Patent Publication Number: US-2012046651-A1

Title: Medical device for glucose monitoring or regulation

Description:
The present invention relates to a medical device suitable for analyte monitoring and for drug delivery, in particular for monitoring of glucose and for the treatment of patients with diabetes. 
     Different medical devices intended for the treatment of patients with diabetes have previously been described: Separate glucose sensors (e.g. electrochemical, viscosimetric, or optical sensors), separate medication delivery devices (e.g. insulin pumps and insulin pens) as well as so-called closed loop systems, i.e. systems integrating glucose sensor and medication delivery. The latter ideally mimics the function of the pancreas, i.e. medication capable of controlling blood glucose level is released subject to blood glucose concentration. 
     A medical system that combines a glucose monitoring unit with a drug infusion unit is described in patent application US 2006/0224141. In this medical system, the analyte monitoring unit is separated from the medication infusion unit. The analyte sensor is based on using electrodes in order to determine a change in electric resistance subject to a change of the analyte concentration. 
     U.S. Pat. No. 5,569,186A discloses a closed loop system, where parts of the medical system are completely implanted in the patient. 
     Another closed loop system is described in patent application WO 03047426A1, where a partially implanted glucose sensor is in communication with an injection pen, whereby the user can adjust the dose to be injected based on the glucose concentration measured by the glucose sensor. 
     The above described closed loop systems for controlling medication infusion have at least two separated units, connected through an electronic interface. 
     WO 89/01794 discloses an implantable glucose sensor for a one part integrated drug delivery system. The sensor includes a liquid infusate, which is put under pressure and flows through a catheter. One section of the catheter contains a microporous membrane, where the concentration of the glucose present in the infusate is equilibrated with a response time between several minutes up to one hour. The equilibrated infusate then flows through a chemical valve formed of a matrix containing concanavalin A, and dextran molecules. The matrix in the chemical valve changes its porosity subject to the glucose concentration present in the infusate, thus regulating the amount of infusate flowing into the body of a patient. 
     When the system, as disclosed in WO 89/01794, is employed to solely monitor the concentration of glucose in the surrounding medium, the catheter contains an additional glucose sensor, such as an enzyme electrode, a fuel cell, or an affinity sensor, whereas the chemical valve is not present. Further proposed is a stand-alone sensor, in which the pressure in the infusate is determined before and after the infusate has passed the chemical valve matrix, whereas the pressure-drop across the chemical valve matrix is inversely proportional to the glucose concentration in the equilibrated infusate. 
     In order to control the blood glucose level in a patient with diabetes, it is necessary to obtain results quickly in order to adjust the delivery of drugs. That is why response times of components within the glucose sensor are a crucial factor for a successful drug delivery program. If, as described in WO 89/01794, an equilibration region has a response time of up to one hour, and a matrix contained in a chemical valve has an additional response time, the drug administration is adjusted to a blood glucose value that is no longer present in the patient, and thus the regulation of the patient&#39;s blood glucose level will not be optimal. 
     Further, if the matrix that determines the pore size is in a fluent state, i.e. new components (such as dextran molecules) arriving with the infusate replace components that are washed away with the infusate into the patient&#39;s body, components that do not contribute to the treatment may enter the patient&#39;s body (concanavalin A is a toxic compound). The matrix is likely to have changed characteristics over time, as the replacement of new components may not take place in an evenly distributed manner (clusters are likely to occur at the entry of the matrix where the infusate with new components arrives at first). 
     Further disclosed in WO2006/103061 is a single-port device whereby body fluid can be extracted through perforations in the walls of the same cannula that transports the insulin. In this disclosure, an amperometric glucose sensor can be mounted either internally inside the walls of the cannula or externally to measure the concentration of glucose in the extracted bodily fluid. This presents several drawbacks. With the glucose sensor affixed inside the cannula or externally, a large amount of body fluid must be extracted and expelled back in the body. Also, with the bulky, complex double-lumen required for this invention, patient comfort is reduced. 
     An object of this invention is to provide a medical device for the measurement of analyte levels in a patient that is rapid and accurate. 
     Another object of this invention is to provide a medical device that enables fine and timely regulation of the analyte levels. 
     A particular object of this invention is to provide a medical device for the measurement of blood glucose levels in a patient that is rapid and accurate, and that enables fine and timely regulation of blood glucose levels. 
     Another particular object of this invention is to provide a medical device for the regulation of blood glucose levels in a patient that provides rapid, accurate and timely regulation of blood glucose levels. 
     It would be advantageous to provide a medical device for analyte measurement and/or regulation that is compact, light weight and economical to manufacture. 
     It would be advantageous to provide a medical device for analyte measurement and/or regulation that is convenient and easy to wear. 
     Objects of this invention have been achieved by providing a medical device for measuring an analyte concentration according to claim  1 , and by providing a method for measuring analyte concentration and regulating analyte levels according to claim  12 . 
     Disclosed herein is a medical device comprising a bidirectional pressure generating means configured to both draw and expel liquids through a porous membrane. The medical device further comprises a sensor adapted to measure a flow resistance, and an implantable member comprising a porous membrane. Said porous membrane reversibly changes its porosity subject to changes in analyte concentration that occur in the medium surrounding the implantable member. In particular, the analyte may be glucose and the medium surrounding the implantable member is a body fluid, in particular interstitial fluid. 
     A liquid delivered by the medical device for administration to a patient, according to an embodiment of the present invention, contains a drug capable of influencing an analyte level (for instance blood glucose level) in the patient, such that the medical device may also be used for drug administration. 
     Also disclosed is a method of measuring an analyte concentration comprising: providing a medical device comprising an implantable member with a porous membrane which changes its porosity subject to changes in analyte concentration occurring in the medium, in particular body fluid, surrounding the implantable member; sucking and expelling a discrete volume of the body fluid through said porous membrane; measuring a value correlated to a resistance against flow of said fluid through said porous membrane; and calculating an analyte concentration based on the measured value correlated to flow resistance through the porous membrane. 
     In case the analyte is glucose said method may, according to an embodiment, further comprise the step of delivering one or more drugs capable of influencing a blood glucose level in a patient according to the measured glucose concentration. 
     According to an exemplary embodiment of this invention, the pressure generating means comprises a bidirectional pump and a reservoir. The bidirectional pump sucks in body fluid and delivers accurate predefined quantities of liquid from the reservoir towards the implantable member. 
     Different types of pumps may be used, such as piston pumps, or peristaltic pumps. One pump especially preferred is described in EP 1527793A1, which is introduced herein by reference. Such a pump is both small in size, as well as capable of delivering precisely small amounts of liquid. The reservoir may be a collapsible reservoir with flexible walls, or a reservoir that has a fixed form, such as standard ampoules made of glass with a movable plug. 
     Typically, the pressure generating means may displace at least one of several fluids through the porous membrane, including expelling the fluid contained in the reservoir through the membrane, and sucking in and expelling interstitial fluid from the patient body. 
     Advantageously, the fluids are displaced in discrete (i.e. non continuous) amounts through the porous membrane. In between the displacement of discrete amounts, the glucose concentration in the porous membrane equilibrates to the concentration in the surrounding medium. When body fluid is sucked into the lumen of the implantable member by under-pressure within the lumen of the implantable member, ultra-filtration takes place and the analyte concentration within the membrane rapidly becomes the same as in the surrounding medium. Once the glucose concentration in the porous membrane corresponds to the glucose concentration in the surrounding solution, the flow resistance measured when the liquid is expelled through the porous membrane serves as a measure for the glucose concentration present in the surrounding solution. 
     In an exemplary embodiment, the sensor adapted to measure a flow resistance comprises a flexible membrane bounding a chamber, the membrane being elastically displaced upon the administration of a pre-determined volume of liquid by the pressure generating means. During its relaxation, the flexible membrane generates a pressure that conveys the liquid through the porous membrane contained in the implantable member. The flexible membrane will relax into its original position at a rate that depends on the membrane&#39;s porosity, which itself depends on the glucose concentration in the surrounding solution. The elastic membrane relaxation (or amplitude decay) rate serves as a measure of the flow resistance. In a preferred embodiment, the membrane displacement may for example be measured with a capacitor. Alternatively the membrane displacement can be measured by other means such as laser or a hall sensor. 
     In an exemplary embodiment, the porous membrane in the implantable member comprises a hydrogel, which changes its porosity reversibly subject to analyte concentration. In case the analyte is glucose, the hydrogel advantageously contains a glucose responsive hydrogel. The glucose responsive hydrogel can be produced by using lectins (in particular concanavalin A), phenylboronic acid based hydrogels and other affinity receptors for glucose, or glucose oxidase or other molecules capable of binding glucose reversibly. In the case of other analytes, suitable affinity receptors known to the person skilled in the art and specific to the analyte such as binding proteins, antibodies (see for instance Miyata et al. 1999: A reversibly antigen-responsive hydrogel. Nature Vol. 399, pp. 766-769) or others can be used. 
     The hydrogel may be held in a tubular member comprising slots. The membrane advantageously is supported by the tubular structure of the implantable member, which may be made of any firm material, such as metallic, plastic, or ceramic materials. The implantable member may be implanted only partially into the patient&#39;s body, which is also referred to as minimally invasive in this field of technology. 
     The inventors have found a hydrogel described in relation to other applications and forms of use that is suitable for use in the present invention, in the particular case where the analyte is glucose. Tang et al. report the synthesis of a mechanically and chemically stable, glucose responsive hydrogel membrane, which can be cast in a number of mechanical forms. The response to changes in glucose concentration was demonstrated to be reversible in both directions, i.e. the transitions between gel and sol phase. Furthermore, the hydrogel showed negligible leakage of Concanavalin A over extended periods. The use of two dextran species with different molecular weights allowed greater control over the gel structure, such that property changes can be restricted to changes in internal porosity of the hydrogel (Tang et al. 2003:  A reversible hydrogel membrane and delivery of macromolecules . Biotechnology and Bioengineering, Vol. 82, No. 1, Apr. 5, 2003). 
     Advantageously, concanavalin A is immobilized within the hydrogel, so that concanavalin A is prevented from entering the patient&#39;s body as it has been reported to have a toxic effect on humans. Methods to immobilize concanavalin A have been reported: Miyata et al. report the synthesis of a concanavalin A copolymerized glucosyloxyethyl methacrylate (GEMA) hydrogel, from which concanavalin A did not leak out and thus a reversible change in porosity of the porous membrane can be achieved (Miyata et al. 2004:  Glucose - responsive hydrogels prepared by copolymerization of a monomer with Con A . Journal Biomaterial Science Polymer Edition, Vol. 15, No. 9, pp 1085-1098, 2004). Kim and Park reported the immobilization of concanavalin A to glucose-containing polymers (Kim J. J. and Park K. 2001:  Immobilization of Concanavalin A to glucose - containing polymers . Macromolecular Symposium, No. 172, pp 95-102, 2001). 
     Within the scope of this invention however, the porous membrane may be made from various glucose responsive hydrogels that are per se known for glucose concentration measurement. In glucose sensors for diabetes care and insulin delivery systems (See for instance: T. Miyata, T. Uragami, K. Nakamae Adv. Drug Deliver. Rev. 2002, 54, 79; Y. Qiu, K. Park Adv. Drug. Deliver. Rev. 2001, 53, 321; S. Chaterji, I. K. Kwon, K. park Prog. Polym. Sci. 2007, 32, 1083; N. A. Peppas J. Drug Del. Sci. Tech. 2004, 14, 247-256). Hydrogels are cross-linked polymeric matrices that absorb large amounts of water and swell. These materials may be physically and chemically cross-linked to maintain their structural integrity. Hydrogels can be sensitive to the conditions of the external environment in the presence of thermodynamically active functional groups. The swelling behavior of these gels may be dependent on pH, temperature, ionic strength, or solvent composition. These properties have been used to design stimuli responsive or “intelligent” hydrogels such as glucose-sensitive polymeric systems. (See for instance: G. Albin, T. A. Horbett, B. D. Ratner, J. Controlled Release, 1985, 2, 153; K. Ishihara, M. Kobayashi, I. Shinohara Polymer J. 1984, 16, 625) 
     Glucose Oxidase-Loaded Hydrogels: 
     The combination of a pH sensitive hydrogel with glucose oxidase (GOD) has been investigated to design glucose responsive hydrogels. Glucose is enzymatically converted by GOD to gluconic acid which lowers the pH of the environment. This enzyme has been combined to different types of pH sensitive hydrogels. For hydrogels that contain polycations, such as poly(N,N′-diethylaminoethyl methacrylate), the lowering of pH leads to hydrogel membrane swelling due to the ionization of the N,N′-diethylaminoethyl side chain. When a membrane swells, molecules diffuse more easily when compared to the collapsed state. If the hydrogel membranes contain polyanions, such as poly(methacrylic acid), pores are closed at high pH value due to electrostatic repulsion among the charges on the polymer chains. After lowering of the pH, pores are open because chains collapse due to the protonation of the methacrylic acid side chains. (Y. Ito, M. Casolaro, K. Kono, I. Yukio J. Controlled Release 1989, 10, 195) 
     Lectin-Loaded Hydrogels: 
     Another approach to design glucose responsive hydrogels consists in combining glucose containing polymers with carbohydrate-binding proteins (lectins) such as Concavalin A (Con A). The biospecific affinity binding between the glucose receptor Con A and glucose containing polymers leads to the formation of a gel capable of reversible sol-gel transition in response to free glucose concentration. A variety of natural glucose containing polymers has been used such as polysucrose, dextran, and glycogen (See for instance: M. J. Taylor, S. Tanna, J. Pharm. Pharmacol. 1994, 46, 1051; M. J. Taylor, S. Tanna, P. M. Taylor, G. Adams, J. Drug Target. 1995, 3, 209; S. Tanna, M. J. Taylor, J. Pharm. Pharmacol. 1997, 49, 76; S. Tanna, M. J. Taylor, Pharm Pharmacol. Commun. 1998, 4, 117; S. Tanna, M. J. Taylor, Proc. Int. Symp. Contr. Rel. Bioact. Mater. 1998, 25, 737B; S. Tanna, M. J. Taylor, G. Adams, J. Pharm. Pharmacol. 1999, 51, 1093). Additionally some synthetics polymers with well defined saccharide residues such as poly(2-glucosyloethyl methacrylate) (PGEMA) have been investigated. (K. Nakamae, T. Miyata, A. Jikihara, A. S. Hoffman J. Biomater. Sci. polym. Ed. 1994, 6, 79.) 
     Hydrogel with Phenylboronic Acid Moieties: 
     The fabrication and handling of glucose responsive hydrogels that incorporate proteins is difficult due to the instability of biological components. To overcome this problem, synthetic hydrogels that contain phenylboronic acid moieties have been investigated. Phenylboronic acid and its derivatives form complexes with polyol compounds, such as glucose in aqueous solution. Indeed, these Lewis acids can reversibly bind the cis-1,2- or -1,3-diols of saccharides covalently to form five- or six-membered rings. (C. J. Ward, P. Patel, T. D. James, Org. Lett. 2002, 4, 477.) The complex between phenylbornic acid and a polyol compound can be dissociated in the presence of a competing polyol compound which is able to form a stronger complex. Following this idea, the competitive binding of phenylboronic acid with glucose and poly(vinyl alcohol) was utilized to construct a glucose-sensitive system. (See for instance: A. Kikuchi, K. Suzuki, O. Okabayashi, H. Hoshino, K. Kataoka, Y. Sakurai, T. Okano Anal. Chem. 1996, 68, 823-828; K. Kataoka, H. Miyazaki Macromolecules 1994, 27, 1061-1062) In this case, the presence of free glucose resulted in swelling of the hydrogel. Despite promising results, the system described above cannot be used for in-vivo monitoring of glucose concentration for two reasons: 
     1) Physiological condition: The reverse binding of phenylbornic acid with polyol was not achieved at physiological conditions (temperature, ionic strength and pH values). 
     2) Selectivity: The binding of phenylboronic acid is not selective. Indeed, phenylboronic acids can form complexes with any saccharides possessing cis-1,2- or -1,3-diols (such as glucose, fructose and galactose and lactate). In healthy individuals glucose is normally present in the range 4-8 mM while fructose and galactose, the most abundant sugars after glucose, are usually present in physiological fluids at sub-mMol levels. (R. Badugu, J. R. Lakowicz, C. D. Geddes, Analyst 2004, 129, 516). Phenylboronic acids have a much greater affinity for fructose than glucose, (J. P. Lorand, J. O. Edwards, J. Am. Chem. Soc. 1959, 24, 769) a feature that may affect the accuracy of glucose measurement. Some formulations of hydrogels with phenylboronic acid moieties have been proposed in order to improve the selectivity of the gel and ensure a better reversibility at physiological conditions. One of the most promising formulations has been presented by G. J. Worsley, G. A. Tourniaire, K. E. S. Medlock, F. K. Sartain, H. E. Harmer, M. Thatcher, A. M. Horgan, J. Pritchard Clinical Chem. 2007, 53, 1820-1826. A tertiary amine monomer (N-[3-(dimethylamino)propyl]-acrylamide) was copolymerized with 3-acrylamidophenylboronic acid to give a glucose responsive hydrogel with a specific affinity for glucose. In this case, an increase of the glucose concentration induces a contraction of the gel. The most probable explanation for the observed contraction is cross-linking of two neighboring boronic acid receptors with favorable stereochemistry by glucose to give a bis-boronateglucose complex. A film of this glucose responsive hydrogel has been loaded with light sensitive crystals of AgBr to design a holographic glucose sensor which demonstrate its ability to measure glucose in human plasma. (See for instance: S. Tanna, T. S. Sahota, J. Clark, M. J. Taylor J. Drug Target. 2002, 10 411; S. Tanna, T. Sahota, J. Clark, M. J. Taylor, J. Pharm. Pharmacol. 2002, 54, 1461) 
     The bidirectional pressure generating means displaces fluid through the porous membrane in two directions, i.e. from the body to the reservoir and from the reservoir to the body (bidirectional fluid displacement). In this bidirectional flow, body fluid (such as interstitial fluid) is first taken inside the needle and then expelled to perform the analyte measurement. Intake of interstitial fluid through the porous membrane allows reaching a steady state for the analyte-dependent flow resistance of the porous membrane more swiftly than upon relying on diffusion processes only. In case the fluid from the reservoir is a medication to be administered to the patient such as insulin, it is beneficial to control the administration rate to closely match a given dose such as a basal rate. Thus the bidirectional operation results in a zero net administration of the medication. 
     In an exemplary method, the determined glucose concentration is calibrated with a further measurement, whereas the further measurement is performed after the glucose responsive porous membrane has been rinsed with the fluid in the reservoir, such that the further measurement determines the glucose concentration present in the fluid in the reservoir. 
     This is an important advantage of the present invention, which adds to its robustness and simplicity: in order to determine a reference value to which the measurements of the analyte concentration can be compared, a single or a succession of discrete volumes of liquid are injected from the reservoir. After rinsing the membrane with the liquid from the reservoir, the porosity of the porous membrane is according to the known analyte concentration of the reservoir and thus can be used as a reference value. In order to calibrate the analyte measurement, simply the first measurement (which measures the analyte concentration of the solution surrounding the implantable member) of the above described series of measurements can be compared to the last measurement (which measures the known analyte concentration of the liquid present in the reservoir of the medical device). Thus, the analyte measurement may be adjusted against influences that may distort the measurement, such as changes in temperature, humidity, stability of electronics, material property such as aging of the hydrogel, and the like. This automatic calibration makes the medical device very simple and robust, as the measurement can be compared to a reference value by simply running a liquid delivery program as indicated above. 
     After some time not delivering any units or drawing body fluid towards the pressure generating means, the porosity of the porous membrane will reach a value that is determined by the analyte concentration surrounding the membrane. The first unit delivered afterwards will be forced through the porous membrane with a porosity determined by the analyte concentration of the surrounding solution, and thus a new measuring cycle with integrated calibration as described above may be commenced. In case it is desired to deliver small amounts of fluid from the reservoir, such as when a medication is to be delivered in small amounts, the calibration may be performed on request or automatically every few cycles (e.g., 10-20) rather than for each measurement. 
     If the medical device is also used for drug administration, advantageously a separate channel for drug delivery may be provided for instance if a large amount of medication is to be administered in a short time interval, as the flow capacity through the porous membrane is limited. This may be achieved by a second lumen in the implantable member, or by a second implantable member, or by a valve contained in the implantable member. The advantage of providing a valve is that only one pressure generating means, as well as only one implantable member, are required. For measuring the analyte level, the pressure generating means applies pressures below the opening pressure of the valve, so that the valve stays closed and fluid can flow in or out of the implantable member only through the porous membrane. If drug administration in amounts larger than is practicable through the porous membrane is required, the pressure generating means raises the pressure above the opening pressure of the valve, so that a certain amount of drug contained in the fluid from the reservoir is administered. If the analyte is glucose, it is thus possible to administer a basal rate of insulin through the pores of the porous membrane and the bolus through the valve. 
     According to an embodiment of this invention, the liquid used in the medical device is a physiological aqueous solution, which is cheap, safe, and storable for a long period of time. Such a solution is employed if the medical device shall be used for continuous glucose monitoring but not for drug administration. 
     According to another embodiment of this invention, the liquid used in the medical device comprises a drug substance with regulatory functions on the blood glucose level of the patient, such as insulin or glucagon for example. In this case, the medical device is not only suitable for glucose monitoring, but also for the administration of medical compounds comprised in the liquid. One or more drug substances may be used, employing one or more reservoirs, and one or more pumps, thus allowing administering multiple drug substances independently. 
     For the administration of a drug, one or more implantable members may be provided, or multiple channels within one implantable member. In such a variant, one implantable member is used for drug administration and may be provided with a valve, whereas a second implantable member may contain a hydrogel as described above for blood glucose monitoring. Furthermore, the implantable member containing the hydrogel may be used for delivering a basal drug rate, whereas the implantable member containing the valve may be used for delivering a bolus drug rate. 
     According to this invention, the medical device may provide a closed loop system, whereby the monitoring of a physiological parameter is linked by means of a control algorithm to the delivery of a drug that regulates said physiological parameter. However, a medical device according to this invention may also be used in a semi closed loop system, where the measurement of a physiological parameter is displayed by means of a display or other communication means, such that the patient receives information or advice concerning the drug delivery required in a given moment. Semi closed loop systems thus do not directly link monitoring and drug delivery, but allow the patient to interact and instruct or control the administration of the drug while receiving information from the monitoring unit. 
     The medical device may be able to communicate with a remote user device. This communication ability can be achieved either by cable or by wireless communication means. The remote user device may be an integral part of another device such as a wristwatch or a mobile phone, or it may constitute a separate device. Its function is to inform and warn the patient in connection with data determined by the medical device. 
     Additionally, there may further be an external alarm system, which may be in direct communication with the medical device or in communication with the remote user device. This external alarm system is suitable to inform doctors or hospitals about the condition of the patient, for example by using internet based services. 
     The medical device may advantageously comprise a disposable unit comprising the implantable member, glucose sensing device and liquid medicine reservoir, and a reusable unit comprising a graphical user interface, a signal processing circuit, and pump power supply and control means. 
     In an embodiment, a method of measuring the concentration of an analyte in interstitial fluid includes the steps of:
         providing a medical device comprising a pressure generating means, a member implantable through the skin of a patient having a lumen which is fluidically connected to the pressure generating means and an analyte responsive porous membrane between lumen and surrounding medium, a means connected with the lumen of the implantable member to measure a signal related to the pressure in the fluid path, and calculation means;   extraction of body interstitial fluid through the porous membrane by applying under-pressure sufficient to fill the lumen of the implantable member;   discharging a portion of liquid towards the analyte responsive membrane, thereby measuring the relaxation of the applied pressure, which is in relation to the analyte concentration of the surrounding medium;   discharging one or more additional portions of liquid from the reservoir through the membrane, thereby measuring the relaxation of the applied pressure, which is in relation to the known analyte concentration in the reservoir; and   calculating the analyte concentration based on the relaxation of the pressure after pumping, using the measurement at the known concentration from reservoir as reference.       

     A method of administration of a drug to control the concentration of a body fluid analyte may include the method of measurement of the concentration of analyte as described above and the further steps of calculating the required amount of the drug to control the concentration of said analyte, and applying the required amount of drug to the patient by the bidirectional pump, which applies a pressure above the opening pressure of the valve. 
    
    
     
       Further objects and advantageous aspects of the invention will be apparent from the claims and the following detailed description of an embodiment of the invention in conjunction of the drawings in which: 
         FIG. 1   a  illustrates a cross-sectional view of an embodiment of the invention comprising a pump, sensing means and an implantable member; 
         FIG. 1   b  illustrates a cross-sectional view of a medical device according to an embodiment of the invention comprising pressure generating means, sensing means and an implantable member; 
         FIG. 1   c  illustrates a perspective exploded view of the medical device of  FIG. 1   b  showing separable disposable and reusable units of the device; 
         FIG. 2   a  illustrates a cross-sectional view of an implantable member without a valve according to an embodiment of the invention; 
         FIG. 2   b  illustrates a three-dimensional view of the implantable member without a valve of  FIG. 2   a;    
         FIG. 2   c  illustrates a three-dimensional partial cross-sectional view of the implantable member without a valve of  FIG. 2   a;    
         FIG. 3   a  illustrates a cross-sectional view of an implantable member with a valve according to an embodiment of the invention, where the valve is closed; 
         FIG. 3   b  illustrates a cross-sectional view of the implantable member with a valve of  FIG. 3   a , where the valve is open; 
         FIG. 3   c  illustrates a three-dimensional view of the implantable member with a valve of  FIG. 3   a;    
         FIG. 3   d  illustrates a three-dimensional partial cross-sectional view of the implantable member with a valve of  FIG. 3   a;    
         FIG. 3   e  illustrates a cross-sectional view of an implantable member with a valve according to another embodiment of the invention; and 
         FIG. 4  illustrates a cross-sectional view of a sensor adapted to measure a flow resistance according to an embodiment of the invention. 
     
    
    
     Referring to the figures, in particular  FIGS. 1   a  to  1   c,  an embodiment of a medical device  1  according to the present invention comprises a bidirectional pressure generating means  2 , a sensor  3  adapted to measure flow resistance, and an implantable member  4  with a porous membrane having a porosity subject to an analyte concentration. 
     The bidirectional pressure generating means  2  is configured to draw body fluid, in particular interstitial fluid, through the porous membrane towards the sensor  3 , and to expel the drawn body fluid, where the flow resistance subject to the porosity of the membrane in the implantable member  4  is measured. Besides measuring the flow resistance, the sensor  3  may be configured to convey liquid towards the implantable member  4  for delivery of a liquid stored in a reservoir of the device, which may be a liquid medicine for regulation of the concentration of analyte in a patient. 
     The medical device  1  is preferably attached to the skin of the patient, by using an adhesive base on the lower surface  5  of the medical device  1 . The connection between the medical device  1  and the patient may be configured such that the connection lasts for several days, but may be removed from the skin at any time. 
     The design of the medical device  1  according to this invention is flexible. In a preferred embodiment, the medical device  1  is flat in order to ensure convenience in use, as it is intended to be worn below the clothing of the patient. 
     A preferred embodiment of bidirectional pressure generating means  2  with a reservoir  20  possessing fixed walls is shown. The reservoir  20  may be a glass ampoule, which are frequently used as standards in insulin delivery devices. It should be noted that the inner volumes of the implantable member and of the sensor are much larger than the volume of body fluid drawn in from the body so that body fluid is not aspirated into the reservoir and does not contaminate the reservoir liquid. 
     The fluid is further conveyed through the sensor by a bidirectional pump  22  ( 22   a ,  22   b ). The bidirectional pump displaces the liquid in precise and interrupted units. 
     The reservoir  20  may alternatively be made of a flexible material (not shown). Flexible walls of the reservoir, which may be made of plastic material, allow pumping the liquid out of the reservoir without applying strong suction. A small piston pump as described in European patent application EP 1527793A1, may for instance be employed. Flexible reservoirs have the advantage that they may be provided in various shapes, such that the reservoir best fits into the medical device. This is of importance as the size of the medical device preferably is minimized for optimal wearing comfort. 
     Referring to  FIG. 1   c,  the medical device may advantageously comprise a disposable unit  36  and a reusable unit  38 . The disposable unit comprises the implantable member  4 , a portion  3   a  of the flow resistance sensor  3 , liquid medicine reservoir  20 , and a portion  22   a  of the bidirectional pump  22 . The reusable unit  38  comprises (optionally) a user input and display interface (not shown), a signal processing circuit, a power supply, a complementary portion  3   b  of the flow resistance sensor  3 , which includes sensor electronics, for example capacitor electrodes, and a complementary portion  22   b  of the bidirectional pump  22 , which includes pump drive means, for example electromagnets. The disposable and reusable units are separable, whereby the disposable unit can be removed after use from the reusable unit and replaced with a new disposable unit. Costly control and user interface components can thus be mounted in the reusable unit and preserved for multiple usage to reduce waste and save costs, without compromising on the safety of use (e.g sterility) of the components in the liquid medicine circuit (the implantable member and liquid medicine reservoir) that should be disposable. 
     An exemplary embodiment of a measurement cycle includes:
         Displacement of body fluid such as interstitial fluid in the direction from the body towards the sensor through the porous membrane (ultrafiltration phase);   Displacement of a defined volume of fluid in the direction from the reservoir towards the body through the porous membrane and measurement of the flow resistance through the porous membrane by means of the flow resistance sensor (body analyte concentration measurement phase), whereby the sucked in body fluid is expelled;   Displacement of one or several cycles of a defined volume of reference fluid from the reservoir through the porous membrane, in the direction from the reservoir towards the body (porous membrane rinsing phase);   Displacement of one more cycles of a defined volume of reference fluid from the reservoir through the porous membrane, in the direction from the reservoir towards the body and measurement of the flow resistance through the porous membrane by means of the flow resistance sensor (reference analyte concentration measurement phase).       

     In case it is not desirable to administer large amounts of fluid from the reservoir or a reference measurement is not necessary at each measurement cycle, the last two steps may be omitted or performed intermittently. 
     In order to determine an analyte concentration in the body, a discrete volume of fluid, for example 50 nl, is thus first displaced through the porous membrane in the direction from the body towards the reservoir. This process corresponds to an ultrafiltration process of interstitial fluid through the porous membrane. The fluid displacement may be performed at low speed to avoid the generation under pressure and of air bubbles. 
     A benefit of actively sucking interstitial fluid through the porous membrane instead of solely relying on a diffusion (dialysis) process of the analyte through the porous membrane is the shorter time required to reach an equilibrium or steady state for the property to flow resistance of the membrane. Another benefit is the smaller porous area required to exchange analyte inside the implantable member as no dialysis zone is required to achieve steady-state analyte concentration in the body and in the implantable member. 
     In the second step, a discrete volume of fluid, for instance 50 nl, is expelled by the pressure generating means through the porous membrane into the body. The flow resistance of the fluid through the porous membrane provides a measure of the analyte concentration, characterized by the relaxation of the flexible membrane of the flow resistance sensor. 
     In order to determine a reference value to which the measurements of the analyte concentration can be compared, a succession of discrete volumes of liquid are injected, for example 50 nano liters separated by 3 seconds, i.e. as soon as the flexible membrane has reached its relaxed state, a new discrete volume of liquid is delivered. Thus, a succession of fluid resistance measurements is performed rapidly, without long pauses in-between the measurements. After a number of pumping steps are delivered, for example 5 steps, the porosity of the porous membrane reaches a value that is determined by the analyte concentration of the liquid contained in the medical device, which is a known value and thus can be used as a reference value. The first step can also be performed after sucking body fluid inside the implantable member and be used to measure the glucose concentration in the solution surrounding the implantable member, the second step will replace for example 80 percent of the equilibrated liquid in the needle lumen (in this example, the pump volume is equal to the active volume in the needle), and after the third step, only about 3 percent of the equilibrated liquid remains in the responsive region of the needle. Therefore, a small number of portions pumped through the porous membrane, e.g. 5 steps, rinse the porous membrane and are enough to obtain a reference value for calibration. 
     In order to calibrate the analyte measurement, the first measurement (which measures the analyte concentration of the solution surrounding the implantable member) of the above described series of measurements can be compared to the last measurement (which measures the analyte concentration of the liquid present in the medical device). 
     Typically, a new measuring cycle is not required more frequently than every five to ten minutes. The lag times of the measurement cycle will thus not unduly restrict the application of the present invention for continuous glucose monitoring, especially in the view of the typical physiological lag time of 8-17 min. between interstitial and blood glucose as is commonly accepted in the literature. 
     Referring to  FIGS. 2   a  to  2   c , an embodiment of the implantable member  4  is shown. The implantable member has the shape of an injection needle, and is divided into two sections: A non-responsive part  6 , and a responsive part  7 . The wall of the non-responsive part is closed, and may be provided in a flexible material such as plastic in order to enhance the wearing comfort for the patient. The wall of the responsive part  7  contains holes  8 , which are filled with a porous membrane  28 . The fraction of the perforation surface area over the total surface area in the responsive part is preferably between 0.1 and 0.5 in order to obtain both enough surface area for the porous membrane as well as to obtain a needle that is robust enough to be introduced into a patient&#39;s skin. For instance, the fraction of the perforation surface area is between 0.2 and 0.3. The needle may be between 5 and 30 mm long, and have a diameter  30  of between 0.1 mm and 1.0 mm. The needle may be made of plastic material, but it may also consist of any other suitable material such as metallic materials, or ceramic materials. 
     The length of the needle part that is below the skin surface of the patient typically measures between 5 mm and 20 mm, whereas the responsive part measures 2 mm to 10 mm and the non-responsive part measures 3 mm to 10 mm. The thickness of the needle wall measures between 10 μm and 40 μm, and most preferably between 20 and 30 μm. The diameter of the needle typically measures 0.3 mm, defining the volume of the lumen  10  of the needle. The needle diameter and the length of the responsive part may be adapted to the pump volume (or vice versa) in order to ensure a convenient calibration method as described previously. 
     When filling the holes  8  with the porous membrane  28 , a spacer may be inserted coaxially within the needle, the spacer having a slightly smaller diameter than the lumen diameter  31 . After the porous membrane has been applied, the spacer is removed, and the lumen will then have a slightly smaller diameter  32 . 
     As the concentration of analyte in the solution surrounding the implantable member  4  changes, the porosity of the porous membrane  28  contained in the holes  8  changes. If the analyte is glucose, preferably the porous membrane contains immobilized concanavalin A and dextran molecules to form a hydrogel, which may be held by an additional supportive structure, such as nylon gauze support with a pore size of 0.1 mm (Tang et al. 2003:  A reversible hydrogel membrane and delivery of macromolecules . Biotechnology and Bioengineering, Vol. 82, No. 1, Apr. 5, 2003). Other glucose responsive compounds, as described previously, may however also be used. 
     The hydrogel is capable of reversibly changing its structure depending on the glucose concentration present. Free glucose molecules competitively and specifically bind to immobilized concanavalin A molecules. A raise in glucose concentration will raise the number of concanavalin A binding sites occupied with glucose molecules and thus enlarging the size of the pores present in the hydrogel. If the glucose concentration decreases, glucose bound to concanavalin A will be replaced by dextran molecules which form an interlinked web-like structure, thus reducing the size of the pores present in the hydrogel. 
     Given a change in glucose concentration in the solution surrounding the implantable member 4 between 0 mmol/l and 30 mmol/l (the normal bandwidth of glucose concentration in the human blood is 4 mmol/l to 8 mmol/l), the effective pore size in the porous membrane would typically range from 10 nm to 100 nm in diameter. 
     Referring to  FIGS. 3   a  to  3   d , another embodiment of the implantable member  4  is shown. For the administration of medication, a valve  14  may be provided within the implantable member. The valve is disposed proximate the free end or tip of the implantable member. A support tube  9  is provided containing holes  8  in a responsive part  7  of the implantable member. A porous membrane containing a glucose responsive hydrogel  28  as previously described is mounted into the holes  8  of the support structure  9 . 
     In order to allow the measurement of the flow resistance through the porous membrane, the valve  14  stays closed up to a critical pressure. When medication is to be administered, pressure generating means create a liquid pressure in the implantable device that exceeds the critical pressure so that the valve is opened and medication can be administered to the patient. Said critical pressure preferably is significantly higher than the pressure used for measuring flow resistance through the porous membrane. Typical values for measuring flow resistance range from 50 to 100 mbar, and thus typical critical pressure values in the valve range from 100 to 400 mbar. These numbers are simply for illustration purpose, other combinations of values that follow the same principle as described above are also contained within the spirit of this invention. 
     The valve  14  may comprise a pressure valve as shown in  FIGS. 3   a  and  3   b  which may be made of elastic material (e.g. rubber). Preferably, the pressure valve comprises opposed elastic protuberances abutting each other under a pre-determined elastic pressure, whereby liquid at a pressure upstream of the valve greater than a pre-determined threshold, forces the protuberances apart to allow outflow of liquid. The valve may however also comprise other constructions, such as a flap valve, or spring and bullet valve, or any other kind of valve that fulfills the required function. 
     Referring to  FIG. 3   e , yet another embodiment of an implantable member  4  is shown, comprising a support structure, tube or sleeve  9  provided with holes  8  in a responsive part  7  of the implantable member and a glucose responsive porous membrane  28 ′ in the form of a tube inserted in the support structure. The glucose responsive porous membrane tube  28 ′ may thus be made separately from the support structure and assembled thereto. The tube  28 ′ may comprise a glucose responsive hydrogel, as previously described, alone or incorporated in or on a non-glucose-responsive porous substrate. The substrate may advantageously comprise a cellulose fibre. The pore size of the cellulose fibre substrate is preferably in the range 10-50 nm, the wall thickness preferably 5-50 um, more preferably 20-30 um. The support sleeve  9  may be made for instance of a steel or titanium alloy with openings  8  of average diameter 20-1000 um, preferably 50-200 um. As described in relation to the other embodiments, for the administration of medication, a valve  14  may be provided within the implantable member. The valve  14  may be used for a bolus administration, whereas a basal rate may be administered through the porous membrane and/or through the valve. 
     Referring to  FIGS. 1 and 4 , a preferred embodiment of the sensor  3  is shown. A precise amount of interstitial fluid is sucked drawn by the bidirectional pressure generating means through the porous membrane by reverse pumping of the liquid in the sensor towards the reservoir. Subsequently, a precise amount of reservoir fluid is forward pumped towards the porous membrane thus expelling the sucked in body fluid and optionally a certain volume of reservoir liquid. During the forward pumping, fluid enters the sensor chamber  17  at the influx channel  15  and displaces a flexible membrane  18  comprised in the flow resistance sensor  3 . Depending on the flow resistance subject to the porosity of the porous membrane in the implantable member, the decay (i.e. relaxation) behavior of the flexible membrane varies. The higher the flow resistance through the porous membrane, the longer it takes for the flexible membrane to reach its original position after displacement caused by the liquid delivered by the pressure generating means. During the return of the flexible membrane  18  back to its rest position, liquid leaves the sensor chamber through the outlet channel  16  and thus the liquid is conveyed towards the implantable member. 
     In a variant, it is possible to measure the analyte concentration during the reverse pumping (sucking in body fluid), whereby the flexible membrane  18  is displaced inwardly towards the sensor chamber  17 . Depending on the flow resistance subject to the porosity of the porous membrane in the implantable member, the decay (i.e. relaxation) behavior of the flexible membrane varies. 
     To measure the displacement of the flexible membrane  18 , advantageously a capacitor  19  is employed. A conductive coating, e.g. a gold coating, is provided on the upper surface of the flexible membrane forming a first capacitor electrode  12 , another fixed position capacitor electrode  11  being placed at a certain distance over the flexible membrane. The capacitance value between the electrodes is representative of the amplitude ( 24 ,  25 ) of displacement of the flexible membrane. Advantageously, a reference capacitor electrode  13  is provided in order to adjust the measured value in case of an external interfering signal. 
     The medical device may be provided with more than one pump and liquid reservoir system to administer a second or further liquid medicine, for example glucagon in conjunction with insulin, such that the device may function as an artificial pancreas with blood glucose regulating and counter-regulating medicines. As illustrated in  FIG. 1   a,  a second pump system  22 ′ may be connected to the implantable member. The second pump system  22 ′ may be constructed in the same manner as the pump  22 , although without the flow resistance sensor  3  to minimize the dead volume in the path of the second pump system  22 ′, and disposed adjacent the pump  22 . 
     As mentioned above, the invention may be used of the sensing of analytes other than glucose by using a porous membrane responsive to the specific analyte to be measured.