Enhanced proteolytic degradation of molecularly engineered PEG hydrogels in response to MMP-1 and MMP-2

Bioactive hydrogels formed by Michael-type addition reactions of end-functionalized poly(ethylene glycol) macromers with cysteine-containing peptides have been described as extracellular matrix mimetics and tissue engineering scaffolds. Although these materials have shown favorable behavior in vivo in tissue repair, we sought to develop materials formulations that would be more rapidly responsive to cell-induced enzymatic remodeling. In this study, protease-sensitive peptides that have increased k_cat values were characterized and evaluated for their effects on gel degradability. Biochemical properties for soluble peptides and hydrogels were examined for matrix metalloproteinase (MMP)-1 and MMP-2. The most efficient peptide substrates in some cases overlap and in other cases differ between the two enzymes tested, and a range of k_cat values was obtained. For each enzyme, hydrogels formed using the peptides with higher k_cat values degraded faster than a reference with lower k_cat. Fibroblasts showed increased cell spreading and proliferation when cultured in 3D hydrogels with faster degrading peptides, and more cell invasion from aortic ring segments embedded in the hydrogels was observed. These faster degrading gels should provide matrices that are easier for cells to remodel and lead to increased cellular infiltration and potentially more robust healing in vivo.