A key attribute missing from current state-of-the-art biomaterials is the ability to be remodeled by the host after implantation. In contrast, the natural extracellular matrix (ECM) is constantly being remodeled by proteases secreted from cells in response to local environmental changes. Mimicking this strategy, we have designed a new protein-based scaffold that can be degraded and remodeled on demand by the growth cones of regenerating neurites. Using recombinant protein techniques, we synthesized a family of biodegradable and biologically active scaffold materials. The scaffolds include peptide sequences derived from natural ECM proteins. Interspersed with these ECM domains are proteolytic sequences readily degraded by tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), two proteases secreted by the growth cones of extending neurites. By altering the primary amino acid sequences of the protease cleavage domains, we can tune the degradation rates of otherwise identical engineered proteins in a controlled and predictable manner over approximately two orders of magnitude. These recombinant proteins are crosslinked to form bulk, protein-based scaffolds with mechanical properties that can be tuned to match that of the spinal cord. Initial cell experiments have shown that the proteins support growth and differentiation of the model PC-12 neuronal-like cell line. By tailoring the scaffold degradation rate to the tPA and uPA secretion levels of specific neuronal populations, we aim to fabricate a scaffold that will promote neurite extension through the matrix by allowing local degradation to occur specifically around the neuronal growth cone while maintaining the bulk integrity of the overall scaffold.