Replicating endothelial shear stress in organ-on-a-chip for predictive hypericin photodynamic efficiency

Photodynamic therapy using Hypericin (Hy-PDT) is an alternative non-invasive treatment that enables selective tumor inhibition and angiogenesis derived from the differential recruitment of endothelial cells in the tumor microenvironment. Most PDT studies were performed on in vitro models without vascular biomechanical simulation. Our work strives to develop a microchip that generates a constant shear stress force to investigate the Hy-PDT efficiency on human umbilical vein endothelial cells (HUVECs). The microchip with a single straight microchannel was composed of the bottom layer (polystyrene), the middle layer (double-sided biocompatible adhesive tape), and the top layer (polyester film) and could produce shear stress in the range of 1.4 - 7.0 dyn cm^-2. The quantification of vascular endothelial growth factor (VEGF), cell viability, and activities of caspases 3 and 7 were assayed to validate the microchip and Hy-PDT efficacy. After the endothelization, static and dynamic cell incubations with Hy were conducted in microchips. Compared to static systems, the shear stress displayed its effect on the increasing release of VEGF and promoted more cell damage and cell death via necrosis during Hy-PDT. In conclusion, the expressive shear stress-dependent manner during PDT treatments suggests that the microchip could be an essential approach in preclinical tests to evaluate the therapeutic outcome considering the endothelial shear stress microenvironment.