CN116087172A - High-sensitivity lateral flow immunity joint inspection device based on surface enhanced Raman imaging - Google Patents
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Abstract
The invention discloses a high-sensitivity lateral flow immunity joint inspection device based on surface enhanced Raman imaging. In the proposed lateral flow mode, whole blood or isolated blood samples (serum and plasma) are first complexed with an antibody-nanoparticle conjugate on a conjugate pad under capillary force and combined with an attached antibody in a Surface Enhanced Raman Scattering (SERS) detection window on an NC membrane to form a "sandwich" structure. The analyte to be detected is captured and enriched on the detection line of the detection window, so that the detection becomes more sensitive and can be quantified. In order to realize the imaging joint inspection of the detection window by the Raman imaging device, the constructed Raman imaging device can be a staring Raman imager or a line scanning Raman imager. The arrangement can carry out Raman spectrum detection on all points of one line, and the Raman imaging detection on a plurality of capturing narrow lines arranged at different positions in the detection window is completed through axial rotation of the narrow line arrays which are radially arranged.
Description
Technical Field
The invention belongs to the field of biological analysis and detection, and mainly relates to a lateral flow joint detection integrated device based on a surface-enhanced Raman imaging system, which can be used for high-precision biomolecule immunity detection.
Background
The lateral flow detection device, also called immunochromatography, can complete all steps of pretreatment, separation, dilution, mixing, chemical reaction, detection and the like of biological samples through driving of capillary force, has the characteristics of rapidness, reliability, simplicity, low cost, easiness in operation and the like, and is widely applied to the fields of biological analysis detection, chemical sensing and medical detection. The traditional lateral flow detection chip is often based on a colloidal gold detection technology, and the detection result is judged only by distinguishing the color by naked eyes. Such detection methods often suffer from insufficient detection accuracy and are subject to subjective factors. Although fluorescence immunochromatography can improve the sensitivity, clinical detection application with higher requirements is difficult to meet.
Raman spectrum is related to the vibrational rotational energy level of a molecule of a substance and is the fingerprint spectrum of the molecule. The raman signal of a molecule is usually weak and is difficult to detect in trace amounts by instrumentation. The surface enhanced Raman overcomes the defect of insufficient sensitivity of the Raman spectrum, can obtain the structure information which is not easy to obtain by the conventional Raman spectrum, and is widely applied to surface research, adsorption interface surface state research, interface orientation and configuration of biological size molecules, conformation, structure analysis and other researches. Meanwhile, the adsorption orientation of the compound at the interface, the change of adsorption state, interface information and the like can be analyzed. Meanwhile, the spatial resolution of Raman measurement is improved to submicron and micron dimensions by adopting a microscopic technology, so that a brand-new experimental technical method, namely Raman spectrum imaging, is introduced for the Raman spectrum technology. This facilitates the extension of conventional single point analysis to simultaneous comparative analysis of samples over a range of space.
Based on the surface enhanced Raman scattering principle, the high-sensitivity detection of the target object can be realized by combining the label of the metal nano particles of the Raman probe, which is important for the detection of the lateral flow chip. There have been many reports on detection using SERS in combination with lateral flow chips. For example, fu Xiuli et al (Fu et al 2016, 2019) developed a SERS-based DNA lateral flow biosensor for simple, rapid and sensitive detection of specific biomarkers that can quantify the number of model targets HIV-1 DNA markers with high reproducibility. Compared with Polymerase Chain Reaction (PCR) and commercial fluorescent kits, the detection limit based on the SERS test strip is reduced by three orders of magnitude, and the detection time is also greatly shortened; chen Ruipeng et al (Chen et al, 2019) propose a vertical flow chromatography detection technique based on surface enhanced raman scattering for multiplex prostate biomarker detection on a single test site. The detection technology remarkably improves the detection sensitivity, and has extremely low background, high stability and reliability in serum sample analysis; zhang Mojun et al (Zhang et al, 2020) developed a novel multiplexed SERS lateral flow immunosensor for detecting mycotoxins in corn with an approximately one order of magnitude increase in sensitivity compared to enzyme-linked immunosorbent assays (ELISA). He Deyun et al (He et al, 2019) established a dual mode (colorimetric/SERS) lateral flow assay based on platinum-coated gold nanorod (aunr@pt) peroxidase simulation and surface enhanced SERS enhancement properties for sensitive, rapid and specific detection of clostridium jejunum in food products. The proposed detection method achieves a wide detection range, a low detection limit, high specificity and excellent sensitivity. Liu Bing et al (Liu et al, 2022) developed a novel point-of-care detection device consisting of a lateral flow immunoassay strip based on surface enhanced raman scattering for ultrasensitive quantitative detection of SP 10. In the design, the SP10 is authenticated through a gold-silver core-shell nanorod SERS nano label, and the detection method has high sensitivity, low cost and very fast analysis process, and can finish the chromatographic process of lateral flow only by 10 minutes. Gao Xuefei et al (Gao et al 2020) developed gold star silica gel sandwich nanoparticles as surface enhanced raman scattering probes for sensing transduction; and a functionalized filter membrane component is designed and constructed in the paper-based lateral flow strip and is used as a built-in plasma separation unit, so that a paper device which is low in cost, disposable, portable and capable of being deployed on site is constructed and is used as a universal instant detection tool for detecting protein biomarkers in whole blood. Su Lihong et al (Su et al, 2021) constructed a dual-mode colorimetric/SERS lateral flow immunoassay for ultrasensitive determination of residual clenbuterol in food based on metal core-shell Au/Au nanosatellites as multifunctional labels. The detection method has higher specificity, higher reproducibility and satisfactory recovery rate in food detection. While these SERS-based lateral flow detection techniques have the advantage of significantly improving detection sensitivity, they have some drawbacks. Particularly in the detection part, the current technology can only scan and detect one or more detection lines on a lateral flow chip, and the improvement of sensitivity and flux is not easy to realize.
The Raman imaging technology is a label-free analysis technology, can simultaneously obtain two-dimensional space information and spectrum information corresponding to each point, can obtain structure and composition information of a target from a molecular level, and is widely applied to the field of biological medicine research. The Raman imaging detection has high spectral resolution better than 0.5 and nm, and can detect a plurality of targets of the Raman targeting marks with high precision. The Raman imaging technology is applied to detection of the lateral flow chip, and Raman targeting markers at different positions on the chip can be detected simultaneously, so that joint detection of multiple targets is realized.
The Raman imager provided by the invention can realize imaging detection of the whole detection area on the chip, is beneficial to improving the efficiency of the detection flow, remarkably reduces the detection time and realizes the automatic combined detection of the immunity and the quantification. The detection technology well solves the problem of insufficient precision of the existing immunodetection technology, has obvious advantages in analysis sensitivity compared with a lateral flow immunodetection method based on colloidal gold or fluorescent markers, and has the advantages of rapidness, simplicity in operation, strong multi-item joint inspection and the like.
Disclosure of Invention
The present invention proposes a low cost, high sensitivity diagnostic technique to help doctors monitor biomarkers related to human disease progression. The platform consists of a novel multi-layer filter paper strip filtering system and a lateral flow component coated with metal nano particles, and is combined with a SERS imaging detection system to carry out clinical biomarker analysis. The lateral flow multi-index immunity joint inspection device based on the surface enhanced Raman imaging comprises a multi-filter paper lateral flow filtering and liquid driving device, a Raman imaging device and an automatic control device. The lateral flow component is arranged in the plastic shell, so that the basic functions of laboratories such as biology, chemistry and the like can be reduced to a chip of a few square centimeters, and a series of steps of pretreatment, separation, mixing, chemical reaction and detection of a sample are completed; the Raman imaging device has high spectral resolution better than 0.5 and nm, can detect a plurality of target objects in samples at different positions simultaneously, and obviously improves the sensitivity of the detection technology; the automatic control device combines the lateral flow detection chip with the high-sensitivity Raman imaging device, and realizes the integration of quantitative joint detection of various high-precision target proteins.
The lateral flow device will remain stable at ambient temperature and support reliable, enhanced detection and quantification of biomarkers in patient samples. The extracted blood will be applied directly to a filter paper and the strip containing pure serum will then be transferred by capillary force to a SERS imaging analyzer for spectroscopic immunoassay of the serum sample. The lateral flow device can also be directly used for injecting blood serum or blood plasma obtained after the pre-separation.
The lateral flow detection chip uses a Raman imaging device for detection; the constructed Raman imaging device can be a staring type Raman imager or a line scanning type Raman imager, and can perform Raman spectrum detection on all points of one line at a time, and realize Raman imaging detection on a plurality of narrow lines of antibodies by axial rotation of a narrow line array which is radially arranged.
The high-sensitivity detection device based on surface enhanced SERS imaging can detect a plurality of targets simultaneously by imaging a plurality of capture narrow lines (targets are imaged singly), and can detect a plurality of analytes by imaging a capture narrow line (targets are imaged in a mixed mode).
The high-sensitivity lateral flow joint inspection device based on the surface enhanced Raman imaging can be used for simultaneously detecting a plurality of lateral flow detection chips.
The lateral flow detection chip device can quantitatively detect various target objects which are marked by Raman targeting and distributed at different positions.
In the lateral flow detection chip, a marker coupled with a detection antibody is used, and the marker comprises nanoparticles with a surface Raman enhancement effect. Such nanoparticles may be nanosatellites, nanorods, or nanospheres, of which the composition is gold or silver or palladium; and different types of raman molecular markers coupled thereto. Such a label may be, but is not limited to, 5' -dithiobis ((2-nitrobenzoic acid) (DTNB), 4-mercaptobenzoic acid (4 MBA), or rhodamine.
The high-sensitivity lateral flow joint inspection device based on the surface enhanced Raman imaging can realize an integrated detection mode.
The invention has the following effects:
the invention combines the lateral flow detection chip and the Raman imaging device, and utilizes the characteristics of high sensitivity enhanced by Raman and rapidness of a microscopic imaging technology to realize the integration of high-precision and multiple quantitative rapid joint inspection.
Drawings
FIG. 1 is a schematic diagram of an integrated lateral flow chip joint inspection device of the present invention.
Reference numeral one indicates: a lateral flow chip 1, an automatic control device 2 and a Raman imaging device 3.
Description of the embodiments
In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention will be described in further detail with reference to the accompanying drawings and examples. It should be understood that the detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the invention.
Examples
The invention constructs a high-sensitivity lateral flow joint inspection device based on a surface enhanced Raman imaging technology.
The device applies the independently developed high-precision Raman imaging device to the traditional lateral flow chip detection technology, and realizes high-precision and low-cost integrated protein quantitative joint detection. As an example, we build a linear confocal raman imager, mainly comprising a microscopic imaging light path part, a linear laser forming part and a slit type spectrometer, wherein a linear laser with the width of 0.3mm, a slit with the width of 0.3mm, a 2400 reticle/mm grating, an area array CCD imager are adopted, the linear laser is optically conjugated with the slit, and the linear laser with the width of 0.3mm shines to excite raman signals on a target object, and the raman signals are collected and focused at the slit by the microscopic imaging light path part, so that the simultaneous detection of the raman spectra of all points of a radial line with the width of 0.3mm can be realized; the method has large single measurement area and avoids the phenomenon of missing the target.
As shown in fig. 1, the device consists of 3 parts, namely a lateral flow chip, a raman imaging device and an automatic control device. After the blood sample is added to the lateral flow loading well, performing filtration pretreatment, separation, mixing, and chemical reaction steps; after a sample belt enters a SERS detection window on an NC film, a Raman imaging device carries out high-precision quantitative detection on the protein-nanoparticle compound distributed at different analysis line positions; the automatic control device combines the lateral flow chip and the Raman imaging device to realize joint inspection integration.
Labels coupled to detection antibodies, including nanoparticles having surface raman enhancing effects, are used in the present invention. Such nanoparticles may be nanosatellites, nanorods, or nanospheres, of which the composition is gold or silver or palladium; and the different types of Raman markers associated with the antibody-surface Raman-enhanced nanoparticle conjugate product can be prepared by a lateral flow filtration process to improve the monodispersity of mass-produced particles, so as to achieve the aim of improving the detection precision.
The lateral flow device operation process in the invention comprises the following steps: and uniformly mixing conjugate of detection antibody-Raman nano particles corresponding to the object to be detected, spraying the conjugate on a conjugate binding pad, fixing corresponding capture antibodies on a plurality of detection lines (T lines) on an NC film, and fixing secondary antibodies on a quality control line (C line). After the sample solution to be detected is added into the sample adding port at the left end, the target substance is pushed forward to the binding pad by capillary action, and is combined with the conjugate on the binding pad to continue to advance to the detection window, and is captured by the antibody fixed on the corresponding detection line, so that a sandwich structure is formed. The composite structure emits a raman enhanced scattering signal upon excitation by raman excitation light.
The arrangement in the present invention uses a raman imaging device to scan the detection area. As an example, raman spectral detection can be performed on all points of a line at a time using a line scanning raman imaging device, and raman imaging detection of multiple lateral flow chips can be achieved by axial rotation of a radially arranged narrow line array. And finally, the respective concentrations of the multiple targets can be quantitatively represented through the loudness of the spectral lines.
The automatic control device combines the high-precision Raman imaging device with the traditional lateral flow chip to form a new generation of high-sensitivity lateral flow joint inspection device based on surface enhanced Raman imaging. The device has the important technical characteristics of high sensitivity, good accuracy, easy quantification and the like, can realize an integrated joint inspection mode of 'sample in and result out', and is beneficial to the application of relevant clinical detection.
Claims (7)
1. A high-sensitivity lateral flow multiple immunity joint inspection device based on surface enhanced Raman imaging is characterized in that,
including lateral flow filtration and liquid drive devices, raman imaging devices, and automated control and data processing devices. The lateral flow device comprises a substrate, a multi-layer sample filter pad, a combination pad, an NC chromatographic membrane, a water absorption pad and a shell, wherein the multi-layer sample filter pad, the combination pad, the NC chromatographic membrane, the water absorption pad and the shell are attached to the substrate; the arrangement which is closely connected in sequence can drive the liquid sample to a required area in a controlled way through capillary force, and the basic functions of a biological laboratory and a chemical laboratory are reduced to a chip with a few square centimeters, so that a series of steps of pretreatment, washing separation, mixing, incubation, immune reaction and detection of the sample are completed; the constructed Raman imaging device has high spectral resolution better than 0.5 and nm, and can realize the detection of a plurality of target objects in different capture areas at the same time; the lateral flow device and the Raman imaging detection system are combined, so that the integration of high-precision protein analyte immunity quantitative joint inspection can be realized.
2. The joint inspection device according to claim 1, wherein: the lateral flow chip mode comprises a sample filtering and absorbing pad positioned below the sample adding hole, can separate and purify whole blood, and transfers the purified serum to a SERS detection window in a strip mode. Serum or plasma obtained after pre-separation can also be directly used for sample injection.
3. The joint inspection device according to claim 1, wherein: the lateral flow immunity chip uses a Raman imaging device to detect; the constructed Raman imaging device can be a staring type Raman imager or a line scanning type Raman imager, and can perform Raman spectral line imaging detection on all points of a radial line with a certain line width at a time; the Raman imaging detection of the lateral flow chips of the antibodies can be realized by axially rotating the chassis carrying the lateral flow chips which are radially arranged at different angles.
4. The joint inspection device according to claim 1, wherein: the high-sensitivity detection device based on surface enhanced SERS imaging can image a plurality of capture narrow lines, so that the aim of simultaneously detecting a plurality of targets (single imaging of the targets) is fulfilled, and a plurality of analytes can be imaged and detected on one capture narrow line (mixed imaging of the targets).
5. The joint inspection device according to claim 1, wherein: according to the surface enhanced SERS imaging joint inspection device, joint inspection of various target objects can be realized by quantitatively detecting the Raman targeting markers distributed at different positions.
6. The joint inspection device according to claim 1, wherein: in the lateral flow detection chip, the used marker coupled with the detection antibody comprises nanoparticles with surface Raman enhancement effect, and the nanoparticles can be a nano structure with gold, silver or palladium as components, wherein the nano structure comprises nano stars, nano rods or nano pellets; and different types of raman labels coupled thereto; such a label may be 5,5' -dithiobis ((2-nitrobenzoic acid) (DTNB), 4-mercaptobenzoic acid (4 MBA), or rhodamine.
7. The joint inspection device according to claim 1, wherein: the high-sensitivity lateral flow joint inspection device based on the surface enhanced Raman imaging can realize the integration of sample pretreatment, washing, separation, mixing, incubation, immune reaction, detection and data processing.
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