Clinical success of implantable tissue engineered scaffolds used for the replacement and/or restoration of damaged and diseased tissues requires that the rate of scaffold degradation matches that of tissue formation and remodeling.

Furthermore, different tissues exhibit different rates of remodeling and healing and may require different stiffnesses to induce desired cellular differentiation and functional tissue regeneration.

Thus, the ability to systematically tune and decouple variations in matrix degradation, stiffness, and immobilized biochemical composition is critical for successful design of tissue engineered constructs.

While synthetic hydrogel scaffolds formed using degradable crosslinkers enables manipulation of biomaterial degradation rate and matrix stiffness, these properties are often coupled making it difficult to tune them independently.

Our lab has developed novel approaches for engineering PEG diacrylate scaffolds with controlled protease-mediated degradation independent of alterations in scaffold stiffness and immobilized adhesion ligands.

Our research has shown that the use of polymerizable macromers containing variable numbers of matrix metalloproteinase (MMP)-sensitive peptide sequences between the terminal reactive groups of the crosslinker, allows for significant variations in protease-mediated scaffold degradation rate without inducing changes in elastic modulus and network physical properties (swelling ratio, crosslink density and mesh size).

Our results also indicate that that increases in MMP-sensitive peptide repeats between crosslinks lead to more rapid proteolytic degradation, enhanced rates of neovascularization in vitro and tissue remodeling in vivo.

Furthermore, we have also performed studies to investigate the impact of specific matrix-metalloproteinase (MMP) peptide sequences and or substrates previously reported to enhanced susceptibility to degradation by MMPs (MMP-2, MMP-9 and MMP-14), on vascularized tissue remodeling.

Our findings indicate that peptide substrate concentration, but not specificity, is the critical regulator of vascularized tissue remodeling.

In most recent studies we also engineered PEG hydrogel scaffolds with a broad range of decoupled and combined variations in integrin-binding peptide (RGD) ligand concentration, elastic modulus and proteolytic degradation rate using free-radical polymerization chemistry.

The modularity of this system enabled a full factorial experimental design to simultaneously investigate the individual and interaction effects of these matrix cues on vascular sprout formation in 3D culture.

Our findings revealed a previously unidentified and optimized combination whereby increases in both immobilized RGD concentration and proteolytic degradation rate were required to significantly and synergistically enhance vascular spouting in 3D culture.

Currently we are exploring this approach in designing gradient-based scaffolds to induce spatial variations in proteolytic degradation for osteochondral tissue engineering and induction of vascularization.