Resorbable synthetic scaffolds designed to regenerate living tissues and organs inside the body have emerged as a clinically attractive technology to replace diseased blood vessels. However, mismatches between scaffold design and in vivo hemodynamic loading (i.e., cyclic stretch and shear stress) can result in aberrant inflammation and adverse tissue remodeling, leading to premature graft failure. Yet, the underlying mechanisms remain elusive. Here, a human in vitro model is presented that mimics the transient local inflammatory and biomechanical environments that drive scaffold‐guided tissue regeneration. The model is based on the coculture of human (myo)fibroblasts and macrophages in a bioreactor platform that decouples cyclic stretch and shear stress. Using a resorbable supramolecular elastomer as the scaffold material, it is revealed that cyclic stretch initially reduces proinflammatory cytokine secretion and, especially when combined with shear stress, stimulates IL‐10 secretion. Moreover, cyclic stretch stimulates downstream (myo)fibroblast proliferation and matrix deposition. In turn, shear stress attenuates cyclic‐stretch‐induced matrix growth by enhancing MMP‐1/TIMP‐1‐mediated collagen remodeling, and synergistically alters (myo)fibroblast phenotype when combined with cyclic stretch. The findings suggest that shear stress acts as a stabilizing factor in cyclic stretch‐induced tissue formation and highlight the distinct roles of hemodynamic loads in the design of resorbable vascular grafts.
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