WO2017175003A1 - Dosage amélioré d'agglutination de particules - Google Patents

Dosage amélioré d'agglutination de particules Download PDF

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Publication number
WO2017175003A1
WO2017175003A1 PCT/GB2017/050982 GB2017050982W WO2017175003A1 WO 2017175003 A1 WO2017175003 A1 WO 2017175003A1 GB 2017050982 W GB2017050982 W GB 2017050982W WO 2017175003 A1 WO2017175003 A1 WO 2017175003A1
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Prior art keywords
mixture
analyte
interval
seconds
optical property
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PCT/GB2017/050982
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English (en)
Inventor
David John Pritchard
Jeffrey Darren BRADY
Rebecca COCHRANE
Liam Ross DEVENNEY
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Axis-Shield Diagnostics Limited
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Publication of WO2017175003A1 publication Critical patent/WO2017175003A1/fr

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    • 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
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54393—Improving reaction conditions or stability, e.g. by coating or irradiation of surface, by reduction of non-specific binding, by promotion of specific binding

Definitions

  • Homogeneous assays have been developed to measure analytes through aggregation of particles that are present in one of the reagents. These assays are rapid and are more easily automated than heterogeneous assays, however they tend to suffer from problems associated with non-specific binding and non-specific aggregation of particles resulting in erroneous results being reported.
  • the present inventors have now surprisingly established that the non-specific binding and non-specific aggregation of particles can be much reduced by introducing an agitation or mixing step after the incubation of the sample with the particle containing reagent.
  • the present disclosure is based, at least in part, on the development of an improved particle agglutination assay method for the determination of a target of interest in a sample fluid.
  • a method for determining the presence (or absence) of an analyte in a sample involves the steps of: mixing a sample obtained from a subject with a particle-containing reagent, to form a mixture. The mixture is then incubated for a first interval of time; during which time the mixture may either be continually agitated or the mixture may be briefly agitated after the first interval of time has passed. An optical property of the mixture may be acquired either during the interval where the mixture is being continually agitated or at the end of the first interval once the mixture has been agitated. Based in part on the optical property of the mixture, a signal indicative of the analyte content of the sample is determined.
  • the step of acquiring an optical property of the sample can include determining an absorbance value, a transmittance value, a reflectance value, an indication of the light scattering characteristic of the sample, a fluorescence value, or a scintillation value.
  • TC1 is an interval where continuous agitation of the mixture is performed. During this interval phase conditions might be such that they favour specific aggregation events and mitigate non-specific aggregation events.
  • optical property values may be acquired during several intervals, referred to as T1 , T2, T3 or T4.
  • T1 represents an interval of time that runs from the time when the combination of the sample with the particle-containing reagent occurs to the time just before initiation of agitation of the mixture occurs.
  • T2 represents an interval of time that occurs after T1 and before initiation of agitation of the mixture.
  • T3 represents an interval of time that occurs after initiation of agitation of the mixture and T4 represents and interval of time that occurs after T3.
  • the first interval of time may be at least 15 seconds, at least 30 seconds, at least 45 seconds, at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, or at least 30 minutes.
  • the process of agitating the mixture can include stirring the mixture with a rod, stirring the mixture with a magnetic puck, stirring the mixture with a rotor, flowing the mixture through a nozzle, applying ultrasonic energy to the mixture, vortexing the mixture or shaking the mixture.
  • the analyte may be a protein, an antibody, an autoantibody, a peptide or a fragment thereof, or a polynucleotide or a fragment thereof.
  • the autoantibody may be an antibody against a citrullinated peptide or a cyclic citrullinated peptide.
  • the process of acquiring an optical property of the mixture includes acquiring one or more than one measurements of the optical property, during or after agitation of the mixture.
  • the process of acquiring an optical property of the mixture includes acquiring more than one measurement of the optical property of the mixture, before, during or after agitation of the mixture, where at least one measurement value is acquired prior to agitation of the mixture and at least one measurement value is acquired during or after agitation of the mixture.
  • measurements may be taken at a frequency of at least 0.01 Hz, at least 0.05 Hz, at least 0.1 Hz, at least 1 Hz, at least 3 Hz, at least 5 Hz, at least 10 Hz, at least 15 Hz, at least 30 Hz, at least 60 Hz, or at least 120 Hz.
  • measurement values may be obtained at least 0.1 seconds, at least 0.5 seconds, at least 1 seconds, at least 2 seconds, at least 3 seconds, at least 5 seconds, at least 10 seconds, at least 15 seconds, at least 30 seconds, at least 60 seconds, at least 120 seconds, at least 240 seconds, at least 360 seconds, or at least 500 seconds after initiation of agitation of the mixture or after cessation of agitation of the mixture.
  • the process of determining a signal indicative of the analyte content of the sample involves comparing the at least one optical property value of the mixture with an optical property represented by a standard value for the analyte of interest and obtaining an analyte quantity value based on the difference between the measured value and the standard value.
  • the process of determining a signal indicative of the analyte content of the sample involves comparing the at least one optical property value against a
  • predetermined threshold value for the analyte of interest assigning positive or negative outcome depending on whether the measured value is greater or lower than the threshold value.
  • the process of determining a signal indicative of the analyte content of the sample includes obtaining one or more measurement values during interval TC1 and determining a quantity value for the analyte from the measurements or assigning a positive or negative outcome based on the measurements.
  • the process of determining a signal indicative of the analyte content includes obtaining one or more measurements during interval T3 and determining an analyte value or identifying whether a positive or negative outcome should be assigned based on the one or more measurements.
  • the process of determining a signal indicative of the analyte content includes comparing one or more measurements obtained during interval T1 with one or more measurements obtained during interval T3, and from the comparison determining either an analyte concentration value or identifying whether a positive or negative outcome applies.
  • the process of determining a signal indicative of the analyte content includes comparing one or more measurements made during interval T2 with one or more measurements made during interval T3, and from these determining either an analyte concentration value or identifying whether a positive or negative outcome applies.
  • the process of determining a signal indicative of the analyte content includes comparing one or more measurements made during interval T3 with one or more measurements made during interval T4, and from these determining either an analyte concentration value or whether a positive or negative outcome applies.
  • the step of comparing values from one interval T1 to T4 with values from another interval T1 to T4 can include subtracting a measurement value obtained during one interval from measurement values in another interval; or the step of comparing values may involve dividing measurement values from one interval with measurement values from another other interval.
  • a homogeneous particle assay method that has a reduced susceptibility to non-specific binding.
  • the assay method can include the following steps: (1) incubating a sample with a particle reagent that includes at least one binding pair member for the analyte of interest whilst monitoring an optical property value of the mixture and obtaining one or more optical property values of the mixture; (2) incubating the particle containing mixture so as to form aggregated particles due to interaction of a target of interest in the sample, if present, with its binding pair member on the particle; (3) agitating the sample to disrupt aggregated particles and continuing to monitor the optical property of the mixture and obtaining further optical property values of the mixture; (4) determining the difference between the optical property values obtained before agitation of the mixture and the optical property values obtained after agitation of the mixture; and (5) determining the amount of target based on the difference in the optical property values.
  • the process of performing the homogeneous particle assay method that has a reduced susceptibility to non-specific binding includes a step of agitation that preferentially disrupts any non-specifically aggregated particles, which generally results in a greater change in the optical property value compared with the change in optical property value that might occur for particles that have aggregated as a result of the specific binding of target of interest with its binding pair member on the particle.
  • the process of performing the homogeneous particle assay method that has a reduced susceptibility to non-specific binding is directed to an antibody that may be potentially present in the sample.
  • that antibody might be an autoantibody.
  • autoantibody might be an anti-citrulinated peptide antibody or an anti-cyclic citrullinated peptide (aCCP) antibody.
  • aCCP anti-cyclic citrullinated peptide
  • the autoantibody may be an antibody against gliadin, cardiolipin, beta 2 glycoprotein 1 , DNA, thyroid peroxidase, thyroglobulin, Intrinsic Factor, Insulin, histone.
  • the process of performing the homogeneous particle assay method that has a reduced susceptibility to non-specific binding the assay might be directed to an antigen that may be potentially present in the sample.
  • the antigen might be a protein, a peptide or fragment thereof, a polynucleotide or fragment thereof, a carbohydrate, a lipid, or a lipopolysaccharide.
  • the disclosure describes a method for determining the presence or absence of an analyte of interest in a sample.
  • the method provides for a reduction in the effects of non-specific binding in a particle based agglutination assay.
  • the sample may be a blood, plasma, serum or other body fluid sample.
  • Particles may be formed using noble metals, such as gold or silver; particles may also be formed using latex or polystyrene; particles may also be formed using fumed silica or other materials suitable for the process.
  • the method can include the steps of obtaining a sample from a subject; mixing the sample with a particle-containing reagent, to form a mixture; and incubating the mixture for a first interval of time to begin to form an agglutinated reaction product.
  • An increase in the degree of aggregation may be followed by monitoring a change in the absorbance of the reaction mixture.
  • Monitoring of the agglutination reaction might be performed by recording a single measurement value at a specific point in time after initial mixing of the sample with the reagent, or monitoring might involve recording a series of measurement values (continuous monitoring) over an interval of time to provide a profile.
  • the first interval of time may be as short as 1 second, but may exceed 30 minutes. In certain aspects the first interval of time might be at least about 1 second, at least about 3 seconds, at least about 5 seconds, at least about 10 seconds, at least about 15 seconds, at least about 30 seconds, at least about 45 seconds, at least about 1 minute, at least about 2 minutes, at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, or at least about 30 minutes.
  • the acquisition of absorbance measurement data may be performed at a frequency of at least about 0.1 Hz, at least about 1 Hz, at least about 3 Hz, at least about 1 5 Hz, at least about 10 Hz, at least about 15 Hz, at least about 30 Hz, at least about 60 Hz, at least about 120 Hz.
  • absorbance readings might be acquired after at least 0.1 seconds, at least 1 seconds, at least 2 seconds, at least 3 seconds, at least 5 seconds, at least 10 seconds, at least 15 seconds, or at least 30 seconds of the specific event.
  • the method can further include agitating the sample reagent mixture after a first interval of time to essentially disrupt the agglutinated particles that have formed within the mixture.
  • the intensity of agitation may generally be selected such that it will result in breaking of aggregates that have formed as a result of non-specific binding, but will not result in disruption of specific binding interactions that have formed between the target of interest and the particle reagents.
  • the method also includes further monitoring of the agglutination process as before for a second interval of time, by either taking a single absorbance measurement at a defined time since agitation of the mixture commenced, or by continually acquiring absorbance values to provide a profile.
  • the second interval of time may also be as short as 1 second, but may exceed 30 minutes.
  • the first interval of time might be at least about 1 second, at least about 3 seconds, at least about 5 seconds, at least about 10 seconds, at least about 15 seconds, at least about 30 seconds, at least about 45 seconds, at least about 1 minute, at least about 2 minutes, at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, or at least about 30 minutes.
  • the method further includes a determination step, in which a determination is made of the extent of the particle agglutination that has occurred as a result of the specific interaction between the particle reagent and the target of interest in the sample, while minimising effects resulting in changes in the measured response due to non-specific binding between particle reagents and other components of the sample.
  • the determination step involves determining a difference in the absorbance value prior to the commencement of the agglutination reaction and the absorbance value following the agitation step to disrupt agglutination predominantly due to non-specific binding.
  • the process of monitoring a change in the absorbance of the reaction mixture can include (i) acquiring a plurality of absorbance measurements as a function of time, before, during and after formation and agitation of the mixture (ii) acquiring a single absorbance measurement at a defined point in time after formation of the mixture, and (iii) acquiring a single absorbance measurement at a defined point in time following agitation of the mixture.
  • the wavelength of light used to illuminate the reaction mixture may be selected according to the composition of the particles used in the assay.
  • the process of agitation of the mixture can involve relatively gentle procedures, such as stirring the reaction mixture with a rod, flowing the mixture through a nozzle, or shaking the reaction mixture. More vigorous means of agitation might include stirring with a magnetic puck, stirring with a rotor, applying ultrasonic energy, or vortexing the mixture in order to disrupt any non-specific bonds between the particles of the reagent.
  • an agitation process will be selected which does not significantly disrupt any specific bonds formed between the target of interest and the particle reagent, but selectively disrupts non-specific interactions.
  • the target of interest may be an antibody that may be present in the sample; the antibody may be an autoantibody.
  • the autoantibody may for example be an antibody against cyclic citrullinated peptide or a citrullinated protein, an antibody against tenascin-c, an antibody against gliadin, an antibody against cardiolipin, an antibody against beta 2 glycoprotein 1 , an antibody against DNA, an antibody against thyroid peroxidase, an antibody against thyroglobulin, an antibody against Intrinsic Factor, an antibody against Insulin, or an antibody against histone.
  • the skilled person will recognise this is a non- exhaustive list and the invention may be applied to numerous other autoantibodies.
  • the target of interest may be a peptide or fragment thereof; or the target of interest may be a polynucleotide or fragment thereof.
  • the disclosure represents a homogeneous particle assay method which has a reduced susceptibility to the effects of non-specific binding.
  • the assay method involves incubating a sample suspected of containing a target of interest with a particle reagent that includes at least one binding pair member for the target linked to the particle. During initial mixing of the sample suspected of containing the target of interest with the particle reagent, the change in absorbance of the mixture may be monitored to obtain a first absorbance value. The reaction mixture may be further incubated so as to form aggregated or agglutinated particles due to interaction of the target of interest in the sample, if present, with its binding pair member on the surface of the particle. The change in absorbance of the reaction mixture may be further monitored to obtain a second absorbance value.
  • the sample particle mixture might be mixed or agitated in order to prevent aggregation of particles or disrupt any particles that might have aggregated as a result of non-specific interactions due to other components within the sample, or due to sample matrix effects.
  • a change in the absorbance of the mixture may be further monitored to obtain a further absorbance value.
  • differences between the various recorded absorbance values can be determined, and from these differences a determination of the amount of target of interest present in the sample may be made based on the differences in absorbance at the specific points during the course of the reaction.
  • the step of agitation preferentially disrupts non- specifically aggregated particles, which results in a greater reduction of absorbance compared with a population of particles that have aggregated due to specific binding of target of interest with binding pair member on the particle.
  • the assay method may be used to determine whether an antibody is potentially present in the sample.
  • the antibody may be an autoantibody.
  • Exemplary autoantibodies can include anti-cyclic citrulinated peptide (aCCP); anti tenascin-c.
  • the assay method may also be used to determine whether a peptide or fragment thereof, a polynucleotide or fragment thereof, a carbohydrate, a lipid, a lipopolysaccharide, or other target of interest may be present in a sample.
  • Turbidimetric determination in the present invention is homogeneous and numerous washing and/or separation steps are not required.
  • determination of the analyte is quick and easy to perform and may, for instance, be readily automated.
  • an automated, homogeneous turbidimetric assay is also fast, allowing for a high throughput of samples, and is relatively cheap to run.
  • it can be performed using a commercially available robot, e. g. the Cobas Mira or Hitachi 917, both of which are available from Roche Diagnostics or the DxC 600 (Synchron) available from Beckman Coulter.
  • a commercially available robot e. g. the Cobas Mira or Hitachi 917, both of which are available from Roche Diagnostics or the DxC 600 (Synchron) available from Beckman Coulter.
  • Such an automated assay is particularly attractive when routine testing of individuals for potential for or propensity to disease is envisaged.
  • a key step is determination of analyte presence or concentration
  • the analyte-containing sample will generally be a body fluid, e.g. urine, cerebrospinal fluid, oral fluid, synovial fluid or emphysema fluid, or more preferably, whole blood or a blood derived sample.
  • the sample used for analysis will preferably be cell-depleted (e. g. serum or plasma).
  • Cell depletion will typically be by removal of at least 70% of the cells from a sample, preferably at least 80% and more preferably at least 90%. Up to substantially 100% of the cells may be removed.
  • Any of the sample fluids, including blood and blood derivatives may be treated to remove any cells and/or any sample components not being assayed for.
  • the sample may also be treated to concentrate or dilute the sample.
  • sample pre-treatment including centrifugation, separation of specific components, or addition of preservatives such as anticoagulants is also appropriate if necessary.
  • the sample may be diluted by adding water, a buffer or other aqueous medium.
  • a sample particularly a whole-blood, serum or plasma sample, may be used directly.
  • the subject from whom the sample is taken and for whom the diagnosis or analysis of risk or probability will be made is a human or non-human animal subject, especially a mammal and preferably a human, canine or feline mammal. Human subjects are most preferred.
  • the subject may be a subject with or without any existing clinical manifestations of disease.
  • the signal generating moiety may be, for example a particle in the case of a turbidimetric assay; a fluorophore as first signal generating moiety, and optionally, also a larger molecule such as a particle or macromolecule as second signal generating moiety in the case of an fluorescence polarisation assay; one or both of the required fluorophores in the case of a FRET assay; or the scintillant and/or the radioisotope in assays using radioactivity.
  • the signal binding moieties may be of greater value to bring several signal binding moieties together to form an extended network. This may be achieved by binding more than one (e.g. 2 to 1000, especially 2 to 100) specific binders to a single signal generating moiety.
  • the signal generating moiety may be the specific binder itself rather than a separate entity. In such cases, it is the act of binding which generates the signal, and such signals are typically physical changes, such as a difference in the scattering properties of the sample, or very small changes in sample temperature due to liberated binding energy.
  • the specific binder is inherently multivalent (e.g.
  • the mass of the binder itself may be the signal generating moiety, because when the specific binders are brought together, a cross-linked network will form generating aggregates of detectable size.
  • analyte antigenic sequences are linked together, either in a single peptide or as antigens attached to a backbone molecule or particle, a cross-linked network will form generating aggregates of detectable size.
  • opacity may be generated by contacting the analyte containing sample, or an aliquot thereof, with an analyte specific binding partner, preferably bound to an opacity generating moiety, such as a nanoparticle or a microparticle.
  • an analyte specific binding partner preferably bound to an opacity generating moiety, such as a nanoparticle or a microparticle.
  • two or more (e.g. 2 to 1000, especially 2 to 100) analyte specific binding partner molecules may be bound to each particle.
  • Analyte specific binding partners useful in the methods of the invention for determination of analyte concentration preferably show no or little cross reactions with other constituents that may be present in the biological fluid.
  • the quantity of analyte specific binding partner used in any case can of course be optimized against analyte-containing standard samples. This is particularly important in methods such as turbidimetry and other methods involving cross-linking/oligomerisation as these effects may be non-linear.
  • opacification arises from the hook effect whereby multiple analyte binding generates the opacification centres.
  • the required degree of binding for this effect will, however, depend upon factors such as the size of the signal generating moieties and the average number of specific binders linked to each of these.
  • analyte specific binding partner may be immobilized by binding or coupling, either directly or indirectly, to any well-known solid support or matrix which is commonly used for immobilization in homogeneous
  • the solid support or matrix preferably takes the form of particles, most preferably particles which may be suspended in aqueous media and are smaller than the wavelengths of red, preferably blue and more preferably ultra-violet light (e.g. less than 250 nm). Nanoparticles are most preferred, especially those having a diameter of between 0.5 and 800 nm, preferably, between 2 and 250 nm, more preferably between 10 and 100 nm.
  • the solid support may be made of glass, silica, latex, metal (e. g. gold) or a polymeric material (e. g. polyethylene).
  • the solid support is made of a polymeric material such as polyethylene.
  • the particles to which the specific binder may be bound in a turbidimetric embodiment are typically spherical.
  • Figure 1 Schematic of assay protocol for turbidimetric assay without additional mix step.
  • Figure 2 Schematic of assay protocol for turbidimetric assay with additional mix step.
  • FIG. 3 ROC curves for assays with and without additional mix step, and associated tables relating to number of samples (320), number of samples from patients without rheumatoid arthritis (220) and samples form patients with rheumatoid arthritis (100), and various statistical analyses of the data.
  • 320 serum samples (220 from patients without rheumatoid arthritis, 100 from patients with rheumatoid arthritis) were assayed using homogeneous assays with and without an additional agitation step.
  • a schematic protocol for assay with no additional mix step is shown in Figure 1
  • a schematic protocol for assay with an additional mix step is shown in Figure 2.
  • the reagents were the same, R1 consisting of a sample diluent that contains factors that assist with aggregation of particles, and R2 containing micro-particles that are coated with a citrullinated peptide that acts as target for anti-CCP antibodies.
  • the time of the first incubation was 200 seconds and the time of the second incubation was 280 seconds.
  • the change in absorbance over 280 seconds after the addition of micro particles was measured.
  • the aCCP antibody concentration was obtained by comparing this change in absorbance to that provided by calibrators containing a known concentration of aCCP antibody.
  • the absorbance values for Read 1 were calculated from the average of 2 values (the first immediately after addition of micro particles and the second 20 seconds later) whilst the absorbance values for Read 2 were calculated from the average of 2 values (the first immediately after the additional agitation step and the second 20 seconds later).
  • the aCCP antibody concentration was obtained by subtracting Read 1 from Read 2 and comparing the response to that provided by calibrators containing a known concentration of aCCP antibody.
  • Receiver Operator Characteristic (ROC) curves were generated against rheumatoid arthritis classification and are shown in Figure 3.
  • Area under the curve (AUC) was 0.92 for the assay with no additional agitation (mix) step, whereas it was 0.99 for the assay that included an additional agitation (mix) step.

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Abstract

La présente invention concerne un procédé pour déterminer la présence ou l'absence d'un analyte dans un échantillon, ledit procédé comprenant les étapes suivantes : mélanger un échantillon obtenu à partir d'un sujet avec un réactif contenant des particules, pour former un mélange ; incuber le mélange pendant un premier intervalle de temps, pendant lequel, soit le mélange peut être agité en continu, soit le mélange peut être brièvement agité après que le premier intervalle de temps s'est écoulé ; acquérir une propriété optique du mélange, soit pendant l'intervalle où le mélange est agité en continu, soit à la fin du premier intervalle une fois que le mélange a été agité, ce par quoi un signal indiquant la teneur en analyte de l'échantillon est déterminé.
PCT/GB2017/050982 2016-04-08 2017-04-07 Dosage amélioré d'agglutination de particules WO2017175003A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4760030A (en) * 1984-09-10 1988-07-26 Syntex (U.S.A.) Inc. Quantitative opaque particle agglutination assay
US5043289A (en) * 1986-09-30 1991-08-27 Serres Pierre F Method and device for assaying immunologically reactive substances of clinical interest
WO2002018950A1 (fr) * 2000-08-28 2002-03-07 The Trustees Of Columbia University In The City Of New York Detection d'anticorps anti-glycolipides par detection de l'agglutination au latex
US20110263042A1 (en) * 2008-02-20 2011-10-27 Axis-Shield Diagnostics Ltd. Assay method for antibodies against cyclic citrullinated peptide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4760030A (en) * 1984-09-10 1988-07-26 Syntex (U.S.A.) Inc. Quantitative opaque particle agglutination assay
US5043289A (en) * 1986-09-30 1991-08-27 Serres Pierre F Method and device for assaying immunologically reactive substances of clinical interest
WO2002018950A1 (fr) * 2000-08-28 2002-03-07 The Trustees Of Columbia University In The City Of New York Detection d'anticorps anti-glycolipides par detection de l'agglutination au latex
US20110263042A1 (en) * 2008-02-20 2011-10-27 Axis-Shield Diagnostics Ltd. Assay method for antibodies against cyclic citrullinated peptide

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRUNO TESTE ET AL: "A low cost and high throughput magnetic bead-based immuno-agglutination assay in confined droplets", LAB ON A CHIP, vol. 13, no. 12, 26 March 2013 (2013-03-26), pages 2344 - 2349, XP055202306, ISSN: 1473-0197, DOI: 10.1039/c3lc50353d *
G. DEGR? ET AL: "Improving agglutination tests by working in microfluidic channels", LAB ON A CHIP, vol. 5, no. 6, 1 January 2005 (2005-01-01), pages 691, XP055383390, ISSN: 1473-0197, DOI: 10.1039/b501695a *

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