Efforts in the past decade have revealed that hydrogels with faster matrix stress-relaxation promotes mesenchymal stem cell (MSC) spreading. For example, alginate-based hydrogels provide tissue-like stress-relaxation useful for studying the impact of matrix viscoelasticity and integrin ligand (e.g., RGD peptide) density on cell fate processes. However, the use of divalent cations to crosslink alginate may inadvertently affect intracellular signaling. Nonetheless, the effect of matrix viscoelasticity on pancreatic cancer cell fate remains elusive. We have recently reported semi-interpenetrating viscoelastic hydrogels composed of gelatin-norbornene-boronate, poly(ethylene glycol)-tetra-thiol (PEG4SH), and poly(vinyl alcohol) (PVA). Immobilized BA groups readily complexed with 1,3-diols on the entrapped PVA, resulting in hydrogels with independently tunable stiffness and stress-relaxation. However, the GelNB-BA/PVA-based hydrogels did not provide fast relaxation time scale to match that of pancreatic stromal tissues. The goal of this work is to prepare a new synthetic hydrogel system with tunable elasticity and fast relaxation. We employed reversible addition-fragmentation chain-transfer (RAFT) polymerization to synthesize poly(oligo(ethylene glycol) methyl ether acrylate-co-hydroxyethyl acrylate-co-acrylamidophenylboronic acid (PEHA) that has pendant BA group for boronate-diol bonding with diol-containing polymer. We further conjugated norbornene (NB) to PEHA, rendering a PEHNBA macromer susceptible to thiol-norbornene hydrogel crosslinking. Using RAFT polymerization, we also synthesized poly(hydroxyethyl acrylate)-dopamine (PHD), a linear polymer that presents 1,2-diols for complexing with BA groups on PEHNBA. Using PEHNBA, thiolated gelatin, and PHD, we designed hydrogels with highly tunable storage moduli (G’) and degree of stress-relaxation. The new viscoelastic hydrogels were used to elucidate the profound impact of matrix mechanics and stromal-cancer cell interactions on invasion of cancer cells into matrix.

Fast relaxing RAFT polymer hydrogels formed by thiol-ene photo-click chemistry and boronate-diol bonding

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