A Biomimetic Microfluidic Tumor Microenvironment Platform Mimicking the EPR Effect for Rapid Screening of Drug Delivery Systems

Abstract

Real-time monitoring of tumor drug delivery in vivo is a daunting challenge due to the heterogeneity and complexity of the tumor microenvironment. In this study, we developed a biomimetic microfluidic tumor microenvironment (bMTM) comprising co-culture of tumor and endothelial cells in a 3D environment. The platform consists of a vascular compartment featuring a network of vessels cultured with endothelial cells forming a complete lumen under shear flow in communication with 3D solid tumors cultured in a tumor compartment. Endothelial cell permeability to both small dye molecules and large liposomal drug carriers were quantified using fluorescence microscopy. Endothelial cell intercellular junction formation was characterized by immunostaining. Endothelial cell permeability significantly increased in the presence of either tumor cell conditioned media (TCM) or tumor cells. The magnitude of this increase in permeability was significantly higher in the presence of metastatic breast tumor cells as compared to non-metastatic ones. Immunostaining revealed impaired endothelial cell-cell junctions in the presence of either metastatic TCM or metastatic tumor cells. Our findings indicate that the bMTM platform mimics the tumor microenvironment including the EPR effect. This platform has a significant potential in applications such as cell-cell/cell-drug carrier interaction studies and rapid screening of cancer drug therapeutics/carriers.

Elucidating the Influences of Size, Surface Chemistry, and Dynamic Flow on Cellular Association of Nanoparticles Made by Polymerization‐Induced Self‐Assembly

“…After 24 h, a complete and confluent layer of HUVECs was observed by both bright field and confocal microscopy (Figure B,C). It has been demonstrated that endothelial cells cultured under such flow conditions have similar morphology and function to that observed in vivo . To further verify the complete formation of a 3D lumen of HUVECs on the top, bottom, and side of the microchannels, an Eclipse TiE Microscope with a Nikon A1R Confocal was utilized to acquire a 3D Z‐stack of the synthetic vessels.…”

“…After the microfluidic chip was successfully coated with HUVECs, nanoparticle suspension in EGM (at 37 °C) was introduced into the SMN at a flow rate of 1.0 µL min −1 . This flow rate was selected to create a physiological shear rate range (from ≈30 to ≈240 s −1 ) found in vivo . After 4 h, chilled 4‐(2‐hydroxyethyl)‐1‐piperazineethanesulfonic acid (HEPES) buffered saline solution (HBSS) was injected to remove non‐associated nanoparticles from the microchannels before HUVECs were collected for analysis by flow cytometry.…”

“…Mitragotri and co‐workers have employed these SMNs to explore the effects of nanoparticle shape and flow on targeting antibody‐coated nanoparticles to lung and brain endothelium . Moreover, variants of the SMN have been developed which incorporate both a SMN and a tumor region, thus allowing rapid screening of cancer drug delivery systems . So far, these realistic SMNs have been employed to investigate the effect of only single physicochemical property of polymeric nanomaterials (e.g., size or surface chemistry alone) on nano–bio interactions under flow conditions.…”

Recent Advances in Microfluidic Platforms Applied in Cancer Metastasis: Circulating Tumor Cells' (CTCs) Isolation and Tumor‐On‐A‐Chip

“…c) A biomimetic platform co‐culturing human breast tumor associated endothelial cells (HBTAEC) and MDA‐MB‐231 cancer cells in vascular and tumor compartments to analyze the permeability of endothelial cells. Reproduced with permission . Copyright 2017, Springer Nature Publishing AG.…”

Electroosmotic pumps with electrochemically active electrodes

“…tests under conditions that more closely resemble those found in vivo. 5 With careful design, these systems can also mimic the in vivo sheer stress of blood and cells in contact with blood flow, which allows them to function normally. [6][7][8] In the same way, care must be taken to avoid exposing cells to unwanted sheer stress as both cell morphology and physiology can be affected.…”