Compressive solid stress correlates with changes in the mechanical properties of developing confined tumors in the context of their microenvironment. Despite several advances to assay compressive solid stresses on cell and tissue behavior, the precise manipulation of compression in a 3D context remains challenging. Here, I introduce the design, generation and validation of a tractable microfluidic system that is able to isolate and manipulate compressive solid stresses in a controlled manner. Utilizing finite element analysis (FEA) I identify specific design parameters that permits application of 30% compression (strain) within my newly designed system. Importantly, particle image velocimetry (PIV) approaches enabled the measurement of strain via bead displacements which revealed that my microfluidic device demonstrates displacements that experimentally validated displacements predicted by FEA. Moreover, since PDMS is gas permeable a pressure sustainability assay was performed and resulted in a mean displacement of ~14m in 14 hours, allowing for calculations of the appropriate amount of air to re-inject into my device to sustain 30% compression. Finally, I was able to demonstrate that 30% compression induces increases in area of patient- derived GBM neurospheres, and furthermore that this compressive solid stress- dependent size increase is functionally linked to integrin signaling through the focal adhesion kinase (pFAK) phosphorylation. I conclude that this novel tractable microdevice that I designed and validated can support the execution of controlled mechanistic studies aimed at elucidating the role of compressive solid stresses in 3D tissues. Accordingly, application of this device has strong potential to lead to new discoveries and therapies.