Abstract:
An implanted sensing device ( 1 ) for monitoring an analyte (e.g. blood-glucose) includes a non-toxic macromolecular material ( 2 ) encapsulated within an envelope ( 3 ) of bio-compatible semi-permeable membrane. A sensor ( 4 ) responds to change of a physical property (e.g. viscosity) of the material ( 2 ) when the analyte contacts the material ( 2 ), to signal the change to a measurement circuit ( 5 ) that together with the sensor ( 4 ) and a transponder ( 6 ) are included within the envelope ( 3 ). The transponder ( 6 ) is interrogated externally of the implanted sensor ( 1 ) by an interrogation unit ( 7 ) to transmit measurement data for processing and storage. The interrogation signal is utilized within the device ( 1 ) to power the circuit ( 5 ) and transponder ( 6 ) and conveys data to the device for re-calibration or resetting of signal-datum values to compensate for aging or drift.

Description:
BACKGROUND OF THE INVENTION 
     This invention relates to sensing devices and systems, and is particularly concerned with sensing devices and systems for use in monitoring the presence or activity of specific chemical analytes. 
     SUMMARY OF THE INVENTION 
     According to one aspect of the present invention a sensing device for use in monitoring the presence or activity of a specific chemical analyte, comprises an enclosure having a membrane-wall that is semi-permeable to said chemical analyte, macromolecular material contained within the enclosure, said material exhibiting physical change in response to contact with said chemical analyte, a sensor contained within the enclosure to respond to said physical change, and means for transmitting a signal from said sensing device dependent on the response of said sensor. 
     The sensing device according to the invention is especially applicable for monitoring the presence or level of activity of a specific bio-chemical, drug or other analyte in vivo, within the body of a human or animal patient. In this context the sensing device may be provided for implant subcutaneously or otherwise within the patient so that the particular analyte can be sensed as it permeates the semi-permeable wall of the device. 
     The said material may be such as to exhibit change in a Theological parameter thereof in response to the analyte. The parameter may be viscosity, and the material, which may be for example a mixture of concanavalin A and ficoll, may be responsive to the presence of glucose to exhibit a change of its viscosity or other parameter. In the context of response to glucose, the sensing device of the invention has particular application for in vivo monitoring of the blood-glucose of diabetic patients. 
     The means for transmitting a signal from the sensing device of the invention may be contained within said enclosure, and said enclosure may be in the form of a capsule wholly or substantially wholly of semi-permeable membrane. Moreover, the means for transmitting a signal from the sensing device may include means for deriving digital data in accordance with the response of the sensor and for transmitting this from said sensing device. 
     According to another aspect of the present invention a sensing system for use in monitoring the presence or activity of a specific chemical analyte, comprises a sensing device and interrogating means that is operable for interrogating said sensing device, said sensing device comprising an enclosure having a membrane-wall that is semi-permeable to said chemical analyte, macromolecular material contained within the enclosure, said, material exhibiting physical change in response to contact with said chemical analyte, a sensor contained within the enclosure to respond to said physical change, and means operable in response to interrogation of said sensing means by said interrogating means for transmitting a signal dependent on the response of said sensor, to said interrogating means. 
     The signal dependent on the response of said sensor may be transmitted to said interrogating means by electromagnetic-wave transmission. Similarly, interrogation of said sensing means may be effected by electromagnetic-wave transmission from said interrogating means. In this latter case, electrical power for the means operable in response to interrogation of said sensing means, may be derived from the electromagnetic-wave interrogating transmission. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     A sensing system, and sensing devices for use therein, all according to the present invention will now be described, by way of example, with reference to the accompanying drawings, in which: 
     FIG. 1 is a block schematic diagram illustrating the sensing system according to the present invention; 
     FIG. 2 is a sectional view of a sensing device according to the invention, that forms part of the system of FIG. 1; 
     FIG. 3 is a block-schematic representation of the electrical circuitry of the sensing device of FIG. 2; 
     FIG. 4 is a block-schematic representation of electrical circuitry that may be used as an alternative to the electrical circuitry of FIG. 3 for the sensing device of FIG. 2; 
     FIG. 5 provides a block-schematic representation of the electrical circuitry of a transponder of the sensing device of FIG. 2; 
     FIG. 6 provides a block-schematic representation of the electrical circuitry of an interrogator unit that forms part of the sensing system of FIG. 1; 
     FIG. 7 is illustrative of a practical implementation of the sensing system of FIG. 1; and 
     FIG. 8 is illustrative of a form of sensing device according to the invention that may be used as an alternative to that of FIG. 2 in the system of FIG.  1 . 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The sensing system to be described is for use for in vivo monitoring of the presence or level of activity of a specific bio-chemical, drug or other analyte within a patient. 
     Referring to FIG. 1, the sensing system includes a sensing device  1  that is implanted subcutaneously in the patient. The sensing device  1  includes a non-toxic macromolecular mixture or compound  2  encapsulated within an envelope  3  of bio-compatible semi-permeable membrane. The mixture or compound  2  has the characteristic that its physical properties change when it is in the presence of the relevant analyte, and the change in the physical condition of the mixture or compound  2  that in this respect takes place when the analyte permeates the wall of the envelope  3  is sensed by a sensor  4 . The sensor  4  is encapsulated with the mixture or compound  2  within the envelope  3 , and supplies an electric signal dependent on the sensed physical-change to a measurement circuit  5 . 
     The circuit  5 , like the device  4 , is encapsulated with the mixture or compound  2  within the envelope  3 , and from the signal supplied by the sensor  4  derives a digital-data signal that provides a measure of the physical condition of the mixture or compound  2  sensed. This signal is supplied to a radio-frequency transponder  6  which is also encapsulated with the mixture or compound  2  within the envelope  3 . 
     The transponder  6  is interrogated externally of the implanted sensing device  1  by actuation of an interrogation unit  7 . The measurement data derived by the circuit  5  is in consequence transmitted from the transponder  6  and this data as received by the unit  7  is either processed and stored within the unit  7  locally, or communicated to a data-acquisition system (not shown). The activity of the chemical analyte within the patient can be determined from the measurement data received from the sensing device  1  and can thus be continually or periodically monitored by the system of the invention. Moreover, suitable alarm and/or other action (for example, administration of a drug) can be taken when the activity of the analyte makes this desirable or necessary in the context of the monitoring operation. 
     The sensing device of the invention has particular application in the monitoring of blood-glucose in diabetic patients. Attempts have been made to develop an in vivo glucose sensor for this purpose, focused on adapting known biosensor-technology. But these attempts have been largely frustrated by problems of bio-compatibility, drift, instability, fouling, infection and electrical interconnection with the implant. However, the principal problems arise from the inherent instability of any enzyme-based system which limits the potential life of the sensing device and the design of a reliable interface between the indwelling sensing device and its associated, external electronics. These problems can be to overcome to a major extent with the sensing system of the present invention in that the enclosure may be bio-compatible and contain a non-toxic macromolecular mixture or compound responsive by physical rather than bio-chemical change to the blood-glucose level of the patient. The physical response of the macromolecular mixture or compound is reversible so that the sensing device can have a very long operational life. 
     Although described.above as utilised as an implant, the sensing device may be used in other contexts where it is desirable or necessary to provide for monitoring the presence or activity of a specific chemical, using self-contained sensing without the necessity for external electrical or other connection with the sensing device. 
     The mixture or compound  2  has an important role in the sensing system and device of the invention in that it exhibits a physical change in response to the analyte that is being monitored. By way of example, the material  2  may be a mixture of concanavalin A and ficoll which exhibits a rheological change to glucose. Other suitable mixtures or compounds may be used, and for longevity and optimum performance may be custom synthesised using molecular-design or molecular-imprinting methods. The involvement of non-proteinaceous synthetic recognition molecules may be found preferable. 
     The physical change of the mixture or compound  2  sensed by the sensor  4  within the sensing device  1  may, as indicated above, be rheological, and may be specifically change of viscosity. By way of alternative, the physical change sensed may be related to electrical conductivity, density, volume, pressure or luminosity or fluorescence. Luminosity or fluorescence may be sensed by the sensor  4  during stimulation of the mixture or compound  2  by visible or non-visible light incident on the device  1  from an externally-located laser. A similar stimulation of a sensed physical property may be achieved using acoustic radiation. 
     The semi-permeable envelope  3  may be fabricated of metallic, semi-synthetic or natural materials, examples of which are sintered titanium, polyvinyl chloride, silicone rubber, nylon and cellulose derivatives. For in vivo applications of the sensing device  1 , the membrane is desirably treated with a chemical such as phosphoryl choline, or derivatives, to minimize cell or protein adhesion. 
     The sensing system of FIG. 1 may be used specifically for monitoring blood-glucose levels in a patient suffering from diabetes, and the sensing device of the system may then take the form shown in FIG.  2 . 
     Referring to FIG. 2, the sensing device in this case has the form of a thin capsule  11  containing for example a mixture of concanavalin A and ficoll, as the macromolecular material  12 . The mixture or compound  12  is encapsulated within a continuous, seamless wall  13  formed wholly or substantially wholly of semi-permeable membrane. A sensor  14  immersed in the mixture or compound  12  within the capsule  11  is connected through the wall of an environmental housing  15  that contains the electronic circuitry of the sensing device  11 . In particular, the housing  15  incorporates a substrate  16  to which the sensor  14  is coupled and which carries measurement and transponder circuitry  17  together with the transponder antenna  18  and a charge-storage capacitor  19 . 
     The capsule  11  is implanted subcutaneously in a patient to respond to change in his/her blood-glucose level. The change of viscosity that occurs in the mixture or compound  12  in response to the change in glucose level permeating the semi-permeable wall  13 , is sensed by the sensor  14  and communicated to the circuitry  17 . In particular, for a concanavalin A—ficoll mixture a large change in viscosity (for example, 1 to 10 mM) is exhibited between the minimum and maximum levels of a patient&#39;s blood-glucose level. The output of the sensor  14  in response to the change is translated within the circuitry  17  into data representative of the viscosity and, correspondingly, of the blood-glucose level, for transmission to the appropriate interrogation unit via the antenna  18 . 
     The sensor  14  in this example may be of a kind which in response to change of viscosity of the mixture or compound  12 , exhibits a change of piezo-mechanical coupling efficiency. This change can be used to create a voltage or phase change in an applied signal. In the case in which phase-change is utilised, the circuitry  17  may take the form illustrated in FIG.  3 . 
     Referring to FIG. 3, an oscillatory waveform is applied to the sensor  14  from an oscillator  20 , and the output signal of the sensor  14  is supplied via a voltage-buffer stage  21  to a phase detector  22  for comparison with the output of a voltage-controlled oscillator  23  in a phase-locked loop that includes a loop-filter  24 . The resultant output signal of the filter  24  is supplied with the output signal of the oscillator  20  to a signal processor  25  to derive the relevant data from the detected phase shift between the two signals, and to supply this to a transponder circuit  26 . 
     Electrical energy to power the electronics of the capsule  11  is derived within the transponder circuit  26  without the need for the capsule  11  to include a battery. The required power is derived from the interrogation signal transmitted from the interrogation unit  7  (FIG.  1 ). This signal received via the antenna  18  charges the storage capacitor  19  and it is from this charge that the circuitry  17  is powered to gather the blood-glucose measurement data and transmit it via the antenna  18  for external use. 
     In an alternative construction of the capsule  11 , the sensor  14  used is of a form that utilises the transmission of acoustic waves within the mixture or compound  12 . The form of sensor  14  and circuitry  17  used in this case is shown in FIG.  4  and will now be described. 
     Referring to FIG. 4, the sensor  14  in this case comprises spaced piezoelectric transducer elements  30  and  31  immersed in the mixture or compound  12 . The element  30  is energised from an oscillator  32  and the consequent vibrations transmitted via the mixture or compound  12  are detected by the element  31 . The resultant signal derived by the element  31 , which can be readily correlated in amplitude and frequency with viscosity of the mixture or compound  12 , is applied via a voltage buffer stage  33  for comparison with the output signal of the oscillator  32 , in a comparator  34 . The output signal of the comparator  34  is utilised within a processor  35  to derive in relation to the output signal of the oscillator  32 , the desired measurement data for indicating blood-glucose level. Data stored in a non-volatile memory  36  sets the datum value against which the measurement data is derived for transmission by a transponder circuit  37 . 
     The transponder  6  of FIG. 1 (or specifically the transponder units  26  and  37  of FIGS. 3 and 4 respectively) may be constructed as illustrated in FIG.  5 . 
     Referring to FIG. 5, the radio-frequency interrogation signal is received in the antenna  18  within a resonant circuit that is formed by an antenna coil  40  with shunt capacitor  41 . The oscillatory output across the coil  40  is supplied via a rectifier  42  to charge the storage capacitor  19  in providing electrical power to the electronics of the capsule  11  via a regulator  43 , and is also supplied via a comparator  44  to a demodulator  45 . The demodulator  45  derives data that is transmitted to the transponder  18  in the interrogation signal, and supplies this to a processor unit  46 . This data is used within the processor unit  46  for protocol synchronisation and to set and/or re-set datum levels for the measurement data signalled by the measurement circuit  5  from the sensor  4  (FIG.  1 ). 
     The data derived by the processor unit  46  is stored in a memory  47 . This stored data is read out and under control of the processor unit  46  is combined with other data in a MUX unit  48  for transmission via a modulator  49  and coil  50  of the antenna  18 . Transmission is controlled by the processor unit  46  in dependence upon power-supply operation as determined by a power on/reset unit  51 . 
     The interrogation unit  7  of the system of FIG. 1 may be as illustrated in FIG.  6 . 
     Referring to FIG. 6, the transmission of the interrogation signal to the sensing device  1  is effected via an antenna  60  that is supplied with the signal from a modulator  61  via a power-amplifier  62 . The modulator  61  modulates the transmitted radio-frequency signal with data that is derived from a control unit  63  that includes digital storage. This data is derived within the unit  63  or within a data-acquisition station (not shown) to which it may be connected, in dependence upon the data that is to be transmitted by the sensing device  1  and the datum levels to which measurement is to be carried out therein. 
     The data signals received by the antenna  60  from the sensing device  1  are amplified in an amplifier  64  and demodulated in a demodulator  65  for supply to the unit  63 . A comparator  66  is active to derive control input signals for the unit  63  dependent upon the transmitted and received signals. 
     The interrogation unit  7  of FIG. 1 may be implemented in the form of a unit that is worn on the wrist in the manner of a wristwatch. This is illustrated in FIG. 7 where a capsule  70  of the same form as capsule  11  of FIG. 2 is to be understood as having been implanted subcutaneously in the wrist of a patient, and the interrogation unit  71  in this case has straps  72  for holding it to the wrist immediately over the implanted capsule  70 . 
     Referring to FIG. 7, an antenna coil  73  is incorporated in the base of the unit  71  beneath the associated electronic circuitry  74 . The unit  71  also incorporates an LCD display  75  and an audible-alarm facility  76  together with push-buttons  77  for setting data.into the circuitry  74  and display  75 . 
     Although there is material advantage in providing the electronic circuitry for deriving the measurement data and its transmission and reception, within the same envelope as the mixture or compound and sensing device, this is not necessarily the case. In particular, as illustrated in FIG. 8, a sensing device comprises two capsules  80  and  81 , the capsule  80  having a semi-permeable wall  82  and containing the macromolecular mixture or compound  83  and immersed sensor  84 . The wall  85  of the capsule  81  on the other hand is non-permeable, and contains components  86  to  89  corresponding directly to the components  16  to  19  respectively of the integrated capsule  11  of FIG.  2 . Electrical connection between the sensor  84  and the circuitry  87  is effected by insulated conductors  90 .