Poroviscoelasto-plasticity of agarose-based hydrogels

Agarose gels are excellent candidates for tissue engineering as they are tunable, viscoelastic, and show a pronounced strain-stiffening response. These characteristics make them ideal to create in vitro environments to grow cells and develop tissues. As in many other biopolymers, viscoelasticity and poroelasticity coexist as time-dependent behaviors in agarose gels. While the viscoelastic behavior of these hydrogels has been considered using both phenomenological and continuum models, there remains a lack of connection between the underlying physics and the macroscopic material response. Through a finite element analysis and complimentary experiments, we evaluated the complex time-dependent mechanical response of agarose gels in various conditions. We then conceptualized these gels as a dynamic network where the global dissociation/association rate of intermolecular bonds is described as a combination of a fast rate native to double helices forming between aligned agarose molecules and a slow rate of the agarose molecules present in the clusters. Using the foundation of the transient network theory, we developed a physics-based constitutive model that accurately describes agarose behavior. Integrating experimental results and model prediction, we demonstrated that the fast dissociation/association rate follows a nonlinear force-dependent response, whose exponential evolution agrees with Eyring's model based on the transition state theory. Overall, our results establish a more accurate understanding of the time-dependent mechanics of agarose gels and provide a model that can inform design of a variety of biopolymers with a similar network topology.