Construction of oxygen and chemical concentration gradients in a single microfluidic device for studying tumor cell–drug interactions in a dynamic hypoxia microenvironment

Abstract

Recent microfluidic advancements in oxygen gradients have greatly promoted controllable oxygen-sensitive cellular investigations at microscale resolution. However, multi-gradient integration in a single microfluidic device for tissue-mimicking cell investigation is not yet well established. In this study, we describe a method that can generate oxygen and chemical concentration gradients in a single microfluidic device via the formation of an oxygen gradient in a chamber and a chemical concentration gradient between adjacent chambers. The oxygen gradient dynamics were systematically investigated, and were quantitatively controlled using simple exchange between the aerial oxygen and the oxygen-free conditions in the gas-permeable polydimethylsiloxane channel. Meanwhile, the chemical gradient dynamics was generated using a special channel-branched device. For potential medical applications of the established oxygen and chemical concentration gradients, a tumor cell therapy assessment was performed using two antitumor drugs (tirapazamine and bleomycin) and two tumor cell lines (human lung adenocarcinoma A549 cells and human cervical carcinoma HeLa cells). The results of the proof-of-concept experiment indicate the dose-dependent antitumor effect of the drugs and hypoxia-induced cytotoxicity of tirapazamine. We demonstrate that the integration of oxygen and chemical concentration gradients in a single device can be applied to investigating oxygen- and chemical-sensitive cell events, which can also be valuable in the development of multi-gradient generating procedures and specific drug screening.

Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment

“…These results demonstrate the importance of oxygen concentration as well as the pH level in the microenvironment to regulate the migration potential of cancer cells. Other two-dimensional microdevices can create stable oxygen gradients generated by oxygen scavengers, which become very useful to screen for cell survival and drug response under different oxygen concentrations [66,138,140,142] (figure 4a).…”

High-throughput screening approaches and combinatorial development of biomaterials using microfluidics

“…Wang et al [84] integrated oxygen and chemical concentration gradients in a single device to assess the efficiency of antitumor drugs tirapazamine and bleomycin on human lung adenocarcinoma A549 cells and human cervical carcinoma HeLa cells. The authors demonstrated a dose-dependent viability decrease induced by the drugs, and a hypoxia-induced cytotoxicity of tirapazamine.…”

Uniform Cell Distribution Achieved by Using Cell Deformation in a Micropillar Array

“…In the biological field, the advantages of the microfluidic device are as follows: (1) easy manipulation of cells owing to device dimensions comparable to the size of the cells, (2) multiple processing capacity on a single device, (3) the ability to manipulate single cells, and (4) well-controlled conditions because of the laminar flow [1,2]. By using such advantages, many biological devices-such as a cell observation device under well-controlled conditions [3], a cell sorting device [4], a single cell analysis device [5], and a cell interaction analyser [6]-have been developed.…”