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
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
  • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
  • A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
• • 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
• • 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
  • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
  • Y10S623/915—Method or apparatus for preparing biological material
  • Y10S623/918—Heart
• • 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
  • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
  • Y10S623/92—Method or apparatus for preparing or treating prosthetic
• • 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
  • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
  • Y10S623/92—Method or apparatus for preparing or treating prosthetic
  • Y10S623/922—Heart

Definitions

• the present invention relates to a graftable biological tissue and a process for its preparation.
• Preservation of biological tissues with glutaraldehyde, particularly porcine bioprosthetic heart valves has made it possible to: a) avoid poor performance of grafted valve tissue preserved by formaldehyde; b) stop performing valve homografts; and c) avoid the undesirable use of antioagulants necessary to prevent thromboembolism associated with the use of non-bioprosthetic (mechanical) heart valves, particularly in children.
• glutaraldehyde-preserved bioprostheses pose problems of their own.
• PBS phosphate saline buffer
• phosphate solutions such as Hanks' solution, PBS, and glutaraldehyde-PBS, have been commonly used and are highly recommended. It is therefore understandable why it has sometimes been recommended instead of PBS buffer, use bicarbonate buffers (of similar buffering capacities and pH ranges) for tissue storage;
• the method comprises bringing the tissue into contact with a hypophosphated solution, said solution having a phosphate content lowered to an effective value to reduce the calcification of said tissue after the graft. this solution not destroying or destabilizing the tissue, and maintaining the tissue in contact with such a hypophosphated solution.
• the method comprises contacting the tissue with an amount of a divalent cation which competes against calcium uptake, effective to reduce calcification of the tissue after the graft, and the maintaining the tissue in contact with said cation.
• the object of the invention is to make various types of graftable biological tissues from numerous animal sources and from numerous regions of the body resistant to calcification.
• the fabric can come from cattle, pigs, horses or rabbits, among others; and i can consist of tendons, ligaments, heart valves, or tissues used to make heart valves, such as the dura and pericardium.
• the invention can be applied to a tissue used to make .en plaque grafts such as cutaneous plaques, pericardial plaques, aortic plaques and eardrums. According to the invention, no significant difference in the rate of calcification has been observed between the pericardium of pigs and the tissues of the tricuspid aortiq and mid milk valves of pigs.
• tissue preparations that are fixed or tanned such as heart valves treated with glutaraldehyde
• unfixed preserved tissues benefit from the invention.
• heart valves or porcine pericardial tissue fixed in glutaraldehyde and treated and then implanted under the skin of rats and rabbits have benefited from an unexpected prolonged attenuation or reduction. calcification after implantation. This prolonged attenuation of calcification is a method of increasing the longevity of grafted tissue, particularly bioprosthetic heart valves.
• a biological tissue, ' maintained before the transplant in a hypophosphated solution advantageously exhibits a prolonged reduction or attenuation of the calcification after the transplant.
• the solutions considered to be hypophosphated are those having phosphate contents below a value which maintains calcification; it is therefore a lower content than those currently used for which no significant reduction or attenuation of the calcification is observed.
• hypophosphated solutions consist of solutions containing significantly less phosphate than the 0.01 to 0.2 M phosphate buffered saline solutions (PBS) conventionally used for the preparation of the tissues before the transplant and these hypophosphated solutions have proved to be effective in attenuating or reducing calcification after transplantation.
• these reduced phosphate contents are lower than the range of phosphate contents normally present in plasma or balanced salt solutions such as Hanks' and Earle's solutions which are between about 0.001 and about 0.002 M.
• Solutions practically devoid of phosphate are solutions which contain only traces of phosphate, such as the quantities corresponding to the impurities present in most of the chemical compounds used for the preparation of conventional solutions for the treatment of tissues.
• the HEPES buffer solutions prepared according to the invention and described below contain approximately 2 to 4 ppr. phosphate ions.
• certain glutaraldehyde solutions prepared according to the invention and described below contain approximately 2 to 23 ppm of phosphate ions used as stabilizers by certain manufacturers. According to the invention, these traces or residues of phosphate are negligible. According to the invention, it is preferred
• OMF particularly solutions substantially free of phosphate.
• hypophosphated solutions of the invention include distilled water, buffer solutions or tissue compatible compositions, such as saline solutions or combinations thereof, such as buffered saline solutions.
• the hypophosphate solution is an unbuffered saline solution and in a particularly preferred embodiment it is a buffered saline solution.
• it is preferred to operate in a tissue-stabilizing range, that is to say without a pH range having no harmful effect on the components of the tissues.
• a preferred pH range is co taken between approximately 7.0 and approximately 7.5 and better still between approximately 7.1 and approximately 7.4.
• the most preferred pH according to the invention is 7.3.
• the buffers used according to one embodiment of the invention are preferably stable, inert with respect to the stabilization process and have sufficient buffering power to maintain an acceptable pH in particular during tissue fixation.
• the choice of the appropriate buffer and its concentration depends on the particular tissue preparation conditions to which several manufacturers have made variations.
• Preferred buffers according to the invention include borate buffers, carbo ⁇ nate, bicarbonate, cacodylate (non-toxic in animals) and other artificial or organic synthetic buffers such as 1 'HEPES (N-2-hydroxy acid thylpiperazine- N'-2-ethanesulfonic acid), KO PS (morpholinepropanesulfonic acid) and PIPES (1,4-piperazinediethanesulfonic acid).
• the concentration of the buffer in the hypophosphated solution is essentially chosen to maintain the tissue in a hypophosphated environment or to effectively replace the phosphate already present in the tissues while simultaneously adjusting the pH of the solution. It is important that the quantity of this buffer used alone—or in combination with solutions such as a saline solution—is effective in bringing or maintaining the tissue immersed in a hypophosphated environment.
• a buffer having a concentration of about 0.001 to about 0.10 M HEPES is used.
• a buffer having a HEPES concentration of approximately 0.002 to approximately 0.050 H is used.
• the buffer which is particularly preferred for fixing by glutaraldehyde has a HEPES concentration of of about 0.02 m.
• the buffered or unbuffered solutions used according to the invention must be inert vis-à-vis the process of stabilization of the tissues caused by fixing agents such as glutaraldé ⁇ hyde. They should therefore not react with the fixing agent nor prevent the fixing agent from achieving the appropriate fixation of the tissues.
• buffers containing primary and secondary amines such as tris(hydroxymethyl)aminom ⁇ thane (TRIS)
• TRIS tris(hydroxymethyl)aminom ⁇ thane
• a short-term exposure of the biological tissue to a hypophosphated or practically phosphate-free solution is ineffective in reducing the calcification.
• the biological tissue must be maintained in a strongly hypophosphated solution between the moment when the tissue is brought out of contact with a phosphate in any one of the various stages and the moment immediately preceding the transplant.
• porcine tissue treated with a hypophosphated solution or a solution practically devoid of phosphate after sampling and during shipping presents significant calcification if solutions that maintain calcification are used during the stages of fixation and stages following fixation of the preparation.
• tissues treated with PBS which is a solution that maintains calcification, after sampling and during shipment, present reduced calcification if substantially phosphate-free solutions are used in the fixation and post-fixation stages of the preparation.
• Tissue treated with substantially phosphate-free solutions after collection, during shipment, during fixation, and the storage and sterilization stages after fixation exhibits the maximum reduction in calcification.
• the biological tissue in a hypophosphated solution during the period following fixation, that is to say during the period of conservation and sterilization, for example in the for aldehyde, immediately following fixation and immediately before grafting. It is particularly preferred to bring the biological tissue into contact with a strongly hypophosphated solution during fixation and to maintain the tissue in contact with such a hypophosphated solution until immediately preceding the grafting.
• the hypophosphated solution is a component of the solution fixation. It is particularly preferred to contact the tissue immediately after collection with a hypophosphated solution and to maintain the tissue in a hypophosphated solution during shipment, fixation and storage and sterilization following fixation until immediately preceding the transplant. '
• the tissue is brought into contact with a highly hypophosphated solution during fixation, this solution being a component of the fixation solution.
• a highly hypophosphated solution is a component of the fixation solution.
• a particularly preferred fixing solution is buffered saline containing about 0.5 to about 0.7% by weight glutaraldehyde.
• a substantially phosphate-free fixative solution consisting of 0.02 M HEPES-buffered saline and containing about 0.625% by weight glutaraldehyde at a pH of about 7.1 to about 7.5 has been shown to be effective in reducing calcification after transplantation and therefore constitutes a particularly preferred embodiment of the invention.
• biological tissue shipped and/or fixed in the presence of calcification sustaining amounts of phosphate for example with about 0.01 to 0.02 M PBS, be rinsed thoroughly or otherwise treated with a hypophosphated solution before the graft to eliminate the phosph and thus reduce or attenuate the calcification of the grafted tissue according to the invention.
• the rinsing or treatment of the graftable tissue containing a quantity of phosphate maintaining the calcification before the grafting is preferably carried out with a solution practically devoid of phosphate.
• any divalent ion which competes effectively for calcium binding sites in the tissue reduces calcification. Consequently, the divalent cations preferably employed are Ba, Mg, Sr, Cu, Zn, Ag and Hg ions. implantation effectively reduce calcification.
• the Mg ion is preferably zero within the scope of the invention.
• the magnesium ions originate from magnesium salt solutions; particular preference is given to water-soluble salt solutions such as magnesium chloride (MgCl 2 ), magnesium sulphate (MgS0 «) and magnesium carbonate (MgC0 3 ).
• the magnesium salt contains magnesium ions in an amount effective to reduce or alleviate calcification of tissue after grafting.
• concentration of magnesium ions and the timing of their contact with the tissue may vary, it is preferred that the tissue be substantially saturated with solutions containing effective amounts of this ion.
• the effective quantities of di-slow cations such as magnesium ions in contact with the tissue are quantities greater than the quantities observed in certain PBS, equilibrated saline solutions and plasma.
• Conventional solutions of PBS generally have a magnesium content and on the order of Q.001" by weight, balanced salt solutions a content of the order of 0.002% by weight and the upper limit in plasma is of the order of about 0.003% by weight.
• the preferred amount of magnesium ion is greater than about 0.003 to about 0.004% by weight.
• the maximum quantity of magnesium ions considered useful in the invention is that necessary to obtain an isotonic solution. Saturating the tissue with solutions containing about 0.03% magnesium ions effectively reduces tissue calcification and is a preferred method.
• the fabric is immersed in a 0.2 weight magnesium chloride solution which constitutes a 0.03% by weight solution of magnesium ions.
• Sols consisting of balanced salt solutions containing more than about 0.0 of the magnesium ions normally present in plasma provide a beneficial effect and are preferably employed.
• harvested porcine valve tissue shipped in HEPES-buffered saline, is fixed in HEPES-buffered saline containing 0.25% by weight magnesium chloride . and 0.625% by weight glutaraldehyde, rinsed in HEPES-buffered saline solution containing 0.26% by weight magnesium chloride, sterilized in HEPES-buffered saline solution containing 0.26% by weight magnesium chloride magnesium and about 4.0% by weight formaldehyde, rinsed and stored in a HEPES-buffered saline solution containing 0.26% by weight magnesium chloride and 0.625% by weight glutaraldehyde, until a time immediately preceding the transplant, advantageously exhibited significant attenuation or reduction of calcification after the transplant.
• the biological tissue with glutaraldehyde in a HEPES-buffered saline solution containing an effective amount of magnesium and to maintain the solution in contact with said HEPES-buffered saline solution. and magnesium ions up to a moment immediately preceding the transplant.
• the biological tissue treated in the absence of effective quantities of divalent cations such as Mg can be rinsed , in sterile solutions, such as solutions of magnesium chloride, immediately before the graft to reduce subsequent calcification .
• a sampled porcine aortic valve tissue is thoroughly rinsed, shipped, fixed with 0.625% glutaraldehyde by weight, sterilized in approximately 4% aldehyde, stored for approximately 4 and 25° C., all in the presence of an isotonic solution (285 ⁇ 15 milliosmoles) hypophosphated containing 0.885% by weight of sodium chloride at pH 7.3, rinsed in saline to remove residual glutaraldehyde immediately prior to implantation and implanted into growing rabbits. Valve tissue was harvested at regular weekly intervals for a total of 6 weeks.
• tissue calcification is assessed by quantitative determination of the weight percentage of calcium in dry tissue by atomic absorption analysis, and assessed histologically by observation of the degree of calcification of sections. tissue stained using the Von Kossa method. Simultaneously and identically, the extent of calcification of heart valve tissue that has been rinsed, shipped, fixed with 0.625% by weight glutaraldehyde, sterilized in approximately 4% formaldehyde, stored between approximately 4 and 25° C., all in the presence of an isotonic 0.02 M phosphate solution and 0.885% by weight sodium chloride at pH 7.3 (0.02 M PBS), rinsed in a solution - saline to remove residual glutaraldehyde immediately prior to implantation and implanted in growing rabbits.
• the histological and quantitative results indicate that the implanted valve tissue treated with the hypophosphate solution shows a marked decrease in calcification compared to the valve tissue treated with 0.02 M PBS.
• Example II Experiments were carried out identical to those of Example I, except that the tissue was implanted in adult rabbits and collected at regular monthly intervals for a total period of six months. , the results of the histological examination and the quantitative assay show that the implanted valve tissue treated with the hypophosphated solution shows a significant decrease in calcification compared to the valve tissue treated with 0.02 M PBS.
• EXAMPLE_III Experiments similar to those of Example II are carried out, except that the hypophosphated solution additionally contains 0.54 g/l of the sodium salt of HEPES during rinsing and shipping and 5 .83 g/l of the sodium salt of HEPES during fixation, storage and sterilization. Also in this case, the results of the histological examination and the quantitative assay indicate that the implanted valve tissue treated with the hypophosphated solution shows reduced calcification compared to the valve tissue treated with PBS 0.02 _•'.. EXAMPLE_IV
• hypophosphated solutions contain more than 0.54 g / 1 d sodium salt of HEPES during rinsing and shipping, 5.39 g / 1 of the sodium salt of HEPES during fixing, storage and sterilization and 2.6 g / 1 of MgCl 2.6H 2 0 during fixing, storage and sterilization.
• results of the histological examination and the quantitative assays show that the valvular tissue implanted with the hypophosphated solution shows a clear reduction in calcification compared to the valvular tissue treated with 0.02 M PBS.
• Example IV The same experiments were carried out as in Example IV except that the tissue was implanted in adult rabbits and collected at regular monthly intervals for a total of 6 months.
• the results of the histological examination and the quantitative assay show that the implanted valvular tissues treated with the hypophosphated solution show a marked and prolonged reduction in calcification compared to the valvular tissues treated with 0.02 M PBS.
• EXAMPLE_VI Experiments similar to those of Example I are carried out, except that the hypophosphated solution also contains cacodylate buffer at a concentration of 0.5 M and that the valve tissue is recovered only after one and two weeks.
• the importance of the calcification observed when the graft is applied is evaluated simultaneously and in an identical manner.
• a solution of 0.012 M in phosphate and at 0.885% by weight of sodium chloride at pH 7.5 (PBS 0.012 M) is used.
• the histological results show that the implanted valvular tissue treated with a hypophosphated solution shows a slight reduction in calcification after one week compared to the valvular tissue treated with 0.012 M PBS. Thereafter, moderate calcification is observed.
• Example VI Experiments identical to those of Example VI are carried out, except that the cacodylate is replaced by 0.1 M borate buffer. The histological results are similar to those of Example 6.
• Example VII Identical experiments to those of Example VII are carried out except that none of the comparative solutions is hypophosphated, the solutions used for fixing, conservation and sterilization being made up of 0.02 M PBS instead of HEPES buffer.
• the results of the histological examination and the quantitative assay show that the implanted valve tissue treated with the phosphated magnesium chloride solution shows a reduction in calcification compared to the valve tissue treated without magnesium chloride.
• Extracted porcine heart valve tissue was treated with hypophosphate or phosphate-containing solutions at various stages of treatment (before fixation, during fixation with glutaraldehyde and after fixation) prior to implantation in rats to assess the degree of attenuation of calcification obtained for each stage of treatment.
• the results in the following table summarize observations made over a period of up to two months after implantation in some cases.
• G indicates the tissue treated with dehydeglutara in 0.02 M PBS;
• F Cincinnati Q indicates tissue treated with aqueous formaldehyde;
• G indicates tissue treated with aqueous glutaraldehyde;
• F indicates tissue treated with formaldehyde in 0.02 M PBS;
• G HEpES indicates tissue treated with glutaraldehyde in 0.002 M HEPES;
• Carbonate is glutaraldehyde treated tissue in carbonate buffer;
• saline/ HEPES means 0.002 M HEPES buffered saline and BSS means balanced saline.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Chemical & Material Sciences (AREA)
• Biomedical Technology (AREA)
• Transplantation (AREA)
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• 1982
  • 1982-03-23 FR FR828204892A patent/FR2523810B1/fr not_active Expired
  • 1982-11-29 US US06/445,345 patent/US4648881A/en not_active Expired - Lifetime
• 1983
  • 1983-03-15 CA CA000423664A patent/CA1221641A/en not_active Expired
  • 1983-03-22 JP JP58501063A patent/JPS59500613A/ja active Granted
  • 1983-03-22 EP EP83900937A patent/EP0105290B1/fr not_active Expired
  • 1983-03-22 WO PCT/FR1983/000057 patent/WO1983003335A1/fr not_active Ceased
  • 1983-03-22 DE DE8383900937T patent/DE3367067D1/de not_active Expired
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• 1984
  • 1984-11-13 US US06/670,786 patent/US4647283A/en not_active Expired - Lifetime
• 1987
  • 1987-03-09 JP JP62053904A patent/JPS62270163A/ja active Granted

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