技术领域technical field
本发明属于生物技术领域，具体涉及一种采用表面增强显微拉曼光谱检测咽拭标本生化成分的方法。The invention belongs to the field of biotechnology, and in particular relates to a method for detecting biochemical components of throat swab specimens by using surface-enhanced micro-Raman spectroscopy.
背景技术Background technique
咽拭子标本就是用医用的棉签，从人体的咽部蘸取少量分泌物，采取的样本就是咽拭子标本，为了检验呼吸道疾病病毒类型，往往通过咽拭子可以方便快捷准确地检测出该病毒类型。目前针对咽拭子标本的检测方法主要有PCR方法、快速抗原方法等，而这些方法虽然各有优点，但操作方法复杂，耗时长、检测灵敏度不高。Pharyngeal swab specimen is to use a medical cotton swab to dip a small amount of secretions from the pharynx of the human body. The sample taken is a throat swab specimen. virus type. At present, the detection methods for throat swab specimens mainly include PCR method, rapid antigen method, etc. Although these methods have their own advantages, the operation method is complicated, time-consuming, and the detection sensitivity is not high.
拉曼光谱是一种无损的光学检测技术，可以获得丰富的分子结构、振动模式、官能团等指纹信息，对蛋白质、核酸、磷脂和糖分的生化成分变化非常敏感。拉曼光谱具有操作过程简单快捷，灵敏度高，水分子干扰小等优点，是广泛应用于分子结构研究的一种分析方法。但由于拉曼光谱信号非常弱，因此拉曼光谱技术在生化领域的应用受到一定的约束。Raman spectroscopy is a non-destructive optical detection technology that can obtain rich fingerprint information such as molecular structure, vibration mode, and functional group, and is very sensitive to changes in the biochemical composition of proteins, nucleic acids, phospholipids, and sugars. Raman spectroscopy has the advantages of simple and quick operation, high sensitivity, and little interference from water molecules. It is an analytical method widely used in molecular structure research. However, due to the very weak Raman spectroscopy signal, the application of Raman spectroscopy in the field of biochemistry is subject to certain constraints.
表面增强拉曼散射是指在金属胶粒和粗糙金属(如银、金、铜等)表面作用下,试样的拉曼散射强度会增加104～106倍。刘鹏等采用表面增强拉曼光谱技术以对样本检测快速、灵敏、无破坏性等众多优点，在分析生化样本成分方面有着非常重要而广泛的应用。秦维等采用机械粗糙、电化学氧化还原、化学刻蚀等方法对纯钛电极表面进行粗糙，在钛基底上获得了表面增强拉曼光谱信号。陈伟炜等测试分析了白术煎剂及其在银胶中的拉曼光谱，并对其进行初步谱峰归属。表面增强拉曼光谱具有独特的超高灵敏度和分辨率的优越性，对生化成分的分析研究中占据很大的优势。咽拭子仅需要少量的生化物质，对生化物质无损采集，制备成咽拭涂片标本，并结合显微技术和表面增强拉曼光谱，从而实现了对标本的无损显微的生化成分分析。Surface-enhanced Raman scattering means that the Raman scattering intensity of the sample will increase by 104 to 106 times under the action of metal colloidal particles and rough metal (such as silver, gold, copper, etc.) surface. Liu Peng et al. used surface-enhanced Raman spectroscopy to detect samples quickly, sensitively, and non-destructively. It has a very important and extensive application in the analysis of biochemical sample components. Qin Wei et al. used mechanical roughening, electrochemical redox, chemical etching and other methods to roughen the surface of pure titanium electrodes, and obtained surface-enhanced Raman spectrum signals on titanium substrates. Chen Weiwei and others tested and analyzed the Raman spectrum of Baizhu decoction and its silver colloid, and carried out preliminary peak assignments. Surface-enhanced Raman spectroscopy has the unique advantages of ultra-high sensitivity and resolution, and has a great advantage in the analysis and research of biochemical components. Pharyngeal swabs only need a small amount of biochemical substances, which are non-destructively collected and prepared into throat swab smear specimens, combined with microscopic technology and surface-enhanced Raman spectroscopy, thus realizing non-destructive microscopic biochemical composition analysis of specimens.
发明内容Contents of the invention
本发明提供了一种采用表面增强显微拉曼光谱检测咽拭标本生化成分的方法，该方法包括表面增强试剂的制备、咽拭标本样品的处理、样品表面增强拉曼光谱的测量，拉曼光谱数据的处理与分析。本方法利用采集的咽拭标本均匀地拖涂在表面平整并洁净无污染的纯铝片上，并滴上制备好的表面增强试剂，在室温下自然晾干，制成咽拭-表面增强拉曼测试片，利用显微拉曼光谱仪的激发光照射咽拭-表面增强拉曼测试片上的咽拭标本，检测在400-1800cm-1范围的拉曼信号，建立咽拭标本表面增强显微拉曼光谱数据库，经过扣荧光，归一化，取平均值进行处理和分析，获得咽拭标本表面增强拉曼光谱的特征，进行不同咽拭标本的生化成分分析。本发明具有检测时间短，成本低，过程方便快捷等优点，能够获得咽拭样品丰富的生化成分信息，从而为腔内粘膜组织的生化特征和变化提供快速、有效的分析方法。The invention provides a method for detecting biochemical components of a throat swab specimen by using surface-enhanced micro-Raman spectroscopy. Spectral data processing and analysis. In this method, the collected throat swab specimens are evenly dragged and coated on a flat, clean and non-polluting pure aluminum sheet, and the prepared surface enhancement reagent is dropped on it, and dried naturally at room temperature to form a throat swab-surface-enhanced Raman The test piece, using the excitation light of the micro-Raman spectrometer to irradiate the throat swab-the throat swab specimen on the surface-enhanced Raman test piece, detect the Raman signal in the range of 400-1800cm-1 , and establish the surface-enhanced micro-Raman of the throat swab specimen Spectral database, after deducting fluorescence, normalizing, and taking the average value for processing and analysis, to obtain the characteristics of enhanced Raman spectrum on the surface of throat swab samples, and to analyze the biochemical components of different throat swab samples. The invention has the advantages of short detection time, low cost, convenient and fast process, etc., and can obtain rich biochemical composition information of throat swab samples, thereby providing a fast and effective analysis method for the biochemical characteristics and changes of intracavitary mucosal tissues.
为了实现上述发明目的，本发明采用的技术方案如下：In order to realize the foregoing invention object, the technical scheme that the present invention adopts is as follows:
（1）表面增强试剂的制备(1) Preparation of surface enhancement reagents
采用盐酸羟胺还原硝酸银的方法制备SH银胶，整个制备增强试剂的过程需保持在恒定室温下进行。The SH silver colloid was prepared by reducing silver nitrate with hydroxylamine hydrochloride, and the whole process of preparing the reinforcing agent should be kept at a constant room temperature.
1）表面增强试剂的制备：取5 mL的浓度为0.06 mol/L的盐酸羟胺溶液，加入到4.5mL 浓度为0.1mol/L的氢氧化钠溶液中；将配制好的混合溶液快速加入90mL浓度为0.0011mol/L的硝酸银溶液中，迅速搅拌至溶液呈均匀的乳灰色，即为SH银胶。在使用银胶时，将SH银胶放入离心机中，设置10000 r/min离心十分钟，吸取上层澄清液丢弃，将离心管中下层的银纳米溶胶收集起来备用，即为表面增强试剂；1) Preparation of surface enhancement reagent: take 5 mL of hydroxylamine hydrochloride solution with a concentration of 0.06 mol/L, and add it to 4.5 mL of sodium hydroxide solution with a concentration of 0.1 mol/L; quickly add the prepared mixed solution to a concentration of 90 mL In the silver nitrate solution of 0.0011mol/L, stir rapidly until the solution is uniform milky gray, which is SH silver colloid. When using silver colloid, put the SH silver colloid in a centrifuge, set 10000 r/min to centrifuge for ten minutes, absorb the supernatant liquid and discard it, and collect the silver nano sol in the middle and lower layers of the centrifuge tube for later use, which is the surface enhancement reagent;
2）将适量银胶放入离心管里高速离心10分钟，取下层高浓度银胶备用；2) Put an appropriate amount of silver glue into a centrifuge tube and centrifuge at high speed for 10 minutes, and remove the high-concentration silver glue for later use;
（2）咽拭标本样品的处理(2) Processing of throat swab samples
将获取的咽拭标本均匀地拖涂在表面平整且光滑洁净无污染的纯铝片上，滴加上上2～3μL表面增强试剂，并使其在室温下自然晾干，制成咽拭-表面增强拉曼测试片。所述的咽拭-拉曼测试片可立即进行测试；或在进行拉曼测试之前存放于-80℃的冰箱或液氮中，在拉曼测试前在室温下自然解冻后进行测试。Evenly drag and smear the obtained throat swab specimen on a flat, smooth, clean and pollution-free pure aluminum sheet, add 2 to 3 μL of surface enhancement reagent dropwise, and let it dry naturally at room temperature to make a throat swab-surface Enhanced Raman test piece. The throat swab-Raman test piece can be tested immediately; or stored in a -80°C refrigerator or liquid nitrogen before the Raman test, and then thawed naturally at room temperature before the Raman test.
（3）样品表面增强拉曼光谱的测量(3) Measurement of sample surface enhanced Raman spectrum
所述的样品表面增强拉曼光谱的测量指利用显微拉曼光谱仪发出的激光照射在滴加过表面增强试剂的咽拭-表面增强拉曼测试片上的咽式标本，同时收集从该测试片上发出的表面增强拉曼信号光，从而检测在400-1800cm-1范围的表面增强拉曼信号，而所述检测装置显微拉曼光谱仪记录在上述光谱区的被咽拭标本散射的表面增强拉曼信号，每个咽拭-拉曼测试片采集5-10个不同位置点处的显微表面增强拉曼光谱。The measurement of the surface-enhanced Raman spectrum of the sample refers to the use of the laser light emitted by the micro-Raman spectrometer to irradiate the pharyngeal specimen on the throat swab-surface-enhanced Raman test piece dripped with the surface-enhanced reagent, and collect the samples from the test piece at the same time. The emitted surface-enhanced Raman signal light is used to detect the surface-enhanced Raman signal in the range of 400-1800 cm-1 , and the detection device micro-Raman spectrometer records the surface-enhanced Raman signal scattered by the throat swab specimen in the above spectral region. For Man signal, each throat swab-Raman test piece collects microscopic surface-enhanced Raman spectra at 5-10 points at different positions.
（4）拉曼光谱数据处理与分析(4) Raman spectroscopy data processing and analysis
将获得的咽拭标本散射拉曼信号经扣除荧光背景，面积归一化处理；将同一咽拭-表面增强拉曼测试片不同位置点处经上述处理后的光谱取平均值，作为一个咽拭样品的拉曼信号；再通过光谱特征实现咽拭标本的生化成分信息和特征的分析。The scattered Raman signal of the obtained throat swab specimen is deducted from the fluorescent background, and the area is normalized; the spectrum of the same throat swab-surface-enhanced Raman test piece at different points after the above treatment is averaged, and used as a throat swab The Raman signal of the sample; and the analysis of the biochemical composition information and characteristics of the throat swab specimen is realized through the spectral characteristics.
所述的铝片是指99.99%的高纯铝片。The aluminum sheet refers to 99.99% high-purity aluminum sheet.
所述的拉曼光谱检测，使用激光功率为50mW,激光激发波长为785nm，光谱的测量范围为400-1800cm-1。The Raman spectrum detection uses a laser power of 50mW, a laser excitation wavelength of 785nm, and a spectral measurement range of 400-1800cm-1 .
与现有技术相比，本发明如下有益效果：Compared with the prior art, the present invention has the following beneficial effects:
1.本发明在采集咽拭标本时使用类似咽拭子采集方法，相比较传统的采集方法，仅需要少量的生化物质是一种微损伤的采集方法。1. The present invention uses a similar throat swab collection method when collecting throat swab specimens. Compared with traditional collection methods, only a small amount of biochemical substances are required, which is a minimally damaged collection method.
2.在标本数量较少的情况下，采用拉曼光谱方法，并结合显微技术，获取丰富的物质生化成分信息。2. In the case of a small number of specimens, the Raman spectroscopy method, combined with microscopic techniques, is used to obtain rich information on the biochemical composition of substances.
3.本发明所述的样品表面增强拉曼光谱的测量范围为400-1800cm-1，对同一个咽拭标本的拉曼光谱进行分析，进一步提高了这种微损伤的表面增强拉曼光谱检测咽拭标本生化成分方法的可行性。3. The measurement range of the sample surface-enhanced Raman spectrum of the present invention is 400-1800cm-1 , and the Raman spectrum of the same throat swab specimen is analyzed, which further improves the surface-enhanced Raman spectrum detection of such micro-damages Feasibility of method for biochemical composition of throat swab specimens.
4.，本发明还具有检测时间短，成本低，过程方便快捷等优点，能够获得咽拭样品丰富的生化成分信息，从而为腔内粘膜组织的生化特征和变化提供快速、有效的分析方法，具有很好的经济效益和社会效益。4. The present invention also has the advantages of short detection time, low cost, convenient and fast process, etc., and can obtain rich biochemical composition information of throat swab samples, thereby providing a fast and effective analysis method for the biochemical characteristics and changes of intraluminal mucosal tissues, It has good economic and social benefits.
附图说明Description of drawings
图1是本发明所述的咽拭标本表面增强显微拉曼光谱的检测方法示意图。图中：1-拭子采集；2-涂抹；3-纯铝片；4-咽拭标本；5-表面增强试剂；6-半导体激光器；7-拉曼光谱仪；8-电脑。Fig. 1 is a schematic diagram of the method for detecting surface-enhanced Raman spectroscopy of a throat swab specimen according to the present invention. In the figure: 1-swab collection; 2-smear; 3-pure aluminum sheet; 4-throat swab specimen; 5-surface enhancement reagent; 6-semiconductor laser; 7-Raman spectrometer; 8-computer.
图2是应用本发明测得的鼻咽部位癌与非癌组织咽拭标本的表面增强显微拉曼光谱图；其中纵坐标为拉曼光谱的强度，单位为任意强度单位（a.u.）；横坐标为拉曼光谱的波数，单位为cm-1。Fig. 2 is a surface-enhanced microscopic Raman spectrum diagram of nasopharyngeal cancer and non-cancer tissue throat swab specimens measured by the present invention; where the ordinate is the intensity of the Raman spectrum, and the unit is arbitrary intensity unit (au); The coordinates are the wavenumbers of Raman spectra, and the unit is cm-1 .
图3 是应用本发明测得的急性心肌梗塞患者与健康人口腔唾液咽拭标本表面增强显微拉曼光谱图；其中纵坐标为拉曼光谱的强度，单位为任意强度单位（a.u.）；横坐标为拉曼光谱的波数，单位为cm-1。Fig. 3 is the surface-enhanced microscopic Raman spectrum of the oral saliva and throat swab specimens of patients with acute myocardial infarction and healthy people measured by the present invention; wherein the ordinate is the intensity of the Raman spectrum, and the unit is arbitrary intensity unit (au); The coordinates are the wavenumbers of Raman spectra, and the unit is cm-1 .
具体实施方式detailed description
附图是实施例利用共聚焦显微拉曼光谱仪所测鼻咽组织咽拭样品的谱图，检测中为了对本发明有进一步的理解，现结合附图对本发明做进一步的说明。Accompanying drawing is the spectrogram of nasopharyngeal tissue and throat swab sample measured by confocal micro-Raman spectrometer in the embodiment. In order to have a further understanding of the present invention in the detection, the present invention will be further described in conjunction with the accompanying drawings.
实施例1 鼻咽咽拭标本的表面增强显微拉曼光谱检测Example 1 Surface-enhanced Raman Spectroscopy Detection of Nasopharyngeal and Pharyngeal Swab Specimens
(1) 表面增强试剂的制备：(1) Preparation of surface enhancement reagents:
1）取5 mL的浓度为0.06 mol/L的盐酸羟胺溶液，加入到4.5mL 浓度为0.1mol/L的氢氧化钠溶液中；将配制好的混合溶液快速加入90mL浓度为0.0011mol/L的硝酸银溶液中，迅速搅拌至溶液呈均匀的乳灰色，即为SH银胶。在使用银胶时，将SH银胶放入离心机中，设置10000 r/min离心十分钟，吸取上层澄清液丢弃，将离心管中下层的银纳米溶胶收集起来备用，即为表面增强试剂；1) Take 5 mL of hydroxylamine hydrochloride solution with a concentration of 0.06 mol/L, and add it to 4.5 mL of sodium hydroxide solution with a concentration of 0.1 mol/L; quickly add 90 mL of the prepared mixed solution with a concentration of 0.0011 mol/L In the silver nitrate solution, stir rapidly until the solution is uniform milky gray, which is SH silver colloid. When using silver colloid, put the SH silver colloid in a centrifuge, set 10000 r/min to centrifuge for ten minutes, absorb the supernatant liquid and discard it, and collect the silver nano sol in the middle and lower layers of the centrifuge tube for later use, which is the surface enhancement reagent;
2）将适量银胶放入离心管里高速离心10分钟，取下层高浓度银胶备用； (2) 咽拭标本样品的处理：2) Put an appropriate amount of silver colloid into a centrifuge tube and centrifuge at high speed for 10 minutes, and remove the lower layer of high-concentration silver colloid for later use; (2) Processing of throat swab samples:
鼻咽咽拭组织标本均匀地拖涂在表面平整且光滑洁净无污染的纯铝片上，滴加上2μL表面增强试剂，并使其在室温下自然晾干，制成咽拭-表面增强拉曼测试片。在进行拉曼测试之前存放于-80℃的冰箱或液氮中备用。Nasopharyngeal and throat swab tissue specimens are evenly dragged and coated on a flat, smooth, clean and non-polluting pure aluminum sheet, 2 μL of surface enhancement reagent is added dropwise, and allowed to dry naturally at room temperature to form a throat swab-surface-enhanced Raman test piece. Store in a -80°C freezer or liquid nitrogen until Raman testing.
(3) 样品表面增强拉曼光谱的测量：(3) Measurement of sample surface enhanced Raman spectrum:
利用显微拉曼光谱仪发出的激光照射在滴加过表面增强试剂的咽拭-表面增强拉曼测试片上的咽式标本，同时收集从该测试片上发出的拉曼信号光，从而检测在400-1800cm-1范围的拉曼信号。Utilize the laser emitted by the micro-Raman spectrometer to irradiate the pharyngeal specimen on the throat swab-surface-enhanced Raman test piece dripped with the surface-enhanced reagent, and collect the Raman signal light emitted from the test piece at the same time, so as to detect the pharyngeal specimen at 400- Raman signal in the 1800cm-1 range.
(4)拉曼光谱数据处理与分析(4) Raman spectrum data processing and analysis
重复步骤（1）-（3），得到多个鼻咽部位不同类型组织咽拭标本的表面增强拉曼光谱数据。对获得的表面增强拉曼光谱（图2）进行扣除荧光背景，面积归一化、取平均谱等预处理；再通过查阅光谱特征峰位（表1），进行不同鼻咽咽拭组织类型的表面拉曼增强光谱的差异对比。由图2可注意到，癌变和非癌变的鼻咽咽拭组织的表面增强拉曼光谱虽然有一定的相似性，但在477、653、725、959、1004、1022、1095、1215、1331、1445、1580 cm-1的光谱峰位存在较明显差异。再对照表一的鼻咽组织表面增强拉曼光谱的振动模式的生化成分归属，从而实现对鼻咽不同组织类型的咽拭标本的生化成分信息和特征的分析。Repeat steps (1)-(3) to obtain surface-enhanced Raman spectroscopy data of throat swab specimens of different types of tissues in multiple nasopharynx. The obtained surface-enhanced Raman spectrum (Figure 2) was preprocessed by subtracting the fluorescence background, normalizing the area, and taking the average spectrum; Difference contrast of surface Raman-enhanced spectra. It can be noticed from Figure 2 that although the surface-enhanced Raman spectra of cancerous and non-cancerous nasopharynx and throat swabs have certain similarities, they are at 477, 653, 725, 959, 1004, 1022, 1095, 1215, 1331, There are obvious differences in the spectral peak positions of 1445 and 1580 cm-1 . Then compare the biochemical composition assignment of the vibration mode of the nasopharyngeal tissue surface-enhanced Raman spectrum in Table 1, so as to realize the analysis of the biochemical composition information and characteristics of the throat swab specimens of different tissue types of the nasopharynx.
实施例2 唾液咽拭标本的表面增强显微拉曼光谱检测Example 2 Detection of surface-enhanced Raman spectroscopy of saliva and throat swab specimens
(1) 表面增强试剂的制备：同实施例1步骤（1）(1) Preparation of surface enhancing reagent: same as step (1) of Example 1
(2) 咽拭标本样品的处理：(2) Processing of throat swab samples:
唾液咽拭标本均匀地拖涂在表面平整且光滑洁净无污染的纯铝片上，滴加上2μL表面增强试剂，并使其在室温下自然晾干，制成咽拭-表面增强拉曼测试片。在进行拉曼测试之前存放于-80℃的冰箱或液氮中备用。The saliva throat swab specimen is evenly dragged and coated on a flat, smooth, clean and pollution-free pure aluminum sheet, 2 μL of surface enhancement reagent is added dropwise, and allowed to dry naturally at room temperature to make a throat swab-surface enhanced Raman test piece . Store in a -80°C freezer or liquid nitrogen until Raman testing.
(3) 样品表面增强拉曼光谱的测量：(3) Measurement of sample surface enhanced Raman spectrum:
利用显微拉曼光谱仪发出的激光照射在滴加过表面增强试剂的咽拭-表面增强拉曼测试片上的咽式标本，同时收集从该测试片上发出的拉曼信号光，从而检测在400-1800cm-1范围的拉曼信号。Utilize the laser emitted by the micro-Raman spectrometer to irradiate the pharyngeal specimen on the throat swab-surface-enhanced Raman test piece dripped with the surface-enhanced reagent, and collect the Raman signal light emitted from the test piece at the same time, so as to detect the pharyngeal specimen at 400- Raman signal in the 1800cm-1 range.
(4)拉曼光谱数据处理与分析(4) Raman spectrum data processing and analysis
重复步骤（1）-（3），得到急性心肌梗塞患者和健康人唾液咽拭标本的表面增强拉曼光谱数据。对获得的表面增强拉曼光谱（图2）进行扣除荧光背景，面积归一化、取平均谱等预处理；再通过查阅光谱特征峰位（表2），进行表面拉曼增强光谱的差异对比。由图2可注意到，心肌梗塞患者和健康人的唾液咽拭组织的表面增强拉曼光谱虽然有一定的相似性。但在477、724、885、922、1135、1445、1656cm-1的光谱峰位存在较明显差异。再对照表一的唾液表面增强拉曼光谱的振动模式的生化成分归属，从而实现对急性心肌梗塞患者唾液咽拭标本的生化成分信息和特征的分析。Repeat steps (1)-(3) to obtain surface-enhanced Raman spectrum data of saliva and throat swabs from patients with acute myocardial infarction and healthy people. The obtained surface-enhanced Raman spectrum (Figure 2) was preprocessed by subtracting the fluorescence background, normalizing the area, and taking the average spectrum; and then comparing the difference of the surface Raman-enhanced spectrum by consulting the characteristic peak positions of the spectrum (Table 2) . It can be noticed from Fig. 2 that although the surface-enhanced Raman spectra of the saliva and throat swabs of myocardial infarction patients and healthy people have certain similarities. However, there are obvious differences in the spectral peak positions at 477, 724, 885, 922, 1135, 1445, and 1656 cm-1 . Then compare the biochemical composition assignment of the vibration mode of the surface-enhanced Raman spectrum of saliva in Table 1, so as to realize the analysis of the biochemical composition information and characteristics of the saliva and throat swab specimens of patients with acute myocardial infarction.
表1：鼻咽组织的表面增强拉曼光谱的主要谱峰位置和谱峰归属Table 1: Main peak positions and peak assignments of surface-enhanced Raman spectroscopy of nasopharyngeal tissue
表2：唾液表面增强拉曼光谱的主要谱峰位置和谱峰归属Table 2: Main peak positions and peak assignments of surface-enhanced Raman spectroscopy of saliva
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| CN201610121028.XACN105738343A (en) | 2016-03-03 | 2016-03-03 | Method for detecting biochemical components of throat swab sample by adopting surface enhanced micro-Raman spectroscopy |
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