Building hierarchical structure into synthetic extracellular matrices with peptoid crosslinked hydrogels




Morton, Logan D.

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The extracellular matrix (ECM) plays a critical role in supporting cellular behavior and tissue function. It provides a complex and dynamic network of proteins and polysaccharides that regulate cell adhesion, migration, proliferation, and differentiation. Natural ECMs are highly organized and hierarchical in structure, with specific biochemical and mechanical properties that vary across different tissues and organs. Mimicking the complexity of natural ECMs in synthetic materials is a major challenge in tissue engineering and regenerative medicine. Synthetic hydrogels, which are water-swollen networks of polymer chains, have emerged as a leading technology in creating synthetic, biomimetic ECMs. However, synthetic hydrogels typically lack the hierarchical structure and biochemical complexity of natural ECMs, which limits their ability to support cell behavior and tissue function or to model complex disease states that are seen in vivo. To address this challenge, research is being conducted on incorporating hierarchical structure and biochemical complexity into synthetic hydrogels. Peptoids are a promising class of peptidomimetics that can be designed to mimic the biochemical and physical properties of natural peptides and proteins. They are highly modular, with a wide range of chemistries that can be used to control their physical and biological properties. Additionally, peptoids are highly stable and resistant to enzymatic degradation, with extremely stable secondary structures that mimic those of peptides, including α-helices, making them attractive for biomedical applications. Herein, we designed peptoids of different secondary structures (helical, nonhelical, and unstructured) with different persistence lengths to decouple stiffness from other properties of the synthetic ECM system. We investigated the relationship between this molecular rigidity and hydrogel stiffness, demonstrating that the stiffness of the hydrogels could be tuned by adjusting the peptoid sequence and length independent of properties like swelling and permeability. We also examine how this range of stiffness impacts cellular behavior, especially for human mesenchymal stem cell (hMSC) manufacturing. We found that all peptoid crosslinked hydrogels were viable cell culture platforms in 2- and 3-dimensional culture for hMSCs and that the stiffness range achieved was significant enough to impact cellular behavior, with hMSCs grown on softer substrates proliferating more, producing more immunosuppressive and regenerative cytokines, and substantially altering their morphology. This work demonstrates the potential of peptoid crosslinked hydrogels as versatile scaffolds for tissue engineering, regenerative medicine, and disease modeling due to their similarities to native ECM with decoupled stiffness and mesh size.


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