Surgery – Diagnostic testing – Liquid collection
Reexamination Certificate
2001-02-27
2003-06-03
Hindenburg, Max F. (Department: 3736)
Surgery
Diagnostic testing
Liquid collection
C600S365000
Reexamination Certificate
active
06572566
ABSTRACT:
BACKGROUND OF INVENTION
The present invention concerns a system for determining the concentration of at least one analyte in a fluid, in particular a body fluid. The system has a first member and at least a second member of which at least one has a recess on its surface and the members are joined together in such a manner that the recess is at least partially closed by a surface of the other member to form a channel. The first and/or second member contain an exchange region which is either in the region of the recess or is located on the part of the other member that is opposite to the recess such that substances can be taken up from the surrounding fluid by means of the exchange region. The system additionally has a sensor which can be used to determine the concentration of at least one analyte in the channel. Furthermore the system has at least one integrated reservoir which is connected to the channel.
Many different methods are known in the prior art for the detection of analyte concentrations in body fluids. If the body fluid is extracorporeal, the analyte determination can be carried out in a conventional manner using a clinical analyser. Portable devices such as so-called blood sugar measuring instruments are used predominantly in the prior art for analytes that have to be measured frequently e.g. the glucose content of blood. However, a disadvantage of the said analytical methods is that it is firstly necessary to withdraw a body fluid which usually limits the application range to single measurements. However, in some fields of medicine and especially in the field of diabetes monitoring it is of major advantage to continuously or at least quasi continuously monitor the glucose level. This enables impending hypoglycaemic states which could lead to the death of the patient to be detected in time and, on the other hand, gives a warning of hyperglycaemic states which are usually associated with long-term damage (blindness, gangrene, etc.). Hence recently much effort has been made to enable a continuous monitoring of the blood glucose concentration. One line of research is directed towards a non-invasive measurement of blood glucose concentration e.g. by measuring a glucose-dependent scattering and/or absorbance of infrared radiation. However, up to now it has still not been possible to develop a product based on such a measurement procedure which is ready to go into mass production due to very unfavourable signal to noise ratios and physiological influencing factors that are difficult to control. Other developments are based on the use of sensors that are directly implanted in the body in order to carry out in-situ measurements. A major problem in this technological field is, however, the considerable drift of the sensors that are used. This problem is partially due to the fact that the sensors come into direct contact or via a membrane with tissue and components of the body fluid. Although suitable membranes can reduce this problem, an ageing of the sensor materials takes place which leads to a drift which is very difficult to compensate over a period of several days. Reference is made to the document U.S. Pat. No. 5,855,801 as an example of the above-mentioned technology.
The problems of directly implanted sensors were largely resolved by microdialysis, ultrafiltration and microperfusion. In the case of microdialysis a perfusion liquid is passed through a catheter and the analyte is determined in the dialysate emerging from the catheter. This leads to numerous requirements with respect to liquid handling and microdialysis systems are larger compared to implanted sensors because, among others, perfusate and dialysate have to be stored. On the other hand the microdialysis method is nowadays the most reliable method for monitoring analyte concentrations in vivo.
A number of microdialysis probes are known in the prior art of which reference is herewith made to the arrangements described in the German Patent Application DE 33 42 170 as a representative. The arrangement described in this patent is commercially available under the name CMA 60 microdialysis catheter. This patent shows that a miniaturization of the arrangement is limited by the necessary manufacturing process. However, a reduction in size is absolutely necessary to encourage a more widespread use of the technology. This would be advantageous since smaller microdialysis probes are much lighter and they can be introduced into the body in a less traumatic manner for the patient. Moreover, smaller microdialysis probes can be operated with less liquid so that it is possible to reduce the size of the liquid reservoir.
A miniaturized microdialysis arrangement is described in the article “A &mgr;TAS base on microdialysis for on-line monitoring of clinically relevant substances” S. Böhm, W. Othius, P. Bergveld in: Micro Total Analysis Systems 1998, D. J. Harrison, A.v.d. Berg, editor Kluwer Academic Publishers, Dordrecht 1998. The arrangement has a part manufactured by microtechnology which comprises a sensor and fluid channels and a holding area for the actual microdialysis probe. The described microdialysis probe has an inner channel through which the perfusion liquid flows in and at the end of this channel there is an outer channel through which the perfusion liquid flows out. The microdialysis takes place through the membrane of the outer channel and the dialysate that forms is conveyed to the sensor. Although a relatively large degree of miniaturization has already been achieved with this arrangement, a number of problems remain unsolved. The described arrangement is primarily based on the conventional principle of microdialysis probes composed of concentric tubes in which an inner tube is surrounded by an outer tube which are in fluid communication with one another. This not only results in technical problems for the manufacture but also sets limits for the miniaturization. Furthermore the above-mentioned arrangement is disadvantageous since the microdialysis catheter has to be glued into a holder. This is disadvantageous for the manufacturing process and the junctions between the fluid channels lead to problems. It was found that such fluid junctions impair the response function of the signals. This is due to the fact that the junctions introduce dead volumes.
An solution to the said problems is mostly achieved by systems according to DE 196 02 861. The embodiments described in this document avoid changes in the cross-section of the measuring path and thus circumvent the resulting effects on the response function of the system. Furthermore the described devices allow miniaturization and nevertheless have the advantages of microdialysis described above. DE 196 02 861 also states that it is very easy to integrate sensor elements since the channel is already covered with a membrane that is permeable to the analyte before the sensor elements are inserted. This prevents a closure or contamination of the channel by insertion of the sensor elements. However, this results in a construction that has the disadvantage that the diffusion path for the analyte from the sample liquid is even longer than is already the case for microdialysis. In order to generate a sensor signal the analyte must firstly diffuse through the membrane into the carrier liquid and subsequently out of the carrier fluid through a membrane to the sensor. An additional disadvantage of the systems described in DE 196 02 861 is that the carrier liquid into which the analyte is taken up has to be externally supplied to the sensor system via openings. Connecting tubes in this manner to a miniaturized device not only means additional manufacturing steps but also causes sealing problems. An uncontrolled infiltration of air bubbles into the system is disadvantageous since this would influence the mass transfer in the microdialysis region and also the signal generation in the detection region.
SUMMARY OF INVENTION
The object of the present invention was to propose a miniaturized analytical system which avoids the current problems of the prior art. In particular i
Hindenburg Max F.
Roche Diagnostics Corporation
Wingood Pamela L
Woodburn Jill L
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