CN1863563A - 用于骨植入物的复合生物材料 - Google Patents
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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- A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
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- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0014—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis
- A61F2250/003—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis differing in adsorbability or resorbability, i.e. in adsorption or resorption time
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- A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
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Abstract
本发明公开了用于骨植入物的生物材料,其由无机相和有机相构成,该无机相由钙盐,主要是磷酸钙、氢氧化物和碳酸盐-磷灰石形成,该有机相由获自乙烯基乙酸盐和巴豆酸的聚合物形成。这些生物材料可以是紧密的或多孔的,并且当它们用作活组织中植入物时,根据相的性质和比例,其具有不同速度的再吸收,并且它们也可以用作可控药物递送系统产生的载体。
Description
技术领域
本发明应用于生物材料,特别是公知称为合成或混合生物材料(复合材料)的合成和应用领域,或者作为药物载体,可控的药物递送系统的其它生物医学应用,在这种情况下,所述生物材料是由碳酸钙一磷酸盐的陶瓷和乙烯基乙酸盐衍生聚合物形成的,当硬组织受到损伤或失掉时,所述生物材料能够作为硬组织的替代物。
背景技术
自从人类开始以来几个世纪,在人体的不同部位替代、重建和/或再生损伤或失掉的骨组织的需要已经成为面临着或多或少成功的挑战。尽管所发现的首先方案之一是不同类型骨移植物的使用,但是由于它们的各种限制,主要涉及获得它们的困难,对于患者而言的麻烦和外科手术风险及其中不定的效果,今天它们正在由其它生物材料所替代。用于这些目的的材料可以制备一个长的清单,包括不同类型的金属、聚合物、陶瓷和玻璃,它们通常称为骨移植物替代物(Senn N.关于通过抗菌脱钙骨移植术的无菌腔的治愈Amer.J.Med.Sc.,98:219-243;1889.,Weber J.M,White E.W.作为用于生物医学应用的新的陶瓷、金属和聚合物材料前体的碳酸盐矿物.Min.Sci.Eng.,5:151;1973,Williams D.F.健康护理应用材料方面的挑战Argew.Chem.Adv.Mater,101(5):678;1989,Hench L.L.,Wilson T.表面活化的生物材料.Science,226:630;1984)。可以说直到现在还没有发现适合不同医学专业的所有骨重建手术紧急情况的理想生物材料。然而,从生物材料的生物相容性,人体对其的耐受性和治愈效果的立场来看,在专家中有着这样广泛的认可,即磷酸钙,特别是羟磷灰石是该领域最有希望的生物材料(Klein C.P.A.T,Dreissen A.A.,of Groot K.,Vanden Hooff A.,骨组织中各种磷酸钙材料的生物降解特性.J.Biomed Mater Head.,17:769-784;1983,Shinazaki K,Mooney V.,骨替代物中多孔羟磷灰石和磷酸钙材料的比较研究.J.Orthop.Head,3:301;1985,Damien C.J.,Parsons J.R.骨移植物和骨移植替代物:目前技术和应用的综述.J.Appl.Biomat.,2:187-208;1991,Jallot E.羟磷灰石骨整合和杨氏模量(Young′s Modulus)之间相关性.Med.Eng.Phys.,20:697,1998)。这是因为这些物质与公知称为“生物学磷灰石”的骨矿物支持体具有很大的化学和结构同一性。这就是为什么主要在过去的30年,这些化合物在临床应用方面已经成功(Cottrell D.A.,Wolford L.M.正颌手术中珊瑚状构造羟磷灰石应用的长期估测.J.Oral Maxillofac.Surg.,56:935;199,.Avers R.A.,Simske S.J.,Nunes CR.,Wolford L.M.人类中多孔块羟磷灰石植入物的长期骨向内生长和残留的宏观硬度.J.OralMaxillofac.Surg.,56:1297;1998,González R,Blardoni F.,Master H.,Pereda O.,Pancorbo E.,Cienega MA.矫形外科学和创伤学中珊瑚状构造羟磷灰石HAP-200作为骨植入物生物材料的长期结果.CENIC Biological Sciences have,32(2):97-101;2001)。
但是,不同专家进行的研究已经可以检查到所述骨主要是由无机支持体(大约65%)构成,其余(35%)是有机物质和水,其中该无机支持体主要由上述这些磷酸钙组成。有机相的大部分由胶原组成,发现该胶原与生物学磷灰石具有紧密的相互关系(Weiner S.,Traub W.胶原纤维中羟磷灰石晶体的组织.FEBS,206(2):262;1986)。
骨组织的组分和结构知识已经刺激了具有不同组分、结构、多孔性和具有“体内”不同生物降解特性的磷酸钙生物材料的研究和开发。今天,存在各种这样类型的植入物,其中有专利US 4976736(1990年12月)、US 5900254(1999年5月)、FR2776282(1999年9月)、US 6001394(1999年12月)和US 6331312(2001年12月)中描述的植入物。刺激骨有机部分的来自于不同性质和来源的天然聚合物生物材料(胶原、quitosane、纤维素)及合成生物材料也已经被开发和应用于这些目的(US5837752(1998年11月)、US 5919234(1999年7月)、美国专利申请2003114552(2003年6月))。最近,对由磷酸钙和羟磷灰石与不同类型天然和合成聚合物制成的合成或混合材料(复合材料)的产生进行了深入的研究,目的是获得下面的产品,该产品具有与骨更相似的化学、物理和机械特性及具有可以获得作为骨植入物替代物的更好功能。
在过去的一些年里已经开发了大量这种类型合成材料(复合材料)的组合,其中可以提到的如下:羟磷灰石、胶原与糖胺聚糖(US 5071436,1991)、磷酸钙与纤维素的混合物(FR2715853,1995)、羟磷灰石与聚乳酸(polilactic acid)(WO9746178,1997)、羟磷灰石与硅酮(US5728157,1998)、磷酸钙与纤维素及它们的衍生物(US6558709,2003)、几种钙盐与几种聚合物制剂(US6579532,2003)、羟磷灰石、骨和几种无机盐与聚乙二醇、蜡、水凝胶和丙烯酸胶乳(US6605293,2003)。
没有发现关于乙烯基乙酸盐和巴豆酸的衍生聚合物与任何无机盐的可能联合可能用作植入物生物材料的报道。
然而,尽管上述产品在一些医学应用方面已经显现了良好的结果,但是他们仍旧不能满足人体不同区域骨重建外科手术的各种日益增加的需要。
对于一些应用,外科医师优选生物材料被很快再吸收的植入,在该地方很快留下了新骨,在其它情况下,根据待治疗损伤的部位和大小,要求植入物在较长的时间期间内保持不变。此外,如果生物材料能以可控方式递送药物,这是非常有利的,因为这允许同时治疗骨的不同病理学,如感染、炎性过程、瘤形成等。
另一方面,许多用于骨植入物的现有生物材料应用于大量人群中不经济可行。
最近,已经开发了来源于乙烯基乙酸盐和巴豆酸的衍生聚合物,其能作为用于持续作用的药物产生的适合载体(古巴专利号1993年的22199,2003年的22880,国际申请PCT/CU99/00002 1999)。
发明内容
本发明也涉及这些聚合物在人类可植入生物材料的产生中用于重建骨组织的新应用和用于其它治疗应用或重建外科手术。
本发明的主要目的是获得具有适合特性以作为骨植入物替代物起作用的合成或混合的生物材料(“复合材料”),其由以不同比例向来自于乙烯基乙酸盐和巴豆酸的衍生聚合物加入的磷酸钙、碳酸盐和氢氧化物、羟磷灰石、碳酸盐-磷灰石或它们的混合物组成。
本发明的另一个目的是根据需要外科手术的部位、骨类型和待治疗损伤的大小,所开发的生物材料可以是密集的或多孔的,并且具有不同的生物降解等级。
我们也研究了由连续层陶瓷-聚合物-陶瓷或聚合物-陶瓷-聚合物形成的这些生物材料,仅仅由聚合物、由陶瓷或由它们两种形成的生物材料才可以获得具有活组织的生物材料接触表面。
作为实施例,为了清楚本发明的进行,我们给出了下面的说明:
所开发的生物材料是由两种类型化合物,无机相(A)和有机相(B)组成。
无机相(A):它是由磷酸钙、氢氧化物、碳酸盐、羟磷灰石和碳酸盐-磷灰石或它们的混合物以不同的比例组成,如下表所示:
表1:生物材料制备中使用的一些无机化合物(A)混合物的组分
混合物 | Caa(PO4)b(H)c(CO3)d(OH)e(子指数(subindexes)的近似值) | 摩尔比率Ca/P | ||||
序号 | a | b | c | d | e | |
1 | 3 | 2 | 0 | 0 | 0 | 1.5 |
2 | 10 | 6 | 0 | 0 | 2 | 1.66 |
3 | 10 | 6 | 0 | 1 | 0 | 1.66 |
4 | 96 | 59 | 4 | 9 | 1 | 1.62 |
5 | 100 | 3 | 0 | 95 | 1 | 33 |
6 | 44 | 33 | 16 | 2 | 1 | 1.3 |
7 | 9 | 5 | 1 | 1 | 2 | 1.8 |
8 | 9 | 4 | 2 | 2 | 2 | 2.25 |
9 | 10 | 3 | 0 | 5 | 1 | 3.3 |
10 | 9 | 6 | 2 | 0 | 2 | 1.5 |
有机相(B)由下述成组分:聚-乙酸乙烯酯-共聚-乙烯醇(POVIAC)分解物,其有1和25%摩尔之间的乙烯醇单体单元,其分子量和纯度与聚乙酸乙烯酯所述的分子量和纯度相似;分子量在10000和250000D之间的聚乙酸乙烯酯,具有0和100ppm之间的单体残留含量,酸度达到0.5%,指乙酸,重金属含量指铅低于20ppm,并且无过氧化物(POVIAC1);具有巴豆酸组分的聚乙酸乙烯酯共聚巴豆酸,以巴豆酸单体单元重量计,在1和40%,单体含量在0和100ppm之间,分子量在10000和25000D之间,并且根据想要掺入到生物材料中的聚合物百分比,在乙醇或丙酮中无可变浓度的过氧化物(CROTAV)或它们的混合物。
具体实施方式
实施例1
用丙酮中POVIAC溶液(25%)逐渐地湿润具有0.1mm平均颗粒大小,(表1)序号10中所示近似组分的钙盐均匀混合物,直到获得糊状物为止。过筛混合物以获得直径在1和2mm之间的颗粒,留其在室温下干燥。将干燥的颗粒放于commiseration研磨机中磨碎,用丙酮再次湿润所获得的粉末,过筛,干燥以获得具有平均颗粒大小从1到2mm的颗粒化紧密物。
因此,所获得的具有约20%聚合物含量的产品适于作为骨植入物材料用以填充骨中空腔诸如肿瘤和囊肿后遗症。
实施例2
向前面实施例中所述无机盐混合物添加乙酰水杨酸,然后适当地混合以获得均匀物质,以相同方式进行该混合以获得具有15%POVIAC1和2.5%ASA的颗粒。该“复合材料”起用于可控药物递送的系统作用(图1)。
实施例3
具有2和2.5mm之间颗粒大小和与混合物2具有相似组分的一部分多孔羟磷灰石HAP-200(González R.;Melo M.C.;Pérez A.;Rodríguez B.C.珊瑚状结构多孔羟磷灰石HAP-200.主要的物理化学特性.Quimica Nova,16(6)11-12月:509-512;1993)颗粒被浸入在POVIAC的25%丙酮悬浮液,并且搅拌(表1)10%具有0.1mm颗粒大小的序号5混合物10分钟。分离颗粒,在空气中干燥。以这种方式获得的产品保持了其原始的多孔结构,该结构整个表面中具有聚合物层阻塞(图2)。
实施例4
用γ射线在25Kgy灭菌后,通过灵长类上肢骨中植入物的方法检测前述实施例中获得的产品,该产品在骨修补中显示了优良的结果,18个月后无不利的局部或系统反应(图3)。
实施例5
用乙醇中CROTAV溶液(26%)逐渐湿润具有0.1mm平均颗粒大小,具有(表1)序号10中所示适合组分的钙盐均匀混合物,直到获得糊状。过筛混合物以获得直径在1和2mm之间的颗粒,留其在室温下干燥。将干燥的颗粒放于commiseration研磨机中磨碎,用乙醇再次湿润所获得的粉末,再次过筛,干燥以获得具有平均颗粒大小从1到2mm的颗粒。
因此,所获得的具有约15%聚合物含量的产品适于作为骨植入物材料用以填充骨中空腔诸如肿瘤和囊肿后遗症。
实施例6
根据实施例5中所述方法制备的两种类型颗粒,一种颗粒具有与混合物2(G2)组分相似的组分,另一种颗粒具有混合物5(G5)的组分,将这两种类型颗粒植入在大鼠骨组织(股骨)中。用γ射线在25Kgy灭菌后,第一种颗粒移植在左侧,另一种颗粒移植在右侧。移出植入物,在手术后进展的不同期间分析该植入物,通过FTIR光谱学方法测定相中组分的变化以及通过化学分析测定摩尔比率Ca/P的变化。发现尽管在90天中颗粒G2没有显著地改变其组分,但是颗粒G5降解的相对快,向其结构中掺入的磷更接近骨的一半组分(图4)。
本发明具有下述优点:
1、获得了物理和机械非常稳定的生物材料,没有分离颗粒的破碎或松散。
2、所获得的生物材料可以是紧密的或多孔的,并且它们具有作为骨移植物替代物的适合生物机械特性。
3、获得了与本发明相的组分对应的具有不同降解速度的生物材料。
4、所开发的生物材料也作为可控的药物递送系统,其可以恢复损伤或失掉的骨,同时用药物,如抗生素、抗炎药等治疗不同骨病理学。
5、所获得的生物材料具有这种多孔性,因此当它们被植入到软组织中或骨中时,它们在其内部形成了新组织生长的活基质,而不会形成“袋子底部(sack bottom)”。
Claims (13)
1、用于骨植入物的复合生物材料,其特征在于其具有多相化学组分,包括钙盐组成的无机相,及乙烯基乙酸盐和巴豆酸的聚合物或共聚物或两者衍生物组成的另一种有机相。
2、如权利要求1所述的用于骨植入物的复合生物材料,其特征在于其具有不明显地紧密或多孔结构,后者具有三维互相连接的孔,孔的直径从5到840μm。
3、如权利要求1或2所述的用于骨植入物的复合生物材料,其特征在于所述无机相由不同比例的磷酸钙、氢氧化物、碳酸盐、羟磷灰石和碳酸盐-磷灰石或它们的混合物组成,其中摩尔比率P/Ca在0和99.9之间变化。
4、如权利要求1、2或3所述的用于骨植入物的复合生物材料,其特征在于无机盐可以是天然或合成来源的,紧密或多孔的,并且是物理一致的以获得成块或颗粒状的期望的物理形式。
5、如权利要求1或2所述的用于骨植入物的复合生物材料,其特征在于其组分中具有0.1和99%之间比例的有机相,该有机相由聚-乙酸乙烯酯-共聚-乙烯醇组分组成,其有1和25%摩尔之间分子量和纯度与聚乙酸乙烯酯的分子量和纯度相似的乙烯醇单体单元。
6、如权利要求1或2所述的用于骨植入物的复合生物材料,其特征在于其组分中具有0.1和99%之间比例的有机相,该有机相由分子量在10000和250000D之间的聚乙酸乙烯酯组成,残留的单体含量在0和100ppm之间,下限酸度达到0.5%,指乙酸,重金属含量指铅小于20ppm,并且无过氧化物。
7、如权利要求1或2所述的用于骨植入物的复合生物材料,其特征在于其组分中具有0.1和99%之间比例的有机相。该有机相由1和40%之间以巴豆酸单体单元计的巴豆酸组分组成,单体含量在0和100ppm之间,分子量在10000和250000D之间,并且无过氧化合物或它们的混合物。
8、如权利要求1、2、3、4或5所述的用于骨植入物的复合生物材料,其特征在于其组分中具有0.1和99%之间比例的有机相,该有机相由乙烯基乙酸盐和巴豆酸的衍生聚合物混合物组成。
9、如权利要求1、2、3、4、5或6所述的用于骨植入物的复合生物材料,其特征在于有机相在整个固体体积中是均一和平均分布的。
10、如权利要求1、2、3、4、5或6所述的用于骨植入物的复合生物材料,其特征在于有机相在整个无机支持体本体上是均一和平均分布的。
11、如权利要求1或8所述的用于骨植入物的复合生物材料,其特征在于当有机相覆盖无机支持体表面时,这种表面是由连续层陶瓷-聚合物-陶瓷或聚合物-陶瓷-聚合物形成,这样生物材料与活组织的接触表面只能由聚合物,由陶瓷或由两者形成。
12、一种用于骨植入物的复合生物材料,其特征在于当它作为骨植入物时,根据其组分中存在的无机相中的化学性质和关系,其具有每天在10-5和3.2%之间的不同速度的再吸收。
13、一种用于骨植入物的复合生物材料,其特征在于当它们被加载有相应的药物和被植入到软组织及骨中时,它们作为可控药物递送系统的用途。
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US7473678B2 (en) * | 2004-10-14 | 2009-01-06 | Biomimetic Therapeutics, Inc. | Platelet-derived growth factor compositions and methods of use thereof |
DE102005038381A1 (de) * | 2005-08-13 | 2007-02-15 | Amedo Gmbh | Schwammartiges Implantat |
CA2630077C (en) | 2005-11-17 | 2014-07-15 | Biomimetic Therapeutics, Inc. | Maxillofacial bone augmentation using rhpdgf-bb and a biocompatible matrix |
CN100372577C (zh) * | 2006-01-19 | 2008-03-05 | 浙江大学 | 一种生物活性壳-核多层微结构纳米粉体及其制备方法 |
EP1991282B1 (en) | 2006-02-09 | 2013-06-19 | BioMimetic Therapeutics, LLC | Compositions and methods for treating bone |
CA2656278C (en) | 2006-06-30 | 2016-02-09 | Biomimetic Therapeutics, Inc. | Compositions and methods for treating rotator cuff injuries |
US9161967B2 (en) * | 2006-06-30 | 2015-10-20 | Biomimetic Therapeutics, Llc | Compositions and methods for treating the vertebral column |
EP2086598B1 (en) | 2006-11-03 | 2015-05-27 | BioMimetic Therapeutics, LLC | Compositions and methods for arthrodetic procedures |
US20080195476A1 (en) * | 2007-02-09 | 2008-08-14 | Marchese Michael A | Abandonment remarketing system |
CN102014977B (zh) * | 2008-02-07 | 2015-09-02 | 生物模拟治疗有限责任公司 | 用于牵引成骨术的组合物和方法 |
KR20110067035A (ko) * | 2008-09-09 | 2011-06-20 | 바이오미메틱 세라퓨틱스, 인크. | 건 및 인대 손상의 치료를 위한 혈소판-유래 성장 인자 조성물 및 방법 |
KR20110135949A (ko) * | 2009-03-05 | 2011-12-20 | 바이오미메틱 세라퓨틱스, 인크. | 혈소판-유래 성장 인자 조성물 및 골연골성 결함의 치료 방법 |
CN101623266B (zh) * | 2009-07-24 | 2012-08-08 | 中国科学院上海硅酸盐研究所 | 磷酸钙/嵌段共聚物复合多孔纳米球及其制备方法 |
WO2011103598A1 (en) | 2010-02-22 | 2011-08-25 | Biomimetic Therapeutics, Inc. | Platelet-derived growth factor compositions and methods for the treatment of tendinopathies |
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CN101578117B (zh) * | 2007-01-15 | 2014-10-15 | 阿山特斯医疗有限公司 | 金属植入物 |
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CN100540073C (zh) | 2009-09-16 |
PT1679090E (pt) | 2010-12-17 |
ES2352734T3 (es) | 2011-02-22 |
ATE481991T1 (de) | 2010-10-15 |
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