A microfluidic device inspired by leaky tumor vessels for hematogenous metastasis mechanism research

Abstract

Endothelial intercellular pores of tumor vessels generally lead to enhanced interstitial flow and may facilitate the migration of tumor cells. The permeability of tumor vessels causes a concentration gradient of growth factors (CGGF) from blood vessels to tumor tissues, which is opposite to the direction of interstitial flow. In this work, exogenous chemotaxis under the CGGF is demonstrated as a mechanism of hematogenous metastasis. A bionic microfluidic device inspired by endothelial intercellular pores of tumor vessels has been designed to study the mechanism. A porous membrane vertically integrated into the device using a novel compound mold is utilized to mimic the leaky vascular wall. The formation mechanism of the CGGF caused by endothelial intercellular pores is numerically analyzed and experimentally verified. The migration behavior of U-2OS cells is studied in the microfluidic device. The device is divided into three regions of interest (ROI): primary site, migration zone, and tumor vessel. The number of cells in the migration zone increases significantly under the CGGF, but decreases under no CGGF, indicating tumor cells may be guided to the vascellum by exogenous chemotaxis. Transendothelial migration is subsequently monitored, demonstrating the successful replication of the key steps in vitro in the metastatic cascade by the bionic microfluidic device.