There have been significant advances in the past decades toward the engineering of materials with biomimetic properties. In particular, hydrogels covalently cross-linked with protease degradable peptides have demonstrated the importance of protease mediated degradation for targeted therapeutic cargo delivery and controlling cell-material interactions. However, the incorporation of such degradation mechanisms into synthetic shear-thinning hydrogels has yet to be accomplished. Herein, we utilize supramolecular self-assembly mediated by the guest-host interaction of hyaluronic acid (HA) separately modified by adamantane (Ad) or cyclodextrin (CD) to form shear-thinning and self-healing hydrogels. In this design, Ad is bound to HA via a proteolytically degradable peptide tether (attached via Michael-addition of a cysteine residue in an Ad-terminated peptide with maleimide modified HA), enabling subsequent proteolytic degradation of the assembly. Upon mixing of the Ad-peptide modified HA and the CD modified HA, a supramolecular hydrogel was formed (G' ≈ 300 Pa at 1 Hz), which displayed shear-thinning (>80% viscosity reduction at 0.5 s-1) and near-instantaneous self-healing properties. Rational, selective modification of amino acid residues near the proteolytic site enabled control over peptide cleavage kinetics, specifically with either collagenases or MMP-2. Hydrogel degradation, mediated by a combination of stochastically governed erosion and proteolytic degradation, was influenced by peptide susceptibility to proteolysis both in vitro and in vivo (>2 fold difference at 3 weeks in vivo) when injected subcutaneously. This material system provides unique opportunities for therapeutic delivery (e.g., growth factors, cells) through facile material formation, ease of injection, and bioresponsive material degradation.
Keywords: degradable; hyaluronic acid; hydrogel; injectable; shear-thinning; supramolecular assembly.