Enzyme-Responsive Materials for Regenerative Medicine

In living materials, the tissue-level structure is constantly being remodeled through the molecular action of cell-secreted enzymes. Bioactive materials have been designed previously to respond to these enzymes through cleavage of individual molecular bonds. However, the resulting changes in the tissue-level material architecture has been underappreciated as a potential material design parameter that can impact cell function. Combining our experimental measurements of chemical reaction rates with a simple model of percolation network theory, we were able to accurately predict how tissue-level network structure evolves in an engineered biomaterial over time. We then demonstrated that encapsulated human endothelial cells respond to these tissue-level structural changes by forming vascular-like networks. In another example of molecular-level design enabling control of tissue-level structure and cell biology, we engineered a material for proliferating neural stem cells. Upon encapsulation, neural stem cells only maintained their stem-like behavior if they could sufficiently remodel the material through the action of a cell-produced enzyme. We further demonstrated that neural stem cell differentiation into more mature cell types is also dependent on tissue-level structure. Thus, this body of work has introduced material remodeling and tissue-level structural dynamics as key design criteria for the field of biomaterials.