Differential Cellular Response to Linear and Strain Stiffening Hydrogel Substrates

The mechanical properties of the substrate upon which cells are cultured have been shown to influence a variety of cell properties including cell adhesion, spreading, protein expression and differentiation. The work presented here examines how the nonlinear mechanical properties of biopolymer gels affect the cellular responses to substrate stiffness. Cell spread area decreases with decreasing substrate stiffness when cells are cultured on linearly elastic polyacrylamide gels but display no spread area sensitivity when cultured on fibrin gels of various moduli. Fibrin gels, and other semiflexible biopolymer networks, exhibit strain stiffening, whereby the elastic modulus of the gel increases with increasing applied strain. Mechanosensitive cells and strain stiffening gels engage in a mechanical feedback loop with cells increasing their applied force and the gel modulus increasing as a result until the cells reach their maximum spread area. Cell applied forces locally induce anisotropy in an initially isotropic matrix providing a mechanism for cell/cell communication over a distance of ~5 cell lengths. This results in alignment of adjacent cells and formation of ring-like multicellular patterns. Finally, due in part to its mechanical properties, fibrin is an appealing scaffold for neural tissue repair. Initial animal studies confirm that salmon derived fibrin mitigates pain and inflammation after injury to the central nervous system