Development of Peptoid-Based Materials to Control Hydrogel Mechanics and Degradation in Artificial Extracellular Matrices

Hydrogels have garnered intense interest as artificial extracellular matrices due to their tailorable permeability, mechanics, and degradability. Synthetic materials are attractive due to their known chemical compositions and reproducibility, but the challenge with their use lies in the lack of complexity as compared to biological systems, especially with regard to sequence-specific bioactivity. Sequence-controlled synthetic biomaterials offer a platform to mimic the bioactivity of natural matrices while engineering properties by design (e.g., enhanced biostability, reduced cross-reactivity, etc.). Peptoids, or N-substituted glycines, are peptidomimetics with sidechains affixed to the amide backbone nitrogen, rather than the α-carbon. Peptoids can be synthesized with full sequence definition using the submonomer technique, which affords incorporation of any sidechain available as a primary amine. Thus, peptoids provide a versatile non-natural platform for advancing biomaterials. Using peptoid crosslinkers, we achieved control over the mechanics of hydrogel platforms by varying monomer sequence and chain structure, in a fashion reminiscent of semiflexible biopolymers. Specifically, peptoid helicity increased the shear moduli of hydrogels due to increased chain stiffness as compared to non-helical peptoids, while keeping hydrogel network connectivity and swelling ratio fixed. Furthermore, we examined the ability of non-natural peptoid monomers to tune material degradation as well. Beginning with a consensus sequence for collagenases, we incorporated systematic peptoid substitutions to modulate substrate recognition and degradation rate, leading to sequences with increased selectivity for matrix metalloproteinases against serum-containing media. Overall, our results suggest that sequence control of synthetic peptoids may expand the functionality of hydrogel scaffolds for tissue engineering and regenerative medicine, particularly with respect to mechanics and degradation in complex biological environments.