Matrices for optimal endogenous progenitor cell recruitment and function

描述：我们提出了一种方法，利用合成的生物材料阵列来招募功能性循环血管生成细胞(CACs)，从而增强新生血管。迫切需要：i)系统地探索可能对内源性CAC招募至关重要的生物材料相关因素，以及ii)有效地为CAC招募和功能寻找最佳的生物材料。我们将使用一种增强的吞吐量方法来寻找CAC招募和持续功能的最佳水凝胶。我们建议使用这些生物材料来利用循环中的CACs，并增强体内的血管生成。具体目标1将描述控制hCAC侵袭和促血管生成功能的生物材料参数。我们假设细胞粘附肽的浓度、生物材料的硬度以及可溶性趋化因子的特性、剂量和释放率都将显著影响hCAC的选择性募集和促血管生成功能。特殊目的2将使用一种新的活体水凝胶阵列来筛选hCAC募集和hCAC介导的小鼠模型血管生成的最佳生物材料参数。我们假设，将水凝胶阵列植入小鼠皮肤折叠室将识别出在随后的后肢缺血模型中改善功能结果的配方。拟议的研究具有重要意义，因为它们将使生物材料能够增强内源性CACs的临床使用，以改善血管生成。组织再生受到血液供应不足的限制，许多疾病(如糖尿病)的特点是缺乏足够的血管系统。因此，利用内源性CACs的物质方法可能会对组织再生方法产生重大影响。拟议的研究是创新的，因为他们使用化学定义的水凝胶阵列来发现选择性CAC招募和功能的生物材料线索，无论是在体外还是在体内。阵列由高度适应性的生物材料组成，使得阵列点的生化和生物物理性质可以广泛变化。这些研究将为更大规模的研究计划提供基础，以阐明体内和体外内源性细胞募集和CAC介导的血管生成的机制。

DESCRIPTION: We propose an approach to use synthetic biomaterial arrays to recruit functional circulating angiogenic cells (CACs), and thereby enhance neovascularization. There is a critical need to: i) systematically explore the biomaterials-associated factors that may be critical to endogenous CAC recruitment, and ii) efficiently discover optimal biomaterials for CAC recruitment and function. We will use an enhanced throughput approach to discover optimal hydrogels for CAC recruitment and sustained function. We propose to use these biomaterials to leverage circulating CACs and enhance angiogenesis in vivo. Specific Aim 1 will characterize biomaterial parameters that control hCAC invasion and pro-angiogenic function. We hypothesize that the concentration of cell adhesion peptides, biomaterial stiffness, and the identity, dosage, and release rate of soluble chemokines will each significantly influence selective hCAC recruitment and pro-angiogenic function. Specific Aim 2 will use a novel in vivo hydrogel array to screen optimal biomaterial parameters for hCAC recruitment and hCAC- mediated angiogenesis in a mouse model. We hypothesize that hydrogel arrays implanted into a mouse skin- fold chamber will identify formulations that will improve functional outcome in a subsequent model of hindlimb ischemia. The proposed studies are Significant, as they will enable identification of biomaterials that enhance clinical use of endogenous CACs to improve angiogenesis. Tissue regeneration is limited by poor blood supply, and many disease states (e.g. diabetes) are characterized by a lack of sufficient vasculature. Therefore, a material approach to leverage endogenous CACs could have a substantial impact on tissue regeneration approaches. The proposed studies are Innovative, as they use chemically-defined hydrogel arrays to discover biomaterial cues for selective CAC recruitment and function, both in vitro and in vivo. The arrays are composed of biomaterials that are highly adaptable, such that the biochemical and biophysical properties of array spots can be broadly varied. These studies will provide a basis for a larger research program to elucidate the mechanisms of endogenous cell recruitment and CAC-mediated angiogenesis in vitro and in vivo.