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WO1991005996A1 - Procede d'analyse - Google Patents

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Publication number
WO1991005996A1
WO1991005996A1 PCT/EP1990/001723 EP9001723W WO9105996A1 WO 1991005996 A1 WO1991005996 A1 WO 1991005996A1 EP 9001723 W EP9001723 W EP 9001723W WO 9105996 A1 WO9105996 A1 WO 9105996A1
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WO
WIPO (PCT)
Prior art keywords
sample
sensor
radiation
optothermal
detection surface
Prior art date
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Application number
PCT/EP1990/001723
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English (en)
Inventor
Per Olof Folkesson Helander
Parvesh Masson
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VARILAB AB
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VARILAB AB
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Filing date
Publication date
Application filed by VARILAB AB filed Critical VARILAB AB
Publication of WO1991005996A1 publication Critical patent/WO1991005996A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/04—Investigating sedimentation of particle suspensions
    • G01N15/05—Investigating sedimentation of particle suspensions in blood
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/171—Systems in which incident light is modified in accordance with the properties of the material investigated with calorimetric detection, e.g. with thermal lens detection

Definitions

  • the present invention relates to the measurement of the erythrocyte sedimentation rate in blood samples.
  • the erythrocyte sedimentation rate (ESR) is the most common analysis for monitoring of the acute phase response in human illness.
  • the cellular and biochemical rationale for the increased sedimentation of red cells in disease states is not well understood.
  • the ESR measurement has been developed empirically through clinical experience over a period of several decades.
  • The- normal way of carrying out ESR measurement is that (a) blood is anticoagulated with one part of sodium citrate to four parts of blood; (b) the blood sample is either withdrawn in special test tubes or the blood is transferred to a capillary or a teflon tube; (c) the test tube or capillary is positioned vertically and protected from direct light or wind in order to avoid temperature fluctuations; and (d) the test result is read after one hour as the height of the clear plasma zone at the top of the vessel measured in millimeters.
  • the amount of haemoglobin may be measured directly in a blood sample without lysing the erythrocytes. This is possible because only that part of the sample which is in close proximity to the sensor is measured. The method is not dependent on absorption of light in a diluted sample, and may hence be utilized in very dense samples.
  • Primarynciples of optothermal spectroscopy by P. Helander, Uppsala J Med Sci 9: 155-158, 1986. It has also been observed that erythrocytes sedimenting towards the surface of a photoacoustic sensor cause an increased signal ("Whole blood -a sedimenting sample studied by photoacoustic spectroscopy" by P.Helander and I. Lundstr ⁇ m, J. Photoacoustics 1:203-215, 1982), although this was not regarded at that time as a quantifiable phenomenon so that there was no suggestion of any diagnostic applications of the technique.
  • the present invention is based on the observation that an optothermal sensor is capable of producing a determination of ESR in blood samples in a far shorter time than required by conventional ESR tests and with at least as great accuracy.
  • the method also lends itself to automation in giving an electrical signal from a relatively simple apparatus capable of processing successive blood samples at intervals of only one or two minutes.
  • a sample of anticoagulated blood is positioned in contact with and vertically above or below an essentially horizontally disposed detection surface of an optothermal sensor and erythrocytes in the sample are permitted to sediment vertically under gravity away from or towards said detection surface, the sample being periodically irradiated through said detection surface at a wavelength or wavelengths substantially absorbed by the erythrocytes whereby heat produced by absorption of said radiation by the sample is detected and provides signals indicative of the erythrocyte sedimentation rate of the sample.
  • the optothermal method has many advantages compared to other methods. Since the measurement takes place in close proximity to the detection surface as explained hereinafter, the system is nearly independent of the sample size for all practical purposes.
  • the conventional ESR estimation is a rather rough procedure without temperature standardization, and with an observation method showing gradually decreased precision as ESR increases.
  • the values obtained in the pathological range are therefore quite imprecise, and the method is more or less of qualitative nature.
  • the short period of observation using optothermic spectroscopy may avoid some variations of sedimentation rate due to temperature fluctuations over the conventional one-hour period.
  • the optothermal sensor may be a thermoacoustic system of the kind described in EP49918.
  • This method is based on a sample cell which consists of a transparent sensitive material connected to piezo-electric crystals and equipped with a light source.
  • a sample is put on one side of the temperature-sensitive material and exposed to light pulses from the opposite side through the support, the light may be absorbed by the sample.
  • the principle of optothermal spectroscopy may also utilize other types of sample cells. If the piezo- electric crystals are replaced by temperature-sensitive detectors positioned adjacent to the sample the absorbance of light is registered as an increase in heat conducted to such detectors rather than expansion of the material.
  • WO 90/08952 Such a system is described in WO 90/08952.
  • Both such systems have in common the use of a transparent detection surface or “window” through which the sample is irradiated by appropriate electromagnetic radiation and into which heat generated in the sample is received to produce an appropriate signal.
  • Particles suspended in a liquid medium will sediment at a certain rate dependent on, for example, their size, shape and relative weight and the viscosity of the liquid medium.
  • a suspension When such a suspension is applied vertically above or below the window of an optothermal sensor and exposed to one or more light pulses, the layer of particles in close proximity to the window will generate a varying signal as the particles sediment towards or away from the window.
  • the absorption of light near the window will increase or decrease as a function of time and the sedimentation properties of the erythrocytes.
  • the optothermal sensor can most conveniently be placed with the sample below the window and with the light coming from above. In this case the signal will decrease as sedimentation proceeds.
  • the optothermal sensor may advantageously be mounted in a flow chamber, whereby the blood sample may initially be agitated or flowing in order to prevent sedimentation.
  • a flow chamber designed to enhance the turbulence of blood flowing therethrough may conveniently be used.
  • the signal reading under such conditions will be at a maximum and can provide a measurement of the amount of haemoglobin in the sample, for example as described in WO 90/08952. If agitation or flow of the sample is then stopped, the erythrocytes begin to sediment and the signal falls at a rate which provides an indication of the ESR.
  • the method of the invention can thus provide a simultaneous measurement of ESR and haemoglobin level in a single sample, thus avoiding separate determinations.
  • Periodic irradiation of the sample may, for example, be achieved by irradiating with radiation which is modulated with respect to amplitude and/or wavelength, this being of advantage since it enables background errors such as overall temperature variations largely to be eliminated.
  • the frequency of signal amplification or other periodic means of electronic sampling can be locked onto the modulation frequency of the incident radiation so that extraneous temperature variations occurring between the pulses are not amplified.
  • the modulation frequency can be related to the rate of conduction of heat from the sample to the sensor.
  • the amplitude of the signals produced by the temperature fluctuations depends in part on the transfer of heat from irradiated sections of the sample at a certain distance from the surface of the transparent solid element. Heat generated at points deeper into the sample is not transferred to the sensor in the time between incidence of the radiation and sampling of the signal from the thermal detector.
  • the maximum depth within the sample from which heat contributes to the signal is termed the "thermal diffusion length" and defines the volume of the sample which is analysed. This definition of the volume makes quantification of an absorbing substance possible.
  • Amplitude modulation of the incident radiation can conveniently be achieved by a conventional mechanical light chopper placed in the collimated light path.
  • Variation of the wavelength of the incident light may, for example, be effected by a laser diode.
  • the modulation frequency should be low, e.g. 2-50 Hz, for example about 16 Hz, more preferably about 8Hz.
  • the thermal diffusion length may be longer to provide a more accurate determination which is less affected by sedimentation.
  • the initial Hgb determination may be at a lower modulation frequency and the ESR assay may then be continued at a higher frequency. It may often be advantageous to measure both the amplitude and the phase of the optothermal signal output since each of these parameters is affected by and can therefore be used to determine the ESR.
  • the periodic irradiation may comprise single pulses of radiation at appropriate intervals. Thus an initial pulse of radiation when the sample is homogeneous will give a response at the thermal detector after a delay which is related almost entirely to the conduction time of heat within the sensor.
  • the response signal from the detector accordingly begins shortly after the application of the radiation pulse (which is preferably of extremely short duration) and builds up to a maximum indicative of Hgb absorption. After some sedimentation has taken place and a clear layer has formed between the sensor and the upper layer of erythrocytes, the heat generated by absorption of the pulse has to traverse not only the material of the sensor but also the above-mentioned clear layer. This provides a time delay in the signal from the detector which is characteristic of the thickness of the clear layer and hence of the extent of sedimentation at the time of the pulse.
  • the pulses of radiation can be applied at regular intervals, and are to be distinguished from the amplitude modulated radiation described above, which has far higher frequency, e.g. 4-16 Hz.
  • Incident light is conveniently led to the sensor by means of an optical fibre system.
  • the light source may, for example, be a laser or a strong lamp. In general, it should be possible to produce incident radiation in the wavelength range 250 nm to 2500 nm.
  • the thermal detector may, for example, be a thermoelectric device such as thermistor or thermocouple or a thermooptical device such as a temperature responsive laser.
  • the solid heat conductive element may conveniently be made of diamond, which has a heat conductance six time that of copper, or sapphire or quartz, all of which are substantially completely transparent to ultraviolet, visible and infrared light.
  • the solid element is conveniently in the form of a block with two opposed ends and at least one side onto which a thermal detector can be mounted. The sample can then be mounted on or thermally contacted with one of the ends (the "sampling end") while the incident radiation enters the block through the opposite end, the path between the radiation source and the sample thus being unobstructed.
  • the distance between the sample and the thermal detector is preferably as small as possible, in order to minimise the time for conduction of heat from the sample to the detector and thereby achieve maximum sensitivity.
  • the specific conductivity of the solid element will be many times that of the sample.
  • the distance of the thermal detector from the end of the element will be of a similar order of magnitude to the dimensions of the sampling end.
  • the thermal detector might be mounted about 1 mm from a sampling end which itself is about 1 mm across.
  • the surface of the sampling end may extend further along the axis passing through the detector to provide a larger, essentially oblong, area in contact with the sample.
  • the thickness of the sample should exceed the thermal diffusion length and is preferably at least twice that length.
  • the thermal detector can readily be made of the same size or smaller than the heat conducting solid element. It is particularly convenient to mount the solid element on the end of an optical fibre; the signal from the thermal detector can be conducted by electrical wires or an optical fibre, conveniently mounted parallel to the optical fibre for the incident radiation. Sensors so arranged can be used in a wide range of applications besides measuring ESR, for example not only in in vitro experiments but also in in vivo. Thus, for example, such a sensor may be inserted into a blood vessel for continuous measurement of haemoglobin content.
  • the thermal detector is advantageously mounted on a surface of the heat conducting solid element which extends parallel to the radiation path. Substantially total internal reflection of the incident radiation at the said parallel surface should then prevent the radiation from reaching the detector. Such internal reflection may be enhanced by attaching the thermal detector to the solid element using an adhesive having a smaller index of refraction than the material of the solid element. Since materials such as sapphire and diamond have a high index of refraction, a wide range of adhesives may be used, including epoxy adhesives, cyanoacrylate adhesives and polyester adhesives. The adhesive may additionally be used to coat the remaining sides of the solid element to minimise egress of light therefrom.
  • Particularly suitable adhesives include electrically conductive glues such as metal epoxy glues, for example a silver epoxy such as Epo-tek H 20 E (manufactured by Epoxy Technology Inc., Mass., USA), since these ensure maximum light retention while also having good thermal and electrical conductivity.
  • electrically conductive glues such as metal epoxy glues, for example a silver epoxy such as Epo-tek H 20 E (manufactured by Epoxy Technology Inc., Mass., USA), since these ensure maximum light retention while also having good thermal and electrical conductivity.
  • the surface of the transparent solid element may be coated with a reflective layer, e.g. a thin layer of aluminium or silver, before attachment of the thermal detector.
  • One or more protective layers e.g. of any appropriate polymer material, may, for example, be applied over the whole sensor, excluding the surface in contact with the sample, in order to achieve this end.
  • modulated radiation provides a thermal diffusion length which, in general, will be relatively short, e.g. about 0.05-2 mm.
  • the ESR values of normal and pathological blood samples range from 2 to 120 mm per hour. The movement of the erythrocytes through the field determined by the thermal diffusion length is thus very small but the ESR may nevertheless be determined accurately in a remarkably short time as compared with conventional ESR measurements.
  • Qualitative evaluation may be effected simply by noting the difference in optothermal signal output at two set times after initiation of sedimentation, e.g. at a time 0-20 seconds after initiation and at a time 40-80 seconds after initiation.
  • the two measurements may conveniently be made about 10 seconds and about 60 seconds after initiation. Any observed deficiency in Hgb levels may advantageously be used as a correcting factor to afford an improved correlation in quantitive terms.
  • a series of reading can be taken and used to construct a sedimentation curve (i.e. a plot of signal output against time) , from which an intermediate angle indicative of ESR can be measured.
  • a sedimentation curve i.e. a plot of signal output against time
  • first and second average sedimentation rates from which a standardised erythrocyte sedimentation rage may be determined using any necessary temperature corrections and/or calibration coefficients. In this way it is possible substantially to correct for variations in the sedimentation rate during the observation period (the rate most commonly increases while initially random erythrocyte aggregates reorientate until they reach an orientation permitting maximum sedimentation velocity) .
  • ESR C.f(T) . (R ⁇ 3 . (R 2 ) (R n)
  • R 2 .... R n are preferably determined shortly after the onset of sedimentation, e.g. as soon as the signals from the detector employed have stabilised. The rates are advantageously determined within 5 minutes, more preferably within 2 minutes of this onset.
  • One convenient technique is to employ a 90 second measuring cycle in which the detector is allowed to stabilise in the initial 10 seconds, the remainder of the cycle being divided into two 40 second periods in each of which are made a number (conveniently 10) of individual or time- averaged readings.
  • the two series of readings can be processed to generate R 1 and R- by, for example, regression analysis to determine the closest fitting straight line plot of signal against time for each series of readings, the gradients of the two plots corresponding to R 1 and R 2 respectively.
  • readings or sets of readings may be adapted to one or more polynomial equations of the form
  • ⁇ is a constant selected to make f(T) equal to 1.0 at normal room temperature (e.g. 22°C) and ⁇ is a constant calculated from sample measurements at a range of temperatures T.
  • the calibration coefficient being chosen so that the regression line has a gradient of as near as possible to 1.0.
  • this procedure is conveniently effected by means of a microprocessor.
  • the signals provided by the sensor may be fitted to a polynomial equation as described above and the ESR computed therefrom.
  • Fig. 1 shows a thermal sensor incorporated into a flow chamber for use in accordance with the invention
  • Figs. 2 and 3 show similar thermal sensors incorporated into alternative forms of flow chambers.
  • a block 1 is formed with a flow chamber 2 having an inlet 3 and an outlet 4.
  • a recess 5 in the block 1 is adapted to receive a thermal sensor 6 which rests on an O-ring 7 abutting against a flange 8.
  • the sensor 6 is pressed into contact with the O-ring 7 by springs 9 held in position by a cap 10.
  • the sensor 6 comprises a body of cruciform vertical cross-section provided with a central, vertical, cylindrical hole into which is set a light path 11 leading to a sapphire window 12.
  • a thermistor 13 is provided laterally to the sapphire window 12 and is connected by electrical leads 14 to the signal sensing device (not shown) .
  • Figs. 2 and 3 The apparatus of Figs. 2 and 3 is essentialy similar except for the positioning of inlet 3 and outlet 4, which are designed in these embodiments to enhance the turbulence of the blood flow in the region of the optothermal sensor.
  • the optothermal sensor used had a sensitive area of 1 mm 2 and an outer diameter of 3mm and was associated with a 20W halogen lamp the light from which was chopped at a frequency of 16.7 Hz.
  • the flow chamber was rinsed with hypochlorite solution between introduction of each blood sample.
  • the blood flow from each sample was stopped once the flow chamber had filled, whereupon the erythrocytes began to sediment away from the sensor resulting in a reducing signal.
  • the signal level was noted at 10 seconds and at 60 seconds after stopping of the flow, and the % Hgb reduction over this interval was calculated from the ratio of these signals.
  • Example 1 An optothermal sensor not attached to a flow chamber was used to test the 1.8 ml samples put aside in Example 1. This dip-sensor was mounted at the end of a fibre-optic tubing and was protected from the surroundings by a layer of adhesive covering all surfaces except the 1 x 1 mm sapphire window. Each blood sample was shaken whereafter the sensor was dipped into the sample and positioned vertically throughout the measurements, which were made 10 seconds and 60 seconds after dipping. The results were processed as in Example 1 and are plotted against ESR in Fig. 6 of the accompanying drawings. The results may be summarised as follows:-
  • Example 1 The procedure of Example 1 was repeated except that the optothermal signal levels were measured continuously over a period of 60 seconds after stoppage of the blood flow.
  • Fig. 7 of the accompanying drawings is a plot of a sedimentation curve so obtained.
  • the initial disturbances in part due to delayed stabilisation of the detection equipment, confirm the advantage of allowing a 10 second delay before taking a first reading.
  • the sedimentation angle (s) affords a good indication of the ESR.
  • Example 1 The procedure of Example 1 was again repeated except that, after a 10 second delay to allow for stabilisation of the signal, signal levels were recorded at 4 second intervals for a total of 80 seconds, the first 10 readings being processed to give an averaged first sedimentation rate R-, and the last 10 readings to give an averaged second sedimentation rate R_. To enhance accuracy the amplitude and the phase of the signals were separately recorded and processed, the former in logarithmic form. Each set of readings was processed to determine the closest fitting straight line plot of signal against time in order to determine the appropriate R 1 and R 2 values.
  • Example 4 The procedure of Example 4 was used to determine ESR values for samples of blood anticoagulated with sodium citrate and for corresponding samples anticoagulated with EDTA (1-2% v/v, ca. 0.6 mmol/1) or with heparin ( ⁇ 1% v/v, ca. 20 U/ml) . Correlation curves for the results are shown in Fig. 9 and Fig. 10 of the accompanying drawings and confirm that the results are independent of the nature of the anticoagulant. Thus any blood sample prevented from coagulation may be tested in accordance with the invention.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

On détermine à des fins de diagnostic la vitesse de sédimentation d'érythrocytes dans un échantillon (2) de sang anticoagulé en mettant le sang en contact avec et verticalement au-dessus ou au-dessous de la surface sensiblement horizontale de détection (12) d'un capteur optothermique. On laisse les érythrocytes contenus dans l'échantillon se déposer sous l'effet de la gravité sur ou sous la surface de détection (12). On irradie périodiquement l'échantillon à travers la surface de détection avec des rayonnements tels que la chaleur générée lorsque l'échantillon absorbe les rayonnements soit détectée par un détecteur (13) et produise des signaux indicatifs de la vitesse de sédimentation des érythrocytes.
PCT/EP1990/001723 1989-10-11 1990-10-11 Procede d'analyse Ceased WO1991005996A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8922909.0 1989-10-11
GB898922909A GB8922909D0 (en) 1989-10-11 1989-10-11 Assay method

Publications (1)

Publication Number Publication Date
WO1991005996A1 true WO1991005996A1 (fr) 1991-05-02

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PCT/EP1990/001723 Ceased WO1991005996A1 (fr) 1989-10-11 1990-10-11 Procede d'analyse

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AU (1) AU6522490A (fr)
GB (1) GB8922909D0 (fr)
WO (1) WO1991005996A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2185927A4 (fr) * 2007-09-04 2013-01-09 Tommy Forsell Dispositif et procédé de détermination de la vitesse de sédimentation des érythrocytes dans un échantillon de sang
US20150268148A1 (en) * 2013-06-19 2015-09-24 Shenzhen Yhlo Biotech Co., Ltd. Full-automatic erythrocyte sedimentation rate analysis meter and detecting method thereof
CN112041658A (zh) * 2018-02-02 2020-12-04 雷恩第一大学 用于确定沉降或乳析的速率的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0049918A1 (fr) * 1980-10-10 1982-04-21 Ab Varilab Procédé de mesure photothermique pour l'étude de l'absorption de lumière par un échantillon d'une substance
EP0142481A2 (fr) * 1983-11-14 1985-05-22 Ab Varilab Procédé d'analyse d'un échantillon d'une substance par des moyens de spectroscopie photo-acoustique ou optothermique et porte-échantillons pour la réalisation du procédé
WO1986005275A1 (fr) * 1985-03-04 1986-09-12 Labsystems Oy Procede de mesure de la sedimentation
EP0282234A1 (fr) * 1987-03-03 1988-09-14 Elizabeth May Dowling Spectroscopie opto-acoustique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0049918A1 (fr) * 1980-10-10 1982-04-21 Ab Varilab Procédé de mesure photothermique pour l'étude de l'absorption de lumière par un échantillon d'une substance
EP0142481A2 (fr) * 1983-11-14 1985-05-22 Ab Varilab Procédé d'analyse d'un échantillon d'une substance par des moyens de spectroscopie photo-acoustique ou optothermique et porte-échantillons pour la réalisation du procédé
WO1986005275A1 (fr) * 1985-03-04 1986-09-12 Labsystems Oy Procede de mesure de la sedimentation
EP0282234A1 (fr) * 1987-03-03 1988-09-14 Elizabeth May Dowling Spectroscopie opto-acoustique

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2185927A4 (fr) * 2007-09-04 2013-01-09 Tommy Forsell Dispositif et procédé de détermination de la vitesse de sédimentation des érythrocytes dans un échantillon de sang
US8900514B2 (en) 2007-09-04 2014-12-02 Tommy Forsell Device for determining the erythrocyte sedimentation rate in a blood sample
US20150268148A1 (en) * 2013-06-19 2015-09-24 Shenzhen Yhlo Biotech Co., Ltd. Full-automatic erythrocyte sedimentation rate analysis meter and detecting method thereof
US9733175B2 (en) * 2013-06-19 2017-08-15 Shenzhen Yhlo Biotech Co., Ltd. Full-automatic erythrocyte sedimentation rate analysis meter and detecting method thereof
CN112041658A (zh) * 2018-02-02 2020-12-04 雷恩第一大学 用于确定沉降或乳析的速率的方法
CN112041658B (zh) * 2018-02-02 2023-11-28 雷恩第一大学 用于确定沉降或乳析的速率的方法

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GB8922909D0 (en) 1989-11-29
AU6522490A (en) 1991-05-16

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