Device and method intended to measure the properties of a complex medium by analysis of the variation in backscattered and/or transmitted light

Disclosed is a device and method intended to measure the properties of a complex medium (2) by analyzing the variation in light backscattered by this complex medium (2) after a prior stirring step. The device and the method include movement element (14) capable of subjecting the receiving element (6) to a stirring movement including at least a back-and-forth movement along a directional vector extending by a not insignificant amount along the longitudinal direction, so as to generate shear stresses in the complex medium (2), thereby destroying aggregates in the complex medium (2) when a container (4) is received and supported by the receiving element (6).

BACKGROUND OF THE INVENTION

The invention relates to the field of measuring the properties of a complex medium.

The invention relates to a device and a process designed to measure the properties of a complex medium by an analysis of the variation in light that is backscattered and/or transmitted by this complex medium after a preliminary stirring stage.

SUMMARY OF THE INVENTION

By way of nonlimiting example, such a device is used for measuring an aggregation time and/or a sedimentation index of a complex medium, such as a blood suspension.

For example, the analysis of the rate of aggregation of a blood suspension makes it possible to identify the elevation of the aggregation of blood in patients suffering from pathologies such as diabetes, hypertension, cerebrovascular accidents, venous return stasis, glaucoma, etc.

Actually, the viscosity of the blood depends on numerous parameters, including the aggregability of the red globules as well as the composition of macromolecules of plasma. The aggregability of the red globules, which is a reversible phenomenon, depends on the flow conditions. The size of the aggregates that are formed can reach 50 to 100 μm in the low shear zones of the microcirculatory network. In these zones, more particularly on the venular side, the aggregates cluster in the center of the vessel, creating, near the wall, a layer of plasma that is devoid of globules; this promotes a reduction of the apparent viscosity of the blood suspension. This reduction can be performed, however, only if the aggregation level is not too high and the aggregates can be destroyed in the passage of the terminal capillaries with a diameter that is smaller than the size of the aggregate, where the shearing increases. In contrast, when the aggregation is too high, the circulation is slowed down and even blocked. The knowledge of aggregation in the blood is therefore useful for the physician seeking to prevent certain hemorheological risks.

According to a first of its aspects, the invention relates to a device that is designed to measure the properties of a complex medium by an analysis of the variation in the light that is backscattered and/or transmitted by the complex medium during a measuring phase after a preliminary stirring stage, with this complex medium comprising aggregates and being contained in a container extending in a longitudinal direction. In this connection, the measuring device comprises receiving means that are capable of accommodating and supporting the container; holding means that are capable of holding this container in a stationary or essentially stationary position with respect to the receiving means when these receiving means are driven by a stirring motion that causes the destruction of the aggregates of said complex medium; means for support of a module for measuring the light that is backscattered and/or transmitted by said complex medium, with the support means being capable of being combined structurally with the measuring module in such a way as to support it and arranged with respect to said receiving means in such a way as to make it possible for the measuring module to emit emission light rays in such a way as to illuminate said complex medium and to receive light rays that are backscattered and/or transmitted by said complex medium at any moment of the measuring phase when this measuring module is structurally combined with the support means.

Such a device is known from the state of the art, in particular by the example given by the document “RBC Laser Diffractometry and RBC Aggregation with a Rotational Viscometer: Comparison with Rheoscope and Myrenne Aggrometer,” M. R. Hardeman, R. M. Bauersachs, H. J. Meiselman. Clin. Hemorheol. Actually, this document describes a device based on the measurement of the light that is backscattered by the complex medium that constitutes the blood suspension.

Its principle is as follows. The blood suspension is illuminated by a light beam in such a way that the more aggregated the red globules, the lower the backscattered light intensity, with the illuminated surface being smaller. The blood suspension—constituting the complex medium—is placed between two coaxial cylinders, one of which can rotate quickly so as to subject the aggregates to a shear that is sufficient for disaggregating them. When the rotating cylinder is suddenly stopped, the aggregates get back together again more or less quickly. The aggregation time is then one of the parameters making it possible to characterize the aggregation capacity of the red globules from the analysis of curves showing the temporal variation in the intensity of the light that is backscattered by the complex medium.

However, the use of this device presents several drawbacks. Firstly, it is necessary, to carry out the measuring, to open the tubes that contain blood samples so as to introduce the blood suspension between the two coaxial cylinders. However, the legislation set in place in recent years relating to the handling of human blood imposed numerous precautions, making this type of handling unworkable. In addition, the cleaning of the thin space between the two coaxial cylinders is particularly difficult and requires a preparation time of approximately 15 minutes per sample. Likewise, the time advised for carrying out the disaggregation of the aggregates for taking the measurement is several minutes, which is prohibitive for routine measurements. Finally, the complex mechanical system that consists in rotating one of the coaxial cylinders relative to the other is of relatively high cost.

Also known from the state of the art is the document WO-A-2008/072870 that describes a device for measuring the rate of aggregation of a blood suspension. This device comprises in particular a container for accommodating the blood suspension and a stirring mechanism to be integrated into the container for disaggregating the aggregations contained in this blood suspension in such a way as to obtain the initial conditions of the measurement as well as an induction unit that makes it possible to put the stifling mechanism into motion.

As above, this device has several drawbacks. Actually, the dimensions of the container necessarily have to be suitable for accommodating a stirring mechanism, which generally involves transferring the blood suspension from a blood sample tube to a special container. In addition, it is essential to introduce the stifling mechanism inside the container, which causes restrictive safety problems taking into account above-mentioned legislative standards with respect to the handling of blood samples. It should also be emphasized that the disaggregation achieved using the stirring mechanism is not optimal.

In a field that is different from that of the stifling mechanisms designed to mix blood with an anti-coagulating liquid, the document FR-A-2 501 057 is also known. The latter has a mechanism for stirring blood in pouches having an oscillating plate whose motion is imparted by three rollers forming an inclined plane. Three roller-support arms are attached to a turntable comprising a gearwheel that engages a pinion attached to the output shaft of a speed reducer driven by an electric motor.

Again, this device has drawbacks. It does not make it possible to stir the pouch enough to achieve disaggregation of the aggregates contained in the blood. Also, in any case, the stirring should be extended for a significant period that is not suitable for routine measurements.

In this context, the invention has as its object to propose a device and a process that are designed to measure the properties of a complex medium that is free of at least one of the above-mentioned limitations.

More particularly, there is an unsatisfied need for a device and a process designed to measure the properties of a complex medium by an analysis of the variation in the light that is backscattered and/or transmitted by the complex medium during a measuring phase after a preliminary stirring stage that makes it possible to carry out an optimum disaggregation of the aggregates in a minimum time interval, without requiring the opening of the container receiving the complex medium that is to be analyzed.

For this purpose, the device and the process according to the invention, furthermore in accordance with the generic definition that the preamble above provides, are essentially characterized in that they comprise means for putting into motion that are capable of imposing on said receiving means a stirring motion comprising at least one back-and-forth movement according to a directional vector extending in a significant proportion in the longitudinal direction in such a way as to cause shear stresses in the complex medium bringing about the destruction of the aggregates of said complex medium when said container is accommodated and supported by the receiving means.

Owing to this arrangement, it is possible to impose on a container, such as a blood sample tube, a motion that can produce shear stresses that are high enough to disaggregate the aggregates contained in the complex medium within a limited time interval. Surprisingly enough, it was actually noted that this motion—similar to the gesture by a nurse who stirs a blood sample tube essentially over its length—makes it possible to obtain a particularly high disaggregation rate in a short time. In addition, such a configuration makes it possible to use a blood suspension that is taken directly from a patient without the necessity for transfusing this blood suspension from the blood sample tube to a container that is specially provided for this purpose. In particular, the stage for cleaning the container is also eliminated, and, after analysis, the sample tube can be reused without the state of the blood suspension having been modified.

It should be noted that a “directional vector extending in a significant proportion in the longitudinal direction” means any directional vector that has a longitudinal component—corresponding to a projection of the directional vector in the longitudinal direction of the container when it is in position in the receiving means—sufficient for disaggregating the aggregates of the complex medium. Preferably, this longitudinal component exceeds any other transverse component extending in a direction that is perpendicular to the above-mentioned longitudinal direction.

It should also be noted that the term of “complex medium” indicates any type of medium that, when it is subjected to shear stresses, changes structure, which brings about the destruction of aggregates or other types of clusters and allows a return to a reproducible initial state.

According to one embodiment, the means for putting into motion are capable of imposing on said receiving means a stirring motion that comprises at least one back-and-forth movement according to a unidirectional translational movement.

According to one embodiment, the means for putting into motion are capable of imposing on said receiving means a stirring motion that comprises at least one back-and-forth movement according to a circular translational movement around an axis of rotation.

According to one embodiment, the means for putting into motion are capable of imposing on said receiving means a stirring motion that comprises at least one back-and-forth movement in a rotation around an axis of rotation. In particular, the axis of rotation can be positioned at a distance that is essentially between 50 and 200 millimeters from the center of gravity of the receiving means, and the back-and-forth movement around the axis of rotation can be essentially between 10° and 90°.

It was noted that such rotational motion is sufficient to bring about very simply high shear stresses inside the container and thus to obtain a high disaggregation rate.

According to one embodiment, the means for putting into motion comprise a motor that has a rotary shaft, a lever arm working with the rotary shaft and connected to the receiving means in such a way that the means for putting into motion are capable of driving the receiving means in movement around the rotary shaft.

According to one embodiment, the holding means are formed by O-ring seals that cover a portion of the inside surface of the receiving means. Thus, the container can be held with receiving means by simple adhesion with the O-ring seals.

According to one embodiment, the holding means are formed by a clamp or a stop part that may or may not be deformable.

According to one embodiment that comprises the module for measuring the light that is backscattered and/or transmitted by said complex medium, the latter comprises a light source that is capable of emitting the emission light rays in the direction of said complex medium in such a way as to illuminate said complex medium, and an optical detector that is capable of receiving the light rays that are backscattered and/or transmitted by said complex medium in response to the illumination of said complex medium.

According to one embodiment, the light source emits monochromatic radiation.

According to one embodiment, the support means of the measuring module are structurally and functionally combined with receiving means of the container in such a way that the stifling motion imposed on the receiving means is also imposed on the measuring module. Cohesion between the measuring module and the receiving means is thus obtained, which makes it possible to ensure the relative position of the measuring module relative to the complex medium contained in the container.

According to one embodiment, the support means of the measuring module are structurally separated from the receiving means in such a way that these support means are in relative motion with respect to these receiving means when said receiving means are in a stirring motion.

According to one embodiment, the receiving means have a window that is arranged relative to the support means in such a way that the emission light rays and the backscattered light rays are able to pass through this window during the measuring phase.

According to another aspect, the invention also relates to a process that is designed to measure the properties of a complex medium by an analysis of the variation in the light that is backscattered and/or transmitted by the complex medium during a measuring phase after a preliminary stifling stage, with this complex medium comprising aggregates and being contained in a container extending in a longitudinal direction, with the process comprising a large number of successive stages, during which:The container is accommodated and supported by receiving means;The container is held in a stationary or essentially stationary position with respect to the receiving means;With the measuring phase consisting in emitting emission light rays in such a way as to illuminate the complex medium and to receive light rays that are backscattered and/or transmitted by said complex medium.

More particularly, according to the invention, the preliminary stirring stage of the container consists in:Putting the receiving means into a stirring motion comprising at least one back-and-forth movement according to a directional vector extending in a significant proportion in the longitudinal direction,In such a way as to cause shear stresses in the complex medium bringing about the destruction of the aggregates of said complex medium when said container is accommodated and supported by the receiving means.

According to one embodiment, the preliminary stifling stage consists in putting the receiving means and the container into a stirring motion comprising at least one back-and-forth movement according to a unidirectional translational movement.

According to one embodiment, the preliminary stifling stage consists in putting the receiving means and the container into a stirring motion comprising at least one back-and-forth movement according to a circular translational movement around an axis of rotation.

According to one embodiment, the preliminary stifling stage consists in putting the receiving means and the container into a stirring motion that comprises at least one back-and-forth movement in a rotation around an axis of rotation.

According to one embodiment, the axis of rotation is positioned at a distance that is essentially between 50 and 200 millimeters from the center of gravity of the receiving means.

According to one embodiment, the back-and-forth movement around the axis of rotation is essentially between 10° and 90°.

According to one embodiment, the container is held by an O-ring seal that covers a portion of the inside surface of the receiving means.

According to one embodiment, the container is held by a clamp or a stop part that may or may not be deformable.

According to one embodiment, during the measuring phase, a light source emits the emission light rays in the direction of said complex medium in such a way as to illuminate said complex medium; an optical detector receives the light rays that are backscattered and/or transmitted by said complex medium in response to the illumination of said complex medium.

According to one embodiment, the light source emits monochromatic radiation.

According to one embodiment, the support means of the measuring module are combined structurally and functionally with the receiving means of the container in such a way that the stirring motion imposed on the receiving means is also imposed on the measuring module.

According to one embodiment, the support means of the measuring module are separated structurally from the receiving means in such a way that these support means are in relative motion with respect to these receiving means when said receiving means are in a stirring motion.

According to one embodiment, the receiving means have a transparent window with respect to the support means of the measuring module in such a way that the emission light rays and the backscattered light rays pass through this window during the measuring phase.

According to one embodiment, the measuring module transmits data collected during the measuring phase to an analysis unit that may or may not have been structurally separate.

According to one embodiment, the analysis unit uses the collected data for calculating the rate of sedimentation of said complex medium after the measuring phase.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1shows, in perspective, a sample embodiment of a device according to the invention that is designed to measure the rate of aggregation of a blood suspension2drawn off from a patient from a sample tube4. The blood suspension2is therefore in the sample tube4, and the measurement can advantageously be taken directly from this sample tube4.

Thus, the measurement can be taken directly in the patient's bed after having carried out the sampling. In addition, it is not necessary to initiate any transfer of the blood suspension2from the sample tube4and to a specific container. The risks of contamination of the medical personnel are therefore limited.

It should be noted that the sample tube4, as is the standard today, has an essentially cylindrical shape that extends in a longitudinal direction. The sample tube4therefore has an essentially circular cross-section, with a radius R, as well as a length L in the longitudinal direction.

This sample tube4could be replaced by any other type of container that is analogous or similar provided that it is at least partly transparent and capable of accommodating a complex medium and that has a shape that extends essentially in a longitudinal direction.

In the same way, within the framework of this sample embodiment, the complex medium is formed by a blood suspension2. However, it could also be considered to take a measurement on a complex medium that is different since the latter is likewise to move from a first aggregation state to a second aggregation state during a preliminary stifling stage as described below.

For the purpose of measuring the aggregation time, the device has as its object to analyze the variation in the light that is backscattered by the blood suspension2immediately after a preliminary stifling stage.

To do this, the device comprises a module6on the inside of which is defined a chamber8into which the sample tube4can be inserted. This chamber8is also essentially cylindrical and has a circular cross-section with a radius that is slightly greater than the radius R of the cross-section of the sample tube4. Consequently, the chamber8makes it possible to accommodate and to support the sample tube4.

According to an advantageous embodiment, the inside surface of the chamber8is covered at least partially by an O-ring seal8aor else a rubbery portion (not shown) that has as its function to hold the sample tube4inside the chamber8and in a position that is stationary or essentially stationary with respect to this chamber8when the module6is driven by a stirring motion. More particularly, the geometry of the chamber8whose radius is adjusted to the radius R of the sample tube4and the simultaneous use of a rubbery portion makes it possible to hold the sample tube4in position.

It should be pointed out, however, that the rubbery portion could be replaced by other analogous or similar holding means. More particularly, the rubbery portion could be replaced by a pressure screw that is capable of compressing the sample tube4inside the chamber8or else by an outside part that is likely to come to rest on the exposed end of the sample tube4. This rubbery portion could alternatively be replaced by any other analogous or similar mechanical means.

The device ofFIG. 1also comprises support means (not shown) of a module10for measuring the light that is backscattered by the blood suspension2. The measuring module10is connected in such a way as to transmit measuring signals to a calculating station12, making it possible to determine, from the measuring signals12aemitted by this measuring module10, the rate of aggregation of the blood suspension2.

The device also comprises means14for putting into motion that are capable of imposing on the module6a stirring motion comprising at least one back-and-forth movement according to a directional vector. According to the invention, this directional vector extends in a significant proportion in the longitudinal direction of the sample tube4when it is held in position inside the chamber8, in such a way as to cause shear stresses in the blood suspension2bringing about at least partially the destruction of the aggregates contained in said blood suspension2. This destruction of the aggregates makes it possible to achieve a reproducible initial state from which the measurements making it possible to determine the properties of the complex medium2can be established.

FIG. 2shows, in perspective and in a more detailed way, on the one hand, the measuring module10and the support means16of this measuring module10, and, on the other hand, the means14for putting the device ofFIG. 1into motion.

In the first place, it should be noted that a portion of the means14for putting into motion are integrated inside a container18. This container18comprises a motor (not shown) at adjustable speed. According to different embodiments, this motor can have any rotational speed of between 200 and 300 rpm. The motor is connected structurally and functionally to an output shaft20by means of a mechanical system—connecting rod/crank, gears, or the like. This mechanical system thus makes it possible to adjust the amplitude and the speed of rotation of the output shaft20of which one end is positioned outside of the container18.

The output shaft20is also connected by fixed connection to a support arm22that supports, also by a fixed connection, the module6. The support arm22has, according to an advantageous embodiment, a length of 80 millimeters.

Alternatively, but while preserving a limited space requirement, the length of the lever arm could be between 50 and 200 millimeters, and its movement in rotation could be between 10° and 90°.

In contrast, the mechanical system is equipped with a position sensor that is arranged in such a way that the support arm22always holds the module6in vertical position when the motor is stopped.

Second, it is necessary to note that the sample embodiment ofFIG. 2shows, in a detailed manner, support means16of the measuring module10.

More particularly, according to this embodiment, the module6comprises a transparent window24that extends essentially in the longitudinal direction of the sample tube4as well as four slots26that are positioned around the transparent window24.

Furthermore, the measuring module10comprises a body28that also extends in a longitudinal direction, four lugs30that are capable of working with the slots26of the module6as well as an optoelectronic unit32that comprises an emission light source32a, such as an infrared-emitting diode with a wavelength of between 800 and 1,000 nanometers, and an optical detector32b, such as a sensor with integrated amplifying photodiodes of the IPL type (Integrated Photodiode Amplifiers).

According to this embodiment, the light source32ahas a power on the order of several milliwatts.

The four lugs30of the measuring module10can be engaged in the slots26of the module6in such a way that the body28is held in position relative to the module6. Thus, the lugs30and the slots26make it possible to combine the measuring module10structurally and functionally with the module6in such a way that the stirring motion imposed on the module6is also imposed on the measuring module10. In this assembled position, the emission light source32ais capable of emitting emission light rays in the direction of the blood suspension2in such a way as to illuminate this blood suspension2through the transparent window24of the module6. In addition, in this assembled position, the optical detector32bis capable of receiving the light rays that are backscattered by the blood suspension2in response to the illumination by the emission light rays.

Alternatively, the support means of the measuring module10could optionally be separated structurally from the module6in such a way that the measuring module10is in relative motion with respect to the module6when said module6is in a stirring motion.

For example, the measuring module could be separated structurally from the module6but positioned relative to the transparent window24in such a way that despite the motion of the module6and therefore of the transparent window24:Emission light rays emitted by the emission light source32acan propagate through the transparent window24to the blood suspension2, andLight rays backscattered by the blood suspension2can propagate through the transparent window24to the optical detector32b.

Advantageously, the emission light source32aand the optical detector32bare placed one above the other and have a predetermined angle of orientation on the order of 30° so that the emission light rays obtained from the emission light source32aare in large part backscattered to the optical detector32b.

The bisector of the angle that is defined by this emission light source32aand this optical detector32bis preferably positioned at mid-height of the sample tube4.

The optoelectronic unit32, and, more particularly, said emission light source32aand said optical detector32bare connected by a flexible cable to a power control and power supply box. In contrast, this optoelectronic unit32is connected to the calculating station12in such a way as to transmit to it the measuring signals12acollected during the measuring phase.

FIG. 3shows, in perspective and in a detailed manner, the device ofFIG. 1in which the measuring module10is structurally combined with the module6, and the sample tube4is inserted into the chamber8of the module6.

Several stages used in a sample embodiment of the process according to the invention will now be described based onFIG. 4that shows, in perspective and in a detailed way, the device ofFIG. 1when the latter is in a stifling motion.

As described above, the process consists in measuring the aggregation time of the blood suspension2by an analysis of the variation in the light that is backscattered by this blood suspension during a measuring phase after a preliminary stifling stage.

During this preliminary stifling stage, the sample tube4that contains the blood suspension2is put into motion. More particularly, the starting of the motor drives the rotation of the output shaft, which makes it possible to pivot the support arm22as well as the module6around the axis of rotation20aof the output shaft20in a back-and-forth motion.

More particularly, the means14for putting into motion impose on the module6a back-and-forth movement according to a directional vector that extends in a significant proportion in the longitudinal direction of the sample tube4in such a way as to cause shear stresses in the blood suspension2that bring about the destruction of the aggregates. This stifling motion advantageously has a stifling frequency of approximately 4 Hz, which makes it possible to impose shear stresses that are high enough to disaggregate the major portion of the aggregates of the blood suspension2. However, a stirring frequency of between 2 and 6 hertz could also be considered and would make it possible to obtain satisfactory results.

After a preliminary stirring stage of approximately 10 seconds, the motor is stopped.

The measuring module10then makes it possible to follow the variation in the light that is backscattered by the blood suspension2in a time interval of approximately 2 minutes. The corresponding measuring signals12aare then transmitted to the calculating station12that, by means of a capture card such as a National Instrument DAQPad-12000 and then a data-processing program, makes it possible—by a method that is well known from the state of the art—to deduce the aggregation time of the blood suspension2.

It should be noted that according to the previously-described embodiment, the means14for putting into motion impose a stirring motion that corresponds to a rotation of the module6around an axis.

However, asFIGS. 5a,5b, and6a,6billustrate, other motions comprising at least one back-and-forth movement according to a directional vector that extends in a significant proportion in the longitudinal direction of the sample tube4could be used.

More particularly, asFIGS. 5aand5billustrate, the device according to the invention, also similar to the embodiment ofFIG. 1, could comprise means14for putting into motion, making it possible to obtain a stirring motion corresponding to a back-and-forth movement according to a unidirectional translational movement.

This unidirectional translational movement can have a directional vector that extends approximately, but not totally, in the longitudinal direction of the sample tube4when the latter is in a position inside the module6. Thus, it is possible to obtain satisfactory results even if the sample tube4is inclined with respect to the direction of translational movement of the means14for putting into motion.

Alternatively, and as illustrated inFIGS. 6aand6b, it would also be possible that the device—also similar to the embodiment of FIG.1—comprises means14for putting into motion making it possible to obtain a stifling motion corresponding to a back-and-forth movement according to a circular translational movement around an axis of rotation20a.

In practice, it is sufficient that the component of the directional vector in the longitudinal direction, corresponding to the projection of the directional vector in the longitudinal direction of the sample tube4when the latter is in position in the module6, is large enough to disaggregate the aggregates of the blood suspension2. This longitudinal component can exceed any other transverse component extending in a direction that is perpendicular to the above-mentioned longitudinal direction.

It should be emphasized that the embodiments described above relate to the measurement of the rate of aggregation of a blood suspension2. However, the device according to the invention is also suitable for taking a measurement of the sedimentation time of the blood suspension2or of any other complex medium.

In this respect, the process for measuring the rate of sedimentation differs from the process for measuring the rate of aggregation in that, after the preliminary stifling phase, the analysis of the variation in the light that is backscattered by the blood suspension2extends into a time interval of approximately one or two hours and no longer only two minutes. The stages after this preliminary stirring phase—and more particularly the stages for analysis of the light that is backscattered by the complex medium—are well known to one skilled in the art today.

It should also be noted that for taking such a measurement of the rate of sedimentation, it is preferable to use a window that extends essentially over the entire length of the container.

It should also be added that the measuring device according to the invention can, according to an advantageous embodiment, make it possible to measure simultaneously the aggregation time and the rate of sedimentation of the blood suspension2.

To do this, a first series of emission rays illuminates the blood suspension2in a first direction; the aggregation time is then measured by analysis of light rays that are backscattered by the blood suspension2. In contrast, a second series of emission rays illuminates the blood suspension2in a second direction; the sedimentation time is then measured by analysis of the through rays or rays that are backscattered by said blood suspension2.