WO2002078532A1

WO2002078532A1 - Implantable sensor

Info

Publication number: WO2002078532A1
Application number: PCT/GB2002/001539
Authority: WO
Inventors: Barry Colin Crane
Original assignee: Diametrics Medical Limited
Priority date: 2001-03-30
Filing date: 2002-04-02
Publication date: 2002-10-10
Also published as: GB0108052D0

Abstract

It is not uncommon for patients to be subjected to multiple blood tests in order to monitor a particular medical condition. An implantable sensor (2) is disclosed for use with an external transmitter/receiver (8) to monitor the value of a parameter within a living mammal. The sensor comprises a light source (12) and an indicator system (26) which is responsive on exposure to said light source to the level of said parameter in a body fluid within said mammal. Detector means (16, 18) detects the response of the indicator means to the value of said parameter. The light source and detector are contained by a capsule (22, 24) which is impermeable to body fluid, but having at least a window allowing transmission of light to and from the tissue or indicator system.

Description

IMPLANTABLE SENSOR This invention relates to implantable sensors and measuring devices for monitoring the level or concentration of a parameter within a living organism.

It is not uncommon for patients to be subjected to multiple blood tests in order to monitor a particular medical condition. In the case of some conditions such as diabetes, blood samples are required to be taken several times a day. This is inconvenient and causes patient management difficulties, particularly in the cases of the elderly and the young. It would be convenient if a device could be provided in which the values of variable parameters, e.g. the level of glucose within the blood, could be monitored without the necessity for serial blood tests.

Against this background, in accordance with one aspect of the invention there is provided an implantable sensor for use with an external transmitter/receiver to monitor the value of a parameter within a living mammal, the sensor comprising a light source and an indicator system which is responsive on exposure to said light source to the level of said parameter in a body fluid within said mammal, and detector means for detecting the response of the indicator means to the value of said parameter.

Another aspect of the present invention is based on the recognition that body fluids and electronic circuits are not happily compatible.

In accordance with this aspect of the invention, there is provided a n implantable sensor for monitoring the value of a parameter in body fluid or tissue of a living organism, the sensor comprising a light source for illuminating tissue or an indicator system either of which exhibits detectable optical properties which are dependent on the level of said parameter in the tissue or the body fluid, and a detector for detecting the exhibited optical properties, said light source, and detector being contained by a capsule which is impermeable to body fluid, but having at least a window allowing transmission of light to and from the tissue or indicator system. The electrical parts of the sensor are thus kept apart from the body fluids by the impermeable capsule, while communication between the light source and the indicator system and between the indicator system and the detector is allowed by passage of light through at least a window. Miniature light sources are available comprising light emitting diode (LED) dyes which can be powered by an induction coil. The LED dye or dyes along with the induction coil, detectors, an application specific integrated circuit (ASIC), for processing data, and a receiver/transmitter can all be laid down on a small board. This board and its components can be considered to be the electronics or hardware part of the preferred implantable sensor. The electronics part is hermetically sealed within a glass or plastic encapsulation shell. This is an important feature of the implantable sensor since no hardware comes into contact with the external biological environment hence eliminating the issue of moisture ingress and corrosion of electronics over prolonged periods of time. This issue would be particularly prominent with electrochemical sensors where electrodes are required to be in contact with the biological environment. In this invention only light traverses the electronics encapsulation material to interrogate the indicator system that is in contact with the biological environment and react with the target analyte. Also the response is only by return light from the indicator system which traverses the encapsulation material to the detectors. The induction coil can be miniaturised since some LEDs require less than 10 microwatts of power for activation.

A waveguide can be incorporated into the encapsulation material to focus the light from the LED to the external chemistries such that it directly adjoins the light source at one end and the indicating chemistry at the other. Similarly the return light from the chemistry can be directed from the chemistry via a separate waveguide directly to the detector(s). To eliminate the possibility of light, either transmitted or return, diffusing laterally through the encapsulation material then the encapsulation material could be made opaque, except for a window or the waveguides used for light transmission or receipt.

Most preferably, the indicator chemistry will be of the equilibrium type to ensure continuous measurement. This also ensures that the target analyte is not consumed and new by product chemicals are not generated as is often the case with electrochemical detection systems. This is an important feature of equilibrium chemical indicator systems since any consumption of the target analyte by a measurement system will affect the local concentration of the analyte and then lead to errors.

The chemical indicator may be one which absorbs light emitted by the LED or responds to exposure to the LED (excitation wavelength) by emitting light at a different wavelength (fluorescent or phosphorescent indicators). It is known that some fluorophores are "bleached" when subject to light at a wavelength where absorption occurs. The consequence of this is that the fluorescent signal can drift over long periods of time. Bleaching is related to the intensity and time that the fluorophore is exposed to the excitation light from the LED and can therefore be minimised by minimising the intensity of the LED light but also by pulsing the light and optimising the duty cycle, i.e. a pulse of say 15 milliseconds every 15-30 minutes would provide adequate continuous monitoring for say feedback to an implantable drug pump and would mean that drift due to bleaching of the fluorophore would be reduced such that the sensor could remain in place for a period of years without incurring inaccuracies.

The chemistries may be laid down on a substrate material which is bound to the encapsulation material. On the biological environment side chemistry/substrate may be covered (and bound) with a dialysis membrane with a molecular weight cut off that is just greater than the molecular weight of the target analyte/metabolite. This in turn is covered by a microporous membrane of a pore size that restricts the passage of blood cells and other blood elements but allows the passage of blood serum. The chemical indicator may be one which absorbs light emitted by the LED or responds to exposure to the LED by emitting light at a different wavelength. In the former case, the amount of light absorption will be a measure of the concentration of the variable parameter. In the second case, the intensity or wavelength of the emitted light may be indicative of such concentration.

The implantable sensor includes detecting means which themselves include or are associated with means for transmitting a signal representative of the sensed value of the parameter to the external transmitter/receiver. The transmitter/receiver may be worn by the patient and may be arranged to interpret the signals received from the detecting means and give a figure representative of the concentration of the parameter in the patient's body fluid. The value may be provided as a constant read-out or one provided from time to time on demand. In the case of a condition which is treatable by periodic or constant administration of a drug such as diabetes, the transmitting/receiving device may be linked to a medicament pump so that a medicament such as insulin is administered in doses and at times to maintain the glucose or other parameter value at an appropriate safe or desirable level. Various implantable drug pumps are available to deliver theraputics to control clinical conditions. Another example is the delivery of L-Dopa to control Parkinson's disease. A sensor in accordance with the invention, can be made to measure the delivered therapeutic or a related metabolite to control the dosage delivered by the pump. In this case the sensor may be inductively powered remotely by the pump or some external power source or it may be "hard wired" to the pump and powered by this means. In general, the pump and the sensor each have a transmitter/receiver such that medicament and control data can be transmitted and received between pump and sensor.

The individual elements in the implantable sensor may be supported on polymeric or ceramic supports and bonded together so as to be implantable as a single unit or chip. The unit preferably includes a microporous membrane which permits blood plasma and soluble salts and metabolites to enter the device but excludes blood cells and tissue cells.

The implantable unit or chip may be presented in a sterile pack which, for measurement of glucose, can be implanted just below the patient's tissue surface, e.g. within z cm of the surface of the skin. Prior to implantation, it may be necessary to hydrate the device to reduce allergic reaction and may be pre-calibrated or calibrated at the point of implantation.

A typical size for the device may be about lcm across and about Imm thick and conveniently may be shaped as a disc. The preferred device is powered by an external transmitter/receiver which will also be arranged to receive signals representative of the parameter being monitored. Within an initial period e.g. about one week, it may be necessary or desirable to carry out 1 to 2 point calibration of the device by taking the patient' s blood sample, performing an accurate parameter analysis and calibrating these figures with data obtained through the external transmitter/receiver. It is possible for the transmitter/receiver to perform, e.g. a sample blood/glucose measurement and for this to be compared with data obtained from the implanted sensor.

The patient may activate the external transmitter/receiver to measure the parameter, e.g. glucose, on demand, but it is preferred to construct the transmitter/receiver into a wristwatch type and size device that can carry out a continuous surveillance during waking and sleeping hours. It may be desirable for the device to include a warning indication if the measured value departs from a predetermined range.

It should be emphasised that the preferred implanted sensor may be very stable since it is designed to measure an equilibrium condition and is not a consumptive device. From time to time, it may be desirable to check the measurements reported by the device, perhaps on a monthly basis, when recalibration may be carried out against an actual blood sample analysis. The lifetime of the device is likely to be of the order of one or more years.

The invention extends to apparatus for monitoring the concentration of a variable parameter within the body of a living organism which comprises an implantable sensor as claimed in anyone of the preceding claims and a transmitter/receiver for powering the light source and recording and/or interpreting signal data relevant to the concentration of said parameter.

In accordance with another aspect of the invention, there is provided an implantable system for delivering a therapeutic, comprising a an implantable sensor to monitor the value of a parameter in body fluid or tissue of a living organism, the sensor comprising a light source for illuminating tissue or an indicator system either of which exhibits detectable optical properties which are dependent on the level of said parameter in the tissue or the body fluid, a detector for detecting the exhibited optical properties, said light source, and detector being contained by a capsule which is impermeable to body fluid, but having at least a window allowing transmission of light to and from the tissue or indicator system; and an implantable pump for delivering a therapeutic in a dose or at a rate responsive to the detected optical properties.

One embodiment of the present invention will now be described with reference to the accompanying schematic drawing which represents an exploded view of the an implanted sensor embodying the invention, and a view of an external transmitter/receiver, both being schematic and not to scale.

The device will be described by way of example for the monitoring of the concentration of glucose within a patient's blood.

The sensor 2 shown in the attached drawing, when assembled has a diameter of approximately I cm and a total thickness of about 2 mm.

A ceramic circuit board in the form of a disc 4 carries an induction coil 6 which receives power from a coil (not shown) within an external transmitter/receiver 8. Disc 4 also has mounted on it a data processing chip 10 which is provided an application specific integrated circuit (ASIC).

The disc 4 also supports LED dyes 12 and 14, detectors 16 an 18 and radio transmitter/ receiver chip 20 all powered from the induction coil 6. The disc 4 is encapsulated by a bio compatible encapsulation shell, e.g. glass or polymeric, such as high density polyethylene shown in two parts shown in two parts 22 and 24, which are sealed together during assembly so that the resulting capsule is impermeable to body fluids and protects the circuit and components on the disc 4.

The coil 6 is able to power and excite the dyes 12 and 14 on disc 4 so as to emit light. The dye 12 emits green light which interacts with fluorescent indicators 26 mounted on a disc 28, which is in close contact with the capsule 22,24. The disc 28 comprises a polymeric film and in the case of glucose, will incorporate an indicator system 26 responsive to the presence of glucose.

A suitable system comprises fluorescent tagged dextran and concanavalin (tagged (DC indicator). The tagged DC indicator forms a lightly bound complex and the fluorescent tags undergo resonant energy transfer emitting at particular wavelengths. This emitted light energy is transmitted back to the detector 16 on disc 4 and the resulting signal is processed by the ASIC 10 before transmission to the external transmitter/receiver 8 where the indicated value of the glucose concentration may be displayed on a display 30.

The dye 14 emits red light which is unaffected by the indicator chemistry and so the intensity of red light returned to the detector 18 is used as a reference by the ASIC 10 in evaluating the intensity of the light detected by the detector 16.

The fluorescent indicator 26 is covered by a dialysis membrane 32 which in turn is covered by a microporous membrane 34. Glucose from the micro-capillary bed within the patient's tissue will diffuse through the microporous membrane 34, the 0.2 micron holes being sufficient to exclude blood and tissue cells, but not plasma, metabolites and salts.

The dialysis membrane 32 is designed to cut off molecular weights larger than that of the analyte to be measured. For glucose it is designed to cut off molecular weights of 200 or more and which will allow glucose and lower molecular weight materials to diffuse through to the indicator system indicator 26. There the glucose will compete with dextran for the concanavalin and in so doing, the emitted radiation from the resonant energy transfer between the dextran and the concanavalin fluorescent tags will be disrupted. The modified fluorescent signal passes to the detector 16 and then to the chip 10 from which the data is processed and transmitted to the external transmitter/receiver 8.

In an embodiment, not illustrated, the glucose representative signal is used to control the operation of an implanted pump so as to control the dose of therapeutic in the form, for example, of insulin. The pump may be contained in the same implant as the sensor, in which case there may be direct electrical communication between the pump and the sensor within the same encapsulation. Alternatively, communication may be wireless, similar to that with the transmitter/receiver 8. In that case the pump may be encapsulated remote from the sensor.

Claims

CLAIMS:

1. An implantable sensor for use with an external transmitter/receiver to monitor the value of a parameter within a living mammal, the sensor comprising a light source and an indicator system which is responsive on exposure to said light source to the level of said parameter in a body fluid within said mammal, and detector means for detecting the response of the indicator means to the value of said parameter.

2. An implantable sensor according to claim 1 , in which the internal transmitter is arranged to transmit wireless signals representative of the sensed value of the parameter to the external receiver.

3. An implantable sensor for monitoring the value of a parameter in body fluid or tissue of a living organism, the sensor comprising a light source for illuminating tissue or an indicator system either of which exhibits detectable optical properties which are dependent on the level of said parameter in the tissue or the body fluid, and a detector for detecting the exhibited optical properties, said light source, and detector being contained by a capsule which is impermeable to body fluid, but having at least a window allowing transmission of light to and from the tissue or indicator system.

4. An implantable sensor according to any preceding claim, in which the light source comprises a light-emitting diode (LED) which is powered by energy induced in an induction coil from an external transmitter.

5. An implantable sensor according to any preceding claim, in which the indicator system comprises a chemical indicator which responds to the presence of the parameter on exposure to the light source by emitting light at a wavelength which is characteristic of said parameter, the intensity of the emitted light being indicative of the concentration of said parameter in the body fluid.

6. An implantable sensor according to anyone of the preceding claims in which the indicator system is responsive to the concentration of glucose within blood of the organism .

7. An implantable sensor according to anyone of the preceding claims in which the light source, induction coil, indicator system and detecting means are mounted on or incorporated in polymeric or ceramic supports and are bonded together to form a single implantable device which is microporous so as to permit blood plasma and soluble salts and metabolites to enter the device to access the detector system, but to exclude blood cells.

8. Apparatus for monitoring the concentration of a variable parameter within the body of a living organism which comprises an implantable sensor as claimed in anyone of the preceding claims and a transmitter/receiver for powering the light source and recording and/or interpreting signal data relevant to the concentration of said parameter.

9. An implantable system for delivering a therapeutic, comprising an implantable sensor to monitor the value of a parameter in body fluid or tissue of a living organism, the sensor comprising a light source for illuminating tissue or an indicator system either of which exhibits detectable optical properties which are dependent on the level of said parameter in the tissue or the body fluid, a detector for detecting the exhibited optical properties, said light source, and detector being contained by a capsule which is impermeable to body fluid, but having at least a window allowing transmission of light to and from the tissue or indicator system; and an implantable pump for delivering a therapeutic in a dose or at a rate responsive to the detected optical properties.