管生成和胰岛细胞存活和/或增殖）比递送单一因子更有效。这些研究有可能大大推进胰岛移植的细胞疗法。 公共卫生相关性：移植胰岛或最终从其他来源移植胰岛素分泌细胞是治疗糖尿病的一种潜在方法，糖尿病是由免疫系统破坏胰岛素分泌细胞引起的。为了加强糖尿病的细胞替代疗法，我们正在开发用于将胰岛或胰岛素分泌细胞移植到腹膜脂肪中的支架。这些支架为细胞生长提供了支持，并可以递送蛋白质，这些蛋白质将在胰岛移植后增强细胞存活和功能。