Pleural effusion cytology is already used in cancer diagnosis, especially in metastatic settings, but its sensitivity can be limited. Tumor cells are easily masked by overwhelming numbers of background blood cells, and cluster structures may be disrupted during processing. Immune-affinity approaches can detect malignant tumor cells (MTCs), yet they may damage cells, dissociate malignant tumor cell clusters (MTCCs), and mask surface biomarkers with conjugated antibodies. Existing label-free microfluidic systems also face a persistent trade-off between throughput, purity, gentle handling, and the ability to separate single cells from clusters in the same platform. Based on these challenges, there is a need to carry out in-depth research on label-free, high-throughput, multi-scale enrichment of both single tumor cells and intact clusters from clinical effusions.
Researchers from Southeast University, Wuxi University of Technology, and Zhongda Hospital of Southeast University reported (DOI: 10.1038/s41378-026-01235-y) in 2026 in Microsystems & Nanoengineering that they had developed a cascaded inertial microfluidic device for enriching single MTCs and intact MTCCs from pleural effusions of lung cancer patients. The system uses parallelized serpentine channels for first-stage background blood-cell depletion and a slanted spiral channel for second-stage size-based sorting. The study focused on clinical pleural effusion samples, seeking a faster and less disruptive route to tumor-cell enrichment for enhanced malignancy diagnosis and metastatic profiling.
The device works in two linked sorting steps. In the first stage, small blood cells are driven toward sidewalls and removed through waste outlets, while larger target cells remain near the core stream for collection. In the second stage, the balance of inertial lift, Dean drag, and local vortex-induced forces separates single tumor cells from larger clusters according to size. Using model particles, the system recovered 91.8% ± 6.6% of 25 µm particles representing clusters and 87.4% ± 7.4% of 15 µm particles representing single tumor cells. In simulated cell tests with A549 lung cancer cells and white blood cells (WBCs), total A549 recovery reached 81.7% ± 1.2% with an overall purity of 76.1% ± 1.3%; single cells collected at outlet 3 showed 75.9% ± 1.3% recovery and 75.8% ± 1.6% purity, while cluster-rich fractions at outlet 4 reached 79.4% ± 3.4% purity. In three patient pleural effusion samples, the chip processed 50 mL in 6.5 min at 8 mL/min, yielding 68% purity for single MTCs and 35% purity for intact MTCCs. Tumor cells were identified by immunofluorescence as DAPI+/Pan-CK+/CD45−.
“This work points to a more revealing form of liquid-biopsy analysis,” the study suggests. “The key advance is not simply capturing more cancer cells, but recovering them in forms that preserve biological meaning.” By retaining intact clusters while sharply reducing background blood cells, the platform could give cytology a clearer view of both tumor burden and metastatic behavior. The findings further indicate that when single cells and clusters are enriched side by side, clinicians may gain a fuller picture of malignancy than from conventional detection strategies that focus mainly on isolated cells.
The study’s implications are practical as well as diagnostic. The chip is label-free, requires no external fields or complex instrumentation, and is compatible with standard downstream staining and microscopic analysis. Its multilayer polymer construction is also described as suitable for scalable, relatively low-cost manufacturing. At the same time, the authors note that the clinical validation remains preliminary, involving only three patient samples, so larger cohorts will still be needed to establish diagnostic sensitivity and prognostic value. Even so, the platform offers a promising route toward faster cytology support, better recovery of fragile tumor clusters, and more actionable assessment of malignancy in pleural effusions.
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References
DOI
10.1038/s41378-026-01235-y
Original Source URL
https://doi.org/10.1038/s41378-026-01235-y
Funding information
This work is supported by the National Natural Science Foundation of China (52375562, 51875103, and 81727801), the Basic Research Program of Jiangsu Province (BK20251358), the Postdoctoral Science Foundation of China (2025M782900), the Postdoctoral Excellence Program of Jiangsu Province (2025ZB268), the Science and Technology Cooperation and Exchange Special Project of Shanxi Province (202304041101032), and the ‘333’ Project of Jiangsu Province.
About Microsystems & Nanoengineering
Microsystems & Nanoengineering is an online-only, open access international journal devoted to publishing original research results and reviews on all aspects of Micro and Nano Electro Mechanical Systems from fundamental to applied research. The journal is published by Springer Nature in partnership with the Aerospace Information Research Institute, Chinese Academy of Sciences, supported by the State Key Laboratory of Transducer Technology.