DE19629070A1 - Reducing calcification of glutaraldehyde fixed porcine cardiac valves - Google Patents

Reducing calcification of glutaraldehyde fixed porcine cardiac valves

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Publication number
DE19629070A1
DE19629070A1 DE19629070A DE19629070A DE19629070A1 DE 19629070 A1 DE19629070 A1 DE 19629070A1 DE 19629070 A DE19629070 A DE 19629070A DE 19629070 A DE19629070 A DE 19629070A DE 19629070 A1 DE19629070 A1 DE 19629070A1
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Prior art keywords
glu
cardiac valves
amine
porcine cardiac
glutaraldehyde fixed
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DE19629070A
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German (de)
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Armin Dr Dr Med Schroll
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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
    • A61L27/36—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
    • 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
    • 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
    • A61L27/3604—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 characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3625—Vascular tissue, e.g. heart 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
    • 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
    • A61L27/3641—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 characterised by the site of application in the body
    • A61L27/3645—Connective tissue
    • 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
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • 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

Abstract

A medium for post-treatment of porcine cardiac valves which have already been fixed with glutaraldehyde comprises an amine of up to 6C in a branched, unbranched or cyclic, saturated or unsaturated aliphatic or aromatic structure.

Description

Beschreibungdescription 1. Technisches Gebiet1. Technical field

Humanmedizin: chirurgischer Herzklappenersatz mit Schweineherzklappen (Bioklappen) (engl. porcine bioprostheses)Human medicine: surgical heart valve replacement with pig heart valves (bio valves) (English porcine bioprostheses)

2. Stand der Technik2. State of the art

Das gebräuchliche Fixierungsmedium für Schweine­ klappen ist Glutaraldehyd in wäßriger Lösung (GLU). GLU beinhaltet Vor- und Nachteile. Unfixierte Klappen werden vom Organismus sowohl enzymatisch wie immunologisch angegriffen, was Zerstörung und Ab­ stoßung zur Folge hat. Durch GLU wird das kollagene Bindegewebe de­ naturiert, es ist stabil gegen enzymatischen Abbau. Ferner wird durch GLU die Endothelschicht zerstört und damit auch die im Endothel lo­ kalisierte immunologische Aktivität. Eine Abstoßungsreaktion findet nicht statt. Jedoch entsteht durch den Verlust der löslichen Proteo­ glykane, der Füllsubstanzen des kollagenen Fasergerüstes, eine Faser­ struktur mit offenen Hohlräumen, in die Blutbestandteile eingelagert werden, wovon die Verkalkung ihren Ausgang nimmt. Wesentlich ist die Vernetzung der Kollagenketten durch die beiden Aldehydgruppen des GLU, was dem Gewebe zusätzliche Festigkeit verleiht. Ebenso wirkt eine GLU-Lösung antimikrobiell und wird zur Aufbewahrung der Klappe verwendet. Bislang ist keine bessere Alternative zu GLU bekannt.The common fixation medium for pigs flap is glutaraldehyde in aqueous solution (GLU). GLU includes Advantages and disadvantages. Unfixed valves are used by the organism both enzymatically and immunologically attacked, which destruction and Ab has the consequence. The collagenous connective tissue is de natured, it is stable against enzymatic degradation. Furthermore, by GLU destroys the endothelial layer and thus also lo in the endothelium calibrated immunological activity. A rejection reaction takes place not instead. However, loss of soluble proteo arises glycans, the filling substances of the collagen fiber structure, a fiber structure with open cavities in which blood components are embedded from where the calcification begins. Is essential the cross-linking of the collagen chains by the two aldehyde groups of the GLU, which gives the fabric additional strength. It also works a GLU solution antimicrobial and is used to store the flap used. No better alternative to GLU is known so far.

3. Aufgabe, gelöst durch die Erfindung3. Problem solved by the invention

Mit dieser Nachbehandlung soll die Calciumaufnahme ("Verkalkung") einer Schweineherzklappe nach erfolgtem Klappenersatz verringert werden. Verkalkte klappen sind nämlich in ihrer Funktion beein­ trächtigt und müssen ausgetauscht werden.With this post-treatment, the calcium intake ("calcification") a pig heart valve after valve replacement has been reduced will. Calcified flaps are affected in their function pregnant and must be replaced.

4. Gewerblich anwendbar4. Applicable commercially

Alle derzeit im Handel befindlichen mit GLU fixierten Herzklappen können durch die Nachfixierung wesentlich verbessert werden hinsicht­ lich ihrer Verkalkung und ihrer mechanischen Haltbarkeit.All heart valves currently on the market with GLU fixed can be significantly improved in terms of post-fixation Lich their calcification and their mechanical durability.

5. Vorteilhafte Wirkung5. Beneficial effect

Der erforderliche chirurgische Klappenaustausch aufgrund von Klappen­ verkalkung geht zurück, weil die Haltbarkeit der Klappe besser ist. Auch die Anwendung bei Jugendlichen wird denkbar. The required surgical valve replacement due to valves Calcification decreases because the flap lasts longer. Use in adolescents is also conceivable.  

6. Ausführung6. Execution

Eine handelsübliche und mit GLU fixierte und in GLU aufbewahrte Schweineklappe wird mit physiologischer Kochsalzlösung mehrmals GLU-frei gewaschen. Anschließend erfolgt die Nachfixierung z. B. mit n-Aminopentan (1% wäßrige Lösung, CAPS-gepuffert, auf pH10,6 ein­ gestellt mit NaOH) über mehrere Tage bei Zimmertemperatur. Die Lö­ sung kann täglich erneuert werden. Wiederum mit Kochsalzlösung wird die Nachfixierungslösung sorgfältig ausgewaschen und nicht mehr in GLU, sondern in 0,2% Paraben-Lösung (0,02% Propyl- und 0,18% Methyl­ paraben) steril aufbewahrt bis zur Verwendung.A commercial pig flap fixed with GLU and stored in GLU is washed several times with GLU-free with physiological saline. Then the post-fixation takes place, for. For example, with n-aminopentane (1% aqueous solution, CAPS-buffered set to p H 10.6 a with NaOH) for several days at room temperature. The solution can be renewed daily. Again with saline, the post-fix solution is carefully washed out and no longer stored in GLU, but in sterile 0.2% paraben solution (0.02% propyl and 0.18% methyl paraben) until use.

Beurteilung der Ca-Aufnahme in vivoAssessment of Ca uptake in vivo

Teilchen von Segeln einer Aortenklappe des Schweins werden mit üb­ licher GLU-Lösung (0,6% wäßriges GLU, Hepes-gepuffert 0,02 molar, MgCl₂ 0,02 molar, Kochsalz 0,084 molar) etwa 1 Woche im Dunkeln bei Zimmertemperatur fixiert. Danach sorgfältiges Auswaschen mit Kochsalz. Der heute übliche Test zur Ermittlung der Ca-Aufnahme in vivo ist die subkutane Implantation von Klappensegel-Teilchen an der jugend­ lichen 3 Wochen alten, männlichen Ratte. Dabei werden in einer Serie von 10 Tieren jeweils am gleichen Tier jeweils ein oder mehrere Teilchen implantiert, die nur GLU-fixiert sind (Vergleich) und Teil­ chen, die zusätzlich nachfixiert wurden (Test). Nach dreiwöchigem Verbleib werden die Segelteilchen den Tieren entnommen, freipräpariert, bis zur Gewichtskonstanz getrocknet, mit Säure aufgelöst und der Ca- Gehalt mit Atomabsorption gemessen und auf Trockengewicht (TG) bezogen.Particles from pigs' aortic valve leaflets are also practiced lary GLU solution (0.6% aqueous GLU, Hepes buffered 0.02 molar, MgCl₂ 0.02 molar, table salt 0.084 molar) in the dark for about 1 week Room temperature fixed. Then carefully wash out with table salt. The most common test today to determine Ca uptake in vivo is the subcutaneous implantation of valve leaflet particles in adolescents 3-week-old male rat. Here are in one Series of 10 animals each on the same animal one or more Particles implanted that are only GLU-fixed (comparison) and part areas that were additionally fixed (test). After three weeks The sail particles are removed from the animals, prepared, dried to constant weight, dissolved with acid and the ca Content measured with atomic absorption and based on dry weight (TG).

Beispielexample

konventionelle GLU-Fixierung: 75,6±18 mg Ca/g TG
zusätzliche Amin-Nachfixierung: 2,27±0,57 mg Ca/g TG
d. h. die Ca-Aufnahme ist um -97% auf nur noch 3% reduziert.conventional GLU fixation: 75.6 ± 18 mg Ca / g TG
additional amine post-fixation: 2.27 ± 0.57 mg Ca / g TG
ie the Ca uptake is reduced by -97% to only 3%.

Beurteilung der maximalen mechanischen HaltbarkeitAssessment of the maximum mechanical durability

Diese erfolgt im mechanischen Belastungstest. Dabei werden auf einem Prüfstand kompletten Schweineklappen in rascher Folge(z. B. Frequenz 12/sec) ein Öffnungs- und Schließungszyklus aufgezwungen. Als Pump­ flüssigkeit dient Wasser mit Glycerin- und Antibiotikazusatz. Es wird die Anzahl Zyklen ermittelt, bis die Klappe die ersten Einrisse zeigt.This is done in the mechanical load test. Doing so on one Test bench complete pig valves in quick succession (e.g. frequency 12 / sec) forced an opening and closing cycle. As a pump liquid serves water with added glycerin and antibiotics. It the number of cycles is determined until the flap begins to tear shows.

Beispielexample

konventionelle Schweineklappe: Haltbarkeit 27,3 Mio Zyklen
zusätzliche Amin-Nachfixierung: 63 Mio Zyklen.conventional pig flap: durability 27.3 million cycles
additional amine post-fixation: 63 million cycles.

Claims (2)

1. Mittel zur Nachbehandlung einer bereits mit Glutaraldehyd fixierten Schweineherzklappe zum Herzklappenersatz, dadurch gekennzeichnet, daß ein Amin verwendet wird, welches aus bis 6 C-Atomen in unverzweigter, verzweigter oder ring­ förmiger, aliphatischer oder aromatischer, gesättigter oder ungesättigter Struktur besteht.1. Means for the aftertreatment of a pig heart valve already fixed with glutaraldehyde for heart valve replacement, characterized in that an amine is used which consists of up to 6 carbon atoms in unbranched, branched or ring-shaped, aliphatic or aromatic, saturated or unsaturated structure. 2. Mittel nach Anspruch 1, dadurch gekennzeichnet, daß das Amin ein primäres, sekundäres oder tertiäres Amin, eine Ammoniumverbindung, ein Mono- oder Mehrfachamin sein kann.2. Composition according to claim 1, characterized in that the Amine a primary, secondary or tertiary amine, a Ammonium compound, can be a mono or multiple amine.
DE19629070A 1996-07-18 1996-07-18 Reducing calcification of glutaraldehyde fixed porcine cardiac valves Withdrawn DE19629070A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE19629070A DE19629070A1 (en) 1996-07-18 1996-07-18 Reducing calcification of glutaraldehyde fixed porcine cardiac valves

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19629070A DE19629070A1 (en) 1996-07-18 1996-07-18 Reducing calcification of glutaraldehyde fixed porcine cardiac valves

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DE19629070A1 true DE19629070A1 (en) 1998-01-29

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001051104A1 (en) * 2000-01-10 2001-07-19 St. Jude Medical, Inc. Biocompatible prosthetic tissue
CN110917399A (en) * 2019-12-09 2020-03-27 沛嘉医疗科技(苏州)有限公司 Anti-calcification method for biomaterial and biomaterial

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001051104A1 (en) * 2000-01-10 2001-07-19 St. Jude Medical, Inc. Biocompatible prosthetic tissue
US6471723B1 (en) 2000-01-10 2002-10-29 St. Jude Medical, Inc. Biocompatible prosthetic tissue
CN110917399A (en) * 2019-12-09 2020-03-27 沛嘉医疗科技(苏州)有限公司 Anti-calcification method for biomaterial and biomaterial

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