WO2001080728A1

WO2001080728A1 - Device for automatically determining glucose content in blood

Info

Publication number: WO2001080728A1
Application number: PCT/EP2001/004685
Authority: WO
Inventors: Oliver Simons
Original assignee: SIMONS, Hans-Jürgen
Priority date: 2000-04-26
Filing date: 2001-04-25
Publication date: 2001-11-01
Also published as: DE10191504D2; AU2001260249A1; DE10020352A1

Abstract

The invention relates to a device for automatically determining glucose content in blood by using photochemical, optical and/or electrochemical measuring and evaluation methods and is characterized by a special implantable module. Said module comprises a multitude of micro-chambers which are filled with a reaction agent (6). Each chamber comprises at least one assigned sensor (7) for identifying changes in the state of the reaction agent. A pre-chamber (4) for receiving blood and/or intercellular fluid is assigned to each micro-chamber, whereby the pre-chambers are sealed by a covering membrane (2). The invention also relates to a device (3) for opening or removing, according to need, each pre-chamber covering membrane (21).

Description

Device for the automatic determination of the blood glucose content

description

The invention relates to a device for the automatic determination of the glucose content of the blood by means of photochemical, optical and / or electronic measurement and evaluation methods according to the preamble of claim 1.

Blood glucose monitors for self-monitoring are state of the art. In such devices, a drop of whole blood is usually applied to a test strip, which is then used to determine the glucose concentration. With the help of a fine lancet, the patient takes blood from the fingertip or the earlobe, for example. The test strip contains a reaction enzyme, for example glucose oxidase. The reaction between blood glucose and enzyme can then be determined photochemically or optically by changing the color of an attached indicator.

There is also the possibility of electronically measuring a decay product of the reaction described above, namely hydrogen peroxide, which produces a defined current flow at an electrode. The amount of current flow then allows an indirect determination of the glucose value.

Regardless of the selected prior art methods, the measuring range of these devices is usually 20 to 600 mg / dl or 1.1 to 33 mmol / l. The achievable accuracy of the portable devices compared to a laboratory measurement, which is usually carried out using the hexokinase method, is around 10 to 15%.

The known devices or devices are disadvantageous for the patient for the following reasons. The blood sugar level of a diabetic patient fluctuates widely during the day. The few measurements that can be carried out during the course of the day, for example two to seven per day, provide too few data points to obtain an assessment of the hyper- and hypoglycic phases. The

The consequences are prolonged hypoglycaemia or accidental hypoglycaemia due to incorrect dosage of the amount of insulin.

Frequent high sugar levels lead to long-term damage such as

Visual disturbances, vascular diseases and necrosis as well as a significantly increased risk of heart attack and stroke. In the case of severe hypoglycaemia, there is a risk that the patient will fall into a life-threatening coma.

Ultimately, multiple measurements a day are painful and cumbersome for the patient. A drop of blood must be obtained for each measurement by pricking the fingertip or the earlobe. The patient must always carry a case with many utensils, which includes the measuring device, a can with test strips, a supply of glucose liquid for calibration and checking the measuring accuracy, lancing lancets and a lancing device. With many of the known devices, it is also necessary to first adjust them to the respective production batch of the test strips by entering a code.

From the above, it is therefore an object of the invention to provide a device for the automatic determination of the glucose content of the blood, which enables accurate and reproducible measurements without burdening the patient, so that an optimal and adapted to the respective detected condition insulin can be given ,

The object of the invention is achieved with a

Device according to the features of claim 1, wherein the subclaims represent at least useful refinements and developments. According to the invention, the blood sugar measuring device is designed to be implantable and capable of collecting blood and / or intercellular liquid, mixing it with glucose oxidase or another suitable reaction medium, in order to then evaluate the mixture with regard to the glucose concentration using optical, photochemical or electronic methods , The device allows a very frequent, quasi-continuous determination of the blood sugar. The measurement data or measurement results obtained can be transmitted inductively or via a high-frequency link to a remote station located outside the body for further processing or evaluation.

The data obtained can be used to control an insulin pump, which can also be designed to be implantable.

In one embodiment of the invention, the blood or the intercellular fluid can first be dialyzed before mixing with the reaction medium takes place.

The reaction chambers for receiving the reaction medium are extremely small, the diameter, for example, in the range between 50 to 100 micrometers and a height of essentially 0.3 mm. A planned high number of reaction chambers and assignment of the preferably optoelectronic sensors allows a very frequent, quasi-continuous measurement, for example every minute.

An integrated control unit can be used to specify the measurement frequency as a function of previously determined blood sugar values, for example to increase the measurement frequency if values outside of a normal or tolerance range have been determined. In the same sense, the number of measurements can be reduced in the normal range when values are determined. Specifically, the implantable assembly, which forms the device for the automatic determination of the glucose content, has a multiplicity of aforementioned microchambers which are filled with the reactant and which are each located above an associated sensor for recognizing the changes in the reactant state. Prechambers for receiving blood or the intercellular fluid are assigned to a respective microchamber, the prechambers being closed with a cover membrane. A device for opening or removing the respective antechamber cover membrane as required then grants the blood or the intercellular liquid access to the reaction mixture.

The reactant in the reaction chamber is enclosed by a biomembrane which is permeable to glucose molecules. The underside of the chamber is transparent to the relevant radiation when optoelectronic sensors are used.

The device for opening the prechamber cover membrane can comprise an electric heater or electrodes, so that when a voltage is applied the membrane melts, rolls to the edge or is destroyed in the electric field. Each individual chamber or each individual heating device can be controlled separately. For this purpose, a control unit for successively opening the cover membranes is provided, which can interact with a device for data evaluation and wireless transmission of the measurement data.

A data memory is provided for the temporary storage of recorded measurement data. The measurement data can be sent on request, for example by querying an acknowledgment signal. In addition to inductive methods, blue tooth interfaces are also suitable for data transmission from the implant to the environment, namely to a data receiver with a display device.

The implant preferably consists of a multilayer stack arrangement. A first wafer is made with the large number of lation-emitting and radiation-sensitive components assigned to them. Such components can also be an integral part of the wafer. A second wafer then has the plurality of recesses or openings for forming the reaction chambers, the second wafer being located above the first wafer in such a way that the optoelectronic components are in contact with the respective chamber bottoms on the radiation side in order to be able to determine color changes in the reaction mixture. This can also be done using fiber optic cables.

A third wafer arranged above the second has the plurality of antechambers for targeted absorption and filling with blood and / or body fluid, each antechamber being spatially assigned to at least one of the reaction chambers. The cover membrane deposited or applied there is then on the surface of the prechamber.

Electronic assemblies for are below the first wafer or at least partially integrated therein

Control of the optoelectronic components and arranged for data acquisition, storage and transmission.

The invention will be explained in more detail below on the basis of an exemplary embodiment and with the aid of figures.

Here show:

Fig. 1 is a schematic representation of the implant in

Partial section;

2 and 5 show a schematic diagram of the closure membranes with heating device and a sectional representation of the antechambers; Fig. 3 is a schematic sectional view of the

Reaction chambers with the optoelectronic components underneath;

Fig. 4 is a schematic representation of a possible

Implantation site with interaction of implant and a data evaluation or counter station; and

6 and 7 an embodiment of the optoelectronic

Sensors.

1, the implant consists of a titanium housing 1 or a plastic housing with a titanium coating. On the surface of the housing, sealing membranes 2 with heating conductors 3 are provided, each of which covers an antechamber 4 at the top. The antechambers have walls made of preferably hydrophilic plastic.

A wafer 5 has a multiplicity of reaction chambers which are filled with a reaction enzyme 6.

On the underside of the reaction chambers 2, 1 there are optoelectronic components 7 which on the one hand emit radiation and on the other hand are radiation-sensitive in order to detect a change in color of the reaction enzyme 6. A processor 8 is used for control and signal evaluation. A transmitting device 9 transmits the measurement data to a remote station with a corresponding display device, as shown in principle in the figure. A primary element 10 takes over the power supply of the implant.

According to the exemplary embodiment, the implant contains five modules stacked one above the other, the uppermost modules ensuring the supply of body fluid or blood to the actual measuring system. The third module below contains the reaction medium mentioned, which contains the glucose molecules contained in the body fluids ω ω M f-υ I- ¹

Cπ o Cπ o Cπ O Cπ ω σ σ

H- H- H-

O Φ Hi

3 Hi

Φ o d

3 tr CO tr Φ H-

H ti o

DJ ω 13

3 Φ cn

H- <

DJ rt φ d Φ H

HΪ I- *

• sweet

Φ o

Listen to CD Φ et 3

CL

Φ Φ co ti H- H-

3 3

G Φ α

3 rr Φ α

Φ H- H- ti 3 Φ ω co

Φ Φ pα

H- H- Φ r rt DJ

Φ H-? V ιQ rt f- ^* - • H- cn O rt 3 O

£?

Φ. DJ ti 3 co 3

<Φ Φ

Φ 3 i ti H- 3 co 13

O φ <! tr ti Φ

H ^* 3 H c Φ ω cP DJ O tr 3-

Hl i- * I- ¹

0 Φ O ti cn co

Φ

3

optical radiation designed to be transparent. The biomembrane allows glucose molecules to enter the chamber.

In the reaction chamber, the glucose contained in the body fluid reacts with the reaction medium. In the exemplary embodiment, the reaction enzyme releases a dye in the course of the reaction which was previously chemically bound to the enzyme. The amount of glucose contained in the body fluid defines the color change in the reaction chamber, which is generated by the color indicator bound to the reaction enzyme.

Alternatively, synthetically produced glucose imprints or other suitable reaction media can also be used.

The optical sensors are designed as silicon wafers below the reaction chambers. Each reaction chamber is assigned a radiation-emitting and a radiation-sensitive component. The color change in the reaction chamber can be measured both in the range of visible light and in the range of infrared radiation. In an advantageous embodiment, laser diodes can be used.

In addition to the optical methods mentioned for evaluation, a photochemical and electrochemical analysis can also be used.

As explained, the lowermost module contains a processor and a data memory, the power supply for the implant and a data transmission device. Here the optical measured values are assigned to a blood sugar value by means of a library and transmitted to a remote station via the transmission module. In addition to a blue tooth interface, the use of the frequency range around 27 kHz is also favorable, since the absorption behavior of the body fluid in this frequency range is low. All modules are sealed with a biocompatible material in order to achieve a biologically inactive and diffusion-tight surface of the implant.

A tablet type with flattened and rounded edges on all sides is advantageously chosen as the housing shape, since the biological compatibility has already been proven here.

The implant can be inserted into the adipose tissue under the skin or directly into the bloodstream. For example, the abdominal region is conceivable here. It is also possible to coat the implant with an anticoagulant or another suitable surface in order to avoid capsule formation in the fatty tissue or formation of a standing socket in the bloodstream.

With the implant, a quasi-continuous determination of the glucose content of the blood or the intercellular fluid and an immediate warning of abnormal blood glucose levels can be carried out. Due to the miniaturized design of the reaction chambers and the associated sensors, a large number of chambers can be accommodated in the implant. Since each chamber can only be used once for a measurement, the number of chambers determines the longevity of the implant and the possible frequency of the measurements. With the appropriate construction, measurements can be taken every minute with the implant remaining in the patient's body for several years.

Immediately repeated measurements with a high frequency of measurement sequences result in improved diagnostics and thus a much more effective diabetes therapy. Long-term damage such as paralysis, amputations, kidney failure, wound healing disorders and blindness can be avoided.

As stated, the implant is preferably powered by a battery as the primary element, but alternatively energy can also be fed from outside the body via an induction field.

In an embodiment of the invention, it is possible to regulate the frequency of the measurements as a function of the previously determined blood sugar value. If the values fall below the standard values, a more frequent measurement is carried out in order to identify potentially life-threatening hypoglycemia in good time. The same applies to very high blood sugar levels, which typically occur as postprandial peaks, i.e. immediately after meals. In the case when the blood sugar is in the normal range, measurements in intervals of 10 or 15 minutes are sufficient so that the overall duration of the implant 12 in the body can be increased.

The blood glucose values determined are transmitted to a remote station 11 located outside the body by means of a radio signal or another suitable method. This remote station can acknowledge the measured data, save it, indicate warning signals when limit values are exceeded and

Show curves. In the event of a temporary separation of the data traffic between implant 12 and remote station 11, the measured values are stored in a memory unit of implant 12 and transmitted en bloc when the data connection is resumed. The memory in the implant 12 is dimensioned such that at least one course of the day can be stored.

The remote station 11 can be carried around at any time and can exchange data with a personal computer via a suitable interface, so that long-term observation and analysis of the blood sugar course by the attending physician is also possible.

A conceivable lighting system for the reaction chambers is to be presented with the aid of FIGS. 6 and 7. An optical system for illuminating and evaluating the reaction in the respective chamber is located under the respective chambers with reagent separated by the aforementioned second biomembrane.

For this purpose, a silicon wafer 14 carries a light-emitting diode 15 and at least one photosensitive diode (measuring diode) 16 on an outer edge.

Via a branched system of optical waveguide tracks 17 introduced on or in the silicon wafer 14, the radiation is distributed to all reaction chambers opposite on the wafer. If the optical waveguide (s) 17 is cheap, the entire silicon wafer 14 is illuminated almost uniformly. Opposite each reaction chamber, i.e. At each individual point of view, the optical waveguide in question is designed such that it can be filled approximately halfway with a liquid which has essentially the same refractive index as the optical waveguide.

The liquid filling area is identified by the reference symbol 18 and the liquid itself by the reference symbol 19.

The liquid 19 can be removed from the corresponding region of the optical waveguide 17 by opening a membrane lying under the liquid container 18. As a result of this removal of the liquid 19, the light now emerges exactly at the defined point at an angle of essentially 90 ° to the optical waveguide path, and radiation energy reaches the reaction chamber in this way. By sequentially opening all the membranes, all of the chambers placed on one or via an optical waveguide can be gradually illuminated.

Claims

claims

1. Device for the automatic determination of the glucose content of the blood by means of photochemical, optical and / or electrochemical measurement and evaluation methods, characterized by an implantable assembly with a large number of microchambers, which are filled with a reactant and which each have an assigned sensor for detecting the Changes in the state of the reactant have a prechamber associated with a respective microchamber for receiving blood and / or intercellular liquid, the prechambers being closed with a cover membrane, and a device for opening or removing the respective prechamber cover membrane as needed.

2. Device according to claim 1, characterized in that the reaction medium is enclosed in the reaction chamber by a biomembrane which is permeable to glucose molecules and the underside of the chamber is transparent to optical radiation.

3. Apparatus according to claim 1 or 2, characterized in that the device for opening the prechamber cover membrane comprises an electric heater or electrodes so that the membrane melts or is destroyed in the electric field when a voltage is applied.

4. Device according to one of the preceding claims, characterized in that a control unit for successively opening the cover membrane and a device for wireless transmission of the measurement data are provided.

5. The device according to claim 4, characterized by a data memory for at least temporarily storing recorded measurement data.

6. The device according to claim 4 or 5, characterized in that the control unit determines the number of cover membranes to be opened and thus the frequency of the measurement value acquisition depending on a predeterminable measurement threshold.

7. Device according to one of the preceding claims, characterized in that the implant consists of a multi-layer stack arrangement.

8. The device according to claim 7, characterized in that the multilayer stack arrangement contains a first wafer with the plurality of radiation-emitting and radiation-sensitive components associated therewith, a second wafer with a plurality of recesses or openings to form the reaction chambers, which so about the first wafer is that the optoelectronic components are optically in contact with the respective chamber bottoms, a third further wafer arranged above the second with a large number of prechambers for targeted absorption and filling with blood and / or body fluid, each prechamber spatially one Reaction chamber is assigned, and includes the cover membrane deposited or applied on the prechamber surface.

9. The device according to claim 8, characterized in that below the first wafer or at least partially integrated therein an electronic assembly for controlling the optoelectronic components and Data acquisition, data storage and data transmission is arranged.

10. The device according to claim 8 or 9, characterized in that the reaction chamber wafer is provided on the top with the biomembrane and on the underside with the radiation-opaque layer.