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 (kcat and Km) 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 g 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. extracellular matrix ͉ biomaterials ͉ proteolytic degradation A dvances in the field of tissue engineering are connected to the performance of biomaterials that help in guiding tissue formation or regeneration. Design principles in biomaterials have typically been influenced by the function of the extracellular matrix (ECM). Because the ECM has been demonstrated to play a key role in signal transduction (1-3), the development of materials that can specifically and molecularly interact with cells has become an emerging area of research (4, 5). The regulation of cell behavior through receptor-mediated adhesion [e.g., by functionalizing materials with integrin-binding oligopeptides (6, 7)] and by growth factors (8) has thus been targeted.We and others have been focusing on the development of synthetic materials that are targeted to assist tissue regeneration (9-11). Placed at the site of a defect, such materials should actively and temporarily participate in the regeneration process by providing a platform on which cell-triggered remodeling could occur. Consequently, these matrices must display some key characteristics of the provisional ECM. One of the critical initial functions of the fibrin-rich network that fills tissue defects after trauma, almost regardless of the injury site, lies in its ability to foster the invasion of inflammatory cells. These cells then initiate the remodeling process by partially degrading the matrix and by secreting molecular signals for attraction and differentiation of other cell types such as fibroblasts that build up new ECM (12). Because the provisional ECM presents itself in such situations often as a biophysical barrier to these cells, invasion and remodeling depend on the action of cell-secreted proteases enabling cell migration by clearing of a path (13,14). Thereby, matrix met...

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