Stiffness of Protease Sensitive and Cell Adhesive PEG Hydrogels Promotes Neovascularization In Vivo

Ryan M. Schweller, Zi Jun Wu, Bruce Klitzman, Jennifer L. West

Materials that support the assembly of new vasculature are critical for regenerative medicine. Controlling the scaffold's mechanical properties may help to optimize neovascularization within implanted biomaterials. However, reducing the stiffness of synthetic hydrogels usually requires decreasing polymer densities or increasing chain lengths, both of which accelerate degradation. We synthesized enzymatically-degradable poly(ethylene glycol) hydrogels with compressive moduli from 2 to 18 kPa at constant polymer density, chain length, and proteolytic degradability by inserting an allyloxycarbonyl functionality into the polymer backbone. This group competes with acrylates during photopolymerization to alter the crosslink network structure and reduce the hydrogel's stiffness. Hydrogels that incorporated (soft) or lacked (stiff) this group were implanted subcutaneously in rats to investigate the role of stiffness on host tissue interactions. Changes in tissue integration were quantified after 4 weeks via the hydrogel area replaced by native tissue (tissue area fraction), yielding 0.136 for softer vs. 0.062 for stiffer hydrogels. Including soluble FGF-2 and PDGF-BB improved these responses to 0.164 and 0.089, respectively. Softer gels exhibited greater vascularization with 8.6 microvessels mm(-2) compared to stiffer gels at 2.4 microvessels mm(-2). Growth factors improved this to 11.2 and 4.9 microvessels mm(-2), respectively. Softer hydrogels tended to display more sustained responses, promoting neovascularization and tissue integration in synthetic scaffolds.