CA1279819C - Use of cross-linked hydrogel materials as image contrast agents in proton nuclear magnetic resonance tomography and tissue phantom kits containing such materials - Google Patents
Use of cross-linked hydrogel materials as image contrast agents in proton nuclear magnetic resonance tomography and tissue phantom kits containing such materialsInfo
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- 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
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- 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
- A61K49/1803—Semi-solid preparations, e.g. ointments, gels, hydrogels
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/806—Electrical property or magnetic property
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/24—Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry
Abstract
USE OF CROSS-LINKED HYDROGEL MATERIALS AS IMAGE CONTRAST
AGENTS IN PROTON NUCLEAR MAGNETIC RESONANCE TOMOGRAPHY AND
TISSUE PHANTOM KITS CONTAINING SUCH MATERIALS
ABSTRACT
Cross-linked hydrogel materials in the swollen state exhibit a range of nuclear magnetic resonance spin density values, spin-lattice or longitudinal relaxation (T1) values, and spin-spin or transverse relaxation (T2) values embracing that of the spectrum of values associated with animal and human tissues, thereby rendering such materials useful in nuclear magnetic resonance tomography equipment contrast determinations in physiological imaging and, as to those cross-linked hydrogel materials having T1 and T2 values substantially shorter than the surrounding tissue, such materials are useful as image contrast agents, for example, in the gastro-intestinal tract.
AGENTS IN PROTON NUCLEAR MAGNETIC RESONANCE TOMOGRAPHY AND
TISSUE PHANTOM KITS CONTAINING SUCH MATERIALS
ABSTRACT
Cross-linked hydrogel materials in the swollen state exhibit a range of nuclear magnetic resonance spin density values, spin-lattice or longitudinal relaxation (T1) values, and spin-spin or transverse relaxation (T2) values embracing that of the spectrum of values associated with animal and human tissues, thereby rendering such materials useful in nuclear magnetic resonance tomography equipment contrast determinations in physiological imaging and, as to those cross-linked hydrogel materials having T1 and T2 values substantially shorter than the surrounding tissue, such materials are useful as image contrast agents, for example, in the gastro-intestinal tract.
Description
~ ~79~
BACE~GROUND OF THE INVENTION
Proton nuclear magnetic resonance (NMR) tomography has become an important tool in biomedical research and medical diagnosis. The image contrast mechanis~s of NMR
are different from X-ray imaging, and provide substantial contrast between certain soft tissues that are nearly identical using radiological techniques~ Further, conventional radiological imaging techniques involve the use of high energy electromagnetic radiation associated with potential cancer induction, whereas the low energy radio waves associated with NMR poses no such risk.
However, while some soft tissu0s provide substantial contrast using NMR techniques, others, particularly those involving the gastrointestinal tract, yield a relatively low level of contrast in proton NMR imaying. This has prompted the development of suitable NMR contrast agents.
While numerous substances, such as vegetable oils and paramagnetic metal salt solutions, such as ferric chloride solutions and solutions of gadolinium oxide, have been used to visualize the lumen of the stomach and intestines in NMR
tomography, none have the coating and filling characteristics which have made barium sulfate so useful in radiological applications. Moreoverr many paramagnetic metal ion containing solutions e.g. those of Cu2+, Cr3+, Fe3+ and Mn2~, are generally toxic at concentrations which sufficiently shorten the spin relaxation times, Tl and T2, of the solution environment to render such solutions useful NMR contrast agents. Runge et al., Radiologv, Vol. 147, pp. 789-791 (1983).
~ ~ 7 ~ ~19 Further, since conventionally available proton NMR
tomography equipment is complex in terms of operator selectable parameters, there is a need for storage stable materials especially in the form of a collection or array, which substantially mimics the range of proton density values, spin-lattice or longitudinal relaxation (Tl) values, and spin-spin or traverse relaxation (T2) values, associated with various animal tissuer for tuning such selectable parameters. Appropriate tuning of the operator selectable parameters enables the operator to optimize the desired contrast characteristies associated with NMR
tomographic images, including, for example, inversion recovering images, partial saturation images, density images, spin echo images, and the like. See in general, Wehrli et al., Magnetic R~ n_~_ Ll~bL~ Vol. 2, pp. 3-16 (1984).
It has now been surprisingly discovered that synthetic substantially non-degradable cross-linked water-swellable hydrogel materials, having in the swollen state between about 5 to about 95~ water and containing functional ~roups which interact with water, possess nuclear magnetic resonance spin density values, and Tl and T2 values sufficiently analogous to the spectrum of values associated with mammalian tissue, such that the aqueous s~ollen materials are highly useful in proton NMR
tomographic imaging techniques, and overcome many of the disadvantages associated with known materials and techniques.
~.~7~8~9 ~, _ It has been further unexpectedly discovered that those hydrogels having Tl and T2 values substantially shorter than that of ~astro-intestinal viscera are highly useful as proton NMR image contrast agents.
Thus, it is an object of the instant invention to provide a method o~ contrasting a proton ~MR tomograph o~
the gastro-instestinal tract, or a portion thereof, by administering to a mammal, including man, an effective image contrasting amount of a physiologically tol~rable, synthetic substantially non-degradable cross-linked hydrogel having, in the aqueous swollen state, spin-lattice or spin-spin relaxation values substantially shorter than the surrounding gastro-intestinal tissue environment.
It is a further object of the instant invention to provide an aqueous coating suspension or slurry of particulate swollen synthetic substantially non-degradable cross-linked hydrogel, said hydrogel having spin-lattice or spin-spin relaxation values substantially shorter than the respective spin-lattice or s~in-spin average relaxation values of gastro-intestinal viscera, for use as proton NMR
contrast agents.
It is yet a further object of the instant invention to provide a collection or array of storage stable swollen cross-linked hydrogel materials possessing a range of nuclear magnetic resonance spin density values, spin-lat-tice relaxation values and spin-spin relaxation values, embracing at least a portion of the spectrum of such values '79~1~3 possessed by distinct anatomic mammalian tissue, and suitable for use in NMR imaging equipment for proton NMR
image contrast determinations.
These and other objects of the invention are apparent from the following disclosure.
DETAILED DISCLOSURE OF THE INVENTION
One embodiment of the instant invention relates to a method of contrasting a proton NMR tomograph o~ the gastro-intestinal tract of a mammal, by administering to the mammal an effective image contrasting amount of a physiologically tolerable cross-linked synthetic substantially non-degradable hydrogel in particulate form, said hydrogel having, in the aqueous swollen state, spin-lattice or spin-spin relaxation times substantially shorter than the surrounding gastro-intestinal tissue environment, and subjecting the mammal to said proton NMR
tomography.
The hydrogel particulate may be administered to the gastro-intestinal tract orally or rectally.
Conveniently, the hydrogel is administered as an aqueous suspension or slurry of particulate swollen cross-linked hydrogel. The size of the hydrogel particles can vary over a wide range, depending upon the desired resolution of the image desired, and the like. In general, the hydrogel particulate can range, in average diameter ,7~
between about lOO~u and about 100 mm, preferably bet~een about 1 mm and about 10 mm, and most preferably between about 2 nm and about 10 mm. The particulate hydrogel material may be in the form of beads, powders or granulates. ~ecause of the crosslinked nature of hydrogel~, they are substantially insoluble, but water-swellable, in aqueous media. Thus, the hydrogels are not absorbed through the gastro-intestinal walls upon admini5tration. Accordingly, the image contrasting cross-linked hydrogels are generally well tolerated and avoid the toxic aspects associated with many paramagnetic metal ion solutions, due to the substantially non-degradable, i.e. non-digestible, nature of the hydrogel material.
In order for the aqueous swollen particulate cross-linked hydrogel material to ex~rt an effective contrasting effect in proton NMR tomography of the gastro-intestinal tract, the hydrogen material chosen should, in the fully swollen state, exhibit relaxation time constants, Tl and T2, substantially less than that of gastro-intestinal viscera. In general, suitable hydrogels exhibit, at a proton resonance frequency of about 10 megahertz (MHz), a Tl relaxation time of between about 10 to about 200 milliseconds ~msec), preferably between about 10 to about lS0 msec, and most preferably between about 20 to about 120 msec, and a T2 relaxation time of between about 1 to about 60 msec, preferably between about 1 to about 50 msec, most preferably between about 2 and about 50 1~7~ 9 msec. At about 10 megahertz, the Tl value of gastro-intestinal viscera characteristically is between about 1S0-700, and the T2 value is between about 20-100, msec.
As the proton resonance frequency is decreased, the respective T1 and T2 values of suitable image contrasting hydrogel materials likewise decrease, as do the Tl and T2 average values of gastro-intestinal viscera.
Si~ilarly, as the proton resonance frequency of the NMR is increased, Tl and T2 values of suitable image contrasting hydrogel materials likewise increase, as do the average Tl and T2 values for the gastro-intestinal tract~
The instant i~age contrasting materials are generally suitable throughout the conventional range of chosen proton resonance frequencies characteristically used in NMR
tomography, e.~. between about 2 to about 30 ~Hz.
Eligible cross-linked hydrogel materials suitable for use as contrast agents in NMR tomography of the gastro-intestinal tract are easily determined by simple comparison of sample swollen cross-linked hydrogel Tl and T2 values with the corresponding average value of gastro-intestinal tissue at a chosen pro~on resonance frequency. Such tests can be conducted in vitro, using representative actual or phantom tissue samples, or in vivo, using live test animals.
-~ 3 ~
rrypical hydrogels found to be suitable as NMR
gastro-intestinal contrast agents characteristically contain between about 5% to about 80~ water, more preferably between about 10% to about 75% water. The hydrogel is advantageously swollen with a saline solution for in vitro comparative purposes in order to mimic the environment of the gastro-intestinal tract.
Moreover, suitable synthetic substantially non-degradable hydrogel materials contain as part of the cross-linked~ three dimensional matrix, hydrophilic functional groups which interact with water. As is well known, these functional groups are to a large extent responsible for the hydrophilic aqueous swelling ability of the hydrogels. Representative hydrophilic groups include hydroxyl, keko, amino, amido, ether, carboxy, sulfoxy, sulfonyl, and the like.
In general, the Tl and T2 relaxation times for a given hydrogel material will be proportional to the aqueous swelling ability of the material. Since the aqueous swellability can be decreased by increasing the amount of crosslinking of the hydrogel, the Tl and T2 values of the fully swollen hydrogel can be decreased by increasing the amount of crosslinking agent incorporated into the hydrogel material. It is believed that the Tl and T2 values are decreased as cross-linking is increased because the average compartment size for the absorbed water is reduced, thereby increasing the interaction between the water molecules and the hydrophilic components of the hydrogel matrix.
Further, increasing the number of ~ a~ L9 , ~ 9 - 214~9-7125 hydrophilic groups present in the hydrogel likewise tends to decrease the Tl and T2 relaxation times as the degree of inter-action of absorbed water is dependent upon the amount and nature of such hydrophilic groups.
Suitable synthetic substantially non-degradable hydrogel materials include the known classes of pharmaceutically acceptable crosslinked hydrogel materials employed in the fields of so~t contact lenses and pharmaceutical medicament diffusion carriers, including without limitation, those crosslinked hydrogel materials described in Wichterle et al. U.S. Patent Nos. 2,976,576 and 3,220,960; Mueller e-t al. U.S. Patent Nos. 4,136,250, 4,192,827 and 4,22~,427, Seiderman U.SO Patent Nos. 3,~39,524, 3,721,657 and 3,767,731, Ewell U.S. Patent No. 3,647,736; O'Driscoll et al. U.S.
Patent Nos. 3,700,761, 3,822,196, 3,816,571 and 3,841,985;
Steckler U.S. Patent No. 3,532,679; Stamberger U.S. Patent Nos.
3,758,448 and 3,772,235, Neefe U.S. Ratent No. 3,803,093; Tanaka et al. U.S. Patent No. 3,813,447; Blank U.S. Patent No.
3,728,317, Isen U.S. Patent No. 3,488,111; and Ohkada et al. U.S.
Patent No. 4,347,198.
Such hydrogels are generally prepared by polymerizing a monomer or mixture of monomers, either in the presence of a cross-linking agent to crosslink the polymer, or in the absence of a cross-linXing agent to ~orm a pre-crosslinked intermediate which is subse~uently crosslinked with a crosslinking agent. Also in the polymerization step there may be present, in addition to a .,~
i~79~ 3 mono~er or mixture of monomers, a polymer or prepolymer substrate upon whach the monomers may be grafted, by poly~eriza~ion, or example. Where mixtures of monomers are employed, the resulting copolymer may be random, alterna~ing, block or graf~ copolymers depending upon the polymcrization techniques, sequence of monomer addition, reaction conditions, nature and reactivity of the monomers employed, and the lik~, Generally the monomer employed is hydrophilic in nature. However, mixtures of hydrophilic and hydrophobic monomers, preferably containing less than 50 mole percent hydrophobic constituents, may be employedO Alternatively, a hydrophobic monomer may be polymerized and subsequently converted to a hydrophilic species, for example as is well known in the polymerization and subsequent hydrolysis of vinyl acetate to form polyvinyl alcohol, which may then be cross-linked with glyoxal, diglycidyl ether or the like.
Suitable hydrophilic monomers commonly employed in the preparation of crosslinked hydrogels useful in the instant invention include, without limitation, acrylic and/or methacrylic acid and the wat r-soluble deriva~ives thereof such as the epoxy or hydroxy substituted lower alkyl esters thereof including eg, the 2-hydroxyethyl, glycidyl, 3-hydroxypropyl, or 2 ,3-dihydroxypropy~ esters therecf; the ethoxylated and polyethoxylated hydroxy substituted lower alkyl esters thereof; the di-~lower alkyl1 aminoloweralkyl acrylates or methacrylates, such as the 2-(dimethylamino)ethyl acrylate, or the 2-(diethylamino)ethyl methacrylate; the water soluble ~79~ 3 amides thereof, such as the unsubstituted amidQs and amides substituted by one or two hydroxyloweralkyl groups, such as N (2-hydroxyethyl)-methacrylamide; water soluble heterocyclic nitrogen containin~ monomers, such as N-vinylpyrrolidone, N-vinyl-succinimide, N-vinyl-pyrrole, 2- and 40vlnylpyridine, 4-vinyl~quinoline, 4-acrylyl-morpholine and the like, mono-olefinic sulfonic acids and their pharmaceutically acceptable salts, such as sodium ethylene sulonate, sodium styrene sulfonate and the like;
hydroxyloweralkyl maleates, fumarates and vinyl ethers, such as 2-hydroxyethyl monomaleate, di(2-hydroxyethyl) maleate, 2-hydroxyethyl vinyl ether, 4~hydroxybutyl vinyl ether and the like.
Preferably, for patient administration ~he crosslinked hydrogels are substantially free of strongly ionic groups, such as sulfonates, free amine groups and the like~ which may adversely interact with gastro-intestinal fluids and upset the electrolytic balance.
Suitable hydrophobic monomers which may be employed include, without limitation, Cl_lg alkyl acrylates or methacrylates; vinyl acetate; Cl_lg alkenes which are unsubstituted or substituted by halo; acrylonitrile;
styrene; di-lower alkyl-acrylamides and -methacrylamides, vinyl Cl_s alkyl ethers, such as propyl vinyl ether, and the like.
Suitable crosslinking a~ents include, without limitation, divinyl benzene, ethylene glycol dimethacrylate, polyethyleneglycol dimethacrylate, ~t'79~ 3 glyoxal, diglycidyl ether, and macromer cross-linking agents such as polytetramethylene oxide having a molecular weight o about 1500 which is capped at both ends by isophorone diisocyanate or 2,4-toluene diisocyanate and subsequently terminated by 2-hydroxyethylmethacrylate, e.g. as described in U.S. Patent No. 4,277,582, or a polysiloxane having a molecular weight of about 400 to about 8500 capped at both ends with 2,4-toluene diisocyanate or isophorone diisocyanate and subsequently terminated by 2-hydroxyethylmethacrylate, e.g. as described in U.S. Patent No. 4,136,250.
If desired, the hydrogel materials may be formulated in the presence of a radio-opaque substance, such as particulate barium sulfate, iobenzamic acid, iocarmic acid, iocetamic acid, iodamide, iodipamide and pharmaceutically acceptable salts thereof. Alternately, the hydrogels may be prepared in the presence of tomograp~ic enhancing aids such as erric (Fe+3) and/or manganese (Mn+2) salts to increase the contrast of the hydrogel material in comparison with the surrounding tissues. A preferred method of preparing hydrogel beads by suspension polymerization is described in U.S. Patent No. 4,224,4~7.
In such process one ma~ incorporate the aforementioned adjuvant ingredients, e.g. for rendering such beads radio-opaque or for enhancing NMR contrast, simply by adding the adjuvant to the suspensiol~ polymerization medium. The amount of adjuvant present will vary, dependent upon the nature thereof. Preferably, no more than 10 percent by weight of hydrogel consists of such adjuvant.
~7g ~9 The hydrogel material generally is administered to the patient orally or rectally as an aqueous slurry or suspension. ~s the hydrogel material is soft, flexible and substantially inert, the slurry or suspension is generally very well tolerated by the patient.
Also, a collection or array of diverse hydrogel samples, possessing varying Tl and T2 constants, preferably exhibiting Tl and T2 constants embracing at least a substantial portion of the spectrum of such constants exhibited by diversemammalian tissues may be employed as tissue phantom kits for adjusting tomography equipment.
Generally, at least three such samples are employed in such kits.
The following examples are presented for the purpose of illustration only and ara not to be construed to limit the nature or scope of the invention in any manner whatsoever. All parts are by weight unless otherwise specified.
`: :
~:79~;~1''3 Exam~
In accordance with the procedure set forth in Example l of U.S. 4,224,427, 48 parts by weight of a ma~romer, 20 parts N-vinyl pyrrolidone and 32 parts of 2-hydroxyethyl methacrylate were polymerized using 0.2 parts o~ tert~butyl peroctoate as a free radical initiator.
The macromer consist~ of poly(tetramethylene oxide) glycol having an average molecular weight of approximately 2000 endcapped with isophorone diisocyanate in an amount of two moles per mole of said glycol r and terminated with l mole of 2-hydroxyethyl methacrylate per mole of said diisocyan-ate, reacted for 72 hours at room temperature. The reac-tion mixture of macromer and monomers with initiator are combined in about 240 parts of an aqueous suspension of magnesium hydroxide (prepared by combining about 180 parts of a 20% by weight aqueous sodium chloride solution with about 12 parts of magnesi~m chloride hexahydrate with stirring at about 80C and adding dropwise about 60 parts of a l-normal sodium hyd,roxide solution) with stirring at 150 rpm under a nitrogen blanket at 80C, the macromer-monomer m;xture allowed to polymerize for 3 hours, and the temperature raised to 100C for one hour, after which the reaction medium is cooled to roo.~ temperature, the magne-sium hydroxide suspending agent neutralized with concen-trated hydrochloric acid and the reaction mixture beads isolated by filtration and washed with water to remove any residual monomer. The resulting polymer spherical beads (diameter approx. l mm) have a water content of approxi-mately 56~ by weight, based upon the weight of swollen crosslinked hydrogel polymer beads. Upon sub~ecting the ~ 9 ~9 swollen crosslinked polymer beads to NMR imaging at 6.4 MHz the following T values were obtained:
Tl ~ 320 + 34 ms T2 ~ 52 + 3 ms.
Example 2 Following the method of Example 1 a crosslinked hydrogel in the form of beads having a diameter of approx.
1 mm and containing 30% by weight of the macromer of Example 1 and 70% by weight 2-hydroxyethyl methacrylate are prepared. The resulting aqueous swollen beads contain approximately 25~ by weight water and when subjected to NMR
imaging at 6.4 MHz exhibit the following T values:
Tl = 1330 + 400 T2 ~ 294 + 55.
Following the method of Example 1, crosslinked hydrogel beads containing 33 % by weight of the macromer of Example 1, 40% by weight n-octyl methacrylate, 27 ~ by weight hydroxyethyl methacrylate are prepared. The resulting aqueous swollen beads contain approximately 27 by weight water and when subjected to NMR imaging at 6.4 MHz exhibit the following T values:
Tl = 390 ~ 120 T2 = 44 ~ 16.
., .
g8~
Following the method of Example 1, crosslinked hydrogel beads containing 3 ~ of the macromer of Example 1, 21% 2-hydroxyethylmethacrylate, 21% N-vinyl pyrrolidone, 27.5% methyl methacrylate and 27.5% ~-ethylhexyl acrylate are prepared. The resulting a~ueous swollen beads contain about 10~ water and when subjected to NMR imaging at 6.4 MHz exhibit the following T values:
Tl = 1800 ~ 220 T2 = 340 1 80.
Example 5 Following the method of Example 1, crosslinked hydrogel beads containing 30~ of the macromer of Example 1 r 20% 2-hydroxyethyl methacrylate and 50% methyl methacrylate are prepared. The resulting aqueous swollen beads contain approximately 9.9% water and when subjected to NMR imaging at 6.4 MHz exhibit the following T values:
Tl = 1670 ~ 400 T2 = 294 * 92-Example 6 à) Crosslinked hydrogel buttons having a diameter ofabout 20 mm and a height of about 10 mm are prepared by placing in a ~old a mixture of 50 parts by weight 2-hydroxyethyl methacrylate, 50 parts by weight dimethyl acrylamide and 0.5 parts ethyleneglycol dimethacrylate in the presence of about 0.1 part benzoin methyl ether AS
initiator and polymeri2ing the reaction mixture under ambient conditions in the presence of an ultraviolet light source for about 8 hours. Upon swelling the crosslinked hydrogel with water, the equilibrated swollen material contained 7~.8% water by weight, and when subjected to NMR
imaging at 6.4 MHz exhibits the following T values:
Tl = 1470 ~ 300 ms T2 = 174 ~ 30 m~.
b~ Alternatively, the aforementioned monomer mixture i5 polymerized in a mold to form substantially spherical beads of crosslinked hydrogel having an average diameter of about 2 mm, which upon equilibration with water under ambient conditions contains approximately 80% water by weight~
Example 7 Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a monomer mixture containing 75 parts 2-hydroxyethyl methacrylate, 25 parts dimethylacrylamide, 0.5 parts ethyleneglycol dimethacrylate as crosslinker and about 0.1 part benzoin methyl ether as polymerization initiator. The products, upon equilibration with water, contain approximately 59 weight percent water and having the following T values at 6.4 MHz Tl = 250 i 60 T2 = 56 ~ 10.
9~
- 18 ~
Example 8 Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a mixture of 100 parts 2-hydroxyethyl methacrylate! 0.5 parts ethyleneglycol dimethacrylate and about 0.1 parts benzoin methyl ether. The products, upon equilibration with water, contain 39.3% water, a Tl value of 1850 ~ 300 and a T2 value of ~24 ~ 100 (at 6.4 MHz).
Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a mixture of 75 parts 2-hydroxyethyl methacrylate, 25 parts methylmethacrylate, 0.5 parts ethyleneglycol dimethacrylate and 0 L 1 part benzoin methyl ether. The products upon equilibration with water, possess a water content of 22.7~
by weight, a Tl value of about 1050 and a T2 value of 248 ' 90 (at 6.4 MHz).
Example 10 Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a mixture of 80 parts methylmethacrylate, 20 parts dimethylacrylamide, 0.5 parts ethyleneglycol dimethacrylate and about 0.1 part benzoin methyl ether. The products, upon equilibration with water, had a water content of 12.5% by weight and, at 6.4 MHz, a Tl value of 1~40 ~ 700 and a T2 value of 234 ~ 100.
1~'7g8~ ~
Example 11 Using the methods of Example 6 9 buttons and spherical beads, respectively, are prepared from a mixture of 30 parts 2-hydroxyethyl methacrylate, 40 parts methyl methacrylate, 30 parts dimethylacrylamide, 0.5 parts ethyleneglycol dimethacrylate and about 0.1 part benzoin methyl ether. The products, upon equilibration with water, have a water content of 27.6% by weight and at 6.4 MHz exhibit a Tl of 220 ~ 110 and a T2 of 40 ~ 19.
xample 12 Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a mixture of 70 parts methyl methacrylate, 30 parts dimethyl acrylamide, 0.5 parts ethyleneglycol dimethacrylate, and 0.1 part benzoin methyl ether. The products produced possess upon equilibration with water, a water content of 22.8% and, at 6.4 MHz, a T2 value of 3~ i 50.
_~m~ 13 Upon the methods of ~xample 6, buttons and spherical beads, respectively, are prepared from a mixture of 50 parts of a fluorinated methacrylate ester of ~he formula Rf--CH2CH2--SCONHCH2CH20CO--C(CH3) = CH2 9~3L9 wherein Rf is a 1:1 mixture of n-CgF17 and n-CloP21, 30 parts methyl methacrylate and 20 parts dimethyl acrylamide, with 0.2 parts ethyleneglycol dimethacrylate and about 0.1 part benzoin methyl ether. The fluorinated methacrylate is prepared by combining one mole of perfluoroalkylthiol of the formula R~CH2CH2SH per mole of 2-isocyanatoethyl methacrylate, adding to the reaction mixture 0.005 mole triethylamine per mole of thiol with mixing under ambient conditions to promote the reaction, reacting the resulting mixture at about 30C for 6 hours, and washing the resulting product with ethanol to remove unreacted material.
The crosslinked hydrogel, upon equilibration in water, had a water content of 11.6~, and, at 6.4 MHz, a T
value of 730 ~ 300 and a T2 value of 172 + 105.
Example 14 Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a mixture of 50 parts methyl methacrylate, 50 parts hydroxyethyl methacrylate, 0.5 parts ethylene glycol dimethacrylate, and about 0.1 part benzoin methyl ether. The resulting crosslinked hyrogel upon equilibration exhibits a water content of 13.9%, a Tl value of 300 ~ 200 and a T2 value of about 64 at 6.4 MHz.
~LX798~9 Example 15 A ~iloxane macromer is prepared according to Example 8 of U.S. Patent No. 4,136,250. A mixture of 30 parts of the siloxane macromer, consisting of polydimethyl siloxane triol ~Dow Corning 1248) having a molecular weight of about 6000 which is endcapped with isophorone diisocyanate in an amount oE 3 moles per mole of siloxane and terminated with 2-hydroxyethyl methacrylate in an amount of 3 moles per mole siloxane, is combined with 40 parts methyl methacrylate and 30 parts dimethyl acrylamide, and O.l part azobisisobutyronitrile catalyst. The mixture is then cast as buttons having a diameter of about 20 mm and a height of about lO mm, and as spherical beads having an average diameter of about 2 mm and cured at a temperature of 50C
for 16 hour.s following by a post cure of 100C for one hour. Upon equilibration with water, the cross-linked polyme~ had a water content of 27.1 ~, and at 64 MHz a Tl value of 170 + 70 and T2 value of 42 + 7.
Example 16 The procedure of Example 15 is repeated using 30 parts of the siloxane macromer with 20 parts of dimethyl/acrylamide and S0 parts methyl methacrylate. The resulting products upon equilibration contain 13.4~ water and at 6.4 MHz have a Tl value of 290 ~ 50.
~L~'7~ 9 Example 17 An array of aqueous swollen hydrogel buttons of Examples 6, 13, 14 and 15 are aligned in a whole body NMR
imaging device at 6.4 MHz to obtain Tl values of 1470 ~ 300 ms, 730 ~ 300, 300 ~ 200 and 170 ~ 70. This compares favorably with tissue samples subjected to NMR imaging at 6.4 MH2, i.~. the Tl value of minced brain obtained is 1470 i 300; pancreas tissue is 730 ~ 300; heart muscle is 390 i 120; and liver is 170 ~ 70.
Example 18 Using the procedure of Example 15, the macromer of Example 1 is reacted with various amounts of selected monomers to obtain crosslinked hydrogels which after equilibration in water are subjected to NMR imaging at 5 MHz to obtain the following results;
_Composition, %l) Product MAC MMA DMA NVP HEMA EHA
.
18a 30 70 18b 30 42 28 18c 20 45 35 18d~ 27.5 _ 33 2?.5 1) MAC = macromer of Example 1 MMA = methyl methacrylate DMA = dimethyl acrylamide NVP = N-vinyl pyrrolidone HEMA = 2-hydroxyethyl methacrylate EH~ = 2-ethylhexyl acrylate ~2'7~ 3 - ~3 Pro erties Products Tl T2 ~H20 18a 155 1~ 23.0 18b 34 4 25.4 18c 43 ~ ~9.0 18d_ 115 17 8.0 . _ _ _. . _ . _ _ ._ ___ When subjected to NMR imaging at 30 MHz, the products of Examples 18a give a Tl value of 555 i 50; 18b gave a Tl value of 259 ~ 29, 18c gave a Tl value of 252 +
10 and 18d gave a Tl value of 252 ~ 8. The products of 18b and 18c are sspecially useful due to their high contrast, as image contrast agents. All of the products of 18a-18d are useful as image contrast agents in NMR imaging machines employiny a combination of Tl and T2 in their imaging technique.
Also, the hydrogels of Examples 7, 11, 15 and 16 are highly valuable as image contrast agents due to their high contrast in the gastro-intestinal tract.
BACE~GROUND OF THE INVENTION
Proton nuclear magnetic resonance (NMR) tomography has become an important tool in biomedical research and medical diagnosis. The image contrast mechanis~s of NMR
are different from X-ray imaging, and provide substantial contrast between certain soft tissues that are nearly identical using radiological techniques~ Further, conventional radiological imaging techniques involve the use of high energy electromagnetic radiation associated with potential cancer induction, whereas the low energy radio waves associated with NMR poses no such risk.
However, while some soft tissu0s provide substantial contrast using NMR techniques, others, particularly those involving the gastrointestinal tract, yield a relatively low level of contrast in proton NMR imaying. This has prompted the development of suitable NMR contrast agents.
While numerous substances, such as vegetable oils and paramagnetic metal salt solutions, such as ferric chloride solutions and solutions of gadolinium oxide, have been used to visualize the lumen of the stomach and intestines in NMR
tomography, none have the coating and filling characteristics which have made barium sulfate so useful in radiological applications. Moreoverr many paramagnetic metal ion containing solutions e.g. those of Cu2+, Cr3+, Fe3+ and Mn2~, are generally toxic at concentrations which sufficiently shorten the spin relaxation times, Tl and T2, of the solution environment to render such solutions useful NMR contrast agents. Runge et al., Radiologv, Vol. 147, pp. 789-791 (1983).
~ ~ 7 ~ ~19 Further, since conventionally available proton NMR
tomography equipment is complex in terms of operator selectable parameters, there is a need for storage stable materials especially in the form of a collection or array, which substantially mimics the range of proton density values, spin-lattice or longitudinal relaxation (Tl) values, and spin-spin or traverse relaxation (T2) values, associated with various animal tissuer for tuning such selectable parameters. Appropriate tuning of the operator selectable parameters enables the operator to optimize the desired contrast characteristies associated with NMR
tomographic images, including, for example, inversion recovering images, partial saturation images, density images, spin echo images, and the like. See in general, Wehrli et al., Magnetic R~ n_~_ Ll~bL~ Vol. 2, pp. 3-16 (1984).
It has now been surprisingly discovered that synthetic substantially non-degradable cross-linked water-swellable hydrogel materials, having in the swollen state between about 5 to about 95~ water and containing functional ~roups which interact with water, possess nuclear magnetic resonance spin density values, and Tl and T2 values sufficiently analogous to the spectrum of values associated with mammalian tissue, such that the aqueous s~ollen materials are highly useful in proton NMR
tomographic imaging techniques, and overcome many of the disadvantages associated with known materials and techniques.
~.~7~8~9 ~, _ It has been further unexpectedly discovered that those hydrogels having Tl and T2 values substantially shorter than that of ~astro-intestinal viscera are highly useful as proton NMR image contrast agents.
Thus, it is an object of the instant invention to provide a method o~ contrasting a proton ~MR tomograph o~
the gastro-instestinal tract, or a portion thereof, by administering to a mammal, including man, an effective image contrasting amount of a physiologically tol~rable, synthetic substantially non-degradable cross-linked hydrogel having, in the aqueous swollen state, spin-lattice or spin-spin relaxation values substantially shorter than the surrounding gastro-intestinal tissue environment.
It is a further object of the instant invention to provide an aqueous coating suspension or slurry of particulate swollen synthetic substantially non-degradable cross-linked hydrogel, said hydrogel having spin-lattice or spin-spin relaxation values substantially shorter than the respective spin-lattice or s~in-spin average relaxation values of gastro-intestinal viscera, for use as proton NMR
contrast agents.
It is yet a further object of the instant invention to provide a collection or array of storage stable swollen cross-linked hydrogel materials possessing a range of nuclear magnetic resonance spin density values, spin-lat-tice relaxation values and spin-spin relaxation values, embracing at least a portion of the spectrum of such values '79~1~3 possessed by distinct anatomic mammalian tissue, and suitable for use in NMR imaging equipment for proton NMR
image contrast determinations.
These and other objects of the invention are apparent from the following disclosure.
DETAILED DISCLOSURE OF THE INVENTION
One embodiment of the instant invention relates to a method of contrasting a proton NMR tomograph o~ the gastro-intestinal tract of a mammal, by administering to the mammal an effective image contrasting amount of a physiologically tolerable cross-linked synthetic substantially non-degradable hydrogel in particulate form, said hydrogel having, in the aqueous swollen state, spin-lattice or spin-spin relaxation times substantially shorter than the surrounding gastro-intestinal tissue environment, and subjecting the mammal to said proton NMR
tomography.
The hydrogel particulate may be administered to the gastro-intestinal tract orally or rectally.
Conveniently, the hydrogel is administered as an aqueous suspension or slurry of particulate swollen cross-linked hydrogel. The size of the hydrogel particles can vary over a wide range, depending upon the desired resolution of the image desired, and the like. In general, the hydrogel particulate can range, in average diameter ,7~
between about lOO~u and about 100 mm, preferably bet~een about 1 mm and about 10 mm, and most preferably between about 2 nm and about 10 mm. The particulate hydrogel material may be in the form of beads, powders or granulates. ~ecause of the crosslinked nature of hydrogel~, they are substantially insoluble, but water-swellable, in aqueous media. Thus, the hydrogels are not absorbed through the gastro-intestinal walls upon admini5tration. Accordingly, the image contrasting cross-linked hydrogels are generally well tolerated and avoid the toxic aspects associated with many paramagnetic metal ion solutions, due to the substantially non-degradable, i.e. non-digestible, nature of the hydrogel material.
In order for the aqueous swollen particulate cross-linked hydrogel material to ex~rt an effective contrasting effect in proton NMR tomography of the gastro-intestinal tract, the hydrogen material chosen should, in the fully swollen state, exhibit relaxation time constants, Tl and T2, substantially less than that of gastro-intestinal viscera. In general, suitable hydrogels exhibit, at a proton resonance frequency of about 10 megahertz (MHz), a Tl relaxation time of between about 10 to about 200 milliseconds ~msec), preferably between about 10 to about lS0 msec, and most preferably between about 20 to about 120 msec, and a T2 relaxation time of between about 1 to about 60 msec, preferably between about 1 to about 50 msec, most preferably between about 2 and about 50 1~7~ 9 msec. At about 10 megahertz, the Tl value of gastro-intestinal viscera characteristically is between about 1S0-700, and the T2 value is between about 20-100, msec.
As the proton resonance frequency is decreased, the respective T1 and T2 values of suitable image contrasting hydrogel materials likewise decrease, as do the Tl and T2 average values of gastro-intestinal viscera.
Si~ilarly, as the proton resonance frequency of the NMR is increased, Tl and T2 values of suitable image contrasting hydrogel materials likewise increase, as do the average Tl and T2 values for the gastro-intestinal tract~
The instant i~age contrasting materials are generally suitable throughout the conventional range of chosen proton resonance frequencies characteristically used in NMR
tomography, e.~. between about 2 to about 30 ~Hz.
Eligible cross-linked hydrogel materials suitable for use as contrast agents in NMR tomography of the gastro-intestinal tract are easily determined by simple comparison of sample swollen cross-linked hydrogel Tl and T2 values with the corresponding average value of gastro-intestinal tissue at a chosen pro~on resonance frequency. Such tests can be conducted in vitro, using representative actual or phantom tissue samples, or in vivo, using live test animals.
-~ 3 ~
rrypical hydrogels found to be suitable as NMR
gastro-intestinal contrast agents characteristically contain between about 5% to about 80~ water, more preferably between about 10% to about 75% water. The hydrogel is advantageously swollen with a saline solution for in vitro comparative purposes in order to mimic the environment of the gastro-intestinal tract.
Moreover, suitable synthetic substantially non-degradable hydrogel materials contain as part of the cross-linked~ three dimensional matrix, hydrophilic functional groups which interact with water. As is well known, these functional groups are to a large extent responsible for the hydrophilic aqueous swelling ability of the hydrogels. Representative hydrophilic groups include hydroxyl, keko, amino, amido, ether, carboxy, sulfoxy, sulfonyl, and the like.
In general, the Tl and T2 relaxation times for a given hydrogel material will be proportional to the aqueous swelling ability of the material. Since the aqueous swellability can be decreased by increasing the amount of crosslinking of the hydrogel, the Tl and T2 values of the fully swollen hydrogel can be decreased by increasing the amount of crosslinking agent incorporated into the hydrogel material. It is believed that the Tl and T2 values are decreased as cross-linking is increased because the average compartment size for the absorbed water is reduced, thereby increasing the interaction between the water molecules and the hydrophilic components of the hydrogel matrix.
Further, increasing the number of ~ a~ L9 , ~ 9 - 214~9-7125 hydrophilic groups present in the hydrogel likewise tends to decrease the Tl and T2 relaxation times as the degree of inter-action of absorbed water is dependent upon the amount and nature of such hydrophilic groups.
Suitable synthetic substantially non-degradable hydrogel materials include the known classes of pharmaceutically acceptable crosslinked hydrogel materials employed in the fields of so~t contact lenses and pharmaceutical medicament diffusion carriers, including without limitation, those crosslinked hydrogel materials described in Wichterle et al. U.S. Patent Nos. 2,976,576 and 3,220,960; Mueller e-t al. U.S. Patent Nos. 4,136,250, 4,192,827 and 4,22~,427, Seiderman U.SO Patent Nos. 3,~39,524, 3,721,657 and 3,767,731, Ewell U.S. Patent No. 3,647,736; O'Driscoll et al. U.S.
Patent Nos. 3,700,761, 3,822,196, 3,816,571 and 3,841,985;
Steckler U.S. Patent No. 3,532,679; Stamberger U.S. Patent Nos.
3,758,448 and 3,772,235, Neefe U.S. Ratent No. 3,803,093; Tanaka et al. U.S. Patent No. 3,813,447; Blank U.S. Patent No.
3,728,317, Isen U.S. Patent No. 3,488,111; and Ohkada et al. U.S.
Patent No. 4,347,198.
Such hydrogels are generally prepared by polymerizing a monomer or mixture of monomers, either in the presence of a cross-linking agent to crosslink the polymer, or in the absence of a cross-linXing agent to ~orm a pre-crosslinked intermediate which is subse~uently crosslinked with a crosslinking agent. Also in the polymerization step there may be present, in addition to a .,~
i~79~ 3 mono~er or mixture of monomers, a polymer or prepolymer substrate upon whach the monomers may be grafted, by poly~eriza~ion, or example. Where mixtures of monomers are employed, the resulting copolymer may be random, alterna~ing, block or graf~ copolymers depending upon the polymcrization techniques, sequence of monomer addition, reaction conditions, nature and reactivity of the monomers employed, and the lik~, Generally the monomer employed is hydrophilic in nature. However, mixtures of hydrophilic and hydrophobic monomers, preferably containing less than 50 mole percent hydrophobic constituents, may be employedO Alternatively, a hydrophobic monomer may be polymerized and subsequently converted to a hydrophilic species, for example as is well known in the polymerization and subsequent hydrolysis of vinyl acetate to form polyvinyl alcohol, which may then be cross-linked with glyoxal, diglycidyl ether or the like.
Suitable hydrophilic monomers commonly employed in the preparation of crosslinked hydrogels useful in the instant invention include, without limitation, acrylic and/or methacrylic acid and the wat r-soluble deriva~ives thereof such as the epoxy or hydroxy substituted lower alkyl esters thereof including eg, the 2-hydroxyethyl, glycidyl, 3-hydroxypropyl, or 2 ,3-dihydroxypropy~ esters therecf; the ethoxylated and polyethoxylated hydroxy substituted lower alkyl esters thereof; the di-~lower alkyl1 aminoloweralkyl acrylates or methacrylates, such as the 2-(dimethylamino)ethyl acrylate, or the 2-(diethylamino)ethyl methacrylate; the water soluble ~79~ 3 amides thereof, such as the unsubstituted amidQs and amides substituted by one or two hydroxyloweralkyl groups, such as N (2-hydroxyethyl)-methacrylamide; water soluble heterocyclic nitrogen containin~ monomers, such as N-vinylpyrrolidone, N-vinyl-succinimide, N-vinyl-pyrrole, 2- and 40vlnylpyridine, 4-vinyl~quinoline, 4-acrylyl-morpholine and the like, mono-olefinic sulfonic acids and their pharmaceutically acceptable salts, such as sodium ethylene sulonate, sodium styrene sulfonate and the like;
hydroxyloweralkyl maleates, fumarates and vinyl ethers, such as 2-hydroxyethyl monomaleate, di(2-hydroxyethyl) maleate, 2-hydroxyethyl vinyl ether, 4~hydroxybutyl vinyl ether and the like.
Preferably, for patient administration ~he crosslinked hydrogels are substantially free of strongly ionic groups, such as sulfonates, free amine groups and the like~ which may adversely interact with gastro-intestinal fluids and upset the electrolytic balance.
Suitable hydrophobic monomers which may be employed include, without limitation, Cl_lg alkyl acrylates or methacrylates; vinyl acetate; Cl_lg alkenes which are unsubstituted or substituted by halo; acrylonitrile;
styrene; di-lower alkyl-acrylamides and -methacrylamides, vinyl Cl_s alkyl ethers, such as propyl vinyl ether, and the like.
Suitable crosslinking a~ents include, without limitation, divinyl benzene, ethylene glycol dimethacrylate, polyethyleneglycol dimethacrylate, ~t'79~ 3 glyoxal, diglycidyl ether, and macromer cross-linking agents such as polytetramethylene oxide having a molecular weight o about 1500 which is capped at both ends by isophorone diisocyanate or 2,4-toluene diisocyanate and subsequently terminated by 2-hydroxyethylmethacrylate, e.g. as described in U.S. Patent No. 4,277,582, or a polysiloxane having a molecular weight of about 400 to about 8500 capped at both ends with 2,4-toluene diisocyanate or isophorone diisocyanate and subsequently terminated by 2-hydroxyethylmethacrylate, e.g. as described in U.S. Patent No. 4,136,250.
If desired, the hydrogel materials may be formulated in the presence of a radio-opaque substance, such as particulate barium sulfate, iobenzamic acid, iocarmic acid, iocetamic acid, iodamide, iodipamide and pharmaceutically acceptable salts thereof. Alternately, the hydrogels may be prepared in the presence of tomograp~ic enhancing aids such as erric (Fe+3) and/or manganese (Mn+2) salts to increase the contrast of the hydrogel material in comparison with the surrounding tissues. A preferred method of preparing hydrogel beads by suspension polymerization is described in U.S. Patent No. 4,224,4~7.
In such process one ma~ incorporate the aforementioned adjuvant ingredients, e.g. for rendering such beads radio-opaque or for enhancing NMR contrast, simply by adding the adjuvant to the suspensiol~ polymerization medium. The amount of adjuvant present will vary, dependent upon the nature thereof. Preferably, no more than 10 percent by weight of hydrogel consists of such adjuvant.
~7g ~9 The hydrogel material generally is administered to the patient orally or rectally as an aqueous slurry or suspension. ~s the hydrogel material is soft, flexible and substantially inert, the slurry or suspension is generally very well tolerated by the patient.
Also, a collection or array of diverse hydrogel samples, possessing varying Tl and T2 constants, preferably exhibiting Tl and T2 constants embracing at least a substantial portion of the spectrum of such constants exhibited by diversemammalian tissues may be employed as tissue phantom kits for adjusting tomography equipment.
Generally, at least three such samples are employed in such kits.
The following examples are presented for the purpose of illustration only and ara not to be construed to limit the nature or scope of the invention in any manner whatsoever. All parts are by weight unless otherwise specified.
`: :
~:79~;~1''3 Exam~
In accordance with the procedure set forth in Example l of U.S. 4,224,427, 48 parts by weight of a ma~romer, 20 parts N-vinyl pyrrolidone and 32 parts of 2-hydroxyethyl methacrylate were polymerized using 0.2 parts o~ tert~butyl peroctoate as a free radical initiator.
The macromer consist~ of poly(tetramethylene oxide) glycol having an average molecular weight of approximately 2000 endcapped with isophorone diisocyanate in an amount of two moles per mole of said glycol r and terminated with l mole of 2-hydroxyethyl methacrylate per mole of said diisocyan-ate, reacted for 72 hours at room temperature. The reac-tion mixture of macromer and monomers with initiator are combined in about 240 parts of an aqueous suspension of magnesium hydroxide (prepared by combining about 180 parts of a 20% by weight aqueous sodium chloride solution with about 12 parts of magnesi~m chloride hexahydrate with stirring at about 80C and adding dropwise about 60 parts of a l-normal sodium hyd,roxide solution) with stirring at 150 rpm under a nitrogen blanket at 80C, the macromer-monomer m;xture allowed to polymerize for 3 hours, and the temperature raised to 100C for one hour, after which the reaction medium is cooled to roo.~ temperature, the magne-sium hydroxide suspending agent neutralized with concen-trated hydrochloric acid and the reaction mixture beads isolated by filtration and washed with water to remove any residual monomer. The resulting polymer spherical beads (diameter approx. l mm) have a water content of approxi-mately 56~ by weight, based upon the weight of swollen crosslinked hydrogel polymer beads. Upon sub~ecting the ~ 9 ~9 swollen crosslinked polymer beads to NMR imaging at 6.4 MHz the following T values were obtained:
Tl ~ 320 + 34 ms T2 ~ 52 + 3 ms.
Example 2 Following the method of Example 1 a crosslinked hydrogel in the form of beads having a diameter of approx.
1 mm and containing 30% by weight of the macromer of Example 1 and 70% by weight 2-hydroxyethyl methacrylate are prepared. The resulting aqueous swollen beads contain approximately 25~ by weight water and when subjected to NMR
imaging at 6.4 MHz exhibit the following T values:
Tl = 1330 + 400 T2 ~ 294 + 55.
Following the method of Example 1, crosslinked hydrogel beads containing 33 % by weight of the macromer of Example 1, 40% by weight n-octyl methacrylate, 27 ~ by weight hydroxyethyl methacrylate are prepared. The resulting aqueous swollen beads contain approximately 27 by weight water and when subjected to NMR imaging at 6.4 MHz exhibit the following T values:
Tl = 390 ~ 120 T2 = 44 ~ 16.
., .
g8~
Following the method of Example 1, crosslinked hydrogel beads containing 3 ~ of the macromer of Example 1, 21% 2-hydroxyethylmethacrylate, 21% N-vinyl pyrrolidone, 27.5% methyl methacrylate and 27.5% ~-ethylhexyl acrylate are prepared. The resulting a~ueous swollen beads contain about 10~ water and when subjected to NMR imaging at 6.4 MHz exhibit the following T values:
Tl = 1800 ~ 220 T2 = 340 1 80.
Example 5 Following the method of Example 1, crosslinked hydrogel beads containing 30~ of the macromer of Example 1 r 20% 2-hydroxyethyl methacrylate and 50% methyl methacrylate are prepared. The resulting aqueous swollen beads contain approximately 9.9% water and when subjected to NMR imaging at 6.4 MHz exhibit the following T values:
Tl = 1670 ~ 400 T2 = 294 * 92-Example 6 à) Crosslinked hydrogel buttons having a diameter ofabout 20 mm and a height of about 10 mm are prepared by placing in a ~old a mixture of 50 parts by weight 2-hydroxyethyl methacrylate, 50 parts by weight dimethyl acrylamide and 0.5 parts ethyleneglycol dimethacrylate in the presence of about 0.1 part benzoin methyl ether AS
initiator and polymeri2ing the reaction mixture under ambient conditions in the presence of an ultraviolet light source for about 8 hours. Upon swelling the crosslinked hydrogel with water, the equilibrated swollen material contained 7~.8% water by weight, and when subjected to NMR
imaging at 6.4 MHz exhibits the following T values:
Tl = 1470 ~ 300 ms T2 = 174 ~ 30 m~.
b~ Alternatively, the aforementioned monomer mixture i5 polymerized in a mold to form substantially spherical beads of crosslinked hydrogel having an average diameter of about 2 mm, which upon equilibration with water under ambient conditions contains approximately 80% water by weight~
Example 7 Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a monomer mixture containing 75 parts 2-hydroxyethyl methacrylate, 25 parts dimethylacrylamide, 0.5 parts ethyleneglycol dimethacrylate as crosslinker and about 0.1 part benzoin methyl ether as polymerization initiator. The products, upon equilibration with water, contain approximately 59 weight percent water and having the following T values at 6.4 MHz Tl = 250 i 60 T2 = 56 ~ 10.
9~
- 18 ~
Example 8 Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a mixture of 100 parts 2-hydroxyethyl methacrylate! 0.5 parts ethyleneglycol dimethacrylate and about 0.1 parts benzoin methyl ether. The products, upon equilibration with water, contain 39.3% water, a Tl value of 1850 ~ 300 and a T2 value of ~24 ~ 100 (at 6.4 MHz).
Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a mixture of 75 parts 2-hydroxyethyl methacrylate, 25 parts methylmethacrylate, 0.5 parts ethyleneglycol dimethacrylate and 0 L 1 part benzoin methyl ether. The products upon equilibration with water, possess a water content of 22.7~
by weight, a Tl value of about 1050 and a T2 value of 248 ' 90 (at 6.4 MHz).
Example 10 Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a mixture of 80 parts methylmethacrylate, 20 parts dimethylacrylamide, 0.5 parts ethyleneglycol dimethacrylate and about 0.1 part benzoin methyl ether. The products, upon equilibration with water, had a water content of 12.5% by weight and, at 6.4 MHz, a Tl value of 1~40 ~ 700 and a T2 value of 234 ~ 100.
1~'7g8~ ~
Example 11 Using the methods of Example 6 9 buttons and spherical beads, respectively, are prepared from a mixture of 30 parts 2-hydroxyethyl methacrylate, 40 parts methyl methacrylate, 30 parts dimethylacrylamide, 0.5 parts ethyleneglycol dimethacrylate and about 0.1 part benzoin methyl ether. The products, upon equilibration with water, have a water content of 27.6% by weight and at 6.4 MHz exhibit a Tl of 220 ~ 110 and a T2 of 40 ~ 19.
xample 12 Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a mixture of 70 parts methyl methacrylate, 30 parts dimethyl acrylamide, 0.5 parts ethyleneglycol dimethacrylate, and 0.1 part benzoin methyl ether. The products produced possess upon equilibration with water, a water content of 22.8% and, at 6.4 MHz, a T2 value of 3~ i 50.
_~m~ 13 Upon the methods of ~xample 6, buttons and spherical beads, respectively, are prepared from a mixture of 50 parts of a fluorinated methacrylate ester of ~he formula Rf--CH2CH2--SCONHCH2CH20CO--C(CH3) = CH2 9~3L9 wherein Rf is a 1:1 mixture of n-CgF17 and n-CloP21, 30 parts methyl methacrylate and 20 parts dimethyl acrylamide, with 0.2 parts ethyleneglycol dimethacrylate and about 0.1 part benzoin methyl ether. The fluorinated methacrylate is prepared by combining one mole of perfluoroalkylthiol of the formula R~CH2CH2SH per mole of 2-isocyanatoethyl methacrylate, adding to the reaction mixture 0.005 mole triethylamine per mole of thiol with mixing under ambient conditions to promote the reaction, reacting the resulting mixture at about 30C for 6 hours, and washing the resulting product with ethanol to remove unreacted material.
The crosslinked hydrogel, upon equilibration in water, had a water content of 11.6~, and, at 6.4 MHz, a T
value of 730 ~ 300 and a T2 value of 172 + 105.
Example 14 Using the methods of Example 6, buttons and spherical beads, respectively, are prepared from a mixture of 50 parts methyl methacrylate, 50 parts hydroxyethyl methacrylate, 0.5 parts ethylene glycol dimethacrylate, and about 0.1 part benzoin methyl ether. The resulting crosslinked hyrogel upon equilibration exhibits a water content of 13.9%, a Tl value of 300 ~ 200 and a T2 value of about 64 at 6.4 MHz.
~LX798~9 Example 15 A ~iloxane macromer is prepared according to Example 8 of U.S. Patent No. 4,136,250. A mixture of 30 parts of the siloxane macromer, consisting of polydimethyl siloxane triol ~Dow Corning 1248) having a molecular weight of about 6000 which is endcapped with isophorone diisocyanate in an amount oE 3 moles per mole of siloxane and terminated with 2-hydroxyethyl methacrylate in an amount of 3 moles per mole siloxane, is combined with 40 parts methyl methacrylate and 30 parts dimethyl acrylamide, and O.l part azobisisobutyronitrile catalyst. The mixture is then cast as buttons having a diameter of about 20 mm and a height of about lO mm, and as spherical beads having an average diameter of about 2 mm and cured at a temperature of 50C
for 16 hour.s following by a post cure of 100C for one hour. Upon equilibration with water, the cross-linked polyme~ had a water content of 27.1 ~, and at 64 MHz a Tl value of 170 + 70 and T2 value of 42 + 7.
Example 16 The procedure of Example 15 is repeated using 30 parts of the siloxane macromer with 20 parts of dimethyl/acrylamide and S0 parts methyl methacrylate. The resulting products upon equilibration contain 13.4~ water and at 6.4 MHz have a Tl value of 290 ~ 50.
~L~'7~ 9 Example 17 An array of aqueous swollen hydrogel buttons of Examples 6, 13, 14 and 15 are aligned in a whole body NMR
imaging device at 6.4 MHz to obtain Tl values of 1470 ~ 300 ms, 730 ~ 300, 300 ~ 200 and 170 ~ 70. This compares favorably with tissue samples subjected to NMR imaging at 6.4 MH2, i.~. the Tl value of minced brain obtained is 1470 i 300; pancreas tissue is 730 ~ 300; heart muscle is 390 i 120; and liver is 170 ~ 70.
Example 18 Using the procedure of Example 15, the macromer of Example 1 is reacted with various amounts of selected monomers to obtain crosslinked hydrogels which after equilibration in water are subjected to NMR imaging at 5 MHz to obtain the following results;
_Composition, %l) Product MAC MMA DMA NVP HEMA EHA
.
18a 30 70 18b 30 42 28 18c 20 45 35 18d~ 27.5 _ 33 2?.5 1) MAC = macromer of Example 1 MMA = methyl methacrylate DMA = dimethyl acrylamide NVP = N-vinyl pyrrolidone HEMA = 2-hydroxyethyl methacrylate EH~ = 2-ethylhexyl acrylate ~2'7~ 3 - ~3 Pro erties Products Tl T2 ~H20 18a 155 1~ 23.0 18b 34 4 25.4 18c 43 ~ ~9.0 18d_ 115 17 8.0 . _ _ _. . _ . _ _ ._ ___ When subjected to NMR imaging at 30 MHz, the products of Examples 18a give a Tl value of 555 i 50; 18b gave a Tl value of 259 ~ 29, 18c gave a Tl value of 252 +
10 and 18d gave a Tl value of 252 ~ 8. The products of 18b and 18c are sspecially useful due to their high contrast, as image contrast agents. All of the products of 18a-18d are useful as image contrast agents in NMR imaging machines employiny a combination of Tl and T2 in their imaging technique.
Also, the hydrogels of Examples 7, 11, 15 and 16 are highly valuable as image contrast agents due to their high contrast in the gastro-intestinal tract.
Claims (10)
1. A method of contrasting a proton NMR tomograph of the gastro-intestinal tract, or a portion thereof, by administering enterally to a mammal an effective image contrasting amount of a physiologically tolerable, synthetic, substantially non-degradable cross-linked hydrogel having, in the aqueous swollen state, spin-lattice or spin-spin relaxation values substantially shorter than the surrounding gastro-intestinal tissue environment; and subject-ing said mammal to said proton NMR tomography.
2. A method according to claim 1 wherein the hydrogel is administered as an aqueous suspension or slurry of particulate swollen cross-linked hydrogel having an average particle diameter between about 100µ and 100 mm.
3. A method according to claim 2, wherein the hydrogel exhibits in the fully swollen state of a proton reconance frequency of about 10 megahertz, a T1 relaxation time between about 10 to about 200 milliseconds and a T2 relaxation time of between about 1 to 60 milliseconds.
4. A method according to claim 2, wherein the hydrogel in the swollen state contains between about 5% and about 80% by weight water.
5. A method according to claim 4, wherein the hydrogel is substantially free of strongly ionic groups.
6. A method according to claim 2, wherein the hydrogel material is in the form of a bead having an average diameter between about 1 mm and 10 mm.
7. A proton nuclear magnetic resonance tomography tissue phantom kit comprising collection of synthetic cross-linked stor-age stable aqueous swollen hydrogels possessing varying T1 and T2 constants as proton nuclear magnetic resonance tomography contrast agents in addition to conventional proton nuclear magnetic reson-ance tomography tissue phantom kit components.
8. A kit according to claim 7 wherein the collection contains at least 3 diverse hydrogel samples.
9. A kit according to claim 8, wherein the hydrogels contain between about 5 and 95% water by weight.
10. A kit according to claim 9 which is suitable for use at resonance frequencies between about 2 and about 30 MHz.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/842,337 US4729892A (en) | 1986-03-21 | 1986-03-21 | Use of cross-linked hydrogel materials as image contrast agents in proton nuclear magnetic resonance tomography and tissue phantom kits containing such materials |
| US842,337 | 1986-03-21 |
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|---|---|
| CA1279819C true CA1279819C (en) | 1991-02-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000532415A Expired - Lifetime CA1279819C (en) | 1986-03-21 | 1987-03-19 | Use of cross-linked hydrogel materials as image contrast agents in proton nuclear magnetic resonance tomography and tissue phantom kits containing such materials |
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Families Citing this family (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63153056A (en) * | 1986-12-17 | 1988-06-25 | 日石三菱株式会社 | Phantom for nmr diagnosis |
| DE3723310A1 (en) * | 1987-07-15 | 1989-01-26 | John Urquhart | PHARMACEUTICAL PREPARATION AND METHOD FOR THE PRODUCTION THEREOF |
| JPS6456043A (en) * | 1987-08-27 | 1989-03-02 | Nippon Oil Co Ltd | Preparation of phantom for nmr diagnosis |
| US5145661A (en) * | 1988-08-31 | 1992-09-08 | Wayne State University | Method and contrast agent for use in magnetic resonance imaging of abscess |
| US5045304A (en) * | 1988-08-31 | 1991-09-03 | Wayne State University | Contras agent having an imaging agent coupled to viable granulocytes for use in magnetic resonance imaging of abscess and a method of preparing and using same |
| US4967764A (en) * | 1988-10-24 | 1990-11-06 | The United States Of America As Represented By The Department Of Health And Human Services | Pressure sensor element to measure contact stress |
| US5125408A (en) * | 1988-10-24 | 1992-06-30 | The United States Of America As Represented By The Of The Department Of Health And Human Services | Pressure sensor element and method to measure contact stress |
| CA1311520C (en) * | 1989-02-24 | 1992-12-15 | Ernest L. Madsen | Contrast resolution tissue mimicking phantoms for nuclear magetic resonance imaging |
| US5393525A (en) * | 1989-07-21 | 1995-02-28 | Nycomed Imaging As | Contrast medium comprising superparamagnetic or ferromagnetic particles capable of increasing viscosity after administration |
| GB8916780D0 (en) * | 1989-07-21 | 1989-09-06 | Nycomed As | Compositions |
| GB9006671D0 (en) * | 1990-03-24 | 1990-05-23 | Univ Manchester | Diagnostic method and compositions |
| DK0526503T3 (en) * | 1990-04-10 | 1997-10-27 | Imarx Pharmaceutical Corp | Polymers as contrast media for magnetic resonance imaging |
| US5368840A (en) * | 1990-04-10 | 1994-11-29 | Imarx Pharmaceutical Corp. | Natural polymers as contrast media for magnetic resonance imaging |
| US5370901A (en) * | 1991-02-15 | 1994-12-06 | Bracco International B.V. | Compositions for increasing the image contrast in diagnostic investigations of the digestive tract of patients |
| US5385719A (en) * | 1991-09-24 | 1995-01-31 | Unger; Evan C. | Copolymers and their use as contrast agents in magnetic resonance imaging and in other applications |
| WO1993010163A2 (en) * | 1991-11-12 | 1993-05-27 | Nepera, Inc. | Adhesive hydrogels having extended use lives and process for the preparation of same |
| US5730130A (en) * | 1993-02-12 | 1998-03-24 | Johnson & Johnson Professional, Inc. | Localization cap for fiducial markers |
| US5532006A (en) * | 1993-04-23 | 1996-07-02 | The Board Of Trustees Of The University Of Illinois | Magnetic gels which change volume in response to voltage changes for MRI |
| US6333971B2 (en) | 1995-06-07 | 2001-12-25 | George S. Allen | Fiducial marker |
| US6675035B1 (en) | 1997-06-20 | 2004-01-06 | Imaging Diagnostic Systems, Inc. | Phantom for optical and magnetic resonance imaging quality control |
| DE69934536T2 (en) * | 1998-04-09 | 2007-10-04 | Nippon Shokubai Co. Ltd. | Crosslinked polymer particles and process for its preparation and use |
| US6318146B1 (en) | 1999-07-14 | 2001-11-20 | Wisconsin Alumni Research Foundation | Multi-imaging modality tissue mimicking materials for imaging phantoms |
| US20030100830A1 (en) * | 2001-11-27 | 2003-05-29 | Sheng-Ping Zhong | Implantable or insertable medical devices visible under magnetic resonance imaging |
| US20040067591A1 (en) * | 2002-10-04 | 2004-04-08 | Wisconsin Alumni Research Foundation | Tissue mimicking elastography phantoms |
| US6965235B1 (en) | 2003-07-24 | 2005-11-15 | General Electric Company | Apparatus to simulate MR properties of human brain for MR applications evaluation |
| JP4063746B2 (en) * | 2003-09-26 | 2008-03-19 | 三井化学株式会社 | (Meth) acrylate with novel thiourethane skeleton |
| US7642775B2 (en) * | 2004-08-25 | 2010-01-05 | Koninklijke Philips Electronics N.V. | MR method of determining local relaxation time values using calibrated phantom |
| US7419376B2 (en) * | 2006-08-14 | 2008-09-02 | Artahn Laboratories, Inc. | Human tissue phantoms and methods for manufacturing thereof |
| WO2011075476A1 (en) * | 2009-12-14 | 2011-06-23 | Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University | Methods and compositions relating to reporter gels for use in mri techniques |
| JP5953318B2 (en) * | 2011-12-28 | 2016-07-20 | 株式会社日立製作所 | Biological simulation phantom and calibration device |
| US10194829B2 (en) | 2015-07-07 | 2019-02-05 | Q Bio, Inc. | Fast scanning based on magnetic resonance history |
| US9958521B2 (en) | 2015-07-07 | 2018-05-01 | Q Bio, Inc. | Field-invariant quantitative magnetic-resonance signatures |
| WO2017044919A1 (en) | 2015-09-12 | 2017-03-16 | Q Bio, Inc | Uniform-frequency records with obscured context |
| US10964412B2 (en) | 2015-10-20 | 2021-03-30 | Q Bio, Inc. | Population-based medical rules via anonymous sharing |
| US11872025B2 (en) | 2016-03-18 | 2024-01-16 | Q Bio, Inc. | System and method for magnetic resonance elastography |
| US10359486B2 (en) | 2016-04-03 | 2019-07-23 | Q Bio, Inc. | Rapid determination of a relaxation time |
| US10222441B2 (en) | 2016-04-03 | 2019-03-05 | Q Bio, Inc. | Tensor field mapping |
| US11650195B2 (en) | 2017-02-03 | 2023-05-16 | Q Bio, Inc. | Iterative medical testing of biological samples |
| US10936180B2 (en) | 2017-03-16 | 2021-03-02 | Q Bio, Inc. | User interface for medical information |
| US11354586B2 (en) | 2019-02-15 | 2022-06-07 | Q Bio, Inc. | Model parameter determination using a predictive model |
| US11360166B2 (en) | 2019-02-15 | 2022-06-14 | Q Bio, Inc | Tensor field mapping with magnetostatic constraint |
| MX2022003462A (en) | 2019-09-27 | 2022-04-19 | Q Bio Inc | Maxwell parallel imaging. |
| US11614509B2 (en) | 2019-09-27 | 2023-03-28 | Q Bio, Inc. | Maxwell parallel imaging |
| US11181601B1 (en) | 2020-05-19 | 2021-11-23 | Wisconsin Alumni Research Foundation | Systems and methods for magnetic resonance phantoms |
| US11614508B1 (en) | 2021-10-25 | 2023-03-28 | Q Bio, Inc. | Sparse representation of measurements |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2976576A (en) * | 1956-04-24 | 1961-03-28 | Wichterle Otto | Process for producing shaped articles from three-dimensional hydrophilic high polymers |
| US3220960A (en) * | 1960-12-21 | 1965-11-30 | Wichterle Otto | Cross-linked hydrophilic polymers and articles made therefrom |
| US3488111A (en) * | 1967-03-16 | 1970-01-06 | Nat Patent Dev Corp | Hydrophilic hydrogel corneal contact lens with hard central insert |
| US3532679A (en) * | 1969-04-07 | 1970-10-06 | Robert Steckler | Hydrogels from cross-linked polymers of n-vinyl lactams and alkyl acrylates |
| US3639524A (en) * | 1969-07-28 | 1972-02-01 | Maurice Seiderman | Hydrophilic gel polymer insoluble in water from polyvinylpyrrolidone with n-vinyl-2-pyrrolidone and methacrylic modifier |
| US3841985A (en) * | 1969-11-28 | 1974-10-15 | Warner Lambert Co | Irradiated composition for soft contact lens |
| US3822196A (en) * | 1969-11-28 | 1974-07-02 | Warner Lambert Co | Fabrication of soft plastic contact lens blank and composition therefor |
| US3816571A (en) * | 1969-11-28 | 1974-06-11 | Warner Lambert Co | Fabrication of soft plastic lens |
| BE759530A (en) * | 1969-11-28 | 1971-04-30 | Griffin Lab Inc | CONTACT LENS AND ITS MANUFACTURING PROCESS |
| US3647736A (en) * | 1970-05-25 | 1972-03-07 | Kontur Kontact Lens Co Inc | Hydrophilic contact lens material |
| JPS4926514B1 (en) * | 1970-09-19 | 1974-07-09 | ||
| US3803093A (en) * | 1971-02-25 | 1974-04-09 | C Neefe | Methyl methacrylate copolymer which may be hydrated |
| US3728317A (en) * | 1971-05-03 | 1973-04-17 | Hydrophilics Int Inc | Optical contact lenses and related devices |
| US3772235A (en) * | 1971-10-05 | 1973-11-13 | Union Optics Corp | Copolymers and hydrogels of unsaturated heterocyclic compounds |
| US3758448A (en) * | 1971-10-05 | 1973-09-11 | Union Optics Corp | Copolymers and hydrogels of unsaturated esters |
| US4192827A (en) * | 1974-06-27 | 1980-03-11 | Ciba-Geigy Corporation | Water-insoluble hydrophilic copolymers |
| US4136250A (en) * | 1977-07-20 | 1979-01-23 | Ciba-Geigy Corporation | Polysiloxane hydrogels |
| DE2839249A1 (en) * | 1977-09-12 | 1979-03-22 | Toray Industries | METHOD OF MANUFACTURING A SOFT CONTACT LENS AND OUTPUT SOLUTION FOR CARRYING OUT THE METHOD |
| US4224427A (en) * | 1978-06-01 | 1980-09-23 | Ciba-Geigy Corporation | Process for preparing hydrogels as spherical beads of large size |
-
1986
- 1986-03-21 US US06/842,337 patent/US4729892A/en not_active Expired - Lifetime
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1987
- 1987-03-19 CA CA000532415A patent/CA1279819C/en not_active Expired - Lifetime
Also Published As
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|---|---|
| US4729892A (en) | 1988-03-08 |
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