Novel pro-healing scaffolds for cell therapies

项目总结/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 有效治疗多种退行性疾病。然而，迄今为止，对不足或病理性的控制， 移植物的再血管化、损伤性炎症和/或失调的组织分化仍然存在 这很难仅仅通过药物治疗来实现。移植微环境本身赋予 许多限制，即细胞移植可能需要适应植入部位，这些部位并不总是概括移植物的特性。 来源器官的细胞组成、分子和/或物理特性，影响移植物的所有因素 长期生存和功能。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克服 这些限制。 在这个多研究者项目中，我们整合了血管生物学的互补专业领域， 细胞免疫学，胰腺组织和干细胞生物学，以及新型生物材料的生物工程， 解决a）我们已经确定的新的生化线索（Slit-2和Netrins）的促修复功能， 发育中的胰腺作为内分泌分化的关键调节剂和血管生成/免疫调节剂 活动，和B）在损伤设置机械提示，我们有重演的功能影响 在发育和成年人胰腺中测量。为落实这些研究，我们会采用 允许空间图案化和时间调节Slit和Netrin创新生物工程方法 血管网络和血管外空间中的蛋白质，以及用于组织的药理学控制 刚度基于支持可行性的初步研究，我们计划剖析依赖于 这些生化和物理线索，并最终影响内分泌反应代谢 作为移植物功能读数的变化。我们将着重实现以下目标： 目的1：研究Slit-2在基于PEG的支架中的工程化对血管重建的影响， 组织移植物的免疫调节。 目的2：评估Netrin功能化支架对未成熟的人成纤维细胞分化和功能的影响。 组织祖细胞 目的3：解决调节支持支架的机械性能对组织祖细胞的影响 生长、分化和功能成熟。 总的来说，这一合作项目的成果将为发展奠定基础， 新一代临床相关支架的生产，将与广泛的医疗领域相关， 需要细胞替代疗法和/或组织再生的病症。

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.