Abstract 999: In vivo breast tumor stiffness and vascular drug delivery recapitulated in a microfluidic tumor-on-a-chip

Abstract

Abstract Biomimetic tissue engineered microfluidic cancer models offer a higher degree of spatial, temporal and structural precision in controlling the physical parameters and component characteristics of the native tumor microenvironment (TME). Current models working to establish a biomimetic in vitro breast TME are limited by their ability to recapitulate various degrees of in vivo complexities and poor correlation of the diffusional gradients of oxygen, nutrients and anti-cancer drugs. To establish a model and address these challenges, we have used poly(ethylene glycol)-fibrinogen (PEG-Fb) as our biomimetic material to engineer 3D breast tumor tissues and recapitulate the mechanical stiffness of core, midpoint and peripherial zones of the native tumor in a vascularized microfluidic chip. To assess the mechanical stiffness, the in vivo breast tumor (MDA-MB-231 flank xenograft in Athymic nude mice) and engineered tumor constructs were subjected to parallel plate compression test using Cell Scale Microsquisher and the resulting force versus displacement data was acquired to calculate Young’s modulus. Tumor mimetic (“high perfusion chip” (HPC) and “low perfusion chip” (LPC), differ with respect to the vascular network surrounding their respective primary and secondary tumor compartments were used in this study. Breast cancer-associated endothelial cells (hBTEC) were seeded in the vascular network and allowed to form a lumen. Metastatic breast cancer cells MDA-MB-231/ human foreskin fibroblast BJ5ta (ATCC) cells were mixed with polymer precursor solution containing PEG-Fb and Eosin Y. The precursor was loaded into the primary tumor compartment and cross-linked for 2 minutes under visible light. Stiffness was modulated by adding poly(ethylene glycol) diacrylate (PEGDA) to the polymer precursor for recapitulating the different zones of the in vivo tumor. hBTEC media was perfused through the endothelial cell networks were continuously monitored for cell behavior and metastasis. In vivo breast tumor stiffness at core, midpoint and periphery was found to be within the range of the 3D engineered breast tumor tissues with time in culture through day 29. In the vascularized microfluidic chip, cell laden biomaterial was incorporated, the cancer cells were observed to undergo key events of the TME such as intravasation, circulating tumor cells in the endothelial vascular channel, adherence and migration to the secondary chamber resulting in metastasis. In the native TME there are regional differences in drug diffusion; TRITC dextran (4.4 kDa) was administered at a constant flow rate through the chips’ vascularized networks and found to have vascular network geometry and engineered tumor construct stiffness dependent differences in diffusion into the primary tumor chamber, mimicking the in vivo phenomena. Citation Format: Benjamin Anbiah, Iman Hassani, Nicole Habbit, Lani Jasper, Deborah Ramsay, Balabhaskar Prabhakarpandian, Robert Arnold, Elizabeth Lipke. In vivo breast tumor stiffness and vascular drug delivery recapitulated in a microfluidic tumor-on-a-chip [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 999.