Analytical and Bioanalytical Chemistry

, Volume 410, Issue 17, pp 3943–3951 | Cite as

Surface plasmon resonance sensing: from purified biomolecules to intact cells

  • Yu-wen SuEmail author
  • Wei WangEmail author


Surface plasmon resonance (SPR) has become a well-recognized label-free technique for measuring the binding kinetics between biomolecules since the invention of the first SPR-based immunosensor in 1980s. The most popular and traditional format for SPR analysis is to monitor the real-time optical signals when a solution containing ligand molecules is flowing over a sensor substrate functionalized with purified receptor molecules. In recent years, rapid development of several kinds of SPR imaging techniques have allowed for mapping the dynamic distribution of local mass density within single living cells with high spatial and temporal resolutions and reliable sensitivity. Such capability immediately enabled one to investigate the interaction between important biomolecules and intact cells in a label-free, quantitative, and single cell manner, leading to an exciting new trend of cell-based SPR bioanalysis. In this Trend Article, we first describe the principle and technical features of two types of SPR imaging techniques based on prism and objective, respectively. Then we survey the intact cell-based applications in both fundamental cell biology and drug discovery. We conclude the article with comments and perspectives on the future developments.

Graphical abstract

Recent developments in surface plasmon resonance (SPR) imaging techniques allow for label-free mapping the mass-distribution within single living cells, leading to great expansions in biomolecular interactions studies from homogeneous substrates functionalized with purified biomolecules to heterogeneous substrates containing individual living cells


Surface plasmon resonance (SPR) Biosensor Label-free Cell biology Drug discovery 



The authors acknowledge financial support from the National Natural Science Foundation of China (21522503), the Natural Science Foundation of Jiangsu Province (BK20150013), and the Science and Technology Fund of Nanjing Medical University (2014NJMUZD018).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Cullen DC, Brown RG, Lowe CR. Detection of immuno-complex formation via surface plasmon resonance on gold-coated diffraction gratings. Biosensors. 1987;3(4):211–25.CrossRefPubMedGoogle Scholar
  2. 2.
    Liedberg B, Nylander C, Lunström I. Surface plasmon resonance for gas detection and biosensing. Sensors Actuators. 1983;4:299–304.CrossRefGoogle Scholar
  3. 3.
    Homola J (2008) Surface plasmon resonance sensors for detection of chemical and biological species. Chem Rev 108(2):462–493Google Scholar
  4. 4.
    Phillips KS, Cheng Q (2007) Recent advances in surface plasmon resonance based techniques for bioanalysis. Anal Bioanal Chem 387(5):1831–1840Google Scholar
  5. 5.
    Méjard R, Griesser HJ, Thierry B. Optical biosensing for label-free cellular studies. TrAC Trends Anal Chem. 2014;53:178–86.CrossRefGoogle Scholar
  6. 6.
    Abadian PN, Kelley CP, Goluch ED. Cellular analysis and detection using surface plasmon resonance techniques. Anal Chem. 2014;86(6):2799–812.CrossRefPubMedGoogle Scholar
  7. 7.
    Yanase Y, Hiragun T, Ishii K, Kawaguchi T, Yanase T, Kawai M. Surface plasmon resonance for cell-based clinical diagnosis. Sensors (Basel). 2014;14(3):4948–59.CrossRefGoogle Scholar
  8. 8.
    Rothenhäusler B, Knoll W. Surface-plasmon microscopy. Nature. 1988;332:615–7.CrossRefGoogle Scholar
  9. 9.
    Nelson BP, Grimsrud TE, Liles MR, Goodman RM, Corn RM. Surface plasmon resonance imaging measurements of DNA and RNA hybridization adsorption onto DNA microarrays. Anal Chem. 2001;73(1):1–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Wang W, Yang Y, Wang S, Nagaraj VJ, Liu Q, Wu J. Label-free measuring and mapping of binding kinetics of membrane proteins in single living cells. Nat Chem. 2012;4(10):846–53.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Syal K, Wang W, Shan X, Wang S, Chen HY, Tao N. Plasmonic imaging of protein interactions with single bacterial cells. Biosens Bioelectron. 2015;63(1):131–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Giebel K, Bechinger C, Herminghaus S, Riedel M, Leiderer P, Weiland U. Imaging of cell/substrate contacts of living cells with surface plasmon resonance microscopy. Biophys J. 1999;76(1 Pt 1):509–16.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Yanase Y, Hiragun T, Kaneko S, Gould HJ, Greaves MW, Hide M. Detection of refractive index changes in individual living cells by means of surface plasmon resonance imaging. Biosens Bioelectron. 2010;26(2):674–81.CrossRefPubMedGoogle Scholar
  14. 14.
    Fabini E, Danielson UH. Monitoring drug–serum protein interactions for early ADME prediction through surface plasmon resonance technology. J Pharm Biomed Anal. 2017;144:188–94.CrossRefPubMedGoogle Scholar
  15. 15.
    Meneghello A, Tartaggia S, Alvau MD, Polo F, Toffoli G. Biosensing technologies for therapeutic drug monitoring. Curr Med Chem. 2017.Google Scholar
  16. 16.
    Halpern AR, Wood JB, Wang Y, Corn RM. Single-nanoparticle near-infrared surface plasmon resonance microscopy for real-time measurements of DNA hybridization adsorption. ACS Nano. 2014;8(1):1022–30.CrossRefPubMedGoogle Scholar
  17. 17.
    Huang B, Yu F, Zare RN. Surface plasmon resonance imaging using a high numerical aperture microscope objective. Anal Chem. 2007;79(7):2979–83.CrossRefPubMedGoogle Scholar
  18. 18.
    Wang S, Shan X, Patel U, Huang X, Lu J, Li J. (2010) Label-free imaging, detection, and mass measurement of single viruses by surface plasmon resonance. Proc Natl Acad Sci U S A. 107(37):16028–32.Google Scholar
  19. 19.
    Yang Y, Yu H, Shan X, Wang W, Liu X, Wang S. Label-free tracking of single organelle transportation in cells with nanometer precision using a plasmonic imaging technique. Small. 2015;11(24):2878–84.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wang W, Wang S, Liu Q, Wu J, Tao N. Mapping single cell–substrate interactions by surface plasmon resonance microscopy. Langmuir. 2012;28(37):13373–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ladd J, Taylor AD, Piliarik M, Homola J, Jiang S. Label-free detection of cancer biomarker candidates using surface plasmon resonance imaging. Anal Bioanal Chem. 2009;393(4):1157–63.CrossRefPubMedGoogle Scholar
  22. 22.
    Yanase Y, Hiragun T, Yanase T, Kawaguchi T, Ishii K, Hide M. Evaluation of peripheral blood basophil activation by means of surface plasmon resonance imaging. Biosens Bioelectron. 2012;32(1):62–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Wang W, Foley K, Shan X, Wang S, Eaton S, Nagaraj VJ. Single cells and intracellular processes studied by a plasmonic-based electrochemical impedance microscopy. Nat Chem. 2011;3(3):249–55.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lu J, Li J. Label-free imaging of dynamic and transient calcium signaling in single cells. Angew Chem Int Ed Eng. 2015;54(46):13576–80.CrossRefGoogle Scholar
  25. 25.
    Liu XW, Yang Y, Wang W, Wang S, Gao M, Wu J. Plasmonic-based electrochemical impedance imaging of electrical activities in single cells. Angew Chem Int Ed Eng. 2017;56(30):8855–9.CrossRefGoogle Scholar
  26. 26.
    Wang Y, Dostalek J, Knoll W. Long range surface plasmon-enhanced fluorescence spectroscopy for the detection of aflatoxin M1 in milk. Biosens Bioelectron. 2009;24(7):2264–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Chabot V, Miron Y, Charette PG, Grandbois M. Identification of the molecular mechanisms in cellular processes that elicit a surface plasmon resonance (SPR) response using simultaneous surface plasmon-enhanced fluorescence (SPEF) microscopy. Biosens Bioelectron. 2013;50:125–31.CrossRefPubMedGoogle Scholar
  28. 28.
    Wark AW, Lee HJ, Corn RM. Long-range surface plasmon resonance imaging for bioaffinity sensors. Anal Chem. 2005;77(13):3904–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Mejard R, Thierry B. Systematic study of the surface plasmon resonance signals generated by cells for sensors with different characteristic lengths. PLoS One. 2014;9(10):e107978.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ziblat R, Lirtsman V, Davidov D, Aroeti B. Infrared surface plasmon resonance: a novel tool for real time sensing of variations in living cells. Biophys J. 2006;90(7):2592–9.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Yashunsky V, Shimron S, Lirtsman V, Weiss AM, Melamed-Book N, Golosovsky M. Real-time monitoring of transferrin-induced endocytic vesicle formation by mid-infrared surface plasmon resonance. Biophys J. 2009;97(4):1003–12.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hide M, Tsutsui T, Sato H, Nishimura T, Morimoto K, Yamamoto S. Real-time analysis of ligand-induced cell surface and intracellular reactions of living mast cells using a surface plasmon resonance-based biosensor. Anal Biochem. 2002;302(1):28–37.CrossRefPubMedGoogle Scholar
  33. 33.
    Yanase Y, Suzuki H, Tsutsui T, Hiragun T, Kameyoshi Y, Hide M. The SPR signal in living cells reflects changes other than the area of adhesion and the formation of cell constructions. Biosens Bioelectron. 2007;22(6):1081–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Hiragun T, Yanase Y, Kose K, Kawaguchi T, Uchida K, Tanaka S. Surface plasmon resonance-biosensor detects the diversity of responses against epidermal growth factor in various carcinoma cell lines. Biosens Bioelectron. 2012;32(1):202–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Deng S, Yu X, Liu R, Chen W, Wang P. A two-compartment microfluidic device for long-term live cell detection based on surface plasmon resonance. Biomicrofluidics. 2016;10(4):044109.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kuo YC, Ho JH, Yen TJ, Chen HF, Lee OK. Development of a surface plasmon resonance biosensor for real-time detection of osteogenic differentiation in live mesenchymal stem cells. PLoS One. 2011;6(7):e22382.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Nand A, Singh V, Wang P, Na J, Zhu J. Glycoprotein profiling of stem cells using lectin microarray based on surface plasmon resonance imaging. Anal Biochem. 2014;465:114–20.CrossRefPubMedGoogle Scholar
  38. 38.
    Fathi F, Rezabakhsh A, Rahbarghazi R, Rashidi MR. Early-stage detection of VE-cadherin during endothelial differentiation of human mesenchymal stem cells using SPR biosensor. Biosens Bioelectron. 2017;96:358–66.CrossRefPubMedGoogle Scholar
  39. 39.
    Yanase Y, Araki A, Suzuki H, Tsutsui T, Kimura T, Okamoto K. (2010) Development of an optical fiber SPR sensor for living cell activation. Biosens Bioelectron. 25(5):1244–7.Google Scholar
  40. 40.
    Peungthum P, Sudprasert K, Amarit R, Somboonkaew A, Sutapun B, Vongsakulyanon A. (2017) Surface plasmon resonance imaging for ABH antigen detection on red blood cells and in saliva: secretor status-related ABO subgroup identification. Analyst. 142(9):1471–81.Google Scholar
  41. 41.
    Abali F, Stevens M, Tibbe AGJ, Terstappen L, van der Velde PN, Schasfoort RBM. Isolation of single cells for protein therapeutics using microwell selection and surface plasmon resonance imaging. Anal Biochem. 2017;531:45–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Nishijima H, Kosaihira A, Shibata J, Ona T. Development of signaling echo method for cell-based quantitative efficacy evaluation of anti-cancer drugs in apoptosis without drug presence using high-precision surface plasmon resonance sensing. Anal Sci. 2010;26(5):529–34.CrossRefPubMedGoogle Scholar
  43. 43.
    Wang W, Yin L, Gonzalez-Malerva L, Wang S, Yu X, Eaton S. In situ drug-receptor binding kinetics in single cells: a quantitative label-free study of anti-tumor drug resistance. Sci Rep. 2014;4:6609.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Yin L, Yang Y, Wang S, Wang W, Zhang S, Tao N. Measuring binding kinetics of antibody-conjugated gold nanoparticles with intact cells. Small. 2015;11(31):3782–8.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Zhang F, Wang S, Yin L, Yang Y, Guan Y, Wang W. Quantification of epidermal growth factor receptor expression level and binding kinetics on cell surfaces by surface plasmon resonance imaging. Anal Chem. 2015;87(19):9960–5.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Berthuy OI, Blum LJ, Marquette CA. Cancer cells on chip for label-free detection of secreted molecules. Biosensors (Basel). 2016;6(1).Google Scholar
  47. 47.
    Mir TA, Shinohara H. Two-dimensional surface plasmon resonance imaging system for cellular analysis. Methods Mol Biol. 2017;1571:31–46.CrossRefPubMedGoogle Scholar
  48. 48.
    Cooper MA. Optical biosensors in drug discovery. Nat Rev Drug Discov. 2002;1(7):515–28.CrossRefPubMedGoogle Scholar
  49. 49.
    Bech EM, Martos-Maldonado MC, Wismann P, Sorensen KK, van Witteloostuijn SB, Thygesen MB. Peptide half-life extension: divalent, small-molecule albumin interactions direct the systemic properties of glucagon-like peptide 1 (GLP-1) analogues. J Med Chem. 2017;60(17):7434–46.CrossRefPubMedGoogle Scholar
  50. 50.
    Binz HK, Bakker TR, Phillips DJ, Cornelius A, Zitt C, Gottler T. Design and characterization of MP0250, a tri-specific anti-HGF/anti-VEGF DARPin(R) drug candidate. MAbs. 2017;9(8):1262–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Bresciani A, Missineo A, Gallo M, Cerretani M, Fezzardi P, Tomei L. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) drug discovery: biochemical toolbox to develop NRF2 activators by reversible binding of Kelch-like ECH-associated protein 1 (KEAP1). Arch Biochem Biophys. 2017;631:31–41.CrossRefPubMedGoogle Scholar
  52. 52.
    Chen S, Feng Z, Wang Y, Ma S, Hu Z, Yang P. Discovery of novel ligands for TNF-alpha and TNF receptor-1 through structure-based virtual screening and biological assay. J Chem Inf Model. 2017;57(5):1101–11.CrossRefPubMedGoogle Scholar
  53. 53.
    Donnelly DJ, Smith RA, Morin P, Lipovsek D, Gokemeijer J, Cohen D. Synthesis and biological evaluation of a novel 18F-labeled adnectin as a PET radioligand for imaging PD-L1 expression. J Nucl Med. 2017.Google Scholar
  54. 54.
    Kong W, Wu D, Hu N, Li N, Dai C, Chen X. Robust hybrid enzyme nanoreactor mediated plasmonic sensing strategy for ultrasensitive screening of anti-diabetic drug. Biosens Bioelectron. 2018;99:653–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Navratilova I, Besnard J, Hopkins AL. Screening for GPCR ligands using surface plasmon resonance. ACS Med Chem Lett. 2011;2(7):549–54.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Navratilova I, Dioszegi M, Myszka DG. Analyzing ligand and small molecule binding activity of solubilized GPCRs using biosensor technology. Anal Biochem. 2006;355(1):132–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Song S, Nguyen AH, Lee JU, Cha M, Sim SJ. Tracking of STAT3 signaling for anticancer drug-discovery based on localized surface plasmon resonance. Analyst. 2016;141(8):2493–501.CrossRefPubMedGoogle Scholar
  58. 58.
    Baird CL, Courtenay ES, Myszka DG. Surface plasmon resonance characterization of drug/liposome interactions. Anal Biochem. 2002;310(1):93–9.CrossRefPubMedGoogle Scholar
  59. 59.
    Danelian E, Karlen A, Karlsson R, Winiwarter S, Hansson A, Lofas S. SPR biosensor studies of the direct interaction between 27 drugs and a liposome surface: correlation with fraction absorbed in humans. J Med Chem. 2000;43(11):2083–6.CrossRefPubMedGoogle Scholar
  60. 60.
    Watanabe K, Matsuura K, Kawata F, Nagata K, Ning J, Kano H. Scanning and non-scanning surface plasmon microscopy to observe cell adhesion sites. Biomed Opt Express. 2012;3(2):354–9.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Yu H, Shan X, Wang S, Tao N. Achieving high spatial resolution surface plasmon resonance microscopy with image reconstruction. Anal Chem. 2017;89(5):2704–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of PharmacyNanjing Medical UniversityNanjingChina
  2. 2.Department of Clinical PharmacologyThe Affiliated Sir Run Run Hospital of Nanjing Medical UniversityNanjingChina
  3. 3.State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical EngineeringNanjing UniversityNanjingChina

Personalised recommendations