[go: up one dir, main page]

WO2011060545A1 - Rapports de mélange sang:chitosane spécifiques produisant un implant en forme de pâte visqueuse avec de bonnes propriétés de manipulation pour une réparation de tissu - Google Patents

Rapports de mélange sang:chitosane spécifiques produisant un implant en forme de pâte visqueuse avec de bonnes propriétés de manipulation pour une réparation de tissu Download PDF

Info

Publication number
WO2011060545A1
WO2011060545A1 PCT/CA2010/001843 CA2010001843W WO2011060545A1 WO 2011060545 A1 WO2011060545 A1 WO 2011060545A1 CA 2010001843 W CA2010001843 W CA 2010001843W WO 2011060545 A1 WO2011060545 A1 WO 2011060545A1
Authority
WO
WIPO (PCT)
Prior art keywords
chitosan
polymer composition
paste
blood
mosm
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA2010/001843
Other languages
English (en)
Inventor
Wei Ouyang
Michael Buschmann
Anik Chevrier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ecole Polytechnique de Montreal
Original Assignee
Ecole Polytechnique de Montreal
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ecole Polytechnique de Montreal filed Critical Ecole Polytechnique de Montreal
Publication of WO2011060545A1 publication Critical patent/WO2011060545A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/50—Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/51—Umbilical cord; Umbilical cord blood; Umbilical stem cells
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0005—Ingredients of undetermined constitution or reaction products thereof
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials resorbable by 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • 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
    • A61L27/3616—Blood, e.g. platelet-rich plasma
    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K3/00—Use of inorganic substances as compounding ingredients
    • C08K3/16—Halogen-containing compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/49—Phosphorus-containing compounds
    • C08K5/51—Phosphorus bound to oxygen
    • C08K5/52—Phosphorus bound to oxygen only
    • C08K5/521—Esters of phosphoric acids, e.g. of H3PO4
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair

Definitions

  • the present invention relates to novel viscous paste-like implant with good handling properties for tissue repair by using specific blood/chitosan mixing ratios and physiological chitosan solutions with different concentrations.
  • Chitosan is a linear polysaccharide composed of -(1-4)-linked D- glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit), which primarily results from the alkaline deacetylation of chitin.
  • Chitosan can exist in many structural conformations, depending on a variety of factors that include the degree of hydration, the counterion mixture and the complexity of original chitin mixture.
  • Chitosan and its amino-substituted derivatives are bioerodible, biocompatible and biodegradable cationic polymers that have been advanced for a wide variety of applications, including tissue engineering, drug and gene delivery, pharmaceutical formulation, scaffolds for cell growth and cell encapsulation, wound healing and surface hemostasis.
  • chitosan A well known property of chitosan is its solubility at acidic pH ( ⁇ 6) and insolubility at neutral pH, making its use in solution with living cells and tissues problematic.
  • Various publications (Chenite, international patent application publication No. WO 99/07416; Chenite et al., 2000, Biomater., 21 : 2155-2161 ; Chenite et al., 2001 , Carbohyd. Polym., 46: 39-47) describe that admixing a polyol-phosphate dibasic salt, i.e. glycerol-phosphate (GP), to an aqueous solution of chitosan can increase the pH of the solution while avoiding precipitation of the chitosan.
  • GP glycerol-phosphate
  • chitosan solutions of substantial concentration (0.5-3%) and high molecular weight (> several hundred kDa) remain liquid, at low or room temperature, for a long period of time with physiologically acceptable neutral pH region between 6.8 and 7.2.
  • physiologically acceptable neutral pH region between 6.8 and 7.2.
  • These chitosan-glycerol phosphate solutions which can gel upon mild heating (for example from 4 to 37°C), while remaining biocompatible, biodegradable and adhesive to human tissues, and thus provide for new opportunities in the delivery of sensitive therapeutics.
  • chitosan As being a thrombogenic polymer, e.g. it can accelerate the coagulation of blood.
  • Chitosan- GP solutions were combined with sheep peripheral whole blood to form a thrombogenic mixture that solidified and adhered to a full-thickness cartilage defect in a sheep model.
  • the obtained results showed that solidification of a chitosan-glycerol phosphate/blood implant in microfracture defects improved cartilage repair compared with microfracture alone by increasing the amount of tissue and improving its biochemical composition and cellular organization (Hoemann et al., 2005, J. Bone Joint Surg., 87A: 2671-2686).
  • a bilateral rabbit cartilage repair model was developed to study the effect of chitosan-GP/blood implants on cartilage repair following marrow stimulation. Results showed that chitosan-GP structurally stabilized the blood clots by inhibiting the clot retraction. Treatment of drilled defects with chitosan-GP/blood clots led to the formation of more integrated and hyaline repair tissue above a more porous and vascularised subchondral bone plate compared to drilling alone (Hoemann et al., 2007, Osteoarthritis & Cartilage, 15: 78-89).
  • Chitosan-GP/blood implants also increase cell recruitment, transient vascularisation, subchondral remodeling and modulate inflammatory and repair cell phenotype suggesting that these events are in part responsible for increase quantity and quality of repair tissue zone (Chevrier et al., 2007, Osteoarthritis & Cartilage, 15: 316-327; and Hoemann et al., 2010, Am. J. Sports Med., 38, 9: 1845-56).
  • the present application provides a pastelike polymer composition prepared by combining a blood component, a chitosan solution and at least one salt.
  • the concentration of chitosan in said chitosan solution is between about 1.0% w/w to 10% w/w; and the ratio of said blood component to said chitosan solution is between about 4:1 to 1 :1 so as to form a paste.
  • the paste-like polymer further comprises a mineral acid (including hydrochloric acid, acetic acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid and/or hydrobromic acid) or an organic acid.
  • the at least one salt is an inorganic salt, such as, for example, sodium salt, chloride salt, potassium salt, calcium salt, magnesium salt, phosphate salt, sulfate salt and/or carboxylate salt.
  • the inorganic salt can be NaCI, KCI, CsCI, CaCI 2 , CsF, KCIO 4 , NaN0 3 and/or CaS0 4 .
  • the at least one salt is an organic salt, such as, for example, glycerol-phosphate.
  • the blood component is whole blood, processed blood, venous blood, arterial blood, blood from bone, blood from bone-marrow, bone marrow, umbilical cord blood and/or placenta blood.
  • the blood component is human blood.
  • the polymer composition has a pH higher than about 6.0 and lower than about 7.8. In another embodiment, the polymer composition has a pH higher than about 6.2 and lower than about 7.8. In still another embodiment, the polymer composition has a pH higher than about 6.2 and lower than about 6.8. In an embodiment, the polymer composition has an osmolality higher than about 200 mOsm/kg and lower than about 600 mOsm/kg. In another embodiment, the osmolality of the polymer composition is higher than about 320 mOsm/kg and lower than about 350 mOsm/kg.
  • the osmolality of the polymer composition is higher than about 324 mOsm/kg and lower than about 344 mOsm/kg.
  • the volume ratio of the blood component.chitosan solution is between 4:1 and 1 :1.
  • the chitosan of the chitosan solution has a degree of deacetylation (DDA) higher than about 20% and lower than about 100%.
  • the DDA is about 81 %.
  • the chitosan of the chitosan solution has a number average molecular weight ( n) ranging from about 1 kDa to about 10 MDa, such as, for example, 232 kDa.
  • the concentration of chitosan in said chitosan solution is about 2% w/w.
  • the present application provides a paste-like polymer composition prepared by combining a blood component, a chitosan solution, a hydrochloric acid solution and a NaCI solution, wherein the ratio of said blood component to said chitosan solution is between about 4:1 to 1 :1 so as to form a paste.
  • the concentration of the chitosan in the chitosan-HCI-NaCI solution is about 2% w/w
  • the concentration of chitosan-HCI-NaCI is about 50 mM
  • the concentration of NaCI is about 150 mM.
  • the blood component the pH of the paste-like polymer, the osmolality of the paste-like polymer, the volume ratio between the blood component and the chitosan solution, the degree of deacetylation of the chitosan in the chitosan solution, the molecular weight ( n ) of the chitosan in the chitosan solution have been described and do apply herein.
  • the present application provides a method for repairing a tissue in a subject in need thereof.
  • the method comprises the step of introducing into said tissue a paste-like polymer composition as defined herein such that the polymer paste-like composition adheres to the tissue and promotes cell proliferation for repairing the tissue.
  • the tissue is cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, maxillofacial tissues, temporomandibular tissues, abscesses, resected tumors and/or ulcers.
  • the present application provides the use of a paste-like polymer composition as defined herein for repairing a tissue of a subject, wherein the polymer composition adheres to the tissue and promotes cell proliferation as well as the use of a paste-like polymer composition as defined herein in the manufacture of a medicament for repairing a tissue of a subject, wherein the polymer composition adheres to the tissue and promotes cell proliferation.
  • the tissue is cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, maxillofacial tissues, temporomandibular tissues, abscesses, resected tumors and/or ulcers.
  • the present application provides a pastelike polymer composition as defined herein for repairing a tissue in a subject, wherein the polymer composition adheres to the tissue and promotes cell proliferation.
  • the tissue is cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, maxillofacial tissues, temporomandibular tissues, abscesses, resected tumors and/or ulcers.
  • the present application provides a method of preparing a paste-like polymer composition for repairing tissue in a subject.
  • the method comprises the steps of dissolving from 1.0% w/w to 10.0% w/w of chitosan in HCI to provide a chitosan-HCI mixture; adding a NaCI solution to the chitosan-HCI mixture to provide a chitosan-HCI-NaCI mixture; and admixing a blood component to the chitosan-HCI-NaCI, wherein the ratio of said blood component to said chitosan is lower than about 4:1 and higher than about 1 :1.
  • the chitosan is dissolved in HCI by heating at a temperature 60°C.
  • the concentration of chitosan in the chitosan-HCI-NaCI mixture is about 2% w/w of chitosan
  • the concentration of hydrochloric acid in the chitosan-HCI-NaCI mixture is about 50 mM
  • the mix ratio is about 2:1.
  • Various embodiments of the chitosan molecular weight, the chitosan degree of deacetylation, blood component, the pH of the paste-like polymer composition, the osmolality of the paste-like polymer composition have been described and do apply herein.
  • Fig. 1 are photographic representations of the runniness (a means of assessing paste-like handling properties) of rabbit whole blood/chitosan-HCI- NaCI mixtures at different times, wherein the sample numbers from left to right are: 1-1 (1.62% chitosan, mix ratio 3:1); 1-2 (1.62% chitosan, mix ratio 2:1); 2- 1 (2.0% chitosan, mix ratio 3:1 ); 2-2 (2.0% chitosan, mix ratio 2:1); Control (Fresh blood without chitosan); pictures were taken at 30 sec (panel A); 2 min (panel B); 5 min (panel C) and 10 min (panel D).
  • Fig. 3 is a histogram showing the mechanical strength of rabbit whole blood/chitosan-HCI-NaCI clots with different chitosan concentrations (1.62% or 2%) at different mix ratios (1 :3 or 1 :2).
  • FIG. 4 are photographic representations of rabbit whole blood/chitosan-HCI-NaCI clots with different chitosan concentrations (1.62% or 2%) and mix ratios (1 :3 or 1 :2) in glass tubes (panels 1 , 4, 7, and 10); after removal from the tubes (panels 2, 5, 8 and 1 1); and after manual crushing for mechanical strength assessment (panels 3, 6, 9 and 12).
  • Fig. 6 is a histogram showing the mechanical strength of human whole blood/chitosan-HCI-NaCI clots with different chitosan concentrations (1.62% or 2%) at different mix ratios (1 :3 or 1 :2) and of fresh blood without chitosan.
  • FIG. 7 are photographic representations of human whole blood/chitosan-HCI-NaCI clots with different chitosan concentrations (1.62% or 2%) and mix ratios (1 :3 or 1 :2) in glass tubes (panels 1 , 4, 7, 10, 13); after removal from the tubes (panels 2, 5, 8, 11 and 14); and after manual crushing for mechanical strength assessment (panels 3, 6, 9, 12 and 15).
  • novel viscous paste-like implant with good handling properties for tissue repair.
  • the novel chitosan preparations comprise a blood component and a salt and are capable of forming a paste.
  • These viscous paste-like implants are prepared by mixing fresh blood with physiological chitosan solutions with specific concentrations and at specific mix ratios (e.g. wherein the blood component is present at a volume equal or higher than the chitosan solution, but less than 4 times the volume of the chitosan solution).
  • a solution containing a specific concentration of chitosan is used to generate the implants (e.g. between 1 % to 10% w/w, such as 2% w/w).
  • the mixture described herein has a faster coagulation time, a diminished running distance and possess attractive handling properties, resulting in a more paste-like and viscous mixtures than previous formulations known in the art.
  • Paste-like mixtures are defined as being thick and viscous.
  • a viscous implant can be obtained by mixing blood with chitosan solutions at specific mix ratios (blood component: chitosan solution range from about 4:1 to 1 :1).
  • the specific mix ratio are calculated as a volume of a chitosan solution with respect to a volume of a blood component.
  • the concentration of chitosan in the solution, prior to its admixture with the blood component is preferably 2.0 % w/w, but can fluctuate between 1.0% and 10.0% w/w.
  • the chitosan composition is prepared by essentially combining of a blood component, chitosan and at least one salt.
  • the chitosan composition is not prepared with additional components which participates to the formation of the paste or the coagulation of the blood (such as coagulation products for example) but can be prepared with other components such as an acid (to facilitate the dissolution of the chitosan), preservatives, etc.
  • the polymer paste-like composition comprises a blood component.
  • a blood component is contemplated herein, such as whole blood, processed blood, venous blood, arterial blood, blood from bone, blood from bone-marrow, bone marrow, umbilical cord blood or placenta blood.
  • the blood component is derived from whole blood to be enriched or depleted for a specific blood component.
  • the volume ratio between the blood component and the chitosan solution is higher than 1 :1 but lower than 4:1 , such as, for example, 3:1 or 2: 1.
  • the polymer paste-like composition also comprises chitosan.
  • the chitosan should be able to form a gel and ultimately a thick and viscous paste when combined with blood. Because the chitosan is for use in the treatment of tissue repair, it must also be preferably of physiological grade.
  • the polymer paste-like composition further comprises at least one salt. Such salt is used for facilitating the dissolution of chitosan in physiological solution.
  • the salt can be an inorganic salt or an organic salt.
  • Inorganic salts include, but are not limited to sodium salt, chloride salt, potassium salt, calcium salt, magnesium salt, phosphate salt, sulfate salt or carboxylate salt, such as, for example, NaCI, KCI, CsCI, CaCI 2 , CsF, KCI0 4l NaN0 3 or CaS0 4 .
  • Organic salts include, but are not limited to glycerol-phosphate.
  • the paste-like polymer can also include an acid, such as a mineral acid of an organic acid.
  • an acid such as a mineral acid of an organic acid.
  • HCI is used at a concentration between about 38 to about 50 mM. However other concentrations of HCI can be used.
  • a preferred embodiment of the current description is described hereinbelow, which is a novel viscous paste-like implant with good handling properties for tissue repair prepared by using specific blood/chitosan mix ratios and physiological chitosan solutions with different concentrations (Table 1 ).
  • Chitosan (1.62% w/w)-HCI (38 mM)-NaCI (160 mM) solution at pH of 6.56 and osmolality of 344 mOsm/kg, and chitosan (2.0% w/w)-HCI (50 mM)- NaCI (150 mM) solution at pH of 6.49 and osmolality of 324 mOsm/kg were mixed with rabbit whole blood.
  • a 0.9 ml pipet of fresh blood was added into cryotubes containing 300 ⁇ 1.62% chitosan (or 2.0% chitosan) solution and three 0.39g stainless steel balls, mixed by hand for 10 seconds (the tube being shaken and reversed about 50 times vigorously).
  • 300 ⁇ was transferred into 3 glass tubes at 37°C by using a 1 ml syringe for preparing 3 clots.
  • One clot was used to test coagulation time and fixed immediately after it coagulated; a second clot was used to test coagulation time and fixed at 60 minutes after mixing; the third clot was used to test coagulation time and mechanical strength after 60 minutes.
  • the coagulation time results showed that rabbit whole blood/chitosan mixtures at mix ratios of 3:1 and 2:1 can coagulate within 6 minutes.
  • This latter composition was particularly useful since its handling properties were much more attractive as it had a more paste-like and more viscous nature that will aid delivery and retention of these implants to challenging sites.
  • compositions described herein can be used to improve the repair and to regenerate cartilaginous tissues and other tissues including without limitation meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, abscesses, resected tumors, and ulcers.
  • the polymer compositions described herein that can be placed or injected into a body site where the mixture aids the repair, regeneration, reconstruction or bulking of tissues.
  • Repaired tissues include for example without limitation cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, abscesses, resected tumors, and ulcers.
  • the tissue that can be repaired or regenerated is for example without limitation cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissue, abscesses, resected tumors, or ulcers.
  • the site of introduction in the body may be surgically prepared to remove abnormal tissues. Such procedure can be done by piercing, abrading or drilling into adjacent tissue regions or vascularized regions to create channels for the polymer composition to migrate into the site requiring repair.
  • a magnetic stir bar was inserted into the beaker; the solution stirred for about 10 minutes in order to hydrate the chitosan powder as much as possible.
  • 0.38 ml of HCI 1 N (Sigma, Product N° 318949) was added to the solution under moderate stirring.
  • the beaker was covered with parafilmTM, and the solution heated to about 60°C for 2 hours, stirred overnight until completely dissolved.
  • a magnetic stir bar was inserted into the beaker; the solution stirred for about 10 minutes in order to hydrate the chitosan powder as much as possible.
  • 0.50 ml of HCI 1 N (Sigma, Product N° 318949) was added to the solution under moderate stirring.
  • the beaker was covered with parafilmTM, and the solution heated to about 60°C for 2 hours, stirred overnight until completely dissolved.
  • samples 1 and 2 were fresh blood/1.62% chitosan-HCI-NaCI (pH 6.6) mixture at mix ratios 3:1 and 2:1 ; samples 3 and 4 were fresh blood/2.0% chitosan-HCI-NaCI (pH 6.5) mixture at mix ratios 3:1 and 2:1 ; sample 5 was fresh blood without chitosan as a control.
  • a clean plastic board was tilted on the bench top at an angle of about 45°. About 0.5 ml mixtures from each sample were pipetted, then three drops of each sample was placed carefully onto the surface of the board (the distance between each sample being about 2 cm). The runniness of the mixtures was observed and photos were taken at 30 seconds, 2 minutes, 5 minutes and 10 minutes.
  • Fresh blood/chitosan-HCI-NaCI mixtures at different chitosan concentrations (1.62% or 2%) and mix ratios (2:1 and 3:1) were prepared as described hereinabove.
  • 300 ⁇ was transferred into 3 glass tubes at 37°C with a 1 ml syringe.
  • Three clots were prepared for each mixture: 1 clot was used to test coagulation time, 1 clot was to test coagulation time and fixed after 60 minutes, 1 clot was used to test coagulation time and mechanical strength after 60 minutes. Coagulation was determined by visualization of the clot at 37°C (all the three glass tubes were used for testing coagulation time).
  • the glass tubes were gently taken from the hot plate vertically every minute, slowly tilted, and the blood mixture was visualized at the bottom of the tube. If the mixture was immobile and formed a clot, it was coagulated; if the mixture was still mobile at the bottom of the tube, it was not yet coagulated. Mechanical strength was tested by putting the clot on the centre of the palm, the clot pressed with a finger until it was crushed, the resistance to compression, liquid expression and crushed appearance observed.
  • the fresh blood/chitosan clots prepared with a mix ratio of 2:1 were not as homogenous (one scored as "between ⁇ and -" and the other as "-") (see Fig. 4 and Table 4).
  • the chitosan-HCI-NaCI solution ( n 232 kDa, 81 % DDA) was prepared as described hereinabove.
  • the pH of the chitosan solution was physiological at 6.6 and the osmolality was also physiological at 317 mOsm/kg (Table 5).
  • the chitosan-HCI-NaCI solution ( n 232 kDa, 81 % DDA) was prepared as described hereinabove.
  • the pH of the chitosan solution was physiological at 6.5 and the osmolality was also physiological at 351 mOsm/kg (Table 5).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Cell Biology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Hematology (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Dermatology (AREA)
  • Surgery (AREA)
  • Molecular Biology (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Reproductive Health (AREA)
  • Materials Engineering (AREA)
  • Botany (AREA)
  • Urology & Nephrology (AREA)
  • Pregnancy & Childbirth (AREA)
  • Biochemistry (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention porte sur une composition polymère en forme de pâte destinée à être utilisée pour réparer un tissu d'un patient, laquelle composition est préparée par combinaison d'au moins un composant sanguin, d'une solution de chitosane ayant une concentration de chitosane comprise entre environ 1,0 % en poids et 10,0 % poids et au moins un sel, le rapport volumique entre ledit composant sanguin et ladite solution de chitosane étant compris entre environ 4:1 et 1:1.
PCT/CA2010/001843 2009-11-19 2010-11-18 Rapports de mélange sang:chitosane spécifiques produisant un implant en forme de pâte visqueuse avec de bonnes propriétés de manipulation pour une réparation de tissu Ceased WO2011060545A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US26275809P 2009-11-19 2009-11-19
US61/262,758 2009-11-19

Publications (1)

Publication Number Publication Date
WO2011060545A1 true WO2011060545A1 (fr) 2011-05-26

Family

ID=44059159

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2010/001843 Ceased WO2011060545A1 (fr) 2009-11-19 2010-11-18 Rapports de mélange sang:chitosane spécifiques produisant un implant en forme de pâte visqueuse avec de bonnes propriétés de manipulation pour une réparation de tissu

Country Status (1)

Country Link
WO (1) WO2011060545A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015061612A1 (fr) * 2013-10-24 2015-04-30 Medtronic Xomed, Inc. Pansement à base de pâte de chitosane
WO2015123778A1 (fr) 2014-02-20 2015-08-27 Polyvalor, Limited Partnership Compositions polymères lyophilisées à mélanger avec un plasma riche en plaquettes en vue de former des implants pour une réparation tissulaire et/ou compositions pour infiltrations intra-articulaires thérapeutiques
US9192692B2 (en) 2013-10-24 2015-11-24 Medtronic Xomed, Inc. Chitosan stenting paste
WO2017009335A1 (fr) * 2015-07-13 2017-01-19 Kiomed Pharma Chitosane pour mélange avec un fluide coagulable
WO2017009346A1 (fr) 2015-07-13 2017-01-19 Kiomed Pharma Chitosane pour mélange avec un fluide coagulable
US10383971B2 (en) 2007-02-19 2019-08-20 Marine Polymer Technologies, Inc. Hemostatic compositions and therapeutic regimens

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2412505A1 (fr) * 2000-06-29 2002-01-03 Caroline D. Hoemann Composition et procede de reparation et de regeneration de cartilage et d'autres tissus

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2412505A1 (fr) * 2000-06-29 2002-01-03 Caroline D. Hoemann Composition et procede de reparation et de regeneration de cartilage et d'autres tissus

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEVRIEIR, A ET AL.: "Chitosan-glycerol phosphate/blood implants increase cell recruitment, transient vascularization and subchondrol bone remodelling in drilled cartilage defects.", OSTEOARTHRITIS AND CARTILAGE., vol. 15, 2007, pages 316 - 327 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10383971B2 (en) 2007-02-19 2019-08-20 Marine Polymer Technologies, Inc. Hemostatic compositions and therapeutic regimens
AU2014340012B2 (en) * 2013-10-24 2018-06-28 Medtronic Xomed, Inc. Chitosan paste wound dressing
WO2015061606A1 (fr) * 2013-10-24 2015-04-30 Medtronic Xomed, Inc. Pâte d'occlusion au chitosane
US9192574B2 (en) 2013-10-24 2015-11-24 Medtronic Xomed, Inc. Chitosan paste wound dressing
US9192692B2 (en) 2013-10-24 2015-11-24 Medtronic Xomed, Inc. Chitosan stenting paste
JP2016534050A (ja) * 2013-10-24 2016-11-04 メドトロニック・ゾーメド・インコーポレーテッド キトサンステント材ペースト
WO2015061612A1 (fr) * 2013-10-24 2015-04-30 Medtronic Xomed, Inc. Pansement à base de pâte de chitosane
AU2014340006B2 (en) * 2013-10-24 2018-06-28 Medtronic Xomed, Inc. Chitosan stenting paste
WO2015123778A1 (fr) 2014-02-20 2015-08-27 Polyvalor, Limited Partnership Compositions polymères lyophilisées à mélanger avec un plasma riche en plaquettes en vue de former des implants pour une réparation tissulaire et/ou compositions pour infiltrations intra-articulaires thérapeutiques
WO2017009335A1 (fr) * 2015-07-13 2017-01-19 Kiomed Pharma Chitosane pour mélange avec un fluide coagulable
FR3038838A1 (fr) * 2015-07-13 2017-01-20 Synolyne Pharma Chitosane pour melange avec un fluide coagulable
FR3038837A1 (fr) * 2015-07-13 2017-01-20 Synolyne Pharma Chitosane pour melange avec un fluide coagulable
WO2017009346A1 (fr) 2015-07-13 2017-01-19 Kiomed Pharma Chitosane pour mélange avec un fluide coagulable

Similar Documents

Publication Publication Date Title
US9427469B2 (en) Soluble physiological chitosan formulations combined with platelet-rich plasma (PRP) for tissue repair
Deng et al. Enhanced gelation of chitosan/β-sodium glycerophosphate thermosensitive hydrogel with sodium bicarbonate and biocompatibility evaluated
WO2011060545A1 (fr) Rapports de mélange sang:chitosane spécifiques produisant un implant en forme de pâte visqueuse avec de bonnes propriétés de manipulation pour une réparation de tissu
US7109163B2 (en) Hemostatic compositions and devices
US7718412B2 (en) Hemostatic compositions containing sterile thrombin
DE69838614T2 (de) Zusammensetzungen von Carboxypolysaccharid-Polyetherkomplexen zur Verwendung zum Vermindern chirurgischer Verwachsungen
CN102727930B (zh) 一种医用可吸收骨创面止血材料及其制备方法
AU2025213618A1 (en) Injectable Gels Comprising Cross-Linked Hyaluronic Acid and Hydroxyapatite, and Methods of Manufacturing Thereof
CN105536039A (zh) 一种可吸收流体止血材料及其制备方法与应用
US20170333477A1 (en) Novel formulation of physiological chitosan-inorganic salt solution/blood mixtures for tissue repair
KR20150022934A (ko) 히알루론산을 기본으로 하는 조성물의 제조 방법
Wei et al. Superwetting injectable hydrogel with ultrastrong and fast tissue adhesion for minimally invasive hemostasis
CN103977449B (zh) 一种共混液体止血复合材料及其制备方法
KR102395184B1 (ko) 단일상도 아니고 이성상도 아닌 히알루론산 가교체, 및 이의 용도
Campiglio et al. An injectable, degradable hydrogel plug for tracheal occlusion in congenital diaphragmatic hernia (CDH)
JPWO2016114355A1 (ja) 癒着防止用組成物
Zhang et al. Nanofibrous chitin/Andrias davidianus skin secretion bioactive sponges with tunable biodegradation rates for bleeding wounds treatment
AU2015305426A1 (en) Bioresorbable tissue repair composition
KR101274608B1 (ko) 커들란 및 젤란검을 유효성분으로 포함하는 유착방지용 조성물 및 이의 제조방법
JP7642954B2 (ja) アルギン酸塩及びこれを含む止血材
KR20250095530A (ko) 생분해성 고분자 미립자를 포함하는 수용성 고분자 필러의 조성물 및 이의 제조방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10831001

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10831001

Country of ref document: EP

Kind code of ref document: A1