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Session PO.TB05.05 - 3D and Tissue Recombinant Models of Cancer  Add to My Itinerary

6764 / 2 - Vascularized tumor-on-chip model

for evaluating chemotherapeutic-mediated
damage to adjacent healthy tissue
 April 10, 2024, 9:00 AM - 12:30 PM  Section 6

Presenter/Authors
D. Ramsey, J. Rosano, C. Gordon, G. Fewell;
SYNVIVO INC., Huntsville, AL
Disclosures
D. Ramsey,
Integra LifeSciences Employment.
J. Rosano, None.
C. Gordon,
Alimetrix Employment.
G. Fewell, None.
Abstract
Introduction: Systemic chemotherapy is an effective anticancer treatment for all stages of breast cancer, with
intravenous (IV) infusion being the principal method of administration. In addition to targeting cancer, systemic
chemotherapy can impact the viability and function of surrounding normal tissues and vasculature. Early-discovery
research tools comparing novel and existing systemic treatment strategies are urgently needed to support
predictive efficacy and toxicity efforts. Microfluidic systems have the potential to fill this need while simultaneously
reducing animal use. The overall goal of the study is to use an advanced microfluidic tumor-on-chip system to
simultaneously evaluate the therapeutic and toxic effects of IV chemotherapy on normal and cancerous tissues.
Materials and Methods: Synthetic Tumor Networks, which are comprised of primary and secondary tissue sites
separated by an interconnected vasculature, were developed using in vivo images and fabricated using soft
lithography. Primary vascular endothelial cells were used to establish microvasculature. A normal breast cell line
(MCF 10A), or a GFP-labeled metastatic human breast cancer cell line (MDA-MB-231/GFP), were cultured in the
tissue sites in a three-dimensional (3D) environment using a human-derived hydrogel. The vascular networks were
perfused with endothelial cell media under physiological fluid flow conditions to establish the model. An EZH2
methyltransferase inhibitor (EZH2 inhibitor III) was delivered by IV infusion to the model tissues. Real-time
monitoring of cellular growth, tumor invasion and extravasation, and cellular viability were performed using
fluorescence microscopy over a two-week period.
Results and Discussion: Metastatic MDA-MB-231/GFP breast cancer cells proliferated rapidly in the primary tumor
site. Tumor intravasation into the vascular channels was observed in models that received no anticancer
treatment, as well as extravasation into the secondary tissue site and invasion of the healthy breast tissue.
Differences in tumor viability and migratory behavior were observed between untreated models or models
receiving IV infusions of the EZH2 inhibitor through the vascular networks. Vascular barrier integrity and normal
breast tissue viability were monitored at early (24-72 hr) and late (7-14 days) timepoints after anticancer treatment
to measure short- and long-term adverse drug impacts. These results provide a unique perspective on the in vivo
realism of an in vitro system for monitoring both therapeutic and toxic effects of systemic chemotherapies.
Conclusions: We have developed a 3D vascularized tumor-on-chip model for monitoring the impacts of systemic
chemotherapeutic agents on tumor and healthy tissues. This model can be used to investigate therapeutic and
toxic effects on multiple tissue types simultaneously using real-time imaging techniques.