WO2010018557A1 - Temperature sensor based on raman scattering for use in molecular diagnostics - Google Patents
Temperature sensor based on raman scattering for use in molecular diagnostics Download PDFInfo
- Publication number
- WO2010018557A1 WO2010018557A1 PCT/IB2009/053597 IB2009053597W WO2010018557A1 WO 2010018557 A1 WO2010018557 A1 WO 2010018557A1 IB 2009053597 W IB2009053597 W IB 2009053597W WO 2010018557 A1 WO2010018557 A1 WO 2010018557A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- temperature
- sample
- group
- stokes
- raman
- Prior art date
Links
- 238000001069 Raman spectroscopy Methods 0.000 title claims abstract description 95
- 239000000523 sample Substances 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 44
- 239000000203 mixture Substances 0.000 claims abstract description 36
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 230000001678 irradiating effect Effects 0.000 claims abstract description 4
- 238000009826 distribution Methods 0.000 claims description 27
- 230000000694 effects Effects 0.000 claims description 26
- 238000005259 measurement Methods 0.000 claims description 17
- 239000002245 particle Substances 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 10
- 238000001514 detection method Methods 0.000 claims description 8
- 230000005855 radiation Effects 0.000 claims description 8
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 8
- 238000001356 surgical procedure Methods 0.000 claims description 8
- 229910052758 niobium Inorganic materials 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 6
- 239000012472 biological sample Substances 0.000 claims description 6
- 239000000032 diagnostic agent Substances 0.000 claims description 6
- 229940039227 diagnostic agent Drugs 0.000 claims description 6
- 229910003327 LiNbO3 Inorganic materials 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 5
- 229910052732 germanium Inorganic materials 0.000 claims description 5
- 150000002500 ions Chemical group 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910052710 silicon Inorganic materials 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 229910052735 hafnium Inorganic materials 0.000 claims description 4
- 239000001095 magnesium carbonate Substances 0.000 claims description 4
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 4
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 4
- 229910052715 tantalum Inorganic materials 0.000 claims description 4
- 229910052721 tungsten Inorganic materials 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 238000002405 diagnostic procedure Methods 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 235000010333 potassium nitrate Nutrition 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 238000009529 body temperature measurement Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 description 27
- 230000008569 process Effects 0.000 description 11
- 230000008859 change Effects 0.000 description 6
- 230000005281 excited state Effects 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 230000009021 linear effect Effects 0.000 description 5
- 230000003595 spectral effect Effects 0.000 description 5
- 229910005833 GeO4 Inorganic materials 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229910052737 gold Inorganic materials 0.000 description 4
- 229910052909 inorganic silicate Inorganic materials 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000013307 optical fiber Substances 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 230000001427 coherent effect Effects 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 230000005283 ground state Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 229910052709 silver Inorganic materials 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000004416 surface enhanced Raman spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- -1 CFH2COOH Chemical compound 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 238000001237 Raman spectrum Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 230000005672 electromagnetic field Effects 0.000 description 2
- 230000005274 electronic transitions Effects 0.000 description 2
- 238000000295 emission spectrum Methods 0.000 description 2
- 238000000881 hyper Raman spectroscopy Methods 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229910002548 FeFe Inorganic materials 0.000 description 1
- 229910005542 GaSb Inorganic materials 0.000 description 1
- 230000005374 Kerr effect Effects 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000001210 attenuated total reflectance infrared spectroscopy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002082 coherent anti-Stokes Raman spectroscopy Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000002324 minimally invasive surgery Methods 0.000 description 1
- 239000002159 nanocrystal Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000009022 nonlinear effect Effects 0.000 description 1
- 238000001560 photoacoustic Raman spectroscopy Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01K—MEASURING TEMPERATURE; MEASURING QUANTITY OF HEAT; THERMALLY-SENSITIVE ELEMENTS NOT OTHERWISE PROVIDED FOR
- G01K11/00—Measuring temperature based upon physical or chemical changes not covered by groups G01K3/00, G01K5/00, G01K7/00 or G01K9/00
- G01K11/12—Measuring temperature based upon physical or chemical changes not covered by groups G01K3/00, G01K5/00, G01K7/00 or G01K9/00 using changes in colour, translucency or reflectance
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/01—Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue
-
- 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
- G01J5/00—Radiation pyrometry, e.g. infrared or optical thermometry
- G01J5/60—Radiation pyrometry, e.g. infrared or optical thermometry using determination of colour temperature
Definitions
- Temperature sensor based on Raman scattering for use in molecular diagnostics
- Subject of the present invention is a method for temperature measurement based on Raman scattering and a temperature sensor for the use in molecular diagnostics.
- Fig. 1 The process of Raman scattering is schematically illustrated in Fig. 1, together with a typical emission spectrum.
- the most important point of Raman scattering is that a typical Raman spectrum in addition to the central Rayleigh band comprises two distinct emission bands: the Stokes (lower energy with respect to the excitation light) and anti-Stokes (higher energy) contributions. These differences in energy are related to the different vibrational levels involved.
- a typical Raman spectrum is symmetric in terms of energetic position, though not in terms of absolute intensities relative to the Rayleigh band.
- the intensities of the Raman bands are only dependent on the number of molecules occupying the different vibrational states when the process began. In other words: the intensities of the Raman bands are only dependent on the temperature of the material in combination with fixed materials properties.
- the ratio between the lower and higher energy levels is given by a Boltzmann distribution (equation 1):
- N j amount of atoms in the higher vibrational state
- E V energy difference between the ground state and the higher vibrational state
- k Boltzmann's constant
- T temperature in Kelvin
- the Raman effect is to be clearly distinguished from processes as fluorescence and/or luminescence.
- the incident light is completely absorbed (into a real excited state) and the system can go to (various) lower states only after a certain resonance lifetime.
- the result of both processes is comparable: a photon with the frequency different from that of the incident photon is produced and the molecule is brought to a higher or lower energy level.
- the major difference is that the Raman effect can take place for any frequency of the incident light.
- the Raman effect is therefore not a resonant effect.
- WO 94/25861 Patent et al.
- This invention relates to a method for the measurement of the local temperature in a sample, comprising the steps of (a) introducing a molecular sensor probe comprising a Raman active compound to the sample or a desired portion of the sample, (b) irradiating the sample or the desired portion of the sample with light of (a) wavelength(s) of from 300 nm to 3 ⁇ m, (c) detecting the intensities of the Stokes and anti-Stokes Raman emission lines of the molecular sensor probe in the sample, (d) calculating the ratio of the intensities of the Stokes and anti-Stokes Raman emission lines of said molecular sensor probe, and (e) assigning said ratio to a temperature.
- compositions comprising a Raman active compound for the use as a diagnostic agent for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 ⁇ m thereby determining the temperature.
- the present invention also concerns a composition
- a composition comprising a Raman active compound for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 ⁇ m thereby determining the temperature.
- a wavelength(s) of from 300 nm to 3 ⁇ m thereby determining the temperature.
- the compositions of the invention for the determination of a local temperature or a temperature distribution in a mammal or a dead body of a mammal.
- Fig. 2 Example of the temperature dependence of the Stokes (+220 cm “ 1) and anti-Stokes (-220 cm “ 1) Raman bands. The large peak at 0 cm “1 is the Rayleigh scattering peak and can be ignored. This figure shows the Raman signal from the transverse optical phonon in GaSb at 3 different temperatures.
- Fig. 3 Temperature dependence of the ratio of Stokes and anti-Stokes Raman emission. This figure directly shows the Boltzmann behavior the ratio as was described in the equation above.
- This invention relates to a method for the measurement of the local temperature in a sample, comprising the steps of (a) introducing a molecular sensor probe comprising a Raman active compound to the sample or a desired portion of the sample, (b) irradiating the sample or the desired portion of the sample with light of (a) wavelength(s) of from 300 nm to 3 ⁇ m, (c) detecting the intensities of the Stokes and anti-Stokes Raman emission lines of the molecular sensor probe in the sample, (d) calculating the ratio of the intensities of the Stokes and anti-Stokes Raman emission lines of said molecular sensor probe, and (e) assigning said ratio to a temperature.
- the present invention also relates to a composition
- a composition comprising a Raman active compound for the use as a diagnostic agent for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 ⁇ m thereby determining the temperature.
- This also includes the use of a composition comprising a Raman active compound for the use as a diagnostic agent for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 ⁇ m thereby determining the temperature, for the preparation of a diagnostic agent.
- the composition or the diagnostic agent is used in methods for treatment of the human or animal body by surgery or therapy and diagnostic methods practiced on the human or animal body.
- these therapeutical and diagnostic methods are selected from the group consisting of determination of temperature or temperature distribution during minimally invasive treatments, during radiation treatments, or during magnetic resonance treatment, determination of temperature or temperature distribution in a cooled body before heart-surgery, and determination of temperature or temperature distribution for the detection of enhanced metabolistic activity.
- the sample is a biological sample. More preferably, the biological sample is selected from the group consisting of a tissue, a living organism, an organ, a cell, a sub-cellular fragment, a living or dead human or animal body or parts thereof.
- Said Raman active compound comprises preferably at least one group with high electron density. Groups with high electron density, which are very suitable for Raman spectroscopy have charges which are delocalized and for this reason can be easily displaced. This is the origin of their large polarisability.
- the delocalized electron density is larger than 0 e/A ⁇ and preferably larger than 0.20 e/A ⁇ .
- said Raman active compound comprises at least one aromatic group or is an ion with at least one lone electron pair or is a carboxylic acid or is selected from the group consisting of M m X ⁇ 3 or M n YC>4, wherein M is selected from the group consisting of Na, K, Li, Mg, Ca and all other metals of the first and second group, X is selected from the group consisting N, C, Cl, Br and I and Y is selected from the group consisting of Si, Ge, Nb, Hf, Ta, Nb, and W and wherein m and n are 1 or 2.
- M m X ⁇ 3 may preferably be selected from the group consisting of NaNO 3 ,
- KNO 3 , Na 2 CO 3 , K 2 CO 3 , MgCO 3 and LiNbO 3 , and M n YO 4 may be selected from the group consisting OfNa 2 SiO 4 , K 2 SiO 4 , Na 2 GeO 4 , YTaO 4 and K 2 GeO 4
- the carboxylic acid may be branched or unbranched, may contain preferably more than one carboxyl group, may be further substituted with -OH or -OR or other groups with a high electron density, such as -F " or -O 2" and may have a chain length of from C j to C 2Q .
- the carboxylic acid may for example be selected from the group Of CH 3 COOH, HOOCCOOH, CFH 2 COOH, CF 3 COOH, H00CCH 2 C00H, HOOCCOCOOH, HOOCCF 2 COOH.
- the Raman active compound may alternatively comprise molecular anions with a high local charge density.
- Such anions may for example be selected from the group consisting Of (VO 4 ) 3" , (WO 4 ) 2" and [Fe i ⁇ Fe ⁇ (CN) 6 ] “ .
- the Raman active compound is immobilized on the surface of a particle or is comprised in a particle.
- a particle has a diameter of from 5 nm to 50 ⁇ m.
- said particle is substantially spherical or disk shaped.
- a particle preferably comprises a metal selected from the group consisting of Cu, Ag and Au for Surface Enhanced Raman scattering (SERS). These materials are chosen, because the plasmon frequencies, which lead to SERS are located in a suitable wavelength range (VIS to near IR, i.e. wavelengths of around 300 nm to around 3 ⁇ m).
- SERS Surface Enhanced Raman scattering
- the particle comprises a selective targeting moiety, e.g. an antibody or functional fragment thereof.
- the temperature to be measured according to this invention is preferably within the range of from 25 0 C to 45 0 C.
- the Raman emission may be based on a linear Raman effect or on a non-linear Raman effect.
- Light irradiation and detection are performed through optical fibers in some embodiments of the invention.
- compositions comprising a Raman active compound for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 ⁇ m thereby determining the temperature.
- a Raman active compound for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 ⁇ m thereby determining the temperature.
- the present invention also relates to the use of any of the above-described compositions for the determination of a local temperature or a temperature distribution in a sample.
- the sample may be a biological sample.
- the biological sample is selected from the group consisting of a tissue, a living organism, an organ, a cell, a sub-cellular fragment, a living or dead human or animal body or parts thereof.
- the temperature or temperature distribution is determined during minimally invasive treatments, during radiation treatments, or during magnetic resonance treatment.
- the temperature or temperature distribution is determined in a cooled body before heart-surgery.
- the temperature or temperature distribution is determined for the detection of enhanced metabolistic activity.
- the temperature to be measured is preferably within the range of from 25 0 C to 45 0 C.
- the Raman emission may be based on a linear Raman effect or on a non-linear Raman effect.
- the light irradiation and detection may in particular embodiments be performed through optical fibers.
- molecular sensor probe and “molecular sensor” relate in the context of the present invention to a composition comprising at least one Raman active substance and can be incorporated into a sample, e.g. at a defined position in the sample, to probe the temperature in the sample or at the defined position in the sample by emitting Raman scattered light upon irradiation with a suitable wavelength.
- Raman active compound refers in general to a molecule, compound or composition that is able to inelastically scatter photons according to the Raman effect.
- Raman scattering result in scattered photons having a frequency different from the frequency of the incident photons and distinguishable Stokes scattering (molecule absorbs energy) and anti-Stokes scattering (molecule loses energy) lines.
- Stokes and anti-Stokes Raman lines with an intensity ratio of at most a factor of 100, the frequencies of the phonons involved should not exceed about 1000 crrf1 for measurements at about room temperature. This does not result in a strong selection criterion, for this reason preferred materials can be selected based on other criteria: a large cross-section for Raman processes and - where necessary - a compatibility with human bodies (e.g. not poisonous).
- covalent materials and materials with large anionic groups are very suitable candidates. All these materials have distributed electron clouds.
- Examples are: NaNO 3 , KNO 3 , Na2CO 3 , K 2 CO 3 , MgCO 3 , Na 2 SiO 4 , K 2 SiO 4 , Na 2 GeO 4 , K 2 GeO 4 , YTaO 4 and LiNbO 3 .
- the Raman effect can be enhanced by using radiation that is absorbed in the material (Franck-Condon enhancement) or by using vibronic enhancement (a lattice vibration coupling two electronic excited states of the material). This does not result in a change of the
- the Raman effect can also be surface-enhanced, i.e. by depositing Raman active moieties on e.g. small disks or spheres of Cu, Ag or Au, an amplification of the Raman effect of up to 10 ⁇ is encountered. This can be due to electrons in the metal surface being excited into an extended surface electronic excited state called a surface plasmon resonance.
- Vibrations normal to the surface are enhanced most strongly.
- Another cause of such a surface-enhancement may be the formation of a charge-transfer complex between the metal surface and the deposited molecule.
- the electronic transitions of many of such charge transfer complexes are in the visible range, so that resonance enhancement occurs. Examples are, e.g. particles comprising Au, or Ag covered with e.g. (VO4) 3" , (WO4) 2" , [FeFe(CN)g] ⁇ groups.
- the Raman scattering material involved is a nano- or micrometer sized material.
- Such materials may be easily functionalized, to result in specificity to a desired target location in the patient (e.g. cancerous cells). Due to the limited size and functionalized nature, the phosphor can be delivered at the desired location (reports have been published that prove that nanocrystals can even be delivered inside a cell), where the molecular temperature sensor can be read out locally through optical techniques.
- the means and methods according to the present invention can be applied to locally measure temperature at the cellular, or even sub-cellular, level.
- Application may be found in a wide range of (future) medical procedures, including minimally invasive procedures. Common to all these treatments is that the temperature of the tissue to be treated changes. Examples may include, without limiting the scope of the invention, the measurement of the local temperature during radiation treatments to prevent too intense treatments, the measurements of the local temperature during magnetic resonance treatments to prevent too intense treatment, measuring the local temperature in tissue, e.g. to detect tissue with enhanced metabolistic activity, and measuring the temperature of any part of the cooled body of patients before heart-surgery to adjust the optimum temperature at selected body parts.
- Optical excitation and detection of the Raman lines can be done through optical fibers. Thermal contact between the measuring unit and the molecular sensor is not required. In this way, the temperature of very small regions can be measured, only limited by the physical size of the molecular sensor. Application on nano-particles enables nano- thermometers.
- a detector may comprise two (or more) photodiodes.
- the wavelength of the light to be detected by each of the photodiodes may be selected by e.g. interference filters.
- the wavelength region can be determined using exchangeable interference filters.
- Microelectromechanical systems (MEMS) technology together with ⁇ - gratings, in some embodiments may even allow wavelength selection.
- MEMS Microelectromechanical systems
- up-conversion principles three-dimensional (“depth") information may be obtained by using focused IR light.
- depth resolution is limited by absorption of light by the sample, e.g. tissue.
- Other applications of the means and methods of the present invention, not related to molecular medicine, are based on the fact that the invention allows local determination of the temperature even in real time.
- the invention can also be used in criminology. By measuring the temperature distribution in dead bodies, the time of death of the body can be estimated quite accurately.
- the means and methods of the present invention may also be used to measure the temperatures and temperature distributions in real time in running engines, rotating tires and the like, in a large temperature range and therefore may be used in engine or tire development.
- Typical steps of the method according to the present invention include: introducing the molecular sensor probe at the desired position in the sample, illuminating the material at a suitable wavelength, measuring the spectral data in the relevant spectral range, determining the ratio Ij/L ⁇ of the two relevant spectral contributions (i.e.: the intensities of the Stokes and the anti-Stokes emission lines); either through integration of (a part of) the spectra, or through determination of the intensities at predetermined spectral positions, using the fact that this ratio follows the Boltzmann distribution of equation 2:
- a “non- linear Raman effect” in the context of the present invention relates to, e.g., Hyper Raman scattering (Hyper Raman spectroscopy), Inverse Raman spectroscopy, Raman induced Kerr effect, Coherent Anti-Stokes Raman scattering (Coherent Anti-Stokes Raman spectroscopy, CARS) and Photoacoustic Raman spectroscopy.
- Hyper-Raman spectroscopy a non-linear effect in which the vibrational modes interact with the second harmonic of the excitation beam is exploited. This requires the observation of vibrational modes which are normally "silent", e.g. the 750 cm ⁇ l mode of CCl 4 .
- temperature differences of substantially less than 1 0 C in samples can be resolved.
- local temperatures are measured in a patient during radiation treatments (e.g. during cancer therapy or for cancer therapy) to prevent too intense treatments.
- local temperatures are measured in a patient during magnetic resonance treatments to prevent too intense treatment.
- Tro intense treatments in the context of these embodiments relate to treatments in which tissue or organ damaging temperatures are locally reached, e.g. temperatures above around 40 0 C.
- the local temperature in a biological tissue is measured, e.g. to detect tissue with enhanced metabolistic activity.
- Enhanced metabolistic activity in this context relates to deviating or conspicuous metabolic activities that produce a higher temperature than under normal circumstances or in the surround tissue.
- Such higher temperatures are e.g. 1-2 0 C higher than the normal tissue or body temperature (i.e. 36 - 37°C in a healthy human) or 1-2 0 C higher than the surrounding tissue.
- An alternative embodiment relates to measuring the temperature of any part of the cooled body of patients before heart-surgery to adjust the optimum temperature at selected body parts.
- "Optimum temperatures" in this context are from 29 to 33 0 C, preferably 30 to 32°C, more preferably around 31°C.
- Raman spectroscopy can be used in achieving optimum re-warming of patients, also locally. This is known to be beneficial for patient recovery.
- the present invention also relates to a device for performing the described methods and for the described uses.
- a device comprises a (tunable) light source, a light delivery means (e.g. an optical fiber), a wavelength-selective device (e.g. a grating) and a photo-detector.
- the photo-detector may for example comprise two (or more) photodiodes.
- the components are standard optical components and are known to a skilled person.
- the wavelength of the light to be detected by each of the photodiodes may be selected by e.g. interference filters. In a simple approach, the wavelength region can be determined, using exchangeable interference filters.
- Example 1 Obtaining Stokes and Anti-Stokes lines in Raman scattering
- the frequencies of the phonons involved should not exceed about 1000 cm "1 for measurements at about room temperature. This does not result in a strong selection criterion, for this reason preferred materials can be selected based on other criteria: a large cross- section for Raman processes and compatibility with human bodies (e.g. not poisonous).
- M represents a metal ion.
- M represents a metal ion. Examples are: o NaNO3, KNO3 o Na2CO3, K2CO3, MgCO3 o Na2SiO4, K2SiO4 o Na2GeO4, K2GeO4 o LiNbO3
- the Raman effect is enhanced (this does not change the ratio but makes the measurements much easier) by using radiation that is absorbed in the material (Franck- Condon enhancement) or by using vibronic enhancement (a lattice vibration coupling two electronic excited states of the material).
- the Raman effect is also surface enhanced. By depositing Raman active moieties on spheres of Cu, Ag or Au, an amplification of the Raman effect of up to 109 is encountered. This can be due to:
- Electrons in the metal surface are excited into an extended surface electronic excited state called a surface plasmon resonance. Molecules in close proximity to the surface experience a very large electromagnetic field. Vibrations normal to the surface are enhanced most strongly
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Pathology (AREA)
- Engineering & Computer Science (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Heart & Thoracic Surgery (AREA)
- Medical Informatics (AREA)
- Biophysics (AREA)
- Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
Abstract
The present invention relates to a method for temperature measurement based on Stokes and anti-Stokes Raman scattering and a molecular temperature sensor probe comprising Raman active compounds. The method comprises the steps of introducing a molecular sensor probe comprising a Raman active compound to a sample, irradiating the sample with light, detecting the intensities of the Stokes and anti-Stokes Raman emission lines of the molecular sensor probe in the sample, calculating the ratio of the intensities of the Stokes and anti-Stokes Raman emission lines of said molecular sensor probe, and finally assigning this ratio to a temperature. The invention also relates to the use of compositions comprising a Raman active compound in methods of treatment and diagnostical methods.
Description
Temperature sensor based on Raman scattering for use in molecular diagnostics
FIELD OF THE INVENTION
Subject of the present invention is a method for temperature measurement based on Raman scattering and a temperature sensor for the use in molecular diagnostics.
BACKGROUND OF THE INVENTION
The determination of physical parameters such as temperature is desired in many technical and medical fields. In molecular medicine such measurements are preferentially done on the (sub)cellular level. Due to the fact that currently available temperature sensors are all much larger (e.g. several hundreds of micrometers) than the typical sizes that are relevant for molecular medicine (typically in the 1 micrometer range), the temperature determination is difficult.
However, (local) temperatures can be measured by exploitation of the Raman effect (see e.g. WO 94/25861 and US 5,755,512).
The process of Raman scattering is schematically illustrated in Fig. 1, together with a typical emission spectrum. The most important point of Raman scattering is that a typical Raman spectrum in addition to the central Rayleigh band comprises two distinct emission bands: the Stokes (lower energy with respect to the excitation light) and anti-Stokes (higher energy) contributions. These differences in energy are related to the different vibrational levels involved. A typical Raman spectrum is symmetric in terms of energetic position, though not in terms of absolute intensities relative to the Rayleigh band. The intensities of the Raman bands are only dependent on the number of molecules occupying the different vibrational states when the process began. In other words: the intensities of the Raman bands are only dependent on the temperature of the material in combination with fixed materials properties. The ratio between the lower and higher energy levels is given by a Boltzmann distribution (equation 1):
— N1 L = exp υ (equation 1)
NQ: amount of atoms in the ground state
Nj : amount of atoms in the higher vibrational state ΔEV: energy difference between the ground state and the higher vibrational state k: Boltzmann's constant T: temperature in Kelvin
This implies that the Stokes spectrum is more intense than the anti-Stokes spectrum, and the ratio between them is a direct measure for the temperature of the material.
The Raman effect is to be clearly distinguished from processes as fluorescence and/or luminescence. For the latter processes, the incident light is completely absorbed (into a real excited state) and the system can go to (various) lower states only after a certain resonance lifetime. For Raman scattering there is no real excited state involved (only a virtual one) and the process is essentially instantaneous. The result of both processes, however, is comparable: a photon with the frequency different from that of the incident photon is produced and the molecule is brought to a higher or lower energy level. But the major difference is that the Raman effect can take place for any frequency of the incident light. In contrast to the fluorescence effect, the Raman effect is therefore not a resonant effect. In WO 94/25861 (Pitt et al.) a method is described for measuring thermal conductivity of a solid sample, particularly a diamond, by employing temperature measurements based on the ratio of Stokes and anti-Stokes Raman lines.
US 5,755,512 (White) describes an apparatus for remotely sensing the temperature of a semi-conductor wafer by measuring the intensities of Stokes and anti-Stokes Raman lines.
SUMMARY OF THE INVENTION
This invention relates to a method for the measurement of the local temperature in a sample, comprising the steps of (a) introducing a molecular sensor probe comprising a Raman active compound to the sample or a desired portion of the sample, (b) irradiating the sample or the desired portion of the sample with light of (a) wavelength(s) of from 300 nm to 3 μm, (c) detecting the intensities of the Stokes and anti-Stokes Raman emission lines of the molecular sensor probe in the sample, (d) calculating the ratio of the
intensities of the Stokes and anti-Stokes Raman emission lines of said molecular sensor probe, and (e) assigning said ratio to a temperature.
Also within the scope of the invention is a composition comprising a Raman active compound for the use as a diagnostic agent for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 μm thereby determining the temperature.
The present invention also concerns a composition comprising a Raman active compound for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 μm thereby determining the temperature. Also within the scope of the present invention is the use of the compositions of the invention for the determination of a local temperature or a temperature distribution in a mammal or a dead body of a mammal.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 : Left: Schematic description of the Stokes and anti-Stokes Raman scattering processes. Right: Typical emission spectrum showing the three spectral components.
Fig. 2: Example of the temperature dependence of the Stokes (+220 cm" 1) and anti-Stokes (-220 cm" 1) Raman bands. The large peak at 0 cm"1 is the Rayleigh scattering peak and can be ignored. This figure shows the Raman signal from the transverse optical phonon in GaSb at 3 different temperatures.
Fig. 3: Temperature dependence of the ratio of Stokes and anti-Stokes Raman emission. This figure directly shows the Boltzmann behavior the ratio as was described in the equation above.
DETAILED DESCRIPTION OF EMBODIMENTS
This invention relates to a method for the measurement of the local temperature in a sample, comprising the steps of (a) introducing a molecular sensor probe comprising a Raman active compound to the sample or a desired portion of the sample, (b)
irradiating the sample or the desired portion of the sample with light of (a) wavelength(s) of from 300 nm to 3 μm, (c) detecting the intensities of the Stokes and anti-Stokes Raman emission lines of the molecular sensor probe in the sample, (d) calculating the ratio of the intensities of the Stokes and anti-Stokes Raman emission lines of said molecular sensor probe, and (e) assigning said ratio to a temperature.
The present invention also relates to a composition comprising a Raman active compound for the use as a diagnostic agent for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 μm thereby determining the temperature. This also includes the use of a composition comprising a Raman active compound for the use as a diagnostic agent for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 μm thereby determining the temperature, for the preparation of a diagnostic agent.
Preferably, the composition or the diagnostic agent is used in methods for treatment of the human or animal body by surgery or therapy and diagnostic methods practiced on the human or animal body.
In particular embodiments, these therapeutical and diagnostic methods are selected from the group consisting of determination of temperature or temperature distribution during minimally invasive treatments, during radiation treatments, or during magnetic resonance treatment, determination of temperature or temperature distribution in a cooled body before heart-surgery, and determination of temperature or temperature distribution for the detection of enhanced metabolistic activity.
Preferably, the sample is a biological sample. More preferably, the biological sample is selected from the group consisting of a tissue, a living organism, an organ, a cell, a sub-cellular fragment, a living or dead human or animal body or parts thereof. Said Raman active compound comprises preferably at least one group with high electron density. Groups with high electron density, which are very suitable for Raman spectroscopy have charges which are delocalized and for this reason can be easily displaced. This is the origin of their large polarisability. The delocalized electron density is larger than 0 e/A^ and preferably larger than 0.20 e/A^.
In preferred embodiments of the invention, said Raman active compound comprises at least one aromatic group or is an ion with at least one lone electron pair or is a carboxylic acid or is selected from the group consisting of MmXθ3 or MnYC>4, wherein M is selected from the group consisting of Na, K, Li, Mg, Ca and all other metals of the first and second group, X is selected from the group consisting N, C, Cl, Br and I and Y is selected from the group consisting of Si, Ge, Nb, Hf, Ta, Nb, and W and wherein m and n are 1 or 2. MmXθ3 may preferably be selected from the group consisting of NaNO3,
KNO3, Na2CO3, K2CO3, MgCO3 and LiNbO3, and MnYO4 may be selected from the group consisting OfNa2SiO4, K2SiO4, Na2GeO4, YTaO4 and K2GeO4 The carboxylic acid may be branched or unbranched, may contain preferably more than one carboxyl group, may be further substituted with -OH or -OR or other groups with a high electron density, such as -F" or -O2" and may have a chain length of from Cj to C2Q. The carboxylic acid may for example be selected from the group Of CH3COOH, HOOCCOOH, CFH2COOH, CF3COOH, H00CCH2C00H, HOOCCOCOOH, HOOCCF2COOH.
The Raman active compound may alternatively comprise molecular anions with a high local charge density. Such anions may for example be selected from the group consisting Of (VO4)3", (WO4)2" and [FeiπFeπ(CN)6]".
In some preferred embodiments of the invention, the Raman active compound is immobilized on the surface of a particle or is comprised in a particle. Such a particle has a diameter of from 5 nm to 50 μm. Preferably, said particle is substantially spherical or disk shaped.
A particle preferably comprises a metal selected from the group consisting of Cu, Ag and Au for Surface Enhanced Raman scattering (SERS). These materials are chosen, because the plasmon frequencies, which lead to SERS are located in a suitable wavelength range (VIS to near IR, i.e. wavelengths of around 300 nm to around 3 μm).
In some particular embodiments, the particle comprises a selective targeting moiety, e.g. an antibody or functional fragment thereof.
The temperature to be measured according to this invention is preferably within the range of from 25 0C to 45 0C.
The Raman emission may be based on a linear Raman effect or on a non-linear Raman effect.
Light irradiation and detection are performed through optical fibers in some embodiments of the invention.
The methods according to the present invention are in some particular embodiments of the invention in vitro methods. Also within the scope of the invention is a composition comprising a Raman active compound for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 μm thereby determining the temperature. The characteristics of such a composition are the same as already described herein above.
The present invention also relates to the use of any of the above-described compositions for the determination of a local temperature or a temperature distribution in a sample. As already discussed herein above, the sample may be a biological sample.
Preferably, the biological sample is selected from the group consisting of a tissue, a living organism, an organ, a cell, a sub-cellular fragment, a living or dead human or animal body or parts thereof.
In some particular embodiments, the temperature or temperature distribution is determined during minimally invasive treatments, during radiation treatments, or during magnetic resonance treatment.
In another particular embodiment, the temperature or temperature distribution is determined in a cooled body before heart-surgery.
In yet another preferred embodiment the temperature or temperature distribution is determined for the detection of enhanced metabolistic activity.
As already stated above, the temperature to be measured is preferably within the range of from 25 0C to 45 0C.
The Raman emission may be based on a linear Raman effect or on a non-linear Raman effect. The light irradiation and detection may in particular embodiments be performed through optical fibers.
The terms "molecular sensor probe" and "molecular sensor" relate in the context of the present invention to a composition comprising at least one Raman active substance and can be incorporated into a sample, e.g. at a defined position in the sample, to
probe the temperature in the sample or at the defined position in the sample by emitting Raman scattered light upon irradiation with a suitable wavelength.
The terms "Raman active compound", "Raman scattering material" and "Raman active substance" are used synonymously herein and relate in general to a molecule, compound or composition that is able to inelastically scatter photons according to the Raman effect. Unlike elastically scattered photons (Rayleigh scattering), Raman scattering result in scattered photons having a frequency different from the frequency of the incident photons and distinguishable Stokes scattering (molecule absorbs energy) and anti-Stokes scattering (molecule loses energy) lines. To obtain Stokes and anti-Stokes Raman lines with an intensity ratio of at most a factor of 100, the frequencies of the phonons involved should not exceed about 1000 crrf1 for measurements at about room temperature. This does not result in a strong selection criterion, for this reason preferred materials can be selected based on other criteria: a large cross-section for Raman processes and - where necessary - a compatibility with human bodies (e.g. not poisonous).
As Raman processes rely on a change in the polarisability, which in turn relies on the possibility to change the charge distribution, covalent materials and materials with large anionic groups are very suitable candidates. All these materials have distributed electron clouds. Such materials are, for example, aromatic organic compounds, materials containing ions with lone electron pairs (e.g. Bi^+, Sb^+, Sn^+), carboxylic acids, materials from the class MXO3 (e.g. X = N, C, Cl, Br, I) or MYO4 (e.g. Y = Si, Ge,Hf, Ta, Nb, W). In both cases M represents a metal ion. Examples are: NaNO3, KNO3, Na2CO3, K2CO3, MgCO3, Na2SiO4, K2SiO4, Na2GeO4, K2GeO4, YTaO4 and LiNbO3.
The Raman effect can be enhanced by using radiation that is absorbed in the material (Franck-Condon enhancement) or by using vibronic enhancement (a lattice vibration coupling two electronic excited states of the material). This does not result in a change of the
Stokes/anti- Stokes intensity ratio but may in some cases facilitate the measurements.
The Raman effect can also be surface-enhanced, i.e. by depositing Raman active moieties on e.g. small disks or spheres of Cu, Ag or Au, an amplification of the Raman effect of up to 10^ is encountered. This can be due to electrons in the metal surface being excited into an extended surface electronic excited state called a surface plasmon resonance.
Molecules in close proximity to the surface experience a very large electromagnetic field.
Vibrations normal to the surface are enhanced most strongly. Another cause of such a
surface-enhancement may be the formation of a charge-transfer complex between the metal surface and the deposited molecule. The electronic transitions of many of such charge transfer complexes are in the visible range, so that resonance enhancement occurs. Examples are, e.g. particles comprising Au, or Ag covered with e.g. (VO4)3", (WO4)2", [FeFe(CN)g]~ groups.
Preferably, the Raman scattering material involved is a nano- or micrometer sized material. Such materials may be easily functionalized, to result in specificity to a desired target location in the patient (e.g. cancerous cells). Due to the limited size and functionalized nature, the phosphor can be delivered at the desired location (reports have been published that prove that nanocrystals can even be delivered inside a cell), where the molecular temperature sensor can be read out locally through optical techniques.
In molecular medicine, the means and methods according to the present invention can be applied to locally measure temperature at the cellular, or even sub-cellular, level. Application may be found in a wide range of (future) medical procedures, including minimally invasive procedures. Common to all these treatments is that the temperature of the tissue to be treated changes. Examples may include, without limiting the scope of the invention, the measurement of the local temperature during radiation treatments to prevent too intense treatments, the measurements of the local temperature during magnetic resonance treatments to prevent too intense treatment, measuring the local temperature in tissue, e.g. to detect tissue with enhanced metabolistic activity, and measuring the temperature of any part of the cooled body of patients before heart-surgery to adjust the optimum temperature at selected body parts.
Optical excitation and detection of the Raman lines can be done through optical fibers. Thermal contact between the measuring unit and the molecular sensor is not required. In this way, the temperature of very small regions can be measured, only limited by the physical size of the molecular sensor. Application on nano-particles enables nano- thermometers.
In case of radiation treatment, the treatment itself might result in Raman scattering in the molecular sensors applied. In such a case, only detection is needed without separately exciting the molecular sensor.
A detector may comprise two (or more) photodiodes. The wavelength of the light to be detected by each of the photodiodes may be selected by e.g. interference filters. In a particular embodiment, the wavelength region can be determined using exchangeable interference filters.
Microelectromechanical systems (MEMS) technology, together with μ- gratings, in some embodiments may even allow wavelength selection. Using up-conversion principles, three-dimensional ("depth") information may be obtained by using focused IR light. However, depth resolution is limited by absorption of light by the sample, e.g. tissue. Other applications of the means and methods of the present invention, not related to molecular medicine, are based on the fact that the invention allows local determination of the temperature even in real time.
The invention can also be used in criminology. By measuring the temperature distribution in dead bodies, the time of death of the body can be estimated quite accurately. The means and methods of the present invention may also be used to measure the temperatures and temperature distributions in real time in running engines, rotating tires and the like, in a large temperature range and therefore may be used in engine or tire development.
Typical steps of the method according to the present invention include: introducing the molecular sensor probe at the desired position in the sample, illuminating the material at a suitable wavelength, measuring the spectral data in the relevant spectral range, determining the ratio Ij/L^ of the two relevant spectral contributions (i.e.: the intensities of the Stokes and the anti-Stokes emission lines); either through integration of (a part of) the spectra, or through determination of the intensities at predetermined spectral positions, using the fact that this ratio follows the Boltzmann distribution of equation 2:
ΔE
I1 112 = exp υ (equation 2) kT
Ij : intensity of the Stokes Raman line L^: intensity of the anti-Stokes Raman line
ΔEV: energy difference between the ground state and the higher vibrational state k: Boltzmann's constant T: temperature in Kelvin
Thus, the Raman effect can be used as an estimation of temperature (see e.g. Fig 2 and 3).
A "non- linear Raman effect" in the context of the present invention relates to, e.g., Hyper Raman scattering (Hyper Raman spectroscopy), Inverse Raman spectroscopy, Raman induced Kerr effect, Coherent Anti-Stokes Raman scattering (Coherent Anti-Stokes Raman spectroscopy, CARS) and Photoacoustic Raman spectroscopy. In "Hyper-Raman spectroscopy" a non-linear effect in which the vibrational modes interact with the second harmonic of the excitation beam is exploited. This requires the observation of vibrational modes which are normally "silent", e.g. the 750 cm~l mode of CCl4.
In "Coherent Anti-Stokes Raman scattering" two laser beams are used to generate a coherent anti-Stokes frequency beam, which can be enhanced by resonance.
With the means and methods according to the present invention, temperature differences of substantially less than 1 0C in samples (e.g. tissues, bodies) can be resolved.
In one embodiment, local temperatures are measured in a patient during radiation treatments (e.g. during cancer therapy or for cancer therapy) to prevent too intense treatments.
In another embodiment, local temperatures are measured in a patient during magnetic resonance treatments to prevent too intense treatment.
"Too intense treatments" in the context of these embodiments relate to treatments in which tissue or organ damaging temperatures are locally reached, e.g. temperatures above around 40 0C.
In yet another embodiment, the local temperature in a biological tissue is measured, e.g. to detect tissue with enhanced metabolistic activity. "Enhanced metabolistic activity" in this context relates to deviating or conspicuous metabolic activities that produce a higher temperature than under normal circumstances or in the surround tissue. Such higher temperatures are e.g. 1-2 0C higher than the normal tissue or body temperature (i.e. 36 - 37°C in a healthy human) or 1-2 0C higher than the surrounding tissue.
An alternative embodiment relates to measuring the temperature of any part of the cooled body of patients before heart-surgery to adjust the optimum temperature at selected body parts. "Optimum temperatures" in this context are from 29 to 33 0C, preferably 30 to 32°C, more preferably around 31°C. In addition, Raman spectroscopy can be used in achieving optimum re-warming of patients, also locally. This is known to be beneficial for patient recovery.
The present invention also relates to a device for performing the described methods and for the described uses. Such a device comprises a (tunable) light source, a light
delivery means (e.g. an optical fiber), a wavelength-selective device (e.g. a grating) and a photo-detector. The photo-detector may for example comprise two (or more) photodiodes. The components are standard optical components and are known to a skilled person. The wavelength of the light to be detected by each of the photodiodes may be selected by e.g. interference filters. In a simple approach, the wavelength region can be determined, using exchangeable interference filters.
The following example describes the invention in greater detail but is not limiting to this invention:
Example 1: Obtaining Stokes and Anti-Stokes lines in Raman scattering
To obtain Stokes and Anti-Stokes lines with an intensity ratio of at most a factor of 100, the frequencies of the phonons involved should not exceed about 1000 cm"1 for measurements at about room temperature. This does not result in a strong selection criterion, for this reason preferred materials can be selected based on other criteria: a large cross- section for Raman processes and compatibility with human bodies (e.g. not poisonous).
As Raman processes rely on a change in the polarisability, which in turn relies on the possibility to change the charge distribution, covalent materials and materials with large anionic groups are used. All these materials have distributed electron clouds.
Such materials are: - Aromatic organic compounds
Materials containing ions with lone electron pairs
Carboxylic acids
Materials from the class MX03 (X = N, C, Cl) or MY04 (Y = Si, Ge). In both cases M represents a metal ion. Examples are: o NaNO3, KNO3 o Na2CO3, K2CO3, MgCO3 o Na2SiO4, K2SiO4 o Na2GeO4, K2GeO4 o LiNbO3 The Raman effect is enhanced (this does not change the ratio but makes the measurements much easier) by using radiation that is absorbed in the material (Franck- Condon enhancement) or by using vibronic enhancement (a lattice vibration coupling two electronic excited states of the material).
The Raman effect is also surface enhanced. By depositing Raman active moieties on spheres of Cu, Ag or Au, an amplification of the Raman effect of up to 109 is encountered. This can be due to:
Electrons in the metal surface are excited into an extended surface electronic excited state called a surface plasmon resonance. Molecules in close proximity to the surface experience a very large electromagnetic field. Vibrations normal to the surface are enhanced most strongly
The formation of a charge-transfer complex between the metal surface and the deposited molecule. The electronic transitions of many of such charge transfer complexes are in the visible, so that resonance enhancement occurs.
Claims
1. A method for the measurement of the local temperature in a sample, comprising the steps of a. introducing a molecular sensor probe comprising a Raman active compound to the sample or a desired portion of the sample; b. irradiating the sample or the desired portion of the sample with light of (a) wavelength(s) of from 300 nm to 3 μm; c. detecting the intensities of the Stokes and anti-Stokes Raman emission lines of the molecular sensor probe in the sample; d. calculating the ratio of the intensities of the Stokes and anti-Stokes Raman emission lines of said molecular sensor probe; and e. assigning said ratio to a temperature.
2. A composition comprising a Raman active compound for the use as a diagnostic agent for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 μm thereby determining the temperature.
3. The composition according to claim 2 for the use in methods for treatment of the human or animal body by surgery or therapy and diagnostic methods practiced on the human or animal body.
4. The composition according to claim 3, wherein the methods are selected from the group consisting of determination of temperature or temperature distribution during minimally invasive treatments, during radiation treatments, or during magnetic resonance treatment, determination of temperature or temperature distribution in a cooled body before heart-surgery, and determination of temperature or temperature distribution for the detection of enhanced metabolistic activity.
5. The method according to claim 1 or the composition according to any one of the claims 2 to 4, wherein the sample is a biological sample.
6. The method according to any one of the claims 1, 5, or the composition according to any one of the claims 2 to 4, wherein said Raman active compound comprises at least one aromatic group or is an ion with at least one lone electron pair or is a carboxylic acid, or is selected from the group consisting of MmXθ3 or MnYC>4, wherein M is selected from the group consisting of Na, K, Li, Mg, and Ca, X is selected from the group consisting N, C, Cl, Br and I, and Y is selected from the group consisting of Si, Ge, Nb, Hf, Ta, Nb, and W and wherein m and n are 1 or 2.
7. The method or the composition according to claim 6, wherein MmXθ3 is selected from the group consisting of NaNO3, KNO3, Na2CO3, K2CO3, MgCθ3 and LiNbO3.
8. The method or the composition according to claim 6, wherein MnYOzJ is selected from the group consisting of Na2SiOzJ, K2SiOzJ, Na2GeOzJ, YTaOzj and K2GeOzJ.
9. The method according to any one of the claims 1, 5 or the composition according to any one of the claims 2 to 4, wherein the Raman active compound comprises anions selected from the group consisting of (VO^", (WOzj)^- and [FeHlFeH(CN)^]".
10. The method according to any one of the claims 1 or 5 to 9 or the composition according to any one of the claims 2 to 9, wherein said Raman active compound is immobilized on the surface of a particle or is comprised in a particle.
11. The method or the composition according to claim 10, wherein said particle has a diameter of from 5 nm to 50 μm.
12. The method according to any one of the claims 1 or 5 to 11, wherein the method is an in vitro method.
13. A composition comprising a Raman active compound for the measurement of the local temperature or a temperature distribution in a sample or portions thereof, wherein said composition is introduced to said sample and wherein the ratio of the intensities of its Stokes and anti-Stokes Raman emission lines is determined upon irradiation with light of (a) wavelength(s) of from 300 nm to 3 μm thereby determining the temperature.
14. The composition according to claim 13, wherein said Raman active compound comprises at least one aromatic group or is an ion with at least one lone electron pair or is a carboxylic acid or is selected from the group consisting of MmXθ3 or MnYC>4, wherein M is selected from the group consisting of Na, K, Li, Mg and Ca, X is selected from the group consisting N, C, Cl, Br and I and Y is selected from the group consisting of Si, Ge, Nb, Hf, Ta, Nb and W and wherein m and n are 1 or 2.
15. The composition according to claim 13, wherein MmXθ3 is selected from the group consisting OfNaNO3, KNO3, Na2CO3, K2CO3, MgCO3 and LiNbO3.
16. The composition according to claim 13, wherein MnYθ4 is selected from the group consisting of Na2SiO^ K2SiO^ Na2GeO^ YTaθ4 and K2Geθ4.
17. The composition according to any one of the claims 13 to 16, wherein said
Raman active compound is immobilized on the surface of a particle or is comprised in a particle.
18. The method or the composition according to claim 17, wherein said particle has a diameter of from 5 nm to 50 μm.
19. Use of a composition according to any one of the claims 13 to 18 for the determination of a local temperature or a temperature distribution in a sample.
20. The use according to claim 19, wherein the sample is a biological sample.
21. The use according to claim 19, wherein the temperature or temperature distribution is determined in a cooled body before heart-surgery.
22. The use according to claim 19, wherein the temperature or temperature distribution is determined for the detection of enhanced metabolistic activity.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08162402.5 | 2008-08-14 | ||
EP08162402 | 2008-08-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010018557A1 true WO2010018557A1 (en) | 2010-02-18 |
Family
ID=41424802
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2009/053597 WO2010018557A1 (en) | 2008-08-14 | 2009-08-14 | Temperature sensor based on raman scattering for use in molecular diagnostics |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2010018557A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017001847A1 (en) * | 2015-07-01 | 2017-01-05 | The Science And Technology Facilities Council | Clinical thermometer |
US10942123B2 (en) | 2016-10-28 | 2021-03-09 | United Kingdom Research And Innovation | Detection of pH |
CN113155311A (en) * | 2021-04-22 | 2021-07-23 | 中国工程物理研究院流体物理研究所 | CARS temperature measurement method and device |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6044285A (en) * | 1997-11-12 | 2000-03-28 | Lightouch Medical, Inc. | Method for non-invasive measurement of an analyte |
US20060050268A1 (en) * | 2004-09-07 | 2006-03-09 | The Regents Of The University Of California | Nanosensors based on functionalized nanoparticles and Surface Enhanced Raman Scattering |
US7413341B1 (en) * | 2004-08-16 | 2008-08-19 | The Research Foundation Of State University Of New York | Imaging methods |
-
2009
- 2009-08-14 WO PCT/IB2009/053597 patent/WO2010018557A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6044285A (en) * | 1997-11-12 | 2000-03-28 | Lightouch Medical, Inc. | Method for non-invasive measurement of an analyte |
US7413341B1 (en) * | 2004-08-16 | 2008-08-19 | The Research Foundation Of State University Of New York | Imaging methods |
US20060050268A1 (en) * | 2004-09-07 | 2006-03-09 | The Regents Of The University Of California | Nanosensors based on functionalized nanoparticles and Surface Enhanced Raman Scattering |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017001847A1 (en) * | 2015-07-01 | 2017-01-05 | The Science And Technology Facilities Council | Clinical thermometer |
GB2556741A (en) * | 2015-07-01 | 2018-06-06 | The Science And Tech Facilities Council | Clinical thermometer |
US10935440B2 (en) | 2015-07-01 | 2021-03-02 | United Kingdom Research And Innovation | Clinical thermometer |
GB2556741B (en) * | 2015-07-01 | 2021-10-27 | Res & Innovation Uk | Clinical thermometer |
GB2595190A (en) * | 2015-07-01 | 2021-11-17 | Res & Innovation Uk | Measuring temperature in a diffusely scattering sample |
GB2595190B (en) * | 2015-07-01 | 2022-03-23 | Res & Innovation Uk | Measuring temperature in a diffusely scattering sample |
US10942123B2 (en) | 2016-10-28 | 2021-03-09 | United Kingdom Research And Innovation | Detection of pH |
US11346785B2 (en) | 2016-10-28 | 2022-05-31 | United Kingdom Research And Innovation | Detection of pH |
CN113155311A (en) * | 2021-04-22 | 2021-07-23 | 中国工程物理研究院流体物理研究所 | CARS temperature measurement method and device |
CN113155311B (en) * | 2021-04-22 | 2023-04-11 | 中国工程物理研究院流体物理研究所 | CARS temperature measurement method and device |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Rocha et al. | Subtissue thermal sensing based on neodymium-doped LaF3 nanoparticles | |
Lin et al. | Surface-enhanced Raman scattering nanotags for bioimaging | |
Matousek et al. | Emerging concepts in deep Raman spectroscopy of biological tissue | |
Liu et al. | Smart NIR linear and nonlinear optical nanomaterials for cancer theranostics: Prospects in photomedicine | |
Quintanilla et al. | Challenges for optical nanothermometry in biological environments | |
Vo-Dinh et al. | Nanoprobes and nanobiosensors for monitoring and imaging individual living cells | |
US5832931A (en) | Method for improved selectivity in photo-activation and detection of molecular diagnostic agents | |
Baker et al. | Depth profiling of calcifications in breast tissue using picosecond Kerr-gated Raman spectroscopy | |
Barnoy et al. | An ultra-sensitive dual-mode imaging system using metal-enhanced fluorescence in solid phantoms | |
CA2955021A1 (en) | Raman-triggered ablation/resection systems and methods | |
WO2005029137A2 (en) | Fiber opticlaser-induced breakdown spectroscopy device and methods of use | |
Lin et al. | Advanced plasmonic technologies for multi-scale biomedical imaging | |
Kannadorai et al. | Dual functions of gold nanorods as photothermal agent and autofluorescence enhancer to track cell death during plasmonic photothermal therapy | |
Cupil‐Garcia et al. | Plasmonic nanoplatforms: from surface‐enhanced Raman scattering sensing to biomedical applications | |
Ilovitsh et al. | Cellular imaging using temporally flickering nanoparticles | |
Zhang et al. | Optical penetration of surface-enhanced micro-scale spatial offset Raman spectroscopy in turbid gel and biological tissue | |
Chai et al. | Influence on the apparent luminescent lifetime of rare-earth upconversion nanoparticles by quenching the sensitizer’s excited state for hypochlorous acid detection and bioimaging | |
Dey et al. | SERS‐based detection of barcoded gold nanoparticle assemblies from within animal tissue | |
Ngo et al. | Raman thermometry nanopipettes in cancer photothermal therapy | |
Lee et al. | Optical and structural properties of nanobiomaterials | |
WO2010018557A1 (en) | Temperature sensor based on raman scattering for use in molecular diagnostics | |
Al-Sammarraie et al. | Silver nanoparticles-based substrate for blood serum analysis under 785 nm laser excitation | |
Lin et al. | Direct and quantitative assessments of near-infrared light attenuation and spectroscopic detection depth in biological tissues using surface-enhanced Raman scattering | |
Gandra et al. | Surface-enhanced Raman scattering for in vivo imaging: the future looks BRIGHT? | |
Ohashi et al. | Temperature dependence of afterglow in zirconia and its optically-stimulated luminescence by bone-through irradiation for biological temperature probe |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09786942 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 09786942 Country of ref document: EP Kind code of ref document: A1 |