Facile Dual Asymmetric Contraction–Expansion Array Integrated Chip Online Coupled with ICP-MS for High-throughput Counting of Circulating Tumor Cells

Circulating tumor cells (CTCs) have emerged as critical biomarkers for early cancer diagnosis. Elemental labeling inductively coupled plasma mass spectrometry (ICP-MS) has high sensitivity and specificity for cell counting. Microfluidic sorting chips combined with ICP-MS, enabling online separation/enrichment and detection of CTCs, could be a promising analytical technique for advancing biomedical research and clinical diagnostics. To this end, a dual asymmetric contraction-expansion array (ACEA-ACEA) integrated chip-ICP-MS online detection platform was developed for the rapid isolation and detection of CTCs in blood samples. The designed integrated chip, consisting of two ACEA channels with different structural parameters, achieved two-stage removal of white blood cells (WBCs) by synergistic inertial lift and Dean forces, thereby greatly improving the CTC purity. The Eu-labeled CTCs focused in a single stream were then directly introduced into ICP-MS from the target outlet for online detection. The peak frequency of Eu labeled on the cell surface could reflect the number of CTCs. The designed integrated ACEA-ACEA chip was used for cell sorting, and a good sorting performance was obtained with a throughput of 300 μL min^-1, CTC recovery of 94.18%, and WBC removal efficiency of 99.46%. The developed method was applied for CTC counting in blood samples collected from 10 healthy individuals and 42 cancer patients. No CTCs were identified in healthy control samples, while the number of CTCs detected in cancer patients' samples ranged from 10 to 176 cells mL^-1. Notably, the number of detected CTCs was positively correlated with the patients' TNM staging [stands for Tumour (T), Node (N) and Metastasis (M)] results. The fabricated ACEA-ACEA chip was sheath-flow-free and external-field-free, and the developed method could be used for the detection of CTCs in blood samples with high throughput, high sensitivity, and high accuracy, exhibiting great application value and potential in medical diagnosis.