WO2020138965A1 - Procédé de diagnostic d'une maladie parodontale, et composition et kit pour celui-ci - Google Patents

Procédé de diagnostic d'une maladie parodontale, et composition et kit pour celui-ci Download PDF

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WO2020138965A1
WO2020138965A1 PCT/KR2019/018497 KR2019018497W WO2020138965A1 WO 2020138965 A1 WO2020138965 A1 WO 2020138965A1 KR 2019018497 W KR2019018497 W KR 2019018497W WO 2020138965 A1 WO2020138965 A1 WO 2020138965A1
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periodontal disease
mmp
diagnosis
prognosis
disease
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PCT/KR2019/018497
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English (en)
Korean (ko)
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김은경
김바울
김진섭
박재형
유승범
손미진
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주식회사 수젠텍
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • the present invention relates to a method for diagnosing periodontal disease, and more particularly, to a method for diagnosing periodontal disease by distinguishing active and inactive type matrix metalloproteinase 8 (MMP-8) from biological samples.
  • MMP-8 matrix metalloproteinase 8
  • Periodontal disease includes gingivitis occurring in the gums and periodontitis occurring in the alveolar bone, and is a disease in which the surrounding tissue supporting the tooth is destroyed, not a disease in which the tooth itself is damaged, and belongs to an inflammatory chronic disease.
  • the inflammation gradually progresses while the patient does not feel it, and the alveolar bone around the tooth is destroyed, and the disease is often recognized only when the tooth needs to be extracted. To prevent this, it is necessary to have a technique that can diagnose periodontal disease early.
  • the inventors of the present invention through the proteomic analysis of saliva or gingival crevicural fluid (GCF), which contains various inflammatory substances in response to the occurrence of periodontal disease, biomarker for periodontal disease And additionally, correlation between biomarkers for diagnosis of periodontal disease with high accuracy was analyzed.
  • GCF gingival crevicural fluid
  • An object of the present invention is to provide a method capable of diagnosing infection of bacteria causing periodontal disease with high accuracy.
  • Another object of the present invention is to provide a method of diagnosing periodontal disease with higher accuracy from the ratio of active and inactive forms of MMP-8 detected from a subject, and the ratio of active and inflammatory disease markers of MMP-8.
  • MMP-8 Microx Metalloproteinase-8 (Matrix Metalloproteinase-8) from a biological sample derived from a subject; An inflammatory disease marker, and a marker derived from a periodontal disease strain; detecting any one or more selected from the group consisting of; And when the level of the marker derived from the MMP-8, inflammatory disease marker or periodontal disease strain detected in the biological sample increases compared to a normal control sample, determining the subject from which the biological sample originated as periodontal disease; It provides a method for providing information necessary for the diagnosis or prognosis of periodontal disease.
  • the step of detecting the MMP-8 may be to distinguish and detect the active MMP-8 and the inactive MMP-8.
  • the step of determining the subject as periodontal disease is that the concentration or concentration ratio of the marker detected from the biological sample satisfies Equation 1 and Equation 2, and satisfies Equation 3 or Equation 4. In some cases, it may include judging as periodontal disease.
  • the biological sample may be any one or more selected from the group consisting of saliva, gingival fluid (GCF) and sublingual fluid (SLF).
  • GCF gingival fluid
  • SLF sublingual fluid
  • the biological sample may be any one or more selected from the group consisting of saliva, gingival fluid (GCF) and sublingual fluid (SLF).
  • GCF gingival fluid
  • SLF sublingual fluid
  • the inflammatory disease markers are C-reactive protein (CRP), secretary immunoglobulin A (sIgA), immunoglobulin (Immunoglobulin), interleukin-1 beta (IL-1beta), interleukin-6 (IL- 6), tumor necrosis factor-alpha (TNF- ⁇ ;Tumor necrosis factor-alpha), beta-glucuronidase ( ⁇ -glucuronidase), lysozyme (Lysozyme), lactoferrin (Lactoferrin) It may be abnormal.
  • the marker derived from the periodontal disease strain may be any one or more selected from the group consisting of Leukotoxin, Karilysin, Cytolysin, Gingipain.
  • the step of determining the periodontal disease may include that performed by a microarray, an antigen-antibody reaction or a mass spectrometry method.
  • the step of determining the periodontal disease may be to further use non-marker clinical information of the subject.
  • the non-marker clinical information may be any one or more selected from the group consisting of measuring the depth of the periodontal pocket of the subject, bleeding or X-ray examination.
  • the active MMP-8 has at least 95% or more homology with any one or more sequences selected from the group consisting of site 1, site 2, site 3 and site 4 listed in Table 1 below. It may be a peptide containing.
  • the inactive MMP-8 may include a peptide having at least 95% homology to any one or more sequences listed in Table 2 below.
  • the present invention is a diagnosis or prognosis of periodontal disease comprising an antibody that specifically binds to an active type MMP-8 (active matrix metalloproteinase-8) and an antibody that specifically binds to an inactive type MMP-8 (pro Matrix Metalloproteinase-8). It provides a composition for.
  • the present invention provides a composition for diagnosing or prognosing periodontal disease comprising a primer or probe specific for nucleic acids encoding active MMP-8 (active matrix metalloproteinase-8) and inactive MMP-8 (pro matrix metalloproteinase-8). to provide.
  • the present invention diagnoses periodontal disease comprising an antibody that specifically binds to the active type MMP-8 (active matrix metalloproteinase-8) and an antibody that specifically binds to the inactive type MMP-8 (pro matrix metalloproteinase-8) or
  • For the diagnosis or prognosis of periodontal disease comprising a prognostic composition and/or a primer or probe specific for nucleic acids encoding active MMP-8 (active matrix metalloproteinase-8) and inactive MMP-8 (pro matrix metalloproteinase-8)
  • a kit for diagnosing or prognosing periodontal disease comprising a composition.
  • the method of providing information necessary for diagnosing or prognosing periodontal disease according to the present invention can be easily determined whether or not periodontal disease occurs by confirming that the level of MMP-8, an inflammatory disease marker, or a marker derived from a periodontal disease strain is increased compared to a normal control sample. can do.
  • periodontal disease can be diagnosed with high accuracy by detecting MMP-8 as an active type and an inactive type, and the degree of disease progression can be grasped by additionally using information on an inflammatory disease marker. This can provide information that can be used for diagnosis, treatment and further monitoring of periodontal disease.
  • 1 is a result of predicting the epitope position of the entire amino acid sequence of the inactive and active MMP-8.
  • Figure 2 shows a sequence region and sequence that are likely to be epitope positions.
  • Figure 4 shows a gel image confirming this after forming the active MMP-8 using the inactive MMP-8.
  • Figure 5 shows the results of confirming the specific binding to each antigen by preparing antibodies that specifically bind to active MMP-8, inactive MMP-8 and sIgA, respectively, according to Experimental Example 2 of the present invention.
  • FIG. 6 is a graph showing a result of calculating a quantitative curve by measuring fluorescence signals according to concentrations of active MMP-8, inactive MMP-8, and sIgA according to Experimental Example 2 of the present invention.
  • FIG. 7 is a graph showing the results of comparing the concentrations of active MMP-8, inactive MMP-8, total MMP-8 and IL-1beta in the normal control group and periodontal disease patient group according to Experimental Example 3 of the present invention.
  • Figure 8 is the ratio of the active MMP-8 / total MMP-8, the ratio of the active MMP-8 / sIgA and the ratio of the total MMP-8 / sIgA of the normal control group and periodontal disease patient group according to Experimental Example 3 of the present invention This graph shows that there is a significant difference.
  • Method for providing information necessary for the diagnosis or prognosis of periodontal disease is selected from the group consisting of MMP-8 (Matrix Metalloproteinase-8), inflammatory disease markers and markers derived from periodontal disease strains from biological samples derived from a subject Detecting any one or more; And when the level of the marker derived from the MMP-8, inflammatory disease marker, or periodontal disease strain in the biological sample increases compared to a normal control sample, determining the subject from which the biological sample originated as periodontal disease.
  • MMP-8 Microx Metalloproteinase-8
  • Periodontal disease in the present invention refers to inflammatory reaction and/or degeneration of the gums and surrounding connective tissue and bone, and includes, but is not limited to, gingivitis, periodontitis, and peri-implantitis.
  • peri-implantitis means that an inflammatory reaction occurs around the implant, including loss of surrounding bone tissue and soft tissue infection after the implant procedure.
  • MMP-8 is a type of collagen degrading enzyme involved in the destruction of periodontal tissue and may be used as a biomarker for diagnosing periodontal disease according to the present invention together with markers derived from inflammatory disease markers and/or periodontal disease strains.
  • MMP-8 may be active type aMMP-8 (active MMP-8).
  • inflammatory disease markers include C-reactive protein (CRP), sIgA (secretary immunoglobulin A), immunoglobulin (Immunoglobulin), interleukin-1 beta (IL-1beta), interleukin-6 (IL-) 6), tumor necrosis factor-alpha (TNF- ⁇ ), beta-glucuronidase, lysozyme, lactoferrin, and destruction of host connective tissue Markers such as MMP, aspartate aminotransferase (AST), tissue (inhibitor of metalloprotease (TPM), Alkaline phosphatase (ALP) that can be used as a marker for bone tissue alteration, receptor activator of NF-kB ligand (RANKL), Osteocalcin, Osteonectin, Osteopontin Can be used without limitation.
  • CRP C-reactive protein
  • sIgA secretary immunoglobulin A
  • immunoglobulin immunoglobulin
  • Immunoglobulin immunoglobulin
  • CRP C-reactive protein
  • SIgA is the most abundant immunoglobulin among body secretions such as saliva, tears, colostrum, and gastrointestinal secretions, and its concentration increases by distinguishing between gingivitis and periodontitis.
  • a biomarker derived from a periodontal disease strain may include any one or more selected from the group consisting of Leukotoxin, Karilysin, Cytolysin and Gingipain possessed by the periodontal disease strain. It can, but is not limited to.
  • the detecting of MMP-8 may be characterized by distinguishing and detecting active MMP-8 and inactive MMP-8.
  • MMP a type of collagen degrading enzyme, is involved in the decomposition and reconstruction of the extracellular matrix, of which the active form of MMP-8 can be detected.
  • Proteins belonging to MMPs are classified into active and inactive forms depending on the presence or absence of a propeptide domain composed of 80 to 90 amino acids.
  • MMP-8 is active in inactive form. It is converted to and the change in the ratio of the inactive form to the active form occurs. These changes can be measured and used to diagnose periodontal disease.
  • the concentration or concentration ratio of the marker detected from the biological sample satisfies Equation 1 and Equation 2, and satisfies Equation 3 or Equation 4, the subject from which the biological sample is derived It can be judged as periodontal disease.
  • the biological sample of the subject when the biological sample of the subject satisfies the expressions 1 and 2, it can be regarded as a patient candidate for periodontal disease, and when the expression 1 or 2 does not satisfy, the periodontal disease is absent or is a mild normal group. I can judge.
  • the equation 3 or equation 4 when the equation 3 or equation 4 is satisfied from the sample of the candidate for the periodontal disease, it is possible to determine the periodontal disease with high accuracy through diagnosis through a multi-step algorithm by determining the patient with periodontal disease.
  • the biological sample refers to saliva, gingival fluid (GCF), sublingual fluid (SLF), and other samples of biological origin.
  • the biological sample may be saliva, gingival fissure, or sublingual deceased solution obtainable from an animal, more preferably a mammal, most preferably a human.
  • the sample can be pretreated before being used for detection.
  • it may include cell lysis, filtration, distillation, extraction, concentration, inactivation of interfering components, addition of reagents, and the like.
  • a step of separating nucleic acids and proteins from the sample may be added to obtain more accurate results when used for detection.
  • the process of separating proteins from biological samples can be performed using known processes, and protein levels can be measured by various methods performed by those skilled in the art.
  • the step of determining periodontal disease through a marker detected from the biological sample may include being performed by a microarray, an antigen-antibody reaction, or mass spectrometry.
  • the amount of antigen-antibody response complex formation in normal subjects without periodontal disease and the amount of antigen-antibody complex formation in suspected periodontal disease patients can be compared, and information necessary for diagnosing periodontal disease through whether or not the above-mentioned concentrations of the proteins are detected Can provide.
  • the antigen-antibody complex means a combination of a periodontal disease biomarker protein and an antibody specific to it, and the amount of formation of the antigen-antibody complex can be quantitatively measured through the signal size of the detection label.
  • the marker protein of the present invention is a known protein
  • the antibody used in the present invention can be produced by a conventional method widely known in the field of immunology using the above-known protein as an antigen.
  • monoclonal antibodies can be prepared using known fusion methods, recombinant DNA and phage antibody library techniques.
  • Immunological analysis can be included without limitation as long as it can measure the binding of the antigen to the antibody.
  • These methods are known in the art, for example, immunocytochemistry and immunohistochemistry, radioimmunoassays, immunochromatograhy, enzyme linked immunoassay (ELISA), immunoblotting (immunoblotting), Farr assay, immunoprecipitation, and immunofluorescence.
  • non-marker clinical information of the subject may be additionally used.
  • the non-marker clinical information may be any one or more selected from the group consisting of measuring the depth of the subject's periodontal pocket, bleeding, and X-ray examination, but is not limited thereto.
  • the active MMP-8 comprises a peptide having at least 95% homology with any one or more sequences selected from the group consisting of site 1, site 2, site 3 and site 4 listed in Table 1 below. It may be.
  • the inactive MMP-8 may include a peptide having at least 95% homology to any one or more sequences listed in Table 2 below.
  • the present invention is a diagnosis or prognosis of periodontal disease comprising an antibody that specifically binds to an active type MMP-8 (active matrix metalloproteinase-8) and an antibody that specifically binds to an inactive type MMP-8 (pro Matrix Metalloproteinase-8). It provides a composition for.
  • the antibody may be a polyclonal antibody or a monoclonal antibody, but may preferably be a monoclonal antibody.
  • the monoclonal antibody can be quantitatively analyzed by performing a color development reaction using a secondary antibody bound with an enzyme such as alkaline phosphatase (AP) or horseradish peroxidase (HRP) and their substrate, or directly to the marker protein. Quantitative analysis can be performed using a combination of AP or HRP enzyme with a monoclonal antibody.
  • AP alkaline phosphatase
  • HRP horseradish peroxidase
  • FITC fluorescein isothiocyanat
  • PE phytoerythrin
  • the reaction between the marker protein and the antibody is immunochromatography, western blot, immunoprecipitation (IP), enzyme-linked immunoabsorbent assays (ELISA), immunostaining immunohistochemistry (IHC) and flow cytometry analysis (FACS) can be confirmed by any one or more protein identification experiments selected from the group consisting of, but is not limited thereto.
  • composition for diagnosing or prognosing periodontal disease may include primers or probes specific for nucleic acids encoding active MMP-8 and inactive MMP-8.
  • the present invention is an antibody specifically binding to the active type MMP-8 (active matrix metalloproteinase-8) and an antibody specifically binding to the inactive type MMP-8 (pro Matrix Metalloproteinase-8) or the active type MMP-8 And a primer or probe specific for nucleic acids encoding inactive MMP-8.
  • the kit according to the present invention can be used for microarray, gene amplification, dipstick rapid kit, ELISA analysis or immunoassay.
  • the kit may be a kit for diagnosing periodontal disease composed of a microarray.
  • the microarray is capable of detecting a protein specifically attached to the antibody by an antigen-antibody reaction by attaching the antibody on a slide glass surface treated with a specific reagent.
  • the kit comprising the antibody may further include one or more additional components necessary for analysis.
  • it may further include a buffer necessary for detection, a stabilizer, an inert protein, a sample collection tool, a negative and/or positive control, etc.
  • the antibody may include radionuclides and fluorescors. ), enzymes (enzyme) and the like.
  • the structure of the active MMP-8 is currently unknown (PDB ID: 2OY4), and the structure of the inactive MMP-8 is currently known as the inactive MMP-3 (PDB ID: 1SLM) and MMP-1 (PDB ID: 1SU3). ), and modeled using a modeler (Andrej Sali, USA, version 9.20) based on the structure of the active MMP-8 (FIG. 3 ).
  • the propeptide of the inactive MMP-8 was isolated and converted to the active MMP-8. At this time, under the judgment that the newly exposed portion is likely to exhibit the unique characteristics of the active type MMP-8 compared to the inactive type, surface exposure degree and polarity were calculated as properties that can affect the immune response. The values are shown in Table 3 below. This was calculated using ENVA (syntekabio, Korea), which can be used for environmental analysis of protein structures.
  • amino acid position including the active site of MMP-8 was selected by selecting a position where the difference in surface exposure and polarity between the active and inactive forms was large.
  • mice For the production of antibodies that specifically bind to active MMP-8, inactive MMP-8 and sIgA, these and adjuvants were mixed and injected into mice, and spleens were extracted from immunized mice.
  • the mouse cancer cells, SP2/0 cells and spleen cells were fused using PEG.
  • the fused cells were confirmed by ELISA, and the fused cells were selected and inoculated into the mouse peritoneal cavity. When ascites were formed in the abdominal cavity after inoculation, the samples were collected and purified using protein G gel.
  • FIG. 5(a) it was confirmed that the antibody that specifically binds to the active MMP-8 antigen does not react with the inactive MMP-8 antigen and has high reactivity with the active MMP-8.
  • FIG. 5(b) confirmed that the antibody that specifically binds to the inactive MMP-8 does not react with the active MMP-8 antigen, and has high reactivity with the inactive MMP-8.
  • Antibodies that specifically bind to sIgA were dispensed into the NC membrane. After mixing the sIgA-specific antibody-conjugated Europium bead and the sIgA antigen (Fitzgerald) in a development buffer, the antibody-dispersed NC membrane was immersed in the development buffer. After 10 minutes, the NC membrane was irradiated with a 365 nm UV lamp to confirm antigen-antibody binding. It can be seen through FIG. 5(c) that sIgA and the antibody formed a specific binding.
  • Active MMP-8 antigen and inactive MMP-8 antigen were diluted in saliva by concentrations according to Table 4 below, and then mixed 1:1 with a saliva storage solution to prepare an antigen solution.
  • the saliva storage solution was used by mixing 1.0 mM PMSF and 2.0 mM EDTA in PBS.
  • the antigen solution and the sample dilution were mixed at a ratio of 1:9 and then dispensed into the sample inlet of the MMP-8 measurement kit.
  • fluorescence signals of inactive MMP-8 and active MMP-8 were measured using a Time Resolved Fluorescence (TRF) measurement equipment. Quantitative curves were drawn using signals measured for each concentration. 6(a) and 6(b) show quantitative curves of the inactive type (pMMP-8) and the active type (aMMP-8), respectively.
  • saliva was collected from 14 subjects in the 20s and 80s who had no periodontal disease and 38 patients with periodontal disease among men and women in their 20s and 80s who visited the Seoul National University Dental Hospital Periodontology Department and One-Stop Consultation Center.
  • the normal control group is based on the case where there is no periodontal disease or the degree of gingivitis is very slight, and the depth of the periodontal pocket is less than 3 mm, and the group of periodontal disease patients is confirmed by bone loss progression on the radiograph and the depth of the periodontal pocket is 5 mm or more Classified as.
  • the clinical sample mixed 1:1 with the saliva storage solution was mixed with the sample diluent 1:9 and dispensed into the sample inlet of the MMP-8 measurement kit.
  • the MMP-8 measurement kit used a diagnostic kit based on Lateral Flow Assay for detecting MMP-8 by immunochromatography. After 10 minutes, fluorescence signals of active MMP-8 and inactive MMP-8 were measured using a Time Resolved Fluorescence (TRF) measurement equipment, and the measured signals were substituted into a quantitative curve to convert the concentration.
  • TRF Time Resolved Fluorescence
  • the fluorescence signal of sIgA was measured in the same manner as in the method of 3-1., except that the clinical sample was mixed with the sample dilution at 1:99, and the measured signal was substituted into a quantitative curve to convert the concentration.
  • the clinical sample mixed 1:1 with the saliva storage solution was mixed 1:1 with the sample diluent and dispensed at 100 ⁇ l in a 96-well plate, and the biotin-conjugate solution was dispensed at 50 ⁇ l and maintained at room temperature for 2 hours. Thereafter, after washing, 100 ⁇ l of streptavidin-HRP solution was dispensed and maintained at room temperature for 1 hour. After washing again, 100 ⁇ l of the TMB substrate reagent was dispensed, and the plate was wrapped with foil to maintain the temperature for 10 minutes at room temperature. After 100 ⁇ l of the reaction stop solution was dispensed, absorbance at 450 nm was measured.
  • Table 5 shows concentrations of inactive MMP-8, active MMP-8, sIgA, and IL-1beta.
  • inactive MMP-8, active MMP-8, sIgA and IL-1beta were all higher in the periodontal disease patient group than in the normal control group. Specifically, sIgA and IL-1beta showed a 1.45-fold and 3-fold concentration increase in the periodontal disease patient group compared to the normal control group. In particular, the inactive MMP-8 was 3.32 times, the active MMP-8 was 4.12 times, and the overall MMP Even at -8, it showed 3.72 times higher concentration difference compared to the normal control group.
  • the ratio of total MMP-8 to active MMP-8 and the ratio of active MMP-8 to sIgA which is one of the inflammatory disease markers, also determines periodontal disease through their significant difference. It can be confirmed that it can be an important factor.

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Abstract

La présente invention concerne un procédé de diagnostic d'une maladie parodontale. Plus particulièrement, une maladie parodontale est diagnostiquée lorsqu'un marqueur de maladie inflammatoire comprenant MMP-8, ou un marqueur dérivé d'une souche provoquant une maladie parodontale est détecté à une concentration accrue, par comparaison avec un échantillon provenant d'un contrôle normal. La détection de MMP-8 est effectuée séparément pour MMP-8 active et MMP-8 inactive, ce par quoi un procédé de diagnostic, une composition et un kit de diagnostic ou de prédiction du pronostic, qui sont de haute précision, peuvent être fournis.
PCT/KR2019/018497 2018-12-26 2019-12-26 Procédé de diagnostic d'une maladie parodontale, et composition et kit pour celui-ci WO2020138965A1 (fr)

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KR10-2018-0169547 2018-12-26
KR10-2019-0174381 2019-12-24
KR1020190174381A KR20200080183A (ko) 2018-12-26 2019-12-24 치주질환 진단 방법, 이를 위한 조성물 및 키트

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Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2009018342A1 (fr) * 2007-07-30 2009-02-05 The Regents Of The University Of Michigan Analyse multi-analyte de biomarqueurs de la salive comme prédicteurs d'une maladie périodontale et péri-implant
KR20160101889A (ko) * 2016-08-18 2016-08-26 서울대학교산학협력단 Odam의 치주질환 바이오마커로서의 용도
KR20160146668A (ko) * 2014-02-27 2016-12-21 오와이 메딕스 바이오케미카 에이비 Ｍｍｐ-8 활성화 생성물, 이의 결정 및 용도

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WO2009018342A1 (fr) * 2007-07-30 2009-02-05 The Regents Of The University Of Michigan Analyse multi-analyte de biomarqueurs de la salive comme prédicteurs d'une maladie périodontale et péri-implant
KR20160146668A (ko) * 2014-02-27 2016-12-21 오와이 메딕스 바이오케미카 에이비 Ｍｍｐ-8 활성화 생성물, 이의 결정 및 용도
KR20160101889A (ko) * 2016-08-18 2016-08-26 서울대학교산학협력단 Odam의 치주질환 바이오마커로서의 용도

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