CN1911454A - 骨植入物 - Google Patents
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Abstract
本发明涉及一种骨植入物，其包含生物惰性基材，所述生物惰性基材覆盖有含有多个凹痕的陶瓷层。该凹痕的总表面积为该陶瓷层总表面积的30－70％。本发明还涉及这种骨植入物的制备方法。该方法包括：(1)将陶瓷层固定在生物惰性基材的表面上；(2)在该陶瓷层中形成多个凹痕，其中该凹痕的总表面积为该陶瓷层总表面积的30－70％；以及(3)将生物聚合物经由共价键合固定在该陶瓷层上。
Description
背景技术
植入物从骨组织松脱是重建手术与关节置换术中的主要问题。其原因曾经被归咎于生长在植入物周围的纤维组织降低植入物/骨界面的完整性与机械稳定性。在20世纪50年代，曾证明钛可永久性地结合至骨中，该方法现今称为骨整合。骨整合植入物的特征在于缺乏相对运动以及在该植入物与骨之间无软组织。参阅例如Branemark，(1983)J.Prosthet.Dent.50：399-410。植入物的表面可涂覆有诱导骨生成的物质，以进一步加强该植入物的骨整合。虽然目前市场上有许多骨植入物，但仍需开发具有优异骨整合的植入物。
发明内容
本发明的基础是以下意外的发现，即在骨植入物上涂覆有凹痕的(indented)羟基磷灰石涂层促进骨整合。
在一方面，本发明公开一种骨植入物，其包含生物惰性基材，所述生物惰性基材覆盖有含有多个凹痕(indentation)的陶瓷层(例如羟基磷灰石层)。所述凹痕的总表面积为所述陶瓷层总表面积的30-70％(例如50-60％)。所述凹痕的总表面积为所有凹痕开放表面积的合。所述陶瓷层的总表面积为所述凹痕的总表面积与无凹陷的表面积之和。
所述生物惰性基材可由各种材料制成，如金属(例如钛或钛合金)和陶瓷材料(例如瓷)。优选地，所述生物惰性基材表面的一部份含有多个宽10-30微米(例如15-20微米)高10-30微米(例如15-20微米)的小突脊，而所述表面的另一部分含有多个宽60-100微米(例如70-90微米)高40-80微米(例如50-70微米)的大突脊。当所述生物惰性基材由金属或金属合金制成时，可将其表面氧化以形成金属氧化物层。
所述陶瓷层优选覆盖具有所述大突脊的所述生物惰性材料表面，但不覆盖具有所述小突脊的所述表面。所述陶瓷层可由诸如羟基磷灰石的无机材料构成。所述陶瓷层的表面亦可经由共价键合固定有生物聚合物。适合的生物聚合物的实例包括蛋白质(例如胶原蛋白)或含有蛋白质的大分子(例如蛋白聚糖)。这种生物聚合物的功能可以是作为细胞附着与迁移的骨架，以帮助新的骨组织再生。如需要，亦可将骨形成促进剂(例如护骨素(osteoprotegrin))共价键合于所述陶瓷层。骨形成促进剂促进骨组织生长和骨量维持。
在另一方面，本发明公开了骨植入物的制备方法。所述方法包括三个步骤：(1)将陶瓷层固定在生物惰性基材的表面上，所述生物惰性基材的表面可以经预处理；(2)在所述陶瓷层中形成多个凹痕，其中所述凹痕的总表面积为所述陶瓷层总表面积的30-70％；以及(3)通过共价键合将生物聚合物固定在所述陶瓷层上。在所述固定步骤之前，可以处理所述生物惰性基材，以在表面的一部分上形成多个宽10-30微米高10-30微米(μm)的小突脊，并在表面的另一部份上形成宽60-100微米高40-80微米的大突脊。优选地，所述生物惰性基材由钛合金制成，并且在所述固定步骤之前将其表面氧化以形成金属氧化物层。
本发明的一个或多个实施方案的细节在下文中描述。本发明的其它特征、目的和优点将从说明书和权利要求书清楚获知。
具体实施方式
本发明涉及一种骨植入物，其包含生物惰性基材，所述生物惰性基材覆盖有含有多个凹痕的生物可降解的陶瓷层。
所述生物惰性基材可由多种材料制成，如金属和陶瓷材料。通常使用钛或其合金。钛是一种生物惰性材料，其帮助骨整合。钛及其合金可商购或者可由已知方法制备。
可以处理所述生物惰性基材的表面以形成具有特定粗糙度的图案(例如在表面的一部分上形成多个小突脊而在另一部分上形成多个大突脊)。所述表面处理可通过机械、化学、电化学以及本领域已知的其它适宜方法进行。通常，多个小突脊可通过化学蚀刻或等离子体喷雾产生。参阅例如Ronold等人，(2003)Biomaterials 24：4559；Jonasova等人，(2004)Biomaterials 25：1187；以及Prado da Silva等人，(2000)Mat.Res.3(3)：61。多个大突脊可通过诸如喷铁砂、磨削准分子激光处理(abrasive excimer laser treatment)、水喷射锤击(water jetpeening)以及电化学显微机械加工产生。参阅例如GonzaAlez-GarcoAa等人，(1999)Thin Solid Films 352：49；Mellali等人，(1996)Surface andCoatings Technology 81：275；Bereznai等人，(2003)Biomaterials 24：4197；Arola等人，(2002)Wear 249：943；以及Madore等人，(1997)J.Micromech.Microeng.，7：270。
举例而言，整个表面可以首先在高温(例如约800℃或更高)及大气压下于煤气炉中热处理(anneal)一段时间，之后冷却至室温。然后在酸溶液中在稍高于室温的温度下蚀刻该表面一段预定的时间，以形成多个宽10-30微米高10-30微米的小突脊。随后可(例如用抗腐蚀胶带)覆盖顶部的表面。然后所述表面的其余部份可以在更浓的酸溶液和更高的温度下进一步蚀刻更长的一段时间，以形成多个宽60-100微米高40-80微米的大突脊。这样得到的基材表面含有具有多个小突脊(例如表面的顶部)的部分，而其余部份则具有多个大突脊。当使用时，可将所述基材置于移植位置，使得具有多个小突脊的部份向外放置(例如与上皮层接触)并使具有多个大突脊的部份向内放置(例如与骨接触)。所述多个小突脊有助于成纤维细胞增殖并减少细菌感染。所述多个大突脊有助于成骨细胞附着。如需要，可将所述基材(例如钛合金)氧化以形成(例如厚5-10微米的)金属氧化物(例如二氧化钛)层，其阻止或延缓对所述基材的腐蚀。
所述生物可降解的陶瓷层可由诸如羟基磷灰石的无机材料构成。羟基磷灰石天然存在于骨、釉质或牙本质中，多年来已被用作骨替代物或涂层材料。参阅例如Frame，(1987)Int.J.Oral MaxillofacialSurgery 16：642-55，以及Parsons等人，(1988)Annals N.Y.Academy ofSciences 523：190-207。羟基磷灰石可通过已知方法制备或自供货商购买。其是纯化合物Ca10(PO4)6(OH)2，或者含有其它离子，如碳酸根、氟离子、氯离子或钡离子。可通过例如等离子体喷雾、溶胶-凝胶处理、离子束或射频溅射、脉冲激光沉积、热等静压和电泳沉积将羟基磷灰石施加在基材表面上以形成羟基磷灰石基陶瓷层。参阅例如Geesnik等人，(1990)Clin.Orthop.261：39-58；Ratner等人，“PlasmaDeposition and Treatment for Biomedical Applications”in PlasmaDeposition，Treatment and Etching of Polymers，edited by R.d’Agostino，Acadimic Press，Inc.，1990；以及Kawakami等人，(1998)Biotechnologyand Bioengineering 32：369-373。通常羟基磷灰石基陶瓷层的厚度介于25-70微米之间。这种促进骨附着生长的层优选施加于具有多个大突脊的基材表面上。为实现之，在将羟基磷灰石基陶瓷层施加于基材上之前将具有多个小突脊的表面覆盖起来，从而仅使具有多个大突脊的表面被所述陶瓷层涂覆。
可通过机械方法(例如喷砂或喷铁砂)或其它适宜的方法来移除陶瓷层的多个部份以形成所述陶瓷层中的多个凹痕。这些凹痕通常具有圆柱形轮廓且直径一般介于350-650微米之间(例如400-600微米)。在这些凹痕中，陶瓷材料通常被完全移除而使基材暴露出来。所述凹痕有助于成骨细胞的募集与保持。所述凹痕可以平均或随机分布在所述陶瓷层中。
所述陶瓷层可共价键合有生物聚合物(例如胶原基生物聚合物)以帮助新骨生长。举例来说，所述陶瓷层的表面首先用诸如氨基或羟基的官能团修饰。可通过等离子体沉积或化学涂覆(chemical priming)将所述官能团引入。用于等离子体沉积的材料包括氨等离子体、烯丙胺等离子体、烯丙醇等离子体以及任何含有氨基、羟基或其它反应基团的气体的等离子体。用于化学涂覆的化合物包括氨基硅烷、羟基硅烷或其它含有氨基、羟基或其它反应基团的硅烷。参阅例如Sano等人，(1993)Biomaterials 14：817-822；以及Wang与Hsiue，(1993)J.PolymerScience，Part A：Polymer Chemistry 31：2601-2607。通常，所述陶瓷层的表面以及所述陶瓷层中凹痕所暴露出来的生物惰性基材表面用官能团修饰。
胶原蛋白是可用于本发明的植入物中的生物聚合物的实例。胶原蛋白，例如I型胶原蛋白，可从人或动物组织如腱、皮肤、骨或韧带中分离。参阅例如Miller与Rhodes，(1982)Methods in Enzymology 82：33-64。其可通过保留端肽的方法(例如美国专利3,114,593)或是通过移除端肽的方法(例如美国专利4,233,360)来纯化。其也可通过使用化学试剂进行交联(例如美国专利5,876,444与6,177,514)或其它方法(例如紫外线)来重建。胶原蛋白可共价键合于羟基磷灰石基陶瓷层。共价键可在胶原蛋白中的官能团(例如羧酸根)与修饰的羟基磷灰石中的官能团(例如氨基)之间直接形成，或是透过诸如交联剂的第三分子间接形成。交联剂是一种具有至少两个官能团的试剂，其中一个官能团可与生物聚合物成键，而另一个官能团可与修饰的羟基磷灰石成键。交联剂的实例包括戊二醛、环氧氯丙烷、2，2，2-三氟乙烷磺酰氯(tresylcholoride)与N-羟基-琥珀酰亚胺。
所述陶瓷层可进一步共价键合有诸如护骨素(osteoprotegerin)的骨形成促进剂。护骨素已在美国专利申请公开2003-0045942及其中引用的文献中详细描述。其可与胶原蛋白一起，例如通过将具有陶瓷层的基材在含有胶原蛋白与护骨素的溶液中浸泡一段适宜的时间而附着于陶瓷层上。然后将所述基材从所述溶液中取出，并通过风干或冷冻干燥来干燥。或者，可在将胶原蛋白固定在陶瓷层后，再通过将具有所述陶瓷层的基材浸泡在含有护骨素的溶液中而使之附着于所述陶瓷层上。
举例而言，本发明的骨植入物可如下制备：首先将钛合金基材的整个表面于盐酸水溶液中蚀刻以形成多个小突脊。除所述基材顶部以外，进一步热处理所述表面以形成多个大突脊。随后，以氧气喷吹所述基材的整个表面以形成金属氧化物层。通过等离子体喷雾在具有多个大突脊的表面上涂覆羟基磷灰石层。然后通过喷砂或喷铁砂来移除部分羟基磷灰石层，从而形成多个凹痕。之后，用氨基或羟基将所述表面官能化。随后通过使胶原蛋白上的官能团与所述表面上的官能团反应而将胶原蛋白固定在所述表面上。可通过相同的方法用护骨素修饰所述表面。
可通过标准手术程序将本发明的骨植入物用于修复骨缺陷(如齿槽骨缺陷)。
以下具体实施例仅作为示范之用，且不对本公开的其他部分有任何限制。相信本领域技术人员无需进一步的说明，根据本文中的叙述就能够最大程度地利用本发明。本文引用的所有出版物均全文引入作为参考。
实施例1：制备材料
制备多孔性羟基磷灰石基基质.通过包括以下反应的湿化学法制备羟基磷灰石粉末： 。通过下列步骤制备多孔性羟基磷灰石基基质：(i)准备包含羟基磷灰石粉末、碳化硅、镁砂与水的浆料；(ii)将网状基材(例如聚氨酯、聚氯乙烯或聚乙二醇)塑造成期望的形状；(iii)将所述浆料涂覆于所述网状基材上；以及(iv)通过离心移除过多的浆料。如果需要，重复步骤(i)-(iv)。将这样得到的含羟基磷灰石的基材在1200℃的温度下烧结然后冷却。所述温度缓慢升高以使所述网状基材逐渐分解而不形成裂缝。这样，获得平均孔径200-350微米的多孔性羟基磷灰石基基质。清洗后，通过γ射线照射(20kGy)对所述基质进行灭菌。
萃取与纯化I型胶原蛋白.从新西兰白兔或其它适宜的哺乳动物的腱萃取并纯化I型胶原蛋白。将所述腱切下，切片并使用冷蒸馏水清洗数次以除去血浆蛋白质，随后于4℃下以含有0.5M NaCl的50mM Tris-HCl溶液(pH 7.4)持续恒速搅拌过夜进行催取。轻轻倒出上清液并以冷蒸馏水清洗剩余物数次以去除盐，然后将其与0.5M HOAc(pH 2.5)一起于4℃下温育过夜，获得含水萃取液。将盐溶液(0.9M氯化钠)加入所述萃取物中，产生沉淀。通过在13000rpm下离心30分钟来收集所述沉淀，并将其溶于0.05M HOAc中，形成含胶原蛋白的溶液。在24-48小时内将另一盐溶液(0.02M Na2HPO4)两次加入所述含胶原蛋白的溶液中，形成沉淀。通过离心收集所述沉淀并将其溶解于50mM醋酸中，得到另一含胶原蛋白的溶液。以5mM醋酸透析所述含胶原蛋白的溶液，最后冷冻干燥之。
实施例2：制备骨植入物
带螺纹的基材购自Crucible Material Corporation(Pittsburgh，PA，USA)。所述基材由钛合金(Ti6Al4V)制成，且直径介于3.25毫米(mm)至5毫米之间，长度介于8毫米至18毫米之间。所述基材的表面首先在煤气炉中于870-1050℃的温度和大气压下回火1-3小时，然后冷却至室温。然后将所述表面于30-50℃下在1-3M盐酸水溶液中蚀刻1-3小时以形成多个小突脊(即宽10-30微米高10-30微米)。然后将所述表面顶部2-3毫米以抗腐蚀胶带覆盖。然后将剩余表面于50-90℃下在1-6M盐酸水溶液中进一步蚀刻3-6小时以形成多个大突脊(即宽60-100微米高40-80微米)。然后以氧喷吹所述表面，形成厚度为5-10微米的金属氧化物层。使用等离子体喷雾技术在这样得到的基材上涂布羟基磷灰石层。所述羟基磷灰石层的厚度为约40-50微米。然后通过喷砂移除部份的羟基磷灰石层，从而形成多个凹痕。所述凹痕的直径介于400-600微米之间。将这样得到的基材以氨基官能化，然后将其与胶原蛋白连接。
实施例3：钙沉积测定
测试下列六个盘的钙沉积：(1)RT：未经处理的钛合金盘，(2)RT-HCl：经HCl蚀刻以形成多个小突脊的钛合金盘，(3)RT-950-HCl：于950℃下回火并以HCl蚀刻以形成多个大突脊的钛合金盘，(4)RT-950-HCl-TiO2：于950℃下回火，以HCl蚀刻形成多个大突脊，并氧化形成金属氧化物层的钛合金，(5)RT-950-HCl-TiO2-HAF：于950℃下回火，以HCl蚀刻形成多个大突脊，氧化形成金属氧化物层，并以羟基磷灰石层完全涂覆的钛合金盘，以及(6)RT-950-HCl-TiO2-HAP：于950℃下回火，以HCl蚀刻形成多个大突脊，氧化形成金属氧化物层并以羟基磷灰石层部分涂覆的钛合金盘。所述盘的直径介于2-3厘米(cm)之间而厚度介于3-5毫米之间。
从人骨肉瘤获得U2成骨细胞，并将其在置于6孔板中的上述各盘上，于含有10％肽牛血清(FBS)和5％抗生素的McCoy氏5A培养基中和37℃下进行培养。培养四天后更换培养基。再培养四天后，测定各盘培养基中的钙含量。在RT-950-HCl-TiO2-HAP、RT-950-HCl-TiO2-HAF与RT-950-HCl-TiO2的培养基中观察到的钙沉积多于RT、RT-HCl与RT-950-HCl的培养基中的钙沉积。结果表明，沉积在RT-950-HCl-TiO2-HAP、RT-950-HCl-TiO2-HAF与RT-950-HCl-TiO2表面上的钙多于沉积在RT、RT-HCl与RT-950-HCl表面上的钙。
实施例4：成骨细胞沉积测定
亦在成骨细胞沉积测定中测试了实施例3中提到的六个盘。在置于6孔板的各盘上，于含有10％FBS及5％抗生素的McCoy氏5A培养基中在37℃下培养从人骨肉瘤获得的U2成骨细胞。培养四天后移除培养基。于电子显微镜下观察各盘的表面。RT的表面上几乎没有成骨细胞出现，因为在移除培养基后，大部分成骨细胞从RT表面上移除。在RT-HCl表面上观察到少量成骨细胞。类似于RT，移除培养基后RT-HCl表面上的大部分成骨细胞被移除。大量成骨细胞沉积在RT-950-HCl表面的多个大突脊上。并且也有大量成骨细胞沉积在RT-950-HCl-TiO2的金属氧化物层的多个大突脊上。沉积在RT-950-HCl-TiO2-HAF的金属氧化物层的多个大突脊上的成骨细胞多于沉积在RT-950-HCl与RT-950-HCl-TiO2上的成骨细胞。而沉积在RT-950-HCl-TiO2-HAP的金属氧化物层的多个大突脊上的成骨细胞多于沉积在RT-950-HCl-TiO2-HAF上的成骨细胞。
其它实施方案
本说明书中所揭露的所有特征均可以任意组合方式来组合。本说明书中所揭露的每个特征都可由起相同、等同或类似目的的另一特征代替。因此，除非另有说明，所揭露的每个特征均仅是一系列等同或类似特征的实例。
根据上述说明内容，本领域技术人员能够容易确定本发明的必要特征，且在不偏离本发明的精神与范围的前提下，能够根据各种用途与条件对本发明做出各种变化与修饰。因此，其它实施方案亦为所附权利要求所涵盖。
Claims (23)
1.一种骨植入物，其包含生物惰性基材，所述生物惰性基材覆盖有含有多个凹痕的陶瓷层，其中所述凹痕的总表面积为所述陶瓷层总表面积的30-70％。
2.如权利要求1所述的骨植入物，其中所述凹痕的总表面积为所述陶瓷层总表面积的50-60％。
3.如权利要求2所述的骨植入物，其中所述生物惰性基材表面的第一部分具有多个宽10-30微米高10-30微米的小突脊，且所述生物惰性基材表面的第二部分具有多个宽60-100微米高40-80微米的大突脊。
4.如权利要求3所述的骨植入物，其中所述小突脊宽15-20微米高15-20微米，而所述大突脊宽70-90微米高50-70微米。
5.如权利要求4所述的骨植入物，其中所述陶瓷层覆盖所述表面的第二部分，但不覆盖所述表面的第一部分。
6.如权利要求5所述的骨植入物，其进一步包含生物聚合物，所述生物聚合物共价键合于所述陶瓷层的表面上。
7.如权利要求6所述的骨植入物，其中所述生物聚合物为胶原基生物聚合物。
8.如权利要求7所述的骨植入物，其中所述生物惰性基材为钛合金基材料。
9.如权利要求8所述的骨植入物，其进一步包含金属氧化物层，所述金属氧化物层位于所述陶瓷层与所述生物惰性基材之间。
10.如权利要求9所述的骨植入物，其进一步包含骨形成促进剂，所述骨形成促进剂共价键合于所述陶瓷层。
11.如权利要求1所述的骨植入物，其中所述生物惰性基材表面的第一部分具有多个小突脊，所述小突脊宽10-30微米高10-30微米，并且所述生物惰性基材表面的第二部分具有多个大突脊，所述大突脊宽60-100微米高40-80微米。
12.如权利要求11所述的骨植入物，其中所述小突脊宽15-20微米高15-20微米，而所述大突脊宽70-90微米高50-70微米。
13.如权利要求12所述的骨植入物，其中所述陶瓷层覆盖所述表面的第二部分，但不覆盖所述表面的第一部分。
14.如权利要求1所述的骨植入物，其进一步包含生物聚合物，所述生物聚合物共价键合于所述陶瓷层的表面上。
15.如权利要求14所述的骨植入物，其中所述生物聚合物为胶原基生物聚合物。
16.如权利要求15所述的骨植入物，其进一步包含骨形成促进剂，所述骨形成促进剂共价键合于所述陶瓷层。
17.如权利要求1所述的骨植入物，其中所述生物惰性基材为钛合金基材料。
18.如权利要求17所述的骨植入物，其进一步包含金属氧化物层，所述金属氧化物层位于所述陶瓷层与所述生物惰性基材之间。
19.骨植入物的制备方法，其包括：
将陶瓷层固定在生物惰性基材的表面上；
在所述陶瓷层中形成多个凹痕，其中所述凹痕的总表面积为所述陶瓷层总表面积的30-70％；以及
通过共价键合将生物聚合物固定在所述陶瓷层上。
20.如权利要求19所述的方法，其进一步包括在所述固定步骤之前，于所述生物惰性基材表面的第一部分上形成多个宽10-30微米高10-30微米的小突脊，以及在所述生物惰性基材表面的第二部分上形成多个宽60-100微米高40-80微米的大突脊。
21.如权利要求19所述的方法，其中所述陶瓷层覆盖所述表面的第二部分，但不覆盖所述表面的第一部分。
22.如权利要求19所述的方法，其中所述生物聚合物为胶原基生物聚合物。
23.如权利要求19所述的方法，其中所述生物惰性基材为钛合金基材料。
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| US11/063,074 US8323348B2 (en) | 2005-02-22 | 2005-02-22 | Bone implants |
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| US (1) | US8323348B2 (zh) |
| EP (1) | EP1693074B1 (zh) |
| JP (1) | JP5089890B2 (zh) |
| CN (1) | CN1911454B (zh) |
| AT (1) | ATE464074T1 (zh) |
| DE (1) | DE602006013528D1 (zh) |
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| US9861406B2 (en) | 2012-08-23 | 2018-01-09 | DePuy Synthes Products, Inc. | Bone fixation system |
| CN107921176A (zh) * | 2015-08-31 | 2018-04-17 | 陶瓷技术有限责任公司 | 植入物 |
| US10004603B2 (en) | 2012-08-23 | 2018-06-26 | DePuy Synthes Products, Inc. | Bone implant |
| CN109289092A (zh) * | 2018-10-22 | 2019-02-01 | 郑州合撷亨商贸有限公司 | 一种医用牙槽骨再生材料的制备方法 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9861406B2 (en) | 2012-08-23 | 2018-01-09 | DePuy Synthes Products, Inc. | Bone fixation system |
| US10004603B2 (en) | 2012-08-23 | 2018-06-26 | DePuy Synthes Products, Inc. | Bone implant |
| US10716606B2 (en) | 2012-08-23 | 2020-07-21 | DePuy Synthes Products, Inc. | Bone fixation system |
| US10772729B2 (en) | 2012-08-23 | 2020-09-15 | DePuy Synthes Products, Inc. | Bone implant |
| CN107921176A (zh) * | 2015-08-31 | 2018-04-17 | 陶瓷技术有限责任公司 | 植入物 |
| CN109289092A (zh) * | 2018-10-22 | 2019-02-01 | 郑州合撷亨商贸有限公司 | 一种医用牙槽骨再生材料的制备方法 |
Also Published As
| Publication number | Publication date |
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| EP1693074B1 (en) | 2010-04-14 |
| EP1693074A2 (en) | 2006-08-23 |
| HK1100486A1 (en) | 2007-09-21 |
| ES2341988T3 (es) | 2010-06-30 |
| US8323348B2 (en) | 2012-12-04 |
| DE602006013528D1 (de) | 2010-05-27 |
| TWI399227B (zh) | 2013-06-21 |
| ATE464074T1 (de) | 2010-04-15 |
| US20060190091A1 (en) | 2006-08-24 |
| EP1693074A3 (en) | 2007-08-22 |
| CN1911454B (zh) | 2011-09-14 |
| JP2006231056A (ja) | 2006-09-07 |
| JP5089890B2 (ja) | 2012-12-05 |
| TW200640509A (en) | 2006-12-01 |
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