Contributed by Subra Suresh, March 10, 2015 (sent for review February 5, 2015)
The separation and analysis of circulating tumor cells (CTCs) provides physicians a minimally invasive way to monitor the response of cancer patients to various treatments. Among the existing cell-separation methods, acoustic-based approaches provide significant potential to preserve the phenotypic and genotypic characteristics of sorted cells, owing to their safe, label-free, and contactless nature. In this work, we report the development of an acoustic-based device that successfully demonstrates the isolation of rare CTCs from the clinical blood samples of cancer patients. Our work thus provides a unique means to obtain viable and undamaged CTCs, which can subsequently be cultured. The results presented here offer unique pathways for better cancer diagnosis, prognosis, therapy monitoring, and metastasis research.
Circulating tumor cells (CTCs) are important targets for cancer biology studies. To further elucidate the role of CTCs in cancer metastasis and prognosis, effective methods for isolating extremely rare tumor cells from peripheral blood must be developed. Acoustic-based methods, which are known to preserve the integrity, functionality, and viability of biological cells using label-free and contact-free sorting, have thus far not been successfully developed to isolate rare CTCs using clinical samples from cancer patients owing to technical constraints, insufficient throughput, and lack of long-term device stability. In this work, we demonstrate the development of an acoustic-based microfluidic device that is capable of high-throughput separation of CTCs from peripheral blood samples obtained from cancer patients. Our method uses tilted-angle standing surface acoustic waves. Parametric numerical simulations were performed to design optimum device geometry, tilt angle, and cell throughput that is more than 20 times higher than previously possible for such devices. We first validated the capability of this device by successfully separating low concentrations (∼100 cells/mL) of a variety of cancer cells from cell culture lines from WBCs with a recovery rate better than 83%. We then demonstrated the isolation of CTCs in blood samples obtained from patients with breast cancer. Our acoustic-based separation method thus offers the potential to serve as an invaluable supplemental tool in cancer research, diagnostics, drug efficacy assessment, and therapeutics owing to its excellent biocompatibility, simple design, and label-free automated operation while offering the capability to isolate rare CTCs in a viable state.
↵1Present address: Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111.
Author contributions: P.L., M.D., S.S., and T.J.H. designed research; P.L., Z.M., L.Z., Y.C., P.-H.H., and J.J.D. performed research; C.I.T. and J.J.D. collected patients’ samples and provided clinical support; P.L., Z.M., Z.P., C.I.T., W.S.E.-D., M.D., S.S., and T.J.H. analyzed data; and P.L., Z.M., Z.P., C.I.T., W.S.E.-D., M.D., S.S., and T.J.H. wrote the paper.
Conflict of interest statement: P.L., Z.P., Y.C., M.D., S.S., and T.J.H. have filed a patent based on the work presented in this paper.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1504484112/-/DCSupplemental.
Freely available online through the PNAS open access option.
