Patent Application
20080027296
An exemplified embodiment of the invention and several examples of sensors will now be described with reference to the accompanying drawings in which
The invention will now be described in terms of its preferred embodiment. This embodiment is set forth to aid in the understanding of the invention, but is not to be construed as limiting.
The exemplified embodiment is described with reference to the drawings. This embodiment is a diagnostic device which can be worn and operated by the patient. One aim of the present invention is to insert the sensors into the skin of a patient substantially without pain, thus avoiding the natural reluctance of the patient to invasive procedures and to reduce the reactions of the body to injury to a minimum. Another aim is to maintain an exact positioning of the implanted parts of the sensors relative to the device, to the skin and to each other leading to measurements with improved reliability. Further, immovable connections between the implantable part of the sensors and the measuring equipment, which becomes possible according to the present invention, greatly improves the reliability of the sensors and makes the constructions much simpler. In addition, the necessary handling by the patient is reduced to a minimum of easy manipulations, like the pressing of a knob, which do not require nimble fingers for implanting the sensors and/or making the connections to the control and measuring instruments.
In contrast to known sensor devices, in the present inventive device the implanted parts of the sensors are inserted by thrust of a pre-stressed flexible surface which is attached to the skin by means of an adhesive layer and forms the base plate of the device. In the ready-to-use position, this flexible surface projects beyond the tips of the implantable parts of the sensors (
a shows a diagnostic device of this kind in section comprising a casing having a cylindrical side-wall 1 a disk-like flexible baseplate 2 in the flat position 1 of the operation mode and a cover 3 which can be moved against the baseplate and used as a release knob to start the implantation and measuring process. The baseplate has a radial segmentation, preferably into 5 to 8 segments 4 (see
b shows the internal constructive elements of such a device as an explosion drawing. The flexible baseplate 2 is depicted in the pre-stressed position 2 of the ready-to-use mode. The cylindrical side-wall 1 has grooves and rectangular openings 10 serving in the attachment between the disposable and the reusable part of the device as guidance and catch mechanism. Radial bridge elements 11 attached to the side wall hold in their center an element 12 with the array of the implantable parts of the sensors. This element 12 consists of a central part 13 which fixes the sensor array in a geometrically well defined axial position, hold a removable protection cap 14 and at its upper surface provides the connections to the reusable parts of the sensors and the measuring means and provides a recognition code. The protection cap provides the necessary long-term sterility and maintains an environment which is required for a long shelf-life.
The means to position the flexible surface in two defined positions is composed in the described embodiment of two pieces, a pressure element 15 and a holding-back element 16. The pressure element 15 has a pressure plate 17 and pressure-pins 18 which press onto the segments 4 of the baseplate. The holding-back element 16 functions also as the casing of the reusable part of the device and is in a reversible way connected to the cylindrical side wall 1 which is at the same time part of the housing of the disposable part of the device. This connection is achieved guided by ribs with flexible barbs 19 which hook into the openings 10. Concentrically positioned catches 20 serve to withhold the pressure plate 17 allowing to maintain the pre-stressed position of the flexible baseplate. These catches are formed in such a way that upon pressure from the top-side by a concentric cylinder 21 attached to the inner surface of the cover 3 they bend and release the pressure plate.
The control and measuring means are fixed in the space between the bottom of the casing 16 of the reusable part and the cover 3 of the device on a support 22. The connective elements to the disposable parts of the sensors are also attached to this support (not shown in the figures).
The handling operations necessary to prepare the device ready-to-use are now described for the embodiment discussed above as example. A very important feature of the subject invention is that the connections between the implanted part of the sensors and the other parts of the device are stationary and therefore no connections have to be made manually after the implantation process. As compared to similar devices of prior art this is a big advantage for reliability, easy handling and user acceptance. This advantage is even further improved by a mounting tool which guides all necessary operations and reduces manual handling essentially to push-pull movements enabling also people with reduced level of manual skill, e.g. elderly patients with manual disablements to correctly use the device. This mounting tool allows also for easy and correct assembly and disassembly if a realization of the device is chosen with a reusable part containing all more expensive elements and a disposable part which contains the elements which should be replaced after each use such as the implanted parts of the sensors and the adhesive to the skin.
The embodiment in
Upon termination of the measurement period, the device is removed from the skin and put back into the mounting tool. This can be done only in one pre-defined position assured by a rib and groove system 28 (see
Upon reading this specification, various alternative embodiments will become obvious to the skilled artisan. For example, the implantation mechanism could be achieved via numerous chemical, mechanical, or electrical devices. For the recognition between the disposable and reusable part of the device several mechanical, optical or magnetic codes could be used and a large variety of sensor arrays as well as control and measuring means can be accommodated with the device.
Preferred sensors for analytes fitting well with the specifications of the subject device can be constructed following state of the art procedures for electrochemical and optical sensors. The construction of electrochemical sensors is straight-forward by coating part of the surface of the implanted part of the sensor with a suitable sensing layer, as will be described e.g. in Example 1 for glucose. For the construction of optical sensors a wide variety of methods can be optimally adapted as described in the following for direct determination of the analyte or for indirect monitoring using suitable indicators. Such general methods can be coupled to analyte-specific enzyme reactions or to specific binding to receptors or antibodies.
It is well known from the literature that clinically relevant analytes such as glucose, alcohol, urea, creatinine etc. can be determined directly by taking NIR, IR or Raman spectra from body fluids (serum, blood, salvia urine etc) and by using statistical techniques such as PLS or PCA or neural networks for evaluation. Many optical arrangements have been claimed in the past for measuring clinical parameters through the finger, the tongue or ear. A disadvantage of these arrangements is that radiation has to cross the skin which shows a large spectroscopic variance not only from individual to individual but can change its spectroscopic properties also for a single individual within a day. The arrangement suggested herein has the advantage that measurements are performed within the tissue using the subject device.
As depicted in
Optical enzyme sensors are based on the fact that an enzymatic reaction in general not only changes the concentration of its substrate but changes also the concentration of molecules such as O2, H3O+ or CO2 that are produced or consumed by the enzymatic reaction. A concentration change of such molecules can easily be followed using absorbing or fluorescing molecules, so called indicators that change their absorption or fluorescence behaviour specifically with the concentration change of above mentioned molecules. In a fibre optical enzyme sensor the reaction phase with enzyme and indicator is fixed to an optical fibre that transmits light from the light source to the reaction phase and back to a detector as described by E. A. H. Hall (Biosensoren, Springer Verlag Berlin, 1995, 351 ff).
Several fiber optical arrangements to follow changes in the concentration of small molecules in a reaction phase containing enzyme and indicator are depicted in
A similar arrangement can also be realized with a single fibre 38. Incident and light transmitted to the detector are then separated at the end of the light transmitting fibre by a semi permeable mirror 39.
Alternatively, an optical fibre can also be stripped off from the optical isolation 40. The reaction phase 41 can then be mounted directly to this part of the fibre. The incident light interacts with the indicator molecules in the reaction phase via the evanescent field to monitor changes in absorption and to excite fluorescence. Emitted light from the fluorophores is analogously coupled into this fibre 38 again via this evanescent field. This evanescent field could be enhanced by covering the surface of the stripped fibre with a thin gold layer. Within this gold layer, a so called surface plasmon could be excited. The electromagnetic field of this evanescent field is by orders of magnitude stronger then the electromagnetic field of the evanescent field of a non covered optical fibre. This surface plasmon effect can therefore be explored to monitor absorption changes more sensitively and to excite more efficiently the fluorescence of fluorophores immobilized within the penetration depth of that evanescent field.
By-products of enzymatic reactions such as H3O+, O2 or CO2 or NH3 can be measured using the following reaction phases:
pH sensors can be constructed by immobilizing pH indicators on the surface. A prerequisite of such indicators is that they have a pKa close to the relevant pH range of the analysis matrix. An indicator that has been used by J. Peterson et al. (Anal. Chem. 1980, 52, 864) is phenol red with a pKa of 7.6. It was demonstrated that such sensors work in the physiological range from 7.4-7.0 with a resolution of 0.01 pH units.
Immobilizing pH sensitive fluorophores is another possibility. Such fluorescence indicators change with pH either the wavelength of excitation or the wavelength of emission. D. W. Lüebbers et al. uses methylumbeliferon (Z. Naturforsch., C: Biol. 1975, 30c, 532) whereas Wolfbeis (Anal. Chem. 1983, 314, 119) takes 8-hydroxy-1,3,6-pyrenetrisulfonic acid. Fluorescein and its derivatives can also be used as fluorimetric pH indicators as demonstrated by Milanovitch (Proc. SPIE-Int. Soc. Opt. Engl. 1984, 494, 18).
Most optical O2 sensors reported to date are based on fluorescence quenching. Linear calibration curves can be obtained by plotting the fluorescence intensity in the absence of O2 versus the intensity of O2 at a given oxygen pressure. A variety of reagent phases have been used in optical oxygen sensors, such as pyrenebutyric acid immobilized on solid substrate or perylenebutyrate.
A blood NH3-optical sensor is described by Smock et al. (Anal. Chem. 1979, 51, 505). The reaction phase consists of a polymer matrix which contains ninhydrin. The optical change is based on the formation of the characteristic Ruhemann Purple colour in the presence of NH3.
Any of the above described optical sensors can be modified for monitoring clinically relevant parameters. The modification includes immobilization of a suitable enzyme within the reaction phase. The substrate of the immobilized enzyme represents the analyte molecule to be monitored. The enzyme acting on the substrate changes the concentration of the chemical parameter for which the optical measurement is sensitive (for instance O2, pH, CO2 etc.). Numerous such enzymes have been suggested in the literature (in Biosensors, Fundamentals and Applications, A. P. F. Turner et al eds, Oxford Sci Publ. 1987 pp. 135). The most prominent one is Glucose Oxidase which catalyzes the reaction from glucose to gluconic acid whereby the O2 and the pH are changed in the reaction phase. By coupling this enzyme to a pH- or O2-optode enables monitoring of glucose in biological fluids as demonstrated by N. Uwira et al. (Adv. Exp. Med. Biol 1984, 169, 913). The catalytic transformation of penicillin to penicillin acid is accompanied by a change in pH which can be monitored by a pH-optode when the enzyme is coupled to the reactive phase containing fluorescein as an indicator as described by O. S. Wolfbeis et al. (Anal. Chem. 1988, 332, 255).
Such sensors can be designed for several analytes like e.g. glucose. A general device fulfilling these requirements is depicted in
A sensor working along this principle has been described by F. F. Bier et al. (Sensors and Actuators 1992, 7, 509) for measuring glucose concentration. Concanavalin A serves as the receptor. Dextran labelled with fluorescein represents the labelled macromolecular ligand that binds to the receptor but does not penetrate the porous membrane. Glucose is the analyte which competes with dextran for the binding sites on concanavalin A. At equilibrium, the level of free fluorescein labelled dextran is measured and is correlated to the external glucose concentration.
The invention will be further characterized by the following examples. These examples are not meant to limit the scope of the invention which has been set forth in the foregoing description. Variations within the concepts of the invention are apparent to those skilled in the art.
The device according to the preferred embodiment as described above was equipped with an array of seven implantable electrodes of 150 μm diameter and 4 mm implantable length. The arrangement of the electrode array is shown in
The pin-like implantable part of the glucose sensors depicted in
The “wired” enzyme sensing layer was formed by crosslinking glucose oxidase to poly[(1-vinylimidazole)osmium(4,4′-dimethylbipyridine)2Cl] via poly(ethylene glycol) diclycidyl ether 400 (Polysciences). The glucose flux restricting layer was formed by sequentially filling the recess and curing twice with 1% solution of cellulose acetate in cyclohexanone; once with a 0.5% solution of Nafion (Aldrich) in n-propanol; and once with a freshly prepared solution of poly(vinylpyridine) acetate (25 mg/ml in water) and polyfunctional aziridine (XAMA-7, E.I.T., Lakewillie, S.C.) (30 mg/ml in water) in a 1:2 volume ratio.
All glucose sensors are connected to an amperometric sytem via multiplexing and operated as working electrodes in connection with the Pt counter and the Ag/AgCl reference electrodes preferentially at a low operating potential of −0.1 V. The signals are processed every two minutes into calculated glucose concentrations. These values are stored in the memory of the in-built microprocessor for off-line downloading and computer analysis and are in parallel transmitted wireless to a wrist-watch which converts the signals into a colour-coded signal message through an LCD dial plate for averting the patient about his actual glucose status and the trend of changes. Alternatively, this wireless transmitted signal can be used as a control element for an insulin infusion pump.
Other endogenous analytes, like lactate, urea, creatinine etc but also drugs and xenobiotics like alcohol can easily be measured using the same principles with appropriate selective enzymes.
As an example, the use of antibiotics can largely be improved esp. in life-threatening conditions by dose-adjustment according to renal function. Success of treatment in severe nosocomial infections is often a question of finding the optimal individualized dosage resulting in high enough plasma levels over sufficient time to kill the pathogens (time over MIC). On the other hand, severe dose-dependent side effects can result due to over-dosage. The severity of the clinical condition and the use of several antibiotics and other drugs in parallel make the choice of the optimal dosage even more problematic. The results of a recent trial of the University of Milan (F. Scaglione, 8th ISAP Symposium, 2002) demonstrated that adjustment of antibiotic treatment in such a condition according to renal clearance could halve the failure rate and of the mortalities (from 10% to 5%) and shorten the length of hospitalization by one third. There are no convenient methods available to determine renal clearance at the bed-side. Serial blood samplings and relatively complicated laboratory analysis prevent the routine application of the creatinine or the inulin clearance test for renal function.
The inulin clearance test is the gold standard for assessing glomerular filtration rate and can be measured after a single bolus injection of 5 g of inulin by following the disappearance over several hours (K. Jung et al. Clin. Chem. 1992, 38, 403-407). Inulin readily equilibrates to the interstitial fluid and therefore its excretion can be readily followed with the subcutaneous diagnostic device of the subject invention.
The sensor for determination of inulin concentration over time was constructed essentially in the same manner as outlined above for glucose in Example 1. The selective electrochemical determination of inulin made use of a two-step enzymatic reaction, first the hydrolysis of inulin via inulinase as described by Kuehnle et al (Nephron 1992; 62: 104-107) followed by amperometric determination of fructose using the enzyme fructose dehydrogenase and the mediator tetrathiafulvalene co-immobilized by cross-linking with glutaraldehyde following the procedure described by S. Capuzano et al (Anal. Bioanal. Chem. 2003; 377: 600-607).The incorporation of sensors with the same construction but omitting inulinase into the array allows for correction of the measured values for unspecific signals.
The sensitivity of the electrode can be further improved by increasing the sensing layer by means such as fluted or dent shaft, nanotubes, porous anorganic or organic coatings or polymers.
In one embodiment for convenient bedside use the cap of the device was constructed in such a way that it incorporated a LCD display showing the calculated clearance in mL/min and the corresponding recommended dose of the selected antibiotics in % of the standard dose chosen by the physician assuming normal renal function. A microprocessor in the device can be loaded with recommended values for a variety of antibiotics and the antibiotics in actual use can be called up onto the display. It is obvious that many variations according to convenience of application of the device are possible.
The example above describes only one of many possible applications. Determination of renal function based on the clearance of inulin or using alternative sensors for creatinine, p-aminohippuric acid or other clinically well established substances can be very important for the correct dosing also of other drugs and for diagnostic purposes.
Adverse drug reactions were conservatively estimated to account for as many as 2.2 million hospital events, and as many as 100,000 deaths a year in the US alone (Pomeranz, JAMA 1998; 279: 1216-1217). An important cause of such adverse drug reactions is caused by inadequate individual dosing due to large variations in the pharmacokinetics of the drugs in different individuals. The reasons for such variations are partly the genetic makeup but also environmental factors, the general condition and concomitant drug treatments of a patient play an important role. For many drugs such unpredictable variations even among normal individuals result in standard deviation in the values observed for the main pharmacokinetic descriptors F, CL and Vss of about 20%, 50% and 30% respectively. This means that 95% of the time the plasma concentration that is achieved with a standard dose will be between 35% and 270% of the target; this is an unacceptably wide range for a drug with a low therapeutic index. The variation in a population with various illnesses and concomitant drug treatments can be even more pronounced.
Of particular interest in this context are drugs with a narrow therapeutic window like e.g. the blood thinner warfarin and indications in which the efficacy of the drug becomes apparent only after prolonged treatment of several weeks like antidepressants and antipsychotic drugs.
As an example a diagnostic device for the simultaneous determination of the pharmacokinetics of 3 frequently used antidepressants fluoxetin, paroxetin and venlafaxine given at sub-therapeutic dose is described.
The sensors for the three drugs were constructed as optical sensors essentially following the design depicted in
Various modifications and changes may be made without departing from the spirit and scope of the invention. For instance, larger molecular weight substances like hormones such as insulin or other proteins can be preferably monitored with sensors using the principle of surface plasmon resonance.
It is obvious that besides the electrochemical principles described for sensors in examples 1 and 2, the optical principles described above, especially in combination with established technologies such as immunodetection, electrochemoluminiscence can form a common detection platform, which greatly facilitates the design and construction of devices according to the subject invention, and allow the determination of several analytes in parallel with sensors of different selectivities. With such a design and the selection of panels of xenobiotics/drugs which are proven to be safe if administered to patients at low dosage for diagnostic purposes and span the involvement of several metabolic pathways for their elimination, a phenotypic profiling of an individual patient at a given time can be achieved. Examples of such compounds are i.a. xanthin, coffein or antipyrin, which results in 3 different metabolites, depending on the individuals P450 isozyme pattern and which can be measured in parallel using the subject sensor device. Such a phenotyping gives a global picture of the individuals drug metabolizing capacity, covers also, but is not restricted to, the important hepatic metabolic functions, e.g. the interplay of the P450 isozymes which can show wide interindividual variations due to the genotype but also due to acquired individual factors such as life style, disease history, concomitant medications, alcohol consumption and other environmental factors. The necessary actual in vivo data from an individual can be conveniently obtained with suitable diagnostic devices according to the subject invention. The data can be downloaded to a diagnostics information system using state-of-the art transmission tools, well established through internet and telecommunication, for further processing. Using advanced algorithms like physiology based pharmacokinetic modeling together with diagnostic data of the patient, such as e.g. age, body mass index, drug treatments allows to provide the physician with relevant information for an individualized drug treatment and optimized dosing schedule. Additional information e.g. of renal function and genomic profiling can further improve the predictions.
The invention has been described with reference to a few specific and preferred embodiments, techniques and applications. However, it will be apparent to one of ordinary skill in the art that many variations and modifications and adaptations to special applications and needs can be made while remaining within the spirit and scope of the invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 03029565.3 | Dec 2003 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP04/14057 | 12/10/2004 | WO | 00 | 4/12/2007 |
