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Single-cell analysis provides a wealth of information regarding the molecular landscape of the tumor cells responding to extracellular stimulations, which has greatly advanced the research in cancer biology. In this work, we adapt such a concept for the analysis of inertial migration of cells and clusters, which is promising for cancer liquid biopsy, by isolation and detection of circulating tumor cells (CTCs) and CTC clusters. Using high-speed camera tracking live individual tumor cells and cell clusters, the behavior of inertial migration was profiled in unprecedented detail. We found that inertial migration is heterogeneous spatially, depending on the initial cross-sectional location. The lateral migration velocity peaks at about 25% of the channel width away from the sidewalls for both single cells and clusters. More importantly, while the doublets of the cell clusters migrate significantly faster than single cells (~two times faster), cell triplets unexpectedly have similar migration velocities to doublets, which seemingly disagrees with the size-dependent nature of inertial migration. Further analysis indicates that the cluster shape or format (for example, triplets can be in string format or triangle format) plays a significant role in the migration of more complex cell clusters. We found that the migration velocity of a string triplet is statistically comparable to that of a single cell while the triangle triplets can migrate slightly faster than doublets, suggesting that size-based sorting of cells and clusters can be challenging depending on the cluster format. Undoubtedly, these new findings need to be considered in the translation of inertial microfluidic technology for CTC cluster detection. 

Circulating tumor cell (CTC) clusters that are shed from the primary tumor into the bloodstream are associated with a poor prognosis, elevated metastatic potential, higher proliferation rate, and distinct molecular features compared to single CTCs. Studying CTC clusters may give us information on the differences in the genetic profiles, somatic mutations, and epigenetic changes in circulating cells compared to the primary tumor and metastatic sites. Microfluidic systems offer the means of studying CTC clusters through the ability to efficiently isolate these rare cells from the whole blood of patients in a liquid biopsy. Microfluidics can also be used to develop in vitro models of CTC clusters and make possible their characterization and analysis. Ultimately, microfluidic systems can offer the means to gather insight on the complexities of the metastatic process, the biology of cancer, and the potential for developing novel or personalized therapies. In this review, we aim to discuss the advantages and challenges of the existing microfluidic systems for working with CTC clusters. We hope that an improved understanding of the role microfluidics can play in isolation, formation, and characterization of CTC clusters, which can lead to increased sophistication of microfluidic platforms in cancer research. 

Inertial migration of spherical particles has been investigated extensively using experiments, theory, and computational modeling. Yet, a systematic investigation of the effect of particle shape on inertial migration is still lacking. Herein, we numerically mapped the migration dynamics of a prolate particle in a straight rectangular microchannel using smoothed particle hydrodynamics at moderate Reynolds number flows. After validation, we applied our model to 2:1 and 3:1 shape aspect ratio particles at multiple confinement ratios. Their effects on the final focusing position, rotational behavior, and transitional dynamics were studied. In addition to the commonly reported tumbling motion, for the first time, we identified a new logrolling behavior of a prolate ellipsoidal particle in the confined channel. This new behavior occurs when the confinement ratio is above an approximate threshold value of K = 0.72. Our microfluidic experiments using cell aggregates with similar shape aspect ratio and confinement ratio confirmed this new predicted logrolling motion. We also found that the same particle can undergo different rotational modes, including kayaking behavior, depending on its initial cross-sectional position and orientation. Furthermore, we examined the migration speed, angular velocity, and rotation period as well as their dependence on both particle shape aspect ratio and confinement ratio. Our findings are especially relevant to the applications where particle shape and alignment are used for sorting and analysis, such as the use of barcoded particles for biochemical assays through optical reading, or the shape-based enrichment of microalgae, bacteria, and chromosomes. 

Abstract A simple, low‐cost, three‐dimensional (3D) lab‐on‐a‐foil microfluidic device for dielectrophoretic separation of circulating tumor cells (CTCs) is designed and constructed. Disposable thin films are cut by xurography and microelectrode array are made with rapid inkjet printing. The multilayer device design allows the studying of spatial movements of CTCs and red blood cells (RBCs) under dielectrophoresis (DEP). A numerical simulation was performed to find the optimum driving frequency of RBCs and the crossover frequency for CTCs. At the optimum frequency, RBCs were lifted 120 µm inz‐axis direction by DEP force, and CTCs were not affected due to negligible DEP force. By utilizing the displacement difference, the separation of CTCs (modeled with A549 lung carcinoma cells) from RBCs inz‐axis direction was achieved. With the nonuniform electric field at optimized driving frequency, the RBCs were trapped in the cavities above the microchannel, whereas the A549 cells were separated with a high capture rate of 86.3% ± 0.2%. The device opens not only the possibility for 3D high‐throughput cell separation but also for future developments in 3D cell manipulation through rapid and low‐cost fabrication.