Skip to main content
Log in

The many facets of Raman spectroscopy for biomedical analysis

  • Review
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

A critical review is presented on the use of linear and nonlinear Raman microspectroscopy in biomedical diagnostics of bacteria, cells, and tissues. This contribution is combined with an overview of the achievements of our research group. Linear Raman spectroscopy offers a wealth of chemical and molecular information. Its routine clinical application poses a challenge due to relatively weak signal intensities and confounding overlapping effects. Nonlinear variants of Raman spectroscopy such as coherent anti-Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS) have been recognized as tools for rapid image acquisition. Imaging applications benefit from the fact that contrast is based on the chemical composition and molecular structures in a label-free and nondestructive manner. Although not label-free, surface enhanced Raman scattering (SERS) has also been recognized as a complementary biomedical tool to increase sensitivity. The current state of the art is evaluated, illustrative examples are given, future developments are pointed out, and important reviews and references from the current literature are selected. The topics are identification of bacteria and single cells, imaging of single cells, Raman activated cell sorting, diagnosis of tissue sections, fiber optic Raman spectroscopy, and progress in coherent Raman scattering in tissue diagnosis. The roles of networks—such as Raman4clinics and CLIRSPEC on a European level—and early adopters in the translation, dissemination, and validation of new methods are discussed.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Krafft C, Dietzek B, Schmitt M, Popp J (2012) Raman and coherent anti-Stokes Raman scattering microspectroscopy for biomedical applications. J Biomed Opt 17(4):040801

    Google Scholar 

  2. Baker M (2010) Laser tricks without labels. Nat Methods 7(4):261–266. doi:10.1038/nmeth0410-261

    CAS  Google Scholar 

  3. Schie IW, Huser T (2013) Methods and applications of Raman microspectroscopy to single-cell analysis. Appl Spectrosc 67(8):813–828. doi:10.1366/12-06971

    CAS  Google Scholar 

  4. Schie IW, Huser T (2013) Label-free analysis of cellular biochemistry by Raman spectroscopy and microscopy. Compr Physiol 3(2):941–956. doi:10.1002/cphy.c120025

    Google Scholar 

  5. Meyer T, Schmitt M, Dietzek B, Popp J (2013) Accumulating advantages, reducing limitations: multimodal nonlinear imaging in biomedical sciences – the synergy of multiple contrast mechanisms. J Biophotonics 6(11–12):887–904. doi:10.1002/jbio.201300176

    Google Scholar 

  6. Tu H, Boppart SA (2014) Coherent anti-Stokes Raman scattering microscopy: overcoming technical barriers for clinical translation. J Biophotonics 7(1–2):9–22. doi:10.1002/jbio.201300031

    Google Scholar 

  7. Harada Y, Takamatsu T (2013) Raman molecular imaging of cells and tissues: towards functional diagnostic imaging without labeling. Curr Pharm Biotechnol 14(2):133–140

    CAS  Google Scholar 

  8. Brauchle E, Schenke-Layland K (2013) Raman spectroscopy in biomedicine – non-invasive in vitro analysis of cells and extracellular matrix components in tissues. Biotechnol J 8(3):288–297. doi:10.1002/biot.201200163

    CAS  Google Scholar 

  9. Krafft C, Dietzek B, Popp J (2009) Raman and CARS microspectroscopy of cells and tissues. Analyst 134(6):1046–1057

    CAS  Google Scholar 

  10. Latka I, Dochow S, Krafft C, Dietzek B, Popp J (2013) Fiber optic probes for linear and nonlinear Raman applications: current trend and future development. Laser Photonics Rev 7(5):698–731

    CAS  Google Scholar 

  11. Harz M, Rosch P, Popp J (2009) Vibrational spectroscopy–a powerful tool for the rapid identification of microbial cells at the single-cell level. Cytometry A 75(2):104–113. doi:10.1002/cyto.a.20682

    CAS  Google Scholar 

  12. Huang WE, Li MQ, Jarvis RM, Goodacre R, Banwart SA (2010) Shining light on the microbial world: the application of Raman microspectroscopy. In: Laskin AI, Sariaslani S, Gadd GM (eds) Advances in applied microbiology, vol 70, Advances in applied microbiology. Elsevier, San Diego, pp 153–186. doi:10.1016/s0065-2164(10)70005-8

    Google Scholar 

  13. Wachsmann-Hogiu S, Weeks T, Huser T (2009) Chemical analysis in vivo and in vitro by Raman spectroscopy–from single cells to humans. Curr Opin Biotechnol 20(1):63–73

    CAS  Google Scholar 

  14. Chan JW (2013) Recent advances in laser tweezers Raman spectroscopy (LTRS) for label-free analysis of single cells. J Biophotonics 6(1):36–48

    CAS  Google Scholar 

  15. Li MQ, Xu J, Romero-Gonzalez M, Banwart SA, Huang WE (2012) Single cell Raman spectroscopy for cell sorting and imaging. Curr Opin Biotechnol 23(1):56–63. doi:10.1016/j.copbio.2011.11.019

    CAS  Google Scholar 

  16. Diem M, Mazur A, Lenau K, Schubert J, Bird B, Miljkovic M, Krafft C, Popp J (2013) Molecular pathology via IR and Raman spectral imaging. J Biophotonics 6(11–12):855–886. doi:10.1002/jbio.201300131

    CAS  Google Scholar 

  17. Krafft C, Steiner G, Beleites C, Salzer R (2009) Disease recognition by infrared and Raman spectroscopy. J Biophotonics 2(1–2):13–28. doi:10.1002/jbio.200810024

    CAS  Google Scholar 

  18. Kendall C, Isabelle M, Bazant-Hegemark F, Hutchings J, Orr L, Babrah J, Baker R, Stone N (2009) Vibrational spectroscopy: a clinical tool for cancer diagnostics. Analyst 134(6):1029–1045

    CAS  Google Scholar 

  19. Nijssen A, Koljenovic S, Bakker Schut TC, Caspers PJ, Puppels GJ (2009) Towards oncological application of Raman spectroscopy. J Biophotonics 2(1–2):29–36

    CAS  Google Scholar 

  20. Downes A, Elfick A (2010) Raman Spectroscopy and related techniques in biomedicine. Sensors 10(3):1871–1889. doi:10.3390/s100301871

    Google Scholar 

  21. Egawa M, Hirao T, Takahashi M (2007) In vivo estimation of stratum corneum thickness from water concentration profiles obtained with Raman spectroscopy. Acta Derm Venereol 87(1):4–8. doi:10.2340/00015555-0183

    Google Scholar 

  22. Matousek P, Stone N (2013) Recent advances in the development of Raman spectroscopy for deep non-invasive medical diagnosis. J Biophotonics 6(1):7–19. doi:10.1002/jbio.201200141

    CAS  Google Scholar 

  23. Tu Q, Chang C (2012) Diagnostic applications of Raman spectroscopy. Nanomedicine 8(5):545–558. doi:10.1016/j.nano.2011.09.013

    CAS  Google Scholar 

  24. Rodriguez-Lorenzo L, Fabris L, Alvarez-Puebla RA (2012) Multiplex optical sensing with surface-enhanced Raman scattering: a critical review. Anal Chim Acta 745:10–23. doi:10.1016/j.aca.2012.08.003

    CAS  Google Scholar 

  25. Vendrell M, Maiti KK, Dhaliwal K, Chang YT (2013) Surface-enhanced Raman scattering in cancer detection and imaging. Trends Biotechnol 31(4):249–257. doi:10.1016/j.tibtech.2013.01.013

    CAS  Google Scholar 

  26. Chrimes AF, Khoshmanesh K, Stoddart PR, Mitchell A, Kalantar-zadeh K (2013) Microfluidics and Raman microscopy: current applications and future challenges. Chem Soc Rev 42(13):5880–5906. doi:10.1039/c3cs35515b

    CAS  Google Scholar 

  27. Kok J, Chen SCA, Dwyer DE, Iredell JR (2013) Current status of matrix-assisted laser desorption ionisation-time of flight mass spectrometry in the clinical microbiology laboratory. Pathology 45(1):4–17. doi:10.1097/PAT.0b013e32835be408

    CAS  Google Scholar 

  28. Willemse-Erix D, Bakker-Schut T, Slagboom-Bax F, Jachtenberg JW, Lemmens-den Toom N, Papagiannitsis CC, Kuntaman K, Puppels G, van Belkum A, Severin JA, Goessens W, Maquelin K (2012) Rapid typing of extended-spectrum beta-lactamase- and carbapenemase-producing Escherichia coli and Klebsiella pneumoniae isolates by use of SpectraCell RA. J Clin Microbiol 50(4):1370–1375. doi:10.1128/jcm. 05423-11

    Google Scholar 

  29. Kloss S, Kampe B, Sachse S, Rosch P, Straube E, Pfister W, Kiehntopf M, Popp J (2013) Culture independent Raman spectroscopic identification of urinary tract infection pathogens: a proof of principle study. Anal Chem 85(20):9610–9616. doi:10.1021/ac401806f

    CAS  Google Scholar 

  30. Stockel S, Meisel S, Elschner M, Rosch P, Popp J (2012) Identification of Bacillus anthracis via Raman spectroscopy and chemometric approaches. Anal Chem 84(22):9873–9880. doi:10.1021/ac302250t

    CAS  Google Scholar 

  31. Stockel S, Meisel S, Elschner M, Rosch P, Popp J (2012) Raman spectroscopic detection of anthrax endospores in powder samples. Angew Chem Int Ed 51(22):5339–5342. doi:10.1002/anie.201201266

    CAS  Google Scholar 

  32. Li JF, Tian XD, Li SB, Anema JR, Yang ZL, Ding Y, Wu YF, Zeng YM, Chen QZ, Ren B, Wang ZL, Tian ZQ (2013) Surface analysis using shell-isolated nanoparticle-enhanced Raman spectroscopy. Nat Protoc 8(1):52–65. doi:10.1038/nprot.2012.141

    CAS  Google Scholar 

  33. Premasiri WR, Sauer-Budge AF, Lee JC, Klapperich CM, Ziegler LD (2013) Rapid bacterial diagnostics via surface-enhanced Raman microscopy. Spectroscopy (Amsterdam, Netherlands) 28(5):52–60

    CAS  Google Scholar 

  34. Lu XN, Samuelson DR, Xu YH, Zhang HW, Wang S, Rasco BA, Xu J, Konkel ME (2013) Detecting and tracking nosocomial methicillin-resistant Staphylococcus aureus using a microfluidic SERS biosensor. Anal Chem 85(4):2320–2327. doi:10.1021/ac303279u

    CAS  Google Scholar 

  35. Gracie K, Correa E, Mabbott S, Dougan JA, Graham D, Goodacre R, Faulds K (2014) Simultaneous detection and quantification of three bacterial meningitis pathogens by SERS. Chem Sci 5(3):1030–1040. doi:10.1039/c3sc52875h

    CAS  Google Scholar 

  36. Neugebauer U, Bocklitz T, Clement JH, Krafft C, Popp J (2010) Towards detection and identification of circulating tumour cells using Raman spectroscopy. Analyst 135(12):3178–3182

    CAS  Google Scholar 

  37. Muratore M (2013) Raman spectroscopy and partial least squares analysis in discrimination of peripheral cells affected by Huntington’s disease. Anal Chim Acta 793:1–10. doi:10.1016/j.aca.2013.06.012

    CAS  Google Scholar 

  38. Pijanka JK, Stone N, Rutter AV, Forsyth N, Sockalingum GD, Yang Y, Sule-Suso J (2013) Identification of different subsets of lung cells using Raman microspectroscopy and whole cell nucleus isolation. Analyst 138(17):5052–5058. doi:10.1039/c3an00968h

    CAS  Google Scholar 

  39. Salman A, Shufan E, Zeiri L, Huleihel M (2013) Detection and identification of cancerous murine fibroblasts, transformed by murine sarcoma virus in culture, using Raman spectroscopy and advanced statistical methods. Biochim Biophys Acta 1830(3):2720–2727. doi:10.1016/j.bbagen.2012.11.023

    CAS  Google Scholar 

  40. Huang Z, Chen G, Chen X, Wang J, Chen J, Lu P, Chen R (2013) Rapid and label-free identification of normal spermatozoa based on image analysis and micro-Raman spectroscopy. J Biophotonics 7(9):671–675. doi:10.1002/jbio.201300003

    Google Scholar 

  41. Pudlas M, Brauchle E, Klein TJ, Hutmacher DW, Schenke-Layland K (2013) Non-invasive identification of proteoglycans and chondrocyte differentiation state by Raman microspectroscopy. J Biophotonics 6(2):205–211. doi:10.1002/jbio.201200064

    CAS  Google Scholar 

  42. McEwen GD, Wu Y, Tang M, Qi X, Xiao Z, Baker SM, Yu T, Gilbertson TA, DeWald DB, Zhou A (2013) Subcellular spectroscopic markers, topography and nanomechanics of human lung cancer and breast cancer cells examined by combined confocal Raman microspectroscopy and atomic force microscopy. Analyst 138(3):787–797. doi:10.1039/c2an36359c

    CAS  Google Scholar 

  43. Harkness L, Novikov SM, Beermann J, Bozhevolnyi SI, Kassem M (2012) Identification of abnormal stem cells using Raman spectroscopy. Stem Cells Dev 21(12):2152–2159. doi:10.1089/scd.2011.0600

    CAS  Google Scholar 

  44. Pudlas M, Koch S, Bolwien C, Thude S, Jenne N, Hirth T, Walles H, Schenke-Layland K (2011) Raman spectroscopy: a noninvasive analysis tool for the discrimination of human skin cells. Tissue Eng C Methods 17(10):1027–1040. doi:10.1089/ten.tec.2011.0082

    Google Scholar 

  45. Pascut FC, Goh HT, George V, Denning C, Notingher I (2011) Toward label-free Raman-activated cell sorting of cardiomyocytes derived from human embryonic stem cells. J Biomed Opt 16(4):045002. doi:10.1117/1.3570302

    Google Scholar 

  46. Kakita M, Okuno M, Hamaguchi HO (2013) Quantitative analysis of the redox states of cytochromes in a living L929 (NCTC) cell by resonance Raman microspectroscopy. J Biophotonics 6(3):256–259. doi:10.1002/jbio.201200042

    CAS  Google Scholar 

  47. Puppels GJ, Olminkhof JH, Segers-Nolten GM, Otto C, De Mul FF, Greve J (1991) Laser irradiation and Raman spectroscopy of single living cells and chromosomes: sample degradation occurs with 514.5 nm but not with 660 nm laser light. Exp Cell Res 195(2):361–367

    CAS  Google Scholar 

  48. Notingher I, Verrier S, Romanska H, Bishop AE, Polak JM, Hench LL (2002) In situ characterisation of living cells by Raman spectroscopy. Spectroscopy (Amsterdam, Netherlands) 15:43

    Google Scholar 

  49. Krafft C, Knetschke T, Funk RH, Salzer R (2006) Studies on stress-induced changes at the subcellular level by Raman microspectroscopic mapping. Anal Chem 78(13):4424–4429

    CAS  Google Scholar 

  50. Neugebauer U, Clement JH, Bocklitz T, Krafft C, Popp J (2010) Identification and differentiation of single cells from peripheral blood by Raman spectroscopic imaging. J Biophotonics 3(8–9):579–587

    CAS  Google Scholar 

  51. Matthaus C, Krafft C, Dietzek B, Brehm BR, Lorkowski S, Popp J (2012) Noninvasive imaging of intracellular lipid metabolism in macrophages by Raman microscopy in combination with stable isotopic labeling. Anal Chem 84(20):8549–8556. doi:10.1021/ac3012347

    Google Scholar 

  52. Schlücker S, Schaeberle MD, Huffman SW, Levin IW (2003) Raman microspectroscopy: a comparison of point, line, and wide-field imaging methodologies. Anal Chem 75(16):4312–4318

    Google Scholar 

  53. Palonpon AF, Ando J, Yamakoshi H, Dodo K, Sodeoka M, Kawata S, Fujita K (2013) Raman and SERS microscopy for molecular imaging of live cells. Nat Protoc 8(4):677–692. doi:10.1038/nprot.2013.030

    CAS  Google Scholar 

  54. Stiebing C, Matthäus C, Krafft C, Keller AA, Weber K, Lorkowski S, Popp J (2014) Complexity of fatty acid distribution inside human macrophages on single cell level using Raman micro-spectroscopy. Anal Bioanal Chem 406(27):7037–7046. doi:10.1007/s00216-014-7927-0

    CAS  Google Scholar 

  55. Schie IW, Nolte L, Pedersen TL, Smith Z, Wu J, Yahiatene I, Newman JW, Huser T (2013) Direct comparison of fatty acid ratios in single cellular lipid droplets as determined by comparative Raman spectroscopy and gas chromatography. Analyst 138(21):6662–6670. doi:10.1039/c3an00970j

    CAS  Google Scholar 

  56. Lau AY, Lee LP, Chan JW (2008) An integrated optofluidic platform for Raman-activated cell sorting. Lab Chip 8(7):1116–1120

    CAS  Google Scholar 

  57. Jess PRT, Garces-Chavez V, Smith D, Mazilu M, Paterson L, Riches A, Herrington CS, Sibbett W, Dholakia K (2006) Dual beam fibre trap for Raman microspectroscopy of single cells. Opt Express 14(12):5779–5791

    CAS  Google Scholar 

  58. Dochow S, Krafft C, Neugebauer U, Bocklitz T, Henkel T, Mayer G, Albert J, Popp J (2011) Tumour cell identification by means of Raman spectroscopy in combination with optical traps and microfluidic environments. Lab Chip 11(8):1484–1490

    CAS  Google Scholar 

  59. Dochow S, Beleites C, Henkel T, Mayer G, Albert J, Clement J, Krafft C, Popp J (2013) Quartz microfluidic chip for tumour cell identification by Raman spectroscopy in combination with optical traps. Anal Bioanal Chem 405:2743–2746

    CAS  Google Scholar 

  60. Neugebauer U, Kurz C, Bocklitz T, Berger T, Velten T, Clement J, Krafft C, Popp J (2014) Raman-spectroscopy based cell identification on a microhole array chip. Micromachines 5:204–215. doi:10.3390/mi5020204

    Google Scholar 

  61. Freitag I, Neugebauer U, Csaki A, Fritzsche W, Krafft C, Popp J (2012) Preparation and characterization of multicore SERS labels by controlled aggregation of gold nanoparticles. Vib Spectrosc 60:79–84

    CAS  Google Scholar 

  62. Braun GB, Lee SJ, Laurence T, Fera N, Fabris L, Bazan GC, Moskovits M, Reich NO (2009) Generalized approach to SERS-active nanomaterials via controlled nanoparticle linking, polymer encapsulation, and small-molecule infusion. J Phys Chem C 113(31):13622–13629. doi:10.1021/jp903399p

    CAS  Google Scholar 

  63. Wang X, Qian X, Beitler JJ, Chen ZG, Khuri FR, Lewis MM, Shin HJC, Nie S, Shin DM (2011) Detection of circulating tumor cells in human peripheral blood using surface-enhanced Raman scattering nanoparticles. Cancer Res 71(5):1526–1532. doi:10.1158/0008-5472.can-10-3069

    CAS  Google Scholar 

  64. Lee S, Chon H, Lee M, Choo J, Shin SY, Lee YH, Rhyu IJ, Son SW, Oh CH (2009) Surface-enhanced Raman scattering imaging of HER2 cancer markers overexpressed in single MCF7 cells using antibody conjugated hollow gold nanospheres. Biosens Bioelectron 24(7):2260–2263. doi:10.1016/j.bios.2008.10.018

    CAS  Google Scholar 

  65. Park H, Lee S, Chen L, Lee EK, Shin SY, Lee YH, Son SW, Oh CH, Song JM, Kang SH, Choo J (2009) SERS imaging of HER2-overexpressed MCF7 cells using antibody-conjugated gold nanorods. Phys Chem Chem Phys 11(34):7444–7449. doi:10.1039/b904592a

    CAS  Google Scholar 

  66. Kim J-H, Kim J-S, Choi H, Lee S-M, Jun B-H, Yu K-N, Kuk E, Kim Y-K, Jeong DH, Cho M-H, Lee Y-S (2006) Nanoparticle probes with surface enhanced Raman spectroscopic tags for cellular cancer targeting. Anal Chem 78(19):6967–6973. doi:10.1021/ac0607663

    CAS  Google Scholar 

  67. Wu LY, Ross BM, Hong S, Lee LP (2010) Bioinspired nanocorals with decoupled cellular targeting and sensing functionality. Small 6(4):503–507. doi:10.1002/smll.200901604

    CAS  Google Scholar 

  68. Sha MY, Xu H, Natan MJ, Cromer R (2008) Surface-enhanced Raman scattering tags for rapid and homogeneous detection of circulating tumor cells in the presence of human whole blood. J Am Chem Soc 130(51):17214–17215. doi:10.1021/ja804494m

    CAS  Google Scholar 

  69. Liu Y, Chang Z, Yuan HK, Fales AM, Vo-Dinh T (2013) Quintuple-modality (SERS-MRI-CT-TPL-PTT) plasmonic nanoprobe for theranostics. Nanoscale 5(24):12126–12131. doi:10.1039/c3nr03762b

    CAS  Google Scholar 

  70. Pallaoro A, Braun GB, Moskovits M (2011) Quantitative ratiometric discrimination between noncancerous and cancerous prostate cells based on neuropilin-1 overexpression. Proc Natl Acad Sci U S A 108(40):16559–16564. doi:10.1073/pnas.1109490108

    CAS  Google Scholar 

  71. Schluecker S (2009) SERS microscopy: nanoparticle probes and biomedical applications. ChemPhysChem 10(9–10):1344–1354. doi:10.1002/cphc.200900119

    CAS  Google Scholar 

  72. Graham D, Mallinder BJ, Whitcombe D, Watson ND, Smith WE (2002) Simple multiplex genotyping by surface-enhanced resonance Raman scattering. Anal Chem 74(5):1069–1074. doi:10.1021/ac0155456

    CAS  Google Scholar 

  73. Bantz KC, Meyer AF, Wittenberg NJ, Im H, Kurtulus O, Lee SH, Lindquist NC, Oh S-H, Haynes CL (2011) Recent progress in SERS biosensing. Phys Chem Chem Phys 13(24):11551–11567. doi:10.1039/c0cp01841d

    Google Scholar 

  74. Dinish US, Balasundaram G, Chang YT, Olivo M (2014) Actively targeted in vivo multiplex detection of intrinsic cancer biomarkers using biocompatible SERS nanotags. Sci Rep 4:4075. doi:10.1038/srep04075

  75. Lee S, Chon H, Lee J, Ko J, Chung BH, Lim DW, Choo J (2014) Rapid and sensitive phenotypic marker detection on breast cancer cells using surface-enhanced Raman scattering (SERS) imaging. Biosens Bioelectron 51:238–243. doi:10.1016/j.bios.2013.07.063

    CAS  Google Scholar 

  76. Nolan JP, Duggan E, Liu E, Condello D, Dave I, Stoner SA (2012) Single cell analysis using surface enhanced Raman scattering (SERS) tags. Methods 57(3):272–279. doi:10.1016/j.ymeth.2012.03.024

    CAS  Google Scholar 

  77. MacLaughlin CM, Mullaithilaga N, Yang GS, Ip SY, Wang C, Walker GC (2013) Surface-enhanced Raman scattering dye-labeled au nanoparticles for triplexed detection of leukemia and lymphoma cells and SERS flow cytometry. Langmuir 29(6):1908–1919. doi:10.1021/la303931c

    CAS  Google Scholar 

  78. Aguiar RP, Silveira L, Falcao ET, Pacheco MTT, Zangaro RA, Pasqualucci CA (2013) Discriminating neoplastic and normal brain tissues in vitro through Raman spectroscopy: a principal components analysis classification model. Photomed Laser Surg 31(12):595–604. doi:10.1089/pho.2012.3460

    CAS  Google Scholar 

  79. Bodanese B, Silveira L, Albertini R, Zangaro RA, Pacheco MTT (2010) Differentiating normal and basal cell carcinoma human skin tissues in vitro using dispersive Raman spectroscopy: a comparison between principal components analysis and simplified biochemical models. Photomed Laser Surg 28:S119–S127. doi:10.1089/pho.2009.2565

    CAS  Google Scholar 

  80. Li YZ, Pan JJ, Chen GN, Li C, Lin SJ, Shao YH, Feng SY, Huang ZF, Xie SS, Zeng HS, Chen R (2013) Micro-Raman spectroscopy study of cancerous and normal nasopharyngeal tissues. J Biomed Opt 18(2):027003. doi:10.1117/1.jbo.18.2.027003

    Google Scholar 

  81. Hutchings J, Kendall C, Shepherd N, Barr H, Stone N (2010) Evaluation of linear discriminant analysis for automated Raman histological mapping of esophageal high-grade dysplasia. J Biomed Opt 15(6):066015. doi:10.1117/1.3512244

    Google Scholar 

  82. Kong K, Rowlands CJ, Varma S, Perkins W, Leach IH, Koloydenko AA, Williams HC, Notingher I (2013) Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy. Proc Natl Acad Sci U S A 110(38):15189–15194. doi:10.1073/pnas.1311289110

    CAS  Google Scholar 

  83. Bielecki C, Bocklitz TW, Schmitt M, Krafft C, Marquardt C, Gharbi A, Knosel T, Stallmach A, Popp J (2012) Classification of inflammatory bowel diseases by means of Raman spectroscopic imaging of epithelium cells. J Biomed Opt 17(7):076030. doi:10.1117/1.jbo.17.7.076030

    Google Scholar 

  84. Sattlecker M, Bessant C, Smith J, Stone N (2010) Investigation of support vector machines and Raman spectroscopy for lymph node diagnostics. Analyst 135(5):895–901

    CAS  Google Scholar 

  85. Bergner N, Bocklitz T, Romeike BFM, Reichart R, Kalff R, Krafft C, Popp J (2012) Identification of primary brain tumors of brain metastases by Raman imaging and support vector machines. Chemometr Intell Lab Syst 117:224–232

    CAS  Google Scholar 

  86. Cals FLJ, Schut TCB, Koljenovic S, Puppels GJ, de Jong RJB (2013) Method development: Raman spectroscopy-based histopathology of oral mucosa. J Raman Spectrosc 44(7):963–972. doi:10.1002/jrs.4318

    CAS  Google Scholar 

  87. Jain R, Calderon D, Kierski PR, Schurr MJ, Czuprynski CJ, Murphy CJ, McAnulty JF, Abbott NL (2014) Raman spectroscopy enables noninvasive biochemical characterization and identification of the stage of healing of a wound. Anal Chem 86(8):3764–3772. doi:10.1021/ac500513t

    CAS  Google Scholar 

  88. Krafft C, Belay B, Bergner N, Romeike BF, Reichart R, Kalff R, Popp J (2012) Advances in optical biopsy–correlation of malignancy and cell density of primary brain tumors using Raman microspectroscopic imaging. Analyst 137(23):5533–5537

    CAS  Google Scholar 

  89. Bergner N, Krafft C, Geiger KD, Kirsch M, Schackert G, Popp J (2012) Unsupervised unmixing of Raman microspectroscopic images for morphological analysis of non-dried brain tumor specimens. Anal Bioanal Chem 403(3):719–725

    CAS  Google Scholar 

  90. Bergner N, Medyukhina A, Geiger KD, Kirsch M, Schackert G, Krafft C, Popp J (2013) Hyperspectral unmixing of Raman micro-images for assessment of morphological and chemical parameters in non-dried brain tumor specimens. Anal Bioanal Chem 405(27):8719–8728. doi:10.1007/s00216-013-7257-7

    CAS  Google Scholar 

  91. Keren S, Zavaleta C, Cheng Z, de la Zerda A, Gheysens O, Gambhir SS (2008) Noninvasive molecular imaging of small living subjects using Raman spectroscopy. Proc Natl Acad Sci U S A 105(15):5844–5849. doi:10.1073/pnas.0710575105

    CAS  Google Scholar 

  92. Jokerst JV, Cole AJ, Van de Sompel D, Gambhir SS (2012) Gold nanorods for ovarian cancer detection with photoacoustic imaging and resection guidance via Raman imaging in living mice. ACS Nano 6(11):10366–10377. doi:10.1021/nn304347g

    CAS  Google Scholar 

  93. Krafft C, Dochow S, Latka I, Dietzek B, Popp J (2012) Diagnosis and screening of cancer tissues by fiber-optic probe Raman spectroscopy. Biomed Spectrosc Imaging 1:39–55

    CAS  Google Scholar 

  94. Matthäus C, Dochow S, Bergner G, Lattermann A, Romeike B, Marple E, Krafft C, Dietzek B, Brehm B, Popp J (2012) In vivo characterization of atherosclerotic plaque depositions by Raman-probe spectroscopy and in vitro CARS microscopic imaging on a rabbit model. Anal Chem 84(18):7845–7851

    Google Scholar 

  95. Kirsch M, Schackert G, Salzer R, Krafft C (2010) Raman spectroscopic imaging for in vivo detection of cerebral brain metastases. Anal Bioanal Chem 398(4):1707–1713

    CAS  Google Scholar 

  96. Dochow S, Latka I, Becker M, Spittel R, Kobelke J, Schuster K, Graf A, Bruckner S, Unger S, Rothhardt M, Dietzek B, Krafft C, Popp J (2012) Multicore fiber with integrated fiber Bragg gratings for background-free Raman sensing. Opt Express 20(18):20156–20169

    Google Scholar 

  97. Dochow S, Bergner N, Matthäus C, Praveen B, Ashok PC, Mazilu M, Krafft C, Dholakia K, Popp J (2012) Etaloning, fluorescence and ambient light suppression by modulated wavelength Raman spectroscopy. Biomed Spectrosc Imaging 1:383–389

    CAS  Google Scholar 

  98. Duraipandian S, Zheng W, Ng J, Low JJH, Ilancheran A, Huang ZW (2013) Near-infrared-excited confocal Raman spectroscopy advances in vivo diagnosis of cervical precancer. J Biomed Opt 18(6):067007. doi:10.1117/1.jbo.18.6.067007

    Google Scholar 

  99. Bergholt MS, Zheng W, Lin K, Ho KY, Teh M, Yeoh KG, So JBY, Huang Z (2011) In vivo diagnosis of esophageal cancer using image-guided Raman endoscopy and biomolecular modeling. Technol Cancer Res Treat 10(2):103–112

    CAS  Google Scholar 

  100. Zavaleta CL, Garai E, Liu JTC, Sensarn S, Mandella MJ, Van de Sompel D, Friedland S, Van Dam J, Contag CH, Gambhir SS (2013) A Raman-based endoscopic strategy for multiplexed molecular imaging. Proc Natl Acad Sci U S A 110(25):E2288–E2297. doi:10.1073/pnas.1211309110

    CAS  Google Scholar 

  101. Garai E, Sensarn S, Zavaleta CL, Van de Sompel D, Loewke NO, Mandella MJ, Gambhir SS, Contag CH (2013) High-sensitivity, real-time, ratiometric imaging of surface-enhanced Raman scattering nanoparticles with a clinically translatable Raman endoscope device. J Biomed Opt 18(9):096008. doi:10.1117/1.jbo.18.9.096008

    Google Scholar 

  102. Bohndiek SE, Wagadarikar A, Zavaleta CL, Van de Sompel D, Garai E, Jokerst JV, Yazdanfar S, Gambhir SS (2013) A small animal Raman instrument for rapid, wide-area, spectroscopic imaging. Proc Natl Acad Sci U S A 110(30):12408–12413. doi:10.1073/pnas.1301379110

    CAS  Google Scholar 

  103. McVeigh PZ, Mallia RJ, Veilleux I, Wilson BC (2013) Widefield quantitative multiplex surface enhanced Raman scattering imaging in vivo. J Biomed Opt 18(4). doi:10.1117/1.jbo.18.4.046011

  104. Karabeber H, Huang R, Iacono P, Samii JM, Pitter K, Holland EC, Kircher MF (2014) Using surface-enhanced Raman scattering nanoparticles and a hand-held Raman scanner. ACS Nano 8(10):9755–9766. doi:10.1021/nn503948b

    CAS  Google Scholar 

  105. Meyer T, Bergner N, Medyukhina A, Dietzek B, Krafft C, Romeike BF, Reichart R, Kalff R, Popp J (2012) Interpreting CARS images of tissue within the C–H-stretching region. J Biophotonics 5(10):729–733

    CAS  Google Scholar 

  106. Meyer T, Bergner N, Bielecki C, Krafft C, Akimov D, Romeike BF, Reichart R, Kalff R, Dietzek B, Popp J (2011) Nonlinear microscopy, infrared, and Raman microspectroscopy for brain tumor analysis. J Biomed Opt 16(2):021113

    Google Scholar 

  107. Medyukhina A, Meyer T, Schmitt M, Romeike BF, Dietzek B, Popp J (2012) Towards automated segmentation of cells and cell nuclei in nonlinear optical microscopy. J Biophotonics 5(11–12):878–888

    Google Scholar 

  108. Medyukhina A, Meyer T, Heuke S, Vogler N, Dietzek B, Popp J (2013) Automated seeding-based nuclei segmentation in nonlinear optical microscopy. Appl Opt 52(28):6979–6994. doi:10.1364/ao.52.006979

    Google Scholar 

  109. Yang YL, Li FH, Gao L, Wang ZY, Thrall MJ, Shen SS, Wong KK, Wong STC (2011) Differential diagnosis of breast cancer using quantitative, label-free and molecular vibrational imaging. Biomed Opt Express 2(8):2160–2174

    Google Scholar 

  110. Baumgartl M, Gottschall T, Abreu-Afonso J, Diez A, Meyer T, Dietzek B, Rothhardt M, Popp J, Limpert J, Tunnermann A (2012) Alignment-free, all-spliced fiber laser source for CARS microscopy based on four-wave-mixing. Opt Express 20(19):21010–21018

    CAS  Google Scholar 

  111. Meyer T, Baumgartl M, Gottschall T, Pascher T, Wuttig A, Matthaus C, Romeike BFM, Brehm BR, Limpert J, Tuennermann A, Guntinas-Lichius O, Dietzek B, Popp JU, Popp J (2013) A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics. Analyst 138(14):4048–4057. doi:10.1039/c3an00354j

    CAS  Google Scholar 

  112. Meyer T, Chemnitz M, Baumgartl M, Gottschall T, Pascher T, Matthaus C, Romeike BFM, Brehm BR, Limpert J, Tunnermann A, Schmitt M, Dietzek B, Popp J (2013) Expanding multimodal microscopy by high spectral resolution coherent anti-Stokes Raman scattering imaging for clinical disease diagnostics. Anal Chem 85(14):6703–6715. doi:10.1021/ac400570w

    CAS  Google Scholar 

  113. Pohling C, Buckup T, Pagenstecher A, Motzkus M (2011) Chemoselective imaging of mouse brain tissue via multiplex CARS microscopy. Biomed Opt Express 2(8):2110–2116

    Google Scholar 

  114. Ji MB, Orringer DA, Freudiger CW, Ramkissoon S, Liu XH, Lau D, Golby AJ, Norton I, Hayashi M, Agar NYR, Young GS, Spino C, Santagata S, Camelo-Piragua S, Ligon KL, Sagher O, Xie XS (2013) Rapid, label-free detection of brain tumors with stimulated Raman scattering microscopy. Sci Transl Med 5(201):201ra119

  115. Kim SH, Lee ES, Lee JY, Lee BS, Park JE, Moon DW (2010) Multiplex coherent anti-Stokes Raman spectroscopy images intact atheromatous lesions and concomitantly identifies distinct chemical profiles of atherosclerotic lipids. Circ Res 106(8):1332–U1358. doi:10.1161/circresaha.109.208678

    CAS  Google Scholar 

  116. Cicchi R, Matthaus C, Meyer T, Lattermann A, Dietzek B, Brehm BR, Popp J, Pavone FS (2014) Characterization of collagen and cholesterol deposition in atherosclerotic arterial tissue using non-linear microscopy. J Biophotonics 7(1–2):135–143. doi:10.1002/jbio.201300055

    CAS  Google Scholar 

  117. Lattermann A, Matthaus C, Bergner N, Beleites C, Romeike BF, Krafft C, Brehm BR, Popp J (2013) Characterization of atherosclerotic plaque depositions by Raman and FTIR imaging. J Biophotonics 6(1):110–121. doi:10.1002/jbio.201200146

    CAS  Google Scholar 

  118. Heuke S, Vogler N, Meyer T, Akimov D, Kluschke F, Rowert-Huber HJ, Lademann J, Dietzek B, Popp J (2013) Multimodal mapping of human skin. Br J Dermatol 169(4):794–803. doi:10.1111/bjd.12427

    CAS  Google Scholar 

  119. (2012) On being second. Nat Methods 9(3):209–209

Download references

Acknowledgments

Financial supports of the EU, the Thüringer Kultusministerium, the Thüringer Aufbaubank, the Federal Ministry of Education and Research, Germany (BMBF), the German Science Foundation (DFG), the Fonds der Chemischen Industrie, and the Carl-Zeiss Foundation are greatly acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christoph Krafft.

Additional information

Published in the topical collection celebrating ABCs 13th Anniversary.

For his notable achievements in the field of analytical chemistry in Europe, Prof. Dr. Jürgen Popp had the honor of holding the “Robert Kellner Lecture” at the Euroanalysis XVII conference in Warsaw in August 2013.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Krafft, C., Popp, J. The many facets of Raman spectroscopy for biomedical analysis. Anal Bioanal Chem 407, 699–717 (2015). https://doi.org/10.1007/s00216-014-8311-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-014-8311-9

Keywords

Navigation