US007169600B2
`
`(12) United States Patent
`H0SS et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,169,600 B2
`Jan. 30, 2007
`
`(54) DEVICE FOR DETERMINING A GLUCOSE
`CONCENTRATION IN A TISSUE FLUID
`
`(*) Notice:
`
`(75) Inventors: Udo Hoss, Sherman Oaks, CA (US);
`Hans-Joerg Pfleiderer, Ulm (DE); Ralf
`Gessler, Baienfurt (DE); Hans-Ulrich
`Zieten, Illerrieden (DE); Rolf
`Fussgaenger, Blaustein-Weidach (DE)
`(73) Assignee: Roche Diagnostics GmbH, Mannheim
`(DE)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 447 days.
`(21) Appl. No.: 10/782,290
`(22) Filed:
`Feb. 19, 2004
`(65)
`Prior Publication Data
`US 2004/O19 1848 A1
`Sep. 30, 2004
`
`Related U.S. Application Data
`(62) Division of application No. 09/620,038, filed on Jul.
`20, 2000, now Pat. No. 6,852,500.
`Foreign Application Priority Data
`(30)
`Jul. 28, 1999
`(DE) ................................ 199 35 165
`
`(51) Int. Cl.
`(2006.01)
`CI2M I/34
`(52) U.S. Cl. ...................................... 435/287.1; 435/14
`(58) Field of Classification Search .................. 435/14,
`435/287.1; 204/409; 205/787
`See application file for complete search history.
`References Cited
`
`(56)
`
`U.S. PATENT DOCUMENTS
`
`5,615,671 A * 4, 1997 Schoonen et al. .......... 600,322
`5,640,954 A
`6, 1997 Pfeiffer et al. .............. 128,635
`
`1/2000 Korf et al. .................. 600,363
`6,013,029 A
`6,091,976 A * 7/2000 Pfeiffer et al. ...
`... 600,347
`6,434.409 B1* 8/2002 Pfeiffer et al. .............. 600/347
`6,591,126 B2. 258 Roeper al - - - -
`- - - o:
`6,852,500 B1* 2/2005 Hoss et al. ................... 435. 14
`6,925,393 B1* 8/2005 Kalatz et al. ................. 702/27
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`DE
`DE
`DE
`WO
`
`4130 742 A1 * 3, 1993
`44 26 694 A1 * 2, 1996
`44 O1 400
`6, 1997
`WO 97.42868
`* 11/1997
`WO 97.42868
`11, 1997
`
`OTHER PUBLICATIONS
`Dempsey et al. (1997). In vitro optimisation of a microdialysis
`system with potential for on-line monitoring of lactate and glucose
`in biological samples. Analyst 122 (185-189), pp. 185-189.
`* cited by examiner
`Primary Examiner Ralph Gitomer
`(74) Attorney, Agent, or Firm—Jill L. Woodburn; Sujatha
`Subrananiam
`
`ABSTRACT
`(57)
`The invention concerns an arrangement for determining the
`concentration of glucose in a tissue fluid. In the microdi
`alysis technology used for this purpose, perfusate-containing
`glucose is transported in intermittent delivery pulses through
`a microdialysis probe inserted into the tissue fluid and
`dialysate obtained in this process is passed to a measuring
`cell to record the glucose content. In order to achieve an
`exact determination of glucose even with a reduced dialysis
`period, it is proposed that the starting content of glucose in
`the perfusate is adapted to the glucose content of the tissue
`fluid by means of a control device in accordance with a
`command variable derived from the measurement signals of
`the measuring cell. When the control deviation is negligible
`the momentary starting content of glucose in the perfusate
`can be determined as a measure for the glucose content of
`the tissue fluid.
`
`26 Claims, 2 Drawing Sheets
`
`Page 1 of 9
`
`

`

`U.S. Patent
`U.S. Patent
`
`Jan. 30, 2007
`Jan. 30, 2007
`
`Sheet 1 of 2
`Sheet 1 of 2
`
`US 7,169,600 B2
`US 7,169,600 B2
`
`
`
`
`
`Fig. 1
`
`Page 2 of 9
`
`Page 2 of 9
`
`

`

`U.S. Patent
`U.S. Patent
`
`Jan. 30, 2007
`Jan. 30, 2007
`
`Sheet 2 of 2
`Sheet 2 of2
`
`US 7,169,600 B2
`US 7,169,600 B2
`
`
`
`46
`
`46
`
`44
`
`
`
`Fig. 2
`Fig. 2
`
`Page 3 of 9
`
`Page 3 of 9
`
`

`

`1.
`DEVICE FOR DETERMINING A GLUCOSE
`CONCENTRATION IN A TISSUE FLUID
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`The present application is a divisional of U.S. patent
`application Ser. No. 09/620,038 filed on Jul. 20, 2000 now
`U.S. Pat. No. 6,852,500 and claims priority to German
`Application No. 19935 165.1 filed Jul. 28, 1999.
`
`10
`
`FIELD OF THE INVENTION
`
`The invention concerns a method and an arrangement for
`determining the concentration of glucose in a body fluid, in
`particular in tissue fluid with glucose-containing perfusate.
`
`15
`
`BACKGROUND AND SUMMARY OF THE
`INVENTION
`
`30
`
`35
`
`40
`
`45
`
`A process and an arrangement of this type are known from
`WO 97/42868. This proposes intermittent delivery pulses in
`order to, on the one hand, enable a continuous signal
`calibration and, on the other hand, to accelerate the mea
`25
`Surement process. In this process the perfusate Volume
`which is at that moment in the microdialysis probe adjusts
`during the resting phases between the delivery pulses to the
`concentration of the tissue glucose as a result of the dialysis
`process whereas adjacent Volume regions in the Subsequent
`liquid column that is transported further at a high flow rate
`remain largely unchanged. A signal peak is observed during
`a delivery pulse in the measuring cell which corresponds to
`the concentration gradient and from which the glucose
`content of the dialysate and thus also of the body fluid can
`be determined. Perfusion fluid containing glucose, the speci
`fied glucose concentration of which defines the baseline
`value of the signal peak, is used for the calibration. A
`prerequisite for this is a linear sensor behaviour during the
`dialysis phases in addition to a complete concentration
`equilibration and it is assumed that the concentration profile
`in the volume transported away from the probe does not
`decay until it reaches the measuring cell. However, espe
`cially the latter assumption is frequently not the case since
`mixing occurs especially when the flow is laminar.
`In addition diffusion exchange disturbs the glucose equi
`librium in the tissue surrounding the probe.
`Taking this as a starting point the object of the invention
`is to avoid the aforementioned disadvantages and in par
`ticular concentration disturbances in the body fluid and to
`enable an exact glucose determination with a reduced dialy
`sis period.
`The feature combinations of determining the glucose
`concentration in a body fluid, in particular tissue fluid, in
`which perfusate containing glucose is passed through a
`microdialysis probe inserted into the body fluid and dialy
`sate obtained in this process is transported to a measuring
`cell, and in which measurement signals that correlate with
`the glucose content of the dialysate are measured at the
`measuring cell, characterized in that the starting content of
`glucose in the perfusate is adjusted to the glucose content of
`the body fluid by means of a control device in accordance
`with a command variable derived from the measurement
`signals of the measuring cell are proposed to achieve this
`object.
`Advantageous embodiments and further developments of
`the invention derive from the following:
`
`50
`
`55
`
`60
`
`65
`
`US 7,169,600 B2
`
`2
`A method as described above characterized in that when
`the control deviation is negligible the momentary starting
`content of the glucose in the perfusate is determined as a
`measure for the glucose content of the body fluid.
`A method as described in either of the preceding para
`graphs characterized in that the starting content of glucose in
`the perfusate is determined from the adjusting variable of an
`adjuster of the control device.
`A method as described in one of the preceding three
`paragraphs, characterized in that the glucose content of the
`perfusate is measured before it is passed into the microdi
`alysis probe.
`A method as described in one of the preceding four
`paragraphs, characterized in that the starting content of
`glucose in the perfusate is influenced by flow mixing two
`perfusion liquids with different glucose concentrations pro
`vided in two separate reservoirs.
`A method as described in one of the preceding five
`paragraphs, characterized in that the perfusate is passed
`through the microdialysis probe (10) in alternating Succes
`sive transport and dialysis intervals at different flow rates,
`the flow rate during the transport intervals being higher than
`during the dialysis intervals.
`A method as described in the preceding paragraph, char
`acterized in that the flow rate during the transport intervals
`is increased to Such an extent that the starting content of
`glucose in the perfusate during passage through the microdi
`alysis probe remains essentially constant and that during the
`dialysis intervals the transport is interrupted or at least the
`flow rate is reduced to Such an extent that the glucose
`concentration of the dialysate approximates the glucose
`content of the body fluid.
`A method as described in one of the preceding seven
`paragraphs, characterized in that the command variable is
`determined by integration or differentiation of the time
`course of the measurement signals.
`A method as described in one of the preceding three
`paragraphs, characterized in that the command variable is
`determined by qualitative detection of signal peaks in the
`time course of the measurement signals.
`A method as described in one of the preceding four
`paragraphs, characterized in that the command variable is
`determined by comparing the actual signal curve of the
`measurement signals with calibrated signal patterns depos
`ited in a storage medium.
`A method as described in one of the preceding five
`paragraphs, characterized in that the command variable is
`determined from the peak value of the signal time course of
`the measurement signals during each transport interval.
`A method as described in one of the preceding six
`paragraphs, characterized in that the command variable can
`be determined according to the glucose content c of the body
`fluid according to the relationship
`
`Sg
`c=|s, 1-, ps, - aco too
`= -- - 1. a.
`
`in which S denotes the peak value and So denotes the base
`line value of the signals measured during a transport interval
`and co is the momentary starting content of glucose in the
`perfusate and a, b are empirically determined correction
`factors compensating for diffusion and mixing and remain
`ing recovery effects during the transport interval.
`
`Page 4 of 9
`
`

`

`3
`A method as described in one of the preceding twelve
`paragraphs, characterized in that the starting content of
`glucose in the perfusate is regulated discontinuously by a
`two-point control process in which the starting content of
`glucose in the perfusate is changed by a predetermined
`adjustment value when there is a control deviation.
`In addition, the feature combinations of the arrangement
`for determining the glucose concentration in a body fluid, in
`particular tissue fluid, comprising a microdialysis probe for
`the diffusion exchange of glucose with Surrounding body
`fluid, a perfusion device for perfusing the microdialysis
`probe with glucose-containing perfusate to obtain dialysate
`and a measuring cell located after the microdialysis probe
`for detecting measurement signals that correlate with the
`glucose content of the dialysate, characterized by a control
`device which adjusts the starting content of glucose in the
`perfusate to the glucose content of the body fluid in accor
`dance with a command variable derived from the measure
`ment signals of the measuring cell are proposed to achieve
`this object.
`Advantageous embodiments and further developments of
`the invention derive from the following:
`The arrangement as described in the preceding paragraph,
`characterized by an evaluation unit to determine the momen
`tary starting content of glucose in the perfusate when the
`25
`control deviation is negligible as a measure for the glucose
`content of the body fluid.
`The arrangement as described in the preceding two para
`graphs, characterized in that the perfusion device has a
`perfusate store and a transport unit for the preferably inter
`mittent transport of perfusate.
`The arrangement as described in the preceding paragraph,
`characterized in that the perfusate store has at least two
`separate reservoirs to hold perfusion liquids with different
`glucose concentrations.
`The arrangement as described in the preceding two para
`graphs, characterized in that the perfusate store has a first
`reservoir containing a glucose-free perfusion liquid and a
`second reservoir containing a glucose-containing perfusion
`liquid.
`The arrangement as described in one of the preceding five
`paragraphs, characterized in that the control device has a
`flow mixer preferably comprising a mixing valve or clock
`pulsed directional control valve as an adjuster to adjust the
`starting content of glucose in the perfusate.
`The arrangement as described in the preceding paragraph,
`characterized in that the inlet side of the flow mixer is
`connected to at least two reservoirs for feeding in perfusion
`fluids with different glucose contents and the outlet side of
`the flow mixer connects a perfusate tube leading to the
`50
`microdialysis probe.
`The arrangement as described in one of the preceding
`seven paragraphs, characterized in that the control device
`has a digitally operated controller preferably in the form of
`a microcontroller.
`55
`Further, the feature combinations of arrangement for
`determining the glucose concentration in a body fluid, in
`particular tissue fluid, comprising a microdialysis probe
`inserted into the body fluid, at least two reservoirs for
`holding perfusion liquids with different glucose contents, a
`transport unit to perfuse the microdialysis probe with glu
`cose-containing perfusate to obtain dialysate and a flow
`through measuring cell located downstream of the microdi
`alysis probe to register measurement signals that correlate
`with the glucose content of the dialysate, characterized by a
`control device connected on the input side to the measuring
`cell which control device has a flow mixer connected on the
`
`30
`
`40
`
`45
`
`60
`
`65
`
`US 7,169,600 B2
`
`5
`
`10
`
`15
`
`35
`
`4
`inlet side to the reservoirs and on the outlet side to the
`microdialysis probe which acts as an adjuster to regulate the
`starting content of glucose in the perfusate are proposed to
`achieve this object.
`The idea behind the invention is to adapt the glucose
`content of the perfusate in a self-adjusting and adaptive
`manner to the glucose concentration of the body fluid.
`Accordingly the method proposed to achieve the above
`mentioned object is to adapt the initial content of the glucose
`in the perfusate to the glucose content of the body fluid by
`means of a control unit according to a command variable
`derived from the measurement signals of the measuring cell.
`This offsets glucose gradients and hence reduces the period
`required for a complete dialysis equilibration. It also avoids
`interfering effects due to glucose gradients even with a high
`flow rate through the microdialysis probe and glucose varia
`tions in the body fluid.
`A particularly preferred embodiment of the invention
`envisages determination of the momentary starting content
`of glucose in the perfusate as a measure for the glucose
`content of the body fluid when the deviation is negligible.
`This enables a quantitative indirect determination of the
`concentration by means of the momentary actual value of
`the regulating variable while the continuously measured
`signals from the measuring cell are only used as regulating
`input variables. Alternatively additionally, it is in principle
`possible to derive the glucose content of the body fluid
`directly from the measurement signals.
`The initial content of glucose in the perfusate is advan
`tageously determined from the adjustable variable of the
`adjuster of the controlling device. This measure enables the
`initial content to be determined accurately for example by
`comparison with normalized values in tables without requir
`ing additional glucose sensors. However, in principle it is
`also possible to measure the glucose content of the perfusate
`before it is passed into the microdialysis probe.
`For a variable adjustment it is advantageous when the
`initial content of glucose in the perfusate is influenced by
`flow mixing two perfusion fluids with different glucose
`concentrations that are kept ready in two separate reservoirs.
`In a particularly preferred embodiment of the invention
`the perfusate is passed through the microdialysis probe in
`alternating consecutive transport and dialysis intervals at
`different flow rates, the flow rate during the transport inter
`vals being higher than during the dialysis intervals. As a
`result the measurement can be shortened as a whole and the
`evaluation can be further simplified since an existing con
`centration gradient can be qualitatively detected by means of
`the measurement signal even if there is only a partial dialysis
`equilibration. The flow rate should be increased during the
`transport intervals to such an extent that the starting content
`of the glucose in the perfusate is essentially maintained as it
`passes through the microdialysis probe. In contrast the
`transport is interrupted or at least the flow rate is reduced
`during the dialysis intervals to Such an extent that the
`glucose concentration in the dialysate approximates the
`glucose content of the body fluid.
`In a particularly simple control process the command
`variable which defines the target value is determined by
`integration or differentiation of the time course of the
`measurement signals or by a qualitative detection of signal
`peaks in the time course of the measurement signals. Alter
`natively the command variable can be determined by com
`paring the actual signal time course of the measurement
`signals with calibrated signal patterns deposited in a storage
`medium. An additional method is to determine the command
`variable from the peak value of the signal time course of the
`
`Page 5 of 9
`
`

`

`US 7,169,600 B2
`
`5
`measurement signals during each transport interval. In order
`to quantitatively define the regulating input signal, the
`command variable can be determined according to the
`glucose content c of the body fluid using the relationship
`
`Sg
`c -si-), is, - a co+co
`= -- - 1. a.
`
`10
`
`in which S denotes the peak value and So denotes the base
`line value of the signals measured during a transport interval
`and co is the momentary starting content of glucose in the
`perfusate and a, b are empirically determined correction
`factors compensating for diffusion and mixing and remain
`ing recovery effects during the transport interval.
`A particularly simple control function envisages that the
`initial content of glucose in the perfusate is adjusted dis
`continuously by a two-point control process in which the
`starting content of the glucose in the perfusate is changed by
`a predetermined adjusting value when there is a deviation.
`With regard to a measuring arrangement, a control device
`is proposed to achieve the above-mentioned object which
`adapts the starting content of the glucose in the perfusate to
`the glucose content of the body fluid on the basis of a
`command variable derived from the measurement signals of
`the measuring cell. An evaluation unit is provided in a
`preferred embodiment which determines the glucose content
`of the body fluid corresponding to the momentary starting
`content of glucose in the perfusate when the deviation is
`negligible.
`The perfusion device contains a store of perfusate and a
`transport unit to transport perfusate. The transport unit
`preferably operates at intervals i.e. at different delivery rates
`in successive time intervals. In order to vary the initial
`glucose content it is advantageous if the perfusate store has
`at least two separate reservoirs to hold perfusion liquids with
`different glucose concentrations. Advantageously the perfu
`sate store has a first reservoir containing a glucose-free
`perfusion liquid and a second reservoir containing a glucose
`containing perfusion liquid. In this case the glucose content
`in the latter should be above the physiological thresholds. A
`controller for adjusting the starting content of the glucose in
`the perfusate which is simple to construct is preferably
`provided by a flow mixer composed of a mixing valve or a
`clock-pulsed directional control valve as the adjuster. In this
`case it is advantageous for the flow mixer to be connected on
`the inlet side with at least two reservoirs to supply perfusion
`fluids with different glucose contents and to discharge into
`a perfusate tube leading to the microdialysis probe.
`The control device advantageously has a controller that
`operates digitally preferably by means of a micro-controller
`in order to process the signal flow in a variable manner.
`
`15
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The invention is elucidated in more detail in the following
`on the basis of an embodiment example shown Schemati
`cally in the drawing.
`FIG. 1 shows a block diagram of a microdialysis arrange
`ment for determining the concentration of glucose in a tissue
`fluid and
`FIG. 2 shows a time-dependency diagram of the perfusate
`flow, the measured glucose signal in the dialysate and the
`adaptively readjusted glucose concentration in the perfusate.
`
`60
`
`65
`
`6
`DETAILED DESCRIPTION OF THE DRAWINGS
`
`The microdialysis arrangement shown in the figure is
`essentially composed of a microdialysis probe 10 that can be
`implanted in the Subcutaneous tissue of a test person, a
`perfusion device 12, 14 for the intermittent perfusion of the
`microdialysis probe 10 with glucose-containing perfusate, a
`flow-through measuring cell 16 to detect the glucose content
`in the dialysate that flows through, a control device 18, 20
`to adjust the starting content of the glucose in the perfusate
`to the glucose content of the tissue fluid and an evaluation
`unit 22 to determine the glucose content of the tissue fluid.
`The microdialysis probe 10 has a dialysis membrane 24
`which enables a diffusion exchange of glucose between the
`perfusate located in the probe and the interstitial liquid
`surrounding the probe while obtaining dialysate. For this
`purpose a flow-through channel is provided in the tube
`shaped double bore probe housing 25 which is at least
`partially bordered by the dialysis membrane 24 and which in
`the proximal probe region is connected on the inlet side with
`a perfusate tube 26 to pass in perfusate and on the outlet side
`with a dialysate tube 28 to discharge the dialysate formed
`from the perfusate during the dialysis process. The dialysate
`can be further transported via the dialysate tube 28 to the
`measuring cell 16 and from there into a collecting vessel 30.
`Suitable microdialysis probes of the described type are
`well-known especially from DE-A 33 42 170 or U.S. Pat.
`No. 4,694,832 and can be obtained from the CMA/Microdi
`alysis AB company located in Solna, Sweden under the
`name “CMA60 Microdialysis Catheter” or “CMA 70 Brain
`Microdialysis Catheter'.
`In order to supply the microdialysis probe 10 at intervals
`with perfusate containing glucose, the perfusion device
`contains a store of perfusate 12 and a transport unit 14. The
`perfusate store 12 is composed of two separate reservoirs 32.
`34 one of which contains a glucose-free perfusion liquid 36
`and the other contains a perfusion liquid 38 to which glucose
`has been added at a specified concentration. The glucose
`concentration of the liquid 38 is expediently more than 4 g/1
`in order that the physiological range of tissue glucose can be
`covered in the perfusate by mixing the liquids 36 and 38 in
`the manner described below. A peristaltic pump 14 operated
`at intervals is provided as a feeding unit to transport the
`perfusate in metered delivery pulses of a few microliters
`through the microdialysis probe 10 and the subsequent
`measuring cell 16. It is preferably located in the dialysate
`tube 28 in order during the transport pauses to isolate the
`microdialysis probe 10 from the measuring cell 16 arranged
`extracorporeally.
`The measuring cell 16 through which perfusion fluid and
`the dialysate contained therein flows, has an electrode sensor
`40 which operates electrochemically-enzymatically for con
`tinuous signal acquisition. The sensor 40 has a measuring
`electrode that is not shown which is supplied with the
`dialysate that serves as the electrolyte and is used to con
`tinuously register as a continuous measuring current, the
`measurement signals that are linearly dependent on the
`glucose content of the dialysate. Further details of this
`measuring principle are known in the prior art in particular
`from DE-A 4401 400 to which special reference is herewith
`made. Obviously the measurement signals also reflect the
`glucose content of the body fluid insofar as a complete
`equilibration of the concentration gradient between the
`perfusate and the body fluid has taken place in the microdi
`alysis probe or the degree of equilibration is known.
`The signals measured by the sensor 40 are electronically
`processed in the Subsequent measurement transducer 42 and
`
`Page 6 of 9
`
`

`

`7
`fed into a digital controller 18 of the controlling device as a
`chronological sequence of digital values by means of a
`clock-pulsed analogue-digital converter. In this case the
`controller 18 is a microcontroller which also forms the
`evaluation unit 22. The output side of the controller 18 is
`connected to a directional control valve 20 as an adjuster of
`the control unit for adjusting the initial content of glucose in
`the perfusate. In a spring-centred first Switch position the
`directional control valve 20 connects the perfusate tube 26
`to the glucose-free reservoir 32 and, in a second electro
`magnetically actuated Switch position, to the glucose-con
`taining reservoir 34. Hence, the glucose concentration in the
`perfusate can be influenced as a regulated variable in a
`synchronized operation by suitable selection of the switch
`ing frequency, by the quantity ratio of the liquids 36, 38
`sucked in by the peristaltic pump 14 and by the flow mixing
`which occurs subsequently in the perfusate tube 26.
`When the microdialysis arrangement is in operation
`according to the above-mentioned diagram in FIG. 2, the
`perfusate is pumped in transport intervals 46 separated by
`resting and dialysis intervals 44 through the microdialysis
`probe 10 and the measuring cell 16. The dialysis intervals
`can be dimensioned Such that the glucose content of the
`perfusate volume resting in the microdialysis probe 10 is
`almost completely adjusted to the tissue glucose by diffusion
`exchange. In contrast the glucose concentration in the per
`fusate remains essentially unchanged during the transport
`intervals 46 due to rapid passage through the probe. The
`degree of equilibration or the recovery depends among
`others on the residence time and the flow rate of the
`perfusate in the microdialysis probe 10. In the embodiment
`example shown in FIG. 2 the duration of the dialysis interval
`is 360 sec when transport is interrupted whereas the duration
`of a transport interval is 180 sec at a flow rate V of 0.08 ul/s.
`With each delivery pulse the dialysate formed in the
`previous dialysis interval is displaced completely in a trans
`port or liquid column from the microdialysis probe 10 at
`least into the dialysis tube 28 and preferably up to the
`measuring cell 16. Accordingly a signal S is registered there
`during the transport intervals 46 which, when there are
`differences in concentration between the tissue and perfusate
`glucose, displays a corresponding peak or extreme value S.
`and a base line value So which corresponds to the starting
`concentration of glucose in the perfusate (middle diagram in
`FIG. 2).
`In order to adjust the starting glucose in the perfusate to
`the tissue glucose, a command variable which corresponds
`to the tissue glucose is derived from the measurement
`signals by means of the evaluation unit 22 and fed into the
`controller 18 to generate the deviation from the controlled
`variable i.e. the momentary value for the starting glucose. In
`this case the command variable correlates with the signal
`peaks S, whereas the control variable can be acquired from
`the base line value So.
`For a particularly simple control it is sufficient that the
`command variable or the control difference is determined by
`a qualitative detection of signal peaks S. and the starting
`content of glucose in the perfusate is discontinuously
`adapted by a two-point control process. In this process the
`initial glucose content c is increased by a predetermined
`value Ap when there is a positive peak (signal peak 48) using
`the adjuster 20 and is correspondingly reduced when there is
`a negative peak (signal dip; not shown). A slight equilibra
`tion or recovery (<50%) during the dialysis intervals is
`already sufficient for this controlled operation and hence its
`duration can be correspondingly reduced.
`
`5
`
`10
`
`15
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`US 7,169,600 B2
`
`8
`The adjusting signal can only be converted in the case of
`constant transport intervals after a dialysis interval is com
`pleted. In order to avoid this dead time, it is also conceivable
`that the duration of the momentary transport interval could
`be extended when there is a deviation to ensure that the
`perfusion liquid containing the re-adjusted glucose content
`can immediately pass into the microdialysis probe 10.
`When the deviation is negligible, a constant signal 50 is
`finally observed which indicates that the initial glucose
`content c, agrees with the actual value c of the tissue
`glucose (FIG. 3 below). Hence an error-prone direct evalu
`ation of the measurement signals is not necessary and the
`method enables the tissue glucose to be determined indi
`rectly from the equilibrium values c, when a constant signal
`50 occurs. This can be accomplished without additional
`measurements by the fact that the initial content of the
`glucose in the perfusate is determined by means of the
`evaluation unit 22 from the actual adjustable variable i.e. the
`Switching frequency of the valve 20, optionally by compari
`son with assigned calibration values.
`One method for the quantitative evaluation of the mea
`Surement signals is to determine the command variable by
`pattern recognition i.e. by comparing the actual signal curve
`of the measurement signals with calibrated signal patterns
`that are deposited in a storage medium. Alternatively the
`deviation can be determined as a difference between the
`peak value and the base line value of the signal curve of the
`measurement signals. Hence in this case the actual values of
`the control variable are recorded by measurement as the base
`line value So.
`As outlined above, the sensor signal is evaluated only
`during the high flow phase. This signal consists of the part
`S. belonging to the dialysis phase and being proportional to
`the tissue glucose concentration and the signal So belonging
`to the high flow rate representing almost the initial perfusate
`glucose concentration. In order to achieve a control which is
`independent of variations in sensitivity, the command vari
`able can be determined according to the glucose content c of
`the tissue liquid using the relationship
`
`in which co is the momentary starting glucose content in the
`perfusate which can be determined by the adjustable vari
`able.
`In order to take into account further influence parameters,
`the tissue glucose concentration may be calculated as fol
`lows:
`
`Sg
`c=|s, 1-, ps, - aco too
`= -- - 1. a.
`
`60
`
`65
`
`where a and b are empirically determined correction factors
`compensating for diffusion and mixing and remaining recov
`ery effects during the transport interval. The peak value S.
`is the sensor value at a definite time point during the
`transport interval. This time point may be determined in
`vitro and is given by the time it takes to push the dialysate
`from the microdialysis probe to the glucose sensing unit, i.e.
`the measuring cell 16. So may be obtained as the mean value
`of the sensor values 60 seconds before and after the time
`point of S.
`
`Page 7 of 9
`
`

`

`It is conceivable that the previously described principle of
`self-adapting control of the glucose content can also be used
`in the case of measurements with a continuous perfusate
`flow. In principle this microdialysis technique is not
`restricted to Subcutaneous measurements on the human
`body. Rather it is possible to examine other body fluids such
`as blood and optionally ex vivo.
`What is claimed is:
`1. A device for determining a glucose concentration in a
`tissue fluid, the device comprising
`a microdialysis probe for a diffusion exchange of glucose
`with Surrounding tissue fluid,
`a perfusion device for perfusing the microdialysis probe
`with glucose-containing perfusate to obtain