Patent Description:
Diabetes mellitus (diabetes) is a disease in which the body does not produce or properly use insulin. Put simply, insulin is a hormone that the body uses to convert sugar and starches into energy. In other words, insulin is the hormone that unblocks cells of the body, allowing glucose to enter these cells to provide food to keep them alive.

People suffering from diabetes are known as diabetics, and diabetics suffer because as glucose (blood sugar) cannot enter their body's cells normally, glucose concentrations in the body (and in particular in the blood) build-up. Without appropriate and timely intervention/treatment, the cells within the body can end up being starved.

As such, many medical practitioners consider the measurement of blood-glucose as being perhaps one of the most important measurements in modern medicine due to the immense public health implications of diabetes. Diabetes is often cited as being one of the leading causes of disability and death throughout the world.

In order to prevent the onset and the progression of complications associated with diabetes, sufferers of both Type I and Type II diabetes are advised to closely monitor the concentration of glucose in their bloodstream. If the concentration is outside the normal healthy range, the patient needs to adjust his or her insulin dosage or sugar intake to counteract the risk of diabetic complications.

It is a recommendation of the medical profession that insulin-dependent patients practice self-monitoring of blood-glucose levels and then, based on the measured blood-glucose level, patients are able to make insulin dosage adjustments prior to injection. These adjustments are extremely important since blood-glucose levels vary over the period of a day due to a variety of reasons, for example, stress, exercise, types of food eaten, absorption rate for the food, long periods without food and hormonal changes.

Traditional methods of monitoring the blood-glucose level involve invasive or minimally invasive techniques.

Historically, and in certain situations, glucose monitoring can be achieved by urine analysis. This method tends to be inconvenient (as a patient needs to wait to urinate before a test can be performed, and the urine capture procedure can be messy and unhygienic) and may not reflect the current status of the blood-glucose level due to the fact that glucose appears in the urine only after a significant period of elevated levels of blood-glucose. This method was, in fact, used by physicians of the past where the diagnosis was made by tasting the patient's urine. Patent number <CIT> describes in detail a modern-day apparatus used for urine testing.

The most common method of measuring blood-glucose level nowadays requires blood to be withdrawn from the patient. The conventional procedure involves pricking the finger, or other body part, to withdraw blood, and then to deposit one or more drops onto a reagent carrier strip having a glucose testing substance thereon. The testing substances change colour or shading in response to the detected amount of blood-glucose. A colour chart is then used to determine the associated numerical value of blood-glucose. One of the technical short falls of this technique is that measurement sensitivity is somewhat limited due to the finite range of colours and boundary spacing.

The pricking procedure is somewhat messy and painful, particularly if the patient has to repeat the procedure several times during the day. Diabetic children, in particular, are often reluctant to undergo regular blood sugar testing. Some patients tend to be squeamish at the sight of blood, particularly when the blood is their own. As a result, compliance with the recommended testing regime can be difficult to attain because, patients often forego the messiness and pain associated with this invasive procedure, thereby leading to over-dosing or under-dosing of insulin, which can lead to (sometimes serious) complications.

Also, some very old and clumsy individuals find the finger pricking and blood withdrawal procedure difficult to perform, which can, again, lead to the measurement not taking place and associated complications.

A further group of individuals who may forego testing is teenagers who find the procedure inconvenient or socially unacceptable, i.e. they are embarrassed to carry out the test in front of their friends or social acquaintances.

A further drawback with this procedure is that the pricking technique is generally accomplished with the aid of a needle, which should be sterile before use, although it is often the case that patients, through inadvertence or neglect, fail to sterilise the needle, thereby leading to the risk of infection, and, even in the case of a sterilised needle, a wound is created which may become infected.

An additional inconvenience associated with the finger pricking and urine sampling techniques and methods is that they require testing supplies such as collection vessels (containers or receptacles), syringes, and test kits. Many of these supplies are disposable and, therefore special methods of disposal are required.

A need therefore exists for a solution to one or more of the above problems, and/or an alternative to the traditional finger-prick test.

Another invasive technique involves using implantable medical devices to measure cardiac signals. In one such invention, the blood-glucose levels are determined based on T- wave amplitude and the QT-interval. Once the blood-glucose level has been detected, the implanted device compares the blood-glucose level against upper and lower acceptable bounds and appropriate warning signals are generated when the levels fall outside these bounds.

The disadvantage of this method is that the instrument has to be inserted inside the human body and so a complex medical procedure may need to be performed. Also, the patient would need to be admitted to hospital and may need to stay for a few days. Additionally, this device would be classified as a "class III" medical device because it is inserted inside the body. A class III medical device is categorised is a high-risk device and would need to go through stringent testing and validation procedures before being granted approval by the medical devices regulatory bodies to enable it to be put into regular use.

Clearly, implanted devices are generally undesirable and a need therefore exists for an alternative to this system.

It has been widely proposed to use a wearable device to carry out continuous or periodic measurements of the concentration of a target substance in the blood. Wearable devices include such items as devices that are worn around the neck (necklace-type devices); that are worn around the wrist or ankle (watch-like devices). etc. However, where the measurement of the target substance involves a complex or highly-sensitive measurement technique, for example, an RF measurement technique, such devices need to be largely, or completely, immune to extraneous variables, such as the location/fit of the sensor during the course of a test procedure.

For example, a watch-type device might be worn tightly by some users, or loosely be others. Where a watch-type device is worn loosely, this can create number of significant variables, such as the location of the device (where it is positioned relative to the user's anatomy) during a test. A loosely-fitted watch-type device may be located further up or down the wrist at different times; or on top, to the side or underneath the wrist at different times - and this variation will inevitably affect the RF properties of the test at that time.

Second, the contact pressure between the antenna (in the case of an RF-based test) will have a significant effect on the results of the RF-based test procedure. A higher contact pressure is likely to result in better RF coupling between the antenna(s) and the user's skin; as well as (where the skin is pressed-in/deformed slightly, a larger contact area too - compared with a similar test undertaken with a lower contact pressure.

Third, the user's anatomical dimensions/measurements need to be taken into account to avoid discrepancies between identical test carried out on otherwise similar users, but with different wrist diameters, for example. This consideration is of particular concern where transmission or reflection RF measurements are to be used.

For example, where an RF signal is to be transmitted through a user's wrist and detected by a receiver antenna located on the opposite side of the wrist, there is a need for a consistent and reproducible alignment between the transmit and receive antennas from one use to the next. If the transmit and receive antennas are not consistently related to one another dimensionally, then there is a possibility that the transmitted RF signal may "miss" the receive antenna and not be detected.

Likewise, where an RF signal is to be transmitted into a user's wrist and reflected back off an RF reflector located on the opposite side of the wrist, there is a need for a consistent and reproducible alignment between the transmit/receive antenna(s) on one side of the wrist, relative to the RF reflector located on the other side of the wrist. If the transmit/receive antenna(s) are not consistently related to the RF reflector dimensionally, then there is a possibility that the RF signal may "miss" the RF reflector and not be detected by the receive antenna.

A need therefore exists for a solution to one of more of the above problems and/or an improved and/or alternative wearable RF measurement device for testing the concentration of a target substance in patient's blood.

Our own earlier patent, <CIT><CIT>] describes a non-invasive measurement technique for determining a concentration of glucose in blood. This patent describes an RF measurement technique in which a transmitted and/or reflected RF signal, that has been modified by a biological tissue structure, is analysed. Variations in the amplitude and phase of the detected signal (compared with the outputted signal) are correlated to blood sugar concentration, thereby yielding a result that is indicative of the blood sugar concentration. This early work provides a foundation upon which the present invention builds.

The scientific literature also is replete with studies apparently showing a strong correlation between the RF properties of blood and its sugar concentration. Such studies are based on in-vitro testing where a sample of blood is extracted from the body of a patient and tested in isolation, i.e. a droplet of blood is placed onto an RF antenna and then analysed. In the case of in-vitro testing, the correlation between blood sugar concentration and the RF properties of the blood sample under test has been found to be quite strong, but this correlation has, unfortunately, been found only to hold true for an individual patient and or for in vitro blood testing- and cannot be generalised for populations or for in vitro testing.

In other words, it is the variation in RF properties of blood, from person-to-person, which has hampered the development and commercialisation of non-invasive blood sugar testing apparatus for the simple reason that the precise relationship (the equation, so to speak) between the blood sugar concentration and the RF properties (e.g. attenuation, phase shift) seems to be unique to each individual patient, and so there is no single correspondence that can be used reliably across populations of patients. This person-to-person variation could be attributable to different patients having different blood properties (e.g. red cell count, white cell count, blood group, cholesterol level, disease, etc.) some or all of which may inevitably vary the RF properties of one individual's blood relative to another individual's.

In addition, even taking into account the disclosure of our own earlier patent (<CIT>), there are other factors that come into play simply because when testing in-vivo (as opposed to in-vitro), there is a complex biological structure involved, which varies tremendously from one patient to the next. Even taking a reasonably "standard" anatomical part (e.g. an ear lobe), there are huge (percentage) variations in dimensions, fat content, skin thickness, flood flow etc., which all have a large effect on the RF properties of the "biological tissue structure", and so any variations in the RF properties cannot easily be attributed to variations in blood sugar concentration (the target substance) where there are so many other factors that can, and do, affect the readings obtained. These variations are described in detail our own earlier patent (<CIT>).

Other known testing devices or techniques are described in the following published patent applications: <CIT>]; <CIT>], <CIT>]; <CIT>]; <CIT>]; <CIT>]; <CIT>]; <CIT>]; <CIT>]; <CIT>]; <CIT>]; <CIT>]; and <CIT>].

A need therefore exists for a solution, which permits reliable, non-invasive, in-vivo testing of a target substance (e.g. sugar) in blood, which provides a generalise solution that can be applied to populations, rather than having to be "calibrated" to individual patient's "variables".

The invention is set forth in the appended independent claim. Preferred and/or optional features of the invention are set forth in the appended dependent claims.

In summary, the present invention is, or relates to, a non-invasive testing apparatus for determining a concentration of a target substance, such as blood sugar, blood alcohol, cholesterol, etc.) in a patient's blood. The apparatus involves applying an output RF signal to the skin of a patient via an antenna, and measuring the amplitude and phase of a response signal which is a function of the output RF signal modified by an interaction with the patient's blood. The apparatus of the invention takes measurements at different output RF frequencies, and plots the response as a function of frequency. The invention is essentially characterised by deriving various derived parameters from the shape of the resulting plots, namely any two or more of: a Q factor of the resonance; a group delay; a shape factor of the plot; and a gradient of the plot at different frequencies. The invention utilises models of the derived parameters as a function of concentration of the target substance in blood to arrive at a determination of the latter. Also disclosed herein is a novel circuit for obtaining the amplitude and phase measurements, a calibration device, and various improvements relating to wearable non-invasive testing apparatus.

The apparatus of the invention, when attempting to determine what the concentration of the target substance is, is concerned principally with derived parameters, rather than the absolute values obtained from the test. The reason for this is that absolute values have been found to vary from patient to patient, or over time - even for the same patient, whereas derived parameters, which are based on the shape of the plot have been found to yield more reliable results. The reason for this is that although the location or scaling of the plot of amplitude/phase vs frequency may shift from test to test, distortion of the plot, that is to say, normalised, relative movements of points of interest in the plots appear to be consistent with their respective models of derived parameters vs target substance concentration from patient to patient and over time. Thus, the invention is capable, in certain embodiments, of providing an accurate test result independently of the patient's physiology and/or the time of testing. This discovery, and the practical application of this discovery in the invention, represents a leap forward in the field of non-invasive blood testing.

In order to improve the robustness of the test, the processor is adapted to: determine a plurality of derived parameters; compare the plurality of derived parameters with respective models of the respective derived parameters as a function of concentration of the target substance in blood; to determine, for each derived parameter, a concentration of the target substance in the patient's blood based on a correlation between the respective derived parameter and the corresponding values of concentration of the target substance in the patient's blood in the respective model; and to apply a statistical model to the resulting determined concentrations of the target substance in the patient's blood based on each derived parameter to arrive at a single, overall determined concentration of the target substance in the patient's blood. This results, in effect, in a "weighted average" or a "best fit" overall result, which can be more reliable and/or robust than relying on a single result from a single derived parameter.

The model can take various forms, although it will be appreciated that each model could comprise a lookup table of derived parameters and their corresponding concentrations of the target substance in the patient's blood, and wherein the processor is adapted to identify the closest match to data in the lookup table or to interpolate between data in the lookup table to arrive at a determined concentration of the target substance in the patient's blood. Additionally or alternatively, each model could comprise an equation defining a relationship between a derived parameter and concentration of the target substance in the patient's blood, and wherein the processor is adapted to use the derived parameter as the argument of the equation to yield the value being the concentration of the target substance in the patient's blood.

Unlike the prior art, and even our own earlier patent (<CIT>), the invention considers the RF properties holistically, rather than attempting to fit certain measured parameters to a particular equation. For example, in <CIT>, the amplitude and phase of a response signal is plotted as a function of frequency, and the position and amplitude of the observed resonances are correlated with a known, previously-determined, relationship between blood sugar concentration and amplitude; and blood sugar concentration and phase. The measured data points are effectively mapped onto the model to yield a test result being an indication of the blood sugar concentration. However accurate this measurement may be for an individual patient, it still requires some form of "standard" for that patient, which is derived by taking, for example, a series of finger-prick tests beforehand to determine the relationship between blood sugar concentration and amplitude, and/or blood sugar concentration and phase for that individual.

The invention, by contrast, does more than just obtain a series of readings of amplitude and phase at different frequencies: it considers the overall shape of the measured relationship between input frequency and the amplitude of a response signal and/or the input frequency and the phase of a response signal. By doing so, the measured relationships can be more subtly analysed and more reliably fitted to a model, from which the blood sugar concentration can be derived.

The non-invasive testing device may compris a main body comprising at least one antenna operatively coupled, in use, to the skin of a patient; and a housing comprising at least one receiver antenna and/or reflector also operatively coupled, in use, to the skin of a patient; the housing being located, in use, on an opposite side of the patient's anatomy to the main body; an adjustable strap connecting the main body to the housing, wherein the strap is formed as a pulley belt affixed at one end to the main body or housing, which is wound around respective rollers of the main body and the housing, and which has a free end, wherein the pulley belt and rollers are configured to centralise the housing relative to the main body such that pulling on the free end of the strap reduces the distance between the main body and the housing, whilst maintaining a substantially constant alignment between the main body and the housing.

Suitably, the substantially constant alignment between the main body and the housing is such that a line normal to a centre of the antenna is maintained in a substantially constant relationship to a line normal to a centre of the receiver antenna and/or reflector. Preferably, the line normal to the centre of the antenna is maintained in alignment with the line normal to the centre of the receiver antenna and/or reflector.

An advantage of this configuration, in certain embodiments, is that the strap self-centralises the main body and/or the housing on the patient's body, thereby ensuring, or at least encouraging, a consistent measurement geometry each time a measurement of the target substance is carried out. By aligning the housing and main body, a transmitted signal can reproducibly be sent from the main body to the housing, and/or reflected off the RF reflector back to the main body, which improves the reproducibility of the test.

Suitably, the strap is manufactured from a flexible material, such as an elastomer like silicone rubber. Suitably, the main body, housing and strap is/are manufactured of hypoallergenic materials, such as silicone rubber, which is latex-free; plastics; and/or metals that are low in nickel or other materials that are known to cause irritation and/or allergic reactions.

Suitably, the pulleys are rollers that are rotatably affixed to the main body and housing. The strap, which is typically a band, can pass around the pulleys to achieve the objects of the invention. In one embodiment, the strap is anchored at one end to the main body, and passes around a user's wrist or other body part to a first roller located to one side of the housing. Then, the strap folds back on itself and passes around the same side of the user's wrist or body part back to the main body. It then crosses over and extends around the opposite side of the user's wrist or body part to a second roller located on an opposite side of the housing. The free end of the strap can then be secured, or it can pass back around the same side of the user's wrist to the main body where is secured. The aforementioned configuration thus provides two (but critically an equal number of) strap lengths on either side of the user's wrist, such that pulling on the free end of the strap causes equal movement of the housing relative to the main body. This usefully keeps the strap lengths on either side of the user's wrist or body part substantially equal, or equal, thus self-centralising the housing and main body.

The non-invasive testing device may comprise a main body comprising at least one antenna having a front surface operatively coupled, in use, to the skin of a patient and an adjustable strap connected to the main body and extending, in use, around a part of the patient's body to retain the antenna adjacent the patient's skin, the non-invasive testing device further comprising: an air bladder, and means for inflating the air bladder to cause the front surface of the antenna to press against the patient's skin with a predetermined force.

Suitably, the means for inflating the bladder inflates the air bladder to a predetermined air pressure, which in-turn causes the front surface of the antenna to press against the patient's skin with a predetermined force. By ensuring that the front surface of the antenna is pressed against the patient's skin with the same predetermined force each time a test is carried out, the reproducibility of the test can be improved.

The means for inflating the air bladder suitably comprises a pump, which may be an electric pump. However, for convenience, and so as to reduce the need for battery power, the means for inflating the air bladder is preferably a manual pump, such as a compressible bladder with a one-way valve, which can be depressed once, or several times, to inflate the air bladder.

Means is suitably provided for causing the front surface of the antenna to press against the patient's skin with a predetermined force, which means may be a pressure-relief valve interposed between the pump and the air bladder. Such a configuration, by setting the pressure-relief valve to a certain pressure setting, can ensure that the air bladder is not over-inflated. Means, for example, an air pressure sensor, may be provided to ensure that the pump is used/operated until the air pressure within the air bladder reaches at least a predetermined air pressure that ensures that the required predetermined force is achieved.

By using an air bladder, the pressure within it can be hydrostatic, which suitably ensures that an even pressure is applied across the surface of the antenna.

Suitably, the air bladder is interposed between the main body and a rear surface of the antenna.

Suitably, the at least one antenna is operatively connected to a driver and a processor, wherein, in use: the or each; the driver is adapted, in use, to output an output signal via at least one of the antennas; and wherein the processor is adapted, in use, to measure a response signal via at least one of the antennas, the response signal being a function of the output signal modified by an interaction with patient's blood, characterised by the processor being adapted to analyse the response signal and to determine from the analysis, a concentration of a target substance in the patient's blood.

The non-invasive testing apparatus may comprise at least one antenna operatively connected to a driver and a processor, wherein, in use: the or each antenna is operatively coupled to the skin of a patient; the driver is adapted, in use, to output an output signal via at least one of the antennas; and wherein the processor is adapted, in use, to measure a response signal via at least one of the antennas, the response signal being a function of the output signal modified by an interaction with patient's blood, characterised by the processor being adapted to analyse the response signal and to determine from the analysis, a concentration of a target substance in the patient's blood.

Suitably, the at least one antenna is operatively coupled to the skin of a patient, and hence to the patient's blood.

A non-invasive testing method comprises the steps of: using a driver, outputting an output signal via at least one antenna to the skin of a patient; measuring, using a processor, a response signal via at least one antennas, the response signal being a function of the output signal modified by an interaction with patient's blood; the method being characterised by the step of analysing the response signal and determining from the analysis, a concentration of a target substance in the patient's blood.

In certain embodiments of the invention, the non-invasive testing apparatus comprises an antenna via which the output signal is sent, and the response signal is received.

In other embodiments of the invention, the non-invasive testing apparatus comprises a first antenna via which the output signal is sent, and a second antenna via which the response signal is received.

The response signal can be either or both of: a transmitted signal (i.e. in which the first and second antennas are placed on opposite sides of a target body part, such as an ear lobe) and/or a reflected signal (i.e. in which the antenna, or the first and second antennas are placed on one side of a body part, and the output signal is reflected off a structure within the body part back to the antenna, or second antenna). In the case of a transmitted signal, the first and second antennas can be placed side-by-side on one side of the target body part, but the gain (the sensitivity of the antenna in a certain direction, as indicated schematically by the lobes in <FIG>) of the first and second antennas is suitably configured (by virtue of the antenna design) to be directional, such that the output signal is directed towards the second antenna, and such that the gain (directionality, or direction of increased sensitivity) of the second antenna is biased/angled towards the direction of the first antenna.

The ability to use one or more antennas on one side of a body part is particularly advantageous for many reasons, chief of which being removing variables such as the dimensions of the body part.

The driver suitably comprises a signal driver adapted to output signals in the <NUM> to <NUM> range. In one embodiment of the invention, the driver is adapted to output a scanning output signal. In other embodiments of the invention, the driver is adapted to output a series of output signals at discrete frequencies or frequency ranges. By outputting output signals over a continuous range of frequencies, or in frequency steps, it is possible to conduct spectroscopic analysis of the patient's blood.

Additionally or alternatively, the driver is suitably configured to output a short- duration (typically <NUM> to <NUM>) burst signal. In such a situation, the processor is suitably adapted to transpose response signal from the time domain to the frequency domain (for example, using a Z-transform) to obtain a frequency spectrum. Such a configuration can greatly shorten the time taken to perform an analysis of the patient's blood.

Additionally or alternatively, the apparatus may comprise a plurality of frequency- matched antennas, that is to say, antennas tuned to particular bandwidths. In such a situation, the driver may be configured to output a corresponding plurality of narrow- bandwidth output signals to each of the frequency-matched antennas. Such a configuration provides a number of distinct advantages: by frequency-matching the antennas to relatively narrow bandwidths, an improved signal resolution and responsiveness can be obtained; and it is possible to multiplex the signals, such that a quasi-spectrum is obtained in much quicker time, that is to say, by simultaneously outputting, and receiving at, a plurality of discrete bandwidths.

The processor can be integrated into the non-invasive testing apparatus, or it can be physically or logically separate from it. In certain embodiments, the invention comprises an
I/O interface that operatively connects the driver and processor to a supplementary processing unit, which can be located, for example, in a dedicated processing unit, smartphone, tablet PC or PC type device. By such means, the complex data processing functions can be carried out in firmware, or an application, of a higher-powered device separate from the main body of the non-invasive testing apparatus itself. It will be appreciated that such a configuration may also enable the supplementary processing unit to be located on a cloud-based server, for example, via the internet, thus enabling a number of users (e.g. the patient, a medical practitioner, relatives and so on) to access the test results in real-time or subsequently.

According to an embodiment of the invention, the or each antenna is operatively coupled to the skin of a patient. Suitably, this can be accomplished by the or each antenna comprising a flat, planar, or patch antenna, which can be placed in direct contact with the user's skin. Additionally or alternatively, a coupling medium may be interposed between the or each antenna and the patient's skin, for example, a gel or cream applied to the skin or antenna prior to carrying out a test. In certain embodiments of the invention, a superstrate material encapsulates the antennae, which material provides a match with the skin.

According to the invention, and further to the foregoing, the processor is adapted, in use, to measure a response signal via at least one of the antennas. The processor may be configured to record the response signal and pass it to a supplementary processor, such as described above. Additionally or alternatively, the processor of the non-invasive testing apparatus itself may be adapted to analyse the response signal and to determine from the analysis, a concentration of a target substance in the patient's blood.

The non-invasive testing apparatus suitably comprises one or more human interface devices (HIDs), such as a start/stop button for initiating and/or terminating a test. The start/stop button, in certain embodiments, may be incorporated into a housing of the non-invasive testing apparatus, for example, as a slide switch interposed between two relatively moveable parts of a housing for the non-invasive testing apparatus. By such means, a user may depress a housing of the non-invasive testing apparatus onto the skin, thereby initiating and/or terminating a test. The HID may additionally comprise indicator means, such as an LED and/or a beeper, to provide feedback to the user, such as "test initiated", "test in progress", "test complete", "test error" etc. It will be appreciated that different combinations of LED colours and flashing sequences, or beep combinations, could be used to signify the different statuses of the non-invasive testing apparatus.

Additionally or alternatively, the HID comprises a display screen, which can be used to display the different non-invasive testing apparatus statuses and/or a test result.

The non-invasive testing apparatus may additionally comprise a memory for storing previous test results, which can be displayed on a display screen of the HID, as desired, but this is an optional, albeit preferred, feature of the invention. Embodiments of the invention may also have the facility to connect directly, or indirectly, via an interface cable to a PC, laptop, tablet device etc., such that the data can be downloaded, e.g. for offline analysis subsequently.

A particular problem that exists in relation to making RF measurements, such as is contemplated by the foregoing embodiment(s) of the invention, is a need for accurate signal generation and signal processing to be able to analyse the results of a test. In particular, when an antenna is used to transmit an RF signal into a sample, and a response detected simultaneously/subsequently, a great deal of signal processing needs to be carried out in order to obtain readings of the parameters of the test sample.

In order to achieve this, it is usually necessary to use a network analyser-type device, which has a sophisticated signal generation component as well as a sophisticated signal processing component. A network analyser is an extremely sensitive device and is generally very costly, which makes it generally unsuitable for use as a portable and/or low-cost device.

Furthermore, a network analyser can be very difficult to configure and can be highly susceptible to physical variables, such as the cable routing and/or configuration etc. when obtaining a result. As a result, it can be extremely difficult to obtain accurate, reproducible, and/or consistent test results in RF-based systems.

Of particular concern, in the context of the invention, is the reproducibility of the test on a given patient from one time to another. One reason for this is the use of fly leads to interconnect the network analyser with the transmit/receive antennas. Even though the fly leads may be well-shielded and efficiently coupled to the antennas, movement of the fly leads during a test procedure can result in errors occurring. Therefore, it is imperative that the test subject/specimen is kept completely still during the test, which can be inconvenient.

More importantly, however, the reproducibility of an RF-based test can be difficult to achieve due to differences in the physical set-up of the system from one test to another. Because it is not possible to precisely reproduce the exact physical configuration of the network analyser and test subject from on test to another (i.e. tests taken at different times, even with the same patient), test results have been found to be error-prone and subject to considerable drift, which may be attributable, in part, to changes in the RF properties of the test subject, but also in terms of the physical set-up during the test.

Unfortunately, it is not easy to differentiate between intrinsic variations (for example changes in the blood sugar level of a test patient) and extrinsic factors (such as differences in the fly lead configuration, RF interference, etc.). This leads RF-based testing being somewhat susceptible to errors and false results.

A need therefore exists for a solution to this problem, which is set forth in the appended claims.

By splitting the RF signal at the node into two components at the node, namely: a first component that analyses the specimen, and a second component that goes through a reference circuit, and then by adjusting the reference circuit such that the difference between the test and reference components is zero, the apparatus effectively becomes immune to many of the extrinsic variables of the test. Furthermore, by carrying out the test in this way, the signal generator can be greatly simplified, as can the signal analysis, which can be carried out by the microprocessor instead of by a network analyser-type device.

Suitably, the RF signal generator comprises a stable resonator circuit capable of outputting an RF signal having a substantially constant amplitude, frequency, and phase. The RF signal generator can, in certain embodiments, comprises means for selectively adjusting any one or more of the amplitude, frequency, and phase of the RF signal at its output. Preferably, the RF signal generator is adapted, in use, to continuously adjust (sweep) any one or more of the frequency, amplitude, and phase of the RF signal at its output; or in certain embodiments, to incrementally adjust (step-change) any one or more of the frequency, amplitude, and phase of the RF signal at its output. This greatly simplifies the RF signal generation, compared with the use of a network analyser.

In certain embodiments, the RF signal generator comprises a quartz crystal resonator; or a plurality of quartz crystal resonators, each being configured to output a different frequency, amplitude and/or phase RF signal. Switch means is suitably provided for selectively connecting a selected one of the plurality of quartz crystal resonators to the RF signal generator's output such that the RF signal generator can selectively output an RF signal having a selected frequency, amplitude and/or phase.

Preferably, the effective signal path lengths of the conductors carrying the first and second signals between the input node and the inputs of a comparator are equal or sustainably equal. This configuration reduces any variability based on signal transmission through the apparatus, and hence inherent differences in the outputs of the two signal paths.

In a preferred embodiment of the invention, the first signal is coupled to the test specimen via one or more antennas. The antenna or antennas may be of any suitable configuration, but especially of any configuration as previously and herein described.

In certain embodiments of the invention, the comparator comprises bridge-type circuit, such as a Wheatstone bridge. A bridge circuit provides a relatively simple, analogue means for obtaining a difference between (and optionally a sum of) two signals at its inputs. Bridge circuits are relatively inexpensive, reliable, and simple devices, which is an advantage in a portable device.

The circuit may further comprise an RF demodulator interposed between the comparator output and the microprocessor input and optionally a low-frequency demodulator interposed between the comparator output and the microprocessor input. The demodulator(s) where provided, are suitably adapted to provide a DC signal or PWM signal at the input of the microprocessor, which is proportional to the difference between the first and second signals.

The data signal indicating the amplitude and phase of the reference circuit where the comparator output is zero, or substantially zero is preferably represented on a display device, such as a display screen, an LCD panel, or one or more dials. This display may be numerical, or graphical. Preferably, means is provided for displaying a concentration of the target substance based on the phase and amplitude values required to cause the reference circuit to equal/balance the test circuit.

One or more fly leads may be used to connecting any one or more of: the RF signal generator and the input node; the comparator output and the microprocessor input; and the microprocessor's control output and the reference circuit. The fly lead or fly leads, where provided, may comprises detachable connectors.

Preferably, the reference circuit comprises both coarse and finely adjustable variable attenuators and variable phase shifters. A possible advantage of this configuration is that the coarse adjustments can be set (roughly) to the settings of a previously-carried-out test, such that the variable attenuator and variable phase shifter settings are approximately correct at the start of a subsequent test. This can speed-up the test procedure considerably if, for example, the settings of the variable attenuator and variable phase shifters are approximately correct at the start of a test.

In another possible embodiment of the invention, the transmit and/or receive antennas are incorporated into a self-adhesive plaster-type device, which can be adhered to the patient's skin. The advantage of this configuration is that, provided the plaster-type device is not removed and/or repositioned between tests, the tests will be constantly carried out on the same part of the body, which removes many of the extrinsic variables described herein, which often plague RF and/or non-invasive testing. However, unless the entire test circuit (signal generator, signal processor, display/output) is also to be incorporated into the plaster-type device (which could/would be uneconomic and difficult in practice), then fly-leads are needed to connect the plaster-type device to the RF signal generator and analyser. However, the use of fly leads, as described herein, can be problematic as they tend to introduce difficult-to-quantify and/or variable and/or unquantifiable variables in the signal transmission system -that is to say, the part of the circuit between the RF signal generator and the antenna(s) and/or between the antenna(s) and the signal analyser.

A need therefore exists for a means for determining, and hence factoring-out, variables in the signal transmission system. A calibration apparatus may be provided, which comprises: an antenna connected to a connector having an input connected, in use, to an RF signal generator and/or analyser; and switch means interposed between an output of the connector and the antenna, the switch means having an input connected to output of the connector, a first output connected to the antenna(s), a second output connected to an open circuit, a third output connected to ground, and a fourth output connected to a reference load, wherein the switch means can be actuated to connect the connector to each of the four outputs individually such that, in use, the antenna can be calibrated relative to a signal transmission system connected to the input of the connector.

The switch means can be of any suitable type, such as a relay, mechanical switch, MEMS switch, a transistor, MOSFET, etc. However, preferably, the switch means comprises a solid-state switch, which is advantageous because it has no moving parts and is therefore less likely to alter the calibration due to physical movement, arcing, vibration, power surges etc..

Suitably, the calibration apparatus is incorporated into a clamp-type tester, which can be clamped onto a body part, such as an ear lobe of a patient. The clamp-type tester suitably comprises opposing antennas (a transmit and a receive antenna) and a calibration apparatus is suitably, therefore provided for each of the antennas.

In a preferred embodiment of the invention, the reference load comprises a 50Ω load.

In order to calibrate the antenna, the switch means can be actuated to cycle an input RF signal to each of its four outputs, namely to the open circuit, shirt-circuit, reference load, and the antenna, and the measured response can be analysed at each of the four switch positions. Then, a calibration algorithm can be applied (such as a calibration matrix) to calibrate the antenna and this factor-out any variables associated with the transmission system. By placing the calibration apparatus immediately before the antenna(s), all of the variables in the transmission system can (in many cases) be accounted for, thus improving the reliability and/or reproducibility of a test procedure.

Where the calibration apparatus is incorporated into a clamp-type tester, as previously described, the switch means may further comprise a fifth output/position, which connects the output of a first connector (associated with a first antenna) to an output of a second connector (associated with a second antenna). This provides a "bypass" or "pass-though" signal path, which bypasses both antennas, and thus enables the transmission system to be calibrated independently of the antennas and any test specimen therebetween.

It will be appreciated that the calibration apparatus can be readily miniaturised, and is relatively inexpensive, and so can be incorporated into a disposable plaster-type antenna device, which can be used on a patient.

A plaster-type antenna with a connector could be worn underneath a wrist-watch type device containing an RF signal generator, RF signal analyser and/or display as described herein.

Various embodiments of the invention shall now be described, by way of example only, with reference to the accompanying drawings, in which:.

Referring to <FIG> of the drawings, an embodiment of a non-invasive testing apparatus <NUM> comprises a main body portion <NUM> formed of a first generally cylindrical part <NUM> and a second generally cylindrical part <NUM> nested, and slidingly receivable within the first part <NUM>. The second part <NUM> has a generally planar end surface <NUM>, upon which are disposed three patch antennas <NUM>, <NUM>, <NUM>, which, in use, are placed in contact with the skin of a patent. The non-invasive testing apparatus <NUM> further comprises an end cap <NUM> which fits over the second part <NUM> when the non-invasive testing apparatus <NUM> is not in use, to protect the patch antennas <NUM>, <NUM>, <NUM>.

The first part <NUM> of the main body <NUM> comprises a display screen <NUM>, an LED indicator <NUM>, a beeper <NUM> and a manual push-button <NUM>, whose functions shall be described below. The main body <NUM> houses a driver circuit (not shown) and a processor (not shown), which are operatively connected to the patch antennas <NUM>, <NUM>, <NUM>.

To use the non-invasive testing apparatus <NUM>, a patient places the end cap <NUM> over the second part <NUM> and presses the push button <NUM> to start a calibration sequence. The end cap <NUM> comprises an insert <NUM>, which is formed from any one or more standard materials (preferably three standard materials) having known properties. When the end cap <NUM> is fitted onto the main body, as shown in <FIG>, the insert <NUM> contacts the patch electrodes <NUM>, <NUM>, <NUM>, enabling the driver (not shown) and the processor (not shown) to start a calibration sequence.

The end cap <NUM> comprises an annular metal rim <NUM> that forms an electrical connection, when placed onto the main body <NUM>, between a pair of electrodes <NUM> located on an abutment edge <NUM> of the first part <NUM> of the main body <NUM>. Forming a connection between the electrodes <NUM> signifies to the processor (not shown) that the end cap <NUM> is correctly seated on the main body <NUM> with the insert <NUM> in contact with the patch electrodes <NUM>, <NUM>, <NUM>.

During the calibration sequence, the display screen <NUM> shows a calibration symbol <NUM>, and a progress indicator <NUM> counts down the calibration sequence. Once the calibration sequence is complete, the LED <NUM> illuminates green and the beeper <NUM> beeps to signify this to the patient.

The end cap <NUM> can then be removed, and the non-invasive testing apparatus <NUM> is ready for use.

As shown in <FIG> of the drawings, the patient presses <NUM> the patch electrodes <NUM>, <NUM>, <NUM> against his/her skin, and the second part <NUM> of the main body <NUM> retracts against the action of a spring, into the first part <NUM>. An internal micro switch (not shown) detects when the second part <NUM> has been fully depressed into the first part <NUM>, thus triggering the start of a test.

At this point, the driver (not shown) sends one or more output signals to one or more of the patch antennas <NUM>, <NUM>, <NUM>, and the processor (not shown) monitors the response(s). The processor (not shown) analyses the responses and calculates a concentration of a target substance (e.g. blood sugar) and indicates this as a numerical value <NUM> on the display screen <NUM>. During the test, the LED <NUM> illuminates amber, and during the calculation the LED <NUM> flashes amber and the progress indicator <NUM> scrolls. Once a result has been calculated, the LED <NUM> illuminates green and the beeper <NUM> beeps to signify this to the patient. A validation symbol <NUM> can also be shown on the display screen <NUM> to indicate the confidence of the test, i.e. whether the test should be repeated.

Another useful feature of the non-invasive testing apparatus <NUM> is that it can also take a pulse reading and display this to the patient during, or after a test.

In the embodiments of <FIG> described above, there are three patch antennas <NUM>, <NUM>, <NUM> formed on a surface <NUM> of the second part <NUM> of the apparatus <NUM>. A first one of the patch antennas comprises a transmitter antenna <NUM>, which is operatively connected to the driver <NUM>. Meanwhile, a second one of the patch antennas comprises a receive antenna <NUM>, which is operatively connected to the processor <NUM>. The third patch antenna <NUM> is interposed between the transmit <NUM> and receive <NUM> antennas.

Referring now to <FIG> of the drawings, it can be seen that the configuration described previously sees the three antennas <NUM>, <NUM>, <NUM> placed side-by-side and in contact with the skin <NUM> of a patient. The antennas <NUM>, <NUM>, <NUM> are encapsulated in a matching material <NUM>, which matches the surface <NUM> of the second part <NUM> with the skin <NUM> of a patient.

The transmit <NUM> and receive <NUM> patch antennas are designed so as to have a directional gain, as indicated schematically by the lobes <NUM>, <NUM> in <FIG>. In alternative embodiments (not shown), the patch antennas <NUM>, <NUM> could be angled relative to the surface <NUM> to obtain a similar effect. Thus, a signal <NUM> is emitted into the patient's skin from the transmit antenna <NUM> at an angle, and the gain <NUM> of the receiver antenna <NUM> is directed towards the transmitted signal <NUM> to receive it. Thus, the processor <NUM> is able to compare <NUM> the difference between the transmitted signal <NUM> and the received signal <NUM> to perform an analysis of the blood within the patient's skin <NUM>.

In certain situations, the skin <NUM> may comprise sub-cutaneous structures <NUM>, such as bone, which reflect the transmitted signal. The third antenna <NUM> is operatively connected to the processor <NUM>, and is configured to pick up signals <NUM> reflected off such structures <NUM>. The third antenna <NUM> can, in certain embodiments, serve both as a transmit and as a receive antenna, in which case it is operatively connected <NUM>, <NUM> to the driver <NUM> and the processor <NUM> to analyse reflected signals <NUM>.

A further alternative embodiment of the invention is shown in <FIG> of the drawings, in which the non-invasive testing apparatus <NUM> comprises a probe jack <NUM> into which the plug <NUM> of a fly lead <NUM> can be inserted. The fly lead <NUM> carries at its free end, a clip device <NUM> comprising opposable pads <NUM> each comprising a transmit <NUM> and a receive <NUM> patch antenna. The clip device <NUM> can be clipped onto the earlobe, or fingertip, say, of a patient, and the test performed in a manner similar to that previously described.

In this configuration, the device could measure the transmission and reflected characteristics of a part of the body that does not have a natural reflecting internal structure like, but not restricted to bone, or cartilage.

In this example, the clip device <NUM> can be clipped onto a protrusion <NUM> manufactured of a calibration material, which protrusion extends from the end cap <NUM>, to enable a calibration sequence to be performed.

In a yet further embodiment of the invention, as shown in <FIG> of the drawings, the non-invasive testing apparatus <NUM> is formed as a wand-type device <NUM>, which can be placed, for example, onto the wrist <NUM> of a user's hand <NUM>. In this embodiment, the directional patch antennas (not visible) are located on the side of the device <NUM>. This enables the device to be applied, but is not limited to the wrist and forearm. The non-invasive testing apparatus <NUM> has one or more antennas (not visible) on its underside, which make contact, in use, with the skin of the patient. Usefully, this configuration can make use of the relatively high blood flows present under the skin in the wrist region (radial pulse region), as well as the presence of hard bone structures (ulna and radius) located close to the skin surface.

In embodiments of the invention, the antennae <NUM>, <NUM>, <NUM> function both in transmission and reflection mode. In this manner both the S21 (transmission) and S11 (reflected) signals are measured. The correlation between the blood glucose level and the S11 parameter is derived, together with the S21 parameters such as the resonance frequency shift, "Q" factor of the resonance, group delay, phase, and amplitude variation. In this manner when both the S21 & S11 data are used together, a more accurate value of the blood glucose level is calculated.

<FIG> of the drawings is a normalized plot of the magnitude <NUM> of the received transmitted <NUM>, <NUM> and received <NUM>, <NUM> signals as a function of frequency <NUM> at different blood glucose levels. As can be seen by observing the transmitted signals <NUM>, <NUM> in the S21 domain, there are characteristic troughs <NUM> whose positions move as a function of blood sugar concentration. The processor is thus adapted to monitor the points of inflection, i.e. their magnitude and frequency, and to compare these measured values with those in a prepopulated lookup table, from which the blood sugar concertation can be derived. Further, it will be noted that the magnitude <NUM> of the S21 plot, at certain frequencies <NUM>, changes dependent on the blood sugar concentration, and the processor can be configured to look-up the magnitude <NUM> at these target frequencies <NUM> in a pre-populated lookup table to determine the blood sugar concentration.

It will also be seen from <FIG>, that in the S21 domain, certain characteristic troughs <NUM> appear at certain blood sugar concentrations. Again, by observing the appearance of these troughs <NUM>, the blood sugar concentration can be observed by reference to lookup tables.

More detailed analysis of the S21 plot <NUM>, <NUM> can reveal finer textured information, such as from the shape and width of the troughs <NUM>, <NUM>, as well as their frequency and amplitudes. More detailed analysis can be used to verify that the observed effects are consistent with a target substance in the blood (e.g. blood sugar) as opposed to other contamination (e.g. blood alcohol), in which the shape of the observed troughs <NUM>, <NUM> might be different.

In the S11 domain (the reflected signal), the analysis is more subtle, and requires the processor to analyse the overall shape <NUM>, <NUM> of the plots <NUM>, <NUM>. It will be apparent from <FIG> that in the S11 domain, there are parts <NUM> of the magnitude <NUM> - frequency <NUM> plot that are largely independent of the concentration of the target substance (e.g. blood sugar), whereas other parts <NUM>, <NUM> are dependent on the concentration of the target substance (e.g. blood sugar). Again, these variations as a function of concentration of target substance can be used to obtain the concentration of a target substance (e.g. blood sugar) using, for example, calculations or look-up tables.

One advantage of using both transmitted signal <NUM>, <NUM> analysis and reflected signal <NUM>, <NUM> analysis, is the ability to cross check the results to obtain higher accuracy readings, or to provide a failsafe against incorrectly interpreting the presence of contaminants. <FIG>, for example, is a schematic scatter graph showing the correlation between the S21 and S11 data <NUM>, and if a test result <NUM> falls outside statistically acceptable boundaries <NUM>, then the confidence of the test result can be questioned, for example, indicating that a re-test is required, or alerting the patient to the possibility of other contamination.

Nevertheless, as can be seen from <FIG> of the drawings, which is a plot on the vertical axis of S21 or S11 measurement versus blood glucose concentration on the horizontal axis at three different frequencies (f1, f2, f3), that there is a correlation between measured S21 or S11 values and the blood glucose concentration. <FIG>, which is schematic, also includes trendlines, which correspond to "polynomial models", or equations, for blood glucose concentration at each of the frequencies. It can be seen that statistical outliers are easily identified from this and can be disregarded from certain test results.

<FIG> of the drawings shows how the frequency specificity shown in <FIG> of the drawings can be capitalized upon by using a number of relatively narrow-band antennas, for example, each being tuned to specific narrow frequency bands <NUM>, <NUM>, <NUM>, <NUM>, <NUM> in which target observations are required. The use of a set of relatively narrow-band antennas enables observations to be made at numerous frequencies simultaneously, thus reducing the time taken for a scan/spectroscopic analysis; as well as increasing the sensitivity of the antennas in their frequency bands, rather than employing a less-sensitive broadband antenna.

The frequency sweep, transmitter & detector circuits may be generated as defined in Patent <CIT> and its derivatives/family.

In another embodiment, an impulse signal may be generated into the biological tissue and the Fast Fourier Transform performed on the received/detected signal in order to derive the frequency response of the system.

Referring to <FIG> of the drawings, a circuit <NUM> comprises an RF signal generator <NUM> adapted, in use, to provide an RF signal at its output <NUM>. The RF signal generator <NUM> is connected, via a fly lead <NUM> to a test device <NUM> in accordance with an aspect of the invention. The fly lead <NUM> connects to an input <NUM> of the test device <NUM>, which connects to an input node <NUM> that splits the RF signal equally into a test component <NUM> and a reference component <NUM>. A resistor, <NUM> is used to balance the test <NUM> and the reference <NUM> components.

The test component <NUM> is transmitted into a sample <NUM> for analysis. Transmission of the test component <NUM> into the sample <NUM> is typically accomplished by way of a transmit and/or receive antenna (not shown), which couples the test component <NUM> of the RF signal to the sample <NUM> and receives a response signal <NUM>.

Meanwhile, the reference component <NUM> of the RF signal passes through an adjustable reference circuit <NUM>, which comprises one or more variable attenuators <NUM>, <NUM>, and one or more variable phase shifters <NUM>, <NUM>.

The output <NUM> of the adjustable reference circuit <NUM>, along with the output <NUM> of the test component <NUM> of the RF signal are provided as inputs to a comparator <NUM>. Typically, the comparator <NUM> comprises an analogue bridge-type circuit, such as a Wheatstone bridge-type device, which has a summing output <NUM>, which is not relevant to this disclosure, and a difference output <NUM>, which is relevant to this disclosure. The difference output <NUM> is the difference between the output <NUM> of the test component <NUM> of the RF signal and the output <NUM> of the adjustable reference circuit <NUM>.

If the output <NUM> of the test component <NUM> of the RF signal is equal to the output <NUM> of the adjustable reference circuit <NUM>, then the difference <NUM> at the output of the comparator <NUM> will be zero. Thus, if the adjustable reference circuit <NUM> can be adjusted such that its amplitude and phase match the specimen under test <NUM>, then the adjustable reference circuit <NUM> will essentially be an analogue of the test specimen <NUM> and the difference output <NUM> of the comparator <NUM> will be zero. The key, therefore, is adjusting the adjustable reference circuit <NUM> to meet these criteria.

In order to achieve this, an RF demodulator <NUM> is provided downstream of the difference output <NUM> and that is connected, via a fly lead <NUM> to a microprocessor <NUM>. An amplifier/demodulator/signal processing device <NUM> may be interposed between the difference output <NUM> and the microprocessor <NUM>, and the details of this <NUM> are beyond the scope of this disclosure as they will be readily-understood by the skilled reader. Nevertheless, it will be appreciated, that the difference <NUM> of the comparator <NUM> provides an input <NUM> for the microprocessor <NUM>, which is suitably a DC signal that is proportional to the difference <NUM> at the output of the comparator <NUM>; and/or a PWM signal that is representative of the difference <NUM> at the output of the comparator <NUM>.

The microprocessor <NUM> has an output <NUM>, which is typically connected, via a fly lead <NUM>, to the adjustable reference circuit <NUM>. The output <NUM> of the microprocessor <NUM> contains signals which can be used to adjust the parameters of the variable attenuators <NUM>, <NUM> and the phase shifters <NUM>, <NUM>.

The microprocessor effectively executes an algorithm, which adjusts the variable attenuators <NUM>, <NUM> and the phase shifters <NUM>, <NUM> incrementally or continuously until the zero-output condition <NUM> at the output of the comparator <NUM> is met.

There are various ways that his may be achieved in practice and they will be readily apparent to a person skilled in the art. Nevertheless, and for the purposes of clarification only, in one possible embodiment of the invention, the variable attenuators <NUM>, <NUM> are adjusted (up/down) until the output <NUM> of the comparator is minimised (i.e. reaches a minima); then, the phase shifters <NUM>, <NUM> can likewise be adjusted (up/down) until the output <NUM> of the comparator <NUM> is minimised yet again. This process can be repeated over and over until such time as the output <NUM> of the comparator <NUM> reaches a minimum, which is ideally a zero output. If/when a zero output, or a substantially zero output <NUM>, of the comparator is obtained, then the amplitude and phase of the adjustable reference circuit <NUM> are essentially an analogue of the test specimen <NUM>. Thus, the adjustment settings of the adjustable reference circuit are equivalent to the amplitude and phase, and hence, are representative, of the parameters of the test specimen <NUM>. These parameters can be outputted <NUM> to a display <NUM> and therefore it is possible to ascertain the amplitude and phase equivalence of the specimen under test.

Ideally, these parameters are not presented to a user in a "raw" state, but are processed in such a way as to provide an indication of the concentration of a target substance, which is ultimately the information that the end-user wants/needs. This can be presented graphically and/or numerically and/or audibly (the latter being beneficial for non-sighted patients and/or where the display may not be easily visible).

It will be appreciated that due to the input node, the test component <NUM> and reference component <NUM> of the RF signal are equal and because they are compared immediately after the specimen test <NUM> and immediately after the adjustable reference circuit <NUM>, they are effectively independent of the remaining conditions of the circuit, namely the fly leads, etc..

It will also be appreciated that in practical embodiments of the invention, the three fly leads <NUM>, <NUM>, <NUM> could/would be combined into a single fly lead, but this is not essential.

Nevertheless, it will be appreciated that the apparatus as described herein, greatly simplifies an RF measurement because it avoids the need for complex signal generating and signal processing devices, such as network analysers. It is also independent of the physical configuration of the set-up and is thus more immune to extraneous variations in its test results.

In certain embodiments of the invention, the RF signal generator <NUM> comprises a signal generator that is adapted to output an RF signal <NUM> at its output, which has a specific frequency, phase, and amplitude. This could, in certain embodiments, be achieved by using a quartz crystal resonator tuned to a particular frequency, although other RF signal generation technologies are within scope of this disclosure. Nevertheless, it will be appreciated that the parameters of the adjustable reference circuit <NUM> can be adjusted, by the microprocessor <NUM>, to obtain an analogue of the sample under test <NUM> for a particular RF signal outputted <NUM> from the RF signal generator. Once a test result has been obtained, and optionally outputted <NUM>, the RF signal generator <NUM> can be adjusted to provide a different RF signal, for example having a different frequency, amplitude and/or phase. The test procedure can be repeated for this new RF signal and a further set of parameters obtained.

The RF signal generator <NUM> can be configured to "sweep" a particular frequency range, that is to say to vary the frequency of the output continuously, in which case the microprocessor <NUM> must be capable of "following" that sweep and determining the parameters of the adjustable reference circuit <NUM> almost in real-time. Alternatively, the RF signal generator <NUM> may be configured to step through a series of discreet frequencies and the microprocessor <NUM> can thus be configured to obtain the parameters of the adjustable reference circuit <NUM> for each increment of the output signal <NUM> of the RF signal generator <NUM>. In either case, it is possible to obtain a "spectral" analysis of the sample under test <NUM> and thus yield the RF properties of the sample under test <NUM>.

Referring now to <FIG> of the drawings, a method by which the microprocessor <NUM> obtains the parameters of the variable attenuators <NUM>, <NUM> and the variable phase shifters <NUM>, <NUM> to achieve the zero-difference output <NUM> is shown. In <FIG>, the difference (Δ) at the output <NUM> is plotted on the vertical axis, and the attenuation (A) and phase (θ) plotted on the horizontal axes. The microprocessor <NUM> varies the parameters of the variable attenuators <NUM>, <NUM> and the variable phase shifters <NUM>, <NUM>, as indicated by the path <NUM> until the difference (Δ) reaches zero <NUM>, or is minimised as much as possible. Obviously, any real surface plot of difference (Δ) versus amplitude (A) and phase (θ) will not be as shown in <FIG>, but <FIG> merely indicates how the microprocessor can "seek" the minimum <NUM> by varying together, or sequentially, the settings of the variable attenuators <NUM>, <NUM> and the variable phase shifters <NUM>, <NUM> of the reference circuit <NUM>.

Turning now to <FIG> and <FIG> of the drawings, a known wearable device <NUM> comprises a main body <NUM>, which has a strap <NUM> that passes around a wearer's wrist <NUM>. The main body <NUM> has a transmit/receive antenna <NUM> on its underside, in contact with the skin of a patient. The transmit/receive antenna <NUM> transmits an RF signal <NUM>, which is detected by a receive antenna <NUM> formed in a housing <NUM> located on the opposite side of a user's wrist. The attenuation and/or phase of the transmitted signal <NUM> is detected by the device <NUM> and a reading is thus obtained.

Additionally or alternatively, the housing <NUM> comprises an RF reflector that reflects a transmitted signal <NUM> back towards the transmit/receive antenna <NUM> of the main body <NUM>. Again, differences in the attenuation and/or phase of the reflected signal <NUM> are picked up by the transmit/receive antenna <NUM> of the wearable device <NUM> and a reading can thus be obtained.

It will be appreciated from the schematic illustration of <FIG>, that the known wearable device <NUM> requires the housing <NUM> to be at a fixed position relative to the main body <NUM> such that the transmitted signal <NUM> can be picked-up by a receiver <NUM> of the housing <NUM>; or so that the transmitted signal <NUM> can be reflected off the reflector of the housing <NUM> back to the transmit/receive antenna <NUM> of the main body <NUM>. To achieve this, some form of predetermined alignment <NUM> is required between the main body <NUM> and the housing <NUM>.

However, referring to <FIG> of the drawings, if the strap <NUM> is adjusted, for example to accommodate a different-sized wrist <NUM>', then the alignment of the main body <NUM> relative to the housing <NUM> is now broken. This can result in the transmitted signal <NUM> "missing" the receiver <NUM> incorporated into the housing <NUM>; or failure of the reflector of the housing <NUM> to reflect back the transmitted signal <NUM> in the manner previously described.

It will be appreciated, therefore, that adjustment of the wrist strap <NUM> to fit different user's wrist sizes can result in the known wearable device <NUM> becoming ineffective.

Turning now to <FIG> and <FIG> of the drawings, a wearable device <NUM> in accordance with embodiments of the invention is described. In this case, the wearable device <NUM> comprises a main body <NUM>, which comprises a transmit/receive antenna <NUM>, which sends a transmit signal <NUM> to a receiver <NUM> incorporated into a housing <NUM> placed opposite the main body <NUM>.

Additionally or alternatively, the transmit/receive antenna <NUM> can send out a signal <NUM> which is reflected off a reflector incorporated into the housing <NUM> to reflect the signal <NUM> back to the transmit/receive antenna <NUM> of the main body. It can be seen that the main body <NUM> and housing <NUM> are aligned and lie on a centreline <NUM>, which, ideally, passes through the centres of the main body <NUM> and housing <NUM> and, preferably still, at right angles to both.

The wearable device <NUM> comprises a strap <NUM>, which has a fixed end <NUM>, which passes around the left-hand side (in the drawing) of the user's wrist <NUM>, around a pully/roller <NUM> connected to the left-hand side (in the drawings) of the housing <NUM> and back around the user's wrist <NUM>. The strap <NUM> passes underneath (in the illustrated embodiment, although it could be over) the main body <NUM>, around a further set of optional guide rollers <NUM> and then around the right-hand side (in the illustrated embodiment) of the user's wrist <NUM> to a further roller <NUM>. The strap <NUM> then passes back around the right-hand side of the user's wrist (in the illustrated embodiment) and terminates in a free end <NUM>, which can be secured <NUM> back on Suitably, the at least one antenna is operatively coupled to the skin of a patient, and hence to the patient's blood.

It will be appreciated that the strap <NUM> has two strap portions <NUM>, <NUM> of approximately equal lengths on either side of the user's wrist <NUM>. This "pulley type" configuration means that when the free end <NUM> of the strap <NUM> is pulled, the strap will shorten equally on either side of the user's wrist <NUM> resulting in the housing <NUM> being drawn towards the main body <NUM> in a substantially straight line - thereby maintaining the desired alignment between the main body <NUM> and the housing <NUM>.

Turning to <FIG> of the drawings, it can be seen that the same wearable device <NUM> has been fitted to a different sized user's wrist <NUM>' and that the alignment of the main body <NUM> relative to the housing <NUM> has been preserved. It will be appreciated by comparing the invention of <FIG> with the prior art as illustrated in <FIG>, that in this case, adjustment of the strap <NUM> does not result in breaking the requisite alignment of the housing <NUM> relative to the main body <NUM> and therefore, the transmitted <NUM> and reflected <NUM><NUM> signals do not "miss" their respective targets, namely the receiver/reflector of the housing <NUM> located on the opposite side of the wrist <NUM> to the main body <NUM>.

Therefore, a wearable device <NUM> in accordance with embodiments of the invention, can be reliably fitted to different wrist sizes and still maintain its functionality, unlike known wearable devices <NUM> (as shown in <FIG> and <FIG>, for example) where adjustment to the strap <NUM> can result in misalignment of the housing <NUM> relative to the main body <NUM>, or in other words - unequal spacing on opposite sides of the wrist between the main body <NUM> and the housing <NUM>.

Turning now to <FIG> and <FIG> of the drawings, another embodiment of a wearable device <NUM> in accordance with certain aspects of the invention is shown, schematically in cross-section. Again, the wearable device <NUM> comprises a main body <NUM> which is held onto a user's wrist <NUM> using an adjustable strap <NUM>. The strap can be adjusted using a clasp <NUM>, buckle or other suitable device.

In <FIG> it can be seen that the wearable device <NUM> is worn loosely around the wrist <NUM> and thus there is a small air gap <NUM> between the underside of the main body <NUM> and the skin surface <NUM> directly beneath it. The main body <NUM> comprises an RF antenna <NUM> which, in order to work correctly, needs to be coupled effectively to the surface <NUM> of the user's skin. With the wearable device <NUM> fitted loosely, as shown in <FIG>, this is not possible or reproducible due to the air gap <NUM> between the antenna <NUM> and the user's skin <NUM>.

To address this issue, the wearable device <NUM> comprises an inflatable air bladder <NUM>, which is interposed between a rear surface <NUM> of the antenna <NUM> and the main body <NUM>. The air bladder <NUM> can be inflated using a pump, which in the illustrated embodiment, comprises a small sac <NUM> that can be pressed repeatedly to expel air into the bladder <NUM> via a small tube <NUM>.

Referring now to <FIG> of the drawings, it can be seen that the sac <NUM> has been pressed <NUM> repeatedly and air within it has been discharged, via the tube <NUM> into the bladder <NUM> which has now become inflated. Interposed between the sac <NUM> and the airbladder <NUM> is a one-way/pressure-relief valve <NUM>, which ensures, on the one hand, that air expelled from the sac <NUM> is directed into the bladder <NUM>; and which also prevents over-inflation of the airbladder. The setting of the pressure-relief valve <NUM> can be adjusted (or factory set) such that the internal air pressure <NUM> within the air sac <NUM> is sufficient to ensure that the force <NUM> applied by the antenna <NUM> onto the surface of the user's skin <NUM> is at least a predetermined press-on force.

It will be appreciated that because the airbladder <NUM> is inflated using air pressure, that the internal pressure <NUM> will be hydrostatic, that is to say applied evenly to the rear surface <NUM> of the antenna <NUM> and thus the press-on force <NUM> of the antenna <NUM> onto the skin surface <NUM> will be substantially even across the entire surface of the antenna <NUM> also.

Not shown in the drawings is an electronic air pressure sensor located within the air bladder <NUM>, which emits an audible and/or visual signal via a display/audible output of the wearable device <NUM> when the internal air pressure <NUM> was in the airbladder <NUM> is below the predetermined pressure. Thus, a user can, when either alerted or wishes to carry out a test, inflate the bladder <NUM> using the sac <NUM> by pressing <NUM> repeatedly upon it. Air from the sac <NUM> will be expelled into the bladder <NUM> to inflate it and - up to the point that the minimum required pressure has been reached, the audible and/or visual signal will sound/display indicating to the user to carry on pressing the sac <NUM>. Upon reaching the desired internal pressure <NUM>, the pressure relief valve <NUM> will operate to prevent further air entering, and thus over-inflating, the airbladder. At the same time, the air pressure sensor will trigger the wearable device <NUM> to stop emitting a "keep pumping" signal and thus the user can be sure that the air bladder has been correctly inflated, and the required press-on force <NUM> has been attained. An RF test, using the antenna <NUM> can then be commenced in a manner described herein.

It will be appreciated that the embodiment of the invention shown in <FIG> and <FIG> enables a wearable device <NUM> to be worn loosely/in accordance with user preference for most of the time, but readily enables the antenna <NUM> to be pressed onto the user's skin <NUM> with a predetermined and easily reproducible force thereby ensuring reproducibility of an RF test carried out using the antenna <NUM>. At the end of the test, the airbladder <NUM> can be deflated, at which point the "comfort setting" of the strap, <NUM> returns to its pre-test state and the user can carry on.

Turning now to <FIG> and <FIG> of the drawings, self-adhesive antenna patch <NUM> in accordance within embodiments of the invention is shown, which has on its underside, one or more antennas <NUM>, <NUM>, <NUM> as described previously with reference to <FIG>, <FIG> and <FIG>, etc. above. The antenna or antennas work in the manner previously described to obtain an RF test result. The underside of the self-adhesive antenna patch <NUM> comprises a central region <NUM> which is non-, or largely non-adhesive surrounded by a self-adhesive region <NUM> that is covered with a water-resistant, pressure-sensitive adhesive - as will be well understood to the skilled reader.

The self-adhesive antenna <NUM> can therefore be stuck onto a patient's skin (not shown) and remain there for a period of time. As such, during the time that the self-adhesive antenna patch <NUM> is adhered to the patient's skin, any test results obtained using the antenna(s) will be independent of variations in the location of the antennas relevant to the patient's body. This overcomes many of the extrinsic variables associated with taking RF readings on a patient that moves a lot.

The top side of the self-adhesive antenna patch <NUM> is shown in <FIG> of the drawings, and comprises a button type connector <NUM>, which provides one or more electrical contacts for a test circuit (not shown) interposed between the connector <NUM> and the antennas on the underside of the self-adhesive antenna <NUM> is a calibration circuit <NUM>, which shall be described below.

Referring to <FIG> of the drawings, the calibration circuit <NUM> is interposed between the connector <NUM> and the antenna, indicated schematically as <NUM> in <FIG>, <FIG>, although it will be appreciated that, in reality, the antennas <NUM> are more like those shown in <FIG> of the drawings. The connector <NUM> comprises a signal line <NUM> to which is applied a test RF signal <NUM> by a signal generator/analyser <NUM> connected, via a fly lead <NUM> to a complimentary connector <NUM> at its free end. The fly lead's connector <NUM> electrically connects to the connector <NUM> of the self-adhesive antenna <NUM> in a manner that will be readily understood. The fly lead <NUM> is shielded by a grounding sheath <NUM>, which is grounded <NUM> in the manner that will be readily understood to the skilled reader.

Therefore, a test signal <NUM> can be sent to the antenna <NUM> via the fly lead <NUM> and the calibration circuit <NUM>.

The calibration circuit <NUM> comprises a solid-state switch, which is a single pole-four throw switch having four output terminals. A first one of the output terminals <NUM> is not connected to anything and thus is an open-circuit connection. A second one of the output terminals <NUM> is connected to the antenna <NUM>. A third one of the output terminals <NUM> is connected to ground <NUM> via a reference load <NUM> (typically a <NUM>-ohm load). Finally, a fourth output terminal <NUM> is connected directly to ground <NUM>.

The input pole <NUM> of the solid-state switch <NUM> can thus be connected to any one of the four output terminals <NUM>, <NUM>, <NUM>, <NUM> to carry out an open-circuit calibration routine, a closed-circuit test routine and a reference load test routine. By putting these test results into a suitable matrix, the transmission system, that is to say the fly lead <NUM> and connectors <NUM>, <NUM> can be calibrated-out and thus the actual RF signal response of the antenna can be more accurately measured regardless of the instantaneous configuration of the fly lead <NUM> and connectors <NUM>, <NUM>.

It will be appreciated that being able to cancel-out any errors in the transmission system represents a big step forward in RF measurement because variables associated with the physical setup of the test apparatus can effectively be ruled-out using an in-situ calibration device. Additionally, because the in-situ calibration device <NUM> is relatively simple and inexpensive, it is possible to make this a "disposable" part of the self-adhesive patch antenna <NUM>, which in-turn facilitates mass production of the same.

The on-board/in-situ calibration apparatus previously described can, of course, be used on a transmit-receive system, such as a clamp-on device as shown in <FIG> of the drawings. Referring to <FIG> of the drawings, the clamp-on probe <NUM> comprises a transmit antenna <NUM> on one side of an earlobe <NUM> and a receive antenna <NUM> located on the opposite side of the earlobe <NUM>.

The probe <NUM> is connected via fly lead <NUM> to a RF signal generator analyser and is thus potentially susceptible to substantial amounts of extrinsic variables. However, by incorporating an on-board calibration device to each of the antennas <NUM>, <NUM>, it is possible to calibrate-out any such extrinsic variables in the manner previously described.

For the sake of completeness, a typical calibration device <NUM> suitable for us in conjunction with the probe <NUM> of <FIG> is shown. In essence, the calibration device comprises two calibration devices as shown in <FIG>, but with the addition of a bypass conductor <NUM> which bypasses the transmit <NUM> and receive antennas <NUM> and so a signal <NUM> can be transmitted from a transmitter <NUM> via a fly lead <NUM>/connector <NUM>, <NUM>, through the bypass conductor <NUM> and back to the signal generator/analyser <NUM> via the same, or a different fly lead <NUM>. It will be appreciated, that in this embodiment, the switch means <NUM> comprises a fifth throw position <NUM>, which enables the test signal <NUM> to be transmitted via the bypass conductor <NUM> directly back to the RF signal generator/analyser <NUM> and therefore, calibrate the fly lead <NUM> and connectors <NUM>, <NUM> out of the system.

It would also be appreciated that either of the switches <NUM> can be set to the previously described positions, namely open-circuit closed-circuit and reference load to calibrate each of the antennas <NUM>, <NUM> independently as well. It will be appreciated that the invention thus overcomes many of the practical restrictions/problems associated with using RF measurements techniques in situations where the subject and/or test equipment can move considerably.

Finally, referring to <FIG> of the drawings, a self-adhesive antenna patch <NUM> has been stuck to the patient's skin <NUM> on the patient's wrist <NUM> in a similar manner to that shown in <FIG> and <FIG> of the drawings. However, rather than having to tighten the strap <NUM>, or inflate an air bladder <NUM> to obtain the required contact between the antennas and the skin <NUM> of the patient's wrist <NUM>, this is semi-permanently achieved by using a self-adhesive antenna patch. The connector <NUM> comprises a button-type connector, which engages a complimentary socket <NUM> provided on the underside of a wearable device <NUM>. Thus, the wearable device <NUM> is able to achieve a calibrated connection to the self-adhesive patch antenna <NUM> whilst ensuring that the self-adhesive patch antenna always stays in the same place relative to the patient's wrist <NUM> from one test to the next.

Embodiments of the invention may allow the measurements taken to be transmitted to external devices to monitor their blood-glucose level whilst using their home computer or smart phone or similar device and allow for remote logging of blood-glucose levels. This feature could prove to be most useful for carefully monitoring the condition of elderly sufferers and enable medical practitioners to provide emergency help should the patient's levels become excessively high or low. Remote monitoring and data logging can also be used to provide a useful tool to the patient or the doctor/healthcare professional to develop a response plan to assist with the management of the disease.

Claim 1:
A non-invasive testing apparatus for determining a concentration of a target substance in a patient's blood, the non-invasive testing apparatus comprising:
an RF signal generator (<NUM>) adapted, in use, to output an output RF signal (<NUM>, <NUM>);
a processor (<NUM>, <NUM>); and
at least one antenna (<NUM>) operatively coupled, in use, to the patient's blood, the or at least one antenna (<NUM>) being operatively connected to the RF signal generator (<NUM>, <NUM>) and the processor (<NUM>,<NUM>), the processor being adapted, in use, to:
measure a transmitted or reflected response signal (<NUM>,<NUM>) via at least one of the antennas, the response signal (<NUM>, <NUM>) being a function of the output RF signal (<NUM>, <NUM>) modified by an interaction with the patient's blood,
measure the amplitude and phase of the response signal (<NUM>,<NUM>) at a plurality of output RF signal frequencies;
plot the measured amplitude and phase of the response signal (<NUM>, <NUM>) as a function of output RF signal frequencies;
using the plot, determine any two or more derived parameters of the response signal (<NUM>, <NUM>) from the group comprising: a Q factor of the resonance; a group delay; a shape factor of the plot; and a gradient of the plot at different frequencies; and to
determine the concentration of the target substance in the patient's blood by:
the processor (<NUM>, <NUM>) being adapted to:
compare the plurality of derived parameters with respective models of the respective derived parameters as a function of concentration of the target substance in blood;
to determine, for each derived parameter, a concentration of the target substance in the patient's blood based on a correlation between the respective derived parameter and the corresponding values of concentration of the target substance in the patient's blood in the respective model; and
to apply a statistical model to the resulting determined concentrations of the target substance in the patient's blood based on each derived parameter to arrive at a single, overall determined concentration of the target substance in the patient's blood.