Immune Cell Responses to Fluid Shear: Overview and Design Considerations for

Fluid flow is ubiquitous throughout the immune system. Immune cells exhibit sensitivity to fluid shear stress, altering their activation and behavior in response to the presence, magnitude, and timing of fluid flow. Therefore, understanding how flow regulates the immune response is crucial for understanding the immune system's contribution to homeostasis, disease progression, and therapeutic interventions. Recent developments have indicated Piezo1, a mechanosensitive ion channel protein, is a crucial mechanism for cell sensing and response to shear, but our understanding of how shear impacts immune function is far from complete. Open questions including: how cells respond to acute vs chronic shear stress exposure, how shear influences cell-cell communication, and direct molecular mechanisms require further investigation. In vitro modeling provides one promising approach to fill this gap, and many systems have been recently developed that incorporate flow to investigate the immune response in model organs and disease states. This review discusses recent advances in our understanding of fluid shear stress's impact on immune cell behavior, and we provide a landscape of in vitro models integrating flow and immune cells. To guide future development, we evaluate five critical design considerations: flow directionality, channel cross-section, culture substrate, recirculation strategies, and TEER compatibility.