GB2428801A - A minimally invasive monitoring system - Google Patents

Abstract

An instrument to perform minimally invasive measurements on various properties of human tissue is based on using energy concentrated in the microwave region of the electromagnetic spectrum and the measurement of transmitted and/or reflected information. Miniature needle antenna structures mounted on biocompatible patches are also disclosed. Said antenna structures may be inserted into the human anatomy in a similar manner to acupuncture needles. The instrument may be used to perform direct measurement of information concerning the state of the biological system, for example, the glucose level. The measurement system comprises: a source of microwave energy (10, 30 40), a means of transmitting and receiving energy (140, 60, 61, 141) and means of monitoring energy levels (20, 21, 22, 23), a means of detecting phase and magnitude information (100), a means of signal processing (110), and a means of outputting information (120).

Description

A MINIMALLY iNVASIVE MONITORING SYSTEM

FIELD OF THE INVENTION

The present invention relates to an instrument for minimally invasively measuring concentrations of constituents contained within biological tissue using energy emitted at frequencies that lie within the microwave region of the electromagnetic spectrum. In the current invention, microwave energy is focussed into biological tissue structures using fine biocompatible needle, or pin, antenna structures mounted on biocompatible patches (pads) that can be attached to the surface of the skin using a biologically acceptable adhesive.

Microwave measurement techniques are used to determine information relating to said biological tissue in terms of changes in the magnitude and/or phase at a spot frequency or over a sweep of frequencies that lie within the microwave region of the electromagnetic spectrum.

More particularly, the invention relates to an instrument capable of directly monitoring biological concentrations, in particular, concentrations of various types of constituents contained within biological fluid; even more specifically, this invention relates to an instrument that can be used to determine glucose concentrations associated with both insulin-dependent and non-insulin dependent diabetes mellitus. This invention is not limited to this application and, for example, may also be used to measure properties of fat tissue and interstitial fluid, or blood.

This description places a heavy emphasis on the development of miniature antenna structures mounted on biocompatible patches (pads) and used to launch microwave energy into biological tissue structures. Said antennas are designed to penetrate the surface of the skin, but the depth of penetration may be limited to the epidermis and the dermis to ensure minimal patient discomfort and provide a system that is user friendly.

The rest of the instrument comprises: a detection system to measure phase and/or magnitude, a signal processor to convert said signals into meaningful information, and an output device to relay said information to a patient, or user, in a user friendly format. Many aspects of the instrument addressed here have been described in detail in UK Patent Application GBo5l38lo.2, which relates to non-invasive measurement techniques for determining concentrations of various constituents, therefore the current description draws upon the information contained within said application, with the addition of two specific embodiments which relate directly to the frequencies discovered whilst gathering experimental data during a set of preliminary experiments designed to validate the idea upon which this invention is based.

In this specification microwave frequency means the frequency range from 300MHZ to 300GHZ. Preferably, the frequency range used in this invention is between 1GHz and 100GHz, but more preferably between 2GHZ and 32GHZ.

BACKGROUND AND PRIOR ART

Given that the primary purpose of the current invention is to enable an accurate and direct measurement of glucose concentration, it is most appropriate to provide a thorough background to the problem and to briefly 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 unbiocks cells within the body, allowing glucose to enter these cells to provide food to keep them alive. 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 glucose concentration within the human body 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. A person whose glucose level is too low is said to be in a state hypoglycaemia, whilst a person whose glucose level is too high is said to be in a state of hyperglycaemia. 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 cells automatically, thus it is required to be able to monitor 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.

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 characteriseci 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 selfadminister 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 or non-insulindependent 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), 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 glucose level and then, based on the measured glucose level, patients are able to make insulin dosage adjustments prior to injection. These adjustments are extremely important since 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.

Currently, the most common method of measuring glucose level requires blood to be withdrawn from the patient. This conventional procedure involves pricking the finger, or other body part, withdrawing blood, and depositing one or more drops onto a reagent carrier strip, which contains a glucose testing substance. Said testing substance changes colour, or shading, in correspondence with the blood-glucose level. A colour chart is then used to determine the associated numerical value of blood-glucose level. 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. On a physical level, the pricking procedure is somewhat messy and painful, particularly if the patient has to repeat the procedure several times each 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.

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 glucose level due to the fact that glucose appears in the urine only after a significant period of elevated levels of glucose. This method was in fact used by physicians of the past where the diagnosis was made from tasting the patient's urine.

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 GlucoWatch 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 GlucoWatch 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.

Many other attempts have been made to develop instruments to monitor glucose levels, these include: electrochemical, spectroscopic technologies (such as near infrared spectroscopy, Ramen Spectroscopy and small scale NMR), measurements on lacrimal fluid (self-sampled tears), and acoustic velocity measurement techniques. However, none of the above methods appear to perform in-vivo measurement of glucose level with sufficient accuracy, repeatability and user friendliness to enable a device to be manufactured and used for routine patient care.

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

SUMMARY OF THE INVENTION

The current invention addresses the need for an alternative instrument to accurately and repeatedly measure glucose levels whilst causing a minimal degree of patient discomfort. The current invention is not limited to the measurement of glucose level, but may be used to measure other biological properties, for example, various properties of skin, fat or the constituents contained within interstitial fluid.

The current invention enables measurements to be performed directly, thus overcoming the need to remove tissue samples, or fluid, and perform external analysis on the properties of interest.

Results obtained to date indicate that it is possible to use the current invention to distinguish between various concentrations of a water-sugar solution. It has been found that a monotonic change in both the real and imaginary components of complex impedance (relating to changes in phase and magnitude) exists for increasing water-sugar concentrations.

The current invention may comprise the following components: A low power source of microwave energy at either a single frequency, a plurality of single frequencies, or a range of frequencies around said single or said plurality of single frequencies; An antenna arrangement to transmit said microwave energy into biological tissue and to receive microwave energy from said biological tissue; A method of sampling portions of said transmitted and received energy; A detector to detect said portions of said transmitted and said received microwave energy in the form of phase and/or magnitude information; A signal processor to calculate changes in said phase and/or magnitude information sampled at various locations between said microwave source and said antenna arrangement; A method of mathematically manipulating and digitally filtering said changes in phase and/or magnitude to provide information regarding the properties of biological tissue; An output device for providing information to the end user in a user friendly format.

The source of microwave energy may be a microwave oscillator followed by a low power amplifier. If it is required to measure a single tissue property, it may be preferable to use a voltage-controlled oscillator (VCO), or a dielectric resonator oscillator combined with a phase locked loop arrangement to ensure fixed frequency operation. On the other hand, if the instrument is required to measure a plurality of tissue properties, for example, glucose, cholesterol and alcohol levels, then it may be preferable to use a frequency synthesiser, or a broadband VCO. In the instance where a plurality of properties is to be measured it may also be preferable to use a plurality of fixed frequency microwave oscillators and a suitable means of multiplexing between said oscillator and the rest of the microwave line-up. Suitable candidates for the low power amplifier include, but are not limited to, monolithic microwave integrated circuits (MMICs) using Gallium Arsenide (GaA) or high electron mobility transistor (HEMT) devices.

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.

Appropriate detection schemes are required to ensure that a signal can be discerned over a wide range of power levels, for example, the signal level may vary over the range odBm to -8odBm.

Directional couplers are used to enable a portion of said transmitted and received signals to be sampled. 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 the biological tissue structure in a forward direction. In the instance where a frequency sweep is used, it may be necessary to include a further directional coupler to enable the frequency of the microwave source to be measured to enable the frequency to be correlated with said phase and/or magnitude information.

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 where the forward power is many orders of magnitude higher than the reflected power, for example, forward power is 10mW and reflected power is iotW, 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, it is still advantageous to use directional couplers with high directivity. 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, Dc 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 and for enabling frequency information to available at the signal processor.

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 iGHz to 6oGHz.

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 co-axial 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 an 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 using this arrangement.

To measure changes in phase and/or 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/or 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 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 preferable to connect a separate detector to each of the 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 measure the frequency at which maxima and/or minima occur in the magnitude and/or phase response characteristic(s). More preferably, a frequency shift in 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. 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 use a frequency divider to reduce the microwave frequency to a value such that a standard microprocessor or signal processor can accept the signals.

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 magnitude and/or phase information derived from transmission and/or reflection measurement to provide the following information regarding the concentration of constituents contained within the biological fluid of interest: absolute level, high level, low level, average level, standard deviation, root of the mean of the squares (RMS), or a plot of concentration as a function of time. Said processor may also be used to calculate, for example, patient insulin requirements in the case of the concentration being glucose in blood.

In the instance whereby the measured microwave signal is of 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, where magnitude and/or phase extraction can be preformed together with said manipulation and signal 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, for example, be a display, an interface to a printer, or an audible alarm.

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 correlation between frequency and the position of the minima and/or maxima points to be carried out. Broadband directional couplers are 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 1GHz to 60GHz 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 first antenna in accordance with the desired concentration of constituents under investigation.

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 permithvity and conductivity over the frequency band of interest; other properties that are related to the structure of surrounding tissues should preferably remain constant. Most preferably, the region where the measurement is performed 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 first aspect of the current invention is a minimally invasive measurement instrument that uses low power energy concentrated in the microwave region of the electromagnetic spectrum to measure transmission characteristics in terms of changes in magnitude and/or phase of said energy. 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 mounted on a patch (or pad) that is made from a biocompatible material and positioned in contact with said biological structure, where said first antenna pierces said biological tissue structure, and is received using a second antenna mounted on a patch (or pad) that is made from a biocompatible material and positioned in contact with said biological structure, where said second antenna pierces said biological tissue structure. Preferably, said biological tissue structure is sandwiched between the monopoles (needles) of said first and second antennas and said monopoles are in alignment.

In accordance with the description given above, a second aspect of the current invention is a minimally 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 mounted onto a patch (or pad) that is made from a biocompatible material, where said first antenna pierces said biological tissue structure, and the reflected signal is received using same first antenna. It is preferable for only the centre pin (monopole) to enter the biological structure (this of course assumes said antenna structure is co-axial). In this embodiment the transmitted microwave energy reaches the anatomical region 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.

The antenna arrangements used in this invention preferably consist of fine needle structures that can be partially, or, in some instances, fully inserted into the biological tissue. The two antenna structures considered here are co- axial and loaded waveguide; for the latter construction, the preferred shape is the cylinder.

For the co-axial structure it is preferable to insert only the centre conductor in to the biological tissue. It is also preferable for the outside diameter of the overall co-axial structure to be less than o.5mm, and more preferably less than 0.15mm. It is also preferable for the diameter of the centre conductor of the co-axial structure to be less than o.mm, and more preferably less than 0.05mm. Since human skin has two principal layers known as the epidermis, which is

the outer layer with a typical thickness of around 12oJ.Lm, and the dermis, with a typically thickness of between and 3.6mm, the length of the centre conductor (the monopole) of said co-axial structure is preferably contained within this range. It should be noted that the dielectric constant of the biological tissue will load the monopole antenna, and such loading will reduce the length of the monopole by a factor proportional to the inverse of the square root of the value of relative permittivity associated with the particular tissue type.

The dermis contains hair follicles, sebaceous glands, nerve endings and fine blood capillaries, and by volume is made up predominantly of the protein collagen, therefore this invention may be used to measure information that may be available when the needle antennas are inserted into these tissue layers.

It is preferable for said antennas to be mounted onto a patch (or pad) made from a biocompatible material that can be adhered to the skin using a biocompatible adhesive. It is also preferable that only the centre conductor (the monopole) protrudes through the bottom surface of said patch and that said monopole is the only element that is allowed to pierce the biological tissue (normally the skin). It may be preferable for the outer conductor and the dielectric material between the inner and outer conductor to be flush with the bottom of the biocompatible pad to enable the whole length of the monopole to be in contact with the biological tissue. In the instance where two antennas are required, it may be preferable for said antennas to be mounted onto a single patch that may be either attached flat to the surface of the biological tissue or may be folded in such a manner that the transmit antenna is located on one side of the biological tissue structure and the receive antenna is located on the opposite side of said biological tissue structure; in this arrangement it is preferable for the two antennas to be aligned. Biological tissue structures that lend themselves well to this arrangement include, but are not limited to, the earlobe and the web between the thumb and first finger.

In the instance where a single antenna is used, said antenna is used as the transmitter and receiver and received information is captured in the form of reflected energy or backscatter.

Considering the co-axial antenna arrangement, it may be necessary to coat the centre conductor (the monopole) and a portion of the outer conductor (in some instances, it may be preferable to coat the complete antenna structure) with a biocompatible material to prevent fluid or tissue ingress getting inside the region of the co-axial structure between the centre conductor and the outer conductor. It may be preferable to use Parylene C as the coating material of choice, although other materials may be used, for example, a Teflon coating or a microwave ceramic. The materials used for the inner and outer conductors of the co-axial structure should be rigid, non-brittle and biocompatible. The material of choice is stainless steel, but this invention is not limited to using this material. The dielectric material between said inner and outer conductors should be a material that exhibits a low loss (low tans) at the frequency, or range of frequencies, of interest; suitable materials may include, but are not limited to, low density PTFE, expanded PTFE, or tape wrapped PTFE.

Considering the loaded waveguide antenna arrangement, due to the fact that this type of antenna does not contain a centre conductor, it is necessary for the complete structure to be inserted into the biological tissue. In the instance where the microwave frequency, or the range of microwave frequencies, of choice is less than 100GHz, it will be necessary to load the antenna with a material that exhibits a high relative permittivity, for example, at an operating frequency of 100GHz, it would be required for a cylindrical structure to be loaded with a loading material that exhibits a relative permittivity of 30 in order for the inner diameter of said structure to be 0.42mm to ensure that the dominant TE11 mode propagates inside said structure. It may be possible to fabricate said co-axial and loaded waveguide antennas using fabrication techniques associated with nanotechnology and precision engineering.

Accordingly, a second aspect of the current invention as a miniature needle antenna arrangement mounted on suitable biocompatible patches (pads) that are attached to a patient using a suitable biocompatible adhesive.

Other elements pertinent to this invention, or further objects, features and advantages of the 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 have been omitted from the

description.

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 current invention.

Figure i shows the system diagram for the instrument set-up to measure transmission characteristics. The main features relating to the instrument are shown together with a pair of pin antennas mounted on biocompatible patches and sandwiched between the biological tissue structure.

Figure 2 shows the system diagram for the instrument set-up to measure reflection (backscatter) characteristics. The main features relating to the instrument are shown together with a pin antenna mounted on a biocompatible patch. The centre conductor (pin) is shown piercing the skin.

Figure 3 shows four possible configurations for the pin antennas mounted on biocompatible patches, which are attached to the surface of the biological tissue using a biocompatible adhesive. The pin antennas are shown inserted inside representative tissue structures with varying depths of penetration.

Figure 4 shows two pin antenna structures mounted on a single strip of biocompatible patch material and attached to the earlobe. The antenna pins are shown as being aligned.

Figure 5 shows two pin antenna structures mounted on a single strip of biocompatible patch material and attached to the web between the thumb and the first finger.

Figure 6 shows a specific embodiment for the microwave elements, including an appropriate phase/magnitude detector, for an instrument set- up to measure transmission characteristics.

Figure 7 provides a table that lists part numbers and gives general details of the components used in the specific embodiment shown in figure 6.

Figure 8 shows a specific embodiment for the microwave elements, including an appropriate phase/magnitude detector, for an instrument set- up specifically to measure reflection (backscatter) information.

Figure 9 shows the top and bottom view of the co-axial pin antennas mounted onto biocompatible patches and the cross section of both a single antenna and two antennas mounted onto biocompatible patches.

Figure 10 show two co-axial antennas mounted on biocompatible patches. The first arrangement shows only the centre conductor in contact with biological tissue and the second arrangement shows the complete co-axial antenna structure in contact with biological tissue. Dimensions associated with the co- axial antenna arrangement are also indicated.

Figure ii shows an arrangement for a loaded cylindrical antenna. In this arrangement the microwave signal is launched into the antenna using an Efield probe launcher used to launch the dominant TE mode.

Figure 12 shows a graph of the results obtained using a water-sugar concentration with increasing levels of sugar concentration. The plot shows changes in the real and imaginary part of the complex impedance as a function of increasing sugar concentration.

Figure 13 shows the experimental arrangement used to obtain the measurement data presented in figure 12.

DETAILED DESCRIPTION OF THE CURRENT INVENTION

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

MAIN ASPECTS OF THE 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 first directional coupler 20 followed by a power control device 30 and a low power amplifier 40. 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, typical VCOs that may be considered for use in this invention exhibit the following range of operating frequencies: 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 30 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 40 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 and the dynamic range of power control is somewhat limited. 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 100mW 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 coupled port from first coupler 20 is connected to the input of a frequency divider (pre-scalar) 50 and the scaled down output frequency is fed into the signal processor/controller no to provide a measurement of the frequency produced by microwave source 10. The orientation of said first directional coupler 20 is such that a portion of the power from microwave source 10 will enter the coupled port.

The output from the amplifier 40 is connected to the input of a second directional coupler 21, whose coupled port is connected to detector/receiver unit ioo. The orientation of said directionaj coupler 21 is such that a portion of forward power from amplifier 40 will enter the coupled port. The output from 21 is connected to the input of a third directionaj coupler 22, whose coupled port is also connected to detector/receiver unit ioo. The orientation of said third directional coupler 22 is such that a portion of forward power from amplifier 40 will also enter the coupled port. The output from 22 is connected to the input of a fourth directional coupler 23, whose coupled port is again connected to detector/receiver unit ioo. The orientation of said fourth directional coupler 23 is such that reflected power from the biological tissue 8o will enter the coupled port. The output from 23 is connected to the input of a co-axial cable assembly 140, and the distal end of said cable assembly 140 is connected to a first antenna arrangement 6o, 74,75, which is used to transmit microwave energy from microwave source io, and low power amplifier 20, into biological tissue structure 8o. In practice, cable assembly 140 may not be required as in certain embodiments coupler 23 may be connected directly to first antenna arrangement 60,74,75.

Second antenna arrangement 61, 78, 79 is connected to the input of a coaxial cable assembly 141, and the distal end of co-axial cable 141 is connected to detector/receiver unit ioo. In practice, cable assembly 141 may not be required since in certain embodiments said detector/receiver unit ioo will be connected directly to said antenna arrangement 61, 78, 79. It may be advantageous to include matching filters between said antenna arrangements and said directional coupler/detector devices to ensure maximum transfer of microwave energy occurs, but said matching filters have not been shown here.

The biological tissue structure is preferably the surface of the skin, 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) 50 provides a first input into signal processor/controller no, where the output frequency produced by microwave source io is identified and stored in memory. Coupled signals from second, third and fourth couplers 21, 22, 23 provide information regarding the forward transmitted and forward reflected signals. The difference in phase and/or magnitude between the energy impinging on second antenna arrangement 6o, 74, 75 and that transmitted from first antenna arrangement 61, 78, 79 provides information regarding the concentration of constituents contained within the biological tissue 80. The signals from the coupled ports of 21, 22 and 23, and the output from 141 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) 50 using said signal processor/controller iio and changes in phase and/or magnitude are calculated. Said signal processor/controller no also sends a control signal to PIN attenuator 30 to control the microwave power level produced by the instrument, and sends a control signal to microwave source io 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 60, 74, 75 (6i, 78, 79) and detector/receiver ioo are given later in this description. The DC energy source for the instrument is derived from a power supply unit i3o; this unit provides the DC supply for the microwave source io, the power amplifier 40 (both gate bias voltage and drain supply voltage), the frequency divider (pre- scalar) 50, the detector/receiver unit ioo, 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 20, 21, 22, 23 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, Dc 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. Most preferably, cable assemblies 140, 141 may take the form of co-axial or flexible waveguide structures. The arrangement shown in figure i enables both transmitted and reflected information to be measured. The arrangement for measuring reflected power only is shown in figure two. The configuration is the same as that given in figure i, except that in this case only one antenna arrangement 6o, 74, 75 is used.

It will be appreciated by those skilled in art of microwave engineering that the microwave components shown in figures i and 2 need not be in the order shown. For example, first directional coupler 20 could be placed after amplifier 40 and before second directional coupler 21. This statement particularly relates to the MMIC amplifier, directional couplers and the antennas used in the current invention.

Preferably, the biological tissue structure 8o chosen for the measurement is a region of the anatomical system that is biologically simple in terms of tissue structure. Ideally, all layers of tissue sandwiched between antenna arrangements 60, 74, 75 and 61, 78, 79 will consist of a minimal number of tissue types and the tissues contained within the chosen structure will be rich in information. Typical setups showing said antenna arrangements piercing said biological tissue structures to varying depths of penetration are given in figure 3. Figure 3 (a) shows a first antenna arrangement 60,74,75 mounted to the surface of the skin with the needle antenna 74 penetrating through the skin (epidermis and dermis) 83, the fat layer 84, and into blood 85, and a second antenna arrangement 61, 78, 79 is shown connected to the opposite side of the tissue structure where needle antenna 78 penetrates as far as the region containing blood 85. Figure 3 (b) shows a similar arrangement with first and second antenna arrangement mounted on the same side of tissue structure 80 and needle antennas 74, 78 again penetrating into the region containing blood 85. Figure 3 (c) shows an arrangement whereby only the first needle antenna arrangement 60, 74, 75 is mounted on the surface of the skin 83 and the needle 74 penetrates the tissue structure 8o to a level whereby it enters blood tissue 85. In this arrangement said first antenna is used to transmit microwave energy and measure reflected energy. Figure 3 (d) shows a similar arrangement to that given in figure 3 (c) except that in this instance the needle 74 only penetrates into the skin; the depth of penetration may be such that the tip of the needle enters the lower epidermis or the dermis. Tissue structures similar to those shown in figure 3 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 looj.Lm and 10mm, thus the propagation loss, even at high microwave frequencies, is such that a low power microwave signal may be launched into said tissue structure 8o, using first antenna arrangement 60, 74, 75, passed through said structure 8o and be received using second antenna arrangement 61, 78, 79, 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 mm of blood, then, at an operating frequency of 10GHz, the total signal attenuation would be 6.36 dB. Arrangements showing antenna structures 60,74,75 and 6i, 78,79 connected to the preferred regions of the anatomy 8o are given in figures 4 and 5. In the arrangements shown in figures 4 and 5 antenna connectors 75, 79 are connected to the rest of the instrument using cable assemblies 140, 141.

Figure 6 gives a specific embodiment for the microwave components including antenna arrangements io, 21, 90, 40, 22, 140, 75, 60, 74, 78, 61, 79, 91, 141, the detector/receiver unit ioo, and a means of measuring phase and magnitude information iio. This configuration enables the transmission measurement to be performed and produces an output that provides direct phase and magnitude information. The output from the gain and phase detector iio is provided in terms of voltage levels; a first voltage representing the signal magnitude and a second voltage representing phase. These signals can be fed into a microprocessor, or other processing unit, where mathematical computation is performed, and the processed signals are fed into an output device. Said signal processing units and output devices are not a part of this specific embodiment and are not shown in figure 6. The specific embodiment shown in figure 6 comprises of a voltage-controlled oscillator (VCO) 10 that produces an output power of 4dBm and can operate over the frequency range of between 4.45GHz and 5GHz. The output from 10 is connected to a first directional coupler 21, which is configured to sample 10% of the power generated by 10, the remaining 90% of the power generated by 10 is fed into the input of a fixed value attenuator 90, whose function is to act as a buffer and reduce the power level by 4dB. The io% coupled power is fed into a frequency divider 101, which divides the source frequency 10 by a factor of two. The output from fixed attenuator 90 is fed into an amplifier 40, which has a gain of 20 dB and produces 2OdBm (100mW) of microwave power when driven into compression. The output from amplifier 40 feeds into the input of a second directional coupler 22, which is a 20dB coupler, thus 1% of the through power is sampled at the coupled port. Said second directional coupler 22 is configured to measure a portion of the forward power produced by amplifier 40. The output from said directional coupler is fed into a first transmission line or cable assembly, 140 and the output from 140 is connected to input Connector 75 of the first antenna assembly. Said connector 75 is connected to a patch (or pad) 60 and said patch 60 is stuck to the surface of the biological tissue structure 80. The first needle antenna 74 punctures said biological tissue structure. Said needle antenna 74 is an integral part of said microwave connector 75 and said connector/ antenna assembly is attached to a biocompatible patch 6o, which is attached to the surface of said biological tissue structure 8o using a biocompatible adhesive. Second needle antenna 78 also punctures biological tissue 8o and the second antenna structure 61,78,79 is positioned opposite first antenna structure 6o, 74, 75, i.e. said antenna structures are placed on opposite sides of the tissue structure 8o and the antenna needles 74/78 are preferably aligned. Second antenna arrangement 61, 78, 79 is connected to the input of a second fixed attenuator 91, which attenuates the received signal by iodB (in the instance whereby the biological tissue structure is thicker than 10mm, or said biological tissue structure causes excessive signal attenuation, attenuator 91 may be omitted. The attenuated version of the received signal is fed into a second transmission line or cable assembly 141 and the output from 141 is fed into the RF input of a second microwave frequency mixer io (RF2). The output from frequency divider ioi is fed into a gain block 102, which is used to boost the power to a level that can be used to drive local oscillator inputs to first and second microwave frequency mixers 104, 105. Said gain block 102 takes the output power from ioi of -6dBm and amplifiers it by 20dB to provide a power level at the output of 102 of + l4dBm, this power level is then split, using a 3dB splitter 103, and +ii dBm is fed into the local oscillator input of a first microwave frequency mixer 104 (LOi) and the remaining + iidBm is fed into the local oscillator input of second microwave mixer 105 (L02). The RF input to first microwave frequency mixer 104 (RFi) is a portion of the forward power taken from the coupled port of second directional coupler 22. The intermediate frequency output (IFi) from said first mixer 104 is the difference between the two input frequencies (RFi-LOi) and is fed into the first input of the gain and phase detector no. The intermediate frequency output (1F2) from said second mixer 105 is the difference between the two input frequencies (RF2-L02) and is fed into the first input of the gain and phase detector iio. Said gain and phase detector iio provides two voltages at its output; the first voltage is proportional to the difference in magnitude between the transmitted signal and the received signal, and the second voltage is proportional to the difference on phase between the transmitted signal and the received signal. Detector/receiver unit ioo is shown here to comprise of microwave elements ioi, 102, 103, 104, 105, 141, and said elements are enclosed by a dotted line. Figure 7 provides a table that gives details of the specific microwave devices used in the specific embodiment shown in figure 6.

Details given in the table include: numbers referring the parts to the blocks given in figure 6, the manufacturer and part number, and the technical

description of the part.

Figure 8 shows a specific embodiment for measuring reflected signal information. The embodiment shown uses the same parts as those used in the embodiment shown in figure 6, with the exception that a third directional coupler 23 is used to measure a portion of the reflected power that travels back from first needle antenna 74. Said third directional coupler 23 samples io% of the reflected power and said reflected power is fed into the RF input of second microwave frequency mixer 105 (RF2). With the exception of RF2, all other signals entering first and second microwave frequency mixers are identical to those shown in figure 6. In this instance, the output voltages produced by the gain and phase detector iio are a measure of the difference in magnitude between the forward transmitted and forward reflected signals, and the difference in phase between the forward transmitted and forward reflected signals.

Figure 9 shows details of co-axial antenna arrangements. Figure 9 (a) shows the top view, where a female coaxial connector 75/79, for example, an SMA, SMB, MCX or SMP, is connected to biocompatible patch 60/61. The bottom view is shown in figure 9 (b), where the inner conductor needle (or pin) antenna 74/78 is shown along with the outer conductor 72/76 and the dielectric material between said inner and outer conductors 37/77. Figure 9(c) shows a side view of the arrangement, where it can be seen that the end of the outer conductor 72/76 and the dielectric material 73/77 is flush with the bottom of the biocompatible patch (or pad) 60,61 and the inner conductor needle (or pin) is shown protruding through the bottom of said patch 60/61.

Figure 9(d) shows two co-axial antenna assemblies mounted on a single biocompatible patch (or pad) 6o. In this arrangement, the two antenna arrangements are adjacent to each other. Figure 10 shows two configurations for the co-axial antenna structures inserted into the biological tissue 8o.

Figure 10(a) shows the co-axial antenna structure with only the centre conductor 74/78 in contact with biological tissue 8o, and figure io(b) shows the complete co-axial antennas inserted into biological tissue 80. In these co- axial antenna structures it is preferable for the outsidediameter of the overall co-axial structure 72/76 (a) to be less than 0.mm, and more preferably less than 0.15mm. It is also preferable for the diameter of the centre conductor 74/78 (b) to be less than o.2mm, and more preferably less than 0.05mm. The length of said centre conductor (c) will be dependent upon the dielectric constant of the tissue that the centre conductor needle is in contact with. In general, the length in free space will be shortened by the inverse of the square root of the relative permiffivity of the biological tissue 8o. It is preferable to coat the inner conductor 74/78 with a conformal coating of biologically acceptable material, for example Parylene C may be used. In the instance whereby the complete co-axial antenna structure is inserted into the biological tissue, a portion of, or, in some cases the complete, co-axial structure may be coated with a biologically compatible material. For the coaxial structures addressed here, the characteristic impedance (Z0) of the structure is given by equation i, shown below: = 138/'IEr log10 a/b (i) Where: Cr is the relative permittivity of the dielectric material between the inner and outer conductor a is the inner diameter of the outer conductor b is the outer diameter of the inner conductor For example, if an antenna assembly with a characteristic impedance of 5O = 15 required and a low density PTFE dielectric with a relative permittivity of 1.4 is used, and the outer diameter of the inner conductor needle is o.imm, then the inner diameter of the outer conductor is required to be 0.27mm.

Figure ii shows the dielectric loaded waveguide antenna structure. In the arrangement shown here a cylindrical waveguide is loaded with a material that exhibits a low loss at the frequency of interest, and has a high relative permittivity in order to shrink the diameter of the structure to a value that is acceptable in terms of piercing the skin whilst causing a minimal degree of discomfort. The arrangement shown in figure io shows the microwave signal launched into the waveguicle probe using an E-field probe 71 connected to a co-axial microwave connector 75/79. In the arrangement shown, a waveguide cavity 70 is used to launch the dominant TE1, mode into the waveguide.

Ideally, the distance between the E-field probe and the closed back wall of 70 is a quarter wavelength (or an odd multiple thereof) at the frequency of operation. If it is required to propagate the dominant, TE11, mode along the cylindrical waveguide, then the diameter (a) of the dielectric rod used to shrink the diameter of antenna structure can be expressed using equation 2, given below: a = (24485 V)/(rf0 V/kEr) (2) Where: Vis the speed of light in a vacuum (3x1o8 m/s) f is the frequency of operation (Hz) r is the relative permeability for a magnetic loading material (magnetic loading factor) Cr1S 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 TE mode of propagation and the calculation for the cut-off frequency for lowest insertion loss at the frequency of operation. For example, if the chosen frequency of operation is 100 GHz, there is no magnetic material present (u=i), and a ceramic dielectric material is used with a relative permittivity of 30, then the inside diameter of the waveguide will be o.mm and the structure will support the dominant TE11 mode of propagation.

Co-axial connector may take a number of forms, for example, sub- miniature A (SMA), SMB, SMC, MCX or another miniature microwave connector that is capable of working at the frequency (ies) of operation relevant to this invention. It may be preferable to use SMP microminiature high frequency connectors where the frequency of operation lies within the range of DC to 40GHZ.

Experimental measurements and preliminary studies have been carried out to validate the current invention; the experimental set-up used and results obtained will now be described. Measurements carried out to date have been performed using sugar-water solutions only.

Figure 12 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 ioo for detecting phase and magnitude information, signal processor and controller iio and a means of displaying said phase and magnitude information 120. Said microwave energy source 10 contained within 200 was coupled into antenna arrangement 74, 72, 75 70 using a coaxial cable assembly 140. Said antenna arrangement 74, 72, 75 was held inside a clamp 153, which was itself connected to a clamp stand and base unit 154, 155. Said antenna 74,72, 75 was positioned in the centre of a vessel 150, 151, which contained a water-sugar solution 8o. VNA was set up to sweep over a range of frequencies within its operating limits and the most interesting changes appeared to happen at a frequency of 5GHz.

Figure 13 shows a graph of the results obtained at 5GHZ, where real and imaginary parts of complex impedance are plotted as a function of increasing water-sugar concentration. It can be seen that there is a monotonic decrease from i8o) to i6o1 in the real part of the complex impedance as the concentration increases. On the other hand, the imaginary part increases from -j50L to -j6o (with the exception of the initial point) as a function of increasing water-sugar concentration. The water-sugar solutions used here were somewhat arbitrary in terms of exactness, but these results provide a good indication that this direct measurement method can be used to differentiate between various concentrations of sugar.

Claims (25)

1. It is claimed: 1. An instrument for minimally invasively measuring concentrations of constituents contained within biological tissue contained within the human biological system comprising: a source, or a plurality of sources, to produce energy at a single frequency, or a plurality of frequencies, contained within the microwave region of the electromagnetic spectrum; a means of transmitting said microwave energy into said biological tissue; a means of receiving microwave energy from said biological tissue after said microwave energy has passed into said biological tissue; a means of measuring a portion of said transmitted and said received microwave energy; a means of converting said portions of microwave energy into phase and/or magnitude information; a means of processing said phase and/or magnitude information and calculating changes in said phase and/or magnitude information; a means of processing and mathematically manipulating said changes in said phase and/or magnitude to provide information that can be used to represent said concentration of said constituents; a means of outputting said information regarding said concentration of said constituents.
2. 2. An instrument for minimally invasively measuring concentrations of constituents contained within biological tissue contained within the human biological system 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 after said microwave energy has propagated through a portion of said biological tissue; a detector to convert portions of said transmitted and said received microwave energy into phase and/or magnitude information; a signal processor to calculate changes in said phase and/or magnitude information and to perform mathematical computation to convert said changes into a format that can be used to represent said concentration of said constituents; an output device to present said information to an end user.
3. 3. An instrument for minimally invasively measuring concentrations of constituents contained within biological tissue contained within the human biological system comprising: a source of microwave energy; an antenna to transmit forward directed microwave energy into biological tissue and to receive forward reflected microwave energy coming back along the same path but in the opposite direction; a detector to convert portions of said transmitted and said received microwave energy into phase and/or magnitude information; a signal processor to calculate changes in said phase and/or magnitude information and to perform mathematical computation to convert said changes into a format that can be used to represent said concentration of said constituents; an output device to present said information to an end user.
4. 4. An instrument according to claims 2 and 3 whereby said antennas are coaxial monopole structures.
5. 5. An instrument according to claims 2 and 3 whereby said antennas are loaded waveguide structures.
6. 6. As claimed in 5 whereby said loaded waveguide structures are cylindrical in shape.
7. 7. An instrument according to claims 2 to 3 and 4 to 5 whereby said antennas are mounted onto a biologically compatible patch.
8. 8. As claimed in 7 whereby said biological patch is attached to the human anatomy using a biocompatible adhesive.
9. 9. An instrument according to claims 2 to 4 and 7 to 8 whereby the centre conductor of the co-axial structure is the only component of the antenna structure that enters the human anatomy.
10. 10. An instrument according to claims 2 to 8 whereby the body of said antennas enters the human anatomy.
11. 11. An instrument according to claims 2 and a combination of claims 4 to 10 whereby two of the said antennas are mounted together onto a single biocompatible patch.
12. 12. An instrument as claimed in any one of the above claims whereby said antennas mounted on said biocompatible patches are attached to the surface of the human anatomy.
13. 13. As claimed in 12 whereby the location of said human anatomy is the skin.
14. 14. An instrument according to claims 2 and a combination of claims 4 to 11 whereby a single biocompatible patch is mounted onto the earlobe in such a manner that one antenna is present on either side of said earlobe.
15. 15. An instrument according to claims 2 and a combination of claims 4 to 11 whereby a single biocompatible patch is mounted onto the web between the thumb and first finger and said biocompatible patch is mounted in such a manner that one antenna is present on either side of said web.
16. i6. As claimed in 14 and 15 whereby the centre conductors of said antennas are in alignment.
17. 17. An instrument as claimed in any of the above claims whereby the concentrations of constituents to be measured are contained within a biological fluid.
18. 18. An instrument as claimed in any of the above claims used to measure the properties of interstitial fluid.
19. 19. An instrument as claimed in any of the above claims used to measure the properties of skin.
20. 20. An instrument as claimed in any of the above claims used to measure the properties of fat tissue.
21. 21. An instrument as claimed in any of the above claims used to provide a general indication of the user's health.
22. 22. An instrument as claimed in any of the above claims used to measure cholesterol level.
23. 23. An instrument as claimed in any of the above claims used to measure the properties of blood.
24. 24. An instrument as claimed in 23 used to measure blood-glucose level.
25. 25. An instrument as claimed in 23 used to measure blood-alcohol level.