Notwithstanding the efforts injected in vascular tissue engineering in the past 30 years, the clinical translation of engineered artery constructs is far from being successful. One common approach to improve artery regeneration is the use of cyclic mechanical stimuli to guide cellular remodeling. However, there is a lack of information on the effect of cyclic strain on cells within a 3D environment. To this end, this work explored the effect of gradual increase in stimulation frequency on the response of human umbilical artery smooth muscle cells (HUASMCs) embedded in a 3D collagen matrix. The results demonstrate that, with an applied strain of 5%, the gradual increase of frequency from 0.1 to 1 Hz improved collagen remodeling by HUASMCs compared to samples constantly stimulated at 1 Hz. The expression of collagen, elastin and matrix metalloproteinase-2 (MMP-2) genes was similar at 7 days for gradual and 1 Hz samples which showed lower amounts than static counterparts. Interestingly the mechanical properties of the constructs, specifically the amplitude of the time constants and the elastic equilibrium modulus, were enhanced by gradual increase of frequency. Taken together, these results show an increase in collagen remodeling by the HUASMCs overtime under incremental cyclic mechanical strain. This work suggests that only the in-depth investigation of the effects of stimulation parameters on the behavior of vSMC under cyclic strain in a 3D environment could lead to the design of optimized control strategies for enhanced vascular tissue generation and maturation in bioreactors.
Keywords: 3D construct; bioreactor; collagen-cell based construct; desensitization; increase frequency; smooth muscle cells.