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CN1120811A - 处理骨内材料的方法 - Google Patents

处理骨内材料的方法 Download PDF

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CN1120811A
CN1120811A CN94191772A CN94191772A CN1120811A CN 1120811 A CN1120811 A CN 1120811A CN 94191772 A CN94191772 A CN 94191772A CN 94191772 A CN94191772 A CN 94191772A CN 1120811 A CN1120811 A CN 1120811A
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R·T·莱蒂伦
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Bayer Oy
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Abstract

一种为消毒和生物适应性以利贮存的外科用包装的骨内材料；它包括用式(I)的双膦酸或其盐或酯在适宜有机溶液中的溶液处理的该骨内材料。式I中X是H、OH、CI、F或甲基而Y是Cl、OH、-(CH2)2-N(CH3)-(CH2)4-CH3、-(CH2)n-CH3或-(CH2)n-NH2(其中n是0或1-8的整数)、-NHZ(其中Z是吡啶基或环庚基)、SZ′(其中Z′是吡啶基或氯取代的苯基)或Y是吡啶基取代的低级烷基链。

Description

处理骨内材料的方法
本发明涉及在将骨内材料，包括欲被用于外科的各种植入物，引入人体之前用双膦酸对其进行处理。本发明特别是涉及将一定量的双膦酸加入该骨内材料的无菌保存介质中。
近年来对人造骨内材料，尤其是如人工关节、骨骼中的固定板、髋部和牙科植入物之类的欲引入人体植入物一直在作大量的研究。就具有高的机械强度和良好的生物亲合性的材料而言已取得了基本的成果。
包含有采用骨内假器官-包括植入物(螺栓植入物、叶片形植入物、针状植入物等)-引入骨组织的外科技术正广泛地用于矫形术及牙科外科，这是因为身体学工程中所取得的进展。
骨内假器官可大致分为两类：一方面是它们包括金属基质，而另一方面是陶瓷和玻璃-陶瓷(生物陶瓷)。金属假器官有卓越的强度性能，但生物适应性相当差。在矫形术和牙外科方面，钛及其合金是最常用的金属假器官。为增强骨的同化和骨的结合过程，通常用比如磷灰石或羟基磷灰石对该金属基质作等离子喷涂，以便促进骨的结合过程。作为骨内的矫形术假器官的例子可以提及Tricon-M和Allopro膝部假器官，Ortholoc胫骨假器官及Monk，DF-80及Authopor髋部假器官。在牙科领域，在常用的金属基质植入物之中可以提及纯钛植入物(Nobelpharma，Swede-VentR，IMZ)。在经涂覆的金属基质植入物中可提及BonefitR，一种带有等离子喷涂钛的钛基质；Steri-OssR，一种羟基磷灰石涂覆的金属合金基质及Calcitec，一种羟基磷灰石涂覆的钛基质。陶瓷植入物例如是以多晶的铝的氧化物、Al2O3(Frialit)为基的。玻璃-陶瓷及生物陶瓷包括玻璃、陶瓷及具有与骨结合能力的玻璃-陶瓷的各种组合物。
欲引入人体的骨内材料在使用前必须在严格的无菌条件下保存。这种保存可在干燥的条件下或在无菌溶液中进行。所有的被用的牙科植入物均包装在无菌注射器中。这些注射器或是空的，或盛有生物盐水溶液。通常牙科植入物包装在数毫升无菌氯化钠溶液的小安瓿中。髋部假器官则包装在无菌容器中，在其各个容器中的全部零件均无液体。
在使用前的假器官和植入物的保存不是一个只涉及杀菌的问题。已知的是，植入物的生物适应性与该材料的表面性质高度相关。因此，最重要的是小心控制表面层并在原子水平作出规定。两种原来用相同材料制成的植入物可得到完全不同的生物活性特性，这取决于材料是经怎样的处理。比如，对这两种相似的植入物而言，两者间的杀菌可以不同，从而导致不同的生物适应性。已经认识到了导致植入物表面失活的，涉及该植入物表面污染的风险的问题，而且已经提出了解决这一问题的各种建议。US4,712,681叙述了以一种无菌和无污染方式包装人造植入物的方法，按该法，将植入物装在用与植入物本身相同的材料制成的内盒中。US4,763,788提出了相当类似的解决污染问题的方法；它主张修改US4,712,681的双盒系统。
值入物表面对周围的颗粒的敏感性被认为是欲待解决的难题。
本发明基于这样的想法：利用此敏感性现象及使此骨内材料表面与对此骨内材料的生物适应性有正影响的反应性密切接触。这具体地是通过添加一种生物适应性促进剂于该骨内材料使用前将欲保存于其中的溶液中。
根据本发明的一个观点，将有效量的双膦酸加于欲被用来保存骨内材料，如人造关节、髋部假器官，固定板、牙科的或其它的植入物的溶液中。采用一直以这种方式，任选地与有计划的双膦酸治疗相结合的方式保存的骨内假器官被强烈地认为，与不向保存该骨内假器官的溶液添加双膦酸的状况相比，将导致低得多的失败率。
双膦酸是合成的有机化合物，结构上与焦磷酸相关，其中焦磷酸的P-O-P键被P-C-P键取代。与焦磷酸相反，双膦酸是阻碍骨组织中的酶水解作用的。该双膦酸是骨吸收作用的有力的抑制剂，而且它们一直成功地被用于治疗各种原因引起的高钙血症。大多数双膦酸已被研究过，但只有氯甲双膦酸、羟乙二膦酸及pamidronate达到了较广泛的临床运用。
这种双膦酸的主要作用是它的抑制骨吸收作用的能力，但与矿化作用相反，有关的是细胞的机理(Fleisch H，Prugs 1991；42：919-44)。这些不同的作用根据各个双膦酸化合物的结构有很大的变化。循环的双膦酸的半保留期是非常短的，数量级为几分钟至几小时。所给剂量的20-50％被骨骼吸收，而其余的排于尿中。在骨中的半保留期则长得多，并取决于骨骼转换率的本身。
为评估下列短期和长期施用这种药剂的耐受性和效果，126篇关于涉及氯甲双膦酸在治疗包含1930个病例的骨疾病的临床研究的公开文献中的一篇述评(Mian M等；Int J Clin Pharmacol Res.1991，11：109-14)表明：氯甲双膦酸治疗没有任何临床的明显的副作用，并证实其耐受性和安全性。
在属于该膦酸族中的很多化合物中氯甲双膦酸被广泛地用于治疗高钙血症和恶性肿瘤的骨质溶解(Bonjour J.P and Rizzoli R，Calcif Tissue Int 1990；46 Suppl：20-25)。全部公开的报告表明：氯甲双膦酸可使其中增加的骨吸收作用是显著紊乱的钙流出的大部分高钙血症和再水合癌症病人的血浆钙正常化(Fleisch H，Prugsl991；42：919-44)。
在该专利文献中还报导了在治疗哺乳动物中钙的磷酸盐(骨无机物)的异常迁移和沉积有用的各种膦酸化合物。所提到的文献有US.3,678,164、3,662,066、3,553,314、3,553,315、3,584,124、3,584,125、及3,641,246。US3,683,080公开了用氯甲双膦酸和其它的各种膦酸治疗包括软组织和关节症状在内的异常钙化。US4,234,645公开了氯甲双膦酸在治疗各种胶原蛋白病时是有用的。
如在上面所讨论的那样，就双膦酸的抑制与各种疾病相关的骨吸收作用的能力而言，已被资料很好地证实。然而从未建议过涉及骨内假器官，如髋部假器官、用于内部刚性固定的板及各种植入；从上腭剥除坏死部份或骨移植后的骨髓炎的外科手术后用这些化合物来促进骨组织的形成。特别是在牙科植入外科手术中，有严重的下颌骨牙槽萎缩病变的病人难于用常规的植入技术治疗。在结合点上常发现连接手术的可移动的固着装置(Adell R et al.，Iht J Oral&Maxillofac Surg 1990，5：347-359)。用于严重地被吸收的脊扩张的自体骨移植物经常吸收到可观的程度(Baker R D et al.，JOral Surg 1970；37：486-89)。
氯甲双膦酸对羟基磷灰石的作用已被大量研究。虽然氯甲双膦酸对羟基磷灰石的效果已被大量资料证实，但一直未建议过用氯甲双膦酸或其它双膦酸来保存涂有羟基磷灰石的，或另外涂覆的，包括植入物在内的骨内假器官。两者都未建议过用双膦酸激活这类假器官或值入物的未涂覆的金属表面。
本发明涉及一种处理外科用的骨内材料的方法，这种处理是有助于使此材料在无菌和生物适应性的条件下贮存，其特征是将此骨内材料置于含有效量的式(I)化合物或其无毒的可药用的盐或酯的水溶液中，其中X是H、OH、Cl、F或甲基，而Y是Cl、OH、-(CH2)2-N(CH3)-(CH2)4-CH3、-(CH2)n-CH3或-(CH2)n-NH2，(其中n是0或1-8的整数)、-NHZ(其中Z是吡啶基或环己基)、SZ′(其中Z′是吡啶基或氯取代的苯基)，或Y是吡啶基取代的低级烷基链；此后，或将此骨内材料从该溶液中取出、干燥和消毒；或将其密封于盛有一种双膦酸溶液的容器中并且消毒。
本发明还涉及出于消毒和生物适应性而包装起来以便贮存的外科用的骨内材料，其特征在于用式(I)的双膦酸或其无毒的，可药用的盐或酯溶于适宜溶剂中的溶液处理所述的骨内材料。
术语“骨内材料”应理解为包括欲引入人体的所有种类的骨内假器官及其零件，如人工关节、髋部假器官、固定骨骼的板和植入物，特别是牙科植入物。
出于本发明的目的，特别有价值的式(I)的成员是氯甲双膦酸，其中的X和Y都是Cl；pamidronate，其中X是OH而Y是-(CH2)2-NH2；alendronic酸，其中X是OH而Y是-(CH2)3-NH2；neridroni酸，其中X是OH而Y是-(CH2)5-NH2；risedronic酸，其中X是OH而Y是3-吡啶基甲基；tiludronate，其中X是H而Y是4-氯苯硫基；YM-175，其中X是H而Y是环庚基氨基；BM-210995，其中X是OH而Y是-(CH2)2-N(CH3)-(CH2)4-CH3；以及羟乙二膦酸，其中X是甲基而Y是OH。出于本发明目的的最佳化合物是氯甲二膦酸或其可药用的盐或酯。
在实施本发明中，可药用的盐和酯可用式(II)描述：其中X和Y的定义如上；而M是H，一种在药学上可接受的阳离子，较佳的是碱金属阳离子，如钠和钾的阳离子，或是烷基，或是芳基部分，如1-4个碳原子的烷基或苯基。
欲加入该处理溶液的双膦酸的适宜量的范围为0.5-100mg/ml，较佳是1-10mg/ml。
该处理，比如可如下地进行：
在制成该骨内假器官后，将它们浸在1-6mg/ml的双膦酸溶液中，时间范围为20分钟-7天。此后可将此骨内假器官干燥和用γ射线辐射消毒，然后在其使用前，在干燥的条件下贮存。可供选择的是，该骨内假器官可贮存于与其浸没过的，相同或相似的双膦酸溶液中。在此情况下，该双膦酸溶液用γ射线辐射消毒。
用双膦酸进行的处理，用于有陶瓷表面的以及无陶瓷表面的骨内假器官上。
通过动物和临床实验，此发明性的想法得以验证。根据两个单独的，用氯甲双膦酸二钠进行的研究，其细节将介绍于后的方法和结果，氯甲双膦酸对骨组织形成的作用已被资料证实。
在第一个试验中，用兔胫骨试验氯甲双膦酸对骨再生的作用。设计一种涉及不对此胫骨进行骨移植的实验模型。该实验揭示了：氯甲双膦酸对供体腔中的，及未用钛螺栓移植的骨移植物时的骨再生有积极的作用。用氯甲双膦酸处理的胫骨的血管化比对比胫骨更快和更完全。
人体研究的结果-其中病人有在一段时间后被取掉临时的植入物-证实：用氯甲双膦酸治疗的病人显示出比未用药的对照组更快的骨形成。
羟基磷灰石及双膦酸分子形成一种表面而不是化学结合体。在该表面中有钙原子区域，因此钙浓度很高。在骨内假器官或其它植入物表面上形成一种层面的羟基磷灰石和双膦酸的组合物有助于在外科手术后的骨再生。
双膦酸对处理植入物的效果也在报导于后的试验中进行了研究。
由于氯甲双膦酸与其以上述式(I)表示的类似物间在结构上和药理学上相近的关系，已被证明可相信式(I)的其余成员对促进骨内假器官，包括值入物在贮存时期的生物适应性也是有效的。实验I.氯甲双膦酸对兔中骨再生的效果
该研究的目的在于确定氯甲双膦酸是否对兔胫骨中的血管化和骨形成有积极的作用，在该骨中已移植了钛螺栓器具。材料及方法
采用16只骨骼成熟的(3.5-3.9kg)New Zealand白色雄兔。将这些动物分成两组。每组内8头动物(16条胫骨)组成。一组接受氯甲双膦酸二钠(BonefosR，Lei ras Oy，Finland)肌肉注射，一周两次。另一组(对照)未作处理。
肌肉注射2.8mg KetalarR(Parke-Davis，Spain)和2.0mlRompun(Bayer，Germany)使这些兔麻醉。
暴露出两种胫骨的近端，然后从手术区除去骨膜。用环锯横截去4mm的一块皮质骨。将一个0.6mm的钛植入物螺丝(Filpin，FilpolDental，Ireland)旋过这块骨。将这块用植入物穿透的骨旋入移植体空腔上3mm处。参看代表该兔胫骨的图1，其中A指的是植入物，T是移植体而F是移植体空腔。该图的上图表示横截面，而下图是俯视看到的胫骨。
将这些动物分成两组：对8只动物作微血管造影，而从另8只动物中取组织染色样品。用两根打了结的钢丝缠绕在此胫骨周围以便确定植入物和移植体空腔的确切位置来进行X射线学检验。参见图2，该图展示了手术区中的胫骨的侧面的X线照片。组织学评价
将8只动物杀死，用以作植入后各时期的组织学评价：14天后(2只兔)、21天(4只兔)及35天后(2只兔)。对照的和用氯甲双膦酸处理的动物数目每次都一样。
胫骨用磷酸盐缓冲的福尔马林固定，然后进行甲苯蓝染色和苏木清曙红(HE)染色。在光学显微镜下检查标本，然后记录下不利的效果或发炎的症状。显微血管造影
用静脉注射戊巴比妥21天后将8只动物杀死(4只作对照，4只被处理)。
在死亡之前暴露出腹动脉和静脉，然后插入18-规格的血管接受器(angiocath)并在适当位置捆牢。采用一个20ml的注射器(含肝素化的盐水)以便灌注该腹动脉。灌注持续到清沏的静脉流出物从该被处理的腹静脉流出为止。然后用装有桔红色硅酮橡胶化合物(Micro-FilR，Canton Biomeolical，Bonlder CO，USA)的100ml的注射器进行注射，直到桔红色的流出物从该腹静脉流出为止。在该化合物注入4小时后，将此胫骨分离。然后将这些标本按该制造者的清洁技术顺序脱水。
用手术刀经此移植物中部截下几个横截面，以便在解剖显微镜下进行观察和拍幻片。借助颜色透明度计算穿过该移植体宿主连接处的脉管绝对数目(Fppley B et al.，J Oral Maxillofac Surg 1988；46：391-98)。
脉管计数以其中的大多数脉管已被观察过的标本进行。按两种不同的需要由一个观察者作脉管计数，然后取平均值。如果两个值间的变化大于10％，进行第三次计数，然后取三数的平均值。用成对的t-试验在两组中进行脉管计数比较；P值小于0.05则认为是明显的。结果
临床观察表明：所有愈合的刨口都无事故。血管形成的评价
当进行脉管计数时，它们中大部分是清晰可见的。然而，难于对骨移植体和骨供体腔结合处小脉管计数。由于同一观察者所得的两值有变化，所以用5个标本进行第三次计数。供体空腔
用氯甲双膦酸处理的兔中的穿入该供体空腔的脉管数比对照物的多。此结果列于下表I，这区别在统计学上是显著的(P＜0.05)。表I穿入供体腔的脉管数(X)
                  X        S.D.    胫骨数对照物                12.3     4.6       8用氯甲双膦酸处理的    26.3     4.0       8
还可从图3和4的照片中看到脉管数的差别。图3所示的是取自用氯甲双膦酸处理的21-天后的标本。植入物和移植体处于该图片中心。可看到供体腔在该移植体右边。可看到的是：很多脉管穿过该供体腔和移植体。图4展示了取自未经处理兔的21-天的标本。只有少数脉管穿过此移植体。移植体
取自用氯甲双膦酸处理的动物的胫骨中的移植体的血管形成比取自对照物的胫骨中的血管形成快而且完全得多。该区别在统计上是明显的(P＜0.05)。结果列于表II。表II穿入移植体的脉管数(X)
                  X      S.D.    胫骨数对照物               4.75     1.7      8用氯甲双膦酸处理的   13.0     4.0      8
用药治疗过的兔中的穿过的脉管比对照组的此脉管更靠近该空腔的中心。在该用药处理过的兔中，取自该标本一侧的脉管数比取自其对侧的脉管数大。组织观察
当在光学显微镜下研究这些标本时，未看到任何不利的组织反应或发炎的症状。供体腔
14天的对比标本显出少量有胶原蛋白的形成，而且在该腔的中部，部分地缺少组织学上可见的成分。用氯甲双膦酸处理过的标本显出比对照物标本更多胶原蛋白的形成。未见到空的空间。在三周时，对照物标本仅在该腔的外沿显出有少量的骨形成。在该腔的内部主要是充有胶原蛋白，而且在该腔和骨之间可清楚地看到一条明显的线。用氯甲双膦酸处理过的供体空腔中几乎完全充满了新骨。在此三周的标本中的新骨间仍发现胶原蛋白。
5周的对照物空腔只部分地充有新骨，而且在大部分腔中在钻成的腔和骨之间的线仍然可见。用氯甲双膦酸处理的腔完全充满了新骨，而且钻孔线是可见的，但该供体腔和旧骨间的溶解已开始。图5说明5周的对照的腔。在腔的中间和钻孔线中可看到骨的再生。在腔的大部分中仍可看到钻出的腔和骨之间的这条线。因成骨细胞导致的新骨形成偶然地在该钻孔线中及该腔的中心发生。图6说明5周的用氯甲双膦酸处理的腔。腔完全充满新骨，钻孔线仍然可见，但在供体腔和皮质骨之间有融合。图7和8是图6的放大图。在图7中可见到坚固的新骨。图8展示了皮质和新骨已几乎完全融合。移植体
在整个阶段，用氯甲双膦酸处理过的组中的移植体上的软组织和骨膜含有的胶原蛋白比对照动物的多。第14天的对照物标本示出带有侵入胶原蛋白的坏死的骨。处理过的移植体于其外沿开始被吸收。图9所示是4周的氯甲双膦酸处理的兔胫骨的测面图。新骨覆盖了移植体。骨膜是完整的，但比上述非手术区的薄。植入物和移植体在这标本的中部。供体腔在移植体右边并且是新骨在正常的空的兔的海棉骨中形成的原因。
21天的移植体被部分吸收。在此处理过的胫骨中看到了该吸收区中的新骨。在氯甲双膦酸处理组中，皮质骨区中的植入物周围的骨形成是坚实的。图10表示氯甲双膦酸处理21天的标本。移植体被部分吸收及被新骨取代。如在图1中一样，字母A和T分别代表植入物和移植体，而E代表邻近移植体和皮质胫骨的新骨。
在处理过的胫骨中，在35天的标本里，新骨形成几乎遍及此移植体。在对照的移植体中只看到固态骨。
通过移植体的微血管化发生了该移植体的再生。在兔胚胎的研究中，Ray(Ray R D Clin Orthop 1977；87：43-48)表示：兔胚胎的微血管化花费了3-4周的时间。在一篇述评文章中，Burchardt(Burchardt H，Clin Orthop 1983；174：28-42)谈到：就再血管化的速度而言，疏松骨和皮质移植物不同。他说：由于端对端地与宿主脉管吻合的结果，疏松的移植物的再血管化可在数小时内发生。再血管化可在2周内完成(Ray R D；参考文献如上)。直到第6天，疏松的移植物尚未被血管穿透(Ray R D；参考文献如上)。根据Eppley及其合作者的报告(Eppley B et al.，J Oral MaxifollfacSurg 1988；46：391-98)选21天作为植入后的再生时间。它们发现：兔中骨移植物的血管化在21天后达到最大值。
就该对照组而论，本研究的结果证实了早期报告的结果(BonjourJ P；Ray R D；二者参考文献见上文)。在用药处理的兔中，血管化发生比在对照组中的快得多。组织学研究清楚表明：用氯甲双膦酸处理形成了更好的骨。该研究结果表明：在有高度的骨再生失败风险的植入物和移植体病人中，双膦酸，特别是氯甲双膦酸是有用的。II.人体试验材料和方法
本研究的材料是20名无牙病人。他们全来到Institute ofDintistry，Uni versity of Turku，以便进行植入操作。在University of Turku的Instituonal Review Board of Facultyof Medicine接受了此项目，以便确定入的研究目标是否有风险。由Institntional Review Board作出的一致的判断是：涉及此种活动的人的研究目标无任何风险。病人给出了许可以便说明临时的植入物。直到此临时的植入物被取出前，10名病人得到日剂量1600mg的氯甲双膦酸二钠，而10名病人得到安慰剂。这种药和安慰剂的分别施用开始于外科手术前一周，并在手术后持续3周。外科技术
采用用5个Astra植入物的常规方法。图11是带有4个Astra植入物的人的下颌骨的前视图，其中A指的是植入物，E是带有骨的植入物而N是下颌神经。为避免对神经功能的干扰，通常将植入物置于下颌神经端之间。在手术时，将临时的4mm的螺丝置于该下颌骨的中线处。骨的重造
以一次单独的手术，在4周(10名病人，相等地来自两组)和12周(10名病人，相等地来自两组)后，用套孔器套出此4mm的临时植入物。将标本埋在丙烯酸块中，并在中线分成两块。对其中的一块作组织学检查。另一块作扫描式电子显微镜检查。在骨-植入物交界处和骨中于三点用SEM/EDXA(能量分散X射线分析)进行电子显微镜检查。在4个不同部位，两个在上皮质骨，一个在植入物中部，一个在其底部，计算以下值：钠、钙、磷、镁和钛。在12点计算钙/磷比和钙/镁比。结果临床处理
所有的创口愈合良好。两个病人因其在愈合期的较低的假牙而有问题。通过取出一部分假牙对他们作了治疗。未记录到任何副作用。一名病人在其髋骨假器官处有疼痛。这些症状在氯甲双膦酸治疗后消失。组织学检查一个月的标本
因为全部下颌骨被明显吸收，所以当移出的植入物的长度为4mm时，在全部标本中活体解剖的骨是皮质的。组织学结果示于图12和13，它们都示出了用图11中的E标出的骨-植入物标本。图13是图12的放大。未发现海绵骨。包覆此植入物的软的牙龈组织是健康的。
组织学检查表明，在用药治疗的下颌骨中的新骨不比对照的下颌骨中的多。没有任何发炎的迹象。在植入物和骨间的空间主要充满胶原蛋白。在相同的点上，骨和植入物间的接触是紧密的。这很自然，因为采用了旋入的Astra植入物。SEM-结果
表III示出了植入临时Astra植入物后4周的人下颌骨中的SEM结果。这10000×SEM图是与图11和12相同的。在图14中用小数字示出了测量矿物浓度的确切的点。这些标准点的平均值列于表III。表III
         CaO   P2O5CaO/P2O5  Mg    Na对照物        56      30       1.8           1.2    8.2用药治疗的    72      40       1.8           0.9    2.8该值为重量百分数。
在两组中，组织学和SEM图片是相似的。在光学和SEM-交选图下未见任何差别。在一个月的标本中，用药治疗的下颌骨中的P2O5和CaO明显大于对照的下颌骨中的P2O5和CaO。这意味着迅速的骨形成已经开始，骨细胞已消溶骨。在用药治疗的病人中的骨生长要比对照病人强。III.浸没研究
在下面的研究中证实了双膦酸对处理植入体使用前的表面的效果。将20只骨骼成熟的兔用于植入包覆了羟基磷灰石的6mm的IMZ-植入物。10只兔在手术前每周两次肌肉注射25mg/kg的氯甲双膦酸。一周两次的术后注射持续18天。其余10只兔在手术前或后未得到任何的有计划氯甲双膦酸处理。在手术中将IMZ-植入物植入每只兔的两个股骨中。手术植入这些兔右股骨的植入物，在其被植入前曾于含6mg/ml氯甲双膦酸的生理溶液中浸过5秒钟。手术植入该兔左股骨的植入物在植入前未用氯甲双膦酸处理。按前述方法作标本分析。进行SEM检查，而新骨(NB)的总量以及与该植入物接触的骨的总量(IB，即骨同化作用)被测定。
20只兔的全部创口愈合而无感染。发现了NB和IB量变化很大。初步结果表明：有计划的用氯甲双膦酸处理这些兔以及将植入物在其被植入前浸于氯甲双膦酸溶液中高度增强了NB和IB形成。在兔的有计划的氯甲双膦酸处理与植入物在氯甲双膦酸溶液中的浸渍的结合取得了最高的NB和IB量。在植入有计划用药处理过的兔中之前将羟基磷灰石包覆的IMZ植入物浸于氯甲双膦酸溶液中导致了比植入经类似的有计划用药处理的兔中的而未处理过的IMZ植入物更快的骨重造。
图15所示是手术植入未用药处理的兔中的未处理植入物。图16展示了手术植入有计划用药治疗的兔中的浸渍过的植入物。在图16中可清楚看到骨形成的进展。

Claims (11)

1.为消毒和生物适应性而有利贮存的外科用的处理骨内材料的方法，其特征在于将此骨内材料浸于含有效量的式(I)双膦酸或其无毒的可药用的盐或酯的水溶液中，
Figure A9419177200021
其中X是H、OH、Cl、F或甲基而Y是Cl、OH、-(CH2)2-N(CH3)-(CH2)4-CH3、-(CH2)n-CH3或-(CH2)n-NH2(其中n是0或1-8的整数)、-NHZ(其中Z是吡啶基或环庚基)、SZ′(其中Z′是吡啶基或氯取代的苯基)或Y是吡啶基取代的低级烷基链；此后或将该骨内材料-从此溶液中取出、干燥和消毒，或者将其-密封在含双膦酸溶液的容器中然后消毒。
2.为消毒和生物适应性而有利贮存的外科包装的骨内材料，其特征在于所述骨内材料用式(I)的双膦酸或其无毒的可药用的盐或酯在适宜溶剂中的溶液处理，其中X是H、OH、Cl、F或甲基，而Y是Cl、OH、-(CH2)2-N(CH3)-(CH2)4-CH3、-(CH2)n-CH3或-(CH2)n-NH2(其中n是0或1-8的整数)、-NHZ(其中Z是吡啶基或环庚基)、SZ′(其中Z′是吡啶基或氯取代的苯基)或Y是吡啶基取代的低级烷基链。
3.权利要求2的包装的骨内材料，其特征在于所述骨内材料被置于含有式(I)双膦酸或其无毒的可药用的盐或酯在适宜溶剂中的消毒溶液的密闭容器中。
4.权利要求2的包装的骨内材料，其特征在于所述骨内材料包含金属或金属合金基质。
5.权利要求4的包装的骨内材料，其特征在于所述骨内材料包含钛或钛基合金的基质，所述基质是用骨结合层包覆的。
6.权利要求5的包装的骨内材料，其特征在于所述基质用含羟基磷灰石灰层包覆。
7.权利要求2或3的包装的骨内材料，其特征在于所述骨内材料是陶瓷或玻璃陶瓷假器官。
8.权利要求2或3的包装的骨内材料，其特征在于该双膦酸化合物系选自由氯甲双膦酸、pamidronate、羟乙二膦酸、alendronic酸、neridronic酸、risedronic酸、tiludronate、YM-175、BM-210995及所述化合物的可药用的盐或酯。
9.权利要求8的包装的骨内材料，其特征在于该化合物是氯甲双膦酸或其可药用的盐或酯。
10.权和要求9的包装的骨内材料，其特征在于该化合物是氯甲双膦酸二钠。
11.权利要求9的包装的骨内材料，其特征在于该化合物是氯甲双膦酸二钠，而该骨内材料是包含钛或钛基合金基质的牙科植入物，所述基质是为含磷灰石的涂层所包覆的。
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Families Citing this family (164)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5646134A (en) * 1994-04-21 1997-07-08 Merck & Co., Inc. Alendronate therapy to prevent loosening of, or pain associated with, orthopedic implant devices
US5652227A (en) * 1995-01-30 1997-07-29 Teronen; Olli Pekka Inhibition of the degradation of connective tissue matrix protein components in mammals
US8172897B2 (en) * 1997-04-15 2012-05-08 Advanced Cardiovascular Systems, Inc. Polymer and metal composite implantable medical devices
US6240616B1 (en) * 1997-04-15 2001-06-05 Advanced Cardiovascular Systems, Inc. Method of manufacturing a medicated porous metal prosthesis
US10028851B2 (en) * 1997-04-15 2018-07-24 Advanced Cardiovascular Systems, Inc. Coatings for controlling erosion of a substrate of an implantable medical device
US6214049B1 (en) 1999-01-14 2001-04-10 Comfort Biomedical, Inc. Method and apparatus for augmentating osteointegration of prosthetic implant devices
WO1999030632A1 (en) * 1997-12-18 1999-06-24 Comfort Biomedical, Inc. Bone augmentation for prosthetic implants and the like
IL125336A0 (en) 1998-07-14 1999-03-12 Yissum Res Dev Co Compositions for inhibition and treatment of restinosis
US7008645B2 (en) * 1998-07-14 2006-03-07 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method of inhibiting restenosis using bisphosphonates
US6984400B2 (en) * 1998-07-14 2006-01-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method of treating restenosis using bisphosphonate nanoparticles
US6331533B1 (en) 1998-11-16 2001-12-18 Merck & Co., Inc. Method for inhibiting dental resorptive lesions
US6680307B1 (en) * 1998-12-04 2004-01-20 Roche Diagnostics Gmbh Use of ibandronate for promoting osseointegration of endoprostheses
JP2002536123A (ja) * 1999-02-09 2002-10-29 スローン − ケタリング・インスティテュート・フォー・キャンサー・リサーチ 抗吸収性骨セメントならびに同種、自家、および異種骨移植片
WO2000064516A1 (en) * 1999-04-22 2000-11-02 Hydromed Sciences A Division Of Gp Strategies Corporation Controlled delivery of bisphosphonates
CA2396393A1 (en) * 2000-01-04 2001-07-12 The Regents Of The University Of California Use of low dosage bisphosphonates to inhibit cardiac and arterial calcification
US20080156657A1 (en) * 2000-02-17 2008-07-03 Butterfield Paul D Conductive polishing article for electrochemical mechanical polishing
US7125477B2 (en) * 2000-02-17 2006-10-24 Applied Materials, Inc. Contacts for electrochemical processing
US7374644B2 (en) * 2000-02-17 2008-05-20 Applied Materials, Inc. Conductive polishing article for electrochemical mechanical polishing
US20040020789A1 (en) * 2000-02-17 2004-02-05 Applied Materials, Inc. Conductive polishing article for electrochemical mechanical polishing
WO2002004038A1 (en) * 2000-07-12 2002-01-17 Hopital Orthopedique De La Suisse Romande Active biocoating for bone implant
CH694935A5 (de) * 2000-07-26 2005-09-30 Straumann Holding Ag Oberflaechenmodifizierte Implantate.
WO2002040073A1 (en) * 2000-11-20 2002-05-23 Université De Genève Endosseous implant
GB0029111D0 (en) * 2000-11-29 2001-01-10 Novartis Ag Organic compounds
CN1608036B (zh) * 2001-08-02 2010-09-22 3M创新有限公司 Al2O3-Y2O3-ZrO2/HfO2材料及其制备和使用方法
US7625509B2 (en) * 2001-08-02 2009-12-01 3M Innovative Properties Company Method of making ceramic articles
CN101538120B (zh) 2001-08-02 2011-08-03 3M创新有限公司 从玻璃制备制品的方法以及所制备的玻璃陶瓷制品
WO2003012000A2 (en) * 2001-08-02 2003-02-13 3M Innovative Properties Company Abrasive particles, and methods of making and using the same
US7563293B2 (en) * 2001-08-02 2009-07-21 3M Innovative Properties Company Al2O3-rare earth oxide-ZrO2/HfO2 materials, and methods of making and using the same
KR100885327B1 (ko) * 2001-08-02 2009-02-26 쓰리엠 이노베이티브 프로퍼티즈 컴파니 연마 입자 및 그의 제조 방법 및 사용 방법
US7989018B2 (en) * 2001-09-17 2011-08-02 Advanced Cardiovascular Systems, Inc. Fluid treatment of a polymeric coating on an implantable medical device
US7285304B1 (en) * 2003-06-25 2007-10-23 Advanced Cardiovascular Systems, Inc. Fluid treatment of a polymeric coating on an implantable medical device
US6863683B2 (en) * 2001-09-19 2005-03-08 Abbott Laboratoris Vascular Entities Limited Cold-molding process for loading a stent onto a stent delivery system
US6596338B2 (en) * 2001-10-24 2003-07-22 Howmedica Osteonics Corp. Antibiotic calcium phosphate coating
US20040131754A1 (en) * 2001-10-24 2004-07-08 Howmedica Osteonics Corp. Antibiotic calcium phosphate coating
US7670612B2 (en) 2002-04-10 2010-03-02 Innercap Technologies, Inc. Multi-phase, multi-compartment capsular delivery apparatus and methods for using same
US8056370B2 (en) * 2002-08-02 2011-11-15 3M Innovative Properties Company Method of making amorphous and ceramics via melt spinning
US7179526B2 (en) * 2002-08-02 2007-02-20 3M Innovative Properties Company Plasma spraying
US20060271168A1 (en) * 2002-10-30 2006-11-30 Klaus Kleine Degradable medical device
IL153699A (en) 2002-12-26 2008-11-26 Prochon Biotech Ltd The composition for transplantation basically
US7758881B2 (en) 2004-06-30 2010-07-20 Advanced Cardiovascular Systems, Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US8435550B2 (en) 2002-12-16 2013-05-07 Abbot Cardiovascular Systems Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US7811496B2 (en) * 2003-02-05 2010-10-12 3M Innovative Properties Company Methods of making ceramic particles
US20040148868A1 (en) * 2003-02-05 2004-08-05 3M Innovative Properties Company Methods of making ceramics
US7175786B2 (en) * 2003-02-05 2007-02-13 3M Innovative Properties Co. Methods of making Al2O3-SiO2 ceramics
US7258707B2 (en) * 2003-02-05 2007-08-21 3M Innovative Properties Company AI2O3-La2O3-Y2O3-MgO ceramics, and methods of making the same
US6984261B2 (en) * 2003-02-05 2006-01-10 3M Innovative Properties Company Use of ceramics in dental and orthodontic applications
US7067169B2 (en) 2003-06-04 2006-06-27 Chemat Technology Inc. Coated implants and methods of coating
US10517883B2 (en) 2003-06-27 2019-12-31 Zuli Holdings Ltd. Method of treating acute myocardial infarction
US20060051407A1 (en) * 2003-06-27 2006-03-09 Yoram Richter Method of treating ischemia-reperfusion injury
US7197896B2 (en) * 2003-09-05 2007-04-03 3M Innovative Properties Company Methods of making Al2O3-SiO2 ceramics
US7141523B2 (en) * 2003-09-18 2006-11-28 3M Innovative Properties Company Ceramics comprising Al2O3, REO, ZrO2 and/or HfO2, and Nb2O5 and/or Ta2O5 and methods of making the same
US7198675B2 (en) 2003-09-30 2007-04-03 Advanced Cardiovascular Systems Stent mandrel fixture and method for selectively coating surfaces of a stent
ES2377727T3 (es) * 2003-10-16 2012-03-30 Straumann Holding Ag Envase para conservar un dispositivo médico, en particular un implante dental
US20050137078A1 (en) * 2003-12-18 2005-06-23 3M Innovative Properties Company Alumina-yttria particles and methods of making the same
US20050137076A1 (en) * 2003-12-18 2005-06-23 3M Innovative Properties Company Transparent fused crystalline ceramic, and method of making the same
JP3920263B2 (ja) * 2003-12-22 2007-05-30 インターナショナル・ビジネス・マシーンズ・コーポレーション 情報処理装置、制御方法、プログラム、及び記録媒体
ITMI20040218A1 (it) * 2004-02-10 2004-05-10 Abiogen Pharma Spa Uso di neridronato sodico per promuovere la neoformazione ossea
US8568469B1 (en) 2004-06-28 2013-10-29 Advanced Cardiovascular Systems, Inc. Stent locking element and a method of securing a stent on a delivery system
US8241554B1 (en) 2004-06-29 2012-08-14 Advanced Cardiovascular Systems, Inc. Method of forming a stent pattern on a tube
WO2006007730A1 (en) * 2004-07-21 2006-01-26 The University Of British Columbia Method of electrolytically depositing a pharmaceutical coating onto a conductive osteal implant
US20060020330A1 (en) * 2004-07-26 2006-01-26 Bin Huang Method of fabricating an implantable medical device with biaxially oriented polymers
US7731890B2 (en) * 2006-06-15 2010-06-08 Advanced Cardiovascular Systems, Inc. Methods of fabricating stents with enhanced fracture toughness
US8747878B2 (en) 2006-04-28 2014-06-10 Advanced Cardiovascular Systems, Inc. Method of fabricating an implantable medical device by controlling crystalline structure
US8778256B1 (en) 2004-09-30 2014-07-15 Advanced Cardiovascular Systems, Inc. Deformation of a polymer tube in the fabrication of a medical article
US8747879B2 (en) * 2006-04-28 2014-06-10 Advanced Cardiovascular Systems, Inc. Method of fabricating an implantable medical device to reduce chance of late inflammatory response
US7971333B2 (en) * 2006-05-30 2011-07-05 Advanced Cardiovascular Systems, Inc. Manufacturing process for polymetric stents
US7332453B2 (en) * 2004-07-29 2008-02-19 3M Innovative Properties Company Ceramics, and methods of making and using the same
US20060041102A1 (en) * 2004-08-23 2006-02-23 Advanced Cardiovascular Systems, Inc. Implantable devices comprising biologically absorbable polymers having constant rate of degradation and methods for fabricating the same
US9283099B2 (en) * 2004-08-25 2016-03-15 Advanced Cardiovascular Systems, Inc. Stent-catheter assembly with a releasable connection for stent retention
US7229471B2 (en) * 2004-09-10 2007-06-12 Advanced Cardiovascular Systems, Inc. Compositions containing fast-leaching plasticizers for improved performance of medical devices
US8173062B1 (en) 2004-09-30 2012-05-08 Advanced Cardiovascular Systems, Inc. Controlled deformation of a polymer tube in fabricating a medical article
US8043553B1 (en) 2004-09-30 2011-10-25 Advanced Cardiovascular Systems, Inc. Controlled deformation of a polymer tube with a restraining surface in fabricating a medical article
US7875233B2 (en) 2004-09-30 2011-01-25 Advanced Cardiovascular Systems, Inc. Method of fabricating a biaxially oriented implantable medical device
US8071574B2 (en) * 2005-02-22 2011-12-06 John Dennis Bobyn Implant improving local bone formation
US20060224226A1 (en) * 2005-03-31 2006-10-05 Bin Huang In-vivo radial orientation of a polymeric implantable medical device
US7381048B2 (en) * 2005-04-12 2008-06-03 Advanced Cardiovascular Systems, Inc. Stents with profiles for gripping a balloon catheter and molds for fabricating stents
US7862552B2 (en) 2005-05-09 2011-01-04 Boston Scientific Scimed, Inc. Medical devices for treating urological and uterine conditions
US7291166B2 (en) * 2005-05-18 2007-11-06 Advanced Cardiovascular Systems, Inc. Polymeric stent patterns
US7658880B2 (en) * 2005-07-29 2010-02-09 Advanced Cardiovascular Systems, Inc. Polymeric stent polishing method and apparatus
US7297758B2 (en) * 2005-08-02 2007-11-20 Advanced Cardiovascular Systems, Inc. Method for extending shelf-life of constructs of semi-crystallizable polymers
US20070038290A1 (en) * 2005-08-15 2007-02-15 Bin Huang Fiber reinforced composite stents
US7476245B2 (en) * 2005-08-16 2009-01-13 Advanced Cardiovascular Systems, Inc. Polymeric stent patterns
US20070045252A1 (en) * 2005-08-23 2007-03-01 Klaus Kleine Laser induced plasma machining with a process gas
US20070045255A1 (en) * 2005-08-23 2007-03-01 Klaus Kleine Laser induced plasma machining with an optimized process gas
US9248034B2 (en) * 2005-08-23 2016-02-02 Advanced Cardiovascular Systems, Inc. Controlled disintegrating implantable medical devices
AU2006292224B2 (en) 2005-09-19 2013-08-01 Histogenics Corporation Cell-support matrix and a method for preparation thereof
US9050391B2 (en) * 2005-10-27 2015-06-09 Nexilis Ag Implant and production method for said implant
ATE537807T1 (de) 2005-10-27 2012-01-15 Thommen Medical Ag Dentalimplantat und verfahren zu dessen herstellung
EP3517137A1 (en) * 2005-11-14 2019-07-31 Biomet 3I, LLC Deposition of discrete nanoparticles on an implant surface
US7867547B2 (en) 2005-12-19 2011-01-11 Advanced Cardiovascular Systems, Inc. Selectively coating luminal surfaces of stents
US20070154713A1 (en) * 2005-12-30 2007-07-05 3M Innovative Properties Company Ceramic cutting tools and cutting tool inserts, and methods of making the same
US20070151166A1 (en) * 2005-12-30 2007-07-05 3M Innovative Properties Company Method of making abrasive articles, cutting tools, and cutting tool inserts
US7598188B2 (en) * 2005-12-30 2009-10-06 3M Innovative Properties Company Ceramic materials and methods of making and using the same
US7281970B2 (en) * 2005-12-30 2007-10-16 3M Innovative Properties Company Composite articles and methods of making the same
US20070151961A1 (en) * 2006-01-03 2007-07-05 Klaus Kleine Fabrication of an implantable medical device with a modified laser beam
US20070156230A1 (en) * 2006-01-04 2007-07-05 Dugan Stephen R Stents with radiopaque markers
US7951185B1 (en) 2006-01-06 2011-05-31 Advanced Cardiovascular Systems, Inc. Delivery of a stent at an elevated temperature
US20070179618A1 (en) * 2006-01-31 2007-08-02 Sdgi Holdings, Inc. Intervertebral prosthetic disc
US20070179219A1 (en) * 2006-01-31 2007-08-02 Bin Huang Method of fabricating an implantable medical device using gel extrusion and charge induced orientation
US20070179615A1 (en) * 2006-01-31 2007-08-02 Sdgi Holdings, Inc. Intervertebral prosthetic disc
US7964210B2 (en) * 2006-03-31 2011-06-21 Abbott Cardiovascular Systems Inc. Degradable polymeric implantable medical devices with a continuous phase and discrete phase
US20070254012A1 (en) * 2006-04-28 2007-11-01 Ludwig Florian N Controlled degradation and drug release in stents
US8069814B2 (en) 2006-05-04 2011-12-06 Advanced Cardiovascular Systems, Inc. Stent support devices
US7761968B2 (en) * 2006-05-25 2010-07-27 Advanced Cardiovascular Systems, Inc. Method of crimping a polymeric stent
US7951194B2 (en) 2006-05-26 2011-05-31 Abbott Cardiovascular Sysetms Inc. Bioabsorbable stent with radiopaque coating
US8752268B2 (en) 2006-05-26 2014-06-17 Abbott Cardiovascular Systems Inc. Method of making stents with radiopaque markers
US20070282434A1 (en) * 2006-05-30 2007-12-06 Yunbing Wang Copolymer-bioceramic composite implantable medical devices
US8343530B2 (en) * 2006-05-30 2013-01-01 Abbott Cardiovascular Systems Inc. Polymer-and polymer blend-bioceramic composite implantable medical devices
US7842737B2 (en) 2006-09-29 2010-11-30 Abbott Cardiovascular Systems Inc. Polymer blend-bioceramic composite implantable medical devices
US7959940B2 (en) * 2006-05-30 2011-06-14 Advanced Cardiovascular Systems, Inc. Polymer-bioceramic composite implantable medical devices
US20080058916A1 (en) * 2006-05-31 2008-03-06 Bin Huang Method of fabricating polymeric self-expandable stent
US20070281073A1 (en) * 2006-06-01 2007-12-06 Gale David C Enhanced adhesion of drug delivery coatings on stents
US8486135B2 (en) 2006-06-01 2013-07-16 Abbott Cardiovascular Systems Inc. Implantable medical devices fabricated from branched polymers
US20070282433A1 (en) * 2006-06-01 2007-12-06 Limon Timothy A Stent with retention protrusions formed during crimping
US8034287B2 (en) * 2006-06-01 2011-10-11 Abbott Cardiovascular Systems Inc. Radiation sterilization of medical devices
US20070286941A1 (en) * 2006-06-13 2007-12-13 Bin Huang Surface treatment of a polymeric stent
US8603530B2 (en) 2006-06-14 2013-12-10 Abbott Cardiovascular Systems Inc. Nanoshell therapy
US8048448B2 (en) 2006-06-15 2011-11-01 Abbott Cardiovascular Systems Inc. Nanoshells for drug delivery
US8535372B1 (en) 2006-06-16 2013-09-17 Abbott Cardiovascular Systems Inc. Bioabsorbable stent with prohealing layer
US20070290412A1 (en) * 2006-06-19 2007-12-20 John Capek Fabricating a stent with selected properties in the radial and axial directions
US8333000B2 (en) 2006-06-19 2012-12-18 Advanced Cardiovascular Systems, Inc. Methods for improving stent retention on a balloon catheter
US8017237B2 (en) 2006-06-23 2011-09-13 Abbott Cardiovascular Systems, Inc. Nanoshells on polymers
US9072820B2 (en) * 2006-06-26 2015-07-07 Advanced Cardiovascular Systems, Inc. Polymer composite stent with polymer particles
US8128688B2 (en) 2006-06-27 2012-03-06 Abbott Cardiovascular Systems Inc. Carbon coating on an implantable device
US20070299511A1 (en) * 2006-06-27 2007-12-27 Gale David C Thin stent coating
US7794776B1 (en) 2006-06-29 2010-09-14 Abbott Cardiovascular Systems Inc. Modification of polymer stents with radiation
US7740791B2 (en) * 2006-06-30 2010-06-22 Advanced Cardiovascular Systems, Inc. Method of fabricating a stent with features by blow molding
US20080009938A1 (en) * 2006-07-07 2008-01-10 Bin Huang Stent with a radiopaque marker and method for making the same
US7823263B2 (en) 2006-07-11 2010-11-02 Abbott Cardiovascular Systems Inc. Method of removing stent islands from a stent
US7998404B2 (en) * 2006-07-13 2011-08-16 Advanced Cardiovascular Systems, Inc. Reduced temperature sterilization of stents
US20080014244A1 (en) * 2006-07-13 2008-01-17 Gale David C Implantable medical devices and coatings therefor comprising physically crosslinked block copolymers
US7757543B2 (en) 2006-07-13 2010-07-20 Advanced Cardiovascular Systems, Inc. Radio frequency identification monitoring of stents
US7794495B2 (en) * 2006-07-17 2010-09-14 Advanced Cardiovascular Systems, Inc. Controlled degradation of stents
US7886419B2 (en) * 2006-07-18 2011-02-15 Advanced Cardiovascular Systems, Inc. Stent crimping apparatus and method
US20080091262A1 (en) * 2006-10-17 2008-04-17 Gale David C Drug delivery after biodegradation of the stent scaffolding
US8016879B2 (en) * 2006-08-01 2011-09-13 Abbott Cardiovascular Systems Inc. Drug delivery after biodegradation of the stent scaffolding
US9173733B1 (en) 2006-08-21 2015-11-03 Abbott Cardiovascular Systems Inc. Tracheobronchial implantable medical device and methods of use
US7923022B2 (en) * 2006-09-13 2011-04-12 Advanced Cardiovascular Systems, Inc. Degradable polymeric implantable medical devices with continuous phase and discrete phase
US8099849B2 (en) 2006-12-13 2012-01-24 Abbott Cardiovascular Systems Inc. Optimizing fracture toughness of polymeric stent
EP1958649A1 (en) * 2007-02-14 2008-08-20 Graftys Injectable calcium-phosphate cement releasing a bone resorption inhibitor
US20080243228A1 (en) * 2007-03-28 2008-10-02 Yunbing Wang Implantable medical devices fabricated from block copolymers
US8262723B2 (en) 2007-04-09 2012-09-11 Abbott Cardiovascular Systems Inc. Implantable medical devices fabricated from polymer blends with star-block copolymers
US7829008B2 (en) * 2007-05-30 2010-11-09 Abbott Cardiovascular Systems Inc. Fabricating a stent from a blow molded tube
US7959857B2 (en) * 2007-06-01 2011-06-14 Abbott Cardiovascular Systems Inc. Radiation sterilization of medical devices
US8293260B2 (en) * 2007-06-05 2012-10-23 Abbott Cardiovascular Systems Inc. Elastomeric copolymer coatings containing poly (tetramethyl carbonate) for implantable medical devices
US20080306582A1 (en) * 2007-06-05 2008-12-11 Yunbing Wang Implantable medical devices with elastomeric copolymer coatings
US8202528B2 (en) * 2007-06-05 2012-06-19 Abbott Cardiovascular Systems Inc. Implantable medical devices with elastomeric block copolymer coatings
US8425591B1 (en) 2007-06-11 2013-04-23 Abbott Cardiovascular Systems Inc. Methods of forming polymer-bioceramic composite medical devices with bioceramic particles
US8048441B2 (en) 2007-06-25 2011-11-01 Abbott Cardiovascular Systems, Inc. Nanobead releasing medical devices
US7901452B2 (en) * 2007-06-27 2011-03-08 Abbott Cardiovascular Systems Inc. Method to fabricate a stent having selected morphology to reduce restenosis
US7955381B1 (en) 2007-06-29 2011-06-07 Advanced Cardiovascular Systems, Inc. Polymer-bioceramic composite implantable medical device with different types of bioceramic particles
EP2240116B1 (en) 2008-01-28 2015-07-01 Biomet 3I, LLC Implant surface with increased hydrophilicity
US9867838B2 (en) 2009-09-01 2018-01-16 Duke University Methods for treating heart failure using bisphosphonate compositions
US8882740B2 (en) * 2009-12-23 2014-11-11 Stryker Trauma Gmbh Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone
US8808353B2 (en) 2010-01-30 2014-08-19 Abbott Cardiovascular Systems Inc. Crush recoverable polymer scaffolds having a low crossing profile
US8568471B2 (en) 2010-01-30 2013-10-29 Abbott Cardiovascular Systems Inc. Crush recoverable polymer scaffolds
US8641418B2 (en) 2010-03-29 2014-02-04 Biomet 3I, Llc Titanium nano-scale etching on an implant surface
US8726483B2 (en) 2011-07-29 2014-05-20 Abbott Cardiovascular Systems Inc. Methods for uniform crimping and deployment of a polymer scaffold
WO2013074587A1 (en) 2011-11-16 2013-05-23 Duke University Bishophonate compositions and methods for treating and/or reducing cardiac dysfunction
EP2828100B1 (en) 2012-03-20 2018-05-16 Biomet 3i, LLC Surface treatment for an implant surface
US9993427B2 (en) 2013-03-14 2018-06-12 Biorest Ltd. Liposome formulation and manufacture
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
US9999527B2 (en) 2015-02-11 2018-06-19 Abbott Cardiovascular Systems Inc. Scaffolds having radiopaque markers
US9700443B2 (en) 2015-06-12 2017-07-11 Abbott Cardiovascular Systems Inc. Methods for attaching a radiopaque marker to a scaffold

Family Cites Families (3)

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