In Silico Modeling of the Rheological Properties of Covalently Cross-Linked Collagen Triple Helices

Biomimetic hydrogels based on natural polymers are a promising class of biomaterial, mimicking the natural extra-cellular matrix of biological tissues and providing cues for cell attachment, proliferation, and differentiation. With a view to providing an upstream method to guide subsequent experimental design, the aim of this study was to introduce a mathematical model that described the rheological properties of a hydrogel system based on covalently cross-linked collagen triple helices. In light of their organization, such gels exhibit limited collagen bundling that cannot be described by existing fibril network models. The model presented here treats collagen triple helices as discrete semiflexible polymers, permits full access to metrics for network microstructure, and should provide a comprehensive understanding of the parameter space associated with the development of such multifunctional materials. Triple helical hydrogel networks were experimentally obtained via the reaction of type I collagen with both aromatic and aliphatic diacids. The complex modulus G* was found from rheological testing in linear shear and quantitatively compared to model predictions. In silico data from the computational model successfully described the experimental trends in hydrogel storage modulus with either (i) the concentration of collagen triple helices during the cross-linking reaction or (ii) the type of cross-linking segment introduced in resulting hydrogel networks. This approach may pave the way to a step change in the rational design of biomimetic triple helical collagen systems with controlled multifunctionality.