Manipulation of Host Tissue to Induce a Hierarchical Microvasculature

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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.