GB2383846A

GB2383846A - Passive biological sensor

Info

Publication number: GB2383846A
Application number: GB0200001A
Authority: GB
Inventors: Gavin V Wheeler; Timothy S Norris
Original assignee: Sentec Ltd
Current assignee: Sentec Ltd
Priority date: 2002-01-02
Filing date: 2002-01-02
Publication date: 2003-07-09
Also published as: GB0200001D0

Abstract

The invention concerns a passive biological sensor 10 comprising: an analyte-sensitive polymer mass 30 arranged so that one or more of its physical characteristics are modifiable in response to concentration of an analyte applied to the polymer mass 30; and a non-electronic sensing assembly 20 for detecting the one or more characteristics of the polymer mass 30 to provide a measure of concentration of the analyte when remotely interrogated. The polymer may be a hydrogel and the sensing assembly may be a magnetostrictive rod or magnetic paddle. The sensor may be remotely interrogated by a processing unit 120. A magnetic field 170 may be applied and the resonant frequency of the rod 20 measured. The frequency depends on, for example, the viscosity or stiffness of the hydrogel 30.

Description

PASSIVE BIOLOGICAL SENSOR Field of the invention The present invention relates to passive biological sensors, for example biological sensors devoid of electronic circuits incorporated therein. Moreover, the invention also relates to a method of measuring analytes within biological systems using the sensors. Furthermore, the invention also relates to apparatus suitable for interrogating the passive biological sensors.

Background to the invention Polymers, for example hydrogels, are known to be responsive when exposed to specific types of analyte ; hydrogels are three-dimensional networks of hydrophilic insoluble polymers. Moreover, many hydrogels are biocompatible which renders them useable within living systems.

For example, in a published United States patent application no. US 6,201, 980, polymers are described which are responsive to analytes such as sugars, urea, ammonia, enzymes, and narcotic substances; for example, the sugars include glucose.

Moreover, the analytes may be ionic species, namely electrolytes, such as hydrogen ions (as in pH measurement), alkaline earth ions, alkali metal ions, and transitional metal ions.

In a scientific publication by Kikuchi et al. in a journal "Analytical Chemistry" Vol. 68, no.

5, March 1996, there is described a glucose-sensitive hydrogel having a chemical structure poly (DMAA-co-MAPB-co-DMAPAA-co-BMA)-PVA ; the hydrogel is capable of exhibiting a reversible volumetric expansion in response to changes in the concentration of a glucose solution applied thereto. The volumetric expansion can be considerable and therefore is easily measurable. For example, a change in glucose concentration of 200 mg/dL can result in a 10% swelling in linear dimensions of the hydrogel.

In a scientific article in the journal Nature 399, pages 766 to 769,1999, Miyata et al. describe a reversibly antigen-responsive hydrogel.

Similarly, Lee and Park in the Journal of Molecular Recognition 9, pages 549 to 557, 1996 describe the synthesis and characterisation of sol-gel phase-reversible hydrogels sensitive to glucose.

It is further known that implantable biological sensors can be fabricated for sensing body analytes. Such sensors comprise analyte-responsive polymers as essential sensing elements. For example, in the United States patent no. US 6, 201,980, there is described a subcutaneously-implantable, biocompatible, hermitically-sealed sensor comprising a sensor electronic circuit in electrical connection to a mechanically-variable plate capacitor. The sensor and its associated variable capacitor are packaged together within a housing. The housing is a pleated, expansible, bellows-shaped cavity including a deformable base. Moreover, the bellows are arranged to function like a spring capable of exhibiting a reversible and predictable displacement for a given force created by a mass of analyte-responsive polymer included within the housing which is in communication via a mesh with extracellular fluid. The mesh performs a function of mechanically constraining the analyte-responsive polymer.

In operation, the mass of polymer changes size in response to analyte concentration and causes the plates of the variable capacitor to move thereby changing its capacitance.

The change in capacitance is sensed by the sensor circuit and relayed, for example by inductive coupling, to external electronic monitoring circuits.

The inventor has appreciated that the subcutaneous implantation of electronic circuits is not an ideal approach for analyte-responsive sensors comprising analyte-responsive polymers as essential sensing elements. A first problem arises with supplying power to the subcutaneous circuit; such power supply entails one or more of implanting a battery subcutaneously and arranging for inductively-coupled power transfer. A second problem concerns reliability for subcutaneously-mounted electronic circuits, in that such circuits need to be of high-reliability because repeated access to such circuits for maintenance purposes, for example for exchanging exhausted batteries, can risk infection being Introduced ; similar considerations pertain to implanted pace-makers to stimulate heart

function. The inventor has thus appreciated that alternative methods and apparatus for sensing changes in the physical properties of analyte-responsive subcutaneouslymounted polymers is required.

Summary of the invention According to a first aspect of the present invention, there is provided a passive biological sensor, characterized in that the sensor comprises: (a) polymer means arranged so that one or more of its physical characteristics are modifiable in response to concentration of an analyte applied to the polymer means; and (b) non-electronic sensing means for detecting the one or more characteristics of the polymer means to provide a measure of concentration of the analyte when remotely interrogated.

The invention is of advantage in that the non-electronic sensing means does not need a electrical power supply provided thereto to function, thereby potentially rendering the sensor at least one of: more reliable, simpler in construction and more robust.

I Preferably, the polymer means is a hydrogel responsive to the analyte. Hydrogels are known to be responsive to analyte concentration, certain types of hydrogel providing considerable physical response.

Preferably, the hydrogel is responsive to one or more of glucose, thyroxin, hormones, narcotics, trace insecticide, fertilizer, antibiotics, pathogens and/or their metabolic byproducts.

Preferably, the polymer means includes the sensing means therein. Such an arrangement is of advantage in that the sensing means is shielded directly from the analyte and/or a biological system in which the sensor is implanted.

Preferably, the sensing means comprises a magnetic device arranged to couple changes in one or more physical characteristics of the polymer means into corresponding magnetic characteristic changes in the sensing means, thereby rendering

the sensing means susceptible to remote magnetic interrogation. Arranging for the sensing means to be magnetically responsive enables the sensor to be remotely interrogated through plant and/or animal tissue, thereby rendering the sensor susceptible to interrogation when implanted into biological systems.

Preferably, the magnetic device comprises a magnetostrictive element susceptible to being excited into resonance by a remote alternating magnetic field, the resonance being susceptible to modification in response to changes in one or more physical characteristics of the polymer means in turn dependent upon analyte concentration to which the polymer means is exposed. Use of a magnetostrictive element within the sensor renders the sensor simple in construction and potentially therefore highly reliable.

Preferably, the magnetostrictive element is an elongate element susceptible to resonating along its associated elongate axis.

Alternatively, the magnetic device is preferably a flexurally-mounted member susceptible to vibrating when excited by an alternating remote magnetic field, the member being mechanically coupled to the polymer means, resonance of the member being modifiable in response to changes in one or more physical characteristics of the polymer means arising from changes in concentration of the analyte. Such a flexurally-mounted member is of advantage in that it is capable of providing a greater magnitude of magnetic response from the sensor, thereby potentially providing a more precise and/or accurate measurement of analyte concentration.

Preferably, the flexurally-mounted member is arranged to vibrate in a rocking mode about a substantially central axis of the member.

Preferably, the polymer means includes a fluidic void between the polymer means and the magnetic device so that the device is more freely capable of vibrating when the polymer means is of a certain spatial extent. Such an arrangement enables the sensor to more accurately and reliably measure a particular threshold concentration of analyte.

Preferably, to provide a distinct change in characteristic at the particular threshold, the fluidic void is a gaseous void.

Preferably, the polymer means, in part of its analyte response range, is arranged to progressively modify the amplitude of vibration of the magnetic device.

Preferably, the magnetic device is a magnetically saturable component arranged to be interrogated by an altemating remote magnetic field and to convert the remote field into higher-frequency magnetic field components susceptible to remote detection. Such an arrangement is of distinct advantage in that frequency discrimination techniques can be employed to distinguish between magnetic fields interrogating the sensor, and return magnetic fields from the sensor.

Preferably, the polymer means includes embedded therein the magnetically saturable component together with a permanent magnet component in mutually spaced apart configuration, magnetic characteristics of the saturable component being modifiable depending upon a spatial separation between said saturable component and said permanent magnet component, said spatial separation being modifiable by changes in physical characteristics of the polymer means in response to analyte concentration presented thereto.

According to a second aspect of the present invention, there is provided a method of measuring concentration of an analyte using the sensor according to the first aspect of the invention, the method comprising the steps of: (a) providing polymer means arranged so that one or more of its physical characteristics are modifiable in response to concentration of an analyte applied to the polymer means; and non-electronic sensing means for detecting the one or more characteristics of the polymer means to provide a measure of concentration of the analyte when remotely interrogated; (b) exposing the analyte to the polymer means; (c) interrogating the sensing means to measure one or more of its physical characteristics; (d) determining from said one or more physical characteristics the concentration of the analyte.

Preferably, in step (c), the sensing means is interrogated using altemating remotelygenerated magnetic fields.

According to a third aspect of the present invention, there is provided an apparatus for interrogating a passive biological sensor according to the first aspect of the present invention, the apparatus comprising: (a) magnetic field generating means for generating an altemating interrogating magnetic field and coupling said field to the sensor; (b) magnetic field detecting means for detecting a return magnetic field component generated by the sensor in response to interrogating field, the return field component being indicative of analyte concentration at the sensor ; (c) processing means for data processing the interrogating field and the return field component to determine therefrom a measure of concentration of said analyte.

Preferably, in the apparatus, the magnetic field detecting means is arranged to be sensitive to return magnetic field components at a mutually different frequency to that of the alternating interrogating magnetic field.

Alternatively, the apparatus is preferably arranged to operate in a burst mode of operation where the interrogating field is generated in bursts, and the return field is detected in quite periods between the bursts of the interrogating field.

According to a fourth aspect of the present invention, there is provided a method of interrogating a sensor according to the first aspect of the present invention, the method using an apparatus according to the third aspect of the invention.

It will be appreciated that any one or more features of the invention can be combined in any combination without departing from the scope of the invention.

Description of the diagrams Embodiments of the invention will now be described, by way of example only, with reference to the following diagrams in which: Figure 1 is an illustration of a first embodiment of a simple passive biological sensor according to the invention; Figure 2 is a schematic illustration of the sensor in Figure 1 incorporated within a biological system and being remotely interrogated using an alternating magnetic field ; Figure 3 is an illustration of a resonant characteristic of a magnetostrictive element included within the sensor of Figure 1 as analyte concentration and corresponding hydrogel viscosity changes; Figure 4 is an illustration of a burst-mode of operation for the sensor in Figure 1; Figure 5 is an illustration of a second embodiment of a passive biological sensor according to the invention ; Figure 6 is an illustration of a rocking mode of vibration of an element of the sensor of Figure 5; Figure 7 is an illustration of an apparatus capable of interrogating the sensors of Figures 1 and 5; Figure 8 is an illustration of a sensor similar to the sensor of Figure 5 but modified to include a fluidic void and a spacer to support an assembly of the sensor of Figure 5; Figure 9 is an illustration of an analyte measurement characteristic exhibited by the sensor of Figure 7;

Figure 10 is an illustration of a third embodiment of a passive biological sensor according to the invention; Figure 11 is an illustration of apparatus adapted for interrogating the sensor of Figure 10; and Figure 12 is an illustration of received signals generated by the apparatus of Figure 11 when interrogating the sensor of Figure 10.

Description of embodiments of the invention Referring to Figure 1, there are shown cross-sectional and exterior views of a passive biological sensor indicated generally by 10. The sensor 10 comprises a magnetostrictive elongate element 20, for example a bar of magnetostrictive material of length 3 mm and diameter 1 mm, encapsulated within a hydrogel mass 30 responsive to one or more biological analytes, for example glucose. The mass 30 in turn is preferably surrounded by an analyte-permeable mesh or membrane 40. The mesh or membrane 40 is, for example, employed when the hydrogel mass 30 is insufficiently mechanically robust where there is a risk of detachment of pieces of the mass 30 within a biological system into which the sensor 10 is incorporated. The mesh or membrane 40 is preferably one or more of woven fine-diameter titanium, surgical steel, a biocompatible polymer, and a layer of permeable protein.

Operation of the sensor 10 when implanted within a biological system 100 having an extemal interface layer 110 will now be described with reference to Figure 2. For example, the system 100 can be a human body and the interface layer 110 can be dermal and epidermal layers of skin of the body. The sensor 10 is preferably surgically injected via a wide-diameter hypodermic needle or inserted into the system 100 via an incision so that a longitudinal axis of the magnetostrictive element 20 is substantially perpendicular to the plane of the interface layer 110 as illustrated.

An apparatus comprising an electronic processing unit 120 electrically coupled to a transducer is offered to the interface layer 110. The transducer includes an annular ferrite magnetic core 130 having a first peripheral annular pole piece 140 and a second central pole piece 150 as illustrated. A coil of wire 160 is formed around the second central pole piece and its wire ends connected to the processing unit 120.

In operation, the processing unit 120 applies a sinusoidally-varying drive current to the coil 160 at a frequency in the order of several hundred kHz to create a correspondingly sinusoidally-varying magnetic field that couples to the magnetostrictive element 20 and causes it to mechanically vibrate in a longitudinal manner as depicted by dotted lines in Figure 2. As the element 20 vibrates, it couples acoustic vibrational energy into the mass 30. Thus, the element 20 and the mass 30 effective vibrate as a coupled damped composite structure.

The processing unit 120 is arranged to sweep the sinusoidally-varying drive signal over a range of frequencies and also to accurately monitor a relative phase angle between current flowing through the coil 160 and a sinusoidal voltage developed thereacross.

The processing unit 120 is thereby capable of detecting when the element 20 exhibits longitudinal mechanical resonance, this resonance being affected by the viscosity and/or spatial extend of the mass 30; the viscosity and/or the spatial extent of the mass is influenced by analyte concentration within the system 100. Thus, by detecting changes in the resonance of the element 20, the processing unit 120 is capable of indirectly obtaining information regarding properties of the mass 30 and hence the concentration of one or more specific analytes within the system 100.

The sensor 10 is of benefit in that it is extremely simple in construction and thereby potentially capable of providing highly reliable operation over long periods of insertion within the system, for example several years. As the sensor does not include a battery, it does not need to be accessed for purposes of exchanging exhausted batteries.

Figure 3 is an illustration of a resonance characteristic of the element 20 as detected by the processing unit 120. The element 20 mechanically and acoustically coupled to its associated mass 30 is capable of exhibiting a resonance response as indicated generally by 200. As the viscosity of the hydrogel mass 30 decreases, for example in

response to a change in analyte concentration within the system 100, the response 200 develops a resonance peak of greater amplitude and greater Q-factor. In general, the Q-factor of the response is relatively low, for example in the order of 2 to 5 in value.

If required, the processing unit 120 can be configured to "ping", namely pulse excite, the element 20 into resonance by burst excitation and then detect signals induced within the coil 160 during quiet periods between drive bursts. Such a mode of operation is illustrated in Figure 4. On account of the Q-factor of resonance of the element 20 being relatively low when embedded within the hydrogel mass 30, for example in the order of 2 to 5, drive bursts indicated by 300 are preferably relatively short, for example a couple of cycles of drive current into the coil 160 substantially at the frequency of elongate resonance of the element 20. Vibration of the element 20 is sensed during quiet sensing periods indicated by 310 during which the processing unit 120 is inhibited from applying drive current to the coil 160; during the sensing periods 310, the processing unit 120 detects minute signals induced in the coil 160 as a consequence of damped longitudinal vibration of the element 20. Such a burst mode of operation is of advantage in that minute vibrations of the element 20 can be detected which would otherwise be swamped by the drive signal in continuous drive operation where current-voltage phase differences across the coil 160 are monitored.

In the burst excitation mode of operation, the drive bursts 300 can be of swept frequency to enable the processing unit 120 to map resonance peaks for the element 20, such resonance peaks corresponding to different Eigen-mode resonances of the element 20 and its associated mass 30. The frequency sweep is preferably substantially at a uniform rate up and down in the manner of a"zigzag"characteristic ; alternatively, the sweep can be abruptly reset after completion of each sweep in the manner of a"sawtooth" characteristic.

Referring now to Figure 5, there are shown views of a passive biological sensor indicated generally by 500. The sensor 500 comprises the mass of analyte-responsive hydrogel 30, and the peripheral membrane or mesh 40. Moreover, the sensor 500 further comprises a resonant assembly indicated by 510. The resonant assembly 510 comprises a peripheral frame 540 coupled centrally via two centrally-disposed torsional hinges 530a, 530b to a central vibrating paddle 520a, 520b.

Preferably, the paddle 520, the hinges 530 and the frame 540 are a unitary part. The part can be fabricated from a metal or metal alloy, for example phosphor bronze or nonmagnetic surgical steel, or microfabricated from silicon, for example in the form of a MEMs component. When the assembly 510 is fabricated from metal or metal alloy, it can be one or more of punched, laser-cut and chemically photoetched from a sheet of corresponding material. When the assembly 510 is fabricated from mono-crystalline silicon, it can be one or more of wet anisotropically etched, dry gaseously etched and epitaxially grown to form the frame 540, the hinges 530 and the paddle 520.

Onto the paddle 520 is bonded or deposited a magnetic layer 550 in elongate form as illustrated. The layer 550 is preferably strongly paramagnetic, for example ferromagnetic, and is magnetically polarise so that first and second free ends of the paddle 520a, 520b respectively are polarised to form north (N) and south (S) poles of a permanent magnetic respectively.

The mesh 40 is preferably fabricated from a biocompatible material, for example a woven or etched titanium mesh or suitably mechanically robust polymer, for example a

stable protein polymer.

In operation, the mass of hydrogel 30 changes in dimension and/or viscosity as the concentration of an analyte to which the hydrogel is exposed via the mesh 40 changes.

When excited by an extemally-generated alternating magnetic field, the paddle 520 vibrates in a rocking motion as illustrated in Figure 6. As the paddle 520 has mass and the hinges 530 function as a compliant spring mount, the paddle 520 is capable of exhibiting a damped fundamental mode resonance corresponding to the aforesaid rocking movement.

As the concentration of analyte changes to which the mass 30 is exposed, the resonance frequency and the resonance Q-factor of the paddle 520 will correspondingly change as illustrated in Figure 3. The resonance frequency and the Q-factor can be externally measured by exciting the sensor 500 into resonance using an externallygenerated alternating magnetic field coupling into the sensor 500.

Preferably, the mass of hydrogel 30 is responsive to glucose concentration. More preferably, the hydrogel is of a type as described in an article by Lee and Park in a publication Joumal of Molecular Recognition 9, pages 549 to 557,1996 having a title "Synthesis and characterisation of sol-gel phase-reversible hydrogels sensitive to glucose" ; this article is hereby incorporated by reference. Such hydrogel renders the sensor 500 suitable for use by diabetics to monitor their blood sugar concentration. If required, the sensors 10,500 can be employed as part of an automatic feedback system for automatically dispensing insulin in response to blood glucose concentration.

Altematively, the mass of hydrogel 30 can be made responsive to oestrogen concentration and a corresponding resonance output of the sensor 10,500 can be used to determine whether or not supplementary extemally oestrogen is required. For example, such monitoring is of advantage in hormone replacement therapy for treating menopause conditions, or for maintaining oestrogen concentration in the case of patients who have undergone hysterectomy and who consequently experience oestrogen deficiency.

As a further altemative, the mass of hydrogel 30 can be made responsive to thyroxin concentration and used to determine an amount of externally applied, for example orally imbibed, thyroxin is required to maintain appropriate body thyroxin levels ; supplementary thyroxin in the order of 50 to 150 microgrammes/day as appropriate can be thereby dispensed automatically or via oral imbibement of medication. Such measurement is especially appropriate for people who have suffered thyroid disease, for example thyroid cancer or goiter-like disorders.

The sensor 500 is preferably of miniature external dimensions. For example, it is desirable that the sensor 500 should be in the order of 5 mm long and 2 mm in diameter.

Such size enables the sensor 500 to be inserted into a human body by using a wide- diameter hypodermic needle or via a small scalpel incision made under local anaesthetic.

More preferably, the sensors 10,500 are implanted into a wrist region or abdominal region of a human body so that the sensors 10,500 can be interrogated using a

miniature external device disposed in the form of a wrist strap or abdominal belt, for example a trouser belt.

In operation, the paddle 520 vibrates in its rocking mode at a significantly lower frequency than the longitudinal resonant frequency of the element 20 of the sensor 10.

For example, the paddle 520 in its torsional mount vibrates a frequency of a few 10's of kHz which means that associated interrogating circuits can be operated at relatively frequency and thereby consume less power in operation. Moreover, in comparison to the element 20 of the sensor 10, the paddle 520 undergoes more physical displacement when vibrating thereby providing a more detectable response signal in associated remote interrogating circuits.

Referring to Figure 7, there is shown an interrogation apparatus indicated generally by 600. The apparatus 600 is suitable for interrogating one or more of the sensors 10,500. The apparatus 600 is mounted in operation outside a biological system into which one or more of the sensors 10, 500 are incorporated. Moreover, the apparatus 600 is operable to interrogating one or more of the sensors 10,500 using alternating magnetic fields which are capable of penetrating into biological systems, unlike radio waves and electrostatic coupling techniques.

The apparatus 600 comprises a microprocessor unit 610 connected to an associated readout display 620; for example, the display 620 can be a miniature liquid crystal readout display when the apparatus 600 is implemented in the form of a wrist-wearable unit and one or more of the sensors are accommodated subcutaneously in a wrist region of a patient.

The apparatus 600 further comprises a programmable signal source 630, a variable current source 640, the coil 160, a phase detector 650, and an analogue-to-digital converter (ADC) 660. Preferably, the ADC 660 is incorporated as an integral part of the microprocessor unit 610.

Interconnection within the apparatus 600 will now be described. The microprocessor unit 610 comprises at output F at which a frequency selection signal is output in operation. The output F is coupled to a frequency control input of the signal source 630.

A sinusoidal signal output from the source 630 is connected to a modulation input of the current source 640 and also to a first input of the phase detector 650. A current output of the current source 640 is connected to the coil 160 for causing an excitation current to flow therethrough; moreover, a connection across the coil 160 indicative of voltage developed across the coil 160 is coupled to a second input of the phase detector 650.

The phase detector 650 is thereby connected to measure a relative phase between current flowing through the coil 160 and a voltage developed thereacross.

Operation of the apparatus 600 will now be described interrogating one or more of the sensors 10, 500. The coil 160 is spatially positioned so that it can couple to the member 20 and/or the assembly 510.

The microprocessor unit 610 outputs a frequency demand signal to the output F which causes the signal source 630 to generate a sinusoidal signal of corresponding frequency to the frequency demand signal. The sinusoidal signal from the source 630 modulates a current output from the current source 640, the source 640 exhibiting a relative high output impedance to the coil 160.

The signal from the source 630 is substantially indicative of instantaneous current flowing through the coil 160 whereas the voltage developed across the coil 160 is indicative of back electro-motive force (e. m. f. ) generated within the coil 160. The phase detector 650 is thereby able to derive a measure of an impedance exhibited by the coil 160.

At longitudinal resonance of the element 20 in the sensor 10, or alternatively rockingmode resonance of the paddle 520 in the sensor 500, the impedance of the coil 160 alters relatively sensitively as the frequency of the output signal from the source 630 is swept in frequency by the microprocessor unit 610. The ADC 660 converts a phase angle indicative output from the phase detector 650 into data which is received by the microprocessor unit 610.

The microprocessor unit 610 is thereby, by sweeping the frequency demand signal at F, capable of measuring impedance changes of the coil 160 with frequency and thereby detecting when the element 20, or the paddle 520, resonate; by applying the resonant

frequency to a look-up table stored in memory of the microprocessor unit 610, the unit 610 is able to determine an equivalent analyte-concentration which the unit 610 proceeds to output to the display 620 for presentation.

The passive biological sensor 500 of Figure 5 can be further modified so as to provide a more distinct characteristic signal from the apparatus 600 and also provide specific measurement of a preferred concentration of analyte. The passive sensor 500 modified in this respect is illustrated in Figure 8, the modified passive biological sensor being indicated generally by 700.

The sensor 700 comprises all parts present in the sensor 500 and further comprises a support 710 and two fluid-filled regions 720,730 above and below the assembly 510 respectively. The fluid-filled regions are preferably filled with a gas, for example nitrogen gas, or a relatively low-viscosity liquid.

The support 710 is preferably molded from a suitable plastic which is inert to the hydrogel mass 30. Moreover, the support 710 includes a ridge for supporting the assembly 510 at its peripheral edge 540 but nevertheless providing clearance for the paddle 520 to vibrate more freely within the gas regions 720,730.

As a consequence, especially when the fluid-filled regions 720,730 are filled with a gas, the paddle 520 is capable of exhibiting a Q-factor of several hundred times when excited into resonance. If driven sufficient strongly, the paddle 520 will vibrate with sufficient amplitude until it repeatedly momentarily contacts onto the hydrogel mass 30 at the limits of its vibration. In the sensor 700, vibration of the paddle is more easily detected because the Q-factor is greater and a greater change of magnetic reluctance occurs which modulates e. m. f. developed across the coil 160.

In operation, when the sensor 700 is exposed to increasing concentrations of analyte, for example within the system 100, the hydrogel mass 30 expands in a downward direction as indicated by an arrow 740. This expansion restricts the maximum vibration amplitude of the paddle 520 of the assembly 510 and results in a sensing characteristic as illustrated in Figure 9. As the mass 30 expands in response to analyte, the amplitude of paddle 520 vibration progressively decreases until a critical level is reached where the

paddle 520 is completely restrained and unable to freely vibrate in its rocking mode as illustrated in Figure 6. Preferably, the sensor 700 is fabricated so that the critical level corresponds to a critical level of analyte ; for example, the sensor 700 can include a hydrogel mass responsive to glucose concentration and the region 720 arranged to be of size such that the critical level corresponds to the onset of coma in diabetics where insulin must be administered. The sensor 700 can thereby be used as a warning device for diabetics to indicate that they need to take urgent action.

In the sensors 10,500, unless associated interrogating apparatus is operated in pulse mode as illustrated in Figure 4, there exists a sensing difficulty in that a small response signal from the sensor 10,500 must be detected in presence of a relatively drive signal.

Such a relatively large ratio in these two signals makes it more difficult to obtain precise measurement from the sensors 10,500.

The inventors have appreciated that it is preferable that a response signal generated from the passive biological sensor according to the invention should be at a different frequency to the frequency of alternating magnetic excitation applied to interrogate the sensor. In order to address the problem, the inventors employ their expertise from a mutually different technical field of magnetic identification tags. In particular, techniques described in a published international PCT application no. PCT/GB99/00081 are especially relevant, this international PCT hereby being incorporated by reference.

When a magnetically saturable material exhibiting a relatively low saturation magnetic field strength, for example 50 A/m, is exposed to a sinusoidally varying excitation magnetic field of sufficient maximum field strength to repeatedly magnetically saturate the material, the material will repeatedly abruptly saturate exhibiting magnetic nonlinearity and thereby generating magnetic field harmonic components at considerably higher frequencies than the sinusoidally varying excitation magnetic field. Frequency discrimination techniques can then be relatively easily applied to separate signal components of the excitation field from those of the magnetically soft material undergoing abrupt saturation. Thus, a frequency transformation can be obtained without the need to incorporate active electronic components within the passive biological sensor.

If a permanent magnet is moved in relatively close proximity to the magnetically saturable material above, the saturation characteristic of the saturable material can be made asymmetrical as will be described later with reference to Figure 12. If the permanent magnet is included within the hydrogel mass 30 together with the magnetically saturable material in spaced-apart configuration, expansion and/or contraction of the hydrogel mass 30 in response to changes in analyte concentration will cause the symmetry of the magnetic saturation of the saturable material to alter, the degree of asymmetry thereby being indicative of analyte concentration.

In this respect, Figure 10 is referred to for describing a passive biological sensor indicated generally by 800. The sensor 800 comprises the hydrogel mass 30 and preferably the mesh or membrane 40 as before. Within the hydrogel mass 30, the sensor 800 further includes an elongate saturable magnetic element 820. The magnetic element can be fabricated in the form of a magnetically saturable wire, for example as manufactured by MXT Inc. based in Ottawa, Canada. Alternatively, the magnetic element 820 can alternatively be a magnetically-saturable planar component having a preferred magnetic easy axis; planar magnetic components exhibiting preferred magnetic easy axes are described in the aforementioned international PCT application no. PCT/GB99/00081. In spaced-apart configuration, the hydrogel mass 30 further includes a permanent magnet component 810 of elongate form. The permanent magnet component 810 preferably has its magnetic axis substantially parallel to the elongate axis of the element 820, or to the easy axis of the element 820 when implemented in planar form.

In operation, the sensor 800 is implanted into a biological system and analytes from the system diffuse through the mesh or membrane 40 into the hydrogel mass 30. The volumetric extent of the mass 30 varies in response to the concentration of analyte, or group of analytes, to which the mass 30 is responsive. As the mass 30 expands, the spatial separation between the permanent magnet component 810 and the magnetic element 820 increases causing the magnetic element 820 to exhibit a more symmetrical magnetic saturation response when interrogated by a sinusoidally-varying magnetic field.

In Figure 11, there is illustrated apparatus capable of interrogating the sensor 800, the apparatus being indicated generally by 900. The apparatus 900 comprises a data

processing unit 910, for example implemented using a microcontroller, an analogue amplifier 920, a high-pass filter 930, a pickup coil 935, a magnetic excitation coil 940, an excitation current drive amplifier 950 and finally a signal source 960.

Interconnection of component parts of the apparatus 900 will now be described with reference to Figure 11. The signal source 960 is coupled at its output to an input of the drive amplifier 950. A coil-driving output of the amplifier 950 is connected to the excitation coil 940. The source 960 is arranged to output a sinusoidal signal at around 160 Hz to the amplifier 950 which in turn is arranged to drive a corresponding sinusoidally-varying magnetizing current through the coil 940. Preferably, the excitation coil 940 has a diameter of 25 mm and comprises in a range of 20 to 50 turns of copper enameled wire on a plastic molded former.

The pickup coil 925 preferably has a diameter in a range of 10 mm to 15 mm and comprises in a range of 50 to 500 turns of fine enameled copper wire, for example 22 s. w. g. , wound onto a plastic molded former. More preferably, the pickup coil 925 is mounted concentrically within the excitation coil 940 so that their magnetic centers coincide. Optionally, the coils 940,950 are accommodated onto a ferrite core in a manner as depicted for the coil 160 in Figure 2.

The pickup coil 935 is coupled to the high-pass filter 930 and therefrom to the amplifier 920. An amplified output from the amplifier 920 is connected to an input port of the processing unit 910 for conversion within the processing unit 910 into a corresponding digital data stream for storage and subsequent analysis.

When the sensor 800 is incorporated into the biological system 100, for example by surgical insertion through an incision, it is preferably orientated so that the element 820 and the permanent magnet 810 are orientated so that their elongate axes are substantially perpendicular to the plane of the interface 110, for example skin dermis and epidermis. Moreover, the coils 935,940 are preferably orientated, as illustrated in Figure 11, so that their magnetic axes are parallel to the elongate axes of the permanent magnet 810 and the element 820 and therefore substantially perpendicular to the plane of the interface layer 110.

The high-pass filter 930 is designed to reject, namely not to transmit, sinusoidal signals corresponding to magnetic excitation applied by the source 960 and its associated amplifier 950 to the excitation coil 940, but readily transmit signal components at frequencies above the excitation, for example signal components greater than 1 kHz when the excitation applied to the coil 940 is at a frequency 160 Hz.

Operation of the apparatus 900 interrogating the sensor 800 will now be described with reference to Figure 12.

In Figure 12, waveforms received by the processing unit 910 are indicated generally by 1000. Time is depicted along an abscissa axis and drive signal magnitude to the excitation coil 940 is depicted along an ordinate axis. The sinusoidal excitation applied to the excitation coil 940 is represented by a curve 1010. A filtered signal provided from the filter 930 and amplified by the amplifier 920 is represented by a curve 1020.

Magnetic saturation transitions occurring in the element 820 give rise to pulses 1030, 1040 where the pulses 1030 correspond to positive flowing excitation current through the excitation coil 940, and the pulses 1040 correspond to negative flowing excitation current through the excitation coil 940.

1 In operation, the source 960 generates a sinusoidal excitation signal at a frequency of substantially 160 Hz. The amplifier 950 amplifies and buffers the signal to drive corresponding current through the excitation coil 940. The coil 940 generates a corresponding sinusoidally varying excitation magnetic field which couples through the interface layer 110 and the system 100 into the sensor 800. The excitation magnetic field exceeds the magnetic saturation limit of the element 820 and causes it to saturate at each sinusoidal half cycle as illustrated in Figure 12. Each time the element 820 saturates, it couples a small proportion of the excitation magnetic field to higher frequency magnetic field components. These higher frequency components couple into the pickup coil 935 which also receives directly-coupled excitation magnetic fields from the excitation coil 940. Thus, an e. m. f. signal generated in the coil 935 corresponds to a summation of directly-coupled magnetic field from the excitation coil 940 and higherfrequency magnetic field components generated from the element 820.

An output signal from the pickup coil 935 couples to the filter 930 which removes components at 160 Hz coupling directly to the excitation coil 940 to the pickup coil 935, but transmits higher-frequency components arising from magnetic saturation in the element 820. As the higher-frequency components are of relatively small magnitude, the amplifier 920 is included to amplify these components prior to presenting them amplified to the processing unit 910.

The processing unit 910 digitizes the amplified higher-frequency components and measures where the peaks therein occur relative to the excitation signal as represented by the curve 1010. The temporal positions of the peaks in the curve 1020 are a function of the spatial separation of the permanent magnet 810 relative to the element 820.

Thus, as the hydrogel mass 30 changes in volumetric size in response to changes in analyte concentration within the system 100, the separation of the permanent magnet 810 from the element 820 changes accordingly and, in turn, causes the temporal positions of the peaks in the curve 1020 to change. For example, when the permanent magnet 810 is brought spatially closer to the element 820, the peaks 1030,1040 are temporally shifted in direction of arrows 1032,1042 respectively to peaks 1034,1044 respectively.

The apparatus 900 is of considerable benefit in that return magnetic field components from the sensor 810 can be relatively easily isolated from excitation magnetic field components and therefore enables more precise and/or accurate measurement of analyte concentration to be achieved. Moreover, the apparatus 900 is potentially relatively simple in form which enables it to be fabricated in miniature form into a housing similar in size to a conventional wrist watch.

It will be appreciated that modifications can be made to embodiments of passive biological sensors described in the foregoing without departing from the scope of the invention. For example, features of the sensors can be combined in any combination without departing from scope of the invention.

For example, the mesh or membrane 40 can be arranged to act as an analyte filter and thereby enhance the analyte selectivity exhibited by the sensors 10,500, 700,800. If required, the mesh or membrane 40 can be a multilayer structure, each layer providing

corresponding selective analyte transmission to the hydrogel mass 30. In such a manner, the sensors 10,500, 700,800 can be rendered highly analyte selective and also the hydrogel mass 30 can be thereby better protected from biological contamination from the system 100, thus imparting the sensors 10,500, 700,800 with longer operating lifetimes, for example several decades.

The sensors 10,500, 700,800 are especially advantageously implemented to be sensitive to glucose concentration for providing an indication of insulin requirements in the case of diabetics. Altemative, by suitable choice of hydrogel mass 30 and/or the mesh or membrane 40, the sensors 10,500, 700,800 can be made responsive to a potentially very large range of substances found in biological systems. The range can include narcotic substances, by-products from disease pathogens, poisons to mention a few.

The sensors 10,500, 700,800 can also be employed outside living organisms, for example used in rivers and reservoirs to test for pollution, insecticides, antibiotics, pathogens, and fertilizer concentrations. For example, the sensors 10,500, 700,800 can potentially be used by salmon farmers in Scotland to monitor aquatic environments in Scottish Lochs where salmon are intensively reared, for example to test for salmon pathogens, aquatic antibiotic and/or vaccine concentrations, and available nutrient levels.

Claims

CLAIMS 1. A passive biological sensor, characterized in that the sensor comprises: (a) polymer means arranged so that one or more of its physical characteristics are modifiable in response to concentration of an analyte applied to the polymer means; and (b) non-electronic sensing means for detecting the one or more characteristics of the polymer means to provide a measure of concentration of the analyte when remotely interrogated.
2. A sensor according to Claim 1, wherein the polymer means is a hydrogel responsive to the analyte.
3. A sensor according to Claim 2, wherein the hydrogel is responsive to one or more of glucose, thyroxin, hormones, narcotics, trace insecticide, fertilizer, antibiotics, pathogens and/or their metabolic byproducts.
4. A sensor according to Claim 1,2 or 3, wherein the polymer means includes the sensing means therein.
5. A sensor according to any one of the preceding claims, wherein the sensing means comprises a magnetic device arranged to couple changes in one or more physical characteristics of the polymer means into corresponding magnetic characteristic changes in the sensing means, thereby rendering the sensing means susceptible to remote magnetic interrogation.
6. A sensor according to Claim 5, wherein the magnetic device comprises a magnetostrictive element susceptible to being excited into resonance by a remote alternating magnetic field, the resonance being susceptible to modification in response to changes in one or more physical characteristics of the polymer means in turn dependent upon analyte concentration to which the polymer means is exposed.

<Desc/Clms Page number 23>
7. A sensor according to Claim 6, wherein the magnetostrictive element is an elongate element susceptible to resonating along its associated elongate axis.
8. A sensor according to Claim 5, wherein the magnetic device is a flexurally- mounted member susceptible to vibrating when excited by an alternating remote magnetic field, the member being mechanically coupled to the polymer means, resonance of the member being modifiable in response to changes in one or more physical characteristics of the polymer means arising from changes in concentration of the analyte.
9. A sensor according to Claim 8, wherein the flexurally-mounted member is arranged to vibrate in a rocking mode about a substantially central axis of the member.
10. A sensor according to Claim 5,8 or 9, wherein the polymer means includes a fluidic void between the polymer means and the magnetic device so that the device is more freely capable of vibrating when the polymer means is a of certain spatial extent.
11. A sensor according to Claim 10, wherein the fluidic void is a gaseous void.
12. A sensor according to Claim 10 or 11, wherein the polymer means, in part of its analyte response range, is arranged to progressively modifying the amplitude of vibration of the magnetic device.
13. A sensor according to Claim 5, wherein the magnetic device is a magnetically saturable component arranged to be interrogated by an alternating remote magnetic field and to convert the remote field into higher-frequency magnetic field components susceptible to remote detection.
14. A sensor according to Claim 13, wherein the polymer means includes embedded therein the magnetically saturable component together with a permanent magnet component in mutually spaced apart configuration, magnetic characteristics of

<Desc/Clms Page number 24>

the saturable component being modifiable depending upon a spatial separation between said saturable component and said'permanent magnet component, said spatial separation being modifiable by changes in physical characteristics of the polymer means in response to analyte concentration presented thereto.
15. A method of measuring concentration of an analyte using the sensor as claimed in Claim 1, the method comprising the steps of: (a) providing polymer means arranged so that one or more of its physical characteristics are modifiable in response to concentration of an analyte applied to the polymer means; and non-electronic sensing means for detecting the one or more characteristics of the polymer means to provide a measure of concentration of the analyte when remotely interrogated ; (b) exposing the analyte to the polymer means; (c) interrogating the sensing means to measure one or more of its physical characteristics; (d) determining from said one or more physical characteristics the concentration of the analyte.
16. A method according to Claim 15, wherein, in step (c), the sensing means is interrogated using alternating remotely-generated magnetic fields.
17. An apparatus for interrogating a passive biological sensor according to Claim 1, the apparatus comprising: (a) magnetic field generating means for generating an alternating interrogating magnetic field and coupling said field to the sensor; (b) magnetic field detecting means for detecting a return magnetic field component generated by the sensor in response to interrogating field, the return field component being indicative of analyte concentration at the sensor; (c) processing means for data processing the interrogating field and the return field component to determine therefrom a measure of concentration of said analyte.
18. An apparatus according to Claim 17, wherein the magnetic field detecting means is arranged to be sensitive to return magnetic field components at a mutually different frequency to that of the alternating interrogating magnetic field.

<Desc/Clms Page number 25>
19. An apparatus according to Claim 17, wherein the apparatus is arranged to operate in a burst mode of operation where the interrogating field is generated in bursts, and the return field is detected in quite periods between the bursts of the interrogating field.
20. A method of interrogating a sensor according to Claim 1 using an apparatus according to Claim 17.
21. A passive biological sensor substantially as hereinbefore described with reference to one or more of Figures 1 to 12.
22. A method of measuring concentration of an analyte using a passive biological sensor substantially as hereinbefore described with reference to one or more of Figures 1 to 12.
23. An apparatus for interrogating a passive biological sensor, the apparatus substantially as hereinbefore described with reference to one or more of Figures 1 to, 12.