WO2014194392A1 - Bionanocomposite pour la régénération osseuse - Google Patents

Bionanocomposite pour la régénération osseuse Download PDF

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Publication number
WO2014194392A1
WO2014194392A1 PCT/BR2014/000176 BR2014000176W WO2014194392A1 WO 2014194392 A1 WO2014194392 A1 WO 2014194392A1 BR 2014000176 W BR2014000176 W BR 2014000176W WO 2014194392 A1 WO2014194392 A1 WO 2014194392A1
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bionanocomposite
bone
biomaterial
pvai
hydroxyapatite
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PCT/BR2014/000176
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English (en)
Portuguese (pt)
Inventor
Cecilia Amélia de Carvalho ZAVAGLIA
Carmen Gilda Barroso Tavares DIAS
Sabina da Memória Cardoso DE ANDRADE
Gilmara de Nazareth Tavares BASTOS
Ana Paula Drummond Rodrigues RODRIGUES
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Universidade Estadual De Campinas - Unicamp
Universidade Federal Do Pará - Ufpa
Instituto Federal De Educação, Ciência E Tecnologia Do Pará
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Publication of WO2014194392A1 publication Critical patent/WO2014194392A1/fr

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    • 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
    • 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • 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
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/62—Polymers of compounds having carbon-to-carbon double bonds
    • C08G18/6212—Polymers of alkenylalcohols; Acetals thereof; Oxyalkylation products thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/77—Polyisocyanates or polyisothiocyanates having heteroatoms in addition to the isocyanate or isothiocyanate nitrogen and oxygen or sulfur
    • C08G18/78—Nitrogen
    • C08G18/79—Nitrogen characterised by the polyisocyanates used, these having groups formed by oligomerisation of isocyanates or isothiocyanates
    • C08G18/791—Nitrogen characterised by the polyisocyanates used, these having groups formed by oligomerisation of isocyanates or isothiocyanates containing isocyanurate groups
    • C08G18/792—Nitrogen characterised by the polyisocyanates used, these having groups formed by oligomerisation of isocyanates or isothiocyanates containing isocyanurate groups formed by oligomerisation of aliphatic and/or cycloaliphatic isocyanates or isothiocyanates
    • 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
    • C08K3/32—Phosphorus-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
    • C08K5/16—Nitrogen-containing compounds
    • C08K5/29—Compounds containing one or more carbon-to-nitrogen double bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L29/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical; Compositions of hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Compositions of derivatives of such polymers
    • C08L29/02—Homopolymers or copolymers of unsaturated alcohols
    • C08L29/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L75/00—Compositions of polyureas or polyurethanes; Compositions of derivatives of such polymers
    • C08L75/04—Polyurethanes
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61L2400/06—Flowable or injectable implant compositions
    • 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
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • 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
    • C08K3/32—Phosphorus-containing compounds
    • C08K2003/321—Phosphates
    • C08K2003/325—Calcium, strontium or barium phosphate

Definitions

  • the present invention relates to a bone restorative bionanocomposite related to losses caused or not by trauma. More specifically, the present invention is directed to a polyvinyl alcohol (PVAI), polyurethane (PU) and hydroxyapatite (HA) bionanocomposite.
  • PVAI polyvinyl alcohol
  • PU polyurethane
  • HA hydroxyapatite
  • Bionanocomposite can be used for facial maxillary graft graft, cranial cap filling and filling, and bone filling after bone cancer tumors removed in different regions of the skeleton.
  • the need for defect-filling materials is high, for example, in facial skull reconstruction, revision of orthoplastic implants, after removal of bone cysts, bone loss due to trauma, infections or resorption.
  • macroporous form implants accelerate the healing process, as they allow for the progressive growth of collagen with the following mineralization of bone tissue through open and interconnected pores (Zavaglia, 2003).
  • Bone is a dynamic tissue as it has a unique ability to self-regenerate or self-reshape to the right extent without leaving a scar, however many bone grafting needs are due to bone defects, whether or not caused by trauma.
  • the need for synthetic bone grafts depends on the complication of bone defects. For example, if the defect is minor, the bone has its own ability to self-regenerate within a few weeks. Thus, surgery is not required. In the case of severe defects and loss of bone volume that do not heal normally, ie when the tissue is difficult to close, the graft is required to restore function without damaging the tissues.
  • There are several methods available for treating bone defects which include the traditional methods of autograft and graft transplantation.
  • Nanocomposites based particularly on hydroxyapatite (HA) and collagen have gained immense recognition as bone grafts not only because of their composition, structure and similarity to natural bone, but also because of their functional properties such as surface and mechanical strength over their constituents. single phase.
  • bone itself is a natural nanocomposite, with a matrix composed mainly of collagen-rich hydroxyapatite (HA) nanocrystallites, so it is a good choice to opt for a HA / collagen nanocomposite as a bone graft material.
  • HA collagen-rich hydroxyapatite
  • H ⁇ / collagen is an indicative system for bone regenerative therapy, probably as one of the most suitable (Murugan and Ramakrishna, 2005; Liu, 2009; Wang, 2009).
  • the graft is often performed with the patient's own bone.
  • bone crest loss is very large, as in the case of defects left by extensive dental extractions in the anatomy of the jaw bones, grafts with biomaterials are used and thus the preservation of the bone crest is guaranteed, which will favor a subsequent implant or restoration of bone. dental prosthesis (Weiss, 2007).
  • the initial stability of the mandible compared with the stability of the maxilla makes it possible to consider the immediate implant loading, which in most cases is much more problematic in relation to bone quality and quantity. Patients with lower quality and less bone were excluded from implant treatment for a long time. However, the advent of bone reconstruction of deficient areas of both the mandible and the maxilla has improved the possibility of treatment for bone deficient patients. Different bone grafting techniques have been developed, and orthognathic surgical procedures adapted to the special requirements of implant surgery have now caused most bone problems to be resolved (Kahnberg, 2005).
  • Natural teeth have been replaced by a variety of materials including bone, animal teeth, human teeth, ivory, sea shells, ceramics and metals.
  • Four groups of materials are currently employed in dentistry, which are metals, ceramics, polymers and composite resins. Despite frequent improvements in the physical properties of these materials, none of them are permanent (Anusavice, 2005).
  • Biomaterials have been presented as an alternative in bone rehabilitation processes. Successful implantation of a biomaterial is associated with the reactions of the patient's organism, such as severity of the inflammatory process triggered, level of patient satisfaction, time required for the restoration of basic activities and time of implantation in the host organism.
  • Biomaterials should be designed and constructed specifically programmed to perform in a given application so as to satisfy the fundamental characteristics such as biocompatibility in which the implanted material and its degradation products must be tolerated by the surrounding tissues and should not cause organ dysfunction throughout be chemically inert and stable, easily sterilized and biofunctional, ie the material must meet the mechanical characteristics necessary to perform the desired function for as long as necessary.
  • PVAI Poly (vinyl alcohol) is a biodegradable synthetic polymer that has attracted special attention as a biomaterial due to its transparency, strength and biocompatibility. It is soluble in water at temperatures above 70 ° C and 9 are presently commercially available compositions PVAI both liquid and particulate and depending on its structure and stereochemistry mixture will influence the specific properties of the 'final product.
  • PVAI residual acetate groups are essentially hydrophobic, which weaken intra and intermolecular bonds between adjacent hydrogen atoms of hydroxyl groups.
  • the melting point is recorded between 210 and 240 C Q 9 C and glass transition temperature of around 85 Q C (Bavaresco, 2004). It may normally have 20-35% crystallinity, but after heat treatment above its glass transition temperature (Tg), it can be increased by up to 70% and significantly improve its mechanical properties (Pepas, 1987).
  • HDI trimer HDT is a solvent-free, medium viscosity aliphatic polyisocyanate based on the hexamethylene disocyanate (HDI homopolymer) trimer.
  • Polyurethanes are from a broad family of polymers that can be potentially useful in tissue engineering in many types of tissue for a large number of medical applications.
  • Biodegradable polyurethane is one of the biocompatible materials used as scaffolds in engineered bone tissue (HILL, 2007 and HUANG, 2009).
  • HILL engineered bone tissue
  • bioactive ceramic particles such as tricalcium phosphate or hydroxyapatite (HA)
  • HA hydroxyapatite
  • a combination of ceramics and polyurethane can improve the bioactivity and mechanical properties of scaffolds (Mathieu, 2001).
  • HA Ca10 (PO4) 6 (OH) 2
  • Hydroxyapatite has been widely used due to its chemical similarity to bone and good biocompatibility (Cystera, 2005). This biological hydroxyapatite is also composed of ions in various concentrations, such as: Ca 2+ , Mg 2+ , Na + , CO 3 2 " , etc., allowing the control of these important ions in body fluids through their release or storage.
  • hydroxyapatite structure allows hydroxyl (OH) groups to be removed relatively easily, generating empty channels between the hexagons formed by the ions. calcium, where they can be led into the structure of ceramic material, other ions and molecules (Hench, 1991).
  • Hydroxyapatite is a bioceramic that has composition and structure similar to the mineral phase of bones and teeth. Depending on its purity, it can withstand heating above 1,200 Q C without decomposing. In addition, it can be modeled like most ceramic materials (Zavaglia, 1993).
  • Hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ) is the major mineral component of bone, and its synthetic form is one of the most widely used biomaterials for skeletal reconstruction due to lack of local or systemic toxicity together. with its osteoconduction properties (Diaz, 2009).
  • a poorly soluble material consisting of pure hydroxyapatite is used.
  • a more soluble ceramic is used, generally consisting of a mixture of hydroxyapatite and other phosphates.
  • HA adsorption capacity
  • This property allows it to be used in implants, as a support for antibiotics and anticancer drugs, and can also be used for prolonged treatment of infections and bone diseases. In the latter case, gradually releasing the necessary medication in the affected region.
  • the pore size and morphology of highly porous foams can be controlled depending on the process parameters (Cystera, 2005).
  • n-HA particles were homogeneously dispersed in the PU matrix, with 80% porosity and 271 KPa compressive strength.
  • the porous structure provided a microenvironment with good adhesion for cell growth and proliferation, having the composite basic requirement for tissue engineering and being potential to be applied in the repair and replacement of human knee and articular cartilage menisci.
  • the value of compressive strength is much lower than that of the present invention, which was on the order of 60 to 110 Mpa.
  • the porosity level of the research material mentioned although it has favored the cellular environment, must have been responsible for the low mechanical resistance, which makes it impossible to repair and replace human knee and articular cartilage menisci because they are impact absorbing sites. that is not the case with the material of the present invention which has an impact absorber in its constitution, the PVAI.
  • the research cited used biphasic composites of synthetic hydroxyapatite and carbon (HAC) and synthetic hydroxyapatite, carbon and sodium acid phosphate (HACF) and in the daily clinical evaluations of the wound, inflammatory reaction, pain sensitivity and wound dehiscence were observed.
  • HAC synthetic hydroxyapatite and carbon
  • HACF synthetic hydroxyapatite, carbon and sodium acid phosphate
  • Chetty (CHETTY, 2007) studied a HA-coated PU-based auricular cartilage implant and found that after 24 and 72 h HA surfaces exhibited significantly more metabolically active cells compared to PU surfaces virgins. This indicates that HA surfaces are cytocompatible to fibroblasts and can potentially be applied to cartilage tissue replacement. However, disadvantageously, it was revealed by microscopic examination that the specimens had a coating defect. Already The present invention provides evidence of a chemical interaction between HA and PU which prevents the recording of bionanocomposite failures.
  • Dou obtained antibacterial HA-gelatin minocidine nanocomposites and concluded that the nanocomposite has good bioactivity and may have antimicrobial activity, and may be a promising biomaterial for use as bone tissue repair and regeneration.
  • the researchers only performed in vitro tests for a nanocomposite material with minocidine, which is an antibiotic drug, which already guarantees the material antibacterial action.
  • minocidine which is an antibiotic drug
  • the good results are proven by in vitro and in vivo tests, without the need to use any kind of drug, because the antibacterial action of the polyurethane is efficient so as not to cause inflammation and infections.
  • the material developed by Dou has no mechanical strength.
  • Huang used a bioactive factor to improve this property in polyurethane and obtained high porosity HA scaffolds of 61 to 65% and suitable macropore sizes from 200 to 600 ⁇ and 4.0 compressive strength. at 5.8MPa.
  • the present invention associates the polyurethane to the hydroxyapatite bioactivity and the bionanocomposite presents mechanical properties much higher than the properties of the mentioned material, by employing PVAI in its composition.
  • the fulcrum is the temporomandibular joint itself (TMJ) which together with the teeth receives a force load during the chewing movement.
  • the developed force can be more or less absorbed by the fulcrum according not only to the amount generated but also to the size of the distance between the resistance elements, in this case the teeth and the fulcrum (TMJ).
  • chewing with the incisors increases the resistance arm and the load on the fulcrum is also increased.
  • the maxillary bones and TMJ are adapted for molar chewing. Mechanical forces developed at molar level are better absorbed and drained. In incisive chewing, the load transferred to the TMJ is almost twice as high.
  • the scaffold developed by the author mentioned above could not be indicated because it does not have in the composition the material with impact absorbing properties, important for chewing action, such as Poly (vinyl alcohol). which exists in the bionanocomposite composition of the present invention.
  • Poly vinyl alcohol
  • the possible inflammatory effect after implantation in subcutaneous tissue was tested, which showed greater biocompatibility, unlike the work by Hill (Hill, 2007) which does not prove the absence of this effect.
  • the invention is a biomaterial with the proven antibacterial action of polyurethane associated with the bioactivity of nanohydroxyapatite, the dispersiveness and impact absorber property of polyvinyl alcohol, which remains in the composition after the synthesis of polyurethane forming with it. a blends, features of great importance for facial maxillary graft that are not verified in the scaffold described above.
  • the mechanical compression properties of the present invention which is important for bone grafts of greater mechanical stress, as is the case of jaw bones, were of the order of 60 to 111 MPa, much higher than 1114 kPa from the work cited above. Furthermore, the present invention demonstrates the cytocompatibility and antibacterial action of the proposed composition employing CHO Chinese rat ovary cells, mouse embryonic fibroblast cells - NIH3T3 and VERO cells, a recommended fibroblast cell line for cytotoxicity testing and proved its antibacterial action, since the animals did not show any pain, inflammation and / or infection during the postoperative period when they were observed.
  • US2011 / 0313538 of 08/03/2007 describes a bone repair scaffold, where the PU is used for forced pore formation and evaporated at the processing temperature, so it does not remain in the final composition.
  • the PU phase which is preferably obtained from polyvinyl alcohol, proves excellent blood compatibility and antibacterial properties, which guarantees a promising proposal of the present bionanocomposite to repair bone loss and orthodontic applications.
  • Micropore and macropore formation is naturally obtained at the time of bionanocomposite processing by reaction of carbon with oxygen other than US2011 / 0313538 A1.
  • US2012 / 0029653 of 16/11/2010 describes a bone regeneration material composed of resorbable materials and collagen. Unlike this application the present invention is applied to maxillary facial graft and promotes collagen production when implanted in the living organism after seven days, demonstrating its superiority since it is not necessary to add another product to the reaction, different from the biomaterial of US2012 / 0029653 which has a collagen phase in its constitution.
  • this patent application US2012 / 002965 relates to a material for treating bone tissue defects and injuries while the physical characteristics of the present bionanocomposite, due to the presence of polyvinyl alcohol, promote a high absorption rate of impact, which specifies it for the mandibular area where the bones in this region receive major impact daily.
  • the present invention has advantages in several respects. Firstly, it proposes a new bionanocomposite suitable for facial maxillary bone grafts that allows the flow of nutrients and ions where bone regeneration is promoted in the area around the scaffold in bone implants. Furthermore, said bionanocomposite has a three-phase constitution based on polyurethane (PU), polyvinyl alcohol (PVAI) and hydroxyapatite (HA).
  • PU polyurethane
  • PVAI polyvinyl alcohol
  • HA hydroxyapatite
  • the present invention advantageously employs PVAI which, due to its physical properties, ensures high impact elasticity and abrasion resistance as well as high biocompatibility and high barrier properties.
  • PVAI itself acts as a dispersant in the mixture, requiring no other resources for this function.
  • Another crucial point is the presence of nanostructured HA that has contributed to the control, amount, random geometry and pore and micropore interconnection that are excellent characteristics for osteoconduction.
  • Another advantage is that this bionanocomposite promotes collagen production when implanted in the living organism after 7 days.
  • the present invention relates to a bone restorative bionanocomposite composed of polyvinyl alcohol (PVAI), polyurethane (PU) and hydroxyapatite (HA).
  • PVAI polyvinyl alcohol
  • PU polyurethane
  • HA hydroxyapatite
  • the polyurethane employed is a reaction product of an isocyanate and a polyvinyl alcohol polyol
  • the isocyanate can be selected from aliphatic isocyanates, 4-diisocyanate butane (BDI), 1,6-diisocyanate hexane (HDI), 4,4 -methylene dicyclohexyl diisocyanate (HMDI), preferably HDT polyisocyanate, hexamethylene diisocyanate trimer (HDI), employed between 1 and 2 g, preferably 2 g.
  • hydroxyapatite is added in a ratio of 25% to 33%, preferably 25%.
  • bionanocomposite for facial maxillary graft grafting, skullcap filling and filling and bone failure filling after removal of bone cancer tumors in different regions of the skeleton.
  • FIG. 1 shows the PVAI-PU / HA biomaterial spectra in the monitored FTIR from 25 Q C to 150 g C.
  • FIG. 2 shows the PVAI-PU / HA biomaterial spectra with FTIR heating.
  • FIG. 4 shows rheology curves of the PVAIPU / HA biomaterial.
  • FIG. 5 shows the X-ray diffractogram of PVAI-PU / HA biomaterial with 25% HA.
  • FIG. 6 shows the X-ray diffractogram of PVAI-PU / HA biomaterial with 33% HA.
  • FIG. 7 shows a graph indicating the average compressive strength of PVAI-PU blend and PVAI-PU / HA bionanocomposites with 25% and 33% HA.
  • FIG. 8 shows the TG-DSC curve of biomaterial with 25% HA.
  • Annex 1 presents the bionanocomposite of the present invention for characterization and biological testing in dimensions, ⁇ 4mm and height equal to 60mm (1) ⁇ 4mm and height equal to 1mm (2) ⁇ 6mm and height equal to 3mm (3) and 2cmx2cm (4).
  • Annex 5 shows the slides after cutting for histological analysis of the region filled with the PVA-PU / HA biomaterial.
  • Annex 7 presents an image of the biomaterial implanted in the subcutaneous tissue of the back of the mouse for 14 days, observed by scanning electron microscopy, where C: fibrous material; BM: biomaterial; CL: fibrous layer; CC: corneal layer.
  • the present invention describes a bone restoration bionanocomposite comprising the following major components: polyvinyl alcohol (PVAI), polyurethane (PU) and hydroxyapatite (HA).
  • PVAI polyvinyl alcohol
  • PU polyurethane
  • HA hydroxyapatite
  • polyurethanes The most commonly used process in the production of polyurethanes is the reaction of a compound with two or more alcohol functional groups, such as a polyether polyol or polyester polyol with an isocyanate, di or polyfunctional (Cordeiro, 2007), (Zhang, 2011) forming urethane bonds.
  • a chain extender may also be used in the reaction, with molar ratio proportions.
  • the preparation of the bionanocomposite of the present invention may be initiated by employing an isocyanate, being selected from aliphatic isocyanates such as 1,4-diisocyanate butane (BDI), 1,6-diisocyanate hexane (HDI), 4,4 -methylene dicyclohexyl diisocyanate (HMDI), preferably HDT polyisocyanate, hexamethylene diisocyanate trimer (HDI) and a polyvinyl alcohol polyol, by weight and without the use of chain extender.
  • an isocyanate being selected from aliphatic isocyanates such as 1,4-diisocyanate butane (BDI), 1,6-diisocyanate hexane (HDI), 4,4 -methylene dicyclohexyl diisocyanate (HMDI), preferably HDT polyisocyanate, hexamethylene diisocyanate trimer (HDI) and a polyvin
  • PU prepolymer 1 to 2 g preferably 2 g of HDT viscous material with preferably 1 g of polyvinyl alcohol particles are used at each reaction. Hydroxyapatite is added in proportions ranging from 25 to 33%, preferably 25% of the bionanocomposite, resulting in a 1: 2 to 1 ratio preferred mixture of PVAI, HDT and HA starting materials respectively.
  • bionanocomposite of the present invention may further comprise optional components to provide some desirable feature not achieved with the aforementioned components.
  • optional components to provide some desirable feature not achieved with the aforementioned components.
  • the bionanocomposite can be packaged in different molds, according to the region in which it will be applied, placed in a greenhouse for curing and then removed and cooled naturally to room temperature, demolded and sent for morphological, mechanical and biological characterization.
  • the bionanocomposite of the present invention has mechanical compression properties which are important for bone grafts of greater mechanical stress, such as maxillary bones ranging from 60 to 111 MPa.
  • mechanical compression properties which are important for bone grafts of greater mechanical stress, such as maxillary bones ranging from 60 to 111 MPa.
  • Example 1 Obtaining PVAI-PU / HA Bionanocomposite
  • the first closed stainless steel mold with a size for cylindrical samples with a diameter of 6 mm and a height of 3 mm.
  • the second closed polypropylene mold with an inner diameter of 4 mm and a height of 60 mm and, third, an open Teflon mold for prism-shaped samples with dimension of 20x20x2 mm 3 .
  • Ed oreenchimento with the mixture material with the molds were inserted in an oven for curing at 120 Q C per 30 min, then removed and cooled naturally to room temperature and demolded.
  • Annex 1 shows the biomaterial obtained in three distinct forms.
  • FTIR monitoring was performed under the same conditions, both in the starting materials and in the PVAI-PU / HA biomaterial.
  • the materials were wrapped in polyethylene (PE) film for better reading in a paper sample holder adapted to the equipment. Material analyzes were performed by subtracting the PE bands from 4000 to 500 cm "1 .
  • Figure 2 shows biomaterial spectra monitored during FTIR formation kinetics with 15 to 75 minute heating where The points of modification of hydroxyl ions and formation of NH group of PU and modifications in phosphate groups (PO) of hydroxyapatite are highlighted.
  • Example 3 Rheological Assays
  • Rheology is responsible for obtaining information on the effect of various factors that influence the processing of polymeric materials. Rheological studies were performed through tests to obtain variables such as processing temperature for hot cure and viscosity, both for the reaction of the PVAI and HDT mixture that formed PVAI-PU and in the PVAI-PU / HA biomaterial mixture.
  • Figures 3 and 4 show the rheology curves of PU and PVAI-PU / HA biomaterial formation, respectively.
  • the ambient temperature range up to 120 and C was used as the cure temperature of the PVAI-PU / HA biomaterial for 30 minutes at this temperature. .
  • Such conditions showed excellent result for cure processing.
  • the presence of nanocrystals may restrict polyol relaxation, leading to viscoelastic behavior, (Wik, 201 1).
  • the material cured in the rheometer at 15 9 showed white color and showed no signs of degradation, this visual morphology was determinant for the further processing to obtain the bionanocomposites with the appropriate characteristics.
  • Example 4 X-ray Diffraction (DR-X) X-ray measurements of PVAI and PVAI + HDT were performed by the x-ray technique on a PHILIPS-binary (scan) (RD) device and PW1800 goniometer, using the powder method, with copper Ka and X-ray sources. sweep in the range of 5 S to 60 and (2 ⁇ ).
  • the phases present in the biomaterials and HA were determined by
  • X-ray powder diffraction in total sample.
  • a PHILIPS-binary X-ray diffractometer with normal focus PW 1800 Goniometer and a copper anode X-ray tube were used.
  • Data acquisition of the records was obtained through an interphase and software, and the treatment of the data with the APD software, Automated Powder Diffaction.
  • the PVAI-PU / HA biomaterial also presents overlapping peaks at 2 ⁇ near 20 e (crystalline) and at 2 ⁇ near 40 Q (amorphous) characteristic of semicrystalline PVAI (ZHANG, 2010) confirming the PVAI remnant under FTIR analysis.
  • mi is the dry mass before soaking in 2 is the wet mass after soaking.
  • the pycnometer was washed with alcohol, dried at room temperature and filled with distilled water, which was measured. The mass of each biomaterial sample was duly measured as well as the mass of the pycnometer and the combined mass of the sample and pycnometer with distilled water three times.
  • the apparent density of the biomaterial was calculated as a function of the pycnometer mass with water, the solid body in the watch glass and the pycnometer mass with the solid body in it.
  • the assay was performed at 22 ° C.
  • Scaffold porosity was determined using liquid displacement or Archimedes principle, a method similar to that reported by (Guan, 2005; Liu, 2010), and five samples were evaluated for each scaffold in the USP Lorraine laboratory at 18 Q C.
  • ASTM D 695-96 which contains compression test guidelines. This test method determines the mechanical properties of rigid, unreinforced and reinforced plastics, including high modulus composites, when loaded under compression at relatively low stress rates or even loading. Standard specimens are used. This process is applicable to a composite module up to 41,370 MPa (6,000,000 psi) (ASTM D 695-96).
  • Compression test is the application of a uniaxial compressive load to a test specimen and the response of this test is obtained by the linear deformation measured between the distance of the plates compressing that specimen.
  • the sample for the pattern should be in the form of a straight cylinder or prism whose length is twice its main width or diameter.
  • Figure 7 shows the values of each mean resistance and standard deviation of the PVAI-PU blend and bionanocomposites with 25% and 33% HA under compression. These values are the result of bionanocomposite tests until deformation of up to 40% of the total length of the specimen. It can be seen that the result with 33% HA content in the PU matrix composite makes the compressive strength higher.
  • Annex 2 shows an image of the surface of PVAI-PU where mainly the PU formed is observed and PVAI particles are not noticeable.
  • Annex 3 shows an image of the inner surface of the biomaterial as used in biological assays, where PVAI microparticles are observed in the domain of bionanocomposite, polyurethane and hydroxyapatite phase, pores and micropores of varying sizes, which have adequate architecture for biomaterial with application in tissue engineering.
  • EDS analysis was performed on both polyvinyl alcohol, hydroxyapatite and biomaterial starting materials to verify how the constituent particles of these materials were chemically altered. After obtaining the SEM material images, images were selected for analysis by EDS. Four (4) points were randomly determined in each image for analysis.
  • the images of the PVAI-PU / HA biomaterial, Annex 4, show EDS bionanocomposite spectra on the left and point determination on the PVAI-PU / HA material on the right attesting that the structure contains the constituent elements of the starting materials and the relationship Ca / P had a range from 2.3 to 3.1.
  • the uniform distribution of these materials will actively influence the ionic balance between biological fluid and biomaterial.
  • Table 1 shows the concentration of the elements that make up the bionanocomposite analyzed by EDS.
  • X-ray fluorescence spectrophotometry (XRF) assay was performed. PVAI-PU / HA biomaterial contents were determined on a Rigaku spectrophotometer, model Rix 3100.
  • the fluorescence assay results show that the Ca / P ratio of hydroxyapatite is higher than the original value, this confirms the excess calcium in the biomaterial hydroxyapatite structure.
  • the amounts values are shown in Table 2.
  • the analyzes were performed with a heating rate of
  • the first endothermic peak near 225 S C refers to the melt temperature of the biomaterial.
  • the second endothermic peak is due to the combustion of organic material when material loss occurs.
  • the third peak corresponds to the reaction of hydroxyapatite in the biomaterial.
  • cytotoxicity index (IC) 50% is estimated by the interpolation curve, as the concentration of the biomaterial extract resulting from the 50% inhibition of MTS incorporation, correlating the average percentage of viable cells in relation to the concentration of the extracts from the biomass. graphic. In the tests carried out through the positive and negative controls it can be verified that both the polyvinyl alcohol components that in reaction with the diisocyanate formed the polyurethane and hydroxyapatite as the composites obtained by the mixture did not present toxicity.
  • NIH3T3 cells were plated at concentrations 5x10 5 and 10 6 cells per biomaterial.
  • the biomaterial was kept in 300 ⁇ of modified Dulbecco's medium (modified Dulbecco's Eagle's medium - DMEM) with 10% fetal bovine serum and also poly-l-lysine for three days in a greenhouse at 37 ° C with 5% CO 2 .
  • Cell proliferation analysis was performed by cell viability testing with tetrazoline-3- (4,5-dimethylthiazol-2yl) -2,5-diphenyl bromide (MTT).
  • VERO cells a fibroblast-type cell line recommended for cytotoxicity testing, were used.
  • Cells were cultured in DMEM (Gibco) supplemented with 10% Fetal Bovine Serum (FBS, Gibco) at 37 9 C with 5% CO 2 in the atmosphere.
  • DMEM Gibco
  • FBS Fetal Bovine Serum
  • Extracts of the analyzed materials were obtained by incubating them in a 24-well culture plate at a rate of 0.2 g of material per ml of 10% SFB DMEM medium at 37 ° C for 48 hours without shaking. After the incubation period, the medium was used to grow VERO cells, thus allowing to evaluate the possible release of toxic substances in the culture medium. Indirect cytotoxicity testing and extract extraction were performed according to international recommendations (ISO-10993-5, 1992; ISO-10993, 1997, NBR-ISO10993, 1999; SJOGREN, 2000).
  • a cell suspension at a concentration of 3x10 6 cells / ml was inoculated into a 96-well culture (Corning Costar Corporation, Cambridge, MA, USA) and grown for 24 hours at 37 ° C. After the 24 hour incubation period, the culture medium contained in the plate was replaced by extracting the materials.
  • the positive toxicity control (CPT) was a DMEM solution containing 10% SFB and 10% phenol and the negative toxicity control (CNT) polystyrene extract.
  • Test results performed by the MTT method demonstrate that NIH3T3 - murine fibroblast cells cultured on the biomaterial are viable as cells plated in the presence of the reagent formed, which can be visualized due to the turquoise staining observed in the images. It was also observed that the use of adhesion protein is of great necessity for cell adhesion. Different cell concentrations were also used on the biomaterial, but regardless of concentration the adhesion was efficient.
  • the animals were anesthetized and sacrificed after 30 days of implantation by cervical dislocation.
  • the implant discs were collected and fixed in 10% formalin, decalcified (DONG, 2009), dehydrated and embedded in paraffin.
  • Each explant was then processed for histological analysis in which 5 ⁇ sections were obtained and stained with Hematoxylin & Eosin (Hill, 2007; Dong, 2009; Kim, 201 1).
  • the biocompatibility of the PU / PVA implant was quantified by the severity of the fibrosis capsule, foreign body reaction and nonspecific inflammatory process. Osteoconduction properties were determined by bone regeneration capacity.
  • the implant slide, Annex 5 shows the presence of thick basophilic, acellular, solid solid masses resembling synthetic bone tissue, interspersed with fibrins, dilated and congested capillaries, sparse giant cells called osteoclasts.
  • Annex 6 we observed the presence of prominent osteocytes in the injured tissue and would need some time to close what does not happen with the implant blade where tissue closure with the bionanocomposite is visible confirming the biointegration and biocompatibility between bionanocomposite and recipient bone. There are also some fibroses on both slides.
  • SWISS mice (30-35g) were divided into three groups of two animals and kept in 12-hour light / dark cycle plastic boxes (Jovanovic, 2010) and room temperature (22 ⁇ 1) Q C, with water and food. ad libitium. The experiment was developed according to the research ethics committee for animal use.
  • mice were anesthetized with ketamine / xylazine 2: 1 diluted in saline. After shaving, a dorsal midline 10 mm incision was made in the animal and the PVA-PU / HA autoclave disc-shaped biomaterial for ⁇ 4 mm and 1 mm thick thermolabile materials was implanted into the subcutaneous space. dorsal spine (Hill, 2007). After surgery the tissues were repositioned and sutured. Postoperatively no medication was used. All animals were closely monitored and received pelleted feed and water ad libitum. The animals were sacrificed in a CO2 chamber for removal of implanted material 1, 7 and 14 days after implantation. (Hafeman, 2012).
  • the biomaterial was removed along with the mouse tissue and fixed in a solution containing 2.5% 25% glutaraldehyde, 4% paraformaldehyde 2.5% sucrose in sodium cacodylate buffer (Khandwekar, 2010), 0, 1 M, pH 7.2 for 2 hours at room temperature. After fixation, the cells were washed 3 times in 0.1 M cacodylate buffer and subsequently spun in solution containing: 1% osmium tethoxide and 0.8% potassium ferrocyanide for 1 hour at room temperature. The material was washed and then dehydrated in increasing series of ethanol (50, 70, 90% and 100%) (Kim 2011; Dias, 2010) for 20 minutes at room temperature.
  • the samples were dried by the critical point method (Model K 850 - Emitech Brand) using CO 2 .
  • the material was mounted on an appropriate support (stub) and metallized with a gold film approximately 2 ⁇ thick. using the Emitech K550-England handset.
  • the analysis was performed under LEO 1450VP scanning electron microscope.
  • Annex 7 shows an image of the biomaterial implanted in the subcutaneous tissue of the back of the mouse for 14 days, obtained by scanning electron microscopy. Overview of the interaction of biomaterial (BM) with subcutaneous tissue layers; B- detail of the region highlighted in A. The intimate contact of the cellular fibrous layer formed around the biomaterial (arrow) and the extensions of the fibrous material that make up the layer are observed; C- Overview of the interaction of the biomaterial with the skin layers. The formation of the fibrous layer is observed around the entire biomaterial; D- detail of the region highlighted in C. The process of cell invasion in the biomaterial is observed.
  • BM biomaterial

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Abstract

La présente invention concerne un bionanocomposite pour la restauration osseuse, présentant des propriétés mécaniques de compression, idéal pour les greffons osseux appelés à subir un effort mécanique important. Ce bionanocomposite peut en outre trouver une application dans la reconstitution et le remplissage de la calotte crânienne et le remplissage d'ouvertures osseuses.
PCT/BR2014/000176 2013-06-07 2014-05-26 Bionanocomposite pour la régénération osseuse WO2014194392A1 (fr)

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CN110404085A (zh) * 2019-08-30 2019-11-05 浙江大学 一种穿颅声学软质超声凝胶材料及其制备方法和应用

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WO2010017282A1 (fr) * 2008-08-05 2010-02-11 Biomimedica, Inc. Hydrogels greffés au polyuréthane

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Publication number Priority date Publication date Assignee Title
CN110404085A (zh) * 2019-08-30 2019-11-05 浙江大学 一种穿颅声学软质超声凝胶材料及其制备方法和应用
CN110404085B (zh) * 2019-08-30 2020-09-22 浙江大学 一种穿颅声学软质超声凝胶材料及其制备方法和应用

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