GB2231742A - Blood flow determination - Google Patents
Blood flow determination Download PDFInfo
- Publication number
- GB2231742A GB2231742A GB9006882A GB9006882A GB2231742A GB 2231742 A GB2231742 A GB 2231742A GB 9006882 A GB9006882 A GB 9006882A GB 9006882 A GB9006882 A GB 9006882A GB 2231742 A GB2231742 A GB 2231742A
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- United Kingdom
- Prior art keywords
- blood flow
- light
- frequencies
- target
- beneath
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 230000017531 blood circulation Effects 0.000 title claims abstract description 58
- 238000000034 method Methods 0.000 claims abstract description 28
- 230000002792 vascular Effects 0.000 claims abstract description 10
- 238000001228 spectrum Methods 0.000 claims abstract description 6
- 239000008280 blood Substances 0.000 claims abstract description 5
- 210000004369 blood Anatomy 0.000 claims abstract description 5
- 230000033001 locomotion Effects 0.000 claims description 33
- 230000009471 action Effects 0.000 claims description 5
- 230000003287 optical effect Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000012937 correction Methods 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000013256 coordination polymer Substances 0.000 description 3
- 210000003414 extremity Anatomy 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 230000002596 correlated effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 101100081581 Chlamydomonas reinhardtii ODA1 gene Proteins 0.000 description 1
- 101100224940 Chlamydomonas reinhardtii ODA2 gene Proteins 0.000 description 1
- 206010011985 Decubitus ulcer Diseases 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 208000004210 Pressure Ulcer Diseases 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000002316 cosmetic surgery Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
- A61B5/026—Measuring blood flow
- A61B5/0261—Measuring blood flow using optical means, e.g. infrared light
Abstract
A method of determination of blood flow including projecting a beam (B) of laser generated light (L) to move (SM) over a surface (T) beneath which blood flow in a vessel or vascular bed is to be determined, collecting (RD) light returning scattered from the beam by the surface and by blood flowing beneath, measuring a spectrum of frequencies in said collected light, determining (DA), (F) from differences in said frequencies blood flow (VS) in a vessel or vascular bed beneath said surface. A reference for the detected frequencies is provided by light returned from the surface. A map of blood flow in a false-colour flow scale can be displayed (DU).
Description
BLOOD FLOW DETERMINATION
This invention relates to the non-invasive determination of blood flow.
In medical practice it is often essential that the pattern of blood flow be determined quickly and accurately. For example, in trauma where a limb may have been reattached, the assessment of pressure sores, plastic surgery for monitoring graft viability and in peripheral vascular diseases. When amputation is likely it is important that the extent of blood flow be known.
Various techniques for blood flow determination have been proposed. One publication, Blood Flow Measurement: Future
Applications and Prospects, Robert F. Rushmer, Medical
Instrumentation Vol. 11 No. 3 May-June 1977, mentions the laser-Doppler method in which a fibre-optic directs light from a laser at the superficial vessels of the skin and reflected light indicates blood flow in these vessels. A much more recent publication, Limb perfusion in the lower limb amputee,
S.L.E. Fairs et al., Prosthetics and Orthotics International, 1987, Vol. 11 80-84, refers to the use and value of the fibre-optic instrument but mentions problems resulting from the movement of the fibre optic, which has to be close to the surface of the area being examined.
It is an object of the present invention to provide a technique for the determination of blood flow which overcomes such problems. In particular it is an object of the present invention to provide a technique by which a map of blood flow over a given area can be produced.
According to the invention there is provided a method of determination of blood flow including:
projecting a beam of laser generated light to move over a surface beneath which blood flow in a vessel or vascular bed is to be determined,
collecting light returning scattered from the beam by the surface and scattered by blood flowing beneath,
measuring a spectrum of frequencies in said collected light,
determining from differences in said frequencies blood flow in a vessel or vascular bed beneath said surface.
According to the invention there is provided a method of determination of blood flow including:
generating and projecting a beam of laser light,
causing said beam of light to move over a surface beneath which blood flow in a vessel or vascular bed is to be determined,
collecting light returned scattered from the beam by the surface and by blood flowing beneath,
detecting scatter-related frequencies in said collected light,
determining from said frequencies blood flow in a vessel or vascular bed beneath said surface.
The blood flow determined in this way may be presented as an image of the surface coloured or shaded in accordance with a scale of blood flow. Light returned from the surface may provide a reference for the determination of blood flow beneath the surface. Thus a map of blood flow for a given area can be produced.
According to the invention there Is provided apparatus to determine blood flow including a low-noise laser, means to direct a beam of light from said laser to a target, means to scan the directed beam over said target, means to collect light from the beam returned from said target, means to detect frequencies In said collected returned light, means responsive to the action of the means to scan said beam and to detected collected light frequencies to determine localised target velocity Information related to the position of the scan on the target and to provide said Information as a scan-based signal.
The apparatus may include means to present said scan-based information as an image of localised velocity information for the target. The velocity information may be presented as Information about blood flow below the surface of the target, which may be presented as a false-colour image of blood flow
The means to detect returned light may be an array of detectors. The beam from the laser may be directed to pass through an aperture in the array to a path also used for the returned light.
The returned light frequencies may include those representing overall movement of the target and these may provide a reference for determination of localised velocity information.
The means to scan the directed beam may include means to drive a mirror directing the beam In a steady swinging motion and a stepwise tilting motion.
Embodiments of the invention will now be described with reference to the accompanying drawings in which:
Figure 1 is an outline schematic drawing of a scanning apparatus,
Figure 2 is an outline schematic drawing of a mirror drive linkage for the scanning apparatus of Figure 1 and
Figure 3 is an outline schematic circuit diagram.
A beam of light, B, from a low-power low-noise laser, L, is directed to be reflected by a movable mirror, SM. Mirror SM is a flat mirror movable in a controlled manner to scan the laser beam
B reflected from mirror SM over an object of interest such as a target T, as indicated by the curved arrows. Light returned from the target is captured by the movable mirror SM and directed to a receiving device RD. Receiving device RD is arranged so that light from the laser passes through an aperture A in the device and collected light falls on the device. Conveniently the device
RD is four photo detectors such as diodes arranged in a square array. Each device has a lens or other optical device to improve the incidence of collected returned light on the receiving device.
The mirror SM is driven to swing about a generally vertical axis by a drive motor DM and linkage to produce a specific motion which is monitored in any convenient manner such as a shaft position encoder to produce a mirror motion information signal
MMI. A suitable linkage is described below. The mirror SM Is driven to tilt about a generally horizontal axis by a lead screw and stepping motor arrangement (not shown). A suitable construction will be readily apparent to those skilled In the art. By a suitable control arrangement, such as a microprocessor or other electronic circuitry, the stepper motor is driven a selected number of steps at the end of each swing about the vertical axis to produce a "raster" scan of the laser beam over the object. Information about the swing of the mirror about the horizontal axis can be provided as part of the signal MMI or otherwise as convenient.
The light returned from the target includes optical frequencies spread over a range from the optical frequency (X) of the light of the beam B by scattering action. This light is collected and directed to the receiving device.
The receiving device RD and associated circuitry produce an output signal related to the shift (~X) of the optical frequency of the scattered light from that of beam B, which shifts result from small movements within the target, such as blood flow. A reference signal is provided by the shifted frequencies of light i + AX) scattered by the target as a whole, rather than beam B Itself, so that movements of the target as a whole can be cancelled out.
The output signal Is processed In suitable electronic circuits. The circuits to process the signal from the receiving device RD conveniently include firstly two analogue amplifiers, one for the two upper diodes and the other for the two lower ones, followed by a differential amplifier DA and then a filter
F. This filter has a response by which the output is proportional to frequency so as to extract the scatter-related information, represented by the 6X component, resulting from blood flow motion.
In one arrangement by use of the information on the vertical and horizontal scanning mirror movement, for example from signal
MMI, a video type signal VS representing the difference frequency reflected from specific parts of the object can be produced in image processer IP and an image displayed or recorded in known manner, to represent the small movements at or within the target.
In Figure 1 a display unit DU responds to signal VS to provide an image IA of part or all of a target and, by way of example, a forearm is shown. On image IA a reference patch Is indicated at RP and the shaded area FI is a flow image which can show in "false colour" the blood flow pattern with greater movement coloured differently from lesser movement in a range of distinct movement values. Clearly to form the image from signal
VS suitable signal processing may be required. For example the signal may have to be stored until a complete frame has been covered by the scanning process. Srorage and processing can be in asuitably-arranged microprocessor or other equipment.
In the specific use to determine blood flow pattern in a body such an image shows distinctly areas in which blood flow is more than in others. Light returned scattered from the skin gives the information about the movement of the body as a whole and enables the removal of information that could confuse the image. In this way the effect of body movement can be cancelled or overcome.
By use of different laser colours (wavelengths) for beam B it is possible to distinguish between blood flow close to the surface of a body (green light) and flow some 2 millimeters below the surface (infra red light). This Is believed to be adequate to determine all relevant blood flow and to be more useful than present imagine techniques which are not depth selective to this degree.
The proper movement of the mirror SM is important to the effective performance of the technique.
Figure 2 shows a suitable linkage to produce the required movement. An arrangement of three levers L1, L2 and L3 is supported at two fixed pivots FP1, FP2 and joined at pivots Pl, P2. Lever L1 extends from pivot FP1 to Pl, lever L2 extends from pivot P1 to pivot P2 and lever L3 extends from pivot P2 to pivot
FP2. Lever L3 extends to a fork FR. Lever L2 has a central slot
SL which receives a crank pin CP. Crank pin CP is driven on a circular path by drive motor DM (Figure 1). The circular movement of crank pin CP in slot SL moves lever L2 to-and-fro on levers L1 and L3, moving on the fixed pivots. Fork FR is thus given a to-and-fro motion.Within fork FR is a wheel W carried on a connecting link CL, pivotted at pivot P3, which link carries the mirror SM, and this mirror in turn is given a swinging motion. Drive motor DM is specifically a d.c. motor so that a smooth swinging motion is produced. The tilting motion Is step-wise so a stepper motor is suitable. If a stepper motor is used it may be possible to derive adequately accurate Information about mirror tilt directly from the drive Information for the stepper motor, thus saving a position indicator.
By suitable choice of dimensions the motion of the mirror is sufficiently linear over an adequate swing to produce the scanning action. In Figure 2:
FPl-Pl = FP2-P2 = 22 millimetres,
FP2-P3 = 144 millimetres,
CL, from P3 to the centre of the wheel 'W', has a length of 132 millimetres,
radius of motion of CP 1 15 millimetres,
the scanning angle of mirror SM is about i6c and the diameter about 150 millimetres in the described embodiment.
Figure 3 shows the circuit diagram for one circuit arrangement for processing the signal from the receiving device.
The component types and values are given in widely-understood nomenclature and by way of example to enable one skilled In the art to produce a suitable circuit with modifications appropriate in a particular embodiment of the invention. Accordingly well-known features such as power supply and constructional techniques will not be described in detail.
A laser power of about one milliwatt is adequate and "intrinsically safe" lasers are suitable. In one embodiment the laser was a Mells Griot Model OSLHR 111 which has a minimum power of one milliwatt and an actual power of about two milliwatts.
As shown in the circuit portion ODU (optical detector unit) the combined outputs from the upper pair of diodes and the combined outputs from the lower pair are taken in parallel to respective amplifiers ODA1, ODA2. This unit is conveniently close to the diodes, which are in a light-tight box. The outputs from these amplifiers are supplied as inputs to respective differential amplifiers DAl, DA2 in circuit portion DAS (differential amplifiers stage). As shown the differential amplifiers are a.c. coupled and have a balance control to permit adjustment to compensate for optical and electrical channel differences. The differential amplifier arrangement provides cancellation of correlated signals which reduces the effect of laser "noise", which is common to both input channels.This also reduces the effect of large changes in signal intensity on passing between light and dark areas on a target during scanning. The scatter-related frequencies of the returned collected light produce an interference pattern in space which is not spatially correlated. The detectors are not at one point in space so their outputs are uncorrelated and are amplified in the circuit. The arrangement thus allows the scatter-related information to pass through as this is uncorrelated.
The output from the differential stage DAS is supplied to a filter (BLF) to limit bandwidth and a filter (FWR) having a frequency weighted response.
The bandwidth filter has the range 230Hz to 4800Hz in the arrangement described. Below 230Hz scanning effect artefacts occur and there are power frequency components at 50Hz (or 60Hz) and harmonics, especially 100Hz (or 120Hz) from lighting. Above about 5000Hz the scatter-related spectrum strength is small with respect to circuit noise.
The frequency weighted response filter FWF basically has a response of gain increasing proportionally with frequency over the bandwidth of interest. By about 10,000Hz the gain has risen to a value of about 10, which does not increase as the frequency increases further.
The r.m.s. to d.c. converter RMS/DC produces an output of a d.c. voltage proportional to the true r.m.s. value of the output waveform from filter FWF. This waveform is the frequency weighted scatter-related spectrum together with circuit noise.
The converter output is thus a measure of the power in the spectrum and of the circuit noise. In the d.c. amplifier DCA the lOOK resistor to the +12v line compensates for most of the offset due to circuit noise and gives more effective use of the range of the converter RMS/DC.
The output of d.c. amplifier DCA is applied to one of two identical output filters OPF1, OPF2, in this case OPF1. Each filter has a cut-off frequency of 160Hz to optimise the outputs having regard to the pixel rate. This reduces image noise without unduly affecting resolution.
A further output from the optical detector ODU is supplied through an intensity amplifier IA to the other filter, OPF2.
The output from filter OPF1 can be considered as the "raw" flow signal and includes not only the scatter-related information but also the noise in the detectors and circuit. The shifts in frequency in the scattered light are the result of the Doppler effect on the frequency of the incident light when scattered by a moving object. The relative directions of movement are also significant.
The chief source of noise, shot noise in the photodlodes, is dependent on the intensity of incident radiation. Compensation for this is achieved by determining the relation between intensity of Incident radiation and noise power in the flow signal. By illuminating the photodetectors in the absence of the scanning laser with a gradually Increasing illumination and noting the "raw" output and the intensity output a correction relationship for use when the photodetectors are used to detect scanned radiation can be produced. A computer can be arranged to determine the correction relationship and apply this to correct the signal in use, as will be understood by those skilled in the art.
Another correction can be made to compensate for the fall-off in signal when scanning at an angle to the surface of a target, such as the corners of rounded targets. As the intensity signal falls the flow signal can be proportionally Increased, i.e. by dividing the raw signal by the intensity signal. This correction appears to be reasonably independent of the angle of incidence at the rounded corners.
A typical scanning speed is 5 millseconds per pixel, where there are 250 pixels per line and 250 lines. At this speed one scan of a target, say a human torso, takes about six minutes.
While the target must not move about during this time the arrangement can cope with the normal small movements made by a person sitting on a chair.
Measurements have been made using a test rig to estimate the accuracy of the technique. Over a flow range of 5 to 50 millilitre per hour a reasonably linear characteristic was obtained, the intensity compensation being used. Measurements also showed that the corner compensation produced satisfactory results.
In the above described embodiment the scanning arrangement can examine a target object about one metre high and half a metre wide placed about two metres away. The "depth of field" is about half a metre at the two metre distance. A field of examination such as this means that a torso or limb can be scanned in one action. Other target sizes and shapes can be handled by suitable and readily-apparent adjustment of arrangement. Smaller and larger targets can be handled and the scan fitted to give an image that fills a display screen.
Some problems arise at the edges of the object if this curves away. However it is possible for a clinician to allow for this in interpreting the image produced, also signal processing can be used to compensate for the effect, as mentioned above.
The techniques described above, by way of non-limiting examples, permit the rapid determination of blood flow in a person without invasion or even contact and will provide considerable assistance to practitioners.
Claims (24)
1. A method of determination of blood flow including:
projecting a beam of laser generated light to move over a surface beneath which blood flow in a vessel or vascular bed is to be determined,
collecting light returning scattered from the beam by the surface and by blood flowing beneath,
measuring a spectrum of frequencies in said collected light,
determining from differences in said frequencies blood flow in a vessel or vascular bed beneath said surface.
2. A method according to Claim 1 including:
presenting said determined blood flow as an image of the surface coloured or shaded in accordance with a scale of blood flow.
3. A method according to Claim 1 including:
causing said beam to move in two directions over the surface.
4. A method according to Claim 1 including:
providing a reference for the detected frequencies of light returned from the surface for the determination of blood flow beneath the surface.
5. A method according to Claim 1 including:
producing from said determined blood flow a map of blood flow for a given area of said surface.
6. A method of determination of blood flow including:
generating and projecting a beam of laser light,
causing said beam of light to move over a surface beneath which blood flow in a vessel or vascular bed is to be determined,
collecting light returning scattered from the beam by the surface and by blood flowing beneath,
detecting scatter-related frequencies in said collected light,
determining from beam-motion information, surface reference information and said frequencies blood flow in a vessel or vascular bed beneath said surface.
7. A method according to Claim 6 including:
projecting said beam over a space of two metres to a target surface in an area of one metre by half a metre.
8. A method according to Claim 6 including:
providing from the detected frequencies of light returned from the surface a reference for the determination of blood flow beneath the surface against movement of said surface.
9. A method according to Claim 6 including:
causing said beam to move in two directions over the surface,
producing from said determined blood flow a map of blood flow for a given area of said surface coloured or shaded in accordance with a scale of blood flow.
l0.A method according to Claim 6 including:
causing said beam to move over the surface in a raster scan.
ll.A method according to Claim 6 including:
providing one raster direction scan motion by a smooth linkage drive, the other by a stepper motion.
12.A method according to Claim 6 including:
reflecting the beam in a movable mirror,
driving the mirror smoothly to-and-fro in one direction of the raster and driving the mirror step-wise in another direction between said smooth drives.
13.A method according to Claim 6 including:
providing from means causing beammotion a beam-motion information signal for use in said determination of blood flow.
14.Apparatus to determine blood flow including a low-noise laser, means to direct a beam of light from said laser to a target, means to scan the directed beam over said target, means to collect light from the beam returned from said target, means to detect frequencies in said collected light, means responsive to the action of the means to scan said beam and to detected collected light frequencies to determine localised target velocity information related to the scan over the target and to provide said information as a scan-based signal.
15. Apparatus according to Claim 14 including means to present said scan-based information as an image of localised velocity information for the target.
16. Apparatus according to Claim 14 in which the velocity information is information about blood flow below the surface of the target.
17. Apparatus according to Claim 14 in which the blood flow velocity information is presented as a false-colour image of the blood flow in the target.
18. Apparatus according to Claim 14 in which the means to detect returned light is an array of detectors.
19. Apparatus according to Claim 18 in which the laser beam is arranged to pass through an aperture in the array and then along a path also used for the returned light.
20. Apparatus according to Claim 14 in which the returned light frequencies include those representing overall movement of the target and these provide a reference for determination of localised velocity information.
21. Apparatus according to Claim 14 in which the means to scan the directed beam include means to drive a mirror directing the beam in a steady swinging motion and a stepwise tilting motion.
22. Apparatus according to Claim 18 in which the detectors are four in number arranged in pairs, the output of detectors in a pair are added to give two combined outputs which are then differenced to provide a signal representing frequencies in said collected light.
23.A method of determination of blood flow including detecting scatter-related frequencies in collected light, substantially as herein described with reference to the accompanying drawings.
24.Apparatus to determine blood flow including means to collect scatter-related frequencies in light returned from a target as blood flow information, substantially as herein described with reference to the accompanying drawings.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB898907101A GB8907101D0 (en) | 1989-03-29 | 1989-03-29 | Blood flow determination |
Publications (3)
Publication Number | Publication Date |
---|---|
GB9006882D0 GB9006882D0 (en) | 1990-05-23 |
GB2231742A true GB2231742A (en) | 1990-11-21 |
GB2231742B GB2231742B (en) | 1994-02-02 |
Family
ID=10654131
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB898907101A Pending GB8907101D0 (en) | 1989-03-29 | 1989-03-29 | Blood flow determination |
GB9006882A Expired - Lifetime GB2231742B (en) | 1989-03-29 | 1990-03-28 | Blood flow determination |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB898907101A Pending GB8907101D0 (en) | 1989-03-29 | 1989-03-29 | Blood flow determination |
Country Status (7)
Country | Link |
---|---|
US (1) | US5588437A (en) |
EP (1) | EP0465524B1 (en) |
JP (1) | JP3239952B2 (en) |
DE (1) | DE69032618T2 (en) |
GB (2) | GB8907101D0 (en) |
IL (1) | IL93909A (en) |
WO (1) | WO1990011044A1 (en) |
Families Citing this family (36)
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1989
- 1989-03-29 GB GB898907101A patent/GB8907101D0/en active Pending
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1990
- 1990-03-27 IL IL9390990A patent/IL93909A/en not_active IP Right Cessation
- 1990-03-28 GB GB9006882A patent/GB2231742B/en not_active Expired - Lifetime
- 1990-03-28 WO PCT/GB1990/000459 patent/WO1990011044A1/en active IP Right Grant
- 1990-03-28 DE DE69032618T patent/DE69032618T2/en not_active Expired - Lifetime
- 1990-03-28 EP EP90905231A patent/EP0465524B1/en not_active Expired - Lifetime
- 1990-03-28 JP JP50517490A patent/JP3239952B2/en not_active Expired - Lifetime
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GB1564315A (en) * | 1976-04-01 | 1980-04-10 | Secr Defence | Method and apparatus for measuring retinal blood flow |
GB2021759A (en) * | 1978-04-24 | 1979-12-05 | Univ Hokkaido | Optical somatomeasuring apparatus |
GB2069284A (en) * | 1979-10-31 | 1981-08-19 | Secr Defence | Measuring retinal blood flow |
GB2132852A (en) * | 1982-12-11 | 1984-07-11 | Zeiss Stiftung | Method and apparatus for forming an image of the ocular fundus |
Also Published As
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DE69032618D1 (en) | 1998-10-08 |
IL93909A (en) | 1999-10-28 |
US5588437A (en) | 1996-12-31 |
GB2231742B (en) | 1994-02-02 |
GB9006882D0 (en) | 1990-05-23 |
EP0465524A1 (en) | 1992-01-15 |
WO1990011044A1 (en) | 1990-10-04 |
JP3239952B2 (en) | 2001-12-17 |
JPH04504213A (en) | 1992-07-30 |
IL93909A0 (en) | 1990-12-23 |
GB8907101D0 (en) | 1989-05-10 |
DE69032618T2 (en) | 1999-01-28 |
EP0465524B1 (en) | 1998-09-02 |
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PE20 | Patent expired after termination of 20 years |
Expiry date: 20100327 |