GB2428093A - A non-invasive monitoring system - Google Patents

Abstract

An instrument to non-invasively measure information concerning biological systems using low power sources emitting energy in the microwave region of the electromagnetic spectrum. Phase and/or magnitude characteristics are measured using microwave measurement techniques and changes in said characteristics are used to provide information concerning said biological systems. More specifically, concentrations of various constituents contained within said biological system may be measured and, even more specifically, this invention may be used to non-invasively measure blood-glucose levels. This instrument comprises: an energy source (10, 170, 20), an antenna arrangement and mechanical attachment mechanism (70, 71, 90, 91, 92), a means of monitoring portions of forward and reflected energy (101, 60, 61, 51), a means of detecting frequency, phase and magnitude (100, 104), a means of signal processing (110), and a means of producing an output in a user friendly format (120).

Description

1 2428093

A NON-INVASWE MONITORING SYSTEM

FIELD OF THE INVENTION

The present invention relates to an instrument for non-invasively monitoring one or more parameters associated with the human biological system using low power microwave energy focussed into tissue structures, and microwave measurement techniques to determine information relating to said biological system in terms of changes in the magnitude and/or phase characteristic(s) as a function of frequency.

More particularly, the invention relates to an instrument capable of monitoring biological concentrations, in particular, concentrations of various types of constituents contained within biological fluid, and can be used to determine blood- glucose levels associated with both insulin-dependent and non-insulin dependent diabetes mellitus.

This invention describes a new instrument to generate and launch low power microwave energy into the biological system in a controlled manner to enable microwave measurements to be automatically carried out and measurement data manipulated to provide the patient with an accurate reading of blood- glucose level.

The instrumentation described in this invention may also be used to provide the patient with information regarding any corrective action necessary, based on the measured data. The instrument can be configured as a miniature, non-obtrusive transceiver to allow information to be transmitted to a personal computer or other remote monitoring station to provide a physician/doctor with information regarding the condition of the patient.

In this specification microwave means the frequency range from 300MHZ to 300GHZ, or where the energy is such that a microwave signal can propagate through a biological tissue structure that forms a part of the human anatomy and relevant characteristics can be discerned using appropriate measurement techniques and mathematical algorithms. Preferably the frequency range used in this invention is between 1GHz and 40GHZ, but more preferably between 8GHz and i8GHz.

BACKGROUND AND PRIOR ART

Given that this invention is related directly to an instrument to enable accurate, non- invasive measurement of blood-glucose level, that is, in this particular instance the biological fluid is blood and the constituent is glucose, it is most appropriate to provide a thorough background to the problem and to address other instruments and methods that are already in existence.

Diabetes mellitus (diabetes) is a disease in which the body does not produce or properly use insulin. In simplest terms, insulin is a hormone needed to convert sugar and starches into energy. In effect, 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. Since the glucose cannot enter the cells, the glucose concentration in the body builds up and, without treatment, the cells within the body end up starving to death. The measurement of blood-glucose is perhaps the most important measurement in medicine, as diabetes has immense public health implications. Diabetes is currently a leading cause of disability and death throughout the world.

The human body cannot store glucose in the cell structure, therefore, in order to keep active, a constant supply of fresh glucose is required to be supplied to the muscles, brain, heart and other organs. It is, therefore, important to keep the blood-glucose level at the correct level to prevent the body from running out of fuel. A person whose blood- glucose level is too low is said to be in a state hypoglycaemia, whilst a person whose blood-glucose level is too high is said to be in a state of hyperglycaemia. A hypoglycaemic brain (a brain through which the flowing blood contains too little glucose) shuts down its activity to conserve energy and so the diabetes sufferer may lose consciousness, but, on the other hand, a hyperglycaemic brain may result in the same action due to the fact that the mechanism (insulin) that transfers glucose out of the capillaries and into the tissues has failed to work. For the human body to function normally it requires a constant delivery of glucose to all of the tissues to enable them to act normally and to survive, and insulin is the mechanism for carrying out this function. Diabetes sufferers do not have this normal insulin mechanism and so the glucose in their bloodstream cannot reach the cells automatically, thus it is required to be able to monitor blood- glucose levels accurately to be able to take the necessary corrective action to ensure that the glucose can reach the cells as and when required.

Typical blood-glucose levels are as follows: Condition Blood- Glucose Level Action Required ____________________ mmol/L mg/dL ____________________ Hyperglycaemic >7 > 200 Patient requires insulin Normal 3 to 7 60 to 120 No action required Hypoglycaemic <3 <60 Patient requires sugar Hypoglycaemia can be symptomatic or asymptomatic, for example, patients suffering from postprandial hypoglycaemia generally have symptoms of adrenergic stimulation including diaphoresis, anxiety, irritability, palpitations, tremor, and hunger. Such symptoms typically occur from about two to four hours postprandially and tend to occur suddenly with symptoms subsiding in about fifteen to twenty minutes.

Hypoglycaemia can be caused by the release of adrenergic and cholinergic hormones.

Postprandial hypoglycaemia is often adiopathic, however, it can be caused by early diabetes, alcohol intake, renal failure and drug treatments. One category of hypoglycaemia is known fasting hypoglycaemia', which may have symptoms of neuroglycopenia including: headache, fatigue and mental dullness. In more severe cases, this can progress to confusion, blurring of vision, seizure and loss of consciousness. Fasting hypoglycaemia can be caused by insulinoma, which results from the wrong dosage of selfadministered insulin or intake of other hypoglycaemic agents, alcohol abuse, liver disease, pituitary insufficiency or adrenal insufficiency.

Diabetes is a chronic life threatening disease for which there is presently no cure. The cause of diabetes is not fully understood, but the following factors have been identified: environment, genetics and viruses. The high glucose levels that often result from this disease can cause severe damage to vital organs, such as the heart, the eyes and the kidneys.

Diabetes can be characterised as two different diseases; one normally starts at childhood and is caused by the failure of the pancreas to produce insulin, and requires daily insulin injections to sustain life. This category of diabetes is referred to by doctors as Type I diabetes, and is also known as: juvenile diabetes, childhood- onset diabetes and insulin-dependent diabetes mellitus (IDDM). Approximately 10% of diabetes patients suffer from Type I diabetes. Diabetics suffering from Type I diabetes are typically required to self- administer insulin using conventional means, for example, a syringe or a pin with needle and cartridge. Continuous subcutaneous insulin infusion via implanted pumps may also be used. Insulin itself is typically obtained from pork pancreas or is made chemically identical to human insulin by recombinant DNA technology or by chemical modification of pork insulin.

The second kind of diabetes normally starts in adulthood and is caused by the build- up of resistance to the action of insulin by tissue and organs contained in the body and can be considered as a metabolic disorder resulting from the body's inability to make enough, or to properly use, insulin. This category of diabetes is referred to by doctors as Type II diabetes, and is also known as adult-onset diabetes and noninsulin-dependent diabetes mellitus (NIDDM). Currently, Type II diabetes is nearing epidemic proportions due to the ever-increasing world population, a greater prevalence of obesity and sedentary lifestyle. Type II diabetes is often manageable with dietary modifications and physical exercise, but may still require treatment with insulin or other oral medications.

Without a high enough level of insulin (as in Type I diabetes), or when the insulin mechanism fails to shift the glucose out of the blood and into the tissues (as in Type II diabetes), blood-glucose levels rise because the necessary glucose cannot reach the cells. Both types of diabetes lead to higher risks of strokes and heart attacks, circulation problems, kidney failure and blindness.

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 counter the risk of diabetic complications. It is a recommendation of the medical profession that insulin dependent patients practice selfmonitoring 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. The most common method of measuring blood- glucose level 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 correspondence with 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. A nonexhaustive list of patents that cover various aspects of this technique is as follows: US5556761, DE3515420, JP20000749l5. A summary of these filings and other associated work is given in the reference section of this document.

The pricking procedure is somewhat messy and painful, particularly if the patient has to repeat the procedure several times during the day. Some patients tend to be squeamish at the sight of blood, particularly when the blood if their own. Often patients forego the messiness and pain associated with this invasive procedure, thereby leading to over-dosing or under-dosing of insulin, which can lead to disaster.

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 infection, and, even in the case of a sterilised needle, a wound is created which may become infected.

A further common glucose monitoring method involves urine analysis. This method tends to be most inconvenient 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 from tasting the patient's urine. Patent number U56o21339 describes in detail a modern day apparatus used for urine testing.

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.

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 (EP1419731). 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.

The most successful minimally invasive measurement technique involves the sampling of interstitial fluid from the skin. A system developed by Cygnus Inc., known as the GilucoWatch G2 Biographer uses low levels of electrical current to extract glucose molecules through the skin. The glucose is extracted from interstitial fluid that surrounds skin cells, rather than from blood. The system gathers and analyses current-time and charge time data to calculate blood-glucose level information. The GilucoWatch G2 Biographer has been given FDA approval and is commercially available. The drawbacks of this system are; it is still necessary to perform the finger prick test in order to calibrate the system and it is still necessary to withdraw a small amount of biological fluid (interstitial fluid) from the body during normal operation. A non- exhaustive list of patents associated with the GlucoWatch G2 Biographer is as follows: W02003o82o98, US6391643, W0o218936, DE69532282T, W096001o9, US2003l35loo, CA248o55o, and US20031954o3.

Many attempts have also been made to develop a painless, patient friendly, cost effective, non-invasive instrument to monitor blood-glucose levels. The non-invasive approaches considered include: electrochemical, spectroscopic technologies, such as near infrared spectroscopy, Ramen Spectroscopy and small scale NMR, measurements on lacrimal fluid (selfsampled tears), and acoustic velocity measurement techniques. However, none of these methods appear to have produced a marketable non-invasive device or method for in-vivo measurement of blood- glucose level that is sufficiently accurate, reliable, patient friendly, convenient and cost-effective enough to be used in routine use.

References [i] to [431 provide details of prior art relating to known instruments associated with blood-glucose monitoring systems and relate directly to the non- optimal methods introduced in the text above. This list has been provided for completeness.

None of the aforementioned instruments, together with associated patents, appear to address the use of microwave measurement techniques for carrying out blood- glucose level monitoring.

SUMMARY OF THE INVENTION

The invention described here overcomes the problems and disadvantages associated with the aforementioned instruments, and provide an alternative instrument for non- invasively monitoring blood-glucose level and concentrations of other biological fluid constituents.

This invention describes a new instrument and method using low power microwave energy and the processing of transmission and/or reflected backscatter information to accurately measure varying concentrations of constituents contained within the biological system, where said biological system is preferably a biological fluid and biological fluid is a bulk concentration of blood-glucose. Preferably, a sensitive phase coherent detector, or receiver, is used to enable magnitude and/or phase information to be measured in the instance whereby small perturbations, caused by small changes in bulk concentration, occur. Subsequent signal processing and stray field control methods enable clutter and noise to be removed from the signal information.

Frequency shift information may also be used to represent changes in concentrations of constituents. In this measurement scheme, shifts in frequency of certain characteristics of the phase and magnitude response may also be used as a representative measure of changes in concentration of constituents. For example, a shift in frequency of a null or minima contained within the magnitude versus frequency response may represent an increase in blood-glucose concentration. Said frequency shift may be measured by comparing the difference between the frequency at which a null point (minima) occurs for normal conditions with the measured frequency null position; alternatively, it may be preferable to measure a percentage change. Variations in temperature and tissue fat may cause frequency additional shifts and these will need to be subtracted or nulled to obtain the frequency shift component that represents only a change in blood-glucose concentration. As an example of measurements performed to validate the current invention, at room temperature of 20 C, a first sample of blood spiked with a controlled concentration of glucose produced a null at a frequency of 13.130GHZ and a second sample of blood spiked with different concentration of glucose produced a null at a frequency of 13.452 GHz (volumes of the two solutions were the same). In this instance, the frequency shift is 322MHz or, in terms of percentage change, this gives a change of 2.39%.

The current invention enables information to be provided directly to the patient or to remote monitoring stations such as a doctor's surgery or a hospital, to enable the necessary corrective action to be taken should the registered levels be outside the limits for healthy person condition and treatment is required.

The invention enables measurements to be taken in real time and enables subsequent data analysis to be performed over periods of time commensurate with quasi- instantaneous operation, thus fluctuations towards the hyperglycaemic and/or the hypoglycaemic state, due to quickly dropping or increasing glucose levels, can be quickly captured to enable corrective action to be taken.

The instrument is totally non-invasive and would be classified as a lowmedium risk (class ha) device, hence medical devices regulatory approval will be relatively straightforward.

Preferably, the invention may be configured using a pair of aligned miniature non- obtrusive transceivers or a single non-obtrusive miniature transceiver, to enable wireless data to be transmitted to a personal computer, or relayed over the telephone line. This aspect of the invention enables the patient to monitor their blood-glucose level whilst using their home computer or personal development assistant (PDA) device. Said devices may be configured to produce an alarm signal or a graph of level fluctuation as a function of time. Said graph could be displayed, for example, as a small window in one of the corners of the main screen of said device. This feature would also enable healthcare workers to remotely monitor the patient's blood-glucose level and inform the patient of corrective action required. 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 patients level 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. A plurality of transceivers could also be used, and the invention is not limited to the antennas being configured as transceivers; they may be configured as transmitters or receivers. It is preferable to position the antennas on the surface of the skin either side of the earlobe or the web region of the hands, between the thumb and first finger. These biological structures are preferable since they are minimally complex in that they contain no bone cartilage, muscle or vital organs. The thickness of said structures is limited to between 2mm and 15mm, surrounding skin and fat tissue is minimal. The properties of said fat tissue should stay constant whilst the concentration of glucose contained within the blood will change. Also, the supply of blood is rich in these regions of the body. Although these regions and structures are preferable, this invention is not limited to using these anatomical tissue structures. In the instance of making microwave measurements on the earlobe, or the web over the frequency range of interest it will usually be the case that near-field measurements will be made, although in other thicker structures and an operating frequency near the upper limits of the region of the frequency microwave spectrum used in this invention, it may be the case that the measurements are classified as being far-field measurements. In terms of definition, the near field is composed of magnetic force fields and exists up to four wavelengths from the output of the antenna, and the far field is an electromagnetic field that exists at a distance greater than four wavelengths from the source.

Accordingly, a first aspect of the present invention is a low power microwave measurement system to enable accurate measurements of concentrations of constituents contained within the biological system; more specifically, said constituents are contained within a biological fluid and said biological fluid is blood.

The instrument comprises the following components: A source of microwave energy to provide a microwave signal at a frequency that yields the most sensitive measurement information for the particular constituent concentration being measured; A means of transferring the microwave energy from the microwave source into the human body in a non-invasive manner and to penetrate or pass into the constituents being measured; A means of non-invasively receiving the microwave energy after it has passed into or impinged upon the constituents being measured; A means of processing the received energy to provide information relating to the concentration of constituents; A means or relaying the information relating to the concentration of constituents in a format that is of use to a patient or other personal.

The source of microwave energy may take the form of any suitable microwave frequency oscillator, such as a voltage controlled (VCO) oscillator, a dielectric resonator (DRO) oscillator, a surface acoustic wave (SAW) oscillator, or a gunn diode oscillator, but this invention is not limited to these devices.

Preferably, a DRO or VCO would be used due to the need to produce an integrated and compact unit. Preferably, said sources would be phase locked to produce a stable frequency. A microellectromechanical (MEM) device may be used as an integral part of said VCO as this device technology offers the advantage of virtually parasitic free operation and can be realised in extremely small footprints. Said source may be operated in continuous wave (CW) or pulsed mode. It is preferable for said PLL to use a temperature compensated crystal oscillator (TXCO) to provide a stable reference, from which said microwave source frequency is derived. TXCO devices are commercially available with frequency stabilities of less than 1 part per million. It may be preferable to use two TXCO devices, where a first device is phase locked to a second device to provide enhanced frequency stability and said first and second devices are a part of a PLL containing a DRO. Said source arrangement may be preferable where blood-glucose concentrations produce a minima (null) or a maxima (peak) at certain frequencies, and changes in said blood-glucose concentrations produce changes in the position of said minima or maxima in frequency space, and said changes are repeatable, but said changes in frequency are relatively small in comparison to the region of the frequency spectrum where said changes are found to occur. For example, normal blood-glucose levels produce a null at 13GHZ and the frequency shift caused by an increase in glucose concentration produces a frequency shift of 10KHz.

The source may also take the form of a frequency synthesiser whereby a plurality of frequencies can be demanded by varying a control signal. Said synthesised source may offer a number of advantages in terms of extending the measurement capability of the instrument. For example, a plurality of different concentrations of constituents may be measured.

The source oscillator may be followed by a low power amplifier or a chain of low power amplifiers to boost the signal produced by said source to a level necessary to ensure a high signal to noise ratio at the receiving device, and to ensure that the instrument has a large enough dynamic range to allow for small changes in concentrations of constituents to be detected. Preferably, said low power amplifiers will take the form of monolithic microwave integrated circuit (MMIC) amplifiers, but this invention is not limited to using these devices. Said devices may produce a variable output power level and be controlled by an external control voltage.

Alternatively, an additional power control device, such as a PIN diode attenuator, may be placed between the output of said source and the input of said low power amplifier, or between the output of said amplifier and the input to the next device in the microwave line-up. It may be necessary to include a power absorbing device at the output of said low power amplifier chain, in order to eliminate the possibility of damage occurring to the output stage due to excessive signal reflection. It is unlikely that said absorbing device would be required when said source is being operated in CW mode, but it may be required when said source is being operated in pulsed mode since it is possible that higher peak power levels with low duty cycle will be generated.

Said power absorbing device may take the form of a microwave circulator and a power dump load, but this invention is not limited to these particular devices.

External power control devices may be inserted anywhere along the microwave component line-up between the output of said frequency source and the input to said power absorbing device.

Microwave energy from said microwave source is transferred into the human body in a non-invasive manner via a first path and is received, after being transmitted through the biological structure or reflected back along the said first path, using a microwave antenna arrangement. In this invention, said antennas may be designed such that they only transmit microwave energy, or only receiver microwave energy, or both transmit and receiver microwave energy; the later devices are known as transceivers. In this invention a single transceiver antenna or a plurality of transmit, receive or transceiver antennas may be used. One preferred embodiment uses a pair of transceiver antennas, but this invention is not limited to this configuration. It is preferable for said antennas to exhibit a gain of greater than 2dBi and have a beam- width of less than 300 over their specified bandwidth of operation. High antenna efficiency can be defined by high gain and narrow beam-width.

The microwave antennas may take a number of forms and the most suitable designs include, but is not limited to; spiral structure, helical structure, patch antenna or patch antenna array, unloaded/loaded cylindrical/rectangular waveguide section, unloaded/loaded conventionalhorn construction and unloaded/loaded inverted horn construction. Said antennas may be linearly or circularly polarised.

A preferred patch antenna is a microstrip patch antenna that is mounted on a flexible substrate. This has the advantage of enabling a conformal structure to be engineered.

Said microstrip patch antennas may consist of a radiating patch on one side of a thin dielectric substrate backed by a ground plane. Said radiating patch could be any arbitrary shape. Regular shapes include: rectangular, circular, semicircular, equilateral triangle, 3o06o09o0 triangular and annular ring. Flexible substrates could be used to enable conformal patch antennas to be produced to obtain good contact with skin surface. Where broadband operation is required, or it is necessary to transmit a plurality of frequencies, broadband microstrip patch antennas are preferable. Broadband operation of said patch antennas can be achieved by using a thick substrate (laminate) layer, with a low relative permittivity, between the radiating patch and the ground plane. It is preferable to limit said substrate thickness to io% of the free space wavelength (o.i?0) at the frequency of operation. The bandwidth of said microstrip patch antennas is also increased by using multi- resonating patches coupled in a planar or stacked configuration. It may be preferable to feed said microstrip patch antennas using feed lines placed between the radiating patch and the ground plane and sandwiched between two dielectric layers. Said arrangement is known as an electromagnetically coupled microstrip antenna and offers the advantage of eliminating spurious feed-network radiation and is particularly advantageous where the dimensions of the radiating patch are similar to those of the microstrip feel line.

It may be preferable to connect said antennas to said microwave source, or other microwave components in said microwave line-up using a balanced to unbalanced (BALUN) converter. Said BALUN enables an unbalanced feed, such as a microstrip line or a co-axial cable, to be connected to the balanced antenna input. In the instance whereby the signal to noise ratio (SNR) of the system is adequate said BALUN may not be required.

In the instance of using loaded/unloaded waveguide antennas, in order to minimise microwave energy escaping from said antennas and following undesirable paths, i.e. a portion of the microwave energy couples into free space, it may be preferable to use a choke flange between the wall of said antenna and the element responsible for guiding the microwave energy (the active face or aperture). Preferably, said choke flange is a quarter wavelength flange, where a groove with a length of a quarter of the wavelength of the operating frequency exists between the wall of said antenna and the element responsible for guiding the microwave energy. Said length may be minimised by loading said groove with a dielectric/magnetic material whose relative permittivity/permeability is greater than unity. Where broadband operation is required, it may be necessary to use a groove whose length is a quarter of the wavelength of the centre frequency of the operating band.

In normal operation, said antennas would be designed to efficiently radiate into the impedance of free space, i.e. 377Q, and operated in the far-field region, but in this invention said antennas are required to efficiently radiate into the impedance of the biological tissue they come into contact with and the microwave energy could propagate into both the far-field and the near-field region. In order to provide an efficient impedance match between said antennas and said tissue, the design of said antenna structures may be optimised to match into, for example, the surface of skin, which may present an impedance of greater than ikQ. Other methods of impedance matching will be discussed later in this description.

If two antennas are used, it may be preferable to ensure that said structures are aligned in order to ensure maximum transmission and minimal radiation propagates via unwanted paths. In this configuration the two apertures face each other, and the biological structure is sandwiched between the said antenna pair. In this arrangement, a clip may be required to ensure that alignment is maintained and that a constant force is exerted between the two antennas to enable the antenna arrangement to be held in position in a stable manner with said biological structure in the centre. Said clip is preferably sprung loaded and the loading is such that excessive force cannot be exerted on said biological structure, thus said antenna arrangement can be attached to the human body with user comfort in mind.

Preferably, said clip is designed to be aesthetically pleasing with ease of operation in mind. Said clip arrangement is preferably made from a nonconductive material and said material is preferably biocompatible, although this feature may not be necessary due to the fact that the instrument will be used non-invasively.

In the case of a single active antenna based instrument, said clip may be used to attach said antenna to biological structure in a similar manner. In this instance a simpler clip arrangement can be afforded due to the fact that this embodiment does not necessitate antenna pair alignment.

In the instance whereby said single active antenna arrangement is used, it may be preferable to use a metallic plate located in the same position as antenna two used in the previous arrangement. The advantage of including said plate is that it will act as a reflector and help focus reflected signals back to the aperture of said first active antenna.

Accordingly, a second aspect of the present invention is an antenna arrangement whereby said antenna (s) are optimised for gain, frequency and beam-width. Said antennas are mounted to the biological structure using a clip arrangement. Unwanted paths for microwave energy to propagate are minimised, a BALUN arrangement may be included to convert between an unbalanced feed and a balanced input, and said devices may be statically impedance matched into the impedance of a single representative biological structure. Said antenna structures may be optimised to operate at a single spot frequency or may be optimised for broadband operation.

To enable said microwave energy to be efficiently transferred between said antenna (s) and the human tissue, it is necessary to provide a good impedance match between the output of the antenna (s) and the human tissue to ensure maximum energy transfer during the process of transmitting energy into the tissue and when receiving signals that have been modified by the concentration of the constituents being measured, where said signal passes through the surface of the tissue and couples into the output of the receive antenna. Said matching maybe achieved by designing said antennas to ensure the best impedance match between the output and a human tissue type that would typically be used during the operation of the instrument. However, preferably, a matching filter will be inserted before the input to the antenna(s) to enable the best impedance between the antenna(s) and the human tissue. In this way, the instrument could be optimised to suit each user. Typical matching filters include: stub tuners, PIN diode phase adjusters, MEM phase shifters and varactor diode tuners, but this invention is not limited to using these devices. In the present invention it may be preferable to use a single or a plurality of MEM phase shifting devices due to the size advantage offered by this new device technology.

It is necessary for a portion of the transmitted and received microwave energy to be measured to enable changes in magnitude and phase to be detected, using appropriate detection schemes, and for said detected signals to be processed and for statistical data to be discerned.

Directional couplers are used to measure a portion of said transmitted and received signals. Said devices may be positioned before a first antenna to enable forward transmitted energy and forward received (reflected) energy to be monitored and also after a second antenna to enable forward transmitted energy to be received after said energy has passed through said biological structure. It may be desirable to measure energy transmission in two directions together with reflected energy (backscatter) caused by energy entering the biological structure of interest and reflected back along the transmission path. In this instance, a forward monitoring and a reverse monitoring directional coupler would be required before a first antenna and after a second antenna.

Said directional couplers are described by the following parameters: coupling factor (C), directivity (D), isolation (C +D), insertion loss (IL), and frequency bandwidth (BW). To be able to differentiate between forward and reverse energy in the situation whereby the forward power is many orders of magnitude higher than the reflected power, for example, forward power is 10mW and reflected power is ioW, said directional coupler must exhibit a high directivity, although a sensitive phase/magnitude detector and appropriate signal processing techniques can be employed to remove the energy vector component present in the direction opposite to the measurement direction. Said portion of microwave energy being measured from said directional couplers is taken from a device output, known as the coupled port. It is normal for said couplers to contain three ports, namely: an input port, an output port and said coupled port.

Typical directional couplers that may be considered for use in this invention include: microstrip, stripline, coplanar, aperture coupled waveguide, TEM line, Lange, tandem, Wilkinson, De Rande, co-axial, 90 hybrid, hybrid ring, branch line, branch line hybrid, hybrid tee and MEM based devices. Other microwave directional couplers will be apparent to a person experienced in the art of microwave engineering. In this invention, microstrip, stripline and MEM based devices are preferred due to the need to keep the design as compact as possible.

Wilkinson and Lange directional couplers may be used specifically to sample the signal from said oscillator where it may be necessary to split the energy into two equal parts to provide a reference frequency for the detector scheme. Wilkinson and Lange directional couplers are often also referred to as 3dB splitters.

In the instance where the instrument is to be used to perform measurements over a wide band of frequencies, or where a plurality of spot frequencies are to be used, and there is a large difference between the frequencies of choice, it may be desirable to use broadband directional couplers. Directional couplers are now commercially available that exhibit a bandwidth of between 1GHz and 6oGHz.

In the instance where the instrument is used to perform measurements in two directions and/or it is required to measure reflected power at the input port of both antennas, it may be desirable to use a single source oscillator and a switching arrangement. In this invention it is preferable to use an electronically controlled switch, such as a PIN diode switch or a MEM device. In such a configuration, the measurement direction would be determined by the contact position of said electronic switch, and said position would be controlled by an analogue or digital signal present on the control line of said device. Said signal will be derived from a digital signal processor or microprocessor unit.

A microwave detector (or receiver) arrangement is used to convert power signals taken from said coupled ports of said directional couplers into voltages representative of magnitude and/or phase of said power signals. There are a number of detection schemes that may be considered; some of which include: homodyne, heterodyne, zero bias schottky diodes, bolt channel schottky diodes, biased coaxial schottky diodes and tunnel diode detectors.

In this invention it is preferable to use a heterodyne detection scheme due to the fact that heterodyne detection schemes enable the extraction of both phase and magnitude information. In the instance whereby the changes in concentrations of said biological fluid are small, it is advantageous to be able to measure phase information as well as magnitude information. It is also possible to measure phase information in an environment where the noise level is greater than that of the signal.

The preferred heterodyne detection scheme uses a microwave mixer to convert the frequency of the measured microwave signal to a lower frequency signal that can be digitally processed by feeding the output of said microwave mixer into the input of a analogue to digital converter (ADC) or other signal processing device. Said mixer also requires a local oscillator signal and in the present invention said local oscillator signal is at a lower frequency than the measured microwave signal. Said local oscillator signal may be derived from microwave frequency source oscillator, but this invention is not limited to this configuration.

To measure changes in phase and magnitude it may be necessary to be able to pole or select the coupled ports of the directional couplers at discrete time intervals and compare differences in phase and magnitude. In this arrangement, a single heterodyne detector would be used and an electronic switch would be used to connect said detector to each of the coupled ports of said directional couplers in turn. In this arrangement, it is preferable to use an electronically controlled switch, which, for example, may take the form of a PIN diode switch, which may be a reflective or an absorptive type. Said switch may be controlled via a microprocessor or other suitable control device. Alternatively, it may be preferred to connect a separate detector to each of the said coupled ports of said directional couplers to enable the information from each of the said coupled ports to be measured simultaneously. The disadvantage with this arrangement is that device noise will vary between the detectors and this could limit the measurement sensitivity of the instrument.

It may be preferable to use a single RF/IF gain and phase detector rather than a mixer and a local oscillator. The use of said device offers the advantage of providing an integrated solution and helps minimise space requirements.

It may be preferable to measure the frequency at which maxima and/or minima occur in the magnitude and/or phase response characteristic(s). More preferably, a frequency shift of said maxima and/or minima in said magnitude and/or phase response characteristic(s) may be used to determine changes in concentrations of constituents contained within biological fluids or, more specifically, the blood- glucose level. In this instance it may be necessary to employ an additional directional coupler, or a 3dB power splitter, to measure the source frequency. It may be preferable to a frequency divider to reduce the microwave frequency such that a standard microprocessor or signal processor can be used to determine the value and to calculate said frequency shift. It will also be necessary to use a detector to detect the maxima and/or minima that occur in the magnitude/phase frequency response characteristic (s) and input this information into said microprocessor or signal processor. Variations in minima and/or maxima with frequency will be captured and processed using said microprocessor or signal processor. It may be preferable to use an analogue maxima minima detector designed using operational amplifiers and passive electronic components. Accordingly, a third aspect of the present invention is a method of detecting a change in frequency of one or more of the features of the magnitude and/or phase response characteristics as a function of a change in concentration of constituents contained within a biological fluid, or, more specifically, a change in blood-glucose concentration. More specifically, said features may be a shift in frequency of a minima or a maxima that occur in the magnitude- frequency response characteristic. A plurality of maxima and/or minima that occur in said magnitude-frequency response characteristic taken over a broadband of microwave frequencies may be used to determine a plurality of constituent concentrations.

A signal processor is required to manipulate and process said magnitude and/or phase information and convert it into a form that provides useful information regarding concentrations of constituents of biological fluid under investigation. Said processor may take the form of a microprocessor, a digital signal processor (DSP), a microcontroller, or another suitable device.

Said processor may manipulate and process the said magnitude and/or phase information derived from said transmission and/or reflection measurement to provide the following information regarding the concentration of constituents contained within the biological fluid of interest: absolute level in milliMoles per litre (mmol/L) or milligrams per decilitre (mg/dL), high level, low level, average level, standard deviation, root of the mean of the squares (RMS), or a pilot of concentration (in mmol/L or mg/dL) as a function of time. Said processor may also be used to calculate patient insulin requirements in the case of the concentration being glucose in blood.

In the instance whereby the measured microwave signal is a low enough frequency such that frequency down conversion is not required, it may be preferable to feed signals taken from said coupled ports of said directional couplers straight into said processor, whereby magnitude and/or phase extraction can be preformed together with said manipulation and processing. In this instance, the processor would require a high frequency ADC unit, which may form an integral part of said processor.

Said manipulated and processed data is sent to an output device, which may be a display, an audible alarm or a monitoring station. In the instance that the data is sent to a remote station this invention will require extra features; said features will be

described later in this description.

In this specification except where the context demands, the term connected' includes not only direct connection but also indirect connection via one or more intermediate components. This statement particularly relates to the MMIC amplifiers, couplers, matching filters and antennas used in the current invention.

It may be preferable to operate the instrument at a plurality of microwave frequencies in order to enable a plurality of concentrations of constituents to be measured. It may also be preferable to perform a broadband frequency sweep to enable the correlation between frequency and the position of the minima and/or maxima points to be carried out. In this instance, the preferred antenna construction may be a spiral antenna construction since this construction offers wide band operation and is often referred to a frequency-independent structure. A broadband directional coupler is also preferable in this configuration since this enables a single coupler to be used rather than a number of separate devices. One such device that is currently commercially available enables microwave signals to be measured over a bandwidth of between 1GHz and 6oGHz and this is the preferred device to use. A synthesised frequency source may be preferable due to the fact that the frequency generated by said source may be digitally controlled using said processor. The local oscillator frequency required for said detector to down-convert the microwave frequency to a frequency that can be accepted by said processor will need to be adjusted in accordance with the microwave frequency that correlates with the desired concentration of constituents under investigation. An alternative method of producing a plurality of microwave frequency sources is to use a plurality of frequency oscillators connected to an electronically controllable switch, where said switch can be used to channel each of the microwave frequency sources to a transmission antenna in accordance with the desired concentration of constituents under investigation. An instrument that enables a plurality of concentrations of constituents to be measured in this manner forms a fourth aspect of the present invention.

Preferably, the anatomical structure used to transfer said microwave energy into the human body and to receive said energy, once it has been absorbed by the constituents being measured and has been transmitted and/or reflected, is the surface of the skin.

Preferably, the measurement antennas are located at a region of the body that is rich in blood flow and can be described as a simple structure in terms of minimal anatomical planes necessary for the signal to pass through before it reaches the structure that contains the constituents of interest. It is also preferable for all tissue structures, other than the biological fluid containing the concentration of constituents, to possess constant values of relative permittivity and conductivity over the frequency band of interest, and other properties that are related to the structure of surrounding tissues should also preferably remain constant. More preferably, this region is the earlobe or the web between the thumb and first finger, but this invention is not limited to using these locations to perform measurements.

In accordance with the description given above, a fifth aspect of the current invention is a non-invasive measurement instrument that uses low power microwave energy and measures transmission characteristics in terms of changes in magnitude and/or phase. Said measurement instrument may be used to measure concentrations of constituents contained within the biological system whereby said low power microwave energy is transmitted through said biological structure using a first antenna positioned in contact with, or positioned nearby, the first face of said biological structure, and is received using a second antenna positioned in contact with, or positioned nearby, the second face of said biological structure. Preferably, said biological structure is sandwiched between said first and second antennas and the apertures (outputs) of said first and second antennas are in alignment. Preferably, a clip arrangement is used to provide said alignment and to ensure that said antennas are securely and comfortably fixed to said biological structure.

In accordance with the description given above, a sixth aspect of the current invention is a non-invasive measurement instrument that uses low power microwave energy and measures reflected signal in terms of changes in magnitude and/or phase.

Said reflected signal may be known as backscatter and contains the measurement information. Said measurement instrument may be used to measure concentrations of constituents contained within the biological system whereby said low power microwave energy is transmitted through said biological structure using a first antenna, and reflected signal is received using same first antenna. In this embodiment the transmitted microwave energy reaches the region of the body where the concentration of constituents is located and once said signal reaches said concentration it is reflected back, along same path as that traversed by said transmitted energy, back to said first antenna. A clip arrangement is use to ensure that said antenna makes good contact with the first face of said biological structure and that said antenna is securely and comfortable fixed to said first face of said biological structure. It may preferable locate a plate in with, or positioned nearby, the second face of said biological structure to maximise microwave energy reflected back to said first antenna. Said plate may be made from a conductive or non- conductive material. Preferably, said biological structure is sandwiched between said first antenna and said plate, and the surface of said plate and the aperture (output) of said first antenna are in alignment to maxim ise strength of said reflected signal.

Accordingly, a seventh aspect of the current invention is a is a noninvasive measurement instrument that uses low power microwave energy and measures both transmitted and reflected energy in terms of changes in magnitude and/or phase.

Preferably, in this embodiment, two antennas are used, and it may be desirable to measure transmitted energy in two directions, and reflected energy at both first and second antennas. This embodiment would contain the features associated with the fifth and sixth aspects of this invention, but combines the two measurement techniques into one instrument. In order to provide hi-directional operation, said first and second antennas would be configured to transmit and receive microwave energy. It may be preferable to perform this function using electronically controlled switches to connect the frequency source to the first or second antenna and to ensure that the antenna not connected to said frequency source is terminated into a matched load, where the nominal resistance for said load is 5O. The preferred embodiment of the seventh aspect of the current invention is an instrument as described in the above description whereby transmission and reflection measurements are performed in one direction only. In this instance said switching arrangement would not be required.

Said measuring instruments detailed in the fourth to seventh aspects of this invention may operate in the near or far fields. Factors governing the field of operation include the thickness of the biological tissue structure and the relative dielectric constant (permittivity) of the biological structure, and the frequency of operation.

An eighth aspect of the current invention is the integration of the active and passive microwave elements to enable the microwave sub- assembly to be packaged into a small volume or space. A combination of state of the art microwave devices, such as MMICs and MEMs, and advanced fabrication technology is used to implement said integrated sub-assembly. It may be preferable to vertically stack said microwave elements to help enable said volume or space reduction. It is preferable to make the interconnections between said microwave elements using conductive tracks of a fixed impedance fabricated onto suitable microwave substrates. It is preferable to keep all microwave interconnections as short possible in order to minimise insertion loss and to reduce emissions of stray microwave energy and limit system noise. Said antennas may be loaded with low loss dielectric and/or magnetic material (s) with high relative permittivity (cr)/permeability (pr) to reduce the dimensions. The antenna dimensions will be reduced by a factor of the square root of said relative permittivity/permeability value. Accordingly, said reduction factor, R, can be described by the following equation: R = Vtr Er thUs, the expression for wavelength, X, with dielectric and/or magnetic loading becomes: A. = C/(f0R), where C is the speed of light in vacuum and 10 is the frequency of operation. It may be preferable to use loaded microstrip patch antennas fabricated on a flexible substrate to minimise the length and width and provide conformability with the surface of the biological structure under consideration. Said miniaturisation of said microwave subassembly may be implemented using a plurality of layers where connectivity between said layers is achieved using platted through holes. In a specific embodiment said integrated microwave sub-assembly may comprise the following elements: source oscillator, MMIC amplifier, PIN diode attenuators, first directional coupler, first matching filter, second directional coupler, third directional coupler, first antenna, second antenna, second matching filter, fourth directional coupler, fifth directional coupler, frequency divider, frequency multiplier, microwave mixer, PIN diode switch, 5O microstrip lines for interconnectivity, ports for input control lines and ports for down-converted information signal to be connected to a processor and the outside In certain instances it may be preferable for said integrated microwave sub-assembly to comprise of said antennas and the microwave connections necessary to directly extract themicrowave signal. In this particular case all other microwave components that comprise the microwave sub-assembly may be contained within, or placed nearby, the processor and display unit. In this particular case it would be preferable to connect said microwave antenna assembly to the remaining elements of said microwave assembly using a co-axial cable assembly or a flexible waveguide assembly. Other means of channelling microwave energy from said antennas will be known to a person skilled in the art.

A ninth aspect of the current invention is the incorporation of said integrated microwave sub-assembly into communications equipment or other devices commonly worn by potential users of the instrument described in the current invention. Preferably, said integrated microwave sub-assembly would be incorporated into a Bluetooth headset as said headsets are becoming commonplace and may enable diabetes sufferers who may currently perform irregular testing, or, in the case of some Type II patients, may not test at all, to test their blood-glucose level without the inconvenience of taking and analysing blood samples or the need to connect additional measurement equipment to their body. This aspect of the current invention may be used to provide a practical alternative for individuals who find conventional methods of testing difficult and/or socially unacceptable.

Other commercially available devices that may be used for non-obtrusive integration of said integrated microwave sub-assembly may include: Walkman headphones, MP3 player headphones, general HiFi music headphones, hearing aids, or other earpieces.

These devices provide a non-exhaustive list of possible devices that the microwave sub-assembly could be integrated into, but this invention is not limited by this list.

The arm of spectacles may also be considered to offer support to said integrated microwave sub-assembly and this concept may be further extended by moulding the arm of said spectacles into a shape that provides a comfortable support for said integrated microwave sub-assembly.

It may be preferred not to incorporate said integrated microwave subassembly into a known device already in existence but to produce a ear clip and assembly specifically for the instrument described in this invention.

Conventional means of transferring measurement information collected from said microwave sub-assembly to said processor unit and said output device may include a co-axial cable assembly or a flexible waveguide assembly. Additional DC or low frequency control signals may also need to be routed along the path between said microwave sub-assembly and said processor and output device; such signals may include: DC power supplies to frequency source and MMIC device (s), a frequency control line and a power level control line. Said signals may be attached to said microwave transmission cables using, for example, cable ties or lacing chord. As an alternative method of transferring information and control signals a tenth aspect of the current invention may include a pair of wireless transceivers; a first transceiver connected to said microwave sub-assembly and a second transceiver connected to said processor unit. In one embodiment said wireless transceivers may take the form of a modulator, a demodulator and an antenna arrangement. There are a number of advantages of including this aspect; these include: removes the inconvenience of using cables to link the said microwave sub-assembly to said processor, the measurement instrument is more user friendly, and the measurement information can be transmitted to a myriad of devices, such as a home computer or a PDA, and can be relayed to remotely located monitoring stations. In the instance where measurement frequencies are at the lower end of the microwave spectrum, it may be preferable to directly transmit the received signals taken from the coupled ports of said directional couplers and include a single detector as a demodulator connected as a an integral part of said processor. In such an arrangement, additional antennas would be required to transmit information signals. An additional low power amplifier, preferably a MMIC, may also be required to boost the signal strength to ensure that the signal is of a high enough amplitude to allow transmission through the medium of free space and be received at the detector, or demodulator, with a high enough signal-to- noise ratio to enable changes in magnitude and/or phase representing changes in concentrations of constituents in biological fluids under investigation to be measured and processed to yield useful information. Other wireless link configurations will be known to persons experienced in the art of microwave communication electronics. Where a modulator and/or a demodulator is integrated with said microwave sub-assembly in order to transmit information signals and receive control signals from said remotely located processor, it is necessary to employ a modulation scheme that provides the most efficient transfer of information with an acceptable error rate. Possible candidates for the modulation scheme of choice include: amplitude, frequency, phase, delta, pulse code and two- tone modulation. Other suitable modulation schemes will be known to a person experienced in the art of microwave or communications engineering.

It may also be preferred to integrate said integrated microwave subassembly and the said processing electronics into a Bluetooth headset, or other suitable headset/headphone assembly, to provide a self contained, totally non-obtrusive measurement system. In this embodiment it would be possible to employ the speaker used in normal operation, to convey conversation or music, to provide an audible alarm to indicate that, for example, blood-glucose levels are outside an acceptable range where the person is said to be in a healthy state.

An eleventh aspect of the present invention is to use an existing communications and/or computing device to constitute said processor and output device. Preferred computing devices include personal computers and personal development assistants (PDA). Other devices include mobile phones and pagers, but this invention is not bounded to this limited range. This aspect of the current invention offers the advantage of allowing the patient to monitor his/her blood-glucose level whilst using devices that they are familiar with. This aspect helps ensure that levels are monitored on a regular basis. One example of the implementation of the use of a personal computer in this manner is where said computer is configured such that a small screen always appears in the bottom right hand corner of the monitor and said screen displays changes in level which could be calibrated in mmol/L or mg/dL and displayed in the form of level variation on the Y' axis and time variation on the X' axis. The microprocessor contained in said computer would be used to mathematically convert changes in magnitude and/or phase information (including frequency shifts of certain characteristics contained within the magnitude and/or phase response profiles), provided by the demodulated signal, into a value of blood- glucose level in mmol/L or mg/dL. Said microprocessor may also perform digital filtering on the magnitude/phase signal (s) and may also be used as the detector to extract said magnitude/phase information. It may also be preferable to use said computer to generate an audible alarm in the event that blood-glucose level falls outside the levels deemed to be safe.

The tenth and eleventh aspects of this invention could be used to implement remote monitoring using, for example, a telephone line or fibre optic link. In one particular embodiment, a standard MODEM is used to transmit processed information concerning blood-glucose level down the telephone line to a remote monitoring station where a healthcare professional or other medical personnel may send a message back to the patient advising the best corrective action to take. This aspect of the current invention could also be used to monitor other conditions and could be especially useful in monitoring elderly people living by themselves in their own homes.

To remove measurement errors caused by, for example, component drift, due to, for example, device ageing, operating temperature and other environmental factors, it may be necessary to perform an instrument calibration before taking measurements on biological systems. Instrument calibration is a twelfth aspect of the current invention and, in the instance whereby the instrument uses an antenna pair, said calibration may be performed by placing a block of known material between said first and second antenna and perform transmission and reflection measurements using said block to provide a calibration point to which all subsequent measurements are referenced. Said calibration material should be made from a material that does not change its properties over time and is temperature stable over a range of temperatures covering the standard operating temperature range. It may be necessary to use more than one calibration material and it may be required to perform said calibration at regular intervals of time. As an alternative to using said calibration materials inserted between said antennas, it may be preferable to connect the apertures (output faces) of said antenna together and perform a transmission and/or reflection measurement routine in order to establish said calibration points; all subsequent measurements taken on said biological system will then be referenced to said points.

In the instance whereby one active antenna is used to both transmit and receive microwave energy, as described by the sixth aspect of the current invention, it is necessary to ensure that said calibration material makes good contact with the aperture of said antenna. Preferably, said calibration material is contained inside a metallic cap and said cap is fitted tightly to the body of said antenna. It may be preferable to provide a screw assembly or locking mechanism to ensure that said calibration material makes good contact with said aperture of said antenna. In this instance, it may be preferable to use a metal plate as a first calibration material. It must be ensured that said plate presents a non-reactive short circuit to the aperture of said antenna. To achieve said short circuit condition, it will be necessary to ensure an exact spacing between said aperture and said plate to cancel out any reactive components presented by the geometry of the antenna and the tissue/free space load.

This invention is not limited to measuring biological constituents, it may also be used to measure non-biological constituents contained within said biological system. It may also be used to measure properties of solid objects or structures that are placed inside, or form a part of, said biological system.

Any of the features of the first to twelfth aspects of the present invention described above may be combined with each other.

Other elements pertinent to this invention are given in the detailed description. The features relating to general microwave engineering concepts and design variants, will be known to a person experienced in the art and may be omitted from the

description.

ADVANTAGES

The use of low power microwave energy, as described in this specification, enable levels of concentrations of constituents contained within a biological fluid to be quantified with a high degree of accuracy due to the possible dynamic range of signal measurements made in this manner, and recent advances in integrated microwave device technology.

The combination of antenna optimisation in terms of gain, directivity and minimisation of unwanted path radiation, together with high sensitivity detector(s) (receiver(s)) used in this invention, enable measurements to be made over a dynamic range in excess of 8o dB; in other words, changes in less than 1 part in 10 million can be measured.

Subsequent signal processing enables noise signals to be removed and signals of low amplitude in comparison to noise levels can be resolved to provide enhanced concentration recognition. The ability of this invention to measure both phase and magnitude may also provide enhanced information regarding concentrations of particular constituents.

This invention draws upon recent advances in miniaturisation of microwave components to enable integration of the active and passive microwave components used in the instrument to enable the microwave sub-assembly to be packaged into a small volume. For example, said sub-assembly may be integrated inside a mobile phone headset or a stand-alone aesthetically pleasing, non-obtrusive moulding that may take the form of an earplug or an earphone and the antenna(s) may be clipped to the earlobe.

This invention also draws upon recent advances in microwave device technology, whereby said active and passive microwave devices that operate over the frequency range of interest in this invention are becoming commercially available. For example, microelectromechanical (MEM) based devices and High Electron Mobility Transistors (HEMTs).

The use of microwave energy together with current advances in communications technology enables the miniature microwave sub-assembly to operate as a stand alone component, whereby wireless technology can be used to transmit the measured signals, using free space as the transmission medium, and subsequent processing of the signals can take place using, for example, a home computer, or the information could be transmitted down the telephone line to a remote data processing or monitoring site, using, for example, a modem and a home computer. Personnel, located at said remote monitoring site, could analyse the information and send a response to the patient using the same communication channel; this response, may, for example, provide details of corrective action required if the blood-glucose level was found to be outside an acceptable range. This aspect of the current invention offers a number of advantages over existing blood-glucose monitoring systems and could provide an alternative to patient care practice.

A further advantage with this invention is that the use of miniature microwave devices provides the ability to integrate the instrument described in this invention into an already acceptable non-obtrusive device. This new invention may, therefore, provide an aesthetically pleasing and socially acceptable alternative method of measuring bloodglucose levels.

BRIEF DESCRIPTION OF DRAWINGS

A brief description of drawings relating to this invention is given below. These drawings are referred to in the detailed description to enable the invention to be fully described. The drawings provide details of specific embodiments of the present invention and provide the information necessary to enable a person skilled in the art of microwave engineering to build an instrument that captures the features of the invention.

Figure 1 shows a block diagram of the instrument. The main features relating to the instrument are shown together with a pair of antennas sandwiched between a biological tissue structure. The clip arrangement used to ensure alignment of the antenna pair and to enable the arrangement to be secured to the biological structure is also shown.

Figure 2 provides an illustration of a typical biological structure used with the instrument described in this invention. The simple structure will be sandwiched between the antenna pair shown in figure 1 and consists of skin, fat and blood. In a typical application it will be required to measure changes in concentration of constituents contained within the blood and so the changes in characteristics of the skin and fat should, in comparison to changes of the characteristics of the blood, remain constant.

Figure 3 shows a pair of measurement antennas connected to the earlobe. It can be seen that the antenna pair are clipped to the earlobe and their apertures (output faces) are aligned. In this diagram the antenna pair is connected to the rest of the instrument using a pair of coaxial cables.

Figure 4 shows the measurement antennas connected to the web of the hand that exists between the thumb and first finger. In this diagram the antenna pair is connected to the rest of the instrument using a pair of coaxial cables.

Figure 5 shows an arrangement to enable a single source of microwave energy to be used to measure transmission and reflection characteristics in two directions. In this arrangement, the two antennas shown are set-up as transceivers. The diagram shows a method of switching the microwave energy in two directions and also includes additional low power amplifiers that may be required to increase received energy levels before entering the detector to ensure that the signal level is higher than the noise floor of the detector.

Figure 6 provides details of an arrangement for measuring a minima (or a maxima) that occurs in the magnitude response. The arrangement shown provides a method of sweeping and measuring the source frequency and the peak amplitudes.

Figure 7 shows a specific embodiment of an instrument for measuring the frequency at which the peak of a null occurs in the magnitude response. A shift in the position of the null (or peak) can be used as an indication of a change in the blood-glucose concentration.

Figure 8 shows a specific embodiment for an instrument used to measure phase and magnitude information. In this embodiment integrated phase/amplitude devices are used and a separate frequency mixer is connected to each of the coupled ports of the directional couplers. The diagram also shows matching filters that are used to ensure that the antennas, which are normally in contact with the surface of the skin, are impedance matched to the characteristics of the skin tissue.

Figure 9 provides a table listing the microwave devices used in the specific embodiment given in figure 8. Names of device manufacturers and part numbers are included.

Figure io shows an alternative specific embodiment of the instrument. In this embodiment, the detector comprises a single microwave frequency mixer and integrated phase/amplitude device. An electronic switch is used to multiplex the two directional couplers with the detector.

Figure ii shows a first arrangement of the microwave devices that are integrated with the antennas into a device worm by a patient. The integration may be achieved using vertical stacking and multiple substrates. In this arrangement the detector is not included.

Figure 12 shows a second arrangement of the microwave devices that are integrated with the antennas into a device worn by a patient. The integration may be achieved using vertical stacking and multiple substrates. In this arrangement the detector is included.

Figure 13 shows three arrangements whereby cables are used to channel the signals from the antennas, which are connected to the biological tissue (the earlobe in this instance) to the rest of the instrument. The arrangements shown are: a) Antennas only located at, or nearby, earlobe, and microwave source, amplifier(s), directional couplers and power control device, together with detector, processor and output device located in a separate enclosure.

b) Antennas and microwave source, amplifier(s), directional couplers and power control device located at, or nearby, earlobe, and detector, processor and output device located in a separate enclosure.

c) Antennas, microwave source, amplifier(s), directional couplers, power control device and the detector located at, or nearby, earlobe, and processor and output device located in a separate enclosure.

Figure 14 shows two arrangements whereby a wireless link is used to channel the signals from the antennas, which are connected to the biological tissue (the earlobe in this instance) to the rest of the instrument. The arrangements shown are: a) Measurement antennas, microwave source, amplifier(s), directional couplers, power control device, modem and first link antenna located at, or nearby, earlobe, and second link antenna, modem, detector, processor and output device located in a separate enclosure.

b) Measurement antennas, microwave source, amplifier(s), directional couplers, power control device, detector, modem and first link antenna located at, or nearby, earlobe, and second link antenna, modem, processor and output device located in a separate enclosure.

Figure 15 shows an embodiment where a wireless link is used to communicate between the microwave assembly located at, or nearby, the earlobe and the rest of the instrument located in a separate enclosure. In the embodiment shown the detector is located with the processor and the output device. Two modulator/demodulator (modem) units and the link antennas are used to enable the data and control signals to be transmitted and received.

Figure 16 shows a second embodiment in which a wireless link is used to communicate between the microwave assembly located at, or nearby, the earlobe and the rest of the instrument located in a separate enclosure. In the embodiment shown the detector is integrated with the other microwave components and the antennas.

The detector uses a separate frequency mixer and local oscillator connected to each of the directional couplers. Two modulator/demodulator (modem) units and the link antennas are used to enable the data and control signals to be transmitted and received.

Figure 17 shows a third embodiment in which a wireless link is used to communicate between the microwave assembly located at, or nearby, the earlobe and the rest of the instrument located in a separate enclosure. In the embodiment shown the detector is integrated with the other microwave components and the antennas. The detector uses a single multipole electronic switch connected to the coupled ports of the directional couplers and a single frequency mixer and local oscillator. Two modulator/demodulator (modem) units and the link antennas are used to enable the data and control signals to be transmitted and received.

Figure 18 illustrates an arrangement whereby the antennas, the microwave components (not including the detector), the modem and the link antenna are integrated into an assembly locater at, or nearby, the earlobe and a PDA or a personal computer is used as the detector, the processor and the output device. A link antenna and a modem is also shown connected to the PDA/personal computer.

Figure 19 illustrates an arrangement whereby the antennas, the microwave components (not including the detector), the modem and the link antenna are integrated into an assembly locater at, or nearby, the earlobe and the measurement information is sent to a remote monitoring station via an external modem and a telephone line.

Figure 20 illustrates an arrangement whereby the antennas, the microwave components (not including the detector), the modem and the link antenna are integrated into an assembly locater at, or nearby, the earlobe and a link antenna, modem, computer, telephone line and a remote monitoring station is configured to enable measurement information to be sent to a remote monitoring station, and also for information, which may be in the form of advised corrective action, to be sent back to the patient and displayed on a computer monitor.

Figure 21 illustrates the use of a laptop computer to perform signal processing and to provide the output display. The laptop computer may or may not include an integrated link antenna and a detector.

Figure 22 illustrates the use of a mobile phone to receive measurement information, process and display information relating to the glucose level and also send the information to a remote monitoring station, via a repeater, and receive information from the remote monitoring station which may be in the form of patient advice or necessary corrective action, and display this information on the screen built into the mobile phone.

Figure 23 shows an antenna arrangement with two co-axially fed patch antennas. The clip arrangement and the biological structure sandwiched between the two antennas is also shown.

Figure 24 shows an antenna arrangement using one co-axially fed patch antenna and a reflective plate. The clip arrangement together with the biological structure, which is sandwiched between the antenna and the reflective plate, is also shown.

Figure 25 shows the top view of a rectangular patch antenna fed using a microstrip line laid on the same plane as the radiating patch. The radiating patch is shown mounted on a dielectric substrate with a ground plane underneath. The width and length of the patch is also labelled.

Figure 26 shows the top view and a cross section through a coaxiafly fed microstrip patch antenna. The coaxial feed is shown offset and the ground plane is larger than the radiating patch.

Figure 27 shows a patch antenna where the feed line is not on the same layer as the radiating patch. In this configuration the feed line is sandwiched between two dielectric layers and is electromagnetically coupled to the radiating patch. A ground plane is shown on the underside of the antenna arrangement.

Figure 28 shows an antenna arrangement using two frequency-independent planar spiral antennas. The clip arrangement together with the biological structure, which is sandwiched between the two antennas, is also shown.

Figure 29 shows an antenna arrangement using one frequency-independent planar spiral antenna and a reflective plate. The clip arrangement together with the biological structure, which is sandwiched between the antenna and the reflective plate, is also shown.

Figure 30 shows a frequency-independent planar spiral antenna consisting of four spirals. The dimensions used to determine the upper and lower operating frequency limits are given and the arrows indicate the direction of the outgoing waves travelling along the conductors resulting in right-circularly polarised radiation outward from the page and leftcircularly polarised radiation into the page.

Figure 31 shows a frequency-independent planar spiral antenna cut from a large ground plane. A coaxial cable is also shown bonded to a first spiral arm with the inner conductor connected to the second spiral arm.

Figure 32 shows an antenna arrangement using two loaded rectangular waveguide antennas with E-field launch probes. The clip arrangement together with the biological structure, which is sandwiched between the two antennas, is also shown.

Figure 33 shows an antenna arrangement using one loaded rectangular waveguide antenna with an E-fleld launch probe, and a reflective plate. The clip arrangement together with the biological structure, which is sandwiched between the antenna and the reflective plate, is also shown.

Figure 34 shows an antenna arrangement using two loaded rectangular waveguide antennas with H-field loop launch probes. The clip arrangement together with the biological structure, which is sandwiched between the two antennas, is also shown.

Figure 35 shows an antenna arrangement using one loaded rectangular waveguide antenna with an H-field loop launch probe, and a reflective plate. The clip arrangement together with the biological structure, which is sandwiched between the antenna and the reflective plate, is also shown.

Figure 36 shows the experimental set-up used to perform non-invasive measurements of phase and magnitude variation with frequency on various types of biological fluid. Two antennas are shown connected to the walls of a vessel containing biological fluid and a vector network analyser is used to provide the microwave source, the detector, the signal processor and the output device. In this arrangement, transmission only is measured and impedance matching filters are not included.

Figure 37 is a graph showing magnitude change results obtained from the measurement set-up shown in figure 36. The graph shows a solid curve representing the magnitude response for a blood-glucose solution with a glucose concentration of 6mmol/L, and the dashed line represents the magnitude response for a blood-glucose solution with a glucoseconcentration of l4mmol/L. It can be seen from the graph that the position of the null has shifted in frequency and that in this instance the frequency shift is 322MHZ. In the actual measurements taken, the variation in power (Y' axis) was between -24dBm and -36dBm.

Figure 38 is a second graph showing phase change results obtained from the measurement set-up shown in figure 36. The graph shows a solid curve representing the phase response for a blood-glucose solution with a glucose concentration of 6mmol/L, and the dashed line represents the phase response for a blood- glucose solution with a glucose concentration of l4mmol/L. It can be seen from the graph that the maximum phase change occurred at 13.130GHz, where the difference is 40 degrees.

Figure 39 shows the experimental set-up used to perform non-invasive measurements of phase and magnitude variation with frequency on various types of biological fluid. The arrangement shows one antenna connected to the wall of a vessel containing biological fluid and a vector network analyser is used to provide the microwave source, the detector, the signal processor and the output device. In this arrangement, reflection only is measured and impedance matching filters are not included.

Figure 40 shows the experimental set-up used to perform non-invasive measurements of phase and magnitude variation with frequency on various types of biological fluid. Two antennas are shown connected to the walls of a vessel containing biological fluid and a vector network analyser is used to provide the microwave source, the detector, the signal processor and the output device. In this arrangement, transmission only is measured and impedance matching filters are included to enable the signals to be matched to the impedance of the vessel walls.

Figure 41 shows the experimental set-up used to perform non-invasive measurements of phase and magnitude variation with frequency on various types of biological fluid.

The arrangement shows one antenna connected to the wall of a vessel containing biological fluid and a vector network analyser is used to provide the microwave source, the detector, the signal processor and the output device. In this arrangement, reflection only is measured and an impedance matching filter is included to enable the signal to be matched to the impedance of the wall of the vessel. In this arrangement a directional coupler is used to tap off the reflected power signal.

Figure 42 shows the experimental set-up used to perform non-invasive measurements of phase and magnitude variation with frequency on various types of biological fluid. Two antennas are shown connected to the walls of a vessel containing biological fluid and a vector network analyser is used to provide the microwave source, the detector, the signal processor and the output device. In this arrangement, transmission and reflection are measured and impedance matching filters are included to enable the signals to be matched to the impedance of the vessel walls. In this arrangement a directional coupler and a spectrum analyser are included to enable a portion of the reflected signal to be taped off and measured.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail by referring to the figures listed in the previous section.

MAIN ASPECT OF THIS INVENTION: The main features relating to the current invention are given in figure one. The microwave line-up consists of a microwave source 10, which is connected to a power control device 170 followed by a low power amplifier 20. Said microwave source 10 may take the form of a myriad of oscillating devices; these include, but are not limited to, the following: voltage controlled oscillators (VCOs), dielectric resonator oscillators (DROs), surface acoustic wave devices (SAWs), or frequency synthesisers. The latter will be used in the instance where it is required to sweep the frequency over a large range. A VCO device may be used where the range of frequencies is more limited, for example, ranges of operation for typical VCOs that may be considered in this invention are: 4.45 GHz to 5 GHz (550 MHz sweep range), 5.6 GHz to 6.8 GHz (1.2GHZ sweep range) and 13.2 GHz to 13.5 GHz (300 MHz sweep range); these figures are for current devices taken from the current Hittite Microwave Corporation data-book. In the instance whereby a single microwave frequency, or a number of discrete frequencies are required, it may be preferable to phase lock the microwave source. The control device 170 may take the form of a PIN diode attenuator, which may be an absorptive or a reflective type. Another method of varying the power level is to vary the gate-source bias voltage on the low power amplifier 20 or replace the PIN attenuator with a second low power amplifier (preferably a microwave monolithic integrated circuit) and use the gate- source bias voltage to vary the power level. The disadvantage with using this power control regime is that certain gate- source voltage levels may cause signal distortion. The low power amplifier 20 may take the form of a single device or a cascade of devices and the chosen line-up may use one of the following device families: Gallium Arsenide Field Effect Transistors (GaAs FETs), Gallium Nitride Field Effect Transistors (GaNi FETs) or Indium Phosphide high-electron-mobility transistors (p-HEMTs); it is preferable to use GaAs FETs in this invention due to the fact that the frequency range of operation of said devices fits into the preferred operating frequency range used in this invention. The output power is preferably less that 100mW when the instrument is operated in continuous wave (CW) mode, but this may be increased when the instrument is operated in pulse mode, where the duty cycle can be much lower than 50%, hence the peak power can be greater than ioomW whilst maintaining an average power of equal to or less than 100mW. This invention is not limited by the power level restrictions given here. The output of the amplifier 20 is connected to the input of a first directional coupler ioi, whose coupled port is connected to the input of a frequency divider (pre-scalar) 104. The orientation of first directional coupler ioi is such that forward power from amplifier 20 will enter the coupled port. The output from 101 is connected to the input of a second directional coupler 60, whose coupled port is connected to a first input to the detector/receiver unit 100. The orientation of the second directional coupler 6o is such that forward power from amplifier 20 will enter the coupled port. The output from 60 is connected to the input of a third directional coupler 61, whose coupled port is connected to a second input of the detector/receiver unit 100. The orientation of the third directional coupler 61 is such that reflected power from the biological tissue 8o will enter the coupled port. The output from 61 is connected to the input of a co-axial cable assembly 40, and the distal end of cable assembly 40 is connected to a first antenna 70, which is used to transmit microwave energy from microwave source 10, and low power amplifier 20, into biological tissue structure 8o. In practice, cable assembly 40 may not be required as in certain embodiments coupler 6i is connected directly to first antenna 70.

Second antenna 71 is connected to matching filter 51, whose function is to provide an impedance match between the output of antenna 71 and the surface of the biological tissue structure 8o to enable maximum power transfer into tissue, which will lead to the highest possible signal strength and ensure that the signal fed into detector 100 is above the noise floor of said detector 100. The output from matching filter 51 is connected to the input of a co-axial cable assembly 41, and the distal end of co-axial cable 41 is connected to a third input of detector/receiver unit 100. In practice, cable assembly 41 may not be required as in certain embodiments said detector/receiver unit 100 will be connected directly to second antenna 71. Matching filter 51 may be excluded from the line up in the instance where it is not required to match the energy to the tissue or where said second antenna 71 has been statically matched to the surface of said biological tissue structure 80 during manufacture. On the other hand, a second matching filter may also be required to transfer energy more efficiently from the microwave source io and low power amplifier 20 into biological tissue structure 8o. Said antennas 70,71 are fixed to biological tissue structure 8o and are aligned using clip arrangement 90 and fasteners 91,92. The biological tissue structure is preferably the earlobe or the web of the hand between the thumb and first finger, but this invention is not limited to using these regions of the human biological system.

The output from frequency divider (pre-scalar) 104 provides a first input into signal processor/controller no, where the output frequency produced by microwave source is identified and stored in memory. Coupled signals from second and third couplers 60,61 provide information regarding the forward transmitted and forward reflected signals, and the signal from the distal end of second co-axial cable-assembly 41 provides information regarding the forward received energy after the microwave energy has passed through biological tissue structure 80. The difference in phase and/or magnitude between the energy impinging on second antenna 71 and that transmitted from first antenna 70 provides information regarding the concentration of constituents contained within the biological fluid (normally blood). The signals from the coupled ports of 6o and 61, and the output from 41 feed into the detector/receiver unit 100, where phase and magnitude information is extracted and fed into signal processor/controller iio. Said phase and magnitude information is correlated with said frequency information supplied by said frequency divider (pre- scalar) 104 using said signal processor/controller no and changes in phase and/or magnitude are calculated. Said signal processor/controller iio also sends a control signal to PIN attenuator 170 to control the microwave power level produced by the instrument, and sends a control signal to microwave source 10 to enable the output frequency to be swept. Said signal processor/controller iio also performs noise filtering, signal conditioning and performs all other signal processing and monitoring functions. The processed information is fed into the output device 120, which presents patient information, provides the necessary user control facilities and acts as an interface to the outside world. Possible embodiments for antennas 70,71, detector/receiver unit 100, signal processor/controller no, and output device 110 are discussed in detail later in this description. The DC energy source for the instrument is derived from a power supply unit iso; this unit provides the DC supply for the microwave source 10, the power amplifier(s) 20 (both gate bias voltage and drain supply voltage), the frequency divider (pre-scalar) 104, the detector/receiver unit 100, the signal processor/controller iio and the output device 120. Preferably the DC power supply is a battery, but where a mains driven system is required, a switched mode power supply unit is preferred over a linear supply due to the ability to offer superior performance in terms of efficiency, smaller size and lighter weight.

Directional couplers ioi,6o,6i are preferably fabricated onto a microwave dielectric substrate with copper, or another suitable metallic coating, on both sides. The preferred arrangement for the couplers is edge-coupled microstrip lines. Other structures include: microstrip stripline, suspended stripline, coplanar microstrip, aperture coupled waveguide, TEM line, Lange, tandem, Wilkinson, De Rande, co- axial, 900 hybrid, hybrid ring, branch line, branch line hybrid, hybrid tee and MEM based devices. Other microwave directional couplers will be apparent to a person experienced in the art of microwave engineering, and this invention is not limited to using the types of couplers listed above. The main constraints associated with the choice of couplers are the need for high directivity and the limitations on size due to the requirement to integrate the instrument into a small package. A detailed description of the integration aspects of this invention is given later in this description. The matching filter 51 may take the form of a microstrip filter, a stub tuner network (microstrip or waveguide), a single or plurality of veractor diodes, a single or plurality of PIN diode phase shifters, or a lumped element inductor- capacitor network. Cable assemblies 40,41 may take the form of co-axial or flexible waveguide structures. Other matching filter 51 arrangements and cable assembly 40,41 structures will be known to a person skilled in the art of microwave engineering.

Preferably, the biological tissue structure 80 chosen for the measurement is a region of the anatomical system that is rich in blood flow and is biologically simple in structure. Ideally, the all layers of tissue sandwiched between antennas 70,71, except the blood itself, will exhibit a constant value of conductance and relative permittivity.

An illustration of a typical biological structure used with the instrument is shown in figure 2, where it is assumed that the structure is symmetrical and consists of only three tissue types; namely: skin 83, fat 84 and blood 85. Of course, the structure will also contain water. The preferred locations of the human anatomy for these measurements to be carried out are the earlobe and the web of the hand between the thumb and the first finger. These structures are preferred due to the fact that they consist mainly of skin, water, blood and fat, and the thickness of the overall structure varies from between about 2mm and 20mm, thus the propagation loss, even at high microwave frequencies, is such that a low power microwave signal may be launched into said tissue structure 80, using first antenna 70, passed through said structure 8o and be received at second antenna 71 where the signal strength will be greater than the noise floor of the detector/receiver unit 100. For example, using a first order approximation, signal attenuation at a frequency of ioGHz will be as follows: blood = -1.5 dB/mm, dry skin = -1.13 dB/mm and fat = -0.22 dB/mm, hence if biological structure 8o consisted of 2mm of skin, mm of fat and 3mm of blood, then, at an operating frequency of 10GHz, the total signal attenuation would be 6.36 dB.

Arrangements showing antenna structures 70,71 connected to the preferred regions of the anatomy 8o using a clip arrangement 90 are given in figures 3 and 4. In the arrangements shown in figures 3 and 4 antennas 70, 71 are connected to the rest of the instrument using cable assemblies 40, 41.

In certain instances it may be preferable to perform measurements in two directions using a single microwave source 10. Figure 5 shows an arrangement to enable full two port measurements to be made; said measurements could be a combination, or all of, the following: transmission from first antenna 70 through biological tissue 80 to second antenna 71, reflection from biological tissue 8o back to first antenna 70, transmission from second antenna 71 through biological tissue 8o to first antenna 70, and reflection from biological tissue 80 back to second antenna 71. An arrangement of electronically controllable switches 30 is used in this invention to enable measurement direction changeover to take place automatically. In the configuration shown in figure 5, three singlepole-two-throw (SPDT) switches are used to enable microwave line-up 10, 170, 20 to be used as a microwave energy source for both first antenna 70 and second antenna 71. In a first configuration, a first electronic switch SPDTi 31 has a first input 1 connected to a first output 2, said first output 2 is connected to first output 2 of second electronic switch SPDT2 32, and said first output 2 is connected to first input 1 of said second electronic switch SPDT2 32. Said input to 32 is connected to the input of transmission line 40, whose output is connected to the input of a first matching filter 50. The output from said first matching filter 50 is fed into the input of a first directional coupler 60, which is configured as a forward power coupler and is used to measure forward power generated by microwave line-up 10,170,20 and whose coupled port is fed directly into detector/receiver unit 100. The output from first coupler 6o is fed into the input to second directional coupler 6i, which is configured as a reverse power coupler and is used to measure reflected forward power from biological tissue structure 8o and transmitted power from first antenna 70 to second antenna 71 after being transmitted through biological tissue structure 8o. A signal booster amplifier 21 is shown connected to the coupled port of second coupler 61. Said amplifier 21 is used to increase the signal strength in the instance where the loss through tissue structure 8o is high or the strength of the signal produced by the microwave line-up 10,170,20 is inadequate. The output from amplifier 21 is fed into detector/receiver unit 100. In the same switch configuration, the second output 3 of first electronic switch SPDT1 31 is connected to the first output 2 of a third electronic switch SPDT 3 33, but both outputs are floating. The third electronic switch SPDT3 33 is also configured so that the switch contact is connected between the second output 3 and the first input 1.

Said second output 3 is connected to ground through a 50Q resistor 35 and said input is connected to the input of transmission line 41, whose output is connected to the input of a second matching filter 51 (N.B. in this switch configuration 51 connected, but is not used). The output from first matching filter 51 is fed into the input of a third directional coupler 62, which is configured as a forward power coupler and is used to measure forward power generated by microwave line-up 10,170,20 and whose coupled port is fed directly into detector/receiver unit 100 (N.B. in this switch configuration 62 it is not used). The output from third coupler 62 is fed into the input to fourth directional coupler 63, which is configured as a reverse power coupler and is used to measure reflected forward power from biological tissue structure 8o and transmitted power from second antenna 71 after being transmitted through biological tissue structure 8o towards first antenna 70 (N.B. in this switch configuration 63 is used only to measure transmitted power from second antenna 71 after being transmitted through biological tissue 8o towards first antenna 70). A signal booster amplifier 22 is shown connected to the coupled port of fourth directional coupler 63.

Said amplifier 22 is used to increase the signal strength in the instance where the loss through tissue structure 8o is high or the strength of the signal produces by the microwave line-up 10,170,20 is inadequate. The output from amplifier 22 is fed into detector/receiver unit 100. Also in this configuration the second output 3 of second electronic switch SPDT2 32 is connected to ground through a 50Q resistor 34. The second configuration for electronic switches SPDTi 31, SPDT2 32 and SPDT3 33 enables second matching filter 51 to be used to match energy from microwave line-up 10,170,20 into biological tissue, third directional coupler 62 to measure forward power, fourth directional coupler 63 to measure reflected power from biological tissue structure 8o via first antenna 70, and second directional coupler 61 to measure received transmitted power after being sent from first antenna 70, propagated through biological tissue 8o and received at second antenna 71. The general operation is the same as that described for the first configuration with all switch positions changed over. The position of the switch contacts is controlled using control signals generated by signal processor/controller iio. The first switch SP2T1 31 uses control line C3 to control the switch position, second switch SP2T2 32 uses control line C4 to control the switch position, and third switch SP2T3 33 uses control line C5 to control the switch position. The electronic switches 31, 32, 33 may take the form of microelectromechanical systems (MEMS) based devices, PIN diode based devices (reflective or absorptive) or metal oxide semiconductor (MOS) devices. Other types of electronic switch will be known to a person skilled in the are of microwave engineering. In this invention it is preferable to use MEMS based switches due to the fact that they enable virtually parasitic- free operation and can be integrated into space-limited designs. Also, MEM switches built on GaAS substrates have been shown to exhibit insertion losses of less than 0.2 dB up to a frequency of 40GHz and switch isolations of greater than 25 dB at 40 GHz and greater than 6o dB at frequencies of less than 5GHZ. Recent MEMS devices have been operated at frequencies of up to tens of gigahertz and so they will operate within the frequency range of choice for the current invention. All other devices and components shown in figure 5 have been addressed in the description relating to figure 1.

INSTRUMENT EMBODIMENTS: We now move on to describe embodiments relating to the current invention. The first embodiment is given in figure 6 and shows the general components and configuration for an instrument that measures magnitude information only and detects positive or negative peak values (maxima or minima) that occur in the magnitude response over the frequency range of interest. The instrument correlates the value of frequency with said maxima or minima using the signal processor/controller no. The microwave source 10 is either a frequency synthesiser or a VCO, whose output frequency can be swept over the range of interest by applying a control voltage, which is derived from the processor/controller iio. The level of microwave energy is controlled using signal attenuator 170 and low power amplifier 20. The frequency is monitored using directional coupler 104, arranged such that the coupled port measures a portion of forward directed power, and said coupled portion of forward power is fed into a divider or frequency pre-scallar 104 to provide a frequency that can be processed by said signal processor/controller iio. The microwave energy signal is transmitted through the biological tissue structure 80 using first antenna 70 and, after propagation through said tissue structure 80, the signal is received at second antenna 71. A magnitude detector 117 is used to detect the signal and a peak detector 118 is used to detected the positive, or negative, going peak. The combination of magnitude detector 117 and the peak detector 118 forms the detector/receiver unit 100. The detected signal from 118 is then fed into the signal processor/controller iio where it is correlated with said frequency information provided by 104. The magnitude detector may take the form of a diode detector with appropriate filtering, or a homodyne detector, which may use a mixer and a local oscillator. Other types of magnitude detectors will be known to a person skilled in the art. The processor/controller iio is used to determine the blood-glucose concentration from said amplitude peak and corresponding frequency information.

Said processor/controller no also sends information to output device 120 whose function is to display the blood-glucose level in a user-friendly format. The signal processor/controller iio may take the form of a microprocessor, a digital signal processor with an integrated microprocessor, or a microcontroller. It may be preferable to use the microprocessor integrated into a commercially available device that already uses a microprocessor to perform other functions, to perform the function of the signal processing/controller iio used in this invention. This aspect of the invention will be described separately in the description. It may also be preferable to use a display, or an output device, integrated into a commercially available system that already requires a display or output device, to provide the display or means of outputting information for the instrument described in this invention. This aspect of the invention will be described separately in the description. It is preferable for that the instrument to be portable and so the power supply 130 may take the form of a battery pack. The clip arrangement 90 and the fasteners 91,92 are preferably made from a plastic material, but a metallic material could also be used. It is preferable for said materials to be biocompatible, but since it may not be necessary for said clip/fastener arrangement 90, 91, 92 to come in contact with the body, these components may not need to be biocompatible. On the other hand, the surface of antennas 70,71 will be in contact with the skin and so provision must be made for said antennas 70,71 to be covered with a biocompatible material. Preferably the cover will be a thin layer of a conformal coating. Suitable materials may include Parylene C, PTFE or certain Teflon formulations.

A specific embodiment for the magnitude detector 117 and the peak detector 188 is shown in figure 7, where a circuit to detect negative polarity and voltage minima detector given. In this embodiment the magnitude detector 117 is a negative polarity detector and consists of a shunt inductor Li 47, a diode Di 44, a series resistor Ri 46 and a shunt capacitor Ci 48. Shunt inductor Li 47 may take the form of a microstrip line, where it is preferably an open circuit or short circuit stub, a lumped element such as a surface mount inductor, or a simple loop of fine wire. Diode Di 44 may take the form of a zero bias schottky diode, a bolt channel schottky diode, a PIN diode or a tunnel diode. A tunnel diode may be preferable due to the desired operating frequency range and the need for temperature stable operation. Resistor Ri 46 may take the form of a surface mount resistor, a through hole resistor, or a device that is fabricated onto a microstrip board by deposition. Capacitor Ci 48 may take the form of a series microstrip line with a line width greater than that of the characteristic impedance of the feed line, or a lumped element, such as a surface mount device, or a through hole device. The purpose of Li 47 is to provide a path to ground and to provide input matching between the transmission line (normally microstrip line) and diode Di 44. Diode Di 44 allows a signal with a negative polarity to pass through to Ri 46, but rejects signals with a positive polarity. Series resistor Ri 46 and shunt capacitor Ci 48 form a single pole low pass filter with a time constant equal to the product of the value of the two said components. The output of the magnitude detector 117 is connected to the input of the peak detector ii8. In this embodiment the peak detector ii8 comprises: a first amplifier A2 24, a diode D2 45, a capacitor C2 49 and a second amplifier A3 25. Amplifiers A2 24 and A3 25 are preferably operational amplifiers and an 8 pin dual-in-line package may be preferable since both A2 24 and A3 25 are contained in a single package. Said package is preferably a surface mount package and said surface mount package is preferably a miniature surface mount package. Diode D2 45 is preferably a low leakage current diode and capacitor C2 49 is preferably a polarised low leakage dielectric type. The combination of A2 24 and D2 45 form a precision rectifier and capacitor C2 49 holds the output voltage at the most negative value allained by the signal input to A2 24. Capacitor C2 49 is charged through D2 45 by the output current from A2 24 to the same value as that input to A2 24 due to the fact that A2 24 is configured as a voltage follower or unity gain amplifier. Second amplifier A3 25 is also configured as a unity gain voltage follower and acts as buffer amplifier to prevent components in the rest of the circuit from loading the voltage at the input to A3 25. Preferably second amplifier A3 25 is a high input impedance device with very low leakage current and has a high enough output current capability to enable it to drive the input to the signal processor/controller no. It may be necessary to provide the facility toreset said detector ii8 prior to taking measurements. This may be achieved by short circuiting capacitor C2 49 to remove any residual charge stored in the electric field existing between the two plates of said capacitor C2 49. It may be preferable to use an electronically controlled switch placed in parallel across said plates of said capacitor C2 49 to enable said residual charge to be removed. It may be preferable to use a voltage controlled MOSFET device with a very low channel resistance to perform this function, but other suitable devices will be known to a person experienced in the art of instrumentation design. The combination of the magnitude detector 117 and the peak detector ii8 form the detector/receiver unit 100. All other elements shown in the embodiment shown in figure 7 are the same as those given in figure 6.

To measure phase and magnitude information it is necessary to change the configuration of the detector/receiver unit 100 from the arrangements given in the embodiments shown in figures 6 and 7. Figure 8 shows a specific embodiment of the instrument to enable both phase and magnitude information to be measured. In this specific embodiment frequency mixers are used and operated such that the local oscillator input frequency is different from that of the RF input frequency, this provides two frequencies at the output of said mixer; the sum of the local oscillator frequency and the RF frequency and the difference between the RF frequency and the local oscillator frequency. In this embodiment said local oscillator frequency is derived from microwave source 10. A portion of the signal from said microwave source 10 is made available using a first directional coupler ioi which is configured with its coupled port arranged to measure a portion of the forward signal produced by 10. The coupled power from 101 is fed into frequency divider (pre-scalar) 104, where the frequency generated by the microwave source 10 is divided by a fixed value (normally an integer) and is then multiplied by a fixed value (normally an integer) to provide a higher frequency using frequency multiplier 105. The division factor for 104 and the multiplication factor for 105 are selected to provide a frequency which enables the output intermediate frequency (IF) signal from frequency mixers 106, 107, io8 to be of a suitable frequency to enable a standard processor, or a low frequency phase/magnitude detector, to be used to detect phase and magnitude information from the measurement signals. In the arrangement given in figure 8 the scaled frequency output signal from 105 is fed into a second directional coupler 102 and the output of 102 is fed into the first input, the local oscillator input, of first mixer io6, the second input to io6, the RF input, is taken from the coupled port of a third directional coupler 6o, which is configured to measure a portion of the forward directed power being transmitted into the biological tissue structure 8o. The output from first frequency mixer 106 is fed into a first integrated phase/magnitude detector 109. Said integrated phase/magnitude detector may take the form of a packaged phase/magnitude demodulator, such as the analogue devices part AD8302. The phase/magnitude information produced by 109 is fed into signal processor/controller 110. Connecting cables, or transmission lines, are used to connect the first and second outputs from the first integrated phase/magnitude detector 109 to signal processor/controller iio. The cable transporting phase information is 142 and the cable transporting amplitude information is 143. The scaled reference frequency taken from the output of frequency multiplier 105 is also used as the local oscillator frequency inputs for second and third frequency mixers 107, 108. The first input, the local oscillator input, to second mixer 107 is derived from the coupled port of second directional coupler 102, which is configured to measure forward directed power. The coupled power from 102 is fed into directional coupler four 103 and the output from 103 is fed into said first input, the local oscillator input, to second frequency mixer 107. The second input, the RF input, going into said second mixer 107 is taken from the coupled port of a fifth directional coupler 6o, which is configured to measure a portion of reflected power coming back via first antenna 70 after the energy has passed into the biological tissue structure 80 and a portion is reflected back in the form of backscatter. The output from said second frequency mixer 107 is fed into a second integrated phase/magnitude detector 112. The phase/magnitude information produced by 112 is fed into the signal processor/controller no. Connecting cables, or transmission lines, are used to connect the first and second outputs from second integrated phase/magnitude detector 112 to signal processor/controller no. The cable transporting phase information is 144 and the cable transporting amplitude information is 145. The first input, the local oscillator input, to third mixer io8 is taken from the coupled port of fourth directional coupler 103, which is configured to measure forward directed power. The coupled power from 103 is fed into said first input, the local oscillator input, of said third frequency mixer io8. The second input, the RF input, going into said third mixer 108 is taken from the output of second matching filter 51, which matches the impedance of the surface of the biological tissue structure 8o with the aperture of second antenna 71. Energy impinging on the aperture of said second antenna 71 is the received energy after the microwave energy from said microwave line-up 10, 101, 170, 20,21, 50, 6o, 61 and 70 leaves said second antenna 70, and is transmitted through biological tissue structure 8o. The output from said third frequency mixer 108 is fed into a third integrated phase/magnitude detector iii. The phase/magnitude information produced by 111 is fed into signal processor/controller iio. Connecting cables, or transmission lines, are used to connect the first and second outputs from second integrated phase/magnitude detector 111 to signal processor/controller iio. The cable transporting phase information is 147 and the cable transporting amplitude information is 146.

Directional couplers 1, 2 and 4 (mi, 102, 103) are preferably 3dB couplers or 3dB splitters, and may take the form of microstrip or stripline devices. It may be preferable to connect low pass filters at the outputs of frequency mixers 106, 107, 108 to ensure that only the difference frequency (RF - Local oscillator frequency) passes into phase/magnitude detectors 109, 112 and iii respectively and that the sum frequencies produced by said frequency mixers 106, 107 and 108 are rejected. In this embodiment two low power amplifiers 20,21 are used to amplify the microwave signal produced by microwave signal source 10, first matching filter 50 is used to provide a static impedance match between first antenna 70 and the surface of the biological tissue structure 80, and second matching antenna i is used to provide a static impedance match between second antenna 71 and the biological tissue structure 80. A PIN diode attenuator 170 is used to control the power level, where a voltage signal C2 derived from signal processor/controller iio determines the level of attenuation provided by said PIN diode attenuator 170. A cable or transmission line 141 connects said control signal between signal processor/controller no and said PIN diode attenuator 170. The microwave frequency is swept or adjusted by applying a signal to the control input of the frequency source 10. Said control signal Ci is derived from signal processor/controller unit nO and the connection between 10 and 110 is made using a cable or transmission line 140. Details of the signal processor/controller iio, output device 120 and DC power supply 130 have already been given, but some aspects of these devices will be elaborated on later in this description. Figure 9 provides a list of preferred devices that may be used in the implementation of the specific embodiment shown in figure 8. The reference numbers given in the table correspond to the numbers provided in figure 8. A region bounded by dotted lines and a lightly shaded box 100 in figure 8 shows the heterodyne detector only, and a box bounded by dotted lines 6oo indicates the complete microwave assembly, which includes the heterodyne detector 100 and the rest of the microwave component line-up (includes frequency source 10, first directional coupler (splitter) wi, PIN diode attenuator 170, first low power amplifier 20, second low power amplifier 21, first matching filter 50, third directional coupler 6o, fifth directional coupler 6i and second matching filter 51).

A further specific embodiment for the instrument is given in figure 10. This embodiment is similar to the embodiment shown in figure 8 and described above except that in this instance the three frequency mixers io6, 107, io8 and the three phase/magnitude detectors 109, lii, 112 are replaced by an electronically controlled single-pole-three-throw switch (SP3T) 113, a single mixer 106, and a single integrated phase/magnitude detector 109. The advantage of this arrangement is that the noise produced by, or injected into, frequency mixer 106 and phase/magnitude detector 109 is common to all phase/magnitude measurements taken from coupled ports of third and fifth couplers 60, 61 and second matching filter 51, thus said noise signals can be subtracted from measurement signals, whereas for the previous embodiment, shown in figure 8, each of the three mixers 106, 107, 108 and also each of the three the phase/magnitude detectors 109, 111, 112 produce different noise signals that cannot be easily subtracted from the measurement, which could limit the measurement sensitivity/capability of the instrument. In the specific embodiment shown in figure 10 the output from the coupled port of third directional coupler 6o is connected to the first switch position of SP3T electronic switch 113 and said coupler is configured to measure a portion of forward directed power from the microwave line- up. Said third coupler may be used to measure the level of forward energy that is being transferred into biological tissue structure 80, or may be used as a reference to enable a comparison to be made between the value of phase and magnitude information measured at this position and that measured at other locations. The output from the coupled port of fifth directional coupler 61 is connected to the second switch position of SP3T electronic switch 113 and said coupler is configured to measure a portion of reflected (backward directed) power from the path consisting of the biological tissue structure 8o and first antenna 70. The output from second matching filter 51 is connected to the third switch position of SP3T electronic switch 113 and provides information relating to the microwave energy after it has been transmitted by said first antenna 70, through biological tissue structure 8o. Second antenna 71 is used to collect said microwave energy and second matching filter 51 is used to ensure that the impedance seen at the surface of biological structure 8o is matched with the impedance seen at the aperture of said second antenna 71. A control signal C6 is used to change the contact position between the aforementioned switch positions of SP3T electronic switch 113. The signal processor/controller no is used to determine the contact position. The analogue or digital control signal is connected to the input control line of SP3T electronic switch 113 using a low frequency cable or transmission line 148. The common output from said SP3T electronic switch 113 is connected to the second input, the RF input, of frequency mixer 106. The second input, the intermediate frequency, connected to frequency mixer 106 is derived from frequency source 10 in a similar manner to that discussed for previous embodiment (description given for figure 8); the difference here is that the output from frequency multiplier 105 is fed directly into the input, the local oscillator input, of frequency mixer io6. Said frequency mixer 106 produces two frequencies; the sum and the difference, but only the difference is if interest in this embodiment of the current invention. It may be preferable to insert a low pass filter at the output of said mixer 106 to filter out the sum frequency signal, but it is generally the case that devices connected to the output of said frequency mixer io6 will not see the sum frequency due to the fact that the local oscillator and the RF frequency are high microwave frequencies, where high microwave frequency is defined as being above ioGHz in this instance; a low pass filter has therefore been omitted from this specific embodiment. The output from said mixer 106, the intermediate frequency output signal, is connected to an integrated phase/magnitude detector 109 and the phase and magnitude information output signals are connected to the signal processor/controller no. Connecting cables, or transmission lines, are used to connect the first and second outputs from second integrated phase/magnitude detector 109 to signal processor/controller iio. The cable transporting phase information is 142 and the cable transporting amplitude information is 143. The signal processor/controller no is used to pole the three positions of SP3T 113 and measure the phase/magnitude information at each switch position to determine the measurement information and calculate the blood-glucose level. Said electronically controlled switch 113 may take the form of a MEM device or a PIN diode switch, which may be an absorptive or reflective type. Preferably the insertion loss of the channel between the input and output should be as low as possible and the level of isolation between the switch contacts should be as high as possible at the frequency of interest. Typical properties for a packaged single-pole- three-throw PIN diode switch that can be operated over the frequency range of between iGHz and i8GHz, and could be used in the current invention, are as follows: a) Reflective type: Maximum insertion loss = 3. 1dB; Minimum isolation = 6odB; Maximum switching speed = ioons.

b) Absorptive type: Maximum insertion loss = 3.3dB; Minimum isolation = 65dB; Maximum switching speed = ioons.

It can be seen from these figures that a trade-off has to be made between insertion loss and isolation. These figures were taken from the Advanced Control Components Inc. current microwave components product catalogue. All other components and configurations given in the specific embodiment shown in figure 10 have been described earlier in the description relating to the current invention.

MICRO WAVE INTEGRATION: We will now turn to the integration aspect of the current invention. This part of the invention is focussed on integrating the microwave elements of the instrument into a compact space to enable the user to connect the device to their person in a non- obtrusive manner. It may be preferable to integrate said microwave elements or circuits into a device that is already commercially available; said aspect will be discussed later in this description. In this invention, two levels of integration are considered and these are shown in figures ii and 12. Figure ii shows the first level of integration, whereby the following microwave components are integrated onto a single, or a stack of, substrate layer(s): frequency source 10, first directional coupler ( dB splitter) ioi, frequency divider (pre-scalar) 104, signal attenuator 170, low power amplifier 20, second directional coupler 60 and third directional coupler 61.

These components are grouped together as 500 and known as the general microwave components. The second level of integration is shown in figure 12 and consists of all of the components in 500 as well as the detector/receiver unit 100 and is grouped together as 600. Figure 12 shows the following extra components: fourth directional coupler (splitter) 63, frequency multiplier 105, electronically controlled single-polethree-throw switch 113 and frequency mixer 106. The first and second antennas 70 and 71 are also connected to integrated microwave component assemblies 500/600.

The preferred method of making the connection between said antennas 70,71 and said microwave assembly 500/600 is to a use co-axial feed or a coaxial via. The drawback with using this method to make the connection between said antennas 70, 71 and said integrated microwave assemblies 500/600 is that normally the feed via introduces an inductance and said inductance needs to be cancelled out, otherwise a mismatch will occur between the antennas 70,71 and the microwave energy source (io, 170, 20, 21, 6o, 61). The preferred method of achieving said cancellation is to connect a capacitor in series with the antenna feed and the integrated microwave assembly soo/6oo. The capacitance of said capacitor should be such that the reactance of the capacitor at the frequency of choice (this may be the centre frequency, where a band of frequencies are used) is the same as the reactance produced by the inductance of the via. In the instance where antennas 70, 71 are patch antennas, it may be preferable to introduce said series capacitor by etching out an annular slot in the patch metallization. It is preferable to use microwave monolithic integrated circuits (MMIC) and microelectromechanical (MEM) devices in the design of integrated microwave assembly line-ups 500/600 since these device technologies enable very small and compact components to be formed. Directional couplers and splitters ioi, 60, 61, 63 are preferably fabricated as microstrip couplers and may be strip-line or coplanar arrangements. It is preferable for all of the microwave components that form 500/600 to be mounted on a single substrate layer, but a multilayer construction may be necessary to ensure the most efficient use of the small amount of space available. Each layer may be connected by co-axial vais and said vias can be constructed of stamped holes containing vacuum deposited metal. It may be preferable to use silicon as the substrate material of choice since it is low cost and offers high level of integration for circuits formed within it. Other substrate materials that may be considered include, but are not limited to, alumina, sapphire, polyolefin, quartz, semi-insulating gallium arsenide, glass-bonded mica, Teflon- quartz filled and silicon resin-ceramic. If a multilayer approach is used then vertical stacking may be used and the lengths of vias should be minimised. The length of microstrip lines used to make interconnections between the microwave components should be minimised to keep insertion loss to a minimum and to reduce noise. It is preferable to use heat sensitive paste rather than solder to make the interconnections.

The integrated microwave line-ups 500/600 are preferably mounted inside a metallic enclosure to screen the circuits from electric and magnetic field pick-up produced by external sources, whilst preventing the circuits contained within the instrument (500/600) from radiating unwanted microwave energy into free-space and coupling into other nearby circuits or systems. Preferred materials for said enclosures include: aluminium, mu-metal and copper. It should be ensured that the distance between the microstrip line interconnects that form a part of the integrated microwave assembly (500/600), and the walls of the enclosure, are carefully chosen in order to prevent box modes from being set-up between said microstrip lines and said box walls. If said modes were allowed to propagate then this would lead to instrument performance limitations and may lead to a non- functioning instrument.

CONFIGURATIONS: Leading on from the integrated microwave assembly aspect of this invention, it is necessary to look at how said integrated microwave assemblies 500/600 can will be used with the rest of the instrument described in this invention. Figure 13 shows possible configurations where a cable assembly 43 is used to convey microwave signals and/or lower frequency information between the measurement site 8o and the rest of the instrument 450. The first configuration, figure 13 (a) shows the antenna pair 70,71 connected to the earlobe 8o using a clip arrangement 90 and integrated microwave assembly 500 is housed with, or very near, said antennas 70,71.

Signals from said microwave assembly 500, in the form of microwave energy taken from the coupled ports of directional couplers 6o,6i and second antenna 71 will be combined with the DC control signals going to the frequency source 10, the PIN diode attenuator 170, and a down converted version of frequency source 10 coming from the output of frequency divider (pre-scalar) 104, and an integrated microwave/DC cable assembly 43 will be used to convey this information to the rest of the instrument 450. In this case, said rest of the instrument 450 consists of the detector/receiver unit 100, the signal processor/controller iio and the output device 120. Said cable assembly 43 may comprise four co-axial cables assemblies and two twisted pairs, or any other appropriate means of channelling multiple microwave and DC signals. The second configuration is shown in figure 13 (b) where integrated microwave assembly 6oo is housed with, or very near, said antennas 70,71. In this instance detector/receiver unit 100 is included within said microwave assembly 6oo, thus cable assembly 43 comprises: a DC control signal going to the frequency source 10, a DC control signal going to the PIN diode attenuator 170, a down converted version of the frequency source 10 coming from directional coupler (splitter) 63, and the intermediate frequency (IF) coming from the output of frequency mixer io6. It may be possible to use four twisted pairs to form cable assembly 43; the limiting factor will be whether or not the frequency of the down converted reference signal and the IF signal will cause excessive insertion loss, for example, if said IF signal is in the range of between DC and 100 megahertz (MHz), then the use of twisted pairs is acceptable. Said cable assembly 43 is used to channel information to the rest of the instrument 450. In this case the rest of the instrument 450 consists of the signal processor/controller iio and the output device 120. The third configuration that uses cable assembly 43 to channel information from the region where antennas 70,71 are situated to the rest of the instrument 450 is shown in figure 13 (c). In this arrangement said antennas 70, 71 and clip arrangement 90 are the only elements of the system located at the measurement site 80. In this instance microwave energy is transmitted using microwave assembly 500 contained within the unit that contains the rest of the instrument 450 and is channelled to first antenna 70, along a first path, where microwave energy is also received via the same first path in the form of a reflected signal; microwave energy is also received at second antenna 71 and is channelled back to the rest of the instrument 450 via a second path. Said channels used to create said paths may take the form of two coaxial cable assemblies or a single assembly containing two co-axial cables. Flexible waveguide assemblies may also be used to form said cable assembly 43. In this instance, the rest of the instrument comprises of the general microwave elements 500, the detector/receiver unit 100, the signal processor/controller iio and the output device 120. Other configurations may offer advantages over the aforementioned configurations using cable assembly 43 to transfer information from the measurement site 8o to the rest of the instrument; one such configuration is shown in figure 14 and uses a wireless link as the means of channelling information. The first configuration for using a wireless link to connect the measurement site 8o to the rest of the instrument 450 is shown in figure 14 (a) and consists of a first modulator/demodulator unit 1000 and a third antenna 700 connected to integrated microwave assembly 500 located at the measurement site 8o, and the rest of the instrument 450. The rest of the instrument 450 comprises: a fourth antenna 701, a second modulator/demodulator unit 1100, a receiver/detector unit 100, a signal processor/controller unit 110 and an output device 120. Said sub- system 450 is positioned at a location that is within reach of the patient and/or appropriate monitoring personnel. The second configuration for using a wireless link to connect the measurement site 8o to the rest of the instrument 450 is shown in figure 14 (b) and consists of a first modulator/demodulator unit 1000 and a third antenna 700 connected to the integrated microwave assembly 600 located at the measurement site, and the rest of the instrument 450. The rest of the instrument 450 comprises: a fourth antenna 701, a second modulator/demodulator unit 1100, a signal processor/controller unit 110 and an output device 120. Said sub-system 450 is positioned at a location that is within reach of the patient and/or appropriate monitoring personnel. The main advantages of replacing cable assembly 43 with said modulator/demodulators iooo,iioo and additional antennas 700,701 are that the instrument does not require cumbersome cables and this feature facilitates the development of an integrated unit comprising: first and second antennas 70,71, the microwave line-up 500/600, the modulator/demodulator unit 1000 and third antenna 700. Said unit may be integrated into a single device located at, or nearby, the measurement site 8o. Said integrated assembly may be used to transmit measurement data to a myriad of external devices to provide information relating to blood-glucose level or other conditions that can be monitored using this instrument.

It may be possible to integrate said integrated assembly into a commercial device that is commonly used in everyday activities, for example, a Bluetooth headset, a pair of headphones, a earpiece, or a hearing aid. Full details of first and second modulator/demodulator units iooo,iioo will be given in the next section of this

description.

WIRELESS OPERATION: The aspects of the current invention relating to wireless operation will now be described. As previously mentioned in this description, the ability to transmit and receive information regarding the condition of a patient over a wireless link is very attractive in both a technological as well as a commercial sense. In order to make this aspect of the invention realisable it is necessary to include two combined modulator/demodulator (modem) 1000, 1100 and antenna 700,701 units; one unit located at the site where the measurements are being taken 80 and at a second unit located at a remote site. The wireless link preferably uses microwave devices and preferably said devices are MMIC and MEM based to enable installation inside very small spaces. The preferred operating frequency for said wireless link is greater than 2GHZ, but lower than 40GHz, but this invention is not limited to using a link that operates in this frequency range. Said frequency range facilitates the use of small device technologies and provides the capability to transmit data over distances commensurate with the normal device operating range. Said range may vary from less than one metre to up to three metres, for example, this distance may be the distance between the earlobe and the patient's waist. In general terms, the modulator/demodulator unit 1000, 1100 and third and fourth antennas 700, 701 provide a means of adding information (measurement information or data) onto a carrier signal, transmitting said carrier and measurement information signal across the medium of free space using a third antenna, receiving an attenuated version of said carrier and measurement information signal using a fourth antenna, and removing said carrier signal from said carrier and measurement information signal to provide a replica of said measurement information signal. Said measurement information signal may be added to said carrier signal be varying the amplitude, phase or the frequency of said carrier signal. The method of varying the above entities is known as modulation and the variations may be described as amplitude modulation, phase (or angle) modulation and frequency modulation. Other modulation schemes include pulse amplitudemodulation, pulse position modulation and pulse code modulation. Yet more suitable modulation schemes will be known to a person skilled in the art of communications engineering. Three embodiments of the instrument configured for wireless operation are given in figures 15, i6 and 17. In the first arrangement shown in figure 15, an integrated microwave line-up 8oo comprises: a frequency source 10, a first directional coupler (splitter) 101, a PIN diode attenuator 170, a low power amplifier 20, a first matching filter 50, a second directional coupler configured to measure a portion of forward directed power 60, a third directional coupler configured to measure a portion of reflected power 61, a first antenna 70, a clip 90 and fastener arrangement 91,92, a biological tissue structure 80, a second antenna 71, a second matching filter 51, a first modulator/demodulator unit 1000 and a third antenna 700. The rest of the instrument is located in a location separate from 8oo and comprises: a fourth antenna 701, a second modulator/demodulator unit 1100, a detector/receiver unit 100, a signal processor/controller unit 110 and an output device 120. In this arrangement the first modulator 1000 demodulates the DC control signals for controlling the operating frequency and the power level and directly modulates the microwave information signals containing information regarding the frequency of operation, the energy being delivered into the biological tissue structure 80, the energy reflected back from the biological tissue structure 8o through first antenna 70, and the energy transmitted through the biological tissue structure 8o after the signal has been collected using second antenna 71 and impedance matched with the surface of said biological tissue structure 8o using matching filter 51. Said DC and measurement information is received at third antenna 700. Second modulator/demodulator iwo modulates said DC control signals generated by signal processor/controller iio and places the information onto an appropriate carrier and transmits said signals using fourth antenna 701. Said second modulator/demodulator unit 1100 also demodulates said microwave information, and detector/receiver unit 100 extracts phase and/or magnitude information. Said phase and/or magnitude information is then processed and manipulated using signal processor/controller iio and the information is output in a user friendly format using output device 120.

The second arrangement for a wireless operated instrument is shown in figure 16.

This arrangement is similar to the arrangement shown in figure 15 except that the detector/receiver unit 100 is included within the integrated microwave line-up 800.

In the specific embodiment given in figure 16 frequency information is obtained from the output of frequency divider 104 and first modulator/demodulator unit 1000 modulates this information onto a carrier and said information is transmitted over the wireless link using third antenna 700. A portion of forward directed information taken from second directional coupler 6o is fed into the RF input of first frequency mixer io6 and a second microwave frequency oscillator 12 is used to generate the local oscillator input for said first mixer. The output frequency from said first mixer, the difference between the RF input frequency and the local oscillator frequency (RF- LO), is known as the intermediate frequency (IF). Said IF is input into first modulator/demodulator unit 1000 and is modulated onto a carrier and transmitted over the wireless link using third antenna 700. A portion of reflected signal information taken from third directional coupler 61 is fed into the RF input of second frequency mixer 107 and a second microwave frequency oscillator 123 is used to generate the local oscillator input for said second mixer. The output frequency from said second mixer, the difference between the RF input frequency and the local oscillator frequency (RF-LO), is known as the intermediate frequency (IF). Said IF is input into first modulator/demodulator unit 1000 and is modulated onto a carrier and transmitted over the wireless link using third antenna 700. A third frequency mixer 108 with a local oscillator signal derived from a third microwave frequency oscillator 14 is used to receive microwave energy from second matching filter 51 and resolve magnitude and/or phase information for a signal transmitted using first antenna 70 and having propagated through biological tissue structure 80. The output frequency from said third mixer, the difference between the RF input frequency and the local oscillator frequency (RF-LO), is known as the intermediate frequency (IF).

Said IF is input into first modulator/demodulator unit 1000 and is modulated onto a carrier and transmitted over the wireless link using third antenna 700. The rest of the instrument is the same as that given in figure 15 except that detector/receiver unit is now contained within microwave assembly 8oo as described above. A third arrangement for a wireless operated instrument is shown in figure 17. This arrangement is similar to the arrangement shown in figure 16 except that the design of the detector/receiver unit 100 has been changed. In this instance an electronically controlled single-pole-three-throw switch SP3T 113 and a single frequency mixer 106 provide a single IF signal, which is multiplexed using said electronically controlled switch 113 to provide a portion of the forward power, a portion of the reflected power and the transmitted power after it has passed through matching filter 51, at the input to first modulator/demodulator unit 1000. Said IF is input into said first modulator/demodulator unit iooo and is modulated onto a carrier and transmitted over the wireless link using third antenna 700. In this configuration the local oscillator frequency input to frequency mixer 106 is derived from microwave frequency source 10 using a frequency divider 104 and a frequency multiplier 105.

The output from said frequency multiplier 105 is fed into the local oscillator input to said frequency mixer 106. The signal from frequency divider 104 is in fact split two ways using second directional coupler 63; a first path feeds into said frequency multiplier 105 and a second path feeds directly into modulator/demodulator unit 1000, where said modulator/demodulator unit 1000 modulates this information onto a carrier and said information is transmitted over the wireless link using third antenna 700. The rest of the instrument is the same as that given in figure 16.

MONITORING, RECORDING AND PATIENT CARE: The following aspect of the current invention involves using the instrument configured for wireless operation, as described in the previous section, and integrating the microwave assembly 8oo and the rest of the instrument 450 into commercially available devices to form a compact, user friendly and socially acceptable system to measure concentrations of constituents contained within a biological fluid and, more specifically, an a new and improved method of blood- glucose monitoring, recording of patient data and relaying patient care information.

For clarity, the present invention will be divided into two discrete units, namely: the integrated microwave assembly 800 with an antenna 700, and the rest of the instrument 450. First of all, the integrated microwave assembly 8oo and transmit/receive (transceiver) antenna 700 connected to the biological tissue structure 8o is considered. This unit may take the form of a stand-alone device, but more preferably the unit will be integrated into a commercially available device in order to provide the facility for non-obtrusive blood-glucose monitoring. There are a myriad of devices that integrated microwave assembly 800 and transceiver antenna 700 may be integrated into; such devices include: a Bluetooth headset and other mobile phone equipment that is normally attached to the biological system, a pair of headphones, a hearing aid, or a standard earphone. Other devices may become apparent as communications technology moves forward and new scientific advancements are made. Secondly, the rest of the instrument 450 shall be considered and it will be seen here that the wireless embodiment of this invention enables measurement information to be channelled using a number of different devices and media. Also, said wireless embodiment enables information not only to be sent from the instrument to a monitoring device, but also enables information to be sent to the instrument to enable the user, or patient, to take corrective action.

Figure 18 shows a first instrument arrangement, where the rest of the instrument 450 comprises: a transceiver antenna 701, a modulator/demodulator unit 1100 and a personal computer or a personal development device (PDA). Said personal computer or PDA contains microwave detector/receiver unit 100, processor/controller unit 110 and output device 120. Preferably said modulator/demodulator unit 1100 and said antenna 701 are integrated into said personal computer/PDA 450. The use of said personal computer/PDA 450 will enable information concerning, for example, blood- glucose level to be displayed in the form of a numerical value, for example, in mmol/L or mg/dL, or provide a graph of blood-glucose level against time. It may be desirable to use a section of the monitor contained within 450 to continuously display said graph. It may be preferable to write a command level programme to enable display to come up automatically when the power supply is applied to said personal computer/PDA device 450. The range of operation over which the wireless link should operate may be up to three metres and it is desirable to be able to monitor the signal strength to ensure that the received data is error free. If the data error rate or the signal strength falls below an acceptable limit the monitoring unit should flag this up as an error or the system should automatically shut down. Preferably unit 450 will include an audible warning alarm to advise the patient that their bloodglucose level is outside a range deemed to be acceptable, and that corrective action is required.

Figure 19 shows a second configuration for 450. In this arrangement measurement information is received using antenna 701 and a modulator/demodulator unit 1100 is used to send said information along a telephone line 930 to a remote monitoring station 910. Said remote monitoring station 910 may process said information and display said information in a user-friendly format for a doctor, or other qualified person, to monitor the patient's blood-glucose level. Said information may be logged using a data storage device or may be printed to provide a patient record in a hard copy format. This aspect of the current invention may be particularly useful for monitoring the general health of elderly patients of for constantly monitoring Type I diabetes sufferers. Figure 20 provides a third configuration for 450. This arrangement takes the concept introduced in figure 19 one step further and includes a computer 940 to enable the patient, or user, as well as a doctor, or other qualified person, to monitor blood-glucose level, or other related or, in some instances, non- related condition(s). This arrangement allows said doctor, or other qualified person, located at a remote site, to analyse the measured information and to send details back to the patient, which relate to the required corrective action necessary should the patient's blood-glucose level be outside limits deemed to be safe or the information indicates that patient is suffering from another condition that requires corrective action to be taken. Said computer 940 may display and record both measurement information sent from said integrated microwave assembly 8oo and antenna 700, as well as the information sent back from doctor, or other qualified person, located at said remote monitoring station 910 via telephone line 930. It would be possible for said remote monitoring station 910 to send an audible alarm message back to said computer 940 to warn patient that an abnormal condition exists and that corrective action is required. Taking this concept one stage further again, it may be desirable to include a means of presenting an audible warning signal within said integrated microwave assembly 8oo. If said assembly 8oo was, for example, integrated into a Bluetooth headset then the headset speaker could be used to provide said means of presenting said audible warning signal. In the instance whereby said computer 940 is switched off, it may be desirable to send said corrective action information, or said warning alarm, generated by said remote monitoring station 910, directly to patient via said means of presenting said audible signal or information. This aspect of the invention would be particularly useful for Type I diabetes sufferers or elderly patients. It could be possible use this aspect of the current invention to enable the voice of a doctor, or medical practitioner, to offer consoling advice or even palliative care to the patient. Figure 21 shows the use of a laptop computer 950 to receive measurement information and provide a means of signal processing 110 and displaying information in a user-friendly format 120. In this instance said laptop computer 950 includes modulator/demodulator unit 1100 and antenna 701 may have been already integrated for portable use. Said arrangement may also be used to communicate between a remote monitoring station and provide information to the patient in the form of advice and required corrective action. Figure 22 shows a further configuration where a mobile phone 900 together with wireless repeaters are used to communicate between the integrated microwave assembly 800, which is attached to the patient, and a remote monitoring station 910. In this configuration an antenna 701 connected to said mobile phone 900 is used to receive measurement information sent from said integrated microwave assembly 8oo and antenna 700. Said mobile phone 900 provides signal processing functions (110) and enables measurement information to be displayed in a user-friendly format (120). Said mobile phone 900 can also be used to transmit measurement information to a remote monitoring station 910 by making use of base station repeaters, which are geographically positioned to enable signals to be transmitted and received all over the world (for international coverage fibre optic links and satellites are utilised, but these are served by said base station repeaters positioned on land throughout the British Isles).

Therefore, said mobile phone 900 may be used to receive information sent from said remote monitoring station 910 and relay necessary corrective action, or other relevant information pertinent to the condition to patient. Said mobile phone 900 may also be used to log measurement data and provide an audible alarm, for example, in the form of a custom ring tone. Information containing said corrective action may also be sent from said remote monitoring station 910 in the form of a text message. The speaker contained within said Bluetooth headset or said headphone speakers may be used to receive audible information relating to the patient's condition and said information may be sent from a doctor, or other medically qualified person (or other person), located at said remote monitoring station 910. The current invention is not limited to using the arrangements presented here and other more suitable arrangements may become known and available as technology advances.

ANTENNA DESIGN AND CONFIGURATIONS: Antenna structures 70, 71 suitable for use in the current invention will now be considered. There are a number of features that are required in order for said antenna structures to be appropriate for use in the current invention and these are listed below: It is preferable for said antenna structure(s) 70, 71 to be flexible and manufactured to be conformal with the biological tissue structure 8o, where said structure is preferably the surface of the skin; It is preferable for the surface of said antenna(s) 70, 71 to be in direct contact with the surface of said biological structure 8o and for said surface of antenna (s) 70, 71 to be coated with a biocompatible material; It is preferable for the antenna feed line(s) 128, 129 to be located on a surface within the antenna structure that is not the same as the antenna aperture or the radiating surface; It is preferable for the feed line (s) 128, 129 to be impedance matched to the input impedance of said antenna(s) 70,71 to prevent reflections occurring at said feed point; It may be preferable for said antenna(s) 70,71 to radiate microwave energy at a single spot frequency; It may be preferable for said antenna(s) 70, 71 to be capable of radiating microwave energy over a band of microwave frequencies; It may be preferable for said antenna(s) 70, 71 to be capable of radiating microwave energy at a plurality of spot frequencies; It may be preferable for said antenna(s) 70, 71 to radiate microwave energy at a plurality of microwave frequencies and each of the said microwave frequencies to have a finite bandwidth and the said frequencies to be spaced far enough apart to ensure that band overlapping cannot occur; It is preferable for the surface area of said antenna(s) 70, 71 to be small enough to enable a pair of said antennas, or a single antenna and a reflective plate, to be attached to the human anatomy in a region where the volume of biological tissue structure 80 available for attachment to be made is limited, for example, the earlobe or the web of the hand between the first finger and the thumb; It is preferable for the structure of said antenna(s) 70, 71 to be non-obtrusive; It may be preferable for the radiation pattern produced by said antenna(s) 70, 71 to have a high directivity; It is preferable for said antenna(s) 70, 71 to provide a gain with respect to an isotropic radiator of greater than odBi; Antenna structures found to be appropriate for use in this invention include: patch antennas, spiral antennas and loaded/unloaded waveguide antennas. Other antenna structures may also be suitable for use in certain applications of the current invention and these will be known to a person experienced in the art of antenna/microwave engineering.

The first antenna structure to be considered for use in the current invention is that using patch antennas. Two arrangements using said patch antenna structures to measure microwave energy transmitted into biological tissue structure 8o and received microwave energy after it has been partially absorbed, partially reflected and partially transmitted through said biological structure 8o, are shown in figures 23 and 24. Figure 23 shows biological tissue structure 8o sandwiched between antenna pair 70,71 with clip 90 and fastener 91 used to ensure alignment between said antenna pair 70,71 and to attach said antenna pair 70,71 to the human anatomy. The first antenna assembly 70 and the second antenna assembly 71 are identical, and comprise: a radiating patch 74, 77, a coaxial feed 128, 129, a dielectric material or substrate 75, 78, a ground plane 76, 79, and a co-axial connector 137, 138. Said co- axial connector may take a number of forms, for example, sub-miniature A (SMA), SMB or SMC or another miniature microwave connector that is capable of working at the frequency (ies) of operation relevant to this invention. Figure 24 shows a similar arrangement to that shown in figure 23 except that in this case said second antenna 71 is replaced by a reflecting plate 73 and a new connecting attachment 72 is used to connect clip 90. Said arrangement shown in figure 24 enables reflection (backscatter) only to be measured whilst the arrangement shown in figure 23 enables both transmission and reflection (backscatter) measurements to be performed. The construction of a rectangular patch antenna consisting of a single patch is shown in figure 25; where the microwave energy is launched into the radiating patch 74, 77 using a microstrip feed line 128, 129 that is fabricated on the same surface 75, 78 as said radiating patch 74, 77. Said surface 75, 78 is a substrate material that may consist of a relative permittivity (dielectric loading constant) and/or a relative permeability (magnetic loading constant) of greater than unity, which is used to shrink the size of said radiating patch 74, 77. A ground plane 76, 79 is attached to the underside of substrate material 75, 78. It is preferable for the area of said ground plane 75/78 to be greater than the area of said radiating patch 74, 77. Dimensions that are of importance to ensure efficient energy propagation from said radiation patch 75, 77 are: patch width (W), patch length (L) and substrate thickness (t); these dimensions are indicated in figure 25. It is preferable for W to be comparable to the wavelength at the desired frequency of operation in order to enhance the radiation emitted from the edges of said radiating patch 74, 77. For the fundamental TM10 mode to propagate, the length L should be slightly less than X/2, where ? is the wavelength in substrate material 75, 78. In relating electrical and physical lengths when designing antennas 70, 71 in the form of patch antennas, pertinent parameters that must be considered are fringing field and effective dielectric constant. Radiation from a patch antenna normally occurs from the fringing fields between the periphery of the patch and the ground plane 76, 79. The fringing fields from said patch 74, 77 are not confined in the substrate material 75, 78, but tend to spread out into the air or the surrounding medium(s), therefore the relative permittivity Sr tends to be slightly lower than it would be if the radiation was confined inside said substrate material 75, 78. Taking this into consideration, the effective length Leff can be expressed using the formula given in equation 1: Leff VSr eff (L + t) (Eq.i) Where Sr eff is said effective dielectric constant of substrate material 75, 78 and it is assumed that said substrate material 75, 78 consists of dielectric material only with a relative permittivity value e. The value of s. eff can be approximated using the formula given in equations 2.

Er effl + [0.63 (Er - i) (W/t)o.1255J (Eq.2) It should be noted that equation 2 should be used only where the ratio of W/t is greater than 0.6 (N.B. this is normally the case).

Generally, the width W of a typical patch antenna is much lower than the substrate thickness t and SO Sr eff is usually quite close to the dielectric constant of the material & (quite often it is assumed that Sr eff is lower than & by a factor of between 0.05 and o.i).

Fringing fields also have an impact on the effective width (Weff) of the radiating patch 74, 77 and the formula given in equation 3 shows how Sr eff can be used to take said fringing fields into account. To enhance the fringing fields emitted from the patch, the width Wis normally slightly increased.

Wff = VEr eff (W + t) (Eq.3) The resonant frequency (/,) and driving point impedance (Z0) of the rectangular patch antenna 70,71 can be described using equations 4 and 5 respectively, given below: fo1.5 108/Leff (Eq.4) (90 [Sr eff (L+t/W+t)12)/ (Sr eff -i) (Eq.5) It can be seen from equation 5 that the width (W) to length (L) ratio has the greatest influence on the driving impedance of said patch antenna (s) 70, 71. The precise nature of the radiation pattern can be adjusted by controlling how the radiating patch is fed. It is normal for the patch to be fed at the centre of an edge, as shown in figure 25, or at one end. In normal operation, the dominant TM10 mode is set-up and the radiated field varies by one half a wavelength along length L, but there is no variation in said radiated field along the width W of said patches 74, 77. Radiation from said patches 74, 77 can be described as being similar to the radiation produced by two slots positioned at the left and right edges of said patches 74, 77, where said slots can be defined as narrow gaps between the radiating patches 74, 77 and the ground planes 76, 79. The patch-to- ground plane spacing is equal to the thickness of the substrates 75, 78 t and is typically about X0/ioo, where ? is the free space wavelength at the frequency of operation or, in the instance where a band of frequencies are used, the wavelength of the centre frequency within said band. At resonance (when the distance from the short circuit to the radiating slot is ?/4) the short circuit transforms a quarter wavelength to become an open circuit and said open circuit combines in parallel with radiation resistance (RR) of a single slot to give an input impedance at resonance as described by equation 6, shown below: RR(12O X0)/W (Eq.6) If W = Xo/2, then RR = 24oQ. If L = Aj2, then a voltage minimum exists at L/2 and a voltage maximum exists at the source and the far end of the patches 73, 77. If the feed lines 128, 129 have a constant amplitude of current along the length of said lines, then this indicates a good match between said lines 128, 129 and said patches 74, 77. If the patches are considered as cavity resonators (boxes) with four out of the eight sides missing then the radiation from said patch antennas 70, 71 is the result of energy leaking out of the resonant cavities (radiation is primarily due to energy leaking from the two gaps of width W). As stated previously, the thickness t of the substrates 75, 78 is typically small relative to the other dimensions of said patches 74, 77, therefore the energy leaking out of the boxes is much smaller than the energy stored within it. In order to achieve wide bandwidth operation, it is necessary to use the substrate material 75, 78 with the highest thickness t and lowest relative permittivity Sr (this assumes only dielectric loading) that is practically possible. These requirements of course may conflict with the requirement to make the patch size as small as possible and also provide a matched feed line. Possible candidates for substrate material 75, 78 are as follows: semi-insulating GaAs (& = 13), silicon (Cr = 11.9, PTFE ceramic, composite (Sr = 10.2), silicon resin-ceramic (Sr = 3 to 25) and Ferrite (Er = 9 to 16).

Other suitable materials may be known to a person experienced in the are of patch antenna design. Materials for the radiating patches 74, 77, the ground-planes 76, 79 and the feed lines 128, 129 may include, but is not limited to: copper, brass, silver, silver platted copper and aluminium. It may be desirable to cover said radiating patch with an insulating material and it may be preferable for said insulating material to be biocompatible. Said insulating cover will affect the performance of said antennas 70, 71 and so the effect of including said cover must be considered. A dielectric cover will in fact cause the resonant frequency of the patch antenna 70, 71 (f) to be lowered, therefore the antenna structure without the cover must be designed to resonate at a slightly higher frequency than the desired operating frequency, or the frequency at the centre of the band of operating frequencies. In general, when said patches 74, 77 are covered with a dielectric, the following properties will change: Sr eff, losses, Q - factor and directive gain. The change in Sr eff causes the greatest change and the amount of change is dependent upon the thickness t and the relative permittivity e. of the substrate. The presence of said cover also produces a change in the near/far field radiation patterns.

Where the instrument is used to measure a plurality of concentrations of constituents contained within a biological fluid 80, it may be desirable to operate said patch antennas 70, 71 in two or more frequency bands, where each band has a high enough bandwidth to facilitate the required frequency sweep within said band. In this instance, patch antennas 70, 71 capable of operating in multiple bands are desirable.

One solution is to use two or more patches 74, 77 and place them side by side, but this solution requires said radiating patches to be mounted onto a substrate 75, 78 with a high loading constant (relative permittivity and/or relative permeability) in order to ensure that the overall area of antennas 70, 71 is small enough to enable the antenna pair to be attached to regions of biological tissue 80 that is of interest. This constraintmay cause this solution to be impractical. A more suitable method of achieving dual- frequency operation may be to employ a technique used to modify the natural modes of operation. For example, an annular ring radiates in the broadside direction when excited in the (1,1), (1,2) or the (1,3) modes of operation. The frequencies for these modes can be adjusted by choosing the inner and outer radii. However, the ratio of the two frequencies is somewhat limited. A change in the frequency of a natural mode can be achieved by properly loading said mode, thus it is possible to practically tune the operating frequencies of these modes independent of each other. Shorting pins and slots in a rectangular patch have been used to obtain dual-frequency operation.

The (o,i), and (0,3) modes are normally used because these modes have the same polarisation and a broadside radiation pattern. In the unloaded state, the frequency ratio of these is nearly three. The concept used here is based on the fact that shorting pins at the nodal line of (0,3) mode will not have much effect on the modal field distribution for this mode but can have a strong effect on the (o,i) modal field; the pins thus raise the (o,i) modal frequency. Similarly if the slots are cut in the patch where the magnetic field of the (0,3) mode is maximum, they can have a strong effect on the (0,3) modal field without causing a large disturbance in the (o,i) modal field, thus the operating frequency of the (0,3) mode can be lowered. By using both pins and slots, it may be possible to vary the frequency ratios by between 1.31 and 3.02.

In designing the most appropriate antenna construction, it is preferable for the feed lines 128, 129 not to be on the same surface as the radiating patches 74, 77 due to the fact that said feed lines 128, 129 will also radiate energy into the biological tissue structure 80. This factor becomes most important when the instrument is operated at high microwave frequencies and high values of relative permittivity and/or relative permeability are used as the substrate material 75, 78, due to these factors causing the radiating patches 74, 77 to become very small. Figure 26 illustrates an alternative form of antenna feed, the co-axial feed. In this arrangement, the centre conductor of the coaxial connector forms feed lines 128, 129 and said feed lines 128,129 are soldered to the radiating patches 74, 77. The main advantage of this feed system is that the position of the feed-point determines the input impedance of the patch 74, 77 and so the feed-point can be simply moved around to adjust said input impedance.

The disadvantages are that a hole has to be drilled in the substrate 75, 78 and the connector protrudes outside the bottom of the ground plane 76, 79, thus the structure is not completely coplanar. Also, to achieve wide bandwidth operation, a thick substrate 75, 78 is required and so the probe length becomes longer, which can give rise to increased spurious radiation emission from the probe, increased surface wave power, and increased feed inductance. However, the feed inductance can be compensated for; the preferred method of compensation is to use a series connected capacitor. One approach used to introduce said series capacitor is to etch out an annular slot in the patch metallization concentric with the probe. All other parameters are the same as those discussed with reference to figure 25. Figure 27 shows an alternative feed arrangement whereby the feed line 128, 129 is electromagnetically (or capacitively) coupled to the radiating patch 74, 77. In this arrangement the substrate layer 75, 78 is made up of two separate dielectric (and/or magnetic) materials and said materials may have different values of relative permittivity (and/or relative permeability). Said feed line 128, 129 is sandwiched between said substrate layers 75, 78, which are themselves placed between said radiating patch 74, 77 and ground plane 76, 79. This method of coupling microwave energy into the radiating patches 74, 77 is also known as proximity coupling and the advantage of this feed configuration is that spurious feed-network radiation coupled into the biological tissue structure 8o is eliminated. Careful choice of the two different relative permittivity values for the substrate material 75, 78 (one for the patch 74, 77 and one for the feed line 128, 129) can be used to optimise the overall performance of the antenna 70, 71. The increased overall thickness of the substrate 75, 78, and the fact that two dielectric materials are now in series, can be used to increase the bandwidth of operation. It may be preferable to include a balanced- to- unbalanced (balun) transformer with certain arrangements to match the unbalanced co-axial, or microstrip, feed 128, 129 to the balanced antenna 70, 71.

The second antenna structure considered for use in the current invention is that using spiral antennas. Said spiral constructions are often known as frequency independent systems and said spiral antennas are often used where a wide signal bandwidth, or high sensitivity to various polarisations is desired. Two arrangements using spiral antenna structures to measure microwave energy transmitted into biological tissue structure 80 and received microwave energy after it has been partially absorbed, partially reflected and partially transmitted through said biological structure 80, are shown in figures 28 and 29. Figure 28 shows biological tissue structure 8o sandwiched between antenna pair 70,71 with clip 90 and fasteners 91,92 used to ensure alignment of said antenna pair 70,71 and to provide a means of attaching said antenna pair 70,71 to the human anatomy. The first antenna assembly and the second antenna assembly 71 are identical. Figure 29 shows a similar arrangement to that shown in figure 28 except that in this case said second antenna 71 is replaced by a reflecting plate 73 and connecting attachment 72 is used to make the connection to said connecting clip 90. Said arrangement shown in figure 29 enables reflection (backscatter) measurements only to be made, whilst the arrangement shown in figure 28 enables both transmission and reflection (backscatter) measurements to be performed. Construction and arrangements of said spirals are given in figures 30 and 31. The overall antenna arrangements comprise: a single or plurality of etched spirals 121, 122, 123, 125, a substrate layer 75, 78, a ground plane 76, 79, a connection between the inner and outer spirals 124 and a co- axial feed 40, 41. On a very basic level, the principle of operation is based on the fact that the spiral system consists of a number of circles of metallization and each circle relates to a range of frequencies of operation. Referring to figure 30, the high frequency limit of operation is determined by spacing P of the input terminal and the low frequency limit is determined by the overall diameter D. The ratio D/P for the construction shown in figure 30 is about 25 to 1. If we take P = 2/10 at the high frequency limit and D = 2/2 at the low frequency limit, then the antenna bandwidth is of the order 5 to 1. In practice, the spiral should be continued to a smaller radius than that shown in figures 30 and 31, but the representation given here enables clarity to be preserved. In general, if the terminal spacing is halved then the bandwidth is doubled. It is often more convenient to cut slots for the antenna 70, 71 from a large ground plane 76, 79 and feed said antenna 70, 71 from a co-axial cable bonded to one of the spiral arms 124 as indicated in figure 31. In this arrangement the spiral acts as a balun transformer. Also, a dummy cable may be bonded to the second arm for symmetry. Microwave radiation from said spiral construction is bidirectional broadside to the plane of said spiral. The radiation patterns in both directions have a single broad lobe, thus the antenna gain tends to be limited to only a few dBi and the input impedance is typically in the range of between 50Q and iooQ. Possible materials for the radiating spirals 121,122,123, 125 and the ground plane 76, 79 may include, but is not limited to: copper, brass, silver, silver platted copper and aluminium. A further printed antenna construction that may be suitable is the dipole.

Said dipole may be less efficient than a patch or a spiral due to the proximity of the dielectric and metallic layers.

Now turning to loaded/unloaded waveguide antenna arrangements. Said antenna construction may take the form of rectangular or cylindrical cavities, which may be filled with air or a material with a relative permittivity and/or relative permeability of greater than unity. Said waveguide structures may come in the form of commonly used antenna constructions, such as the horn antenna or the horn antenna with a focussing lens. Figures 32 and 33 show the first embodiment of the waveguide antenna arrangement. This arrangement uses straight waveguide sections and E-field probes to launch the microwave energy into the antenna structure. Two arrangements, which use waveguide antenna structures with E-field launch probes to measure microwave energy transmitted into biological tissue structure 8o and received microwave energy after it has been partially absorbed, partially reflected and partially transmitted through said biological structure 80, are shown in figures 32 and 33. Figure 32 shows biological tissue structure 8o sandwiched between antenna pair 70,71 with clip 90 and fasteners 91,92 used to ensure alignment of said antenna pair 70,71 and to provide a means of attaching said antenna pair 70,71 to the human anatomy. The first antenna assembly 70 and the second antenna assembly 71 are identical. Figure 33 shows a similar arrangement to that shown in figure 32 except that in this case said second antenna 71 is replaced by a reflecting plate 73 and attachment 72 is used to make a connection to said connecting clip 90. Said arrangement shown in figure 33 enables reflection (backscatter) only to be measured whilst the arrangement shown in figure 32 enables both transmission and reflection (backscatter) measurements to be performed. Said antennas 70, 71 comprise: a waveguide section (which also acts as a ground plane) 76, 79, an E-field launch probe 74, 77, a loading material 75, 78 and a microwave connector 137, 131. It is preferable for said E-field launch probe 74, 77 to be positioned a quarter wavelength from the closed end-wall of antenna 70, 71 to ensure that a maximum E-field is set-up at this location. If it is not possible to position said probe a quarter wavelength from the end wall then it is preferable to extend the distance to another odd multiple of said quarter wavelength. Said quarter wavelengths are determined by the frequency of operation (or the centre frequency when a band of frequencies are used) and the relative permittivity and/or relative permeability of the loading material 75, 78. The length of said E-field probe 74, 77 is preferably equal to half the height of the waveguide. The overall size of said waveguide probe antenna may be minimised by using loading materials 75, 78 with high values of relative permittivity and/or relative permeability. It may be preferable to use a new sub-miniature microwave connector range (the SMP range) for connector 137, 131 rather than using the more conventional SMA, SMB or SMC range. The advantages of using SMP connectors are that they can be used to mate to a cable with a diameter as low as 1.2mm, they are compact, and they can be operated from DC to 40 GHz.

Figures 34 and 35 show the same arrangements as those shown in figures 32 and 33 respectively, except that in this instance H- field ioop probes 74, 77 are used to launch the microwave energy into antennas 70,71 instead of the E-field probes structures used previously. In this arrangement it is preferable to use a small loop, which carries a high current. The circumference of the loop is preferably about one half-wavelength at the frequency of operation (or the centre frequency where the instrument is operated over a band of frequencies). It is possible to maximise the operating bandwidth by maximising the size of the wire used to make said loops.

It may be preferable to include a choke flange at the aperture of antennas 70,71 to prevent energy leaking from said antennas 70,71 and causing coupling via external paths. One specific embodiment of said choke flange is that where a groove is milled into the face of said antennas 70,71, where the diameter of said groove and the position of said groove are a quarter wavelength at the frequency of operation (or the centre frequency when a band of frequencies is required).

If said horn antenna or said loaded rectangular/cylindrical waveguide antenna structure is used and the physical dimensions are such that is possible to support the dominant TE10/TE11 modes of propagation in air, i. e. r is unity, then it is not required to load the antenna structure with a dielectric or magnetic material. On the other hand, if a horn antenna, or a loaded rectangular/cylindrical waveguide antenna structure is used and the physical dimensions are such that is not possible to support the dominant TE10/TE11 modes of propagation in air then the antenna must be loaded with a suitable dielectric or magnetic material whose relative permittivity/permeability is greater than unity. As an example, a suitable material to achieve said dielectric loading is a material known as ECCOSTOCK HiK500F from Emerson and Cuming Microwave Products Ltd. This material exhibits a relative permittivity of up to 30, and a dissipation factor (tan 6) of less than 0.002 over a frequency range of between 1GHz and ioGHz, thus indicating that 0.2% of the energy will be dissipated inside the material over said frequency range. Other relevant properties for this material may include: dielectric strength of greater than 300V/mm and an operating temperature range of between -56 C and 204 C. This material also exhibits low out gassing and low water absorption properties. If this material is used and the dominant, TE11, mode of operation for a cylindrical waveguide is to be set up in a loaded waveguide antenna 70, 71, then the diameter (Dr) of the dielectric rod used to shrink the diameter of antenna 70,71 can be expressed by equation 7, given below: (2.4485 C)/(,rfo Vpr6r) (Eq. 7) Where: C is the speed of light in a vacuum (3x1o8 m/s) f is the frequency of operation (Hz) Llr is the relative permeability for a magnetic loading material (magnetic loading factor) Er is the relative permittivity for an electric loading material (dielectric loading factor) The factor 2.4485 comes from the solution of the Bessel function for a cylindrical waveguide that supports the fundamental TE11 mode of propagation and the calculation for the cut-off frequency for lowest insertion loss at the frequency of operation. If, for example, the above material with an Sr of 30 is used, and the system is operated at a frequency of 8GHz, then the required diameter for the dielectric rod (Dr) is 5.34mm. Therefore, dielectric or magnetic loading is necessary to accommodate efficient propagation at the frequency of choice, where the antenna structure supports the most efficient low-loss mode and it must be ensured that this is the case for the antenna structures 70,71 used in the current invention. Other suitable antenna structures may be known to a person skilled in the art of antenna design.

EXPERIMENTAL ARRANGEMENTS AND RESULTS: Experimental measurements and preliminary studies have been carried out to validate the current invention; the experimental set-ups used and results obtained will now be described. Measurements carried out to date have been performed using sugar-water solutions, pure glucose solutions and representative bloodglucose solutions. Since the primary purpose of developing the ideas behind this invention was to produce an attractive alternative to current non-invasive blood-glucose measurement, only results relating to the blood-glucose solutions will be presented in this description. Said bloodglucose solutions consisted of human blood containing controlled amounts of glucose solution. Said blood-glucose solutions used for these experiments were prepared by a microbiologist and said blood samples were taken from a controlled store and came from the same stock as that used for University teaching laboratory studies. All experiments described here were carried out in a controlled environment and a risk analysis was performed prior to commencement of the experimental studies. All experiments described here used a purpose built vessel to hold fixed volumes of biological fluid 8o (in this case glucose spiked blood).

Said vessel 150 was made out of 3.85mm thick sheets of Perspex and glued together using superglue, where it was ensured that said vessel 150 was made water tight. The inner dimensions of said vessel was: 43.85mm high, 39.21mm wide and 3.9omm thick; providing a maximum volume for biological fluid 8o to be contained of 6.7o5cm3. These dimensions are given in figure 36 for the purpose of clarity. Figure 36 also shows the experimental arrangement used to perform the measurements described in this description. A 10MHz to 50GHZ E8364B PNA series Vector Network Analyser (VNA) 200 was used as a means of providing the following system components using one test and measurement instrument: microwave frequency source 10 to produce microwave energy for launching into biological tissue structure 80, detector 100 for detecting phase and magnitude information, signal processor and controller 110 and a means of displaying said phase and magnitude information 120. Said microwave energy source 10 contained within 200 was coupled into a first antenna 70 using a first coaxial cable assembly 40. Said first antenna 70 and said second antenna 71 were constructed using WR75 E- field co-axial to waveguide adaptor assemblies, which were tuned to operate over a frequency range of between 9GHz and 16GHz. Said first and second antennas 70,71 were clamped to the outer walls of said Perspex vessel 150 using a mechanical G-clamp. The apertures of said first and second antennas 70,71 were aligned by eye. Said second antenna 71 was connected to the detector or receiver unit 100 contained within 200 using a second coaxial cable assembly 41. Said Perspex vessel 150 was mounted on a stand 151, which had a mounting base 152. Said stand 151 and said mounting base 152 was manufactured from a PTFE material. For the measurements taken here the VNA 200 was set up as follows; frequency sweep: 11.5GHz to 15.5GHz, IF bandwidth: 1KHz, output power: 3dBm, and reference position: -30dB. The two blood-glucose concentrations used in these experiments were 6mmol/L and l4mmol/L. Disposable pipettes were used to transfer the blood-glucose solutions between controlled storage containers and said Perspex vessel 150. Said Perspex vessel was washed out, using a concentrated bleach solution, after said blood-glucose solution was removed from said Perspex vessel 150. Used blood-glucose solution was held in a separate disposable vessel and disposed of in the proper manner. Disposable gloves were used during the time that said blood-glucose solutions were being handled. In the first experiment, the Perspex vessel 150 was first cleaned using a solution of concentrated bleach and rinsed using tap water, said vessel 150 was then filled with blood-glucose solution with a glucose concentration of 6mmmol/L using said pipette. Magnitude and phase response was then measured over the frequency range of 11.5 GHz to 15.5GHz and the resultant responses were recorded. Said blood-glucose solution was then transferred from Perspex vessel to separate vessel for disposal using same pipette. After said transfer, said pipette was disposed of in the proper manner. Said Perspex vessel 150 was then removed from experimental set-up and was cleaned using a concentrated bleach solution and rinsed out using tap water. Said vessel 150 was then filled with a second blood-glucose solution, with a glucose concentration of l4mmmol/L, using a pipette. Magnitude and phase response was then measured over the frequency range of 11.5 GHz to 15.5GHZ and the resultant responses were recorded. Said blood-glucose solution was then transferred from Perspex vessel to separate vessel for disposal using same pipette. After said transfer, said pipette was disposed of in the proper manner. Said Perspex vessel 150 was then removed from experimental set-up and was cleaned using a concentrated bleach solution and rinsed out using tap water. The results from said measurements are shown in figures 37 and 38. Figure 37 shows the magnitude response, where magnitude is shown on the Y axis and is given in decibels with reference to a milli-Watt (dBm), and frequency is shown on the X axis and is given in gigahertz (GHz). The curve representing the 6mmol/L glucose concentration is shown using a solid line and the curve representing the l4mmol/L concentration is shown using a dotted line. It can be seen that a null occurs for each concentration and that there is a marked difference in frequency between the positions of said nulls. For the 6mmol/L glucose concentration the null occurred at 13.130GHz and for the l4mmol/L glucose concentration the null occurred at 13.452 GHZ, thus a frequency shift of 322MHZ has been observed here. Figure 38 shows the phase response, where phase is shown on the Y axis and is given in degrees and frequency is shown on the X axis and is given in GHz. The curve representing the 6mmol/L glucose concentration is shown using a solid line and the curve representing the l4mmol/L concentration is shown using a dotted line. It can be seen that there is a phase change between the 6mmol/L glucose concentration and the l4mmol/L glucose concentration and that the maximum change appears to occur at a frequency of 13.130GHZ. At this frequency the phase for the 6mmol/L glucose concentration is 122 and the phase for the l4mmoIl/L concentration is 82 , giving a phase difference of 400. It can be concluded from these result that there appears to be a marked change in the frequency at which a null occurs in the magnitude response for two representative blood-glucose concentrations and there is also a marked change in the phase when two blood-glucose solutions of the same volume were measured. In order to validate these results, the measurements were repeated over the duration of 8 hours and the results appeared to be consistent. During the measurement run, the magnitude measurement for the l4mmol/L blood-glucose concentration was taken in the evening and the trace was stored to hard disk on the E8364B; the same measurement was then repeated the next morning using a separate sample of the same blood-glucose concentration, and it was found that the new trace sat exactly on top of the stored trace. This measurement was performed to provide additional information to enable validation of the idea presented in this patent application. During the experimental procedure, the concentrations of pre- prepared blood-glucose solutions were checked using a Roche Accu-Chek Advantage finger prick unit (serial number: 3201163 8300438879) and Roche test strips (Reference: 3137899, lot: 446143, date: 29/02/04). The 6mmol/L blood- glucose concentration measured 5.8mmol/L and the l4mmOl/ L blood-glucose concentration measured 13.9mmol/L. These measurements were used to validate the blood-glucose concentrations used for these experiments. Figures 39 to 42 show other experimental arrangements that were considered during the initial validation measurements.

These experimental arrangements are similar that shown in figure 36, except that directional coupler 61 has been included to measure reflected (backscatter) signals, matching filters 50,51 have been included in certain arrangements, spectrum analyser 300 has been included where both transmission and reflection measurements are to be made simultaneously, and additional interconnects 400, 401, 402, 403, 404, 405, 407, 408 have been included for completeness. Said interconnects are preferably SMA type and may be male-to-female, female-to-female, or male- to male depending on the gender of the input/output port of the devices used in the specific arrangement. Full details of these arrangements will become apparent by studying figures 39 to 42 provided at the end of this patent specification.

Claims (104)

1. CLMMS

   It is claimed: 1. An instrument for non-invasively measuring concentrations of constituents contained within a biological system using microwave energy comprising: a source of microwave energy; a means of non-invasivelly transmitting microwave energy into tissue structures contained within the human biological system; a means of non-invasively receiving microwave energy from tissue structures contained within the human biological system; a means of converting said energy into magnitude and/or phase information; a means of processing said magnitude and/or phase information to provide information regarding concentration of constituents, and a means of outputting information regarding concentration of constituents.
2. 2. An instrument for measuring concentrations of constituents contained within a biological system using microwave energy comprising: a source of microwave energy; a first antenna to transmit forward directed microwave energy into biological tissue; a second antenna to receive forward directed microwave energy from biological tissue after said microwave energy from said first antenna has propagated through said tissue; a detector to convert portions of said transmitted microwave energy and said received microwave energy into changes in magnitude and/or changes in phase; a processor to convert said changes in magnitude and/or phase into a format that can be used to represent useful information regarding the concentration of constituents contained within a biological fluid, and an output device to present said information to an end user.
3. 3. An instrument for measuring concentrations of constituents contained within a biological system using microwave energy comprising: a source of microwave energy; an antenna to transmit forward directed microwave energy into biological tissue and to receive forward reflected microwave energy back along the same path from said biological tissue in the form of backscatter; a detector to convert portions of said transmitted microwave energy and said reflected microwave energy into changes in magnitude and/or changes in phase; a processor to convert said changes in magnitude and/or phase into a format that can be used to represent useful information regarding the concentration of constituents in said biological fluid, and an output device to present said information to an end user.
4. 4. An instrument for measuring concentrations of constituents in a biological system using microwave energy comprising: a source of microwave energy; a first antenna to transmit forward directed microwave energy into biological tissue and to receive forward reflected microwave energy back along the same path from said biological tissue in the form of backscatter; a second antenna to receive forward directed microwave energy from biological tissue after said microwave energy from said first antenna has propagated through said tissue; a detector to convert portions of said transmitted, said reflected and said received microwave energy into changes in magnitude and/or changes in phase; a processor to convert said changes in magnitude and/or phase into a format that can be used to represent useful information regarding the concentration of constituents in said biological fluid, and an output device to present said information to an end user.
5. 5. An instrument for measuring concentrations of constituents in a biological system using microwave energy comprising: a source of microwave energy; a first antenna to: a) transmit microwave energy through biological structure to a second antenna; b) receive forward reflected microwave energy back along the same path from said biological tissue in the form of backscatter; c) receive reverse transmitted microwave energy from a second antenna; a second antenna to: a) transmit microwave energy through biological structure to a first antenna; b) receive reverse reflected microwave energy back along the same path from said biological tissue in the form of backscatter; c) receive forward transmitted microwave energy from a first antenna; a detector to convert portions of said transmitted, said reflected and said received microwave energy into changes in magnitude and/or changes in phase; a processor to convert said changes in magnitude and/or phase into a format that can be used to represent useful information regarding the concentration of constituents in said biological fluid, and an output device to present said information to an end user.
6. 6. An instrument for measuring concentrations of constituents contained within a biological system using microwave energy comprising: a source of microwave energy; a means of non-invasively transmitting microwave energy into tissue structures contained within the human biological system; a means of non-invasively receiving microwave energy from tissue structures contained within the human biological system; a means of monitoring output frequency produced by said source of microwave energy and feeding said frequency information into a signal processing unit; a means of monitoring magnitude and/or phase changes of transmitted signal as a function of change in said frequency and feeding said magnitude and/or phase change information into a signal processing unit; a means of processing received microwave signals to provide information regarding concentration of constituents, and a means of outputting information regarding said concentration of constituents.
7. 7. As claimed in 6 whereby said change in transmitted signal is a shift in frequency of a null contained within the magnitude response.
8. 8. As claimed in 6 whereby said change in transmitted signal is a shift in frequency of a peak contained within the magnitude response.
9. 9. As claimed in 6 whereby said change in transmitted signal is a shift in frequency of a null contained within the phase response.
10. 10. As claimed in 6 whereby said change in transmitted signal is a shift in frequency of a peak contained within the phase response.
11. ii. As claimed in any one of claims 6 to 10 whereby a frequency shift is detected using a frequency pre-scalar and a microprocessor.
12. 12. As claimed in any one of claims 6, 7 and 9 whereby said null position is detected using a null detector and a microprocessor.
13. 13. As claimed in any one of claims 6, 8 and 10 whereby said peak position is detected using a peak detector and a microprocessor.
14. 14. As claimed in 12 and 13 whereby said peak and/or null detectors use operational amplifiers and discrete components.
15. 15. As claimed in 12 and 13 whereby said peak and/or null detectors are a part of the processor.
16. 16. An instrument for measuring concentrations of constituents in a biological system using microwave energy transmitted over a wireless link comprising: a source of microwave energy; a means of non-invasively transmitting microwave energy into tissue structures contained within the human biological system; a means of non-invasively receiving microwave energy from tissue structures contained within the human biological system; a means of modulating said received information; a means of transmitting modulated information; a means of receiving modulated information; a means of demodulating information; a means of converting demodulated signals into magnitude and/or phase information; a means of processing said magnitude and/or phase information to produce information regarding concentration of constituents, and a means of outputting information regarding concentration of constituents.
17. 17. An instrument for measuring concentrations of constituents in a biological system using microwave energy transmitted over a wireless link comprising: a source of microwave energy; a means of non-invasively transmitting microwave energy into tissue structures contained within the human biological system; a means of non-invasively receiving microwave energy from tissue structures contained within the human biological system; a means of converting said microwave energy into magnitude and/or phase information; a means of modulating said information; a means of transmitting modulated information; a means of receiving said modulated information; a means of demodulating said information; a means of processing magnitude and/or phase information to produce information regarding concentration of constituents, and a means of outputting information regarding concentration of constituents.
18. 18. An instrument according to claims i6 and 17 whereby free-space is used as the communication channel over which said modulated information is transmitted.
19. 19. An instrument according to claims 1 to 6, 16 and 17 whereby said source of microwave energy produces a plurality of narrow bandwidth frequencies.
20. 20. An instrument according to claims 1 to 6, 16 and 17 whereby said source of microwave energy produces a plurality of frequencies and each frequency has a wide enough bandwidth to enable a frequency shift around a centre frequency without overlapping into an adjacent frequency range.
21. 21. As claimed in 19 and 20 whereby each frequency is used to measure a separate parameter associated with the biological system.
22. 22. As claimed in 21 whereby each entity is a concentration of a constituent contained within a biological fluid.
23. 23. As claimed in 20 whereby a shift in frequency is used to characterise a change in concentration of a plurality of constituents associated with each frequency range.
24. 24. An instrument according to claims 1 to 6, 16 and 17 whereby a combination of change in phase and/or magnitude and/or frequency shift is used to measure the changes in parameters associated with the biological system.
25. 25. As claimed in 24 whereby said parameters are concentrations of constituents contained within the human biological fluid.
26. 26. An instrument according to claims 1 to 6, 16, and 17 whereby a dielectric resonator oscillator or a voltage controlled oscillator or a frequency synthesiser is used to provide the source of microwave energy.
27. 27. An instrument according to claims 1 to 6, 16 and 17 further comprising a matching filter to enable the microwave energy to be efficiently coupled to the surface of the human body.
28. 28. A matching filter according to claim 27 wherein said filter comprises a stub tuner.
29. 29. A matching filter according to claim 27 wherein said filter comprises a PIN diode phase shifter.
30. 30. A matching filter according to claim 27 wherein said filter comprises a single or a plurality of varactor tuning diodes.
31. 31. An instrument according to claims 1 and 5 further comprising a switching network to enable said means of transmitting microwave energy and said means of receiving microwave energy to be reversed to enable transmission measurements to be performed in two directions.
32. 32. An instrument according to claims 1 and 5 further comprising a switching network to enable said means of transmitting microwave energy and said means of receiving microwave energy to be reversed to enable reflection measurements to be performed in two directions and allow backscatter information to be gathered.
33. 33. An instrument according to claims 1 to 6, 16 and 17 wherein a heterodyne detection scheme is used to measure phase and magnitude information from the received microwave signals.
34. 34. An instrument according to claims 1 to 6, 16 and 17 wherein a phase and magnitude integrated circuit detector is used to obtain phase and magnitude information from the microwave signals.
35. 35. An instrument according to claims 1 to 6, 16 and 17 whereby the phase and magnitude information is derived from one of the sources of microwave energy listed in claim 26.
36. 36. An instrument according to claim 1 whereby said means of noninvasivelly transmitting microwave energy is a single antenna.
37. 37. An instrument according to claim 1 whereby said means of noninvasively transmitting microwave energy is a plurality of antennas.
38. 38. Antennas in accordance with claims 36 and 37 whereby said antennas can be operated as transceivers.
39. 39. An instrument according to claims 2 to 6, 16 and 17 whereby said antenna(s) is a (are) spiral antenna(s).
40. 40. An instrument according to claims 2 to 6, 16 and 17 whereby said antenna(s) is a (are) patch antenna(s).
41. 41. An instrument according to claims 2 to 6, 16 and 17 whereby said antenna(s) is a (are) waveguide antenna(s).
42. 42. As claimed in 40 and 41 whereby said antenna(s) is (are) dielectrically and/or magnetically loaded.
43. 43. As claimed in 40 whereby said antennas are configured for broadband operation using a thick substrate layer and/or a dielectric material with a high relative permittivity.
44. 44. As claimed in 40 whereby the feed-line is electromagnetically coupled to said radiating patch to prevent feed-line radiation into free space and direct feed line coupling into biological tissue.
45. 45. An antenna arrangement consisting of a pair of antennas according to claims 39, 40 and 41 is claimed.
46. 46. An antenna arrangement consisting of a single antenna as claimed in 39, 40 and 41 and a reflective plate.
47. 47. As claimed in 46 whereby said plate is positioned in contact with the second face of said biological structure to maximise signal reflection and backscatter information.
48. 48. As claimed in 46 whereby said plate is made from a metallic material.
49. 49. As claimed in 46 whereby said plate is made from a non-metallic material.
50. 50. An antenna arrangement as claimed in 45 whereby a clip arrangement is used to provide a mechanism to align said antenna pair and enable said antenna pair to be attached to the human anatomy.
51. 51. An antenna arrangement as claimed in 46 whereby a clip arrangement is used to provide a mechanism to align said antenna and said reflective plate and enable said antenna/plate arrangement to be attached to the human anatomy.
52. 52. An antenna arrangement using a single antenna as claimed in 39, 40 and 41 together with a clip arrangement to enable said antenna pair to be attached to the human anatomy.
53. 53. An antenna/clip arrangement as claimed in 39 to 53 whereby said antenna(s) is (are) in contact with the human anatomy.
54. 54. As claim 53 whereby the part of the human anatomy used is the surface of the skin.
55. 55. As claimed in 50 to 53 whereby said clip arrangement is made from a non- metallic material that is biocompatible with the surface of the skin.
56. 6. As claimed in 50 to 53 whereby said clip arrangement is made from a metallic material that is biocompatible with the surface of the skin.
57. 57. As claimed in 50 to 56 whereby said antenna/clip arrangement is connected to the earlobe.
58. 58. As claimed in 50 to 56 whereby said antenna/clip arrangement is connected to the web of the hand between the thumb and the first finger.
59. 59. A method of system calibration using a dielectric and/or magnetic calibration material placed between two said antennas and performing an initial measurement and measurement data is used as a reference point.
60. 6o. As claimed in 59 where said material is stable in terms of property variation with temperature, atmospheric conditions and frequency.
61. 6i. As claimed in 59 whereby clip arrangement described in 50 is used to sandwich said calibration material between said antenna pair.
62. 62. A method of system calibration by connecting the faces of said antennas together and performing an initial measurement and measurement data is used as a reference point.
63. 63. As claimed in 59 whereby clip arrangement described in 50 is used to ensure that the faces of said antenna pair are connected together and the antenna faces are aligned.
64. 64. A method of system calibration using a metallic cap connected to single antenna or each antenna in the antenna pair and performing an initial measurement and using measurement data as a reference point.
65. 6. As claimed in 64 whereby said metallic cap is fitted to the end of said antenna (s) and said cap comes into contact with the face of said antenna (s).
66. 66. As claimed in 64 whereby the distance from face of said antenna and end cap is a controlled distance and said distance is always repeatable so as to provide a constant reference point.
67. 67. As claimed in 64 whereby said metallic cap is filled with a dielectric and/or magnetic calibration material.
68. 68. As claimed in 67 where said material is stable in terms of property variation with temperature, atmospheric conditions and frequency.
69. 69. An instrument according any 1 to 6, 16 and 17 or any other related claims listed in this description where said antennas are integrated into a commercial Bluetooth headset.
70. 70. An instrument according to claims 1 to 6, 16 and 17 or any other related claims listed in this description where said antennas are integrated into a set of headphones.
71. 71. An instrument according to claims 1 to 6, i6 and 17 or any other related claims listed in this description where said antennas are integrated into a hearing aid.
72. 72. An instrument according to claims 1 to 6, 16 and 17 or any other related claims listed in this description where said antennas are integrated into an ear phone.
73. 73. An instrument according to claims 2 to 6, 16 and 17 whereby said antenna(s) and said detector (or means of signal conversion) are integrated into a miniature microwave assembly.
74. 74. As claimed in 73 where miniature microwave devices are used to implement the microwave detector assembly.
75. 75. As claimed in 73 whereby vertical stacking is used to achieve said integration.
76. 76. An instrument described in any of the above claims where said antenna(s) and said detector (or means of signal conversion) are integrated into any one of a combination of, or all of, the devices given in claims 69 to 72.
77. 77. An instrument according to claims i6 and 50 to 53 whereby said antenna(s), said modulation device and said transmitting device are contained in a miniature microwave assembly and said assembly is integrated into any one of, a combination of, or all of, the devices given in claims 69 to 72.
78. 78. An instrument according to claims 17 and 50 to 53 whereby said antenna(s), said detector, said modulation device and said transmitting device are contained in a miniature microwave assembly and said assembly is integrated into any one of, a combination of, or all of, the devices given in claims 69 to 72.
79. 79. An instrument according to claims 1 to 6, 17 and 50 to 53 whereby said antenna(s), said detector, said modulation device and said transmitting device are contained in a miniature microwave assembly and said assembly is integrated into a miniature self-contained unit.
80. 80. An instrument according to claims 1 to 6, 17 and 50 to 53 whereby said antenna(s) are integrated into any one of, a combination of, or all of, the devices given in claims 69 to 72 and a co-axial cable assembly is used to transmit microwave energy from the rest of the instrument and send received microwave energy to the rest of the instrument.
81. 81. An instrument according to claims 1 to 6, 16 and 17 whereby said processing and/or said outputting device is a home computer.
82. 82. An instrument according to claims 1 to 6, 16 and 17 whereby said processing and/or said outputting device is a wristwatch.
83. 83. An instrument according to claims 1 to 6, 16 and 17 whereby said processing and/or said outputting device is a personal development assistant.
84. 84. An instrument according to claims 1 to 6, 16 and 17 whereby said processing and/or said outputting device is a lap top computer.
85. 85. An instrument according to claims 1 to 6, 16 and 17 whereby said processing and/or said outputting device is a mobile phone.
86. 86. An instrument according to claims 17 whereby said phase/magnitude detection, information processing and outputting device is performed using wireless a laptop computer.
87. 87. An instrument according to claims 17 whereby said phase/magnitude detection, information processing and outputting device is performed using a personal development assistant.
88. 88. An instrument according to claims 17 whereby said phase/magnitude detection, information processing and outputting device is performed using a mobile phone.
89. 89. An instrument according to claims 17 whereby said phase/magnitude detection, information processing and outputting device is performed using a home computer.
90. 90. An instrument according to claims 17 whereby said phase/magnitude detection, information processing and outputting device is performed using a wristwatch.
91. 91. An instrument according to claims 1 to 6, 17 and 50 to 53 whereby said antenna(s) are integrated into any one of, a combination of, or all of, the devices given in claims 69 to 72 and a co-axial cable assembly is used to convey microwave energy to and from any one of, a combination of, or all of the devices listed in claims 86 to 90.
92. 92. An instrument according to claims 1 to 6, i6 and 17 and any other related claims listed in this description that transmits information via a modem to a remote monitoring station.
93. 93. As claimed in 16 and 92 whereby the instrument described in this invention transmits information directly to a modem and said information is sent down a telephone line to a remote monitoring station.
94. 94. As claimed in 92 whereby the instrument described in this invention transmits information to a home computer via a modem and said information is sent down a telephone line via said computer and said modem to a remote monitoring station.
95. 95. As claimed in 92 whereby the instrument described in this invention transmits information to a mobile phone and said information is sent via mobile phone link (base station and satellite) to a remote monitoring station.
96. 96. An instrument according to claims 1 to 6, 16 and 17 and any other related claims listed in this description, which can receive information via a modem connected to a remote monitoring station and an output device used to display details of corrective action required.
97. 97. As claimed in 96 whereby received information sent from remote monitoring station is viewed on a home computer or a laptop computer or a mobile phone or a personal development assistant.
98. 98. As claimed in 96 whereby received information sent from remote monitoring station is picked up as an audible alarm.
99. 99. An instrument according to any of the above claims where the remote monitoring facility can be used to monitor the general health of a patient or the person using the instrument.
100. 100. An instrument according to any of the above claims where the remote monitoring facility can be used to provide patient care by displaying information concerning treatment and/or necessary corrective action to the patient or person using the instrument.
101. 101. An instrument as claimed in any of the above claims whereby measurements are carried out on biological structures contained within the human body.
102. 102. As claimed in 101 whereby said biological structure is a biological fluid.
103. 103. As claimed in 101 whereby the instrument described in this invention is used to measure levels of concentration of constituents contained within said biological fluid.
104. 104. As claimed in 103 whereby said biological fluid is blood containing a concentration of glucose and the instrument described in this invention is used to measure the blood-glucose concentration.

     References: [i] W0o3o73925: NON-INVASIVE TISSUE GLUCOSE LEVEL MONITORING Measurements of ultraviolet radiation or light [2] W02003o82o98: IMPROVING PERFORMANCE OF AN ANALYTE MONITORING DEVICE - Mathematical algorithm and techniques used for processing spec jfically related to Gluco Watch G2 Biographer, Cygnus Inc. [31 EP1419731: SYSTEM AND METHOD FOR MONITORING BLOOD-GLUCOSE LEVELS USING AN IMPLANTABLE MEDICAL DEVICE - Measures T-wave amplitude and QT interval derived from cardiac signals [4] WO9932897: NMR APPARATUS AND METHOD FOR NON-INVASIVE IN-VWO TESTING OF A PATIENTS BODY FLUID GLUCOSE LEVELS - An instrument based on small scale nuclear magnetic resonance spectroscopy [51 US20040018486: METHOD AND DEVICE FOR PREDICTING PHYSIOLOGICAL VALUES - A mixtures of Experts algorithm related to the Cygnus system [61 EPo236o23: NON-INVASIVE BLOOD-GLUCOSE LEVEL MONITORING METHOD - Considers lachrymalfluid taken from the lachrymal glands [7] W0o3o87775: METHOD AND APPARATUS FOR NON-INVASIVE MONITORING OF BLOOD SUBSTANCES USING SELF-SAMPLED TEARS -Looks at fluid samples taken by making contact with an eye region to obtain tear fluid samples [8] US20020082487: NON-INVASIVE TISSUE GLUCOSE LEVEL MONITORING - Uses a light source directed to mucosal area [9] US5ii98i9: METHOD AND APPARATUS FOR NON-INVASIVE MONITORING OF BLOOD- GLUCOSE - Considers acoustic velocity measurements for monitoring the effect of glucose concentration upon the density and adiabatic compressibility of the serum [io] U52004o2252o6: NON-INVASIVE ANALYTE MEASUREMENT DEVICE HAVING INCREASED SIGNAL TO NOISE RATIOS - Uses attenuated total reflection infrared spectroscopy [ii] W09956613: ANALYTE MONITORING DEVICE AND METHODS OF USE - Considers analyte monitoring using an electrochemical sensor [12] US2005002o887: MEDICAL MONITORING DEVICE AND SYSTEM -A portable device for calculating statistical data from a patient - controller, display, statistical analysis [13] W02004o69164: WIRELESS BLOOD-GLUCOSE MONITORING SYSTEM Introduces a remote wireless non-invasive device and uses near infrared spectroscopy (79 [14] US200500lol37: METHOD AND DEVICE FOR SAMPLING AND ANALYZING INTERSTITIAL FLUID AND WHOLE BLOOD SAMPLES - Invasively samples and analyses sub-dermalfiuid and is suitable for bedside or home use [15] WOo3o25562: NON-INVASIVE BLOOD-GLUCOSE MONITORING BY INTERFEROMETRY Monitors glucose using interftrometry [i6] U520040127779: METHOD AND APPARATUS FOR NON-INVASIVE BLOOD CONSTITUENT MONITORING - A finger clip assembly and a pair of emitters and a photodiode and at least one wavelength of light [17] US2003225321: METHOD AND APPATATUS FOR NON-INVASIVE GLUCOSE SENSING THROUGH THE EYE - A plurality of wavelengths of light used to sense blood- glucose level through the aqueous humor of the eye [i8] CA2480550: IMPROVING PERFORMANCE OF AN ANALYTE MONITORING SYSTEM - Considers the use of one or more microprocessors and improved mathematical algorithms [19] DE69914319T: SIGNAL PROCESSING FOR MEASUREMENT OF PHYSIOLOGICAL ANALYTES - A method for continuously measuring concentration of target chemical analytes and processing analyte-specjfic signals [20] U52004o18486: METHOD AND DEVICE FOR PREDICTING PHYSOILOGICAL VALUES - Measures concentration of target analytes present in a biological system using a series of measurements obtained from a monitoring system and a Mixtures of Experts algorithm [21] DE69532282T (WO9600lo9Al): DEVICE AND METHOD FOR SAMPLING OF SUBSTANCE USING ALTERNATING POLARITY - Considers the sampling of a substance using one or more sampling chambers and conducting electric current used to extract a substance from the subject [22] US2003l35loo: SENSOR ELEMENT FOR MEASURING THE AMOUNT OF CONCENTRATION OF ONE OR MORE ANALYTES - Uses continual transdermal extraction of analytes present in a biological system using reverse iontophoresis [23] U520031954o3: MONITORING OFPHYSIOLOGICALANALYTES - Measurement of concentration of target chemical analytes where techniques are introduced to reduce the effect of interfering species on sensor sensitivity [24] WO0218936: METHODS OF MONITORING GLUCOSE LEVELS IN A SUBJECT AND USES THEREOF - lontophoresis used to extract glucose from the patient [25] US6391643: KIT AND METHOD FOR QUALITY CONTROL TESTING OF A GLUCOSE MONITORING SYSTEM - Uses transdermal extraction of analytes present in the biological system using reverse iontophoresis -lo [26] W09932897: NMR APPARATUS AND METHOD FOR NON-INVASIVE IN- VIVO TESTING OF A PATIENT'S BODY FLUID GLUCOSE LEVELS - A magnet assembly for a small scale NMR spectroscopy apparatus suitable for laboratory or home use [27] EPo35o546: INSTRUMENT AND METHOD FOR NONINVASIVE TESTING FOR GLUCOSE AND OTHER BODY FLUID CONSTITUENTS Nuclear magnetic resonance apparatus [28] CA1288475: INSTRUMENT FORNONINVASIVE TESTING FOR GLUCOSE AND OTHER BODY FLUID CONSTITUENTS Nuclear magnetic resonance apparatus -foxed magnet, magnetizable coil and circuit for energising the coil for energising and realigning molecules [29] CN1116307: MINIMUM PRODEDURE SYSTEM FOR THE DECERMINATION OF ANALYTES - Reflectance reading taken from one surface of an inert porous matrix impregnated with a reagent that interacts with the anlayte to produce a light absorbing reaction [30] JP2001264336: SELF BLOOD-GLUCOSE TESTING MEANS - Based on methods of data storage [31] US6021339: URINE TESTING APPARATUS CAPABLE OF SIMPLY AND

     ACCURATELY MEASURUNG A PARTIA URINE TO INDICATE URINARY

     GLUCOSE VALUE OF TOTAL URINE - A urine multisensor system [32] WOo3o73926: NON-INVASIVE TISSUE GLUCOSE LEVEL MONITORING - Light source or radiation at a wavelength directed to mucosal area, i.e. gums, eyeballs and skin of eyelids [33] DE3515420: BLOOD-GLUCOSE TESTING UNIT - Plastic housing with receptacles for test strip, needle, disinfectant and cotton wool pad [341 US5556761: TEST STRIP FOR BLOOD-GLUCOSE TESTING - Reagent incorporating a dye colour [] JP20000749l5: VISUAL STRIP FOR TESTING GLUCOSE IN BLOOD Strip consisting of three components - spreading upper layer, an intermediate layer containing reagents and a support [36] WO200400676o: CALIBRATION TECHNIQUE FOR NON-INVASIVE MEDICAL DEVICES - Technique using optical sensors to perform calibration without removal of blood or bodily fluids [] WOo2323o3: GLUCOSE MESURIEMENT UTILISING NON-INVASIVE ASSESSMENT METHODS - Measures static level at the surface of the skin and also extracts a sample of glucose from the skin 1t [38] US5383452: METHOD, APPARATUS AND PROCEDURE FOR NON-INVASIVE

     MONITORING BLOOD-GLUCOSE BY MEASURING THE POLARISATION RATIO

     OF BLOOD LIMINESCENCE - Measures rotations of polarisation of light emitted from the biological particle chromophores dissolved together with sugar in human liquids [39] US2003o765o8: NON-INVASIVE BLOOD-GLUCOSE MONITORING BY INTERFEROMETRY (Measures variations of the refractive index of the aqueous humor which can be related to variation in glucose concentration) [40] U52002o16534: NON-INVASIVE TISSUE GLUCOSE LEVEL MONITORING - Light source or radiation at a wavelength directed to mucosal area, i.e. gums, eyeballs and skin of eyelids [41] RU2233111: APPARATUS FOR NON-INVASIVE MONITORING OF GLUCOSE CONCENTRATION (VARIANTS) Thermister sensors cemented onto human skin, warning alarm and computer with display [42] U52004o97796: METHOD AND SYSTEM OF MONITORING A PATIENT - Measurement of patient analytes using an attenuated total reflection infrared total spectroscopy method [43] US2005o2o893: OPTICAL SPECTROSCOPY PATHLENGTH MEASUREMENT SYSTEM - Measurement of Faraday rotation to estimate mean photon pathlengths through tissue