Abstract
Tumor spheroids are considered a valuable three dimensional (3D) tissue model to study various aspects of tumor physiology for biomedical applications such as tissue engineering and drug screening as well as basic scientific endeavors, as several cell types can efficiently form spheroids by themselves in both suspension and adherent cell cultures. However, it is more desirable to utilize a 3D scaffold with tunable properties to create more physiologically relevant tumor spheroids as well as optimize their formation. In this study, bioactive spherical microgels supporting 3D cell culture are fabricated by a flow-focusing microfluidic device. Uniform-sized aqueous droplets of gel precursor solution dispersed with cells generated by the microfluidic device are photocrosslinked to fabricate cell-laden microgels. Their mechanical properties are controlled by the concentration of gel-forming polymer. Using breast adenocarcinoma cells, MCF-7, the effect of mechanical properties of microgels on their proliferation and the eventual spheroid formation was explored. Furthermore, the tumor cells are co-cultured with macrophages of fibroblasts, which are known to play a prominent role in tumor physiology, within the microgels to explore their role in spheroid formation. Taken together, the results from this study provide the design strategy for creating tumor spheroids utilizing mechanically-tunable microgels as 3D cell culture platform.
Highlights
Tumor spheroids have been extensively investigated as a three-dimensional (3D) tissue model to study various aspects of cancer physiology, as they can mimic 3D solid tumor tissues more closely than conventional two-dimensional monolayers [1,2,3]
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To visualize the biomarker expression of cells encapsulated in microgels at different stages of growth, immunofluorescent labeling of CD80 and CD206 for macrophage and E-cadherin (E-cad) for MCF-7 cells was performed [23,38,39]
Summary
Tumor spheroids have been extensively investigated as a three-dimensional (3D) tissue model to study various aspects of cancer physiology, as they can mimic 3D solid tumor tissues more closely than conventional two-dimensional monolayers [1,2,3]. With the increasing importance of patient-specific therapeutic approach, they are increasingly investigated as tissue-based high-throughput screening platforms for drug discovery applications that can overcome the limitations of conventional molecule-based screening This is made possible largely due to the availability of several methods to efficiently develop spheroids in large quantities, both in templated (e.g., microwells) and suspension (e.g., hanging drop) cultures [4,5,6]. Flow-focusing microfluidics have recently gained significant interest in the field of biomedical engineering, as they can generate liquid droplets with controlled, monodisperse size and architecture with high yield and biocompatibility [17,18,19] These droplets are used to encapsulate a wide array of biologically relevant molecules (e.g., therapeutic molecules, proteins) and species (e.g., bacterial and mammalian cells) for delivery applications. The results of this study are expected to delineate the combined effects of co-culture and ECM mechanics on the tumor spheroid formation
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