WO2004026358A1 - Reinforcing plate comprising chitosan - Google Patents

Reinforcing plate comprising chitosan Download PDF

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Publication number
WO2004026358A1
WO2004026358A1 PCT/FR2003/002752 FR0302752W WO2004026358A1 WO 2004026358 A1 WO2004026358 A1 WO 2004026358A1 FR 0302752 W FR0302752 W FR 0302752W WO 2004026358 A1 WO2004026358 A1 WO 2004026358A1
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WO
WIPO (PCT)
Prior art keywords
chitosan
reinforcement plate
plate according
polymer
fibers
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PCT/FR2003/002752
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French (fr)
Inventor
Richard Cancel
Richard Wallace
Gérard Sassi
Alain Domart
Christophe Viton
Original Assignee
Richard Cancel
Richard Wallace
Sassi Gerard
Alain Domart
Christophe Viton
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Application filed by Richard Cancel, Richard Wallace, Sassi Gerard, Alain Domart, Christophe Viton filed Critical Richard Cancel
Priority to AU2003276354A priority Critical patent/AU2003276354A1/en
Publication of WO2004026358A1 publication Critical patent/WO2004026358A1/en

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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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides

Definitions

  • the present invention relates to a reinforcing plate comprising chitosan for medico-surgical applications.
  • tissue reinforcement plates This type of operation often causes post-operative problems due to the post-surgical adhesion of tissues, in particular the tissues of the visceral wall with the peritoneal membrane or the altered tissues of the abdominal wall with the peritoneal membrane.
  • the reinforcing plates described in the prior art do not generally make it possible to avoid these adhesions.
  • Reinforcement plates are known in the prior art: international patent application WO 01/80774 describes a polypropylene reinforcement plate comprising so-called colonization perforations; this reinforcing plate takes part in the cicatrization by the fact that it generates a localized immune reaction inducing a fibrosis.
  • This immune reaction is an inflammation reaction, generated around the wound due to the presence of plaque.
  • the fibrosis generated combined with the resorption of the plaque, causes an uncontrolled scarring of the wound and induces phenomena of adhesion of the tissues.
  • This reinforcing plate therefore does not allow an orderly healing of the wound, nor the return of the injured tissue to a state close to its native state.
  • Chitosan is a compound known in the state of the art, in particular for its properties of biocompatibility, bio-resorbability and also for its non-stick and healing properties. These exceptional properties have been used, in medicine and surgery, in various compositions such as gels, or in various products such as dressings and plasters.
  • American patent 5,679,658 describes the use of N, 0-carboxymethyl chitosan as a washing solution or gel at the end of the operation, to limit post-surgical adhesion.
  • An object of the present invention is therefore to provide a biocompatible and bioresorbable reinforcing plate comprising chitosan, which, in addition to its reinforcing function, prevents post-operative adhesions and participates in the healing and regeneration of tissues so that that the injured tissue returns to its native state.
  • the present invention relates more specifically to a tissue reinforcement plate, in particular of the abdominal wall, characterized in that it consists entirely or partly of chitosan, the degree of acetylation of which is less than 60%.
  • the degree of acetylation is called molar fraction of N-acetylglucosamine residues relative to all of the monomer units constituting the copolymer called chitosan.
  • the second type of unit is then represented by the glucosamine residues.
  • the degree of acetylation of the chitosan is between 0 and 40% and is preferably less than 5%.
  • said chitosan is in the form of fibers, filament or son of chitosan.
  • the reinforcing plate also comprises at least one other polymer.
  • This other polymer is present in a very minor amount relative to the amount of chitosan.
  • this polymer is in the form of fibers, filament or son, and is mixed or associated with fibers, filaments or son of chitosan.
  • this polymer is hydrophilic.
  • the polymers are chosen from natural hydrophilic polymers, such as in particular polysaccharides, proteins, polyhydroxyesters.
  • the polymers are chosen from synthetic hydrophilic polymers, such as in particular polyamides or polyacrylics.
  • the reinforcing plate further comprises at least one hydrophobic polymer.
  • this hydrophobic polymer is in the form of fibers, filaments or threads.
  • the hydrophobic polymers associated with chitosan in the reinforcement plate of the invention are one or more polymers chosen from the group comprising polypropylene, polyesters and in particular poly (ethylene terephthalate) and polyurethanes.
  • the materials constituting the reinforcement plate of the invention can be woven or non-woven.
  • the invention also relates to the use of the reinforcement plate according to the invention for its intraperitoneal or extraperitoneal application.
  • the invention also relates to the use of the reinforcing plate in traumatic, visceral or muscular surgery, and also in cosmetic surgery.
  • the object of the present invention is therefore to provide a reinforcing plate comprising chitosan, optionally in combination with other compounds.
  • the inherent properties of chitosan and the combined properties of chitosan and the other compounds with which it is associated remarkably lead both to the prevention of post-surgical adhesion between tissues, and to the healing and regeneration of fabrics, possibly on either side of the reinforcement plate.
  • the chitosan used for carrying out the invention is in the form of fibers.
  • the reinforcing plate according to the invention is made entirely of chitosan fibers.
  • the degree of acetylation of the chitosan fibers used is less than 60%, preferably between 0 and 40%, and very preferably less than 5%.
  • the degree of acetylation affects the absorbability of chitosan. Indeed, the more the degree of acetylation increases, the higher the biodegradation and bioresorption kinetics.
  • the degree of acetylation also influences the solubility of the chitosan fibers used in the composition of the reinforcing plate according to the invention, and it is observed that up to a degree of acetylation equal to 50%, the solubility increases. , whereas, when the degree of acetylation exceeds 50%, the solubility decreases and becomes zero from 70%.
  • the degree of acetylation is not the only factor to take into account, for the solubility of chitosan: the pH also has an influence, because chitosan has a pH range of limited solubility.
  • the chitosan fibers of the reinforcing plate according to the invention are only soluble at pH values between 1 and 6, while for degrees of acetylation between 40% and 70%, these chitosan fibers are soluble whatever the pH.
  • the reinforcement plate according to the invention if it is desired that the implanted reinforcement plate is rapidly absorbed, it is possible to implant a reinforcement plate based on of chitosan with a high degree of acetylation. This application may be preferred when the wound healing is expected to be rapid or when it is desired to reduce the discomfort caused to the patient by the presence of this implant. On the contrary, if it is desired that the implanted reinforcing plate remains in place for a period of several weeks, or even several months, it is possible to implant a reinforcing plate based on chitosan with a low degree of cetylation.
  • the reinforcing plates according to the invention have biocompatibility properties and antifungal, anti-viral, anti-bacterial and bacteriostatic properties and are therefore particularly suitable for abdominal surgery. They allow the prevention of the occurrence of post-operative infections, in particular when the risks of infection are great as in the case of eventrations, ulcers, abscesses or invasive interventions of the viscera of the digestive system where the bacterial flora is very important.
  • the reinforcing plates according to the invention are also remarkable in that they do not generate an immune reaction in situ which avoids secondary inflammatory problems.
  • the reinforcing plates according to the invention also make it possible to avoid disorders linked to post-surgical adhesions.
  • Post-surgical adhesion caused by various factors, consists of joining two surfaces or segments of normally separated organs. This adhesion can lead to an inflammatory reaction and / or to the formation of fibrous tissue.
  • the reinforcing plate according to the invention has non-stick properties and can be interposed between the viscera and the abdominal wall where, on the one hand, it constitutes a physical barrier between the two tissues capable of joining and on the other hand, it actively participates in the possible reconstruction of a tissue following accidental or pathological destruction.
  • the reinforcing plate according to the invention finally has bio-stimulating properties due, in particular, to the biological and hemostatic properties of chitosan; it accelerates the coagulation of blood at the level of the wound and contributes to cell migration, to the production of extracellular matrix, cell proliferation and the final regeneration of tissue similar to native tissue.
  • the reinforcing plate consists mainly of chitosan fibers as well as some fibers of at least one other polymer.
  • this or these polymers are hydrophilic. Their hydrophilicity gives them sensitivity to the aqueous medium and, by extension, specific resorbability.
  • this (these) other (s) polymer (s) is natural or synthetic.
  • the combination of chitosan, and in particular of chitosan fibers, and of these polymers makes it possible to modulate the longevity of the reinforcing plate according to the invention, when it is implanted.
  • the reinforcing plate according to the invention comprises a few fibers of at least one hydrophobic synthetic polymer.
  • this hydrophobic polymer is polypropylene. It can be associated in the reinforcement plate either with chitosan alone, or with a combination of chitosan and another hydrophilic polymer. It provides hydrophobic and mechanical reinforcement properties to the reinforcement plate according to the invention.
  • Polypropylene is known for its healing properties and in particular for promoting fibrosis. However, the fibrosis induced by polypropylene alone takes place in an anarchic manner. The inventors have demonstrated that the presence of a small amount of polypropylene in the reinforcement plate according to the invention unexpectedly accelerates the healing of the wound and improves its quality.
  • chitosan and polypropylene fibrosis normally induced by polypropylene does not take place and there is a significant acceleration of an ordered healing.
  • the synergistic effect of chitosan and polypropylene will allow a controlled and structured reconstitution of the tissues making it possible to obtain at the end of healing a tissue similar to the native tissue.
  • the reinforcement plates according to the invention can be manufactured in the form of a nonwoven plate obtained by molding chitosan alone or chitosan in combination with other hydrophilic and / or hydrophobic polymers. When applied to the wound, the nonwoven plates will form an integral physical barrier between the two tissues it separates. The regeneration of one and / or the other tissue will therefore be done independently.
  • the reinforcing plate according to the invention consists of fibers, filaments or son of chitosan.
  • the chitosan used is dissolved in water in the presence of a weak acid, of the acetic acid type, and the collodion formed is extruded; the filaments obtained at the extrusion outlet are subjected to a coagulating action, preferably to the action of a coagulating gas, very preferentially to the action of ammonia gas, and are drawn, simultaneously or not with coagulation, for the lengthen and orient the crystal structure of the fibers constituting the filaments to improve the mechanical properties of the resulting thread or filament.
  • the reinforcing plate according to the invention is made from mixtures or combinations of threads: threads or filaments of chitosan, and synthetic or natural fibers. These associations can be mixtures of fibers, subjected or not to twists, and in particular twists of threads of different natures. In these embodiments, the quantity of chitosan fibers remains in majority compared to the quantity of fibers of other polymers.
  • the reinforcing plates can also be woven from chitosan fibers or a mixture of polymers.
  • the reinforcing plate according to the invention can be used in vascular surgery, in particular at the level of the portion of the aorta, and more particularly for the operation of the aneurysm of the abdominal aorta, which presents great risks of disembowelment. It can also be used during surgery of the intraperitoneal viscera by intercalating it between the viscera and the peritoneum. It can also be used to reduce a hernia by inserting it between the peritoneum and the abdominal wall.

Abstract

A reinforcing plate for biological tissue, characterized in that it comprises chitosane, i.e. chitosane fibers, whereby the degeree of acetylation is less than 60 %, and use of said reinforcing plate in traumatic, visceral, muscular or esthetic surgery .

Description

PLAQUE DE RENFORT COMPRENANT NOTAMMENT DU CHITOSANE REINFORCEMENT PLATE INCLUDING IN PARTICULAR CHITOSANE
La présente invention concerne une plaque de renfort comprenant du chitosane pour des applications médicochirurgicales .The present invention relates to a reinforcing plate comprising chitosan for medico-surgical applications.
La chirurgie de l'abdomen et notamment les interventions invasives sur les viscères ou la réduction des hernies nécessitent souvent l'application de plaques de renfort des tissus. Ce type d'opération engendre souvent des problèmes post-opératoires dus à l'adhésion postchirurgicale de tissus, notamment les tissus de la paroi viscérale avec la membrane péritonéale ou les tissus altérés de la paroi abdominale avec la membrane péritonéale. Les plaques de renfort décrites dans l'état de la technique ne permettent généralement pas d'éviter ces adhésions.Surgery of the abdomen and in particular invasive interventions on the viscera or reduction of hernias often require the application of tissue reinforcement plates. This type of operation often causes post-operative problems due to the post-surgical adhesion of tissues, in particular the tissues of the visceral wall with the peritoneal membrane or the altered tissues of the abdominal wall with the peritoneal membrane. The reinforcing plates described in the prior art do not generally make it possible to avoid these adhesions.
On connaît dans l'art antérieur des plaques de renfort : la demande de brevet internationale WO 01/80774 décrit une plaque de renfort en polypropylène comportant des perforations dites de colonisation ; cette plaque de renfort participe à la cicatrisation par le fait qu'elle génère une réaction immunitaire localisée induisant une fibrose. Cette réaction immunitaire est une réaction d'inflammation, générée autour de la plaie du fait de la présence de la plaque. Toutefois la fibrose générée, combinée avec la résorption de la plaque, provoque une cicatrisation anarchique de la plaie et induit des phénomènes d'adhésion des tissus. Cette plaque de renfort ne permet donc pas une cicatrisation ordonnée de la plaie, ni le retour du tissu lésé à un état proche de son état natif.Reinforcement plates are known in the prior art: international patent application WO 01/80774 describes a polypropylene reinforcement plate comprising so-called colonization perforations; this reinforcing plate takes part in the cicatrization by the fact that it generates a localized immune reaction inducing a fibrosis. This immune reaction is an inflammation reaction, generated around the wound due to the presence of plaque. However the fibrosis generated, combined with the resorption of the plaque, causes an uncontrolled scarring of the wound and induces phenomena of adhesion of the tissues. This reinforcing plate therefore does not allow an orderly healing of the wound, nor the return of the injured tissue to a state close to its native state.
Le chitosane est un composé connu dans l'état de la technique, notamment pour ses propriétés de biocompatibilité, de bio-résorbabilité et aussi pour ses propriétés anti-adhésives et cicatrisantes. Ces propriétés exceptionnelles ont été utilisées, en médecine et en chirurgie, dans diverses compositions telles que des gels, ou dans divers produits tels que des pansements et des emplâtres. En chirurgie, le brevet américain 5,679,658 décrit l'utilisation de N,0-carboxyméthyl chitosane comme solution ou gel de lavage en fin d'opération, pour limiter l'adhésion post-chirurgicale. Le brevet américain 5,888,988 décrit l'utilisation d'un gel et/ou d'une poudre à base de N,0-carboxyméthyl chitosane pour tenter de limiter les phénomènes d'adhésions post-chirurgicales ; la composition est appliquée au niveau de la plaie entre les deux surfaces susceptibles d'adhérer. Néanmoins, la formulation gel ou poudre utilisée ne permet pas d'obtenir le résultat voulu de manière satisfaisante : le gel, aussi bien que la poudre, présentent l'inconvénient de se disperser dans l'espace adjacent à la plaie et de ne pas rester localisés sur la plaie durant le laps de temps nécessaire à la cicatrisation et la régénération des tissus. Cette dispersion provoque un anéantissement de l'effet recherché.Chitosan is a compound known in the state of the art, in particular for its properties of biocompatibility, bio-resorbability and also for its non-stick and healing properties. These exceptional properties have been used, in medicine and surgery, in various compositions such as gels, or in various products such as dressings and plasters. In surgery, American patent 5,679,658 describes the use of N, 0-carboxymethyl chitosan as a washing solution or gel at the end of the operation, to limit post-surgical adhesion. American patent 5,888,988 describes the use of a gel and / or a powder based on N, 0-carboxymethyl chitosan in an attempt to limit the phenomena of post-surgical adhesions; the composition is applied to the wound between the two surfaces liable to adhere. However, the gel or powder formulation used does not make it possible to obtain the desired result in a satisfactory manner: the gel, as well as the powder, has the disadvantage of dispersing in the space adjacent to the wound and of not remaining localized on the wound during the time necessary for healing and tissue regeneration. This dispersion causes the desired effect to be destroyed.
Un but de la présente invention est donc de proposer une plaque de renfort biocompatible et bioresorbable comprenant du chitosane, qui, outre sa fonction de renfort, empêche les adhésions post-opératoires et participe à la cicatrisation et à la régénération des tissus de manière à ce que les tissus lésés reviennent à leur état natif. La présente invention concerne plus précisément une plaque de renfort des tissus, notamment de la paroi abdominale, caractérisée en ce qu'elle est constituée en tout ou partie de chitosane dont le degré d'acetylation est inférieur à 60 %. On appelle degré d'acétylation, la fraction molaire des résidus N-acétylglucosamine par rapport à l'ensemble des unités monomères constituant le copolymère appelé chitosane. Le deuxième type d'unité est alors représenté par les résidus glucosamine. De préférence, le degré d' acetylation du chitosane est compris entre 0 et 40 % et est de préférence inférieur à 5 %.An object of the present invention is therefore to provide a biocompatible and bioresorbable reinforcing plate comprising chitosan, which, in addition to its reinforcing function, prevents post-operative adhesions and participates in the healing and regeneration of tissues so that that the injured tissue returns to its native state. The present invention relates more specifically to a tissue reinforcement plate, in particular of the abdominal wall, characterized in that it consists entirely or partly of chitosan, the degree of acetylation of which is less than 60%. The degree of acetylation is called molar fraction of N-acetylglucosamine residues relative to all of the monomer units constituting the copolymer called chitosan. The second type of unit is then represented by the glucosamine residues. Preferably, the degree of acetylation of the chitosan is between 0 and 40% and is preferably less than 5%.
Suivant un mode de réalisation préféré de l'invention, ledit chitosane se présente sous forme de fibres, de filament ou de fils de chitosane.According to a preferred embodiment of the invention, said chitosan is in the form of fibers, filament or son of chitosan.
Avantageusement, la plaque de renfort comprend en outre au moins un autre polymère. Cet autre polymère est présent en quantité très minoritaire par rapport à la quantité de chitosane. Avantageusement, ce polymère se présente sous forme de fibres, de filament ou de fils, et est mélangé ou associé à des fibres, filaments ou fils de chitosane.Advantageously, the reinforcing plate also comprises at least one other polymer. This other polymer is present in a very minor amount relative to the amount of chitosan. Advantageously, this polymer is in the form of fibers, filament or son, and is mixed or associated with fibers, filaments or son of chitosan.
Avantageusement, ce polymère est hydrophile.Advantageously, this polymer is hydrophilic.
Suivant une première variante de l'invention, les polymères sont choisis parmi les polymères hydrophiles naturels, tels que notamment des polysaccharides , des protéines, des polyhydroxyesters .According to a first variant of the invention, the polymers are chosen from natural hydrophilic polymers, such as in particular polysaccharides, proteins, polyhydroxyesters.
Suivant une seconde variante de l'invention, les polymères sont choisis parmi les polymères hydrophiles synthétiques, tels que notamment les polyamides ou les polyacryliques.According to a second variant of the invention, the polymers are chosen from synthetic hydrophilic polymers, such as in particular polyamides or polyacrylics.
Suivant un mode de réalisation particulier de l'invention, la plaque de renfort comprend en outre au moins un polymère hydrophobe. Suivant un mode de réalisation particulier, ce polymère hydrophobe se présente sous forme de fibres, filaments ou fils.According to a particular embodiment of the invention, the reinforcing plate further comprises at least one hydrophobic polymer. According to a particular embodiment, this hydrophobic polymer is in the form of fibers, filaments or threads.
Avantageusement, les polymères hydrophobes associés au chitosane dans la plaque de renfort de l'invention sont un ou plusieurs polymères choisis parmi le groupe comprenant le polypropylène, les polyesters et notamment le poly(éthylène téréphtalate) et les polyuréthanes .Advantageously, the hydrophobic polymers associated with chitosan in the reinforcement plate of the invention are one or more polymers chosen from the group comprising polypropylene, polyesters and in particular poly (ethylene terephthalate) and polyurethanes.
Les matériaux constituant la plaque de renfort de l'invention peuvent être tissés ou non tissés. L'invention concerne également l'utilisation de la plaque de renfort selon l'invention pour son application intrapéritonéale ou extrapéritonéale .The materials constituting the reinforcement plate of the invention can be woven or non-woven. The invention also relates to the use of the reinforcement plate according to the invention for its intraperitoneal or extraperitoneal application.
L'invention a également pour objet l'utilisation de la plaque de renfort en chirurgie traumatique, viscérale ou musculaire, et également en chirurgie esthétique.The invention also relates to the use of the reinforcing plate in traumatic, visceral or muscular surgery, and also in cosmetic surgery.
L'invention se comprendra mieux à la lumière de la description qui suit, qui illustre non limitativement l'invention. L'objet de la présente invention est donc de proposer une plaque de renfort comprenant du chitosane, éventuellement en association avec d'autres composés. Les propriétés propres du chitosane et les propriétés combinées du chitosane et des autres composés avec lesquels il est associé conduisent de manière remarquable à la fois à la prévention de l'adhésion post-chirurgicale entre les tissus, et à la cicatrisation et à la régénération des tissus, éventuellement de part et d'autre de la plaque de renfort. De préférence, le chitosane utilisé pour la réalisation de l'invention est sous forme de fibres.The invention will be better understood in the light of the description which follows, which illustrates, without limitation, the invention. The object of the present invention is therefore to provide a reinforcing plate comprising chitosan, optionally in combination with other compounds. The inherent properties of chitosan and the combined properties of chitosan and the other compounds with which it is associated remarkably lead both to the prevention of post-surgical adhesion between tissues, and to the healing and regeneration of fabrics, possibly on either side of the reinforcement plate. Preferably, the chitosan used for carrying out the invention is in the form of fibers.
Dans un premier mode de réalisation, la plaque de renfort selon l'invention est constituée entièrement en fibres de chitosane. Avantageusement, le degré d' acetylation des fibres de chitosane utilisées est inférieur à 60 %, de préférence compris entre 0 et 40 %, et très préférentiellement inférieur à 5 %.In a first embodiment, the reinforcing plate according to the invention is made entirely of chitosan fibers. Advantageously, the degree of acetylation of the chitosan fibers used is less than 60%, preferably between 0 and 40%, and very preferably less than 5%.
Le degré d' acetylation influe sur la résorbabilité du chitosane. En effet, plus le degré d' acetylation croît, plus la cinétique de biodégradation et de biorésorption est élevée.The degree of acetylation affects the absorbability of chitosan. Indeed, the more the degree of acetylation increases, the higher the biodegradation and bioresorption kinetics.
Le degré d' acetylation influe aussi sur la solubilité des fibres de chitosane entrant dans la composition de la plaque de renfort selon l'invention, et l'on observe que jusqu'à un degré d' acetylation égal à 50 %, la solubilité croît, alors que, lorsque le degré d' acetylation dépasse 50 %, la solubilité décroît pour devenir nulle à partir de 70 %. Toutefois, le degré d' acetylation n'est pas le seul facteur à prendre en compte, pour la solubilité du chitosane : le pH a également une influence, car le chitosane a un domaine de pH de solubilité restreint. Par exemple, pour des degrés d' acetylation inférieurs à 5 %, les fibres de chitosane de la plaque de renfort selon l'invention ne sont solubles qu'à des valeurs de pH comprises entre 1 et 6, alors que pour des degrés d' acetylation compris entre 40 % et 70 %, ces fibres de chitosane sont solubles quel que soit le pH.The degree of acetylation also influences the solubility of the chitosan fibers used in the composition of the reinforcing plate according to the invention, and it is observed that up to a degree of acetylation equal to 50%, the solubility increases. , whereas, when the degree of acetylation exceeds 50%, the solubility decreases and becomes zero from 70%. However, the degree of acetylation is not the only factor to take into account, for the solubility of chitosan: the pH also has an influence, because chitosan has a pH range of limited solubility. For example, for degrees of acetylation of less than 5%, the chitosan fibers of the reinforcing plate according to the invention are only soluble at pH values between 1 and 6, while for degrees of acetylation between 40% and 70%, these chitosan fibers are soluble whatever the pH.
Suivant l'application qui veut en être faite, il est donc possible d'adapter la plaque de renfort selon l'invention : si l'on souhaite que la plaque de renfort implantée se résorbe rapidement, on peut implanter une plaque de renfort à base de chitosane à haut degré d' acetylation. Cette application peut être préférée quand la cicatrisation de la plaie est prévue pour être rapide ou quand on souhaite réduire la gêne occasionnée chez le patient par la présence de cet implant. Au contraire, si l'on souhaite que la plaque de renfort implantée reste en place pendant une durée de plusieurs semaines, voire plusieurs mois, on peut implanter une plaque de renfort à base de chitosane à faible degré d' cetylation. Cette application peut être préférée quand on souhaite prolonger l'action du chitosane, notamment, sur la cicatrisation et la régénération des tissus. Les plaques de renfort selon l'invention présentent des propriétés de biocompatibilité et des propriétés antifongiques, anti-virales, anti-bactériennes et bactériostatiques et sont donc particulièrement adaptées à la chirurgie de l'abdomen. Elles permettent la prévention de la survenue d'infections post-opératoires, notamment lorsque les risques d'infection sont grands comme dans le cas d'éventrations, d'ulcères, d'abcès ou d'interventions invasives des viscères de l'appareil digestif où la flore bactérienne est très importante.Depending on the application that wants to be made, it is therefore possible to adapt the reinforcement plate according to the invention: if it is desired that the implanted reinforcement plate is rapidly absorbed, it is possible to implant a reinforcement plate based on of chitosan with a high degree of acetylation. This application may be preferred when the wound healing is expected to be rapid or when it is desired to reduce the discomfort caused to the patient by the presence of this implant. On the contrary, if it is desired that the implanted reinforcing plate remains in place for a period of several weeks, or even several months, it is possible to implant a reinforcing plate based on chitosan with a low degree of cetylation. This application may be preferred when it is desired to prolong the action of chitosan, in particular, on the healing and regeneration of tissues. The reinforcing plates according to the invention have biocompatibility properties and antifungal, anti-viral, anti-bacterial and bacteriostatic properties and are therefore particularly suitable for abdominal surgery. They allow the prevention of the occurrence of post-operative infections, in particular when the risks of infection are great as in the case of eventrations, ulcers, abscesses or invasive interventions of the viscera of the digestive system where the bacterial flora is very important.
Les plaques de renfort selon l'invention sont également remarquables en ce qu'elles ne génèrent pas de réaction immunitaire in situ ce qui évite les problèmes inflammatoires secondaires. Les plaques de renfort selon l'invention permettent également d'éviter les troubles liés aux adhésions postchirurgicales. L'adhésion post-chirurgicale, provoquée par divers facteurs, consiste en un accolement entre deux surfaces ou segments d'organes normalement séparés. Cette adhésion peut conduire à une réaction inflammatoire et/ou à la formation de tissu fibreux. Or, la plaque de renfort selon l'invention présente des propriétés anti-adhésives et peut être intercalée entre les viscères et la paroi abdominale où d'une part, elle constitue une barrière physique entre les deux tissus susceptibles de s'accoler et d'autre part elle participe activement à la reconstruction éventuelle d'un tissu suite à une destruction accidentelle ou pathologique.The reinforcing plates according to the invention are also remarkable in that they do not generate an immune reaction in situ which avoids secondary inflammatory problems. The reinforcing plates according to the invention also make it possible to avoid disorders linked to post-surgical adhesions. Post-surgical adhesion, caused by various factors, consists of joining two surfaces or segments of normally separated organs. This adhesion can lead to an inflammatory reaction and / or to the formation of fibrous tissue. However, the reinforcing plate according to the invention has non-stick properties and can be interposed between the viscera and the abdominal wall where, on the one hand, it constitutes a physical barrier between the two tissues capable of joining and on the other hand, it actively participates in the possible reconstruction of a tissue following accidental or pathological destruction.
La plaque de renfort selon l'invention présente enfin des propriétés bio-stimulantes dues, notamment, aux propriétés biologiques et hémostatiques du chitosane ; elle accélère la coagulation du sang au niveau de la plaie et contribue à la migration cellulaire, à la production de matrice extracellulaire, à la prolifération des cellules et à la régénération finale d'un tissu semblable au tissu natif.The reinforcing plate according to the invention finally has bio-stimulating properties due, in particular, to the biological and hemostatic properties of chitosan; it accelerates the coagulation of blood at the level of the wound and contributes to cell migration, to the production of extracellular matrix, cell proliferation and the final regeneration of tissue similar to native tissue.
Dans un second mode de réalisation de l'invention, la plaque de renfort est constituée principalement de fibres de chitosane ainsi que de quelques fibres d'au moins un autre polymère. Avantageusement, ce ou ces polymères sont hydrophiles. Leur hydrophilie leur confère une sensibilité au milieu aqueux et par extension une résorbabilité spécifique. Suivant un mode de réalisation particulier de l'invention, cet (ces) autre (s) polymère (s) est naturel ou synthétique. La combinaison de chitosane, et notamment de fibres de chitosane, et de ces polymères permet de moduler la longévité de la plaque de renfort selon l'invention, lorsqu'elle est implantée.In a second embodiment of the invention, the reinforcing plate consists mainly of chitosan fibers as well as some fibers of at least one other polymer. Advantageously, this or these polymers are hydrophilic. Their hydrophilicity gives them sensitivity to the aqueous medium and, by extension, specific resorbability. According to a particular embodiment of the invention, this (these) other (s) polymer (s) is natural or synthetic. The combination of chitosan, and in particular of chitosan fibers, and of these polymers makes it possible to modulate the longevity of the reinforcing plate according to the invention, when it is implanted.
Suivant une variante, la plaque de renfort selon l'invention comprend quelques fibres d'au moins un polymère synthétique hydrophobe. De préférence, ce polymère hydrophobe est le polypropylène. Il peut être associé dans la plaque de renfort soit à du chitosane seul, soit à une association de chitosane et d'un autre polymère hydrophile. Il apporte des propriétés hydrophobes et de renfort mécanique à la plaque de renfort selon l'invention. Le polypropylène est connu pour ses propriétés cicatrisantes et notamment pour favoriser la fibrose. Cependant la fibrose induite par le polypropylène seul se déroule de manière anarchique. Les inventeurs ont mis en évidence que la présence d'une faible quantité de polypropylène dans la plaque de renfort selon l'invention accélère de manière inattendue la cicatrisation de la plaie et en améliore la qualité. En effet, et de manière surprenante, les inventeurs ont constaté une action conjuguée entre le chitosane et le polypropylène : la fibrose normalement induite par le polypropylène n'a pas lieu et l'on constate une accélération significative d'une cicatrisation ordonnée. Ainsi, l'effet synergique du chitosane et du polypropylène va permettre une reconstitution contrôlée et structurée des tissus permettant d'obtenir en fin de cicatrisation un tissu similaire au tissu natif.According to a variant, the reinforcing plate according to the invention comprises a few fibers of at least one hydrophobic synthetic polymer. Preferably, this hydrophobic polymer is polypropylene. It can be associated in the reinforcement plate either with chitosan alone, or with a combination of chitosan and another hydrophilic polymer. It provides hydrophobic and mechanical reinforcement properties to the reinforcement plate according to the invention. Polypropylene is known for its healing properties and in particular for promoting fibrosis. However, the fibrosis induced by polypropylene alone takes place in an anarchic manner. The inventors have demonstrated that the presence of a small amount of polypropylene in the reinforcement plate according to the invention unexpectedly accelerates the healing of the wound and improves its quality. Indeed, and surprisingly, the inventors have found a combined action between chitosan and polypropylene: fibrosis normally induced by polypropylene does not take place and there is a significant acceleration of an ordered healing. Thus, the synergistic effect of chitosan and polypropylene will allow a controlled and structured reconstitution of the tissues making it possible to obtain at the end of healing a tissue similar to the native tissue.
Les plaques de renfort selon l'invention peuvent être fabriquées sous forme d'une plaque non tissée obtenue par moulage de chitosane seul ou de chitosane en association avec d'autres polymères hydrophiles et/ou hydrophobes. Lorsqu'elles sont appliquées sur la plaie, les plaques non tissées vont former une barrière physique intégrale entre les deux tissus qu'elle sépare. La régénération de l'un et/ou de l'autre tissu se fera donc de manière indépendante.The reinforcement plates according to the invention can be manufactured in the form of a nonwoven plate obtained by molding chitosan alone or chitosan in combination with other hydrophilic and / or hydrophobic polymers. When applied to the wound, the nonwoven plates will form an integral physical barrier between the two tissues it separates. The regeneration of one and / or the other tissue will therefore be done independently.
Suivant un mode de réalisation particulier de l'invention, la plaque de renfort selon l'invention est constituée de fibres, filaments ou fils de chitosane. Dans ce mode de réalisation, le chitosane utilisé est solubilisé dans l'eau en présence d'un acide faible, du type acide acétique, et le collodion formé est extrudé ; les filaments obtenus en sortie d'extrusion sont soumis à une action coagulante, de préférence à l'action d'un gaz coagulant, très préférentiellement à l'action du gaz ammoniac, et sont étiré, simultanément ou non à la coagulation, pour les allonger et orienter la structure cristalline des fibres constituant les filaments pour améliorer les propriétés mécanique du fil ou du filament résultant.According to a particular embodiment of the invention, the reinforcing plate according to the invention consists of fibers, filaments or son of chitosan. In this embodiment, the chitosan used is dissolved in water in the presence of a weak acid, of the acetic acid type, and the collodion formed is extruded; the filaments obtained at the extrusion outlet are subjected to a coagulating action, preferably to the action of a coagulating gas, very preferentially to the action of ammonia gas, and are drawn, simultaneously or not with coagulation, for the lengthen and orient the crystal structure of the fibers constituting the filaments to improve the mechanical properties of the resulting thread or filament.
Suivant un autre mode de réalisation particulier de l'invention, la plaque de renfort selon l'invention est constituée à partir de mélanges ou d'associations de fils : des fils ou filaments de chitosane, et des fibres synthétiques ou naturelles. Ces associations peuvent être des mélanges de fibres, soumis ou non à des torsions, et notamment des torsades de fils de natures différentes. Dans ces modes de réalisations, la quantité de fibres de chitosane reste majoritaire par rapport à la quantité de fibres d'autres polymères. Les plaques de renfort peuvent également être tissées à partir de fibres de chitosane ou d'un mélange de polymères .According to another particular embodiment of the invention, the reinforcing plate according to the invention is made from mixtures or combinations of threads: threads or filaments of chitosan, and synthetic or natural fibers. These associations can be mixtures of fibers, subjected or not to twists, and in particular twists of threads of different natures. In these embodiments, the quantity of chitosan fibers remains in majority compared to the quantity of fibers of other polymers. The reinforcing plates can also be woven from chitosan fibers or a mixture of polymers.
La plaque de renfort selon l'invention peut être utilisée en chirurgie vasculaire, notamment au niveau de la portion de l'aorte, et plus particulièrement pour l'opération de l'anévrisme de l'aorte abdominale, qui présente de grands risques d'éventration. Elle peut également être utilisée au cours de la chirurgie des viscères intrapéritonéaux en l'intercalant entre les viscères et le péritoine. Elle peut encore être utilisée pour réduire une hernie en l'intercalant entre le péritoine et la paroi abdominale. The reinforcing plate according to the invention can be used in vascular surgery, in particular at the level of the portion of the aorta, and more particularly for the operation of the aneurysm of the abdominal aorta, which presents great risks of disembowelment. It can also be used during surgery of the intraperitoneal viscera by intercalating it between the viscera and the peritoneum. It can also be used to reduce a hernia by inserting it between the peritoneum and the abdominal wall.

Claims

REVENDICATIONS
1. Plaque de renfort des tissus biologiques caractérisée en ce qu'elle a pour constituant principal du chitosane dont le degré d' acetylation est inférieur à 40 %, et de préférence inférieur à 5 % .1. Reinforcement plate for biological tissues, characterized in that its main constituent is chitosan, the degree of acetylation of which is less than 40%, and preferably less than 5%.
2. Plaque de renfort selon la revendication 1, caractérisée en ce ledit chitosane se présente sous forme de fibres ou de filaments ou de fils de chitosane.2. Reinforcement plate according to claim 1, characterized in that said chitosan is in the form of fibers or filaments or chitosan son.
3. Plaque de renfort selon l'une quelconque des revendications 1 ou 2, caractérisée en ce qu'elle comprend en outre au moins un autre polymère, présent en quantité très minoritaire par rapport à la quantité de chitosane.3. Reinforcement plate according to any one of claims 1 or 2, characterized in that it further comprises at least one other polymer, present in an amount very minor compared to the amount of chitosan.
4. Plaque de renfort selon l'une quelconque des revendications 2 ou 3, caractérisée en ce que ledit autre polymère se présente sous forme de fibres, filaments ou fils, et est mélangé ou associé, avec ou sans torsion, à des fibres, filaments ou fils de chitosane.4. Reinforcement plate according to any one of claims 2 or 3, characterized in that said other polymer is in the form of fibers, filaments or threads, and is mixed or associated, with or without twisting, with fibers, filaments or son of chitosan.
5. Plaque de renfort selon l'une quelconque des revendications 3 ou 4 , caractérisée en ce que ledit polymère est hydrophile.5. Reinforcement plate according to any one of claims 3 or 4, characterized in that said polymer is hydrophilic.
6. Plaque de renfort selon la revendication 5, caractérisée en ce que ledit polymère est choisi parmi les polymères hydrophiles naturels, tels que notamment des polysaccharides, des protéines, des polyhydroxyesters.6. Reinforcement plate according to claim 5, characterized in that said polymer is chosen from natural hydrophilic polymers, such as in particular polysaccharides, proteins, polyhydroxyesters.
7. Plaque de renfort selon la revendication 5, caractérisée en ce que ledit polymère est choisi parmi les polymères hydrophiles synthétiques, tels que notamment les polyamides ou les polyacryliques .7. Reinforcement plate according to claim 5, characterized in that said polymer is chosen from synthetic hydrophilic polymers, such as in particular polyamides or polyacrylics.
8. Plaque de renfort selon l'une quelconque des revendications 3 à 7, caractérisée en ce qu'elle comprend en outre au moins un polymère hydrophobe.8. Reinforcement plate according to any one of claims 3 to 7, characterized in that it further comprises at least one hydrophobic polymer.
9. Plaque de renfort selon la revendication 8, caractérisée en ce que ledit polymère est choisi parmi le groupe comprenant le polypropylène, les polyesters et les polyuréthanes .9. Reinforcement plate according to claim 8, characterized in that said polymer is chosen from the group comprising polypropylene, polyesters and polyurethanes.
10. Plaque de renfort selon l'une quelconque des revendications 1 à 9, caractérisée en ce que les matériaux la constituant sont tissés ou non tissés.10. Reinforcement plate according to any one of claims 1 to 9, characterized in that the materials constituting it are woven or nonwoven.
11. Utilisation de chitosane pour la fabrication d'une plaque de renfort destinée à être appliquée intrapéritonéalement ou extrapéritonéale ent.11. Use of chitosan for the manufacture of a reinforcing plate intended to be applied intraperitoneally or extraperitoneally.
12. Utilisation de chitosane pour la fabrication d'une plaque de renfort destinée à être utilisée en chirurgie traumatique, viscérale ou musculaire.12. Use of chitosan for the manufacture of a reinforcing plate intended to be used in traumatic, visceral or muscular surgery.
13. Utilisation de chitosane pour la fabrication d'une plaque de renfort destinée à être utilisée en chirurgie esthétique. 13. Use of chitosan for the manufacture of a reinforcing plate intended to be used in cosmetic surgery.
PCT/FR2003/002752 2002-09-23 2003-09-18 Reinforcing plate comprising chitosan WO2004026358A1 (en)

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