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Rapid vascularization at the infarcted site is crucial for cardiac repair following myocardial infarction. Thymosin β4 (Tβ4), a 43-amino acid peptide, is both angiogenic and cardioprotective. Tβ4 in soluble form was previously shown to promote cell migration from quiescent adult cardiac explants. Here we developed a collagen–chitosan hydrogel for the encapsulation of Tβ4, which allowed its controlled release over 28 days to elicit localized and prolonged effects. Contrastingly, Tβ4 was fully released over 3 days when encapsulated in collagen-only hydrogels due to charge repulsion and lack of interconnected pores as shown by SEM. The charge of encapsulated molecules affected their release from collagen–chitosan hydrogels. While the release of neutral polyalanine was size-controlled diffusion, that of negatively-charged Tβ4 and positively-charged polylysine was affected by electrostatic interactions of peptides with collagen/chitosan molecules. Hydrogels with encapsulated Tβ4 significantly increased cell migration and outgrowth of CD31-positive capillaries from mouse and rat epicardial explants in vitro, compared to Tβ4-free and soluble controls. Potential advantage of Tβ4 over commonly-used angiogenic growth factors is that it can induce recruitment and differentiation of both endothelial and smooth muscle cells necessary for vascular stability. Importantly, Tβ4-encapsulated collagen–chitosan hydrogels promoted angiogenesis in vivo upon subcutaneous injection, compared to collagen-only hydrogels.Sustained release of encapsulated thymosin β4 from collagen–chitosan hydrogels results in migration of cells from adult mouse and rat epicardial explants, subsequent endothelial tube formation and angiogenesis in vivo.