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WO1993003671A1 - Procede d'imagerie par resonance magnetique utilisant des agents de contraste diamagnetiques - Google Patents

Procede d'imagerie par resonance magnetique utilisant des agents de contraste diamagnetiques Download PDF

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Publication number
WO1993003671A1
WO1993003671A1 PCT/US1991/005757 US9105757W WO9303671A1 WO 1993003671 A1 WO1993003671 A1 WO 1993003671A1 US 9105757 W US9105757 W US 9105757W WO 9303671 A1 WO9303671 A1 WO 9303671A1
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WIPO (PCT)
Prior art keywords
imaging
microspheres
mri
carried out
technique
Prior art date
Application number
PCT/US1991/005757
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English (en)
Inventor
Kenneth J. Widder
James L. Barnhart
Original Assignee
Molecular Biosystem, 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 Molecular Biosystem, Inc. filed Critical Molecular Biosystem, Inc.
Priority to EP19920902640 priority Critical patent/EP0599839A4/en
Priority to CA002115582A priority patent/CA2115582A1/fr
Priority to PCT/US1991/005757 priority patent/WO1993003671A1/fr
Priority claimed from CA002115582A external-priority patent/CA2115582A1/fr
Publication of WO1993003671A1 publication Critical patent/WO1993003671A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/563—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution of moving material, e.g. flow contrast angiography

Definitions

  • the field of this invention is magnetic resonance imaging (MRI) , and more particularly MRI imaging using contrast agents.
  • MRI magnetic resonance imaging
  • contrast agents for improving magnetic resonance imaging of protons have consisted of magnetizable substances comprising metals or metallic compounds.
  • Such contrast agents may be paramagnetic, ferromagnetic, or superparamagnetic, which act through dipole interactions with tissue protons. Where the substance is toxic, such as gadolinium, it can be administered in chelated form.
  • ultrafine particles of a ferromagnetic or superparamagnetic material such as magnetite (Fe 3 0 4 ) , have been dispersed in a biodegradable matrix material, and formed into microspheres which are capable of passing through capillaries.
  • magnetite Fe 3 0 4
  • Patents 4,675,173 and 4,849,217 A preferred biodegradable material is human serum albumin.
  • Albumin is not known to have any MRI contrast-producing properties. It is the magnetizable particles dispersed in the albumin which produces the MRI contrast effect.
  • gas microbubbles are strong scatterers of ultrasonic waves in fluid media, and may therefore be useful as an imaging agent for ultrasonic echographic imaging (U.S. Patent 4,276,885).
  • the preparation and use of sonication-produced ultrasonic imaging agents is disclosed in United States Patents 4,572,203, 4,718,433 and 4,774,958.
  • microbubbles as an MRI contrast agent.
  • MRI utilizes radio frequency pulses and magnetic field gradients applied to a subject in a strong field to produce the images.
  • the scientific principles and mechanisms involved are entirely different from ultrasonic imaging which utilizes high frequency sound waves.
  • MRI TERMINOLOGY Artifacts Undesirable features in NMR images which do not correspond to true anatomical or pathological conditions which may be caused by non-ideal effects in the imaging process.
  • Echo Time (ET) A timing parameter in an NMR pulse sequence which describes the time delay between the RF excitation pulse and acquisition of the NMR signal.
  • FID Free induction decay, which is the fundamental signal detected in NMR.
  • FOV Field of view
  • Magnetic Susceptibility The constant of proportionality which relates the degree of magnetization of a material to the strength of an applied magnetic field.
  • Pulse Sequence A series of RF pulses used in conjunction with gradient magnetic fields and NMR signal reception to produce NMR images.
  • Repetition Time (TR) The time to repeat parameter in an NMR pulse sequence which comprises the interval between repetitions of RF excitation pulses.
  • RF Radio Frequency.
  • Tl Spin-lattice relaxation time or longitudinal relaxation time which is the characteristic time constant for spins to tend to align themselves with an external magnetic field.
  • T2 Spin-spin or transverse relaxation time which is the characteristic time constant for loss of phase coherence among spins oriented at an angle to a static magnetic field.
  • T2* The apparent transverse relaxation time which combines the true T2 of a sample with additional factors producing a loss of phase coherence of the NMR signal; such as magnetic field inhomogeneities.
  • Tl-Weighted .An MR image which is made using pulse sequence parameters which emphasize differences in the Tl of the subject.
  • T2-Weighted An MR image which is made using pulse sequence parameters which emphasize differences in the T2 of the subject.
  • the method of magnetic resonance imaging of this invention which is particularly applicable for vascular system imaging, employs a diamagnetic contrast agent.
  • the diamagnetic agent comprises gas-carrying, non-magnetic microparticles predominantly of diameters less than 8 microns.
  • This contrast agent is introduced into the blood before or during the MRI examination.
  • MRI imaging is carried out by a T2-weighted technique.
  • the portion of the blood containing the diamagnetic imaging agent is contrasted by its difference in magnetic susceptibility. This is believed to be caused by the gas bubbles producing magnetic susceptibility gradients which result in a shortened T2*.
  • the segment of blood being imaged with the assistance of the diamagnetic contrast agent will experience an enhanced signal loss and will appear dark against the surrounding tissues.
  • the method of this invention can be used for examinations of the circulatory system for pathological conditions which may exist in the capillaries, in the heart or in the arteries or veins. Specifically, it is expected that angiograms and venogra s of clinical image quality can be obtained.
  • DETAILED DESCRIPTION The method of this invention can be practiced with gas-microbubbles, which may be encapsulated by non-magnetic materials, or which are associated with particulates which are non-magnetic.
  • Diamagnetic imaging agents for use in the method of this invention comprise gas-carrying, non-magnetic microparticles which are predominately of less than 8 microns diameter so they can pass through capillaries.
  • microbubbles may be produced and administered as described in United States patents 4,572,203 and 4,718,433. (For other methods of microbubble generation, see Schlepper, i ⁇ mer. Heart J.. 115:399-408, 1988; and Butler, et al.. Ultrasound Imaging. 12:150, JUDSt. 9.2, 1990.)
  • the magnetic resonance imaging method of this inven- tion preferably employs microspheres consisting of gas microbubbles encapsulated by a stabilized biocompatible material.
  • the "ALBUNEX" microspheres of Molecular Biosystems, Inc. are an example of the kind of imaging agent which can be used most effectively in the method of this invention.
  • the microsphere contrast agent nor the blood or tissues being imaged are magnetic substances. They are diamagnetic. Nevertheless, image contrast effects can be obtained because of differences in magnetic susceptibility.
  • the MRI method of this invention involves magnetic susceptibility effects. Such effects have been discussed in the literature primarily as a problem to be overcome or avoided. As stated in “Enhanced Magnetic Resonance Imaging, (cited above) at pages 35 to 36: “Abrupt changes in magnetic susceptibility distort the magnetic field locally. like any other static magnetic field inhomogeneitity. As a result, the shape of anatomic structures can become warped in both spin-echo and gradient-echo techniques.” Large air filled cavities in the body such as the sinus or bowel can result in reduced image intensity due to a magnetic susceptibility effects. Ludeke, et al., Ma . Res. Ima .. 3:329-343, 1985, studied these effects using image artifacts in images of phantoms containing air. It was proposed that procedures should be used to correct image distortions caused by susceptibility variations created by air-filled cavities in the body.
  • Encapsulated gas-center microspheres for use in the method of this invention can be prepared as described in U.S. Patent 4,844,882, or by the continuous single-stage method described in U.S. Application Ser. No. 244,844, which is co-owned with the present application.
  • a suitable product of this kind is presently described as an ultra-sonic imaging agent. It is available from Molecular Biosyste s, Inc. of San Diego, CA, being called by the registered trademark "ALBUNEX".
  • microbubble preparations which can be used in the method of this invention are also available for ultrasonic imaging applications. These include air- carrying galactose particles ["Echovist”, Schering AG, West Germany, as described by Fritzsch, et al.. Invest. Radiol. (Suppl) 23:S302-S305, 1988; and, "Levovist”, Schering AG, West Germany, as described by Smith, et al., J. Am. College Cardiology. 13:1622-1628, 1989]. The methods of manufac- turing products corresponding to "Echovist” and "Levovist” are described in published European patent applications Nos. 0 035 467 and 0 122 624.
  • galactose (1988 gr.) and palmitic acid (120 gr.) are dissolved in ethanol, sterile filtered, and the solution is evaporated to dryness.
  • the dried material is milled under aseptic conditions to a grain size in a range of 1 to 5 microns.
  • the microparticles are mixed with water and shaken vigorously until a homogeneous suspension results. This causes air bubbles to become associated with the particles, being on the particle surfaces or in intracrystal1ine crevices.
  • a preferred MRI contrast agent as prepared for administration comprises a sterile aqueous medium containing a dispersion of microspheres predominately of diameters of less than 8 microns.
  • the microspheres consist of gas microbubbles encapsulated by a stabilized biocompatible material.
  • the preferred microspheres have centers of air surrounded by heat-insolubilized human serum albumin. Other gases can be used such as oxygen, carbon dioxide, or nitrogen.
  • the aqueous medium may consist of an albumin solution, normal saline, or other aqueous medium suitable for intravenous injection.
  • the medium as well as the microspheres should be sterile.
  • microspheres or other gas-carrying microparticles should be of diameters of less than 10 microns, and preferably predominately of less than 8 microns for easy passage through capillaries. For example, microparticles in the range from 2 to 6 microns are suitable.
  • the "ALBUNEX" product of Molecular Biosystems, Inc. which is especially suitable for use in the method of this invention, can -lo ⁇ be prepared by sonication of a 5% aqueous solution of human serum albumin by the process of co-owned application Serial No. 244,844.
  • the air-center albumin encapsulated microspheres are about 90% below 8 microns.
  • the microspheres can be highly concentrated, such as up to 5 x 10 8 microspheres per milliliter.
  • the "ALBUNEX" product has excellent stability at ordinary room temperatures; being stable from 6 to 12 months or longer.
  • the imaging agents used in the method of this invention should contain gas-carrying particles or microspheres at concentrations of at least 1 x 10 4 microspheres per milliliter of imaging agent. In preferred embodiments higher concentration are used, viz. concentrations of at least 1 x 10 6 microspheres per milliliter.
  • the contrast agent is administered into the circulating blood of a human subject, or other mammal, either prior to or during the MRI examination.
  • a bolus of the imaging agent may be introduced into a vein or artery by hypodermic injection or by catheter.
  • the introduction site may be at or close to the site where the examination is to be made.
  • the imaging agent can be transferred through the bloodstream to the site of examination.
  • the preferred microspheres are sized so that they pass readily through capillaries. It is therefore feasible to introduce the contrast agent into a peripheral vein for transfer through the circulatory system.
  • an effective imaging amount may range from 3 to 50 milliliters, depending upon the purpose of the examination. More specifically, the amount administered may be from 3.5 to 20 milliliters when employing concentrations of at least 1 x 10 microspheres per milliliter in imaging the heart or vascular system.
  • the method of this invention is believed to be particularly adapted for blood flow examinations, as in angiography.
  • the rate of blood flow and course of the administered microspheres can be directly observed.
  • the method is therefore adapted for imaging the vasculature to produce contrast-enhanced MR angiograms.
  • T2-weighted MRI imaging When an imaging amount of the diamagnetic agent used in the method of this invention has reached the site to be imaged, it is preferred to carry out T2-weighted MRI imaging.
  • the portion of the blood containing the imaging agent is contrasted by its difference in magnetic susceptibility, producing a shortened T2* effect.
  • An echo planar technique may be used, which utilizes a single radio frequency excitation pulse.
  • the MR imaging may be carried out by techniques using a series of radio frequency excitation pulses in fast MRI where the time-to- repeat (TR) is substantially less than 1 second, such as less than 100 milliseconds.
  • Fast imaging techniques may be employed as described in "Enhanced Magnetic Resonance Imaging", Runge, Ed. (1989) , cited above, at pages 31-35.
  • a fast gradient echo technique may be used with a series of radio frequency pulses and time-to-repeat (TR) of less than 100 milliseconds.
  • TR time-to-repeat
  • a low flip angle (less than 90°) is preferably employed with gradient- reversal echos.
  • FLASH sequences include "spoiling-Flash” as one type, and "refocusing-Flash” as another.
  • spoiling sequences the coherence of transverse magnetization is destroyed between excitation pulses, and the observed signal is based on the steady-state level of longitudinal magnetization.
  • refocusing sequences the coherence of transverse magnetization is preserved. Both types use gradient-reversal echos.
  • sequences in which the transverse magnetization is spoiled In T2-weighted imaging with a diamagnetic agent this should improve the contrast obtained by shortened T2* effects.
  • the method of this invention is also believed to be applicable to multiecho MR angiography as described by Du oulin, et al. Mag. Res. Med.. 5:47-57 (1987); and 6:275-286 (1988).
  • the technique described by Dumoulin, et al. has been called phase contrast angiography.
  • EXPERIMENTAL TESTS The practicality of the method of this invention is shown by the following experiments.
  • the MRI equipment used was a General Electric CSI 2 Tesla unit with GE Acustar S-150 self-shielded gradient coils. This equipment is designed for use with "GRASS” and "EZGRASS” sequences, as well as other sequences, including Spin Echo and Echo Planar.
  • a lOcc bottle substantially filled with "ALBUNEX” was used as a specimen.
  • This sample consisted of air-containing microspheres ranging in size primarily from 2 to 6 microns at a concentration of around 1 x 10° microspheres per milliliter. The amount of encapsulated air was estimated to be about 2% by volume of the "ALBUNEX" sample.
  • a comparative sample consisted of a lOcc glass test tube filled with tap water. These samples were subjected to a Spin Echo sequence which was Tl-weighted. No differences in image intensity were observed between the two samples.
  • the samples were then examined by the "GE EZGRASS" pulse sequence with T2-weighting.
  • the field of view was 60mm, the TR 500 milliseconds, the TE 16 milliseconds, and the slice thickness was 1.0 cm. Images were obtained in a 20 bit resolution pixel format without frame averaging. The resulting images were transferred to a work station where the image data was scaled and converted to an eight-bit format and analyzed and formatted. Signal intensity values from this image analysis ranged from zero (white) to 255 (black) .
  • the T2-weighted "EZGRASS" image of the "ALBUNEX" sample produced a significant increase in signal loss. This signal loss was not observed from the water sample.
  • the water sample had a signal intensity value of 56 as compared with 249 for the "ALBUNEX” sample.
  • the procedure was repeated with a sample in which the "ALBUNEX" microspheres had been disrupted to permit their air centers to escape leaving the albumin wall material without entrapped air. No image enhancement was observed.
  • the disrupted "ALBUNEX” residue and the water sample were comparable. This indicated that the previously observed enhancement was caused by the air-centers of the microspheres and not by the albumin, although the amount of air present was very small (viz. about 2% of the sample volume).
  • a rat was anesthetized and a catheter placed in its tail vein. The rat was placed in the imaging cradle of the GE Acustar MRI unit described above. .An "ALBUNEX" sample like that described above was used, 5 cc being injected slowly into the rat. An Echo Planar sequence was used with TE of approximately 16 milliseconds. Observing the rat's right heart ventricle, a decrease in signal intensity was measured due to the "ALBUNEX" of 134 as compared with 53 for the blood.
  • the resulting images were transferred to a work station where the image data was scaled and converted to an eight-bit format and analyzed and formatted. Signal intensity values ranged from zero (white) to 255 (black) . A positive essentially linear relationship was found between loss of signal intensity and the amount of air contained in the microspheres.

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Abstract

Procédé d'imagerie par résonance magnétique (IRM) qui emploie un agent de contraste diamagnétique comportant des micro-particules non magnétiques porteuses de gaz. Lesdites micro-particules sont de préférence des microsphères constituées de minuscules bulles de gaz encapsulées dans un matériau biocompatible stabilisé. Ledit procédé est particulièrement utile pour visualiser le système vasculaire, dans l'angiographie ou la phlébographie par exemple.
PCT/US1991/005757 1991-08-13 1991-08-13 Procede d'imagerie par resonance magnetique utilisant des agents de contraste diamagnetiques WO1993003671A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP19920902640 EP0599839A4 (en) 1991-08-13 1991-08-13 Method of mri imaging using diamagnetic contrast agents.
CA002115582A CA2115582A1 (fr) 1991-08-13 1991-08-13 Methode d'imagerie a resonance magnetique utilisant des agents de contraste diamagnetiques
PCT/US1991/005757 WO1993003671A1 (fr) 1991-08-13 1991-08-13 Procede d'imagerie par resonance magnetique utilisant des agents de contraste diamagnetiques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA002115582A CA2115582A1 (fr) 1991-08-13 1991-08-13 Methode d'imagerie a resonance magnetique utilisant des agents de contraste diamagnetiques
PCT/US1991/005757 WO1993003671A1 (fr) 1991-08-13 1991-08-13 Procede d'imagerie par resonance magnetique utilisant des agents de contraste diamagnetiques

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5540909A (en) * 1994-09-28 1996-07-30 Alliance Pharmaceutical Corp. Harmonic ultrasound imaging with microbubbles
US5605673A (en) * 1993-07-30 1997-02-25 Alliance Pharmaceutical Corp. Stabilized microbubble compositions for ultrasound
DE19626530A1 (de) * 1996-07-02 1998-01-15 Byk Gulden Lomberg Chem Fab MR-Kontrastmittelzubereitungen
US5798091A (en) * 1993-07-30 1998-08-25 Alliance Pharmaceutical Corp. Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
US5804162A (en) * 1995-06-07 1998-09-08 Alliance Pharmaceutical Corp. Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients

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US4657756A (en) * 1980-11-17 1987-04-14 Schering Aktiengesellschaft Microbubble precursors and apparatus for their production and use
US4775522A (en) * 1983-03-04 1988-10-04 Children's Hospital Research Foundation, A Division Of Children's Hospital Medical Center NMR compositions for indirectly detecting a dissolved gas in an animal
US4900540A (en) * 1983-06-20 1990-02-13 Trustees Of The University Of Massachusetts Lipisomes containing gas for ultrasound detection

Patent Citations (3)

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US4657756A (en) * 1980-11-17 1987-04-14 Schering Aktiengesellschaft Microbubble precursors and apparatus for their production and use
US4775522A (en) * 1983-03-04 1988-10-04 Children's Hospital Research Foundation, A Division Of Children's Hospital Medical Center NMR compositions for indirectly detecting a dissolved gas in an animal
US4900540A (en) * 1983-06-20 1990-02-13 Trustees Of The University Of Massachusetts Lipisomes containing gas for ultrasound detection

Non-Patent Citations (2)

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Title
"Von Nostrand's Scientific Encyclopedia", published 1967, by D. Von Nostrand's Company, Inc., (Princeton, New Jersey), see page 1063. *
See also references of EP0599839A4 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6372195B1 (en) 1993-07-30 2002-04-16 Alliance Pharmaceutical Corp. Mixed gas microbubble compositions
US6706253B2 (en) 1993-07-30 2004-03-16 Ernest G. Schutt Osmotically stabilized microbubble preparations
US5626833A (en) * 1993-07-30 1997-05-06 Alliance Pharmaceutical Corp. Ultrasound imaging method using microbubbles
US5639443A (en) * 1993-07-30 1997-06-17 Alliance Pharmaceutical Corp. Stabilized microbubble compositions
US5695741A (en) * 1993-07-30 1997-12-09 Alliance Pharmaceutical Corp. Stable microbubble precursors
US7141235B2 (en) 1993-07-30 2006-11-28 Imcor Pharmaceutical Co. Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
US5720938A (en) * 1993-07-30 1998-02-24 Alliance Pharmaceutical Corp. Systems for the formation of microbubbles
US7005120B2 (en) 1993-07-30 2006-02-28 Imcor Pharmaceutical Company Osmotically stabilized microbubble preparations
US5798091A (en) * 1993-07-30 1998-08-25 Alliance Pharmaceutical Corp. Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
US6939531B2 (en) 1993-07-30 2005-09-06 Imcor Pharmaceutical Company Ultrasonic imaging system utilizing a long-persistence contrast agent
US6258339B1 (en) 1993-07-30 2001-07-10 Alliance Pharmaceutical Corp. Osmotically stabilized microbubble preparations
US6287539B1 (en) 1993-07-30 2001-09-11 Alliance Pharmaceuticals Corp. Methods of imaging using osmotically stabilized microbubble preparations
US5605673A (en) * 1993-07-30 1997-02-25 Alliance Pharmaceutical Corp. Stabilized microbubble compositions for ultrasound
US6953569B2 (en) 1993-07-30 2005-10-11 Imcor Pharmaceutical Company Mixed gas microbubble compositions
US6280704B1 (en) 1993-07-30 2001-08-28 Alliance Pharmaceutical Corp. Ultrasonic imaging system utilizing a long-persistence contrast agent
US6280705B1 (en) 1993-07-30 2001-08-28 Alliance Pharmaceutical Corp. Kits & systems for ultrasonic imaging
US6056943A (en) * 1994-09-28 2000-05-02 Alliance Pharmaceutical Corp. Methods of ultrasound imaging using phospholipid stabilized microbubbles
US6036644A (en) * 1994-09-28 2000-03-14 Alliance Pharmaceutical Corp. Enhanced methods of ultrasound imaging using multiple frequencies
US5540909A (en) * 1994-09-28 1996-07-30 Alliance Pharmaceutical Corp. Harmonic ultrasound imaging with microbubbles
US6019960A (en) * 1994-09-28 2000-02-01 Alliance Pharmaceutical Corp. Systems for harmonic ultrasound imaging
US5733527A (en) * 1994-09-28 1998-03-31 Alliance Pharmaceutical Corp. Methods for harmonic imaging with ultrasound
US7374744B2 (en) 1994-09-28 2008-05-20 Imcor Pharmaceutical Co. Harmonic ultrasound imaging with microbubbles
US5804162A (en) * 1995-06-07 1998-09-08 Alliance Pharmaceutical Corp. Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients
US6193952B1 (en) 1995-06-07 2001-02-27 Alliance Pharmaceutical Corp. Stabilized gas emulsions containing phospholipid for ultrasound contrast enhancement
DE19626530A1 (de) * 1996-07-02 1998-01-15 Byk Gulden Lomberg Chem Fab MR-Kontrastmittelzubereitungen

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