Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy

描述(申请人提供)：基于细胞的疗法为治疗慢性疾病提供了一种新的方法。通过分泌激素或其他因素重述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低氧环境中存活，与宿主血管系统连接以交换营养和废物，并将分泌的因子输送到循环中。要做到这一点，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，在体内扩大移植移植物的方法可能也很重要。我们提出的假设是，能够传递生物活性多肽的微孔聚合物支架可以创造一个促进细胞植入、存活和增殖的微环境。以细胞为基础的治疗的一个经典范例是胰岛移植治疗1型糖尿病，在这种情况下，胰腺中分泌胰岛素的β细胞被破坏，导致高血糖及其并发症。最近的试验提供了胰岛移植可以有效的概念证据，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蛋白质的微孔支架上，这些蛋白质可以影响宿主组织(例如血管形成)或增强移植的胰岛的功能。这些因素将调节微环境以促进胰岛的植入、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植入和功能的假设。(Ii)解决使用聚合物支架运送血管生成因子将改善糖尿病小鼠模型移植后胰岛存活和功能的假说。(3)验证一种假说，即聚合物支架可在移植后提供抑制胰岛细胞死亡和/或增加胰岛细胞质量的因子，从而增强胰岛的植入和功能。(4)确定提供影响不同过程(例如，血管生成和胰岛细胞存活和/或增殖)的多种生长因素组合是否比提供单一因素更有效。这些研究有可能极大地推进胰岛移植的细胞疗法。 与公共卫生相关：移植胰岛，或最终移植来自其他来源的胰岛素分泌细胞，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治疗，我们正在开发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支持，并能传递蛋白质，这些蛋白质将在胰岛移植后增强细胞存活和功能。

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.