DE19963034A1 - Glucose level detection system based on measurement of interstitial fluid, uses heating device or ultrasound to reduce time offset between concentration in interstitial fluid and blood - Google Patents

Abstract

The system includes a sampling device (2) for removing interstitial fluid (ISF). A device (1) is provided for reducing the time offset between the glucose concentration present in the interstitial fluid and that in the blood of the patient. The device may be a heating device heats a skin area prior to removal of the ISF from it, an ultrasound device, or a unit for administering material to promote blood circulation.

Description

The present invention relates to a system for determining the level of glucose User based on measurements in interstitial fluid.

Results of the Diabetes Control and Complications Trial (DCCT) have shown that with a intensive control of the blood sugar level the late effects of diabetes mellitus (nephropathy, Neuropathy, retinopathy) can be successfully reduced (DCCT, 1993). For determination In order to determine the blood sugar concentration, the patient must put a drop of blood on a test strip bring, which is then analyzed. To obtain the drop of blood, it is necessary that the patient pricks the fingertip with a lancet. The pain associated with it leads to ensure that the measurements, which are usually made about 4-5 times a day during intensive treatment should be carried out much less frequently in practice and therefore worse The blood sugar level is checked.

For this reason, it is necessary to develop new ways of developing measuring systems for the slide to develop better control without blood and therefore without painful finger pricking get along. One approach is to use interstitial fluid (ISF) instead of blood as a sample medium. Interstitial fluid is the fluid in the interstitial space men (interstitium). Various methods for obtaining interstiti now exist eller liquid and various researchers have regardless of the method of extraction shown that it is possible in principle to lower the glucose concentration in interstitial rather than in blood Determine fluid (Kayashima, 1991; Bantle, 1997; Tamada, 1995; Jensen, 1995; Guy, 1996).

(Kayashima, S .; et al .: "New noninvasive transcutaneous approach to blood glucose monitoring: successful glucose monitoring on human 75 g OGTT with novel sampling chamber" IEEE Trans. Biomed. Eng. 38 (8); 752757; 1991
Bantle, JP; Thomas, W .: "Glucose measurement in patients with diabetes mellitus with dermal interstitial fluid" J. Lab. Clin. Med. 130 (4); 436-441; 1997
Tamada, et al .: "Measurement of glucose in diabetic subjects using noninvasive transdermal extraction" Nature Medicine 1 (11); 1198; 1995
Jensen, BM; et al .: "Glucose content in human skin: relationship with blood glucose levels" Scand. J. Clin. Lab. Invest. 55; 427-432; 1995
Guy, RH; Potts, RO; Tamada, JA: "Noninvasive techniques for in vivo glucose sensing" Diabetes, Nutrition & Metabolism 9; 42-46; 1996)

The investigations have shown that the measured glucose concentration in interstitial Do not correlate liquid directly with the values measured in blood. In the stationary state the glucose concentration in the interstitium reaches a certain, but usually con constant, percentage of blood glucose concentration. It is under stationary conditions the interstitial glucose concentration between 67% -106% relative to the blood glucose (Kayashima 1991; Kimura 1993; Roe, 1998).

Kimura, J .: "Noninvasive blood glucose concentration monitoring method with suction effusion fluid by ISFET boisensor" Appl. Biochem. Biotechnol. 41 (1-2); 55-58; 1993
Roe, JN; Smoller, BR: "Bloodless glucose measurement" Critical Reviews in therapeutic drug carrier systems 15 (3); 199-241; 1998

In the event of changes in the glucose concentration over time, a time offset between the Changes in blood and interstitium were observed. This time offset is between 2 and 60 minutes (Roe, 1998; Jensen 1995; Tamada, 1995, Kayashima 1991), the glucose concentration concentration in the interstitium lags behind the blood glucose concentration. The size of the time offset is depending on the type of sample collection and physiological parameters (Roe, 1998; Tamada, 1995).

For both stationary and dynamic examinations, it is crucial which of them Tissues (subcutaneous, dermal, epidermal) the sample is obtained and how long the time span that is required to obtain a sufficient sample volume.  

The large bandwidth of the time offset in the literature data shows that the time offset at least can fluctuate inter-individually but also intra-individually.

It was also found that the time offset of the glucose concentrations by the Diffu distance that the glucose molecules have to travel between the blood and interstitium, be is influenced. From this one can conclude for the place of the withdrawal of interstitial fluid, that in places with high capillary density the time offset is smaller than in less well supplied ones Tissue volumes.

Because for many years blood was the primary parameter for assessing the status of the diabetic has been used, a new measurement method with the glucose concentration in blood must be narrow correlate to fit into existing treatment regimens. For the establishment on ISF based systems, it is crucial that an accurate and precise Cor relation between the blood glucose values measured in the interstitial space exists. On otherwise, all those working in the medical environment, as well as patients for the Ver use of this measurement method and changes compared to the blood glucose concentration new be trained (Roe 1998).

Since in addition to technical and physiological parameters are responsible for the size of the time shift dynamic glucose changes in the blood and interstitium, this means that basically all procedures based on the use of interstitial fluid are affected by the problem of the time shift. If the time offset exceeds a certain limit value, the respective method cannot be used for individual measurements to determine the interstitial glucose concentration, since there is no information about

• a) the trend of glucose change
• b) the size of the current time offset
• c) the rate of change

the importance of the glucose value determined in interstitial fluid cannot be assessed can. Therefore there is a time offset for so-called "spot measurements", in which between the one individual measurements are longer intervals, particularly critical.

For example, would the blood glucose concentration be at a rate of 3 mg / dl / min decrease and the time offset of the concentration measured in ISF is 30 min, see above a glucose concentration of 160 mg / dl in ISF would result in a glucose concentration of 70 mg / dl in blood. Without knowledge of the points a) to c) described above, the Diabetics do not assess the measured value and would possibly need the urgently measures to avoid hypoglycaemia and would be life-threatening threatened.

For this reason, it is necessary to determine the time lag between blood and glucose readings Minimize ISF to such an extent that the measured values change under dynamic conditions correspond as well as possible and the time offset from measurement to measurement if possible keep stant. In this way, it is possible to determine a glucose level that the Blood glucose level represents.

So far, only devices for measuring glucose concentration have been in the prior art known in ISF that accept the described time offset, such as. B. the in US 5,820,570 method described. Accordingly, the prior art has the disadvantage that the glucose concentration determined in ISF does not match that currently in the blood matches.

According to the invention it was found that the time shift between interstitial and blood glucose concentration fluctuates because the physiological framework changes. This must be controlled by targeted influencing in order to minimize the time delay.

The following parameters influence the time offset:
Extravasation
Blood flow
Glucose consumption in the cells
Diffusion coefficient
Diffusion path

To solve the problems of determining the glucose concentration in inter The following liquid (methods and devices) are used for critical liquid Influencing and minimizing the time offset between blood glucose concentration and inter actual glucose concentration in dynamic changes described.

First of all, basic possibilities are shown which make it possible to use the physiolo manipulate factors that affect the time offset. Later become technical Possible solutions for putting the principles into practice are presented.

By using these newly developed methods, methods for determining the Glucose concentration in interstitial fluid also for single measurements (spot measurements) can be used because the measured interstitial Glucose concentration correlated better with the current blood glucose concentration.

The following are the basic principles and opportunities for technical implementation described the invention:

Increase in extravasation

By changing the properties of the vascular endothelium, the extravasation of liquid speed (from plasma into the interstitial fluid) and glucose.

Measures to increase extravasation can be:
The application of ultrasound
The application of certain pharmaceuticals (e.g. capsaicin, histamine)
Change in blood flow to a certain volume of tissue

Increase in blood flow

The glucose in the interstitial tissue comes from the capillaries. The lower the blood flow in a tissue volume (low blood flow rate or complete Blood flow in the capillaries), the less precisely this represents in this tissue volume available capillary blood is the blood glucose concentration currently present in the rest of the body. This is all the more true with rapidly changing blood glucose levels.

Prerequisite for the adjustment of the interstitial glucose concentration to the blood glucose Concentration is an effective exchange between capillaries and interstitial space. This Exchange is achieved through high blood circulation. Because the physiological fluctuations blood flow is extremely large (up to a factor of 100), measures must be taken to ensure a minimum blood flow in the tissue volume in question to be reproducible and enable minimized time offsets.

By locally changing the blood flow to the tissue evo under observation The diffusion coefficients are also influenced lumens. The number also changes of the perfused capillaries and thus the distances between the active capillaries, whereby the diffusion distances are reduced.

The blood flow can be increased locally by a number of measures:

• - local change in temperature,
• - change in blood flow as a response to chemical irritation of the nociceptors,
• - Blood circulation change as a stimulus response to mechanical irritation from Mechano- and Nozi zeptors,
• - Change of the environmental conditions to generate a systemic reaction (e.g. Än change in outside temperature).

An increase in blood flow also has an increase in the number of at the same time blood flow through the capillaries. This increases the number of open and perfused capillaries per tissue volume, which increases the distance between the perfused capillaries and thus the diffusion distance is reduced.

Increase in the diffusion coefficient

The two compartments blood and interstitium are separated by the vascular membrane (vascular endothelium). The exchange of glucose molecules between the two compartments must take place via this membrane. The basis of the exchange of molecules through a membrane is Fick's 1st law:

J = - D (dc / dx)

where J is the flux (number of diffusing particles per unit of time); c the concentration differences limit on both sides of the membrane and x is the diffusion distance. D is the diffusion coefficient ent.

This makes it clear that the flux or the speed of the concentration equalization of the Concentration difference c and the diffusion coefficient D is dependent.

The diffusion coefficient D goes according to the equation

D = (kT) / (6πηr) (k = Boltzmann constant; η = viscosity of the medium; r = molecular size)

the temperature T.

From these equations it can be seen that by influencing the diffusion coefficient the flux can be changed. This can be done in two ways: First, you can Increase the temperature of the tissue locally and thereby increase the blood flow, on the other hand one locally increases the blood flow in the examined tissue and thereby also the temperature heights.  

Influencing or taking into account the glucose consumption by cells

There are also cells in the skin that consume glucose, causing those in the interstitium measured glucose concentration changed in relation to the glucose concentration in the blood becomes. If this glucose consumption by suitable, for. B. pharmacological measures, mi nimized, the glucose concentration in the interstitium can indicate the glucose concentration in the blood be approached. Alternatively, mechanisms can be developed to reduce consumption Determine cells in the observed tissue. If the consumption of the cells is known, the Effect on the ratio of glucose concentrations to be taken into account.

According to the influencing parameters mentioned above, the following invention relates to a system for determining the glucose level of a user using a removal device for ent taking interstitial fluid, as well as a means of reducing a time delay between a glucose concentration in interstitial fluid and a glucose concentration tration in the patient's blood.

Withdrawal devices for withdrawing interstitial fluid can be of various types his. In the context of this invention, removal devices are preferably invasive or minimally invasive needles, cannulas, catheters etc. However, this term should also be used Embodiments may be included that are not actually invasive, such as Ultrasound devices and iontophoresis. In particular, are as removal devices Suitable cannulas, which are inserted into the dermis to get interstitial fluid from there remove. It is also possible to have one or more small openings in the skin through which interstitial fluid can escape. The creation of the Perforations mentioned can for example by needles such. B. in US 5,820,570 described or laser exposure (see e.g. WO 97/07734). Another class of Withdrawal devices are based on a removal device being implanted in the body will, d. H. stays there for a longer period of time. Such removal devices are for example semipermeable catheters, as used in the microdialysis or field Ultrafiltration are known. Such catheters have a semi-permeable membrane the interstitial fluid or at least parts thereof which contain the analyte, can step through. Such catheters are, for example, in US 5,174,291 and US  4,77,953. Semipermeable catheters are particularly suitable for continuous or quasi continuous monitoring of the glucose concentration is suitable. Under a quasi Continuous monitoring of the glucose level is understood as a procedure for that of the catheter for the removal of interstitial fluid over a certain period of time in the body remains and serves to add an analyte at regular intervals or continuously win. Such a procedure is in the area of microdialysis, ultrafiltration, so known as micro perfusion.

An essential feature of the present invention are means for reducing a temporal Chen offset between the glucose concentration in interstitial fluid and the glucose Concentration in the patient's blood. A possible means of reducing the temporal Offset is a heating device with which an area of skin from which a removal of interstiti eller liquid should be heated before removal. A heater can be used have, for example, a heating element which is heated by current flow. Together With such a heating device, it is advantageous to provide a temperature sensor, which is the temperature of the heating element or even better the temperature of the skin area from which a removal is to take place. In addition to the classic temperature sensors such as tempe temperature-dependent resistors and thermoelectric elements, for example, an In infrared measuring device can be used for temperature monitoring. In addition to the pure tempe Temperature measurement and regulation can be used to ensure adequate warming of the skin to achieve areales and, on the other hand, to avoid burns, to precede a time measurement unit hen which absorbs the duration of the heating and after a predetermined or user-adjustable time either outputs a signal that prompts the user, a Take interstitial fluid or an automatic withdrawal initiates. Automatic removal can be done, for example, by one with a spring prestressed cannula is inserted into the skin area, and inter political fluid is analyzed. A system in which a heating pre direction and a removal device are integrated and heating and removal in the same Positioning of the device on the skin surface can be done. For example, this is possible if a heating device is provided that has a pressure surface for pressing to the skin surface in which there is a recess. The withdrawal device  In this embodiment, the device can be cut through the recess onto the underlying skin area access.

Another means of reducing the time offset is an ultrasound unit, with the Ultra sound is applied to the skin area from which ISF is to be removed. Appropriate nete ultrasonic units are for example in the documents US 5,231,975 and US 5,458,140. Even when using an ultrasound unit, it is beneficial if this Unit is integrated together with the removal device in a system, so that the loading A compact handling unit is available to the user and he does not have a separate compo must handle. Similar to the case of the heater, it is also in use an ultrasound unit favorable when the ultrasound to reduce the time ver set and the removal of ISF in the same positioning of the system on the skin upper area can take place. Accordingly, the ultrasound device preferably has a pressure surface for pressing against a skin surface in which there is a recess through which the removal device can access the underlying skin area.

A further embodiment of the means for reducing the time offset consists in a ver Delivery unit for a circulation-promoting substance on a skin area. The label circulation-promoting substance includes both individual substances such as capsaicin and Mixtures of substances in which, for example, the primary circulation-promoting substance in a gel or is embedded in an emulsion. An administration unit can for example consist of egg nem absorbent material such as a fleece, which with the circulation-promoting substance is soaked. The area of skin from which the removal is to take place can be made by pressing the fleece It should be provided with the circulation-promoting substance on the skin surface. Also at In this embodiment of the invention, it is advantageous to provide a time measuring device which Measures time from the administration of the blood circulation promoting substance on the skin surface and either after a predetermined time or after a time to be selected by the user Outputs signal or initiates a withdrawal.

In the context of this invention, removal device and the means for reducing the temporal offset separate functional units, which however (even preferred) in one Handling device can be combined.  

For the above-mentioned embodiments of the invention, it is also advantageous if the system has an oximeter with which the degree of blood flow to a skin area from which ISF is to be withdrawn. Based on a measurement of the Blood flow levels can be either the intensity of the heating or the exposure to ultrasound are regulated as well as the duration of exposure. With the oximeter, for example be monitored when a pre-selected level of blood flow is reached and it can either a signal is issued that a removal is to take place or the system executes the removal automatically take.

The system according to the invention can also have an analysis unit for determining the glucose concentration include concentration in the extracted ISF. It has been found that ISF principally addresses the can be analyzed in the same way as is common for blood. So come to analysis the ISF both questioned photometric measurements that discolored a test chemical is determined as well as electrochemical determinations. Both procedures are for blood sugar measuring devices well known, so that they are not discussed in more detail at this point. Furthermore, the ISF's glucose content can also be reagent-free by taking an infrared spectrum. Another method of determination, especially for continuous Measurements is based on an electrochemical measuring cell, in which the glucose and glucose oxidase (GOD) amount of hydrogen peroxide or sow consumed material is determined. In such sensors, the glucose-consuming enzyme in the Be The sensor can be immobilized or the enzyme is taken as a solution of the ISF or added to a dialysate or ultrafiltrate.

A peculiarity of the extraction of interstitial fluid compared to a glucose determiner mung in the blood is that the available amounts of fluid are smaller in the Usually less than 1 µl. Accordingly, detection systems must be used with these small amounts of liquid. Extraction devices are particularly advantageous with a cannula that is inserted into the interstitium with its distal end and at its proximal end interstitial fluid emerges. To keep fluid losses low and the To assist removal by capillary action, the inner diameter of the cannula should precede preferably less than 0.2 mm. It is also beneficial if the proximal end of the  The cannula from which the ISF emerges ends in the immediate vicinity of a test element, so that the ISF is applied directly to the test element.

The present invention will now be described with reference to specific embodiments purifies:

Fig. 1 system with a sampling cannula and a heating element in cross section;

Fig. 2 top view of the system of Fig. 1;

Fig. 3 cuff to increase blood circulation;

Fig. 4 Separate liquid extraction unit.

The device in Fig. 1 has a heating element ( 1 ), a liquid extraction element ( 2 ) and an analysis unit ( 3 ). In the heating element, a temperature sensor is integrated, which on the one hand monitors the temperature on the skin surface to avoid damage and on the other hand in conjunction with the control electronics ( 4 ) determines the time period in which the desired target temperature has been applied, and then determines the extraction process automatically triggers table. The element for liquid extraction, ie the removal device, contains a pressure ring ( 21 ), as can be seen in FIG. 2. The pressure ring is surrounded by the heating element ( 1 ). In the center of the pressure ring there is a recess through which the cannula ( 22 ) can be inserted into the skin. To drive the cannula, the device has a push button, by means of which the user can insert the cannula into the dermis. The system also has means to limit the depth of penetration of the cannula into the skin. Before preferably the depth of penetration can be set by the user within a designated area.

Detectors for determining the liquid volume obtained and for monitoring the sample quality (contamination with blood) are integrated in the liquid extraction unit ( 2 ). The analysis unit ( 3 ) can consist of conventional glucose measuring devices (optical, electro-chemical).

Fig. 3 shows a unit for increasing the blood flow in the form of a cuff. The cuff ( 30 ) is attached to the subject's arm. A heating wire ( 31 ) is integrated in the cuff and is supplied with current via an electrical control unit ( 32 ). The control unit limits the temperature of the heating wire on the one hand and defines the duration of the heat application on the other. There is a recess ( 33 ) in the cuff, which serves as an access for a liquid extraction unit.

Fig. 4 shows a separate removal device ( 40 ) for liquid extraction. In the event of a separation of the functional unit removal device and the means for reducing the time offset, the removal device can be implemented as shown in FIG. 4.

The analysis unit ( 42 ) for detecting the glucose concentration of the sample medium and the output unit (display) ( 43 ) for the optical display of the measured value are integrated in the handle ( 41 ). The sample liquid is fed through the cannula ( 44 ) from the skin of the test subject / patient to the analysis unit.

Claims (13)

1. A system for determining a user's glucose level, including

• - a removal device ( 2 , 40 ) for removing interstitial fluid (ISF),
• - A means ( 1 , 31 ) for reducing a time lag between a glucose concentration in interstitial fluid and in the patient's blood.

2. System according to claim 1, wherein the means is a heating device ( 1 , 31 ), which heats a skin area before removal of ISF from this skin area. 3. The system of claim 1, wherein the means is an ultrasound device for applying Ultrasound is on a user's skin area. 4. The system of claim 1, wherein the agent is an administration unit for a blood circulation-promoting substance on a skin area for the removal of ISF. 5. System according to claim 2 or 3, wherein the removal device is a pressure surface for pressing against the skin area, and has a recess in the pressure surface, through which the removal device can be inserted into the skin area. 6. System according to any one of claims 1 to 4, comprising a time measuring unit, the time from the beginning of the action of the means for reducing the time offset on one Skin area measures and either a signal after reaching a predetermined exposure time which indicates to the user that he can take ISF or automatically initiates an ISF withdrawal. 7. The system of claim 1, wherein the withdrawal device includes a cannula ( 22 , 44 ). 8. The system of claim 7, wherein the cannula has a distal end for receiving ISF, and has a proximal end which is connected to a test element, so that from the ISF emerging from the cannula is fed directly to the test element. 9. System according to claim 1 or 7, which has a pressure ring ( 21 ) which is pressed for the removal of ISF against a skin area in order to generate an increased internal pressure in this skin area and the removal device ( 22 ) is arranged such that a removal from the skin area inside the pressure ring. 10. System according to claim 1, comprising an analysis unit for determining the glucose concentrations tration in the extracted ISF. 11. System according to claim 1, in which a quasi-continuous removal of ISF takes place. 12. System according to one of claims 1 to 4, comprising an oximeter with which the The degree of blood flow to a skin area from which an ISF is removed is determined. 13. The system of claim 1, wherein the means for reducing a time offset is in the form of a sleeve ( 30 ).