• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    This invention relates to the field of medicine and concerns a method for preparing organ transplants. The purpose of the invention is to increase the degree of preservation of the biophysical properties of the original organs. For this, organs removed from fish, birds, and mammals are treated with solutions of di-, tri-, or polycarboxylic acids or HsI chlorides and hydrides, taken in a concentration of 0.02–3.2% at room temperature for 3–48 hours. CO with
    公开号:SU1291020A3
    申请号:SU813266255
    申请日:1981-03-30
    公开日:1987-02-15
    发明作者:Фрэфель Вольфганг；Феликс Лихти Хайнц；Брунетти Массимо
    申请人:Золько Базель Аг (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to medicine and concerns a method for preparing organ transplants.
    The aim of the invention is to be obtained both from people (autologous grafts) and from tel, cattle, horses, sheep, pigs, geese, turkeys.
    outside the degree of conservation of biophysical 5 Pheasants and other animals (inadequate properties of the original organs,
    It has been established that by intra- and / or intermolecular cross-linking of macromolecules of the intercellular matrix of organs
    transplants). At the same time, organs and parts of organs of animals are preferable because of their greater accessibility, especially for young animals.
    or parts of the organs can be significantly- about whose organs possess superior
    To the least, preserve the initially existing biophysical properties (in the case of vascular prostheses, axial and radial elasticity, as well as the smooth state of the inner surface of the vessels). This crosslinking differs from the known methods in that it is realized not through the formation of Schiff bases, but through chemically more stable amino acid bonds between the amino groups, respectively, due to the ester bonds of the alcoholic hydroxyl groups of peptide chains, the intercellular matrices and carboxyl I groups of DI-, tri- or polycarboxylic acid, which is used as a crosslinking agent.
    The proposed method consists of the fact that organs or parts of organs of fish, birds or mammals, preferably higher mammals, are processed to cross-link the intercellular matrix macromolecules by forming amide bonds and L-ester bonds between amino groups, respectively, between alcoholic hydroxyl groups of peptide chains and carboxyl1. groups of di-, tri- or polycarboxylic acids of aliphatic, cycloaliphatic, aromatic or heterocyclic series.
    The matrix can be processed at an additional stage of the process by a dialdehyde. The dialdehyde treatment serves mainly for the binding of non-cross-linked amino groups. This increases the excess negative charge, which, according to the invention, reduces the risk of thrombosis, for example, in vascular transplantation,
    The starting materials used are, in particular, arteries, veins, heart valves, as well as the pericardium, etc., obtained from birds and higher mammals. Transplants
    can be obtained both from humans (autologous grafts), and from tel, cattle, horses, sheep, pigs, geese, turkeys.
    Phezans and other animals (adequate to
    transplants). At the same time, organs and parts of organs of animals are preferable because of their greater accessibility, especially for young animals.
    five
    five
    0
    elasticity.
    The organs and organs of the organs are immediately removed from the surrounding tissues by the ambassador, the collaterals are tied up with a ligature. They are then processed or stored in water, physiological saline solution or in another physiological aqueous solution, for example, tween.
    0, 80 (polyoxyethylene derivatives of sorbitanoleate), or in a non-aqueous liquid, for example dimethyl sulfoxide, with the addition of a small amount of sodium azide.
    An optional stage of the method is cross-linking. chains of the components of the extracellular matrix. It is based on the linking of two, three or more amino groups (the predominant part of lysine radicals 11 11minogaphs), respectively, of the alcoholic hydroxyl groups of the peptide chains by aliphatic, cycloaliphatic, aromatic or heterocyclic di-, tri- or polycarboxylic acids, by means of amo-acid, cycloaliphatic, aromatic, or heterocyclic di-, tri-, or polycarboxylic acids by means of amo-acid, cycloaliphatic, aromatic, or heterocyclic di-, tri-, or polycarboxylic acids; m
    Of these carboxylic acids, those that do not contain either oxo groups (aldehyde and ketone groups) or amino groups are particularly suitable. In particular, such di-, tri- or polycarboxylic acids are taken into account, which do not contain any functional groups other than carboxyl and hydroxyl
    groups. I.
    As aliphatic dicarboptic and tricarboxylic acids, compounds with up to 12 carbon atoms, i.e., are preferred. oxalic, malonic, narthen, block, glutaric, adipic, pyg, g melinova, corkova, sebacine and dodecanedicarboxylic, tartaric acid, and mucous acid, as tricarboxylic acids - tricarballoic acid and citric acid.
    0
    Of the cycloaliphatic di-, trinyl, polycarboxylic acids, cyclopentadicarboxylic and cyclohexanedicarboxylic acids are suitable, for example, cyclohexane-1,4-dicarboxylic acid.
    Phthalic, isophthalic and terephthalic acids in particular should be mentioned as aromatic dicarboxylic acids, and trimeic and trimellitic acids as aromatic tricarboxylic acids.
    Of the heterocyclic di-, tri-, and polycarboxylic acids, furan-2,5-dicarboxylic tetrahydrofuran-2,5-decarboxylic acid, oxidized starches, and carboxymethylcellulose are taken into account.
    The distance between the two amphibian groups available for crosslinking and suitable for carrying out the solubility in solvents in the case of the preferred groups mentioned requires a narrower upper and lower limit. Therefore, on the one hand, aliphatic dicarboxylic acids with 3-12 carbon atoms, i.e. from malonic to decandicarboxylic acid. On the other hand, higher molecular weight polycarboxylic acids, such as oxidized starches, also justify themselves.
    Crosslinking can be achieved on the basis of all the methods used in chemistry to form an amide bond between the amino and carboxyl groups. In particular, the acid chlorides, azides or anhydrides of these carboxylic acids can react with the free amino groups of the extracellular matrix. Similarly, free di-, tri-, poly-carboxylic acids can be coupled to the free amino groups of the intercellular matrix using a suitable coupling reagent (carbodiimides, e.g. dicyclohexylcarbodimimide).
    The reaction is generally carried out in an anhydrous organic diluent, such as tetrahydrofuran, dioxane, pyridine, dimethylformamide, dimethyl acetamide, dimethyl sulfoxide and hexamethylphosphoric triamide, or in a mixture of two or more solvents
    If water soluble: a coupling reagent, for example N-ethyl-N - (3-dimethylaminopropyl) -carbodiimide hydrochloride, is used, then water is also suitable as a solvent.
    Such stabilized organs and parts of organs can undergo tanning or crosslinking (optional) in the second stage of the process with dialdehyde, resulting in an effect on the possibly free amino groups of the collagen-peptide chain with the formation of the bases. This treatment is also preferred because prostheses obtained with glutaral dialdehyde are already practically sterile.
    Any dialdehyde is suitable as dialdehyde, formaldehyde, diapdehyde starch and, in particular, glutaric dialdehyde are preferred. The reaction with dialdehyde is preferably carried out in an aqueous solution (for example, according to the method according to Swiss Patent No. 595105 or Patent CUIA No. 3093439).
    The resulting grafts are then thoroughly washed with water, sterilized and stored until use in sealed plastic bags. The products are sterilized exclusively by chemical means using propene-1,2-oxide (see further under the name K-1-solution), propyloactone (lactone / 3-hydroxy-propionic acid) or ethylene oxide.
    Dentures were implanted in hybrid dogs weighing 20–25 kg a) on both dogs in each of the Arterias femorales distal inguinal ligaments using the method of P. Walter et al. (Helv. Chir. Acta 46 (1979), 81 et seq.); b) on both carotids; c) on .Aorta abdominalis caudally disposed of by Arteria renoles (P.Walter and H.Schmitz, Der heterol.oge Getasser-satz, C.30, Editio Condor. Aulendotz 1976); r) on the infrarenal Vena cav interior no to the method of S.Horseh et al. (Longenbecks Arch. Chir 344 (1978), 225 et seq.) For comparison, parallel experiments were carried out with prostheses made of Teflon (P) and dacro; on (P), as well as with umbilical veins, which were tanned only with glutaraldehyde. The percent closure, gt implant, was measured after six weeks.
    The implantation site on the hip ;;: the renal joint of the dog is subjected to a high mechanical load.
    Comparative results are indicative: Teflon (P) and Umhilicolvene implants have a closure of 100%, Dacron implants (P) have a closure of 77%, while the proposed implants according to Example 9 have a closure of 50%. The values obtained with comparative experiments are statistically significant
    In experiments that continued for 6 May under physiologically favorable conditions, it was on Agtiria Cacitis that the percentage of closure of implants according to Example 9 dropped to 20% (the value obtained is statistically significant). During the experiments that continued. –I 6 months in the infrarenal region, thrombosis was not observed.
    Example 1 Calf carotids are released from the surrounding ligament and are bound by collateralists. After the mechanical preparation, they are washed with deionized water and dried with filter paper, placed on a glass rod with a diameter of 3 mm for example, and placed in tetrahydrofuran-filled measuring cylinder 1. The contents of the measuring cylinder are shaken every 1-2 hours. After 5 hours, the liquid was replaced with new tetrahydrofuran. After another 2-3 hours, the glass rod is removed.
    The next day, the arteries are introduced into a 2% (w / v) solution of chlorine-adipic acid hydride in tetrahydrofuran and left in the solution for 24 hours. The solution is shaken or forced to circulate with a pump. After this, the arteries are placed in pure tetrahydrofuran, then in a mixture of tetrahydrofuran with water (1: 1 by volume) and finally in phosphate buffered saline solution and left in it for 30-60 minutes. As a result, the arteries are ready for sterilization or hydrolysis. using ficin, papain or the like.
    a) Sterilization with prop-152 oxide,
    Arteries for 16-24 hours (possibly also for a longer time) to 0206
    A solution of propy-152-oxide in a mixture of ethanol with water (1: 1 by volume) is placed in a 1% (1 / w / v) solution. Then they are sterilely placed in a PBS solution and sealed with it in a sterile plastic bag.
    The PBS-pacTBOp is prepared as follows.
    320 grams of sodium chloride, 8 grams of potassium chloride, 51.2 grams of secondary sodium phosphate dihydrate, 8.0 grams of primary potassium phosphate, 5.2 grams of calcium chloride dihydrate and 4.0 grams of hexahydrate 5 chloride are dissolved in 40 liters of water. magni.
    To store the arteries in a mixture of ethanol and water, it is enough to place them in the specified aqueous-alcoholic solution of propylene oxide and put it together in a plastic bag with liquid 0.
    b). Sterilization with propiolactone (lactone-xxy propionic acid),
    Approximately 900 ml of deionized water and a solution of the following salts: 0.236 g of sodium chloride, 0.248 g of potassium chloride, 0.363 g of calcium chloride dihydrate, 0.190 g of magnesium chloride hexahydrate, and 0.172 g of 0% potassium phosphate. Using approximately Oj in an aqueous solution of caustic soda, the pH of the solution is adjusted to /, 4. Then 11.782 g of a bicarbonate is dissolved in the solution. sodium volume and volume is adjusted to 5 to 1000 ml by the addition of water. Immediately before sterilization of the arteries, 8.6 ml (10.83 g) of propiolactone are added to 1 l of this solution, arteries are placed in the mixture and they are sealed together with the liquid into a plastic bag.
    at). Sterilization with ethylene oxide.
    Placed in a solution of PBS or physiological saline salt solution together with liquid are sealed in a plastic bag. Sterilized by the fact that the closed plastic bag in the sterilization apparatus is treated with gaseous ethylene oxide for 4 hours at 25-30 C.
    Note 2. Four mechanically prepared arteries of the calf are individually placed on glass rods 4 mm thick and placed in a 500 ml measuring cylinder filled with pyridine. After an hour they become so tough.
    That the glass rods can be removed. The liquid is drained and replaced with new pyridine. After an hour, the pyridine is updated again. After another hour, the arteries are introduced into the mixture, which is prepared as follows: with a syringe, add 2 ml (2.5 g) of adipic acid chloride to a mixture of 98 ml of pyridium a and 2 ml of dimethylformamide; precipitate of adipylpyridinium chloride. When it is defended, it is covered with a porcelain sieve. The arteries are then placed on a sieve so that they are completely covered with liquid, however, they do not come into contact with the sediment. After 18 hours, the arteries are removed from the liquid and immersed for 30 minutes in K-1-solution (see Example 6). They are then washed four times with 0.05 N of sterile aqueous solution of acetic acid and twice with sterile phosphate buffer (1/15 molar ) with a pH of 8. They are placed in sterile PBS-pacTBOp and, together with this liquid, sealed in a plastic bag.
    Example 10 calf arteries are mechanically dissected and for 3 hours they are placed vertically in a 500 ml measuring cylinder filled with tetrahydrofuran. They are then individually placed in glass tubes about 2 cm wide and shaken (each with 40 ml of a 0.06% (w / v) solution of adipic acid in a mixture of tetrahydrofuran and water (4: 1 by volume). 40 ml of a 2% (w / v) solution of dicyclohexylcarbodiimide in tetrahydrofuran is added in 1 h and shifted with shaking and vibrations with the solution already in. After 3 h, the arteries are placed in K-1 solution (see Example 6 ). The next day they are washed with 40 ml of sterile mixture of ethanol and water (1: 1 by volume), sterile phosphate buffer 1 / 15 molar) with pH 8 and place them in sterile PBS-pacTBOp. Finally, they are sealed together with a PBS solution into a plastic bag.
    Example4. After mechanical preparation, 10 calf arteries are placed in a 500 ml measuring cylinder filled with dimethylformamide. After 3 hours, they are individually placed in glass tubes with an internal diameter of approximately 2 cm and
    0
    five
    0
    five
    0
    five
    0
    five
    0
    five
    they are poured over 40 ml of each (), 06% oh (dog / vol) adipic acid solution in a mixture of dimethylformamide and water (4: 1). After an hour, add 40 ml of a 2% (by volume) solution of dicyclohexylcarbodiimide in dimethylformamide and mix by shaking and vibrating with the adipic acid solution already injected. After 3 hours, the liquid from each tube was poured and replaced by a VO ml of K-1-α-solution. The next day, the arteries are washed with 40 ml of sterile mixture of ethanol and water (1: 1 by volume) and sterile phosphate buffer (1/15 molar) with a pH of 9. Finally, they are added to a sterile PBS solution and together with him sealed in a plastic bag.
    Example 5. 4 calf arteries are freed from binding tissue and the collate is ligated. The arteries are then applied for 2 hours in 60 ml of a 0.02% w / v adipic acid aqueous solution. They are then placed in 60 ml of an aqueous solution that contains adipic acid at a concentration of 0.2 g per liter and H-ethyl-K - - (3-dimethylaminopropyl) -carbodiimide-hydrochloride at a concentration of 25 g per liter. After 20 hours, arteries are introduced into K-1 solution, and after 24 hours, into sterile PBS-pacTBOp. Together with him they are sealed in a sterile plastic bag.
    PRI me R 6. Mechanical dissected arteries are placed for 2 hours in 60 ml of a solution of 0.1% (w / v) cork acid in water, then in 60 ml of an aqueous solution which contains 0.24 g per liter cork acid and 25 g L-ethyl-K - (3-dimethylaminopropyl) -carbodiimide-hydrochloride. After 20 hours, the arteries are introduced into the K-1-solution, after the next 24 hours, into a sterile PBS-pacTBop and together with it sealed in a sterile plastic bag,
    The K-1 solution is prepared as follows.
    720 ml of water and 720 ml of ethanol are mixed. 16.9 ml (14.1 g) of propium-1,2-oxide is added to this solution. This solution is always prepared fresh and used immediately after preparation for sterilization,
    Pr 7 p. Carotides are tel as described in Example 1, mechanically
    9,
    prepared and washed with water, then placed in 200 ml of tetrahydrofuran. After 7 days, the arteries are placed in a 3.2% (w / v) solution of dodencarboxylic acid dichloride anhydride in tetrahydrofuran and left to lie in it for 48 hours. They are then placed for 16 hours in tetrahydrofuran, for 8 hours in a buffer solution tetrahydrofuran (1: 1 by volume) with a pH of 4.5 and for 1 day in an aqueous buffer solution with a pH of 4.5. Now they are ready for sterilization or hydrolysis.
    Example 8. After the mechanical treatment, 10 arteries are placed in a flat plate and 500 ml of a 1% aqueous solution of citric acid in water (weight / volume) is poured. After 2 h, the arteries are placed in a 500 ml measuring cylinder in a vertical position and filled with a solution of 0.2 g of citric acid and 10 g of N-tylen-K - (3-methylaminopropyl) -carbodiimide hydrochloride in 500 ml of water. . A day later, the arteries are washed for 20 minutes in running water and then placed in a sterile physiological saline solution. Together with a saline solution, the arteries are placed in plastic bags, the bags are sealed and sterilized with ethylene oxide, as described in Example 1.
    Example 9. After the mechanical treatment, 10 arteries are tensed onto glass rods and installed in a measuring cylinder of 500 ml filled with a saturated aqueous solution of DL-camphoric acid (DL-1,2,2-trimethylcyclopentane-1,3-cis-dicar boom acid). After 4 hours, the arteries, without removing them from the rods, are placed in a 500 ml measuring cylinder and filled with a solution of 0.25 g of DL-camphoric acid and 10 g of H-ethyl-K - (3-dimethylamino-propyl) -carbodiimide- hydrochloride in 500 ml of water. After 4 hours, the rods are gently pulled out of the arteries, and every other day, the arteries are washed with running water for half an hour, placed in a sterile physiological saline solution and sealed with it in plastic bags, then immediately sterilized with ethylene oxide, as described in example 1.
    Example 10. 100 carotid collaterals of bodies t and bulls long
    12

    about
    , 2, s
    ten
    "five
    20
    291020to
    2-4 cm each stack a 200 ml beaker and pour 200 ml of tetrahydrofuran. During the day, the liquid is replaced twice with fresh portions. Approximately every. Mix the contents of the glass for 2 hours. The next day, the liquid is replaced with a solution of 20 ml / l of adipic acid chloride and 38 ml / l of triethylamine in tetrahydrofuran. From time to time, the beaker is inverted to mix its contents. The next day, the liquid from the beaker is poured and the collaterals are poured with 200 ml of tetrahydrofuran. After 2 h, it is replaced with a mixture of tetrahydrofuran and citrate-phosphate buffer solution with a pH of 4.5 in a volume ratio of 1: 1, and after i2 h with a pure citrate-phosphate buffer solution with a pH of 4.5. A day later, the collaterals were washed with running water for a quarter of an hour, placed 25 in a sterile saline solution in a plastic bag, sealed and sterilized with ethylene oxide, as described in Example 1.
    PRI me R 11. Cut out from the pericardial calf 10 round pieces with a diameter of 3 cm and hold them for half an hour in the water. Each of the pieces is placed on a rod-like template with a diameter of about 8 mm, and protrudes about 2 cm from the plate. After that, the pieces of the pericardium are pressed from all sides in the direction from the center with the help of a smooth modeling wooden stick to the template in such a way that as a result they take the form of bags with a diameter of about 8 and a height of about 12 cm. pericardium placed under a 100-watt heat lamp for 20 minutes, then they dry up and can be removed from the templates, while maintaining their shape. They are then placed in a beaker with 150 ml of tetrahydrofuran, followed by the fact that they are completely covered with liquid. After 3 and 6 hours, tetrahydrofuran in the beaker was replaced with fresh portions. The next day, tetrahydrofuran was replaced with a 3.5% solution (w / v) dodecanoic acid chloride in tetrahydrofuran and the pericardium sacs were left in it for 24 hours.
    thirty
    35
    40
    50
    55
    Then the liquid in the glass is replaced with pure tetrahydrofuran, through A h to a mixture of tetrahydrofuran and citrate-phosphate buffer solution with a pH of 4.5 in a volume ratio of 1: 1, and after another h with a pure citrate-phosphate buffer solution with pH 4.5. The next day, the bags from the pericardium are placed in a physiological solution of sodium chloride, then together with this solution in plastic bags, the bags are sealed and sterilized with ethylene oxide. So treated
    fO
    to replace damaged eardrums.
    权利要求:
    Claims (1)
    [1]
    The invention The method of preparing organ transplants, including the removal of organs from animals and their treatment with chemical reagent solutions, is characterized in that DI-, tri- or polycarboxylic are used as chemical reagents in order to preserve the degree of preservation of the biophysical properties of the original organs. acids or their acid chlorides concentration 0.02-3, 2%, and the treatment is carried out at
    Pericardium pieces can be used at room temperature for 3-48 hours.
    to replace damaged eardrums.
    The invention The method of preparing organ transplants, including the removal of organs from animals and their treatment with chemical reagent solutions, is characterized in that DI-, tri- or polycarboxylic are used as chemical reagents in order to preserve the degree of preservation of the biophysical properties of the original organs. acids or their acid chlorides concentration 0.02-3, 2%, and the treatment is carried out at
    room temperature for 3-48 hours
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    同族专利:
    公开号 | 公开日
    EP0037381A2|1981-10-07|
    KR840002036B1|1984-11-06|
    AR229240A1|1983-07-15|
    EP0037381A3|1982-03-17|
    PL230425A1|1981-12-23|
    MX157885A|1988-12-20|
    ES8203218A1|1982-04-01|
    CA1158807A|1983-12-20|
    KR830004831A|1983-07-20|
    IN155668B|1985-02-23|
    AT9867T|1984-11-15|
    JPH029827B2|1990-03-05|
    DE3166676D1|1984-11-22|
    ZA812120B|1982-04-28|
    PL127208B1|1983-10-31|
    JPS56151038A|1981-11-21|
    ES500876A0|1982-04-01|
    US4383832A|1983-05-17|
    EP0037381B1|1984-10-17|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    CH252980|1980-03-31|
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