Rapid 3D Extrusion of Synthetic Tumor Microenvironments

Abstract

Solid tumors house an assortment of complex and dynamically changing microenvironments in which signaling events between multiple cell types are known to play a critical role in tumor progression, invasion, and metastasis. To deepen our understanding of this biology, it is desirable to accurately model these structures in vitro for basic studies and for drug screening; however, current systems fall short of mimicking the complex organization of cells and matrix in vivo. Here we demonstrate the generation of spatially-organized 3D hydrogels of cells and matrix produced from a simple concentric flow device in a single step. Multiple cell types are pre-seeded in different spatial domains such as concentric regions of vessel-like tubular structures to reproducibly establish heterotypic cellular environments in 3D. Using macrophages and breast adenocarcinoma cells as an example of a paracrine loop that regulates metastasis, we explored the effects of clinical drug treatments and observed a dose-dependent modulation of cellular migration. This versatile and tunable approach for tissue fabrication will enable a means to study a wide range of microenvironments and may provide a clinically-viable solution for personalized assessment of patient response to therapeutics.

Biomaterials and emerging anticancer therapeutics: engineering the microenvironment

“…In another study, drug inhibition of tumor cell-macrophage paracrine interactions was analyzed using co-culture of breast adenocarcinoma cells and macrophages in alginate hydrogel fibers. Gefitinib, an EGFR inhibitor, and a Rac1 inhibitor were both able to impair macrophage migration to cancer cells, and the 3D cell distribution and cancer cell-macrophage ratio affected drug responses 76 . Although generally faster than in vivo models, 3D tumor models for drug testing typically require increased processing time relative to 2D cell monolayers.…”

Engineering of Hydrogel Materials with Perfusable Microchannels for Building Vascularized Tissues

“…In addition to single tube structures, more diverse geometries mimicking more biomimetic structures can be generated by changing the design of microfluidic devices. Grolman et al demonstrated the generation of hollow microfibers in “straight,” “serpentine,” and “helically packed” architectures by adding an extra gelating outer flow (CaSO 4 solution) . Cheng et al developed a capillary‐based coaxial microfluidic device for the fabrication of perfusable microfibers ( Figure A) .…”

“…Gorlman et al modeled the tumor microenvironment by coculturing human breast adenocarcinoma cells and mouse macrophage cells in extruded hollow microfibers in different patterned geometries. The results showed the channel geometries could affect macrophage‐tumor cell signaling . Wong et al demonstrated that chemotherapeutic drug in different formulation performed different transendothelial transport ability, distribution, and function in a vascularized tumor model in vitro …”

Bridging the Gap: From 2D Cell Culture to 3D Microengineered Extracellular Matrices

“…3D printing of cells most often uses hydrogel encapsulation of cells to form a 3D structure[217]–[220]. Yoo and colleagues 3D printed multi-layered collagen hydrogels which contained layers of human skin fibroblasts and keratinocytes[218].…”