Abstract

Stimulated Raman scattering (SRS) microscopy for biomedical analysis can provide a molecular localization map to infer pathological tissue changes. Compared to spontaneous Raman, SRS achieves much faster imaging speeds at reduced spectral coverage. By targeting spectral features in the information dense fingerprint region, SRS allows fast and reliable imaging. We present time-encoded (TICO) SRS microscopy of unstained head-and-neck biopsies in the fingerprint region with molecular contrast. We combine a Fourier-domain mode-locked (FDML) laser with a master oscillator power amplifier (MOPA) to cover Raman transitions from ${1500 {-} 1800}\;{{\rm cm}^{- 1}}$. Both lasers are fiber-based and electronically programmable making this fingerprint TICO system robust and reliable. The results of our TICO approach were cross-checked with a spontaneous Raman micro-spectrometer and show good agreement, paving the way toward clinical applications.

© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

Tumorous tissue is usually diagnosed by histopathologists through evaluation of stained sections. The optimal choice of dyes delivers a specific coloring to generate the contrast needed for diagnosis. However, the sample processing is time consuming and, once the tissue is stained, it is contaminated with the used labels and cannot easily be used for further molecular pathology. Also, the labeling with external substances changes the biochemical environment, which can hamper the understanding of the molecular origin of diseases. The inelastic Raman scattering allows for an optical interrogation of vibrational and rotational molecular transitions, which can be used to identify and locate certain molecules in unlabeled tissue. The classical, spontaneous Raman scattering suffers from very low efficiency requiring long acquisition times. This typically hinders imaging of larger specimens in a time critical environment, e.g., in a clinical setting. Non-linear Raman techniques, like stimulated Raman scattering (SRS) microscopy [18], can significantly reduce image acquisition times. Further, they can generate histological Raman images similar to stained sections commonly evaluated in histopathology [9,10]. Typically, the high wavenumber CH stretch region between ${2800}\;{{\rm cm}^{- 1}}$ to ${3000}\;{{\rm cm}^{- 1}}$ is addressed by coherent Raman techniques since it provides high Raman signals that allow for fast imaging with up to video rate acquisition rates [11,12]. However, in this high wavenumber region, the information density of the Raman spectra is limited and, thus, the possibilities to generate additional contrast in the tissue is hindered. In contrast, the fingerprint region between ${400}\;{{\rm cm}^{- 1}}$ to ${2000}\;{{\rm cm}^{- 1}}$ has many distinct Raman bands that allow for highly specific hyperspectral Raman imaging. For example, the presence of cancer can be investigated through the Raman bands associated to proteins and amino acids in the fingerprint region [1315]. Thus, in this report, we investigate fingerprint Raman imaging of human tissue sections employing the time-encoded (TICO) SRS microscopy technique—a detailed description is found in [16,17].

The schematic setup is illustrated in Fig. 1. As two laser sources, a fiber-based pump laser at 1064 nm and a wavelength-swept Fourier-domain mode-locked (FDML) laser around 1300 nm are combined to probe the spectral region from ${1500}\;{{\rm cm}^{- 1}}$ to ${1800}\;{{\rm cm}^{- 1}}$, covering the Amide I vibrational modes. Cryo sections of healthy human inferior nasal turbinate and tumorous hypopharynx tissue were imaged using 64 spectral points. These hyperspectral TICO-Raman microscopy images are compared to spectra from a spontaneous Raman micro-spectrometer showing high similarity and faster acquisition compared to spontaneous Raman spectroscopy. The TICO-Raman technique concept encodes the wavelength of the stimulated Raman transitions in time. To address different Raman transition energies, a rapidly wavelength-swept laser is combined with a monochromatic pulsed pump laser. The different energies are sampled by synchronizing the two lasers and subsequently tuning the delay between the two lasers.

 figure: Fig. 1.

Fig. 1. Schematic setup of the fingerprint Raman imaging setup. A Fourier-domain mode-locked (FDML) laser is combined with a fiber-based pump laser to generate the stimulated Raman process. The pump laser is based on a master oscillator power amplifier (MOPA) architecture, allowing us to encode the stimulated Raman transitions in time (TICO-Raman [16]). The resulting stimulated Raman gain (SRG) of the probe light is measured in transmission. Cryo sections of nasal turbinate (1) and tumorous hypopharynx tissue (2) biopsies were imaged in the spectral window from ${1500}\;{{\rm cm}^{- 1}}$ to ${1800}\;{{\rm cm}^{- 1}}$ in the fingerprint region and compared to spontaneous Raman spectra (see inset).

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This delay is controlled by a phase locked operation of all light sources and the detection unit. The synchronization time pattern is generated on an arbitrary waveform generator and controls the whole system making it fully reprogrammable. As Raman probe laser, an all fiber-based rapidly wavelength-swept FDML [18] laser acts as a broadband tunable light source. The main application of FDML lasers is very fast optical coherence tomography because of their narrow linewidth [19] and low noise behavior [20,21]. For Raman, the broadband continuous wavelength sweeps of ${\sim}{150}\;{\rm nm}$ and up to multi-MHz sweep rates [22] in the near infrared allow us to rapidly change the energy difference between pump and probe laser and, therefore, to tune the addressed Raman transition in SRS spectroscopy. The pump laser is a high-power fiber-based master oscillator power amplifier (MOPA) [23,24]. The MOPA pump laser is fully electronically programmable in pulse length and repetition rate and allows us to change the delay between FDML sweep and pump pulse arbitrarily, thus freely addressing all possible Raman transitions using the TICO SRS concept [17]. Thus, this flexible timing capability allows us to tailor the system parameters to the desired Raman sensing application. The stimulated Raman signal is detected in transmission with a balanced photodetector in form of a stimulated Raman gain (SRG) of the FDML probe laser in the sample arm, whereas a reference arm is used for balancing. Beside the analog balancing for subtracting the FDML DC offset and reducing the common mode noise, an additional digital balancing step is employed to ensure a detection down to the shot-noise limit [17]. For imaging, a TICO-Raman spectrum is measured for every pixel, and the specimen is moved in raster-scan patterns to generate a hyperspectral Raman image. The detailed system employed here is similar in numbers to the one described earlier [16,17]. The employed FDML laser for measuring in the fingerprint region is centered at 1300 nm with a freely adjustable span of up to 150 nm, a sweep rate of ${\sim}{420}\;{\rm kHz}$, and up to 40 mW output power. The MOPA laser for pumping the SRS process is built around a laser diode at 1064 nm. An electro optical modulator allows us to control the pulse length, pulse shape, repetition rate, duty cycle, and the modulation pattern. The seed pulses are amplified in two single mode ytterbium-doped fiber amplifier stages followed by a double clad Ytterbium power amplifier. In this study, we choose the spectral region from ${1500 {-} 1800}\;{{\rm cm}^{- 1}}$ and focused on the Amide I band around ${1640}\;{{\rm cm}^{- 1}}$, since it can indicate a change of the secondary protein structure [13,25]. To this end, we employed 64 spectral points from 1500 to ${1800}\;{{\rm cm}^{- 1}}$, leading to an acquisition time of ${\sim}{155}\;{\unicode{x00B5}\rm s}$ for a single TICO-Raman spectrum. For a higher signal-to-noise ratio (SNR), we typically average 20–50 consecutive spectra, leading to a hyperspectral pixel dwell time of 3.1–7.8 ms for the acquisition of 64 spectral points. Typically, the images consisted of ${500} \times {500}$ pixels leading to a hyperspectral image cube of ${64} \times {500} \times {500}$ voxels at a total acquisition time of 775–1938 s or approximately 13–32 min. The image acquisition parameters were 600 ps long pump pulses with a pulse peak power of 1.3 kW, while the FDML laser was operated in continuous wave (CW) mode with 3.8 mW on the sample. The repetition rate of the pump laser is synchronized to the sweep rate of ${\sim}{420}\;{\rm kHz}$ of the FDML laser. The TICO spectra were smoothed with a Savitzky Golay filter using four neighboring points and polynomials up to second order. Without any other postprocessing steps, the spectra were then utilized for the green and blue channel in RGB color mode. For sample preparation, the tissue biopsies were prepared in 20 µm thick slices by cryo sectioning using an embedding medium for the cutting process. Besides sectioning of a human hypopharynx carcinoma, we also imaged healthy tissue obtained from a human nasal inferior turbinate biopsy. All patients were treated at the Department of Otorhinolaryngology, University Hospital Schleswig-Holstein, Campus Lübeck, and have given their written informed consent. The study was approved by the local ethics committee of the University of Lübeck (approval number 16-278). In addition to the TICO imaging results, we cross-checked the specimen with a Raman micro-spectrometer (Horiba Xplora Plus) with an excitation wavelength of 532 nm, 10 mW CW power at the sample, and a 600 lines/mm grating. The entrance slit of the spectrometer was 100 µm wide resulting in a spectral resolution of ${2.5}\;{{\rm cm}^{- 1}}$. The overall measuring time of a single spontaneous Raman spectrum was 50 s with five averaged measurements each lasting 10 s for optimal results. As first tissue type, we imaged a tissue biopsy of unstained, healthy human inferior turbinate (Fig. 2). We probed 64 spectral points with 20 times averaging for a ${500} \times {500}$ pixels image covering a field of view of ${500}\;{\unicode{x00B5}{\rm m}} \times {500}\;{\unicode{x00B5}{\rm m}}$. This results in a pixel dwell time of ${\sim}{3.1}\;{\rm ms}$ for the acquisition of 64 spectral points. The acquisition time for a single spectral point is, therefore, ${\sim}{48}\;{\unicode{x00B5}\rm s}$. The hyperspectral Raman image in Fig. 2(a) shows two spectral components color coded in cyan and green. For this visualization, the spectral integration bands were chosen empirically to yield the best disjunct morphologic image information. The cyan channel represents the integrated Raman signal from ${1630 {-} 1650}\;{{\rm cm}^{- 1}}$. This Raman transition is associated with the Amide I band of proteins [26]. The green color in Fig. 2(a) is the integrated Raman signal from ${1540 {-} 1580}\;{{\rm cm}^{- 1}}$. To analyze this empirical spectral choice for the two color channels, we investigate the TICO-Raman spectra in two regions of interest (ROIs) together with spontaneous Raman spectra acquired from the same tissue types. The spectra are found to be in good agreement. The cyan channel [Fig. 2(b)] shows the narrowband Amide I band with a sufficient spectral resolution considering the acquisition of 64 spectral points in a ${300}\;{{\rm cm}^{- 1}}$ wide window. To validate the spectral resolution of our TICO setup, we measured benzonitrile around ${1600}\;{{\rm cm}^{- 1}}$ (cf. Supplement 1, Fig. S1). The green channel from ${1540 {-} 1580}\;{{\rm cm}^{- 1}}$ contains the highly dense spectral region of biomolecule modes involving phenylalanine, tryptophane, the coenzyme NADH, nucleic acids, etc. [26]. For image generation, two spectral integration windows were empirically found to yield the highest morphological separation. Although this empirical approach of visualizing the hyperspectral image data cube is very simple, it leads to very disjunct morphological images. This approach is further supported by the good agreement with spontaneous Raman spectra [Figs. 2(b) and 2(c)].

 figure: Fig. 2.

Fig. 2. (a) Hyperspectral TICO-Raman image of healthy human inferior turbinate. Green represents the Raman signal from ${1540 {-} 1580}\;{{\rm cm}^{- 1}}$, while the window from ${1620 {-} 1640}\;{{\rm cm}^{- 1}}$ is color-coded cyan to visualize the Amide I mode of proteins. The TICO-Raman spectra over ROI1 (cyan) and ROI2 (green) are in good agreement with spontaneous Raman spectra of the same tissue type (black). (FOV: ${500} \times {500}\;{\unicode{x00B5}{\rm m}},\;{500} \times {500}\;{\rm pixel}$.)

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The TICO-Raman spectra in Figs. 2(b) and 2(c) were created by spatial averaging over the ${15} \times {15}$ pixel large ROIs in Fig. 2(a) leading to an acquisition time of 698 ms, while the spontaneous Raman spectra took 50 s. Here, only compared in a ${300}\;{{\rm cm}^{- 1}}$ wide window, spontaneous Raman covers a wider spectral range and can achieve pixel dwell times down to ${\sim}{50}\;{\rm ms}$ [27] for certain samples. Combined with advanced spectral analysis techniques [2830] spontaneous Raman provides a better spectral analysis compared to SRS systems utilizing only a part of the relevant spectral range. However, depending on the application, focusing on a specific spectral Raman feature is sufficient for many applications, where SRS techniques allow faster imaging. The second tissue type we imaged was cryo sections of tumorous, unstained human hypopharynx carcinoma (Fig. 3). We found this tissue to yield less signal strength and less spectroscopic richness compared to the healthy tissue. Yet, the Amide I band could still be clearly resolved with similarities to the spontaneous Raman spectra [cf. Fig. 3(b)]. Figure 3(a) shows a protein localization map using the Amide I band at ${1646}\;{{\rm cm}^{- 1}}$. The spectral integration window was chosen to be only ${10}\;{{\rm cm}^{- 1}}$ wide to accommodate the narrow spectroscopic feature of Amide I. Due to the lower signal intensity, the best imaging results were achieved with 50 times averaging. The same power levels were used, and the spectra are again Savitzky Golay filtered as described above. Due to the higher amount of averaging, the pixel dwell time increased to ${\sim}{7.8}\;{\rm ms}$ for 64 spectral points and 121 µs for a single spectral point. In comparison to the spontaneous Raman spectrum shown in Fig. 3(b), the TICO-Raman spectrum in Fig. 3(b) was averaged over a ${40} \times {40}$ pixel ROI, leading to a spectral acquisition time of ${40} \times {40} \times {7.7}\;{\rm ms} = {12.3\;{\rm s}}$. Comparing the integration time of 48–121 µs per spectral point in this TICO-Raman application to other SRS systems, imaging in the fingerprint region [25,31,32] with a sub 10 µs pixel dwell time for a single spectral point the TICO system is here ${\sim}{10 {-} 25}$ times slower. Compared to spectral focusing SRS systems [8,31,32], which are conceptionally equivalent to TICO-Raman—both use a pulse and a wavelength sweep/chirp —SNR differences can occur due to the different probe power. The fast sweeping rate of the CW FDML laser and the pulse on demand pump laser capabilities allow a feature tailored probing of the Raman spectra [33] with less spectral points in future works. This approach is already motivated by the simple data processing used to color code the images, not utilizing the full TICO-Raman data. First experiments contrasting the TICO data with a simple PCA analysis did not directly lead to clear additional information. However, more advanced analysis may provide additional contrast as shown in [4,13,2732].

 figure: Fig. 3.

Fig. 3. (a) TICO-Raman molecular localization map of the Amide I vibrational modes in the spectral window from ${1640 {-} 1650}\;{{\rm cm}^{- 1}}$ of human tumorous pharynx tissue. Representative Raman spectra are presented in (b), showing a spatially averaged TICO spectrum over the ${40} \times {40}\;{\rm pixel}$ ROI [dotted box in (a)] in red and a spontaneous Raman spectrum of the same tissue type in black. The Amide I band was clearly detected and spectrally resolved. (FOV: ${500} \times {500}\;{\unicode{x00B5}{\rm m}}$, ${500} \times {500}\;{\rm pixel}$.)

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During our study of healthy and tumorous tissue of head and neck area biopsies, we found that the signal intensity decreased in tumorous tissue and only the Amide I band prevailed as the information-bearing spectroscopic feature. The Amide I Raman band at ${1646}\;{{\rm cm}^{- 1}}$ is indicative of the $\alpha$-helix structure of proteins [29] and can be useful for biomedical analysis, as pathological changes often feature a specific protein conformation that can be sensed through vibrational Raman spectroscopy. Small changes in the molecular geometry and hydrogen bonding of the peptide group can, thereby, be detected [26]. For example, it has been reported that amyloid plaques in brain tissue provide a blue\shifted Amide I band [25], whereas a broadening of the Amide I transition was observed in laryngeal cancer tissue [14,15]. Hence, the spectral resolution and wavenumber assignment are important parameters of an SRS system. This may allow observation of minute changes to the spectral shape and position of Raman bands for exact labeling of the Raman signals in future biomedical TICO-Raman applications.

This report investigated the TICO-Raman technology for hyperspectral fingerprint imaging of healthy human nasal turbinate and human hypopharynx carcinoma tissue biopsies. In both samples, we observed a clear presence of Amide I Raman signal associated to primary $\alpha$-helix structure of proteins [29]. We compared our findings to spontaneous Raman spectra of similar tissue types and found the spectra to be in good agreement in shape and position of the spectral features with the Amide I band. The healthy nasal turbinate tissue showed a more intricate Raman signature possibly arising from phenylalanine, coenzymes, or nucleic acids [26]. Furthermore, more detailed spectral analysis can be incorporated into the system by extending the coverage of the TICO system from ${250 {-} 3150}\;{{\rm cm}^{- 1}}$ [16]. While 64 spectral points are sufficient to capture spectral shifts of ${\sim}{5}\;{{\rm cm}^{- 1}}$ in a ${300}\;{{\rm cm}^{- 1}}$ window, a larger spectral coverage would require more spectral points to match the spectral width of ${\sim}{10}\;{{\rm cm}^{- 1}}$ for the Raman bands in the fingerprint region. The current simple data processing does not make full use of the spectral richness of the fingerprint region. This may be solved by multivariate analysis methods or machine learning approaches, which can extract the rich spectral features for hyperspectral image generation that are already widely used for stimulated [4,31,32] and spontaneous Raman applications [2830]. We showed here that the TICO-Raman system can yield adequate image contrast and signal level in relevant biological tissue in the fingerprint region. The possible speed advantage compared to spontaneous systems, the fiber-based design, flexibility, and spectral tailoring capability of the TICO-Raman system can have a significant advantage when moving this technology to a clinical application in the future.

Funding

European Regional Development Fund (CELLTOM); State of Schleswig Holstein (SH Chair); Bundesministerium für Bildung und Forschung (13GW0227B); European Research Council (646669); Deutsche Forschungsgemeinschaft (EXC 2167-390884018).

Disclosures

The authors declare no conflicts of interest.

Data Availability

Data underlying the results presented in this paper are not publicly available at this time but may be obtained from the authors upon reasonable request.

Supplemental document

See Supplement 1 for supporting content.

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References

  • View by:

  1. C. W. Freudiger, W. Yang, G. R. Holtom, N. Peyghambarian, X. S. Xie, and K. Q. Kieu, Nat. Photon. 8, 153 (2014).
    [Crossref]
  2. C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, Science 322, 1857 (2008).
    [Crossref]
  3. W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, Ann. Rev. Phys. Chem. 62, 507 (2011).
    [Crossref]
  4. Y. Ozeki, W. Umemura, Y. Otsuka, S. Satoh, H. Hashimoto, K. Sumimura, N. Nishizawa, K. Fukui, and K. Itoh, Nat. Photon. 6, 845 (2012).
    [Crossref]
  5. C. Krafft, I. W. Schie, T. Meyer, M. Schmitt, and J. Popp, Chem. Soc. Rev. 45, 1819 (2016).
    [Crossref]
  6. T. Meyer, O. Guntinas-Lichius, F. von Eggeling, G. Ernst, D. Akimov, M. Schmitt, B. Dietzek, and J. Popp, Head Neck 35, E280 (2013).
    [Crossref]
  7. T. Gottschall, T. Meyer, M. Baumgartl, C. Jauregui, M. Schmitt, J. Popp, J. Limpert, and A. Tünnermann, Laser Photon. Rev. 9, 435 (2015).
    [Crossref]
  8. D. Fu, G. Holtom, C. Freudiger, X. Zhang, and X. S. Xie, J. Phys. Chem. B 117, 4634 (2013).
    [Crossref]
  9. M. Ji, D. A. Orringer, C. W. Freudiger, S. Ramkissoon, X. Liu, D. Lau, A. J. Golby, I. Norton, M. Hayashi, N. Y. Agar, G. S. Young, C. Spino, S. Santagata, S. Camelo-Piragua, K. L. Ligon, O. Sagher, and X. S. Xie, Sci. Transl. Med. 5, 201ra119 (2013).
    [Crossref]
  10. K. S. Shin, A. T. Francis, A. H. Hill, M. Laohajaratsang, P. J. Cimino, C. S. Latimer, L. F. Gonzalez-Cuyar, L. N. Sekhar, G. Juric-Sekhar, and D. Fu, Sci. Rep. 9, 20392 (2019).
    [Crossref]
  11. B. G. Saar, C. W. Freudiger, J. Reichman, C. M. Stanley, G. R. Holtom, and X. S. Xie, Science 330, 1368 (2010).
    [Crossref]
  12. C. L. Evans, E. O. Potma, M. PuorisHaag, D. Côté, C. P. Lin, and X. S. Xie, Proc. Natl. Acad. Sci. USA 102, 16807 (2005).
    [Crossref]
  13. N. Stone, C. Kendall, J. Smith, P. Crow, and H. Barr, Faraday Discuss. 126, 141 (2004).
    [Crossref]
  14. S. K. Teh, W. Zheng, D. P. Lau, and Z. Huang, Analyst 134, 1232 (2009).
    [Crossref]
  15. K. Lin, W. Zheng, C. M. Lim, and Z. Huang, Biomed. Opt. Express 7, 3705 (2016).
    [Crossref]
  16. S. Karpf, M. Eibl, W. Wieser, T. Klein, and R. Huber, Nat. Commun. 6, 6784 (2015).
    [Crossref]
  17. S. Karpf, M. Eibl, W. Wieser, T. Klein, and R. Huber, J. Spectrosc. 2017, 1 (2017).
    [Crossref]
  18. R. Huber, D. C. Adler, and J. G. Fujimoto, Opt. Lett. 31, 2975 (2006).
    [Crossref]
  19. W. Wieser, W. Draxinger, T. Klein, S. Karpf, T. Pfeiffer, and R. Huber, Biomed. Opt. Express 5, 2963 (2014).
    [Crossref]
  20. T. Pfeiffer, M. Petermann, W. Draxinger, C. Jirauschek, and R. Huber, Biomed. Opt. Express 9, 4130 (2018).
    [Crossref]
  21. T. Klein and R. Huber, Biomed. Opt. Express 8, 828 (2017).
    [Crossref]
  22. W. Wieser, B. R. Biedermann, T. Klein, C. M. Eigenwillig, and R. Huber, Opt. Express 18, 14685 (2010).
    [Crossref]
  23. S. Karpf, M. Eibl, B. Sauer, F. Reinholz, G. Huttmann, and R. Huber, Biomed. Opt. Express 7, 2432 (2016).
    [Crossref]
  24. M. Eibl, S. Karpf, H. Hakert, T. Blömker, J. P. Kolb, C. Jirauschek, and R. Huber, Opt. Lett. 42, 4406 (2017).
    [Crossref]
  25. M. Ji, M. Arbel, L. Zhang, C. W. Freudiger, S. S. Hou, D. Lin, X. Yang, B. J. Bacskai, and X. S. Xie, Sci. Adv. 4, eaat7715 (2018).
    [Crossref]
  26. Z. Movasaghi, S. Rehman, and I. U. Rehman, Appl. Spectrosc. Rev. 42, 493 (2007).
    [Crossref]
  27. E. Gaufrès, S. Marcet, V. Aymong, N. Y.-W. Tang, A. Favron, F. Thouin, C. Allard, D. Rioux, N. Cottenye, M. Verhaegen, and R. Martel,J. Raman Spectrosc. 49, 174 (2018).
    [Crossref]
  28. M. A. S. de Oliveira, M. Campbell, A. M. Afify, E. C. Huang, and J. W. Chan, Biomed. Opt. Express 10, 4411 (2019).
    [Crossref]
  29. M. S. Bergholt, W. Zheng, K. Lin, K. Y. Ho, M. Teh, K. G. Yeoh, J. B. So, and Z. Huang, Technol. Cancer Res. Treat. 10, 103 (2011).
    [Crossref]
  30. H. Høgset, C. C. Horgan, J. P. K. Armstrong, M. S. Bergholt, V. Torraca, Q. Chen, T. J. Keane, L. Bugeon, M. J. Dallman, S. Mostowy, and M. M. Stevens, Nat. Commun. 11, 6172 (2020).
    [Crossref]
  31. B. Figueroa, W. Fu, T. Nguyen, K. Shin, B. Manifold, F. Wise, and D. Fu, Biomed. Opt. Express 9, 6116 (2018).
    [Crossref]
  32. C.-S. Liao, P. Wang, C. Y. Huang, P. Lin, G. Eakins, R. T. Bentley, R. Liang, and J.-X. Cheng, ACS Photon. 5, 947 (2018).
    [Crossref]
  33. H. Hakert, M. Eibl, S. Karpf, and R. Huber, in Advances in Microscopic Imaging, E. Beaurepaire, ed. (Optical Society of America, 2017), paper 1041408.

2020 (1)

H. Høgset, C. C. Horgan, J. P. K. Armstrong, M. S. Bergholt, V. Torraca, Q. Chen, T. J. Keane, L. Bugeon, M. J. Dallman, S. Mostowy, and M. M. Stevens, Nat. Commun. 11, 6172 (2020).
[Crossref]

2019 (2)

M. A. S. de Oliveira, M. Campbell, A. M. Afify, E. C. Huang, and J. W. Chan, Biomed. Opt. Express 10, 4411 (2019).
[Crossref]

K. S. Shin, A. T. Francis, A. H. Hill, M. Laohajaratsang, P. J. Cimino, C. S. Latimer, L. F. Gonzalez-Cuyar, L. N. Sekhar, G. Juric-Sekhar, and D. Fu, Sci. Rep. 9, 20392 (2019).
[Crossref]

2018 (5)

B. Figueroa, W. Fu, T. Nguyen, K. Shin, B. Manifold, F. Wise, and D. Fu, Biomed. Opt. Express 9, 6116 (2018).
[Crossref]

C.-S. Liao, P. Wang, C. Y. Huang, P. Lin, G. Eakins, R. T. Bentley, R. Liang, and J.-X. Cheng, ACS Photon. 5, 947 (2018).
[Crossref]

E. Gaufrès, S. Marcet, V. Aymong, N. Y.-W. Tang, A. Favron, F. Thouin, C. Allard, D. Rioux, N. Cottenye, M. Verhaegen, and R. Martel,J. Raman Spectrosc. 49, 174 (2018).
[Crossref]

T. Pfeiffer, M. Petermann, W. Draxinger, C. Jirauschek, and R. Huber, Biomed. Opt. Express 9, 4130 (2018).
[Crossref]

M. Ji, M. Arbel, L. Zhang, C. W. Freudiger, S. S. Hou, D. Lin, X. Yang, B. J. Bacskai, and X. S. Xie, Sci. Adv. 4, eaat7715 (2018).
[Crossref]

2017 (3)

2016 (3)

2015 (2)

T. Gottschall, T. Meyer, M. Baumgartl, C. Jauregui, M. Schmitt, J. Popp, J. Limpert, and A. Tünnermann, Laser Photon. Rev. 9, 435 (2015).
[Crossref]

S. Karpf, M. Eibl, W. Wieser, T. Klein, and R. Huber, Nat. Commun. 6, 6784 (2015).
[Crossref]

2014 (2)

C. W. Freudiger, W. Yang, G. R. Holtom, N. Peyghambarian, X. S. Xie, and K. Q. Kieu, Nat. Photon. 8, 153 (2014).
[Crossref]

W. Wieser, W. Draxinger, T. Klein, S. Karpf, T. Pfeiffer, and R. Huber, Biomed. Opt. Express 5, 2963 (2014).
[Crossref]

2013 (3)

D. Fu, G. Holtom, C. Freudiger, X. Zhang, and X. S. Xie, J. Phys. Chem. B 117, 4634 (2013).
[Crossref]

M. Ji, D. A. Orringer, C. W. Freudiger, S. Ramkissoon, X. Liu, D. Lau, A. J. Golby, I. Norton, M. Hayashi, N. Y. Agar, G. S. Young, C. Spino, S. Santagata, S. Camelo-Piragua, K. L. Ligon, O. Sagher, and X. S. Xie, Sci. Transl. Med. 5, 201ra119 (2013).
[Crossref]

T. Meyer, O. Guntinas-Lichius, F. von Eggeling, G. Ernst, D. Akimov, M. Schmitt, B. Dietzek, and J. Popp, Head Neck 35, E280 (2013).
[Crossref]

2012 (1)

Y. Ozeki, W. Umemura, Y. Otsuka, S. Satoh, H. Hashimoto, K. Sumimura, N. Nishizawa, K. Fukui, and K. Itoh, Nat. Photon. 6, 845 (2012).
[Crossref]

2011 (2)

W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, Ann. Rev. Phys. Chem. 62, 507 (2011).
[Crossref]

M. S. Bergholt, W. Zheng, K. Lin, K. Y. Ho, M. Teh, K. G. Yeoh, J. B. So, and Z. Huang, Technol. Cancer Res. Treat. 10, 103 (2011).
[Crossref]

2010 (2)

W. Wieser, B. R. Biedermann, T. Klein, C. M. Eigenwillig, and R. Huber, Opt. Express 18, 14685 (2010).
[Crossref]

B. G. Saar, C. W. Freudiger, J. Reichman, C. M. Stanley, G. R. Holtom, and X. S. Xie, Science 330, 1368 (2010).
[Crossref]

2009 (1)

S. K. Teh, W. Zheng, D. P. Lau, and Z. Huang, Analyst 134, 1232 (2009).
[Crossref]

2008 (1)

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, Science 322, 1857 (2008).
[Crossref]

2007 (1)

Z. Movasaghi, S. Rehman, and I. U. Rehman, Appl. Spectrosc. Rev. 42, 493 (2007).
[Crossref]

2006 (1)

2005 (1)

C. L. Evans, E. O. Potma, M. PuorisHaag, D. Côté, C. P. Lin, and X. S. Xie, Proc. Natl. Acad. Sci. USA 102, 16807 (2005).
[Crossref]

2004 (1)

N. Stone, C. Kendall, J. Smith, P. Crow, and H. Barr, Faraday Discuss. 126, 141 (2004).
[Crossref]

Adler, D. C.

Afify, A. M.

Agar, N. Y.

M. Ji, D. A. Orringer, C. W. Freudiger, S. Ramkissoon, X. Liu, D. Lau, A. J. Golby, I. Norton, M. Hayashi, N. Y. Agar, G. S. Young, C. Spino, S. Santagata, S. Camelo-Piragua, K. L. Ligon, O. Sagher, and X. S. Xie, Sci. Transl. Med. 5, 201ra119 (2013).
[Crossref]

Akimov, D.

T. Meyer, O. Guntinas-Lichius, F. von Eggeling, G. Ernst, D. Akimov, M. Schmitt, B. Dietzek, and J. Popp, Head Neck 35, E280 (2013).
[Crossref]

Allard, C.

E. Gaufrès, S. Marcet, V. Aymong, N. Y.-W. Tang, A. Favron, F. Thouin, C. Allard, D. Rioux, N. Cottenye, M. Verhaegen, and R. Martel,J. Raman Spectrosc. 49, 174 (2018).
[Crossref]

Arbel, M.

M. Ji, M. Arbel, L. Zhang, C. W. Freudiger, S. S. Hou, D. Lin, X. Yang, B. J. Bacskai, and X. S. Xie, Sci. Adv. 4, eaat7715 (2018).
[Crossref]

Armstrong, J. P. K.

H. Høgset, C. C. Horgan, J. P. K. Armstrong, M. S. Bergholt, V. Torraca, Q. Chen, T. J. Keane, L. Bugeon, M. J. Dallman, S. Mostowy, and M. M. Stevens, Nat. Commun. 11, 6172 (2020).
[Crossref]

Aymong, V.

E. Gaufrès, S. Marcet, V. Aymong, N. Y.-W. Tang, A. Favron, F. Thouin, C. Allard, D. Rioux, N. Cottenye, M. Verhaegen, and R. Martel,J. Raman Spectrosc. 49, 174 (2018).
[Crossref]

Bacskai, B. J.

M. Ji, M. Arbel, L. Zhang, C. W. Freudiger, S. S. Hou, D. Lin, X. Yang, B. J. Bacskai, and X. S. Xie, Sci. Adv. 4, eaat7715 (2018).
[Crossref]

Barr, H.

N. Stone, C. Kendall, J. Smith, P. Crow, and H. Barr, Faraday Discuss. 126, 141 (2004).
[Crossref]

Baumgartl, M.

T. Gottschall, T. Meyer, M. Baumgartl, C. Jauregui, M. Schmitt, J. Popp, J. Limpert, and A. Tünnermann, Laser Photon. Rev. 9, 435 (2015).
[Crossref]

Bentley, R. T.

C.-S. Liao, P. Wang, C. Y. Huang, P. Lin, G. Eakins, R. T. Bentley, R. Liang, and J.-X. Cheng, ACS Photon. 5, 947 (2018).
[Crossref]

Bergholt, M. S.

H. Høgset, C. C. Horgan, J. P. K. Armstrong, M. S. Bergholt, V. Torraca, Q. Chen, T. J. Keane, L. Bugeon, M. J. Dallman, S. Mostowy, and M. M. Stevens, Nat. Commun. 11, 6172 (2020).
[Crossref]

M. S. Bergholt, W. Zheng, K. Lin, K. Y. Ho, M. Teh, K. G. Yeoh, J. B. So, and Z. Huang, Technol. Cancer Res. Treat. 10, 103 (2011).
[Crossref]

Biedermann, B. R.

Blömker, T.

Bugeon, L.

H. Høgset, C. C. Horgan, J. P. K. Armstrong, M. S. Bergholt, V. Torraca, Q. Chen, T. J. Keane, L. Bugeon, M. J. Dallman, S. Mostowy, and M. M. Stevens, Nat. Commun. 11, 6172 (2020).
[Crossref]

Camelo-Piragua, S.

M. Ji, D. A. Orringer, C. W. Freudiger, S. Ramkissoon, X. Liu, D. Lau, A. J. Golby, I. Norton, M. Hayashi, N. Y. Agar, G. S. Young, C. Spino, S. Santagata, S. Camelo-Piragua, K. L. Ligon, O. Sagher, and X. S. Xie, Sci. Transl. Med. 5, 201ra119 (2013).
[Crossref]

Campbell, M.

Chan, J. W.

Chen, Q.

H. Høgset, C. C. Horgan, J. P. K. Armstrong, M. S. Bergholt, V. Torraca, Q. Chen, T. J. Keane, L. Bugeon, M. J. Dallman, S. Mostowy, and M. M. Stevens, Nat. Commun. 11, 6172 (2020).
[Crossref]

Cheng, J.-X.

C.-S. Liao, P. Wang, C. Y. Huang, P. Lin, G. Eakins, R. T. Bentley, R. Liang, and J.-X. Cheng, ACS Photon. 5, 947 (2018).
[Crossref]

Cimino, P. J.

K. S. Shin, A. T. Francis, A. H. Hill, M. Laohajaratsang, P. J. Cimino, C. S. Latimer, L. F. Gonzalez-Cuyar, L. N. Sekhar, G. Juric-Sekhar, and D. Fu, Sci. Rep. 9, 20392 (2019).
[Crossref]

Côté, D.

C. L. Evans, E. O. Potma, M. PuorisHaag, D. Côté, C. P. Lin, and X. S. Xie, Proc. Natl. Acad. Sci. USA 102, 16807 (2005).
[Crossref]

Cottenye, N.

E. Gaufrès, S. Marcet, V. Aymong, N. Y.-W. Tang, A. Favron, F. Thouin, C. Allard, D. Rioux, N. Cottenye, M. Verhaegen, and R. Martel,J. Raman Spectrosc. 49, 174 (2018).
[Crossref]

Crow, P.

N. Stone, C. Kendall, J. Smith, P. Crow, and H. Barr, Faraday Discuss. 126, 141 (2004).
[Crossref]

Dallman, M. J.

H. Høgset, C. C. Horgan, J. P. K. Armstrong, M. S. Bergholt, V. Torraca, Q. Chen, T. J. Keane, L. Bugeon, M. J. Dallman, S. Mostowy, and M. M. Stevens, Nat. Commun. 11, 6172 (2020).
[Crossref]

de Oliveira, M. A. S.

Dietzek, B.

T. Meyer, O. Guntinas-Lichius, F. von Eggeling, G. Ernst, D. Akimov, M. Schmitt, B. Dietzek, and J. Popp, Head Neck 35, E280 (2013).
[Crossref]

Draxinger, W.

Eakins, G.

C.-S. Liao, P. Wang, C. Y. Huang, P. Lin, G. Eakins, R. T. Bentley, R. Liang, and J.-X. Cheng, ACS Photon. 5, 947 (2018).
[Crossref]

Eibl, M.

M. Eibl, S. Karpf, H. Hakert, T. Blömker, J. P. Kolb, C. Jirauschek, and R. Huber, Opt. Lett. 42, 4406 (2017).
[Crossref]

S. Karpf, M. Eibl, W. Wieser, T. Klein, and R. Huber, J. Spectrosc. 2017, 1 (2017).
[Crossref]

S. Karpf, M. Eibl, B. Sauer, F. Reinholz, G. Huttmann, and R. Huber, Biomed. Opt. Express 7, 2432 (2016).
[Crossref]

S. Karpf, M. Eibl, W. Wieser, T. Klein, and R. Huber, Nat. Commun. 6, 6784 (2015).
[Crossref]

H. Hakert, M. Eibl, S. Karpf, and R. Huber, in Advances in Microscopic Imaging, E. Beaurepaire, ed. (Optical Society of America, 2017), paper 1041408.

Eigenwillig, C. M.

Ernst, G.

T. Meyer, O. Guntinas-Lichius, F. von Eggeling, G. Ernst, D. Akimov, M. Schmitt, B. Dietzek, and J. Popp, Head Neck 35, E280 (2013).
[Crossref]

Evans, C. L.

C. L. Evans, E. O. Potma, M. PuorisHaag, D. Côté, C. P. Lin, and X. S. Xie, Proc. Natl. Acad. Sci. USA 102, 16807 (2005).
[Crossref]

Favron, A.

E. Gaufrès, S. Marcet, V. Aymong, N. Y.-W. Tang, A. Favron, F. Thouin, C. Allard, D. Rioux, N. Cottenye, M. Verhaegen, and R. Martel,J. Raman Spectrosc. 49, 174 (2018).
[Crossref]

Figueroa, B.

Francis, A. T.

K. S. Shin, A. T. Francis, A. H. Hill, M. Laohajaratsang, P. J. Cimino, C. S. Latimer, L. F. Gonzalez-Cuyar, L. N. Sekhar, G. Juric-Sekhar, and D. Fu, Sci. Rep. 9, 20392 (2019).
[Crossref]

Freudiger, C.

D. Fu, G. Holtom, C. Freudiger, X. Zhang, and X. S. Xie, J. Phys. Chem. B 117, 4634 (2013).
[Crossref]

Freudiger, C. W.

M. Ji, M. Arbel, L. Zhang, C. W. Freudiger, S. S. Hou, D. Lin, X. Yang, B. J. Bacskai, and X. S. Xie, Sci. Adv. 4, eaat7715 (2018).
[Crossref]

C. W. Freudiger, W. Yang, G. R. Holtom, N. Peyghambarian, X. S. Xie, and K. Q. Kieu, Nat. Photon. 8, 153 (2014).
[Crossref]

M. Ji, D. A. Orringer, C. W. Freudiger, S. Ramkissoon, X. Liu, D. Lau, A. J. Golby, I. Norton, M. Hayashi, N. Y. Agar, G. S. Young, C. Spino, S. Santagata, S. Camelo-Piragua, K. L. Ligon, O. Sagher, and X. S. Xie, Sci. Transl. Med. 5, 201ra119 (2013).
[Crossref]

W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, Ann. Rev. Phys. Chem. 62, 507 (2011).
[Crossref]

B. G. Saar, C. W. Freudiger, J. Reichman, C. M. Stanley, G. R. Holtom, and X. S. Xie, Science 330, 1368 (2010).
[Crossref]

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, Science 322, 1857 (2008).
[Crossref]

Fu, D.

K. S. Shin, A. T. Francis, A. H. Hill, M. Laohajaratsang, P. J. Cimino, C. S. Latimer, L. F. Gonzalez-Cuyar, L. N. Sekhar, G. Juric-Sekhar, and D. Fu, Sci. Rep. 9, 20392 (2019).
[Crossref]

B. Figueroa, W. Fu, T. Nguyen, K. Shin, B. Manifold, F. Wise, and D. Fu, Biomed. Opt. Express 9, 6116 (2018).
[Crossref]

D. Fu, G. Holtom, C. Freudiger, X. Zhang, and X. S. Xie, J. Phys. Chem. B 117, 4634 (2013).
[Crossref]

Fu, W.

Fujimoto, J. G.

Fukui, K.

Y. Ozeki, W. Umemura, Y. Otsuka, S. Satoh, H. Hashimoto, K. Sumimura, N. Nishizawa, K. Fukui, and K. Itoh, Nat. Photon. 6, 845 (2012).
[Crossref]

Gaufrès, E.

E. Gaufrès, S. Marcet, V. Aymong, N. Y.-W. Tang, A. Favron, F. Thouin, C. Allard, D. Rioux, N. Cottenye, M. Verhaegen, and R. Martel,J. Raman Spectrosc. 49, 174 (2018).
[Crossref]

Golby, A. J.

M. Ji, D. A. Orringer, C. W. Freudiger, S. Ramkissoon, X. Liu, D. Lau, A. J. Golby, I. Norton, M. Hayashi, N. Y. Agar, G. S. Young, C. Spino, S. Santagata, S. Camelo-Piragua, K. L. Ligon, O. Sagher, and X. S. Xie, Sci. Transl. Med. 5, 201ra119 (2013).
[Crossref]

Gonzalez-Cuyar, L. F.

K. S. Shin, A. T. Francis, A. H. Hill, M. Laohajaratsang, P. J. Cimino, C. S. Latimer, L. F. Gonzalez-Cuyar, L. N. Sekhar, G. Juric-Sekhar, and D. Fu, Sci. Rep. 9, 20392 (2019).
[Crossref]

Gottschall, T.

T. Gottschall, T. Meyer, M. Baumgartl, C. Jauregui, M. Schmitt, J. Popp, J. Limpert, and A. Tünnermann, Laser Photon. Rev. 9, 435 (2015).
[Crossref]

Guntinas-Lichius, O.

T. Meyer, O. Guntinas-Lichius, F. von Eggeling, G. Ernst, D. Akimov, M. Schmitt, B. Dietzek, and J. Popp, Head Neck 35, E280 (2013).
[Crossref]

Hakert, H.

M. Eibl, S. Karpf, H. Hakert, T. Blömker, J. P. Kolb, C. Jirauschek, and R. Huber, Opt. Lett. 42, 4406 (2017).
[Crossref]

H. Hakert, M. Eibl, S. Karpf, and R. Huber, in Advances in Microscopic Imaging, E. Beaurepaire, ed. (Optical Society of America, 2017), paper 1041408.

Hashimoto, H.

Y. Ozeki, W. Umemura, Y. Otsuka, S. Satoh, H. Hashimoto, K. Sumimura, N. Nishizawa, K. Fukui, and K. Itoh, Nat. Photon. 6, 845 (2012).
[Crossref]

Hayashi, M.

M. Ji, D. A. Orringer, C. W. Freudiger, S. Ramkissoon, X. Liu, D. Lau, A. J. Golby, I. Norton, M. Hayashi, N. Y. Agar, G. S. Young, C. Spino, S. Santagata, S. Camelo-Piragua, K. L. Ligon, O. Sagher, and X. S. Xie, Sci. Transl. Med. 5, 201ra119 (2013).
[Crossref]

He, C.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, Science 322, 1857 (2008).
[Crossref]

Hill, A. H.

K. S. Shin, A. T. Francis, A. H. Hill, M. Laohajaratsang, P. J. Cimino, C. S. Latimer, L. F. Gonzalez-Cuyar, L. N. Sekhar, G. Juric-Sekhar, and D. Fu, Sci. Rep. 9, 20392 (2019).
[Crossref]

Ho, K. Y.

M. S. Bergholt, W. Zheng, K. Lin, K. Y. Ho, M. Teh, K. G. Yeoh, J. B. So, and Z. Huang, Technol. Cancer Res. Treat. 10, 103 (2011).
[Crossref]

Høgset, H.

H. Høgset, C. C. Horgan, J. P. K. Armstrong, M. S. Bergholt, V. Torraca, Q. Chen, T. J. Keane, L. Bugeon, M. J. Dallman, S. Mostowy, and M. M. Stevens, Nat. Commun. 11, 6172 (2020).
[Crossref]

Holtom, G.

D. Fu, G. Holtom, C. Freudiger, X. Zhang, and X. S. Xie, J. Phys. Chem. B 117, 4634 (2013).
[Crossref]

Holtom, G. R.

C. W. Freudiger, W. Yang, G. R. Holtom, N. Peyghambarian, X. S. Xie, and K. Q. Kieu, Nat. Photon. 8, 153 (2014).
[Crossref]

B. G. Saar, C. W. Freudiger, J. Reichman, C. M. Stanley, G. R. Holtom, and X. S. Xie, Science 330, 1368 (2010).
[Crossref]

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, Science 322, 1857 (2008).
[Crossref]

Horgan, C. C.

H. Høgset, C. C. Horgan, J. P. K. Armstrong, M. S. Bergholt, V. Torraca, Q. Chen, T. J. Keane, L. Bugeon, M. J. Dallman, S. Mostowy, and M. M. Stevens, Nat. Commun. 11, 6172 (2020).
[Crossref]

Hou, S. S.

M. Ji, M. Arbel, L. Zhang, C. W. Freudiger, S. S. Hou, D. Lin, X. Yang, B. J. Bacskai, and X. S. Xie, Sci. Adv. 4, eaat7715 (2018).
[Crossref]

Huang, C. Y.

C.-S. Liao, P. Wang, C. Y. Huang, P. Lin, G. Eakins, R. T. Bentley, R. Liang, and J.-X. Cheng, ACS Photon. 5, 947 (2018).
[Crossref]

Huang, E. C.

Huang, Z.

K. Lin, W. Zheng, C. M. Lim, and Z. Huang, Biomed. Opt. Express 7, 3705 (2016).
[Crossref]

M. S. Bergholt, W. Zheng, K. Lin, K. Y. Ho, M. Teh, K. G. Yeoh, J. B. So, and Z. Huang, Technol. Cancer Res. Treat. 10, 103 (2011).
[Crossref]

S. K. Teh, W. Zheng, D. P. Lau, and Z. Huang, Analyst 134, 1232 (2009).
[Crossref]

Huber, R.

Huttmann, G.

Itoh, K.

Y. Ozeki, W. Umemura, Y. Otsuka, S. Satoh, H. Hashimoto, K. Sumimura, N. Nishizawa, K. Fukui, and K. Itoh, Nat. Photon. 6, 845 (2012).
[Crossref]

Jauregui, C.

T. Gottschall, T. Meyer, M. Baumgartl, C. Jauregui, M. Schmitt, J. Popp, J. Limpert, and A. Tünnermann, Laser Photon. Rev. 9, 435 (2015).
[Crossref]

Ji, M.

M. Ji, M. Arbel, L. Zhang, C. W. Freudiger, S. S. Hou, D. Lin, X. Yang, B. J. Bacskai, and X. S. Xie, Sci. Adv. 4, eaat7715 (2018).
[Crossref]

M. Ji, D. A. Orringer, C. W. Freudiger, S. Ramkissoon, X. Liu, D. Lau, A. J. Golby, I. Norton, M. Hayashi, N. Y. Agar, G. S. Young, C. Spino, S. Santagata, S. Camelo-Piragua, K. L. Ligon, O. Sagher, and X. S. Xie, Sci. Transl. Med. 5, 201ra119 (2013).
[Crossref]

Jirauschek, C.

Juric-Sekhar, G.

K. S. Shin, A. T. Francis, A. H. Hill, M. Laohajaratsang, P. J. Cimino, C. S. Latimer, L. F. Gonzalez-Cuyar, L. N. Sekhar, G. Juric-Sekhar, and D. Fu, Sci. Rep. 9, 20392 (2019).
[Crossref]

Kang, J. X.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, Science 322, 1857 (2008).
[Crossref]

Karpf, S.

S. Karpf, M. Eibl, W. Wieser, T. Klein, and R. Huber, J. Spectrosc. 2017, 1 (2017).
[Crossref]

M. Eibl, S. Karpf, H. Hakert, T. Blömker, J. P. Kolb, C. Jirauschek, and R. Huber, Opt. Lett. 42, 4406 (2017).
[Crossref]

S. Karpf, M. Eibl, B. Sauer, F. Reinholz, G. Huttmann, and R. Huber, Biomed. Opt. Express 7, 2432 (2016).
[Crossref]

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K. S. Shin, A. T. Francis, A. H. Hill, M. Laohajaratsang, P. J. Cimino, C. S. Latimer, L. F. Gonzalez-Cuyar, L. N. Sekhar, G. Juric-Sekhar, and D. Fu, Sci. Rep. 9, 20392 (2019).
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N. Stone, C. Kendall, J. Smith, P. Crow, and H. Barr, Faraday Discuss. 126, 141 (2004).
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M. S. Bergholt, W. Zheng, K. Lin, K. Y. Ho, M. Teh, K. G. Yeoh, J. B. So, and Z. Huang, Technol. Cancer Res. Treat. 10, 103 (2011).
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M. Ji, D. A. Orringer, C. W. Freudiger, S. Ramkissoon, X. Liu, D. Lau, A. J. Golby, I. Norton, M. Hayashi, N. Y. Agar, G. S. Young, C. Spino, S. Santagata, S. Camelo-Piragua, K. L. Ligon, O. Sagher, and X. S. Xie, Sci. Transl. Med. 5, 201ra119 (2013).
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B. G. Saar, C. W. Freudiger, J. Reichman, C. M. Stanley, G. R. Holtom, and X. S. Xie, Science 330, 1368 (2010).
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H. Høgset, C. C. Horgan, J. P. K. Armstrong, M. S. Bergholt, V. Torraca, Q. Chen, T. J. Keane, L. Bugeon, M. J. Dallman, S. Mostowy, and M. M. Stevens, Nat. Commun. 11, 6172 (2020).
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N. Stone, C. Kendall, J. Smith, P. Crow, and H. Barr, Faraday Discuss. 126, 141 (2004).
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Y. Ozeki, W. Umemura, Y. Otsuka, S. Satoh, H. Hashimoto, K. Sumimura, N. Nishizawa, K. Fukui, and K. Itoh, Nat. Photon. 6, 845 (2012).
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E. Gaufrès, S. Marcet, V. Aymong, N. Y.-W. Tang, A. Favron, F. Thouin, C. Allard, D. Rioux, N. Cottenye, M. Verhaegen, and R. Martel,J. Raman Spectrosc. 49, 174 (2018).
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S. K. Teh, W. Zheng, D. P. Lau, and Z. Huang, Analyst 134, 1232 (2009).
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E. Gaufrès, S. Marcet, V. Aymong, N. Y.-W. Tang, A. Favron, F. Thouin, C. Allard, D. Rioux, N. Cottenye, M. Verhaegen, and R. Martel,J. Raman Spectrosc. 49, 174 (2018).
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C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, Science 322, 1857 (2008).
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Y. Ozeki, W. Umemura, Y. Otsuka, S. Satoh, H. Hashimoto, K. Sumimura, N. Nishizawa, K. Fukui, and K. Itoh, Nat. Photon. 6, 845 (2012).
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E. Gaufrès, S. Marcet, V. Aymong, N. Y.-W. Tang, A. Favron, F. Thouin, C. Allard, D. Rioux, N. Cottenye, M. Verhaegen, and R. Martel,J. Raman Spectrosc. 49, 174 (2018).
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W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, Ann. Rev. Phys. Chem. 62, 507 (2011).
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B. G. Saar, C. W. Freudiger, J. Reichman, C. M. Stanley, G. R. Holtom, and X. S. Xie, Science 330, 1368 (2010).
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C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, Science 322, 1857 (2008).
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C. W. Freudiger, W. Yang, G. R. Holtom, N. Peyghambarian, X. S. Xie, and K. Q. Kieu, Nat. Photon. 8, 153 (2014).
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M. Ji, M. Arbel, L. Zhang, C. W. Freudiger, S. S. Hou, D. Lin, X. Yang, B. J. Bacskai, and X. S. Xie, Sci. Adv. 4, eaat7715 (2018).
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M. S. Bergholt, W. Zheng, K. Lin, K. Y. Ho, M. Teh, K. G. Yeoh, J. B. So, and Z. Huang, Technol. Cancer Res. Treat. 10, 103 (2011).
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M. Ji, D. A. Orringer, C. W. Freudiger, S. Ramkissoon, X. Liu, D. Lau, A. J. Golby, I. Norton, M. Hayashi, N. Y. Agar, G. S. Young, C. Spino, S. Santagata, S. Camelo-Piragua, K. L. Ligon, O. Sagher, and X. S. Xie, Sci. Transl. Med. 5, 201ra119 (2013).
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D. Fu, G. Holtom, C. Freudiger, X. Zhang, and X. S. Xie, J. Phys. Chem. B 117, 4634 (2013).
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K. Lin, W. Zheng, C. M. Lim, and Z. Huang, Biomed. Opt. Express 7, 3705 (2016).
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ACS Photon. (1)

C.-S. Liao, P. Wang, C. Y. Huang, P. Lin, G. Eakins, R. T. Bentley, R. Liang, and J.-X. Cheng, ACS Photon. 5, 947 (2018).
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Analyst (1)

S. K. Teh, W. Zheng, D. P. Lau, and Z. Huang, Analyst 134, 1232 (2009).
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Ann. Rev. Phys. Chem. (1)

W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, Ann. Rev. Phys. Chem. 62, 507 (2011).
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Appl. Spectrosc. Rev. (1)

Z. Movasaghi, S. Rehman, and I. U. Rehman, Appl. Spectrosc. Rev. 42, 493 (2007).
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Biomed. Opt. Express (7)

Chem. Soc. Rev. (1)

C. Krafft, I. W. Schie, T. Meyer, M. Schmitt, and J. Popp, Chem. Soc. Rev. 45, 1819 (2016).
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Faraday Discuss. (1)

N. Stone, C. Kendall, J. Smith, P. Crow, and H. Barr, Faraday Discuss. 126, 141 (2004).
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Head Neck (1)

T. Meyer, O. Guntinas-Lichius, F. von Eggeling, G. Ernst, D. Akimov, M. Schmitt, B. Dietzek, and J. Popp, Head Neck 35, E280 (2013).
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J. Phys. Chem. B (1)

D. Fu, G. Holtom, C. Freudiger, X. Zhang, and X. S. Xie, J. Phys. Chem. B 117, 4634 (2013).
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J. Raman Spectrosc. (1)

E. Gaufrès, S. Marcet, V. Aymong, N. Y.-W. Tang, A. Favron, F. Thouin, C. Allard, D. Rioux, N. Cottenye, M. Verhaegen, and R. Martel,J. Raman Spectrosc. 49, 174 (2018).
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Supplementary Material (1)

NameDescription
Supplement 1       System resolution

Data Availability

Data underlying the results presented in this paper are not publicly available at this time but may be obtained from the authors upon reasonable request.

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Figures (3)

Fig. 1.
Fig. 1. Schematic setup of the fingerprint Raman imaging setup. A Fourier-domain mode-locked (FDML) laser is combined with a fiber-based pump laser to generate the stimulated Raman process. The pump laser is based on a master oscillator power amplifier (MOPA) architecture, allowing us to encode the stimulated Raman transitions in time (TICO-Raman [16]). The resulting stimulated Raman gain (SRG) of the probe light is measured in transmission. Cryo sections of nasal turbinate (1) and tumorous hypopharynx tissue (2) biopsies were imaged in the spectral window from ${1500}\;{{\rm cm}^{- 1}}$ to ${1800}\;{{\rm cm}^{- 1}}$ in the fingerprint region and compared to spontaneous Raman spectra (see inset).
Fig. 2.
Fig. 2. (a) Hyperspectral TICO-Raman image of healthy human inferior turbinate. Green represents the Raman signal from ${1540 {-} 1580}\;{{\rm cm}^{- 1}}$ , while the window from ${1620 {-} 1640}\;{{\rm cm}^{- 1}}$ is color-coded cyan to visualize the Amide I mode of proteins. The TICO-Raman spectra over ROI1 (cyan) and ROI2 (green) are in good agreement with spontaneous Raman spectra of the same tissue type (black). (FOV: ${500} \times {500}\;{\unicode{x00B5}{\rm m}},\;{500} \times {500}\;{\rm pixel}$ .)
Fig. 3.
Fig. 3. (a) TICO-Raman molecular localization map of the Amide I vibrational modes in the spectral window from ${1640 {-} 1650}\;{{\rm cm}^{- 1}}$ of human tumorous pharynx tissue. Representative Raman spectra are presented in (b), showing a spatially averaged TICO spectrum over the ${40} \times {40}\;{\rm pixel}$ ROI [dotted box in (a)] in red and a spontaneous Raman spectrum of the same tissue type in black. The Amide I band was clearly detected and spectrally resolved. (FOV: ${500} \times {500}\;{\unicode{x00B5}{\rm m}}$ , ${500} \times {500}\;{\rm pixel}$ .)

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