Raman-based optical imaging is a promising analytical tool for noninvasive, label-free chemical imaging of lipid bilayers and cellular membranes. Imaging using spontaneous Raman scattering suffers from a low intensity that hinders its use in some cellular applications. However, developments in coherent Raman imaging, surface-enhanced Raman imaging, and tip-enhanced Raman imaging have enabled video-rate imaging, excellent detection limits, and nanometer spatial resolution, respectively. After a brief introduction to these commonly used Raman imaging techniques for cell membrane studies, this review discusses selected applications of these modalities for chemical imaging of membrane proteins and lipids. Finally, recent developments in chemical tags for Raman imaging and their applications in the analysis of selected cell membrane components are summarized. Ongoing developments toward improving the temporal and spatial resolution of Raman imaging and small-molecule tags with strong Raman scattering cross sections continue to expand the utility of Raman imaging for diverse cell membrane studies.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Singer SJ, Nicolson GL. 1.  1972. The fluid mosaic model of the structure of cell membranes. Science 175:720–31 [Google Scholar]
  2. Nicolson GL. 2.  2014. The Fluid–Mosaic Model of Membrane Structure: still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years. Biochim. Biophys. Acta 1838:1451–66 [Google Scholar]
  3. Maxfield FR, Tabas I. 3.  2005. Role of cholesterol and lipid organization in disease. Nature 438:612–21 [Google Scholar]
  4. Leth-Larsen R, Lund RR, Ditzel HJ. 4.  2010. Plasma membrane proteomics and its application in clinical cancer biomarker discovery. Mol. Cell Proteom. 9:1369–82 [Google Scholar]
  5. Raman CV, Krishnan KS. 5.  1928. A new type of secondary radiation. Nature 121:501–2 [Google Scholar]
  6. Matthews Q, Brolo AG, Lum J, Duan X, Jirasek A. 6.  2011. Raman spectroscopy of single human tumour cells exposed to ionizing radiation in vitro. Phys. Med. Biol 5619–38 [Google Scholar]
  7. Ando J, Palonpon AF, Sodeoka M, Fujita K. 7.  2016. High-speed Raman imaging of cellular processes. Curr. Opin. Chem. Biol. 33:16–24 [Google Scholar]
  8. Stewart S, Priore RJ, Nelson MP, Treado PJ. 8.  2012. Raman imaging. Annu. Rev. Anal. Chem. 5:337–60 [Google Scholar]
  9. Opilik L, Schmid T, Zenobi R. 9.  2013. Modern Raman imaging: vibrational spectroscopy on the micrometer and nanometer scales. Annu. Rev. Anal. Chem. 6:379–98 [Google Scholar]
  10. Butler HJ, Ashton L, Bird B, Cinque G, Curtis K. 10.  et al. 2016. Using Raman spectroscopy to characterize biological materials. Nat. Protoc. 11:664–87 [Google Scholar]
  11. Terhune RW, Maker PD, Savage CM. 11.  1965. Measurements of nonlinear light scattering. Phys. Rev. Lett. 14:681–84 [Google Scholar]
  12. Duncan MD, Reintjes J, Manuccia TJ. 12.  1982. Scanning coherent anti-Stokes Raman microscope. Opt. Lett. 7:350 [Google Scholar]
  13. Zumbusch A, Holtom GR, Xie XS. 13.  1999. Three-dimensional vibrational imaging by coherent anti-Stokes Raman scattering. Phys. Rev. Lett. 82:4142–45 [Google Scholar]
  14. Evans CL, Potma EO, Puoris'haag M, Cote D, Lin CP, Xie XS. 14.  2005. Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy. PNAS 102:16807–12 [Google Scholar]
  15. Volkmer A, Cheng J-X, Xie XS. 15.  2001. Vibrational imaging with high sensitivity via epidetected coherent anti-Stokes Raman scattering microscopy. Phys. Rev. Lett. 87:023901 [Google Scholar]
  16. Evans CL, Xie XS. 16.  2008. Coherent anti-Stokes Raman scattering microscopy: chemical imaging for biology and medicine. Annu. Rev. Anal. Chem. 1:883–909 [Google Scholar]
  17. Cheng J-X, Xie XS. 17.  2004. Coherent anti-Stokes Raman scattering microscopy: instrumentation, theory, and applications. J. Phys. Chem. B 108:827–40 [Google Scholar]
  18. Müller M, Zumbusch A. 18.  2007. Coherent anti-Stokes Raman scattering microscopy. ChemPhysChem 8:2156–70 [Google Scholar]
  19. El-Diasty F. 19.  2011. Coherent anti-Stokes Raman scattering: spectroscopy and microscopy. Vib. Spectrosc. 55:1–37 [Google Scholar]
  20. Cheng JX, Xie XS. 20.  2015. Vibrational spectroscopic imaging of living systems: an emerging platform for biology and medicine. Science 350:aaa8870 [Google Scholar]
  21. Saar BG, Freudiger CW, Reichman J, Stanley CM, Holtom GR, Xie XS. 21.  2010. Video-rate molecular imaging in vivo with stimulated Raman scattering. Science 330:1368–70 [Google Scholar]
  22. Müller M, Schins JM. 22.  2002. Imaging the thermodynamic state of lipid membranes with multiplex CARS microscopy. J. Phys. Chem. B 106:3715–23 [Google Scholar]
  23. Rinia HA, Burger KNJ, Bonn M, Müller M. 23.  2008. Quantitative label-free imaging of lipid composition and packing of individual cellular lipid droplets using multiplex CARS microscopy. Biophys. J. 95:4908–14 [Google Scholar]
  24. Wurpel GWH, Schins JM, Müller M. 24.  2002. Chemical specificity in three-dimensional imaging with multiplex coherent anti-Stokes Raman scattering microscopy. Opt. Lett. 27:1093 [Google Scholar]
  25. Jüngst C, Winterhalder MJ, Zumbusch A. 25.  2011. Fast and long term lipid droplet tracking with CARS microscopy. J. Biophotonics 4:435–41 [Google Scholar]
  26. Cheng J-X, Jia YK, Zheng G, Xie XS. 26.  2002. Laser-scanning coherent anti-Stokes Raman scattering microscopy and applications to cell biology. Biophys. J. 83:502–9 [Google Scholar]
  27. Kano H. 27.  2008. Molecular vibrational imaging of a human cell by multiplex coherent anti-Stokes Raman scattering microspectroscopy using a supercontinuum light source. J. Raman Spectrosc. 39:1649–52 [Google Scholar]
  28. Fu Y, Wang H, Huff TB, Shi R, Cheng JX. 28.  2007. Coherent anti-Stokes Raman scattering imaging of myelin degradation reveals a calcium-dependent pathway in lyso-PtdCho-induced demyelination. J. Neurosci. Res. 85:2870–81 [Google Scholar]
  29. Imitola J, Cote D, Rasmussen S, Xie XS, Liu Y. 29.  et al. 2011. Multimodal coherent anti-Stokes Raman scattering microscopy reveals microglia-associated myelin and axonal dysfunction in multiple sclerosis-like lesions in mice. J. Biomed. Opt 16021109 [Google Scholar]
  30. Bélanger E, Henry FP, Vallée R, Randolph MA, Kochevar IE. 30.  et al. 2011. In vivo evaluation of demyelination and remyelination in a nerve crush injury model. Biomed. Opt. Express 22698–708 [Google Scholar]
  31. Wang H-W, Le TT, Cheng J-X. 31.  2008. Label-free imaging of arterial cells and extracellular matrix using a multimodal CARS microscope. Opt. Commun. 281:1813–22 [Google Scholar]
  32. Pliss A, Kuzmin AN, Kachynski AV, Prasad PN. 32.  2010. Nonlinear optical imaging and Raman microspectrometry of the cell nucleus throughout the cell cycle. Biophys. J. 99:3483–91 [Google Scholar]
  33. Nan X, Cheng J-X, Xie XS. 33.  2003. Vibrational imaging of lipid droplets in live fibroblast cells with coherent anti-Stokes Raman scattering microscopy. J. Lipid Res. 44:2202–8 [Google Scholar]
  34. Nan X, Potma EO, Xie XS. 34.  2006. Nonperturbative chemical imaging of organelle transport in living cells with coherent anti-Stokes Raman scattering microscopy. Biophys. J. 91:728–35 [Google Scholar]
  35. Lyn RK, Kennedy DC, Stolow A, Ridsdale A, Pezacki JP. 35.  2010. Dynamics of lipid droplets induced by the hepatitis C virus core protein. Biochem. Biophys. Res. Commun. 399:518–24 [Google Scholar]
  36. Brown DA, London E. 36.  1998. Functions of lipid rafts in biological membranes. Annu. Rev. Cell Dev. Biol. 14:111–36 [Google Scholar]
  37. Pike LJ. 37.  2003. Lipid rafts: bringing order to chaos. J. Lipid Res. 44:655–67 [Google Scholar]
  38. Wurpel GWH, Schins JM, Müller M. 38.  2004. Direct measurement of chain order in single phospholipid mono- and bilayers with multiplex CARS. J. Phys. Chem. B 108:3400–3 [Google Scholar]
  39. Potma EO, Xie XS. 39.  2005. Direct visualization of lipid phase segregation in single lipid bilayers with coherent anti-Stokes Raman Scattering microscopy. ChemPhysChem 6:77–79 [Google Scholar]
  40. Li L, Wang H, Cheng J-X. 40.  2005. Quantitative coherent anti-Stokes Raman scattering imaging of lipid distribution in coexisting domains. Biophys. J. 89:3480–90 [Google Scholar]
  41. Li L, Cheng J-X. 41.  2008. Label-free coherent anti-Stokes Raman scattering imaging of coexisting lipid domains in single bilayers. J. Phys. Chem. B 112:1576–79 [Google Scholar]
  42. Zhang D, Wang P, Slipchenko MN, Cheng J-X. 42.  2014. Fast vibrational imaging of single cells and tissues by stimulated Raman scattering microscopy. Acc. Chem. Res. 47:2282–90 [Google Scholar]
  43. Fu D, Lu F-K, Zhang X, Freudiger C, Pernik DR. 43.  et al. 2012. Quantitative chemical imaging with multiplex stimulated Raman scattering microscopy. J. Am. Chem. Soc. 134:3623–26 [Google Scholar]
  44. Suhalim JL, Chung C-Y, Lilledahl MB, Lim RS, Levi M. 44.  et al. 2012. Characterization of cholesterol crystals in atherosclerotic plaques using stimulated Raman scattering and second-harmonic generation microscopy. Biophys. J. 102:1988–95 [Google Scholar]
  45. Zhang D, Wang P, Slipchenko MN, Ben-Amotz D, Weiner AM, Cheng J-X. 45.  2013. Quantitative vibrational imaging by hyperspectral stimulated Raman scattering microscopy and multivariate curve resolution analysis. Anal. Chem. 85:98–106 [Google Scholar]
  46. Zhang X, Roeffaers MBJ, Basu S, Daniele JR, Fu D. 46.  et al. 2012. Label-free live-cell imaging of nucleic acids using stimulated Raman scattering microscopy. ChemPhysChem 13:1054–59 [Google Scholar]
  47. Yue S, Li J, Lee SY, Lee HJ, Shao T. 47.  et al. 2014. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab. 19:393–406 [Google Scholar]
  48. Slipchenko MN, Le TT, Chen H, Cheng J-X. 48.  2009. High-speed vibrational imaging and spectral analysis of lipid bodies by compound Raman microscopy. J. Phys. Chem. B 113:7681–86 [Google Scholar]
  49. Zhang D, Slipchenko MN, Cheng J-X. 49.  2011. Highly sensitive vibrational imaging by femtosecond pulse stimulated Raman loss. J. Phys. Chem. Lett. 2:1248–53 [Google Scholar]
  50. Liao C-S, Slipchenko MN, Wang P, Li J, Lee S-Y. 50.  et al. 2015. Microsecond scale vibrational spectroscopic imaging by multiplex stimulated Raman scattering microscopy. Light Sci. Appl. 4:e265 [Google Scholar]
  51. Li J, Cheng J-X. 51.  2014. Direct visualization of de novo lipogenesis in single living cells. Sci. Rep. 4:6807 [Google Scholar]
  52. Hu F, Wei L, Zheng C, Shen Y, Min W. 52.  2014. Live-cell vibrational imaging of choline metabolites by stimulated Raman scattering coupled with isotope-based metabolic labeling. Analyst 139:2312 [Google Scholar]
  53. Lee HJ, Zhang W, Zhang D, Yang Y, Liu B. 53.  et al. 2015. Assessing cholesterol storage in live cells and C. elegans by stimulated Raman scattering imaging of phenyl-diyne cholesterol. Sci. Rep. 5:7930 [Google Scholar]
  54. Kim H, Bryant GW, Stranick SJ. 54.  2012. Superresolution four-wave mixing microscopy. Opt. Express 20:6042 [Google Scholar]
  55. Wang P, Slipchenko MN, Mitchell J, Yang C, Potma EO. 55.  et al. 2013. Far-field imaging of non-fluorescent species with subdiffraction resolution. Nat. Photonics 7:449–53 [Google Scholar]
  56. Silva WR, Graefe CT, Frontiera RR. 56.  2016. Toward label-free super-resolution microscopy. ACS Photonics 3:79–86 [Google Scholar]
  57. Hildebrandt P, Stockburger M. 57.  1984. Surface-enhanced resonance Raman spectroscopy of rhodamine 6G adsorbed on colloidal silver. J. Phys. Chem. 88:5935–44 [Google Scholar]
  58. Creighton JA, Blatchford CG, Albrecht MG. 58.  1979. Plasma resonance enhancement of Raman scattering by pyridine adsorbed on silver or gold sol particles of size comparable to the excitation wavelength. J. Chem. Soc. Faraday Trans. 2 75:790 [Google Scholar]
  59. Grabar KC, Brown KR, Keating CD, Stranick SJ, Tang S-L, Natan MJ. 59.  1997. Nanoscale characterization of gold colloid monolayers: a comparison of four techniques. Anal. Chem. 69:471–77 [Google Scholar]
  60. Blatchford CG, Campbell JR, Creighton JA. 60.  1982. Plasma resonance–enhanced Raman scattering by absorbates on gold colloids: the effects of aggregation. Surf. Sci. 120:435–55 [Google Scholar]
  61. Curtis AC, Duff DG, Edwards PP, Jefferson DA, Johnson BFG. 61.  et al. 1988. Preparation and structural characterization of an unprotected copper sol. J. Phys. Chem. 92:2270–75 [Google Scholar]
  62. Huang HH, Yan FQ, Kek YM, Chew CH, Xu GQ. 62.  et al. 1997. Synthesis, characterization, and nonlinear optical properties of copper nanoparticles. Langmuir 13:172–75 [Google Scholar]
  63. Moskovits M. 63.  1985. Surface-enhanced spectroscopy. Rev. Mod. Phys. 57:783–826 [Google Scholar]
  64. Moskovits M. 64.  2013. Persistent misconceptions regarding SERS. Phys. Chem. Chem. Phys. 15:5301 [Google Scholar]
  65. McNay G, Eustace D, Smith WE, Faulds K, Graham D. 65.  2011. Surface-enhanced Raman scattering (SERS) and surface-enhanced resonance Raman scattering (SERRS): a review of applications. Appl. Spectrosc. 65:825–37 [Google Scholar]
  66. Jamieson LE, Asiala SM, Gracie K, Faulds K, Graham D. 66.  2017. Bioanalytical measurements enabled by surface-enhanced Raman scattering (SERS) probes. Annu. Rev. Anal. Chem. 10:415–37 [Google Scholar]
  67. Pallaoro A, Braun GB, Moskovits M. 67.  2015. Biotags based on surface-enhanced Raman can be as bright as fluorescence tags. Nano Lett. 15:6745–50 [Google Scholar]
  68. Sabatté G, Keir R, Lawlor M, Black M, Graham D, Smith WE. 68.  2008. Comparison of surface-enhanced resonance Raman scattering and fluorescence for detection of a labeled antibody. Anal. Chem. 80:2351–56 [Google Scholar]
  69. Goddard G, Brown LO, Habbersett R, Brady CI, Martin JC. 69.  et al. 2010. High-resolution spectral analysis of individual SERS-active nanoparticles in flow. J. Am. Chem. Soc. 132:6081–90 [Google Scholar]
  70. Han XX, Jia HY, Wang YF, Lu ZC, Wang CX. 70.  et al. 2008. Analytical technique for label-free multi-protein detection based on western blot and surface-enhanced Raman scattering. Anal. Chem. 80:2799–804 [Google Scholar]
  71. Pavel I, McCarney E, Elkhaled A, Morrill A, Plaxco K, Moskovits M. 71.  2008. Label-free SERS detection of small proteins modified to act as bifunctional linkers. J. Phys. Chem. C 112:4880–83 [Google Scholar]
  72. Zanchet D, Micheel CM, Parak WJ, Gerion D, Williams SC, Alivisatos AP. 72.  2002. Electrophoretic and structural studies of DNA-directed Au nanoparticle groupings. J. Phys. Chem. B 106:11758–63 [Google Scholar]
  73. Chen JIL, Chen Y, Ginger DS. 73.  2010. Plasmonic nanoparticle dimers for optical sensing of DNA in complex media. J. Am. Chem. Soc. 132:9600–1 [Google Scholar]
  74. Fabris L, Dante M, Nguyen T-Q, Tok JBH, Bazan GC. 74.  2008. SERS aptatags: new responsive metallic nanostructures for heterogeneous protein detection by surface enhanced Raman spectroscopy. Adv. Funct. Mater. 18:2518–25 [Google Scholar]
  75. Indrasekara ASDS, Paladini BJ, Naczynski DJ, Starovoytov V, Moghe PV, Fabris L. 75.  2013. Dimeric gold nanoparticle assemblies as tags for SERS-based cancer detection. Adv. Healthc. Mater. 2:1370–76 [Google Scholar]
  76. Chen D, Feng H, Li J. 76.  2012. Graphene oxide: preparation, functionalization, and electrochemical applications. Chem. Rev. 112:6027–53 [Google Scholar]
  77. Liu Z, Guo Z, Zhong H, Qin X, Wan M, Yang B. 77.  2013. Graphene oxide based surface-enhanced Raman scattering probes for cancer cell imaging. Phys. Chem. Chem. Phys. 15:2961 [Google Scholar]
  78. Huang J, Zong C, Shen H, Liu M, Chen B. 78.  et al. 2012. Mechanism of cellular uptake of graphene oxide studied by surface-enhanced Raman spectroscopy. Small 8:2577–84 [Google Scholar]
  79. Liu Q, Wei L, Wang J, Peng F, Luo D. 79.  et al. 2012. Cell imaging by graphene oxide based on surface enhanced Raman scattering. Nanoscale 4:7084–89 [Google Scholar]
  80. Lin D, Qin T, Wang Y, Sun X, Chen L. 80.  2014. Graphene oxide wrapped SERS tags: multifunctional platforms toward optical labeling, photothermal ablation of bacteria, and the monitoring of killing effect. ACS Appl. Mater. Interfaces 6:1320–29 [Google Scholar]
  81. Rodríguez-Lorenzo L, Álvarez-Puebla RA, Pastoriza-Santos I, Mazzucco S, Stéphan O. 81.  et al. 2009. Zeptomol detection through controlled ultrasensitive surface-enhanced Raman scattering. J. Am. Chem. Soc. 131:4616–18 [Google Scholar]
  82. Aldeanueva-Potel P, Carbó-Argibay E, Pazos-Pérez N, Barbosa S, Pastoriza-Santos I. 82.  et al. 2012. Spiked gold beads as substrates for single-particle SERS. ChemPhysChem 13:2561–65 [Google Scholar]
  83. Rycenga M, Camargo PHC, Li W, Moran CH, Xia Y. 83.  2010. Understanding the SERS effects of single silver nanoparticles and their dimers, one at a time. J. Phys. Chem. Lett. 1:696–703 [Google Scholar]
  84. McLintock A, Cunha-Matos CA, Zagnoni M, Millington OR, Wark AW. 84.  2014. Universal surface-enhanced Raman tags: individual nanorods for measurements from the visible to the infrared (514–1064 nm). ACS Nano 8:8600–9 [Google Scholar]
  85. Mulvihill MJ, Ling XY, Henzie J, Yang P. 85.  2010. Anisotropic etching of silver nanoparticles for plasmonic structures capable of single-particle SERS. J. Am. Chem. Soc. 132:268–74 [Google Scholar]
  86. Kleinman SL, Sharma B, Blaber MG, Henry A-I, Valley N. 86.  et al. 2013. Structure enhancement factor relationships in single gold nanoantennas by surface-enhanced Raman excitation spectroscopy. J. Am. Chem. Soc. 135:301–8 [Google Scholar]
  87. Liang H, Li Z, Wang W, Wu Y, Xu H. 87.  2009. Highly surface-roughened “flower-like” silver nanoparticles for extremely sensitive substrates of surface-enhanced Raman scattering. Adv. Mater. 21:4614–18 [Google Scholar]
  88. Steinigeweg D, Schütz M, Schlücker S. 88.  2013. Single gold trimers and 3D superstructures exhibit a polarization-independent SERS response. Nanoscale 5:110–13 [Google Scholar]
  89. Rycenga M, Xia X, Moran CH, Zhou F, Qin D. 89.  et al. 2011. Generation of hot spots with silver nanocubes for single-molecule detection by surface-enhanced Raman scattering. Angew. Chem. Int. Ed. 50:5473–77 [Google Scholar]
  90. Lin HX, Li JM, Liu BJ, Liu DY, Liu J. 90.  et al. 2013. Uniform gold spherical particles for single-particle surface-enhanced Raman spectroscopy. Phys. Chem. Chem. Phys. 15:4130–35 [Google Scholar]
  91. Yuan H, Liu Y, Fales AM, Li YL, Liu J, Vo-Dinh T. 91.  2013. Quantitative surface-enhanced resonant Raman scattering multiplexing of biocompatible gold nanostars for in vitro and ex vivo detection. Anal. Chem. 85:208–12 [Google Scholar]
  92. Talley CE, Jackson JB, Oubre C, Grady NK, Hollars CW. 92.  et al. 2005. Surface-enhanced Raman scattering from individual Au nanoparticles and nanoparticle dimer substrates. Nano Lett. 5:1569–74 [Google Scholar]
  93. Zhang P, Guo Y. 93.  2009. Surface-enhanced Raman scattering inside metal nanoshells. J. Am. Chem. Soc. 131:3808–9 [Google Scholar]
  94. Gandra N, Singamaneni S. 94.  2013. Bilayered Raman-intense gold nanostructures with hidden tags (BRIGHTs) for high-resolution bioimaging. Adv. Mater. 25:1022–27 [Google Scholar]
  95. Hu C, Shen J, Yan J, Zhong J, Qin W. 95.  et al. 2016. Highly narrow nanogap-containing Au@Au core-shell SERS nanoparticles: size-dependent Raman enhancement and applications in cancer cell imaging. Nanoscale 8:2090–96 [Google Scholar]
  96. Lang P, Yeow K, Nichols A, Scheer A. 96.  2006. Cellular imaging in drug discovery. Nat. Rev. Drug Discov. 5:343–56 [Google Scholar]
  97. Ludwig JA, Weinstein JN. 97.  2005. Biomarkers in cancer staging, prognosis and treatment selection. Nat. Rev. Cancer 5:845–56 [Google Scholar]
  98. Lee S, Chon H, Lee J, Ko J, Chung BH. 98.  et al. 2014. Rapid and sensitive phenotypic marker detection on breast cancer cells using surface-enhanced Raman scattering (SERS) imaging. Biosens. Bioelectron. 51:238–43 [Google Scholar]
  99. Dinish US, Balasundaram G, Chang Y-T, Olivo M. 99.  2014. Actively targeted in vivo multiplex detection of intrinsic cancer biomarkers using biocompatible SERS nanotags. Sci. Rep. 4:4075 [Google Scholar]
  100. Nima ZA, Mahmood M, Xu Y, Mustafa T, Watanabe F. 100.  et al. 2014. Circulating tumor cell identification by functionalized silver-gold nanorods with multicolor, super-enhanced SERS and photothermal resonances. Sci. Rep. 4:4752 [Google Scholar]
  101. Bodelón G, Montes-García V, Fernández-López C, Pastoriza-Santos I, Pérez-Juste J, Liz-Marzán LM. 101.  2015. Au@pNIPAM SERRS tags for multiplex immunophenotyping cellular receptors and imaging tumor cells. Small 11:4149–57 [Google Scholar]
  102. Wessel J. 102.  1985. Surface-enhanced optical microscopy. J. Opt. Soc. Am. B 2:1538 [Google Scholar]
  103. Hayazawa N, Inouye Y, Sekkat Z, Kawata S. 103.  2000. Metallized tip amplification of near-field Raman scattering. Opt. Commun. 183:333–36 [Google Scholar]
  104. Anderson MS. 104.  2000. Locally enhanced Raman spectroscopy with an atomic force microscope. Appl. Phys. Lett. 76:3130 [Google Scholar]
  105. Stöckle RM, Suh YD, Deckert V, Zenobi R. 105.  2000. Nanoscale chemical analysis by tip-enhanced Raman spectroscopy. Chem. Phys. Lett. 318:131–36 [Google Scholar]
  106. Deckert V, Deckert-Gaudig T, Diegel M, Götz I, Langelüddecke L. 106.  et al. 2015. Spatial resolution in Raman spectroscopy. Faraday Discuss. 177:9–20 [Google Scholar]
  107. Zhang R, Zhang Y, Dong ZC, Jiang S, Zhang C. 107.  et al. 2013. Chemical mapping of a single molecule by plasmon-enhanced Raman scattering. Nature 498:82–86 [Google Scholar]
  108. Yang Z, Aizpurua J, Xu H. 108.  2009. Electromagnetic field enhancement in TERS configurations. J. Raman Spectrosc. 40:1343–48 [Google Scholar]
  109. Mehtani D, Lee N, Hartschuh RD, Kisliuk A, Foster MD. 109.  et al. 2005. Nano-Raman spectroscopy with side-illumination optics. J. Raman Spectrosc. 36:1068–75 [Google Scholar]
  110. Ossikovski R, Nguyen Q, Picardi G. 110.  2007. Simple model for the polarization effects in tip-enhanced Raman spectroscopy. Phys. Rev. B 75:045412 [Google Scholar]
  111. Marr JM, Schultz ZD. 111.  2013. Imaging electric fields in SERS and TERS using the vibrational stark effect. J. Phys. Chem. Lett. 4:3268–72 [Google Scholar]
  112. Sonntag MD, Klingsporn JM, Garibay LK, Roberts JM, Dieringer JA. 112.  et al. 2012. Single-molecule tip-enhanced Raman spectroscopy. J. Phys. Chem. C 116:478–83 [Google Scholar]
  113. Langelüddecke L, Singh P, Deckert V. 113.  2015. Exploring the nanoscale: fifteen years of tip-enhanced Raman spectroscopy. Appl. Spectrosc. 69:1357–71 [Google Scholar]
  114. Opilik L, Bauer T, Schmid T, Stadler J, Zenobi R. 114.  2011. Nanoscale chemical imaging of segregated lipid domains using tip-enhanced Raman spectroscopy. Phys. Chem. Chem. Phys. 13:9978 [Google Scholar]
  115. Nakata A, Nomoto T, Toyota T, Fujinami M. 115.  2013. Tip-enhanced Raman spectroscopy of lipid bilayers in water with an alumina- and silver-coated tungsten tip. Anal. Sci. 29:865–69 [Google Scholar]
  116. Richter M, Hedegaard M, Deckert-Gaudig T, Lampen P, Deckert V. 116.  2011. Laterally resolved and direct spectroscopic evidence of nanometer-sized lipid and protein domains on a single cell. Small 7:209–14 [Google Scholar]
  117. Böhme R, Richter M, Cialla D, Rösch P, Deckert V, Popp J. 117.  2009. Towards a specific characterisation of components on a cell surface-combined TERS-investigations of lipids and human cells. J. Raman Spectrosc. 40:1452–57 [Google Scholar]
  118. Böhme R, Cialla D, Richter M, Rösch P, Popp J, Deckert V. 118.  2010. Biochemical imaging below the diffraction limit—probing cellular membrane related structures by tip-enhanced Raman spectroscopy (TERS). J. Biphotonics 3:455–61 [Google Scholar]
  119. Alexander KD, Schultz ZD. 119.  2012. Tip-enhanced Raman detection of antibody conjugated nanoparticles on cellular membranes. Anal. Chem. 84:7408–14 [Google Scholar]
  120. Wang H, Schultz ZD. 120.  2014. TERS Detection of αvβ3 integrins in intact cell membranes. ChemPhysChem 15:3944–49 [Google Scholar]
  121. Xiao L, Wang H, Schultz ZD. 121.  2016. Selective detection of RGD-integrin binding in cancer cells using tip enhanced Raman scattering microscopy. Anal. Chem. 88:6547–53 [Google Scholar]
  122. Neugebauer U, Rösch P, Schmitt M, Popp J, Julien C. 122.  et al. 2006. On the way to nanometer-sized information of the bacterial surface by tip-enhanced Raman spectroscopy. ChemPhysChem 7:1428–30 [Google Scholar]
  123. Neugebauer U, Schmid U, Baumann K, Ziebuhr W, Kozitskaya S. 123.  et al. 2007. Towards a detailed understanding of bacterial metabolism—spectroscopic characterization of Staphylococcus epidermidis. . ChemPhysChem 8:124–37 [Google Scholar]
  124. Cialla D, Deckert-Gaudig T, Budich C, Laue M, Möller R. 124.  et al. 2009. Raman to the limit: tip-enhanced Raman spectroscopic investigations of a single tobacco mosaic virus. J. Raman Spectrosc. 40:240–43 [Google Scholar]
  125. Hermann P, Hermelink A, Lausch V, Holland G, Möller L. 125.  et al. 2011. Evaluation of tip-enhanced Raman spectroscopy for characterizing different virus strains. Analyst 136:1148 [Google Scholar]
  126. Olschewski K, Kämmer E, Stöckel S, Bocklitz T, Deckert-Gaudig T. 126.  et al. 2015. A manual and an automatic TERS based virus discrimination. Nanoscale 7:4545–52 [Google Scholar]
  127. Klingsporn JM, Sonntag MD, Seideman T, Van Duyne RP. 127.  2014. Tip-enhanced Raman spectroscopy with picosecond pulses. J. Phys. Chem. Lett. 5:106–10 [Google Scholar]
  128. Prescher JA, Bertozzi CR. 128.  2005. Chemistry in living systems. Nat. Chem. Biol. 1:13–21 [Google Scholar]
  129. Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. 129.  2002. A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed. 41:2596–99 [Google Scholar]
  130. Tornøe CW, Christensen C, Meldal M. 130.  2002. Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem. 67:3057–64 [Google Scholar]
  131. Baskin JM, Prescher JA, Laughlin ST, Agard NJ, Chang PV. 131.  et al. 2007. Copper-free click chemistry for dynamic in vivo imaging. PNAS 104:16793–97 [Google Scholar]
  132. Yamakoshi H, Dodo K, Okada M, Ando J, Palonpon A. 132.  et al. 2011. Imaging of EdU, an alkyne-tagged cell proliferation probe, by Raman microscopy. J. Am. Chem. Soc. 133:6102–5 [Google Scholar]
  133. Yamakoshi H, Dodo K, Palonpon A, Ando J, Fujita K. 133.  et al. 2012. Alkyne-tag Raman imaging for visualization of mobile small molecules in live cells. J. Am. Chem. Soc. 134:20681–89 [Google Scholar]
  134. Wei L, Yu Y, Shen Y, Wang MC, Min W. 134.  2013. Vibrational imaging of newly synthesized proteins in live cells by stimulated Raman scattering microscopy. PNAS 110:11226–31 [Google Scholar]
  135. Wei L, Hu F, Shen Y, Chen Z, Yu Y. 135.  et al. 2014. Live-cell imaging of alkyne-tagged small biomolecules by stimulated Raman scattering. Nat. Methods 11:410–12 [Google Scholar]
  136. Alfonso-García A, Pfisterer SG, Riezman H, Ikonen E, Potma EO. 136.  2016. D38-cholesterol as a Raman active probe for imaging intracellular cholesterol storage. J. Biomed. Opt 21061003 [Google Scholar]
  137. Chen Z, Paley DW, Wei L, Weisman AL, Friesner RA. 137.  et al. 2014. Multicolor live-cell chemical imaging by isotopically edited alkyne vibrational palette. J. Am. Chem. Soc. 136:8027–33 [Google Scholar]
  138. Chen Y, Ren J-Q, Zhang X-G, Wu D-Y, Shen A-G, Hu J-M. 138.  2016. Alkyne-modulated surface-enhanced Raman scattering-palette for optical interference-free and multiplex cellular imaging. Anal. Chem. 88:6115–19 [Google Scholar]
  139. Liu Z, Tabakman S, Welsher K, Dai H. 139.  2009. Carbon nanotubes in biology and medicine: in vitro and in vivo detection, imaging and drug delivery. Nano Res. 2:85–120 [Google Scholar]
  140. Liu Z, Tabakman SM, Chen Z, Dai H. 140.  2009. Preparation of carbon nanotube bioconjugates for biomedical applications. Nat. Protoc. 4:1372–81 [Google Scholar]
  141. Liu Z, Li X, Tabakman SM, Jiang K, Fan S, Dai H. 141.  2008. Multiplexed multicolor Raman imaging of live cells with isotopically modified single walled carbon nanotubes. J. Am. Chem. Soc. 130:13540–41 [Google Scholar]
  142. Liu Z, Tabakman S, Sherlock S, Li X, Chen Z. 142.  et al. 2010. Multiplexed five-color molecular imaging of cancer cells and tumor tissues with carbon nanotube Raman tags in the near-infrared. Nano Res. 3:222–33 [Google Scholar]
  143. Jeanmaire DL, Van Duyne RP. 143.  1977. Surface raman spectroelectrochemistry. J. Electroanal. Chem. Interfacial Electrochem. 84:1–20 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error