WO2010020938A1 - Dispositif et procédé d’administration de cellules souches augmenté par des ultrasons - Google Patents

Dispositif et procédé d’administration de cellules souches augmenté par des ultrasons Download PDF

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Publication number
WO2010020938A1
WO2010020938A1 PCT/IB2009/053625 IB2009053625W WO2010020938A1 WO 2010020938 A1 WO2010020938 A1 WO 2010020938A1 IB 2009053625 W IB2009053625 W IB 2009053625W WO 2010020938 A1 WO2010020938 A1 WO 2010020938A1
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WO
WIPO (PCT)
Prior art keywords
microbubbles
bloodstream
tissue
interest
cell
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Application number
PCT/IB2009/053625
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English (en)
Inventor
Christopher Stephen Hall
Chien Ting Chin
Klaus Tiemann
Alexander Ghanem
Original Assignee
Koninklijke Philips Electronics, N.V.
University Of Bonn
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Application filed by Koninklijke Philips Electronics, N.V., University Of Bonn filed Critical Koninklijke Philips Electronics, N.V.
Publication of WO2010020938A1 publication Critical patent/WO2010020938A1/fr

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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
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/41—Detecting, measuring or recording for evaluating the immune or lymphatic systems
    • A61B5/414—Evaluating particular organs or parts of the immune or lymphatic systems
    • A61B5/416—Evaluating particular organs or parts of the immune or lymphatic systems the spleen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/48—Diagnostic techniques
    • A61B8/481—Diagnostic techniques involving the use of contrast agent, e.g. microbubbles introduced into the bloodstream
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B17/22004—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves
    • A61B2017/22005—Effects, e.g. on tissue
    • A61B2017/22007—Cavitation or pseudocavitation, i.e. creation of gas bubbles generating a secondary shock wave when collapsing
    • A61B2017/22008—Cavitation or pseudocavitation, i.e. creation of gas bubbles generating a secondary shock wave when collapsing used or promoted
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
    • A61B5/4839—Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery

Definitions

  • the following relates to the medical arts and related arts. It finds particular application in delivery of stem cells to a targeted organ or tissue, and is described with particular reference thereto. The following is generally applicable to targeted intravascular (i.e., intravenous or intra-arterial) delivery of stem cells, drug delivery microcapsules, micromachines, or other cell-sized objects to a targeted organ or tissue of interest.
  • targeted intravascular i.e., intravenous or intra-arterial
  • drug delivery microcapsules i.e., micromachines, or other cell-sized objects to a targeted organ or tissue of interest.
  • Some stem cell therapies entail delivery of undifferentiated or partially differentiated stem cells to an organ or tissue of interest. Once at the organ or tissue of interest, the stem cells multiply by mitosis and differentiate in a manner comporting with the targeted biological environment so as to replace injured or dead cells and rejuvenate or heal the organ or tissue of interest.
  • the stem cells may be derived from various sources, such as adult stem cells, bone marrow stem cells, embryonic or placental stem cells, or so forth.
  • One delivery approach is an intra-organ injection in which a catheter or other interventional instrument is inserted directly into musculature of the targeted organ or into tissue of interest so as to provide direct delivery of the stem cells.
  • This approach is highly invasive, and has exhibited some adverse consistency issues.
  • Another approach for stem cell delivery that has been attempted is intravascular delivery.
  • the stem cells are injected into the blood stream in the hope that some stem cells will collect in the targeted organ or tissue of interest.
  • This approach has the disadvantage of being a poorly targeted delivery system. In many cases a large majority of the stem cells end up being removed by the spleen or other blood filtering organs of the body.
  • a method of delivering cell-sized objects to a targeted organ or tissue of interest comprises: introducing the cell sized objects into the bloodstream; introducing microbubbles into the bloodstream; and locally agitating the introduced microbubbles, the agitating being substantially localized to the targeted organ or tissue of interest, the local agitating of the introduced microbubbles enhancing transendothelial migration of the cell sized objects into the targeted organ or tissue of interest.
  • an apparatus for delivering cell sized objects to a targeted organ or tissue of interest comprises: an intravascular delivery device configured to deliver the cell-sized objects and microbubbles into the bloodstream; and an ultrasound system; and a therapy controller configured to control the intravascular delivery system to control delivery of the cell-sized objects and the microbubbles into the bloodstream and to control the ultrasound system to ultrasonically agitate intravascular microbubbles in the targeted organ or tissue of interest so as to enhance transendothelial migration of the cell-sized objects into the targeted organ or tissue of interest.
  • a method of delivering cell sized objects to a targeted organ or tissue of interest comprises: performing a transendothelial migration-enhancing process on vasculature of the targeted organ or tissue of interest; and introducing the cell sized objects into the bloodstream, the cell sized objects preferentially undergoing transendothelial migration out of the vasculature of the targeted organ or tissue of interest due to the transendothelial migration-enhancing process.
  • One advantage resides in a less invasive or non-invasive delivery mechanism for stem cells or other diagnostic or therapeutic agents.
  • Another advantage resides in improved targeting of intravascular delivery of stem cells or other cell-sized objects to an organ or tissue of interest.
  • Another advantage resides in providing targeted intravascular delivery of stem cells or other cell-sized objects to substantially any soft organ or tissue of interest.
  • FIGURE 1 diagrammatically shows a delivery system for intravascular delivery of cell-sized objects to an organ or tissue of interest.
  • FIGURE 2 diagrammatically shows a stem cell delivery process suitably performed by the system of FIGURE 1.
  • FIGURE 3 diagrammatically shows another stem cell delivery process suitably performed by the system of FIGURE 1.
  • a system for delivering cell-sized objects to a targeted organ or tissue of interest is described.
  • a subject 10 is disposed on a subject support 12, such as a table, gurney, chair, or so forth.
  • the cell-sized objects to be delivered are stem cells; however, more generally other types of cells may be delivered, or other cell-sized objects may be delivered such as drug delivery microcapsules, micromachines, or so forth.
  • the system provides for intravascular delivery of a stem cells serum 14 containing stem cells or other cell-sized objects for delivery to the organ or tissue of interest.
  • the intravascular delivery system also delivers microbubbles that are locally agitated in the vasculature of the targeted organ or tissue of interest in order to enhance transendothelial migration of the stem cells or other cell-sized objects into the targeted organ or tissue of interest.
  • the microbubbles are in the form of an ultrasonic contrast agent with microbubbles 16, and the microbubbles are agitated in the vasculature by applied ultrasonic energy.
  • the commercial ultrasonic contrast agent SonoVueTM available from Bracco Inc., Milano, Italy
  • substantially any kind of gas-filled, lipid-coated microbubbles or other stabilized microbubbles can be used.
  • the use of the illustrated ultrasonic contrast agent with microbubbles 16 advantageously allows the microbubble distribution in the bloodstream to be monitored by ultrasonic imaging.
  • the introduced microbubbles have sizes between about one-half micron and about twenty microns.
  • the intravascular delivery system includes an intravascular delivery controller 20 configured to start and stop delivery of the stem cells serum 14 and of the contrast agent with microbubbles 16 responsive to suitable control signals.
  • a common intravascular delivery pathway such as a single intravascular tube 22, delivers both the stem cells serum 14 and the contrast agent with microbubbles 16.
  • the intravascular delivery controller 20 includes suitable fluid switching valves to introduce a selected one, or both, of the fluids 14, 16 into the intravascular tube 22 for entry into the subject 10.
  • separate intravascular pathways such as two intravascular tubes 22, 24, can be provided to enable separate delivery of the two fluids 14, 16.
  • the ultrasound contrast agent including extant microbubbles 16 is introduced into the bloodstream
  • the microbubbles may be intravascularly introduced by introducing a gaseous precursor into the bloodstream, which is then converted in the bloodstream into microbubbles by application of ultrasonic energy.
  • the stem cell delivery techniques disclosed herein make use of the ultrasound-mediated microbubble effect (UME).
  • UAE ultrasound-mediated microbubble effect
  • This technique involves an intravascular injection or infusion of gas-filled lipid-coated microbubbles and localized or focused application of ultrasonic energy to induce oscillation, disruption, or both oscillation and disruption, of microbubbles in a localized vicinity.
  • the mechanical movement of microbubbles under ultrasonic agitation induces cellular response on adjacent endothelium through shear forces and direct deformation.
  • UME is also believed to cause inflammatory action.
  • the UME produces small holes or perturbations in capillaries that may remain for several hours or longer before healing. Thus, after application of ultrasonic energy small transient pores are induced in the capillaries.
  • UME has been used to deliver molecular- sized agents, e.g., genetic material, into targeted tissue. See, e.g. Bekeredjian et al, "Ultrasound-targeted microbubble destruction can repeatedly direct highly specific plasmid expression to the heart", Circulation vol. 108, pp. 1022-26 (2003). UME has also been used in conjunction with intravascular delivery of bone-marrow mononuclear cells or endothelial progenitor cells to promote neocapillary formation in ischemic skeletal muscle tissue and in myocardial tissue.
  • agents e.g., genetic material
  • UME has also been used in conjunction with intravascular delivery of bone-marrow mononuclear cells or endothelial progenitor cells to promote neocapillary formation in ischemic skeletal muscle tissue and in myocardial tissue.
  • UME transendothelial migration of cell-sized objects such as stem cells from the bloodstream into an organ or tissue of interest.
  • transendothelial migration is believed to be enhanced by the weakening or breakdown of cellular membranes induced by UME. While this mechanism may be active in transendothelial migration of stem cells, the inventors have also observed a substantial increase in pro-inflammatory cytokine levels due to UME. The cytokine levels peaked around 15 minutes after the UME.
  • an ultrasound system 30 provides controlled ultrasonic energy to external ultrasonic transducers 32 disposed on the subject 10 or to internal ultrasonic transducers 34 delivered inside the subject 10 by a suitable interventional instrument 36 such as a cathether.
  • the ultrasonic transducers 32, 34 are shown diagrammatically in FIGURE 1; in general, the transducers can be concentric electrode arrangements for focused ultrasonic delivery, arcuate electrode arrangements for ultrasonic imaging, tranducer arrays, or so forth.
  • the ultrasound system 30 may be configured to perform ultrasound imaging, and toward that end the illustrated ultrasound system 30 includes a display 40 for displaying acquired ultrasound images.
  • the ultrasound system 30 further includes an illustrated keyboard 42 or other user input device to enable a radiologist, physician, or other user to control lthe ultrasound system 30.
  • a therapy controller 44 controls the intravascular delivery controller 20 and the ultrasound system 30 to perform UME assisted targeted delivery of stem cells to an organ or tissue of interest.
  • a contrast thresholder 46 optionally triggers the UME when the microbubble concentration in the tissue or organ of interest (or in the vasculature thereof) rises above a selected threshold or other selected criterion. Alternatively, the UME can be started a preselected time interval after intravascular injection of the microbubbles is initiated.
  • the therapy controller 44 and contrast thresholder 46 can be variously embodied, for example as software executing on a processor of the ultrasound system 30, software executing on a general-purpose laptop or desktop computer, or so forth.
  • the therapy controller 44 controls the intravascular delivery controller 20 to initiate intravascular introduction of the ultrasonic contrast agent with microbubbles 16 in a starting operation 50.
  • the therapy controller 44 controls the ultrasound system 30 to monitor influx of the microbubbles into the targeted organ or tissue of interest using ultrasonic imaging 52.
  • another imaging modality can be used for the imaging, such as magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • the microbubbles are suitably tagged with a magnetic contrast agent having a magnetic susceptibility detectable by MRI in the subject 10.
  • the contrast thresholder 46 performs a triggering operation 54 and provides a signal when the concentration of microbubbles in the organ or tissue of interest rises above a selected threshold or other selected criterion.
  • the therapy controller 44 controls the ultrasound system 30 to inject ultrasonic energy focused onto the organ or tissue of interest so as to agitate the microbubbles to produce the UME effect in the vasculature of the organ or tissue of interest in an agitation operation 56.
  • the therapy controller 44 also controls the intravascular delivery controller 20 to stop the intravascular delivery of microbubbles in an operation 58 which may be performed immediately after the contrast thresholder 46 provides the UME initiation signal, or sometime thereafter.
  • the intravascular delivery of microbubbles continues throughout the agitation operation 56.
  • the ultrasonic imaging may continue during the agitation operation 56, for example by temporally interleaving ultrasound imaging and UME agitation operations. If the imaging 52 employs MRI or another modality, or a second ultrasound system is available, then imaging may be performed simultaneously with the local ultrasonic agitation.
  • the stem cells serum 14 is not intravascularly delivered until after the agitation operation 56 is completed.
  • a delay 60 is interposed between termination of the agitation operation 56 and initiation of intravascular stem cell serum delivery.
  • the therapy controller 44 controls the intravascular delivery controller 20 to initiate intravascular delivery of the stem cells serum 14 in a stem cells delivery operation 64.
  • the delay 60 is about 15 minutes, so that delivery of the stem cells approximately coincides with the peak of the in pro-inflammatory cytokine levels which occurs about 15 minutes after the UME agitation. Longer or shorter delays are also contemplated, and the delay 60 is optionally omitted entirely.
  • the stem cells delivery 64 may be terminated after a preselected time interval, or may be terminated responsive to a suitable monitoring feedback signal.
  • a suitable monitoring feedback signal For example, if the stem cells serum 14 is magnetically tagged, then optional MRI imaging 66 can be used to track the accumulating concentration of stem cells in the organ or tissue of interest, and the stem cells delivery 64 is suitably terminated when the monitoring 66 indicates a desired stem cell concentration has been achieved.
  • the time delay 60 is believed to have the additional advantage of allowing the inflammatory effect or other transendothelial cell migration-enhancing process to mature so as to maximally enhance the transendothelial migration of the subsequently introduced stem cells.
  • the general approach of stressing the vasculature in the organ or tissue of interest, followed by a delay to allow the stress to mature, followed by intravascular introduction of stem cells, may also be employed in conjunction with a vasculature stress other than UME.
  • a vasculature stress other than UME may also be employed in conjunction with a vasculature stress other than UME.
  • delay 60 is believed to be beneficial, in other embodiments no such delay is included.
  • the therapy controller 44 controls the intravascular delivery controller 20 to initiate simultaneous intravascular introduction of both the ultrasonic contrast agent with microbubbles 16 and the stem cells serum 14 in a starting operation 70.
  • the therapy controller 44 controls the ultrasound system 30 to monitor influx of the microbubbles into the targeted organ or tissue of interest using ultrasonic, magnetic resonance imaging (MRI), or other imaging 72.
  • the contrast thresholder 46 performs a triggering operation 74 and provides a signal when the concentration of microbubbles in the organ or tissue of interest rises above a selected threshold or other selected criterion.
  • the therapy controller 44 controls the ultrasound system 30 to inject ultrasonic energy focused onto the organ or tissue of interest so as to agitate the microbubbles to produce the UME effect in the vasculature of the organ or tissue of interest in an agitation operation 76.
  • the therapy controller 44 also controls the intravascular delivery controller 20 to stop the simultaneous intravascular delivery of microbubbles and stem cells in an operation 78 which may be performed immediately after the contrast thresholder 46 provides the UME initiation signal, or sometime thereafter. In some embodiments, the intravascular delivery of microbubbles continues throughout the agitation operation 76.
  • This transducer is suitably excited by a drive system providing pulsed-wave delivery.
  • the eight-ring transducer is positioned so that the region to be treated is at the focus of the transducer.
  • the transducer can either be mechanically moved over the region to be treated, or the focus can be electronically steered over the region to be treated.
  • Microbubbles are injected and observed to come into the field of view by ultrasonic imaging.
  • the stem cells are administered by a suitable intravascular delivery system employing a catheter, needle, or the like.
  • UME mediated targeted stem cell delivery as disclosed herein has been performed in vivo by the inventors, using rats as test subjects.
  • Human mesenchymal stem cells (MSCs) were isolated from hip bone marrow, diluted with Ca 2+ - and Mg 2+ -free phosphate -buffered saline (PBS), filtered, laid over 15 ml Ficoll-PaqueTM Plus (available from Amersham Pharmacia Biotech, Uppsala, Sweden) and centrifuged.
  • MSCs mesenchymal stem cells
  • Mononuclear cells were isolated and maintained as monolayers in 10 ml growth medium ⁇ -MEM supplemented with 2 mg/ml L-glutamine, 50 U/ml penicillin, 50 ⁇ g/ml streptomycin and 20% (v/v) of a selected batch of fetal calf serum (all chemicals were obtained from Gibco BRL, Düsseldorf, Germany). Non-adherent cells were removed after 2 days at 37°C in a humidified 5% CO 2 atmosphere. In some subjects the UME target zone was set in the anterior Ie ft- ventricular wall in non-ischemic myocardium, while in other subjects UME was aimed at the anteroseptal peri-infarction borderzone.
  • An ultrasound system from Philips Research North America, Briarcliff Manor, NY, USA was used to provide b-mode high-resolution ultrasound imaging at a frequency of about 15 MHz so as to image anatomical structures.
  • low- frequency (about 1.2 MHz) high-energy focused ultrasound energy was applied.
  • the ultrasonic transducers incorporated an acoustic coupler designed for small animals and filled with degassed water, and was mounted on a stepper-motor stage which allowed movement of the treatment zone in three dimensions.
  • Reatime guidance using b-mode imaging allowed precise and interactive positioning of the focal zone of the UME focused ultrasound energy into a selected segment of myocardium.
  • the UME focal zone of the treatment ultrasound transducer was about 1 mm in diameter and 6 mm in length. To create a larger treatment zone (about 30 cm), spatial coordinates obtained from the realtime b-mode imaging were used in driving the motor stage and generating the ultrasound pulses so as to scan the focal zone.
  • SonoVueTM (available from Bracco Inc., Milano, Italy) was infused into a femoral vein cannulated with a PE-50 tube at approx. 100 ⁇ l/minute.
  • the microbubble agent was agitated continuously during injection using a syringe pump. Flow rate was adjusted to achieve suitable left-ventricular opacification without shadowing. Steady state conditions were achieved about two minutes after start of the SonoVueTM infusion.
  • the scanning of the UME ultrasound focus was performed so as to ensure uniform delivery of ultrasound-pulses across the target zone during the a selected phase of the cardiac cycle and to ensure sufficient replenishment time for fresh microbubbles following localized destruction of microbubbles by the UME agitation.
  • Pulses were applied at a 0.2 Hz rate, and each pulse consisted of a sinusoidal excitation with the following parameters: 1.2 MHz; 10.000 cycles; 4.4 MPa peak negative pressure. In total the target zone of each heart received a sequence of 30 spatially distributed pulses repeated twice.

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Abstract

La présente invention concerne un procédé d’administration d’objets de taille cellulaire à un organe ou un tissu cible d’intérêt consistant à introduire (64, 70) les objets de taille cellulaire dans la circulation sanguine, à introduire (50, 70) des microbulles dans la circulation sanguine, et à agiter localement (56, 76) les microbulles introduites, l’agitation étant sensiblement localisée à l’organe ou au tissu ciblé d’intérêt, l’agitation locale des microbulles introduites augmentant la migration transendothéliale des objets de taille cellulaire vers l’organe ou le tissu cible d’intérêt. L’appareil pour mettre en œuvre ledit procédé comprend un dispositif d’administration intravasculaire (20, 22, 24) conçu pour administrer les objets de taille cellulaire et les microbulles dans la circulation sanguine, un système à ultrasons (30, 32, 34, 36), et un régulateur de traitement (44) conçu pour réguler l’administration des objets de taille cellulaire et les microbulles dans la circulation sanguine et l’agitation par ultrasons des microbulles  intravasculaires dans l’organe ou le tissu cible d’intérêt.
PCT/IB2009/053625 2008-08-18 2009-08-17 Dispositif et procédé d’administration de cellules souches augmenté par des ultrasons WO2010020938A1 (fr)

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US61/089,642 2008-08-18

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013046076A1 (fr) * 2011-09-28 2013-04-04 Koninklijke Philips Electronics N.V. Administration automatisée à médiation par ultrasons
WO2021158510A1 (fr) * 2020-02-05 2021-08-12 FUJIFILM Cellular Dynamics, Inc. Appareil et procédés pour l'administration d'une suspension cellulaire

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WO1999039697A1 (fr) * 1998-02-06 1999-08-12 Point Biomedical Corporation Procede d'administration de medicaments par ultrasons
WO2001024705A1 (fr) * 1999-10-06 2001-04-12 Imarx Therapeutics, Inc. Techniques ameliorees permettant de delivrer des agents bioactifs
US20020151792A1 (en) * 1998-02-06 2002-10-17 Conston Stanley R. Method for ultrasound triggered drug delivery using hollow microbubbles with controlled fragility
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WO2006131840A2 (fr) * 2005-06-07 2006-12-14 Koninklijke Philips Electronics, N.V. Procede et appareil d'apport de medicaments par ultrasons et therapie thermique avec fluides convertible par phase
WO2008065561A1 (fr) * 2006-11-28 2008-06-05 Koninklijke Philips Electronics, N.V. Appareil d'imagerie et de thérapie ultrasonores tridimensionnelles

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US20050123482A1 (en) * 1989-12-22 2005-06-09 Unger Evan C. Ultrasound imaging and treatment
WO1999039697A1 (fr) * 1998-02-06 1999-08-12 Point Biomedical Corporation Procede d'administration de medicaments par ultrasons
US20020151792A1 (en) * 1998-02-06 2002-10-17 Conston Stanley R. Method for ultrasound triggered drug delivery using hollow microbubbles with controlled fragility
US6740039B1 (en) * 1999-08-20 2004-05-25 Koninklijke Philips Electronics N.V. Methods and apparatus for displaying information relating to delivery and activation of a therapeutic agent using ultrasound energy
WO2001024705A1 (fr) * 1999-10-06 2001-04-12 Imarx Therapeutics, Inc. Techniques ameliorees permettant de delivrer des agents bioactifs
WO2005020918A2 (fr) * 2003-08-27 2005-03-10 The Regents Of The University Of California Concentration ultrasonique de capsules d'administration de medicaments
WO2006131840A2 (fr) * 2005-06-07 2006-12-14 Koninklijke Philips Electronics, N.V. Procede et appareil d'apport de medicaments par ultrasons et therapie thermique avec fluides convertible par phase
WO2008065561A1 (fr) * 2006-11-28 2008-06-05 Koninklijke Philips Electronics, N.V. Appareil d'imagerie et de thérapie ultrasonores tridimensionnelles

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013046076A1 (fr) * 2011-09-28 2013-04-04 Koninklijke Philips Electronics N.V. Administration automatisée à médiation par ultrasons
CN103826692A (zh) * 2011-09-28 2014-05-28 皇家飞利浦有限公司 自动化超声介导递送
US9643000B2 (en) 2011-09-28 2017-05-09 Koninklijke Philips N.V. Automated ultrasound mediated delivery
WO2021158510A1 (fr) * 2020-02-05 2021-08-12 FUJIFILM Cellular Dynamics, Inc. Appareil et procédés pour l'administration d'une suspension cellulaire

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