Manipulation of Host Tissue to Induce a Hierarchical Microvasculature

摘要 重建外科医生的任务是修复软组织丢失，而不考虑病因。完毕 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 修理。然而，植入后缓慢而随机的血管形成往往会导致失败并排除 真正的组织再生和功能。天然微血管网络的特点是组织成树状 起源于大型摄食容器的分枝模式。我们的目标是利用互补性 基于严格的初步数据的再生策略，使这一技术快速发展 分级微血管系统。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 微血管穿刺术(MP)。在这种方法中，使用针在针孔中创建小穿孔 受体血管系统，以促进细胞外渗和血管生成，而不会导致血栓或 大量出血。这种诱导的血管生成可用于随机地血管化相邻放置的 水凝胶支架，导致24小时内灌流，新生血管增加一倍。有了这个引人入胜的 结果，我们建议使用一种新兴的原位微工程技术来推进MP方法。我们有 基于可控细胞外基质模拟材料的颗粒水凝胶支架(GHS) 微孔率，改善细胞渗透，引导血管网络的形成，在体外和体内。 我们的假设是，定制的GHS可以与MP协同使用，以加速和精确指导 分级的微血管发育。为了验证这一假设，我们将重点关注以下三个独立的因素 具体目标：1)设计和优化GHS以指导微血管发育；2)评估 MP促进微血管发育的特性及3)MP与GHS的偶联效应 以加速和精确引导分级微血管的发展。这些项目的顺利完成 研究应显著改善软组织重建手术中使用的支架的血管化。另外， 它为进一步研究建立作为血液基石的分级微血管系统奠定了基础 血流调节、氧气扩散和免疫细胞调节。因此，我们的新方法适用于 广泛推进再生医学的巨大潜力。

Abstract 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.