Biomechanical 3D tumor models on a micro-milled high-throughput force sensor array

Abstract

The tumor microenvironment plays a critical role in drug resistance, with extracellular matrix (ECM) mechanics, cell-cell crosstalk, and transport barriers contributing to poor therapeutic outcomes. Traditional two-dimensional (2D) cultures fail to capture these features, and drug efficacy in 2D often does not translate to three-dimensional (3D) models or in vivo tumors. Here, we introduce a 3D tumor model integrated with a high- throughput biomechanical sensor array that enables simultaneous measurement of cellular forces, matrix remodeling, and molecular transport. Fabricated using a scalable and cost-effective micro-milling approach, the platform allows parallel generation of multiple tumor constructs within a single dish. Using patient-derived pancreatic ductal adenocarcinoma (PDA) cells and stromal fibroblasts, we show that responses to gemcitabine and all-trans retinoic acid (ATRA) in 3D differ markedly from 2D cultures, consistent with clinical observations. By integrating biochemical and biomechanical readouts, this technology provides a more physiologically relevant tumor model and a powerful tool for preclinical drug testing and personalized medicine.