CN101629906A - Method and system for detecting special chemical substance in the detected object - Google Patents

Abstract

The invention pertains to the field of trace chemical substance detection, relates to a method and system for detecting whether special chemical substance is contained in the detected object. The method includes delivering sample of the detected object to a probe comprising nano-scale surface structure in order to make the sample in contact with the nano-scale surface structure; irradiating the nano-scale surface structure with a laser beam; scattering the laser beam by the sample and the nano-scale surface structure in order to generate a scattered light; obtaining the spectrum of the scattered light; analyzing the spectrum signal by a spectrum analyzer in order to detect whether special chemical substance is contained in the detected object. The invention provides simple and non-invasive detection method, which is convenient for carrying and easy to operate. The method and the system can be applied in fields of counter-terrorism, criminal investigation, medical diagnosis, disease prevention, industrial process monitoring, environment cleaning and monitoring, counterfeit goods detection, product identification, detection of methanol and ethanol content in alcohol, quality control of food and medicament or the like.

Description

Detect the method and system of particular chemicals in the measurand

The application requires the right of priority of 12/176, No. 383 patented claim of U.S. US and 12/246, No. 616 patented claim of U.S. US.Wherein, U.S. US 12/246, No. 616 patented claims be common transfer the possession of be in unsettled U.S. US12/176 in the checking process, a part continuity (CIP) application of No. 383 patented claims, U.S. US 12/176, No. 383 patented claims be common transfer the possession of be in U.S. US 11/681 in the checking process, a part of No. 157 patented claims continues patented claim, this is in the unsettled U.S. US 11/681 in the checking process, the applying date of No. 157 patented claims is on March 1st, 2007, and title is " a trace chemistry optic probe ".U.S. US 11/681, No. 157 patented claims are the common U.S. US 10/987 that transfers the possession of, No. 842 patented claims (have now been authorized and have been U.S. US 7,242, No. 469 patents) continuation application, and U.S. US 10/987, No. 842 patented claims are again the U.S. US 10/852 that submitted on May 24th, 2004, a part of No. 787 patented claims (now having authorized 7,384, No. 792 patents into U.S. US) continues patented claim.U.S. US10/852, No. 787 patented claims have required No. 60/473,283, the US that submitted on May 27th, 2003 and 60/473, No. 2876 provisional application of US, and the right of priority of 60/520, No. 222 provisional application of US of submitting on November 17th, 2003.

Technical field

The invention belongs to trace chemistry material (chemical substance of denier) detection range, relate to a kind of method that whether contains particular chemicals in the measurand that detects, be specifically related to a kind of method that detects the trace chemistry material with the light scattering probe, relate in particular to a kind of light scattering probe and a kind of chemical probe of improvement of using and detect the method that whether contains particular chemicals in the measurand, and this detection system.

Background technology

Although in fact Raman detector has the sensitivity of Single Molecule Detection (SMD), because some technical difficulties, conventional Raman probe still is subjected to many restrictions on using.Especially, detect for the trace chemistry material, the main restriction that Raman spectroscopy is used comes from weak Raman scattering signal.People once attempted to make great efforts to solve this problem of weak scattering signal of Raman sensory field.Yet the achievement of these effort is still very limited, fails to make the Raman detector can be in practice and be applied to the trace detection of the extreme sensitivity chemical substance of active demand economically.

As everyone knows, sensitive surface coarse or nanostructured produces the scattered signal of strengthening.Particularly, nano structural material has been widely used in fields such as sensing, bio-science, material science, semiconductor.Adopting a big promising application of the sensing technology of nano structural material is surface enhanced Raman spectroscopy (SERS) and surface enhanced resonant raman spectroscopy (SERRS).Have been found that than common Raman scattering, its Raman scattering signal can strengthen 10 when molecule is attracted on precious metal (for example Ag, Au and Cu, but be not limited to Ag, Au and the Cu) surface of nanostructured ⁴～10 ¹⁴Doubly.Especially, if the nano surface particle is kept apart, the Raman scattering signal can significantly strengthen.Strengthen the factor that effect depends on several respects, wherein, the size of lip-deep nano particle and intergranular distance are extremely important.It is found that the size of nano particle reduces, the enhancing of Raman scattering signal increases.Further, the variable in distance between contiguous nano particle island, the enhancement effect of Raman scattering changes equally.Yet conventional technology such as the VLSI (very large scale integrated circuit) photoetching technique, when making nanostructured surface, reduces nanoparticle size for the enhancing that realizes scattered signal and reduces surperficial going up between nano particle apart from still having run into technical difficulty.

With SERS (Surface-Enhanced Raman Scattering, Surface enhanced raman spectroscopy) and SERRS (Surface-Enhanced Resonant Raman Scattering, when serrs) technology is applied to the trace chemistry material and detects, be difficult to obtain one of main difficult problem that those routine techniquess that on-contaminated nanostructured precious metal surface remains this field face.Molecular adsorption and measurement subsequently need be convenient in an on-contaminated nanostructured precious metal surface.Acquisition just because of uncontamination nanostructured precious metal surface is restricted, even the detection of trace chemistry material can reach part per billion level (ppb), utilize SERS and SERRS to go the The Application of Technology of explosive detection and/or other trace chemistry materials still very limited.

Yet existing document does not provide an effective method to go to make and encapsulate on-contaminated nanostructured precious metal surface, thereby realizes utilizing the rig-site utilization of SERS and SERRS technology for detection trace chemistry material.In addition, existing document does not provide a kind of method to remove to make the nano structural material of the nano-array that has good control yet, described nano-array requires to have the nano particle that size is reduced and optimizes, and the distance of these lip-deep nano particles also will be reduced and optimize, to realize the enhancing of scattered signal.

In the common pending application that is in the checking process of the present invention, disclosed the nanostructured surface of improvement greatly, utilized the demand of these nanostructured surfaces constantly to increase, so that Raman probe can effectively be put in the practical application of active demand.

Therefore, this Technology Need provides a kind of effective structure, so that Raman probe is applied to anti-terrorism, criminal investigation, medical diagnosis, prevention from suffering from the diseases, Industrial Process Monitoring, environment cleaning and monitoring, food and drug quality control or the like field.

Summary of the invention

On the one hand, the present invention relates to a kind of method that whether comprises particular chemicals in the measurand that detects, the detection non-invasively of this method and disease, forbidden drug user mode or the relevant chemical substance of smoking state are with auxiliary definite disease, forbidden drug user mode or smoking state.Method of the present invention comprises: will be transferred to a detector that comprises a nanoscale surface structure from the sample (as body fluid) that measurand (as patient) obtains, body fluid and this nano level surface structure are contacted; With this body fluid of a laser beam irradiation and nanoscale surface structure; Body fluid and this laser beam of nanoscale surface structure scattering produce scattered light; And, use a spectroanalysis instrument to analyze this scattered light, whether to contain with specified disease in the identification measurand, to use forbidden drug or the relevant chemical substance of smoking, to determine patient's disease, forbidden drug user mode or smoking state as the key foundation of disease, forbidden drug user mode or the smoking state of determining patient.

On the other hand, the present invention also provides the another kind of method that whether comprises particular chemicals in the measurand that detects, detection non-invasively and disease, forbidden drug user mode or the relevant chemical substance of smoking state are with auxiliary definite disease, forbidden drug user mode or smoking state.This method comprises: will be transferred to a detector that comprises a nanoscale surface structure from the sample (as body fluid) that measurand (as patient) obtains, body fluid and this nano level surface structure are contacted; With this body fluid of a laser beam irradiation and nanoscale surface structure; Body fluid and this laser beam of nanoscale surface structure scattering produce scattered light; Obtain the Raman spectrum of this scattered light; And, discern near the spectral signal of a predetermined wavelength, described spectral signal comprises a near spectrum peak the predetermined wavelength in the Raman spectrum at least, whether to contain with specified disease in the identification measurand, to use forbidden drug or the relevant chemical substance of smoking, to determine patient's disease, forbidden drug user mode or smoking state as the key foundation of disease, forbidden drug user mode or the smoking state of determining patient.

Comprise blood, saliva, urine, serum, tear, sweat, seminal fluid and juice as the body fluid as test sample described in the method for the present invention, juice comprises gastric juice (secreting gastric juice), female juice again, or the like.Can adopt the inventive method to include but not limited to lung cancer, breast cancer, cancer of the stomach, cirrhosis, renal failure, ulcerocancer, oophoroma, the cancer of the uterus, cervical carcinoma, carcinoma of mouth, cancer of the esophagus, thyroid cancer, laryngocarcinoma, leukaemia, colon cancer, carcinoma of urinary bladder, prostate cancer, bronchiolar carcinoma, acquired immune deficiency syndrome (AIDS), dopy, diabetes with the disease that detects relative particular chemicals; And smoking state.The present invention also can be used for detecting measurand and whether illegally uses medicine, and described medicine includes but not limited to heroin, dexoxyn, cocaine, caffeine, morphine, codeine, amphetamine, ephedrine, papaverine, narcotine and MDMA.The body fluid volume that is transferred to detector can be from about 100pl to 1ml.Analytical procedure can comprise the Raman spectrum that obtains scattered light, and analyzes this Raman spectrum, to determine whether to contain the particular chemicals with certain disease association, further to determine patient's disease.Analytical procedure also can comprise near the spectral signal the predetermined wavelength in the identification Raman spectrum, this spectral signal can comprise near at least one spectrum peak this predetermined wavelength in this Raman spectrum, to determine whether to contain the particular chemicals with certain disease association, further to determine patient's disease.Analytical procedure can comprise that also whether the signal to noise ratio (S/N ratio) of judging spectrum peak in the Raman spectrum is greater than predetermined threshold value; Surpass predetermined threshold if reach spectrum peak, then send signal, this signal is used to point out the particular chemicals that contains with certain disease association, may be ill with the prompting patient.The predetermined threshold of signal to noise ratio (S/N ratio) can be about 3 or higher.Can adopt the inventive method can be carcinoma of mouth with the disease that detects relative particular chemicals, and wherein body fluid is saliva, and analytical procedure comprises analyzes 560cm in the Raman spectrum ^-1Or 1100cm ^-1Near spectral signal is further to diagnose patient whether to suffer from carcinoma of mouth according to this result.Also can be breast cancer, wherein body fluid be saliva, and analytical procedure comprises analyzes 560cm in the Raman spectrum ^-1Or 1100cm ^-1Near spectral signal is to determine further according to analysis result whether patient suffers from breast cancer.Also can be lung cancer, wherein body fluid be serum, and analytical procedure comprises analyzes 745cm in the Raman spectrum ^-1Near spectral signal is to determine further according to analysis result whether patient suffers from lung cancer.Also can be acquired immune deficiency syndrome (AIDS) (virus), wherein liquid be saliva, and analytical procedure can comprise analyzes 870cm in the Raman spectrum ^-1Whether near spectral signal has infected AIDS virus with further patient.Also can detect forbidden drug, described liquid can be saliva, and wherein analytical procedure comprises and analyzes 1030cm in the Raman spectrum at least ^-1And 1535cm ^-1Whether near the spectral signal of a crest contains the relevant chemical substance of forbidden drug to detect, and further determines patient's forbidden drug user mode.Also can detect patient's glucose level, described liquid is saliva, and wherein analytical procedure may comprise 1123cm in the analysis Raman spectrum ^-1Spectral signal is to detect the glucose level of diabetic.Also can detect the chemical substance relevant with smoking, body fluid is saliva, and wherein analytical procedure can comprise 1029cm in the analysis Raman spectrum ^-1Near spectral signal is further to know patient's smoking state.Detect patient's glucose level, described liquid is saliva, and wherein analytical procedure can comprise 1130cm in the analysis Raman spectrum ^-1About spectral signal, whether suffer from diabetes with further patient.Analytical algorithm can comprise Dendrographic algorithm and principal component analysis (PCA) algorithm.

The inventive method can comprise further that by the molecule in the surface adsorption body fluid of nanoscale surface structure, wherein scattering step comprises the lip-deep molecular scattering laser beam that is attracted to the nanoscale surface structure.Described nanoscale surface structure can comprise a conductive material.This conductive material can comprise a precious metal.Described detector can further comprise a substrate, and wherein the nanoscale surface structure is made up of the many holes in suprabasil many cylinders or substrate.Described detector can comprise further that one is positioned at suprabasil conductive layer, and wherein said cylinder is arranged on the conductive layer.Described detector can comprise further that one is positioned at suprabasil conductive layer, and wherein said hole to small part is formed in the conductive layer.Distance between contiguous cylinder or the contiguous hole in 10 nanometers (nm) in 1000 nanometers (nm) scope.

The inventive method also relates to the detection to food composition.This method comprises: the raman spectral signal of determining a chemical substance; Foodstuff samples solution from this measurand of food is contacted with the first nanoscale surface structure of one first detector, wherein first detector comprises a substrate, and described nanoscale surface structure comprises a plurality of holes in suprabasil a plurality of cylinder and the substrate; The first nanoscale surface structure with this foodstuff samples solution of a laser beam irradiation and first detector; This foodstuff samples solution and first this laser beam of nanoscale surface structure scattering produce a scattered light; Use a spectroanalysis instrument to obtain first Raman spectrum from this scattered light; Discern the spectral signal in first Raman spectrum, identify whether there is described chemical substance in this food.

On the other hand, the present invention relates to the detection method of food composition.This method comprises: the reference sample solution that contains certain chemical substance is contacted with the first nanoscale surface structure of first detector; Obtain first Raman spectrum of this reference solution and this Nanosurface, determine the spectral signal of this chemical substance in this first Raman spectrum; Make from the foodstuff samples solution of food and contact with the second nanoscale surface structure in one second detector; The second nanoscale surface structure with this foodstuff samples solution of a laser beam irradiation and second detector; This foodstuff samples solution and second this laser beam of nanoscale surface structure scattering produce a scattered light; Use a spectroanalysis instrument to obtain one second Raman spectrum from this scattered light; Discern the spectral signal in second Raman spectrum, identify whether there is described chemical substance in this food.

The present invention relates to the another kind of method that detects food composition.This method comprises: a kind of reference sample solution that contains certain chemical substance is contacted with the first nanoscale surface structure of one first detector, wherein the first nanoscale surface structure is included in lip-deep a plurality of nano particles of first detector, perhaps a plurality of cylinders or hole, the neighbor distance between them is in the scope of 10nm-1000nm; Obtain first Raman spectrum from this reference solution and this Nanosurface, determine near the spectral signal of this a chemical substance predetermined wavelength in first Raman spectrum, wherein said spectral signal comprises near at least one spectrum peak this predetermined wavelength; Foodstuff samples solution from food is contacted with the second nanoscale surface structure of second detector, and wherein first detector and second detector have essentially identical Nanosurface structure; With this foodstuff samples solution of a laser beam irradiation and the second nanoscale surface structure; This foodstuff samples solution and second this laser beam of nanoscale surface structure scattering produce scattered light; Use spectroanalysis instrument to obtain second Raman spectrum from this scattered light.Discern near the spectral signal the predetermined wavelength in second Raman spectrum, identify whether there is this chemical substance in this food, wherein this identification step comprises: determine whether the spectrum peak in this Raman spectrum or the signal to noise ratio (S/N ratio) of this spectrum peak exceed-predetermined threshold; If this spectrum peak or this signal to noise ratio (S/N ratio) exceed this predetermined threshold, identify this chemical substance.

The enforcement of the inventive method can comprise following one or multinomial content.Set up step to comprise: a reference sample solution that contains certain chemical substance is contacted with the second nanoscale surface structure of second detector; Obtain second Raman spectrum by this reference solution and Nanosurface, determine the spectral signal of this chemical substance in the Raman spectrum.First detector and second detector have essentially identical Nanosurface structure.Detector can further comprise and is positioned at suprabasil conductive material.This method can further comprise: in irradiating step, to the conductive material making alive in the first nanoscale surface structure, shift with the electric charge between the molecule that strengthens the conductive materials in the conductive material and the first nanoscale surface structure.Conductive layer can comprise a precious metal.Detector can comprise to small part and is present in a plurality of holes in the conductive material.Described a plurality of cylinder can be formed on the conductive material.Identification step can comprise near the spectral signal the predetermined wavelength in identification first Raman spectrum.This spectral signal can comprise near at least one spectrum peak this predetermined wavelength.Identification step can comprise: determine whether the spectrum peak in the Raman spectrum or the signal to noise ratio (S/N ratio) of this spectrum peak exceed a predetermined threshold; If this spectrum peak or this signal to noise ratio (S/N ratio) exceed this predetermined threshold, confirm to identify this chemical substance.This method can further comprise, if this food contains this chemical substance really, then uses the concentration of this this chemical substance of spectral signal strength detection.Described food can include but not limited to dairy products, candy, beverage, wine, meat, seafood, tealeaves, fresh or canning vegetables, fruit, grain, cereal, cornflakes, potato block or protein food.Described dairy products can include but not limited to milk, milk powder, cheese, cheese cake, sour milk, ice cream or toffee.Described chemical substance can include but not limited to melamine, honey element, sodium cyclohexylsulfamate, sucrose, starch, nitrite, nitrate, Sudan red 1, II, III and IV, malachite green, acephatemet (methamidophos), orthene, DDT (dichloro-diphenyl-trichloro-ethane), DDV (DDVP), the malathion, Folithion, decis, cypermethrin, parathion-methyl, phosmet, Rogor, nitrofuran, furazolidone, chloromycetin, duomycin (aureomycin), Ciprofloxacin, clenbuterol hydrochloride or Enrofloxacin.Described chemical substance can comprise pesticide, insecticide or microbiotic.Described food can comprise dairy products, and wherein said chemical substance comprises melamine, and spectral signal comprises one or more about 678cm ^-1, 698cm ^-1, 712cm ^-1Or 1648cm ^-1The spectrum peak at place.This method can further comprise adds acetonitrile in described foodstuff samples solution, and wherein spectral signal can comprise one or more about 918cm ^-1-921cm ^-1Spectrum peak.Described chemical substance can comprise protein, and wherein said spectral signal can comprise one or more greatly about 1658cm ^-1Spectrum peak.Described chemical substance can comprise starch, and wherein said spectral signal can comprise one or more greatly about 473cm ^-1Spectrum peak.The first nanoscale surface structure of first detector can comprise that a plurality of average neighbor distance are a plurality of cylinders or the hole of 10nm-1000nm.This method can further be included in a surface of first detector and go up the introducing nano particle, and wherein the first nanoscale surface structure comprises the nano particle on first detector surface.This method can further be included in this nano particle that suspends in the foodstuff samples solution; With the surface that this foodstuff samples solution is incorporated into first detector.

The present invention also provides a kind of system that detects particular chemicals in the measurand, comprise a laser instrument, at least one light scattering probe, one spectrometer and the spectroanalysis instrument that is attached thereto, described light scattering probe comprises a probe and a detector, described probe links to each other with spectrometer with laser instrument respectively by optical fiber, and described detector has nanoscale surface structure (the light scattering probe is designated hereinafter simply as the Raman probe).

Described spectrometer and spectroanalysis instrument are Raman spectrometer and Raman spectrum analysis instrument.

Described nanoscale surface structure comprises a conductive material, and this conductive material comprises a precious metal.

Described detector further comprises a substrate, and wherein the nanoscale surface structure comprises a plurality of holes in suprabasil a plurality of cylinder or the substrate.

Described detector comprises that further one is positioned at suprabasil conductive layer, and wherein said a plurality of cylinders are formed in the conductive layer.

Described detector comprises that further one is positioned at suprabasil conductive layer, and wherein said a plurality of holes to small part is formed in the conductive layer.

Described probe comprises bandpass filter, the lens combination that is positioned on the laser instrument input light path and is positioned at reflector group, bandpass filter, lens on the detector scattering output light path.

Imbody of the present invention following one or more advantages.The inventive method provides the method for simple and non-invasive detection particular chemicals, and mensuration can be further used for disease detection with the particular chemicals of disease association.Adopt system of the present invention to be easy to carry and easy operating, the result of detection can be advantageously used in disease early prevention and the screening of open-air medicinal usage.The result that the inventive method is measured can be advantageously used in the early detection and the diagnosis of disease.In addition, the inventive method sense cycle is short, thereby may be very helpful to the treatment process of monitoring of diseases and drug use.The inventive method can be measured the particular chemicals that multiple disease patient is contained from patient's body fluid, these diseases include but not limited to carcinoma of mouth, breast cancer, lung cancer, cancer of the stomach, cirrhosis, renal failure, ulcerocancer, oophoroma, the cancer of the uterus, cervical carcinoma, carcinoma of mouth, cancer of the esophagus, thyroid cancer, laryngocarcinoma, leukaemia, colon cancer, carcinoma of urinary bladder, prostate cancer, bronchiolar carcinoma, diabetes, acquired immune deficiency syndrome (AIDS).The present invention also can detect the chemical substance relevant with using forbidden drug and smoking.

On the one hand, detected trace chemistry material can be gas, liquid and solid form, and wherein gas can be the solid that comes under a certain specific vapour pressure.Laser beam is not mapped on the sample in detection, and scattered light is not collected from sample yet, and like this, detection is " remote measurement with non-invasive ".Molecule is adsorbed on the detector surface.The molecule that is adsorbed has and obtains many scattering cross-sections greatly than freely being present in molecule in gas, the liquid or solid.When laser beam is beaten on captive molecule, Raman scattering takes place, and spectrometer and analyser obtain the Raman spectrum of molecule.Since each compound all has its distinctive Raman spectrum, so just can use Raman fingerprint principle and go to identify unknown chemical substance.Such application includes, but not limited to the trace chemistry material into Homeland Security explosive detection, chemical and biological weapons and forbidden drug smuggling; For the diet material safety detects residues of pesticides; Early stage medical diagnosis on disease; Environmental monitoring; Industrial Process Monitoring, or the like.

On the other hand, laser beam irradiation scribbles the detector of the sample solution that contains the suspended nano particle.Directly from the sample collection scattered light.The disclosure technology is suitable for detecting the objectionable constituent in the grain and checks and approves composition, to measure the concentration of useful component in the grain.The application of method of the present invention also includes but not limited to: detect counterfeit goods, for example less milk powder of protein; Product (for example jewel) is identified, the constituent analysis of tablet, the detection of methyl alcohol and ethanol content in the wine.

Below in conjunction with accompanying drawing, describe the present invention in detail by preferred embodiment, those of ordinary skills will more understand purpose of the present invention and advantage.

Description of drawings

Following accompanying drawing is the part of book as an illustration, and the diagram embodiments of the invention are used for illustrating principle of the present invention together with the invention description.

Figure 1A-1C for example understands the apparatus structure that uses Surface enhanced raman spectroscopy to carry out the detection of trace chemistry material.

Fig. 2 for example understands the design of Raman probe.

Fig. 3 A and 3B are respectively the synoptic diagram that uses the Raman probe that passenger and luggage are checked on the airport.

The synoptic diagram that Fig. 4 is to use the Raman probe that public building is carried out safety monitoring.

The synoptic diagram that Fig. 5 is to use the Raman probe to carry out environmental monitoring.

Fig. 6 is to use the Raman probe to check the synoptic diagram of food security.

Fig. 7 is to use the synoptic diagram of detection of Raman probe and disease association chemical substance.

Fig. 8 has and does not have Raman to pop one's head in to carry out the synoptic diagram of production quality control.

Fig. 9 is to use the Raman probe to carry out counterfeit goods detection, the safety of Food ﹠ Drink and the synoptic diagram of quality inspection and drug identification.

Figure 10 is the cut-open view that is used to make the multilayer layer structure of nanostructured.

Figure 11 A is the cut-open view of the hole that forms in multilayer layer structure shown in Figure 10 by oxidation.

Figure 11 B is the top view of the multilayer layer structure shown in Figure 11 A.

Figure 11 C is that multilayer layer structure shown in Figure 11 B is along the cut-open view of A-A line.

Figure 12 is at the cut-open view of the structrural build up nanostructured of multilayer stratiform after wet chemical etching technique or chemically mechanical polishing (CMP).

Figure 13 is at the cut-open view of the structrural build up nanostructured of multilayer stratiform after removing the restraining barrier of hole bottom and being etched to conductive layer.

Figure 14 A is the cut-open view of precious metal deposition back in the structrural build up nanostructured of multilayer stratiform.

Figure 14 B is the cut-open view of removing behind the precious metal of top layer in the structrural build up nanostructured of multilayer stratiform.

Figure 15 is the cut-open view of removing after the oxide layer in the structrural build up nanostructured of multilayer stratiform.

Figure 16 A-16D, 16G and 16H are at the cut-open view of the structrural build up nanostructured of multilayer stratiform after corresponding manufacture craft.

Figure 16 E and 16F are at the top view of the structrural build up nanostructured of multilayer stratiform after corresponding manufacture craft.

Figure 17 for example understands the raman spectral signal that detects relevant chemical substance by disclosed Raman probe in an oral cavity carninomatosis people saliva.

Figure 18 for example understands the raman spectral signal that detects relevant chemical substance by disclosed Raman probe in a breast cancer patient saliva.

Figure 19 A understands that for example using disclosed Raman to pop one's head in detects the raman spectral signal of relevant chemical substance in the saliva of a lung cancer patient.

Figure 19 B understands that for example using disclosed Raman to pop one's head in detects the raman spectral signal of relevant chemical substance in the serum of a lung cancer patient.

Figure 20 for example understands the raman spectral signal that detects relevant chemical substance by disclosed Raman probe in an oophoroma patient serum.

Figure 21 for example understands the raman spectral signal that detects relevant chemical substance by disclosed Raman probe in an acquired immune deficiency syndrome (AIDS) patient saliva.

Figure 22 for example understands the raman spectral signal that detects relevant chemical substance by disclosed Raman probe in a forbidden drug user saliva.

Figure 23 for example understands by disclosed Raman probe, through making comparisons with the raman spectral signal of N-first-2-5-pyrrolidone (metabolic product of nicotine), contains the raman spectral signal of N-first-2-5-pyrrolidone a smoker saliva detecting.

Figure 24 is to use disclosed Raman probe to detect the process flow diagram that wherein whether contains the particular chemicals diagnosis by patient's body fluid.

Figure 25 A and 25B have illustrated the spectral signal of illegal and harmful chemical (melamine) in Raman spectrum of variable concentrations in the dairy products.

Figure 26 has illustrated with acetonitrile 918cm ^-1Raman peaks is interior mark reference, detects the spectral signal of melamine in Raman spectrum in the milk liquid.

Figure 27 has illustrated the spectral signal of illegal harmful chemical (melamine) in Raman spectrum of variable concentrations in the dairy products.

Figure 28 has illustrated Raman spectrum to discern unauthorized or illegal chemical addition agent in the milk powder.

Figure 29 is for guaranteeing the process flow diagram of harmful chemical in the food safety detection food.

Embodiment

Referring to Figure 1A, light scattering probe 100 comprises a probe 110 and one detector 105.Detector 105 comprises a nanoscale surface structure.The nanoscale surface structure can comprise a plurality of nano-pillar 108, shown in Figure 1B, and a plurality of nanoaperture, or the surface structure of other nano-scale.In certain embodiments, as described below, the surface that can be coated in detector 105 by the colloidal suspension solution that will contain nano particle makes the nanoscale surface structure.Solution can be evaporated subsequently, and nanoparticle deposition is to the surface.

With the Nanosurface that comprises nano-pillar 108 is example, a fluid sample can be guided on the nano-pillar 108 of detector 105.Described fluid sample can comprise patient or forbidden drug user's body fluid, with the use according to testing result auxiliary judgment disease or definite medicine.The example of body fluid can comprise blood, saliva, urine, serum, tear, sweat and gastric juice.Described sample can also comprise a food samples, detects the harmful or illegal adjuvant in the food for guaranteeing food security.The example of food comprises dairy products, and for example milk, milk powder (for example babies ' formula milk powder), cheese, sour milk, ice cream, toffee and other contains milk deli and proteinaceous food.Probe 110 and detector 105 are loaded in the probe assembly 120.

Probe assembly 120 can reduce pressure by a vacuum pump and reduce the pollution of impurity to sensitive surface.

Laser instrument 141 emitted laser bundles shine on the detector 105 through optical fiber 125 conduction, shown in Fig. 1 C.Probe 110 is near detector 105.In this application, RamanNanoChip ^TMRefer to the detector that comprises a nanoscale surface structure, described nanoscale surface structure is used to adsorb the molecule of chemistry, biology or medical sample, thereby uses the light scattering probe to detect.By the 110 collection scattered lights of popping one's head in, be transmitted to spectrometer 140 and spectroanalysis instrument 150 through optical fiber 130 again.Obtain the Raman spectrum of scattered light by spectroanalysis instrument 150.Spectral signal in the Raman spectrum is identified, and compares with the database that contains multiple molecular spectrum signal.If detect to find to have surpassed the threshold value of certain molecule, output signal then, certain molecule that exceeds standard to be used for pointing out this sample to contain, and this a part may with a kind of disease association.In instructions of the present invention, " spectral signal " of the present invention can be meant one or more spectrum peaks, one or more spectrum paddy, and other wave spectrum shape for example relatively peak height, peak line width, peak shape or the like, they have characterized the one or more molecular links in biological, medicine or the chemical material.

Referring to Fig. 2, probe 110 can receive the laser projections from input laser fiber 125, projects on the detector 105 by a bandpass filter 170, a lens combination 175-1 and 175-2 successively.Scattered light is got back on one group of catoptron 180-1 and the 180-2 by projection, by another bandpass filter 185 and calibration lens 190, through collecting optical fiber 130 outputs.

Fig. 3 A has illustrated Surface enhanced raman spectroscopy (SERS) is applied to transportation safety and other local facility structures, monitors passenger 200-1,200-2 and 200-3 here to carry out passenger's examination.For the examination passenger, the probe assembly 120 that has embed-type detector 105 is placed in the passageway 210.Near the spectroanalysis instrument 150 in office probe assembly 120 is communicated with by optical fiber or at a distance.The sensitive surface of 110 alignment detectors 105 of popping one's head in, and be packaged in together.Passage 210 can be an artificial draft, is under slight negative pressure and/or the high slightly temperature, to strengthen the volatilization of objectionable impurities.If passenger, passenger 200-2 for example, have explosive, harmful chemical substance, chemical weapons, chemical and biological weapons, nuclear weapon or anaesthetic, the small number of molecules of these materials will evaporate in the air, is adsorbed to the surface of detector by these molecules of custom-designed sample collecting system.Raman spectrum will be recorded also and the database on office's main frame is compared.In case detect objectionable impurities, the early warning signal will be triggered, and further take suitable safety practice.

Fig. 3 B has shown the application implementation situation of monitoring luggage in freight transportation, and luggage 215 passes through goods examination passage 220 via 230 transportations of a travelling belt.The probe assembly 120 that has embed-type detector 105 is positioned in goods examination passage 220 everywhere.Probe assembly 120 is the spectroanalysis instrument 150 in the office near optical fiber is communicated with or at a distance.The pop one's head in surface of 110 alignment detectors 105, and they are packaged in together, to detect any explosive, chemistry or chemical and biological weapons or the Harmful chemicals in the luggage 215.This facility can be applied to other place, for example post office, railway station, customs inspection post, traffic control zone or the like.This facility can easily be used to detect gunpowder or other explosive or dangerous material.

Fig. 4 will use the Surface enhanced raman spectroscopy of detector to be applied to synoptic diagram in public's building safety, and the public builds 250 for example airport, railway or bus stop, court building, government buildings, auditorium, cinema, law court and other public buildings.Light scattering probe 100 comprises probe 110 and the detector 105 that links together, and is distributed in public's building or other defence zone.Light scattering probe 100 is used to monitor many different molecular substances, so that early detection any danger or that detrimental substance enters guarded region to be provided.The special example of supervision on hazardous substances includes but not limited to the detection of (comprising anthrax, drugs or the like) of explosive, chemistry or chemical and biological weapons.

Fig. 5 will use the Surface enhanced raman spectroscopy technology of detector to be applied to monitor the synoptic diagram that is discharged into the harmful chemical in the environment.Light scattering probe 100 is distributed on the potential pollution source periphery, and for example factory 260, or by near the highway of a large amount of automobiles 270.Light scattering probe 100 is distributed in monitored area everywhere, and the Raman diffused light of generation is transmitted to the spectroanalysis instrument 150 of main frame, with content and the concentration of determining to be discharged into the material in the environment.Test sample can be, but be not limited to soil, water, lake, river, beach, well, plant or the like.This application can extend to automobile exhaust gas and detect, and only probe assembly need be installed near the auto exhaust mouth.

Fig. 6 will use the Surface enhanced raman spectroscopy technology of detector to be applied to detect food quality and safe synoptic diagram.Light scattering probe 100 is placed on the places near food 280, and described food can be an apple or other fruit, vegetables, or other may be because of transportation, food processing and even the contaminated food of food growth course.The molecule of remains of pesticide or other pollutant is inhaled into light scattering probe 100.Detector is used for detecting any suspicious harmful chemical in the food.

Fig. 7 will use the Surface enhanced raman spectroscopy technology of detector to be applied to detect chemical substance with disease association, to be used for the matter monitoring of early stage disease detection and diagnosis.Light scattering probe 100 places near the patient 290.Result of study shows, if a people finds to suffer from disease (for example lung cancer) through examination, just contains some special chemical substances in the gas that he breathes out, for example alkene and benzene derivative.The Raman sensing technology can obtain the finger-print of those compounds in breath test, thus the chemical substance of identification and some special disease associations, for example cancer.It is in order to carry out physical examination that light scattering probe 100 places the patient next door.Patient expired gas is blown on the light scattering probe 100.Detector in the probe assembly receives the air that enters, and produces Raman diffused light, and the molecule that contains in this Raman diffused light and the air-flow from patient is relevant.Probe is collected scattered light and is sent it to spectroanalysis instrument 150, obtains Raman spectrum.The breath test of using the Raman sensing technology can be used for early stage medical diagnosis on disease with the chemical substance of detection with disease association, and described disease includes but not limited to lung cancer, breast cancer, cancer of the stomach, cirrhosis, renal failure, ulcerocancer or the like.Under the situation of testing human body fluid, body fluid is manually dripped on the detector, in order to sample conveniently, also the Raman sensing device can be connected to and to constitute an intelligent closet on the closet, for real-time abnormal signal monitoring is carried out in disease and drug test.This application comprises equally to be discerned and classifies protein, DNA and RNA.All specimen of above-mentioned application can contact with detector to strengthen sensitivity and the intensity that Raman scattering detects.The trace chemistry material of the use Raman light scattering of the disclosure detects the field that can also be applied to other, include but not limited to, detect and the relevant chemical substance of Alzheimer's (senile dementia), detect chemical substance--the glucose relevant with diabetes, and detect the carrotene that shows antioxidant level, to be used for the early-stage cancer examination.

Fig. 8 is having detector (RamanNanoChip for example ^TM) situation under in the commercial production quality management, use the synoptic diagram of Raman scattering.Such application including, but not limited to, the wet chemicals concentration of on-line monitoring on wet chemical process production line, the stand-off monitoring of chemicals airtight container, the trace chemistry material is surveyed, the semiconductor wafer flaw evaluation reaches food, fruits and vegetables storage monitoring, or the like.

Fig. 9 is that application surface enhancing Raman scattering technology is carried out counterfeit goods identification and examination, and the synoptic diagram of food security examination.Such application can comprise for example food, medicinal material and medicine examination.Under these situations, may need or not need detector.The laser that is excited in the test is directly beaten on sample.Along with the improvement of Raman spectrometer total system, the past, irrealizable new application became a reality.Raman spectrum from the scattered light of tested material demonstrates distinctive composition, shows to have illegal adjuvant in commodity.Potential counterfeit goods, for example milk powder, wine and tablet can be used as material and place under the Raman detector and detect and screen.Application of the present invention can extend to the legitimacy of signature and banknote and identify, the raman scattering spectrum of signature and banknote generation is compared with the spectrum of legal signature and banknote, thereby detect false signature and counterfeit money.

Figure 10-15 has shown the processing step on a series of making nanostructured precious metal of the present invention surface.One sandwich construction 302 (Figure 10) comprises a substrate 305, one conductive layers 310 and an alumina layer 315.Substrate 305 can be, for example n type silicon chip (the 3-8 Ω-cm) or (the 30-50nm SiO of oxidation ₂) p type silicon (5-10m Ω-cm).Conductive layer 310 can comprise Ti and Ni, and it is deposited in the substrate 305, has not only conducted electricity but also heat conduction.The thickness of conductive layer 310 can be optimised, makes it i) adhere to subsequently the precious metal film of deposition, for example Ag or Au film or the like; Be conductive film ii), in the practical application sensitive surface applied electrical bias; Iii) be heat-conducting layer, reduce the temperature of sensitive surface.The thickness of conductive layer 310 generally can be controlled at

Scope in.

Aluminium lamination 315 is deposited on the conductive layer 310.Aluminium lamination 315 can have 99.999% purity, and thickness is in the 1.0-10.0 mu m range.Substrate 305, conductive layer 310 and alumina layer 315 are filling N ₂Reacting furnace in 400 ℃-500 ℃ annealing 2-5 hour, make aluminium film recrystallization.Carry out oxidation subsequently, on alumina layer 315, form porous structure, shown in Figure 11 A and 11B.The porous structure that forms on the alumina layer 315 comprise many by inwall 314 around hole 312, its along the cut-open view of horizontal line A-A shown in Figure 11 C.In Figure 12, carry out the wet oxidation corrosion, to remove the porous Al at top ₂O ₃Layer and restraining barrier.Carry out for the second time that oxidation consumption falls all metallic aluminiums, make the Al of the porous at restraining barrier and top ₂O ₃Layer just in time is positioned on the conductive metal layer.

In Figure 13, carry out restraining barrier and reaming that oxide etch is removed the hole bottom.Wet etching makes hole 312 extend downward conductive layer.The thickness of formed porous oxide coatings can be controlled by the technological parameter of control aluminium physical vapor deposition (PVD), oxidation and wet etching course subsequently.The porous structure of self assembly is formed naturally a hexagonal array.Aperture (d) and interpore distance (D) depend on the character of the oxidation voltage (V), current density (i) and the electrolytic solution that are applied, and wet etching reaming process afterwards.

Referring to Figure 14 A, precious metal for example Ag is deposited on the porous layer 315 with filling pore 312 and layer 320 of formation.Layer 320 can form with PVD or plating mode.In Figure 14 B, one deck precious metal 320 is removed, and has kept the precious metal 320-N in the hole 312.Carry out wet method metal erosion or CMP once more and be filled in the height of the precious metal 320-N in the hole with further control.In Figure 15, the aluminium film 315-AL of aluminium oxide 315 and porous aluminium lamination 315 bottom remnants is removed, and forms a nanostructured surface 300, and it contains a nano-pillar 320-N array.

Nano-pillar 320-N is straight basically, perpendicular to substrate 305 and conductive layer 310.Nano-pillar 320-N can have substantially the same or close width.Adjacent nano-pillar 320-N is separated by the gap, and the distance of these gaps and conductive layer 310 remains unchanged basically.

The geometric configuration of the photoetching cover that uses in the above-mentioned manufacturing process and the dimensional requirement of sensing chip and the zone of metal gasket are complementary, and metal gasket is positioned on the corner of chip.For field studies, chemicals detects sensing chip and adopts different semiconductor packagings to encapsulate, for example, and lead-in wire bonding, upside-down method of hull-section construction, system level chip (SOC), or the like, these will further describe in another patented claim.

In certain embodiments, nanostructured can be made by different technology, shown in Figure 16 A-16F.Pair of lamina structure 362 comprises a conductive layer 335 and a substrate 330.Conductive layer 335 can be made by titanium (Ti) or nickel (Ni), can be not only to have conducted electricity but also heat conduction.Substrate 330 can be a n type silicon chip (3-8 Ω-cm) or (30-50nm SiO2) p type silicon chip of oxidation (5-10m Ω-cm).The controllable thickness of conductive metal layer 335 is in scope.Adhesion layer (for example being made by Ag) can be to be deposited on the metal level 335.The thickness of conductive layer 335 can be optimized, and applies electrical bias thereby the trace chemistry material is detected sensitive surface, further, reduces the temperature of sensitive surface for the susceptibility that strengthens the detection of trace chemistry material.

In Figure 16 B, noble metal layers 340 is deposited on the top of conductive layer 335.Precious metal can be a silver layer, and for example thickness is the Ag of 10-200nm.In Figure 16 C, second metal level 345 is deposited on the top of noble metal layers 340.Second metal 345 can comprise that purity is 99.999% aluminium, and thickness is in the 1.0-10.0 mu m range.Aluminium lamination 345 is filling N subsequently ₂Annealed 2-5 hour for 400 ℃-500 ℃ in the reacting furnace, make aluminium film recrystallization.

In Figure 16 D, make the porous structure of Woelm Alumina 345 ' form by oxidation technology.Figure 16 E is its top view, and this porous structure is formed naturally the hexagon nanoaperture array of self assembly, and it comprises many holes 348 that centered on by hexagon hole wall 349.The centre distance of adjacent pores 348 is D.Remove the anodic oxide coating and restraining barrier at top by a wet chemical process after, carry out for the second time that oxidation technology consumes all metallic aluminiums, so that the porous Al at restraining barrier and top ₂O ₃Layer 345 ' is positioned on the noble metal layers 340 just.Carry out wet etching then and widen hole 348, and remove the restraining barrier of hole 348 bottoms.When carrying out wet etching, shown in Figure 16 F, hole 348 is widened, around inwall 349 attenuation of hole.Can control etching process to form a large amount of nano-pores 348 that is centered on by inwall 349.Can also corrode between hole 348 and contact each other, produce the hexagonal array of an accurate triangle nano-pillar 349 '.

In Figure 16 G, noble metal layers 340 is corroded, and hole 348 extends downwardly into the titanium layer 335 of conduction.In Figure 16 H, carry out wet oxidation erosion removal aluminium oxide, remove the aluminium that remains in hole 348 bottoms succeeded by the wet method metal erosion.The aluminium film 315 of aluminium oxide 315 and porous aluminium lamination 315 bottom remnants is removed, and forms a nano column array with controllable height, diameter and clear and definite intercolumnar distance.This array can have accurate leg-of-mutton periodic hole.

Nano-pillar is straight basically, perpendicular to substrate 330 and conductive layer 335.Nano-pillar 320-N can have substantially the same or close width.Adjacent nano-pillar is separated by the gap, and the distance of these gaps and conductive layer 335 remains unchanged basically.

In certain embodiments, the nanoscale surface structure is produced on the surface that can be coated on detector 105 by the colloidal suspension solution that will contain nano particle.Described nano particle can be made by metal material (for example Au, Ag etc.), oxide material (for example titania, silicon dioxide, zinc paste etc.) or polymeric material.Oxide or polymer beads can cover with the metallic ion coating or with conductive material.Colloidal suspension solution can comprise single nano particle or nano particle group.This solution forms the nanoscale surface structure after being applied in detector surface.This solution is volatilizable, stays nano particle target molecule is adsorbed onto detector surface.

In certain embodiments, use aforesaid light scattering probe 100 to obtain the Raman spectrum of patient's body fluid, can detect chemical substance with disease association by analyzing this Raman spectrum, to be used for further identifying disease.Referring to Figure 17, shown the spectrum peak of two features from a Raman spectrum that obtains from carcinoma of mouth patient's saliva sample, respectively at 560cm ^-1(at 540cm ^-1-570cm ^-1In the zone) and 1100cm ^-1(at 1085cm ^-1-1105cm ^-1In the zone) near, and the healthy individual of not suffering from carcinoma of mouth does not have this two spectrum peaks.560cm ^-1And 1100cm ^-1Characteristic spectrum peak and C-S, S-S and the O-P-O (PO at place ₂) molecular vibration that causes of key is relevant, for example contains the biological sample of halfcystine, ATP, ADP and other phosphates.The identification of spectral signal can comprise the following steps: to be cm in the Raman frequency shift unit with each spectral signal at first ^-1Select a spectrum peak in the Raman peaks of (wave number); Determine background scattering intensity; Calculate intensity, relative intensity or the integral area at peak.Calculate signal to noise ratio (S/N ratio) with peak intensity and background.If signal to noise ratio (S/N ratio) is higher than a predetermined threshold (for example 3 or higher), the spectral signal of Raman peaks just is identified.The identification of the spectral signal that the chemical substance that detection is relevant with disease and medicine is used can be adopted statistical study and several algorithm (for example Dendrograph and principal component analysis (PCA)).If 560cm ^-1And 1100cm ^-1Near two spectral signals are all identified, can regard as so to detect and the Cancer-Related chemical substance in oral cavity, and patient may suffer from carcinoma of mouth or carcinoma of mouth is early stage.Doctor and patient should further detect, and whether suffer from carcinoma of mouth or carcinoma of mouth is early stage with diagnosis.

System and method disclosed by the invention can also be used to measuring glucose level, to be used to assess diabetic conditions.1115cm ^-1To 1135cm ^-1Characteristic spectrum peak in the zone, for example 1124cm ^-1, relevant with the molecular vibration of glucose, from the Raman spectrum that the saliva sample of diabetic obtains, can measure glucose level, with key foundation as diagnosing diabetes.The intensity of this Raman peaks, relative intensity or integral area can be used for the concentration of glucose of evaluating patient body fluid, thereby determine the diabetes rank.Similarly, referring to Figure 18-20, the chemical substance relevant with breast cancer also can be at about 560cm of the Raman spectrum of saliva ^-1And 1100cm ^-1The place demonstrates spectral signal (Figure 18).The chemical substance relevant with lung cancer and oophoroma may be at about 745cm of the Raman spectrum of blood serum sample ^-1The place has a spectral signal (Figure 19 B and Figure 20).745cm ^-1The characteristic spectrum peak at place is relevant with the molecular vibration that the C-S key in the phosphate causes.The chemical substance relevant with acquired immune deficiency syndrome (AIDS) may be at the 865cm of the Raman spectrum of blood serum sample ^-1-885cm ^-1In the zone, 870cm for example ^-1The place has a spectral signal (Figure 21).System and method disclosed by the invention can also be used to carrying out the detection of forbidden drug, for example heroin, dexoxyn, cocaine, caffeine, morphine, codeine, amphetamine, ephedrine, papaverine, narcotine, MDMA or the like.Figure 22 shows is from a dexoxyn solid (a kind of forbidden drug), a Raman spectrum of the saliva sample of medication individuality and a dexoxyn user's saliva sample not.From the Raman spectrum of drug use person's saliva sample at about 1030cm ^-1And 1535cm ^-1Locate have a characteristic peak, this characteristic peak to show and used forbidden drug.Method and system disclosed by the invention can also be used for detecting the excitant (for example hormone) in sportsman's body in international athletic competition (such as the Olympic Games).

Similarly, referring to Figure 23, the chemical substance relevant with the state of smoking state and passive smoking also shows spectral signal, at about 1029cm of smoker's saliva sample Raman spectrum ^-1The spectral signal that the place demonstrates is not present in the healthy individual of non-smoking.About 1029cm ^-1The characteristic spectrum peak at place is relevant with the molecular vibration pattern of N-first-2-5-pyrrolidone (cotinine), and N-first-2-5-pyrrolidone is the metabolic product of nicotine.

One or more during the detection that utilizes Raman disclosed by the invention probe to carry out the chemical substance of non-invasive and disease association can comprise the following steps:, at first obtain body fluid (step 2010) from a patient or forbidden drug user referring to Figure 24.Because Raman scattering detector disclosed by the invention has high sensitivity, the amount of body fluid can be quite little.For example, the body fluid volume that obtains from patient can be from about 100pl to 1ml.The example of body fluid can comprise blood, saliva, urine, serum, tear, sweat and gastric juice.After centrifugal, body fluid changes a detector that includes a nanoscale surface structure (RamanNanoChip for example over to ^TM) (step 2020).Molecule in the body fluid is adsorbed on the nanoscale surface structure.With laser beam irradiation body fluid, nanoscale surface structure be adsorbed to molecule (step 2030) on the nanoscale surface structure.Collection is through body fluid, nanoscale surface structure and be adsorbed the scattered light (step 2040) of molecule.

Obtain Raman spectrum (step 2050) from scattered light.One or more spectral signals in the spectrum are used to discern the chemical substance with disease association, further to determine disease (step 2060).Can by the inventive method detect with its relevant chemical substance disease comprise lung cancer, breast cancer, cancer of the stomach, cancer of the esophagus, thyroid cancer, laryngocarcinoma, cirrhosis, renal failure, ulcerocancer, oophoroma, the cancer of the uterus, cervical carcinoma, carcinoma of mouth, colon cancer, carcinoma of urinary bladder, prostate cancer, bronchiolar carcinoma, acquired immune deficiency syndrome (AIDS) and dopy.As mentioned above, one or more spectral signals are at the predetermined wavelength place of Raman spectrum.With the wavelength and the feature of the spectral signal of the chemical substance of disease association to be measured be special for disease to be measured.For example, the spectral signal of the chemical substance in carcinoma of mouth and the breast cancer saliva sample may be at about 560cm ^-1Or 1100cm ^-1The place.The spectral signal of the chemical substance in the lung cancer blood serum sample is greatly about the 745cm of Raman spectrum ^-1The place.One spectral signal can comprise a spectrum peak.When spectrum peak during greater than certain predetermined threshold, spectral signal is identified.For example, with respect to noise background, when the signal to noise ratio (S/N ratio) of spectrum peak about just identified 3 the time.

In certain embodiments, light scattering probe disclosed by the invention and chemical detection method can be applicable to the food security field, comprise that the illegal adjuvant in the examination food is verified effective constituent.Described food is dairy products for example, can comprise milk, milk powder (as babies ' formula milk powder), cheese, cheese cake, sour milk, ice cream, toffee, contain milk deli and contain protein food.Nearest serious together food security incident is about the illegal melamine that adds in dairy products (for example babies ' formula milk powder, ice cream and biscuit etc.).Method and system disclosed by the invention can be used for detecting the wine product for example existence and the content thereof of grape wine methyl alcohol equally, and nitrite, honey element (sodium cyclohexylsulfamate) and other food additives in the food, beverage, wine product (as claret and grape wine).

As mentioned above, referring to Fig. 1,8 and 9, the milk sample solution is the milk liquid that has added the melamine of 1ppm, 2ppm, 5ppm and 50ppm respectively.These milk sample solutions are added to respectively on the detector (105 among Fig. 1), use above-mentioned light scattering probe method to obtain Raman spectrum.The volume of food samples solution is generally 100pl-1ml.

Illegal and the harmful chemical (melamine) of variable concentrations can detect the correlation spectrum signal at Raman spectrum in the dairy products.Figure 25 A shows is to have added the Raman spectrum of milk sample solution that concentration is the melamine of 0ppm (not containing melamine), 1ppm, 2ppm and 5ppm respectively.Raman spectrum shown in Figure 25 A and the 25B has Raman peaks near 700cm-1, lay respectively at about 678cm ^-1(peak A), 698cm ^-1(peak B) and 712cm ^-1(peak C) locates.In addition, as can be seen, 678cm in these three Raman peaks ^-1The concentration that the relative intensity of peak A near increases the expression melamine increases.By contrast, 712cm ^-1Near peak C relative intensity reduces to represent that melamine concentration increases.By melamine concentration relatively is that the Raman spectrum of 5ppm (Figure 25 A) and 50ppm (Figure 25 B) can clearly be seen this two trend.

In another example, acetonitrile solvent is added to the interior mark reference of measuring as Raman scattering in the sample milk solution.Discover, do with acetonitrile that solvent does not influence or the faint Raman scattering intensity that influences test solution.Referring to Figure 26, use said system and method to obtain Raman spectrum as the milk solution of 5ppm from a melamine concentration of having added acetonitrile, spectral signal is positioned at 700cm ^-1Neighbouring (peak A, B and C).

In another example, Raman spectrum detects the spectral signal (Figure 27) that in aqueous solution concentration is respectively the illegal and harmful chemical (melamine) of 1ppb and 100ppb.

In certain embodiments, referring to Figure 1B, Figure 16 F, 16E and 16H, go up coating one metallic film in the nano-pillar 108 (or hole) of the Nanosurface of detector 105.This metallic film is electrically connected with electrode.This metallic film can form by a precious metal is for example golden.Detector is immersed in the sample solution, and sample solution just is applied on the detector surface like this.On electrode and metallic film, apply electrical bias.Electrical bias can be controlled in-3.0～+ scope of 3.0V in, this can strengthen the absorption of Nanosurface to sample molecule (for example melamine molecule), strengthen local electro permanent magnetic, reach the electric charge transfer that strengthens between sample molecule and the Nanosurface structure, thereby make the Raman scattering strength-enhanced of the sample molecule that is adsorbed onto Nanosurface.The laser beam of incident projects on the detector, detects scattered light when sample solution is applied electrical bias.Can carry out Raman light scattering after cancelling electrical bias measures.

In certain embodiments, use ion exchange column and from sample, separate chaff interference.Sample flow is through pillar, and chaff interference is trapped and analyte stream comes out.Such pillar, for example the C18 post can be used for equally according to the similar compound of (retention time) separation chemistry performance of the different residence time.Final purification of samples can be so that detection limit increases 2-6 the order of magnitude.

In certain embodiments, the detection of chemical substance or medical diagnosis on disease can use an integrating device to carry out in the food, and Chemical Decomposition and light scattering that this device can carry out trace chemistry material, biomaterial etc. detect.The details of this integrating device discloses in common 11/761, No. 453 patented claim of U.S. US of transferring the possession of, and this application is called " integrated chemical separated light scattering device ", and the applying date is on June 12nd, 2007, incorporates its disclosure by reference at this.

In certain embodiments, the detection method of disclosed light scattering probe and chemistry not only can be used for detecting the illegal or objectionable constituent in the food, can also be used to detect effective or neutral composition.As shown in figure 28, be starch, sucrose, milk powder A (the first milk powder brand) from top to bottom, added the milk powder B (the second milk powder brand) of sucrose, the Raman spectrum of milk powder C (the 3rd milk powder brand).Should not contain starch and sucrose in the normal milk powder.Because starch and sucrose white powder, be not easy to detect with common test method if they are mixed in the milk powder.This Raman spectrum is at about 473cm ^-1There is a very strong peak (Figure 28 topmost) at the place, proves and contains starch in the milk powder.This feature Raman peaks can be used for detecting the starch that whether mixed in the milk powder.This detection method is applicable to and detects mixing up of unauthorized starch-containing material that described starch-containing material is flour, ground rice, soy meal, dehydrated potato powder, sweet potato flour or the like for example.

The disclosure system and method can also be used to the existence of sucrose in the examination milk powder.From the top down second Raman spectrum demonstrates several strong Raman peaks (greatly about 850cm among Figure 28 ^-1, 940cm ^-1, 1020cm ^-1, 1130cm ^-1At the place).The set feature of these Raman peaks clearly (is mixed with sucrose since relate on the packaging label of milk powder B in the spectrum of the milk powder B that is mixed with sucrose (among Figure 28 the 4th from the top down), it is legal that Here it is), but be not present in the spectrum (among Figure 28 the 3rd from the top down) of the milk powder A that does not add sucrose.On the other hand, clearly, because its packaging label does not relate to sucrose, this milk powder is illegal to the set feature of the Raman peaks that sucrose is relevant in the spectrum (Figure 28 bottom) of milk powder C.Note that Raman test shows the starch that both mixed among the milk powder C sucrose that also mixed, and in its packing, do not indicate.

In addition, the disclosure method and system can be applied to measure for example protein content in the dairy products of food.The high concentration of protein can reflect that its Raman peaks is at 1658cm by higher acid amides I concentration in the food ^-1Near.With respect to other spectral signature, 1658cm ^-1The intensity at place can be used for for example qualitative assessment of protein level in the milk powder of food.For example, three different powdered milk samples among Figure 28 (among Figure 28 lower three spectrum) have similar protein content level.Be positioned at 1658cm in the milk powder A spectrum ^-1More significant peak show that the protein content of milk powder A is higher slightly than milk powder B and milk powder C.

Therefore, the disclosure method and system is to detect protein content in the milk powder, and whether has the effective ways of sucrose, starch and illegal adjuvant (for example melamine).In addition, the disclosure system is simply compact, is easy to carry.Because of its fast turn-around cycle (5-10 minute, even shorter time), material detects and can be easy to carry out at the scene, thereby can be to containing dairy products in very wide environmental field, and for example fresh milk and milk powder are identified timely and effectively with quality and examined.

The harmful chemical that uses the disclosure Raman probe to detect in the food can comprise following one or more step: referring to Figure 29, at first determine to appear at the spectral signal (step 2200) harmful or unauthorized, effective composition or protein (acid amides I) in the food.As mentioned above, this can measure and realize by carrying out Raman scattering on the Nanosurface structure that a reference solution harmful or effective constituent is applied to a light scattering detector.Wavelength and spectral characteristic (peak height, peak width etc.) can be saved in the database of spectroanalysis instrument (150 among Fig. 6).For the peak height of this spectral signal is determined a threshold value, this threshold value corresponds to a certain predetermined concentration of this chemical substance in the reference solution.In certain embodiments, calculate the signal to noise ratio (S/N ratio) of this spectrum peak.If this signal to noise ratio (S/N ratio) exceeds certain threshold value (for example 3), confirm to identify this chemical substance.

In certain embodiments, the detector that is used for determining spectral signal contains and is used to detect or the quantitative essentially identical nanostructured of detector of food chemical substance.In other words, for the detector that is used for determining the detector of spectral signal and is used to carry out the food field test, the size and dimension of their nano-pillar or nanoaperture, the spacing of nano-pillar and nanoaperture, and the material of nano-pillar and nanoaperture composition is essentially identical.For example, identical detector model can be used for two purposes.This method can guarantee the optimum matching of spectral characteristic between measure spectrum and the spectral signal.This method can also make those come from the noise minimization of the difference of different detectors on structure and material is formed.

In certain embodiments, be used for determining that the Nanosurface structure of compound raman spectral signal can prepare by a test solution that comprises target compound and nano granule suspension.Initial detector surface can be a relatively flat.Test solution is applied to detector surface.After the evaporation, one deck is adsorbed with the nanoparticle deposition of target compound molecule to detector surface, is used to determine the Raman scattering measurement of Raman signal.Except target compound was substituted by a food samples solution or patient's body fluid, identical program was followed in the detection of material in food composition or the patient's body fluid.In order to improve assay sensitivity and to reduce noise, the identical nano particle and identical solvent of preferred use in Raman signal test and open-air material detect.In other words, Size Distribution and the material that is used for the nano particle of definite raman spectral signal and field survey formed basic identical.

At first obtain food samples (step 2210 Figure 29) from a food.In view of the high sensitivity of disclosed Raman scattering detector, the amount of food samples solution can be quite little.For example, the amount of food samples solution can be in the scope of 100pl-1ml.The example of food samples comprises dairy products, candy, beverage, wine, meat, aquatic products (for example fish, shrimp etc.), tealeaves, fresh or canning vegetables, fruit, grain, cereal, cornflakes or potato block, or the like.Food samples is produced or is dissolved in the solution, changes a detector (step 2220) that comprises the nanoscale surface structure then over to.Molecule in the food samples solution is adsorbed to the nanoscale surface structure.With laser beam irradiation food samples solution, nanoscale surface structure be adsorbed to molecule (step 2230) on the nanoscale surface structure.Collection is through the light (step 2240) of food samples solution, nanoscale surface structure and the molecular scattering that is adsorbed.This test can also be adopted the bulk testing sample of the test reagent that contains the precious metal that mean grain size is 2-100nm (for example silver-colored Ag, golden Au etc.) nano particle.So, gather through biased sample solution, have or do not have the nanoscale surface structure and the light (step 2240) of the molecular scattering that is adsorbed.

Obtain Raman spectrum (step 2250) from scattered light.One or more spectral signals in the identification spectrum to measure harmful or illegal adjuvant and composition, are perhaps verified the existence and the concentration (step 2260) of effective constituent.Harmful or the illegal adjuvant or the example of composition comprise the compound in the common fertilizer, herbicide, pesticide, insecticide, microbiotic, hormone and antiseptic, melamine for example, honey element (sodium cyclohexylsulfamate), sucrose, starch, nitrite, nitrate, Sudan red 1, II, III and IV, malachite green, acephatemet, orthene, DDT, DDV, the malathion, fenifrothion, decis, cypermethrin, parathion-methyl, phosmet, nitrofuran (for example furazolidone), Rogor, duomycin, Ciprofloxacin, clenbuterol hydrochloride, the ethyl Ciprofloxacin, or the like.The wavelength of correlation spectrum signal and feature are special for each detected compound and amount thereof in the Raman spectrum, as above to the description of Figure 25 A-28.One spectral signal can comprise a spectrum peak.When this spectrum peak exceeded certain threshold value, this spectral signal was identified, and described threshold value can pre-determine by the reference solution that analysis contains this compound, as mentioned above.For example, this spectrum peak with respect to the signal to noise ratio (S/N ratio) of noise background greater than determining to identify this spectral signal at 3 o'clock.

Although invention has been described by preferred embodiment, should be understood that so openly can not explain the restriction of the present invention of opposing.To those skilled in the art, above-mentionedly openly make various conversion and to revise all be conspicuous.Therefore, in connotation of the present invention and scope, appended claims should be interpreted as having contained all conversion and modification.For example, the Nanosurface structure that is applicable to the open system and method for the present invention should not be limited to above-mentioned example.Described Nanosurface structure can comprise nano-pillar, nanometer hole (or hole) and other Nanosurface structures and be deposited on nano particle on the detector surface.

Claims (49)

1. method that detects particular chemicals in the measurand, its step comprises:

1) will contain one first detector of one first nanoscale surface structure from the sample delivery to of measurand, described sample is contacted with the first nanoscale surface structure;

2) with the described sample of a laser beam irradiation and the first nanoscale surface structure;

3) described sample and the described laser beam of the first nanoscale surface structure scattering, generation-scattered light;

4) first spectrum of the described scattered light of acquisition;

5) use a spectroanalysis instrument to analyze described first spectrum, to detect in the measurand whether contain particular chemicals.

2. the method for claim 1 is characterized in that, described measurand is a human body, and described sample is the body fluid of this human body.

3. method as claimed in claim 2 is characterized in that described body fluid comprises blood, saliva, urine, serum, tear, sweat, gastric juice, seminal fluid and juice.

4. method as claimed in claim 2, it is characterized in that, described particular chemicals for include but not limited to lung cancer, breast cancer, cancer of the stomach, cirrhosis, renal failure, ulcerocancer, oophoroma, the cancer of the uterus, cervical carcinoma, carcinoma of mouth, cancer of the esophagus, thyroid cancer, laryngocarcinoma, leukaemia, colon cancer, carcinoma of urinary bladder, prostate cancer, bronchiolar carcinoma, acquired immune deficiency syndrome (AIDS), the chemical substance that diabetes are relevant; Or with use forbidden drug or the relevant chemical substance of smoking.

5. method as claimed in claim 4, it is characterized in that, described forbidden drug is an anaesthetic, includes but not limited to heroin, dexoxyn, cocaine, caffeine, morphine, codeine, amphetamine, ephedrine, papaverine, narcotine and MDMA.

6. method as claimed in claim 2 is characterized in that, the volume of described body fluid is 100pl-1ml.

7. the method for claim 1 is characterized in that, the described first nanoscale surface structure comprises a conductive material.

8. method as claimed in claim 7 is characterized in that described conductive material comprises a precious metal.

9. method as claimed in claim 7, it is characterized in that, in described step 2) in to the conductive material making alive in the described nanoscale surface structure, shift with the electric charge between the molecule that strengthens the conductive materials in described conductive material and the described nanoscale surface structure.

10. the method for claim 1 is characterized in that, described first detector further comprises a substrate, and wherein said nanoscale surface structure comprises a plurality of holes in described suprabasil a plurality of cylinders or the described substrate.

11. method as claimed in claim 10 is characterized in that, described first detector further comprises one and is positioned at described suprabasil conductive layer, and wherein said a plurality of cylinders are formed on the described conductive layer.

12. method as claimed in claim 10 is characterized in that, described first detector further comprises one and is positioned at described suprabasil conductive layer, and wherein said a plurality of holes to small part is formed in the described conductive layer.

13. method as claimed in claim 10 is characterized in that, the distance between adjacent described cylinder or the adjacent described hole is 10nm-1000nm.

14. the method for claim 1, it is characterized in that, by the molecule in the described sample of surface adsorption of the described first nanoscale surface structure, wherein by being attracted to the described laser beam of lip-deep molecular scattering of the described first nanoscale surface structure.

15., it is characterized in that described first spectrum is first Raman spectrum as the described method of arbitrary claim among claim 1 and the 7-14; Described spectroanalysis instrument is the Raman spectrum analysis instrument; Analyze near the spectral signal the predetermined wavelength in described first Raman spectrum.

16. method as claimed in claim 15 is characterized in that, described step 5) is discerned near at least one spectrum peak the predetermined wavelength in described first Raman spectrum by described Raman spectrum analysis instrument.

17. method as claimed in claim 16 is characterized in that, whether the signal to noise ratio (S/N ratio) of determining described spectrum peak is greater than a predetermined threshold; If greater than predetermined threshold, then provide caution signal.

18. method as claimed in claim 17 is characterized in that, the predetermined threshold of described signal to noise ratio (S/N ratio) is more than or equal to 3.

19. method as claimed in claim 15 is characterized in that, described measurand is a human body, and described sample is the saliva of this human body, analyzes 560cm in described first Raman spectrum ^-1Or 1100cm ^-1Near spectral signal is to detect and the Cancer-Related chemical substance in oral cavity.

20. method as claimed in claim 15 is characterized in that, described measurand is a human body, and described sample is the saliva of this human body, analyzes 560cm in described first Raman spectrum ^-1Or 1100cm ^-1Near spectral signal is to detect the chemical substance relevant with breast cancer.

21. method as claimed in claim 15 is characterized in that, described measurand is a human body, and described sample is the serum of this human body, analyzes 745cm in described first Raman spectrum ^-1Near spectral signal is to detect the chemical substance relevant with lung cancer.

22. method as claimed in claim 15 is characterized in that, described measurand is a human body, and described sample is the saliva of this human body, analyzes 870cm in described first Raman spectrum ^-1Near spectral signal is to detect the chemical substance relevant with acquired immune deficiency syndrome (AIDS).

23. method as claimed in claim 15 is characterized in that, described measurand is a human body, and described sample is the saliva of this human body, analyzes 1030cm in described first Raman spectrum at least ^-1And 1535cm ^-1In a wave number near spectral signal, to detect and the relevant chemical substance of use forbidden drug.

24. method as claimed in claim 15 is characterized in that, described measurand is a human body, and described sample is the saliva of this human body, analyzes 1029cm in described first Raman spectrum ^-1Near spectral signal is to detect the chemical substance relevant with smoking.

25. method as claimed in claim 15 is characterized in that, described measurand is a human body, and described sample is the saliva of this human body, analyzes 1124cm in described first Raman spectrum ^-1Near spectral signal is to detect the chemical substance relevant with diabetes.

26. method as claimed in claim 15 is characterized in that, uses described first Raman spectrum of a kind of Algorithm Analysis, described algorithm comprises Dendrographic algorithm or principal component analysis (PCA) algorithm.

27. method as claimed in claim 15 is characterized in that, described measurand is a food; Described sample is a food samples solution; Determine the spectral signal of a chemical substance in Raman spectrum; Detect and whether have described chemical substance in the described food.

28. method as claimed in claim 27 is characterized in that, introduces nano particle on a surface of described first detector, the wherein said first nanoscale surface structure comprises the described nano particle on described first detector surface.

29. method as claimed in claim 28 is characterized in that, the described nano particle that suspends in the described sample solution is added to described sample solution on the surface of described first detector.

30. method as claimed in claim 27 is characterized in that, a reference sample solution that contains described chemical substance is contacted with the second nanoscale surface structure of one second detector; Obtain second Raman spectrum by described reference solution and the described second nanoscale surface structure, determine the spectral signal of chemical substance described in the Raman spectrum.

31. method as claimed in claim 30 is characterized in that, described first detector and second detector have substantially the same nanoscale surface structure.

32. method as claimed in claim 27 is characterized in that, is present in the described food if detect described chemical substance, then uses spectral signal to measure the concentration of described chemical substance.

33. method as claimed in claim 27, it is characterized in that described food includes but not limited to dairy products, candy, beverage, wine, meat, seafood, tealeaves, vegetables fresh or canning, fruit, grain, cereal, cornflakes, potato block or protein-contg food.

34. method as claimed in claim 33 is characterized in that, described dairy products include but not limited to milk, milk powder, cheese, cheese cake, sour milk, ice cream or toffee.

35. method as claimed in claim 27, it is characterized in that described chemical substance includes but not limited to melamine, honey element, sodium cyclohexylsulfamate, sucrose, starch, nitrite, nitrate, Sudan red 1, II, III and IV, peacock green, acephatemet, orthene, DDT, DDV, malathion, fenifrothion, decis, cypermethrin, parathion-methyl, phosmet, Rogor, nitrofuran, furazolidone, chloromycetin, duomycin, Ciprofloxacin, clenbuterol hydrochloride or ethyl Ciprofloxacin.

36. method as claimed in claim 27 is characterized in that, described food is dairy products, and described chemical substance comprises melamine, analyzes 678cm in described first raman spectral signal ^-1, 698cm ^-1Or 712cm ^-1Near, perhaps 1648cm ^-1Near spectral signal.

37. method as claimed in claim 27 is characterized in that, described chemical substance is a protein, analyzes 1658cm in described first raman spectral signal ^-1Near spectral signal.

38. method as claimed in claim 27 is characterized in that, described chemical substance is a starch, analyzes 473cm in described first raman spectral signal ^-1Near spectral signal.

39. method as claimed in claim 27 is characterized in that, this method further comprises:

First group of nano particle is incorporated on the surface of described first detector, the wherein said first nanoscale surface structure comprises the described first group of nano particle on described first detector surface;

Second group of nano particle is incorporated on the surface of described second detector, the wherein said second nanoscale surface structure comprises the described second group of nano particle on described second detector surface.

40. method as claimed in claim 39 is characterized in that, described first group of nano particle and second group of nano particle have substantially the same size distribution and material.

41. method as claimed in claim 39 is characterized in that, described first group of nano particle suspends in described food samples solution.

42. system that detects particular chemicals in the measurand, comprise a laser instrument, at least one light scattering probe, one spectrometer and a spectroanalysis instrument, described light scattering probe comprises a probe and a detector, described probe links to each other with spectrometer with laser instrument respectively by optical fiber, and described detector has the nanoscale surface structure.

43. system as claimed in claim 42 is characterized in that, described spectrometer and spectroanalysis instrument are respectively Raman spectrometer and Raman spectrum analysis instrument.

44., it is characterized in that described nanoscale surface structure comprises a conductive material as claim 42 or 43 described systems, described conductive material comprises a precious metal.

45. as claim 42 or 43 described systems, it is characterized in that described detector further comprises a substrate, wherein the nanoscale surface structure comprises a plurality of holes in suprabasil a plurality of cylinder or the substrate.

46. system as claimed in claim 45 is characterized in that, the distance between adjacent described cylinder or the adjacent described hole is 10nm-1000nm.

47. system as claimed in claim 45 is characterized in that, described detector comprises that further one is positioned at described suprabasil conductive layer, and wherein said a plurality of cylinders are formed on the described conductive layer.

48. system as claimed in claim 45 is characterized in that, described detector comprises that further one is positioned at described suprabasil conductive layer, and wherein said a plurality of holes to small part is formed in the described conductive layer.

49. system as claimed in claim 42 is characterized in that, described probe comprises and is positioned at bandpass filter, the lens combination on the described laser instrument input light path and is positioned at reflector group, bandpass filter, lens on the described detector scattering output light path.

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