Effects of Shear Stress Gradients on Ewing Sarcoma Cells Using 3D Printed Scaffolds and Flow Perfusion

Area of Science:

• Biomedical Engineering
• Cancer Biology
• Materials Science

Background:

• Three-dimensional (3D) in vitro tumor models are crucial for drug discovery.
• Modeling tumor microenvironment complexity, like permeability gradients, is challenging in vitro.
• Ewing sarcoma (ES) exhibits shear stress-dependent ligand secretion, making it ideal for studying heterogeneous responses.

Purpose of the Study:

• To combine 3D scaffolds and flow perfusion bioreactors to simulate tumor microenvironment gradients.
• To evaluate the impact of scaffold architecture and mechanical stimulation on tumor cell phenotype.
• To identify potential diffusional limitations in drug delivery within solid tumors.

Main Methods:

• Fabricated poly(propylene fumarate) scaffolds with pore size gradients using extrusion-based 3D printing.
• Cultured ES cells under flow perfusion conditions on the 3D printed scaffolds.
• Utilized computational fluid modeling to confirm shear stress gradients and estimate cell exposure.

Main Results:

• Observed enhanced ES cell proliferation in scaffold layers with lower permeability and increased surface area under flow perfusion.
• Demonstrated that shear stress gradients affect ES cell signaling pathways, including the insulin-like growth factor-1 pathway.
• Showed that cellular responses were dependent on scaffold gradient orientation and the presence of flow-derived shear stress.

Conclusions:

• 3D printed scaffolds combined with flow perfusion effectively model solid tumor heterogeneity in vitro.
• This approach can aid in predicting drug delivery limitations and developing customized cancer therapies.
• The study provides a platform for future drug testing and understanding tumor response to microenvironmental factors.