WO2007023452A1 - Improved raman spectroscopy - Google Patents

Improved raman spectroscopy Download PDF

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Publication number
WO2007023452A1
WO2007023452A1 PCT/IB2006/052899 IB2006052899W WO2007023452A1 WO 2007023452 A1 WO2007023452 A1 WO 2007023452A1 IB 2006052899 W IB2006052899 W IB 2006052899W WO 2007023452 A1 WO2007023452 A1 WO 2007023452A1
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WO
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Prior art keywords
frequency
sample
scattering signal
raman scattering
analytes
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Application number
PCT/IB2006/052899
Other languages
French (fr)
Inventor
Gerhardus Lucassen
Sieglinde Neerken
Original Assignee
Koninklijke Philips Electronics N.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO2007023452A1 publication Critical patent/WO2007023452A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/636—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited using an arrangement of pump beam and probe beam; using the measurement of optical non-linear properties
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/28—Investigating the spectrum
    • G01J3/44—Raman spectrometry; Scattering spectrometry ; Fluorescence spectrometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering
    • G01N21/658—Raman scattering enhancement Raman, e.g. surface plasmons
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering
    • G01N2021/653—Coherent methods [CARS]
    • G01N2021/655—Stimulated Raman

Definitions

  • the present invention relates to an improved Raman spectroscopy apparatus and method.
  • Raman Scattering is a well known technique for detecting the presence of molecules.
  • RS Raman Scattering
  • a sample is irradiated with light and photons from the incident light are scattered by molecules in the sample. Most of the scattered photons scatter elastically but a small fraction scatter in-elastically at different wavelengths to the incident wavelength. The process behind this in-elastic scattering is termed the Raman effect.
  • a plot of intensity of the scattered light verses the wavelength difference of the incident and scattered light is termed a Raman spectra and is indicative of the scattering molecules.
  • the Raman effect is weak and hence not very sensitive to analyte concentration.
  • Several techniques have been developed to enhance the Raman effect.
  • the sample receives the normal laser light beam, and an additional beam of photons tuned to the wavelength that the sample Raman scatters to. This "stimulates” or amplifies the Raman effect by a factor of four to five.
  • SERS Surface - Enhanced Raman Scattering
  • Another technique is termed Surface - Enhanced Raman Scattering (SERS) which utilises the fact that Raman scattering from an analyte that is located close to certain metal surfaces can be many times greater than that from the analyte alone in solution. SERS is strongest on silver but may be observed on gold and copper as well. It is has been proposed that SERS arises from two mechanisms. The first is an enhanced electromagnetic field produced at the surface of the metal. When the wavelength of the incident light is close to the plasmon wavelength of the metal, conduction electrons in the metal surface are excited into an extended surface electronic excited state called a surface plasmon resonance. Molecules adsorbed or in close proximity to the surface experience an exceptionally large electromagnetic field. Vibrational modes normal to the surface are thus strongly enhanced.
  • the second mode of enhancement is by the formation of a charge-transfer complex between the surface and analyte molecule.
  • the electronic transitions of many charge transfer complexes are in the visible, so that resonance enhancement occurs.
  • So called Surface enhanced resonance spectroscopy (SERRS) is a technique which can detect analyte concentrations in the femto-molar range.
  • the method involves analysing a colloid solution or solid metal substrates of noble, for example silver or gold nano-particles in solution and target molecules, for example, DNA strands which are in contact with or in close proximity to the nano-particles.
  • specific capture molecules may be used to bind the target molecules and attach them to the metal surface.
  • Raman spectroscopy techniques having sensitivities in the sub- femto molar detection limit, particularly when used to detect small quantities of analytes . For example for identification of bacterial DNA in infectious diseases.
  • Embodiments of the present invention aim to provide a sensitive Raman spectroscopy technique.
  • a method of detecting Raman active analytes located at a conducting surface comprising: irradiating a sample containing the Raman active analytes with radiation having a frequency substantially tuned to a plasmon resonance band of the conducting surface to generate an enhanced Raman scattering signal; irradiating the sample with radiation having a frequency substantially tuned to a frequency of the enhanced Raman scattering signal to stimulate the enhanced Raman scattering signal; detecting the stimulated enhanced Raman scattering signal.
  • an apparatus for detecting Raman active analytes located at a conducting surface in a sample comprising: a radiation source for irradiating the sample containing the Raman active analytes with radiation having a frequency substantially tuned to a plasmon resonance band of the conducting surface to generate an enhanced Raman scattering signal; a radiation source for irradiating the sample with radiation having a frequency substantially tuned to a frequency of the enhanced Raman scattering signal to stimulate the enhanced Raman scattering signal; and a detector for detecting the stimulated enhanced Raman scattering signal.
  • the sample is also irradiated with radiation having a frequency substantially tuned to an absorption band of the analytes.
  • the sample may comprise a colloid solution of metal particles which together form the conducting surface.
  • the analytes each comprise a target molecule, which may comprise protein or DNA.
  • Each target molecule may be linked to a dye molecule, the absorption band being an absorption band of the dye molecules.
  • Figure 1 is a schematic diagram of a system embodying the present invention
  • Figure 2 is a schematic diagram of an analyte absorbed at a metal surface.
  • a spectroscopy system 1 comprises a pump laser source 2 for irradiating a sample 3 with a pump laser beam 2a comprising laser light of frequency/;.
  • the sample 3 is a colloid solution comprising noble, for example silver or gold, or copper nano-particles and target molecules, for example DNA strands, in close proximity to the nano-particles.
  • a target molecule 10 typically protein or a DNA strand in the sample 3 is bound to the surface of a nano-particle 11 by a specific capture molecule 12.
  • a dye molecule 13 is attached to the capture molecule 12.
  • DNA in itself is not very sensitive to Raman spectroscopy when excited in the visible wavelength range and so the purpose of the Dye molecules is to generate a strong scattering signal and hence indicate the presence of the specific target molecules to which they are linked.
  • Such solutions and methods for their preparation are well known to those skilled in the art of Raman spectroscopy of biological molecules.
  • the frequency of the pump laser beam is selected so that it is within the surface plasmon resonance band of the metal nano-particles in the colloid solution of sample 3 and an electronic absorption band of the dye molecules.
  • the pump laser source 2 thus causes SERRS scattering from the sample 3.
  • the system further comprises a probe laser source 4 for irradiating the sample 3 with a probe laser beam 4a of tunable frequency /2.
  • the probe laser beam is directed by a mirror 5 to a beam splitter 6. From the beam splitter 6 both the pump laser beam 2a and the probe laser beam 4a pass collinearly to the sample 3.
  • the system 1 may be arranged so that both beams are spatially separated when they enter the sample 3.
  • the probe laser beam 4a is tunable across the frequency range of the Raman signal generated by the pump laser beam 2a.
  • the frequency of probe laser may be tuned to match the frequency of each peak in the Raman signal generated by the pump laser beam.
  • the probe laser beam thus causes the stimulated Raman gain effect described above in the introduction to amplify further the SERRS effect caused by the pump laser beam 2a.
  • the combined effect of the pump laser source 2 and the probe laser source 4 gives rise to a new triple enhanced RAMAN effect having enhancement via 1) pump laser excitement of the dye molecules in their electronic resonance band 2) surface plasmon excitation by the pump laser and 3) the stimulated Raman effect of probe laser.
  • SESRRS Surface Enhanced Stimulated Resonance Raman Spectroscopy
  • Figures 3a and 3b each shows a intensity v wavelength plot of a possible plasmon resonance band 20 and a dye absorption band 21 and also indicates a pump beam wavelength ⁇ i and a probe beam wavelength ⁇ 2 for generating SESRRS.
  • the SESRRS signal 7 generated in this may be measured in the probe forward direction by a detector 8, for example a photodiode or photo multiplier tube, having passed through a filter 9 which filters out elastically scattered photons.
  • a signal 8a is fed from the detector 8 to a chopper 8b which in a standard way chops the pump beam to enable phase lock loop measurements to be made.
  • the gain from the stimulated Raman effect depends on sample length. There is an optimum sample length for maximising the gain resulting from the electronic excitation of the dye molecules. If the sample length is too long the gain resulting from the electronic excitation of the dye molecules decreases because of self-absorption of the light. It will therefore be appreciated that an optimum sample length for the SEERRS system 1 exists that will depend upon the sample under analysis. Improved results will be obtained even if the frequency of the pump laser beam is not tuned to an electronic absorption band of the dye molecules and thus the pump laser beam is generating SERS rather than SERRS.

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • General Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Analytical Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nonlinear Science (AREA)
  • Optics & Photonics (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

There is described a Raman spectroscopy system (1) for detecting Raman active analytes located at a conducting surface (11) in a sample (3). The system (1) comprises a pump laser (2) for irradiating the sample (3) with laser light having a frequency substantially tuned to a plasmon resonance band of the conducting surface (11) and also substantially tuned to an electronic absorption band of the analytes to generate an enhanced Raman scattering signal. In addition, the system (1) comprises a probe laser (4) for irradiating the sample with laser light having a frequency substantially tuned to a frequency of the enhanced Raman scattering signal to stimulate the enhanced Raman scattering signal yet further.

Description

IMPROVED RAMAN SPECTROSCOPY
The present invention relates to an improved Raman spectroscopy apparatus and method.
Raman Scattering (RS) is a well known technique for detecting the presence of molecules. During Raman spectroscopy, a sample is irradiated with light and photons from the incident light are scattered by molecules in the sample. Most of the scattered photons scatter elastically but a small fraction scatter in-elastically at different wavelengths to the incident wavelength. The process behind this in-elastic scattering is termed the Raman effect. A plot of intensity of the scattered light verses the wavelength difference of the incident and scattered light is termed a Raman spectra and is indicative of the scattering molecules.
The Raman effect is weak and hence not very sensitive to analyte concentration. Several techniques have been developed to enhance the Raman effect.
In stimulated Raman spectroscopy, the sample receives the normal laser light beam, and an additional beam of photons tuned to the wavelength that the sample Raman scatters to. This "stimulates" or amplifies the Raman effect by a factor of four to five.
Another technique is termed Surface - Enhanced Raman Scattering (SERS) which utilises the fact that Raman scattering from an analyte that is located close to certain metal surfaces can be many times greater than that from the analyte alone in solution. SERS is strongest on silver but may be observed on gold and copper as well. It is has been proposed that SERS arises from two mechanisms. The first is an enhanced electromagnetic field produced at the surface of the metal. When the wavelength of the incident light is close to the plasmon wavelength of the metal, conduction electrons in the metal surface are excited into an extended surface electronic excited state called a surface plasmon resonance. Molecules adsorbed or in close proximity to the surface experience an exceptionally large electromagnetic field. Vibrational modes normal to the surface are thus strongly enhanced. The second mode of enhancement is by the formation of a charge-transfer complex between the surface and analyte molecule. The electronic transitions of many charge transfer complexes are in the visible, so that resonance enhancement occurs. So called Surface enhanced resonance spectroscopy (SERRS) is a technique which can detect analyte concentrations in the femto-molar range. Typically, the method involves analysing a colloid solution or solid metal substrates of noble, for example silver or gold nano-particles in solution and target molecules, for example, DNA strands which are in contact with or in close proximity to the nano-particles. To improve specificity, specific capture molecules may be used to bind the target molecules and attach them to the metal surface. By using a pump laser having a frequency in the surface plasmon resonance band of the metal nano-particles SERS (described above) occurs. To increase signal strength even further, dye molecules that have an electronic absorption frequency close to the plasmon resonance are attached to the capture molecules. The laser excitation of both plasmons in the nano-particle surfaces and the dye molecules in the electronic resonance band gives extremely high Raman signal enhancement, so called SERRS.
It is desirable to have Raman spectroscopy techniques having sensitivities in the sub- femto molar detection limit, particularly when used to detect small quantities of analytes . For example for identification of bacterial DNA in infectious diseases.
Embodiments of the present invention aim to provide a sensitive Raman spectroscopy technique.
According to the present invention there is provided a method of detecting Raman active analytes located at a conducting surface, the method comprising: irradiating a sample containing the Raman active analytes with radiation having a frequency substantially tuned to a plasmon resonance band of the conducting surface to generate an enhanced Raman scattering signal; irradiating the sample with radiation having a frequency substantially tuned to a frequency of the enhanced Raman scattering signal to stimulate the enhanced Raman scattering signal; detecting the stimulated enhanced Raman scattering signal. According to the invention there is also provided an apparatus for detecting Raman active analytes located at a conducting surface in a sample, the apparatus comprising: a radiation source for irradiating the sample containing the Raman active analytes with radiation having a frequency substantially tuned to a plasmon resonance band of the conducting surface to generate an enhanced Raman scattering signal; a radiation source for irradiating the sample with radiation having a frequency substantially tuned to a frequency of the enhanced Raman scattering signal to stimulate the enhanced Raman scattering signal; and a detector for detecting the stimulated enhanced Raman scattering signal. Preferably, the sample is also irradiated with radiation having a frequency substantially tuned to an absorption band of the analytes.
The sample may comprise a colloid solution of metal particles which together form the conducting surface. In a preferred embodiment the analytes each comprise a target molecule, which may comprise protein or DNA.
Each target molecule may be linked to a dye molecule, the absorption band being an absorption band of the dye molecules.
An embodiment of the invention will now be described by way of example only with reference to the accompanying drawing in which:
Figure 1 is a schematic diagram of a system embodying the present invention; Figure 2 is a schematic diagram of an analyte absorbed at a metal surface.
Figures 3a and 3b each shows an intensity v wavelength plot of a possible plasmon resonance band and a dye absorption band. Referring now to Figure 1 of the drawings, a spectroscopy system 1 comprises a pump laser source 2 for irradiating a sample 3 with a pump laser beam 2a comprising laser light of frequency/;. In this example, the sample 3 is a colloid solution comprising noble, for example silver or gold, or copper nano-particles and target molecules, for example DNA strands, in close proximity to the nano-particles. As illustrated in figure 2, in a preferred embodiment, a target molecule 10, typically protein or a DNA strand in the sample 3, is bound to the surface of a nano-particle 11 by a specific capture molecule 12. A dye molecule 13 is attached to the capture molecule 12. As is known in the art, DNA in itself is not very sensitive to Raman spectroscopy when excited in the visible wavelength range and so the purpose of the Dye molecules is to generate a strong scattering signal and hence indicate the presence of the specific target molecules to which they are linked. Such solutions and methods for their preparation are well known to those skilled in the art of Raman spectroscopy of biological molecules.
The frequency of the pump laser beam is selected so that it is within the surface plasmon resonance band of the metal nano-particles in the colloid solution of sample 3 and an electronic absorption band of the dye molecules. In a known fashion, as described above, the pump laser source 2 thus causes SERRS scattering from the sample 3. In addition, the system further comprises a probe laser source 4 for irradiating the sample 3 with a probe laser beam 4a of tunable frequency /2. The probe laser beam is directed by a mirror 5 to a beam splitter 6. From the beam splitter 6 both the pump laser beam 2a and the probe laser beam 4a pass collinearly to the sample 3. Alternatively, the system 1 may be arranged so that both beams are spatially separated when they enter the sample 3.
The probe laser beam 4a is tunable across the frequency range of the Raman signal generated by the pump laser beam 2a. In other words, the frequency of probe laser may be tuned to match the frequency of each peak in the Raman signal generated by the pump laser beam. The probe laser beam thus causes the stimulated Raman gain effect described above in the introduction to amplify further the SERRS effect caused by the pump laser beam 2a.
The combined effect of the pump laser source 2 and the probe laser source 4 gives rise to a new triple enhanced RAMAN effect having enhancement via 1) pump laser excitement of the dye molecules in their electronic resonance band 2) surface plasmon excitation by the pump laser and 3) the stimulated Raman effect of probe laser. We have termed this new technique Surface Enhanced Stimulated Resonance Raman Spectroscopy (SESRRS).
Figures 3a and 3b each shows a intensity v wavelength plot of a possible plasmon resonance band 20 and a dye absorption band 21 and also indicates a pump beam wavelength λi and a probe beam wavelength λ2 for generating SESRRS.
The SESRRS signal 7 generated in this may be measured in the probe forward direction by a detector 8, for example a photodiode or photo multiplier tube, having passed through a filter 9 which filters out elastically scattered photons.
In a preferred embodiment, a signal 8a is fed from the detector 8 to a chopper 8b which in a standard way chops the pump beam to enable phase lock loop measurements to be made.
The gain from the stimulated Raman effect depends on sample length. There is an optimum sample length for maximising the gain resulting from the electronic excitation of the dye molecules. If the sample length is too long the gain resulting from the electronic excitation of the dye molecules decreases because of self-absorption of the light. It will therefore be appreciated that an optimum sample length for the SEERRS system 1 exists that will depend upon the sample under analysis. Improved results will be obtained even if the frequency of the pump laser beam is not tuned to an electronic absorption band of the dye molecules and thus the pump laser beam is generating SERS rather than SERRS.
Having thus described the present invention by reference to a preferred embodiment it is to be well understood that the embodiment in question is exemplary only and that modifications and variations such as will occur to those possessed of appropriate knowledge and skills may be made without departure from the spirit and scope of the invention as set forth in the appended claims and equivalents thereof. In the claims, any reference signs placed in parentheses shall not be construed as limiting the claims. The word "comprising" and "comprises", and the like, does not exclude the presence of elements or steps other than those listed in any claim or the specification as a whole. The singular reference of an element does not exclude the plural reference of such elements.

Claims

1. A method of detecting Raman active analytes located at a conducting surface, the method comprising: irradiating (2) a sample (3) containing the Raman active analytes with radiation (2a) having a frequency (fi) substantially tuned to a plasmon resonance band of the conducting surface to generate an enhanced Raman scattering signal; irradiating (4) the sample (3) with radiation (4a) having a frequency (f2) substantially tuned to a frequency of the enhanced Raman scattering signal to stimulate the enhanced Raman scattering signal; detecting (8) the stimulated enhanced Raman scattering signal (7).
2. A method according to claim 1 further comprising irradiating the sample with radiation having a frequency substantially tuned to an absorption band of the analytes.
3. A method according to claim 1, wherein the sample comprises a colloid solution of metal particles which together form the conducting surface.
4. A method according to claim 1, wherein the analytes each comprises a target molecule and the target molecule is linked to a dye molecule, the absorption band being an absorption band of the dye molecules.
5. A method according to claim 1, wherein the analytes each comprises a target molecule and the target molecule is bound to a capture molecule for attaching the target molecule to the surface.
6. A method according to claim 1, comprising tuning the frequency of the radiation having a frequency substantially tuned to a frequency of the enhanced Raman scattering signal across a frequency range of the enhanced Raman scattering signal.
7. An apparatus for detecting Raman active analytes located at a conducting surface in a sample, the apparatus comprising: a radiation source (2) for irradiating the sample (3) containing the Raman active analytes with radiation having a frequency (fi) substantially tuned to a plasmon resonance band of the conducting surface to generate an enhanced Raman scattering signal; a radiation source (4) for irradiating the sample (3) with radiation having a frequency (f2) substantially tuned to a frequency of the enhanced Raman scattering signal to stimulate the enhanced Raman scattering signal; and a detector (8) for detecting the stimulated enhanced Raman scattering signal.
8. An apparatus according to claim 7 further comprising: a radiation source for irradiating the sample with radiation having a frequency substantially tuned to an absorption band of the analytes.
9. An apparatus according to claim 7, wherein the analytes each comprises a target molecule and the target molecule is linked to a dye molecule, the absorption band being an absorption band of the dye molecules.
10. An apparatus according to claim 7, wherein the analytes each comprises a target molecule and each target molecule is bound to a capture molecule for attaching the target molecule to the surface.
11. Apparatus according to claim 7 wherein the radiation source for irradiating the sample with radiation having a frequency substantially tuned to a plasmon resonance band of the conducting surface is further tuned to a frequency substantially tuned to an absorption band of the analytes.
12. An apparatus according to claim 7, wherein the radiation source for irradiating the sample with radiation having a frequency substantially tuned to a frequency of the enhanced Raman scattering signal is tunable across the frequency range of the enhanced Raman scattering signal.
PCT/IB2006/052899 2005-08-25 2006-08-22 Improved raman spectroscopy WO2007023452A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103712960A (en) * 2013-12-26 2014-04-09 无锡利弗莫尔仪器有限公司 Photo-thermal detection device employing cascaded phase-locked detection mode and detection method for detection device
KR101401634B1 (en) 2013-02-25 2014-06-02 한국광기술원 Plasmon tunable visible laser using opto-mechanical effect of nano structures
CN106153600A (en) * 2015-05-14 2016-11-23 汎锶科艺股份有限公司 Finished product pesticide detection device

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US20040135997A1 (en) * 2002-06-12 2004-07-15 Selena Chan Metal coated nanocrystalline silicon as an active surface enhanced raman spectroscopy (SERS) substrate
GB2408796A (en) * 2003-12-01 2005-06-08 Stephen Richard Elliott Raman gain or loss effect optical sensor chip
US20050147980A1 (en) * 2003-12-30 2005-07-07 Intel Corporation Nucleic acid sequencing by Raman monitoring of uptake of nucleotides during molecular replication
US20050147976A1 (en) * 2003-12-29 2005-07-07 Xing Su Methods for determining nucleotide sequence information

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US20040135997A1 (en) * 2002-06-12 2004-07-15 Selena Chan Metal coated nanocrystalline silicon as an active surface enhanced raman spectroscopy (SERS) substrate
GB2408796A (en) * 2003-12-01 2005-06-08 Stephen Richard Elliott Raman gain or loss effect optical sensor chip
US20050147976A1 (en) * 2003-12-29 2005-07-07 Xing Su Methods for determining nucleotide sequence information
US20050147980A1 (en) * 2003-12-30 2005-07-07 Intel Corporation Nucleic acid sequencing by Raman monitoring of uptake of nucleotides during molecular replication

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101401634B1 (en) 2013-02-25 2014-06-02 한국광기술원 Plasmon tunable visible laser using opto-mechanical effect of nano structures
CN103712960A (en) * 2013-12-26 2014-04-09 无锡利弗莫尔仪器有限公司 Photo-thermal detection device employing cascaded phase-locked detection mode and detection method for detection device
CN106153600A (en) * 2015-05-14 2016-11-23 汎锶科艺股份有限公司 Finished product pesticide detection device

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