CN1874798A - Bone cement compositions having fiber-reinforcement and/or increased flowability - Google Patents

Bone cement compositions having fiber-reinforcement and/or increased flowability Download PDF

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CN1874798A
CN1874798A CN 200480032523 CN200480032523A CN1874798A CN 1874798 A CN1874798 A CN 1874798A CN 200480032523 CN200480032523 CN 200480032523 CN 200480032523 A CN200480032523 A CN 200480032523A CN 1874798 A CN1874798 A CN 1874798A
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compositions
fiber
component
calcium salt
copolymer
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CN100438929C (en
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布赖恩·M·阿米蒂奇
艾拉·艾森
肖恩·克尔
马克·富尔默
迈克尔·莱米克
威廉·希弗
帕特里克·利米
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Synthes USA LLC
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Norian Corp
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Abstract

The present invention relates in general to implantable compositions, and method for preparing same, containing a calcium salt-containing component, optionally demineralized bone, a plurality of discrete fibers, optionally a flow additive, and optionally continuous reinforcing fibers or an array of organized fibers in the form of mesh. Advantageously, the discrete fibers have a specific aspect ratio (length/diameter) from about 50:1 to about 1000:1. The addition of a small amount of discrete fibers and/or the continuous reinforcing fibers or fiber mesh can cause drastic increases in certain mechanical properties including flexural strength, flexural strength, flexural toughness, and/or screw pullout strength.

Description

Bone cement compositions with flowability of fiber reinforcement and/or increase
The U.S. Provisional Application No.60/500 that the application requires JIUYUE in 2003 to submit in 5th, the U.S. Provisional Application No.60/574 that on May 25th, 346 and 2004 submitted to, 532 rights and interests, this paper introduce in full above-mentioned application each whole disclosures as a reference.
Invention field
The present invention relates generally to implantable compositions and its method of preparation, compositions comprises the systematism fiber alignment (array oforganized fibers) of the component that contains calcium salt, a large amount of discontinuous fibre (discrete fibers), optional demineralization bone (demineralized bone), optional flowing additive and optional continuous fortifying fibre or web form.Advantageously, discontinuous fibre has from about 50: 1 to about 1000: 1 specific draw ratio (length/diameter).A small amount of discontinuous fibre and/or continuous fortifying fibre or fibroreticulate adding can cause some mechanical performance to comprise the rapid increase of bending strength, crooked toughness and/or bolt pull off strength (screw pulloutstrength).
Background of invention
A specific area of being concerned about about bone cement or calcium phosphate compositions concentrates on and adds viscosity modifier so that the compositions quasi-liquid maybe can flow.Flowability is a Consideration, and especially to be used as auxiliary agent damaged or when increasing other implantable apparatus in the body stable to fill space, treatment bone in the bone when bone cement or calcium phosphate compositions.Do not having under the enough mobile situation, generally be shaped bone cement (bone cement) to be fit to specific bone space or damaged with hands.But, when needs or wish that the packing ratio surgeon can enter hole in the big bone of hole, space or damaged area, space or when damaged, can not use noncurrent bone cement (cement).In addition, noncurrent bone cement can not be produced filling specific hole, space or damaged by original position easily, but must be made in advance.If molded bone cement is not suitable for maybe can not forcing like this by the once suitable relatively external pressure of surgeon doing, then it does not produce and promotes healing and/or the long enough implantable structures of osteanagenesis.
Another specific area of being concerned about about bone cement or calcium phosphate compositions concentrates on fiber normally long fiber or fleece and strengthens its bone cement.Most of prior art of implantable composite (compositematerials) concentrates on the strong resilient substrate that is full of with reinforcing filler granule, palpus or net.The pottery bone cement is often enough strong, but frangible, is not enough to resist heavy damage (for example ftractureing from top to bottom) to play the effect of host material.Polymer normally can be resorbent, finishes this enhancement function usually.With traditional can not resorbent metal or composite compare, can resorbent embedded material such as polyactide and poly-Acetic acid, hydroxy-, bimol. cyclic ester for example have bio-compatible, biodegradable and do not need the advantage of removing after after a while, for example fix or repair in the application at bone.These character are even more important for being designed to be used for bone space for example or damaged healing and/or the implantation substrate of regrowth as temporary placement implant (with to make component sometimes stable).
In addition, for most of composites (composites), reinforcing material is different from host material, wishes scalable beneficial property set from each component, the preferred simultaneously not too desirable feature of each component that reduces.Therefore, the fiber of use (being total to) polymer composition of being essentially pottery usually or having different chemical character.But, seldom have proposition in ceramic substrate, to comprise can to absorb again or the prior art of the implantable material of Biodegradable fibers.Can be people such as Xu at J.Biomed.Mater.Res., 2000, the 52nd rolls up, and finds an example of fibre-reinforced ceramic substrate in the paper (" Xu paper ") of being entitled as in the 107-114 page or leaf " Reinforcement of a Self-Setting Calcium PhosphateCement with Different Fibers ".
The Xu paper discloses with aromatic polyamides (KEVLAR) fiber, carbon, E-type glass and the enhanced water base calcium phosphate bone cement of POLYGLACTIN.It discloses the fibre length of 3mm, 8mm, 25mm, 75mm and 200mm, fiber volume fraction loading in the CPC powder is 1.9%-9.5%, it comprises the mixture of tetracalcium phosphate and anhydrous dicalcium phosphate, and it reacts in aqueous environment and forms hydroxyapatite.POLYGLACTIN fiber in the Xu paper is 90/10 copolymer of Acetic acid, hydroxy-, bimol. cyclic ester/lactide, and has about 200 microns measurement diameter.
Therefore, wish to obtain a kind of fibre-reinforced and/or flowable implantation composite that contains calcium salt, its particular combinations owing to constitutive property demonstrates the improvement of crucial mechanical performance, especially fibre length, fibre diameter or width, fiber draw ratio, flowing additive mix, continuous fiber/bracing frame (stent)/anastomose closes etc., or the combination of a plurality of variablees.
Summary of the invention
One aspect of the present invention relates to a kind of implantable compositions, comprising: (a) contain the component of calcium salt, the component of preferred phosphoric acid calcium comprises amorphous calcium phosphate, crystallized calcium phosphate, CaHPO 4, CaHPO 4H 2O, α-Ca 3(PO 4) 2, α-bar-Ca 3(PO 4) 2, β-Ca 3(PO 4) 2, γ-Ca 3(PO 4) 2, Ca 5(PO 4) 3OH, Ca 10(PO 4) 6(OH) 2, Ca 4O (PO 4) 2, CaP 4O 11, α-Ca 2P 2O 7, β-Ca 2P 2O 7, γ-Ca 2P 2O 7, Ca (H 2PO 4) 2NH 2O, wherein n is 0 to 5 real number, Ca 8H 2(PO 4) 65H 2O, or calcium pyrophosphate; Calcium sulfate comprises Ca (SO 4) 2, α-Ca (SO 4) 21/2H 2O, β-Ca (SO 4) 21/2H 2O; Or their combination in any; Be that about 50: 1 to about 1000: 1 and fibre length are about 15mm or following discontinuous fibre (b) for absorbing homopolymer or copolymer (specifically from about 1wt% to about 5wt%), draw ratio again.In one embodiment, implantable compositions also comprises the demineralization bone.In another embodiment, compositions can comprise continuous reinforcing fiber.Advantageously, also comprise flowing additive, include but not limited to hyaluronic acid, hyaluronate, na phosphates (sodium phosphate salt) or their combination (randomly also comprising continuous reinforcing fiber) according to compositions of the present invention.
In another embodiment, the component that contains calcium salt is substantially by forming as the bone cement of solid constituent with as about phosphate sodium solution of 0.01 to about 0.2mol/kg of liquid component, and wherein bone cement comprises mono calcium phosphate hydrate, type alpha tricalcium phosphate and calcium carbonate.Under a kind of preferable case of this embodiment, the amount of mono calcium phosphate hydrate is about 3.3wt% of solid constituent, and the amount of type alpha tricalcium phosphate is about 84.4wt% of solid constituent, and the amount of calcium carbonate is about 12.3wt% of solid constituent.In another embodiment, the amount of sodium ascorbyl phosphate can be about 0.15mol/kg solution, and liquid component can be about 0.48 to about 0.65, about 0.52 to about 0.60 to the ratio of solid constituent, or about 0.56.In another embodiment, the amount of sodium ascorbyl phosphate can be about 0.075mol/kg solution, and liquid component can be about 0.41 to about 0.55, about 0.47 to about 0.53 to the ratio of solid constituent, or about 0.50.
In another embodiment, the component that contains calcium salt is made up of bone cement and about sodium ascorbyl phosphate of 0.01 to about 0.2mol/kg substantially, and wherein bone cement comprises mono calcium phosphate hydrate, type alpha tricalcium phosphate, calcium carbonate, barium sulfate.Under a kind of preferable case of this embodiment, the amount of mono calcium phosphate hydrate is about 2.9wt% of solid constituent, the amount of type alpha tricalcium phosphate is about 73.4wt% of solid constituent, the amount of calcium carbonate is that the about 10.7wt% of solid constituent and the amount of barium sulfate are about 13wt% of solid constituent.Under another situation of this embodiment, the amount of sodium ascorbyl phosphate can be about 0.075mol/kg solution, and liquid component can be about 0.41 to about 0.55 to the ratio of solid constituent, and is preferred about 0.50, or about 0.42 to about 0.47, preferred about 0.45.
In another embodiment, composition in its entirety demonstrates aspect bending strength than the increase that contains calcium salt component and flowing additive component about 50% to about 900% separately, about 75% to about 800% increase aspect bolt pull off strength (screw pulloutstrength), aspect crooked toughness at least about 35 times increase, or in their increase of some combined aspects.In addition or on the other hand, compositions demonstrates aspect bending strength as a whole than the increase that contains calcium salt component and flowing additive component about 200% to about 700% separately.In addition or on the other hand, compositions is demonstrating aspect the bolt pull off strength as a whole than the increase that contains calcium salt component and flowing additive component about 150% to about 600% separately.In addition or on the other hand, compositions is demonstrating aspect the crooked toughness as a whole than the increase that contains 50 times of calcium salt component and flowing additive components separately at least.
In another embodiment, the present invention relates to a kind of implantable compositions, comprise the solid and the liquid component of following form: (a) contain the component of calcium salt, comprise amorphous calcium phosphate, crystallized calcium phosphate, CaHPO 4, CaHPO 4H 2O, α-Ca 3(PO 4) 2, α-bar-Ca 3(PO 4) 2, β-Ca 3(PO 4) 2, γ-Ca 3(PO 4) 2, Ca 5(PO 4) 3OH, Ca 10(PO 4) 6(OH) 2, Ca 4O (PO 4) 2, CaP 4O 11, α-Ca 2P 2O 7, β-Ca 2P 2O 7, γ-Ca 2P 2O 7, Ca (H 2PO 4) 2NH 2O, wherein n is 0 to 5 real number, Ca 8H 2(PO 4) 65H 2O, or calcium pyrophosphate; Calcium sulfate comprises Ca (SO 4) 2, α-Ca (SO 4) 21/2H 2O or β-Ca (SO 4) 21/2H 2O; Or their combination in any; (b) fibre length is no more than a large amount of discontinuous of about 15mm and can absorbs homopolymer or copolymer fibre again.In one embodiment, implantable compositions also comprises the demineralization bone.Advantageously, liquid component can be about 0.41 to about 0.55 to the ratio of solid constituent in the implantable compositions, demonstrating aspect the bending strength than containing of the increase of calcium salt component with implantable compositions with the flowing additive of choosing wantonly about 50% to about 900%, about 75% to about 800% increase aspect the bolt pull off strength, aspect crooked toughness at least about 35 times increase, or in their increase of some combined aspects.
In another embodiment, the present invention relates to a kind of implantable compositions, comprise the solid and the liquid component of following form: (a) contain the component of calcium salt, comprise amorphous calcium phosphate, crystallized calcium phosphate, CaHPO 4, CaHPO 4H 2O, α-Ca 3(PO 4) 2, α-bar-Ca 3(PO 4) 2, β-Ca 3(PO 4) 2, γ-Ca 3(PO 4) 2, Ca 5(PO 4) 3OH, Ca 10(PO 4) 6(OH) 2, Ca 4O (PO 4) 2, CaP 4O 11, α-Ca 2P 2O 7, β-Ca 2P 2O 7, γ-Ca 2P 2O 7, Ca (H 2PO 4) 2NH 2O, wherein n is 0 to 5 real number, Ca 8H 2(PO 4) 65H 2O, or calcium pyrophosphate; Calcium sulfate comprises Ca (SO 4) 2, α-Ca (SO 4) 21/2H 2O or β-Ca (SO 4) 21/2H 2O; Or their combination in any; Discontinuously can absorb homopolymer or copolymer fibre again (b) in a large number; (c) comprise the bundle that can absorb homopolymer or copolymer fibre again or the continuous fortifying fibre of net.In another embodiment, implantable compositions also comprises the demineralization bone.Advantageously, liquid component can be about 0.41 to about 0.55 to the ratio of solid constituent in the implantable compositions, with implantable compositions in the increase that demonstrates aspect the bending strength than the implantable compositions about 50% to about 900% that does not have a large amount of discontinuous fibres, about 75% to about 800% increase aspect the bolt pull off strength, aspect crooked toughness at least about 35 times increase, or in their increase of some combined aspects.
Another aspect of the present invention relates to a kind of implantable compositions, comprises: (a) contain the component of calcium salt, comprise amorphous calcium phosphate, crystallized calcium phosphate, CaHPO 4, CaHPO 4H 2O, α-Ca 3(PO 4) 2, α-bar-Ca 3(PO 4) 2, β-Ca 3(PO 4) 2, γ-Ca 3(PO 4) 2, Ca 5(PO 4) 3OH, Ca 10(PO 4) 6(OH) 2, Ca 4O (PO 4) 2, CaP 4O 11, α-Ca 2P 2O 7, β-Ca 2P 2O 7, γ-Ca 2P 2O 7, Ca (H 2PO 4) 2NH 2O, wherein n is 0 to 5 real number, Ca 8H 2(PO 4) 65H 2O, or calcium pyrophosphate; Calcium sulfate comprises Ca (SO 4) 2, α-Ca (SO 4) 21/2H 2O or β-Ca (SO 4) 21/2H 2O; Or their combination in any; (b) draw ratio is a large amount of discontinuously can absorb homopolymer or copolymer fibre or their combination again to about 500: 1 in about 50: 1, wherein the end of fiber is modified and is formed pearl, ball, Os Canitis (dogbone) shape or dumbbell shape, and fiber is pulled out resistance (for example knot or crimped fibre) by texturing (textured) with increase.In another embodiment, implantable compositions also comprises the demineralization bone.Advantageously, compositions also comprises continuous reinforcing fiber.In another embodiment, also comprise flowing additive, comprise hyaluronic acid, hyaluronate, na phosphates or their combination according to compositions of the present invention; Randomly comprise continuous reinforcing fiber.
In another embodiment, the present invention relates to a kind of implantable compositions, comprise the solid and the liquid component of following form: the basic component of forming by the bone cement that comprises mono calcium phosphate hydrate, type alpha tricalcium phosphate, calcium carbonate that contains calcium salt; Demineralization bone and about na phosphates of 0.01 to about 0.2mol/kg; With the capacity flowing additive that comprises hyaluronic acid, hyaluronate, na phosphates or their combination, so that implantable compositions utilization be no more than about 40 pounds maximum injection pressure flow through about No. 12 to about No. 18 syringe needle, liquid component is about 0.41 to about 0.55 to the ratio of solid constituent in the wherein implantable compositions.In one embodiment, compositions also comprises continuous reinforcing fiber.Advantageously, also comprising a large amount of fibre lengths according to compositions of the present invention is no more than about 15mm, draw ratio and a large amount of discontinuously can absorbs homopolymer or copolymer fibre or both (and randomly also comprising continuous reinforcing fiber) again to about 1000: 1 in about 50: 1.
But another aspect of the present invention relate to prepare biodegradable to small part, can absorb, perhaps have the implantable method for compositions of these combinations again to small part to the small part biofacies, this method may further comprise the steps: (a) mixed flow additive and the component that contains calcium salt form the flowable compositions that contains calcium salt, and said composition can be utilized and be no more than about 40 pounds maximum injection pressure and be injected into by about No. 12 or bigger syringe needle; (b) compositions of a large amount of discontinuous fibers of mixing and flowable phosphoric acid calcium forms the fibre-reinforced component that contains calcium salt.In one embodiment, the flowable compositions that contains calcium salt also can comprise the demineralization bone.Advantageously, a large amount of discontinuous fibers can be draw ratio be about 50: 1 to about 1000: 1 and fibre length be no more than about 15mm can absorb homopolymer or copolymer again.
But another aspect of the present invention relates to provides biodegradable to small part, can absorb again, perhaps have the implantable method for compositions of these combinations to the small part biofacies to small part, and this method may further comprise the steps: the component or the flowable compositions that contains calcium salt of (a) mixing a large amount of discontinuous fibers and containing calcium salt form the fibre-reinforced component that contains calcium salt; (b) the fibre-reinforced component that contains calcium salt is incorporated into the damaged inside of bone space and/or bone, top and/or near so that to small part coating and/or fill the bone space and/or bone damaged, thereby form implantable fibre-reinforced composite.In one embodiment, the demineralization bone is incorporated in the fibre-reinforced component that contains calcium salt.Advantageously, a large amount of discontinuous fibers can be draw ratio be about 50: 1 to about 1000: 1 and simultaneously fibre length be no more than about 15mm can absorb homopolymer or copolymer again.
Also advantageously, implantable fibre-reinforced composite can demonstrate the increase than the compositions of flowable phosphoric acid calcium about 50% to about 900% aspect bending strength, about 75% to about 800% increase aspect the bolt pull off strength, aspect crooked toughness at least about 35 times increase, or in their increase of some combined aspects; Or both.
In one embodiment, method comprises that also grinding contains the component of calcium salt.In addition or on the other hand, the component that method also comprises the mixed flow additive and contains calcium salt forms the compositions of flowable phosphoric acid calcium, and said composition can be utilized and be no more than about 40 pounds injection pressure and be injected into by about No. 12 or bigger syringe needle.In addition or on the other hand, method also comprise handle bone space, bone damaged, near its interior body region or their some combinations to accept implantable compositions.In addition or on the other hand, method be included in also that bone space, bone are damaged, near the interior body region or their some combinations near it, on every side and/or positioned internal and/or fixing continuous reinforcing fiber.In addition or on the other hand, method also comprise handle to small part coating and/or the bone space that comprises implantable fibre reinforced composites of filling and/or bone is damaged and/or near its interior body region to form bio-compatible and/or semi permeability surface.
But another aspect of the present invention relates to provides biodegradable to small part, can absorb, perhaps have to the small part biofacies the implantable method for compositions of these combinations again to small part, this method may further comprise the steps: (a) mixed flow additive and the component that contains calcium salt form the flowable compositions that contains calcium salt, and said composition can be utilized and be no more than about 40 pounds maximum injection pressure and be injected into by about No. 12 or bigger syringe needle; (b) compositions of a large amount of discontinuous fibers of mixing and flowable phosphoric acid calcium forms the fibre-reinforced component that contains calcium salt; (c) compositions of flowable phosphoric acid calcium or the fibre-reinforced component that contains calcium salt are incorporated into the damaged inside of bone space and/or bone, top and/or near, so that to small part coating and/or fill the bone space and/or bone damaged, thereby form implantable composite.In one embodiment, the flowable compositions that contains calcium salt also can comprise the demineralization bone.Advantageously, a large amount of discontinuous fibers can be draw ratio be about 50: 1 to about 1000: 1 and fibre length be no more than about 15mm can absorb homopolymer or copolymer again.Also advantageously, implantable composite can demonstrate the increase than the compositions of flowable phosphoric acid calcium about 50% to about 900% aspect bending strength, about 75% to about 800% increase aspect the bolt pull off strength, aspect crooked toughness at least about 35 times increase, or in their increase of some combined aspects; Or both.
In one embodiment, method comprises that also grinding contains the component of calcium salt.In addition or on the other hand, method also comprise handle bone space, bone damaged, near its interior body region or their some combinations to accept implantable compositions.In addition or on the other hand, method be included in also that bone space, bone are damaged, near the interior body region or their some combinations near it, on every side and/or positioned internal and/or fixing continuous reinforcing fiber.In addition or on the other hand, method also comprise handle to small part coating and/or the bone space that comprises implantable fibre reinforced composites of filling and/or bone is damaged and/or near its interior body region to form bio-compatible and/or semi permeability surface.In one embodiment, implantable compositions also can comprise the demineralization bone.
DESCRIPTION OF THE PREFERRED
One aspect of the present invention relates to the compositions that is used as fibre-reinforced bone cement in any in numerous application, and it comprises component (being bone cement) and a large amount of discontinuous fiber and optional continuous reinforcing fiber or the fleece that contains calcium salt.In another aspect of the present invention, compositions also comprises the demineralization bone.
But generally mean according to compositions of the present invention and to be used for bio-absorbable and/or can to absorb application, implantable medical treatment device etc. again.Particularly, this application or device can be including, but not limited to (bone) void fillers, the fracture stabilization adminicle, the marrow inner fixing device, pin, anchor, " can inject nail " (metaphysis and/or the backbone area that for example are used for bone), " can inject bolt " etc., replace and/or combine with one or more other conventional equipment, conventional equipment can be including, but not limited to bone fixing head (cranium face for example, maxillofacial, orthopedic, skeleton etc.), bolt, nail, clip, bail, nail, pin or bar, anchor (for example is used for seam, bone etc.), support, bracing frame, net is (for example inflexible, expandable woven fabric, knitted fabric, fabric etc.), sponge, the implant that is used for cell parcel or organizational project, or be used for the implant that medicine or therapeutant send (carrier for example in the mode of discussing below, inside growth inducing catalyst of bone such as the morphogenetic protein of bone, somatomedin, peptide etc., antivirin, antibiotic etc.), monofilament or multifilament structure, sheet, coating, film (porous for example, micropore, can be resorbent etc.), foam (for example opening chamber or closed chamber), the bolt stiffener, skull reconstruct and/or their combination.
Implantable compositions can be molded (for example bonding or joint) or inject.Implantable compositions of the present invention hardens into the solid that can use the orthopedic instrument machining of standard.For example, hardening composition can maybe can use orthopedic grinding tool of standard or cutter to be shaped by boring to accept bolt or pin.Can do not have under the situation of fragment by as the machining and the treatment compositions of holing.
The component that contains calcium salt is generally bone cement, but can advantageously comprise one or more following calcium phosphate compound: CaHPO 4(this chemical compound is commonly called monetite or anhydrous dicalcium phosphate), CaHPO 4H 2O, Ca 3(PO 4) 2(for example α-, α-bar-, β-or γ-crystal form), Ca 5(PO 4) 3OH, Ca 10(PO 4) 6(OH) 2, Ca 4O (PO 4) 2, CaP 4O 11, Ca 2P 2O 7, Ca 8H 2(PO 4) 65H 2O, Ca (H 2PO 4) 2NH 2(for example when n=1, this chemical compound is commonly called mono calcium phosphate hydrate to O; When n=0, this chemical compound is commonly called anhydrous phosphoric acid one calcium), calcium pyrophosphate etc.In some embodiments, in containing the component of calcium salt, Ca can partly be replaced by at least a other element, and element includes but not limited to Sr, Ba, Mg, Fe, Al, Y, Li, Na, K, Ag, Pd, Zn, Pb, Cd, H, Co, Ni, Mn or other rare earth metal.In some of the other embodiments, (PO 4) part can be in addition or all or part ofly on the other hand replaced by at least a other parts, this other parts include but not limited to PO 3, VO 4, BO 3, SO 4, CO 3, SiO 4Deng, or their combination.In the embodiment that also has, (OH) part if present, can partly be replaced by at least a other parts in addition or on the other hand, and this other parts include but not limited to F, Cl, O, CO 3, I, Br etc. or their combination.The component that contains calcium salt can comprise or be the form of homogenous solid solution, subtractional solid solution (substitutional solid solution), interstitial solid solution, general crystallized product, amorphous products etc. or its combination, and can be in addition or comprise nonstoichiometric defect on the other hand.
In another embodiment, the component that contains calcium salt can comprise the component that contains non-calcium phosphate, and it includes but not limited to calcium phosphite; Calcium carbonate; Calcium sulfate is as Ca (SO 4) 2, α-Ca (SO 4) 21/2H 2O or β-Ca (SO 4) 21/2H 2O; Calcium silicates; Calcite; The hydrogenation calcite; Aragonite etc. or their combination.
In a kind of preferred embodiment, the component that contains calcium salt is a bata-tricalcium phosphate base bone cement compositions.In another preferred embodiment, the component that contains calcium salt is the bone cement compositions based on type alpha tricalcium phosphate.In another preferred embodiment, the component that contains calcium salt is the bone cement compositions based on hydroxyapatite.In going back a preferred embodiment, the component that contains calcium salt is based on crystallization CaHPO 4Bone cement compositions.In another embodiment, the component that contains calcium salt is the bone cement compositions based on amorphous calcium phosphate.In another embodiment, the component that contains calcium salt does not comprise tetracalcium phosphate.In yet another embodiment, the component that contains calcium salt does not comprise anhydrous dicalcium phosphate.In going back an embodiment, the component that contains calcium salt does not comprise the combination that tetracalcium phosphate closes anhydrous dicalcium phosphate.
In a more preferred embodiment, the component that contains calcium salt for as any one of following United States Patent (USP) described in bone cement compositions: 4,503,157; 4,880,610; 5,047,031; 5,053,212; 5,129,905; 5,164,187; 5,178,845; 5,279,831; 5,336,264; 5,496,399; 5,569,442; 5,571,493; 5,580,623; 5,683,496; 5,683,667; 5,697,981; 5,709,742; 5,782,971; 5,820,632; 5,846,312; 5,885,540; 5,900,254; 5,952,010; 5,962,028; 5,964,932; 5,968,253; 6,002,065; 6,005,162; 6,053,970; 6,334,891; Or their some combinations, the full content that this paper specially introduces them is as a reference.
In another preferred embodiment, the component that contains calcium salt is for comprising mono calcium phosphate hydrate or Ca (H 2PO 4) 2H 2O, type alpha tricalcium phosphate or Ca 3(PO 4) 2, and/or calcium carbonate or CaCO 3, and the bone cement that solidifies (setting) solution (for example salt and/or buffer components have about concentration of 0.01 to about 0.2mol/kg) that comprises na phosphates and/or buffer agent.
Unless this paper defines in addition, term " na phosphates " is meant Na 3HPO 4, Na 2HPO 4, NaH 2PO 4Or their combination in any.
In one embodiment, the component that contains calcium salt also comprises barium apatite (Ba 5(OH) (PO 4) 3).
As mentioned above, implantable compositions of the present invention can comprise liquid component as described below.Liquid component is to the variable ratioization of the component that contains calcium salt and demineralization bone (when using).In one embodiment, by the weight based on implantable composition weight, liquid is about 0.4 to about 0.75 to component and demineralization bone (when the using) ratio that contains calcium salt; Be 0.45 to about 0.65, preferred about 0.50 in another embodiment; Be about 0.55 to about 0.65 in another embodiment.
The pH that contains the component of calcium salt is generally neutral (or just acid as mild as a dove) or alkalescence.In one embodiment, the pH that contains the component of calcium salt can be about 6.5 to about 10.5.In another embodiment, the pH that contains the component of calcium salt can be about 6.8 to about 10, about 7 to about 9.5, or about 7.2 to about 9.5.
Although always do not need acidic components in bone cement, the component that contains calcium salt according to the present invention can randomly comprise more a spot of inorganic and/or organic acid, preferred organic acid.In this case, can use any organic acid, its object lesson includes but not limited to acetic acid, adipic acid, ascorbic acid, benzoic acid, butanoic acid, citric acid, cinnamic acid, formic acid, fumaric acid, gallic acid, gluconic acid, glutamic acid, 1,3-propanedicarboxylic acid, glyceric acid, hydroxyacetic acid, gluconic acid, hydroxycinnamic acid, isopropylformic acid., M-phthalic acid, lactic acid, malonic acid, maleic acid, malic acid, naphthoic acid, oxalic acid, phthalic acid, picolinic acid, propanoic acid, salicylic acid, decanedioic acid, succinic acid, tartaric acid, p-phthalic acid etc. or their combination.Preferred organic acid can include but not limited to 'alpha '-hydroxy acids such as hydroxyacetic acid, lactic acid etc., acetic acid, ascorbic acid and their combination.In one embodiment, acidic components comprise citric acid.In another embodiment, acidic components do not comprise citric acid.The example of the mineral acid of can be in addition or using except organic acid includes but not limited to nitric acid, nitrous acid, hydrochloric acid, sulphuric acid, independent ionized sulphuric acid such as NaHSO 4, KHSO 4, Ca (HSO 4) 2Deng, phosphoric acid, independent or dual ionized phosphoric acid such as NaH 2PO 4, KH 2PO 4, LiH 2PO 4, Li 2HPO 4, Na 2HPO 4, K 2HPO 4, MgHPO 4Deng the ammonification form (for example ammonium nitrate, ammonium chloride, sulphuric acid diammonium, ammonium hydrogen sulfate, triammonium phosphate, diammonium phosphate, Ammonium biphosphate etc.) of, phosphonic acids, above-mentioned acid etc. or their combination.When existing, the acidic components in the bone cement are usually less than about 5wt% of component that contains calcium salt or bone cement, preferably less than about 4wt%, for example from about 0.2wt% to about 1.5wt%, from about 2wt% to about 4wt%, from the about 3.5wt% of about 2.5wt%, or from about 0.1wt% to about 1wt%.
In one embodiment, the component concentrations that contains calcium salt in the compositions is greater than about 30%, for example greater than about 40%, and greater than about 41%, greater than about 45%, or greater than about 50%.In another embodiment, the component concentrations that contains calcium salt in the compositions is less than about 80%, for example less than about 70%, or less than about 60%.In another embodiment, the component concentrations that contains calcium salt in the compositions can be about 40% to about 60%, perhaps from about 47% to about 53%, and from about 42% to about 47%, from about 52% to about 57%, or from about 45% to about 50%.In an embodiment also, the component concentrations that contains calcium salt in the compositions can be about 48% to about 58%, from about 42% to about 50%, or preferred about 50%.
As mentioned above, in some embodiments, implantable compositions can comprise the demineralization bone.Term used herein " demineralization bone " is meant the bone less than the about 8wt% of its original mineral content.
The demineralization bone can be from Graffon Osteotech, Eatontown, and New Jersey or Musculoskeletal Transplant Foundation, Edison, New Jersey obtains; Maybe can be by using diluted mineral acid as for example hydrochloric acid, hydrobromic acid, hydroiodic acid or sulphuric acid; Chelating agen; Or complex forms acid as citric acid, lactic acid or hypophosphorous acid processing bone and prepares.United States Patent (USP) 4,172,128 referring to people such as Thiele; With people's such as Lane 4,990,333.The demineralization bone can derive from any animal.In one embodiment, the demineralization bone derives from cattle or people's bone.In another embodiment, the demineralization bone derives from people's bone.
In one embodiment, the demineralization bone derives from patient's oneself bone (self bone).
In another embodiment, the demineralization bone derives from the different animals (comprising corpse) (allograft bone) of same species.
In one embodiment, implantable compositions comprises demineralization bone and the mixture that contains the component of calcium salt.When implantable compositions comprised the mixture of demineralization bone and the component that contains calcium salt, the quantity of demineralization bone can change.In one embodiment, in demineralization bone and the total amount that contains the component of calcium salt, the amount of demineralization bone is that about 0.05wt% is to about 30wt%; In another embodiment, in demineralization bone and the total amount that contains the component of calcium salt, the amount of demineralization bone is that about 1wt% is to about 20wt%; In another embodiment, in demineralization bone and the total amount that contains the component of calcium salt, the amount of demineralization bone is that about 1wt% is to about 10wt%.
Can use the demineralization bone of any appropriate particle size.For example, the particle diameter of demineralization bone is generally about 50 to about 850 microns.In another embodiment, the particle diameter of demineralization bone is generally about 210 to about 600 microns.Can by known method as grind and sieve obtain having required particle diameter the demineralization bone (referring to Perry ' s Chemical Engineering Handbook, 21 chapters, 12-19 page or leaf (Don W.Green, ed.1984)).
In another embodiment, implantable compositions also can comprise radiopaque reagent so that radiopaque bone cement to be provided.The non-limitative example of radiopaque reagent comprises barium sulfate, barium apatite and iodine.In one embodiment, implantable compositions comprises barium sulfate.
Fiber according to the present invention can be in vivo can be resorbent or can not be resorbent (but still generally bio-compatible) at least.
In another embodiment, the draw ratio of fiber can be from about 50: 1 to about 950: 1, from about 50: 1 to about 750: 1, from about 50: 1 to about 500: 1, from about 50: 1 to about 250: 1; Or from about 50: 1 to about 100: 1.
In another embodiment, the length of fiber can be no more than about 8.5mm.In another embodiment, the length of fiber can be at least about 2.5mm.In another embodiment, the length of fiber can be from about 2.5mm to about 8.5mm.In another embodiment, the length of fiber can be from about 0.5mm to about 1.5mm.In another embodiment, the length of fiber is about 1.0mm or still less.
In another embodiment, the diameter of fiber or width are no more than about 50 microns for for example being no more than about 500 microns, or are no more than about 25 microns.In going back an embodiment, the diameter of fiber or width can be about 10 microns to about 25 microns or about 15 microns to about 20 microns.
In another embodiment, can resorbent fiber can comprise and be selected from following monomeric homopolymer or copolymer: the L-lactide; L-lactic acid; The D-lactide; D-lactic acid; D, the L-lactide; Acetic acid, hydroxy-, bimol. cyclic ester; α-hydroxybutyric acid; α-hydroxyl valeric acid; Alpha-hydroxy acetic acid; The Alpha-hydroxy caproic acid; The Alpha-hydroxy enanthic acid; The Alpha-hydroxy capric acid; The Alpha-hydroxy myristic acid; Alpha-hydroxy is sad; The Alpha-hydroxy stearic acid; Butyric ester; Hydroxyl valerate; β-propiolactide; β-propiolactic acid; γ-Ji Neizhi; β-caprolactone; Gamma-butyrolacton; Pivalolactone; Tetramethyl glycolide; The tetramethyl hydroxyacetic acid; Dimethyl hydroxyl acetic acid; Propylene carbonate; Dioxanone (dioxanone); Form those monomers of liquid crystal (being total to) polymer; Form cellulosic those monomers; Form those monomers of cellulose acetate; Form those monomers of carboxymethyl cellulose; Form those monomers of hydroxypropyl emthylcellulose; Polyurethane precursor, comprise and be selected from polycaprolactone, poly-(oxirane), poly-(ethylene glycol), poly-(adipic acid second diester), the macromolecular diol class of poly-(epoxy butane) and their mixture, the vulcabond of selecting oneself, isoflurane chalcone diisocyanate (isophoronediisocyanate), cyclohexane diisocyanate, the isocyanate functional compound of hydrogenation methylene two penylene vulcabond and their mixture, with be selected from ethylenediamine, 1, the 4-butanediol, 1, the 2-butanediol, 2-amino-1-butanols, thio-diethylene glycol (thiodiethylene diol), 2-sulfydryl ether, 3-hexin-2, the 5-glycol, the cahin extension agent of citric acid and their mixture; Collagen, alginate (for example sodium alginate or calcium), polysaccharide such as chitin and chitosan, poly-(fumaric acid propylene diester); With their any mixture.
In yet another embodiment, can absorb fiber again and comprise poly-(L-lactide) (being total to) polymer, poly-(D, L-lactide) (being total to) polymer, poly-Acetic acid, hydroxy-, bimol. cyclic ester (being total to) polymer, polycaprolactone (being total to) polymer, poly-(tetramethyl hydroxyacetic acid) (being total to) polymer, poly-dioxanone (being total to) polymer, poly butyric ester (being total to) polymer, poly-hydroxyl valerate (being total to) polymer, poly-(L-lactide-co-glycolide) copolymer, poly-(Acetic acid, hydroxy-, bimol. cyclic ester-altogether-propylene carbonate) copolymer, poly-(Acetic acid, hydroxy-, bimol. cyclic ester-altogether-caprolactone) copolymer, poly-(Acetic acid, hydroxy-, bimol. cyclic ester-altogether-dioxanone-altogether-propylene carbonate) copolymer, poly-(the tetramethyl hydroxyacetic acid-altogether-dioxanone-altogether-propylene carbonate) copolymer, poly-(Acetic acid, hydroxy-, bimol. cyclic ester-altogether-caprolactone-altogether-the L-lactide-altogether-propylene carbonate) copolymer, poly-(butyric ester-altogether-hydroxyl valerate) copolymer, liquid crystal (being total to) polymer, their compositions or their copolymer.Preferably, can absorb fiber again and comprise poly-(L-lactide-co-glycolide) copolymer.
In one embodiment, poly-(L-lactide-co-glycolide) copolymer comprises at least about 15% Acetic acid, hydroxy-, bimol. cyclic ester repetitive with at least about 15% L-lactic acid repetitive.In another embodiment, poly-(L-lactide-co-glycolide) copolymer comprises about 82% Acetic acid, hydroxy-, bimol. cyclic ester repetitive and about 18% L-lactic acid repetitive.In another embodiment, poly-(L-lactide-co-glycolide) copolymer comprises about 18% Acetic acid, hydroxy-, bimol. cyclic ester repetitive and about 82% L-lactic acid repetitive.
In a kind of preferred embodiment, can absorb again that fiber can comprise or by poly--L-lactide (for example PLLA) homopolymer, poly-Acetic acid, hydroxy-, bimol. cyclic ester (PGA) homopolymer or they each other copolymer or form with one or more other the biodegradable or monomeric copolymer of bio-compatible.For example, poly-(L-lactide-co-glycolide) copolymer comprises in copolymer: L-lactide dimer or L-lactic acid monomer repetitive; With Acetic acid, hydroxy-, bimol. cyclic ester dimer or hydroxyacetic acid repetitive.Though repetitive is for the polymer analog that is formed by monomer or dimer, (being total to) polymer title depends on the polymerization that is used to form these copolymers usually.But, quoting of (being total to) polymer to for example lactide, Acetic acid, hydroxy-, bimol. cyclic ester or lactide-co-glycolide used herein should be understood to mean (being total to) polymer with basic repeat unit structure, and be irrelevant with the character of the chemical compound (monomer or dimer) that forms them.Poly-(L-lactide-co-glycolide) copolymer is for preferably can absorb fiber again according to of the present invention.
When poly-(L-lactide-co-glycolide) copolymer fibre is used for according to compositions of the present invention, preferred copolymer comprises at least 11% every kind L-lactide and Acetic acid, hydroxy-, bimol. cyclic ester component repetitive, preferably at least about 13%, more preferably at least about 15%, for example at least about 17%.Therefore, preferred poly-(L-lactide-co-glycolide) copolymer fibre according to the present invention can comprise 11% to 89% L-lactide repetitive and 89% to 11% glycolide units, preferred about 13% to about 87% L-lactide repetitive and about 87% to about 13% glycolide units, more preferably from about 15% to about 85% L-lactide repetitive and about 85% to about 15% glycolide units, for example about 17% to about 83% L-lactide repetitive and about 83% to about 17% glycolide units.In one embodiment, above-mentioned percentage ratio is represented the percentage by weight of component repetitive.In another embodiment, above-mentioned percentage ratio is represented the molar percentage of component repetitive.In a kind of preferred embodiment, poly-(L-lactide-co-glycolide) copolymer fibre comprises the lactide component of about 82wt% and the Acetic acid, hydroxy-, bimol. cyclic ester component of about 18wt%.
In another preferred embodiment, when poly-(L-lactide-co-glycolide) copolymer fibre is used for according to compositions of the present invention, copolymer can comprise about 2% to about 40% L-lactide component repetitive or about 2% to about 40% Acetic acid, hydroxy-, bimol. cyclic ester component repetitive, for example about 5% to about 30% L-lactide component repetitive or about 5% to about 30% Acetic acid, hydroxy-, bimol. cyclic ester component repetitive.In another preferred embodiment, when poly-(L-lactide-co-glycolide) copolymer fibre was used for according to compositions of the present invention, copolymer can comprise in about 40% to about 60% every kind of L-lactide and the Acetic acid, hydroxy-, bimol. cyclic ester component repetitive.In one embodiment, above-mentioned percentage ratio is represented the percentage by weight of component repetitive.In another embodiment, above-mentioned percentage ratio is represented the molar percentage of component repetitive.
In one embodiment, implantable compositions according to the present invention comprises the distribution that has identical basic chemical composition or have the copolymer fibre compositions of various chemical composition, this can advantageously allow biological property relevant with bone space/damaged healing/regeneration and/or the finishing of replying, and for example angiogenesis, bone are inwardly grown, mechanicalness loss of energy etc. or their combination in the bone reconstruct, collagen formation, vivo degradation, body.
In another embodiment, the third repetitive can be present in according in poly-(L-lactide-co-glycolide) copolymer of the present invention, for example D-lactide dimer, D, L-lactide (or Study of Meso-Lactide) dimer, 6-caprolactone (or pentylidene carboxylate) monomeric open loop structure or D-lactic acid monomer depend on the polymerization that is used to form these copolymers equally.
Perhaps, also have can the absorbing again of other type, biodegradable and/or bio-compatible monomer or dimer randomly to be present in according in the copolymer of the present invention as repetitive.This other suitable monomer or dimer comprise such as but not limited to 'alpha '-hydroxy acids,, Alpha-hydroxy stearic acid sad etc. as α-hydroxybutyric acid, α-hydroxyl valeric acid, Alpha-hydroxy acetic acid, Alpha-hydroxy caproic acid, Alpha-hydroxy enanthic acid, Alpha-hydroxy capric acid, Alpha-hydroxy myristic acid, Alpha-hydroxy, their addition product (for example butyric ester, hydroxyl valerate etc.), their dehydration product dimer, or their derivant, or their mixture; Lactide or lactic acid addition product or derivant, as β-propiolactide or β-propiolactic acid, or their mixture; Other ring-type, straight or branched ester, as γ-Ji Neizhi, β-caprolactone, gamma-butyrolacton, pivalolactone etc., Acetic acid, hydroxy-, bimol. cyclic ester or hydroxyacetic acid addition product or derivant, as tetramethyl glycolide, tetramethyl hydroxyacetic acid, dimethyl hydroxyl acetic acid etc., or their mixture; Carbonic ester such as propylene carbonate; The cellulose repetitive includes but not limited to for example cellulose, cellulose acetate, carboxymethyl cellulose, hydroxypropyl emthylcellulose etc.; Polyurethane precursor, comprise and be selected from polycaprolactone, poly-(oxirane), poly-(ethylene glycol), poly-(adipic acid second diester), the macromolecular diol class of poly-(epoxy butane) and their mixture, be selected from the own diester of two Carbimide .s, isoflurane chalcone diisocyanate, cyclohexane diisocyanate, the isocyanate functional compound of hydrogenation methylene two inferior phenylene diisocyanates and their mixture, with be selected from ethylenediamine, 1, the 4-butanediol, 1, the 2-butanediol, 2-amino-1-butanols, thio-diethylene glycol, 2-sulfydryl ether, 3-hexin-2, the 5-glycol, the cahin extension agent of citric acid and their mixture; Collagen, alginate (for example sodium alginate or calcium), chitin, chitosan, poly-(fumaric acid propylidene alcohol ester); Or their combination or mixture.
When existing, in one embodiment, total amount based on monomeric unit, the 3rd and/or other type of optional can absorb again and/or bio-compatible monomer or the dimer amount in poly-(L-lactide-co-glycolide) copolymer fibre according to the present invention can be less than about 5mol%, for example less than about 2mol%, perhaps from about 0.1mol% to about 1.5mol% or from about 1mol% to 5mol%.In another embodiment, based on the total amount of monomeric unit, the 3rd and/or other type of optional can absorb again and/or bio-compatible monomer or the dimer amount in poly-(L-lactide-co-glycolide) copolymer fibre according to the present invention can be extremely about 20mol% of about 5mol%.
In addition or on the other hand, can comprise according to fiber of the present invention or by above-mentioned monomer/dimer any one or multiple can absorb homopolymer again or copolymer forms.For example, poly-(L-lactide-co-glycolide) copolymer according to the present invention preferably shows as far as possible near the statistical random distribution of monomer or dimer repetitive, considers may influencing of reactivity ratio difference between various monomers or the dimer.Although wish that generally two or more can absorb again and/or the monomeric copolymer of bio-compatible is random, in arranging, can exist according to the repetitive of copolymer fibre of the present invention come from this reactivity ratio difference some alternately, block, steric regularity or other non-random (non random) feature.In another embodiment, copolymer can comprise block copolymer, segmented copolymer, alternate copolymer etc., or their combination.
In another embodiment, fibre fractionation can be can not absorb again and/or but still what biodegradablely (for example still do not having under the serious Cytotoxic situation; Promptly at least fully biocompatible).Suitable can not absorb again and/or still the example of how many biodegradable fibrous materials can include but not limited to polyester fiber, as polycaprolactone, poly-(p-phthalic acid ethylidene alcohol ester), poly-(p-phthalic acid butylidene alcohol ester) etc., and their combination or copolymer; Bioactive glass fiber; Aramid fibre, aramid fibre for example, those as can on market, having bought with trade name KEVLAR; The aliphatic amide fiber, as nylon 6,6, nylon 6,9, nylon 6,10, nylon 6,12, nylon 6 etc., and their combination or copolymer; Polyurethane fiber, polyurethane-urea for example, as polyether urethane urea, polyester urethanes urea, Merlon urethanes urea etc., polyether urethane, polyester urethanes, Merlon urethanes, polyester urethane esteramides etc., and their combination or copolymer; Polyethers fiber, for example poly-(alkylene oxide) or poly-(aklylene glycol)) as poly-(oxirane), poly-(ethylene glycol) etc., and their combination or copolymer; Poly-(ether ether ketone) etc., and their combination or copolymer; Polycarbonate; Polyimide fiber; Poly-(aziridine) fiber; Poly-dioxanone fiber; Liquid crystal (being total to) polymer, those as can be on market having bought with trade name VECTRAN from Celanese; Or the like; And copolymer fibre with repetitive of above-listed any aforementioned polymer or copolymer fibre.Other alternative type that can not absorb fiber again can include but not limited to carbon fiber; Glass fiber; Metallic fiber such as stainless steel fibre, titanium fiber, metallic alloy fiber etc. and their combination in any; Or the like; With their combination.
Can form fiber of the present invention can absorb again (being total to) polymer can be advantageously by the various forms of sour dimers of polymerization (for example L-lactide, Acetic acid, hydroxy-, bimol. cyclic ester or other optional dehydration product acid dimer such as D-lactide, D, L-lactide etc. or their combination) and any required cyclic ester monomer (if present) preparation.Perhaps, can absorb (being total to) polymer again can be by the above-mentioned bio-compatible acid of polymerization (for example L-lactic acid, hydroxyacetic acid or other optional acid monomers such as D-lactic acid etc., or their combination)) only monomeric form and required cyclic ester monomer (if present) preparation.In another optional embodiment, can absorb (being total to) polymer again can be by the dimerization form of more monomeric mixture (for example L-lactic acid, hydroxyacetic acid or other optional acid monomers such as D-lactic acid etc. or their combination) and above-mentioned absorbent components again (for example L-lactide, Acetic acid, hydroxy-, bimol. cyclic ester or the sour dimer of other optional dehydration product such as D-lactide, D, L-lactide etc., or their combination) and required ring-type and/or two polyester (if present) preparation.
For example, any polymerization that can form polyactide or poly-glycolide copolymer all can be used to poly-(L-lactide-co-glycolide) copolymer of preparation, and especially any copolymer that can form makes biodegradation or resorbable and mechanical performance (for example before implantation and in the process) be enough to satisfy the method for the requirement of the application of using copolymer.For example, a kind of this polymerization can be at United States Patent (USP) 6,096, finds in 855, and this paper introduces its whole disclosures as a reference.United States Patent (USP) 4,157,437 and international publication number WO97/36553 in poly-(D, L-lactide-co-glycolide) and the copolymerization process of other random copolymer that is used to produce again absorbing material disclosed, this paper also introduces its whole disclosures as a reference.
Advantageously, can form according to (being total to) polymer of fiber of the present invention no matter their polymerization how, all must have enough molecular weight that can carry out (for example mechanically) in required application.Usually, can all the monomer and/or the two polyarylene block copolymer substituent groups of (promptly preferably at least about 98mol%, more preferably at least about 99mol%, most preferably at least about 99.5mol%) obtain enough high molecular basically by polymerization.Term used herein " molecular weight " should be understood to mean extent of polymerization, or monomer or unitary number average of dimer or weight-average value in the copolymer chain.Molecular weight used herein can estimate by a large amount of known methods, as by gel infiltration or exclusion chromatography (GPC or SEC), and by characteristic or intrinsic viscosity analysis (I.V.), or by making related science and technology of equal value to estimating molecular weight of copolymer.
When measuring by GPC or SEC with respect to polystyrene standard, in one embodiment, (processed or create before the fiber) can show at least about 75 according to (being total to) of the present invention polymer, the number-average molecular weight of 000 gram/mole, for example from about 150,000 gram/moles to about 1,000,000 gram/mole or from about 250,000 gram/moles to about 900,000 gram/moles.In another embodiment, this measurement also produces the weight average molecular weight at least about 125,000 gram/moles, for example at least about 250,000 gram/moles or from about 400,000 gram/moles to about 2,500,000 gram/mole.Perhaps, in some embodiments, number-average molecular weight can be in about 16,000 gram/moles and about 75, between the 000 gram/mole or about 18, between 000 gram/mole and about 50, the 000 gram/moles, number-average molecular weight can be about 50,000 gram mole and about 150, between the 000 gram/mole or between about 60,000 gram/moles and about 120,000 gram/moles.In another embodiment, this measurement can also demonstrate about 1.3 to about 3.5 polydispersity (being the ratio of weight average molecular weight to number-average molecular weight), and for example from about 1.6 to about 2.8 or from about 1.85 to about 2.5.But, the required application of use fiber should determine the tolerance interval of molecular weight values usually, for example, be used for medicine send, nod the copolymer of surface transplant or enhanced biological degradability or extremely important other application of resorbable can preferably have above-mentioned scope lower area or even lower number average and/or weight average molecular weight, and can preferably have middle part or upper area or even higher number average and/or weight average molecular weight in above-mentioned scope at pin, bar, anchor, nail or other machinery is strengthened and/or load-bearing is used in using copolymer.
When in chloroform during with the measurement of concetration I.V. of about 0.1%w/v, in one embodiment, can show intrinsic viscosity according to (being total to) of the present invention polymer (processed or manufacture fiber before) at least about 1.0dL/g, for example from about 2.5dL/g to about 8dL/g, from about 3dL/g to about 7dL/g, or from about 4dL/g to about 6.5dL/g.In another embodiment, the intrinsic viscosity of poly-(L-lactide-co-glycolide) copolymer of the present invention can be greater than about 4.5dL/g.But, the required application of use fiber should determine the tolerance interval of inherent viscosity usually, for example, be used for medicine and send, nod the copolymer of surface transplant or enhanced biological degradability or extremely important other application of resorbable and can preferably have characteristic or the intrinsic viscosity lower, and can preferably have in above-mentioned scope or even above characteristic or intrinsic viscosity being used for pin, bar, anchor, nail or other fiber that machinery is strengthened and/or the load-bearing composite applications is used than above-mentioned scope.
Can have low moisture (or water) content (promptly with the component that contains calcium salt is mixed before) according to fiber of the present invention, for example be no more than about 1.5wt% or be no more than about 1wt%.In one embodiment, moisture or water content can be no more than about 500ppm, for example are no more than about 250ppm, or are no more than about 150ppm.In another embodiment, can be no more than about 200ppm according to the moisture or the water content of fiber of the present invention, or be no more than about 100ppm.
In some cases, can remove step through super-dry and/or VOC (VOC) according to fiber of the present invention, so that remove water, organic solvent, unreacted monomer/dimer or other low-molecular-weight and/or volatile impurity or the chemical compound that in (being total to) polymer fiber, exists.This drying/remove step can include but not limited to introduce noble gas (for example dried nitrogen of doing, argon etc. or comprise the mixture of this class gas), using vacuum (for example makes pressure be no more than about 10Torr, for example be no more than about 5Torr, or be no more than about 1Torr), the temperature of using raising is (for example at least about 50 ℃, for example at least about 65 ℃, as from about 70 ℃ to about 120 ℃, and preferably, if copolymer is partially crystallizable at least, then the temperature of Ti Gaoing is not more than under its fusing point about 5 ℃, for example is not more than under its fusing point about 10 ℃), or their combination in any.This drying/remove step be enough to usually to make moisture can accept or preferred boundary in a period of time.When carrying out, step can advantageously comprise uses temperature that improves and the combination of using vacuum, and carries out about at least 4 hours, for example at least about 12 hours, perhaps is no more than about 24 hours, or from about 16 hours to about 20 hours.
Can show the degree of crystallinity of wide region according to (being total to) of the present invention polymer fiber, preferred value depends on the required application of using them.In one embodiment, fiber of the present invention is a hypocrystalline, and can show about 15% to about 30% degree of crystallinity, and for example about 20% to about 30%, according to appointment 20% to about 26%.In another embodiment, fiber of the present invention can show the degree of crystallinity less than about 15%.In another embodiment, fiber of the present invention can show about 15% to about 50% degree of crystallinity.In yet another embodiment, fiber of the present invention can show less than about 10%, less than degree of crystallinity about 5%, less than about 1%, maybe can show and not have degree of crystallinity substantially (promptly less than about 0.5%, preferably less than about 0.1%, or at least by one or more experimental techniques can not detection by quantitative to).Can when using this term in this article, reflect and the noncrystalline of fiber or volume, crystal region cross section that amorphous domain is compared or the relative scale of passing the linear path of sample by the practical measuring technique of knowing in a large number " degree of crystallinity ".The suitable experimental technique of measuring degree of crystallinity includes but not limited to differential scanning calorimetry (DSC), x-ray scattering or diffraction method (for example XRD, WAXD, WAXS etc.) etc.
Also can show the perfect crystalline degree (or crystallization degree of imperfection) of wide region according to (being total to) of the present invention polymer fiber, preferred value depends on the required application of using them equally.Can be by for example DSC or other practical measuring technique perfect crystalline degree or degree of imperfection of knowing, and be mentioned in this article aspect the melting heat (Δ Hf), its representative (for example is joule every gram at the energy of fusing or the required per unit material of removing crystallization copolymer crystal, J/g, or burnt every milligram in the least, mJ/mg) crystalline relative integrity degree of the copolymer of aspect or degree of imperfection.In one embodiment, fiber of the present invention is a hypocrystalline, and can show the melting heat less than about 50J/g.For example less than about 30J/g or less than about 25J/g.In another embodiment, fiber of the present invention can show the melting heat of about 50J/g to about 70J/g.In another embodiment, fiber of the present invention can show extremely about 15J/g, the about 0.1J/g melting heat to about 10J/g, about 15J/g to about 25J/g of about 0.5J/g, maybe can show and not have melting heat substantially (promptly less than about 0.1J/g, or at least by one or more experimental techniques can not detection by quantitative to).
Fusing point and glass transition temperature according to (being total to) of the present invention polymer fiber also can vary widely, and preferred value depends on the required application of using them.Can be by for example DSC or other practical measuring technique fusing point and glass transition temperature of knowing, and depend on the speed that temperature raises or reduces usually.Utilize speed to test for about 5 ℃/min carries out standard DSC to the variations in temperature of about 20 ℃/min, especially about 10 ℃/min.When existing, in one embodiment, the fusing point of the fiber of the present invention by standard DSC thermometrically can be between about 90 ℃ and about 165 ℃, and for example about 110 ℃ to about 155 ℃, or about 130 ℃ to about 150 ℃.In another embodiment, the glass transition temperature of the fiber of the present invention by standard DSC thermometrically can be between about 30 ℃ and about 100 ℃, for example between about 40 ℃ and about 60 ℃.
Although preferred value can vary widely, but especially depend on their required application of use and they are formed the method for goods or device for described application, in one embodiment, can show mechanical performance according to (being total to) of the present invention polymer fiber by following variation:
The mechanical behavior value scope
Bending modulus about 3 is to about 14GPa
Bending strength about 100 is to about 200MPa
Stretch modulus (secant under 0.2% strain) about 5 is to about 9GPa
Tensile strength about 50 is to about 175MPa
Shear strength about 90 is to about 175MPa
Since according to fiber of the present invention and/or compositions implant and body in use in using, therefore may need the body internal reaction that this fibrid and/or compositions sterilization are for example caused because of infection, foreign body repulsion etc. with minimizing.Can absorb fiber degradable in the presence of water again owing to of the present invention, it is especially suitable therefore being different from autoclaved sterilizing methods.This class sterilizing methods can include but not limited to be exposed to oxirane, be exposed to γ-radiation, is exposed to electron beam source, is exposed to cold (or low temperature) at least plasma source, or their combination.The method for disinfection that depends on reconditioning and persistent period may be introduced branch, grafting or crosslinked feasible method to copolymer fibre of the present invention for a kind of.Depend on that the sterilizing methods of reconditioning and persistent period can be in addition or change surface chemical property and/or electronic structure on the other hand, this can improve or reduce the compatibility (for example by fiber moistening, reaction bonding etc.) between fiber and the substrate.
The list of these sterilization methods or multiple dose carry out on copolymer according to the present invention, goods or device with the quantity that is enough to prevent, suppress or reduce the body internal reaction.In a kind of preferred embodiment, sterilization comprises that single dose is exposed to γ-radiation or oxirane.In another preferred embodiment, sterilization comprises that single dose exposes according to poly-(L-lactide-co-glycolide) copolymer of the present invention or installs γ-radiation to 25kGy.
(being total to) polymer fiber and/or the compositions that comprise them often show about 1 month to about 2.5 years for example about 2 months to the interior or external absorption again of about 2 years complete body." fully again absorb " used herein is meant that when visual examination implant site does not have the sign of (be total to) polymeric material or do not surpass about 1000 gram/moles by number-average molecular weight or be no more than the situation of oligomeric materials of degraded generation of (being total to) polymer of about 500 gram/moles when analyzing the sample of degradation polymer implant site.In another embodiment, after implanting or after being exposed to the phosphate buffered saline (PBS) that pH is about 7.4 (± 0.2) (PBS) solution under the temperature of about 37 ℃ (± 1 ℃), generally should keep their engineering properties of at least a portion according to fiber of the present invention and/or compositions.
The size of fibrous material for example draw ratio also is an important consideration.Term used herein " draw ratio ", at least about fiber according to the present invention, should be understood that it is the length over diameter that preferentially refers to relative cylindrical fiber (circular cross section relatively), perhaps the length of prism-shaped, irregular or other non-cylindrical fiber (mainly having non-circular cross sections) is to length and width degree.
Draw ratio according to fiber of the present invention can advantageously be about 50: 1 to about 1000: 1, about 50: 1 to about 950: 1, about 50: 1 to about 750: 1, about 50: 1 to about 600: 1, about 50: 1 to about 350: 1, about 50: 1 to about 200: 1, about 50: 1 to about 100: 1, or about 50: 1 to about 75: 1.In a kind of more preferably embodiment, draw ratio is about 62: 1.
In one embodiment, implantable compositions according to the present invention comprises the distribution of fiber draw ratio, perhaps fully in described scope or part in described scope and part described scope outside (above and/or following), this can advantageously allow to adjust, and for example angiogenesis, bone are inwardly grown, bone reconstruct, collagen formation, vivo degradation, the internal loss of mechanical performance body etc. or its make up relevant biological property and/or reply with bone space/damaged healing/regenerate.
The fiber that is used for compositions of the present invention has about 0.1mm usually to about 15mm, preferred about 0.1mm length of about 8.5mm extremely.The applicant finds that the fiber of shorter length is anti-and is separated (for example fiber sedimentation in water-bearing media), and is optimized for and can injects compositions.When being used for injecting compositions, fiber preferably has the length of about 0.1mm to about 15mm, and more preferably from about 0.25mm is to about 1.25mm, most preferably from about 1mm.
The diameter of fiber or width are generally at least about 5 microns to about 500 microns, and about 10 microns to about 500 microns, about 10 microns to about 100 microns, about 10 microns to about 25 microns, or about 15 microns to about 25 microns.In a kind of preferred embodiment, the width of fiber is about 16 microns.Bound by theory not, think have than the fiber of this wide diameter or width may aspect the component that contains calcium salt is mixed and/or fiber containing and producing difficulty aspect the dispersing uniformity in the component substrate of calcium salt.But when using than long fibre (same, as to have described the influence of fiber draw ratio to composite character above), the fiber that has than major diameter or width also may be the difficulty that effectively maybe can overcome in the mixing.
In one embodiment, can will have and make fibre bundle than the fiber of minor diameter or width and form the fiber that has than major diameter or width by for example assembling, weave, tie up etc. (, but not have the excessive intention that limits) hereinafter for convenience with tying up.For example, can add than large-diameter fiber or fibrage bundle and increase porous (cellular) inwardly growth and accelerated degradation time.When using, fibre bundle can be about 100 microns to about 500 microns.
In one embodiment, implantable compositions according to the present invention comprises the distribution of fibre length and/or diameter/width, and this can advantageously allow to adjust with bone space/damaged healing/regenerate biological property that for example angiogenesis, bone are inwardly grown, bone reconstruct, collagen formation, vivo degradation, the internal loss of mechanical performance body etc. or its combination are relevant and/or reply.
(for example can absorb fiber again according to (being total to) of the present invention polymer fiber, as poly-(L-lactide-co-glycolide)) be generally straight chain only slight branch, grafting or crosslinked (for example, at least about 98%, preferably be positioned on the straight chain polymer skeleton at least about 99% monomer or dimer, rather than in side chain or graft side chain or in crosslinked connection chain).
The geometry of fiber ends also has material impact to performance of composites.Usually, owing to often make fiber, therefore must cut off the fiber (for example according to described herein draw ratio restriction be trimmed to its diameter) of continuous fiber to obtain Len req by continuation method.In this case, fiber ends generally is cut, fractures etc., and is considered to flat substantially and/or undistinguishable.But the fiber that has feature on endways can have favorable influence to the fibre property in the compositions according to the present invention.For example, can the one or more ends by for example adding thermal fiber make terminal fusing or burning and therefore (separately) form the half-spherical tip pearl and on fiber ends or group of fibers, form pearl or ball.For example, fibre diameter is about 15 to about 20 microns and arrange (hexagonal array that a fiber is arranged promptly) very closely near about seven cylindric (L-lactide-co-glycolide) copolymers that gather of fibril clump (multifibrillar) cylinder set with 2-3-2, be heated to temperature at least about 55 ℃, for example at least about 75 ℃, or at least about 100 ℃, ball or pearl on end separately, thereby forming effective diameters in conjunction with seven fibrous structures is about 45 to about 60 microns fibril clump fiber, keeps similar length simultaneously.Can also realize other version of fiber ends, for example form Os Canitis shape short fiber, as the paper " Bone-ShapedShort Fiber Composites-An Overview " people such as Zhu, Mat.Sci.﹠amp; Eng., 2002, A326, described in the 208-227, this paper specially introduces its whole disclosures as a reference.
Be different from flat substantially and/or during undistinguishable (this is common to most of short fibers) shape, above-mentioned draw ratio restriction can be relaxed, and especially is in the lower end of ratio when fiber ends is changed or has.Therefore, be changed or had in fiber ends and be different from flat substantially and/or during undistinguishable shape, the draw ratio scope can keep identical or advantageously become about 50: 1 to about 500: 1, for example about 75: 1 to about 500: 1,100: 1 to about 250: 1 according to appointment.Be changed or had in fiber ends and be different under the situation flat substantially and/or undistinguishable shape, can use fibre diameter or width to calculate draw ratio away from end.
Equally, when fiber is pulled out resistance (for example knot or crimped fibre) by texturing with increase, can use the diameter or the width of the fiber of elongate form to calculate draw ratio.
No matter whether their end is changed, all can randomly handle surface according to fiber of the present invention with the chemical constitution that changes them, their physical arrangement, their frame for movement, their electronic structure, their magnetic structure, their adhesive property, or their some combinations.The example of this processing can include but not limited to place on the fiber surface regular or irregular rib line (ribs) (for example based on reinforcing bar), kink or crimped fibre, chemically adhere to calcium ion or component to fiber surface form rich calcium surface, chemically handle fiber (for example with strong acid or highly basic), handle fiber (for example corona discharge or plasma discharge) with physical method, with the electric charge on the electronics method change fiber surface etc., or their combination.
When being injected into, compositions of the present invention advantageously comprises flowing additive.Bound by theory not, the applicant thinks that flowing additive has improved the viscosity that can inject compositions, stop or postponed to be separated, and strengthened to utilize and be no more than about 40 pounds maximum injection pressure and make and to inject compositions by for example about No. 12 flowabilities to about No. 18 syringe needle.In preferred embodiments, the viscosity that can inject compositions is extremely about 500cPs of about 1cPs, and preferably about 1cPs is to about 300cPs.
When using, by the solid constituent weight of compositions, the amount of flowing additive is generally about 0.05% to about 5%, about 0.1% to about 2.5%, or about 0.25% to about 1%.In one embodiment, when using, by the solid constituent of compositions and the weight of liquid component, the amount of flowing additive is about 0.22%.
The non-limitative example of useful flowing additive comprises hyaluronic acid, hyaluronate, na phosphates or their combination.In a kind of preferred embodiment, flowing additive comprises hyaluronate sodium and preferably is made up of hyaluronate sodium basically.
Weight with solid constituent is benchmark, can advantageously be extremely about 20wt% of about 0.1wt% according to the fibre weight that comprises in the compositions of the present invention, preferred about 1% to about 10%, for example about 1% to about 8%, about 1% to about 5%, about 1% to about 3%, or about 1% to about 2.5%.Although the fiber carrying capacity less than about 1% may have certain influence to the character of compositions,, improve to obtain to surpass the best complex material character that contains the calcium salt component separately usually for optimum efficiency need have about 1wt% or higher fiber carrying capacity.In preferred embodiments, be benchmark with the weight of solid constituent, compositions comprises the fiber of about 3wt%.In another embodiment, be benchmark with the weight of solid constituent and liquid component, compositions comprises the fiber of about 3wt%.
Compare with the independent same mechanical performance that contains the calcium salt component, can advantageously cause the increase of some mechanical performance of compositions (bending strength, bolt pull off strength, crooked toughness, fracture toughness, flexible life, strain are to fracture, fracture strength, ultimate tensile strength, tensile strength, tensile modulus, tension toughness etc. and their combination) according to fiber in the compositions of the present invention and the combination that contains the calcium salt component.In one embodiment, the existence of fiber causes the bending strength at least about 10% to increase in the composite, preferably at least about 20%, and more preferably at least about 50%, for example at least about 100%, at least about 200%, or at least about 350%.In this embodiment, the existence of fiber causes increasing less than about 1000% bending strength usually in the composite, is generally less than approximately 900%, for example is no more than approximately 800%, or is no more than about 700%.Can advantageously carry out the test of bending strength according to ASTM C-1161 standard method of test.In another embodiment, the existence of fiber causes the crooked toughness (" crooked toughness " used herein is defined in bending load/stress in the test that bending strength test for example carries out according to ASTM C-1161 standard method of test to the area under displacement/strain curve) at least about 25 times to increase in the composite, preferably at least about 35 times, for example at least about 50 times, at least about 60 times, at least about 75 times, or at least about 100 times.In yet another embodiment, the existence of fiber causes the bolt pull off strength at least about 50% to increase in the composite, preferably at least about 75%, and for example at least about 100%, at least about 125%, at least about 150%, or at least about 200%.In this embodiment, the existence of fiber causes increasing less than about 900% bolt pull off strength usually in the composite, is generally less than approximately 800%, for example is no more than approximately 700%, or is no more than about 600%.Advantageously carry out bolt and pull out test by measuring from the brill system screwed hole at 8 * 50mm rectangular surfaces middle part of 6 * 8 * 50mm moulded products to pull out the 25mm#3 screw rod of tension or maximum load that the 3mm long bolt needs perpendicular to this surface about 30 to the angles of about 45 degree, use has the load cell of the heap(ed) capacity of 100-1000N under about 0.5in/min speed.
In some embodiments, the favourable increase of some mechanical performance that preferably introduce to produce because of fiber is without to performance crucial other mechanical performance (for example compressive strength, bending strength, fracture bending merit (flexural work of fracture) etc.) the big reduction of compositions according to the present invention in its (body in) is used.In one embodiment, the existence of fiber causes reducing less than about 20% compressive strength usually in the composite, sometimes less than about 10%, for example is no more than about 8% or be no more than about 5%.Is that the cylindric sample of about 12mm can advantageously carry out compression test by INSTRON under the crosshead speed of about 0.1 inch per minute clock test cross-sectional diameter for about 6mm and length.
In one embodiment, there is not the compressive strength of the enhanced fiber reinforcement compositions of continuous fiber to be at least about 15MPa; In another embodiment, at least about 35MPa.In one embodiment, not having the compressive strength of the enhanced fiber reinforcement compositions of continuous fiber is about 15 to about 80MPa; In another embodiment, about 20 to about 60MPa; In another embodiment, about 35-40MPa.
In one embodiment, there is not the bending strength of the enhanced fiber reinforcement compositions of continuous fiber to be at least about 6MPa; In another embodiment, at least about 8MPa.In one embodiment, not having the bending strength of the enhanced fiber reinforcement compositions of continuous fiber is about 6 to about 12MPa; In another embodiment, about 7 to about 10MPa; In another embodiment, about 8MPa.
In one embodiment, there is not the crooked merit of fracture of the enhanced fiber reinforcement compositions of continuous fiber to be at least about 400J/m 2In another embodiment, at least about 900J/m 2In one embodiment, not having the crooked merit of fracture of the enhanced fiber reinforcement compositions of continuous fiber is about 400 to about 2400J/m 2In another embodiment, about 750 to about 1500J/m 2In another embodiment, about 900 to about 1200J/m 2The crooked merit that ruptures is the tolerance of toughness, and it can be measured by any required method well known by persons skilled in the art.
Except most of mechanical performance, compare with the compositions of non-fibre-reinforced phosphoric acid calcium, use is the brittleness that they reduce according to another advantage of fiber reinforcement compositions of the present invention, especially in the cranium face is used, viscoelasticity stability and machinery/structural intergrity with their increases, mainly aspect the graft failure (catastrophic implant failure) of opposing or elimination sudden change, but also in the field as opposing or eliminate cracks can spread, opposing or elimination crackle form, opposing or eliminate space formation etc. or their combined aspects, all can be owing to for example cerebral dura mater moves especially little move or pollex takes place.When the component that contains calcium salt generally provides little mechanical strength/stability, these move and/or little move in process of setting especially remarkable.Because these enhanced physical performances, implant of the present invention can be holed or machining as required.
To be shaped or to be injected into that unified shape is used to implant or the ability of other application in order to have, also can randomly comprise flow behavior or the formability/morphotropism of flowing additive with enhancing composition according to compositions of the present invention with hands.This flowing additive be shaped by conventional memory fluid or the liquid solidification mode (for example by flow through the hole as injection orifice or by free-flow as perfusion, with hands shaping etc. or their combination) be essential being configured as in the present composition of application of shape.This flowing additive by conventional solid mechanical molding mode (for example by fill or the solid forming technique as with hands shaping, machine compression, machine shape etc. or their combination) be configured as in the present composition of application of shape and choose wantonly.In one embodiment, flowing additive can randomly be present in and has the component that contains calcium salt and do not have in the compositions of fibre fractionation.
Can include but not limited to micromolecule organic compound, polymer/oligomer material and their solution according to flowing additive of the present invention, in the time of in joining compositions (or only joining in the component that contains calcium salt), (syringe needle of plurality font size has less diameter to allow to flow through for example about 8-number or bigger syringe needle fully to change its viscosity, thereby need the low threshold viscosity that they can flow through), preferred about 12-number or bigger, for example about 14-number or bigger, about 15-number or bigger, or about 18-number or bigger.According to syringe needle, think that abundant energy of flow generation is no more than 50 pounds injection force, preferably is no more than 40 pounds.In one embodiment, flowing additive regulate to add the viscosity of its compositions (or only being the component that contains calcium salt), makes that compositions can the number of flowing through size be about 8 to about 18 syringe needle, perhaps about 8 to about 15, about 12 to about 18, or about 12 to about 15.
When existing, the amount that joins the flowing additive of compositions (or only joining the component that contains calcium salt) can be (perhaps in the flowing additive and the weight that contains the component of calcium salt and randomly also have fibre fractionation to make up) about 0.01% to about 1.5% of composition weight, about 0.1% to about 1%, or about 0.05% to about 1%.In another embodiment, the amount of flowing additive can be composition weight (perhaps in flowing additive and the weight that contains the component of calcium salt and randomly also have fibre fractionation to make up) about 1.5% to about 5%.In a kind of preferred embodiment, when using, the amount of flowing additive is (perhaps in the flowing additive and the weight that contains the component of calcium salt and randomly also have fibre fractionation to make up) about 0.5% of composition weight.
The suitable example of flowing additive can be including but not limited to hyaluronic acid; Hyaluronate such as sodium, potassium, lithium etc., or their combination; Alginate such as sodium, potassium, lithium etc.; Starch compound, it can native form (for example extract from one or more plants, or purification) by any method, denatured form or exist with many chemical modification derivative forms (for example alkoxy derivative, esterification derivative, ionization modified starch, Oxytarch, graft starch, crosslinked starch etc. or their mixture); Saturated, monounsaturated and/or polyunsaturated oils, as from plant and/or animal sources, extract or isolating those, plant and/or animal sources for example include but not limited to sunflower, Flos Carthami, Semen arachidis hypogaeae, Semen Ricini, Semen Sesami, Cortex cocois radicis, Semen sojae atricolor, corn, Semen Allii Tuberosi, Fructus Canarii albi, vegetable, tripalmitin, stearic, olein etc. or their derivant or compositions, and be natural extract, synthetic, or the form of modification or processing in some aspects, for example partially or completely hydrogenation, partially or completely dehydrogenation, partially or completely saponification, partially or completely acidify, partially halogenated etc.; Wax, include but not limited to Hydrocarbon wax (polyolefin-wax for example, as Tissuemat E, polypropylene wax etc. or their copolymer), low ester type waxes, monoesters wax, low ether wax, monoether wax etc., or their combination, and be natural extract, the synthetic or form of modification or processing in some aspects, for example partially or completely hydrogenation, partially or completely dehydrogenation, partially or completely saponification, partially or completely acidify, partially halogenated etc.; Cellulosic cpd, for example include but not limited to: natural or synthetic cellulose, cotton, regenerated cellulose (artificial silk for example, cellophane etc.), cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate-propionate, cellulose acetate butyrate, cellulose propanoic acid butyrate, celluloid, methylcellulose, ethyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, cellulosate and their combination or copolymer, and be natural extract, synthetic, or the form of modification or processing in some aspects, for example partially or completely esterification, partially or completely nitrated, partially or completely regeneration, etherificate partially or completely, partially or completely acidify, partially or completely acid neutralization etc., or their combination; Surface activity biomolecule or (being total to) polymer; Poly-(ethylene glycol) and/or poly-(oxirane) oligomer, homopolymer or copolymer; From the body material such as the autologous bone marrow aspirate, from body blood material etc. or their combination; Blood material of the bone marrow aspirate of xenobiotic such as allogenic bone marrow aspirate, allosome, allogenic blood material, allosome etc. or their combination; Deng, or their combination.In a kind of preferred embodiment, flowing additive comprises hyaluronic acid and/or hyaluronate.In another preferred embodiment, flowing additive comprises hyaluronate sodium.In yet another embodiment, flowing additive can comprise chrondroitin, glycosamine, hyaluronic acid, their salt or their mixture.
When flowing additive comprised hyaluronic acid or hyaluronate, hyaluronic acid or hyaluronate can obtain from any suitable source, for example include but not limited to bacterial fermentation; Extract in driven logistics body (for example joint fluid etc.), tissue, bone etc. or their combination and/or separate; External chemically synthetic wholly or in part; Deng; Or their combination.Never the character of hyaluronic acid that obtains in the homology or hyaluronate (for example molecular weight) can be different widely.In one embodiment, the number-average molecular weight (for example recording with respect to suitable standard such as poly(ethylene oxide) standard by GPC or SEC) of hyaluronic acid or hyaluronate can advantageously be at least about 1000 gram/moles, preferably at least about 5000g/mol.In another embodiment, the number-average molecular weight of hyaluronic acid or hyaluronate can be about 10000 gram/moles to about 5000000 gram/moles, for example about 50000 gram/moles are to about 3000000 gram/moles, about 10000 gram/moles are to about 1000000 gram/moles, or about 150000 gram/moles are to about 2000000 gram/moles.In another embodiment, this measurement also can obtain the weight average molecular weight at least about 1500 gram/moles, preferably at least about 8000 gram/moles.In yet another embodiment, this measurement also can obtain the weight average molecular weight of about 15000 gram/moles to about 25000000 gram/moles, for example about 75000 gram/moles are to about 10000000 gram/moles, about 15000 gram/moles are to about 5000000 gram/moles, or about 250000 gram/moles are to about 4000000 gram/moles.In an embodiment also, this measurement can show about 1.3 to about 10 polydispersity (being the ratio of weight average molecular weight to number-average molecular weight), and for example about 1.6 to about 8, about 1.5 to about 4, about 2 to about 7, about 4 to about 9, or about 1.8 to about 2.5.
When using oligomer or (being total to) polymer flow additive, can use separately or use with aqueous solution, aqueous solution can advantageously comprise dissolving salt, pH buffer agent etc. or their combination.Dissolving salt can include but not limited to: three replacement salt of the list replacement salt of single replacement salt of monacid list replacement salt, binary acid, the dibasic salt of binary acid, ternary acid, the dibasic salt of ternary acid, ternary acid, single replacement salt of tetra-atomic acid, the dibasic salt of tetra-atomic acid, three replacement salt of tetra-atomic acid, four replacement salt of tetra-atomic acid etc. or their combination.The salt substituent group can be metallic element ion, organic ion such as ammonium ion, alkyl phosphate ion, dialkyl ammonium ion, trialkyl ammonium ion, tetraalkyl ammonium ion, organic ammonium ion, metal ligand complex etc. or their combination.The example of suitable dissolving salt includes but not limited to: the carbonate of Qu Daiing partially or completely, the phosphate of Qu Daiing partially or completely, the silicate of Qu Daiing partially or completely, hydroxide salt, phosphite, partially or completely replace phosphonate, nitrate, the sulfate of Qu Daiing partially or completely, the sulphite of Qu Daiing partially or completely, halide salts such as chloride salt, the salt (for example this paper lists) of the organic or inorganic acid of Qu Daiing partially or completely, ammonium salt, alkali metal salt such as sodium or potassium salt, alkali salt such as calcium salt, transition metal salt etc. or their combination.The pH buffer agent can include but not limited to any or multiple dissolving salt that this paper lists, and above-mentioned acid is any or multiple, for example corresponding to the acid of salt.
In a kind of preferred embodiment, flowing additive comprises and contains the preferred Na of na phosphates 2HPO 4Aqueous solution, for example substantially by distilled water and Na 2HPO 4Solution composition.In another preferred embodiment, flowing additive comprises and contains Na 2HPO 4And NaH 2PO 4Aqueous solution, for example substantially by distilled water, Na 2HPO 4And NaH 2PO 4Solution composition.In another embodiment, flowing additive comprises the aqueous solution that contains sodium chloride, and preferably is made up of saline substantially.When aqueous solution contains salt or buffer components, the concentration of this component in solution can be generally about 0.005m to about 0.5m, preferred about 0.01m is to about 0.25m, for example about 0.01m is to about 0.1m, about 0.05m is to about 0.2m, about 0.075m is to about 0.25m, or about 0.15m is to about 0.25m, and " m " represents the molar concentration of representing with mole every kilogram solution.
As mentioned above, implant compositions can also comprise medicine or therapeutant (for example carrier, the inside growth inducing catalyst of bone such as bone morphogenetic protein matter, somatomedin, peptide etc., antiviral agents, antibiotic etc.), monofilament or multifilament structure, sheet, coating, film (for example porous, micropore, can be resorbent etc.), foam (for example opening chamber or closed chamber), bolt reinforce, skull reconstruct and/or their combination.
According to comprising therapeutant in the compositions of the present invention.For example, these therapeutants can be present in the component that contains calcium salt, are present in the fibre fractionation or on it, or among both.Therapeutant can be added in separately the component, floods in fiber, is adhered to fiber surface, and/or is included in one or more components as controlled release preparation.Therapeutant can be including but not limited to antibiotic, chemotherapeutics, somatomedin (especially bone inductive factor) as bone morphogenetic protein matter, endothelial cell growth factor (ECGF), insulin-like growth factor etc. or their combination.
When therapeutant is antimicrobial, in implant compositions, can exist a kind of and be no more than three kinds usually, be no more than two kinds of antimicrobials usually.The non-limitative example of useful antimicrobial comprises: anti-amebic, for example arsthinol, bialamicol, carbarsone, cephaeline, chlorbetamide, chloroquine, clefamide, chlortetracycline, dehydroemetine, the dibromo propamidine, diloxanide, difetarsone, emetine, Amebacilin, glaucarubin, glycobiarsol, 8-hydroxyl-7-iodo-5-quinoline sulfonic acid, nioform, diiodohydroxyquinoline (Iodoquinol), paromomycin, phanquinone, polybenzarsol, propamidine, quinfamide, scenidazole, sulfarside, teclozan, tetracycline, thiocarbamizine, thiocarbarsone, tinidazole; Antibiotics, for example aminoglycoside is (as amikacin, apramycin, arbekacin, bambermycin, butyrosin, dibekacin, dihydrostreptomycin, astromicin, gentamycin, isepamicin, Kaniamycin, micronomicin, neomycin, the 9-undecylenic acid neomycin, netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, trospectomycin), Amphenicols (azidamfenicol, chloromycetin, florfenicol, thiamphenicol), ansamycins (rifamide, rifampicin, rifamycin, rifapentine, rifaximin), beta-lactam (carbacephems, Loracarbef, carbapenems (biapenem, Primaxin, Meropenem, panipenem), cephalosporin (cefaclor, cefadroxil, cefamandole, ceftriaxone, cefazedone, cefazolin sodium, cefcapene povoxil, cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefinenoxine, Cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, Cefpodoxime Proxetil, cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, rocephin, cefuroxime, cefuzonam, celospor, cefalexin, cefaloglycin, Cefalorne, cephalosporin, cefalotin, cefapirin sodium, cefradine, pivcefalexin), cephamycin-type (Keiperazon, cefmetazole, cefminox, cefotetan, cefalotin), monobactams (aztreonam, carumonam, tigemonam), oxacephens (flomoxef, latamoxef), penicillin (Amdinocillin, the Amdinocillin ester, the amoxicillin, the ampicillin, the apalcillin, the aspoxicillin, azidocillin, the azlocillin, bacampicillin, penicillin, penicillin sodium, carbenicillin, carindacillin, clometacillin, cloxacillin, the ciclacillin, dicloxacillin, epicillin, fenbenicillin, the flucloxacillin, the hetacillin, Takacillin, the metampicillin, methicillin sodium, the mezlocillin, sodium nafcillin, oxazacillin, penamecillin, penethamate hydriodide, benethamine penicillin G, benzathine penicillin G, the .alpha.-aminodiphenylmethane. benzylpenicillin, calcium benzylpenicillinate, penicillin G hydrabamine, scotcil, aquacillin, penicillin N, penicillin, penicillin V, penicillin V benzathine, penicillin V hydrabamine, penimepicycline, penicillin-152, piperacillin, pivampicillin, propicillin, quinacillin, the sulbenicillin, sultamicillin, talampicillin, temocillin, ticarcillin), ritipenem), but woods amine (clindamycin, lincomycin), Macrolide (azithromycin, carbomycin, clarithromycin, dirithromycin, erythromycin, erythromycin acistrate, erythromycin estolate, gluconic acid erythromycin, erythromycin lactobionate, erythromycin propionate lauryl sulfate, erythromycin octadecanoate, josamycin, kitasamycin, midecamycin, mikamycin, oleandomycin, primycin, rokitamycin, rosamicin, Roxithromycin, spiramycin, triacetyloleandomycin), polypeptide (amfomycin, bacitracin, capreomycin, colistin, endomycin, enviomycin, fusafungine, Gramicidin S, Gramicidin, mikamycin, polymyxin, pristinamycin, ristocetin, teicoplanin, thiostrepton, tuberactin, tyrocidine, Tyrothricin, vancomycin, viomycin, virginiamycin, the zinc bacitracin), Tetracyclines (apicycline, chlortetracycline, clomocycline, demeclocycline, doxycycline, guamecycline, lymecycline, meclocycline, metacycline, minocycline, oxytetracycline, penimepicycline, pipacycline, Rolitetracycline, Sancycline, tetracycline), cycloserine, mupirocin, tuberin (Tuberin); Synthetic antibacterial agents; for example 2,4-diaminopyrimidine (brodimoprim; textroxoprim; trimethoprim); itrofurans (furaltadone; furazolium chloride; nifuradene; nifuratel; nifurfoline; nifurpirinol; nifurprazine; nifurtoinol; nitrofirantoin); quinolones and analog (cinoxacin; ciprofloxacin; clinafloxacin; difloxacin; enoxacin; fleroxacin; flumequine; grepafloxacin; lomefloxacin; Miloxacin; nadifloxacin; nadilixic acid; norflaxacin; ofloxacin; oxolinic acid; Pazufloxacin; pefloxacin; pipemidic acid; piromidic acid; rosoxacin; rufloxacin; Sparfloxacin; temafloxacin; tosufloxacin; trovafloxacin); sulfonamide (acetyl group sulfamethoxy-pyrazine; benzylsulfamide; sodium benzenesulfochloramine; chloramine-T; dichloramine-T; N 2-formyl sulfasomidine, N 4-β-glucosylsulfanilamide; mafenide; 4 '-(methyl sulfonamides) sulfanilamide anilid; noprylsulfamide; phthalylsulfacetamide; phthalylsulfathiazole; salazosulfadimidine; succinylsulfathiazole; sulfabenzamide; sulfacetamide; sulfachlorpyridazine; sulfachrysoidine; sulfacitine; sulfadiazine; sulfadicramide; sulfadimethoxine; sulfadoxine; sulfaethylthiadiazole; sulfaguanidine; Sulfadimethyloxazolylguanidine; sulfalene; sulfaloxic acid; sulfamerazine; sulfameter; sulfadimidine; ayerlucil; deposulf; Sulfamethoxazole; sulfamethoxypyridazine; sulfametrole; sulfamidochrysoidine sulfamoxole; sulfanilamide; the 4-4-sulfanilamidosalicylic acid; N 4-N4-sulfanilyl sulfanilamide, sulfacarbamide, N-sulfanilyl-3, the 4-proglumide, sulfanitran, Sulfaperin, sulfaphenazole, sulfaproxyline, 2-sulfanilamidopyrazine., sulfadiazine, sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea, sulfatolamide, domian, sulfafurazole), sulfone class (acedapsone, acediasulfone, acetosulfone sodium, dapsone, diathymosulfone, glucosulfone sodium, solapsone, succisulfone, sulfanilic acid, to sulfanilylbenzylamide, sulfoxone sodium, thiazosulfone), clofoctol, hexedine, hexamethylenamine, the anhydromethylene-citric acid hexamethylenamine, methenamine hippu, mandelamine, hexal, nitroxoline, taurolidine, xibornol (xibomol); The antimicrobial drug that suppresses leprosy bacillus, as acedapsone, acetosulfone sodium, clofazimine, dapsone, diathymosulfone, glucosulfone sodium, hydnocarpic acid, solapsone, succisulfone, sulfoxone sodium, antifungal, as the allylamine butenafine, naftifine, terbinafine, imidazoles (bifonazole for example, butoconazole, cholordantoin, chlormidazole, croconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole, omoconazole, Oxiconazole Nitrate, Sertaconazole, sulconazole, tioconazole), thiocarbamate (tolcilate, tolindate, tolnaftate), triazole type (fluconazol, itraconazole, Saperconazole, terconazole (triaconazole)), acrisorcin, amorolfine, xenysalate, bromosalicylchloranilide, buclosamide, calcium propionate, adermykon, ciclopirox, cloxiquine, Coparaffinate (coparaffinate), two hydrochloric acid dimazole, exalamide, flucytosine, haloxon, hexetidine, loflucarban, nifuratel, potassium iodide, propanoic acid, PTO, salicylaniline, sodium propionate, sulbentine, tenonitrozole, triacetin, ujothion, 9-undecylenic acid, zinc propionate; Or the like.
Other useful in the present invention antibacterial comprises beta-lactamase inhibitor (for example clavulanic acid, sulbactam, Tazobactam Sodium); Chloromycetin (for example azidamfenicol, chloromycetin, thiaphenicol); Fusidinic acid; Synthetic medicament such as trimethoprim randomly combine with sulfonamide) and nitro glyoxaline (for example metronidazole, tinidazole, nimorazole); Antimycobacterial medicament (for example capreomycin, clofazimine, dapsone, ethambutol, isoniazid, pyrazinamide, rifabutin, rifampicin, streptomycin, thioamides); Antiviral agents (for example acryclovir, amantadine, zidovudine, ganciclovir, idoxuridine, ribavirin, trifluridine, vidarabine); Interferon (for example interferon-ALPHA, interferon beta); And disinfectant (for example chlorhexidine, gentian violet, octenidine, povidone iodine, quaternary ammonium compound, silver sulfadiazine, triclosan).
Antibacterial can comprise treating and results from the medicine of disease of Gram-positive and/or gram negative bacteria.Preferred antibacterial includes but not limited to amikacin, gentamycin, tobramycin, vancomycin and their salt.
Therapeutant also can comprise therapeutant biology, as protein.Can add bone photo and close protein, strengthen absorption again, angiogenesis, cell input (cell entry) and propagation, mineralising, bone formation, osteoclast and/or osteoblastic growth etc. to change the physical property of compositions.The special protein of being concerned about is various collagens, especially the I type.Other protein comprises osteonectin (osteonectin), bone sialoprotein (Bsp), α-2HS-glycoprotein, bone Gla-albumen (Bgp), substrate Gla-albumen, the bone phosphoglucoprotein, the bone phosphoprotein, the bone protein polysaccharide, protolipids, bone morphogenetic protein (BMP-1 for example ,-2A ,-2B,-3 ,-3b ,-4,-5,6 ,-7,-8 ,-8b ,-9,-10 ,-11 ,-12,-13 ,-14 ,-15), cartilage-inducing factor, platelet derived growth factor (PDGF-,-2), endothelial cell growth factor (ECGF) ((ECGF-1 ,-2a ,-2b), SGF (SKF=IGF-2), insulin-like growth factor (IGF-1, IGF-2), fibroblast growth factor (ODGF-1 ,-2 ,-3,-4 ,-5 ,-6,-7,-8 ,-9 ,-10,-11,-12 ,-13 ,-14,-15,-16 ,-17 ,-18,-19,-20 ,-21 ,-22,-23), colony stimulating factor, transforming growth factor ((for example TGF-β), VEGF (VEGF), growth/differentiation factor (GDF-1,-3 ,-5 ,-6,-7,-8 ,-9 ,-9B,-10,-11 ,-15 ,-16), BMP (OP-1=BMP-7, OP-2=BMP-8, OP-3=BMP-8b), brown growth hormone (brown growthhormone), parathyroid hormone (PTH), insulin, calcitonin etc.Protein can also comprise and the cartilage proteins associated, as chondrocalcin (chondrocalcining) albumen; With the dentin proteins associated, as phosphoprotein, glycoprotein and Gla protein; Or with enamel proteins associated matter, as amelognin and glaze albumen (enamelin).The structural protein of being concerned about comprises fibrin, Fibrinogen, keratin, tubulin, elastin laminin etc.Can in blood plasma or serum, use haemproteins, for example serum albumin separately or jointly.
Therapeutant also can comprise non-albumen somatomedin such as prostaglandin and statins (for example simvastatin, lovastatin).
In one embodiment, therapeutant is a kind of somatomedin, as but be not limited to bone morphogenetic protein, endothelial cell growth factor (ECGF), insulin-like growth factor etc. or their combination.
Can use the therapeutant of any appropriate amount.For example, the amount of the antimicrobial that exists in the compositions can be is enough to be provided at the amount that reduces the product of growth of microorganism speed in the product area at least compared with the control.In many embodiments, antibiotic amount will be enough to provide diameter be at least about 10mm, usually at least about the inhibition zone of 15mm, it presses people's such as Poser United States Patent (USP) 5,968,253 is described by the antibiotic activity analysis to measure, and this paper specially introduces its full text content as a reference.The amount of the therapeutant that uses in the compositions can be with factor as repairing variations such as site, patient age and health status, and can be determined by those skilled in the art.
The implant compositions that comprises therapeutant also is used for this material of local delivery to the physiological portion of for example being concerned about.For example, the implant compositions that comprises antimicrobial be used for need be in time expand (extended period of time) discharge the method for antimicrobial in the local environment, wherein the time period be generally at least about 5 days, usually at least about 10 days with more generally at least about 20 days, wherein implant compositions can discharge antimicrobial in their local environment 40 days long or longer, depend on the concrete compositions of preparing product.Therefore, the compositions that comprises antimicrobial promptly as the antimicrobial bank, wherein needs the time of local delivery antimicrobial prolongation as the antimicrobial delivery vector that prolongs.Theme composition is specifically as the osseous tissue especially local antimicrobials delivery vector of cancellous bone tissue.
For the mechanical performance that obtains further to improve (rigidity/modulus for example, toughness, compressive strength, shear strength, tensile strength, bending strength, strain is to fracture, fracture strength, ultimate tensile strength, tensile strength, tensile modulus, tension toughness etc. or their combination) be used for implanting or other especially high load capacity or heavily stressed application, can randomly comprise the systematism fiber alignment according to compositions of the present invention, for example constitute net, continuous fortifying fibres etc. (just are commonly referred to " fortifying fibre continuously " hereinafter for convenience's sake, do not limit the material that can be used as the systematism fiber alignment), to strengthen mechanical stability or to provide or some original position mechanical property of enhancing composition.When being used for this paper compositions, when determining the concentration of other component with respect to compositions, percentage ratio or ratio, should not use the content and/or the weight of continuous fortifying fibre.
That suitable continuous fortifying fibre according to the present invention can be is biodegradable, can absorb and/or biocompatible again, and can include but not limited to metal, metal alloy, pottery, polymer, copolymer etc. or their composite (composite) or the expandable and/or nondistensible net of mixture; Expandable and/or the nondistensible bag or the balloon that comprise metal, metal alloy, pottery, polymer, copolymer etc. or their composite or mixture; Woven fabric; Knitted fabric; Metal, metal alloy, pottery, polymer, copolymer etc. or their composite or the cage of mixture; The molded porous form of making by metal, metal alloy, pottery, polymer, copolymer etc. or their composite or mixture; Foam, for example foam of polymers, copolymer foam or composite foam; Or the like; Or their composite or combination.Perhaps, continuously fortifying fibre can be can not be resorbent.Example according to continuous fortifying fibre of the present invention can include but not limited to: the nylon fiber of braiding (net), woven cotton fiber, the knitted cotton fiber, cotton cheese cloth, polyactide (being total to) polymer hawser net, the braiding and/or coating can absorb suture again, the multifilament polymer can absorb bobbin (being made into net) again, Synthes Maxillofacial of Paoli, those of PA sale can absorb and/or biocompatible molded net again, stainless steel cloth, the titanium cage, woven mesh bag those as on market, having bought with trade name OPTIMESH from Spinology (Minn.).Or the like, or their combination.
Compare with the same mechanical performance of independent compositions (or independent contain calcium salt component), can advantageously cause the increase of some mechanical performance of compositions (for example bending strength, bolt pull off strength, crooked toughness, fracture toughness, flexible life, strain are to fracture, fracture strength, ultimate tensile strength, tensile strength, tensile modulus, tension toughness etc. and their combination) according to the adding of continuous fortifying fibre in the compositions of the present invention.In one embodiment, the existence of continuous fortifying fibre causes the bending strength at least about 10% to increase in the composite, preferably at least about 20%, and more preferably at least about 50%, for example at least about 100%, at least about 200%, or at least about 350%.In this embodiment, in the composite continuously the existence of fortifying fibre cause bending strength to increase usually less than about 1000%, be generally less than approximately 900%, for example be no more than approximately 800%, or be no more than about 700%.In another embodiment, the existence of continuous fortifying fibre causes the bolt pull off strength at least about 50% to increase in the composite, preferably at least about 75%, for example at least about 100%, at least about 125%, at least about 150%.In this embodiment, in the composite continuously the existence of fortifying fibre cause bolt pull off strength to increase usually less than about 900%, be generally less than approximately 800%, for example be no more than approximately 700%, or be no more than about 600%.In yet another embodiment, in the composite continuously the existence of fortifying fibre cause crooked toughness (" crooked toughness " used herein is defined in bending load/stress in the test that bending strength test for example carries out according to ASTM C-1161 standard method of test to the area displacement/strain curve under) increase at least about 25 times, preferably at least about 35 times, for example at least about 50 times, at least about 60 times, at least about 75 times, or at least about 100 times.
In some embodiments, when adding continuous fortifying fibre, preferably introduce the favourable increase of some mechanical performance that produces without to performance crucial other physics and/or mechanical performance (for example compressive strength, be pressed into intensity, formability/syringeability, setting time etc. and their combination) the big reduction of compositions according to the present invention in its (in body) application because of fortifying fibre continuously.In one embodiment, in the composite continuously the existence of fortifying fibre cause compressive strength to reduce usually less than about 20%, be generally less than approximately 10%, for example be no more than about 8% or be no more than about 5%.
In another embodiment, when use conventional memory fluid to be shaped or the liquid solidification mode (for example by flow through hole such as injection orifice or by free-flow as perfusion, with hands shaping etc. or their combination) when handling, can utilize that continuous fortifying fibre channelling component flows in the bone space/damaged, goes up, near inner and/or ability according to compositions of the present invention.In this embodiment, when continuous reinforcing fiber materials is inflatable relatively equably or not inflatable, the flow direction can be mainly by and/or away from continuous reinforcing fiber materials, perhaps, fortifying fibre optionally relatively expands in one or more locations/regions and not too or not expands with relative in other locations/regions continuously, then flow to advantageously (with inferior strategic point) away from relative not too or not expanding position/zone, and therefore towards more expansible relatively locations/regions.
When in compositions according to the present invention, using one or more continuous fortifying fibres, generally will determine the size of continuous fortifying fibre with respect to the space that is filled/handles and/or damaged size.Perhaps or additionally, the other factors of determining continuous fortifying fibre size can include but not limited to: space and/or damaged size, be used for filling/handle mechanical stability level of space and/or damaged amount of composition, space and/or damaged position, space and/or damaged implant needs etc., or their some combinations.
Form in order to have that global shape is used to implant or the ability of other application, (it comprises not only that liquid also is included in and can dissolve in the liquid or diffluent those viscosity and/or granular solids generally to have liquid component according to compositions of the present invention, for example solidify solution (setting liquid), be included in salt wherein, flowing additive etc., if present,) and solid constituent (it comprises that those do not dissolve or not diffluent solid material in liquid, the chemical compound of the phosphoric acid calcium that for example limits above, other undissolved relatively calcium salt, other undissolved relatively phosphate, fiber etc., but do not comprise any continuous fortifying fibre, if present).Gu the ratio of these two kinds of components is called as the liquid of composite/or L/S ratio.Advantageously, the L/S ratio of compositions should make compositions to be formed and (for example use hands, by conventional solid mechanical molding mode, by conventional viscoelasticity/solidifying liq forming mode or the like, or their some mixed deformations) become the applicable shapes of required application and make compositions can keep shape to solidify fully up to generation substantially.In one embodiment, L/S is than greater than about 0.3, be preferably greater than about 0.4, for example greater than about 0.41, greater than about 0.45, or greater than about 0.50.In another embodiment, L/S is than less than about 0.8, preferably less than about 0.7, for example less than about 0.60.In a kind of preferred embodiment, the L/S ratio can be about 0.41 to about 0.55, perhaps about 0.47 to about 0.53, about 0.42 to about 0.47, or about 0.41 to about 0.45.In another preferred embodiment, it is about 0.48 that the L/S ratio can be, perhaps about 0.42, about 0.45, or about 0.52.In another embodiment, the L/S ratio can be greater than 0.50 to about 0.60 or greater than 0.50 to about 0.55.In another embodiment, the L/S ratio can be greater than 0.45 to less than 0.50 or about 0.46 to less than 0.50.In a kind of preferred embodiment, the L/S ratio is about 0.50.
Another aspect of the present invention relates to the method for preparation and implant compositions, wherein compositions comprises the component (for example bone cement) that contains calcium salt, a large amount of discontinuous fibre, randomly comprises flowing additive and randomly comprise continuous fortifying fibre or fleece, said composition can be advantageously for biodegradable to small part, can absorb again and/or part biological is compatible at least to small part.This method can have following steps, but will be appreciated that following order can change:
Randomly grind the component contain calcium salt, especially when need be than this component of small particle diameter;
Randomly mix above-mentioned flowing additive, especially for use conventional memory fluid to be shaped or the liquid solidification mode (for example by flow through hole such as injection orifice or by free-flow as perfusion, with hands shaping etc. or their combination) compositions handled;
Randomly mix demineralization bone (for example with hands, use impeller or use pneumatic blender) and form the component that contains calcium salt/demineralization bone;
Mix a large amount of discontinuous fibers (for example with hands, use impeller or use pneumatic blender) and form the fibre-reinforced component that contains calcium salt;
Randomly handle space and/or damaged (for example in bone), and/or, be used for accepting according to compositions of the present invention near its interior body region;
Randomly the space and/or damaged near, on every side and/or positioned internal and/or the continuous fortifying fibre of grappling, especially for use conventional memory fluid to be shaped or the liquid solidification mode (for example by flow through hole such as injection orifice or by free-flow as perfusion, with hands shaping etc. or their combination) compositions handled;
Introduce fibre-reinforced component to space and/or damaged inside, above and/or near so that apply and/or fill space and/or damaged at least in part, thereby form implantable fibre-reinforced composite; With
Randomly handle comprise implantable fibre reinforced composites to small part coating and/or the space of filling and/or damaged and/or near its interior body region, with form bio-compatible and/or semi-transparent surperficial with excessivelying (for example, by the exposure usable surface to catalysis and/or reactive compound chemically to change usable surface; Solidify (set) or quicken solidifying of usable surface place's compositions; Protect usable surface and randomly protect whole implantable fibre reinforced composites to avoid replying of undesirable immune response; At the usable surface place and/or randomly induce the immunne response of increase in whole implantable fibre reinforced composites inside; Foundation have only some required biologic artifact can by and/or enter, exclude the semi-transparent layer of crossing of some other undesired biologic artifact simultaneously; Or the like; Or their some combinations).
In another embodiment, the method according to this invention can have following steps, but will be appreciated that following order can change:
Randomly grind the component contain calcium salt, especially when need be than this component of small particle diameter;
Mix above-mentioned flowing additive and form flowable composition, randomly have the demineralization bone, especially for use conventional memory fluid to be shaped or the liquid solidification mode (for example by flow through hole such as injection orifice or by free-flow as perfusion, with hands shaping etc. or their combination) compositions handled;
Randomly mix demineralization bone (for example with hands, use impeller or use pneumatic blender) and form the component that contains calcium salt/demineralization bone;
Randomly mix a large amount of above-mentioned discontinuous fibers (for example with hands, use impeller or use pneumatic blender);
Randomly handle space and/or damaged (for example in bone), and/or, be used for accepting according to compositions of the present invention near its interior body region;
Randomly the space and/or damaged near, on every side and/or positioned internal and/or the continuous fortifying fibre of grappling, especially for use conventional memory fluid to be shaped or the liquid solidification mode (for example by flow through hole such as injection orifice or by free-flow as perfusion, with hands shaping etc. or their combination) compositions handled;
Introduce flowable component to space and/or damaged inside, above and/or near so that apply and/or fill space and/or damaged at least in part, thereby form implantable composite; With
Randomly handle comprise implantable composite to small part coating and/or the space of filling and/or damaged and/or near its interior body region, with form bio-compatible and/or semi-transparent surperficial with excessivelying (for example, by the exposure usable surface to catalysis and/or reactive compound chemically to change usable surface; Solidify or quicken solidifying of usable surface place compositions; Protect usable surface and randomly protect whole implantable composites to avoid the influence of undesirable immunne response; At the usable surface place and/or randomly induce the immunne response of increase in whole implantable composite inner; Foundation have only some required biologic artifact can by and/or enter, exclude the semi-transparent layer of crossing of some other undesired biologic artifact simultaneously; Or the like; Or their some combinations).
Another aspect of the present invention relates to by providing implantable compositions according to the present invention to handle bone damaged or fill the method in bone space, wherein implantable compositions can be advantageously for biodegradable to small part, can absorb again and/or part biological is compatible at least to small part.This method can have following steps, but will be appreciated that following order can change:
Randomly grind the component contain calcium salt, especially when need be than this component of small particle diameter;
Randomly mix above-mentioned flowing additive, randomly have the demineralization bone, especially for use conventional memory fluid to be shaped or the liquid solidification mode (for example by flow through hole such as injection orifice or by free-flow as perfusion, with hands shaping etc. or their combination) compositions handled;
Randomly mix demineralization bone (for example with hands, use impeller or use pneumatic blender) and form the component that contains calcium salt/demineralization bone;
Mix a large amount of discontinuous fibers (for example with hands, use impeller or use pneumatic blender) and form the fibre-reinforced component that contains calcium salt;
Randomly pretreatment space and/or damaged (for example in bone), and/or near its interior body region, be used for accepting according to compositions of the present invention;
Randomly the space and/or damaged near, on every side and/or positioned internal and/or the continuous fortifying fibre of anchor, especially for use conventional memory fluid to be shaped or the liquid solidification mode (for example by flow through hole such as injection orifice or by free-flow as perfusion, with hands shaping etc. or their combination) compositions handled;
Introduce the fibre-reinforced component that contains calcium salt to space and/or damaged inside, above and/or near so that apply and/or fill space and/or damaged at least in part, thereby form implantable fibre-reinforced composite; With
Randomly post processing comprise implantable fibre reinforced composites to small part coating and/or the space of filling and/or damaged and/or near its interior body region, with form bio-compatible and/or semi-transparent surperficial with excessivelying (for example, by the exposure usable surface to catalysis and/or reactive compound chemically to change usable surface; Solidify or quicken solidifying of usable surface place compositions; Protect usable surface and randomly protect whole implantable fibre reinforced composites to avoid the influence of undesirable immunne response; At the usable surface place and/or randomly induce the immunne response of increase in whole implantable fibre reinforced composites inside; Foundation have only some required biologic artifact can by and/or enter, exclude the semi-transparent layer of crossing of some other undesired biologic artifact simultaneously; Or the like; Or their some combinations).
In another embodiment, treatment in accordance with the present invention bone method damaged or filling bone space can have following steps, but will be appreciated that following order can change:
Randomly grind the component contain calcium salt, especially when need be than this component of small particle diameter;
Mix above-mentioned flowing additive and form the compositions of flowable phosphoric acid calcium, especially for use conventional memory fluid to be shaped or the liquid solidification mode (for example by flow through hole such as injection orifice or by free-flow as perfusion, with hands shaping etc. or their combination) compositions handled;
Randomly mix demineralization bone (for example with hands, use impeller or use pneumatic blender) and form the component that contains calcium salt/demineralization bone;
Randomly mix a large amount of above-mentioned discontinuous fibers (for example with hands, use impeller or use pneumatic blender);
Randomly pretreatment space and/or damaged (for example in bone), and/or near its interior body region, be used for accepting according to compositions of the present invention;
Randomly the space and/or damaged near, on every side and/or positioned internal and/or the continuous fortifying fibre of grappling, especially for use conventional memory fluid to be shaped or the liquid solidification mode (for example by flow through hole such as injection orifice or by free-flow as perfusion, with hands shaping etc. or their combination) compositions handled;
Introduce the flowable component that contains calcium salt to space and/or damaged inside, above and/or near so that apply and/or fill space and/or damaged at least in part, thereby form implantable composite; With
Randomly post processing comprise implantable composite to small part coating and/or the space of filling and/or damaged and/or near its interior body region, with form bio-compatible and/or semi-transparent surperficial with excessivelying (for example, by the exposure usable surface to catalysis and/or reactive compound chemically to change usable surface; Solidify or quicken solidifying of usable surface place compositions; Protect usable surface and randomly protect whole implantable composites to avoid the influence of undesirable immunne response; At the usable surface place and/or randomly induce the immunne response of increase in whole implantable composite inner; Foundation have only some required biologic artifact can by and/or enter, exclude the semi-transparent layer of crossing of some other undesired biologic artifact simultaneously; Or the like; Or their some combinations).
Another aspect of the present invention relates to and is used to store, prepares, mixing and/or administration be according to the test kit or the packaging system of compositions of the present invention.Advantageously, test kit or packaging system can independently comprise the composite component in the compartment at least two.In this embodiment, the solid portion (for example bone cement) that contains the component of calcium salt according to the present invention can be present in the compartment, it also randomly comprises fibre fractionation to form solid or " doing " component compartment, and the liquid part (for example solidifying solution) that contains the component of calcium salt according to the present invention can be present in another compartment, and it also randomly comprises the flowing additive component to form liquid or " wetting " component compartment.A non-limitative example of two compartment test kits is described in United States Patent (USP) 6,149, and in 655, this paper specially introduces its full content as a reference.
Compositions of the present invention can comprise randomly that one or more detergents or surfactant are to improve the mixed performance and the denseness (consistency) of bone cement.When using, in the liquid of compositions and the gross weight of dried component, the amount of detergent or surfactant is that about 0.01wt% is to about 2.5wt%.
The useful surfactant and the non-limitative example of cleaning agent comprise anion surfactant, as for example docusate sodium, sodium lauryl sulphate and sodium lauryl sulfate; Nonionic surfactant, as for example stearic acid, cetab, glyceryl monooleate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (4) sorbitan mono-laurate, polyoxyethylene (20) anhydrous sorbitol glycerol monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene (20) anhydrous sorbitol tristearate, polyethylene glycol oxide (20) sorbitan monooleate, polyethylene glycol oxide (5) sorbitan monooleate, polyethylene glycol oxide (20) sorbitan trioleate, polyethylene glycol oxide (20) anhydrous sorbitol list isostearate, polyvinyl alcohol, the anhydrous sorbitol diisopstearate, the anhydrous sorbitol dioleate, anhydrous sorbitol list isostearate, sorbitan mono-laurate, sorbitan monooleate, the anhydrous sorbitol monopalmitate, sorbitan monostearate, anhydrous sorbitol sesquialter isostearate, sorbitan sesquioleate, the anhydrous sorbitol sesquistearate, anhydrous sorbitol three isostearate sorbitan trioleates, the anhydrous sorbitol tristearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate (isopropyl palpitate), lanoline, lanolin alcohol, aqueous lanoline (hydrous lanolin), lecithin, triglyceride, monoethanolamine, oleic acid, Polyethylene Glycol, the polyethyleneglycol cetyl ether, the polyethyleneglycol stearyl ether, polyethyleneglycol Laurel ether, polyethyleneglycol oil ether, GREMAPHOR GS32, polypropylene glycol, Myrj 52, polyoxyethylene 50 stearate, triethanolamine, methylcellulose, carboxymethyl cellulose, the copolymer of hydroxypropyl emthylcellulose and oxirane and expoxy propane such as PLURONIC  surfactant (can be from BASF, Mount Olive New Jersey obtains); And cationic surfactant, as for example chlorination alkyl dimethyl (benzyl) ammonium and benzethonium chloride; With their combination.
After the mixing, bone cement of the present invention is applied to bone space and/or the damaged place of bone, and makes it leave standstill the end time being enough to form under the temperature of sclerotic bone cement.The time that bone cement sclerosis needs changes with the amount of the existence of the composition of for example bone cement such as water content, pH, additive, fiber and type and temperature.Typically, it is about 5 minutes to about 60 minutes that bone cement is enough to the hardened time, preferred about 5 minutes to about 20 minutes.Bone cement is enough to hardened temperature and is generally about 0 ℃ to about 45 ℃, and more preferably from about 20 ℃ to about 40 ℃, normal physiologic temperature most preferably from about, promptly 37 ℃.
If desired, can quicken (shortening) firm time by adding promoter.The firm time (referring to people's such as Hirano United States Patent (USP) 5,152,836) that for example, can have the liquid component accelerated bone cement of the interpolation water soluble salt of high concentration such as sodium succinate, sodium lactate, sodium acetate and sodium chloride by use.For example, when liquid component comprised the firm time that adds salt accelerated bone cement, in the weight of liquid component, the amount that adds salt was no more than about 30wt%.
In addition or on the other hand, can comprise United States Patent (USP) 6,083 according to test kit of the present invention or system, those test kits described in 229 and 6,149,655 and/or the content of system, the full content that this paper specially introduces them is as a reference.
The percentage rate retention of above-mentioned mechanical performance or above-mentioned molecular weight (percent retention) is expressed as the ratio of the character of the compositions (for example pure implantable component or the bone cement that contains calcium salt) that does not add any fiber based on the premixed character of not using fiber or when using in this article.
Embodiment
Will be by with reference to the following examples explanations the preferred embodiments of the invention and contrast embodiment, comprise that they are used for explanation but never limit the scope of the invention.
The comparative example 1: the prior art bone cement compositions
Below listed this paper in the table 1 and be used for correlated concrete bone cement compositions.
Comparative example # Ca(H 2PO 4) 2·H 2O α-Ca 3(PO 4) 2 CaCO 3 BaSO 4 Na 2HPO 4Solution
1A 3.3 84.4 12.4 - 0.075m，L/S＝0.48
1B 2.9 73.4 10.7 13 0.075m，L/S＝0.45
1C 3.3 84.4 12.4 - 0.075m，L/S＝0.52
Comparative example 1A by on market with trade name NORLAN SRS  from Norian Corp.ofChester, the bone cement that PA obtains is transformed into.Comparative example 1B is with trade name NORIAN XR on market TMFrom Norian Corp.of West Chester, the radiopaque bone cement that PA obtains.Comparative example 1C serves as reasons on market with NORLAN CRS  from Norian Corp.ofChester, and what PA obtained solidifies bone cement soon by changing Na 2HPO 4Content is from about 0.15m to about 0.075m with by changing L/S than being transformed into from about 0.56 to about 0.52.
Embodiment 1: according to the implantable compositions that can absorb fiber again that comprises of the present invention
Below listed concrete fibre-reinforced compositions in the table 2.
Table 2
Embodiment # Calcium phosphate compositions Can absorb fiber again
1D Comparative example 1A 1% (3mm * 16-20 μ m) L6 fiber
1E Comparative example 1A 2% (3mm * 16-20 μ m) L6 fiber
1F Comparative example 1A 2% (6mm * 16-20 μ m) L6 fiber
1G Comparative example 1A 1% (8mm * 16-20 μ m) L6 fiber
1H Comparative example 1A 2% (8mm * 16-20 μ m) L6 fiber
1J Comparative example 1A 2% (8mm * 16-20 μ m) L6 Os Canitis fiber
1K Comparative example 1A 1% (3mm * 16-20 μ m) LACTOMER fiber
1L Comparative example 1A 2% (3mm * 16-20 μ m) LACTOMER fiber
1M Comparative example 1A 2% (3mm is long) LACTOMER 9-1 fiber
The L6 fiber is that (wt: short copolymer fibre wt), and can be from U.S.Surgical of New Haven on market, CT has bought for 82% Acetic acid, hydroxy-, bimol. cyclic ester and 18% lactide.L6 Os Canitis fiber has altered fiber ends, so fiber is Os Canitis or dumbbell shape.The LACTOMER fiber is Acetic acid, hydroxy-, bimol. cyclic ester-L-lactide copolymer fiber, and can be from U.S.Surgical of New Haven on market, and CT has bought.LACTOMER 9-1 fiber is short multifilament (promptly 〉=5-fiber) bobbin.
The solid constituent of the bone cement by mixing comparative example 1A and respective numbers and kind can absorb fiber again, with mortar and pestle milled mixtures, the liquid component that adds the bone cement of comparative example 1A, the slip that obtains is configured as standard shape (being used for test subsequently), and the slip that allows to be shaped solidified (set for) at least 24 hours, the compositions of embodiment 1D-1M above forming.
Embodiment 2: according to the implantable compositions that comprises continuous fortifying fibre of the present invention
Below table 3 listed concrete continuous fiber or the enhanced compositions of fleece.
Table 3
Embodiment # Calcium phosphate compositions Continuous fiber or fleece
2A Comparative example 1A The LACTOMER cable grid
2B Comparative example 1A Cotton cheese cloth
The LACTOMER cable grid comprises the Acetic acid, hydroxy-, bimol. cyclic ester-L-lactide copolymer fiber that twines and weave, and can buy from U.S.Surgical of New Haven CT on market.
By the solid constituent of grinding the bone cement of comparative example 1A with mortar and pestle, the liquid component that adds the bone cement of comparative example 1A, the slip that obtains is configured as standard shape (being used for test subsequently), place continuous fortifying fibre or fleece around the outside of shaping slip, applying light pressure embeds continuous fortifying fibre or fleece wherein, and allow the enhanced formed body of this continuous fiber to solidify at least 24 hours, the compositions of embodiment 2A-2B above forming.
Embodiment 3: according to the implantable compositions that comprises flowing additive of the present invention
Following table 4 has been listed concrete flowing/Injectable composition.
Table 4
Embodiment # Calcium phosphate compositions Flowing additive 1 Na 2HPO 4Solution
3A Comparative example 1A The 0.3wt% hyaluronate sodium 0.15m，L/S＝0.48
3B Comparative example 1B The 0.3wt% hyaluronate sodium 0.075m，L/S＝0.42
3C Comparative example 1B The 0.6wt% hyaluronate sodium 0.075m，L/S＝0.42
3D Comparative example 1B The 0.6wt% hyaluronate sodium 0.075m，L/S＝0.52
3E Comparative example 1B The 1.4wt% hyaluronate sodium 0.075m，L/S＝0.42
1Based on not comprising Na 2HPO 4The weight of solution.
By the solid constituent of grinding the bone cement of comparative example 1A or 1B with mortar and pestle, the liquid component that adds the bone cement of hyaluronate sodium-sodium radio-phosphate,P-32 solution and comparative example 1A or 1B, this can be flowed/injectable compositions is injected into standard shape (being used for test subsequently), and this shaping form was solidified 24 hours at least, embodiment 3A-3E's flows/Injectable composition above forming.
Embodiment 4: according to the implantable compositions that can absorb fiber and flowing additive again that comprises of the present invention
Below listed a kind of concrete flowing/injectable fibre-reinforced compositions in the table 5.
Table 5
Embodiment Calcium phosphate compositions Flowing additive 1 Can absorb fiber again 2
4A Comparative example 1A The 0.3wt% hyaluronate sodium 1% (3mm * 16-20 μ m) LACTOMER fiber
1Based on not comprising Na 2HPO 4The weight of solution.
2The LACTOMER fiber is Acetic acid, hydroxy-, bimol. cyclic ester-L-lactide copolymer fiber, and can be from U.S.Surgical of New Haven on market, and CT has bought.
The solid constituent of the bone cement by mixing comparative example 1A with can absorb fiber again, with mortar and pestle milled mixtures, the liquid component that adds the bone cement of flowing additive and comparative example 1A, this can be flowed/injectable fibre-reinforced compositions is injected into standard shape (being used for test subsequently), and this shaping serosity was solidified 24 hours at least, embodiment 4A's flows/injectable fibre-reinforced compositions above forming.
Embodiment 5: according to the implantable compositions that can absorb fiber and continuous fortifying fibre again that comprises of the present invention
Following table 6 has been listed a kind of concrete fiber reinforcement and the enhanced compositions of net.
Table 6
Embodiment Calcium phosphate compositions Can not absorb fiber again 1 Bracing frame or fleece
5A Comparative example 1A 1% (3mm * 16-20 μ m) LACTOMER fiber The LACTOMER cable grid
1The LACTOMER fiber is Acetic acid, hydroxy-, bimol. cyclic ester-L-lactide copolymer fiber, and can be from U.S.Surgical of New Haven on market, and CT has bought.The LACTOMER cable grid comprises the Acetic acid, hydroxy-, bimol. cyclic ester-L-lactide copolymer fiber that twines and weave.
The solid constituent of the bone cement by mixing comparative example 1A and respective numbers and kind can absorb fiber again, with mortar and pestle milled mixtures, the liquid component that adds the bone cement of comparative example 1A, the slip that obtains is configured as standard shape (being used for test subsequently), place continuous fortifying fibre or fleece around the outside of shaping slip, applying light pressure embeds continuous fortifying fibre or fleece wherein, and allow the enhanced form of this continuous fiber to solidify at least 24 hours, the compositions of embodiment 5A above forming.
Embodiment 6: according to the implantable compositions that can not absorb fiber again that comprises of the present invention
Following table 7 has been listed a kind of concrete fiber reinforcement and the enhanced compositions of net.
Table 7
Embodiment Calcium phosphate compositions Can absorb fiber again 1
6A Comparative example 1A 2% (6-10mm * 20 μ m) glass fibre
1Glass fibre can obtain from Owens-Corning of Ohio on market for short E-glass fibre.
The solid constituent of the bone cement by mixing comparative example 1A with can not absorb fiber again, with mortar and pestle milled mixtures, the liquid component that adds the bone cement of comparative example 1A, the slip that obtains is configured as standard shape (being used for test subsequently), and this shaping serosity was solidified 24 hours at least, the compositions of embodiment 6A above forming.
Embodiment 7: according to the comparison of the bending strength of implantable compositions of the present invention
Compared the bending strength of compositions of embodiment 1D-1J, 2A-2B, 5A and 6A and the bending strength of comparative example 1A (in contrast), the result is presented in the following table 8.
Table 8
Embodiment # Enhancement component Bending strength (ASTM C-1161)
1A Do not have ～5MPa
1D 1% (3mm * 16-20 μ m) L6 fiber 5.9MPa
1E 2% (3mm * 16-20 μ m) L6 fiber 10MPa
1F 2% (6mm * 16-20 μ m) L6 fiber 12.4MPa
1G 1% (8mm * 16-20 μ m) L6 fiber 6.9MPa
1H 2% (8mm * 16-20 μ m) L6 fiber 9.4MPa
1J 2% (8mm * 16-20 μ m) L6 Os Canitis fiber 8.8MPa
2A The LACTOMER cable grid 14.4MPa
2B Cotton cheese cloth (cotton cheesecloth) 8.4MPa
5A 1% (3mm * 16-20 μ m) LACTOMER fiber and LACTOMER cable grid 15.8MPa
6A 2% (6-10mm * 20 μ m) glass fibre 8.9MPa
The compositions of embodiment 1D-1J, 2A-2B, 5A and 6A all demonstrates the bending strength value of raising owing to their reinforcing agent, for absorbing fiber and the combination of absorption mesh " bracing frame " more again, demonstrate the maximum raising (increase about 216%) of comparison than the basic bone cement of embodiment 1A.
Embodiment 8: according to the comparison of the bolt pull off strength of implantable compositions of the present invention
Compared the bolt pull off strength of compositions of embodiment 1K, 2A and 5A and the bolt pull off strength of comparative example 1A (in contrast), the result is presented in the following table 9.
Table 9
Embodiment # Enhancement component 1，2 The bolt pull off strength
1A Do not have ～9.9 ft lbfs
1K 1% (3mm * 16-20 μ m) LACTOMER fiber 27.1 ft lbf
2A The LACTOMER cable grid 33.6 ft lbf
5A 1% (3mm * 16-20 μ m) LACTOMER fiber and LACTOMER cable grid 61 ft lbfs
1Based on not comprising Na 2HPO 4The weight of solution.
2The LACTOMER fiber is Acetic acid, hydroxy-, bimol. cyclic ester-L-lactide copolymer fiber, and can be from U.S.Surgical of New Haven on market, and CT has bought.
The compositions of embodiment 1K, 2A and 5A all demonstrates the remarkable increase of bolt pull off strength value owing to their reinforcing agent, for absorbing fiber and the combination of absorption mesh " bracing frame " more again, have the maximum raising (increase about 516%) of comparison than the basic bone cement of embodiment 1A.
Embodiment 9: according to the comparison of the crooked toughness of implantable compositions of the present invention
Compared the crooked toughness of compositions of embodiment 5A and the crooked toughness of comparative example 1A (in contrast), crooked toughness is collected (glean) by the load of finishing according to ASTM C-1161 to elongation bending strength area under a curve and is obtained.The result is presented in the following table 10.
Table 10
Embodiment # Enhancement component 1，2 Crooked toughness (area under the curve/embodiment 1A area under the curve)
1A Do not have 1.0
5A 1% (3mm * 16-20 μ m) LACTOMER fiber and LACTOMER cable grid ～88
1Based on not comprising Na 2HPO 4The weight of solution.
2The LACTOMER fiber is Acetic acid, hydroxy-, bimol. cyclic ester-L-lactide copolymer fiber, and can be from U.S.Surgical of New Haven on market, and CT has bought.
The compositions of embodiment 5A is owing to their reinforcing agent demonstrates the remarkable increase of crooked toughness values, for absorbing fiber again and can absorbing the combination of continuous fortifying fibre net again, has the about 88 times increases of comparison than the basic bone cement of embodiment 1A.
Embodiment 10: according to the comparison of the compressive strength of implantable compositions of the present invention
The compressive strength of compositions of embodiment 1K, 3A and 4A and the compressive strength of comparative example 1A (in contrast) have been compared.The result is presented in the following table 11.
Table 11
Embodiment # Non-bone cement component 1， 2 Compressive strength
1A Do not have (L/S=0.48) 53.4MPa
1K 1% (3mm * 16-20 μ m) LACTOMER fiber (L/S=0.48) 51MPa
3A 0.3wt% hyaluronate sodium (L/S=0.48) 46.1MPa
4A 1% (3mm * 16-20 μ m) LACTOMER fiber and 0.3wt% hyaluronate sodium (L/S=0.48) 48.1MPa
1Based on not comprising Na 2HPO 4The weight of solution.
2The LACTOMER fiber is Acetic acid, hydroxy-, bimol. cyclic ester-L-lactide copolymer fiber, and can be from U.S.Surgical of New Haven on market, and CT has bought.
The compositions of embodiment 1K, 3A and 4A all demonstrates lower compressive strength because their hang down the interpolation component of quantity and weakens.Only the compressive strength of the existence of the independent flowable of 0.3wt% reduction composite is measured (compare with comparative example 1A and reduce about 14%) significantly, the existence that can absorb fiber separately again of 1wt% carrying capacity reduces the much smaller amount of the compressive strength of composite (compare only reduce about 4.5% with comparative example 1A), but as if fiber-flowing additive combination provides medium compressive strength loss (comparing 9.9% loss of only having an appointment with comparative example 1A), although total the higher component carrying capacity of 1.3wt% is arranged.Therefore the fiber among the embodiment 4A and the synergism of flowing additive have been described.
Embodiment 11: the preparation of compositions that comprises demineralization bone and calcic bone cement
To the 0.075m Na that comprises 55 weight portions 2HPO 4Ceramic mortar in add hyaluronic acid (0.30 weight portion).In the aqueous solution that obtains, add 7 weight portion demineralization bone powder (MusculoskeletalTransplant Foundation, Edison, NJ), the mixture that obtains left standstill under 25 ℃ 3 minutes, and the NORIAN SRS that adds 93 weight portions (can be from Norian Corp., the commercial calcium bone cement that Paoli, PA obtain).Grind down the mixture that obtains 2 minutes with pestle at 25 ℃, obtain demineralization bone/calcium calcium bone cement composite (composite).
Embodiment 12: the fibre-reinforced preparation of compositions that comprises demineralization bone and calcic bone cement
Can make preparation in the following method comprise the fibre-reinforced compositions of demineralization bone and calcium salt.
The LACTOMER fiber (can be from U.S.Surgical with NORIAN SRS (93 weight portion) and 1% (3mm * 16-20 μ m) with mortar and pestle, New Haven, the Acetic acid, hydroxy-, bimol. cyclic ester that CT obtains-L-lactide copolymer fiber) is ground to together, form calcium salt/fiber thickener, drying composite forms calcium salt/fibre blend.In another mortar, to the 0.075mNa that contains 55 weight portions 2HPO 4Ceramic mortar in add hyaluronic acid (0.30 weight portion).(NJ), the mixture that obtains left standstill under 25 ℃ 3 minutes for Musculoskeletal Transplant Foundation, Edison, and added calcium salt/fibre blend to add 7 weight portion demineralization bone powder in the aqueous solution that obtains.Grind down the mixture that obtains 2 minutes with pestle at 25 ℃, obtain fibre-reinforced demineralization bone/calcium calcium bone cement composite.
Embodiment 13: the preparation of fibre-reinforced calcic bone cement
(can be with mortar and pestle from U.S.Surgical with NORIAN SRS (97 weight portion) and 3 weight portion LACTOMER fibers, New Haven, the Acetic acid, hydroxy-, bimol. cyclic ester that CT obtains-L-lactide, (wt: wt) copolymer fibre) (1mm * 16 μ m) was ground to together in 82: 18, form calcium salt/fiber thickener, drying composite forms calcium salt/fibre blend.Dividually, to comprising Na 2HPO 47H 2O (0.58 weight portion) and NaH 2PO 4H 2The ceramic mortar of water (48.9 weight portion) solution of O (0.20 weight portion) adds hyaluronate sodium (0.25 weight portion).The mixture that obtains was left standstill under 25 ℃ 3 minutes, and add calcium salt/fibre blend.Ground down the mixture that obtains 2 minutes with pestle at 25 ℃, obtain fibre-reinforced calcium bone cement composite, its liquid-solid ratio is 0.5, and viscosity is 50cps.The result of the mechanical test of the bone cement of embodiment 13 is presented in the following table 12.
Table 12
Test The result
Bending strength 8MPa
Bending modulus 5-7GPa
Crooked merit ruptures 900-1200J/m 2
Compressive strength 35-40MPa
Modulus of compressibility 2-3GPa
Although described the present invention with reference to certain preferred embodiments, do not departing from the scope of the present invention under the situation of accessory claim restricted portion especially, those skilled in the art obviously can make and change and change.

Claims (50)

1. implantable compositions comprises:
(a) contain the component of calcium salt, the component that wherein contains calcium salt is amorphous calcium phosphate, crystallized calcium phosphate, CaHPO 4, CaHPO 4H 2O, α-Ca 3(PO 4) 2, α-bar-Ca 3(PO 4) 2, β-Ca 3(PO 4) 2, γ-Ca 3(PO 4) 2, Ca 5(PO 4) 3OH, Ca 10(PO 4) 6(OH) 2, Ca 4O (PO 4) 2, CaP 4O 11, α-Ca 2P 2O 7, β-Ca 2P 2O 7, γ-Ca 2P 2O 7, Ca (H 2PO 4) 2NH 2O, wherein n is 0 to 5 real number, Ca 8H 2(PO 4) 65H 2O, or calcium pyrophosphate; Ca (SO 4) 2, α-Ca (SO 4) 21/2H 2O, β-Ca (SO 4) 21/2H 2O; Or their combination in any; With
(b) about 1wt% is to the discontinuous fibre of about 5wt%, and it is for can absorb homopolymer or copolymer again, and draw ratio is about 50: 1 to about 1000: 1, and has about 15mm or following fibre length.
2. the compositions of claim 1, wherein the draw ratio of fiber is about 50: 1 to about 500: 1.
3. the compositions of claim 1, wherein the draw ratio of fiber is about 50: 1 to about 250: 1.
4. the compositions of claim 1, wherein the length of fiber is about 0.1mm about 8.5mm extremely.
5. the compositions of claim 4, wherein the length of fiber is about 0.5mm about 1.5mm extremely.
6. the compositions of claim 1, wherein the diameter of fiber or width are no more than about 500 microns.
7. the compositions of claim 6, wherein the diameter of fiber or width are no more than about 50 microns.
8. the compositions of claim 7, wherein the diameter of fiber or width are about 10 microns to about 25 microns.
9. the compositions of claim 8, wherein the diameter of fiber or width are about 15 microns to about 20 microns.
10. the compositions of claim 1, wherein can absorb fiber again and comprise poly-(L-lactide) (being total to) polymer, poly-(D, L-lactide) (being total to) polymer, poly-Acetic acid, hydroxy-, bimol. cyclic ester (being total to) polymer, polycaprolactone (being total to) polymer, poly-(tetramethyl hydroxyacetic acid) (being total to) polymer, poly-to dioxanone (being total to) polymer, poly butyric ester (being total to) polymer, poly-hydroxyl valerate (being total to) polymer, poly-(L-lactide-co-glycolide) copolymer, poly-(Acetic acid, hydroxy-, bimol. cyclic ester-altogether-propylene carbonate) copolymer, poly-(Acetic acid, hydroxy-, bimol. cyclic ester-altogether-caprolactone) copolymer, poly-(Acetic acid, hydroxy-, bimol. cyclic ester-common-to dioxanone-common-propylene carbonate) copolymer, poly-(tetramethyl hydroxyacetic acid-common-to dioxanone-common-propylene carbonate) copolymer, poly-(Acetic acid, hydroxy-, bimol. cyclic ester-altogether-caprolactone-altogether-the L-lactide-altogether-propylene carbonate) copolymer, poly-(butyric ester-altogether-hydroxyl valerate) copolymer, liquid crystal (being total to) polymer, their combination or their copolymer.
11. the compositions of claim 10 wherein can absorb fiber again and comprise poly-(L-lactide-co-glycolide) copolymer.
12. the compositions of claim 11, wherein poly-(L-lactide-co-glycolide) copolymer comprise at least about the Acetic acid, hydroxy-, bimol. cyclic ester repetitive of 15wt% with at least about the L-lactic acid repetitive of 15wt%.
13. the compositions of claim 1, the amount that wherein can absorb fiber again are about 1% to about 3% of composition weight.
14. the compositions of claim 13, the amount that wherein can absorb fiber again are about 1% to about 2.5% of composition weight.
15. the compositions of claim 14, the amount that wherein can absorb fiber again is about 2% of a composition weight.
16. the compositions of claim 1, the component that wherein contains calcium salt is substantially by as the bone cement of solid constituent with as about 0.01 to about 0.2mol/kg na phosphates solution composition of liquid component, and wherein bone cement comprises mono calcium phosphate hydrate, type alpha tricalcium phosphate and calcium carbonate.
17. the compositions of claim 16, wherein the amount of na phosphates is about 0.15mol/kg solution, and wherein the ratio of liquid component and solid constituent is about 0.48 to about 0.65.
18. the compositions of claim 16, wherein the amount of na phosphates is about 0.075mol/kg solution, and wherein the ratio of liquid component and solid constituent is about 0.41 to about 0.55.
19. the compositions of claim 18, wherein liquid component is about 0.47 to about 0.53 with the ratio of solid constituent.
20. the compositions of claim 19, wherein liquid component is about 0.50 with the ratio of solid constituent.
21. the compositions of claim 16 also comprises flowing additive, flowing additive comprises hyaluronic acid, hyaluronate, na phosphates or their combination.
22. the compositions of claim 21, wherein flowing additive comprises hyaluronate sodium.
23. the compositions of claim 23, wherein flowing additive is made up of hyaluronate sodium substantially.
24. the compositions of claim 21, wherein compositions has the viscosity of about 1cPs to about 500cPs.
25. the compositions of claim 21, wherein the amount of flowing additive is about 0.1% to about 1% of a composition solid composition weight.
26. the compositions of claim 25, wherein the amount of flowing additive is about 0.05% to about 0.5% of a composition solid composition weight.
27. the compositions of claim 1 also comprises the demineralization bone.
28. the compositions of claim 1 also comprises antimicrobial.
29. the compositions of claim 1 also comprises continuous fortifying fibre.
30. the compositions of claim 1 also comprises continuous fortifying fibre net.
31. the compositions of claim 21, it demonstrates the increase than component that contains calcium salt separately and flowing additive component: bending strength about 50% to about 900%, bolt pull off strength about 75% is to about 800%, and crooked toughness is at least about 35 times, or their some combinations.
32. the compositions of claim 21, its bending strength of about 200% to about 700% that demonstrates than component that contains calcium salt separately and flowing additive component increases.
33. the compositions of claim 21, its bolt pull off strength of about 150% to about 600% that demonstrates than component that contains calcium salt separately and flowing additive component increases.
34. the compositions of claim 21, its crooked toughness of at least 50 times that demonstrates than component that contains calcium salt separately and flowing additive component increases.
35. the compositions of claim 34, its bending strength of about 200% to about 700% that demonstrates than component that contains calcium salt separately and flowing additive component increases.
36. the compositions of claim 35, its bolt pull off strength of about 150% to about 600% that demonstrates than component that contains calcium salt separately and flowing additive component increases.
37. the compositions of claim 36, its bolt pull off strength of about 150% to about 600% that demonstrates than component that contains calcium salt separately and flowing additive component increases.
38. the compositions of claim 1, the compressive strength that does not wherein have enhanced component that contains calcium salt of continuous fiber and discontinuous fibre are about 15 to about 80MPa.
39. the compositions of claim 1, the bending strength that does not wherein have enhanced component that contains calcium salt of continuous fiber and discontinuous fibre are about 6 to about 12MPa.
40. the compositions of claim 1, the crooked merit that fractures that does not wherein have enhanced component that contains calcium salt of continuous fiber and discontinuous fibre are about 400 to about 2400J/m 2
41. an implantable compositions comprises the solid and the liquid component of following form:
The basic component of forming by the bone cement that comprises mono calcium phosphate hydrate, type alpha tricalcium phosphate, calcium carbonate that contains calcium salt; With about na phosphates of 0.01 to about 0.2mol/kg; With
Flowing additive, wherein the amount of flowing additive be enough to make implantable compositions be no more than flow through under about 40 pounds maximum injection pressure about No. 12 to about No. 18 syringe needle,
The ratio of liquid component and solid constituent is about 0.41 to about 0.55 in the wherein implantable compositions.
42. the compositions of claim 41, wherein flowing additive is hyaluronic acid, hyaluronate, na phosphates or their combination.
43. the compositions of claim 42 comprises that also it is discontinuously can absorb homopolymer or copolymer fibre again to about 1000: 1 in about 50: 1 that a large amount of fibre lengths are no more than about 15mm and draw ratio.
44. the compositions of claim 43 also comprises the demineralization bone.
45. the compositions of claim 41 also comprises antimicrobial.
46. the compositions of claim 41, wherein said composition its demonstrate increase than component that contains calcium salt separately and flowing additive component: bending strength about 50% to about 900%, bolt pull off strength about 75% is to about 800%, and crooked toughness is at least about 35 times, or their some combinations.
47. one kind prepares implantable method for compositions, this implantable compositions be biodegradable to small part, to small part can be resorbent, at least part biological compatible or their combination, this method may further comprise the steps:
(a) mixed flow additive and the component that contains calcium salt form the flowable compositions that contains calcium salt, and said composition is injected into by about No. 12 or bigger syringe needle being no more than about 40 pounds maximum injection pressure; With
(b) compositions of a large amount of discontinuous fibres of mixing and flowable phosphoric acid calcium forms the fibre-reinforced component that contains calcium salt.
48. the method for claim 47, the compositions that wherein contains calcium salt also comprises the demineralization bone.
49. the method for claim 47, wherein a large amount of discontinuous fibres are draw ratio be about 50: 1 to about 1000: 1 and fibre length be no more than about 15mm can absorb homopolymer or copolymer again.
50. the method for claim 47, wherein contain calcium salt component its demonstrate increase than component that contains calcium salt separately and flowing additive component: bending strength about 50% to about 900%, bolt pull off strength about 75% is to about 800%, and crooked toughness is at least about 35 times, or their some combinations.
CNB2004800325239A 2003-09-05 2004-09-07 Bone cement compositions having fiber-reinforcement and/or increased flowability Expired - Lifetime CN100438929C (en)

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