Kareen L.K. Coulombe, PhD

Associate Professor of Engineering
Director of Graduate Studies in Biomedical Engineering
Institute for Biology, Engineering and Medicine
Brown University

Angiogenic Biomaterials for Revascularization of Ischemic Tissue

Vascular perfusion, largely controlled by the high surface area and altered resistance provided by the microcirculation, is vital to maintain tissue integrity and function. Impaired tissue perfusion due to injury, ischemia, or disease threatens proper function of this microcirculatory network, stimulating maladaptive remodeling and disrupting broader tissue function. Thus, there exists a critical need to regenerate the local microvasculature of target tissues. We hypothesize that sustained, local delivery of an optimized combination of growth factors from customized biomaterials will stimulate angiogenesis and facilitate vascular remodeling to increase perfused microvascular density. We developed a fully defined, injectable collagen I and alginate hydrogel that sustains local protein release for >14 days in vitro. Leveraging biomimicry of the native ECM with covalent heparin-modification of the alginate and shear-thinning behavior, the unloaded, defined biomaterial alone enhanced average vessel size 15-fold and endothelial cell recruitment 12-fold when compared to Matrigel. We used an iterative fractional factorial design of experiments (DOE) approach and an in vivo subcutaneous gel plug assay to identify VEGF, bFGF, Shh, IGF-1, and PDGF as the most potent proangiogenic factors from 10 total. Empirical evaluation of 1-, 2-, and 3-protein combinations of these factors identified VEGF, IGF-1, and PDGF (VIP) as an optimal protein cocktail for local, in vivo vascularization, enhancing perfused vascular density by 6-fold vs. the defined biomaterial alone. The VIP-biomaterial formulation increased ischemic skin wound closure, providing a promising revascularization therapy for local microvascular regeneration and demonstrating translational potential of this therapeutic approach.

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