Diversity Supplement: Manipulation of Host Tissue to Induce a Hierarchical Microvasculature

父母补助金（Parent Grant） 重建外科医生的任务是恢复软组织损失，无论病因如何。超过 在过去的二十年里，水凝胶支架已经成为组织血管重建和外科手术的重要平台。 修复.然而，它们在植入时缓慢且随机的血管化通常会导致失败并阻止 真正的组织再生和功能。天然微血管网络的特征是有组织的树状结构 从大型的营养血管中产生的分支模式我们的目标是利用互补性 再生策略基于严格的初步数据，使快速发展， 分级微脉管系统。为了实现我们的目标，我们最近开发了一种创新的显微外科手术， 称为血管微穿刺术（MP）。在该方法中，使用针在孔中产生小穿孔。 接受者脉管系统，以促进细胞外渗和血管生成，而不引起血栓形成或 严重出血。这种诱导的血管生成可用于使相邻放置的血管随机血管化。 水凝胶支架，导致24小时内灌注和新血管形成加倍。有了这个引人注目的 因此，我们建议使用新兴的原位微工程技术来推进MP方法。我们有 开发了基于细胞外基质模拟材料的颗粒状水凝胶支架（GHS）， 在体外和体内，微孔可以改善细胞浸润并引导血管网络形成。 我们的假设是，定制的全球统一制度可以协同使用与MP，以加快和准确地指导 分级微血管发育。为了验证这一假设，我们将重点关注以下三个独立的 具体目的：1）设计和优化GHS以引导微血管发育，2）评价 MP促进微血管发育的特性; 3）评估MP和GHS的耦合效应 以加速和精确地引导分级微血管的发育。成功完成这些 研究应显著改善用于软组织重建手术的支架的血管化。还有， 它为进一步研究建立一个层次化的微血管系统奠定了基础，微血管系统是血液的基石。 流量调节、氧扩散和免疫细胞调节。因此，我们的新方法 广泛推进再生医学的巨大潜力

Summary (Parent Grant) Reconstructive surgeons are tasked with the restoration of soft tissue loss irrespective of etiology. Over the past two decades, hydrogel scaffolds have become a vital platform for tissue revascularization and surgical repair. However, their slow and random vascularization upon implantation often precipitates failure and precludes true tissue regeneration and function. Native microvascular networks are characterized by organized tree-like branching patterns that originate from large feeding vessels. Our objective is to utilize complementary regenerative strategies based upon rigorous preliminary data that enables the rapid development of this hierarchical microvasculature. To achieve our objective, we recently developed an innovative microsurgical tactic termed vascular micropuncture (MP). In this method, small perforations are created using a needle in the recipient vasculature to facilitate cellular extravasation and angiogenesis, without causing thrombosis or significant hemorrhage. Such induced angiogenesis can be used to randomly vascularize an adjacently placed hydrogel scaffold, leading to perfusion within 24 h and a doubling of neovascularization. With this compelling result, we propose to advance the MP method using an emerging in situ microengineering technology. We have developed granular hydrogel scaffolds (GHS) based on an extracellular matrix mimetic material with controlled microporosity that improves cell infiltration and guides vascular network formation both in vitro and in vivo. Our hypothesis is that customized GHS can be synergistically used with MP to hasten and precisely guide hierarchical microvascular development. To test this hypothesis, we will focus on the following three independent specific aims: 1) To design and optimize GHS to guide microvascular development, 2) To evaluate the effect of MP characteristics to hasten microvascular development and 3) To evaluate the coupling effects of MP and GHS to hasten and precisely guide hierarchical microvascular development. The successful completion of these studies should markedly improve the vascularization of scaffolds used in soft tissue reconstructive surgery. Also, it sets the platform for further investigation in building a hierarchical microvasculature that is cornerstone to blood flow regulation, oxygen diffusion, and immune cell modulation. Consequently, our novel approach holds immense potential for broadly advancing regenerative medicine.