DE10164429B4 - Device for measuring enzymatic constituents in the interior of a human or animal body - Google Patents

Abstract

contraption to measure the activity of Enzymes in the esophagus and in the intestinal tract of humans or animals by means of a probe, consisting of a probe body and one or more sensor modules contained in the probe body, characterized in that the sensor module on the surface contains sensory element, which is made of an electrically conductive or optically transparent material and is covered by a substrate which is to be measured with the Enzyme reacts, this biochemical reaction to a change the electrical or optical property of the sensory element leads and this change is measured.

Description

The invention relates to a device for measuring in the esophagus and in the intestinal tract of humans or animals according to the preamble of claim 1 (US Pat. DE 695 15 554 T2 ).

A Variety of medical examinations has been in recent years demonstrated that the measurement of enzymatic components in the esophagus and in the intestinal tract is of great importance.

at Diseases such as the so-called Barrett's Esophagus is after Current state of science assume that the cause for the changes to look at the mucosa in this area due to a reflux from the small intestine is. Reflux into the esophagus was considered for years as reflux only from the stomach and the associated acidity of the esophageal mucosa as cause for all diseases seen at this point. The investigations in However, more recent times also describe a reflux from the small intestine. In a work by Fein et. Al. (Fiber Optic Technique for 24-Hour Bile Reflux Monitoring, Digestive Deseases and Sciences, Vol. 1, January 1996) describes this duodenogastric reflux. It has been shown to be a correlation between duodenogastric Reflux and the incidence of Barrett's esophagus (Wickborn et al., On the corrosive properties of bile and pancreatic juice on living tissue, Arch. Surg. 1974; 108: 680-684 and Pera et al., Epithelial cell hyperproliferation after biliopancreatic reflux into the esophagus of advice, Ann. Thorac. Surg. 1998; 65: 779-786).

There previously as a measuring method for the duodenogastric reflux only pH measurement and bilirubin detection This is not available in a continuous measurement method sufficient for exposure of pancreatic enzymes to the esophageal mucosa demonstrated. When there is a reflux from the duodenum to the stomach assume that the pH rises in the stomach. This has been repeated described. Under these circumstances, find a reflux of pancreatic enzymes In the stomach, there is a good chance that the Enzymes their aggressiveness maintained. Now if there is another reflux into the esophagus, this is with a change connected on the mucosa and in consequence arises with high probability the observed change, finally to diseases such as Barrett Oesophaugus.

Of the sheer proof of pH changes and bilirubin concentrations enough not to a statement, since both effects initially not as a cause of the tissue changes come into question. Desirable is the direct evidence of the presence of pancreatic enzymes in the esophagus.

a direct and continuous detection of pancreatic enzymes in the esophagus currently not available. For the investigation are currently indirect Procedure providing proof of a duodeno-gastric and subsequently also duodeno-esophageal Reflux serve, so pH-metry and bilirubin monitoring are available (Bechi et al., Long term ambulatory enterogastric reflux monitoring - validation of a new fiberoptic technique, Dig. Dis. Sci. 38: 1297-1306, 1993; Emde et al. Technical aspects of intraluminal pH-metry in man: Current status and recommendations, Good 28: 1177-1188, 1987).

at the pH-metry is a 24 h recording by means of glass or antimony probes the pH levels are carried out in the stomach and / or esophagus. readings are usually won every 5 seconds.

at The bilirubin measurement is performed by means of a fiber optic sensor demonstrated the presence of bilirubin. Here, too, several hours of measurements carried out, at sampling rates of usually 5 seconds.

Both Methods describe the reflux, but not the quality of his Content. For the proof of the pancreatic enzymes in the refluxate is so far only a sample is used, which is then laboratory-examined. Disadvantages here are the time-discontinuous monitoring, the burden on the patient and staff through the sampling and at the same time very high financial expense. Another disadvantage is the time gap between sampling and laboratory result (Hostein et al., Intragastric pH monitoring is not suitable for diagnosis of duodenogastric reflux, Dig. Dis. Sci. 36: 1341-1343, 1991).

In the DE 695 15 554 T2 a method and a device of the type mentioned for the measurement of enzymes on surfaces will be described. The activity of the enzyme is determined indirectly, via a pH change between the surface of a solid and the inner wall surface of a thin tube caused by the reaction of the enzyme with the substrate. The pH change in this case reflects the concentration of the reaction product.

This method or device has a number of properties which are a practical use for the measurement of enzymes that are not close to the surface, but arbitrarily located in the body fluid, very adversely affect.

So may be the pH of body fluids through external influences, such as. Drastically change food intake and thus the measurement result undesirable influence.

By the peristalsis of the esophagus, of the stomach or intestinal tract is the required exact and constant Placement of the tube excessive in situ difficult and can only be achieved by immobilizing the organs. This in turn is associated with a patient burden and can hardly performed on an outpatient basis become. Because the substrate solution is in open contact with the body's interior, In addition, it must be ensured that the substrate has no toxicity.

Of the necessary transport of the substrate liquid also requires one considerable technical effort, the system susceptible to failure and expensive.

moreover the method is limited to the detection of enzymes that cause a pH change.

OBJECT OF THE INVENTION

Derived From this prior art, it is an object of the invention, a Device of the type mentioned above to develop on safe, however also simple way of measuring the enzymes in the esophagus and the intestinal tract of humans or animals. The device should be used as a disposable part and a continuous measurement over a longer Allow period.

These The object is achieved by the Characteristics of the device according to claim 1 solved, the accompanying subclaims show Further advantageous embodiments of the invention.

Corresponding the device according to the invention gets a probe into the esophagus or the intestinal tract of humans or animals. The probe consists of a probe body and one or more sensor modules containing a substrate, which react specifically with the enzyme to be measured. The sequence the biochemical reaction is designed in such a way that the due to the biochemical reaction induced change at the substrate, to a electrically or optically measurable change in the sensor module leads.

The Sensor module is incorporated in the probe body and is in contact with the body fluid with at least one surface the esophagus or the intestinal tract. The sensor module contains on the surface or in a recess at least one sensory element, which consists of an electrically conductive or optically permeable Material exists and that covered with a layer of enzyme substrate is. Advantageously, the substrate is located in a depression, the e.g. cylindrically or conical can be trained.

ever after selected Measuring method, the sensor module can be designed differently. A particularly simple embodiment is the coupling of the biochemical Reaction with an electrical impedance measurement. Here is the Effect that used in the biochemical reaction of the substrate with the enzyme a structural change of the substrate, which leads to a change in the electrical conductivity of the substrate or leads to a change in capacity. Both sizes are measurable by suitable electronics.

There Water or aqueous Tonal solutions, like they in the body fluids be present, have a relatively high dielectric constant and also the electrical Leitfä ability while the substrate conversion changes only slightly, you can help to increase the sensitivity of the substrate with additives, which to an increase in Sensitivity lead. These additives must be body friendly be there at the resolution of the substrate are released. Advantageously, they exist therefore of carbon, e.g. finely pulverized activated carbon or graphite-coated Glass beads. By the resolution of the substrate upon enzyme attack becomes the impedance of the substrate changed significantly, so that the impedance change can be measured with relatively little electronic effort.

The Probe can be catheter-shaped be constructed. In this case, the feeding of the electrodes takes place with AC voltage as well as signal transmission via a cable to an outside of the body located device, which contains the necessary electronics and also the presentation allows the readings.

alternative can provide the necessary electronics along with a battery that has a Power supply ensures that it is housed in the probe. In this case, the probe can enter the intestinal tract in a natural way wander through and transmit the measurement results to the outside by radio, where the evaluation in a device he follows. That way you can Enzyme profiles over the intestinal tract are recovered.

You choose an optical evaluation method, serves as a substrate as an optical Filter whose transmission depends on the structure of the substrate. Also in this case one can see the effect by adding optically absorbing Substances, e.g. Charcoal or physiologically harmless dyes, strengthen the measuring effect. In the implementation of the substrate, these substances are released and the transmission over the Distance increased. Technically leaves this in a simple way by measuring the transmission over a filled with the substrate mixture cuvette on the one hand a radiator, e.g. an LED, and on the another side specific to the irradiated wavelength Contains detector, realize. Due to their small size LED and detector can be included a preamplifier electronics be housed directly in the probe. About a probe cable, the necessary electrical energy supplied and the measured values to a Evaluation and display device be passed on. However, the optical path can also have a optically conductive Fiber, e.g. above two strands, one strand being the undamped one Signal and the other strand transmits the signal. Light source and detector in this case are outside the probe in the evaluation or display device. This way you can be special achieve compact designs.

On the sensor module can be applied different sensory elements. These can be differ in the nature of the substrate and thus different Be sensitive to enzymes. In this way, different enzymes can be measured become. The geometry of the sensory elements can also change differ in order to meet different questions, e.g. when an enzyme is to be measured in different regions and / or different activities are expected, e.g. due to different concentrations or activities by a pH influence on the activity of the enzyme. For the more precise Determination of these influences and also for the purpose of obtaining further insights may be in the sensor module a pH probe of conventional design to be integrated with.

The Advances in the development of new electronic components allow the measurement and analysis of very low currents. Therefore For example, the sensor module may be connected to the sensory elements e.g. in microstructured Mold made of silicon. By etching, the required depressions are generated and by galvanic or Vacuum coating the corresponding electronic conductors as well the electrode surfaces be applied. The sensor module can then be cast in a housing Be sure to get both smooth surfaces as well as an electrolyte access to the electronic To conductors or a preamplifier prevent. By these methods, a small designs can be implemented which leads to a very low patient burden during the Duration of the measurement leads. In addition, by extensive automation, the production comparatively reasonably priced.

[Example]

1 Carrier in catheter design with sensory element

In the following, the function of the device will be explained in more detail using an example for the measurement of trypsin. A probe ( 1 ) with cable ( 2 ) made of biocompatible material has laterally a recess ( 3 ), with two in the plastic incorporated electrodes ( 4 ) made of stainless steel, which are coated with gold. In the recess between the electrodes is a mixture ( 5 ) from a trypsin sensitive protein and carbon particles. The electrodes each have an electrical contact on the rear side ( 6 ), which leads through the probe to a cable firmly connected to the probe.

The probe can be inserted into the esophagus using the cable. The cable has a plug at the end ( 7 ), which is connected to an electronic evaluation unit.

The Evaluation unit acts on the electrodes located in the sensor module with a sinusoidal AC voltage fixed frequency and measures the current flowing through the electrodes electrical Electricity. The over the electrodes are flowing current is a function of electrode area, resistivity the substrate mixture, the capacity of the substrate mixture, the AC frequency and temperature. As long as no trypsin the Substrate mixture changed are all Constant parameter, therefore, the current flowing through the substrate mixture becomes be constant. In the presence of trypsin, the structure of the Substrate mixture due to the biochemical degradation of the protein changed. This structural change causes an increasing spatial Separation of the carbon particles, thus a change in electrical resistance and also the capacity the substrate mixture. High levels of trypsin can go up to the full resolution lead the substrate mixture. Both the electrical ohmic resistance as well as the capacity change the substrate mixture can used as a measured variable be, with the time course of Meßgrößenänderung present on the sensor surface activity proportional to trypsin.

1

probe

2

electric wire

3

recess

4

electrodes

5

protein and carbon particles

6

electrical Contact

7

plug

Claims (8)

Device for measuring the activity of enzymes in the esophagus and in the intestinal tract of humans or animals by means of a probe, consisting of a probe body and one or more sensor modules contained in the probe body, characterized in that the sensor module on the surface contains sensory element, which is made of an electrically conductive or optically transparent material and is covered by a substrate which is to be measured with the Enzyme reacts, this biochemical reaction to a change the electrical or optical property of the sensory element leads and this change is measured. Device according to claim 1, characterized that by the degradation of the substrate in the sensor module, an electrical impedance change generated, which correlates with the degradation of the substrate, this impedance change is measured and in terms of resistance and / or capacitance and / or phase shift is evaluated. Device according to claim 1, characterized that by the degradation of the substrate in the sensor module, the optical permeability changed a route will and this change the optical transmission is measured. Device according to claim 1, 2 or 3, characterized that the sensor modules contain different substrates and thus several enzymes can be measured simultaneously. Device according to claim 1, 2 or 3, characterized that the sensor modules a substrate of different preparation and the nature of the treatment, the reaction rate of the substrate is affected by the enzyme. Device according to claims 1 to 5, characterized that the enzyme to be measured is trypsin and a simple protein serves as a substrate. Device according to Claims 1 to 6, characterized that the probe in addition contains one or more pH sensors for measuring the pH. Device according to Claims 1 to 6, characterized that the probe contains an electronics for signal evaluation and by means of telemetric principle, the information by radio to an outside of the body located evaluation and display unit are forwarded.