Designing Biomaterials to Promote the M1-to-M2 Macrophage Transition and Enhance Angiogenesis

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Abstract Dysfunctional angiogenesis is implicated in several pathologies that affect tens of millions of patients in the U.S. alone. A lack of healthy vascularization can result in lethal complications, including tissue death and limb amputation, and current solutions fail to promote stable vasculature. Therefore, there is a demand for strategies that can support healthy vascularization throughout the angiogenic process. As high-level regulators of angiogenesis and healing, macrophages are an attractive target for pro-angiogenic cell therapies. Intensely responsive to environmental stimuli, macrophages have been shown to exhibit a pro-inflammatory (M1) phenotype in early healing, then a less-inflammatory M2 phenotype dominates later stages. Although the roles of macrophage phenotypes in angiogenesis are poorly understood, studies suggest that M1 macrophages induce sprouting of new blood vessels, then M2 macrophages promote stabilization. In vivo, the M2 population can derive from circulating monocytes, or from the phenotypic switching of pre-existing M1 macrophages, but it is unknown to what extent each group is present or what they contribute to angiogenesis. We have previously shown that IL-4 causes M1-activated macrophages to switch to an M2 phenotype with some increased angiogenic functions, compared to IL-4-treated M0 macrophages. We hypothesize that M1-derived M2 macrophages are a unique phenotype essential to angiogenesis, and that promoting the M1-to-M2 switch with biomaterials will enhance angiogenesis in vivo. Aim 1 will thoroughly investigate the differences between M0- derived and M1-derived M2 macrophages in vivo using next-generation sequencing, producing the unique gene signatures and functional phenotypes of each group. In Aim 2, PLGA microparticles will be loaded with the M2- promoting drug simvastatin, then co-cultured with M0 or M1 macrophages to facilitate phagocytosis. The macrophages will then be injected into a murine model of wound healing, and as the microparticles degrade and release simvastatin, the drug will promote M2 polarization intracellularly. It is expected that the group undergoing the M1-to-M2 transition will augment angiogenesis. This study will increase our understanding of the roles of macrophage phenotype during angiogenesis, and will result in a translational pro-angiogenic biomaterials-based cell therapy.