Analytical and Bioanalytical Chemistry

, Volume 408, Issue 2, pp 609–618 | Cite as

A nanoaggregate-on-mirror platform for molecular and biomolecular detection by surface-enhanced Raman spectroscopy

  • Gregory Q. Wallace
  • Mohammadali Tabatabaei
  • Mariachiara S. Zuin
  • Mark S. Workentin
  • François Lagugné-Labarthet
Research Paper


A nanoaggregate-on-mirror (NAOM) structure has been developed for molecular and biomolecular detection using surface-enhanced Raman spectroscopy (SERS). The smooth surface of the gold mirror allows for simple and homogeneous functionalization, while the introduction of the nanoaggregates enhances the Raman signal of the molecule(s) in the vicinity of the aggregate-mirror junction. This is evidenced by functionalizing the gold mirror with 4-nitrothiophenol, and the further addition of gold nanoaggregates promotes local SERS activity only in the areas with the nanoaggregates. The application of the NAOM platform for biomolecular detection is highlighted using glucose and H2O2 as molecules of interest. In both cases, the gold mirror is functionalized with 4-mercaptophenylboronic acid (4-MPBA). Upon exposure to glucose, the boronic acid moiety of 4-MPBA forms a cyclic boronate ester. Once the nanoaggregates are added to the surface, detection of glucose is possible without the use of an enzyme. This method of indirect detection provides a limit of detection of 0.05 mM, along with a linear range of detection from 0.1 to 15 mM for glucose, encompassing the physiological range of blood glucose concentration. The detection of H2O2 is achieved with optical inspection and SERS. The H2O2 interferes with the coating of the gold mirror, enabling qualitative detection by visual inspection. Simultaneously, the H2O2 reacts with the boronic acid to form a phenol, a change that is detected by SERS.

Graphical abstract

A nanoaggregate-on-mirror platform is SERS-active over the aggregate regions. When functionalized with a Raman reported the platform can be used to detect glucose based on changes to the observed SERS signal


Surface-enhanced Raman spectroscopy Nanoaggregate-on-mirror 4-Mercaptophenylboronic acid Glucose Hydrogen peroxide 



The authors gratefully acknowledge the Nanofabrication Facility at Western University. This research was funded by the Canada Research Chairs program in “Photonics and Nanosciences” (F.L.-L.). The authors also acknowledge the Natural Sciences and Engineering Research Council of Canada.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

216_2015_9142_MOESM1_ESM.pdf (100 kb)
ESM 1 (PDF 100 kb)


  1. 1.
    Fleischmann M, Hendra PJ, McQuillan AJ (1974) Raman spectra of pyridine adsorbed at a silver electrode. Chem Phys Lett 26(2):163–166CrossRefGoogle Scholar
  2. 2.
    Jeanmaire DL, Van Duyne RP (1977) Surface Raman spectroelectrochemistry. Part I. Heterocyclic, aromatic, and aliphatic amines adsorbed on the anodized silver electrode. J Electroanal Chem 84(1):1–20CrossRefGoogle Scholar
  3. 3.
    Albrecht MG, Creighton JA (1977) Anomalously intense Raman spectra of pyridine at a silver electrode. J Am Chem Soc 99(15):5215–5217CrossRefGoogle Scholar
  4. 4.
    Moskovits M (1985) Surface-enhanced spectroscopy. Rev Mod Phys 57(3):783–826CrossRefGoogle Scholar
  5. 5.
    Campion A, Kambhampati P (1998) Surface-enhanced Raman scattering. Chem Soc Rev 27(4):241–250CrossRefGoogle Scholar
  6. 6.
    Kneipp K, Wang Y, Kneipp H, Perelman LT, Itzkan I, Dasari RR, Feld MS (1997) Single molecule detection using surface-enhanced Raman scattering (SERS). Phys Rev Lett 78(9):1667–1670CrossRefGoogle Scholar
  7. 7.
    Nie S, Emory SR (1997) Probing single molecules and single nanoparticles by surface-enhanced Raman scattering. Science 275(5303):1102–1106CrossRefGoogle Scholar
  8. 8.
    De Angelis F, Gentile F, Mecarini F, Das G, Moretti M, Candeloro P, Coluccio ML, Cojoc G, Accardo A, Liberale C, Zaccaria RP, Perozziello G, Tirinato L, Toma A, Cuda G, Cingolani R, Di Fabrizio E (2011) Breaking the diffusion limit with super-hydrophobic delivery of molecules to plasmonic nanofocusing SERS structures. Nat Photonics 5(11):682–687CrossRefGoogle Scholar
  9. 9.
    Tabatabaei M, Najiminaini M, Davieau K, Kaminska B, Singh MR, Carson JJL, Lagugné-Labarthet F (2015) Tunable 3D plasmonic cavity nanosensors for surface-enhanced Raman spectroscopy with sub-femtomolar limit of detection. ACS Photonics 2(6):752–759CrossRefGoogle Scholar
  10. 10.
    Aravind PK, Metiu H (1982) Use of a perfectly conducting sphere to excite the plasmon of a flat surface. 1. Calculation of the local field with applications to surface-enhanced spectroscopy. J Phys Chem 86(26):5076–5084CrossRefGoogle Scholar
  11. 11.
    Aravind PK, Rendell RW, Metiu H (1982) A new geometry for field enhancement in surface-enhanced spectroscopy. Chem Phys Lett 85(4):396–403CrossRefGoogle Scholar
  12. 12.
    Mubeen S, Zhang S, Kim N, Lee S, Krämer S, Xu H, Moskovits M (2012) Plasmonic properties of gold nanoparticles separated from a gold mirror by an ultrathin oxide. Nano Lett 12(4):2088–2094CrossRefGoogle Scholar
  13. 13.
    Brolo AG (2012) Plasmonics for future biosensors. Nat Photonics 6(11):709–713CrossRefGoogle Scholar
  14. 14.
    Cheng XR, Wallace GQ, Lagugné-Labarthet F, Kerman K (2015) Au nanostructured surfaces for electrochemical and localized surface plasmon resonance-based monitoring of α-synuclein–small molecule interactions. ACS Appl Mater Interfaces 7(7):4081–4088CrossRefGoogle Scholar
  15. 15.
    Galarreta B, Tabatabaei M, Guieu V, Peyrin E, Lagugné-Labarthet F (2013) Microfluidic channel with embedded SERS 2D platform for the aptamer detection of ochratoxin A. Anal Bioanal Chem 405(5):1613–1621CrossRefGoogle Scholar
  16. 16.
    Hughes J, Izake EL, Lott WB, Ayoko GA, Sillence M (2014) Ultra sensitive label free surface enhanced Raman spectroscopy method for the detection of biomolecules. Talanta 130:20–25CrossRefGoogle Scholar
  17. 17.
    Li L, Hutter T, Steiner U, Mahajan S (2013) Single molecule SERS and detection of biomolecules with a single gold nanoparticle on a mirror junction. Analyst 138(16):4574–4578CrossRefGoogle Scholar
  18. 18.
    Masson J-F, Breault-Turcot J, Faid R, Poirier-Richard H-P, Yockell-Lelièvre H, Lussier F, Spatz JP (2014) Plasmonic nanopipette biosensor. Anal Chem 86(18):8998–9005CrossRefGoogle Scholar
  19. 19.
    Yang J, Palla M, Bosco FG, Rindzevicius T, Alstrøm TS, Schmidt MS, Boisen A, Ju J, Lin Q (2013) Surface-enhanced Raman spectroscopy based quantitative bioassay on aptamer-functionalized nanopillars using large-area Raman mapping. ACS Nano 7(6):5350–5359CrossRefGoogle Scholar
  20. 20.
    Yang T, Guo X, Wu Y, Wang H, Fu S, Wen Y, Yang H (2014) Facile and label-free detection of lung cancer biomarker in urine by magnetically assisted surface-enhanced Raman scattering. ACS Appl Mater Interfaces 6(23):20985–20993CrossRefGoogle Scholar
  21. 21.
    Zhao L, Blackburn J, Brosseau CL (2015) Quantitative detection of uric acid by electrochemical-surface enhanced Raman spectroscopy using a multilayered Au/Ag substrate. Anal Chem 87(1):441–447CrossRefGoogle Scholar
  22. 22.
    Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, Lin JK, Farzadfar F, Khang Y-H, Stevens GA, Rao M, Ali MK, Riley LM, Robinson CA, Ezzati M (2011) National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 378(9785):31–40CrossRefGoogle Scholar
  23. 23.
    Chen C, Xie Q, Yang D, Xiao H, Fu Y, Tan Y, Yao S (2013) Recent advances in electrochemical glucose biosensors: a review. RSC Adv 3(14):4473–4491CrossRefGoogle Scholar
  24. 24.
    Ward Muscatello MM, Stunja LE, Asher SA (2009) Polymerized crystalline colloidal array sensing of high glucose concentrations. Anal Chem 81(12):4978–4986CrossRefGoogle Scholar
  25. 25.
    Doi R (2014) Precise micromolar-level glucose determination using a glucose test strip for quick and approximate millimolar-level estimation. Anal Methods 6(23):9509–9513CrossRefGoogle Scholar
  26. 26.
    Sun X, Stagon S, Huang H, Chen J, Lei Y (2014) Functionalized aligned silver nanorod arrays for glucose sensing through surface enhanced Raman scattering. RSC Adv 4(45):23382–23388CrossRefGoogle Scholar
  27. 27.
    Ding Y, Wang Y, Su L, Zhang H, Lei Y (2010) Preparation and characterization of NiO-Ag nanofibers, NiO nanofibers, and porous Ag: towards the development of a highly sensitive and selective non-enzymatic glucose sensor. J Mater Chem 20(44):9918–9926CrossRefGoogle Scholar
  28. 28.
    Ferri S, Kojima K, Sode K (2011) Review of glucose oxidases and glucose dehydrogenases: a bird’s eye view of glucose sensing enzymes. J Diabetes Sci Technol 5(5):1068–1076CrossRefGoogle Scholar
  29. 29.
    Mano N, Heller A (2004) Detection of glucose at 2 f. concentration. Anal Chem 77(2):729–732CrossRefGoogle Scholar
  30. 30.
    Hu C, Yang D-P, Zhu F, Jiang F, Shen S, Zhang J (2014) Enzyme-labeled Pt@BSA nanocomposite as a facile electrochemical biosensing interface for sensitive glucose determination. ACS Appl Mater Interfaces 6(6):4170–4178CrossRefGoogle Scholar
  31. 31.
    Zhang Y, Li Y, Wu W, Jiang Y, Hu B (2014) Chitosan coated on the layers’ glucose oxidase immobilized on cysteamine/Au electrode for use as glucose biosensor. Biosens Bioelectron 60:271–276CrossRefGoogle Scholar
  32. 32.
    Yuan J, Cen Y, Kong X-J, Wu S, Liu C-L, Yu R-Q, Chu X (2015) MnO2-nanosheet-modified upconversion nanosystem for sensitive turn-on fluorescence detection of H2O2 and glucose in blood. ACS Appl Mater Interfaces 7(19):10548–10555CrossRefGoogle Scholar
  33. 33.
    Wilson R, Turner APF (1992) Glucose oxidase: an ideal enzyme. Biosens Bioelectron 7(3):165–185CrossRefGoogle Scholar
  34. 34.
    McCreery RL (2005) Magnitude of Raman scattering. In: Raman spectroscopy for chemical analysis. Wiley, pp. 15–33Google Scholar
  35. 35.
    Shafer-Peltier KE, Haynes CL, Glucksberg MR, Van Duyne RP (2002) Toward a glucose biosensor based on surface-enhanced Raman scattering. J Am Chem Soc 125(2):588–593CrossRefGoogle Scholar
  36. 36.
    Lyandres O, Shah NC, Yonzon CR, Walsh JT, Glucksberg MR, Van Duyne RP (2005) Real-time glucose sensing by surface-enhanced Raman spectroscopy in bovine plasma facilitated by a mixed decanethiol/mercaptohexanol partition layer. Anal Chem 77(19):6134–6139CrossRefGoogle Scholar
  37. 37.
    Torul H, Ciftci H, Dudak FC, Adguzel Y, Kulah H, Boyac IH, Tamer U (2014) Glucose determination based on a two component self-assembled monolayer functionalized surface-enhanced Raman spectroscopy (SERS) probe. Anal Methods 6(14):5097–5104CrossRefGoogle Scholar
  38. 38.
    Fang H, Kaur G, Wang B (2004) Progress in boronic acid-based fluorescent glucose sensors. J Fluoresc 14(5):481–489CrossRefGoogle Scholar
  39. 39.
    Kanayama N, Kitano H (1999) Interfacial recognition of sugars by boronic acid-carrying self-assembled monolayer. Langmuir 16(2):577–583CrossRefGoogle Scholar
  40. 40.
    Kong KV, Ho CJH, Gong T, Lau WKO, Olivo M (2014) Sensitive SERS glucose sensing in biological media using alkyne functionalized boronic acid on planar substrates. Biosens Bioelectron 56:186–191CrossRefGoogle Scholar
  41. 41.
    Kong KV, Lam Z, Lau WKO, Leong WK, Olivo M (2013) A transition metal carbonyl probe for use in a highly specific and sensitive SERS-based assay for glucose. J Am Chem Soc 135(48):18028–18031CrossRefGoogle Scholar
  42. 42.
    Wallace GQ, Zuin MS, Tabatabaei M, Gobbo P, Lagugné-Labarthet F, Workentin MS (2015) Gold nanosponges (AuNS): a versatile nanostructure for surface-enhanced Raman spectroscopic detection of molecules and biomolecules. Analyst 140(21):7278–7282CrossRefGoogle Scholar
  43. 43.
    Murray-Methot M-P, Menegazzo N, Masson J-F (2008) Analytical and physical optimization of nanohole-array sensors prepared by modified nanosphere lithography. Analyst 133(12):1714–1721CrossRefGoogle Scholar
  44. 44.
    Wallace GQ, Tabatabaei M, Lagugné-Labarthet F (2014) Towards attomolar detection using a surface-enhanced Raman spectroscopy platform fabricated by nanosphere lithography. Can J Chem 92(1):1–8CrossRefGoogle Scholar
  45. 45.
    Gobbo P, Biondi MJ, Feld JJ, Workentin MS (2013) Arresting the time-dependent H2O2 mediated synthesis of gold nanoparticles for analytical detection and preparative chemistry. J Mater Chem B 1(33):4048–4051CrossRefGoogle Scholar
  46. 46.
    de la Rica R, Stevens MM (2012) Plasmonic ELISA for the ultrasensitive detection of disease biomarkers with the naked eye. Nat Nanotechnol 7(12):821–824CrossRefGoogle Scholar
  47. 47.
    Tabatabaei M, Sangar A, Kazemi-Zanjani N, Torchio P, Merlen A, Lagugné-Labarthet F (2013) Optical properties of silver and gold tetrahedral nanopyramid arrays prepared by nanosphere lithography. J Phys Chem C 117(28):14778–14786CrossRefGoogle Scholar
  48. 48.
    Li J, Chen L, Lou T, Wang Y (2011) Highly sensitive SERS detection of As3+ ions in aqueous media using glutathione functionalized silver nanoparticles. ACS Appl Mater Interfaces 3(10):3936–3941CrossRefGoogle Scholar
  49. 49.
    Sun F, Bai T, Zhang L, Ella-Menye J-R, Liu S, Nowinski AK, Jiang S, Yu Q (2014) Sensitive and fast detection of fructose in complex media via symmetry breaking and signal amplification using surface-enhanced Raman spectroscopy. Anal Chem 86(5):2387–2394CrossRefGoogle Scholar
  50. 50.
    Cao X, Wang N, Jia S, Shao Y (2013) Detection of glucose based on bimetallic PtCu nanochains modified electrodes. Anal Chem 85(10):5040–5046CrossRefGoogle Scholar
  51. 51.
    Niu X, Lan M, Zhao H, Chen C (2013) Highly sensitive and selective nonenzymatic detection of glucose using three-dimensional porous nickel nanostructures. Anal Chem 85(7):3561–3569CrossRefGoogle Scholar
  52. 52.
    Wang H-C, Zhou H, Chen B, Mendes PM, Fossey JS, James TD, Long Y-T (2013) A bis-boronic acid modified electrode for the sensitive and selective determination of glucose concentrations. Analyst 138(23):7146–7151CrossRefGoogle Scholar
  53. 53.
    Zhao Q, Chen S, Huang H, Zhang L, Wang L, Liu F, Chen J, Zeng Y, Chu PK (2014) Colorimetric and ultra-sensitive fluorescence resonance energy transfer determination of H2O2 and glucose by multi-functional Au nanoclusters. Analyst 139(6):1498–1503CrossRefGoogle Scholar
  54. 54.
    Ryckeboer E, Bockstaele R, Vanslembrouck M, Baets R (2014) Glucose sensing by waveguide-based absorption spectroscopy on a silicon chip. Biomed Opt Express 5(5):1636–1648CrossRefGoogle Scholar
  55. 55.
    Song J, Xu L, Zhou C, Xing R, Dai Q, Liu D, Song H (2013) Synthesis of graphene oxide based CuO nanoparticles composite electrode for highly enhanced nonenzymatic glucose detection. ACS Appl Mater Interfaces 5(24):12928–12934CrossRefGoogle Scholar
  56. 56.
    Wang G-L, Xu X, Wu X, Cao G, Dong Y, Li Z (2014) Visible-light-stimulated enzymelike activity of graphene oxide and its application for facile glucose sensing. J Phys Chem C 118(48):28109–28117CrossRefGoogle Scholar
  57. 57.
    Tang Y, Yang Q, Wu T, Liu L, Ding Y, Yu B (2014) Fluorescence enhancement of cadmium selenide quantum dots assembled on silver nanoparticles and its application to glucose detection. Langmuir 30(22):6324–6330CrossRefGoogle Scholar
  58. 58.
    Li Y, Zhong Y, Zhang Y, Weng W, Li S (2015) Carbon quantum dots/octahedral Cu2O nanocomposites for non-enzymatic glucose and hydrogen peroxide amperometric sensor. Sens Actuators B Chem 206:735–743CrossRefGoogle Scholar
  59. 59.
    Hong X, Peng Y, Bai J, Ning B, Liu Y, Zhou Z, Gao Z (2014) A novel opal closest-packing photonic crystal for naked-eye glucose detection. Small 10(7):1308–1313CrossRefGoogle Scholar
  60. 60.
    Ceja-Fdez A, Lopez-Luke T, Torres-Castro A, Wheeler DA, Zhang JZ, De la Rosa E (2014) Glucose detection using SERS with multi-branched gold nanostructures in aqueous medium. RSC Adv 4(103):59233–59241Google Scholar
  61. 61.
    Kennedy DC, McKay CS, L-l T, Rouleau Y, Pezacki JP (2011) Carbon-bonded silver nanoparticles: alkyne-functionalized ligands for SERS imaging of mammalian cells. Chem Commun 47(11):3156–3158CrossRefGoogle Scholar
  62. 62.
    Bi X, Du X, Jiang J, Huang X (2015) Facile and sensitive glucose sandwich assay using in situ-generated Raman reporters. Anal Chem 87(3):2016–2021CrossRefGoogle Scholar
  63. 63.
    Huang Y, Wang W, Li Z, Qin X, Bu L, Tang Z, Fu Y, Ma M, Xie Q, Yao S, Hu J (2013) Horseradish peroxidase-catalyzed synthesis of poly(thiophene-3-boronic acid) biocomposites for mono-/bi-enzyme immobilization and amperometric biosensing. Biosens Bioelectron 44:41–47CrossRefGoogle Scholar
  64. 64.
    Şenel M, Nergiz C, Dervisevic M, Çevik E (2013) Development of amperometric glucose biosensor based on reconstitution of glucose oxidase on polymeric 3-aminophenyl boronic acid monolayer. Electroanalysis 25(5):1194–1200CrossRefGoogle Scholar
  65. 65.
    Ji W, Xue X, Ruan W, Wang C, Ji N, Chen L, Li Z, Song W, Zhao B, Lombardi JR (2011) Scanned chemical enhancement of surface-enhanced Raman scattering using a charge-transfer complex. Chem Commun 47(8):2426–2428CrossRefGoogle Scholar
  66. 66.
    Dong J, Guo G, Xie W, Li Y, Zhang M, Qian W (2015) Free radical-quenched SERS probes for detecting H2O2 and glucose. Analyst 140(8):2741–2746CrossRefGoogle Scholar
  67. 67.
    Rasti N, Toyserkani E, Ismail F (2011) Chemical modification of titanium immersed in hydrogen peroxide using nanosecond pulsed fiber laser irradiation. Mater Lett 65(6):951–954CrossRefGoogle Scholar
  68. 68.
    Nilsson S, Klett O, Svedberg M, Amirkhani A, Nyholm L (2003) Gold-coated fused-silica sheathless electrospray emitters based on vapor-deposited titanium adhesion layers. Rapid Commun Mass Spectrom 17(14):1535–1540CrossRefGoogle Scholar
  69. 69.
    van den Meerakker JEAM, Metsemakers JP, Giesbers JB (2002) The etching of Ti adhesion layers in H2O2 solutions. J Electrochem Soc 149(5):C256–C260CrossRefGoogle Scholar
  70. 70.
    Syamala Kiran M, Itoh T, K-i Y, Kawashima N, Biju V, Ishikawa M (2010) Selective detection of HbA1c using surface enhanced resonance Raman spectroscopy. Anal Chem 82(4):1342–1348CrossRefGoogle Scholar
  71. 71.
    Yuko S, Yamamoto MI, Ozaki Y, Itoh T (2014) Fundamental studies on enhancement and blinking mechanism of surface-enhanced Raman scattering (SERS) and basic applications of SERS biological sensing. Front Phys 9(1):31–46CrossRefGoogle Scholar
  72. 72.
    Tabatabaei M, Caetano FA, Vedraine S, Norton PR, Ferguson SSG, Lagugné-Labarthet F (2013) Directing GPCR-transfected cells and neuronal projections with nano-scale resolution. Biomaterials 34(38):10065–10074CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Gregory Q. Wallace
    • 1
    • 2
  • Mohammadali Tabatabaei
    • 1
    • 2
  • Mariachiara S. Zuin
    • 1
    • 2
  • Mark S. Workentin
    • 1
    • 2
  • François Lagugné-Labarthet
    • 1
    • 2
  1. 1.Department of ChemistryUniversity of Western OntarioLondonCanada
  2. 2.Centre for Advanced Materials and Biomaterials ResearchUniversity of Western OntarioLondonCanada

Personalised recommendations