Understanding How Microstructure and Interstitial Fluid Pressure Gradient Modulate Cell Invasion in a Bioprinted Tumor-On-a-Chip

This project will study how the matrix (the mixture of proteins and other molecules that surrounds cells and provides structural and biochemical support to tissues) and the surrounding interstitial (between the spaces) fluid pressure can impact cancer cells within a biomimetic (biology imitating) model. The chemical and physical signals lead to cancer cells invading nearby tissue. A well-known physical signal is interstitial fluid pressure, and biomimetic pressure modeling can improve the current cancer models. The project aims to create interstitial pressure around breast cancer cells and measure the cell response over time. Light-assisted bioprinting technology and microfluidics will be used to construct the tunable solid tumor model. Microfluidic design and hydrogel parameters will be applied to explore the role of pressure gradients in regulating cell migration and metastasis. The results of this project can be used to design tunable cancer models for drug screening applications. In addition, the proposed research will positively impact Science-Technology-Engineering-Mathematics (STEM) education by training undergraduate students at the New Jersey Institute of Technology (NJIT). A summer training program will be developed to broaden the participation of underrepresented groups and community college students in academia.The investigators hypothesize that the metastatic and migratory behavior of solid tumor cells in three-dimensional (3D) microtissues can be modulated by matrix pore size, fluid-induced pressure, and matrix stiffness gradients. The 3D microtissue is an aggregate of cells and essential microenvironment cues with a pre-defined assembly. Microtissue advancement toward patient- and stage-dependent models requires understanding how the microstructure and biophysical cues of the tumor environment can regulate cells' invasiveness and metastatic behavior. Three research tasks are proposed to study the role of fluid-induced pressure in directing tumor cell invasion. First, a tumor spheroid-laden microtissue model with controlled microstructure will be 3D bioprinted, characterized, and optimized. The parameters of a photocrosslinkable gelatin-based bioink will be adjusted based on the desired fluid-induced pressure. Second, the correlations between cells’ invasive behavior and microstructure will be quantified via real-time cell tracking and measurements of gene expressions over time. Numerical simulation will also be used to identify the localized pore pressure and hypoxia gradients in the model. Third, the cross-correlation of tumor vasculature and interstitial pressure gradient in controlling tumor cell migration will be quantified and assessed to identify their impacts. Statistical analysis will be performed to determine the governing structural parameters in the solid tumor microtissue model. The accomplishment of this project will enhance our understanding of the mechanisms of drug resistance in invasive cancers such as triple-negative breast cancer.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.