Abstract
Evidence continues to emerge that cancer is a disease not only of genetic mutations, but also of altered mechanobiological profiles of the cells and microenvironment. This mutation-independent element might be a key factor in promoting development and spread of cancer. Biomechanical forces regulate tumor microenvironment by solid stress, matrix mechanics, interstitial pressure, and flow. Compressive stress by tumor growth and stromal tissue alters cell deformation and recapitulates the biophysical properties of cells to grow, differentiate, spread, or invade. Such solid stress can be introduced externally to change the cell response and to mechanically induce cell lysis by dynamic compression. In this work, we report a microfluidic cell culture platform with an integrated, actively modulated actuator for the application of compressive forces on cancer cells. Our platform is composed of a control microchannel in a top layer for introducing external force and a polydimethylsiloxane (PDMS) membrane with monolithically integrated actuators. The integrated actuator, herein called micro-piston, was used to apply compression on SKOV-3 ovarian cancer cells in a dynamic and controlled manner by modulating applied gas pressure, localization, shape, and size of the micro-piston. We report fabrication of the platform, characterization of the mechanical actuator experimentally and computationally, and cell loading and culture in the device. We further show the use of the actuator to perform both repeated dynamic cell compression at physiological pressure levels and end point mechanical cell lysis, demonstrating suitability for mechanical stimulation to study the role of compressive forces in cancer microenvironments. Finally, we extend cell compression applications in our device to investigating mechanobiologically related protein and nuclear profiles in cyclically compressed cells.
Highlights
Extensive efforts have been made to study the role of gene mutations in cancer, and an accumulation of multiple mutations has been proposed as being necessary for cancer development
This piston was used to apply mechanical compression on ovarian cancer cells cultured on the glass surface enclosing the bottom layer (Figure 1)
We have introduced a flexible multilayer microdevice with a micro-piston suspended into the cell culture chamber for dynamic mechanical cell stimulation and compression
Summary
Extensive efforts have been made to study the role of gene mutations in cancer, and an accumulation of multiple mutations has been proposed as being necessary for cancer development. Biomechanical forces regulate the tumor microenvironment by solid stress, matrix mechanics, interstitial pressure, and flow [4]. Cancer cells alter their own biophysical properties and exert physical forces during primary tumor growth and to spread, invade, or metastasize [6, 7]. All these examples point that phenotypes may become dominant over genotypes of the tumor cells depending on the microenvironment [1]. There are no coherent quantitative data on the nature and level of mechanical forces that influence the interactions between the physical microand nano-environment and cancer cells [7]
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