CN102946912B - 具有增强的亲水性的医学植入物 - Google Patents

具有增强的亲水性的医学植入物 Download PDF

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CN102946912B
CN102946912B CN201180023035.1A CN201180023035A CN102946912B CN 102946912 B CN102946912 B CN 102946912B CN 201180023035 A CN201180023035 A CN 201180023035A CN 102946912 B CN102946912 B CN 102946912B
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G.希塞李
P.王
J.哈菲斯
J.克鲁登
D.W.约翰斯
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Abstract

诸如整形外科植入物的装置包含热塑性树脂例如聚芳基醚醚酮（PEEK），并包含陶瓷物类，例如沸石，以增强其亲水性。所述陶瓷物类可为表面涂层，可结合入或嵌入所述热塑性树脂中，或可既为表面涂层又结合入或嵌入树脂中。在某些实施方案中，所述陶瓷物类为结合入所述装置、尤其是所述装置暴露表面处的沸石，且不含抗菌金属离子。通过手术将所述装置引入体内。

Description

具有增强的亲水性的医学植入物
本申请要求2010年5月7日提交的美国临时专利申请序列号为No. 61/322,403的优先权，其公开内容通过引用结合于本文中。
背景
可植入医学装置因包括整形外科应用（例如，髋部置换、脊椎程序、膝部置换、骨折修复等）的多种原因而植入身体。考虑到这些装置所需的结构整体性，制造材料有所限制并通常由金属、塑料和复合材料组成。
这些装置带来的好处常被感染抵消，所述感染有些情况下会导致脓毒病和死亡。最常见的引起感染的生物体是表皮葡萄球菌（Staphylococcus epidermidis）和金黄色葡萄球菌（Staphylococcus aureu）。表皮葡萄球菌是人皮肤和黏膜常见（normal）细菌群的主要成分。它是在医院环境中经常定居于（colonize）接受外科植入的患者的常见病原体，原因是该微生物能附着在医学装置上并形成生物膜。此外，新青霉素抗性的金黄色葡萄球菌（MRSA）是一种对于许多抗生素具有抗性的葡萄球菌，因而特别令人关注。其它革兰氏阳性细菌、革兰氏阴性细菌和真菌生物体也是可能引起问题的致病微生物。
因为微生物与医学装置的表面紧密地相邻，所述微生物会被医学装置吸引或排斥，这取决于不同的非特异性相互作用的总和。在生物学系统中，疏水/亲水相互作用在宽范围的微生物感染的发病机理中扮演重要角色。
许多细菌可在生物工程植入物上形成多细胞被覆物（coatings）即生物膜。生物膜通过提供稳定的保护性的生长环境促进微生物的增殖和传播。这些生物膜常可导致大面积全身感染（broad systemic infection）。
在许多情况中，当受粘性生物膜保护的生物体接种于植入物时，必须除去植入物并使用一种或多种抗生素对患者进行延长治疗试图来治愈该感染，此后再重新植入新植入物。此过程不仅让患者经受更多损伤和痛苦，而且还极端昂贵。
并不意外的是，已有大量研究致力于防止细菌和真菌生物体定居整形外科植入物表面，这些研究使用例如抗生素的可结合至这些装置表面的抗菌剂。
已发现包括聚醚酮酮（polyetherketoneketone，PEKK）和聚醚醚酮（PEEK）的热塑性树脂是用于这些植入物的有用的材料。PEEK因其弹性模量与骨骼紧密匹配而特别适合。然而PEEK是疏水材料且细菌易于附着于此类表面。它还是一种不带显著表面电荷的有机材料。因此，可能需要开发包含一种或多种热塑性树脂的医学植入物，所述热塑性树脂具有减弱的疏水性，和/或具有净负电荷，尤其是当植入时在暴露表面处。
发明简述
现有技术的缺点已被本文公开的实施方案克服，所述实施方案涉及装置，例如结构整形外科材料，尤其是体内装置例如外科植入物，更具体来讲是整形外科植入物，更具体来讲是脊椎植入物。在某些实施方案中，所述装置为骨传导性的（osteoconductive）且包含热塑性树脂，所述热塑性树脂例如聚芳基醚醚酮（Polyaryletheretherketone，PEEK）或聚醚酮酮（PEKK）且包含例如沸石的陶瓷物类（ceramic species）以增加树脂的亲水性和/或负电荷。所述陶瓷物类不含抗菌金属离子例如银、铜、锌、汞、锡、铅、金、铋、镉、铬和铊离子。所述陶瓷物类可为表面涂层，可结合入或嵌入所述热塑性树脂中，或既为表面涂层又结合入或嵌入所述树脂中。
在某些实施方案中，所述陶瓷物类为结合入所述装置中、尤其是所述装置暴露表面处的沸石。通过手术将所述装置引入体内。保持在X射线下观察时的辐射不透明度。
发明详述
本文公开的实施方案涉及陶瓷结合医学植入物的应用，所述医学植入物包含热塑性树脂例如PEEK、PEKK或其类似物，所述应用用以改变聚合物的疏水性并赋以聚合物（例如在聚合物暴露表面处）负电荷，以最小化或消除生物膜的形成，和/或破坏生物膜的完整性且因此破坏其保护细菌的能力。
尽管本发明人无意被任何特定实施理论限制，但是仍认为生物膜的生长是因为细菌附着于植入物。植入物（此时带有附着的细菌）的疏水性阻碍了抗菌剂进攻包含细菌的生物膜。具有离子性质的PEEK/沸石组合令抗菌剂部分渗透和杀灭细菌病原体的能力得以增强，而不是被纯（naked）PEEK的疏水表面性质所排斥。
所有的细菌都更好地附着于疏水表面，且从疏水表面上将细菌分开可能更难。
骨骼形成的第一阶段是蛋白质吸附。通常，对成骨细胞最重要的蛋白质（即，RGD肽）附着于带负电表面。此外，该带电表面允许蛋白质以恰当的构象附着，使得最佳数量的蛋白质附着。骨骼形成的第二阶段为前造骨细胞（pre-osteoblast）附着至该吸附的蛋白质。然后这些细胞形成成熟的造骨细胞、展开“枝叶”(spread phyllopodia)并开始造骨细胞成熟/增殖过程。成熟的造骨细胞产生ECM(胞外基质)，ECM与细胞结合，矿化为编织骨。PEEK为高度疏水性的，这阻碍了使骨骼形成过程开始所必需的蛋白质吸附。通过将沸石结合至PEEK结构中，产生了负电荷表面，所述负电荷表面具有启动蛋白质吸附过程的能力。
此外，组织不能很好地附着于纯PEEK；所述组织仅仅倚靠PEEK生长并形成在这两种材料间具有最小附着的界面。此界面提供了非常易于形成细菌生物膜的区域，所述生物膜甚至来自手术后较长时间后才到来的全身性细菌（systemic bacteria）。由于PEEK与例如沸石的陶瓷的复合材料表面的亲水本性和/或电荷会促进成纤维细胞和造骨细胞的生长和粘附，这与生长中的组织相互作用，界面将在手术后很快消失且此处生物膜的潜在可能性将大幅减少甚至消除。
在某些实施方案中，所述装置配置为用于脊椎融合（关节融合术），所述脊椎融合常用于稳定由于结构性畸形、损伤、退化等而不稳定的脊柱。融合是将脊骨中的一个或多个椎骨结合在一起（“融合”）以减少或消除其间相对运动或修复其间空间关系的外科技术。脊椎融合包括后外侧融合、前腰椎体间融合、后腰椎体间融合、前/后脊椎融合、颈椎融合、胸椎融合和椎板间融合(interlaminar fusion)。在某些实施方案中，所述装置用于插入相邻椎骨间的椎间空间。在某些实施方案中，将融合位点确定在相邻椎骨之间，并在所述位点植入骨移植物。在某些实施方案中，所述植入物为脊椎体间笼（interbody spinal cage），所述体间脊椎笼包含钛、碳纤维、生物相容性材料例如聚醚醚酮（PEEK）、聚醚酮酮（PEKK）、或其它合成物质。在某些实施方案中，将沸石粒子结合入PEEK体间笼。在某些实施方案中，所述笼装载有骨传导性和/或骨诱导性试剂以促进融合。优选地，将陶瓷粒子结合入树脂以赋予树脂暴露表面负电荷。术语“暴露表面”意欲包括在植入时暴露于或接触身体组织和/或液体的可植入装置的一个或多个表面。
天然沸石或合成沸石皆可用于制造本文公开的实施方案中的沸石。“沸石”是具有三维骨架结构的铝硅酸盐，以式XM2/nO•Al2O3•YSiO2•ZH2O表示，其中M代表可离子交换的离子，通常为一价或二价金属离子，n代表（金属）离子的原子价(atomic valency)，X和Y分别代表金属氧化物和二氧化硅的系数，且Z代表结晶水的数目。这样的沸石的实例包括A型沸石、X型沸石、Y型沸石、T型沸石、高二氧化硅沸石、钠沸石、丝光沸石、方沸石、斜发沸石、菱沸石和毛沸石。
沸石可以包含合适量的沸石粒子、通常为20重量%沸石粒子的低密度聚乙烯、聚丙烯、超高分子量聚乙烯或聚苯乙烯的粒料母料形式获得。当以此种方式提供时，包含沸石粒子的树脂粒料可容易地与用于制造植入物或用于制造施用于植入物的涂层的树脂混合，如美国专利第6,582,715号所述，其公开内容通过引用结合于本文中。通常结合入植入物树脂中的沸石粒子量介于0.01至10重量%，更优选0.01至8.0重量%，最优选0.1至5.0重量%。用于涂布陶瓷抑或将陶瓷结合入树脂中的方法无特别限制，且可包括喷涂、涂装(painting)或浸涂。例如，当配混（compounding）入PEEK时，应保护所述PEEK以避开潮湿和污染源。所述配混可通过共混（blending）进行。所述陶瓷物类可为表面涂层，可结合入或嵌入所述热塑性树脂中，或可既为表面涂层又结合入或嵌入树脂中。
其它适合的树脂包括低密度聚乙烯、聚丙烯、超高分子量聚乙烯或聚苯乙烯、聚氯乙烯、ABS树脂、硅树脂、橡胶和其混合物。这些物质可被配剂成包含合适量、通常约20质量%的沸石粒子。对于植入物装置，优选UHMWPE。
所述母料是将颜料和/或添加剂（例如，沸石粉）在热处理期间包封到载体树脂中、然后冷却并切成粒状的浓缩混合物。使用母料使得加工设备可以在塑料生产工艺期间经济地且简单地将添加剂引入原料聚合物（稀释树脂(let down resin)）。
所述结合入树脂并植入的沸石不含抗菌金属离子。
在高温和高剪切力的条件下，将所述沸石结合入所述树脂，例如通过将掺杂金属的沸石混入熔融PEEK（熔点介于300℃和400℃之间），然后模塑成型和加工所述复合共混物。
实施例
将约5%重量的沸石粉与粉状或颗粒状PEEK彻底混合。将混合物升至温度400℃并在此温度下使用高剪切力加工。所述沸石和PEEK在加工前必须为干燥的以将分解和产品中空隙的形成减至最少。
所述材料可形成为颗粒以供进一步加工，铸塑成块、挤出成棒或注塑成最终需要的形状。
所述块或棒状材料可用机器加工为适合用作整形外科植入物或使抗菌PEEK找到应用的其它设计的形状。植入物可设计成通过在表面切割凹槽或通过生产工件本体中有孔的产品以提供更大的表面积。可进一步通过铺砂(sanding)或磨料喷砂(abrasiveblasting)增加表面积。

Claims (5)

1.医学植入物，所述医学植入物包含具有结合入其中的沸石粒子的热塑性树脂，所述沸石粒子不含抗菌金属离子并且具有以式XM2/nO·Al2O3·YSiO2·ZH2O表示的三维骨架结构，其中M代表可离子交换的离子，n代表离子的原子价，X和Y分别代表金属氧化物和二氧化硅的系数，且Z代表结晶水的数目，其中所述沸石粒子以足以赋予所述植入物暴露表面负电荷的量存在于所述树脂中。
2.权利要求1的植入物，其中所述植入物为体间脊椎笼。
3.权利要求1的植入物，其中所述热塑性树脂包括PEEK。
4.沸石粒子在制备用于最小化患者体内生物膜的形成的方法的装置中的用途，所述装置包含具有结合入其中的所述沸石粒子的热塑性树脂，所述沸石粒子不含抗菌金属离子并且具有以式XM2/nO·Al2O3·YSiO2·ZH2O表示的三维骨架结构，其中M代表可离子交换的离子，n代表离子的原子价，X和Y分别代表金属氧化物和二氧化硅的系数，且Z代表结晶水的数目。
5.权利要求1的医学植入物，其中所述医学植入物具有表面，其中所述沸石粒子以有效地赋予所述表面亲水性的量存在。
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