Manipulating the host-biomaterial interface for enhanced scaffold vascularization

Abstract This research is significant as it will facilitate a new generation of regenerative scaffolds. Voluminous soft tissue loss is often encountered after injury, and reconstructive procedures are suboptimal. Over the past two decades, collagen-based scaffolds have become vital to surgeons by providing a platform for tissue revascularization and reconstruction. However, their slow random vascularization upon implantation often leads to failure and prevents true recapitulation of native tissue vascular hierarchy. Thus, scaffolds which could rapidly guide microvascular development would be exceedingly relevant to replacing ‘like tissue with like tissue’, a hallmark of reconstructive surgery. This proposal’s objective is to develop a coordinated engineering-surgical approach for rapid and guided scaffold vascularization. We have developed a novel microsurgical tactic, termed vascular “micropuncture” (MP), which increases the angiogenic capabilities of the rat recipient macrovasculature to quickly vascularize an adjacently placed bulk scaffold. We believe the resulting capillary outgrowth is induced by the instantaneous extravasation of immune cells, especially macrophages. While this partially expedites vascularization in an adjacently placed bulk collagen scaffold, the resulting neo-microvasculature has a random pattern. Currently used bulk scaffolds have nanoscale pores that are orders of magnitude smaller than cell size and lack interconnectivity. This does not permit for rapid and guided cell infiltration; hence vascularization is slow and random. To address this, we have pioneered the development of in situ forming extracellular matrix (ECM)- mimetic granular scaffolds with customizable microarchitectures and cell permeating capabilities. Our preliminary data suggests that our microporous granular scaffolds are well suited to guide MP-induced vascularization. Our central hypothesis is that customized microporous granular scaffolds can be used alongside MP to enhance and guide vascularization. The rationale is that completion of these studies will reveal how to best optimize complementary tactics for the multifaceted problem of guided engineered tissue vascularization. Our central hypothesis will be tested by three specific aims: 1) To develop ECM-mimetic in situ forming microporous granular hydrogel scaffolds that regulate cellular activities pertinent to accelerating angiogenesis in vitro and in vivo; 2) Controlling scaffold vascularization by varying recipient MP interval and diameter; and 3) Controlling macrophage infiltration and vascular architecture by scaffold design. We will pursue these aims using innovative combinatorial techniques from both the surgical and engineering sciences. The expected outcome is a rapidly vascularized scaffold having a controllable microvascular hierarchy while also creating experimental techniques at the engineering-microsurgery interface. These results will have a positive impact by laying the foundation in developing new and translatable reconstructive approaches for large volume tissue loss.