WO2007054317A1 - Determining a value of a physiological parameter - Google Patents

Abstract

A device (13) for determining a present value of a physiological parameter over time, the device (13) comprising a body fluid extraction unit (2) adapted to extract a body fluid sample from a body under investigation (1), a coupling unit (6) adapted to bring the extracted body fluid sample in functional contact with one of a plurality of test units (8), each of the test units (8) being indicative of the present value of the physiological parameter when brought in functional contact with the extracted body fluid sample, and an evaluation unit (10) adapted to determine the present value of the physiological parameter based on an analysis of the one of the plurality of test units (8) brought in functional contact with the extracted body fluid sample.

Description

DETERMINING A VALUE OF A PHYSIOLOGICAL PARAMETER

The present application claims the benefit of the filing date of European Patent Application 05024417 filed November 9, 2005, and of United States Provisional Patent Application 60/734,945, filed November 9, 2005, the disclosure of which is hereby incorporated herein by reference.

The invention relates to devices for determining a value of a physiological parameter.

The invention further relates to methods of determining a value of a physiological parameter.

Moreover, the invention relates to a test unit apparatus for such a device or method.

In diabetes, the tight control of glucose metabolism is lost because the release of insulin from the beta cells of the pancreas is lacking -so-called "type 1 diabetes" - or abnormal -so-called "type 2 diabetes" (see Mathis, D, Vence, L and Benoist, C "β- CeIl death during progression to diabetes", Nature 414:792-798, 2001 ; Bell, GI, and Polonsky, KS "Diabetes mellitus and genetically programmed defects in beta-cell function", Nature 414:788-791, 2001).

Thus, people with type 1 diabetes have to administer insulin from external sources for survival. People with type 2 diabetes are usually not dependent on exogenous insulin administration, but may require it for control of blood glucose levels if this is not achieved with diet alone or with oral hypoglycemic drugs (see Moller, DE "New drug targets for type 2 diabetes and the metabolic syndrome", Nature 414:821-827, 2001). Administration of exogenous insulin by means of the subcutaneous route provides the basis of the current insulin therapy (see Owens, DR "New horizons- alternative routes for insulin therapy", Nat Rev Drug Discov 1 :529- 540, 2002).

In the majority of the insulin-requiring diabetic patients, insulin is administered in the form of a bolus subcutaneous injection. However, an increasing number of patients is using external pumps to administer insulin in the form of a continuous subcutaneous infusion, so-called "insulin pump therapy" (see Owens, DR "New horizons- alternative routes for insulin therapy", Nat Rev Drug Discov 1 :529- 540, 2002; Lenhard, MJ, and Reeves, GD "Continuous subcutaneous insulin infusion: a comprehensive review of insulin pump therapy", Arch Intern Med 161 :2293-2300, 2001).

With regard to glucose monitoring, large prospective clinical studies have suggested that tight blood glucose control is essential to minimize micro- and macrovascular complications in both type 1 and type 2 diabetes (see The Diabetes Control and Complications Trial Research Group "The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus", N Engl J Med 329:977-986, 1993; UK

Prospective Diabetes Study (UKPDS) Group "Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)", Lancet 352:837-853, 1998).

Present blood glucose monitoring techniques based on blood collection by fingers ticking and subsequent glucose determination with single use test elements (i.e., test strips) cannot be applied frequently enough to detect the early stages of blood glucose excursions (see Gough, DA, Kreutz-Delgado, K and Bremer, TM "Frequency characterization of blood glucose dynamics", Ann Biomed Eng 31 :91- 97, 2003). Thus, even highly motivated patients who carefully perform frequent fmgerstick measurements may miss substantial fluctuation in glucose levels, particularly episodes of nocturnal hypoglycemia (see Boland, E, Monsod, T, Delucia, M, Brandt, CA, Fernando, S and Tamborlane, WV "Limitations of conventional methods of self-monitoring of blood glucose: lessons learned from 3 days of continuous glucose sensing in pediatric patients with type 1 diabetes", Diabetes Care 24:1858-1862, 2001).

There has been a significant effort put forth by the research community toward the development of painless and continuous methods for monitoring blood glucose levels (see Gough, DA, and Armour, JC "Development of the implantable glucose sensor. What are the prospects and why is it taking so long?", Diabetes 44:1005-9, 1995; Klonoff, DC "Current, emerging, and future trends in metabolic monitoring", Diabetes Technol Ther 4:583-8, 2002; Kerner, W "Implantable glucose sensors: Present status and future developments", Exp Clin Endocrinol Diabetes 109 (Suppl 2):S341-S346, 2001; Klonoff, DC, "Continuous glucose monitoring", Diabetes Care 28:1231-9, 2005). However, because of stability problems with the available sensor techniques, no reliable continuous glucose monitor has so far been developed.

In the following, intermittent blood glucose monitors will be described.

Currently a blood glucose testing system widely used by diabetic patients consists of a test strip and a measuring instrument. For analyzing a blood sample, a test strip is manually removed from a separate storage container and the rear or contact end of the test strip is inserted into the test strip holder of the instrument. After pricking the finger with a lancet, the testing end of the test strip is placed into the blood that has accumulated on the patient's finger. Due to capillary action, the blood is drawn through a capillary channel to the reagent materials contained in the test strip. The reagent materials then chemically react with the glucose drawn into the test strip to cause a detectable signal. The test strip is then disposed of after use.

In the following, a multiple test strip device will be described.

Recently, several blood glucose testing systems have been brought to market in which the measuring instrument is adapted to receive a magazine containing a multitude of single-use test strips. The test strips are accommodated in slots or cavities of the magazine. To perform a blood glucose measurement, one of the test strips is mechanically removed from the magazine and positioned in the test strip holder with the testing end of the test strip projecting out from the instrument. When in this testing position, the testing end of test strip can be placed into the blood being analyzed. After the blood has been analyzed, the used test strip is ejected from the instrument.

In the following, continuous glucose monitors will be described.

Because of the potential risks associated with continuous blood glucose monitoring (e.g., infection, bleeding, clotting, sensor fouling), most of the studies in the recent past have focused on the interstitial fluid (ISF) of the peripheral tissues as an alternative site for the continuous monitoring of glucose levels (see Klonoff, DC "Current, emerging, and future trends in metabolic monitoring", Diabetes Technol Ther 4:583-8, 2002; Kerner, W "Implantable glucose sensors: Present status and future developments", Exp Clin Endocrinol Diabetes 109 (Suppl 2):S341-S346, 2001; Klonoff, DC "Continuous glucose monitoring", Diabetes Care 28:1231-9, 2005.)- The approaches for measuring ISF glucose levels thus far proposed fall into two general categories: ex vivo and in vivo approaches.

In the in vivo approach, a glucose sensor is inserted directly into the subcutaneous tissue. A commercially available technology based on this approach is the ,,MiniMed Continuous Glucose Monitoring System" (CGMS; Medtronic MiniMed Inc., Northridge, CA). This device consists of an enzyme-tipped catheter sensor that is inserted into the subcutaneous tissue and wired to a pager-sized glucose monitor worn externally (see Mastrototaro, JJ "The MiniMed continuous glucose monitoring system", Diabetes Technol Ther 2 (Suppl 1):S13-S18, 2000). There are several limitations of the CGMS, such that, due to stability problems, the device requires rigorous calibration with blood glucose measurements obtained by fingerstick testing and that the patient has no access to real-time glucose recordings. The data collected over a recommended 3 -day period may be reviewed retrospectively by a healthcare professional.

In the ex vivo approach, ISF is extracted from peripheral tissues and then transported to a glucose sensor that is located outside the body. This approach has been the basis of commercially available devices, which measure glucose from ISF that has been extracted either by means of a microdialysis catheter (see Maran, A, Crepaldi, C, Tiengo, A, Grassi, G, Vitali, E, Pagano, G, Bistoni, S, Calabrese, G, Santeusanio, F, Leonetti, F, Ribaudo, M, Di Mario, U, Annuzzi, G, Genovese, S, Riccardi, G, Previti, M, Cucinotta, G, Giorgino, F, Bellomo, A, Giorgino, R, Poscia, A and Varalli, M "Continuous subcutaneous glucose monitoring in diabetic patients: a multicenter analysis", Diabetes Care 25:347-352, 2002) or a process denoted as "reverse iontophoresis" (see Tamada, JA, Bohannon, NJ and Potts, RO "Measurement of glucose in diabetic subjects using noninvasive transdermal extraction", Nat Med 1 :1 198-1201, 1995). The latter device is worn on the wrist or arm, and samples ISF that is drawn through the skin into an electrolyte by applying an electric field between two electrodes placed on the skin (i.e., reversed iontophoresis). The electrodes are coupled to the skin by the electrolyte. Glucose can then be measured using a glucose sensor in contact with the electrolyte. There are several limitations of this device, such that it may cause skin irritations and that a large number of readings are erroneous because of interferences from skin sweating and temperature fluctuations.

Other systems based on the ex vivo approach are under development (see Kerner, W "Implantable glucose sensors: Present status and future developments", Exp Clin Endocrinol Diabetes 109 (Suppl 2):S341-S346, 2001; Klonoff, DC "Continuous glucose monitoring", Diabetes Care 28:1231-9, 2005).

The ISF sampling methods that are utilized by these systems include microdialysis (see Schoemaker, M, Andreis, E, Roper, J, Kotulla, R, Lodwig, V, Obermaier, K, Stephan, P, Reuschling, W, Rutschmann, M, Schwaninger, R, Wittmann, U, Rinne, H, Kontschieder, H and Strohmeier, W "The SCGMl System: subcutaneous continuous glucose monitoring based on microdialysis technique", Diabetes Technol Ther 5:599-608, 2003) and open flow microperfusion (see Trajanoski, Z, Brunner, GA, Schaupp, L, Ellmerer, M, Wach, P, Pieber, TR,

Kotanko, P and Skrabal, F "Open-flow microperfusion of subcutaneous adipose tissue for on-line continuous ex vivo measurement of glucose concentration", Diabetes Care 20:1114-1121, 1997; Schaupp, L, Ellmerer, M, Brunner, GA, Wutte, A, Sendlhofer, G, Trajanoski, Z, Skrabal, F, Pieber, TR and Wach, P "Direct access to interstitial fluid in adipose tissue in humans by use of open-flow microperfusion", Am J Physiol Endocrinol Metab 276:E401-E408, 1999; Regittnig, W, Ellmerer, M, Fauler, G, Sendlhofer, G, Trajanoski, Z, Leis, HJ, Schaupp, L, Wach, P and Pieber, TR "Assessment of transcapillary glucose exchange in human skeletal muscle and adipose tissue", Am J Physiol Endocrinol Metab 285:241-51, 2003). The ISF sampling by these methods involves the insertion of a microperfusion or microdialysis catheter into the subcutaneous tissue and the continuous transport of an isotonic fluid through the catheters by means of a pumping system. The catheters are typically constructed from two tubular cannulae where the smaller inner cannula is mounted concentrically within the bigger outer cannula. The perfusion fluid enters the catheters via the inlet tubing, moves through the inner cannula to the tip of the probe, and streams back in the space between inner cannula and the outer cannula which in the case of microdialysis contains a dialysis membrane (see Lδnnroth, P, Jansson, PA and Smith, U "A microdialysis method allowing characterization of intercellular water space in humans", Am J Physiol Endocrinol Metab 253:E228- E231, 1987; Ungerstedt, U "Microdialysis - principles and applications for studies in animals and man", J Intern Med 230:365-73, 1991), or in the case of microperfusion possesses laser-drilled wholes in its wall (see Schaupp, L, Ellmerer, M, Brunner, GA, Wutte, A, Sendlhofer, G, Trajanoski, Z, Skrabal, F, Pieber, TR and Wach, P "Direct access to interstitial fluid in adipose tissue in humans by use of open-flow microperfusion", Am J Physiol Endocrinol Metab 276:E401-E408, 1999).

Diffusional exchange occurs between the perfusate and the interstitial fluid adjacent to the outer cannula as the perfusion medium passes by the perforations or the membrane of the outer cannula. The medium then flows through the outlet tubing to a sensor flow chamber outside the body. However, because of sensor stability problems, no reliable monitoring of the glucose concentration is so far possible with approaches using microdialysis or microperfusion techniques for sampling of ISF (see Hovorka, R, Chassin, LJ, Wilinska, ME, Canonico, V, Akwi, JA , Federici, MO, Massi-Benedetti, M, Hutzli, I, Zaugg, C, Kaufmann, H, Both, M, Vering, T, Schaller, HC, Schaupp, L, Bodenlenz, M and Pieber, TR "Closing the loop: the ADICOL experience", Diabetes Technol Ther 6:307-18, 2004). US 5,242,382 discloses continuous or periodic measurement of blood gas parameters and blood pressure by separating plasma from blood and then using that plasma to measure the blood parameters. Plasma is separated from blood in vivo with a filter implanted within a blood vessel, and the separated plasma is removed to extracorporeal apparatus for analyzing blood gas parameters or measuring blood pressure. The use of plasma is equivalent to the use of whole blood for measuring blood gas parameters as the gas parameters reside in the plasma, not in the separated blood cells which remain in the blood vessel.

US 3,918,910 discloses a system for detecting the particular constituent of a fluid which comprises a cassette for holding a plurality of chemical reaction-testing strips each provided with a plurality of carriers containing reagents; means for drawing out said chemical reaction-testing strips one after another from the cassette and bringing a test fluid filled in a container into contact with the respective reagent carriers of the strip, means for producing an electric signal corresponding to the degree of a chemical reaction between the test fluid and any of said reagent carriers, and means for printing out data denoting the degree of said chemical reaction.

EP 0,542,260 discloses a test strip automatic supply device having a cylindrical container provided with a slit which is formed in a side wall thereof so as to contain an elongate test strip, a container supporting table having, in an upper portion thereof, a semi-cylindrical concave surface provided with an opening which is formed in a middle portion of the concave surface so as to allow a test strip fitted in the slit of the container to fall through and be taken out, and a carrying stage which receives and transports a test strip falling from the slit. While the transporting stage is transporting a test strip, optical means finds whether the test strip is faced up or down. The device has such a function that side reversing mechanism flips it over during transportation if it is face down. An operator only has to put test strips in the container. The tests strips are automatically let out of the container one at a time.

WO 1996/39209 discloses a method and an apparatus for maximizing the total amount of blood processed during an apheresis procedure by optimizing the concentration of anticoagulant in a donor/patient and the associated extracorporeal tubing set is provided. A simplified model of an anticoagulant accumulation in a donor/patient's body is used to calculate an optimal anticoagulant infusion rate profile to the donor/patient during a blood processing procedure. A maximum acceptable anticoagulant concentration in the donor/patient acts as an upper limit on the rate at which anticoagulant may be infused to the donor/patient using the optimized infusion rate profile. A minimum acceptable anticoagulant level acts as a lower limit in optimally controlling the anticoagulant concentration in the extracorporeal tubing set. Both the maximum acceptable anticoagulant level in the donor/patient and the minimum acceptable anticoagulant level in the extracorporeal tubing set may be customized for a specific donor/patient thereby allowing the optimized infusion rate profile and the extracorporeal tubing set anticoagulant concentration to be customized for the specific patient.

It is an object of the invention to allow for an efficient determination of a value of a physiological parameter.

In order to achieve the object defined above, a device for determining a present value of a physiological parameter over time, a device for determining a value of a physiological parameter, a method of determining a present value of a physiological parameter over time, a method of determining a value of a physiological parameter, and a test unit apparatus according to the independent claims are provided. According to an exemplary embodiment of the invention, a device for determining a present value of a physiological parameter over time is provided, the device comprising a body fluid extraction unit adapted to extract a body fluid sample from a body under investigation, a coupling unit adapted to bring the extracted body fluid sample in functional contact with one of a plurality of test units, each of the test units being indicative of the present value of the physiological parameter when brought in functional contact with the extracted body fluid sample, and an evaluation unit adapted to determine the present value of the physiological parameter based on an analysis of the one of the plurality of test units brought in functional contact with the extracted body fluid sample.

According to another exemplary embodiment of the invention, a device for determining a value of a physiological parameter is provided, the device comprising a body fluid extraction unit adapted to extract a body fluid sample from a body under investigation, a coupling unit adapted to bring the extracted body fluid sample in functional contact with a test unit being indicative of the value of the physiological parameter when brought in functional contact with the extracted body fluid sample, a marker sensing unit adapted to sense at least one value of at least one marker parameter of the extracted body fluid sample, and an evaluation unit adapted to determine the value of the physiological parameter based on an analysis of the test unit brought in functional contact with the extracted body fluid sample, wherein the evaluation unit is adapted to perform a calibration for the determination of the value of the physiological parameter based on the sensed at least one value of the at least one marker parameter.

According to still another exemplary embodiment of the invention, a method of determining a present value of a physiological parameter over time is provided, the method comprising extracting, by means of a body fluid extraction unit, a body fluid sample from a body under investigation, bringing, by means of a coupling unit, the extracted body fluid sample in functional contact with one of a plurality of test units, each of the test units being indicative of the present value of the physiological parameter when brought in functional contact with the extracted body fluid sample, and determining, by means of an evaluation unit, the present value of the physiological parameter based on an analysis of the one of the plurality of test units brought in functional contact with the extracted body fluid sample.

According to yet another exemplary embodiment of the invention, a method of determining a value of a physiological parameter is provided, the method comprising extracting, by means of a body fluid extraction unit, a body fluid sample from a body under investigation, bringing, by means of a coupling unit, the extracted body fluid sample in functional contact with a test unit being indicative of the value of the physiological parameter when brought in functional contact with the extracted body fluid sample, sensing, by means of a marker sensing unit, at least one value of at least one marker parameter of the extracted body fluid sample, and determining, by means of an evaluation unit, the value of the physiological parameter based on an analysis of the test unit brought in functional contact with the extracted body fluid sample, and performing, by means of the evaluation unit, a calibration for the determination of the value of the physiological parameter based on the sensed at least one value of the at least one marker parameter.

According to still another exemplary embodiment of the invention, a test unit apparatus for a device for determining a value of a physiological parameter (for instance for use with a device having the above-mentioned features) is provided, the test unit apparatus comprising at least one test unit comprising a physiological parameter indicating portion and comprising a marker parameter indicating portion, wherein the physiological parameter indicating portion is indicative of a value of a physiological parameter when brought in functional contact with an extracted body fluid sample, and wherein the marker parameter indicating portion is indicative of at least one marker parameter of the extracted body fluid sample when brought in functional contact with the extracted body fluid sample.

According to one exemplary aspect of the invention, a medical device is provided in which a current value of a parameter related to a (human or animal) body under examination is determined or monitored over any desired interval of time. For instance, the device may monitor the glucose level of a type 1 diabetes patient or of a type 2 diabetes patient over night, for instance regularly. In such a scenario, a body fluid sample, for instance an interstitial fluid (ISF) sample , may be drawn from the patient in an invasive manner and brought in contact with a particular test unit from an array or magazine of test units (for instance a disk or drum magazine of test strips). When the body fluid sample gets in contact with a particular one of the plurality of the test units, the test units may be characteristically modified (for example due to a chemical reaction between the body fluid sample and a reactive substance of the test unit), wherein the degree of modification may allow to derive the actual value of the physiological parameter (for instance a glucose concentration of the body fluid sample). The characteristic modification of the test unit brought in fluid communication with the body fluid sample may be detected and analyzed by an evaluation unit which may compute the present value of the physiological parameter. Subsequently, such a measurement procedure may be repeated with another one of the (single-use) test units. The different test units of the test unit array may be moved (for instance rotated) manually or automatically so that, at a particular instance of time, a particular one of the test units may be brought in contact with a particular one of body fluid samples in a coupling area. By using a plurality of single-use (for instance disposable) sensor units, the reliability and the stability of the physiological parameter monitoring system may be significantly improved as compared to an approach in which a single sensor is used for the measurement a plurality of times.

According to another exemplary aspect of the invention, a medical device for determining a value of a physiological parameter is provided in which a single (or more than one) test unit is characteristically modified in accordance with the value of the physiological parameter. The same body fluid sample is, simultaneously or sequentially, investigated by means of a marker sensing unit which may sense another parameter, a so-called (endogenous) marker parameter, of the extracted body fluid sample. The evaluation unit may then compute the value of the physiological parameter based on the information derived from the test unit after being brought in fluid communication with the body fluid sample, wherein the calculation of the current value of the physiological parameter is calibrated based on the detected value of the marker parameter. It may happen that, for instance as a consequence of the extraction procedure for extracting the body fluid sample from the human or animal body, the concentration of a physiological substance in the body fluid sample may differ from an in vivo concentration of the physiological substance in the human being or the animal from, for example due to undesired concentration or dilution effects. In order to avoid any deterioration of the measurement of the value of the physiological substance or parameter, one or more other characteristic marker parameters may be determined so that this information may be used to correct the estimated value of the physiological parameter. For instance, a level of one or more endogenous markers (for instance a concentration of ions like Sodium and/or Potassium) in the body fluid sample may allow for a mathematical correction of the value of the physiological parameter, for instance the glucose concentration in interstitial fluid. As marker parameters, it may be advantageous to use a marker having a concentration inside the body which is well known and sufficiently stable. Then, a comparison between the measured value and the expected value is a reliable measure for the parasitic concentration or dilution of both, marker and physiological substance, due to the experimental measurement process.

According to an exemplary aspect of the invention, to achieve the goal of tight blood glucose control in diabetes, frequent blood glucose measurements - if desired in conjunction with insulin administrations at appropriate dosages and timing - may be made possible. Thus, a minimally invasive glucose monitor may be provided that can reliably substitute for fingerstick measurements.

Next, further exemplary embodiments of the invention will be described.

In the following, further exemplary embodiments of the device for determining a present value of a physiological parameter over time will be described. However, these embodiments also apply for the device for determining a value of a physiological parameter, for the method of determining a present value of a physiological parameter over time, for the method of determining a value of a physiological parameter, and for the test unit apparatus according to the independent claims.

The device may be adapted for determining a glucose concentration, a cholesterol concentration, a lactate concentration, an oxygen concentration, an ion concentration, an amount of bacteria, an amount of virus, and a medicament concentration as the physiological parameter. In other words, the physiological parameter may be a concentration of a physiologically active substance in the body or at a special position inside the body. Thus, the physiological parameter may be any medically relevant parameter characterizing the body fluid and/or the state of the body from which the body fluid has been taken. Such information may be used to determine whether and to which amount it is necessary or not necessary to provide any medicament, perform any treatment, initiate any alarm, repeat measurement or control any parameter.

For instance, a patient suffering from diabetes may be the subject of the investigation, and the glucose concentration and/or an insulin concentration of such a person may be estimated.

The device may be adapted for determining the physiological parameter continuously (or quasi-continuously) over time. In this respect, the term "continuously" (or quasi-continuously) may particularly denote that no or only small intervals are between points of time in which the value of the physiological parameter is monitored. By such an investigation, a time dependence of the physiological parameter may be derived from the investigations. Alternatively, it may be possible to determine the physiological parameter intermittently over time, that is to repeat the determination of the physiological parameter after expiry of a particular time interval. For instance, the glucose concentration of a patient may be determined every 15 minutes, every 30 minutes or every 60 minutes.

The body fluid extraction unit may be adapted to extract the body fluid sample by microdialysis, microperfusion, ultrafiltration, a porous tissue contactor, reversed iontophoresis, suction technique using one or more microneedles, and transdermal extraction (for instance using ultrasound and/or osmotic extraction buffer).

The technique of "microdialysis" as such is disclosed in Schoemaker, M,

Andreis, E, Roper, J, Kotulla, R, Lodwig, V, Obermaier, K, Stephan, P, Reuschling, W, Rutschmann, M, Schwaninger, R, Wittmann, U, Rinne, H, Kontschieder, H and Strohmeier, W "The SCGMl System: subcutaneous continuous glucose monitoring based on microdialysis technique", Diabetes Technol Ther 5:599-608, 2003, to which explicit reference is made herewith with regard to examples as to how to perform microdialysis in the context of the invention.

The technology of "microperfusion" as such is disclosed in Trajanoski, Z,

Brunner, GA, Schaupp, L, Ellmerer, M, Wach, P, Pieber, TR, Kotanko, P and Skrabal, F "Open- flow microperfusion of subcutaneous adipose tissue for on-line continuous ex vivo measurement of glucose concentration", Diabetes Care 20:1114- 1121, 1997; Schaupp, L, Ellmerer, M, Brunner, GA, Wutte, A, Sendlhofer, G, Trajanoski, Z, Skrabal, F, Pieber, TR and Wach, P "Direct access to interstitial fluid in adipose tissue in humans by use of open- flow microperfusion", Am J Physiol Endocrinol Metab 276:E401-E408, 1999; Regittnig, W, Ellmerer, M, Fauler, G, Sendlhofer, G, Trajanoski, Z, Leis, HJ, Schaupp, L, Wach, P and Pieber, TR "Assessment of transcapillary glucose exchange in human skeletal muscle and adipose tissue", Am J Physiol Endocrinol Metab 285:241-51, 2003, to which explicit reference is made herewith with regard to examples as to how to perform microperfusion in the context of the invention.

An interstitial fluid sampling by microdialysis or microperfusion may involve the insertion of a microperfusion or microdialysis catheter into the subcutaneous tissue and the continuous transport of an isotonic fluid through the catheters by means of a pumping system. The catheters may be constructed from two tubular cannula, wherein a smaller inner cannula is mounted concentrically within a bigger outer cannula. The perfusion fluid may enter the catheters via an inlet tubing, move through an inner cannula to a tip of the probe, and may stream back in the space between inner cannula and the outer cannula which in the case of microdialysis may contain a dialysis membrane (see Lonnroth, P, Jansson, PA and Smith, U "A microdialysis method allowing characterization of intercellular water space in humans", Am J Physiol Endocrinol Metab 253:E228-E231, 1987; Ungerstedt, U "Microdialysis - principles and applications for studies in animals and man", J Intern Med 230:365-73, 1991), or in the case of microperfusion may possess laser-drilled wholes in its wall (see Schaupp, L, Ellmerer, M, Brunner, GA, Wutte, A, Sendlhofer, G, Trajanoski, Z, Skrabal, F, Pieber, TR and Wach, P "Direct access to interstitial fluid in adipose tissue in humans by use of open-flow microperfusion", Am J Physiol Endocrinol Metab 276:E401-E408, 1999). Diffusional exchange may occur between the perfusate and the interstitial fluid adjacent to the outer cannula as the perfusion media passes by the perforations or the membrane of the outer cannula. The medium may then flow through the outlet tubing to a sensor flow chamber outside the body.

The technique of "ultrafiltration" as such is disclosed in US 5,002,054, to which explicit reference is made herewith with regard to examples as to how to perform ultrafiltration in the context of the invention.

An exemplary embodiment of a "porous tissue contactor" will be described below in more detail with reference to Fig. 3.

A "suction technique using microneedles" is disclosed as such in US 6,689,100, to which explicit reference is made herewith with regard to examples as to how to perform this technique in the context of the invention.

The technology of "transdermal extraction using ultrasound and/or osmotic extraction buffer" is disclosed as such in Kost, J, Mitragotri, S, Gabbay, RA, Pishko, M and Langer, R "Transdermal monitoring of glucose and other analytes using ultrasound", Nat Med 6:347-350, 2000, and in Chuang, H, Taylor, E and Davison, TW "Clinical Evaluation of a continuous minimally invasive glucose flux sensor placed over ultrasonically permeated skin", Diabetes Technol Ther 6:21-30, 2004, to which explicit reference is made herewith with regard to examples as to how to perform transdermal extraction using ultrasound and/or osmotic extraction buffer in the context of the invention.

The technology of "reversed iontophoresis" is disclosed as such in Tamada,

JA, Bohannon, NJ and Potts, RO "Measurement of glucose in diabetic subjects using noninvasive transdermal extraction", Nat Med 1 :1 198-1201, 1995, to which explicit reference is made herewith with regard to examples as to how to perform reversed iontophoresis in the context of the invention. Such a device may be worn on the wrist or arm of a patient, and may sample interstitial fluid that is drawn through the skin and to an electrolyte by applying an electric field between two electrodes placed on the skin. The electrodes may be coupled to the skin by the electrolyte. Glucose or any other physiological parameter can then be measured using a glucose sensor in contact with the electrolyte.

The body fluid extraction unit may be adapted to extract the body fluid sample as at least one of the group consisting of interstitial fluid, blood, lymph, cerebrospinal fluid, urine and tissue. The term interstitial fluid (ISF) may, in the context of this application, particularly denote liquid located between the cells in tissue of the body. Particularly, interstitial fluid may also denote (fatty) fluid between cells in the epidermis being a basis for the barrier function of the skin. Interstitial fluid may be a good choice for a sample to determine the glucose concentration of a patient (for instance suffering from diabetes) in a soft manner.

The device may comprise a multiple test unit device including the plurality of test units. Such a multiple test unit device may be realized as a replaceable or substitutable device. Such a multiple test unit device may be a disk-shaped magazine or a cylindrical magazine. Thus, a magazine may be a flat circular disk or a cylindrical drum. Test units (for instance test strips) may be accommodated in slots or cavities of such a magazine. To perform a measurement, one of the test units may be positioned so as to contact a body fluid sample to be investigated. When in this testing position, the testing end of the test strip can be placed into the body fluid sample being analyzed. After the body fluid sample has been analyzed, the used test strip may be ejected from the instrument or may be stored in a waste container.

Such a multiple test unit device may be designed in a similar manner as disclosed in one of the documents US 6,475,436, US 5,510,266, US 5,660,791, US 5,489,414, US 5,720,924, US 5,863,800, US 5,798,031, and may be manufactured in accordance with a method as disclosed in US 2005/0125162 or US 5,407,554.

The multiple test unit device may be a rotatable magazine. The rotation may be controlled by means of the evaluation unit. Energy for the rotation may be provided by muscle force of a user or by an electric energy supply of the device, for instance a battery.

The plurality of test units may be test strips. Each of these test strips may have a particular portion which is foreseen to be brought in contact with the body fluid sample in order to initiate or promote a characteristic alteration of at least one property of this test strip region indicative of the current value of the physiological parameter to be monitored.

Apart from this physiological parameter indicative test strip region, one or more further test strip regions may be provided, for instance for a measurement of another parameter of the body fluid. The device may comprise a detection unit adapted for performing the analysis of the one of the plurality of test units brought in functional contact with the extracted body fluid sample. Such a detection unit may be an optical detection unit, an electrical detection unit, and/or a chemical detection unit.

An optical detection unit may determine information concerning the physiological parameter as a consequence of a modification of at least one optical property of a test unit after being brought in contact with the body fluid sample. For instance, the colour, the reflectivity, the absorption or a fluorescence property of such a test strip may be altered in a characteristic manner in dependence of the value of the physiological parameter.

Alternatively, the detection may be performed in an electrical manner, for instance using an effect like a modification of an ohmic resistance, a conductivity, a capacity, a magnetic parameter or the like of the test strip.

A chemical detection may be based on the fact that a test unit, after being brought in contact with the body fluid sample, may have modified chemical or biochemical characteristics, for instance a modified pH value, a modified concentration of a chemical substance, or the like.

For instance, a test unit may comprise glucose oxidase as sensor-active substance. In the presence of glucose, glucose oxidase may be chemically modified so that an electrical voltage may be generated (which may be measured in the context of an electrochemical detection) and/or that a dye may be generated (which may be measured in the context of a photometric detection). Reagent materials chemically react with the glucose brought in contact with the test strip to cause an electrical signal (so-called electrochemical measuring technique) or a color change (so-called colorimetric measuring technique) in the test strip. Subsequently, the electrical signal or the color change is evaluated by the measuring instrument.

The evaluation unit may be a microprocessor. Such a microprocessor may be a central processing unit (CPU). It may be manufactured as an integrated circuit (for instance monolithically integrated in a semiconductor substrate) and can be manufactured, for instance, in silicon technology. Such a microprocessor may have computational resources and may, for instance, have access to a memory device (for instance an EEPROM) for storing data. Such an evaluation unit may further control the entire or a part of the functionality of the device and may receive control commands from a user interface.

Furthermore, the evaluation unit may initiate output of information to a user interface, for instance provide the result of the monitoring in a graphical manner (in real time or as a retrospective). For example, the microprocessor may generate outputable information indicative of the current glucose value of the body under investigation.

The device may comprise a body fluid transportation unit adapted to transport the extracted body fluid through at least a part of the device. Such a body fluid transportation unit may be a micropump or a miniature pump.

The body fluid transportation unit may comprise a marker sensing unit adapted to sense at least one value of at least one marker parameter of the extracted body fluid sample. Particularly, such a marker parameter may be an endogenous marker parameter. In this regard, explicit reference is made to the disclosure with respect to calibration using endogenous markers of WO 88/05643.

The term "endogenous marker" may particularly denote a substance whose concentration is known and regulated in the body fluid sample, for instance in interstitial fluid. By determining (or knowing) a concentration of one or more such markers both in the interstitial fluid and in the body fluid sample, possible disturbing influences of the body fluid extraction procedure on the fluid levels of the substances (that is to say concentration or dilution of different substances in the body fluid) can be estimated and then used to compensate for influences of the extraction process on the value of the physiological parameter in the extracted fluid. By taking such a measure, it may be possible to estimate the value of the physiological parameter in the body from the value of the physiological parameter in the extracted body fluid sample. Thus, it may be possible to compensate for errors in the estimation procedure which relate to the fact that body fluid is extracted form the body. Therefore, both can be achieved, a higher reliability of the measured parameter and a soft treatment of the body under investigation.

Additionally or alternatively, the marker sensing unit may be adapted to sense an exogenous marker parameter of the extracted body fluid sample.

The term "exogenous marker" may particularly denote a substance which is introduced from external into a (for example human) body under investigation. Further, the term "exogenous marker" may particularly denote a substance which is not produced by the (for example human) body, but may be produced artificially or by another organism. Examples for such exogenous markers are mannitol or innulin. Mannitol is a sugar-like substance which is essentially not metabolized by the human body and thus remains in the body with an essentially constant concentration in different regions of the body for a significant time. Based on blood and interstitial fluid samples extracted from the human body, a measured concentration of mannitol can be used, in good approximation, as a measure for the recovery (or exchange efficiency) of the interstitial fluid sample.

Exemplary marker parameters are ion concentrations of the extracted body fluid sample, for instance of interstitial fluid, and particularly Na⁺ or K⁺ ion concentrations.

The marker sensing unit and the detection unit may be provided as separate devices or as a common device. Realizing both functionalities in one and the same unit may have the advantage that the device is small in size and cheap in manufacture. Providing both units as separate elements may allow for an individual optimization of the functionality of the marker sensing unit and of the detection unit.

The marker sensing unit may be adapted to provide the sensed at least one value of the at least one marker parameter to the evaluation unit. The evaluation unit may be adapted to determine the present value of the physiological parameter based on an analysis of the one of the plurality of test units brought in functional contact with the extracted body fluid sample and based on an analysis of the sensed at least one value of the at least one marker parameter. Therefore, by considering both simultaneously, namely the estimated value of the physiological parameter and the derived value of the marker parameter, the reliability of the calculated physiological parameter may be improved. Thus, the significance of result data output by the device may be improved.

The marker sensing unit may be adapted to provide the sensed at least one value of the at least one marker parameter to the evaluation unit, which may then perform a calibration for the determination of the present value of the physiological parameter based on the sensed at least one value of the at least one marker parameter. By taking this measure, an estimated value of the physiological parameter which is valid for the milieu in the interstitial fluid can be recalculated into the corresponding concentration in another milieu, for instance in the blood. By taking this measure, the basis of decision, for instance which amount of medicament (for example insulin) should be supplied to the patient may be improved.

Each of the plurality of test units may comprise a physiological parameter indicating portion and may comprise a marker parameter indicating portion. Such a test unit or array of test units may be used within the device according to exemplary embodiments of the invention, or in another context.

The device may comprise an energy supply unit adapted to supply at least a part of the device with energy. For instance, units like the evaluation unit, a memory device, a pump, an optical detection unit, or the like may require electrical energy which may be provided by such an energy supply unit. The energy supply unit may be provided rechargeable or replaceable.

For instance, the energy supply unit may be a battery, a fuel cell,or a solar cell. Realizing the energy supply unit by a battery, a single use battery or a rechargeable accumulator may be used. When using a solar cell, no separate energy supply unit is required and light of the environment may be used as source of energy for operating the device.

The device may further comprise a waste collector unit adapted to collect body fluid sample after transportation through at least a part of the device. Thus, when the interstitial fluid or any other body sample device, if desired in combination with any buffer or auxiliary liquids provided by the device, have been used and need to be disposed, such fluids may be collected in a waste collector unit.

The device may further comprise a reservoir unit adapted to hold an injection fluid adapted to be injected into the body under investigation. Thus, the device may also control injection, infusion or insertion of any material into the body under investigation, for instance buffers, test fluids, medications or the like.

The reservoir unit may be adapted to hold a glucose regulating substance (that is particularly any substance which may have an influence on the glucose level in an organism), like insulin, an insulin-like growth hormone, adrenaline or the like.

Particularly, the reservoir unit may be adapted to hold a medication as the injection fluid. Therefore, as a consequence of the determination of the value of physiological parameter, the evaluation of the device may decide that it is necessary to inject a particular amount of medication into the patient's body. For instance, when it has been detected that the glucose level has become too high, insulin may be injected in the body of the person. For instance, when it has been detected that the glucose level has become too low, glucose may be injected in the body of the person.

The reservoir unit may be adapted to hold insulin as the injection fluid. However, the reservoir unit may, additionally or alternatively, be adapted to hold aldosterone or bi-carbonate or any other physiologically active substance as the injection fluid.

For instance, the hormone aldosterone may be injected into a body under investigation, as a reaction to the determination of corresponding values of a physiological parameter like an ion concentration, for instance the Potassium concentration. Aldosterone regulates the electrolyte and water concentrations in the human body. It increases resorption of Sodium ions from the kidney, thus increasing the Sodium level in the blood. Secretion of Potassium ions and water ions is promoted. Consequently, the Potassium level in the blood is reduced. Simultaneously, water is retained. Therefore, aldosterone also has an influence on the regulation of the blood volume and the blood pressure.

Another example for a physiological parameter and an assigned medication is the lactate or oxygen concentration in blood (as physiological parameter) and a bicarbonate infusion (as the medication). In case of blood circulation distortions in tissue, the oxygen concentration may be reduced and the lactate concentration may be increased due to a less efficient glucose metabolism. If the presence of such a scenario is detected by measuring the lactate or oxygen concentration in blood as the physiological parameter, substances like bicarbonate or oxygen may be injected in order to locally improve blood circulation.

Furthermore, the evaluation unit may be adapted to control or regulate release of the injection fluid from the reservoir unit into the body under investigation. In such an embodiment, the device may be an autarkic and automatic system which may measure a value of one or more physiological parameters and, as a consequence of such a measurement, may initiate injection of a certain amount of medication into a person's body. Therefore, the evaluation unit may be adapted to control or regulate release of the injection fluid from the reservoir unit into the body under investigation based on the determined present value of the physiological parameter.

In the following, further exemplary embodiments of the test unit apparatus will be described. However, these embodiments also apply for the device for determining a value of a physiological parameter, for the device for determining a present value of a physiological parameter over time, for the method of determining a present value of a physiological parameter over time, and for the method of determining a value of a physiological parameter according to the independent claims.

The test unit apparatus may be adapted as a magazine comprising a plurality of the test units. Such a magazine may be a disk-shaped magazine or a cylindrical magazine. Such a magazine may be a flat circular disk or a cylindrical drum.

Two exemplary aspects underlying embodiments of the present invention are:

1) to use a multiple test strip device to sequentially measure the ISF glucose sampled continuously or intermittently by means of techniques such as microdialysis, microperfusion, ultrafiltration, porous tissue contactor, transdermal extraction, reversed iontophoresis, suction technique using microneedles, or transdermal extraction using ultrasound and/or osmotic extraction buffer.

2) additionally or alternatively, determine the levels of endogenous markers (e.g., ions, like Na⁺ and K⁺) in the sampled fluid in order to calibrate the glucose values obtained with the multiple test strip device.

Endogenous markers may be defined as substances whose concentrations are known and tightly regulated in the ISF. Thus, by knowing the concentrations of the markers both in ISF and extracted fluid, possible confounding influences of the extraction process on the fluid levels of the substances (e.g. concentration or dilution of the substances in the fluid) can be quantified and then used to compensate for influences of the extraction process on the glucose levels in the extracted fluid, thereby improving the estimation of the blood glucose concentrations from the glucose values obtained with the multiple test strip device

Embodiments of the glucose measuring device may offer one or more of the following advantages:

- The sampling of interstitial fluid and determination of the glucose may be automated.

- Sufficiently frequent sampling and measurements of glucose (for instance every 30 minutes) may be performed, so that the early stages of blood glucose excursions can be detected.

- In comparison to fϊngerstick measurements, glucose determination can be performed with reduced discomfort.

- Embodiments of the system may reliably substitute for fϊngerstick measurements in the treatment of diabetes.

- Embodiments of the system may allow to detect early stages of blood glucose excursions in patients particularly with type 1 diabetes. This may be especially useful during periods of sleep.

- Embodiments of the system may be combined with an insulin infusion pump to build a glucose-controlled insulin infusion device (i.e. an artificial pancreas) particularly for the treatment of type 1 diabetes.

Thus, a therapy system for patients suffering from diabetes, particularly type 1 diabetes, is provided according to an exemplary embodiment. A continuous glucose measurement may be provided, in which multiple (single-use) sensor strips may be employed so that the reliability and stability of the measurement may be improved as compared to a continuous glucose measurement with a single sensor.

A measurement of the physiological parameter, for instance glucose, may be accompanied by a measurement of an endogenous marker, like an ion concentration. It is believed that endogenous markers have an essentially identical concentration in interstitial fluid and in blood. Thus, in case that an extraction process for extracting the body fluid sample should modify the concentration of the glucose and the endogenous marker, such a distortion may be detected by analyzing the measured value of the endogenous marker(s) and the distortion can be removed or reduced by calculating a corrected value of the physiological parameter.

According to an exemplary embodiment, a glucometer is provided which works on the basis of a measurement strip magazine. A body fluid sample to be examined may be extracted by means of a catheter like instrument. Thus, the glucose concentration may be measured quite frequently, for instance once or twice an hour, or every 10 seconds.

A patient suffering from diabetes may carry the device in a similar manner like a mobile phone or a wristwatch. In case that the device measures that the glucose concentrations falls below a lower threshold value or exceeds an upper threshold value, the device may alarm the patient and/or may initiate an increase or a decrease of the insulin level.

The body fluid sample (for example ISF) may be extracted from any desired part of the human body, for instance from the fatty tissue close to the belly, from the overarm, or from the femoral. According to an exemplary embodiment, the glucose level of a patient treated in an intensive care unit may be controlled or regulated. It is believed that treating a patient in an intensive care unit with an increased glucose level may increase the probability that the patient survives.

The aspects defined above and further aspects of the invention are apparent from the examples of embodiment to be described hereinafter and are explained with reference to these examples of embodiment.

The invention will be described in more detail hereinafter with reference to examples of embodiment but to which the invention is not limited.

Fig. 1 shows a device for determining a value of a physiological parameter according to an exemplary embodiment of the invention.

Fig. 2 shows a device for determining a value of a physiological parameter according to an exemplary embodiment of the invention.

Fig. 3 shows a device for determining a value of a physiological parameter according to an exemplary embodiment of the invention.

Fig. 4 shows a device for determining a value of a physiological parameter according to an exemplary embodiment of the invention.

Fig. 5 shows a test unit apparatus according to an exemplary embodiment of the invention. Fig. 6 shows a diagram illustrating the time dependence of a glucose level measured in different scenarios.

The illustration in the drawing is schematically. In different drawings, similar or identical elements are provided with the same reference signs.

In the following, referring to Fig. 1 , a device 13 for determining a present value of glucose according to an exemplary embodiment of the invention will be described.

The device 13 comprises a body fluid extraction unit 2 adapted to extract body fluid from a region of an organism, particularly interstitial fluid from tissue 1 of a human patient.

Furthermore, the device 13 comprises a coupling unit 6 to bring the extracted body fluid, particularly interstitial fluid, in contact with one test strip 8 of a magazine 9 of test strips 8. When the test strip 8 is brought in contact with the interstitial fluid, a colour of the test strip 8 is modified accordingly so as to be indicative of the value of the glucose concentration of the interstitial fluid.

Furthermore, an evaluation unit 10 which may also be denoted as a control unit is provided as a microprocessor which determines the actual value of the glucose concentration in the interstitial fluid or in the blood of the patient based on an analysis of the test unit 8 after being brought in functional contact with the interstitial fluid sample.

As an alternative to the provision of the magazine 9 with the plurality of test units 8, it is also possible to use a single test unit 8. The evaluation unit 10 may initiate rotation of the magazine 9 after expiry of a certain time interval, for instance every five minutes. Thus, the value of the glucose may be determined again, thus intermittently over time.

The multiple test unit device 9 is, in the described embodiment, a cylindrical magazine which can be rotated under control of a user or under control of the microprocessor 10.

The coupling unit 6 comprises an optical detection unit for optically detecting a colour or a reflectivity of the test strip 8 after being brought in contact with the interstitial fluid. The detected information may then be supplied to the microprocessor 10.

A pump 4 pumps the extracted interstitial fluid through the device 13. A marker sensing unit 5 senses the value of endogenous markers, like a Sodium ion concentration and/or a Potassium ion concentration. The evaluation unit 10 is provided with the information determined by the marker sensing unit 5 and may then determine the value of the glucose concentration based on an analysis of the information from the optical detection device 6 in combination with the information provided by the marker sensing unit 5.

Thus, the process of evaluating the glucose concentration in the blood can be calibrated by means of the determined marker information.

A battery 12 is provided as an energy supply unit to supply several components of the device 13 with electrical energy. A waste collector unit 11 collects interstitial fluid after being transported through the device 13. The system 13 of Fig. 1 allows for an intermittent monitoring of glucose and for a continuous monitoring of endogenous markers.

Fig. 1 illustrates the system 13 in which the glucose in the extracted fluid is monitored with multiple single-use test strip elements 8, and the fluid levels of the endogenous markers are continuously monitored using continuous sensors 5. By means of the pump 4, ISF of a peripheral tissue 1 is transported from the ISF sampling unit 2 through an inlet conduit 3 to the endogenous marker sensing element 5, in which the sensing of the endogenous markers is performed continuously. After passing the endogenous marker sensing element 5, the ISF is guided to the coupling unit 6 in which the extracted ISF is sequentially brought into contact with the test strips 8 accommodated in the magazine 9. The magazine 9 is rotatable so that the test strips 8 can be contacted individually. The coupling unit 6 is also adapted for the optical evaluation of the color change occurring in the glucose sensing area 7 on the test strip 8 (and may be adapted, additionally or alternatively for electrically connecting test strip 8 with the microprocessor 10 so that the electrical signals produced in glucose sensing area 7 of the test strip 8 can be transferred to the microprocessor 10). The microprocessor 10 also acquires signals from the endogenous marker sensing element 5. By using both the glucose and endogenous marker signals, the microprocessor 10 calculates blood glucose concentrations. The ISF not drawn into the test strips 8 flows from the coupling unit 6 to the waste collector 1 1. The battery 12 is provided for energy supply.In the following, referring to Fig. 2, a device 13 for determining a present value of glucose according to an exemplary embodiment of the invention will be described.

This embodiment allows for intermittent monitoring of glucose and endogenous markers. Fig. 2 shows the system 13 in which both glucose and endogenous marker(s) in the extracted fluid are monitored with multiple single-use test strip elements 8. By means of the pump 4, the ISF of the peripheral tissue 1 is transported from the ISF sampling unit 2 through the inlet conduit 3 to the coupling element 6, in which the extracted ISF is sequentially brought into contact with the test strips 8 accommodated in the magazine 9.

In contrast to the sensor configuration in Fig. 1, each of the test strips 8 has not only a sensing area for glucose 7 but also sensing areas for the endogenous markers 5. Thus, in the sensor configuration of Fig. 2, the fluid drawn into capillary of the single-use test strips 8 is analyzed concurrently for glucose and endogenous markers. Furthermore, similar to Fig. 1 , the ISF not drawn into the test strips 8 flows from the coupling unit 6 to the waste collector 11.

In the following, referring to Fig. 3, a device 13 for determining a present value of glucose according to an exemplary embodiment of the invention will be described.

This embodiment allows for glucose sensing with multiple single-use test elements in the ISF extracted by means of Porous Tissue Contactors (PTC).

Fig. 3 illustrates an embodiment of the system 13 comprising a PTC 2 inserted into the subcutaneous tissue 1, two connecting tubes 3, 15, a miniature pump 4, a coupling unit 6, a rotatable magazine 9 housing single-use test elements 8, a microprocessor 10, a battery 12, and a reservoir 19 with two fluid chambers 1 1, 14 separated by movable septa 20. An isotonic, ion- and glucose- free perfusate from the fluid chamber 14 is pumped through the inlet tubing 15 into the longitudinal bore 16 of the non-porous soft cannula 18 up to its distal end. Due to the pressure differential created by the miniature pump 4, the fluid emerged at the distal end of the non- porous soft cannula 18 is then forced to flow into the porous layer 17 on top of the impervious cannula wall 18. As the fluid moves longitudinally through the porous layer 16, diffusional exchange of substances occurs between the perfusate and the surrounding tissue fluid. After emerging at the proximal end of the porous layer, the medium then flows through the outlet tube 13 into the coupling unit 6. In the coupling unit 6, the medium is sequentially brought into contact with the test strips 8 which contain sensing elements for glucose 7 and conductivity 5. The medium drawn into the capillary of the single-use test strips 8 is then analyzed concurrently for glucose and conductivity. The microprocessor 10 acquires the glucose and conductivity data from the coupling unit 6 and converts them into blood glucose readings. The ISF not drawn into the test strips 8 flows from the coupling unit 6 to the waste fluid chamber 11. In this exemplary embodiment, ions are used as endogenous markers. It has been shown that the ionic concentrations in the plasma are tightly regulated and are very close to the concentrations in the ISF (see Schaupp, L, Ellmerer, M, Brunner, GA, Wutte, A, Sendlhofer, G, Trajanoski, Z, Skrabal, F, Pieber, TR and Wach, P "Direct access to interstitial fluid in adipose tissue in humans by use of open- flow microperfusion", Am J Physiol Endocrinol Metab 276:E401-E408, 1999; Trajanoski, Z, Brunner, GA, Schaupp, L, Ellmerer, M, Wach, P, Pieber, TR, Kotanko, P and Skrabal, F "Open-flow microperfusion of subcutaneous adipose tissue for on-line continuous ex vivo measurement of glucose concentration", Diabetes Care 20:11 14- 1121, 1997). Therefore, when an ion- free perfusate is employed, the exchange efficiency during the sampling process of an ion can be estimated as the ratio of the ion concentration in the PTC effluent to the ion concentration in the plasma. In addition, in vivo experiments have shown that the exchange efficiency of ions, like Na⁺ and K⁺, equal the exchange efficiency of glucose. Because of this property, the glucose concentration in the ISF can be estimated as the glucose concentration in the PTC effluent divided by the ionic exchange efficiency. The ionic exchange efficiency itself can be easily monitored by applying the electrical conductivity measurement. This is possible, because the electrical conductivity equals the weighted sum of all ionic concentrations in a fluid.

In the following, referring to Fig. 4, a device 13 for determining a present value of glucose according to an exemplary embodiment of the invention will be described.

The embodiment of Fig. 4 illustrates glucose monitoring and glucose- controlled insulin infusion.

Fig. 4 illustrates another exemplary embodiment of the system 13. In this embodiment, the glucose monitoring with multiple single-use test strip elements is coupled with glucose-controlled insulin infusion means. The system comprises the PTC 2 inserted into the subcutaneous tissue 1, two connecting tubes 3, 15, two miniature pumps 4, 4^', a coupling unit 6, a rotatable magazine 9 housing single-use test elements 8, a microprocessor 10, a battery 12, and a reservoir 19 with two fluid chambers 11, 14 one filled with a perfusate fluid containing insulin 21 at a high concentration (e.g., 100 U/ml). Pump 4 transports the perfusate fluid from the perfusate chamber 14 via the inlet tubing 15 into the PTC 2, and pump 4' sucks the ISF from the PTC through the outlet tubing 3 to the coupling unit 6, in which the ISF is sequentially brought into contact with the test strips 8, which contain sensing elements for glucose 7 and conductivity 5. Again, the ISF drawn into the capillary of the single-use test strips 8 is then analyzed concurrently for glucose and conductivity. The microprocessor 10 acquires the glucose and conductivity data from the coupling unit 6 and converts them into blood glucose readings. Based on the blood glucose readings, the microprocessor 10 calculates the appropriate insulin delivery rate. Subsequently, the insulin delivery rate is adjusted by altering the flow rate of pump 4 (e.g., between 0.5 and 7.0 microl/min). The flow rate of pump 4' may be similar or lower than that of pump 4 (e.g., 0.5 microl/min). Also, pump 4' may operate discontinuously. Again, the ISF not drawn into the test strips 8 flows from the coupling unit 6 to the waste fluid chamber 11.

In the following, referring to Fig. 5, a test unit apparatus 9 according to an exemplary embodiment of the invention will be explained.

Such a test unit apparatus may be implemented as the magazine 9 of any one of the devices 13 as illustrated in Fig. 1 to Fig. 4.

The test unit apparatus 9 for the device 13 for determining a value of a physiological parameter comprises a plurality of test units 8 as circumferential teeth of a rotatable disk-shaped substrate 50. Each of the test units 8 comprises a physiological parameter indicating portion 51 and comprises a marker parameter indicating portion 52.

The physiological parameter indicating portion 51 is indicative of a value of a physiological parameter - like a glucose concentration - when brought in functional contact with an extracted body fluid sample - like an interstitial fluid sample. The marker parameter indicating portion 52 is indicative of one or more marker parameters - like an ion concentration - of the extracted body fluid sample when brought in functional contact with the extracted body fluid sample. Fig. 6 shows a diagram illustrating the time (plotted along the abscissa of the diagram) dependence of a glucose level (plotted along the ordinate of the diagram) measured in different scenarios.

The diagram of Fig. 6 illustrates the time course of (blood) plasma glucose

62, and glucose in the interstitial fluid of adipose tissue 61 of an anesthetized piglet during an intravenous endotoxin infusion. After the placement of a Porous Tissue Contactor (PTC ) into the abdominal subcutaneous adipose tissue of the piglet, the PTC was perfused with an isotonic, ion-free perfusate solution containing insulin at a concentration of 1 U/ml. Effluent samples from the PTCs were collected continuously in 30-min fractions, and blood samples were taken frequently from the right carotid artery.

The concentrations of glucose in plasma 62 were determined using a glucose oxidase method (Cobas Mira; Roche Diagnostics, Rotkreuz, Switzerland) and the glucose concentrations in the effluents of the PTC 60 were measured using a multiple test strip device (Accu-Chek Compact plus; Roche Diagnostics, Mannheim, Germany). The conductivity in the plasma and the PTC effluent samples were determined using a contactless conductivity detector (TraceDec, I: S. T, Strasshof, Austria).

Since the mixing between the perfusate and the ISF was not complete at the employed flow rates (i.e. the effluent concentration is lower than the interstitial concentration), the ISF glucose concentration 61 was calculated as the glucose concentration in the effluent 60 divided by the ratio of the measured conductivity in the probe effluents and the conductivity in plasma. As can be seen, during the baseline period, the glucose concentration in the blood plasma of the piglet was about 80 mg/dl. Due to the start of the intravenous endotoxin infusion after the baseline period of 60 min, the glucose concentrations in plasma decreased to a nadir of 35 mg/dl at 120 min. The plasma glucose concentration increased slowly thereafter and by the end of the experiment at 240 min the plasma glucose concentration was 45 mg/dl. During the whole experiment, the glucose concentration time course in the ISF around the PTC 61 was similar to that observed in plasma 62.

The temporal pattern of change in plasma glucose and ISF glucose observed during such experiments demonstrates that estimation of plasma glucose concentrations is possible with the described technique.

In the following, further details concerning the experiments of Fig. 6 will be explained.

An aim of the study in the context of Fig. 6 was to employ a porous tissue contactor for ISF sampling from subcutaneous adipose tissue and to examine whether a stable relationship between the blood glucose concentration and the glucose concentration in the sampled ISF exists when this porous tissue contactor is simultaneously used to deliver insulin to this tissue.

For the study, porous tissue contactors were fabricated from a porous polyethylene (PE) sheet of hydrophilic type (sheet thickness: 0.6 mm, Average Pore Size: 7-16 μm; Porex Technologies Corporation, Fairburn, GA, USA), a porous PE sheet of hydrophobic type (sheet thickness: 0.6 mm, Average Pore Size: 40-100 μm;

Porex Technologies Corporation, Fairburn, GA, USA), PTFE tubing (OD: 1.0 mm, ID: 0.5 mm; Bohlender GmbH, Grϋnsfeld, D), and syringe needles (0.5 x 25 mm, 21- gauge; BD Microlance, Becton Dickinson, Fraga).

Using a sharp surgical blade, two 10 mm long cut-out portions were formed in the wall of 150 mm long PTFE tubes. The two cut-out portions were separated by approximately 5 mm and were provided in the middle of the tubes. In order to control the depth of the cuts and to avoid cutting through the tubes, a stainless steel wire (OD: 0.25mm) was inserted into the lumen of the PTFE tubes before starting the cutting. Furthermore, using a sharp surgical blade, stripes with a width of ~0.5 mm and a length of 40 mm were cut away from the hydrophobic and hydrophilic porous PE sheets. After removing the stainless steel wire from a PTFE tube, a porous stripe was slid into the cut-out portions of the PTFE tube and the end portions of the porous stripe (~ 5mm) were then press fit into the PTFE tube portions adjacent to the cut-out portions. Finely, for making the connections to a Tygon tubing, the tips and hubs of syringe needles were cut off by use of a small triangle file, and the excised needle shafts were then pushed into the ends of the PTFE tubes.

A piglet aged 3 months and weighing -30 kg was fasted overnight with free access to water. In the morning, the piglet was anesthetized by intramuscular injection of ketamine and pentobarbital sodium. The piglet was placed in supine position on a heating blanket and intubated orotrachealy. Thereafter, mechanical ventilation was started and respirator settings were adjusted to maintain blood gas values within the physiologic range. Anesthesia was maintained by adding halothane to the inspiratory gas mixture. A catheter was placed in the right carotid artery to allow blood withdrawal during the experiment and another catheter was inserted into the right femoral vein to be used for all study infusions. A third catheter was placed suprapubically into the bladder. After placement of these catheters, halothane inhalation was stopped and anesthesia was subsequently maintained by intravenous infusion of piritramide and pancuroniumbromide. After a baseline period of one hour, the piglet received an intravenous infusion of an endotoxin {Escherichia coli lipopolysaccharide). The piglet was monitored thereafter for 4 hours and then killed with an intravenous bolus injection of KCl.

Shortly after the insertion of the bladder catheter, a hydrophilic and a hydrophobic PTC was placed into the abdominal subcutaneous adipose tissue of the piglet. A 16-gauge catheter with an insertion needle fitted coaxially within the catheter (BD Angiocath; Becton-Dickinson, Sandy, Utah) was used to facilitate the placement of the PTCs.

The 16-gauge catheter and the needle were inserted through the skin, and advanced under the skin until ~60 mm of the proximal catheter portion was placed under the skin. The proximal end portion of the catheter and needle were then brought out through the skin. After carrying out this tunneling procedure, the insertion needle was withdrawn and the PTC was inserted into the 16-gauge catheter. The full length of the porous part of the PTC was then positioned in the tissue by holding the PTC on one end and withdrawing the 16-gauge catheter from the tissue at the same time.

After the placement of the hydrophilic and hydrophobic PTC, two Tygon tubes were used to connect the inlet and outlet of each PTC with a perfusate reservoir and a sample vial, respectively. The Tygon tubes of each PTC were then inserted into a peristaltic pump, which continuously pumped perfusate fluid from the reservoir via the inlet tubing to the PTC, and sucked ISF from the PTC through the outlet tubing to the sampling vial. Continuing for the duration of 270 min, the PTCs were perfused with an isotonic, ion-free perfusate solution containing insulin at a concentration of 1 U/ml. Both PTCs were perfused with a high perfusion rate during the first 160 min of the experiment (-1.3 μl/min), and with a lower perfusion rate (-0.5 μl/min) during the last 90 min of the experiments. The perfusate solutions was made up before the experiment by mixing an ion-free, isotonic mannitol solution (275 mM; Fresenius Kabi, Graz, Austria) with appropriate amounts of bovine albumin (10 g/1; Sigma Aldrich, Vienna, Austria) and human insulin (1 U/ml; Actrapid, Novo Industries, Copenhagen, Denmark).

Effluent samples from the PTCs were collected continuously in 30-min fractions, and arterialized blood samples were taken every 30 min.

After the experiments, the concentrations of glucose were determined in the plasma and effluent samples using a glucose oxidase method (Cobas Mira; Roche Diagnostics, Rotkreuz, Switzerland). The conductivity in the plasma and the PTC effluent samples were determined using a contactless conductivity detector (TraceDec, I:S.T, Strasshof, Austria).

Since the mixing between the perfusate and the ISF is not complete at the employed flow rates (i.e. the effluent concentration is lower than the interstitial concentration), the ISF glucose concentration was calculated as the glucose concentration in the effluent divided by the extent of the mixing between perfusate and ISF (also called recovery). The recovery in the PTC effluents was determined by applying the ionic reference technique. In this calibration technique, the extent of the mixing between perfusate and ISF is calculated as the ratio of the measured conductivity in the probe effluents and the conductivity in plasma. This is possible, because the conductivity in the plasma is tightly regulated and is very close to the conductivity in the ISF. Thus the formula used to calculate the ISF glucose concentration (GI) is: GI = GE / SR - GE / (CE / CP)

where GE is the measured effluent glucose concentration, SR is the recovery, and CE and CP are the conductivity values in effluent and plasma samples, respectively. Because each probe effluent sample was collected over a specified time interval, the derived interstitial glucose values was considered valid at the midpoint of the interval.

Results of the experiment conducted in the piglet are depicted in Fig. 6.

It should be noted that the term "comprising" does not exclude other elements or steps and the "a" or "an" does not exclude a plurality. Also elements described in association with different embodiments may be combined.

It should also be noted that reference signs in the claims shall not be construed as limiting the scope of the claims.

Claims

C L A I M S

1. A device (13) for determining a present value of a physiological parameter over time, the device (13) comprising a body fluid extraction unit (2) adapted to extract a body fluid sample from a body under investigation (1); a coupling unit (6) adapted to bring the extracted body fluid sample in functional contact with one of a plurality of test units (8), each of the test units (8) being indicative of the present value of the physiological parameter when brought in functional contact with the extracted body fluid sample; an evaluation unit (10) adapted to determine the present value of the physiological parameter based on an analysis of the one of the plurality of test units (8) brought in functional contact with the extracted body fluid sample.

2. The device (13) of claim 1, adapted for determining at least one of the physiological parameters selected from the group consisting of an endogenous metabolite, a gas, a fluid, and an electrolyte.

3. The device (13) of claim 1 or 2, adapted for determining at least one of the physiological parameters selected from the group consisting of a glucose concentration, a lactate concentration, an oxygen concentration, an ion concentration, a cholesterol concentration, an amount of bacteria, an amount of virus, a drug concentration and a medicament concentration.

4. The device (13) of any one of claims 1 to 3, adapted for determining the physiological parameter quasi-continuously over time or intermittlently over time.

5. The device (13) of any one of claims 1 to 4, wherein the body fluid extraction unit (2) is adapted to extract the body fluid sample by at least one of the group consisting of microdialysis, microperfusion, ultrafiltration, porous tissue contactor, reversed iontophoresis, suction technique using at least one microneedle, and transdermal extraction using ultrasound and/or osmotic extraction buffer.

6. The device (13) of any one of claims 1 to 5, wherein the body fluid extraction unit (2) is adapted to extract the body fluid sample as at least one of the group consisting of interstitial fluid, blood, lymph, cerebrospinal fluid, urine and tissue.

7. The device (13) of any one of claims 1 to 6, comprising a multiple test unit device (9) including the plurality of test units (8).

8. The device (13) of claim 7, wherein the multiple test unit device (9) is a disk-shaped magazine or a cylindrical magazine.

9. The device (13) of claim 7 or 8, wherein the multiple test unit device (9) is rotatable magazine.

10. The device (13) of any one of claims 1 to 9, wherein the plurality of test units (8) are a plurality of test strips.

11. The device (13) of any one of claims 1 to 10, comprising a detection unit (6) adapted for performing the analysis of the one of the plurality of test units (8) brought in functional contact with the extracted body fluid sample.

12. The device (13) of claim 11, wherein the detection unit (6) is adapted for at least one of the group consisting of an optical detection, an electrical detection, and a chemical detection.

13. The device (13) of any one of claims 1 to 12, wherein the evaluation unit (10) is a microprocessor.

14. The device (13) of any one of claims 1 to 13, comprising a body fluid transportation unit (4) adapted to transport the extracted body fluid through at least a part of the device (13).

15. The device (13) of claim 14, wherein the body fluid transportation unit (4) is a pump.

16. The device (13) of any one of claims 1 to 15, comprising a marker sensing unit (5) adapted to sense at least one value of at least one marker parameter of the extracted body fluid sample.

17. The device (13) of claim 16, wherein the marker sensing unit (5) is adapted to sense an endogenous marker parameter of the extracted body fluid sample.

18. The device (13) of claim 16 or 17, wherein the marker sensing unit (5) is adapted to sense an exogenous marker parameter of the extracted body fluid sample.

19. The device (13) of any one of claims 16 to 18, wherein the marker sensing unit (5) is adapted to sense an ion concentration of the extracted body fluid sample.

20. The device (13) of claim 19, wherein the marker sensing unit (5) is adapted to sense a Sodium ion concentration and/or a Potassium ion concentration.

21. The device (13) of any one of claims 16 to 20 wherein the marker sensing unit (5) and the detection unit (6) are provided as separate devices.

22. The device (13) of any one of claims 16 to 20, wherein the marker sensing unit and the detection unit are provided as a common device (6).

23. The device (13) of any one of claims 16 to 22, wherein the marker sensing unit (5) is adapted to provide the sensed at least one value of the at least one marker parameter to the evaluation unit (10), wherein the evaluation unit (10) is adapted to determine the present value of the physiological parameter based on an analysis of the one of the plurality of test units (8) brought in functional contact with the extracted body fluid sample and based on an analysis of the sensed at least one value of the at least one marker parameter.

24. The device (13) of any one of claims 16 to 22, wherein the marker sensing unit (5) is adapted to provide the sensed at least one value of the at least one marker parameter to the evaluation unit (10), wherein the evaluation unit (10) is adapted to perform a calibration for the determination of the present value of the physiological parameter based on the sensed at least one value of the at least one marker parameter.

25. The device (13) of any one of claims 16 to 24, wherein each of the plurality of test units (8) comprises a physiological parameter indicating portion and comprises a marker parameter indicating portion.

26. The device (13) of any one of claims 1 to 25, comprising an energy supply unit (12) adapted to supply at least a part of the device with energy.

27. The device (13) of claim 26, wherein the energy supply unit (12) is one of the group consisting of a battery, a fuel cell, and a solar cell.

28. The device (13) of any one of claims 1 to 27, comprising a waste collector unit (11) adapted to collect body fluid sample after transportation through at least a part of the device (13).

29. The device (13) of any one of claims 1 to 28, comprising a reservoir unit (14) adapted to hold an injection fluid (21) adapted to be injected into the body under investigation (1).

30. The device (13) of claim 29, wherein the reservoir unit (14) is adapted to hold a medication as the injection fluid (21).

31. The device (13) of claim 29 or 30, wherein the reservoir unit (14) is adapted to hold a glucose regulating substance.

32. The device (13) of any one of claims 29 to 31, wherein the reservoir unit (14) is adapted to hold at least one of the group consisting of insulin, glucagon, aldosterone and bi-carbonate as the injection fluid (21).

33. The device (13) of any one of claims 29 to 32, wherein the evaluation unit (10) is adapted to control or regulate release of the injection fluid (21) from the reservoir unit (14) into the body under investigation (1).

34. The device (13) of any one of claims 29 to 33, wherein the evaluation unit (10) is adapted to control or regulate release of the injection fluid (21) from the reservoir unit (14) into the body under investigation (1) based on the determined present value of the physiological parameter.

35. A device (13) for determining a value of a physiological parameter, the device (13) comprising a body fluid extraction unit (2) adapted to extract a body fluid sample from a body under investigation (1); a coupling unit (6) adapted to bring the extracted body fluid sample in functional contact with a test unit (8) being indicative of the value of the physiological parameter when brought in functional contact with the extracted body fluid sample; a marker sensing unit (5) adapted to sense at least one value of at least one marker parameter of the extracted body fluid sample; an evaluation unit (10) adapted to determine the value of the physiological parameter based on an analysis of the test unit (8) brought in functional contact with the extracted body fluid sample, wherein the evaluation unit (10) is adapted to perform a calibration for the determination of the value of the physiological parameter based on the sensed at least one value of the at least one marker parameter.

36. A method of determining a present value of a physiological parameter over time, the method comprising extracting, by means of a body fluid extraction unit (2), a body fluid sample from a body under investigation (1); bringing, by means of a coupling unit (6), the extracted body fluid sample in functional contact with one of a plurality of test units (8), each of the test units (8) being indicative of the present value of the physiological parameter when brought in functional contact with the extracted body fluid sample; determining, by means of an evaluation unit (10), the present value of the physiological parameter based on an analysis of the one of the plurality of test units (8) brought in functional contact with the extracted body fluid sample.

37. A method of determining a value of a physiological parameter, the method comprising extracting, by means of a body fluid extraction unit (2), a body fluid sample from a body under investigation (1); bringing, by means of a coupling unit (6), the extracted body fluid sample in functional contact with a test unit being indicative of the value of the physiological parameter when brought in functional contact with the extracted body fluid sample; sensing, by means of a marker sensing unit (5), at least one value of at least one marker parameter of the extracted body fluid sample; determining, by means of an evaluation unit (10), the value of the physiological parameter based on an analysis of the test unit (8) brought in functional contact with the extracted body fluid sample, and performing, by means of the evaluation unit (10), a calibration for the determination of the value of the physiological parameter based on the sensed at least one value of the at least one marker parameter.

38. A test unit apparatus (9) for a device (13) for determining a value of a physiological parameter, the test unit apparatus (9) comprising at least one test unit (8) comprising a physiological parameter indicating portion (51) and comprising a marker parameter indicating portion (52); wherein the physiological parameter indicating portion (51) is indicative of a value of a physiological parameter when brought in functional contact with an extracted body fluid sample; wherein the marker parameter indicating portion (52) is indicative of at least one marker parameter of the extracted body fluid sample when brought in functional contact with the extracted body fluid sample.

39. The test unit apparatus (9) of claim 38, adapted as a magazine comprising a plurality of the test units (8).