WO2011161292A1 - Polymer and magnesium particle material for biomedical applications - Google Patents

Polymer and magnesium particle material for biomedical applications Download PDF

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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
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Prior art keywords
material
step
according
μιτι
implant
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PCT/ES2011/070440
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Spanish (es)
French (fr)
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
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Priority to ES201030950A priority Critical patent/ES2372341B8/en
Priority to ESP201030950 priority
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/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/446Composite 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58Materials at least partially resorbable by the body

Abstract

The present invention relates to a polymeric matrix and magnesium particle material that is biocompatible and absorbable and has medical applications, specifically as a material for osteosynthesis and in tissue engineering for regenerating dry tissue.

Description

AND POLYMER COMPOSITE PARTICLES FOR BIOMEDICAL APPLICATIONS MAGNESIUM

The present invention relates to a polymeric matrix material and particles of biocompatible, resorbable magnesium medical applications, in particular as osteosynthesis material and bone tissue engineering.

STATE OF THE ART The search for new strategies and materials for repair and regeneration of damaged bone tissue is a priority motivated by socio-economic challenge stems from the increase in bone diseases associated with aging populations in advanced societies. In the 50 bioinert materials they were sought, with minimal interaction with the biological environment. The second generation of biomaterials, in the eighties, led to the development of bioactive materials pursuing a controlled environment reaction. Since 2000, the goal has been to develop third-generation biomaterials that allow tissue regeneration rather than replacement. Many of the developed materials are ceramic bioactive, bioactive glasses, synthetic or biological polymers, and their compounds.

Bioactive inorganic materials have similar clinical interest to the mineral phase of bone composition. The resorption rate of the bioceramic and bioactive glasses can be adjusted with crystalline hydroxyapatite for long periods of time, while there are other calcium phosphates that have a greater capacity to resorb but little resistance to withstand loads.

Biological polymers such as collagen and hyaluronic acid are materials used for tissue reconstruction. However, their weakness is related to the potential risk of disease transmission and difficulties in handling. On the other hand, 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, pins, screws and plates , constituting a versatile alternative. Although their degradation products are metabolized and eliminated by the body, when in very high concentrations can cause a local pH decrease, compromising the viability of the tissues. In general, the fragile nature of the bioactive ceramic materials and low mechanical properties of biodegradable polymers discourages its use in applications where high load bearing is required, as in most orthopedic applications. The composites of organic-inorganic origin tend to mimic nature bone combining the toughness of a polymer with the compressive strength of a ceramic, which results in materials with better mechanical properties and degradation profiles. As reinforcing materials have been used both as bioglasses hydroxyapatite (ME Navarro, Development and Characterization of Biodegradable materials for bone regeneration, Doctoral Thesis, UPC, 2005). The use of composite materials loaded with metals has been researched in this field. However, it seems to be an effective way to control degradation of the metal, as observed during the degradation of nanocomposites Cu with low density polyethylenes (S Cai, Xia X, Xie C, Biomaterials 26 (2005) 2671-2676 ).

Include the development of biodegradable metallic materials for components subjected to loads. Mg alloys, widely investigated today, were introduced in the first half of the last century. Its main advantage compared with other metallic biomaterials is their low density (1, 7 to 2.0 g / cm 3). Additionally, its fracture toughness is higher than that of ceramic materials, with an elastic modulus value (41 to 45 GPa) very close to the natural bone (<20 GPa). One of the problems associated with their use was associated with rapid corrosion rate in vivo (D. Williams, Med. Device Technol. 17 (2006), 9, p8-10), which produced a significant accumulation of hydrogen (1 liter per gram of Mg). Because of this problem use fell into disuse with the development of stainless steels. At present there are numerous efforts are being made to slow down degradation and increase their mechanical properties (MP Staiger, AM Pietak, J Huadmai, G Dias, Biomaterials 27 (2006) 1728-1734 and WD Müller, ML Nascimento , M Sedéis, M. Corsico, LM Gassa, MAF Melé Lorenzo, Mal res. 10 (2007) 5-10]. Unfortunately, this is being achieved from the introduction of alloying elements which, once degraded the implant, they could pose biocompatibility problems.

Tissue Engineering pursues the use of porous, decorated with bioactive molecules or scaffold in which to grow cells to generate implantable constructs that promote tissue regeneration in the patient. The vast majority of developed scaffolds are based on polymeric material nature.

An essential to ensure osteoconduction on scaffolding aspect is that its porosity is interconnected (Hing et al. J. Mater. Sci .: Mater. Med. 16 (2005) 469-475), to allow not only cell colonization , but also adequate vascularization. It is considered that for adequate vascularization colonization and pore size should be in the range of 200 to 500 μιτι. However, this requirement is limited by the need for scaffolding has adequate mechanical resistance to compression and a value equal to or slightly greater than the elastic modulus of the bone to prevent collapse when subjected to loads in vivo. The effect of porosity on the elastic modulus is different for different types of materials, metallic materials being the only offer a combination of rigidity and close to the bone (40-80%) porosity. Consequently, numerous recent studies with porous materials made of metal (Ti, Mg, NiTi). Among them, only Mg can be considered biodegradable. Use in aqueous environments advises against rapid degradation rate, as discussed above.

DESCRIPTION OF THE INVENTION

The present invention provides biodegradable material for the manufacture of useful devices as osteosynthesis material or for bone regeneration, and its preparation process.

A first aspect of the present invention relates to a material (hereinafter material of the invention) comprising the mixture of:

to. a polymer matrix comprising a biodegradable polymer, and b. magnesium particles.

This invention focuses on the development of hybrid materials based on biocompatible and biodegradable polymer particles charged with Mg, a degradation profile modulated by the volume fraction and particle size of Mg. Hopefully, thus, the rate of release of hydrogen during the degradation process is tolerated by human tissue, allowing repair and / or regeneration of bone tissue as reabsorption occurs. Among the advantages of using Mg include its biocompatibility and osteoconductive properties. Moreover, the ions released during the degradation process are soluble in physiological media and are easily excreted through urine.

Biodegradable polymers of the present invention may be natural or synthetic and may optionally include one or more bioactive agents. In a preferred embodiment the biodegradable polymer can be, but not limited to, polycaprolactone (PCL), polyfumarates, polylactic acid (PLA), polyglycolic acid (PGA) or any combination thereof. Preferably the biodegradable polymer is selected from polycaprolactone (PCL), polyfumarates, polylactic acid (PLA), polyglycolic acid (PGA) and any combination thereof.

In a more preferred embodiment the biodegradable polymer is a copolymer comprising at least polylactic acid. In a more preferred embodiment the weight ratio of polylactic acid to another component of the copolymer is between 100: 0 to 60:40.

The magnesium in the material of this invention may be present with or without alloying elements, preferably containing no alloying elements.

Preferably the magnesium particles have a size of between 50 and 500 μιτι considering its use in tissue engineering (bone regeneration). Most preferably, the magnesium particles have a size between 50 and 250 μιτι. Furthermore, the magnesium particles are preferably less than 50 μιτι size considering use as osteosynthesis material (bone repair).

In another preferred embodiment the volume percentage of particles of magnesium to total material is less than or equal to 70%.

polymer assembly / Mg has dimensions greater than that of the dense or porous resorbable polymers mechanical properties (strength, modulus). The selection of polymer will depend on its application, using semicrystalline forms (L-polylactic acid, also known as L-PLA, PLLA PLLA or L-), when higher mechanical performance (or long term degradation) are required, or amorphous forms ( DL-PLA) is constructed as the two isomeric forms of PLA, if minor mechanical loads (or times required under reabsorption). Copolymers may also be used to modulate both the mechanical properties and degradation rates. For example the L-PLA has an elastic modulus of 3 GPa, while combining the DL-PLA with polycaprolactone (PCL) in a ratio 40PCL 60PLA, a moldable material is obtained manually.

A second aspect of the present invention relates to a process for obtaining the material of the invention, comprising the steps:

to. mixing the polymer forming the matrix and the magnesium particles, and

b. processing the product obtained in step (a).

In a preferred embodiment the mixing of step (a) is performed by a technique that may be, but not exclusively, gel casting, solvent casting with particle release, rolling membranes, phase separation, lyophilization, fiber bonding, extrusion, etc. Preferably the mixing of step (a) is performed by a technique selected from gel casting, solvent casting with particle release, rolling membranes, phase separation, lyophilization, extrusion and fiber bonding.

Preferably step (a) comprises adding an organic solvent. More preferably, the solvent employed is chloroform. While any organic solvent may be used to facilitate the dispersion of the magnesium particles in the polymer matrix.

In another preferred embodiment, the method comprises a further step of evaporating the solvent used in step (a) and further processing of the product obtained in this additional step. Preferably, evaporation is performed by orbital shaking. After evaporation can obtain a sheet product that can be prepared by cutting prior to processing and this processing any method of forming polymers known to one skilled in the art.

In another preferred embodiment the processing of step (b) is a thermomechanical processing and compaction molding. In a more preferred embodiment the thermomechanical processing of step (b) is conducted at a temperature range between 100 and 200 ° C. And in a further preferred embodiment the thermomechanical processing of step (b) is conducted at a temperature range of between 130 and 170 ° C.

In a third aspect, the present invention relates to the use of the material of the invention for the manufacture of an implant or biomedical device.

In a fourth aspect, the present invention relates to an implant or biomedical device fabricated from the material of the present invention.

Preferably the implant is to permit bone repair, as osteosynthesis material, more preferably when the magnesium particles have a size below 50 μιτι. According to another preferred embodiment, the implant is for bone tissue regeneration in bone tissue engineering, more preferably the magnesium particles have a size of between 50 and 500 μιτι, preferably that the magnesium particles have a size between 50 and 250 μιτι. Being a dense material, the possibility that the whole pol mer / Mg collapse and change its architecture by effect of mechanical stress in vivo would be lower, thus facilitating to play its role of scaffold both regeneration and vascularization occurs bone tissue surface. The use of a fully biodegradable material provides important advantages over the use of conventional metal alloys such as eliminating the effect dunnage ( "stress shielding") and possibility of post-operative diagnostics using electromagnetic fields. Throughout the description and claims the word "comprises" and its variants are not intended to exclude other technical features, additives, components or steps. To those skilled in the art, other objects, advantages and features of the invention will emerge partly from the description and partly from the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention.

DESCRIPTION OF THE FIGURES

Fig 1. Images corresponding to optical microscopy. A) aspect of the specimens of polymer loaded with Mg; and B) cross section thereof; The C image corresponds to an electronic scanning image showing a detail of interíaz polymer / Mg.

Fig. 2. Variation of load versus depth for the L-PLLA and PLLA L- / Mg.

Fig.3. Voltage-displacement curve for L-PLLA with and without magnesium.

Fig. 4. Viability of human mesenchymal stem cells cultured on L-PLLA samples / Mg. Results are expressed as percentage of cell viability measured after 1 day, at an arbitrary value of 100 was assigned.

EXAMPLES

The invention will be illustrated by tests performed by the inventors, which show the specificity and effectiveness of the material of the invention and its preparation process for the manufacture of a biomaterial for bone regeneration. Synthesis material

It has been prepared composite polylactide in form L- isomeric (L-PLLA) and a nominal volume fraction of 30% Mg. The mixture has occurred prior dissolution of the polymer in chloroform. Once dissolved we proceeded to mixing with the Mg powder with an average size of about 250 microns, and then the solvent evaporation. The images in Figure 1 show the appearance of the material after mixing (A), and the cross-sections examined in the electronic optical microscope (B) and (C).

Once dried, it has proceeded to its cutting and subsequent extrusion molding at a temperature of 160 ° C. The microstructural analysis reveals a homogeneous distribution of Mg powder.

Measurement of material properties

The mechanical properties of the polymeric are generally inadequate for use as biomaterial, either for use as a scaffold, as fillers, etc. Therefore, the combination of mechanical properties polymer / metal is necessary to increase the mechanical performance which alone the polymer is unable to provide, and asemejarlas to bone. The mechanical characterization has been made through techniques instrumented indentation to measure simultaneously the hardness and elastic modulus of the composite. Measurements were made using a ultramicroindentador Nanotest 600 with a Berkovich diamond tip. Its Young's modulus (Ei) and Poisson coefficients (vi) are 0.07 GPa and 1141, respectively. The indentation tests were carried out on different samples of PLLA L- and L-PLLA / Mg using loads of 500 mN, strain rates in the loading and unloading curves 12.5 nms "1 and 15 s with pressure peak in the load curve (500 mN). as can be seen in Figure 2, curves loading and unloading substantial differences. First, the greater penetration in the case of L-PLLA stands manifest their lower hardness. Moreover, corresponding to the discharge curve for the composite slope is greater than in the case of pol mer, indicating that the Young's modulus for the composite material is superior to the polymer.

In Table 1 the values of hardness (H), the Young's modulus reduced (E R), and Young's modulus (E) for the polymer with and without magnesium are collected, v represents the value of Poisson 's ratio used for calculating the module.

Figure imgf000012_0001

Table 1: Hardness and modulus determined from measurements ultramicroindentación.

The elastic modulus of L-PLLA depends on the degree of polymerization having the monomer chains. Note that a volume fraction of 30% of Mg virtually the elastic modulus value triples, approaching the value corresponding to the cortical bone.

Compression tests show a clear increase in the maximum voltage attained during the test. In Figure 3 can be seen as during the compression test polymer without magnesium does not suffer any, thus involving frangible deformation, however the magnesium reinforced polymer plastic deformation manifests similar to that presented metals. None of compression tests performed on samples of L-PLLA / Mg break was reached, showing deformation barrel.

In Table 2 the values ​​of elastic limit (σο) and maximum load (Omax) registered in the compression test are collected.

Figure imgf000013_0001

Table 2: Mean values of elastic limit (σο) and maximum load (a max) recorded in the compression test comparing the values of Young's modulus and corresponding stress at yield, obtained for reinforced polymer magnesium with the corresponding the trabecular bone can be seen as reinforcing magnesium allows obtaining composite polymer / metal similar to those of human bone mechanical properties, thus allowing better transfer of load between the artificial material and bone tissue.

Assays In vitro biocompatibility of magnesium reinforced polymer biocompatibility was tested using human mesenchymal stem cells from bone marrow. Cells were cultured up to 15 days on samples of PLLA L- Mg, preincubated in culture medium for at least 1 h. After these incubation times metabolic activity quantified as parameter associated with cell viability, using the commercial reagent AlamarBIue ™. Figure 4 shows cell viability increased with culture time on the composite polymer / metal.

Claims

What is claimed
Material comprising the mixture of:
to. a polymer matrix comprising a biodegradable polymer, and b. magnesium particles.
Material according to claim 1, wherein the biodegradable polymer is selected from polycaprolactone, polyfumarates, polylactic acid, polyglycolic acid and any combination thereof.
Material according to any one of claims 1 or 2 wherein the biodegradable polymer is a copolymer comprising at least polylactic acid.
Material according to claim 3, wherein the weight ratio of polylactic acid to another component of the copolymer is between 100: 0 to 60:40.
Material according to any one of claims 1 to 4 wherein the volume percentage of particles of magnesium to total material is less than or equal to 70%.
Material according to any one of claims 1 to 5, wherein the magnesium particles have a size of between 50 and 500 μιτι.
Material according to claim 6 wherein the magnesium particles have a size of between 50 and 250 μιτι.
8. Material according to any one of claims 1 to 5, wherein the magnesium particles have a size below 50 μιτι.
9. Procedinniento of obtaining the material as defined in any one of claims 1 to 8, comprising the steps:
to. mixing the polymer forming the matrix and the magnesium particles, and
b. processing the product obtained in step (a).
10. Method according to claim 9, wherein the mixing step (a) is performed by a technique selected from gel casting, solvent casting with particle release, rolling membranes, phase separation, freeze bonding of fibers and extrusion.
eleven . Process according to any one of claims 9 or 10, wherein the process comprises adding an organic solvent in step (a).
12. The method of claim 1 1 wherein the solvent used in step (a) is chloroform.
13. Process according to any one of claims 1 1 to 12, wherein the method comprises a further step of evaporating the solvent added in step (a), and subsequently the product obtained in this additional step is processed.
14. Method according to claim 13, wherein the evaporation of the solvent in the additional step is performed by orbital shaking.
15. Process according to any one of claims 9 to 14, the processing of step (b) is a thermomechanical processing and compaction molding.
16. Method according to claim 15, wherein the thermomechanical processing of step (b) is conducted at a temperature range between 100 ° C and 200 ° C. 17. Method according to claim 16, wherein the thermomechanical processing of step (b) is conducted at a temperature range between 130 ° C and 170 ° C.
18. - Use of material as defined in any one of claims 1 to 8 for producing an implant or biomedical device.
19. - implant or biomedical device fabricated from a material as defined in any one of claims 1 to 8. 20. An implant manufactured from such a material as defined in any one of claims 1 to 5 for use in repairing bone tissue as osteosynthesis material.
twenty-one . - implant according to claim 20 wherein the magnesium particles have a size below 50 μιτι
22. - An implant manufactured from such a material as defined in any one of claims 1 to 5, for use in bone tissue regeneration in bone tissue engineering.
23. - An implant according to claim 22 wherein the magnesium particles have a size of between 50 and 500 μιτι.
24. Implant according to claim 23 wherein the magnesium particles have a size of between 50 and 250 μιτι.
PCT/ES2011/070440 2010-06-21 2011-06-20 Polymer and magnesium particle material for biomedical applications WO2011161292A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015142631A1 (en) * 2014-03-17 2015-09-24 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Magnesium composite-containing scaffolds to enhance tissue regeneration
EP3299037A1 (en) * 2016-09-27 2018-03-28 Regedent AG Barrier system and method of forming a barrier system, a method of regenerating a bone and a reinforcement member

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 (en) * 2014-03-17 2015-09-24 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Magnesium composite-containing scaffolds to enhance tissue regeneration
EP3119447A4 (en) * 2014-03-17 2017-11-08 University of Pittsburgh - Of the Commonwealth System of Higher Education Magnesium composite-containing scaffolds to enhance tissue regeneration
EP3299037A1 (en) * 2016-09-27 2018-03-28 Regedent AG Barrier system and method of forming a barrier system, a method of regenerating a bone and a reinforcement member

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ES2372341B8 (en) 2013-09-27
ES2372341A1 (en) 2012-01-18

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