WO2009021111A1 - Améliorations de l'écoulement pour la délivrance de biomatériaux - Google Patents

Améliorations de l'écoulement pour la délivrance de biomatériaux Download PDF

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Publication number
WO2009021111A1
WO2009021111A1 PCT/US2008/072468 US2008072468W WO2009021111A1 WO 2009021111 A1 WO2009021111 A1 WO 2009021111A1 US 2008072468 W US2008072468 W US 2008072468W WO 2009021111 A1 WO2009021111 A1 WO 2009021111A1
Authority
WO
WIPO (PCT)
Prior art keywords
syringe
solution
needle
ultrasonic transducer
biomaterial
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.)
Ceased
Application number
PCT/US2008/072468
Other languages
English (en)
Inventor
Bart Lipkens
Jr. Walter M. Presz
Stanley Kowalski Iii
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.)
FloDesign Inc
Original Assignee
FloDesign 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 FloDesign Inc filed Critical FloDesign Inc
Publication of WO2009021111A1 publication Critical patent/WO2009021111A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/3129—Syringe barrels
    • A61M5/3134—Syringe barrels characterised by constructional features of the distal end, i.e. end closest to the tip of the needle cannula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/34—Constructions for connecting the needle, e.g. to syringe nozzle or needle hub
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/34—Constructions for connecting the needle, e.g. to syringe nozzle or needle hub
    • A61M5/347—Constructions for connecting the needle, e.g. to syringe nozzle or needle hub rotatable, e.g. bayonet or screw

Definitions

  • This invention relates in general to a flow delivery system that delivers a material such as a biomaterial into a body, and in particular to such a system for delivery of an aqueous solution containing solely a biomaterial or a mixture of a biomaterial and a biocompatible fluid lubricant, where such a system involves ultrasonic transducers, acoustic pulse and wave propagation, an acoustic radiation force, a contoured nozzle design for flow resistance reduction, and a control system that utilizes feedback control.
  • Medical procedures often involve the non-surgical implanting of biomaterials into the body.
  • a dermal filler material such as collagen
  • the biomaterial can be solid and load-bearing and is typically suspended as an aqueous solution of the biomaterial particles.
  • the solution is then injected with a syringe through a needle at the desired site.
  • a very fine needle e.g., 27 gauge (0.0075 inch ID) to 30 gauge (0.0055 inch ID)
  • These relatively small ID needles limit the diameter of the suspended particles that may pass through the needle orifice.
  • the diameter of the particle will typically range from 1-20 microns.
  • the size of the deformable asymmetric particles will usually be 500-800 microns in length and less than 20 microns in width. It has been determined that larger particles are desirable in some situations. However, the larger particles pose a problem when used with the smaller needles required in the facial derma. The larger particles can bridge or agglomerate resulting in clogging of the small orifice needle. Larger particles also result in a greater amount of force needed to translate the syringe plunger. The higher force may cause the surgeon to tremble and slight perturbations of the hand could result in scaring of the patient. Therefore, it is desirable to have applied forces equivalent to a low viscidity Newtonian fluid.
  • biomaterials for example, in the urinary tract (specifically, in the urinary outflow of the bladder into the urethra) or in the lower esophageal area connecting the esophagus to the stomach.
  • the malfunctioning of these sphincters is usually in the form of improper or incomplete closure of the sphincters, which leads to medical conditions such as urinary incontinence and gastroesophageal reflux disease (GERD) or heartburn, respectively.
  • GDD gastroesophageal reflux disease
  • Treatment of these medical conditions may include injections of a viscous material dispersed in a solution, such as collagen, in the vicinity of the associated sphincter to augment or bulk up and fortify the tissue and thereby assist in the adequate closure of the corresponding sphincter for re-establishment of normal sphincter control.
  • a biomaterial such as collagen into the human body
  • various other body passages and tissues for example, for correcting wrinkles not only in the facial derma but in other areas of the body as well.
  • FIG. 1, including FIGs. l(a)-l(d), are various views of a prior art syringe and needle flow delivery system 10.
  • the syringe 12 is made of glass and typically comprises a larger ID section into which the plunger 14 fits.
  • a tapered section 16 At the nozzle or discharge end of the syringe 12 is a tapered section 16 that significantly reduces the cross section of the syringe 12 at that location.
  • a plastic housing 18 contains a needle 20, which may also include a catheter as an integral part thereof or as a separate component connected therewith, and is fitted over the glass syringe 12.
  • the glass syringe/plastic housing assembly is held in place by an outer plastic sleeve 22 into which the plastic housing 18 is screwed.
  • the glass syringe 12 is also held in place inside the outer plastic sleeve 22.
  • a significant disadvantage of this prior art embodiment is the lack of a smooth continuous transition from the narrow opening of the glass syringe 12 into the distal end of the needle 20. In this configuration, there is a large plenum 24 located between the exit opening of the glass syringe 12 and the distal opening of the needle 20. This plenum 24 prevents the smooth and continuous operation of the syringe/needle system 10.
  • the filler material When the physician pushes the plunger 14 to inject the filler material, the filler material is first squeezed through the narrow constriction at the exit of the glass syringe 12, then the material will expand into the larger plenum 24, and the filler material is squeezed again to enter the needle 20.
  • Measurement of the force necessary to push the filler material through this prior art syringe/needle flow delivery system 10 has demonstrated a significant oscillatory behavior, typically disliked by the physician, along with elevated force levels. This force requirement derives from the existence of the plenum 24 between the needle 20 and the glass syringe 12.
  • a flow delivery system includes a syringe and a needle and/or a catheter that delivers an aqueous solution of a material, such as a biomaterial or a mixture of a biomaterial and a biocompatible fluid lubricant, preferably at a constant applied force.
  • a material such as a biomaterial or a mixture of a biomaterial and a biocompatible fluid lubricant
  • the force required to flow the solution is significantly reduced compared to prior art flow delivery systems.
  • continuous and smooth transitions at various locations in the cross-sectional area of the physical structure of the flow delivery system reduce the flow resistance and thus reduce the force necessary to transport and expel the material through the system.
  • the transitions include those located at the nozzle within the syringe and the transition between the proximal end of the syringe and the distal end of the needle.
  • a contoured nozzle connects the main body of the syringe to the distal end of the needle.
  • the contoured nozzle is designed to reduce the steady resistance to the flow of the solution through the syringe. To achieve a steady flow velocity of the solution through the syringe, a smaller force is necessary compared to that in a prior art needle/syringe flow delivery system operating at the same steady velocity.
  • the contoured nozzle may also function as an acoustic horn. Acoustic waves and pulses generated in the solution within the syringe body propagate towards the junction between the needle and the syringe.
  • the contoured nozzle allows for transmission of the acoustic waves or pulses into the needle.
  • the cross-sectional area reduction from the syringe to the needle serves as a mechanical amplifier of the acoustic pressure amplitude. Therefore, the contoured nozzle functioning as an acoustic horn allows for the transmission and amplification of acoustic waves and pulses into the needle. Without such a design of the acoustic horn, most of the acoustic energy would be reflected back into the syringe body and would not be transmitted into the needle.
  • An example of a preferred contoured nozzle design is that of a cosine function profile.
  • an ultrasonic transducer is fitted or disposed around the casing surrounding the syringe body and is used to excite radial acoustic waves in the solution within the syringe.
  • the ultrasonic transducer is tuned to a radial resonance frequency of the syringe cavity. Relatively high amplitude acoustic waves can be achieved in this manner.
  • the acoustic radiation force exerted by the acoustic field on the suspended particles in the solution can be used to align the particles in circle shaped patterns at the stable locations of the acoustic radiation force.
  • the same ultrasonic transducer can be driven in a periodic frequency sweeping pattern that translates the suspended particles towards the center of the syringe. Aligning the particles in the center of the syringe channel will enhance the expulsion of the particles out through the needle.
  • the same ultrasonic transducer can be driven by a modulated frequency signal that results in shape changes of the suspended particles; for example, into oblong shapes. Through frequency control it is possible to deform the suspended particles into elongated particles, i.e., along the syringe axis, which will be easier to extrude out from the needle. This reduces the force required for extrusion.
  • the same ultrasonic transducer can be used to send a relatively strong compressive pulse which propagates down the syringe into the needle and ultimately reaches the proximal end of the needle.
  • the strong pulse creates a large velocity of the solution in the vicinity of the needle to generate an outflow of solution from the syringe into the human body.
  • a subsequent weaker expansion wave may be used to bring the system back to equilibrium, after which a second compressive pulse is used to send a second stream of solution into the human body.
  • This action of the ultrasonic transducer results in a pulsed flow of the solution flowing from the syringe into the human body, without the need of an external applied force.
  • the mechanical plunger typically utilized in a syringe can be eliminated.
  • the ultrasonic transducer is disposed inside the syringe such that it functions as the plunger of the syringe. This allows the plunger to be omitted as no mechanical force from the plunger is required to transport and expel the particle containing solution.
  • the ultrasonic transducer excites axial acoustic waves or pressure pulses in the solution within the syringe and needle. Similar to the previous embodiment, a strong pulse can be generated by the transducer resulting in a pulsed flow of the solution exiting from the needle opening.
  • the ultrasonic transducer can also be used as a sensor.
  • the signal received by the ultrasonic transducer can then be employed in a feedback control system.
  • the feedback control system allows the operation of the syringe in constant force mode which facilitates the operation of the system by a physician such that the physician merely applies a small constant force to deliver the solution.
  • the feedback control system drives the amplitude of the ultrasonic actuator, which assists in the delivery of the solution as needed and on command.
  • a similar control system can be employed to deliver the solution at constant speed.
  • FIG. 1, including FIGs. l(a)-l(d), are various views of an embodiment of a prior art syringe/needle flow delivery system
  • FIG. 2 is a cross-sectional view of an embodiment of a flow delivery system of the present invention having a syringe with a contoured nozzle and a needle;
  • FIG. 3 is detailed cross-sectional view of the contoured nozzle of FIG. 2;
  • FIG. 4 including FIGs. 4(a)-4(d), are various views of another embodiment of the flow delivery system of the present invention having a contoured nozzle separate from the syringe;
  • FIG. 5, including FIGs. 5(a)-5(b), are various views of another embodiment of a flow delivery system of the present invention having an ultrasonic transducer disposed around the syringe body;
  • FIG. 6, including FIGs. 6(a)-6(b), are graphs of exemplary voltage waveforms used in a pulsed flow application of the ultrasonic transducer of FIG. 5;
  • FIG. 7, including FIGs. 7(a)-7(b), are various views of another embodiment of a flow delivery system of the present invention having an ultrasonic transducer disposed within the syringe body;
  • FIG. 8 is a view of the flow delivery system of FIG. 5(b) employing feedback control to maintain constant force.
  • FIGs. 2 and 3 there illustrated is an embodiment of a flow delivery system 30 which reduces the amount of plunger force required to transport and expel an aqueous solution of solely a biomaterial or a mixture of a biomaterial and a biocompatible fluid lubricant into, e.g., a human body at a desired location, such as, for example, the facial derma or a sphincter; specifically, the sphincter associated with the urinary tract or with the esophageal tract.
  • the biomaterial may comprise collagen or other known materials used as bulking agents to augment or build up the tissue in the desired area to correct for improper sphincter operation or to cure cosmetic defects (e.g., wrinkles).
  • the biocompatible fluid lubricant may comprise a non cross-linked collagen or other known materials that form a homogeneous mixture with the preferred biomaterial.
  • the amount of lubricant required in the mixture with the biomaterial is that which provides for proper intrudability of the biomaterial into the internal body tissue at the desired location and which also provides for proper extrudability of the biomaterial through and out from the flow delivery system.
  • the system 30 incorporates a syringe (e.g., preferably cylindrical and made from glass) with both a nozzle portion 32 and a geometrically smooth transition portion 34 located where the converging section of the syringe 12 meets the distal end of the needle 20.
  • the syringe/needle flow delivery system 30 of FIGs. 2 and 3 includes a syringe 12, a plunger 14, a plastic housing 18 that contains the needle 20, and an outer plastic casing 22 that holds together the syringe 12 and the needle 20.
  • the needle 20 may also include a catheter formed as an integral portion of the needle as an extension thereof. Alternatively, the catheter may be connected at an exit end of the needle. Thus, any reference herein to the needle 20 also includes reference to a catheter.
  • the nozzle 32 and smooth transition portion 34 are both preferably integral portions of the syringe 12.
  • the flow delivery system 30 of FIGs. 2 and 3 contains a contoured or streamlined nozzle 32 as part of the syringe 12 which together with the smooth transition portion 34 of the syringe 12, reduces resistance to the flow of the solution from the syringe 12 into the needle 20. This facilitates the flow of the solution through the syringe 12 and out from the needle 20. It also reduces the likelihood that the biomaterial particles in the aqueous solution will clog in the needle 20 or catheter or upstream of the needle in the nozzle 32 or transition portion 34.
  • the distal end of the needle 20 may reside within the syringe 12, as best illustrated in FIG. 3.
  • no plenum 24 exists between the opening in the syringe 12 and the distal end of the needle 20.
  • FIG. 4 illustrates various views of portions of another embodiment of a syringe and nozzle flow delivery system according to an aspect of the present invention.
  • This embodiment includes a contoured or streamlined nozzle 32 separate from the syringe 12 that, when connected with the syringe 12, allows for a smooth and continuous reduction of the internal cross-sectional diameter (ID) of the syringe 12 from the wider section fitting the plunger 14 to the smaller section with preferably an identical ID as that of the needle 20.
  • ID internal cross-sectional diameter
  • the needle 20 fits flush against the nozzle 32, thereby allowing for a smooth and continuous transition from the syringe 12 to the needle 20.
  • FIG. 5 illustrates another embodiment of a flow delivery system 30.
  • This embodiment is similar to that of FIGs. 2 and 3, except that an ultrasonic transducer 40 is fitted around the outer casing 22 of the glass syringe 12.
  • the ultrasonic transducer 40 when driven by appropriate electrical signals from a controller (e.g., FIG. 8), excites acoustic waves through the wall of the syringe 12 into the solution containing the biomaterial or mixture of a biomaterial and lubricant located inside the syringe 12.
  • the ultrasonic transducer 40 may be tuned to a radial resonance frequency of the syringe cavity. Relatively high amplitude acoustic waves can be achieved in this manner.
  • the acoustic radiation force exerted by the acoustic field on the suspended particles in the solution can be used to align the particles in circle shaped patterns at the stable locations of the acoustic radiation force.
  • the ultrasonic field generated by the transducer 40 facilitates the extrusion of the biomaterial solution through the syringe 12 and out from the needle 20 and, where included, the catheter. This occurs through the combined effects of: (a) vibratory excitation of the suspended particles in the solution; (b) concentration and translation of the particles toward the syringe axis; and (c) shaping the particles into oblong shapes.
  • Periodic frequency sweeping of an ultrasonic standing wave field can also be used to translate the concentrated particles, for example towards the center of the syringe 12.
  • a modulated ultrasonic excitation of the transducer 40 results in deforming the suspended particles in the solution into oblong shapes aligned with the axis of the syringe 12.
  • the streamlined nozzle 32 employed either as an integral part of, or separate from the syringe 12 acts as an ultrasonic acoustic horn and amplifies the pressure of the wave.
  • the ultrasonic transducer 40 may comprise a piezoelectric transducer. Typical materials that may be used for the piezoelectric transducer include PZT-4 and PZT-8, but other materials may be used. Also, other types of actuators and/or transducers may be used. Typical frequencies of operation may be in the range of 500,000 cycles per second up to several million cycles per second.
  • a different usage of the embodiment of the flow delivery system 30 of FIG. 5 is that of an ultrasonic pump of the biomaterial or mixture of biomaterial and lubricant contained within the solution in the syringe 12.
  • a relatively strong compressive pulse is generated in the biomaterial. This pulse propagates through the nozzle 32 and into the needle 20. At the end of the needle 20 the compressive pulse accelerates the biomaterial located at the proximal end of the needle 20. When the velocity of the material reaches a certain threshold, the material starts flowing, and a small amount of biomaterial is delivered from the needle 20.
  • the strong compressive pulse is followed by a weaker expansion wave which allows the system 30 to reach equilibrium, and the plunger 14 drops by a small amount to compensate for the solution that has escaped the syringe 12 and the needle 20.
  • the system 30 is then ready for the next compressive pulse and subsequent delivery of the next amount of solution. Usage of the embodiment in this manner results in a pulsed flow system.
  • Another application of this embodiment is as an assisting device to the physician, i.e., it allows the physician to operate the syringe and needle flow delivery system 30 with a smaller externally applied force.
  • the compressive pulse provides acceleration to the material in the needle and assists the physician in delivering the material.
  • FIG. 7 illustrates yet another embodiment of the present invention.
  • the ultrasonic transducer 40 is embedded inside the body of the syringe 12, and functions much like a plunger 14. Through the action of the ultrasonic wave field a reduction in the necessary external force to extrude the biomaterial out from the needle or needle and catheter is achieved. Similar actions are taking place as in the previous embodiments; that is, ultrasonic radiation force, concentration and translation of particles, and vibratory excitation of particles.
  • FIG. 7 it is also possible to use the embodiment of FIG. 7 as a pulsed flow system, when excited by the voltage waveforms of FIG. 6. In this case, the velocity of the biomaterial solution in the proximal end of the needle 20 is sufficient to flow from the needle 20 into the delivery medium. As such, it may be possible to eliminate the use of the plunger 14 or any other type of mechanical force to transport and expel the solution.
  • a second potential use of this system 30 is as an assisting device to the physician which allows the physician to operate the device with reduced external force.
  • the flow delivery system 30 of the present invention may include a controller 50 connected with the piezoelectric transducers 40.
  • the piezoelectric transducer 40 is used during part of the operating cycle as a driver (transmitter) and during another part of the operating cycle as a sensor (receiver).
  • the signal obtained during the sensing mode is sent to the micro-chip controller 50, where a control algorithm varies the voltage sent to the transducer 40 through an amplifier 52 during the driving cycle to maintain a constant force operation of the system 30. In this way, the physician has to employ a reduced and constant force to inject the biomaterial into the delivery medium.
  • the controller Whenever an increased resistance is sensed by the transducer 40 during the expulsion process, the controller sends an increased voltage signal to the transducer 40 that compensates for the increase in friction force, and thereby allowing the physician to operate the device with the same constant force as he was originally using.
  • a similar type controller 50 may be utilized in an open- or closed-loop system to provide the various driving voltages illustrated in FIG. 6 or may provide the various frequency signals discussed hereinabove in the embodiments of FIGs. 5 and 7 to the ultrasonic transducer 40 to achieve the desired acoustic waves propagating in the flow delivery system 30 of the present invention.

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  • Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Abstract

L'invention concerne un système de délivrance pour une solution aqueuse d'un biomatériau ou d'un mélange d'un biomatériau et d'un lubrifiant fluide biocompatible, ledit système comprenant une seringue et une aiguille ou une combinaison aiguille et cathéter. Une buse profilée connecte la seringue à l'aiguille et réduit la force de piston nécessaire pour expulser la solution de l'aiguille. Un transducteur à ultrasons génère des ondes et des impulsions de pression acoustique dans la solution. La force de rayonnement acoustique du champ acoustique aligne les particules dans la solution dans la direction de l'axe de la seringue et facilite l'expulsion. La force de rayonnement acoustique change également la forme du biomatériau en formes oblongues, réduisant ainsi la force d'expulsion nécessaire. Par ailleurs, l'excitation vibratoire du biomatériau par le champ ultrasonore facilite l'expulsion de la solution. Des impulsions de pression importantes peuvent former des gouttelettes de la solution à l'ouverture de l'aiguille.
PCT/US2008/072468 2007-08-08 2008-08-07 Améliorations de l'écoulement pour la délivrance de biomatériaux Ceased WO2009021111A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95460207P 2007-08-08 2007-08-08
US60/954,602 2007-08-08

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WO2009021111A1 true WO2009021111A1 (fr) 2009-02-12

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5131394A (en) * 1990-03-28 1992-07-21 Gehlbach Steve M Ultrasonic guided needle
US20020000681A1 (en) * 2000-05-24 2002-01-03 Gupta Ram B. Method of forming nanoparticles and microparticles of controllable size using supercritical fluids and ultrasound
US20030221561A1 (en) * 1999-12-06 2003-12-04 Simcha Milo Ultrasonic medical device
US20030229304A1 (en) * 2001-03-21 2003-12-11 Eilaz Babaev Ultrasonic catheter drug delivery method and device
US20040173541A1 (en) * 2003-03-06 2004-09-09 Hitachi, Ltd. Water treatment method and water treatment device
US20050075620A1 (en) * 2001-01-26 2005-04-07 Yoni Iger Method and apparatus for the delivery of substances to biological components
US20060000284A1 (en) * 2004-06-30 2006-01-05 Sherman Jason T System and method for determining the operating state of orthopaedic admixtures

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5131394A (en) * 1990-03-28 1992-07-21 Gehlbach Steve M Ultrasonic guided needle
US20030221561A1 (en) * 1999-12-06 2003-12-04 Simcha Milo Ultrasonic medical device
US20020000681A1 (en) * 2000-05-24 2002-01-03 Gupta Ram B. Method of forming nanoparticles and microparticles of controllable size using supercritical fluids and ultrasound
US20050075620A1 (en) * 2001-01-26 2005-04-07 Yoni Iger Method and apparatus for the delivery of substances to biological components
US20030229304A1 (en) * 2001-03-21 2003-12-11 Eilaz Babaev Ultrasonic catheter drug delivery method and device
US20040173541A1 (en) * 2003-03-06 2004-09-09 Hitachi, Ltd. Water treatment method and water treatment device
US20060000284A1 (en) * 2004-06-30 2006-01-05 Sherman Jason T System and method for determining the operating state of orthopaedic admixtures

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