Activating physical crosslinking in synthetic extracellular matrices by switch peptides

Cells in the body are encapsulated in a complex network of proteins and polysaccharides called the extracellular matrix (ECM), which has a vital role in regulating cell behavior. To study the processes by which cells receive, process, and exchange information with the ECM, materials that mimic certain specific properties of the ECM are needed. A critical ECM property that remains difficult to precisely control is its Viscoelastic properties, i.e., its response to mechanical stress over time.

Cryptic sites are signaling peptides (small natural molecules) buried within the ECM network that are revealed upon enzymatically triggered rearrangements of proteins. Control over Viscoelastic properties is one role of natural cryptic sites, where changes can influence various physio- pathological processes, including wound healing, inflammation, and tumor growth, among others. Synthetic materials capable of mimicking the process by which cryptic sites are exposed, and influence viscoelasticity will promote our understanding of dynamic processes taking place in the natural ECM.

Two types of versatile hydrogel platforms, comprised of either a linear polymer or a more complex polymer architecture called a bottlebrush polymer, form the basis of the proposed hydrogels. They will be lightly chemically crosslinked before addition of “switch peptides,” which are designed to undergo an enzyme-triggered structural change. Upon enzymatic action, the switch peptides will rearrange to form sequences that have a tendency to self-assemble in a dynamic manner, creating secondary physical crosslinks that change the viscoelasticity of the hydrogel.

Overall, understanding the connections between enzyme-triggered peptide rearrangements and changes in the physical properties of these hydrogels, combined with their interactions with cells, will open new directions in the field of cell-responsive hydrogels.