WO2001002031A2 - Traitement anti-calcification cible - Google Patents

Traitement anti-calcification cible Download PDF

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Publication number
WO2001002031A2
WO2001002031A2 PCT/US2000/017606 US0017606W WO0102031A2 WO 2001002031 A2 WO2001002031 A2 WO 2001002031A2 US 0017606 W US0017606 W US 0017606W WO 0102031 A2 WO0102031 A2 WO 0102031A2
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Prior art keywords
treatment
followed
calcification
treated
concentration
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PCT/US2000/017606
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English (en)
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WO2001002031A3 (fr
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Dan Simionescu
Agneta Simionescu
Jean-Marie Girardot
Marie-Nadia Girardot
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Biomedical Design, Inc.
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Priority to AU56397/00A priority Critical patent/AU5639700A/en
Publication of WO2001002031A2 publication Critical patent/WO2001002031A2/fr
Publication of WO2001002031A3 publication Critical patent/WO2001002031A3/fr

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    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/02—Treatment of implants to prevent calcification or mineralisation in vivo

Definitions

  • the present invention relates generally to treating biomaterials destined for implantation in a human patient so as to render such materials resistant to calcification, and more particularly relates to methods for targeting anticalcification treatment to particular biological tissue that has been previously fixed, i.e. chemically cross-linked, so as to render it more resistant to calcification following its implantation in the human patient. Still more particularly, the invention relates to treatments of this type that are targeted to specific biomaterials of a certain character that have heretofore been difficult to effectively render resistant to calcification.
  • Collagen concentration for example, varies from about 90% (w/w) in pericardium, to about 40% in aortic cusps, and to only about 25% in aortic wall tissue.
  • elastin accounts for only 1- 5% in pericardium and about 10-15% in cusps whereas it may account for up to about 50% of aortic wall tissue.
  • cell types and numbers differ significantly between these three tissues.
  • Anticalcification treatment of glutaraldehyde fixed tissues such as that disclosed in U.S. Patent No. 4,976,733 and the treatment of tissues not cross-linked by glutaraldehyde in Nos. 5,447,536 and 5,733,339 were shown to be quite effective in reducing calcification of collagenous tissues, such as pericardium and porcine aortic leaflets; however, elastin-containing aortic wall tissue has proven to be less susceptible to reduction of calcification by the above-mentioned treatments. As a result, the investigation has continued for other anticalcification treatments that would specifically target tissue relatively low in collagen, for example tissue having relatively greater amounts of elastin.
  • the molecular substrates that can promote deposition of calcium salts in BHV and other implanted organs may generally be divided into two categories: (a.) cell- derived elements, such as lipid membranes which may contain calcium-transporting channels and calcium ATPases, integrins, cadherins, selectins and annexins, as well as cytoskeletal protein structures present in the close vicinity of devitalized cells, cell enzymes, calmodulin, mitochondria, the cell nucleus and other calcium-binding components, and (b.) extracellular matrix calcium-binding components, such as elastin-associated microfibrillar proteins (EAMF) , collagens, proteoglycans, proteolytic enzymes, such as etalloproteinases (MMPs) , matrix phosphatases, and other non-collagenous proteins.
  • cell- derived elements such as lipid membranes which may contain calcium-transporting channels and calcium ATPases, integrins, cadherins, selectin
  • a common element that appears to characterize these calcifiable substrates is the ubiquitous presence of one or more high affinity calcium-binding sites or calcium- trapping pockets which, by means of carboxyl and/or hydroxyl groups, attract and immobilize calcium ions.
  • the three-dimensional conformation of these sites is stabilized in the "correct" shape by intramolecular bridges, such as disulfide bonds, and hydrophobic interactions.
  • Anticalcification methods have now been devised that take into consideration the character of these molecular substrates that account for calcium deposition in tissues. These new methods accordingly target or challenge such substrates with specific compounds in such a way as to reduce or inhibit overall tissue calcification, without compromising any previously obtained cross-linking or calcification resistance that may have been obtained as a result of treatment with other reagents.
  • cell-targeted treatments generally fall into two main classes: cell-targeted treatments and matrix- targeted treatments.
  • the cell-targeted class of treatment includes three general categories; however, in some instances treatments from different classes or from different categories within one class may be used in combination and, as such, may produce an effect that is greater than the effect produced by either class or category of treatment alone.
  • progression from reversible, physiological calcium-binding towards the irreversible deposition of calcium salts into or onto these substrates can be effectively stopped by treatments that destabilize, modify and/or destroy the original conformation of high affinity calcium-binding sites and/or by treatments that permanently block the access and influx of counterions into otherwise unaltered sites.
  • injured cells are protected from degeneration and calcium overload by treating tissue containing such cells to reduce calcium influx into the cells or prevent oxidative and/or enzymatic damage.
  • a calcium channel blocking agent such as nifedipine (NIF) or diltiazem hydrochloride (DIL) , an antioxidant, or an agent, such as captopril (CAP) , that inhibits damaging enzymes.
  • Potential cell-related calcification substrates such as the cytoskeletal proteins actin, yosin, troponin and actinin, can also be removed, extracted or inactivated by using an appropriate extractant, such as a high potassium salt/MgATP mixture (KMA) .
  • KMA potassium salt/MgATP mixture
  • the structure of calcium-binding components, such as EAMF and MMPs and the like, in extracellular matrices can be appropriately modified to reduce the capacity thereof either to calcify per se or to induce calcification in adjacent components.
  • a suitable cleaving agent such as cyanogen bromide (CB)
  • CB cyanogen bromide
  • DTT dithiothreitol
  • NEM N-ethylmaleimide
  • a category of treatment permanently blocks the access and influx of counterions into such sites in cells.
  • a second category of treatment provides antioxidants which prevent oxidative damage and inhibit the action of enzymes that promote calcification of cells.
  • a third category extracts cell-related potential calcification sites.
  • Another category of treatment destabilizes, modifies and/or destroys the original conformation of such high affinity calcium-binding sites and is principally effective against calcification in matrices.
  • Tissues and biomaterials generally that can benefit from this technology may be characterized as being constituents of either biologic or synthetic origin which, once implanted in a human, are expected to directly or indirectly suffer the effects of calcification while implanted in a patient. Because these biomaterials are expected to be susceptible to concomitant calcium overload, oxidative damage and/or enzymatic hydrolysis, the incorporation of protective agents into these biomaterials provides them with reduced susceptibility towards calcification as well as increased biostability and durability.
  • Biological tissues as a result of modified extracellular matrix components or injured cells or both, will frequently present calcifiable substrates to which attention needs to be given; they may be cardiovascular tissues or non-cardiovascular tissues.
  • cardiovascular tissues examples of the former group include cardiac valves with or without associated stents, i.e. aortic, mitral, pulmonary and tricuspid valves, pericardium and blood vessels, such as (a) arterial segments of large, medium or small caliber, e.g. aortic, carotid or coronary, and (b) venous segments of large, medium or small caliber with or without accompanying venous valves, e.g. saphenous, jugular or cavae.
  • cardiac valves with or without associated stents i.e. aortic, mitral, pulmonary and tricuspid valves
  • pericardium and blood vessels such as (a) arterial segments of large, medium or small caliber, e.g. aortic, carot
  • non-cardiovascular tissue group examples include tendons, ligaments, articulations, aponeuroses, cartilages, organ capsules and sheaths, membranes, such as fasciae and dura matter, conduits, such as esophagus, trachea, hepatic ducts and ureter, and cavitary organs from the digestive and urinary tracts.
  • implanted tissue may be heterologous, homologous or autologous, i.e. of animal or human origin.
  • the biomaterials which may be treated prior to implantation may be whole tissues, organs or products thereof which are composed of extracellular matrix components, both with and without cells, and they may be in solid, liquid or gel form, e.g. in the form of sheets, sponges or fibers. They may also be products of tissue engineering or of guided tissue regeneration, wherein scaffolds and scaffolds with cells are used.
  • the biomaterials which are to be treated by the invention may have been previously chemically processed for removal of selected components, such as antigenic determinants, cell remnants, lipids, sugars and the like. As earlier indicated, such tissues may also have been chemically fixed or cross-linked using glutaraldehyde or other procedures. These tissues may also be further processed by pre- or post-fixation treatments with various anticalcification compounds, e.g. 2-aminooleic acid, phosphonates, detergents, ions and dyes; moreover, these biomaterials may be freeze-dried or dehydrated tissues. They may also be tissues or organs that were preserved by deep-freezing in the presence of cryoprotectants , as well as tissues or organs preserved in antibiotic-containing cold solutions.
  • various anticalcification compounds e.g. 2-aminooleic acid, phosphonates, detergents, ions and dyes
  • lipid membranes from injured cells which may contain naturally occurring calcium channels and calcium ATPases, integrins, cadherins, selectins and annexins may be protected from calcium overload and/or degeneration by treating such tissue with a calcium channel blocking agent and/or an antihypertensive agent that is capable of preventing oxidative damage and inhibiting the action of enzymes which have been reported to cause calcification.
  • nifedipine i.e., 1, 4-Dihydro-2 , 6-dimethyl-4-(2- nitrophenyl) -3 , 5-pyridinedicarboxylic acid dimethyl ester, nimodipine, nisoldipine, nitredipine, nicardipine, nilvadipine, amlodipine, lacidipine, verapamil, diltiazem hydrochloride (DIL), i.e., 1, 5-Benzothiazepin-4 ( 5H) one, 3- (acetyloxy) -5- [ 2- (dimethylamino) ethyl ] -2 , 3-dihydro-2- (4-methoxyphenyl) -monohydrochloride, trifluoperazine, bepridil, cinnarizine, fendiline, flunarizine, lidoflazine, pheny
  • agents capable of preventing oxidative damage which may also have antihypertensive properties
  • agents capable of preventing oxidative damage include captopril (CAP), i.e., 1- (3-Mercapto-2-methyl-l- oxopropyl) -L-proline, quinalapril, enalapril, lisinopril and zofenopril.
  • CAP captopril
  • cell-related calcification substrates e.g. cytoskeletal proteins such as actin, yosin, troponin and actinin, as well as cell enzymes, calmodulin, mitochondria, cell nuclei and other calcium-binding or calcium-trapping components.
  • cell-related calcification substrates e.g. cytoskeletal proteins such as actin, yosin, troponin and actinin
  • cell enzymes calmodulin
  • mitochondria cell nuclei and other calcium-binding or calcium-trapping components.
  • KMA potassium salt/MgATP mixture
  • Other suitable cell extractants may also be used.
  • extraction treatments may be advantageously used in combination with treatment by proteolytic enzyme inhibitors, such as PMSF, leupeptin, benzamidine and soybean trypsin inhibitor.
  • One preferred treatment is to use an appropriate cleaving agent, such as cyanogen bromide (CB) , to cleave such proteins at methionine (Met) residues;
  • CB cyanogen bromide
  • alternative cleaving agents are well known in the art and include hydroxylamine, N-bromosuccinimide, N-chlorosuccinimide, thiocyanobenzoic acid, ortho-iodosobenzoic acid and trifuoroperazine.
  • DTT dithiothreitol
  • reducing agents such as ammonium sulfite, dithioerythritol , sodium sulfite, tri-n-butylphosphine and beta- mercaptoethanol, and then preventing the reversal of such reduction by reacting with a reagent that will bond with a sulfhydryl group.
  • blocking reagents include alkylating reactants, such as N- ethylmaleimide (NEM) , dithiobis-(2-nitrobenzoic acid), iodoacetamide, iodoacetate, p-hydroxymercuri-benzoate and the methanethiosulfonates.
  • alkylating reactants such as N- ethylmaleimide (NEM) , dithiobis-(2-nitrobenzoic acid), iodoacetamide, iodoacetate, p-hydroxymercuri-benzoate and the methanethiosulfonates.
  • NEM N- ethylmaleimide
  • dithiobis-(2-nitrobenzoic acid) dithiobis-(2-nitrobenzoic acid)
  • iodoacetamide iodoacetate
  • p-hydroxymercuri-benzoate p-hydroxymercuri-benzoate
  • Treatments are carried out using the cell-targeted agents at appropriate concentrations, temperatures, pH and durations as generally known in this art for use of such reagents.
  • CAP or similar agents may be used at a concentration of from 1-200 ⁇ iM (preferably 25-75 mM) , at about 15-40°C, and at about pH 6-8 for about 2-72 hours.
  • NIF, DIL and related calcium channel blocking agents would be used at concentrations of about 0.1-50 mM (preferably about 5-25 M) under otherwise similar conditions.
  • Cell extractants are used at a similar pH and for a similar duration at temperatures in the range of about 0-20°C.
  • KMA may be used at a KCl concentration between about 0.4 M and about 1.5 M and usually between 0.5-0.8 M and MgATP at concentrations between 0.01-10 mM and usually between about 0.05-8 mM.
  • any sequence of treatments with agents from the three categories of cell-targeted agents may generally be used, when such a combination of treatments are employed, the following sequences are most often used: Category 1 followed by Category 2; Category 2 followed by Category 1; Category 3 followed by Category 2; Category 3 followed by Category 1; and Category 3 followed by Category 1 and Category 2.
  • a cleaving agent such as CB is used at a concentration of about 1-200 M (preferably about 10-50 mM) , at a similar pH and temperature as for CAP, but for a shorter duration of about 1-24 hours, e.g., about 3 hours.
  • a reducing agent such as DTT
  • DTT might be employed at a concentration of about 1-200 mM (preferably about 25-75 mM) and at other conditions as for CAP, and treatment with such an agent is preferably followed by treatment with a blocking agent, such as NEM, at a similar concentration and about the same temperature and pH as for CAP, but for a duration of about 12-48 hours, e.g., 24 hours.
  • the matrix- targeted class of treatment precede the cell-targeted treatment.
  • treatment with CB, or treatment with DTT preferably followed by reaction with an alkylating agent would usually be carried out prior to treatment with a Category 2 agent, with optional treatment thereafter with a Category 1 agent.
  • the aforementioned treatments are usually carried out in a buffered aqueous solution, e.g. using a borate buffer or HEPES, PIPES, MOPSO or the like. Washing is carried out following the anticalcification treatment and prior to sterilization. Normal saline or a buffered aqueous solution, as described above, may be used at about 0-40°C for 15 minutes to 4 hours, with the optional inclusion of up to about 25% isopropanol or another lower alkanol. When a combination of treatment steps is used, washing or rinsing between steps is desirable but not always necessary so long as there is washing prior to sterilization.
  • the anticalcification treatment may be applied to tissue that is not cross-linked, such as cryopreserved homografts, or to tissue that is cross-linked.
  • tissue that is not cross-linked such as cryopreserved homografts
  • the treatment is applied to cross-linked tissues, it is generally performed after fixation treatment of the biological tissue, although it may be performed previous thereto, or even both before and after.
  • a cell extractant or a reducing agent is used, treatment is preferably carried out prior to fixation.
  • the present treatment is carried out in combination with another type of anticalcification treatment, such as treating with 2-aminooleic acid as described in the '733 patent, the present treatment is preferably carried out subsequent thereto, except for treatment with a cell extractant or a reducing agent, which is preferably carried out prior to such other type of anticalcification treatment.
  • BHV tissue may be desirable to treat cell- containing BHV tissue to block calcium channels and/or reduce oxidizing and/or enzymatic damage, and/or extract or inactivate certain proteins, such as actin and myosin, in combination with modifying proteins in the extracellular matrix that may have a propensity to bind calcium per se or to induce calcification (as by partially cleaving such proteins and/or reducing cyclizing S-S bonds followed by alkylating) ; as a result of such treatment, overall calcification of BHV tissue is found to be very effectively reduced.
  • certain proteins such as actin and myosin
  • treatment with two agents in categories one and two i.e. a combination of a calcium-channel- blocking agent and an antioxidant and/or enzyme inhibitor
  • certain of the treatments described with respect to one class may also have some beneficial effects upon targets from the other class.
  • treatment with CAP in addition to protecting targeted cells, also inhibits the action of MMPs and phosphatases; similarly, treatment with CB or by DTT/NEM may also have an anticalcification effect upon certain cell-derived substrates.
  • EXAMPLE 1 Cell Targeted Treatment
  • Glutaraldehyde Samples were treated with 0.2% glutaraldehyde in phosphate-buffered saline, pH 7.4, for 12 days at room temperature.
  • Tissues were then sterilized for 24 hours at 37°C using 1% glutaraldehyde, 20% isopropanol in phosphate- buffered saline, pH 7.4, followed by 24 hours incubation at 40°C in 0.2% glutaraldehyde in phosphate-buffered saline, pH 7.4, and then stored in the same solution; (b) Glutaraldehyde plus 2-aminooleic acid - additional samples were treated with 0.2% glutaraldehyde in phosphate-buffered saline, pH 7.4, for 12 days at room temperature followed by incubation in an aqueous buffered solution of 2-aminooleic acid according to the '733 patent, and then rinsed.
  • Tissues were then sterilized for 24 hours at 37°C in 1% glutaraldehyde, 20% isopropanol in borate- buffered saline, pH 7.4, followed by 24 hours incubation at 40°C in 0.2% glutaraldehyde in borate- buffered saline, pH 7.4, and stored in the same solution;
  • (c) Glutaraldehyde plus 2-aminooleic acid plus CAP - additional samples were treated with 0.2% glutaraldehyde in phosphate-buffered saline, pH 7.4, for 12 days at room temperature, followed by treatment with aminooleic acid (as above) , followed by incubation in 50 mM CAP in borate-buffered saline, pH 7.4 , in 10% isopropanol for 24 hours at 37°C and then rinsed.
  • Tissues were then sterilized for 24 hours at room temperature in 1% glutaraldehyde, 20% isopropanol in borate-buffered saline, pH 7.4, followed by 24 hours incubation at 40°C in 0.2% glutaraldehyde in borate-buffered saline, pH 7.4, and stored in the same solution; (d) Glutaraldehyde/AOA plus NIF - additional tissues were treated as in Example 1 group (b) (in which tissues were glutaraldehyde-fixed, then treated with 2-aminooleic acid) .
  • Tissues were then rinsed and incubated in 5 mM NIF in borate buffer saline, pH 7.4, containing 20% isopropanol for 24 hours at 37°C. After rinsing in borate buffer saline, pH 7.4, containing 20% isopropanol, tissues were sterilized in 1% glutaraldehyde 20% isopropanol in borate buffer saline, pH 7.4 for 24 hours at 37°C, followed by 24 hours incubation at 40°C in 0.2% glutaraldehyde in borate buffer saline, pH 7.4, and then stored in the same solution.
  • EDC(sulfo-NHS) -type fixation Additional tissues first fixed according to the teaching of the '339 patent using EDC plus sulfo-NHS and hexanediamine and/or suberic acid in HEPES buffer, and then sterilized according to U.S. patent number 5,911,951, e.g., by incubation for 24 hours at 40°C in 25 mM EDC, 20% isopropanol in 10 mM HEPES, pH 6.5, and stored in the same solution;
  • EDC sulfo-NHS
  • CAP CAP
  • Additional tissue was fixed with EDC (sulfo-NHS) as indicated above and then further incubated in 50 mM CAP in 10 mM HEPES, pH 6.5, in 10% isopropanol for 24 hours at 37°C and then rinsed. Tissues were then sterilized according to the '951 patent and stored in the same solution; and
  • EDC/sulfo-NHS-fixed plus NIF - additional tissues were fixed as in Example 1 group (e) (in which tissues were fixed using the EDC/sulfo-NHS process) .
  • Tissues were then rinsed and incubated in 5 mM NIF in HEPES buffered saline, pH 6.5, containing 20% isopropanol, for 24 hours at 37°C. After rinsing in HEPES buffer saline, pH 6.5, containing 20% isopropanol, tissues were sterilized according to the "951 patent and stored in the same solution.
  • Wistar rats Wistar rats. Samples were explanted at 4 and 8 weeks, and calcium was quantitated by Atomic Absorbtion Spectrophotometry (AAS) . Selected samples from each experimental condition were processed for histology and stained with hematoxylin and eosin (H&E) for cells, and with von Kossa reagent for calcium deposits. The results are set forth in the table that follows.
  • Tissues were sterilized for 24 hours at room temperature in 1% glutaraldehyde, 20% isopropanol in borate-buffered saline, pH 7.4, followed by 24 hours incubation at 40°C in 0.2% glutaraldehyde in borate-buffered saline, pH 7.4, and stored in the same solution.
  • EDC sulfo-NHS
  • EDC sulfo-NHS
  • CB CB
  • Tissues were then sterilized according to the '951 patent and stored in the same solution. Following the foregoing treatments, the sterilized roots were washed in normal saline, and cusps were dissected away from the aortic walls. For calcification studies, 20 wall coupons and 20 cusp halves were randomly selected from each experimental condition and were implanted subdermally in three-week old, male Wistar rats. Samples were explanted at 4 and 8 weeks, and calcium was quantitated by AAS. Selected samples from each experimental condition were processed for histology and stained as in Example 1. The results are tabulated in the table which follows.
  • Tissues were then rinsed and incubated for 24 hours at 37°C in 5 mM NIF in borate buffer saline, pH 7.4, containing 20% isopropanol. After rinsing in borate buffer saline, pH 7.4, containing 20% isopropanol, tissues were sterilized for 24 hours at 37°C in 1% glutaraldehyde and 20% isopropanol in borate buffer saline, pH 7.4, followed by 24 hours incubation at 40°C in 0.2% glutaraldehyde in borate buffer saline, pH 7.4, and stored in the same solution.
  • Glutaraldehyde/AOA plus CB plus CAP - additional tissue was treated as in Example 2 group (c) - (in which tissues were glutaraldehyde-fixed, then treated with aminooleic acid, and then treated with CB) . Tissues were further rinsed and incubated for 24 hours at 37°C in 50 mM CAP in borate buffer saline, pH 7.4, containing 10% isopropanol.
  • the tissues were sterilized for 24 hours at 37°C in 1% glutaraldehyde and 20% isopropanol in borate buffer saline, pH 7.4, followed by 24 hours incubation at 40°C in 0.2% glutaraldehyde in borate buffer saline, pH 7.4, and stored in the same solution.
  • Glutaraldehyde/AOA plus CB plus NIF - additional tissue was treated as in Example 2 group (c) - (in which tissues were glutaraldehyde-fixed, then treated with aminooleic acid, and then treated with CB) . Tissues were further rinsed and incubated for 24 hours at 37°C in 5 M NIF in borate buffer saline, pH 7.4, containing 20% isopropanol.
  • the tissues were sterilized for 24 hours at 37°C in 1% glutaraldehyde and 20% isopropanol in borate buffer saline, pH 7.4, followed by 24 hours incubation at 40°C in 0.2% glutaraldehyde in borate buffer saline, pH 7.4, and stored in the same solution.
  • EDC/sulfo-NHS - additional tissue was treated as in Example 1 group (e) (in which tissues were fixed with the EDC sulfo-NHS process, followed by sterilization) .
  • EDC/sulfo-NHS plus CAP plus NIF - additional tissue was treated as in Example 1 group (f) (in which tissues were fixed with the EDC sulfo-NHS process, then treated with CAP) . Tissues were then rinsed and incubated for 24 hours at 37°C in 5 mM NIF in HEPES buffered saline, pH 6.5, containing 20% isopropanol. After rinsing in HEPES buffer saline, pH 6.5, containing 20% isopropanol, tissues were sterilized according to the "951 patent and stored in the same solution.
  • EDC/sulfo-NHS plus CB plus CAP - additional tissue was treated as in Example 2 group (e) (in which tissues were fixed with the EDC sulfo-NHS process, then treated with CB) . Tissues were then rinsed and incubated for 24 hours at 37°C in 50 mM CAP in HEPES buffered saline, pH 6.5, containing 10% isopropanol.
  • tissues were sterilized according to the "951 patent and stored in the same solution.
  • reagents may be fully compatible with each other, in which case a combination of treatments may be performed simultaneously, and as such, simultaneous treatment is often considered to be the equivalent of sequential treatment with agents from certain categories.
  • cardiovascular tissues i.e. porcine aortic roots with walls and cusps or porcine aortic wall segments alone, such was done for purposes of allowing reasonable comparison, and it should be understood, as set forth in the description, that the invention is considered to be applicable to a wide variety of biomaterials destined for implantation in mammals, particularly humans, where calcification is considered to be a distinct problem because of its adverse effect on ultimate lifetime.

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Abstract

La présente invention concerne des procédés permettant de conférer aux biomatériaux une résistance accrue à la calcification, grâce à un traitement au moyen d'agents à ciblage cellulaire et/ou à ciblage matriciel. En l'occurrence, on utilise des agents à ciblage cellulaire qui bloquent les canaux calcium, ou qui préviennent l'atteinte oxydative des cellules, et/ou qui inhibent des enzymes. D'autres traitements des biomatériaux permettent d'éliminer des composants de liaison au calcaire issus des cellules, ou cibler des matrices extracellulaire, notamment par un clivage de protéines au moyen du bromure de cyanogène, ou par réduction des liaisons bisulfure donnant des groupes sulfhydryles qui sont ensuite alkylés. Différentes combinaisons de ces traitements permettent également d'augmenter la résistance à la calcification de tissus cardio-vasculaires ayant préalablement subi des traitements de fixation chimique ou d'anti-calcification.
PCT/US2000/017606 1999-07-01 2000-06-27 Traitement anti-calcification cible WO2001002031A2 (fr)

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US7955788B2 (en) 2003-10-30 2011-06-07 Medtronic, Inc. Bioprosthetic tissue preparation with synthetic hydrogels
RU2597564C1 (ru) * 2015-06-17 2016-09-10 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний" (НИИ КПССЗ) Способ прогнозирования риска кальцификации биологических протезов клапанов сердца
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US11395726B2 (en) 2017-09-11 2022-07-26 Incubar Llc Conduit vascular implant sealing device for reducing endoleaks

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US9737400B2 (en) 2010-12-14 2017-08-22 Colibri Heart Valve Llc Percutaneously deliverable heart valve including folded membrane cusps with integral leaflets
US10973632B2 (en) 2010-12-14 2021-04-13 Colibri Heart Valve Llc Percutaneously deliverable heart valve including folded membrane cusps with integral leaflets
RU2597564C1 (ru) * 2015-06-17 2016-09-10 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний" (НИИ КПССЗ) Способ прогнозирования риска кальцификации биологических протезов клапанов сердца
US11395726B2 (en) 2017-09-11 2022-07-26 Incubar Llc Conduit vascular implant sealing device for reducing endoleaks

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