Novel pro-healing scaffolds for cell therapies

项目摘要/摘要 促进伤口愈合和支持细胞移植植入的策略可能最终导致 治疗多种退行性疾病的有效方法。然而，到目前为止，对不充分或病态的控制 移植血管重建、损伤性炎症和/或组织分化失调 仅靠药物治疗很难达到。移植微环境由其自身传授 许多约束，即细胞移植可能需要适应植入部位，而这些部位并不总是概括 来源器官的细胞组成、分子和/或物理性质，影响移植物的所有因素 长期的生存和功能。可重建的组织工程技术的快速发展 模拟天然组织微环境的结构和分子线索提供了新的克服机会 这些限制。 在这个多研究人员的项目中，我们整合了血管生物学方面的互补专业知识， 细胞免疫学、胰腺组织和干细胞生物学，以及新生物材料的生物工程 地址a)我们在 发育中的胰腺作为内分泌分化的关键调节器和血管生成/免疫的调节器 活动，以及b)在损伤背景下重述我们所拥有的机械提示的功能影响 在发育中的人和成人的胰腺中进行测量。为落实这些研究，我们会采用 创新的生物工程方法，允许缝隙和网状结构的空间构图和时间调制 血管网络和血管外空间中的蛋白质，以及对组织的药物控制 僵硬。在支持可行性的初步研究的基础上，我们计划剖析依赖于 这些生化和生理信号，以及最终它们对代谢的内分泌反应的影响 随着移植功能的读出而改变。我们将重点抓好以下几个目标： 目的1：研究在聚乙二醇基支架中构建的Sit-2对血管重建和血管再生的影响。 组织移植物的免疫调节。 目的2：评价网织蛋白功能化支架对未成熟细胞分化和功能的影响 组织祖细胞。 目的3：研究调节支架力学性能对组织祖细胞的影响 生长、分化和功能成熟。 总体而言，这一合作项目的成果将为开发和 生产与临床相关的新一代支架，将与广泛的医疗领域相关 需要细胞替代疗法和/或组织再生的情况。

Project Summary/Abstract Strategies to promote wound healing and support engraftment of cell transplants may ultimately lead to effective treatments for many degenerative diseases. Yet, to date control over insufficient or pathologic revascularization of transplants, damaging inflammation, and/or dysregulated tissue differentiation remains difficult to achieve solely by pharmacologic treatments. The transplant microenvironment by its own imparts many constrains, i.e. cell transplants may need to adapt to sites of implantation that not always recapitulate the cellular composition, molecular and/or physical properties of the organ of origin, all factors impacting on grafts long-term survival and function. The rapid progress in tissue engineering technologies capable of reconstituting structural and molecular cues mimicking native tissue microenvironments offers new opportunities to overcome these limitations. In this multi-investigator project, we integrate complementary areas of expertise on vascular biology, cellular immunology, pancreatic tissue and stem cell biology, as well as bioengineering of novel biomaterials to address a) pro-repair functions of novel biochemical cues (Slit-2 and Netrins) that we have identified in the developing pancreas as critical regulators of endocrine differentiation and modulators of vasculogenic/immune activities, and b) the functional impact of recapitulating in injury settings mechanical cues that we have measured in the developing and adult human pancreas. To implement these studies we will adopt an innovative bioengineering approach that allow for spatial patterning and temporal modulation of Slit and Netrin proteins in vascular networks and extra-vascular spaces, as well as for pharmacologic control of tissue stiffness. Based on preliminary studies supporting feasibility, we plan to dissect repair mechanisms dependent on these biochemical and physical cues, and ultimately their impact on endocrine responses to metabolic changes as read-out of grafts function. We will focus on the following aims: Aim 1: To investigate the impact of Slit-2 engineered in PEG-based scaffolds on the revascularization and immunomodulation of tissue grafts. Aim 2: To assess the effects of Netrin-functionalized scaffolds on the differentiation and function of immature tissue progenitors. Aim 3: To address the impact of tuning the mechanical properties of support scaffolds on tissue progenitors growth, differentiation and functional maturation. Collectively, results from this collaborative project will establish the ground-work for the development and production of a new generation of clinically-relevant scaffolds that will be relevant to a wide range of medical conditions requiring cell replacement therapies and/or tissue regeneration.