Spatially localized recruitment of anti-inflammatory monocytes by SDF-1 alpha-releasing hydrogels enhances microvascular network remodeling

Tissue repair processes are characterized by the biphasic recruitment of distinct subpopulations of blood monocytes, including classical (inflammatory) monocytes (IMs, Ly6C(hi)Gr1(+)CX3CR1(lo)) and non-classical anti-inflammatory monocytes (AMs, Ly6C(lo)Gr1(-)CX3CR1(hi)). Drug-eluting biomaterial implants can be used to tune the endogenous repair process by the preferential recruitment of pro-regenerative cells. To enhance recruitment of AMs during inflammatory injury, a novel N-desulfated heparin-containing poly(ethylene glycol) diacrylate (PEG-DA) hydrogel was engineered to deliver exogenous stromal derived factor-1 alpha (SDF-1 alpha), utilizing the natural capacity of heparin to sequester and release growth factors. SDF-1 alpha released from the hydrogels maintained its bioactivity and stimulated chemotaxis of bone marrow cells in vitro. Intravital microscopy and flow cytometry demonstrated that SDF-1 alpha hydrogels implanted in a murine dorsal skinfold window chamber promoted spatially-localized recruitment of AMs relative to unloaded internal control hydrogels. SDF-1 alpha delivery stimulated arteriolar remodeling that was correlated with AM enrichment in the injury niche. SDF-1 alpha, but not unloaded control hydrogels, supported sustained arteriogenesis and microvascular network growth through 7 days. The recruitment of AMs correlated with parameters of vascular remodeling suggesting that tuning the innate immune response by biomaterial SDF-1 alpha release is a promising strategy for promoting vascular remodeling in a spatially controlled manner. (C) 2015 Elsevier Ltd. All rights reserved.