Collaborative Research: Mimicking Stress-Mediated Invasive Solid Tumor Using Bioprinted Microtissue and Acoustofluidics

In solid tumors, chemical and physical signals lead to cancer cells invading nearby tissue and vascularized systems. A well-known physical signal is the interstitial fluid pressure in the tumor region, and existing tumor models have difficulties regulating such a volumetric pressure. It is known that tumor regions with high interstitial pressure typically resist the delivery of the anti-cancer drugs and therapeutics. The goal of this project is to create and study how interstitial pressure can regulate the tumor cell response in a biomimetic (biology mimicking) tumor model. Bioprinting technology and hydrogel engineering will be used to construct the model. The tumor microenvironment will be introduced using the controlled formation of cell spheroids. Physical forces will be induced by acoustic waves, and their role in drug mass transport and the metastatic behavior of tumor cells will be studied. Successful development of such a model will represent a paradigm shift in the cancer community by improving patients’ quality of life, potentially prolonging survival, and opening up new clinical trials to test various new drug formulations. The educational objective is to broaden the participation of underrepresented minorities in STEM fields. This will be accomplished through various educational activities by integrating the research into project-based educational activities for undergraduate students and summer internships for underrepresented students. The tumor microenvironment (TME) is highly complex, with a distinct extracellular matrix composition and leaky vasculature that regulate the tumorigenic function of tumor cells. The investigators hypothesize that acoustic-driven, flow-induced pressure, hydrogel bioprinting, and theoretical simulation could be employed to replicate TME-associated pressure gradients and hypoxic conditions for an invasion behavior in tumor cells. A novel way is proposed for regulating biophysical pressure using the acoustic field in cell-laden microtissue models. A tumor-spheroid-laden microfluidic device equipped with interdigital transducers that generate surface acoustic waves will be developed and used to test the hypothesis. Through digital light processing bioprinting, the project aims to create a high-resolution vascular microtissue with spatial gradients of stiffness and pore sizes. Then, a wide range of acoustic fields (in the megahertz regime) will be made to induce pressure fields onto the tumor spheroids and characterize the tumor cells' invasion markers. Finally, a multi-physics theoretical and numerical approach will be developed to help quantify the variation of acoustic radiation forces within a fluid-saturated poroelastic environment and estimate the induced pressure field. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.