Round lumen-based microfluidic devices for modelling cancer metastasis

Most cancer related deaths are not caused directly by primary tumor, but by secondary tumors formed through metastasis to other organs. Metastasis is a complex cascade that we poorly understand due to the limitations of current in-vitro models. Hence, we focus on modeling cancer metastasis on chip, via introducing the relevant physiological factors in the tumor microenvironment (TME). To bring current chip devices one step closer to correct morphology (e.g. of (micro)vessels, and breast-duct) in TME, we fabricate round luminal channels. For this, we exploit different techniques, such as 3D sugar-printing, needle casting and femtosecond laser (FSL) to form lumens either in hydrogel or PDMS.
In 3D sugar-printing technique, sugar glass is printed as fibers and cast in surrounding material (unpolymerized hydrogel, or synthetic polymers); the sugar glass is selectively dissolved after polymerization of surrounding material, that results in interconnected perfusable lumens. We also achieved this with micro-needle technique; The needle removal after hydrogel polymerization, left behind a lumen. For the fabrication of smaller dimension interconnected lumens, we utilized FSL technique. FSL beam can induce strong absorption in glass, that induces internal modification; Following wet chemical etching removes modified material, leaving behind lumens.
When the lumens are seeded with endothelial cells, they form the (micro)vasculature. Combined with a neighboring lumen for cancer cell culture, the process of cancer invasion, migration through ECM, and intravasation can be studied. Up until now, we could mimic breast duct, blood, and lymphatic micro-vessels on chip using luminal channels. Cell-cell tight junctions were present, as a basis for further study of metastatic cascade. We are currently generating human B-cell lymphoma-on-chip as an innovative model to investigate dissemination of malignant B-cells. In the middle channel of a three inter-connected lumina device, we culture fibroblastic reticular cells (FRCs) in a collagen/fibrin hydrogel. When the FRCs have formed a network, diffuse large B-cell lymphoma cells (DLBCL) are added in one of side channels. We could observe DLBCL migration into the FRC-containing hydrogel, which was specific for some DLBCL subtypes. In future work, we will incorporate vessels in TME to study metastasis.