WO2011161292A1 - Matériau composé de polymère et de particules de magnésium pour applications biomédicales - Google Patents

Matériau composé de polymère et de particules de magnésium pour applications biomédicales Download PDF

Info

Publication number
WO2011161292A1
WO2011161292A1 PCT/ES2011/070440 ES2011070440W WO2011161292A1 WO 2011161292 A1 WO2011161292 A1 WO 2011161292A1 ES 2011070440 W ES2011070440 W ES 2011070440W WO 2011161292 A1 WO2011161292 A1 WO 2011161292A1
Authority
WO
WIPO (PCT)
Prior art keywords
magnesium particles
implant
μιτι
size
polymer
Prior art date
Application number
PCT/ES2011/070440
Other languages
English (en)
Spanish (es)
Inventor
José Luis GONZÁLEZ CARRASCO
Marta MULTIGNER DOMÍNGUEZ
Marcela LIEBLICH RODRÍGUEZ
Marta MUÑOZ HERNÁNDEZ
Emilio Frutos Torres
Laura SALDAÑA QUERO
Nuria VILABOA DÍAZ
Original Assignee
Consejo Superior De Investigaciones Científicas (Csic)
Ciber-Bbn
Fundación De La Investigación Biomédica Del Hospital Universitario De La Paz
Fundación Universidad Alfonso X El Sabio
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 Consejo Superior De Investigaciones Científicas (Csic), Ciber-Bbn, Fundación De La Investigación Biomédica Del Hospital Universitario De La Paz, Fundación Universidad Alfonso X El Sabio filed Critical Consejo Superior De Investigaciones Científicas (Csic)
Publication of WO2011161292A1 publication Critical patent/WO2011161292A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—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
    • A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • 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

Definitions

  • the present invention relates to a polymeric matrix material and biocompatible and reabsorbable magnesium particles with medical applications, in particular as osteosynthesis material and in bone tissue engineering.
  • Bioactive inorganic materials of clinical interest have a composition similar to the mineral phase of bone.
  • the reabsorption rate of bioactive and bioceramic glasses can be adjusted with crystalline hydroxyapatite for long periods of time, while there are other calcium phosphates that have a greater capacity to reabsorb but little resistance to withstand loads.
  • Biopolymers such as collagen and hyaluronic acid are materials in use for tissue reconstruction.
  • its weakness is related to the potential risk of disease transmission and Difficulties handling
  • synthetic polymers such as polycaprolactone (PCL), polyfumarates, polylactic acid (PLA), polyglycolic acid (PGA) and their copolymers (PLGA) are currently used for the manufacture of sutures, nails, screws and plates , constituting a very versatile alternative.
  • PCL polycaprolactone
  • PLA polyfumarates
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PLGA copolymers
  • Tissue Engineering pursues the use of porous scaffolds, decorated or not with bioactive molecules, on which to grow cells to generate implantable constructs that promote tissue regeneration in the patient.
  • the vast majority of scaffolds developed are based on polymeric materials.
  • the present invention provides biodegradable material for the manufacture of useful devices such as osteosynthesis material or for bone regeneration, and its method of production.
  • a first aspect of the present invention relates to a material (from now on material of the invention) comprising the mixture of:
  • a polymeric matrix comprising a biodegradable polymer, and b. magnesium particles
  • This invention focuses on the development of hybrid materials based on biocompatible and biodegradable polymers loaded with Mg particles, with a degradation profile modulated by the volume and size fraction of the Mg particles. It is expected that, in this way, the rate of hydrogen release during the degradation process will be tolerated by human tissues, allowing the repair and / or regeneration of bone tissue as its reabsorption occurs.
  • Mg its biocompatibility and osteoconductive properties stand out.
  • the ions released during the degradation process are soluble in physiological media and are easily excreted in the urine.
  • the biodegradable polymers of the present invention may be natural or synthetic and, optionally, may include one or more bioactive agents.
  • the biodegradable polymer may be, but not only, polycaprolactone (PCL), polyfumarates, polylactic acid (PLA), polyglycolic acid (PGA) or any combination thereof.
  • the biodegradable polymer is selected from polycaprolactone (PCL), polyfumarates, polylactic acid (PLA), polyglycolic acid (PGA) and any combination thereof.
  • the biodegradable polymer is a copolymer comprising at least polylactic acid.
  • the weight ratio of polylactic acid to the other component of the copolymer is between 100: 0 to 60:40.
  • the magnesium present in the material of this invention may be present with or without alloy elements, it being preferable that it does not contain alloy elements.
  • the magnesium particles have a size between 50 and 500 ⁇ if their use in tissue engineering (bone regeneration) is considered. More preferably, the magnesium particles have a size between 50 and 250 ⁇ . On the other hand, the magnesium particles preferably have a size of less than 50 ⁇ if their use as osteosynthesis material (bone repair) is considered.
  • volume percentage of the magnesium particles with respect to the total material is less than or equal to 70%.
  • the polymer / Mg assembly has mechanical characteristics (strength, modulus) superior to that of dense or porous resorbable polymers.
  • the selection of the polymer will depend on its application, using semi-crystalline forms (L-polylactic acid, also known as L-PLA, PLLA or L-PLLA), when greater mechanical performance (or long degradation periods), or amorphous forms ( DL-PLA) since it is built by two isomeric forms of PLA, if lower mechanical loads (or shorter resorption times) are required.
  • Copolymers could also be used to modulate both mechanical properties and degradation rates.
  • the L-PLA has an elastic modulus of 3 GPa, while combining the DL-PLA with polycaprolactone (PCL) in a 60PLA 40PCL ratio, a manually moldable material is obtained.
  • a second aspect of the present invention relates to a process for obtaining the material of the invention, which comprises the steps:
  • step (a) processing of the product obtained in step (a).
  • step (a) is carried out by a technique that can be, but not exclusively, gel casting, dissolution and casting with particle release, membrane lamination, phase separation, lyophilization, fiber bonding, extrusion, etc.
  • the mixing of step (a) is performed by a technique that is selected from gel casting, dissolution and casting with particle release, membrane lamination, phase separation, lyophilization, fiber bonding and extrusion.
  • step (a) comprises the addition of an organic solvent. More preferably, the solvent employed is chloroform. While any organic solvent that facilitates the dispersion of magnesium particles in the polymer matrix can be used.
  • the process comprises an additional stage of evaporation of the solvent used in step (a) and subsequent processing of the product obtained in this additional stage.
  • evaporation is performed by orbital agitation.
  • a laminar product can be obtained, which can be prepared by cutting before processing. Any polymer forming method known to any person skilled in the art is processed.
  • step (b) is a thermomechanical processing of compaction and molding.
  • thermomechanical processing of step (b) is performed at a temperature range of between 100 and 200 ° C.
  • thermomechanical processing of step (b) is performed at a temperature range of between 130 and 170 ° C.
  • the present invention relates to the use of the material of the invention for the manufacture of a biomedical implant or device.
  • the present invention relates to a biomedical implant or device manufactured from the material of the present invention.
  • the implant is to allow bone repair, as an osteosynthesis material, more preferably when the magnesium particles are smaller than 50 ⁇ .
  • the implant is for the regeneration of bone tissue in bone tissue engineering, more preferably the magnesium particles have a size between 50 and 500 ⁇ , it being preferable that the magnesium particles have a size between 50 and 250 ⁇ .
  • the magnesium particles Being a dense material, the possibility that the polymer / Mg set collapse and modify its architecture due to the effect of mechanical loads in vivo would be lower, which would facilitate it to play its role as scaffold while regeneration and vascularization of the bone tissue on the surface.
  • Fig. 1 Optical microscopy images corresponding to: A) appearance of the Mg-loaded polymer specimens; and B) cross section thereof; Image C corresponds to an electronic scanning image showing a detail of the polymer / Mg interface.
  • Fig. 3 Voltage-displacement curve for the L-PLLA with and without magnesium.
  • Fig. 4 Viability of human mesenchymal stem cells cultured on L-PLLA / Mg samples. The results are expressed as a percentage of the cell viability measured after 1 day, to which an arbitrary value of 100 was assigned.
  • a polylactic acid composite material in its L-isomeric form (L-PLLA) and a nominal volume fraction of 30% Mg has been prepared.
  • the mixture has been produced after dissolving the polymer in chloroform. Once dissolved it has been mixed with the Mg powder, with an average size of about 250 microns, and then evaporation of the solvent.
  • the images in Figure 1 show the appearance of the material after mixing (A), and the cross sections examined in the optical (B) and electron microscope (C).
  • the mechanical properties of polymers are generally insufficient for use as a biomaterial, whether for application as scaffolding, as filler material, etc. Therefore, the combination of polymer / metal mechanical properties is necessary to increase the mechanical performance that the polymer alone is unable to offer, and resemble those of the bone.
  • the mechanical characterization has been carried out through instrumented indentation techniques, which allow the hardness and elastic modulus of the composite material to be measured simultaneously. The measurements have been made using a Nanotest 600 ultra-microindentator with a Berkovich type diamond tip. Its Young's modulus (Ei) and Poisson's coefficients (v ⁇ ) are 1,141 GPa and 0,07, respectively.
  • Table 1 shows the values of the hardness (H), the reduced Young's modulus (E R ), and the Young's modulus (E) for the polymer with and without magnesium, v represents the value of the Poisson coefficient used for the calculation of the module.
  • Table 1 Hardness and module values determined from ultra-microindentation measurements.
  • the elastic modulus of the L-PLLA depends on the degree of polymerization of the monomer chains. It should be noted that with a volume fraction of 30% Mg, the value of the elastic modulus almost triples, approaching the value corresponding to the cortical bone.
  • Table 2 shows the values of elastic limits ( ⁇ ) and maximum load (Omax) recorded in the compression test.
  • Table 2 Average values of elastic limit ( ⁇ ) and maximum load (a max ) recorded in the compression test Comparing the values of Young's modulus and the tension corresponding to the elastic limit, obtained for the magnesium reinforced polymer with the corresponding to the trabecular bone, it can be seen how magnesium reinforcement allows to obtain polymer / metal composite materials with mechanical properties similar to those of human bone, thus allowing a better load transfer between this artificial material and bone tissue.
  • Biocompatibility assays The in vitro biocompatibility of the magnesium reinforced polymer has been tested using human mesenchymal stem cells from bone marrow. The cells were grown for up to 15 days on the L- samples PLLA Mg, previously incubated in culture medium for at least 1 h. After these incubation times the metabolic activity was quantified, as a parameter associated with cell viability, using the commercial reagent AlamarBIue TM. Figure 4 shows that cell viability increases with the culture time on polymer / metal composites.

Abstract

La présente invention concerne un matériau de matrice polymère et de particules de magnésium, biocompatible et réabsorbable pour des applications médicales, concrètement à utiliser en tant que matériau d'ostéosynthèse et en ingénierie tissulaire osseuse pour la régénération de tissu osseux.
PCT/ES2011/070440 2010-06-21 2011-06-20 Matériau composé de polymère et de particules de magnésium pour applications biomédicales WO2011161292A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP201030950 2010-06-21
ES201030950A ES2372341B8 (es) 2010-06-21 2010-06-21 Material compuesto de polímero y partículas de magnesio para aplicaciones biomédicas.

Publications (1)

Publication Number Publication Date
WO2011161292A1 true WO2011161292A1 (fr) 2011-12-29

Family

ID=45370883

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/ES2011/070440 WO2011161292A1 (fr) 2010-06-21 2011-06-20 Matériau composé de polymère et de particules de magnésium pour applications biomédicales

Country Status (2)

Country Link
ES (1) ES2372341B8 (fr)
WO (1) WO2011161292A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015142631A1 (fr) * 2014-03-17 2015-09-24 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Échafaudages contenant un composite de magnésium pour amplifier la régénération tissulaire
EP3299037A1 (fr) * 2016-09-27 2018-03-28 Regedent AG Système de protection et procédé pour former un système de protection, procédé de régénération d'un os et membre de renfort

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020127265A1 (en) * 2000-12-21 2002-09-12 Bowman Steven M. Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration
US20060024377A1 (en) * 2004-01-16 2006-02-02 Ying Jackie Y Composite materials for controlled release of water soluble products
US20070191963A1 (en) * 2002-12-12 2007-08-16 John Winterbottom Injectable and moldable bone substitute materials
US20080249638A1 (en) * 2007-04-05 2008-10-09 Cinvention Ag Biodegradable therapeutic implant for bone or cartilage repair

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020127265A1 (en) * 2000-12-21 2002-09-12 Bowman Steven M. Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration
US20070191963A1 (en) * 2002-12-12 2007-08-16 John Winterbottom Injectable and moldable bone substitute materials
US20060024377A1 (en) * 2004-01-16 2006-02-02 Ying Jackie Y Composite materials for controlled release of water soluble products
US20080249638A1 (en) * 2007-04-05 2008-10-09 Cinvention Ag Biodegradable therapeutic implant for bone or cartilage repair

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015142631A1 (fr) * 2014-03-17 2015-09-24 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Échafaudages contenant un composite de magnésium pour amplifier la régénération tissulaire
EP3119447A4 (fr) * 2014-03-17 2017-11-08 University of Pittsburgh - Of the Commonwealth System of Higher Education Échafaudages contenant un composite de magnésium pour amplifier la régénération tissulaire
EP3299037A1 (fr) * 2016-09-27 2018-03-28 Regedent AG Système de protection et procédé pour former un système de protection, procédé de régénération d'un os et membre de renfort

Also Published As

Publication number Publication date
ES2372341B1 (es) 2013-01-24
ES2372341B8 (es) 2013-09-27
ES2372341A1 (es) 2012-01-18

Similar Documents

Publication Publication Date Title
Liu et al. Delivery of growth factors using a smart porous nanocomposite scaffold to repair a mandibular bone defect
JP5881669B2 (ja) コラーゲン／ヒドロキシアパタイト複合骨格及びその生成方法
Si et al. Controlled degradable chitosan/collagen composite scaffolds for application in nerve tissue regeneration
Okamoto et al. Synthetic biopolymer nanocomposites for tissue engineering scaffolds
Dong et al. Degradation and biocompatibility of porous nano-hydroxyapatite/polyurethane composite scaffold for bone tissue engineering
Turco et al. Alginate/hydroxyapatite biocomposite for bone ingrowth: a trabecular structure with high and isotropic connectivity
Misra et al. Polyhydroxyalkanoate (PHA)/inorganic phase composites for tissue engineering applications
Cui et al. The nanocomposite scaffold of poly (lactide-co-glycolide) and hydroxyapatite surface-grafted with L-lactic acid oligomer for bone repair
Mi et al. Morphology, mechanical properties, and mineralization of rigid thermoplastic polyurethane/hydroxyapatite scaffolds for bone tissue applications: effects of fabrication approaches and hydroxyapatite size
Gyawali et al. Citrate-based biodegradable injectable hydrogel composites for orthopedic applications
Mahanta et al. Nanohybrid scaffold of chitosan and functionalized graphene oxide for controlled drug delivery and bone regeneration
Hu et al. Biodegradable poly (lactic acid-co-trimethylene carbonate)/chitosan microsphere scaffold with shape-memory effect for bone tissue engineering
Hixon et al. A comparison of cryogel scaffolds to identify an appropriate structure for promoting bone regeneration
Scott et al. Advances in bionanomaterials for bone tissue engineering
Alves Cardoso et al. Gelation and biocompatibility of injectable Alginate–Calcium phosphate gels for bone regeneration
Jančář et al. Mechanical response of porous scaffolds for cartilage engineering
Sa et al. Beneficial effects of biomimetic nano-sized hydroxyapatite/antibiotic gentamicin enriched chitosan–glycerophosphate hydrogel on the performance of injectable polymethylmethacrylate
Meskinfam Polymer scaffolds for bone regeneration
Ganguly et al. Electrospun and 3D printed polymeric materials for one-stage critical-size long bone defect regeneration inspired by the Masquelet technique: Recent Advances
Rad et al. Osteogenic differentiation of adipose-derived mesenchymal stem cells using 3D-Printed PDLLA/β-TCP nanocomposite scaffolds
Kalambettu et al. Fabrication and in vitro evaluation of Sulphonated Polyether Ether Ketone/nano Hydroxyapatite composites as bone graft materials
Wang et al. Biomimetic scaffolds with programmable pore structures for minimum invasive bone repair
WO2011161292A1 (fr) Matériau composé de polymère et de particules de magnésium pour applications biomédicales
KR101815367B1 (ko) 균일하게 분산된 인산칼슘계 마이크로스피어를 포함하는 아크릴계 골시멘트 복합체 및 이의 제조방법
Zadeh et al. A comprehensive in vitro study of the carbon nanotube enhanced chitosan scaffolds for cancellous bone regeneration

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: 11797653

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: 11797653

Country of ref document: EP

Kind code of ref document: A1