Straining mode-dependent collagen remodeling in engineered cardiovascular tissue.

Similar to native cardiovascular tissues, the mechanical properties of engineered cardiovascular constructs depend on the composition and quality of the extracellular matrix, which is a net result of matrix remodeling processes within the tissue. To improve tissue remodeling, and hence tissue mechanical properties, various mechanical conditioning protocols, such as strain-based or flow-based conditioning, have been applied to engineered cardiovascular constructs with promising results. We hypothesize that tissue remodeling is dependent on the mode of straining. Therefore, the effects of two modes of straining, being either static or dynamic, were quantified on several indices of tissue remodeling. Differences in matrix composition (collagen and glycosaminoglycans [GAGs]) and maturity (collagen cross-links) were quantified with time on gene expression and protein levels. In addition, the secretion of specific collagen remodeling markers (matrix metalloproteinase-1), collagen synthesis marker (procollagen type I carboxy-terminal propeptide, PIP), and collagen degradation marker (carboxyterminal telopeptide of type I, ICTP) was investigated with time. Static strain stimulated collagen gene expression and production with time. Dynamic straining resulted in (1) lower collagen gene expression and production, but (2) enhanced collagen cross-link expression and density, and GAG production, and (3) stimulated collagen remodeling processes, as expressed by enhanced production of remodeling markers. Thus, despite a lower collagen production, the quality of the neotissue was enhanced by a dynamic straining component. These straining mode-dependent remodeling responses allow us for the first time to balance collagen and cross-link production and, thus, to fine tune tissue mechanical properties via mechanical conditioning protocols. This is of utmost importance for cardiovascular tissue engineering, where insufficient mechanical properties are currently a main limiting factor for present in vivo application.