Gradient-on-a-Chip with Reactive Oxygen Species Reveals Thresholds in the Nucleus Response of Cancer Cells Depending on the Matrix Environment

Shirisha Chittiboyina; Rahim Rahimi; Farzaneh Atrian; Manuel Ochoa; Babak Ziaie; Sophie A Lelièvre

doi:10.1021/acsbiomaterials.7b00087

Gradient-on-a-Chip with Reactive Oxygen Species Reveals Thresholds in the Nucleus Response of Cancer Cells Depending on the Matrix Environment

ACS Biomater Sci Eng. 2018 Feb 12;4(2):432-445. doi: 10.1021/acsbiomaterials.7b00087. Epub 2017 Jun 29.

Authors

Shirisha Chittiboyina¹, Rahim Rahimi^{2

3}, Farzaneh Atrian¹, Manuel Ochoa^{2

3}, Babak Ziaie^{2

3

4}, Sophie A Lelièvre^{1

3

4}

Affiliations

¹ Department of Basic Medical Sciences, 625 Harrison Street, Purdue University, West Lafayette, Indiana 47907, United States.
² Department of Electrical and Computer Engineering, 465 Northwestern Avenue, Purdue University, West Lafayette, Indiana 47907, United States.
³ Birck Nanotechnology Center, Purdue University, 1205 W State Street, Purdue Discovery Park, West Lafayette, Indiana 47907, United States.
⁴ Purdue University Center for Cancer Research, Purdue University, 201 South University Street, West Lafayette, Indiana 47907, United States.

PMID: 33418734
DOI: 10.1021/acsbiomaterials.7b00087

Abstract

Oxidative stress-mediated cancer progression depends on exposure to reactive oxygen species (ROS) in the extracellular matrix (ECM). To study the impact of ROS levels on preinvasive breast cancer cells as a function of ECM characteristics, we created a gradient-on-a-chip in which H₂O₂ progressively mixes with the cell culture medium within connected microchannels and diffuses upward into the ECM of the open cell culture window. The device utilizes a paper-based microfluidic bifurcating mixer insert to prevent leakage and favor an even fluid distribution. The gradient was confirmed by measuring H₂O₂ catalyzed into oxygen, and increasing oxidative DNA damage and protective (AOP2) response were recorded in 2D and ECM-based 3D cell cultures. Interestingly, the impact of ROS on nuclear shape and size (annunciating phenotypical changes) was governed by the stiffness of the collagen I matrix, suggesting the existence of thresholds for the phenotypic response to microenvironmental chemical exposure depending on ECM conditions.

Keywords: 3D cell culture; DNA damage; cancer progression; cell nucleus; nuclear morphology; oxidative stress.