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Medical Patent Abstract
The invention relates to a method and device for the monitoring
of a medical microsample in the flow measuring cell of an analyzer
with regard to position and absence of bubbles by means of an alternating
voltage applied to the measuring cell, the measuring cell being
provided with a multitude of electrode systems placed one behind
the other, each system comprising a number of single electrodes
for measuring a substance contained in the microsample by means
of a measurement voltage which essentially is a DC voltage. To monitor
the exact position of the microsample and/or to detect air bubbles
in the area of each electrode system, the alternating voltage and
the measurement voltage are simultaneously and directly applied
to the single electrodes of the corresponding electrode system,
and the measured AC component respectively the measured impedance
gives a measure for the position of the microsample and the absence
of bubbles.
Medical Patent Claims
What is claimed is:
1. A device for monitoring a microsample in a flow measuring cell
of an analyzer comprising: at least one electrode system comprising
at least two single electrodes positioned within said flow measuring
cell, wherein said electrode system is configured for measurement
of at least one substance contained in the microsample by application
of a measurement voltage which is essentially a DC voltage, and
detection of absence of bubbles and/or positioning of said microsample
by application of an alternating voltage to said flow measuring
cell, both the alternating voltage and the measurement voltage are
simultaneously and directly applied to the single electrodes of
the respective electrode system, and the measured AC component or
the measured impedance provides a measure for the position of the
microsample and/or the absence of bubbles; and a circuit for producing
the voltages to be applied to the single electrodes, which circuit
has a summation point at which the alternating voltage for the purpose
of monitoring the microsample with regard to position and/or absence
of bubbles is superposed on the DC voltage serving as measurement
voltage.
2. A device according to claim 1, wherein an electrode system includes
a working electrode and a reference electrode, both electrodes serving
as electrical contacts for measuring the impedance between working
electrode and reference electrode.
3. A device according to claim 1, wherein an electrode system includes
a working electrode, a counter-electrode and a reference electrode,
the working electrode and the counter-electrode serving as electrical
contacts for measuring the impedance between working electrode and
counter-electrode.
4. A device according to claim 3, wherein the working electrode
is positioned in front of the reference electrode, and the counter-electrode
is positioned behind the reference electrode in flow direction of
the microsample.
5. A device according to claim 3, wherein counter-electrodes are
placed both in front of and behind the working electrode in flow
direction of the microsample, both counter-electrodes being electrically
short-circuited.
6. A device according to claim 3, wherein the counter-electrode
and the working electrode are positioned opposite each other in
the measuring cell.
7. A device according to claim 1, wherein the summation point is
connected with the inverting input terminal of an operational amplifier.
8. A device according to claim 1, wherein each electrode system
is provided with a device for measuring impedance, which is configured
as a circuit for superposing an alternating voltage on a DC voltage.
9. A method for monitoring a microsample in a flow measuring cell
of an analyzer comprising: providing an analyzer including a flow
measuring cell and a device comprising at least one electrode system,
each said system comprising at least two single electrodes; introducing
a microsample into said flow measuring cell, said microsample passing
said electrode system; measuring at least one substance contained
in the microsample by applying a measurement voltage to said flow
measuring cell, which said measurement voltage is essentially a
DC voltage; and detecting the absence of bubbles and/or position
of said microsample in an area of said at least one electrode system
by applying an alternating voltage to said flow measuring cell simultaneous
with said measurement voltage via two single electrodes of said
at least one electrode system, and detecting the AC component or
impedance.
10. A method according to claim 9, wherein the microsample in the
flow measuring cell is moved along until a predetermined value for
impedance or conductance is obtained, which indicates that the microsample
is positioned precisely in the area of the respective electrode
system.
11. A method according to claim 9, wherein the sample position
and/or absence of bubbles of the microsample are determined in the
area of each electrode system.
Medical Patent Description
FIELD OF THE INVENTION
The present invention relates to monitoring systems and methods
thereof, and in particular to a device and method for monitoring
a medical microsample in the flow measuring cell of an analyzer.
BACKGROUND OF THE INVENTION
In measuring medical samples a fundamental distinction is made
between one-way sensors and flow measuring cells. In the case of
a one-way sensor the sample is introduced into the sensor and brought
into contact with measuring electrodes. The basic requirement for
an accurate and error-free measurement is a suitable positioning
of the sample in the measuring cell. It is a known procedure to
check the positioning via special measuring contacts, to which an
AC voltage is applied, such that an impedance measurement will produce
a signal which provides information regarding the position of the
sample. Due to the distance between the electrodes for the measurement
proper and the electrodes for position-checking, errors in the measurement
result may occur.
From WO 99/32881 a one-way measuring cell is known which avoids
the above disadvantage by applying an alternating voltage to the
measuring electrodes themselves. It is possible in this way to check
the exact positioning of the sample as a first step and then to
proceed to the measurement itself or to reject the sample if the
positioning is found to be at fault. Furthermore, flow cells with
a multitude of electrode systems are unknown, which are suitable
for a series of measurements or for continuous measurement and which
determine the concentration of diverse analytes in a sample. Conditions
in flow cells of this sort differ fundamentally from those in one-way
cells. It is for instance not sufficient in this type of flow cells
to check the positioning of the sample prior to measuring, as it
will of course change during the measurement process. A further
problem occurs if electrochemical reactions due to the measurement
voltage cause bubble formation at an electrode, which is undesirable
and may result in measurement errors.
SUMMARY OF THE INVENTION
It is against the above background that the present invention provides
certain unobvious advantages and advancements over the prior art.
In particular, the inventors have recognized a need to improve methods
and/or devices for monitoring the positioning and the absence of
bubbles in a medical microsample in the flow cell of an analyzer
in such a way, that reliable measurement results may be obtained
in flow cells with a multitude of electrode systems and that a simple
design is guaranteed.
This object is achieved by the various embodiments of the present
invention by providing that both the alternating voltage and the
measurement voltage are simultaneously and directly applied to the
single electrodes of the respective electrode system and by using
the measured AC component or the measured impedance as a measure
for the position of the microsample and the absence of bubbles.
According to an embodiment of the present invention, the alternating
voltage--for example, for measuring impedance or conductance--is
coupled in via two single electrodes of the electrode system that
are already used for measuring a substance contained in the sample.
Although the present invention is not limited to specific advantages
or functionality, the following is noted: The measuring cell need
not be provided with additional electrodes for applying the alternating
voltage, i.e., for impedance measurement. Impedance measurement
may directly be used to detect undesirable air bubbles in the area
of the respective electrode system. The presence of bubbles is indicated
by a change in impedance or conductance. Air bubbles are detected
in places where their presence would negatively influence the measurement
result (for instance, adhering to an electrode or counter-electrode),
but are ignored in places where they do not influence the measurement
result (i.e., at the walls of the measuring cell). The quality of
the wetting of single electrodes of the electrode system may be
assessed (for instance, when measuring glucose or lactate). Impedance
measurement may also be used to determine the exact positioning
of the microsample in the area of each single electrode in sample
channels with a multitude of electrode systems, thus permitting
the sample volume to be kept small. According to the invention the
microsample in this case is moved along in the flow cell until a
predetermined impedance or conductance value is obtained, which
indicates that the microsample is exactly positioned in the area
of the relevant electrode system. Measurement of the impedance or
conductance may take place simultaneously with the measurement of
the substance in the microsample.
Simultaneous measurement offers the advantage that a change in
the sample taking place during analyte measurement (e.g., gas formation
at the working electrode, change in pH value, etc.) may be monitored
via the simultaneous conductance measurement at the exact point
in time of the analyte measurement.
In accordance with the various embodiments of the present invention,
repetitive measurements of microsamples with short cycle times may
be carried out with high precision and reliability. The occurrence
of gas bubbles can be recognized immediately during the measurement
process and may thus be taken into account. A further advantage
in comparison to measurement with one-way sensors lies in the fact
that in serial measurements the time-consuming and awkward replacement
of the sensors, which often entails a time-intensive calibration
of the sensor, is avoided.
In accordance with the various embodiments of the present invention,
the possibility to determine the position of the sample during measurement
permits a substantial reduction in sample volume as compared with
state-of-the-art methods; an advantage which becomes increasingly
important as the number of analytes to be measured increases.
In accordance with one embodiment of the present invention, a device
for monitoring a medical microsample in a flow measuring cell of
an analyzer is provided comprising at least one electrode system
comprising at least two single electrodes positioned within the
flow measuring cell, and a circuit for producing the voltages to
be applied to the single electrodes. The electrode system is configured
for measurement of at least one substance contained in the microsample
by application of a measurement voltage which is essentially a DC
voltage, and detection of absence of bubbles and/or positioning
of the microsample by application of an alternating voltage to the
flow measuring cell. Both the alternating voltage and the measurement
voltage are simultaneously and directly applied to the single electrodes
of the respective electrode system, and the measured AC component
or the measured impedance provides a measure for the position of
the microsample and the absence of bubbles. The circuit has a summation
point at which the alternating voltage for the purpose of monitoring
the medical microsample with regard to position and absence of bubbles
is superposed on the DC voltage serving as measurement voltage.
In accordance with another embodiment of the present invention,
a method for monitoring a medical microsample in a flow measuring
cell of an analyzer is provided comprising providing an analyzer
including a flow measuring cell and a device comprising at least
one electrode system, each system comprising at least two single
electrodes; introducing a microsample into the flow measuring cell,
the microsample passing the electrode system; measuring at least
one substance contained in the microsample by applying a measurement
voltage to the flow measuring cell, which measurement voltage is
essentially a DC voltage; and detecting the absence of bubbles and/or
position of the microsample in an area of the at least one electrode
system by applying an alternating voltage to the flow measuring
cell simultaneous with the measurement voltage via two single electrodes
of the at least one electrode system, and detecting the AC component
or impedance measured.
The device according to an embodiment of the present invention
is suitable for electrode systems comprising one working electrode
and one reference electrode (pseudo-reference electrode), where
both electrodes serve as electrical contacts for the impedance measurement
between working electrode and reference electrode, as well as for
three-electrode systems comprising a working electrode, a counter-electrode
and a reference electrode, where the working electrode and the counter-electrode
serve as electrical contacts for the measurement of the impedance
between working electrode and counter-electrode.
For the detection of air bubbles, in accordance with an embodiment
of the present invention, a counter-electrode can be placed both
in front of and behind the working electrode in the direction of
flow of the micro-sample, the two counter-electrodes being electrically
short-circuited.
Another advantageous variant or embodiment of the present invention
provides that the counter-electrode and the working electrode be
positioned opposite each other in the measuring cell.
In the case of measuring cells which are furnished with more than
one electrode system, which systems are placed one behind the other
in the flow direction of the sample, it is of advantage to provide
each electrode system with a separate device for measuring impedance
or conductance, in order to be able to separately monitor positioning
and bubble occurrence for each electrode system.
These and other features and advantages of the present invention
will be more fully understood from the following detailed description
of the invention taken together with the accompanying claims. It
is noted that the scope of the claims is defined by the recitations
therein and not by the specific discussion of features and advantages
set forth in the present description.
BRIEF DESCRIPTION OF THE DRAWINGS
The embodiments of the present invention will now be explained
in detail with reference to the attached drawings, in which:
FIG. 1 schematically presents a first variant of a device according
to the present invention for the monitoring of the positioning and
the absence of bubbles in a medical microsample in a flow cell of
an analyzer;
FIG. 2 shows a second variant of a device according to the invention;
FIGS. 3 and 4 show different electrode systems of a device according
to an embodiment of the present invention;
FIG. 5 shows three successive stages of a measurement process with
a device according to an embodiment of the present invention; and
FIGS. 6 and 7 show further electrode systems for a device according
to an embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 presents the first variant of a device for the monitoring
of position and bubble formation in a medical microsample P in a
flow cell or measurement capillary 1 of an analyzer not shown here
in detail, where the counter-electrode CE and the working electrode
WE of an amperometric electrode system 2 are used as contact points
between which the impedance or conductance of the microsample is
measured, for instance for the measurement of glucose concentration
in a blood sample. Further electrode systems may be placed behind
electrode system 2 but are not shown in the drawing.
The circuit realizes a potentiostatic design based on the addition
principle. By using an adder the target value of the voltage at
the reference electrode RE may be built up by superposition of a
number of different input voltages. The operational amplifier O.sub.1
varies its output voltage (corresponding to the voltage at the counter-electrode
CE) until the sum of the currents at the summation point S(=inverting
terminal of the operational amplifier O.sub.1) equals zero.
The operational amplifier O.sub.2 is configured as a voltage follower
(impedance transformer) and is used for high-resistance measurement
of the voltage at the reference electrode RE which should not be
subjected to current flow. At the output terminal of O.sub.2 the
reference electrode voltage from a low-resistance voltage source
is present and via the resistor R is coupled to the summation point
S preceding the operational amplifier O.sub.1.
In the present example the reference electrode voltage is built
up by superposing a DC component U.sub.=(e.g., 350 mV) and an AC
component U.sub.-(e.g., a sinusoidal alternating voltage of 1 kHz
with an amplitude of 9 mV r.m.s) indicated in the drawing by a DC
voltage source 4 and an AC voltage source 5. Both sources are connected
to the summation point S via resistors R. For bubble detection and
position-monitoring the optimal choice for the frequency of the
AC component lies in the range from 1 kHz to 5 kHz.
At the summation point the following equations hold: i.sub.1+i.sub.2+i.sub.3=0
i.sub.3=U.sub.-/R i.sub.2=U.sub.=/R i.sub.1=-(i.sub.2+i.sub.3)=-(U.sub.=+U.sub.-)/R
U.sub.RE=i.sub.1i *R=-(U.sub.=+U.sub.-) and thus, U.sub.RE=-(U.sub.=+U.sub.-)
The reference electrode voltage is the sum of the voltages of the
voltage sources 4 and 5. Due to the use of the impedance transformer
O.sub.2 the reference electrode is practically current-free.
The sensor current flows from the output terminal of O.sub.1 via
the counter-electrode CE, the working electrode WE and the ampere-meter
A to ground.
For the evaluation process the DC component (containing the information
pertaining to analyte concentration, e.g., glucose concentration)
and the AC component (containing the impedance information) are
separated by known filter circuits not shown in FIG. 1 (e.g., a
band-pass for the AC component and a low-pass for the DC component).
With the device described above the microsample P may be exactly
positioned in the area of the electrode system 2 of the measuring
cell 1 (correct positioning is indicated by the measured conductance
attaining a previously known value). A deviation from the previously
known value, caused for instance by an air bubble in the area of
the working electrode WE, indicates a disturbance in the system
and the necessity of a repetition of the measurement of the relevant
substance in the sample.
The direction of sample flow in the measuring cell 1 is indicated
by arrows 7. The counter-electrodes are typically placed last in
flow direction whilst the sequential placement of the reference
electrode and the working electrode may vary with the given application.
For single measurements it is typical if the reference electrode
RE of each electrode system is wetted first by the microsample.
In systems for continuous measurement, where short down-times are
desirable, it is typical if the working electrode WE is placed first.
In the variant shown in FIG. 2 the measuring cell 1 is provided
with an amperometric electrode system 2 consisting of a working
electrode WE and a pseudo-reference electrode RE. The potentiostatic
three-electrode system of FIG. 1 may be changed into a two-electrode
system if the sensor currents arising during analyte determination
are very small (order of magnitude of a few nano-amperes).
Regarding the electronic circuit this change is effected by connecting
the output terminal of the operational amplifier O.sub.1 with the
non-inverting input terminal of the operational amplifier O.sub.2.
Since in the two-electrode system a (small) current flows through
the reference electrode RE this electrode is no longer called a
reference electrode but rather a pseudo-reference electrode.
A voltage drop across the electrolyte resistance or across the
electrode interface resistance of the pseudo-RE is not compensated
and will show up at larger sensor currents by a degradation of the
region of measurement linearity.
The functionality of the circuit is based on the fact that all
control activity is eliminated and that the sum of the voltages
from the DC-source 4 and the AC-source 5 is applied to the terminal
of the pseudo-RE, such that the sensor current flows from the reference
electrode RE via the working electrode WE and the amperemeter A
to ground. As regard to the separation of the DC and AC component
the description of FIG. 1 applies.
If an air bubble 6 adheres to the edge of the working electrode
WE next to the reference electrode RE, it is typical--as shown in
FIG. 3--to place yet another counter-electrode CE' between working
electrode WE and reference electrode RE and to short-circuit the
counter-electrodes CE and CE' electrically, which leads to better
detectability of air bubbles in the area.
Further advantages will result from positioning the single electrodes
as shown in FIG. 4, where working electrode WE and counter-electrode
CE are placed opposite each other in the measuring cell or measurement
capillary 1. The reference electrode RE may be placed on the side
of the working electrode WE (as shown) or it may also be placed
on the side of the counter-electrode CE.
In FIG. 5 the exact positioning of a microsample P in the measuring
cell 1 is shown in various stages, the measuring cell being provided
with an electrode system 2, for instance for measuring glucose,
and with an electrode system 3, for instance for measuring lactate.
As can be seen from this example exact positioning of the microsample
in the area of each electrode system 2 or 3 is possible, without
the necessity of completely filling the measuring cell with sample
fluid. Thus the volume of sample sucked into the measuring cell
need only be large enough to ensure wetting of the three-electrode
system.
In principle the method of sample positioning and bubble detection
described may also be applied with potentiometric electrode systems.
As shown in FIG. 6 one and the same measuring cell 1 may be provided
with potentiometric electrodes for the measurement of e.g., Na.sup.+,
D.sup.+ and Cl.sup.-, in addition to amperometric electrode systems
2 and 3.
The reference electrode RE in the electrode system 2 is placed
downstream of the working electrode WE.
FIG. 7 shows an example of a circuit design in which one may change
between analyte measurement and bubble-detection/sample-positioning
by means of a switch 8. According to the position of the switch
either impedance measurement or analyte determination is performed.
Since potentiometric electrodes are characterized by very high resistance
and since the Nernst equation describes the electrode potentials
for current-free electrodes, any current flow would lead to appreciable
deviations from potential equilibrium and thus to disturbances during
analyte measurement. For this reason it is of advantage to switch
between measurements. The switch might also be realized by fast
electronic switches.
The device according to an embodiment of the invention can also
be used to measure the impedance of a carrier fluid (perfusion fluid)
introduced into the tissue of a patient, after equilibration with
the tissue fluid, the impedance value being used to assess the degree
of mixing or enrichment.
A change of the substances carried by the carrier fluid may be
determined by measuring the impedance or conductance. Such .mu.-perfusion
systems are described in U.S. Pat. No. 5,097,834. The .mu.-perfusion
method uses a thin, biluminal catheter whose exterior wall is perforated.
An ion-free perfusion solution is pumped through the interior lumen
to the catheter tip, where it is reversed and sucked off via the
exterior lumen. The perforations of the exterior wall give rise
to an exchange of fluids (diffusion, convection); tissue fluids
or interstitial fluids and their substances enter the perfusion
flow, which is directed to the catheter outlet and subsequently
to the sensor. The degree of enrichment or mixing with ions from
the interstitium can be determined by a conductance measurement,
since the conductivity of the ion-free fluid and the conductivity
of the interstitial fluid are known. This will permit computation
of the recovery rate.
Finally, the device may also be used for the measurement of the
impedance of the dialysate after dialysis and the measured impedance
may be used to compute the recovery rate.
The .mu.-dialysis method is very similar to the .mu.-perfusion
method described above, apart from the fact that instead of a perforated
catheter a catheter is used whose exterior wall is a dialysis membrane.
Such membranes have a MW-cutoff of approx. 20,000 Dalton, i.e.,
they are permeable for low-molecular substances, such as glucose
and electrolytes, and the carrier flow in the catheter is enriched
with these low-molecular substances by diffusion. A conductance
measurement in a sensor downstream of the catheter permits the determination
and checking of the recovery rate in analogy to the example given
above.
It is noted that terms like "preferably", "commonly",
and "typically" are not utilized herein to limit the scope
of the claimed invention or to imply that certain features are critical,
essential, or even important to the structure or function of the
claimed invention. Rather, these terms are merely intended to highlight
alternative or additional features that may or may not be utilized
in a particular embodiment of the present invention.
For the purposes of describing and defining the present invention
it is noted that the term "substantially" is utilized
herein to represent the inherent degree of uncertainty that may
be attributed to any quantitative comparison, value, measurement,
or other representation. The term "substantially" is also
utilized herein to represent the degree by which a quantitative
representation may vary from a stated reference without resulting
in a change in the basic function of the subject matter at issue.
Having described the invention in detail and by reference to specific
embodiments thereof, it will be apparent that modifications and
variations are possible without departing from the scope of the
invention defined in the appended claims. More specifically, although
some aspects of the present invention are identified herein as preferred
or particularly advantageous, it is contemplated that the present
invention is not necessarily limited to these preferred aspects
of the invention.
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