EP0610428A1 - Systeme de commande et de controle musculaires - Google Patents

Systeme de commande et de controle musculaires

Info

Publication number
EP0610428A1
EP0610428A1 EP92924167A EP92924167A EP0610428A1 EP 0610428 A1 EP0610428 A1 EP 0610428A1 EP 92924167 A EP92924167 A EP 92924167A EP 92924167 A EP92924167 A EP 92924167A EP 0610428 A1 EP0610428 A1 EP 0610428A1
Authority
EP
European Patent Office
Prior art keywords
muscle
assist system
cardiac assist
skeletal muscle
cardiac
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.)
Withdrawn
Application number
EP92924167A
Other languages
German (de)
English (en)
Inventor
Pierre André GRANDJEAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medtronic Inc
Original Assignee
Medtronic Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Medtronic Inc filed Critical Medtronic Inc
Publication of EP0610428A1 publication Critical patent/EP0610428A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36042Applying electric currents by contact electrodes alternating or intermittent currents for stimulation of grafted tissue, e.g. skeletal muscle
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/80Constructional details other than related to driving
    • A61M60/855Constructional details other than related to driving of implantable pumps or pumping devices
    • A61M60/871Energy supply devices; Converters therefor
    • A61M60/882Devices powered by the patient, e.g. skeletal muscle powered devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/10Location thereof with respect to the patient's body
    • A61M60/122Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body
    • A61M60/126Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body implantable via, into, inside, in line, branching on, or around a blood vessel
    • A61M60/148Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body implantable via, into, inside, in line, branching on, or around a blood vessel in line with a blood vessel using resection or like techniques, e.g. permanent endovascular heart assist devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/10Location thereof with respect to the patient's body
    • A61M60/122Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body
    • A61M60/165Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body implantable in, on, or around the heart
    • A61M60/191Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body implantable in, on, or around the heart mechanically acting upon the outside of the patient's native heart, e.g. compressive structures placed around the heart
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/20Type thereof
    • A61M60/289Devices for mechanical circulatory actuation assisting the residual heart function by means mechanically acting upon the patient's native heart or blood vessel structure, e.g. direct cardiac compression [DCC] devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/40Details relating to driving
    • A61M60/465Details relating to driving for devices for mechanical circulatory actuation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/50Details relating to control
    • A61M60/508Electronic control means, e.g. for feedback regulation
    • A61M60/515Regulation using real-time patient data
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/80Constructional details other than related to driving
    • A61M60/839Constructional details other than related to driving of devices for mechanical circulatory actuation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/362Heart stimulators
    • A61N1/365Heart stimulators controlled by a physiological parameter, e.g. heart potential
    • A61N1/36514Heart stimulators controlled by a physiological parameter, e.g. heart potential controlled by a physiological quantity other than heart potential, e.g. blood pressure
    • A61N1/36557Heart stimulators controlled by a physiological parameter, e.g. heart potential controlled by a physiological quantity other than heart potential, e.g. blood pressure controlled by chemical substances in blood
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/05General characteristics of the apparatus combined with other kinds of therapy
    • A61M2205/054General characteristics of the apparatus combined with other kinds of therapy with electrotherapy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/33Controlling, regulating or measuring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/33Controlling, regulating or measuring
    • A61M2205/3303Using a biosensor
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00Measuring parameters of the user
    • A61M2230/04Heartbeat characteristics, e.g. ECG, blood pressure modulation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00Measuring parameters of the user
    • A61M2230/20Blood composition characteristics
    • A61M2230/205Blood composition characteristics partial oxygen pressure (P-O2)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00Measuring parameters of the user
    • A61M2230/60Muscle strain, i.e. measured on the user
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/20Type thereof
    • A61M60/247Positive displacement blood pumps
    • A61M60/253Positive displacement blood pumps including a displacement member directly acting on the blood
    • A61M60/268Positive displacement blood pumps including a displacement member directly acting on the blood the displacement member being flexible, e.g. membranes, diaphragms or bladders
    • A61M60/274Positive displacement blood pumps including a displacement member directly acting on the blood the displacement member being flexible, e.g. membranes, diaphragms or bladders the inlet and outlet being the same, e.g. para-aortic counter-pulsation blood pumps

Definitions

  • the present invention relates generally to cardiac assist systems and more particularly, relates to control and monitoring of cardiac assist systems which are powered by skeletal muscle.
  • a technique holding a great deal of promise is to power the cardiac assist system from a surgically modified skeletal muscle.
  • the cardiac assist system is thus powered by normal biochemical processes.
  • U.S. Patent No. 4,813,952 issued to Khalafalla teaches a number of configurations of a skeletal muscle powered cardiac assist system.
  • One problem peculiar to a skeletal muscle powered cardiac assist system is that the skeletal muscle must be conditioned to with stand the constant load of continuous contraction/relaxation demanded of the myocardium.
  • U.S. Patent No. 4 ,411,268 issued to Cox teaches a technique for conditioning the skeletal muscle.
  • One embodiment of the present invention employs a chronically i plantable oximeter which is positioned within the skeletal muscle of a cardiac assist system. It is preferably a two wave length reflectance oximeter which measures the relative oxygen level within the skeletal muscle as it powers the cardiac assist system.
  • the two wavelength reflectance signal is sent to be processed within the implantable pulse generator of the cardiac assist syste .
  • Circuitry which is internal to the implantable pulse generator determines the relative oxygen level and performs a trend analysis concerning the chronic sufficiency of the vascularization of and circulatory support to the skeletal muscle.
  • This data is stored in memory within the implantable pulse generator. This memory may be interrogated by medical personnel using telemetry to obtain status and trend information concerning the cardiac assist system.
  • the data may be analyzed by medical personnel to determine the effectiveness of conditioning, the sufficiency of maintenance stimulation, the adequacy of vascularization, and the chronic prognosis for the cardiac assist system. This enables the medical personnel to manually modify the conditioning regimen, change the maintenance stimulation, institute various drug therapies, and plan for necessary surgical intervention.
  • a chronically biocompatible pressure transducer is implanted within the skeletal muscle tissue.
  • This transducer produces electrical signals sufficient to enable an implantable pulse generator to measure the timing and extent of contraction and relaxation of the skeletal muscle in the performance of cardiac assistance.
  • the timing indications are important because they permit the implantable pulse generator to stimulate the skeletal muscle at the appropriate time to optimize the assist.
  • contraction of the skeletal muscle should be delayed until immediately following contraction of the myocardium. Contraction of the skeletal muscle during the contraction of the myocardium will increase rather than decrease the load on the human heart.
  • the stimulation should cause simultaneous contraction to achieve maximum benefit.
  • Measurement of timing and extent of skeletal muscle contractions permits the implantable pulse generator to monitor and control the conditioning regimen. This is important from a system viewpoint as it permits efficient energy utilization, as various phases of the conditioning process require the use of substantial stimulation energy. Such monitoring and control are important medically, because prior to complete conditioning, the skeletal muscle will readily fatigue, possibly resulting in excess loading of the myocardium.
  • An additional embodiment of the present invention employs a sensor to determine cardiac demand.
  • this is an activity sensor although other types of sensors may be used, such as blood oxygen level.
  • the duty cycle is lowered to improve overall efficiency.
  • the duty cycle is increased ensuring that the patient's heart obtains greater assistance at higher loads. Above a very high rate, the duty cycle is again decreased to improve overall hemodynamic efficiency and as a safety measure.
  • the nature of the skeletal muscle stimulation is also changed with cardiac demand. At low demand levels, the number of pulses in a given burst and the amplitude are decreased to improve efficiency. As demand is increased, pulse count and amplitude are increased to increase the amount of cardiac assistance. Pulse count and amplitude are again decreased at excessively high cardiac rates as a safety measure.
  • a further embodiment of the present invention employs a chronically implantable temperature sensor which is positioned within the skeletal muscle of a cardiac assist system.
  • the sensor preferably employs a thermoresistive device, such as a thermistor, coupled to the implantable pulse generator of the cardiac assist system.
  • a circuit in the implantable pulse generator senses the changes in resistance of the thermistor which correspond to temperature changes within the skeletal muscle.
  • the implantable pulse generator is thus able to monitor the efficiency of the work output of the skeletal muscle.
  • Circuitry within the implantable pulse generator changes the timing and characteristics of the generated pulses in relation to naturally occurring and paced heart contractions to optimize muscle activity. This improves the efficiency of the cardiac assist system by minimizing parasitic heat production. It also ensures that the myocardium obtains maximum assistance from contractions of the skeletal muscle.
  • FIG. 1 is a first embodiment of the present invention wherein the skeletal muscle is wrapped about the myocardium;
  • FIG. 2 is an alternative embodiment of the present invention wherein the skeletal muscle is wrapped about the descending aorta;
  • FIG. 3 is an alternative embodiment of the present invention wherein the skeletal muscle performs counter pulsation of the descending aorta;
  • FIG. 4 is a plan view of an oximetry probe
  • FIG. 5 is a block diagram of a implantable pulse generator
  • FIG. 6 is a graphical representation of the oximetry return in an oxygen sufficient environment
  • FIG. 7 is a graphical representation of the oximetry return in an oxygen insufficient environment
  • FIG. 8 is a plan view of an implantable pressure transducer
  • FIG. 9 is a block diagram of an alternative embodiment of the implantable pulse generator.
  • FIG. 10A is a graph of stimulation pulses applied to the unconditioned muscle
  • FIG. 10B is the contraction pattern resulting from the stimulation of Fig. 6A;
  • FIG. IOC is the waveform of the contraction as viewed by the pressure sensor
  • FIG. 10D is the differentiated pressure sensor signal showing that the skeletal muscle is unconditioned
  • FIG. HA is a graph of stimulation signals applied to the conditioned muscle
  • FIG. 11B is the contraction pattern resulting from the stimulation of Fig. 11A;
  • FIG. lie is the waveform of the contraction as viewed by the pressure sensor;
  • FIG. 11D is the differentiated pressure sensor signal showing that the skeletal muscle is fully conditioned
  • FIG. 12 shows the timing relationship between the cardiac pacing pulse and skeletal muscle stimulation signals for the embodiments of Figs. 1, 2, and 3;
  • FIG. 13 is a block diagram of an alternative embodiment of the implantable pulse generator
  • FIG. 14 is a graphical representation of pulse amplitude as a function of activity level
  • FIG. 15 is a graphical representation of pulses per burst as a function of activity level
  • FIG. 16 is a graphical representation of synchronization ratio as a function of activity level
  • FIG. 17 is a graphical representation of stimulation rate as a function of cardiac rate with decreasing synchronization ratio
  • FIG. 18 is a plan view of a sensing lead with temperature sensor attached;
  • FIG. 19 is a block diagram of an alternative embodiment of the implantable pulse generator;
  • FIG. 20 is a graphical representation of the timing relationship between contractions of the human heart and the pulses produced by the implantable pulse generator;
  • FIG. 21 is a graphical representation of the force produced by conditioned and unconditioned skeletal muscle;
  • FIG. 22 is a graphical representation of the temperature sensed for unconditioned, conditioned but improperly timed, and conditioned and properly timed skeletal muscle contractions; and FIG. 23 is a graphical representation of the change in temperature over time for conditioned and unconditioned skeletal muscle.
  • the present invention employs one or more sensors implanted within the skeletal muscle of a skeletal muscle- powered cardiac assist system to chronically monitor the adequacy of circulatory support.
  • the cardiac assist system may be configured in a variety of ways as described in U.S. Patent No. 4,813,952 issued to Khalafalla, herein incorporated by reference. Several of these configurations are discussed herein by way of illustration and are not intended to limit the present invention.
  • FIG. l is an embodiment of the present invention wherein skeletal muscle 22 is wrapped about human heart 100.
  • Skeletal muscle 22 is conditioned as a "slow twitch" muscle as described by Cox in- U.S. Patent No. 4,411,268, herein incorporated by reference.
  • Implantable pulse generator 36 is coupled to pacing lead 34 to produce a demand pacemaker as taught by Cox.
  • implantable pulse generator 36 stimulates skeletal muscle 22 to contract in synchrony with human heart 100. Assistance to human heart 100 is provided by the simultaneous contraction of skeletal muscle 22 to increase systolic pressure in descending aorta 102 and elsewhere in the circulatory system.
  • a sensor 106 is implanted upon or within skeletal muscle 22 to determine the adequacy of chronic support.
  • the data measured by sensor 106 is transferred to implantable pulse generator 36 via lead 104 where it is processed, stored, and may be telemetered percutaneously using normal implantable pulse generator telemetry circuitry for analysis by medical personnel.
  • implantable pulse generator 36 may also employ activity sensor 105 in addition to the other sensors.
  • the activity sensor input is used by implantable pulse generator 36 to adjust the various parameters of the skeletal muscle stimulation regimen as explained below.
  • the parameters to be adjusted include duty cycle, and pulse width, amplitude, count and interval.
  • FIG. 2 is an alternative embodiment of the present invention.
  • skeletal muscle 22 is wrapped about artificial chamber 20 inserted in series with descending aorta 102.
  • implantable pulse generator 36 stimulates skeletal muscle 22 to contract following evacuation of human heart 100. This is accomplished by the insertion of a delay between a paced or sensed beat of human heart 100 and the stimulation of skeletal muscle 22.
  • FIG. 3 is a further embodiment wherein artificial chamber 20 is coupled external to descending aorta 102.
  • skeletal muscle 22 is stimulated to counter pulse human heart 100. This raises diastolic pressure, thereby increasing perfusion of human heart 100. This is accomplished by the insertion by implantable pulse generator 36 of a sufficient delay between a sensed or paced contraction of human heart 100 and stimulation of skeletal muscle 22 to cause the desired counter pulsation.
  • FIG. 4 is a plan view of lead 104 wherein sensor 106 employs an oximeter for measuring adequacy of oxygen level within skeletal muscle 22.
  • U.S. Patent No. 4,813,421 issued to Baudino, et al. herein incorporated by reference, describes in greater detail the preferred embodiment of an oximeter probe within sensor 106 and lead 104.
  • Lead 104 is a typical chronically implantable lead. It contains an insulated, bifurcated proximal connector assembly 220 which sealingly plugs into implantable pulse generator 36. The proximal end of connector assembly 220 contains terminal pins 224 and 226. A third conductor within lead 104 is terminated at ring terminal 222. The main body of lead 104 is covered with biocompatible outer sheath 218 of silicone rubber or polyurethane. Anchoring sleeve 228 facilitates securing of the proximal end of lead 104 in the manner well-known in the art.
  • FIG. 5 is an overall block diagram of the circuitry within implantable pulse generator 36 for embodiments employing an oxygen sensor.
  • Demand pacer 300 is constructed according to circuitry known in the art of pacing and communicates with human heart 100 via lead 34.
  • Demand pacer 300 notifies delay logic 302 via line 360 of a contraction of human heart 100. This may be the result of either a sensed natural heart contraction or an artificially generated pacing pulse. In either situation, delay logic 302 generates a delay appropriate to the particular embodiment (see above) and signals stimulation generator 304 by line 358 to stimulate skeletal muscle 22 via lead 32: Stimulation generator 304 may also contain muscle conditioning circuitry, which is not shown for clarity. U.S. Patent No. 4,411,268 issued to Cox should be consulted for a more detailed description of skeletal muscle conditioning. Delay logic 302 also provides timing 308 with a begin sensing signal via line 338.
  • Timing 308 notifies voltage driver 306 via lines 334 and 336 when to energize infrared LED 312 and red LED 314, respectively.
  • Current driver 310 coupled via common line 362 to voltage driver 306, maintains the illumination of each LED to enable photosensor 316 to measure the reflected return.
  • Infrared LED 312, red LED 314, and photosensor 316 are all located within sensor 106 and coupled to implantable pulse generator 36 by lead 104 as shown.
  • Lines 364, 366, and 368 comprise the three conductors of lead 104 (see also Fig. 4) .
  • the sensed return of photosensor 316 is transferred to current mirror 318 via line 368 for processing. After processing, the resultant is transferred to IR sample and hold 332 and red sample and hold 330 by line 346. The signal is gated to the proper sample and hold circuit by timing 308 using gating signals on lines 340 and 342.
  • IR/RR division network 328 compares the infrared and red signals received via lines 344 and 348 to sense color shifts.
  • the periodic sensor outputs of IR/R division network 328 are sent by line 350 to memory 322 for storage awaiting readout by medical personnel.
  • Each measured signal is time tagged by the output of real time clock 320 on line 352.
  • Medical personnel can access the time-tagged sensor data stored in memory 322 by telemetry techniques common in the implantable device field. Preferably this access is via a radio frequency signal prepared by telemetry transmitter ' 324 as modulated with data received on line 356 from memory 322. This radio frequency signal is transmitted by radio frequency antenna 326. The signal is received outside of the body by antenna 402, demodulated by telemetry receiver 404 and processed and presented to medical personnel by programmer 400 in the manner known in the art.
  • implantable pulse generator 36 is through the use of a microprocessor controlled general purpose implantable pulse generator such as PrometheusTM pulse generator manufactured by Medcronic, B.V. of the Netherlands.
  • a microprocessor controlled general purpose implantable pulse generator such as PrometheusTM pulse generator manufactured by Medcronic, B.V. of the Netherlands.
  • the primary advantage of such an implementation is the ease with which such a programmable device can change modes of operation. This is particularly useful when doing clinical research.
  • a description of the use of such a device may be found in the paper "Pulse Generator for Biomechanical Cardiac Assistance by Counter- Pulsation Technique", by Grandjean, et al. , published in the "Record of the Conference on Skeletal Muscle for cardiac
  • FIG. 6 is a graphical representation 406 of the sensed signals from a skeletal muscle 22 which is adequately supported by the vascular system.
  • the amplitude of the reflected light 408 is relatively sharply peaked within the region of visible red wavelengths 410.
  • This indication when read from memory 322 via telemetry indicates that skeletal, muscle 22 was receiving sufficient support for its workload at the time tag of the sensor reading.
  • a complete series of such signals stored within memory 322 verifies that skeletal muscle 22 continues to be healthy.
  • FIG. 7 shows the response 412 of sensor 106 when skeletal muscle 22 is not adequately supported by the vascular system.
  • the amplitude of reflected light 414 is shifted to the blue wavelengths 416 and is not sharply defined.
  • Medical personnel upon seeing this indication from memory 322 will conclude that skeletal muscle 22 is not receiving sufficient oxygen for its workload. Continuation of this state indicates a high risk of ischemia to a portion or all of skeletal muscle 22.
  • Immediate medical action includes reduction of the physical load on skeletal muscle 22 by reducing the duty cycle of stimulation pulses. Total cessation of stimulating pulses will place skeletal muscle 22 at rest without any load. Skeletal muscle 22 may respond to additional conditioning as taught by Cox. In severe cases, surgical intervention may be required.
  • FIG. 8 is a plan view of sensor 106A employing a chronically implantable pressure transducer within sensor 106A.
  • This pressure transducer is preferably of the type disclosed in U.S. Patent No. 4,485,813 issued to Anderson, et al. , herein incorporated by reference.
  • the pressure transducer is piezoelectric.
  • Piezoresistive pressure sensors are disclosed in U.S. Patent No. 4,407,296 issued to Anderson and U.S. Patent No. 4,432,372 issued to Monroe, also incorporated by reference.
  • Pressure sensor 106A has a distal tip 10 at the end of hollow and rigid shank 12. Tines 11 are appended to aid in attachment. These work particularly well with transvenous pacing leads.
  • the pressure capsule 18 is hermetically sealed. Bore 16 provides fluid communication with pressure capsule 18. Because pressure capsule 18 uses a piezoelectric element, incident forces present produce a voltage across terminals 420 and 422. This signal is coupled to implantable pulse generator 36A via conductors 56 and 58 which run the length of lead 104.
  • FIG. 9 is a block diagram of implantable pulse generator 36A incorporating circuitry for processing the output of the pressure transducer.
  • the implantable pulse generator 36A contains two basic portions. The first of these is primarily a demand pacemaker 110, which is readily known in the art. Its components include terminal 114, which couples transvenous lead 34 to sense amplifier 112 via line 115 and also directs artificial pacing pulses from pulse generator 113 to the myocardial tissue. Sense amplifier 112 attempts ro detect naturally occurring heartbeats. If one is found, the artificial pacing pulse is inhibited.
  • Skeletal muscle 22 is coupled to implantable pulse generator 36A via terminal 121 which couples to electrical lead 32 to deliver the electrical stimulation energy.
  • This stimulation energy is supplied by pulse generator 120.
  • the signals used to condition skeletal muscle 22 are generated by conditioning generator 122 and supplied to terminal 121. The generation of such conditioning signals is discussed more extensively in U.S. Patent No. 4,411,268, issued to Cox, which is incorporated herein by reference.
  • Sensor logic 109 also notifies logic 119 via line 125 of the timing of the actual contraction of skeletal muscle 22. This permits logic 119 to properly time the stimulation signal to skeletal muscle 22 as explained below.
  • Trigger circuit 123 and OR-gate 118 function as described by Cox to time the generation of the. stimulation pulse to skeletal muscle 22 in relation to the contraction of human heart 100. A discussion of this timing for the various embodiments may be found below.
  • FIG. 10A shows the stimulation patterns used to perform the conditioning.
  • Skeletal muscle stimulation is different from cardiac stimulation in that the skeletal muscle does not have an all or nothing response to the electrical stimulus as does the myocardium.
  • the skeletal muscle exhibits a gradual recruitment of fibers with increases in pulse amplitude and pulse wi.dth.
  • Threshold for skeletal muscle 22 is the pulse amplitude/width needed to start muscle force recruitment.
  • Pulse 602 i ⁇ the stimulation pulse produced by pulse generator 120. It is generated to occur at the correct time in relation to the contraction of human heart 100.
  • pulse 602 must have a voltage greater than capture threshold 600.
  • Pulses 604, 606, 608, and 610 are conditioning pulses produced by conditioning generator 122. The pulse rate is dependent upon the specific nature of skeletal muscle 22 as taught by Cox, but it is typically in a range of 20-30hz. To optimally perform conditioning, pulses 604, 606, 608, and 610 have a voltage in excess of capture threshold 600.
  • FIG. 10B shows the response of unconditioned skeletal muscle 22 to receipt of pulses 602, 604, 606, 608, and 610. Notice that each produces a contractile force 614, 616, 618, 620, and 622, respectively. This occurs with unconditioned muscles which are known as "fast-twitch" muscles. A more detailed explanation may be found in the Cox reference.
  • FIG. 10C shows the response of pressure sensor 106A' to the contractions of Fig. 10B. These result in pressure peaks 624, 626, 628, 630, and 632, respectively.
  • FIG. 10D shows the result of differentiation by sensor processing 107 of the sensor signal of Fig. IOC. This differentiation produces sharp peak pairs 634, 636, 638, 640, and 642, respectively, indicating the inflection points. From this waveform, a simple analog filter and detector known to those in the art could easily determine that skeletal muscle 22 is unconditioned.
  • FIGS. 11A 11B, lie, and 11D show the corresponding waveforms for skeletal muscle 22 after complete conditioning.
  • the contractile response is shown in Fig. 11B as waveform 646. Notice that: individual conditioning pulses no longer produce major contractile peaks. This occurs because skeletal muscle 22 has been conditioned to act as a "slow-twitch" muscle, similar to myocardial tissue.
  • the conditioned response of Fig. 11B is sensed by pressure sensor 106A
  • the resulting waveform 648 of Fig. lie is produced.
  • Pulse 602 has a voltage in excess of capture threshold 600. This pulse which is produced by pulse generator 120, stimulates the contraction of skeletal muscle 22.
  • Conditioning pulses 604, 606, 608, and 610 (see also Fig. 10A) produced by conditioning generator 122 have been replaced by maintenance pulses 603, 605, 607, and 609, respectively. The maintenance pulses must yet have a voltage greater than capture threshold 600. However, because of the smoother contraction pattern of the conditioned skeletal muscle, . pulse width, pulse amplitude, pulse spacing and pulse number can be safely adjusted to save energy.
  • Conditioning generator 122 switches from conditioning pulses to maintenance pulses in response to a notification of a conditioning accomplished signal from sensor logic 109 via line 124.
  • FIG. 12 shows the timing relationship between stimulation of the myocardium and stimulation of skeletal muscle 22 for the various embodiments of Figs, l, 2, and 3. For simplicity it is assumed that all myocardial contractions are artificially stimulated by pacing pulses 700, 702, 704, and 706 at a fixed rate. These might also be natural contractions which inhibit the pacing pulse, but the rate would then not be constant.
  • stimulating pulses 708, 712, 716, and 720 occur at the same time as pacing pulses 700, 702, 704, and 706, respectively.
  • Maintenance pulse groups 710, 714, 718, and 722 occur as explained above.
  • the timing for this embodiment is easily accomplished for paced beats of human heart 100, since the timing is coincident.
  • stimulating pulses 708, 712, 716, and 720 are generated immediately upon sensing a naturally occurring R-wave.
  • Skeletal muscle 22 is stimulated by pulses 724, 728, 732, and 736 for the embodiment of Fig. 2. These are delayed for a period following the corresponding pacing pulse (or sensed R-wave) sufficient to enable human heart 100 to empty. Contraction of skeletal muscle 22 too soon will increase the load on human heart 100. A delay which is too long will cause skeletal muscle 22 to pump less than the optimal quantity of blood. The exact delay is easily measure by pressure sensor 106A as explained above. The delay may be made a function of rate, stroke volume, etc. It may be determined empirically by medical personnel or simply programmed to the nominal values known in the art. Stimulation pulses 740, 744, and 748 cause skeletal muscle 22 to counterpulse the descending aorta. This increases the total perfusion through the coronary system, thereby assisting human heart 100. These pulses are timed to occur approximately one-half heart cycle after contraction of human heart 100.
  • FIG. 13 is a block diagram of implantable pulse generator 36B having circuitry for processing the output of activity sensor 105. It includes a pacing generator 754 which operates in the demand mode as is known in the art. Basically, the electrical activity of the patient's heart is onitored via pacing lead 34. Whenever a naturally occurring contraction of the heart is found, sense amplifier 756 detects it and notifies pacing generator 754. If this naturally occurring contraction is sensed within the allotted time, the output of pacing generator 754 is inhibited. However, if pacing generator 754 determines that sufficient time has elapsed since the last contraction of the heart, it produces a pulse which is conveyed to the heart via pacing lead 34 to artificially stimulate the desired contraction.
  • pacing generator 754 determines that sufficient time has elapsed since the last contraction of the heart, it produces a pulse which is conveyed to the heart via pacing lead 34 to artificially stimulate the desired contraction.
  • stimulation generator 766 The main purpose of stimulation generator 766 is to produce a burst of pulses to cause contraction of skeletal muscle 22 in the proper timing relation to the contraction of the patient's heart. To do so, OR-gate 760 produces an output whenever sense amplifier 756 senses a naturally occurring contraction or pacing generator 754 supplies an artificial pacing pulse. In either situation, timing logic 762 is started to generate the desired amount of delay. This delay is nearly zero for the embodiment of Fig. l, because maximum assistance to the myocardium is provided when skeletal muscle 22 contracts at the same time as the heart.
  • the embodiment of Fig. 2 requires a much longer delay. This period is on the order of one-half of the cardiac cycle (i.e. R-to-R interval) .
  • the embodiment of Fig. 3 requires yet a slightly longer delay, being somewhat greater than one-half of the cardiac cycle. This is necessary because this embodiment is intended to increase diastolic pressure in the aorta.
  • the output of timing logic 762 is a pulse which is synchronous with the naturally sensed or artificially stimulated contraction of the patient's heart but delayed in time according to the specific embodiment as described above. This pulse is supplied to duty cycle timing circuit 764.
  • This circuit is simply a variable digital counter which produces an output corresponding to a variable number of pulses received from timing logic 762.
  • the normal output of duty cycle timing circuit 764 is one pulse for each pulse received from timing logic 762. This corresponds to the one-for-one stimulation mode of skeletal muscle 22. A lesser ratio of output pulses to input pulses is determined by overall cardiac rate and anticipated cardiac demand.
  • the anticipated cardiac demand may be determined in a number of ways known in the art of cardiac pacing. These include, without limitation, measurement of venous blood oxygen level, measurement of blood ph, determination of respiratory rate, computation of minute volume, and measurement of stroke volume.
  • the preferred mode of the present invention uses an activity sensor such as found in Medtronic Activitrax R pacemakers. Those of skill in the art will readily be able to substitute yet other sensors to determine anticipated cardiac demand.
  • an activity sensor 105 is mounted permanently to the housing of implantable pulse generator 36B.
  • This activity sensor is preferably a piezo ⁇ electric crystal which converts mechanical energy received at the housing of implantable pulse generator 36B to electrical energy. It has been shown in the literature that activity sensing in this way is a very good means for anticipating cardiac demand.
  • the output of activity sensor 105 is amplified and integrated by signal processing circuit 752. The result is a signal indicative cf anticipated cardiac demand which is transferred to duty cycle timing circuit 764.
  • The. output of duty cycle timing circuit 764 is a pulse train which is a variable number of counts of the output of timing logic 762. The exact relationship is described in more detail below.
  • Stimulation generator 766 receives the output of duty cycle timing circuit 764 and generates an output burst of energy corresponding to each of the output pulses of duty cycle timing circuit 764.
  • the number of pulses in this burst is determined in part by the output of signal processor 752 such that additional pulses are added to the burst when the anticipated cardiac demand becomes high.
  • Conditioning generator 768 supplies conditioning pulses as needed.
  • the stimulation pulses of stimulation generator 766 are combined with the conditioning pulses of conditioning generator 768 and supplied to skeletal muscle 22 by stimulation lead 32.
  • FIG. 14 is a graphical representation of a relationship between the pulse amplitude and the anticipated cardiac demand.
  • anticipated cardiac demand corresponds to the appropriate cardiac rate which is determined from the output of activity sensor 105. This is computed in the manner known in the art from U.S. Patent No. 5,479,402 issued to Anderson, et al.
  • points 502 and 504 correspond to very low and low anticipated cardiac demand, respectively. These are on the order of less than 70 beats per minute.
  • stimulation generator 766 supplies output pulses of minimum amplitude. These pulses must be greater than the stimulation threshold of skeletal muscle 22. However, considerable energy is saved through using an amplitude which is only slightly greater than this threshold.
  • Points 506 and 508 correspond to average and high anticipated cardiac demand, respectively. These correspond to rates in the range of 70 to 120 beats per minute although the exact values are patient dependent. At this demand level, the cardiac loading is sufficient to benefit from the additional amplitude and therefore additional assurance of capture. Point 510 is above 120 pulses per minute for most patients. Again notice that this is the anticipated cardiac demand and not the actual heart rate.
  • FIG. 15 is a graphical representation of the number of pulses in a given stimulation burst as a function of anticipated cardiac demand. The ranges along the abscissa are as explained above for most patients. Average and high anticipated cardiac demand again require the greatest number of pulses per burst and therefore the highest energy demand. The number of pulses per burst is decreased at very high anticipated demands because efficiency is impaired if the individual pulses occur too frequently.
  • FIG. 16 is a graphical representation of the synchronization ratio performed by the variable counter of duty cycle timing circuit 764.
  • a one-to-one synchronization ratio is used for average anticipated cardiac demand. This* provides the greatest chronic assistance to the myocardium with the least battery consumption by implantable pulse generator 36B.
  • the synchronization ratio is greater for less than average anticipated cardiac demand because less assistance is actually required.
  • the synchronization ratio increases as the anticipated cardiac demand increases to ensure the fatigue of skeletal muscle 22 is minimized.
  • FIG. 17 is a graphical representation of actual cardiac rates on the abscissa in relation to actual rates of stimulation of skeletal muscle 22 along the ordinate. Shown is the change in duty cycle with actual rate.
  • the duty cycle is one-for-one in the typical patient in the range of 50 to 100 beats per minute.
  • the actual cardiac rate is 100 beats per minute and the rate of stimulation of skeletal muscle 22 is 100 beats per minute. Above that rate, skeletal muscle 22 is stimulated only once for every two cardiac cycles.
  • the duty cycle becomes one stimulation of skeletal muscle 22 for every three cardiac cycles.
  • FIG. 18 is a plan view of lead 104 with temperature sensor 106B attached to the distal end.
  • the outer covering of lead 104 is outer sheath 156 which is of a chronically implantable biocompatible material such as medical grade silicone rubber or polyurethane.
  • the proximal end of lead 104 contains bifurcated connector 158 which sealingly inserts into implantable pulse generator 36C. Sealing ring pairs 160 and 162 complete the seal against the ingress of bodily fluids.
  • Lead 104 contains two electrically separated conductors which couple the thermistor of temperature sensor 106B with implantable pulse generator 36C. These two conductors are electrically coupled to terminal pins 164 and 166.
  • the distal end of lead 104 contains temperature sensor 106B.
  • thermoresistive device which is housed within rigid housing 154.
  • rigid • housing 154 is a titanium cylinder which is insulated inside and outside with medical grade silicone rubber.
  • the two terminals of the thermistor within rigid housing 154 are coupled to the two conductors within the body of lead 104.
  • the thermistor is thermally coupled to distal tip 150 of temperature sensor 106B which is preferably comprised of a biocompatible material such as titanium.
  • Distal tip 150 is not insulated to promote heat conduction to the thermistor of temperature sensor 106B and therefore must be of a biocompatible material.
  • Tine structures 152 assist in the chronic attachment of temperature sensor 106B within skeletal muscle 22.
  • FIG. 19 is a block diagram of the circuitry of implantable pulse generator 36C, which processes the output of temperature sensor 106B.
  • Pacing lead 34 electrically couples implantable pulse generator 36C to human heart 100 as is shown in Fig. 1.
  • Pacing generator 800 supplies artificial pacing pulses whenever it determines that a naturally occurring pacing event has not transpired at the correct time. Sensing for such a naturally occurring pacing event is facilitated by sense amplifier 802 which is coupled to pacing lead 34 via line 814. The amplified signal is sent to pacing generator 800 by line 816.
  • the amplified naturally occurring pacing signal is also sent to OR-gate 808 by line 818.
  • OR-gate 808 also receives an indication of an artificial pacing signal via line 820. In either event the output of OR-gate 808 on line 824 indicates the time at which a contraction of human heart 100 has been stimulated, whether naturally or artificially.
  • Timing logic 806 provides a signal via line 826 to notify stimulation generator 812 to produce a pulse to stimulate contraction of skeletal muscle 22. This signal occurs at a predetermined delay after the contraction of human heart 100. The exact amo nt of this delay is based upon two factors. The first of these is the configuration of the cardiac assist system. As explained above, this delay is necessary to provide the contraction of skeletal muscle 22 at the proper time relative to human heart 100.
  • Conditioning generator 810 provides the pulses used to condition skeletal muscle 22 as a "slow twitch" muscle as taught by Cox. These pulses are transferred to skeletal muscle 22 by line 828 and lead 32, along with the stimulation pulses of stimulation generator 812. After skeletal muscle 22 has been fully conditioned as taught by Cox, the conditioning pulses may be replaced by maintenance pulses which differ from conditioning pulses by their lower amplitude and hence lower power req irements. The change to maintenance pulses is triggered by signal processor 804 via line 830 under the conditions as discussed below.
  • Signal processor 804 is coupled to temperature sensor 106B by the two conductors of lead 104 as explained above. Signal processor 804 uses circuitry known in the art to measure the resistance of the thermistor of temperature sensor 106B, and therefore, the temperature of skeletal muscle 22. Based upon the temperature sensed, signals are sent via lines 822 and 830 to vary the delay of the stimulation pulses and change to maintenance pulses, respectively.
  • FIG. 20 is a graphical representation 900 of a single cycle containing a pacing pulse 902 occurring at time tl and the corresponding pulses transferred to skeletal muscle 22. Stimulation pulse 904 is that pulse which is intended to cause the primary contraction of skeletal muscle 22. It • occurs at time t2 following a delay 908.
  • delay 908 is a part determined by the configuration of the cardiac assist system and in part by signal processor 804.
  • conditioning/maintenance pulses 906 are generated at times t3a, t3b, t3c, and t3d. These pulses are produced by conditioning generator 810 in accordance with the teaching of Cox.
  • FIG. 21 is a graphical representation of the force of contraction of skeletal muscle 22 for one unconditioned cycle 918 and one conditioned cycle 910.
  • the force curve for the conditioned cycle 910 is smooth and continuous and is representative of a slow twitch muscle.
  • the force curve for the unconditioned cycle 918 is discontinuous and is characteristic of a fast twitch muscle.
  • Force peaks 912, 914, 916, and 920 are secondary contractions corresponding to the conditioning pulses, occurring at times t3a, t3b, t3c, and t3d, respectively. These specific curves show ideal responses. Actual measurement of these specific curves using a thermistor would probably be very difficult.
  • FIG. 21 is a graphical representation of the force of contraction of skeletal muscle 22 for one unconditioned cycle 918 and one conditioned cycle 910.
  • the force curve for the conditioned cycle 910 is smooth and continuous and is representative of a slow twitch muscle.
  • the force curve for the unconditioned cycle 918 is discontinuous and is
  • Temperature curve 919 corresponds to the ideal situation of a properly timed contraction of a fully conditioned skeletal muscle 22.
  • the two key characteristics of this curve are its smooth and continuous nature and the relatively low peak temperature at peak 922.
  • Temperature curve 921 is delayed somewhat and reaches a much higher temperature peak 923.
  • This higher temperature peak is readily sensed by signal processor 804 as an improperly timed stimulation pulse.
  • the higher temperature results from the much larger component of isometric and much smaller component of isotonic activity associated with the improperly timed contraction.
  • signal processor 804 Upon sensing this elevated temperature peak 923, signal processor 804 notifies timing logic 806 via line 822 to shorten delay 908 (see also Figs. 19 and 20) .
  • Temperature curve 924 is characteristic of an unconditioned skeletal muscle 22. This temperature curve
  • FIG. 23 is a graphical representation of the differentiated temperature curves 919 and 924 wherein curve 934 corresponds to curve 919 and curve 938 corresponds to curve 924.
  • signal processor 804 can much more readily distinguish between conditioned and unconditioned skeletal muscle 22. Because curve 934 represents fully conditioned skeletal muscle 22, it has a smooth and continuous temperature curve as explained above, and the corresponding differentiated curve has a single zero crossing at point 936. Differential curve 938, on the other hand, has zero crossings at 940, 944, 948, and 952. This is easily detected by signal processor 804 either digitally or by frequency discrimination using well known techniques.
  • the foregoing muscle control and monitoring methods and systems can also be used in various applications beyond monitoring skeletal muscles.
  • Exemplary applications include stimulating and training particular muscles to regain control of their deficient functions.
  • the foregoing methods can be used to stimulate the diaphragms, and the upper and lower limb muscles.
  • Other applications include assisting deficient organs, such in cardiomyoplasty or cardiac assist applications, and neo-sphincter applications where a transferred muscle is stimulated to augment or replace the sphincter function in incontinent patients.

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Abstract

Sont décrits un appareil et un procédé pour contrôler le fonctionnement du muscle squelettique utilisé dans un système d'assistance cardiaque mû par le muscle squelettique. Le contrôle à plus long terme est réalisé par un détecteur d'oxygène qui détermine l'adéquation de l'assistance circulatoire au muscle squelettique. Un muscle squelettique bénéficiant d'une assistance adéquate peut offrir chroniquement l'assistance cardiaque souhaitée. Une assistance insuffisante signifie que le muscle squelettique va se fatiguer facilement si l'on ne parvient pas à une vascularisation suffisante. Si l'assistance circulatoire est chroniquement insuffisante, le risque d'ischémie devient important et peut nécessiter une intervention chirurgicale supplémentaire. Une préoccupation à plus court terme réside dans l'adéquation de la préparation nécessaire pour pouvoir utiliser, à des fins d'assistance du myocarde à contraction lente, un muscle squelettique à contraction rapide. Un transducteur de pression sert à mesurer l'adéquation de la préparation. Un troisième type de contrôle donne une indication, à l'aide d'un détecteur d'activité, des variations des besoins cardiaques. Cette indication des besoins cardiaques peut être utilisée pour faire varier la sollicitation du muscle squelettique en réglant le cycle d'utilisation. La technique de contrôle et de commande à plus court terme met en oeuvre un détecteur de température pour surveiller l'efficacité de l'assistance cardiaque par le muscle squelettique. Cette efficacité peut être améliorée par l'ajustement de la relation de phases entre la contraction cardiaque et la stimulation du muscle squelettique.
EP92924167A 1991-10-31 1992-10-30 Systeme de commande et de controle musculaires Withdrawn EP0610428A1 (fr)

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CA2120617A1 (fr) 1993-05-13
AU3058092A (en) 1993-06-07
WO1993008874A1 (fr) 1993-05-13
JPH06510461A (ja) 1994-11-24

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