Incorporating Hierarchical Structure into Hydrogels with Bioinspired Peptoid Polymers

Tissue engineering offers great promise as a therapy for damaged tissues, a replacement for whole organs, or a platform for drug screening; however, many synthetic biomaterial scaffolds do not replicate the complexity of the natural extracellular matrix, especially with regard to sequence-specific bioactivity and hierarchical structure. Hence, our work aims to bridge this gap using a bioinspired polymer in synthetic hydrogel scaffolds. Specifically, peptoids are non-natural polymers composed of N-substituted glycines, which preserve the monomer level structure and hierarchical chain order of biopolymers. Using synthetic peptoid crosslinkers, we achieved control over two key properties of hydrogels: 1) bulk mechanics and 2) enzymatic degradability. We controlled hydrogel mechanics by varying peptoid chain stiffness, in a fashion reminiscent of semiflexible biopolymers. Specifically, helical peptoids increased the shear moduli of hydrogels due to increased chain stiffness as compared to non-helical peptoids, while keeping all other hydrogel parameters fixed. These changes in mechanics impacted the amount of secreted factors from encapsulated stem cells, such as indoleamine 2,3-dioxygenase (IDO). Furthermore, we examined the ability of peptoids to tune hydrogel degradability via proteolysis. We substituted peptoids into key sites of proteolytically degradable substrates, enabling a tailored material response to matrix metalloproteinases secreted by cells. Overall, our results suggest that sequence control of synthetic peptoids may provide effective strategies for expanding the functionality of biomaterial scaffolds for tissue engineering, particularly with respect to mechanics and degradation in complex biological environments.