Engineering Vascular Bioreactor Systems to Closely Mimic Physiological Forces .

models of the vasculature play an important role in biomedical discovery research, with diverse applications in vascular biology, drug discovery, and tissue engineering. These models aim to replicate the conditions of the human vasculature including physical geometry, employing appropriate vascular cells exposed to physiological forces. However, vessel biology is complex, with multiple relevant cell types, precise three-dimensional (3D) architectural arrangement, an array of biological cues and pressure, flow rate, and shear stress stimulation that are difficult to replicate outside of the body. Vessel bioreactors typically comprise core modules, common to most systems: a 3D tubular scaffold to support cells, media and nutrient exchange for cell viability, a pumping module, and sensor arrays for monitoring. In our comprehensive review of the literature, foundational elements such as maintenance of cell viability, nutrient exchange with flow, use of 3D scaffolds, and basic sensing capabilities are well established. However, most bioreactor systems fail to adequately replicate combinations of physiologically relevant stimuli-including pressure, shear stress, and flow rate-independently, as system input parameters. At the root of this deficiency is the field's reliance on simple pumping systems designed for other applications, making it necessary to add resistors and compliance chambers to even approach human vascular conditions. As vascular biology research rapidly progressed it became increasingly clear that combinations of physical forces strongly influence cell phenotype, gene expression, and in turn can be drivers of pathology. We highlight the need for renewed innovation in vascular bioreactor development with a focus on the importance of providing appropriate physiological forces in the same system. Impact statement systems modeling aspects of the human vasculature are increasingly important in tissue engineering and biomedical research. Current systems maintain basic cell viability and facilitate nutrient exchange but poorly replicate physiological forces, reliant on simplistic pumping systems. Our review highlights the need to more accurately mimic arterial pressure, flow rate, and shear stress in the same system. Innovation in this area would improve modeling of the vasculature, significantly impacting tissue engineering and vascular biology in this area.