Abstract
Circulating tumor cells (CTCs) have tremendous potential to indicate disease progression and monitor therapeutic response using minimally invasive approaches. Considering the limitations of affinity strategies based on their cost, effectiveness, and simplicity, size-based enrichment methods that involve low-cost, label-free, and relatively simple protocols have been further promoted. Nevertheless, the key challenges of these methods are clogging issues and cell aggregation, which reduce the recovery rates and purity. Inspired by the natural phenomenon that the airflow around a windmill is disturbed, in this study, a windmill-like hole array on the SU-8 membrane was designed to perturb the fluid such that cells in a fluid would be able to self-mix and that the pressure acting on cells or the membrane would be dispersed to allow a greater velocity. In addition, based on the advantages of fluid coatings, a lipid coating was used to modify the membrane surface to prevent cell aggregation and clogging of the holes. Under the optimal conditions, recovery rates of 93% and 90% were found for A549 and HeLa cells in a clinical simulation test of our platform with a CTC concentration of 20–100 cells per milliliter of blood. The white blood cell (WBC) depletion rate was 98.7% (n = 15), and the CTC detection limit was less than 10 cells per milliliter of blood (n = 6). Moreover, compared with conventional membrane filtration, the advantages of the proposed device for the rapid (2 mL/min) and efficient enrichment of CTCs without clogging were shown both experimentally and theoretically. Due to its advantages in the efficient, rapid, uniform, and clog-free enrichment of CTCs, our platform offers great potential for metastatic detection and therapy analyses.
Highlights
Circulating tumor cells (CTCs), which are shed from a primary tumor and released into the bloodstream, play a seed-like role in the process of cancer metastasis and cause as much as 90% of the cancer-associated morta lity[1–3]
Due to loss of the epithelial phenotype related to epithelial-mesenchymal transition (EMT) during tumor metastasis[21], the effect of CTC capture based on epithelial cell adhesion molecular (EpCAM) expression, including CellSearch, has been questioned
The processed blood sample passed through the column-filter microdevice at a constant flow rate, labeled leukocytes removed in the column, and CTCs were retained on the membrane
Summary
Circulating tumor cells (CTCs), which are shed from a primary tumor and released into the bloodstream, play a seed-like role in the process of cancer metastasis and cause as much as 90% of the cancer-associated morta lity[1–3]. The possibility of isolating CTCs from peripheral blood makes it possible for CTCs to serve as a “liquid. Due to the extreme rarity and high heterogeneity of CTCs as well as their vulnerability, the isolation and detection CTCs from whole blood are extremely. Various techniques that are mostly based on specific tumor markers (affinity-based strategies) and biophysical properties (label-free strategies) have been developed for the effective isolation and detection of CTCs9. Affinity-based capture depends on the immunochemical interactions between specific antigens expressed on the cell surface and their corresponding antibodies immobilized on magnetic beads[11–13] or patterned structures[14–18]. Due to loss of the epithelial phenotype related to epithelial-mesenchymal transition (EMT) during tumor metastasis[21], the effect of CTC capture based on epithelial cell adhesion molecular (EpCAM) expression, including CellSearch, has been questioned. Label-free strategies, with their unique advantages of easy operations and low costs, can capture epithelial and mesenchymal phenotypes, which are more suitable for the critical requirements for clinical application
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