CA1274773A - Contrast agents for ultrasonic imaging and method of use - Google Patents

Contrast agents for ultrasonic imaging and method of use

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Publication number
CA1274773A
CA1274773A CA000524419A CA524419A CA1274773A CA 1274773 A CA1274773 A CA 1274773A CA 000524419 A CA000524419 A CA 000524419A CA 524419 A CA524419 A CA 524419A CA 1274773 A CA1274773 A CA 1274773A
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Prior art keywords
microbubbles
protein
solution
sonication
further characterized
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CA000524419A
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French (fr)
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Steven B. Feinstein
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01S—RADIO DIRECTION-FINDING; RADIO NAVIGATION; DETERMINING DISTANCE OR VELOCITY BY USE OF RADIO WAVES; LOCATING OR PRESENCE-DETECTING BY USE OF THE REFLECTION OR RERADIATION OF RADIO WAVES; ANALOGOUS ARRANGEMENTS USING OTHER WAVES
    • G01S15/00—Systems using the reflection or reradiation of acoustic waves, e.g. sonar systems
    • G01S15/88—Sonar systems specially adapted for specific applications
    • G01S15/89—Sonar systems specially adapted for specific applications for mapping or imaging
    • G01S15/8906—Short-range imaging systems; Acoustic microscope systems using pulse-echo techniques
    • G01S15/899—Combination of imaging systems with ancillary equipment
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
    • A61B2090/3925—Markers, e.g. radio-opaque or breast lesions markers ultrasonic

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  • Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Radar, Positioning & Navigation (AREA)
  • Remote Sensing (AREA)
  • Acoustics & Sound (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Physics & Mathematics (AREA)
  • Epidemiology (AREA)
  • Computer Networks & Wireless Communication (AREA)
  • Hematology (AREA)
  • Biophysics (AREA)
  • Pathology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Surgery (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Ultra Sonic Daignosis Equipment (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE
A method of ultrasonic imaging for use in medical pro-cedures is disclosed. The method comprises providing specifically defined microbubbles formed by sonicating a biocompatible liquid comprising a sonicated aqueous protein solution, preferably a 5% solution of human serum albumin, and denaturing the protein therein by heat or chemical methods; injecting the microbubbles into an animal or human to thereby alter the acoustic properties of an area to be imaged; and then ultrasonically scanning the area so as to obtain an ultrasound scanning image.

Description

~3 CONTRAST AGENTs FOR I~LTRASON I C I MAG I NG
AND MET~IOD O~: USE

FIELD OF INVE~TION
T~is invention relates to the field of ultrasonic imaging techniques, and more specifically, to a medical procedure which utilizes ~hese ~echni~ues as a diagnostic tool.

BACKGROUND OP INVENTION
Various technologies exist in which parts of an animal or human body may be imaged so as to aid in diagnosis and therapy. Recently, there have been advances in techniques for ultrasonically imaging various parts of the body;
these techniques when applied to thR heart in particular are known as "echocardiography." An ultrasonic scanner is used to generate and receive sound waves. T~e ultrasonic scanner is placed on the body surface overlying the area to be imaged. The sound waves generated by the scanner are directed toward the area to be imaged. The scanner then detects sound waves reflected from the underlying area and translates that data into images.
While such ultrasonic scanners are known in the art, a brief review will be set forth in order to more fully explain the present invention. When ultrasonic energy is transmitted through a substance, the acoustic properties of the substance will depend upon the velocity of the transmissions and the density of the substance. Changes in the substance's acoustic properties (or acoustic imped-ance) will be most prominent at the interface of different substances (i.e., solids, liquids and gases). As a con-sequence, when ultrasonic energy is directed through vari-ous media, the changes in acoustic properties will change the reflection characteristics, resulting in a more intense sound reflection signal received by the ultra-sonic scanner.
Early ultrasonic imaging techniques such as echocardi-i,~

~2~

ograms ~ffered from a lack o~ olarity. As a result, ex-tensive efforts were undertaken to improve the ultrasonic scanners and related equipment. In addition, beginning in 1968, "contrast" agen~s were injected into the bloodstream in an effort to obtain clearer or "enhanced" ultrasonic images. The prior art contrast agents were liquids con-taining microbubbles of gas, which sometimes were encapsu-lated with gelatin or saccharine and sometimes were pro-duced by mechanically agitating, i.e., handshaking, mix-tures of various liquids. Other prior art contrast agents are disclosed in an article by J. Ophir, et al. entitled "Ultrasonic Backscatter from Contrast Produced by Collagen Microspheres" in Ultrasonic Imaging by Academic Press, Inc.
1980.
The contrast agents themselves are intense sound wave reflectors because of the acoustic diferences between the liquid and the gas microbubbles dissolved therein; thus, when the contrast agents are injected into and perfuse the microvasculature of tissue, clearer images of such tissue , may be produced. However, notwithstanding the use of such contrast agents, the image produced, for example of the myocardial tissue, is of relatively poor quality, is highly variable and is not quantifiable due to the variable size and persistence associated with prior art microbubbles.
Further, the problems of air emulsion toxicity have not yet been investigated.
In a-ttempting to find a safe, reproducible, quantifi-able contrast agent for use in producing an enhanced ultra-sonic image of the tissue under study, researchers have used saccharine and gelatin encapsulated microbubbles of nitrogen or carbon dioxide gas having a mean size of ap-proximately 75 microns, pressurized gas in liquids (e.g., H202), and mechanically agitated (hand shakenl mixtures of liquid solutions. However, since the pulmonary artery capillaries are about 8 to 10 microns in diameter, the 75 micron encapsulated microbubbles may not cross the capil-larv beds and, as a re ~lt, tbeir use would require adirect injection into the area to be imaged or an arterial injection involving the same risks as the invasive approach or angiography discussed above. Further, microbub~les produced by agita~ing various liquids other than by soni-cating them) have wide variability of size. Variable amounts of such non-encapsulated agitated microbubbles can pass through capillaries, but the present state of the art has only prod~ced qualitative data due to the inability to control the variables described above. These contrast agents all work to some degree, but suffer from a number of problems including the fact that the size of the bubbles is not uni~orm.
~ Iy research has demonstrated the feasibility of an im-proved ultrasonic imaging method as described in published PCT Application WO 84/02838, and in my corresponding United States Patent 4,~72,203, issued February 26, 1986. One of my previously disclosed methods utilizes biodegradeable metal-containing microparticles, and another disclosed method utilizes a biocompatible liquid. More specifically, the latter method involves subjecting a biocompatible liquid to high frequency energy in the range o~ about 5000 to 30,000 Hz so as to produce microbubbles having substan tially uniform diameter; in~ecting the bubbles into a mam mal to thereby alter the acoustic properties of a predeter-mined area; and ultrasonically scanning an area including the predetermined area so as to obtain an enhanced image of the predetermined area. Microbubbles may have a mean particle size of up to 20 microns. lhe useable viscous liquid, as disclosed, is to be selected from solutions of dextrose, sorbitol, relatively nontoxic radio-opaque dye, and mixtures thereof.

~2~3 SU~ RY OF rHI. INV~NTION
The p~esent invention is directe-l to an improvement in my ultrasonic imaging method hy wllich smaller and more un;form microbubbles are producecl, and particularl~ to the novel use of specifically defined semi-soli(l contrast agents.
In t~e first embodiment of the present invention, a viscous solution (e.g., 5~ lluman serum albumin) is sub-jected to high frequency (5,000 to 30,000 Hz) ultrasonic energy. As a result, microbubbles ~ving a diameter of appro~imately Z to 4 microns are produced. For each of reference such microbubbles will be referred to herein as "sonicated" micro~ubbles. As described in great detail hereinhelo~, ~ch sonicated microbubbles have been found to be improved contrast agents.
In a second embodiment of the present invention, microbubbles or microspheres comprising protein or derivatives thereof in an aqueous solution are formed into stable contrast agents by any of a number of methods kno~n in the art for physically (via heat) or chemically alter-ing the protein or derivatives to denature or fix the material. For example, the use of heat applied to the con-trast agent after formation thereof, or during formation as a result of the sonication of the same is one method for denaturing the protein ma~erial to form stable contrast agents. ~s a second method, fixation (i.e., chemical de-naturation) of the protein material using formaldehyde or gluteraldehyde may also be utilized to form stable contrast agents.
T~e contrast agents of the presellt inventioll are cle-tectecl by conventional ultrasonic scanning e~uipment and translatecl into images in t~e manner described above.

.~

~1 2~73 s Thus, while overcomin~ many of t1~ problcms associ-ated with tbe prior art, the present invention makcs pos-sible tlle production of uni~ue images of various or~an systems. A1thoug11 the invention tecbni~ue is applicable to various animal and human body or~an systems, its novcl features and advantages may be l)etter understood from t1~e following description of i~s use in obtaining images of myocardial tissue and perfusion or hlood flow patterns.
In reviewing the description, it should be Xept in mind that the heart is a "pum~" fed by many blood vessels which, during the course of time, may become partially or totally blocked, causing damage to the heart tissue. In the past, information concerning the heart tissue 1~as obtained using radionuclide imaging or surgery;
the angiogram produced no direct data regarding the tis-sue, but rather required the dra~ing of inferences from data obtained ~ith respect to the major l~lood vessels and wall motions of the heart.

DETAILED DESCRIPTION OF THE INVENTION
The met ~d of this invention uses e~uipment like that described in mv prior U.S. Patent 4,572,203. This com-prises ultrasonic scanning equipment consisting of a scan-ner and imaging apl)aratus. The e~ui1)1nent prod1lces visual ;mages of a predetermined area, in this case, the heart region of a human body. Typically, t~,e scanner is placed directly on the skin over the area to be imaged. rhe scan-ner houses various electronic coml~onents incluc1ing ultra-sonic transducers. T11c scanner produces ultrasonic ~avcs ~hicl11)erfor1n a sector scan of the he3rt region. 111e u1trasonic ~aves are reflecte~ by the various 1)ortions of ',~

~7~

the heart region and are received by the generating trans-ducer and processed in accordance with pulse-echo methods known in the art. After processing, signals are sent to the imaging apparatus ~also well known in tl~ art) for viewing.
In the method of the present invention, after the patient is "prepped'l and the scanner is in place, the sonicated microbubble or microparticle contrast agent is injected, for example, through an arm vein. The contrast agent flows through the vein to the right venous sid~ of the heart, through t~R main pulmonary artery leading to the lungs, across the lungs, through the capillaries7 into the pulmonary vein and finally into the left atrîum and the left ventricular cavity of the heart.
The present invention is directed to both sonicated microbubbles. While not to be bound by any theoTy, the sonicated microbubbles of the present invention produce noticeably clearer and more detailed images of the myo-cardial tissue and microvasculature. This has been demon-~strated experimentally. The microbubbles were injected into the pulmonary artery of a dog and have crossed the capillary beds of the lung to enter the left atrium and the left ventricular cavity into the aorta through the coro-nary arteries and eventually into the left ventricular tissue enhancing the image thercof.
With the method of this invention, observ~tions and diagnoses can be made with respect to the amount of time required for the blood to pass thxough the lungs, blood flow patterns, the size o the le~t atrium, th.e competence of the mitral valve ~which separates the left atrium and left ventricle), chamber dimensions in the left ventricular cavity, and wall motion abnormalities. Up~n ejection of the contrast agent from the left ventricle, the competence of the aortic valve also may be analyzed, as well as the ejection fraction or percentage of volume ejected from the left ventricle. Finally, the contrast patterns in the ~3 tissue will indicake which areas, iE any, ~re not bcing adequa~ely perfused.
In sunnmary, such a pattern of images will help diag-nose unusual blood flow ch~racteristics within t~.e hear~, valvular competence, chamber sizes and wall motion, and will provide a potential indicator of myGcardial perfusion.
In a presently preferred embodiment of the invention, a solution of protein or derivatives thereof, capable of forming microbubbles or microspheres when sonica~ed in ac-cordance with ~he above-described procedure, is used. One example of a useful solution is a 5% aqueous solution of human serum albumin, referred to herein as albumin. Al-bumin in solution is commercially availa~le from any of a number of sources. While not being bound by any particular theory of operation, it appears that sonication of the solution un~er conditions discussed above causes the forma-tion of microbubbles. The resulting microbubbles are sub-stantially different from those described above in that the walls of the microbubbles are significantly more stable, thereby making th~e microbubbles themselves more stable.
The stability of these microbubbles is believed to be a result of the ~act that the sonicator heats the albumin to a temperature sufficient to denature the protein. The sonication also creates bubbles primarily in the range of
2-4 microns. The size distribution of microbubbles formed, as described above, out of a commercially available aqueous solution of 5~ albumin was studied. Substantially all of the microbubbles were in the range of 2-4 microns, as deterrnined by a Coulter Counter, using techniques well-known in the art. OE the microbubbles produced, approxi-mately 8 million per milliliter Iml.) of solution are in the 2-4 micron range, approximately 1 million microbubbles per ml. in the 4-5 micron range, less than 0.5 million microbubbles per ml. in the 5-6 micron range, and rela-tively negligible amounts of microbubbles in the range above 6 microns are formed.

~3 ~ s all alternative to heat treatment o the ~icrobub-bles as a result of sonication, the protein can ~e de-natured and the microbubbles stabilized by heat treatment to a tempeTature in the range of 50 to 60 Centigrade, with the actual temperature in the range depending on the protein, proteins used or protein derivatives used. The ~ecific temperature and conditions for denaturation of the various proteins which may be used for the present invention are generally known in the art.
The microbubbles formed from 5% albumin may, in the alternative, be sta~ilized to form a commercially, clin-ically usable contrast agent ~y treatment with various chemical agents which chemically denature, or "fix", the protein, and derivatives thereof. Chemical denaturation of the protein (or derivatives) may be accomplished by either binding the protein with a difunctional aldehyde, such as gluteraldehyde. For the latter procedure of stabilizing the invented microbubble contrast agent, the microbubbles may be reacted with 0.25 grams of 50% aqueous gluteraldehyde per gram of protein at pH4.5 for 6 hours.
The treated contrast agent is thén gently and extensively washed to remove as much of the unreacted gluteraldehyde as possible.
The microspheres formed from 5% albumin which has been sonicated as described are stabilized and exist for 48 hours or longer. This may be compared with the above-described sonicated sugar solutions which last a few minutes to a few hours. Thereafter, they are no longer effective contrast agents.
This invented echo contrast agent permits left heart imaging from intra~enous injections. The sonicated al-bumin microbubbles, when injected into a peripheral vein are capable of transpulmonary passage. This results in echocardiographic opacification of the left ventricle ~L~
cavity as well as myocardial tissue. The sonicated al-bumin microbubbles are small, stable and echo reflective 9 ~ "~3 targets.
A total of 72 intravenous injections of sonic~ted al-bumin microbubbles were performed in 5 dogs~ Three to 10 ml of contrast solution, containing ~ minimum of 500,000 bubbles per ml, were injected into t~e dorsal forepaw vein in each trial. No significant changes were noted in hear~
rate, blood pressure or arterial blood gases. LV cavity opacification was graded from O (no opacification) to ~3 ~full LV opacification) with the duration noted in seconds~
The overall successful transpulmonary opaci.fication rate was 78~ (56/72 trials). LV tissue opacification was al-ways preceded by +3 LV capacity opacification. Successful transpulmonary passage of the sonicated albumin micro-spheres was obser~ed if (a~ the RV contrast opacification was ~3, (b) the average sphere size was 4 microns, or less, and (c) the sphere concentration was at least one million per milliliter. The results are set forth below in Table 1.

LV Cavity ~pacificatin Co~trast in LV
Grade Trials cavity ~seconds?
~3 11 2~ + 8 +2 14 18 + ~
~1 31 12 ~ 17 0 16 o Thus, as shown here, successful opacification of the LV cavity and myocardial tissue is TIOW feasible using per-ipheral venous injections of sonicated albumin micro-spheres.
Besides the scanner briefly described above, there exist other ultrasonic scanners, examples of ~hich are dis-closed in U.S. Patent Nos. 4~143,554 and 4,315,435 basically, these patents relate to various techniques i.ncluding dynamic cross-sectional echography (DCE) for pro-~3 lo ducing sequenti~l two-dlmensional images of cross-sectional slices of animal or human anatomy by means of ultrasound energy at a frame rate sufficient to enable d~lamic ~isu-alization of moving ~rgans. Types o-f apparatus utilized in DCE are generally called DCE scanners and transmit and receive s~.ort, sonic pulses in the form of narrow beams or lines. The reflected signals' strength is a function of time, which is converted to a position using a nominal sound speed, and is displayed on a cathode ray tube or other suitable devices in a manner somewhat analogous to radar or sonar displays. While DCE can be used to produce images of many organ systems including the liver, gall bladder, pancreas and kidney, it is frequently used for visualization of tissue and major blood vessels of the heart.
The bubbles may be used for imaging a wide variety of areas, even when injected at a peripheral venous site.
Those areas include (without limitation): ~1) the venous drainage system to the heart; (2) the myocardial tissue and perfusion characteristics during an exercise treadmill test or the like, and (3) myocardial tissue after an oral ingestion or intra~enous injection of drugs designed to in-crease blood flow to the tissue. Additionally, the micro-s may be useful in delineating changes in the myo-~ . ~
cardial tissue perfusion due to interventions such as (1)coronary artery vein grafting; (2) coronary artery angio-plasty (balloon dilation of a narrowed artery); (3) use of thrombolytic agents (such as streptokinase) to dissolve clots in coronary arteries; or (4) perfusion defects or changes due to a recent heart attack.
Furthermore, at the time of a coronary angiogram (or a digital subtraction angiogram) an injection of the micro-particles may yrovide data with respect to tissue perfusion characteristics that would augment and complement the data obtained from the angiogram procedure, which identifies only the anatomy of th.e blood vessels.

:lL2~L77~

~ hrough the use of the microbu~bles of the present in-vention, other non-cardiac organ systems including without limitation the liver, spleen, kidney, etc. that are pres-ently imaged by ultrasonic techniques may be susceptible to an en ~ancement of such currentl y obtai:nable image s, and/
or the generation of new images showing perfusion and flow characteristics that had not previously been susceptible to imaging using prior art ultrasonic imagin~ techniques.

Claims (9)

PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. The method of producing an ultrasonic imaging agent characterized by the steps of preparing an aqueous protein solution, subjecting said solution to high frequency sonication while heating the solution sufficiently to denature portions of the protein, and forming a dispersion of microbubbles of relatively uniform size stabilized by the denatured protein.
2. The method of claim 1 further characterized by preparing said aqueous protein solution from albumin.
3. The method of claim 1 further characterized by forming said stabilized dispersion of microbubbles with a mean bubble diameter of less than 6 microns.
4. The method of any one of 1, 2, or 3 characterized by forming asid stabilized microbubbles with diameters primarily in the range of 2 to 4 microns.
5. The method of any one of 1, 2, or 3 further charac-terized by heating said solition sufficiently by means of the sonication to denature said protein portions.
6. The method of claim 1 further characterized by said protein being human serum albumin.
7. The method of claim 6 further characterized in that said human serum albumin is at a concentration of about 5%, said sonication is carried out by applying ultrasonic energy at about 5,000 to 30,000 Hz.
8. The method of claim 6 further characterized in that said sonication is carried out by applying ultrasonic energy at about 20,000 Hz.
9. The stabilized ultrasonic imaging agent produced according to any one of claims 1, 2 or 3.
CA000524419A 1985-12-05 1986-12-03 Contrast agents for ultrasonic imaging and method of use Expired CA1274773A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US06/805,975 US4718433A (en) 1983-01-27 1985-12-05 Contrast agents for ultrasonic imaging
US805,975 1985-12-05

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CA1274773A true CA1274773A (en) 1990-10-02

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US (2) US4718433A (en)
EP (1) EP0224934B1 (en)
JP (1) JPS62181033A (en)
AT (1) ATE72124T1 (en)
AU (1) AU575735B2 (en)
CA (1) CA1274773A (en)
DE (1) DE3683735D1 (en)

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