Using Chemistry To Recreate the Complexity of the Extracellular Matrix: Guidelines for Supramolecular Hydrogel–Cell Interactions

Abstract

Hydrogels have emerged as a promising class of extracellular matrix (ECM)-mimicking materials in regenerative medicine. Here, we briefly describe current state-of-the-art of ECM-mimicking hydrogels, ranging from natural to hybrid to completely synthetic versions, giving the prelude to the importance of supramolecular interactions to make true ECM mimics. The potential of supramolecular interactions to create ECM mimics for cell culture is illustrated through a focus on two different supramolecular hydrogel systems, both developed in our laboratories. We use some recent, significant findings to present important design principles underlying the cell−material interaction. To achieve cell spreading, we propose that slow molecular dynamics (monomer exchange within fibers) is crucial to ensure the robust incorporation of cell adhesion ligands within supramolecular fibers. Slow bulk dynamics (stress−relaxation�fiber rearrangements, τ 1/2 ≈ 1000 s) is required to achieve cell spreading in soft gels (<1 kPa), while gel stiffness overrules dynamics in stiffer gels. Importantly, this resonates with the findings of others which specialize in different material types: cell spreading is impaired in case substrate relaxation occurs faster than clutch binding and focal adhesion lifetime. We conclude with discussing considerations and limitations of the supramolecular approach as well as provide a forward thinking perspective to further understand supramolecular hydrogel−cell interactions. Future work may utilize the presented guidelines underlying cell−material interactions to not only arrive at the next generation of ECM-mimicking hydrogels but also advance other fields, such as bioelectronics, opening up new opportunities for innovative applications.

Molecularly Engineered Supramolecular Thermoresponsive Hydrogels with Tunable Mechanical and Dynamic Properties

“…SLS experiments (Figure C) revealed a slightly angle-dependent Rayleigh ratio ( R ) at low angles, similar to the PNIPAM precursor, which was a random coil at 10 °C . Moreover, the Rayleigh ratio was much smaller as compared to BTA-EG 4 , forming micrometer-long fibers itself (Figure S7), , suggesting the formation of small aggregates for BTA-PNIPAM . DLS experiments with CONTIN fitting corroborated the presence of small nanostructures with a hydrodynamic diameter ( D h ) of ∼12 nm (Figure S8), while cryo-TEM confirmed the presence of spherical micellar structures with a diameter of ∼5–8 nm (Figure D).…”

“…Additionally, remodeling of the ECM is crucial for healthy morphogenesis of most organs, such as intestines and lungs. − This ECM degradation is mostly regulated through enzymes, like metalloproteases . Importantly, any discrepancy in ECM stiffness and dynamics might contribute to the development of diseases, like fibrosis − or cancer. − With the goal to better understand the influence of the mechanical and dynamic properties of the ECM on cellular behavior, many different material types have been developed as mimics of the ECM. − …”