Device for determining the concentration of at least one substance in living tissue.

The invention relates to a device for determining the concentration of at least one present in organic tissue substance, preferably the glucose concentration, with the tissue can be introduced subcutaneous needle, and a pumping and suction device for supplying a perfusion fluid and for removal after its partial equilibration with the tissue present is and the degree of interaction with the tissue can be determined by endogenous or exogenous marker variables of the perfusion fluid, and with an analyzing device with measuring devices for detecting the concentration of the substance to be determined and the marker sizes.

In the medical field there is often the need for frequent or continuous analysis of the composition of the body fluids in order to detect and eliminate disturbances in the homeostasis can. To make frequent blood removing unnecessary, have existed for many years, attempts to place sensors in the body of patients in order to continuously obtain information.

One particularly popular application of this case is the continuous determination of the concentration of glucose in the organism. For example, methods and apparatuses for dialysis are known from U.S. Patents 4,221,567, 4,253,456 and 4,516,580, in which at least one cannula or catheter is introduced into the blood stream. About dialysis membranes a complete equilibration of a measuring liquid is obtained with the blood, which is then on the substance of interest, for example glucose, analyzed. At the one side of the measuring liquid and on the other side of the body fluid, such as blood, applied membranes, which must be large enough for sufficient equilibration, it is, however, soon to impurities or to clogging of the membranes by body substances, so that the replacement of the substance in question is hindered quickly. When the introduced into the bloodstream of foreign bodies, such as needles and catheters, there is also the constant risk of infection, thrombosis or embolism. Also available for a long time to be maintained therapies few blood vessels are available which thrombose soon, so that the process can not continue.

For this purpose a device of the kind mentioned has become known from the now WO88 / 05643, which avoids the aforementioned disadvantages. A as "glucose-Pen" Marked embodiment has an approximately shaped pen shaped case here, having a hypodermic needle at one end. Inside the case there is a piston pump with a reservoir for the perfusion fluid, from which by means of the piston both the perfusate pumped out by displacement of the piston chamber as can be sucked into the vacant behind the piston container. By means of a lever device can be moved manually with a most necessary gear piston and perfusion be adjusted by a first lumen in the hypodermic needle to the openings in the wall and collected simultaneously by a second, for example, concentrically arranged lumens by the suction in the collection container. If possible, short of the hypodermic needle is then to the withdrawal conduit, an analysis device having a measuring tube for the substance to be determined and the marker size attached. It is thus possible for a short time, for example, be on the order of about 1 minute or less, liquid pumped through the hypodermic needle and collected again after its partial equilibration. After a short time can have a visual display or an audible indicator, the true concentration of the substance of interest, such as blood sugar, can be detected, which is calculated by the analysis unit of the concentration of the marker substance and the substance of interest. In order to obtain a uniform flow rate for the required time of tissue perfusion, a plurality of operation are conceivable. Thus, for example on the lever device whose lever is operated again and again during the Perfusionsperiode, a uniform perfusion rate can be achieved. The lever can to, for example via a spring or other energy storage device, be brought again to its initial position. The perfusion rate during the sampling period lies in the range 1 to 10 ul / min. The disadvantage of this is only the complicated structure of this "glucose-Pen", in particular the production of the multi-lumen subcutaneous needle is technically difficult and expensive.

Object of the invention is to propose a device which is starting easier and more cost-effectively by the cited prior art, should remain the main advantages of the generic device obtained.

This object is achieved by a single-lumen subcutaneous needle is provided, the lumen is connected to the analysis means that the analysis device whose output is connected to the pumping and suction device, and that the direction of flow of the perfusion fluid in the lumen of the hypodermic needle when switching on the pump is reversible for suction. With this very simple device a few .mu.l of perfusate being pumped into the hypodermic needle after the insertion of the hypodermic needle, the perfusion solution passed through the analysis device and a Nullpunktseichung can be made. After partial equilibration of the perfusate with the signals present at the hypodermic tissue perfusate is drawn from the needle and again brought into contact with the sensors of the analyzer, wherein the substance to be determined and the marker magnitude, such as the electrical conductivity measured and from these values actual concentration, for example, the glucose concentration is calculated. To Nullpunktseichung the perfusion fluid should be in the example substantially ion- and glucose free.

Another advantage of the device according to the invention it should be mentioned that single lumen Subcutannadeln can be performed correspondingly thinner, so that the patient, for example, has in the several times to be performed daily tissue sugar analysis to carry a lower pain burden.

In order to increase the exchange surface of the hypodermic needle, the invention provides that the hypodermic needle along the axis having a slot-shaped extension, and that the hypodermic needle has at least one further opening in the wall region adjacent to the front opening. Preferably, a plurality of openings are arranged in several rows on the circumference of the needle.

In one embodiment of the invention it is provided that the analysis means on both sides of a conical plug-in connection comprising, by which the analyzing device is connected on one side with the subcutaneous needle and on the other side via a connecting line with the pumping and suction device, wherein the connector providing an electrical connection between the evaluation unit and analysis means of releasable contacts. The plug connections guarantee easy changing the needle or the analysis device.

In order to take care that the partially equilibrated perfusion can not mix with the perfusion fluid in the piston pump is provided in a development of the invention that between the pump and suction device and the analysis device is a multi-way valve is arranged, through which the pump and suction means is in a first position of the valve with the subcutaneous needle and in a second position with an opening for the supply of outside air. The einsaugbare via the valve bubble then separates the two liquid columns.

In one embodiment of the invention it is provided that the pumping and suction device has a piston pump whose piston chamber is designed as a perfusion container, and that a charged during the pumping stroke energy store is provided for the suction stroke. When preferably manually operable piston pump the patient must press a lever device only after insertion and later release, whereby the Analysiervorgang automatic. Energy storage is used as a spring. Through small pumping movements during Equilibriervorganges find the flow direction of the perfusate in the lumen of the hypodermic needle can be repeatedly reversed, whereby a higher Equilibrationsgrad is achieved.

An advantageous development of the invention is that a mechanism is provided in the pump drive, which provides between pump and suction stroke, in Equilibrierphase the perfusion fluid, small pumping and sucking movements of the piston of the piston pump. Thus, the pumping movements are performed in the Equilibrationsphase by a mechanism, to which the required energy can also be supplied via the pump stroke triggering lever means.

It can also be provided in a further development of the invention that a perfusion container and at least one container is provided for an administrable drug, and that the pumping and suction device in a third position of the selector valve to the perfusion container, and in at least one other position, each with a container for a medicament in communication.

According to the invention it can be provided for a glucose-enhancing hormone, a container for a rapidly acting insulin, a container for long-acting insulin and a container.

A development of the invention provides that the perfusion container and container for medicines are easily deformable plastic bags and, together with the multi-way valve and the corresponding connecting lines form a replaceable unit. This can then be applied due to the measured value of the concentration of the substances to be determined recognizable, required amount of medication without further stitch exposure of the patient via the hypodermic needle already introduced. After the perfusion container and the container is emptied of the drug, they can be together with the multi-way valve and the necessary connecting lines replaced as a unit with a new one.

It is provided in a further development of the invention that the replaceable unit is connected to the pumping and suction means connected via a pressure-tight connection, preferably via a septum or an O-ring seal, the interior of the area between the multiway valve and the pressure-tight connection line section the connecting line to the volume corresponding to at least a suction stroke. The line portion lying between the septum and O-ring sealing point and multi-way valve can accommodate, due to its internal volume a suction stroke entirely, whereby the subsequent pumping and suction device is not contaminated. The required volume can be realized either by a coiled capillary or by correspondingly large expansion in line with a capillary but has the advantage that it ensures the functioning of the device completely independent of position, as by mixing the liquid column in the capillary not unintentionally, with air can.

To safely avoid contamination of the pumping and suction device, the invention is provided according to a development that the replaceable unit between the pressure-tight connection and the multi-way valve comprises an elastically deformable by the pressure applied membrane. It is also possible to use, instead of the diaphragm, a gas-permeable duch bacteria filter, which is impermeable to liquids.

If the device is intended to remain for longer time on the patient, it is advantageous if a deformable connecting pipe and an electric connection are provided between the conical socket connection to the multi-way valve and the analyzing device. The hypodermic needle, together with analyzing means forms here a unit which is movably connected to the other components of the device-containing housing.

For cases where the total consumed perfusate can not be derived in the tissue, it is advantageous if a collecting container is provided for the perfusion fluid, which is a position of the multiway valve with the pumping and suction device in connection.

The pumping and suction device can remain in the body of the device, which according to the invention a controlled by a microprocessor precision pump can be used, which is the great demands in terms of reliability and reproducibility so without cleaning and maintenance for a long time. The microprocessor controls the same time the multi-way valve, with a suitable display for the user merely notes how "Attach needle", "prick needle", "Remove the needle", etc. appear.

The administration of slow-acting insulin that the rapid acting insulin and the glucose-enhancing substance can be advantageously controlled by the microprocessor of the evaluation unit. It is of advantage if the Gewebszuckerwerte and the emitted amounts of insulin are stored in a memory as long as possible, so that the calculated algorithms for the administration of insulin by a learning effect over time can be improved. It is also possible to control the pumping or suction power of the pumping and suction device with the aid of the microprocessor so that the marker size, such as the conductivity, remains substantially constant. After reaching a desirable Equilibration between 5 to 20% of the tissue concentration which suction can be switched off eventually.

Furthermore, the invention provides that the rapid reversal of the flow direction of the perfusion fluid during a pumping operation of the precision pump with lower pressurized pump chamber in suction can be connected via a connecting line to the hypodermic needle in another position of the valve.

Especially, when the analysis device is connected via a flexible connecting line to the housing of the apparatus and long signal paths are present, the invention provides that in the analysis means comprises a pre-amplifier is incorporated.

In all embodiments, the analysis means may for better mixing of the fluid to be measured on the input side a change in the flow cross-section, for example in the form of a knob having which projects into the perfusion fluid and the perfusion fluid swirled.

To help secure the measurement results can range from the analysis means first the concentration of the marker size, then the concentration of the substance of interest, and then at least once more, the concentration of the marker size can be determined, or in two separate leads, the marker size and the concentration of the substance of interest simultaneously and continuously are measured and from these measurements to calculate the actual concentration of the substance of interest, such as the tissue sugar.

Finally, the invention provides, that a combined ion sensor or conductivity sensor as well as a glucose sensor are provided in the analysis means, the analysis means with the combined sensors has a filling volume of about 10 .mu.l or less.

The invention is explained in more detail below with reference to drawings. Show it:<ul><li>1 shows a device according to the invention in a schematic representation,</li><li>Figure 2 and 3 variants of FIG. 1,</li><li>Figure 4a and 4b embodiments of the apparatus in detail and</li><li>5 shows a trace.</li></ul>

The apparatus shown in Fig. 1 has a fixed to a housing 1, single-lumen subcutaneous needle 2 with a front opening 2 'in the wall of which openings 3 are arranged to the surrounding tissue. 4 In the housing 1 a composed of a piston pump 5 and a lever device 6 pumping and suction device 7 is arranged to promote perfusion. In the connecting line 8, the piston chamber 9 of the piston pump 5 and the lumen 10 of the hypodermic needle 2, is directly the output of the hypodermic needle 2 analysis means 11 associated with non-illustrated sensors for detecting the concentration of the substance to be measured and the label sizes of perfusion ,

The means of the push button 12 moving in the direction of pumping piston 13 of the piston pump 5 displaces few microliters perfusion fluid from the piston chamber 9, wherein the perfusate the analysis means 11 passes on its way to the hypodermic needle 2 for zero. At the same time applied to the housing 1 and the pushbutton 12 spring 14 is tensioned. Pumping through small movements of the lever means can now possibly be provided in addition for a repeated reversal of the flow direction of the perfusate in the lumen 10 of the hypodermic needle 2, whereby a sufficient Equilibration is achieved. After releasing the push button 12 of the lever device 6 of the suction stroke is on the spring 14 accomplished and brought back the partially equilibrated perfusate with the analysis means 11 in contact and measured.

To prevent that already equilibrated perfusate and fresh perfusate from the piston chamber 9 mix, a multi-way valve is in the connecting line 8 arranged 15, an air bubble 17 is drawn by means of which via an opening 16 in the housing 1 for the separation of the different fluids in the connecting line 8 can be.

A connected to the analyzing device 11 evaluation unit 18 and a display 19 pass the measured values ​​to the display.

In the embodiment shown in FIG. 2, the pumping and suction device 7 consists of a precision pump 20, the piston 13 is moved by a stepper motor 21. The individual suction and pumping movements of the precision pump 20, as well as the respectively required valve positions of the multiway valve 15 are controlled by a microprocessor 22nd While in the embodiment of FIG. 1 of the Perfusatbehälter is realized through the piston chamber 9 of the piston pump, in this case the separate Perfusatbehälter 23 and the reservoir 24 for the medicament to be administered together with the multi-way valve 15 constitute a replaceable unit 25 that the through line section 26 connecting line 8 is connected to the precision pump 20th

To protect the precision pump 20 from contamination, an elastically deformable membrane may be placed 43 before the septum 28th

When using more than one medication to correct the detected fault, even more medicament container 24 could be attached. For example, might in the case of glucose monitoring, a container for a rapidly acting insulin, another medicament container for a long-acting insulin, and a further medication container to raise the blood sugar, for example glucagon, be present.

The lead portion 26 of the connecting pipe 8 is closed by a septum 27, through which the unit 25 connects to the provided with a needle 28 working area 29 of the precision pump 20th The precision pump may be constructed similarly as is known micro liter pipettes, such as a piston which is sealed with one or more O-rings against the casing.

It is also possible to use other pumps, such as to use a roller pump that compresses a deformable tube, a diaphragm pump or a pressure vessel with a compressed medium. A convenient place for the arrangement of a roller pump 44 would be given, for example, on a deformable trained line section 26, since the suction and pumping operations can be performed without unintentionally pump fluid into the needle 2, or bring it to malfunction.

The interior of the conduit section 26 between the valve 15 and the septum 27 is sized so that the volume of a suction stroke of the precision pump can be accommodated without 20 with their in the housing 1 remaining portions contaminating the precision pump with one of the media to be transported. With the aid of the valve 15 the precision of pump 20 can be connected in defined working positions, with the hypodermic needle 2, with the Perfusatbehälter 23, with the containers 24 for medicines as well as with the opening 16 for supplying outside air.

Furthermore, it is also possible to connect the hypodermic needle 2 through the valve 15, and a dashed line in Fig. 2 indicated with the connecting line 40 behind the piston 13, pump chamber 41 of the pump 20. The negative pressure produced during the pump in the pump chamber 41 then ensures a rapid reversal of the flow direction of the perfusate in the hypodermic needle. 2

The analysis means 11 with the ion sensor or conductivity sensor 31 and the glucose sensor 32 communicates with the line replaceable unit 25 via a conical plug connection 30, preferably a Luer lock, in conjunction. With a conical plug-in connection 30 'of the same design, the hypodermic needle 2 is connected to the analysis device eleventh

It can be accomplished automatically 18 and an electrical connection 34 between the analysis device 11 with the glucose sensor 32 and the conductivity meters 31 of a part, and the evaluation unit, where it could be a plug-in connection or sliding contacts 35, for example. The microprocessor 22 is connected via a line 40 to the evaluation unit 18 in connection.

At least one container 24 for the medicament to be administered (insulin) or a separate container may be added a small amount of the substance to be measured (glucose), and a marker substance (eg, sodium chloride), wherein the concentration is in the range of typically observed concentrations.

Fig. 3 shows another possible embodiment of the device which has been specially designed, as an "artificial pancreas" standing for more with the patients. This embodiment differs essentially only in so far from that shown in Fig. 2, as between the plug-in connection 30, which connects to the multi-way valve 15 on the one hand, and the analyzing means 11 on the other hand, a flexible connection line 33 is such that the needle 2, for example, in this case is made ​​of soft, atraumatic material, can be easily mounted in subcutanene tissue, and the rest of the device is mounted elsewhere on the body. This has the advantage that changes in position of the device can not exert pressure on the train or needle. 2 The analysis means 11 should be as close as possible attached to the hypodermic needle 2, the connector 30 'between analyzer 11 and needle 2 allows an exchange of the analyzer 11, and the needle 2 may still remain in the tissue. Otherwise, the analysis means may be directly connected to the needle 2 11 course. In addition to the liquids transported connecting line 33 and an electrical connection 34 to the evaluation unit 18 must be present, for example, electrical contacts 35, for example a plug connection or sliding contacts, which are closed simultaneously with the connection of the connector 30th When the signals from the analysis means 11 are often very weak and prone to failure, and a pre-amplifier 36 may be housed in the analyzer 11th For better mixing of the perfusate prior to the measurement, the knob 39 is arranged for varying the flow cross-section at the input of the analysis means eleventh

For prolonging the device in the body when used as an artificial pancreas or other "closed feedback" system, it may be beneficial to provide also an additional collection container 37 which receives the spent perfusate after the measurement, so it does not in the body must be pumped. Even this collection container 37 may be made of easily deformable material. is further shown with 38, the O-ring seal instead of the Durchstichseptums 27 and the needle 28 may be used, wherein. by attaching a closure cap which is not shown, 25 can be taken care of before the insertion of the exchangeable unit for sterility This cap is removed in the device immediately before insertion of the unit 25th

As shown in detail in Fig. 4, the hypodermic needle 2 'can have in the region of the front opening 2 of a slot-like expansion 42, so that the exchange surface of the hypodermic needle 2 is also increased. According to Fig. 4b, the extension also connect directly to the front opening 2 '.

In operation, the apparatus of the invention following, substantially self-running steps are possible: <ul><li>1. Before the hypodermic needle 2 is introduced into the body, a solution is prepared by the analysis means 11 sent that contains about a lot of substance to be determined and the marker substance, as they will be expected at the current measurement, whereby the steepness of the sensors can be determined. For example, to the drug solution, for example, insulin, the substance to be determined, such as glucose and the marker substance, such as sodium chloride, may be added. The mixture is then sucked air 15 through the valve and the connection line 8, and the analysis means 11 by discharging purified air. Subsequently, a perfusate, which is free of substance to be determined and the marker substance, pumped through the analyzer 11 to recalibrate to zero.</li><li>2. After plugging and inserting the hypodermic needle, the perfusate is pumped into the needle and quickly applied to the hypodermic needle, a negative pressure to attract the pumped into the needle perfusate again before it can seep into the body. Possibly the perfusate can additionally by small pumping movements in the lumen of the hypodermic needle can be moved back and forth to a partial equilibration is reached. In Ensuing suction stroke, the concentration of the substance of interest, such as glucose and the marker size, for example, the conductivity as a measure of the degree of equilibration.</li><li>3. The inert perfusate can be subsequently explained in the body or as shown in Fig. 3, are pumped into a separate collecting container.</li><li>4. Thereafter, the multi-way valve is switched and pumped, the required amount of the drug, such as insulin or a blood-sugar-increasing substance, such as glucagon in the tissue. The optimum amount of the drug without the assistance of the patient can also be calculated by the microprocessor 19 due to the collected measurements, the patient can then possibly confirm the proposed amount of the drug by pressing a key.</li><li>5. After the application of the medicament a connection to the outside air or to the perfusion container is produced via the valve 15 again rinsed and the rest of the medicament with the perfusion fluid or air from the hypodermic needle into the tissue.</li><li>6. When using the device as an artificial "pancreas", the needle can remain in the body and the measuring operation and the insulin administration may be repeated automatically at appropriate intervals, whereby the needle can be held by intermittent rinsing with the perfusion solution free from clogging and the perfusion solution also antiplatelet agents may be added.</li></ul>

In practice, the following volumes, timings and pressures have proven to as quickly as possible to achieve adequate equilibration of perfusion to the tissue: - Injection of approximately 20 microliters to 150 microliters (preferably about 50 to 100 microlitres) of perfusion fluid through a hypodermic needle with an external cross-section of about 0.4 mm and a length between 10 and 20 mm within about 1 second. - Instant applying a reduced pressure between 200 mbar and 700 mbar, preferably 400 mbar (or an absolute pressure between 300 mbar and 800 mbar, preferably 600 mbar). - Within 20 seconds it comes within a sensor with a filling capacity of about 10 microliters to equilibration 5-20%, wherein the suction of air through the selection of the correct pressure should be avoided.

Fig. 5 shows the approximately exponential course of the equilibration on the sensor, wherein the observed mathematical function of the calculation of the actual concentration of the substance to be measured is used. The dashed lines show the reached after 10 seconds and 40 seconds equilibration of 5% or 10% of the tissue fluid. By controlling the pumping and suction device, the degree of equilibration, for example, as indicated by the dotted line, are held constant.