Hydrogel Formation with Enzyme-Responsive Cyclic Peptides.

Self-assembling peptides (SAPs), which form hydrogels through physical cross-linking of soluble structures, are an intriguing class of materials that have been applied as tissue engineering scaffolds and drug delivery vehicles. For feasible application of these tissue mimetics via minimally invasive delivery, their bulk mechanical properties must be compatible with current delivery strategies. However, injectable SAPs which possess shear-thinning capacity, as well as the ability to reassemble after cessation of shearing can be technically challenging to generate. Many SAPs either clog the high-gauge needle/catheter at high concentration during delivery or are incapable of reassembly following delivery. In this chapter, we provide a detailed protocol for topological control of enzyme-responsive peptide-based hydrogels that enable the user to access both advantages. These materials are formulated as sterically constrained cyclic peptide progelators to temporarily disrupt self-assembly during injection-based delivery, which avoids issues with clogging of needles and catheters as well as nearby vasculature. Proteolytic cleavage by enzymes produced at the target tissue induces progelator linearization and hydrogelation. The scope of this approach is demonstrated by their ability to flow through a catheter without clogging and activated gelation upon exposure to target enzymes.