Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics.

Synthetic hydrogels have been molecularly engineered to mimic the invasive characteristics of native provisional extracellular matrices: a combination of integrin-binding sites and substrates for matrix metalloproteinases (MMP) was required to render the networks degradable and invasive by cells via cell-secreted MMPs. Degradation of gels was engineered starting from a characterization of the degradation kinetics (k(cat) and K(m)) of synthetic MMP substrates in the soluble form and after crosslinking into a 3D hydrogel network. Primary human fibroblasts were demonstrated to proteolytically invade these networks, a process that depended on MMP substrate activity, adhesion ligand concentration, and network crosslinking density. Gels used to deliver recombinant human bone morphogenetic protein-2 to the site of critical defects in rat cranium were completely infiltrated by cells and remodeled into bony tissue within 4 wk at a dose of 5 microg per defect. Bone regeneration was also shown to depend on the proteolytic sensitivity of the matrices. These hydrogels may be useful in tissue engineering and cell biology as alternatives for naturally occurring extracellular matrix-derived materials such as fibrin or collagen.

Fundamental studies of biodegradable hydrogels as cartilage replacement materials.

Through intelligent control of monomer chemistry and gelling techniques, biodegradable hydrogels with a range of mechanical strengths and degradation timescales have been constructed. A diacrylated, copoly(ethylene glycol-b-dl-lactic acid) (PEG-b-PLA) macromer was used to produce synthetic networks with equilibrium water contents (EWC) above 70% and initial compressive moduli values exceeding 1 MPa, demonstrating its viability as a cartilage replacement material. Experiments have shown that the mechanical strengths, EWCs, and useful lifetimes of these water-swellable networks are coupled to their copolymer chemistry as well as their processing conditions. A systematic study utilizing photopolymerized gels has been undertaken to elucidate the controlling factors behind the bulk-degradation process, as well as monitor changes in network structure with degradation. A statistical model will be used in conjunction with the experimental data to explain the exponential modulus decay and complex mass loss behavior observed during degradation for these hydrogels.