All tissues in the body consist of multiple cells types that work together to perform biological functions. However, the majority of matrices used in biomaterials are optimized for only a single cell type. To more fully recapitulate the in vivo environment, biomaterials will need to be developed that can respond differently to the various cell types that exist within a tissue. This is especially true for injury sites, where the local inflammatory response and immune cell infiltration plays an important role in regenerative processes. There are many differences cell types, but enzymes are an especially useful tool for material design since they perform a chemical function. Proteases have been used extensively in biomaterials, but almost exclusively for degrading matrices for cell migration. In this work, we utilize proteases to create reactive groups which will form cross-links after cleavage from specific cell-secreted proteases.1 We used peptide sequences which generate an N-terminal cysteine after enzymatic cleavage (Figure 1A). These cysteines, but not cysteines within the peptide sequences, will react with a cyanobenzothiazole (CBT) moiety to form a new crosslink (Figure 1B). By creating materials in which crosslinks form from proteases secreted by specific cells we can use proteolytic activity to prevent cells from migrating in these hydrogels.