Skip to main content

Advertisement

SpringerLink
Log in

Nickel-Doped Microfluidic Chip for Rapid and Efficient Immunomagnetic Separation and Detection of Breast Cancer Cell-Derived Exosomes

  • Original Article
  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

Breast cancer cell-derived exosomes have high potential as biomarkers for continuous biopsies and longitudinal monitoring in breast cancer. However, it is extremely difficult to separate exosomes with high recovery and high purity from complex media, such as urine, plasma, saliva and cell culture supernatants. Here, we designed a flexible and simple microfluidic chip for exosome separation. The capture zone of the chip is a three-dimensional structure of interlaced cylinders doped with nickel powder. Exosomes were separated from cell culture supernatant by the immunomagnetic separation method in continuous flow mode and were detected by fluorescence imaging with high sensitivity. The chip achieved a high exosome recovery rate (> 74%) and purity (> 67%) at an injection rate of 3.6 mL/h. Thus, this chip was demonstrated to be a cutting-edge platform for the separation and detection of exosomes. It could also be applied to separate and detect other types of exosomes, microbubbles and cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

All data generated and analyzed during this study are included in this article.

References

  1. Siegel, R. L., Miller, K. D., Fuchs, H. E., & Jemal, A. (2022). Cancer statistics, 2022. CA:A Cancer Journal for Clinician, 72, 7–33. https://doi.org/10.3322/caac.21708.

    Article  Google Scholar 

  2. Paskeh, M. D. A., Entezari, M., Mirzaei, S., Zabolian, A., Saleki, H., Naghdi, M. J., Sabet, S., Khoshbakht, M. A., Hashemi, M., Hushmandi, K., Sethi, G., Zarrabi, A., Kumar, A. P., Tan, S. C., Papadakis, M., Alexiou, A., Islam, M. A., Mostafavi, E., & Ashrafizadeh, M. (2022). Emerging role of exosomes in cancer progression and tumor microenvironment remodeling. Journal of Hematology & Oncology, 15, 83. https://doi.org/10.1186/s13045-022-01305-4.

    Article  CAS  Google Scholar 

  3. Zhang, X., Yuan, X., Shi, H., Wu, L., Qian, H., & Xu, W. (2015). Exosomes in cancer: small particle, big player. Journal of Hematology & Oncology, 8, 83. https://doi.org/10.1186/s13045-015-0181-x.

    Article  CAS  Google Scholar 

  4. Kalluri, R., & LeBleu, V. S. (2020). The biology, function, and biomedical applications of exosomes. Science, 367, eaau6977. https://doi.org/10.1126/science.aau6977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kumar, D. N., Chaudhuri, A., Aqil, F., Dehari, D., Munagala, R., Singh, S., Gupta, R. C., & Agrawal, A. K. (2022). Exosomes as Emerging Drug Delivery and Diagnostic modality for breast Cancer: recent advances in isolation and application. Cancers (Basel), 14, 1435. https://doi.org/10.3390/cancers14061435.

    Article  CAS  PubMed  Google Scholar 

  6. Hu, C., Jiang, W., Lv, M., Fan, S., Lu, Y., Wu, Q., & Pi, J. (2022). Potentiality of Exosomal Proteins as Novel Cancer biomarkers for Liquid Biopsy. Frontiers in Immunology, 13, 792046. https://doi.org/10.3389/fimmu.2022.792046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shao, Y., Shen, Y., Chen, T., Xu, F., Chen, X., & Zheng, S. (2016). The functions and clinical applications of tumor⁃derived exosomes. Oncotarget, 7, 60736–60751. https://doi.org/10.18632/oncotarget.11177.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lin, S., Yu, Z., Chen, D., Wang, Z., Miao, J., Li, Q., Zhang, D., Song, J., & Cui, D. (2020). Progress in Microfluidics-Based exosome separation and Detection Technologies for diagnostic applications. Small (Weinheim An Der Bergstrasse, Germany), 16, e1903916. https://doi.org/10.1002/smll.201903916.

    Article  CAS  PubMed  Google Scholar 

  9. Li, P., Kaslan, M., Lee, S. H., Yao, J., & Gao, Z. (2017). Progress in Exosome isolation techniques. Theranostics, 7, 789–804. https://doi.org/10.7150/thno.18133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jiang, Z., Liu, G., & Li, J. (2020). Recent progress on the isolation and detection methods of Exosomes. Chemistry-An Asian Journal, 15, 3973–3982. https://doi.org/10.1002/asia.202000873.

    Article  CAS  PubMed  Google Scholar 

  11. Lane, R. E., Korbie, D., Trau, M., & Hill, M. M. (2019). Optimizing size exclusion chromatography for Extracellular Vesicle Enrichment and Proteomic Analysis from clinically relevant samples. Proteomics, 19, e1800156. https://doi.org/10.1002/pmic.201800156.

    Article  CAS  PubMed  Google Scholar 

  12. Abramowicz, A., Widlak, P., & Pietrowska, M. (2016). Proteomic analysis of exosomal cargo: the challenge of high purity vesicle isolation. Molecular BioSystems, 12, 1407–1419. https://doi.org/10.1039/c6mb00082g.

    Article  CAS  PubMed  Google Scholar 

  13. Hassanpour, Tamrin, S., Sanati, Nezhad, A., & Sen, A. (2021). Label-free isolation of Exosomes using Microfluidic Technologies. Acs Nano, 15, 17047–17079. https://doi.org/10.1021/acsnano.1c03469.

    Article  CAS  PubMed  Google Scholar 

  14. Woo, H. K., Sunkara, V., Park, J., Kim, T. H., Han, J. R., Kim, C. J., Choi, H. I., Kim, Y. K., & Cho, Y. K. (2017). Exodisc for Rapid, Size-Selective, and efficient isolation and analysis of Nanoscale Extracellular vesicles from Biological samples. Acs Nano, 11, 1360–1370. https://doi.org/10.1021/acsnano.6b06131.

    Article  CAS  PubMed  Google Scholar 

  15. Lee, K., Shao, H., Weissleder, R., & Lee, H. (2015). Acoustic purification of extracellular microvesicles. Acs Nano, 9, 2321–2327. https://doi.org/10.1021/nn506538f.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhao, Z., Yang, Y., Zeng, Y., & He, M. (2016). A microfluidic ExoSearch chip for multiplexed exosome detection towards blood-based ovarian cancer diagnosis. Lab on a Chip, 16, 489–496. https://doi.org/10.1039/c5lc01117e.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Moura, S. L., Pallarès-Rusiñol, A., Sappia, L., Martí, M., & Pividori, M. I. (2022). The activity of alkaline phosphatase in breast cancer exosomes simplifies the biosensing design. Biosensors & Bioelectronics, 198, 113826. https://doi.org/10.1016/j.bios.2021.113826.

    Article  CAS  Google Scholar 

  18. Théry, C., Witwer, K. W., Aikawa, E., Alcaraz, M. J., Anderson, J. D., Andriantsitohaina, R., Antoniou, A., Arab, T., Archer, F., Atkin-Smith, G. K., et al. (2018). Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular vesicles and update of the MISEV2014 guidelines. Journal of Extracellular Vesicles, 7, 1535750. https://doi.org/10.1080/20013078.2018.1535750.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yu, Z., Lin, S., Xia, F., Liu, Y., Zhang, D., Wang, F., Wang, Y., Li, Q., Niu, J., Cao, C., Cui, D., Sheng, N., Ren, J., Wang, Z., & Chen, D. (2021). ExoSD chips for high-purity immunomagnetic separation and high-sensitivity detection of gastric cancer cell-derived exosomes. Biosensors & Bioelectronics, 194, 113594. https://doi.org/10.1016/j.bios.2021.113594.

    Article  CAS  Google Scholar 

  20. Malic, L., Zhang, X., Brassard, D., Clime, L., Daoud, J., Luebbert, C., Barrere, V., Boutin, A., Bidawid, S., Farber, J., Corneau, N., & Veres, T. (2015). Polymer-based microfluidic chip for rapid and efficient immunomagnetic capture and release of Listeria monocytogenes. Lab on a Chip, 15, 3994–4007. https://doi.org/10.1039/c5lc00852b.

    Article  CAS  PubMed  Google Scholar 

  21. Liu, C., Guo, J., Tian, F., Yang, N., Yan, F., Ding, Y., Wei, J., Hu, G., Nie, G., & Sun, J. (2017). Field-free isolation of Exosomes from Extracellular vesicles by Microfluidic Viscoelastic flows. Acs Nano, 11, 6968–6976. https://doi.org/10.1021/acsnano.7b02277.

    Article  CAS  PubMed  Google Scholar 

  22. Wunsch, B. H., Smith, J. T., Gifford, S. M., Wang, C., Brink, M., Bruce, R. L., Austin, R. H., Stolovitzky, G., & Astier, Y. (2016). Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. Nature Nanotechnology, 11, 936–940. https://doi.org/10.1038/nnano.2016.134.

    Article  CAS  PubMed  Google Scholar 

  23. Momen-Heravi, F., Balaj, L., Alian, S., Mantel, P. Y., Halleck, A. E., Trachtenberg, A. J., Soria, C. E., Oquin, S., Bonebreak, C. M., Saracoglu, E., Skog, J., & Kuo, W. P. (2013). Current methods for the isolation of extracellular vesicles.Biological Chemistry, 394, 1253–1262. https://doi.org/10.1515/hsz-2013-0141.

Download references

Funding

This research was supported by the Natural Science Foundation of Chongqing, China (No. cstc2020jcyj-msxmX0367) and the Chongqing Medical Scientific Research Project (Joint Project of Chongqing Health Commission and Science and Technology Bureau, No. 2022MSXM136).

Author information

Author notes

    Authors and Affiliations

    1. Department of Breast Diseases, Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC), Chongqing University Cancer Hospital, No. 181 Hanyu Rd, Shapingba District, 400030, Chongqing, China

      Huiying Fang & Mei Liu

    2. Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Rd, Yuzhong District, 400010, Chongqing, China

      Wei Jiang

    Authors
    1. Huiying Fang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Mei Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Wei Jiang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Contributions

    Huiying Fang and Mei Liu contributed equally to this work. Material preparation, data collection and analysis were performed by Huiying Fang and Mei Liu. The manuscript was written by Wei Jiang.

    Corresponding author

    Correspondence to Wei Jiang.

    Ethics declarations

    Ethics Approval

    Not applicable.

    Consent to Participate

    Not applicable.

    Consent for Publication

    Not applicable.

    Conflict of Interest

    The authors declare no competing interests.

    Additional information

    Publisher’s Note

    Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

    Huiying Fang and Mei Liu contributed equally to this work.

    Rights and permissions

    Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Fang, H., Liu, M. & Jiang, W. Nickel-Doped Microfluidic Chip for Rapid and Efficient Immunomagnetic Separation and Detection of Breast Cancer Cell-Derived Exosomes. Appl Biochem Biotechnol 195, 3109–3121 (2023). https://doi.org/10.1007/s12010-022-04272-1

    Download citation

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12010-022-04272-1

    Keywords

    Search

    Navigation