DE19546535C2 - Measuring cartridge for liquid or gaseous samples, process for their operation and their use - Google Patents

Description

The invention relates to a measuring cartridge for liquid or gaseous samples and a method for Operate and their use, preferably from Kör perfluids, especially blood, by means of of a method that provides an integrated sample preparation, sensor calibration, validation and Quality assurance includes.

With conventional invasive or minimally invasive Blood analyzes, for example, are the problems especially in that

• a) disruptive external input during blood sampling cause later incorrect measurement;
• b) when taking blood, a transfer from fuel ze is required in another container,  besides confusion also changes cannot be excluded;
• c) when injecting blood samples into an analyte Sengerät u. U. blood can leak and sick pathogens can be released;
• d) for the exact determination of the most important blood pair meter too much time passes until the analysis Er results from the central laboratory for diagnosis lie;
• e) during storage the pH and thus the bicarbonate balance can change, which in turn affects the binding capacity for cations (e.g. Ca ²⁺ );
• f) hemolysis occurs during storage, which prohibits a measurement;
• g) it when transferring from the blood collection syringe into the transport containers and further out in the laboratory these vessels in the different laboratory measuring devices come to dangerous mix-ups;
• h) it was previously used for bedside monitoring a portable handheld meter for those important most blood parameters did not provide quality assurance, which the reliability and validity of the measured guaranteed values.

State of the art in the field of blood analysis is a venous or arterial decrease and an um  fill in prepared special containers, whereby for Anticoagulation mostly still in the syringe or in A small amount of heparin was added to the sample container becomes. Because this sampling method is not under Exclusion of air is carried out, the content may increase on dissolved gases, especially oxygen and Carbon dioxide in the process or during transport to the La change bor. Again, this can be related gender, chemical equilibria to change with other important parameters, e.g. B. the pH value, lead to protein ion binding capacity. Can too metabolic processes in the sampling vessels Change parameters to be measured, e.g. B. Degradation of Glu cose etc. The clinical chemical devices are common so big, complex and expensive that only bigger companies such central laboratories can afford nen.

In contrast, the general practitioner needs very often a quick and safe information about the clinico-chemical parameters, if necessary to be able to intervene in time if there is a serious danger nen.

Especially in the field of emergency medicine Great progress has been made in recent years. The acceleration of the Blood analysis by the electrochemical methods of the Electrolyte determination with the help of appropriate Table vending machine that ent ion-selective electrodes hold. Although such devices are always immediately are ready to drive, the blood to be analyzed samples nevertheless sent to an (emergency) laboratory  because these devices are only operated stationary can be and the effort for the necessary qua qualified personnel and one corresponding workload required.

Latest trends in clinical chemistry and laboratory medicine aim to Points of care closer to the sick, d. H. to the Bring sick bed. In this context ge wins the so-called bedside monitoring, d. H. determining important parameter right next to the patient, strong in importance. The great demand for cost reduction tion, higher sample throughput, greater decentralization tion, and reduced training requirements Personnel have research and development worldwide motivated in this area to be easy to use utilizing, inexpensive, reliable and portable devices to develop for bedside measurements.

Exemplary of this new and optimal medical Diagnostics in this context is development the first portable measuring device for quick determination blood electrolytes and other substances the US company I-Stat. The handheld meter in question represents the top of the development that he above try to meet the mentioned requirements. It is mainly based on electrochemical measuring Methods with miniaturized measuring electrodes and on U.S. Patents 5,063,081, 5,096,669 and 5,112,455. Patent US 5,096,669 describes a disposable Real-time liquid analysis device, which is plugged into a handheld device for reading the data must become. A disadvantage of this flat construction  Measuring cartridge is the sample task. At a Blood analysis needs a certain amount of blood in one small intake trough, of which the Then sample by capillary forces into the measuring section is transported after a small snap lid has been closed. In this case, if something is wrong dexterity blood spattered what u. U. at infectious blood endangers the Operator leads. It also happens unwanted equilibration with the Um ambient air, what the oxygen, the bicarbonate and pH determination makes inaccurate. With the I-Stat-Sys The sample cartridge is then placed in the handheld measuring device inserted, where then automatically in the corresponding Cartridge with calibration solutions external pressure are released. To the blood test and the calibration solutions on the sensors Let the flow flow in as the next step from Handheld device also exists in the cartridge the compressed air chamber are opened, the solutions presses through the measuring channels by means of overpressure. After actual measurement, d. H. Reading the sensor sig nale, the cartridge is thrown away. The structure of the Cartridge is not because of this complex construction simple and why not cheap to manufacture it cannot be offered under a few dollars. This puts the cost of this on-site clinical Analysis much higher than for the traditional one Laboratory analysis using appropriate large machines. I-Stat are also responsible for the design a wide variety of materials for analysis dispose of what additional money may cost. Alone for cost reasons, this system can only be used  enforce extreme emergencies. Is technological the cartridge with the integrated chemo and bios sensors are too complex and inconsistent, so that there are no system-related measurement errors be excluded.

US Patent 5,063,081 to I-Stat describes making some of the hand mentioned in the above measuring device used sensors with the techniques of Microfabrication. The thin-film techno used logic, with photo-lithography and evaporation pro working under vacuum is not cheap and is only worthwhile for very large quantities that are in the In case the bedside measurement is not yet given. It is also known that such miniaturized thin film sensors very sensitive to temperature fluctuations, contamination, etc. react.

U.S. Patent 5,112,455 describes the above did the hand-held measuring device use the method of Evaluation that in the present case of development from I-Stat absolutely different than usual (= dev until the measured value is stable) has taken place. The reason is that in the above mentioned sample cartridge uses micro sensors become dry there, d. H. without liquid con are built in and stored and delivered become. At the first contact of sample or calibra tion liquid with the dry sensors the latter penetrates the sensor membrane to the inside Lead electrode and slowly builds the measurement signal nal on. This soaking process lasts until on position of all thermodynamic equilibria  long (a few minutes). That's why it describes Patent a chemometric extrapolation method the be the final analyte proportional measurement signal already emerges after a few seconds. This method however, is less reliable than the real one Equilibrium data used for evaluation because a Different, sample matrix-dependent diffusion sion behavior of the potential determining substances is taken into account. Also known is the appendix Talk time of an ion selective electrode from the Number and concentration of interfering ions. This is cannot be standardized. Therefore in practice all elec trochemical measurements usually only under Equilibrium or steady state conditions guided. When analyzing blood, it can also depending on the individual coagulation behavior, too Protein deposits on the sensor surfaces com men using chemometric extrapolation method cannot be detected, leading to incorrect measurements leads. There is also a com in the evaluation device complicated time-controlled process of data acquisition solution and evaluation, which knows the price ter increased. For all of these reasons, this could Development of the company I-Stat not yet on the market push through. Also the disposal of the measuring cartridge because of the variety of different materials not easy.

An alternative, from US Pat. No. 5,114,859 is Electrochemical measurement method known, in which the Sensor before measuring a sample in a calibra solution and to measure this chamber leaves through a tight sealing opening to with  to get in touch with the sample. Of course, kick here the undesirable drift phenomena mentioned above when using dry sensors. Here is a precise mechanical movement of the measuring sensors or necessary due to the individual calibration solutions. Big problems arise with this version the necessary tight seal between the one individual liquid compartments with the sensor "be driven". As the analyt-sensitive Zone of the sensors must be arranged laterally, rubs the sealing material over the sensitive measuring zone and leads to unwanted artifacts. For example lead fine grinding marks on the surface io Nenselective membranes can be extended accordingly responsiveness and / or destruction of one important, necessary for the correct measurement Surface layer. Another feature of this Pa tentes is that with calibration solution compartments complicated, sensor-carrying blood collection Syringe is placed in a tabletop device for evaluation. This takes over the mechanical relative transport of sensor and measuring compartment. The patent describes only sensors of conventional, too expensive techno logic for a single-use article. The disposal is not easy.

Another cartridge is known from U.S. Patent 5,145,565 known for taking blood, which is also between a needle and a syringe body using standard discrete Luer coupling can be installed. This Cartridge also contains in separate comparisons all calibration solutions required for the later measurement solution using suitable sensors are required,  taking all solutions through absorbent, inert carriers materials are solidified in these chambers. This is important for measurement. In this blood sampling Cartridge there are no sensors. The latter are separated from it and can also be used several times the. The individual sensors are in a suitable, further arrangement then housed later the cartridge opened on one side is moved. she are in electrical contact with a larger one Desktop device that contains the electronics. Act here so it’s not an automatic one Handheld meter for bedside measurements. The disadvantage is here that the individual measuring cartridges from the patient on their way to the electrochemical reader ver can be exchanged. Here too, the sensor top surface by means of a "cleaning" zone, the one Transfer of sample to the individual calibration solutions and vice versa, attacked. It is also known that potential adulterating protein Deposits cannot be removed in this way. Elec In this way, poisonous chemicals from one sample to the next be transmitted. Another disadvantage is the compli graced structure of the individual cartridge versions, the stands in the way of inexpensive mass production. On under no circumstances can the device be operated in just one hand held operated.

From German patent DE 30 46 016 C2 a complete automatic analyzer with one Pipette known. Here are corresponding microscopes sensors housed in the intake duct of a pipette, so that when pipetted out of a storage container the sensor analysis can be carried out at the same time  can. The sensor-equipped pipette suction tip is open at the bottom and must of course for the purpose of calibra tion are immersed in appropriate solutions. Therefore this machine is very complicated and expensive constructed. He can hardly become a handheld miniatu be standardized. He also needs one in an egg sample collected in a suitable vessel. He combines not sampling with a measurement.

From Austrian Patent No. 376 117 is a liquid and / or gas test device direction known that a blood analysis using Sen sensors performed in the sampling syringe are even installed in different places. This increases the cost of manufacturing them usually very cheap syringes considerably. They must be delivered sterile. Also contains the his patent no preferred method of measurement, the potash bration and measurement would simplify. The Disposal complicated syringes with integrated electrical connections are also a pro blem. You can not, as with hospital garbage usual to burn. The cable connection between Syringe and measuring device requires a laborious han animals.

From a European that has since been withdrawn Patent application 0 317 847 A1 is a sensor-equipped Cartridge known, which is also between the syringe and Needle can be positioned, and the one Plug with an electronic measurement and evaluation Device is in electrical contact. Here is missing also the description of a suitable and  reliable measuring method, which is the probability measuring errors greatly reduced and also un trained personnel. For example in the disclosure no evidence of how the sensors are to be calibrated. Any calibration with additional standard solutions to be sucked in and or other additional operations difficult the on-site analysis is faulty and required also evaluating arithmetic operations. Is annoying also that the electrical contact of this cartridge by means of a cable connection to the desktop device freedom of operation of the operating personnel is restricted. The secure positioning of the entire assembly during the measuring process is also not described. An exposed syringe is dangerous and can lead to danger in the case of infectious material. The sensor manufacturing technology according to the invention with miniaturized versions of the traditional, handmade macro electrodes also does not deliver inexpensive device for security reasons can be thrown away after each measurement. Is too the return of a with this Adapter measured blood sample in the body extremely problematic because it comes in contact with the blood sensor membranes contain materials that are highly toxic.

European patent application 0 399 227 A1 writes almost the same arrangement as before with the difference that here in a measuring assembly retractable, planar, electrochemical measuring sensors based on high-temperature thick-film technology (Kera mik) are used after each use  to be thrown away. Here is the multi-analyte potash brier solution either in separate, gas-tight bottles supplied or there is only one even before taking the blood in the syringe. Since the usual medical syringes but not from one long-term gas-impermeable material, these syringes must have a special, gas-tight Received coating. So you can't get cheap ones Use routine syringes to do what the analysis is very more expensive. Can also be provided by the here One-point calibration no malfunction of a sen determine sors. Fiddling with this device tion is therefore due to the lack of automatic potash only possible for an expert. The handha exercise is also very complicated; the operating personal has the handheld measuring device in one hand and in the other the syringe with the sensor assembly that with a thick, shielded cable to each other are connected. There can be no further operations, such as calibration, rinsing, measuring, etc. more to lead. It is also known that micro reference elements treading are not very reliable. One for sure Functional control necessary for safety reasons is in this European patent application not fenbart. The sensor arrays are ceramic-based not because of their metal content for the conductor tracks together with the other hospital waste by incineration dispose.

Another development in this area describes the German patent application DE 44 27 725 A1. Here he you save yourself the injection of the to be measured Blood sample in a suitable hand-held measuring device  through that all measurement necessary for blood analysis electrodes are placed in the sampling syringe. Before the blood sample is taken, there are the Measuring sensors behind one or between two fuel Zen pistons in a suitable calibration and condi tionation solution. When drawing up the final blood the syringe or syringe Piston the calibration solution and replace the calibration solution through the blood, leaving a soft piston rim the sensor surfaces from the calibration solution free. The disadvantage of this innovation is the inte of the individual, mostly planar sensors in the usually cylindrical piston wall of the fuel ze what the necessary vacuum tight piston guide difficult. Also before using this device blood collection in the space behind the syringe piston manufactured with the calibration solution be filled, which requires a special production. You also need the necessary heparin units given in front of the syringe plunger before taking blood air bubbles should be avoided. This creates significant design problems, the u. U. only by a rectangular syringe structure are to be solved. Such syringes are currently in not known to medical technology, are likely have sealing problems and because of the special manufacture only too expensive for this application. The pro The destruction of potential determining (meas value-influencing) surface layers through the Displacement of the plunger remains unaffected solves.

The object of the invention is compared to the known Solutions a safe, reliable, cost-effective and improved manageable solution beat.

The task of  Invention is characterized by the characterizing features of Claim 1 or 12 in relation to the measuring cartridge and by the features of claims 10 and 14 in relation resolved on the procedure. The use of the Measuring cartridge is specified in claims 32-34. The Subclaims indicate advantageous configurations.

The present invention solves the problems of the Stan of technology, especially that of operation security, reliability, correctness, handling, Constriction due to cable connections, costs and disposal in that all the necessary sensors for the Blood analysis miniaturized in a suitable way Device (measuring cartridge or module) between han usual syringe body and needle used who that according to the invention the cheapest planar Type of sensor that is printed on paper can be calibration and quality assurance Functional control takes place automatically, so that one can really speak of a process that in one hand expires. The sensor according to the invention advanced, pinnable hand analysis arrangement preferably for blood has two standardized Luer plug Connection ports, one for a tight connection the typical, uncritical and therefore inexpensive Blood collection syringe and a second opposite lying to attach the hypodermic needle or connection to an arterial catheter. The so easily attachable measuring cartridge between needle and Syringe can be used in the sense of an ergonomic Handling in the outer shape the diameter of the Syringe body to be adjusted because of the outer shape the blood measuring and collecting device according to the invention  is irrelevant. The individual chemical or biochemical sensors for the main blood parameters are easy to dispose of, miniaturized and are in direct electrical connection with contact ten on the outer surface of the measuring module. The corresponding counter contacts to the electrical connector dung, for the operation of amperometric and impedimetri shear sensors and for reading the relevant According to the invention, sensor signals are located in one associated special hand-held measuring device. By a suitable, controlled insertion technology, for example by a nipple in the measuring module and a corresponding recess in the appropriate opening in the Hand-held measuring device can be the sensor-specific Contacts of the individual sensors for the measurement pre close quickly and reliably.

The measuring cartridge preferably consists of non-conducting materials such as extrudable plastics which also medical items such as syringes be manufactured. Poly, for example, are suitable carbonate, polypropylene or PMMA. From disposal the use of metals should be avoided become. For this reason, the sensor ver bonds preferably made of a non-metallic electron-conducting material such as graphite, glassy car bon, carbon paste or a conductive polymer manufactured. Are preferred for structuring the Cartridge injection molding techniques used (claim 6, 7, 9).

The type of chemical and biosensors integrated in the measuring cartridge is irrelevant. In principle, they can also be optical, especially if they are based on the integrated optics. Preferably, however, electrochemical micro processors are used, which are "printed" on a paper-like carrier with a particularly inexpensive technology (double matrix membrane type). The pH value, pCO ₂ value and the electrolytes Li ⁺ , Na ⁺ , K ⁺ , Ca ²⁺ , Mg ²⁺ , Cl ^- , and others are detected potentiometrically with suitable ion-selective electrodes, oxygen, glucose, lactate, among others preferably determined with amperometric biosensors. With the help of biosensors, blood or urine samples, for example for drugs or doping agents, can be examined using immunological and / or enzymatic principles. In addition to the various chambers for receiving the calibration solutions, the measuring cartridge can also contain immunological rinse buffers and enzyme substrate solutions as well as an antibody-loaded or antigen-laden solid phase. By means of suitable fluidic controls, all im muno assays can therefore also be carried out using the ELISA method (claims 22, 23).

The individual measuring sensors are according to the invention in the measuring cartridge from an injection moldable or another mass-producible plastic type preferred positioned in series and stand with their ana ly-sensitive measuring surfaces according to the corresponding Calibration in direct contact with that using the Syringe drawn sample. The measuring channel between the Both Luer connectors can be of any shape and size have sung. It can be straight or very many sensors are meandering. A special  ders preferred embodiment results when the Circular cross at the entrance and exit cut rectangular and in the area of the sensor measuring zone has a linear structure, because then it is production-related just a precisely fitting multi-sensor strip a suitable carrier (e.g. paper or plastic Foil) must be inserted and glued in such a way that the individual measuring sensors in this strip in the created later by joining the module parts together the measuring channel come to rest while the also in this simple double matrix membrane technology manufactured planar sensor leads (= signal Lei due to the design, automatically up to be led to the edge of the measuring module. There you can contacted by counter contacts in the handheld meter become. This connection exists for disposal reasons according to the invention from a non-contact metallic electron conductor such. B. graphite or be made of a conductive polymer.

Instead of electron-conducting measurement signal derivation conditions between the preferably planar measuring electrode the back and the tap contacts on the measurement Cartridge housings can also be used with electrolyte gel filled indentations as an internal derivative of the planar ion selective and gas permeable membranes ver be applied. This structure is particularly suitable for amperometric measuring cells. A thermodynamic reversible internal potential derivation for the use These sensors can also be implemented that in the ion-selective membrane, the inner one Electrolytic solution and in the phase of the electron line tendency connection (e.g. graphite, graphite plus  Polypyrene, polypyrene, polyetylene) stable and light disposable redox systems with higher standards exchange current density in a concentration range of 0.1% to saturated are introduced (claim 10, 11).

From a production point of view, it doesn't come here required sealing problems to the exact fit the planar sensors in the sample (blood) channel are not what simplifies the production considerably. The individual sensors work potentiometrically, impedi metric (alternating current at different frequencies) or amperometric according to the known principles Superstructures. A preferred and particularly inexpensive Sensor production form is that of screen printing technology (here low temperature thick film technology) or that of automatic printing of flow or filter paper or materials with similar properties a dispenser (see DE 41 37 261 C2). Here ge shows that the batch scatter is so small are that you can do with a single point calibration is coming.

The simply in the place of the later by together lead the two cartridges arising Messka nal glued multi-sensor test strips design-related contact lines to the outside Edge of the measuring module with. But it can be fictional also according to redox systems and / or electrolyte gel filled cavities can be switched in between. The latter are formed by appropriately shaped recesses gene in the measuring channel also with injection molding technology easy to manufacture. By including a tra  traditional electrode construction with internal potential Leakage electrolytes are special according to the invention temperature-insensitive sensors created. Purpose the measuring cartridge according to the invention is moderate produced in two matching halves. Then access to the measuring channel is given. It be according to the invention there is also the possibility of both To provide halves with sensors so that the individual measuring sensors later after joining the halves and glue are also opposite. There by easily 4 to 10 of these per cm to accommodate inexpensive sensors.

According to the invention for micro measuring modules for micro Blood tests but also similarly simple and inexpensive, through silicon technology (e.g. containment sensors according to DE 41 15 414 C2) sensors that can be mass-produced, in the corresponding recesses of the planar measuring Channels can be pressed in and glued, used. At corresponding micro sensors can be used in this case the measuring channel in Si technology can be designed. In this version significantly more sensors can be Accommodate the route. The individual microsensors are on the back with the connection concerned brought into contact with the external contacts. At a minimally invasive sampling (e.g. in infants) the Si technological solution is preferred sets because here only a blood amount of far below 1 ml is sufficient for reliable measurement.

According to the invention, all potentiometric measurement Electrodes with one and the same micro reference elec  trode can be measured, or each has its own zen, while for the amperometric sensors others re, less polarizable can be used. Alterna tiv can also with the insertion of the invention according syringe measuring cartridges arrangement in the Handheld needle pierce a septum and behind it in a gel-solidified or non-solidified Electricity key electrolytes were found in the Handheld macro reference electrode inside gene, which also makes a particularly stable, even easily current-carrying reference potential arises, which integrates them into the respective micro sensors reference electrodes for their perfect function be checked for what is a quality assurance Measure amounts to.

According to the invention, the measurement process in the Blutana lyse started automatically by closing essen this electrolytic connection between measuring channel in the cartridge and external reference electrode a resistance measuring circuit with a contact zone in the sen sor range is closed (drastic resistance humiliation). According to the invention is the off-set span voltage between the micro reference electrodes in the measuring mo dul, due to the design no larger current key, and the macro reference Electrode in the handheld measuring device with an accuracy of a few microvolt known. This is the case with the microprocessor evaluation considered. The reference electrode in the handheld meter can be of the same type as the sensor management. The current key electrolyte corresponds a total of at least 0.01 gram equiva lenten (claim 12).  

According to the invention, instead of potentiometry or amperometric sensors (chemo- and bio sensors) also impedimetric. At the latter becomes complex to determine salary AC resistance level at higher frequencies evaluated. You need next to a very thin one analyte-selective membrane only two electron-conducting Micro lead electrodes and no potential constants Reference electrodes and are also extremely inexpensive can be produced planar.

According to the invention, all of the above can be described prior art calibration, Handling and function control problems be solved that in the measuring cartridge next to the measuring chamber (measuring channel) further connected Kam or compartments and at least one transport channel for the sample to be taken, whose content automatically changes according to the fiction method bypassing the sensors. Two between the cartridge halves can form a channel Spacer can be arranged. This can also be used for Use pressure and to seal the sensor film (Claim 9). The measuring channel can also be Cutouts in one half of the cartridge and anodized Bonding can be formed against a glass plate. On in this way flow cells with Fas Realize solutions in the microliter range (Claim 13). The chambers can be manufactured in one or both of the cartridge halves to be relaxed. One of these chambers, the one much larger volume than the measuring channel (e.g. 3 ml compared to 300 µl), contains according to the invention  at least two, easily displaceable by pressure Pistons, the defined multi-analyte calibration solutions separate from each other by one from the outside Syringe plunger caused air pressure (for example wise) or through the sample one after the other (after each other) in contact with the sensors what a much more reliable two-point Calibration results. The latter demands from the Biosensors much simpler design conditions the slope of the calibration line was not sufficient must be known, which in turn is a use simple, inexpensive, amperometric disposable sensors based on paper. For the potentiometris chemosensors results from a two-point Calibration with a much higher accuracy longer shelf life because of the Nernst slope is also determined.

In another embodiment of the invention it is also possible to use the calibration solution in two different, separate chambers in one or insert both cartridge halves through gastight foils with the appropriate pressure tear, are sealed. Another, not Zwin The necessary chamber can be an adsorber material contain and as a collection or transport container serve for the measured solutions.

The measuring cartridge according to the invention has before two standardized Luer plug connection ports for tight connection of an inexpensive, commercially available Syringe and hypodermic needle a simple, be moving fluidics control, through the individual cam  with the measuring channel or according to the requirements changes in the procedure concerned, or connected to the needle and syringe can. As fluidic controls are, for example wise slide or check valves suitable. The The position of the valves depends on the respective process step (calibration, sample measurement) from (claim 6).

The method of reliable Bed side measurement of the most important blood parameters using of an automatically measuring handheld measuring device in an execution version by sucking the blood into the syringe, what by appropriate, so let out fluid position is reached. Around the blood volume to be drawn - on the measuring cartridge adjusted - the syringes can keep constant piston according to the invention up to a stop or the maximum syringe volume can be moved. After that according to the invention with the complete syringe arrangement Needle and cartridge in a designated opening pushed the handheld meter, being fiction according to the fluidics control by automatic on passport pressure is switched so that the first at the calibration solutions in contact with the sensors can kick when the syringe plunger is in the direction Emptying is moved. The Flui dik control one for the external reference electrode necessary electrolytic connection between measuring chamber and needle created. The automatic measurement This will start gang when a flawless electrolytic connection has been determined. The double dimensions according to the invention usually deliver  trix membrane sensors their equilibrium potential in a few seconds. The syringe plunger is fiction according to an integrated in the handheld meter preferably spring-tensioning mechanism, under constant Press the syringe so that there is enough time for the formation and acquisition of the measurement signals under The influence of the calibration solutions remains. Instead of this energy-saving spring drive can be used at Verwen rechargeable power batteries, such as those from Drills are also known as an actuator Push rod of the syringe plunger into the desired one Move direction. According to the different calibration and conditioning solutions reached the sample (preferred wise blood) the sensors and can be analyzed accordingly be settled. Then it becomes like the calibration solutions in the collecting or transport chamber of the Measuring cartridge directed. You can because of the well known and minimal dilution with the known calibration solutions for determining other parameters as well be transported to a laboratory.

In a further preferred embodiment according to the invention the measuring cartridge is already a manufacturer moderately common with a suitable one for all sensors filled with the most sterile calibration solution possible. For this purpose, the input and output ports are with a gas seal, to ent just immediately before taking the blood sealed foil and the entire measuring module is also welded into one gas-tight, metallized plastic film. Before the the blood module is actually invented in accordance with the corresponding for a few seconds Hand-held measuring device, where the data for one  accurate one-point calibration for later blood Measurement can be saved. The handheld meter is preferably battery or battery operated and has no annoying connecting cables. The data out can be given via displays, printers or by means of data remote transmission. This preferably indicates Handheld meter a control display on which Faults, measurement errors, etc. indicates (claim 19, 20). The technical maturity of the planar double matrix Membrane sensors is due to the degree of automation so high that the specimen spreading areas are well known and one-point calibrations (constant Enable calibration curve slope). Once a Sensor can leave these areas, the handheld device show which parameter u. U. less reliable could be. This results in an automatic Quality assurance. After that, the gas-tight Foils on the two luer ends of the cartridge removed, the needle and syringe connected and the Sample up to a certain volume that is large compared to the volume of the measuring channel. The calibration solution becomes the small one Measuring channel (approx. 0.3 ml) displaces and mixes with the sample in the syringe plunger. Then the entire arrangement, as in the first invention Version more or less with the needle down pointing (air bubble on top) into the handheld meter puts. The sample-filled needle pierces like the one septum behind which is the power key electrolyte of an external macro reference electrode be finds. At the same time there is a fluidic control ver behind the needle luer port by adjusting pressure changes that a diaphragm the electrolytic Kon  clock of the measuring channel with the external reference electrode maintained, but the sample with a syringe movement in the emptying direction into a collecting or transport chamber is transported. One in the hand measurement The software housed in the device then compares the Reference electrode potentials of the micro sensors with the the external macro reference electrode where prescribed Tolerance limits must not be exceeded fen. Then the sample measurement signals are acquired and according to the previous calibration Measured values calculated. Then the syringe plunger automatically moves in the direction of emptying and the Sample / standard mixture from the syringe displaces there for the pure sample in the narrow measuring channel. This mix is also measured with the sensors and by the Software in the handheld device according to the well-known method of Standard addition evaluated. Through the fiction according to automated second measurement according to the standard dard addition can be suspected of being faulty or unreliable measurement confirmed or invalidated be tested. Within specified tolerance limits can be averaged from both measured values become. As with a standard addition evaluator systematic measurement errors are recognized immediately, provides this procedure with redundant measured values a drastically increased reliability. It is one quality assurance measure.

The total volume of isotonic, physiological Multi-analyte calibration solution, the manufacturer permanently included in the measuring module is in usually less than a milliliter. More appropriate This calibration solution contains according to the invention  also the necessary amount of heparin, the one Prevents blood clotting and substances that Stabilize the reference electrode potential. The external Reference electrode is designed to be used for ampero metric measurements in the micro-ampere range is resilient, this allows more complicated three-elec Troden measuring arrangements with the associated potentio states no longer apply.

After a blood Analysis, the syringe and the needle are present as so far it has also been incurred for disposal. The measuring cartouche The blood sample can be disposed of separately be, or to examine for other parameters taking into account the dilution by the exact known calibration solutions in the laboratory sent. With a combustion technology Disposal must be taken into account that this module when using non-metallic electron conductors cannot contain metal. With some sensors on Perometric type gold and silver quantities may fall in the range below a millionth of a gram. The mem bran chemicals for potentiometric micro Electrodes are in the microgram range and included no CFCs, so that in the event of a combustion, too no dioxin formation has to be feared.

This simple procedure according to the invention thus solves all the problems mentioned above. The danger that the patient's blood to be measured is released in an uncontrolled manner is set or through too long contact with the Air is irreversibly changed, is at the Erfin excluded. It enables a safe qua  si automatic bedside monitoring with integrated Quality assurance in the simplest way, without that certain other calibration and control operas operations by the operating personnel of a handheld device.

According to the measuring module is correspondingly ge identifies so that the handheld meter the respective Sensor equipment and the necessary values of the potash brier solution when first used. This can be done by mechanical or electrical devices but also by means of a simple barcode Readers happen.

It goes without saying that a person skilled in the art has more Can use versions of suitable fluidic circuits, to the effect of simple and quasi-automatic Two-point calibration or the standard addition perform.

Fig. 1 shows schematically a preferred embodiment of the measuring cartridge for blood sampling and analysis and the simple construction of two assembly halves.

The Fig. 2 schematically outlines the individual Ver method steps for calibration and measurement by the method of two-point calibration.

Fig. 3 shows schematically an embodiment in which the multi-analyte calibration solution is already stored in the measurement channel and is used as a standard addition solution.

Fig. 4 shows schematically another embodiment for the method of two-point calibration via calibration solutions which are separated by means of movable pistons.

Embodiment 1 Version of the measuring cartridge with laminated paper sen soren

The two halves of the measuring cartridge 1 a and 1 b in Fig. 1 can be produced inexpensively in this shape with sufficient production tolerance from a suitable, easy-to-care-for plastic material. For handling reasons, they should not be significantly larger than the syringe body when put together. The advantage here is that, because of the known construction of the double matrix membrane sensors, it is not necessary to insert a metallic conductor that is difficult to dispose of into the plastic material. The Strei fen 4 with any number of laminated paper strips 4 a ... 4 z preferably has a shape such that the contact surfaces when inserted into the correspondingly shaped housing extend to the recess 7 in the lid 1 b and thereby form the contact surfaces 5 .

In one half or in both (not shown) at least one, but preferably 3 storage chambers 8 , 9 , 10 are introduced in addition to the measuring channel 6 by injection molding or other shaping mass production processes, the latter having a volume of less than 10% of that of the chambers 8 , 9 , 10 has, while at least one further, not ge shown te chamber under the sensor level 4 is so large ( Fig. 1 not to scale) that it can accommodate all the chamber volume and the ben volume together.

The chambers 8 and 9 contain defined multi-analyte calibration solutions corresponding to the sensor analyte in a lower and upper concentration range, so that the important slope of the calibration line and its position can be reliably determined by a two-point calibration. If certain minimum criteria installed by software in the handheld measuring device are not met, an unreliability indicator for this parameter is signaled. For the purpose of conditioning and preservation, the calibration solutions also contain other substances and possibly also a poorly soluble salt that remains on the walls during transport through the measuring channel and thus also the sample with a constant ion concentration of an ion corresponding to the solubility product that is never included in the sample. As a result, an additional micro-reference electrode can be built up without an annoying diffusion potential by means of a further ion-selective sensor for one of these ions (cations or anions). An example is the addition of a lanthanum fluoride suspension. Meßelek trode is a fluoride-selective electrode. The storage chambers are closed gas-tight after filling, which can be done, for example, with the help of a metalized film, which then breaks for use at a defined pressure. When storing calibration solutions that contain gas standards, the entire measuring module is welded into a gas-tight film and some calibration solution is bound or introduced into this film to compensate for the partial pressure of the measuring gases in question.

The chamber 10 serves for the intermediate storage of a portion of the sample. If necessary, a small amount of the sparingly soluble salt is stored here together with some heparin (in the case of a blood test).

The chamber 10 and the measuring channel 6 are left open. They are closed or opened by the fluidic control introduced in the recess 3 . The fluidic control is adjusted by mechanical counterpressure when the measuring module (or cartridge) is inserted into the handheld measuring device, in accordance with the requirements of the respective method.

The two halves of the measuring cartridge are brought together and glued using a sealing plastic spacer. The two Luer ports 2 a, 2 b are then sealed gas-tight, 2 a being the needle side and 2 b being the syringe side.

The automated sequence of the measuring method according to the invention is outlined schematically in FIG. 2. In the first step (a) and (b), the syringe conveys only a defined amount of air into the measuring cartridge, whereby a first calibration solution 11 is transported via a corresponding valve control 3 into the measuring channel 6 and fills it, which is represented by the same hatching . In the second step (b) and (c), the sample (the blood) 13 is removed via the chamber (the compartment) 10 by means of the corresponding fluidics control. Part of the blood is also in the syringe. Now the measuring cartridge together with the fuel and needle is inserted into a corresponding opening of the hand-held measuring device, with the fluidic control being switched over simultaneously and automatically and the individual chemo and biosensors being in contact with the corresponding counter-contacts of the hand-held measuring device via a latching mechanism on their contacts 5 become. At the same time, the needle tip is pushed through the septum into the current key electrode of the external reference electrode. The automatic measuring process is started by establishing a perfect electrolytic connection.

The double matrix membrane sensors used have already reached their stable measured value after these minimal operating operations. A software logic built into the hand-held measuring device then compares all sensor signals that occur in contact with the first calibration solution with the known, small variations in manufacturing technology and, if necessary, then signals any deviations. After a certain waiting time of a few seconds, the syringe plunger automatically moves in the direction of emptying through the mechanism integrated in the hand-held measuring device and thus presses the sample (the blood) 13 under constant pressure into the measuring cartridge. The sample flows back from the fluidic control system via the chamber 10 ( FIGS. 2c-d) and is deflected by the fluidic control system at the needle end into the chamber 9 , where it is protected from mixing by an air bubble, the second calibration solution 12 displaced in turn passing through the fluidic control the syringes past flows into the measuring duct 6 at the sensors 4 and in turn the previously introduced therein first Ka libri redemption 11 in the chamber 8 displaced before by the same fluidic control on the needle also exit back into the chamber 8 reached. Fig. 2e then shows the final state. The sample liquid has completely displaced the second calibration solution from the measuring channel and can be measured.

Embodiment 2 Version with sensors based on silicon technology gie

In an advantageous micro version, a complete microscope-equipped flow construction with silicon contacts is pressed and glued into a corresponding recess in both measuring cartridge halves 1 a and 1 b. It is only necessary to ensure that the rear side contacts are conductively connected to the corresponding measuring cartridge bushings. With the micro version, all process versions can of course also be carried out.

Embodiment 3 Device for performing the alternative procedure rens the one-point calibration with standard addition

Fig. 3 shows an advantageous device for carrying out the alternative means of measurement protection by the standard addition-from value method. Here can be dispensed with the fluidics control, if the needle tip after penetrating through the septum receives a flow resistance through a solidified gel, so that a simple slot pressure valve in the measuring cartridge is opened when the sample is re-injected, which is the calibration solution can flow into the chamber 14 . In this version of the method and the device, the calibration solution is already provided by the manufacturer in the measuring channel 6 in contact with the sensors 4 a... Here is the measurement process, as described above, so that first the measuring cartridge is measured alone in the measuring device. Then, after removing the gas-tight closures via the Luer connections 2 a and 2 b, they are fitted with a needle and syringe and the sample is drawn. The rest, the installation of the complete arrangements in the hand-held measuring device, is done analogously to the first embodiment. Because of the very narrow and small measuring channel 6 , the sample located there does not mix very quickly with the syringe content. Therefore, the sample can be measured first and then the sample mixed with the standard solution. If the volume of the measuring channel and thus that of the standard solution (calibration solution) can be neglected compared to the amount of sample taken, the evaluation is simplified. Another preferred embodiment based on this is created when the sample is drawn into the syringe via a second valve-controlled by-pass. Then the handling is exactly the same as in the first example. After inserting it into the handheld device with the corresponding automatic valve displacements, the multi-analyte calibration solution, which should be in the middle of the expected concentrations, is first measured. A logic software then checks the plausibility of these values on the basis of the known sample variations, and only then does the device give the green light for the mechanism of syringe emptying, in which case the sample and standard mix after the calibration solution has been displaced from the measuring channel in a collection chamber. After measuring the sample signals, the syringe plunger moves back towards the filling and brings the sample-standard mixture from the chamber back into the measuring channel, where another measurement takes place. Because of the small volume of the measuring channel compared to the sample volume, the unmixed residual amount of sample can be neglected.

Embodiment 4

Embodiment 4 describes a measuring cartridge and a method with two-point calibration by means of piston-separated calibration solutions 11 , 12 . As outlined in Fig. 4 above and in illustration a, measuring chamber 6 and calibration chamber 15 are connected via an opening 17 . The volume of the measuring chamber 6 is significantly less than the volume of the calibration chamber 15 (z. B. 300 ul to 3 ml).

In the calibration chamber 15 , two calibration solutions 11 and 12 are arranged by three stamps 16 in separate areas. The stamps 16 are easily movable, sealing pistons. In a first method step, the sample 13 is drawn into a sample collection chamber (not shown) or into a syringe. The measuring cartridge is then placed in a hand-held measuring device, where the process steps described below run from. By the syringe pressure when emptying the measuring cartridge, the sample 13 is conveyed into the calibration chamber 15 and the individual punches 16 are moved past the opening 17 (representations b and c in FIG. 4 below). Due to the resulting stamp pressure, the two calibration solutions 11 , 12 (two-point calibration) and then the sample 13 itself (evaluation, illustration d) are passed through the measuring chamber 6 in succession.

Claims (34)

1. Measuring cartridge for liquid or gaseous samples with
a first connection ( 2 a) for a sampling device,
a second connection ( 2 b) for a Pumpvor direction, and
at least two chambers arranged between the first connection ( 2 a) and the second connection ( 2 b),
at least one of the chambers containing one or more calibration or conditioning solutions (calibration chamber ( 8 , 9 , 15 )),
characterized by
that at least one chemical or biochemical sensor ( 4 a to 4 z) is arranged in the area of at least one of the chambers (measuring chamber ( 6 )) and
between individual chambers and / or the two connections ( 2 a, 2 b) and individual chambers fluid control elements are arranged. 2. Measuring cartridge according to claim 1, characterized in that the measuring chamber ( 6 ) is filled with a calibration or conditioning solution. 3. Measuring cartridge according to one of the preceding Claims, characterized, that the individual chambers are parallel to each other are arranged.   4. Measuring cartridge according to one of the preceding An sayings, characterized, that the fluidic controls as Ab close at opposite ends of each Chambers are formed. 5. Measuring cartridge according to one of the preceding claims, characterized in that the fluidic control elements are arranged between the respective ends of the chambers and one of the two connections ( 2 a, 2 b). 6. Measuring cartridge according to one of the preceding claims, characterized in that the measuring cartridge comprises a sample collecting chamber ( 10 ). 7. Measuring cartridge according to one of the preceding claims, characterized in that the measuring cartridge comprises a further chamber ( 9 ) with a second calibration or conditioning solution ( 12 ). 8. Measuring cartridge according to one of the preceding claims, characterized in that
that the measuring chamber ( 6 ) is connected to a calibration chamber ( 15 ) and
that at least one calibration or conditioning solution is arranged between displaceable stamps in the calibration chamber ( 15 ). 9. Measuring cartridge according to claim 8, characterized in that in the calibration chamber ( 15 ) two Kali brier- or conditioning solutions ( 11 , 12 ) between three movable stamps ( 16 ) is net angeord. 10. A method for operating a measuring cartridge according to one of the preceding claims 6 to 9, characterized by the following steps:

• 1. Sampling
  • 1. Filling the sample collection chamber ( 10 ) and / or the pump device with the sample ( 13 )
• 2. Calibration
  • 1. Insert the measuring cartridge ( 1 ) in a handheld measuring device
  • 2. Contact the at least one sensor ( 4 a to 4 z) with a calibration solution ( 11 )
• 3rd measurement
  • 1. Contact the at least one sensor ( 4 a to 4 z) with the sample ( 13 ) from the sample collection chamber ( 10 ) and / or the pump device.

wherein the sample ( 13 ) and calibration solution ( 11 ) are separated from each other by air and / or stamp and the calibration takes place before and / or after the sampling. 11. A method of operating a measuring cartridge according to claim 10, characterized by the following further step:

• 1. bringing the at least one sensor ( 4 a to 4 z) into contact with a second calibration solution ( 12 ) (two-point calibration),

wherein the sample ( 13 ) and the individual calibration solutions ( 11 , 12 ) are separated from one another by air and / or stamp. 12. Measuring cartridge for liquid or gaseous samples with
a first connection ( 2 a) for a sampling device,
a second connection ( 2 b) for a Pumpvor direction, and
at least one between said first terminal (2 a) and the second terminal (2 b) located chamber, characterized in that
that the chamber ( 6 ) contains one or more calibration or conditioning solutions and
in the area of the chamber ( 6 ) at least one chemical or biochemical sensor ( 4 a to 4 z) is arranged. 13. Measuring cartridge according to claim 12, characterized in that fluidic control elements are arranged between the one or more chambers and the two connections ( 2 a, 2 b) and / or between several chambers. 14. A method for operating a measuring cartridge according to claim 12 or 13, characterized by the following steps:

• 1. Calibration
  • 1. Insert the measuring cartridge ( 1 ) in a handheld measuring device
  • 2. Calibration of the at least one sensor in contact with the calibration solution ( 4 a to 4 z)
• 2. Sampling
  • 1. Remove the measuring cartridge ( 1 ) from the handheld measuring device
  • 2. Fill a chamber with the sample
• 3rd measurement
  • 1. Insert the measuring cartridge ( 1 ) into the handheld measuring device
  • 2. Measurement of the sample by means of the at least one sensor in contact with the sample ( 4 a to 4 z)

15. A method of operating a measuring cartridge according to claim 14, characterized by the following further step:

• 1. Standard addition method
  • 1. Measurement of the sample mixed with the calibration solution using the at least one sensor ( 4 a to 4 z)

16. Measuring cartridge according to one of claims 1 to 9 or claim 13, characterized in that the fluidics controls connecting channels between the individual chambers and / or deflections kungen and / or valves such as sliding or turning valves or foils tearing under pressure. 17. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that the measuring chamber ( 6 ) has a meandering shape. 18. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that the measuring chamber ( 6 ) has a rectangular cross section. 19. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that the measuring chamber ( 6 ) has a volume less than 1000 µl. 20. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that at least one measuring cartridge chamber is designed as a savings in at least one measuring cartridge half ( 1 a, 1 b). 21. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that at least one measuring cartridge chamber is designed as a recess in a half between two measuring cartridges ( 1 a, 1 b) arranged spacer. 22. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that the sampling device is a hypodermic mix needle or connector to one arterial catheter. 23. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that the pumping device is a syringe. 24. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that the at least one sensor ( 4 a to 4 z) is an impedimetric, amperometric, potentiome cal or optical sensor. 25. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that the at least one sensor ( 4 a to 4 z) is a double matrix membrane sensor or a containment sensor structured by means of silicon technology. 26. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that the electrical Sensorzu- and Sensorabli lines with contacts arranged in the region of the measuring cartridge housing ( 5 ) are conductively connected. 27. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that a gel-shaped electrolyte or a redox system is arranged between the at least one sensor ( 4 a to 4 z) and the electrical sensor feed and sensor leads. 28. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that at least one reference electrode is arranged in the region of the measuring chamber ( 6 ). 29. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that the measuring cartridge ( 1 ) consists of plastic or silicon and is structured by means of injection molding or semiconductor structuring techniques. 30. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that the calibration or conditioning solution ( 11 , 12 ) contains further ingredients such as heparin or sparingly soluble salts. 31. Measuring cartridge according to one of claims 1 to 9, 12 or 13, characterized in that a mechanical or electrical marking or a barcode marking for detecting specific data of the measuring cartridge is attached to the measuring cartridge ( 1 ). 32. Use of a measuring cartridge according to one of claims 1 to 9, 12, 13 or 16 to 31 for the analysis of body fluids such as blood or urine for drugs, doping agents, electrolytes (z. B. Li ⁺ , Na ⁺ , K ⁺ , Ca ^{2 +} , Mg ²⁺ , Cl ^- , HCO ₃ , NH ₃ ), oxygen, carbon dioxide, pH or metabolic factors such as glucose, lactate, urea (BUN), uric acid, creatinine, pyrovate, ascorbin, phosphate, cholesterol, blood lipids , Triglycerides, phenylalanine, bilirubin, thyrosine, protein and enzymes such as lactate dehydrogenase, creatine kinase (CK), aspartate amino transferase (ASAT), alkaline and acidic phosphatase, lipase, amylase or cholinesterase. 33. Use of a measuring cartridge according to one of the Claims 1 to 9, 12, 13 or 16 to 31 in egg handheld meter. 34. Use of a measuring cartridge according to one of the Claims 1 to 9, 12, 13 or 16 to 31 in egg handheld meter with integrated reference electrode de.