WO1992009309A2 - Procede de sterilisation de liquide - Google Patents

Procede de sterilisation de liquide Download PDF

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Publication number
WO1992009309A2
WO1992009309A2 PCT/US1991/008900 US9108900W WO9209309A2 WO 1992009309 A2 WO1992009309 A2 WO 1992009309A2 US 9108900 W US9108900 W US 9108900W WO 9209309 A2 WO9209309 A2 WO 9209309A2
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WO
WIPO (PCT)
Prior art keywords
alcohol
group
solution
diglycidyl ether
reducing agent
Prior art date
Application number
PCT/US1991/008900
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English (en)
Other versions
WO1992009309A3 (fr
Inventor
Roger Tu
Kalathi Thyagarajan
Harriet Chan Myers
Original Assignee
Baxter International Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Baxter International Inc. filed Critical Baxter International Inc.
Priority to JP4502817A priority Critical patent/JPH06503018A/ja
Publication of WO1992009309A2 publication Critical patent/WO1992009309A2/fr
Publication of WO1992009309A3 publication Critical patent/WO1992009309A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
    • A61L2/0088—Liquid substances
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/20—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom three- or four-membered rings

Definitions

  • This invention relates to a method of sterilizing medical devices using liquid sterilants. More particularly, this invention relates to a method of sterilizing implantable biological devices using polyepoxy solutions.
  • SAL Sterility Assurance Level
  • the level of SAL acceptable by the medical industry is 6, which represents the probability that a surviving target organism remains after the lapse of a specified time period is less than 1 x 10 " .
  • the amount of time necessary to achieve the acceptable SAL for a particular sterilization procedure as used on a specific target organism is calculated from a measured unit of time known as the D-value.
  • the D-value generally represents the amount of time necessary to achieve a single ninety (90) percent reduction in the count level of viable target organisms after the application of the sterilization procedure, with a lower D- value representing a more efficient procedure.
  • the D-value time also depends upon the conditions under which the procedure is performed, such as the temperature and the specific sterilant being used. Sterilization can be accomplished by subjecting the device to a variety of means for denaturing the microbes, such as ultraviolet radiation, extreme heat, and a variety of chemical disinfectants. Many of the chemical sterilants are liquids or are used in liquid solutions.
  • biological prosthetic devices are packaged and stored submerged in the liquid sterilizing solution to maintain their natural flexibility and to inhibit microbial proliferation during the storage period.
  • Biological devices are implanted within living bodies, usually to replace a diseased or damaged natural part that has been surgically removed. It is also particularly important, therefore, that the sterilant used be capable of reducing and suppressing to an acceptably low level the population of microbes on the device without leaving a chemical residue that is toxic or inhibits infiltration of host cells into the implanted device. Microbial viability depends upon the action of certain essential enzyme systems. When these enzyme systems are interrupted, the result is an irreversible change in specialized proteins that are necessary to continuation of the microbial life cycle. It is particularly desirable, therefore, to find a chemical sterilant effective at relatively low temperatures that interferes with the enzyme systems necessary to the microbial life cycle.
  • a method for sterilizing a medical device comprising contacting the device with an effective amount of at least one polyepoxy compound so as to substantially reduce the microbial population thereon.
  • an aqueous solution containing from 2 to 4 volume percent of a glycidyl ether is used to sterilize a medical device such as a biological implantable device.
  • DESCRIPTION OF THE DRAWING Figure 1 is a log graph illustrating the number of surviving Bacillus pumilus with time upon exposure to various sterilizing solutions containing 2% by volume of ethylene glycol diglyeidyl ether.
  • Figure 2 is a log graph illustrating the number of surviving Bacillus pumilus with time upon exposure to various sterilizing solutions containing 2% by volume of ethylene glycol diglycidyl ether.
  • Figure 3 is a log graph comparing the number of surviving Bacillus pumilus upon exposure at various temperatures to sterilizing solutions containing either 2% or 4% by volume of ethylene glycol diglycidyl ether.
  • DETAILED DESCRIPTION OF THE EMBODIMENTS it is contemplated that various types of implantable biological tissue derived from numerous animal sources and parts of the anatomy can be sterilized with less danger of toxic residue than with conventional sterilization procedures.
  • the tissue can be derived from various sources, including but not limited to, bovine, porcine, horse, sheep, kangaroo, and rabbit. All kinds of implantable tissue, such as tendons, ligaments, heart valves and tissue used to construct heart valves, such as dura mater and pericardium, as well as tissue used for augmentation, such as skin patches, pericardial patches, aortic patches, and tympanic membranes are suitable for sterilization according to the present invention. Moreover it is contemplated that the surfaces of non-biological items such as surgical instruments, medical devices, valve conduits and the like made of plastic, cloth, or metal, can be effectively treated according to the present invention.
  • polyepoxy compounds particularly glycidyl ethers such as those registered under the trademark name Denacol® (manufactured by Nagase Chemical Ltd, Hyogo-ken, Japan) are particularly effective and liquid sterilants for use in sterilizing medical devices.
  • Polyepoxy compounds have epoxy functional groups
  • n is an an integer from 1 to about 6 are preferred.
  • Nonlimiting examples of the polyepoxy ethers that can be used as liquid sterilants for medical devices are glycerol polyglycidyl ether, trimethylol polyglycidyl ether, diglycerol polyglycidyl ether, polyglycerol polyglycidyl ether, ethylene and polyethylene glycol diglycidyl ether, propylene and polypropylene glycol diglycidyl either, neopentyl glycol diglycidyl ether and 1,6-hexanediol diglycidyl ether, among others.
  • diglycidyl ether of glycol polyglycidyl ether of polyol
  • diglycidyl ester of dicarboxylic acid diglycidyl ether of polyol
  • monoglycidyl ether of polyol four types are preferred: diglycidyl ether of glycol, polyglycidyl ether of polyol, diglycidyl ester of dicarboxylic acid and monoglycidyl ether of polyol.
  • the epoxy compounds used as sterilants are generally used in an aqueous solution or formulation at a concentration of less than about 10 volume percent.
  • concentration of the polyepoxy compound in the sterilizing solution is no more than from about 2 to 4 volume percent.
  • the polyepoxy compounds used in the practice of this invention are known to be systemically toxic as well as intracutaneously irritating and mutagenic, at the low concentrations required to effectively sterilize medical instruments as taught herein, the residual sterilant remaining on the devices has been found to have substantially no toxic effects on living matter.
  • epoxy compounds are not very soluble in water, a sufficient amount of a surfactant or a biocompatible surface tension-reducing compound, such as an alcohol having from 1 to about 5 carbon atoms, can be used to reduce the surface tension and promote dissolution of the polyepoxy compound in water.
  • a surfactant or a biocompatible surface tension-reducing compound such as an alcohol having from 1 to about 5 carbon atoms, can be used to reduce the surface tension and promote dissolution of the polyepoxy compound in water.
  • care must be taken as well that the surface tension-reducing agent is not harmful to the tissue in the device.
  • Suitable alcohols include biocompatible aliphatic and aromatic alcohols, preferably aliphatic alcohols containing from 1 to about 5 carbon atoms.
  • Aliphatic alcohols include but are not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, t-butanol, cyclo-hexanol, n-octanol, allyl alcohol, and the like.
  • Suitable biocompatible aromatic alcohols include benzyl alcohol, cresol, carbinol, and the like. These alcohols are generally effective in themselves in destroying microorganisms and thus cooperate with and enhance the sterilizing capacity of the polyepoxy compounds.
  • Suitable organic surfactants include anionic, cationic, and nonionic surfactants and their salts.
  • the preferred salts of the surfactants in the present invention include sodium and potassium.
  • Anionic surfactants useful in the present invention are those having a relatively large hydrophobic region of hydrocarbon residues, including aliphatic and aromatic groups, bonded to a negatively charged ionic group.
  • the aliphatic residues may be branched chained, straight chained, cyclic, heterocyclic, saturated, or unsaturated. These hydrophobic residues can be connected directly to an anionic group, such as carboxylate, sulfate, or sulfonate; or can be connected thereto through an intermediate linkage, such as an ester, amide, sulfonamide, ether, or aryl group.
  • Anionic surfactants in one embodiment of the present invention are those having one or more carboxylates bonded to an alkyl side chain, to a steroid, or to amino acids in the side chain, such as in the bile acids.
  • the surface tension reducing compounds are selected from the group consisting of ethanol and isopropanol.
  • the medical device is submerged in the liquid sterilant or liquid sterilant solution under conditions of time and temperature selected to assure that at least about 90 percent of the microbial life present on the medical device will be killed.
  • the percent kill can usually be increased just by increasing the temperature of the solution and/or extending the sterilization time.
  • the temperature of the solution is maintained in the range from room temperature to about 100 degrees C. for surgical instruments or medical devices in general, but for biological devices the preferred temperature range is from about 20 (room temperature) to about 45 degrees C. to avoid damage to the tissue.
  • the optimum sterilization time is related to the quantity of microorganism present and the level of sterility assurance desired. Consequently, the time can be varied according to needs.
  • the interplay between time and temperature illustrated in the examples hereinafter dictates that if the temperature is increased, the time of exposure needed to achieve any selected level of sterility would necessarily decrease. Accordingly, if the temperature is decreased, the exposure time would have to be increased significantly.
  • the sterilization time needed to reduce the population of microorganism by about 90 percent ranges from about 5 to 120 hours, preferably 4 to 60 hours. If the device is packaged and stored in the solution, of course, sterilization can continue throughout the shelf life of the packaged device.
  • a sterilant composition is considered potentially effective if it shows about a 90% reduction of the organisms being tested.
  • an effective solution shows a complete destruction of a large quantity (10 to 10 ) of test organisms within an acceptable time frame, usually from about 7 to about 8 hours) . It is known that in many cases a microorganism in solution is easier to kill than one located on a surface or substrate. Therefore, the sterilant compositions herein are considered particularly effect if the organism destroyed is on a surface rather than in solution or on tissue.
  • sterilant solutions were evaluated using various concentrations of sterilant, combinations of additives and conditions of time and temperature to determine the efficiency of the sterilants for killing microbes.
  • In vitro tests were conducted by placing a known concentration of Bacillus pumilus or Microascus cinereus into 100 ml. of the sterilant solution. At designated, timed intervals, aliquot samples were withdrawn and immediately processed by a filtration/rinsing procedure utilizing 0.45 micron membrane filter and USP Fluid A rinse to remove sterilant residue. The survivors on the membrane filters were cultured on Tryptic Soy Agar, by incubating at 30-35 degrees C. for 14 days before a count of survivors was taken.
  • microbes used were Bacillus pumilus, American Type Culture Collection #27142, at an initial concentration of 10 spores per ml. of test solution and Microascus cinereus. American Edwards Laboratory #80-076, at an initial concentration of 10 spores per ml. of test solution.
  • the sterilant used was ethylene glycol diglycidyl ether (Denacol® EX 810) in aqueous solution to which as surface tension reducing agents were added 200 proof ethanol (E) , 0.1 volume percent of 2 , 4 , 6-tris- (dimethylaminomethyl)phenol (DMP - 30), and 0.007 volume percent of salicylic acid in distilled water in concentrations shown in Table 1 below.
  • the pH of the sterilization solution was adjusted to 9.5-10.0 with IN HCl.
  • D 10 values liquid sterilant exposure time at temperature needed to affect a 90% reduction in the microbial population
  • Table 1 A summary of the results appears in Table 1 below.
  • Figure 1 is a log graph comparing the effect over time of exposure to 2% solutions of the*sterilant in combination with different surface tension reducing agents upon the above described Bacillus pumilus populations. The effect of varying the temperature from room temperature to 37 degrees C. can also be seen.
  • Figure 2 is a log graph comparing the effect with time of exposing Bacillus pumilus to different concentrations of sterilant and surface tension reducing agent at a constant temperature of 37 degrees C.
  • the effect of increasing the alcohol content of the solution from 5 to 20 volume percent was pronounced when the concentration of sterilant was 2 volume percent, but little benefit was gained from increasing the concentration of sterilant from 4 to 6 volume percent at a constant 20 volume percent concentration of alcohol.
  • the log graph in Figure 3 compares the effect of 2 and 4 volume percent concentrations of sterilant at temperatures of 37 and 45 degrees C. upon populations of Bacillus pumilus. The best results are achieved by using a 4% solution at a temperature of 45 degrees C.
  • EXAMPLE 2 Four types of in vitro biological tests were performed to evaluate the effects of ethylene glycol diglycidyl ether upon cell culture.
  • the grafts had an approximate outside diameter of 0.6 cm, an inside diameter of 0.4 cm, and a surface area of 3.2 cm sq/cm of length and had been packaged in 70 volume percent of ethanol. To remove the ethanol from the grafts, they were rinsed in 300 ml. of normal saline for a minimum of two minutes.
  • test extract solutions used were prepared by exposing sections of graft to normal saline or cottonseed oil for a period of 120 hours at 37 degrees C. to collect the residual sterilant therefrom.
  • Saline and cottonseed oil closely mimic the effect of bodily contact upon a device in their ability to remove residual sterilant from the test articles.
  • Test 1 a procedure designed to evaluate the blood compatibility of the sterilant (Blood Compatibility) , assesses the degree of hemolysis and the clotting time of blood contacted with an extract test solution prepared with a saline extract.
  • the extract was exposed to oxalated whole rabbit blood for one hour, after which the absorbance of the solution was measured spectroscopically for hemoglobin content caused by lysis of the red cells in the blood.
  • pieces of graft (Solid) that had been washed but not extracted were also tested using the above procedure.
  • the saline extract containing residual sterilant was exposed to sheep plasma and visually observed to determine the effects on clotting time.
  • Test 2 was designed to assess the inhibitory effect of an aqueous extract of residual sterilant on the normal growth of cells in culture (%ICG) using the following procedure. Human fibroblast cells were added to a test solution containing an equivalent mixture of a normal saline extract (37° C/120 hours) of the test article and cell culture media and were incubated for 72 hours. The amount of cell growth during the incubation period was determined by calculating the protein concentration of the incubated extract and comparing it with the protein concentration of a negative control solution prepared by adding an equal amount of cells to a test solution containing an equal amount of normal saline and cell growth media. This method yields a quantitative assessment of cytotoxicity.
  • AO agar overlay test
  • human fibroblast cells were cultured in a petri dish to form a confluent monolayer.
  • the cells were then overlayed with bacto agar, and the agar layer was allowed to solidify before 1.0 cc of the test solution was placed on the solidified agar. After 24 hours, the cells were examined under microscope (X100) for damage or lysis.
  • the agar overlay test (AO) was also conducted substituting a section of solid graft (Solid) for the test solution.
  • Test 4 the cytotoxic effect of the sterilant was tested using the Medium Eluate Method (MEM) .
  • MEM Medium Eluate Method
  • a monolayer of human fibroblast cells was incubated in the presence of a normal saline/cell growth medium extract of the graft for 24 hours.
  • a negative control was prepared by incubating a monolayer of human fibroblast cells in growth medium in the place of the graft extract. The cells were then examined for evidence of damage of lysis under a microscope (lOOx) .
  • the designation "pass" was given to samples in which cell destruction was not significantly greater than that found in the negative control.
  • Test 5 the solution was injected into each of five mice intravenously (for normal saline) or intraperitoneally (for cottonseed oil) at a dosage of 1.0 ml./20g. of body weight. The animals were observed for 72 hours post injection for any adverse reactions, and the observations were compared against those of the negative control animals.
  • Test 6 the effect of the extract upon contact with the dermis of rabbits was evaluated. Ten test sites and five control sites on the backs of each of two rabbits were injected intracutaneously with 0.2 ml. of the test solution. The test sites were examined for signs of irritation visualized as erythema and/or edema at 24, 48 and 72 hours.
  • NS Normal saline
  • CSO cottonseed oil
  • Pass indicates that the results of the particular effect being tested (ie. , the amount of lysed red blood cells) are not significantly worse for the test solution than for a negative control sample. From the test methods employed, the polyepoxy compound shows no signs of cytotoxicity or systemic toxicity and does not appear to be intracutaneously irritating or hemolytic.
  • EXAMPLE 3 In this study three polyepoxy sterilants were tested: glycerol polyglycidyl ether, polyglycerol polyglycidyl ether, and ethylene glycol diglycidyl ether. Samples collected from each of three bovine carotid glutaraldehyde fixed grafts stored in 30 volume percent ethanol were used in each of the following tests. The grafts were approximately 0.540 cm. in outside diameter, 0.443 cm. in inside diameter, 10 cm. in length, and had a surface area of approximately 3.09 cm. sq. per cm. of length. The results of the tests appear below in Table 3.
  • Test 7 the cytotoxicity of diffusible components of the test solution through an agar layer (AO) was evaluated as in Test 3 above. For this study only a 2 cm. section of graft was evaluated. The section was removed from each test article, and the sections were rinsed separately in 100 ml. normal saline for 5 minutes with occasional flushing of the graft section by squeezing. The rinsing step was repeated 5 times prior to testing.
  • Test 8 The inhibitory effect of a sterile water extract of residual sterilant on the normal growth of cells in culture (%ICG) was performed using the method of Test 2 above. For this study a 20 cm. section of graft removed from each test article was rinsed separately in 100 ml. of normal saline for 5 minutes with occasional flushing of the graft section by squeezing. The rinsing was repeated 5 times prior to testing. The test article was then extracted in sterile water at 37 degrees C. for approximately 120 hours, the extract was then filter sterilized, mixed with an equivalent volume of cell growth medium, and evaluated.
  • EDGE ethylene glycol diglycidyl ether
  • DDE diglycerol diglycidyl ether

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Abstract

Procédé de stérilisation de dispositifs médicaux utilisant une solution de composés de polyépoxy, en particulier des éthers de glycidyle tels que ceux déposés sous la marque Denacol R. Ces composés de polyépoxy sont particulièrement efficaces à des concentrations aussi faibles que celles comprises entre 2 et 4 pourcent en volume dans la solution aqueuse dans le but de stériliser des dispositifs médicaux biologiques, tels que des valvules du c÷ur ou des greffes vasculaires, sans causer de dommages aux tissus de l'implant et sans laisser de résidus sur le dispositif, résidus qui seraient toxiques aux tissus du patient.
PCT/US1991/008900 1990-11-28 1991-11-25 Procede de sterilisation de liquide WO1992009309A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4502817A JPH06503018A (ja) 1990-11-28 1991-11-25 液体殺菌方法

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Application Number Priority Date Filing Date Title
US62022290A 1990-11-28 1990-11-28
US620,222 1990-11-28

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WO1992009309A2 true WO1992009309A2 (fr) 1992-06-11
WO1992009309A3 WO1992009309A3 (fr) 1992-07-09

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JP (1) JPH06503018A (fr)
CA (1) CA2095253A1 (fr)
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4225795A1 (de) * 1992-07-31 1994-02-03 Schuelke & Mayr Gmbh Synergistisch Tb-wirksame Kombination aus Carbonsäuren und Alkoholen
DE4317083A1 (de) * 1993-02-11 1994-08-18 Menno Chemie Vertrieb Gmbh Desinfektionsmittel mit parasitizider Wirksamkeit
US5674298A (en) * 1994-10-21 1997-10-07 The Board Of Regents Of The University Of Michigan Calcification-resistant bioprosthetic tissue and methods of making same
US5679122A (en) * 1993-08-14 1997-10-21 Minnesota Mining & Manufacturing Company Filter for the filtration of a fluid flow
WO2001062304A1 (fr) * 2000-02-24 2001-08-30 St. Jude Medical, Inc. Procede de sterilisation d'articles
WO2002058745A1 (fr) * 2000-12-06 2002-08-01 Frey, Rainer Procede pour conserver des protheses biologiques, protheses biologiques conservees et solution de conservation
US6468660B2 (en) 2000-12-29 2002-10-22 St. Jude Medical, Inc. Biocompatible adhesives
EP1468606A1 (fr) * 2003-04-17 2004-10-20 Air Liquide Santé (International) Procédé pour la désinfection chimique et thermique
US7481973B2 (en) * 2003-04-17 2009-01-27 L'air Liquide Sante International Composition and process for chemical and thermal disinfection

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4394370A (en) * 1981-09-21 1983-07-19 Jefferies Steven R Bone graft material for osseous defects and method of making same
WO1984001894A1 (fr) * 1982-11-12 1984-05-24 American Hospital Supply Corp Sterilisation chimique de tissu biologique implantable
EP0306256A2 (fr) * 1987-08-31 1989-03-08 Koken Co. Ltd. Valve bioprosthétique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4394370A (en) * 1981-09-21 1983-07-19 Jefferies Steven R Bone graft material for osseous defects and method of making same
WO1984001894A1 (fr) * 1982-11-12 1984-05-24 American Hospital Supply Corp Sterilisation chimique de tissu biologique implantable
EP0306256A2 (fr) * 1987-08-31 1989-03-08 Koken Co. Ltd. Valve bioprosthétique

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4225795A1 (de) * 1992-07-31 1994-02-03 Schuelke & Mayr Gmbh Synergistisch Tb-wirksame Kombination aus Carbonsäuren und Alkoholen
DE4317083A1 (de) * 1993-02-11 1994-08-18 Menno Chemie Vertrieb Gmbh Desinfektionsmittel mit parasitizider Wirksamkeit
US5679122A (en) * 1993-08-14 1997-10-21 Minnesota Mining & Manufacturing Company Filter for the filtration of a fluid flow
US5674298A (en) * 1994-10-21 1997-10-07 The Board Of Regents Of The University Of Michigan Calcification-resistant bioprosthetic tissue and methods of making same
WO2001062304A1 (fr) * 2000-02-24 2001-08-30 St. Jude Medical, Inc. Procede de sterilisation d'articles
US6379615B1 (en) 2000-02-24 2002-04-30 St. Jude Medical, Inc. Methods of sterilizing articles
WO2002058745A1 (fr) * 2000-12-06 2002-08-01 Frey, Rainer Procede pour conserver des protheses biologiques, protheses biologiques conservees et solution de conservation
US7014655B2 (en) 2000-12-06 2006-03-21 Rainer Frey Method for conserving biological prostheses, conserved biological prostheses and conserving solutions
US6468660B2 (en) 2000-12-29 2002-10-22 St. Jude Medical, Inc. Biocompatible adhesives
US6780510B2 (en) 2000-12-29 2004-08-24 St. Jude Medical, Inc. Biocompatible adhesives
EP1468606A1 (fr) * 2003-04-17 2004-10-20 Air Liquide Santé (International) Procédé pour la désinfection chimique et thermique
US7481973B2 (en) * 2003-04-17 2009-01-27 L'air Liquide Sante International Composition and process for chemical and thermal disinfection

Also Published As

Publication number Publication date
WO1992009309A3 (fr) 1992-07-09
EP0559819A1 (fr) 1993-09-15
JPH06503018A (ja) 1994-04-07
CA2095253A1 (fr) 1992-05-29

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