Mechanical Stimulation Induces Capillary Alignment in a Fibrin-Based .

Generation of bioartificial blood vessels with a physiological three-layered wall architecture is a long pursued goal in vascular tissue engineering. While considerable advances have been made to resemble the physiological and morphology and function in bioartificial vessels, only very few studies have targeted the generation of a , including its characteristic vascular network known as the which are essential for graft nutrition and integration. In healthy native blood vessels, capillary are aligned longitudinally to the vessel axis. Thus, inducing longitudinal alignment of capillary tubes to generate a physiological morphology and function may be advantageous in bioengineered vessels as well. In this study, we investigated the effect of two biomechanical stimulation parameters, longitudinal tension and physiological cyclic stretch, on tube alignment in capillary networks formed by self-assembly of human umbilical vein endothelial cells in equivalents of fibrin-based bioartificial blood vessels. Moreover, the effect of changes of the biomechanical environment on network remodeling after initial tube formation was analyzed. Both, longitudinal tension and cyclic stretch by pulsatile perfusion induced physiological capillary tube alignment parallel to the longitudinal vessel axis. This effect was even more pronounced when both biomechanical factors were applied simultaneously, which resulted in an alignment of 57.2 ± 5.2% within 5° of the main vessel axis. Opposed to that, a random tube orientation was observed in vessels incubated statically. Scanning electron microscopy showed that longitudinal tension also resulted in longitudinal alignment of fibrin fibrils, which may function as a guidance structure for directed capillary tube formation. Moreover, existing microvascular networks showed distinct remodeling in response to addition or withdrawal of mechanical stimulation with corresponding increase or decrease of the degree of alignment. With longitudinal tension and cyclic stretch, we identified two mechanical stimuli that facilitate the generation of a prevascularized -equivalent with physiological tube alignment in bioartificial vascular grafts. Impact statement Fibrin-based bioartificial vessels represent a promising regenerative approach to generate vascular grafts with superior biocompatibility and hemocompatibility compared to currently available synthetic graft materials. Precapillarization of bioartificial vascular grafts may improve nutrition of the vessel wall and integration of the graft into the target organism's microvasculature. In native vessels, physiological alignment is pivotal for proper function of the . Thus, it is necessary to induce longitudinal capillary alignment in the of bioengineered vessels as well to secure long-term graft patency and function. This alignment can be reliably achieved by controlled biomechanical stimulation .