CN106456835A - 增材制造制备的抗菌制品 - Google Patents
增材制造制备的抗菌制品 Download PDFInfo
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- CN106456835A CN106456835A CN201580016202.8A CN201580016202A CN106456835A CN 106456835 A CN106456835 A CN 106456835A CN 201580016202 A CN201580016202 A CN 201580016202A CN 106456835 A CN106456835 A CN 106456835A
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- antibiotic
- acid
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Abstract
用于植入在哺乳动物对象中的通过其中将聚合物材料与所选择的抗生素同时沉积的增材制造制备的抗生素洗脱制品,该增材制造方法可为选择性激光烧结方法或选择性激光熔化方法或选择性热烧结方法或电子束熔化方法。该抗生素洗脱制品可为临时或永久矫形骨骼组件、矫形关节置换组件和/或用于可植入设备的外部硬壳。一种或多种骨生长促进组合物可与聚合物材料同时沉积。该可植入设备可为心脏起搏器、脊髓刺激器、神经刺激***、用于将药物递送至脑脊液中的鞘内给药泵、用于递送化疗和/或解痉药的输液泵、胰岛素泵、渗透泵和肝素泵。
Description
技术领域
本文所公开的各种实施方案主要涉及可植入医疗设备。更具体地,本文涉及在其结构和其表面上具有抗菌特性的可植入医疗设备。
技术背景
已经开放了许多类型的医疗设备用于植入患者的身体中。例如,对于牙科医生,为他们的患者提供定制的牙科假体和/或植入物以替代非功能性或缺失的牙齿已成为常见的做法。这种替代假体和/或植入物能够被单独设计并制备来用于精确安装至具体的预定部位。对于异常或不规则的心脏收缩率患者,在其胸部区域或者他们腹部中的皮肤下安装心脏起搏器设备已经成为了常规惯例。现在,具有虚弱的退行性疾病影响到其关节和/或骨骼元件的患者能够对通过用人造植入物来替代患部结构例如更换髋关节组件、膝关节组件、肩关节组件等等所恢复的他们的生活质量有一个大的估量。经常向遭受极端创伤造成严重骨折的患者提供骨折固定板、夹具、针、钉、髓内棒等从而在愈合过程中将骨折的骨骼段固定在一起和/或置换被破坏或丢失的骨骼段。然而,所有这些类型的可植入设备使患者遭受沿着作为定植部位的设备外表面和/或其周围的安装后感染的风险。特殊的问题是植入设备表面上的感染性生物膜的。感染更严重的情况通常会导致微生物渗透到植入物的内部结构组件中,需要将它们移除和更换。
已经采取了多种方法来试图避免在植入医疗设备的表面和周围发生的安装后感染。例如,已经开发出具有抗菌和/或抗真菌添加剂的柔性回弹的有机硅基涂层用于在制备植入物时包覆医疗植入物的外表面。这样的涂层通常由以下步骤制备:第一,在合适的溶剂中溶解合适的有机硅,所述有机硅例如甲基三甲氧基硅烷、甲基三乙酰氧基硅烷、四氯硅烷、乙烯基三甲氧基硅烷、γ-脲基丙基三甲氧基硅烷等,所述溶剂例如甲苯、二甲苯、正己烷、四氢呋喃、环己酮等。第二,在合适的溶剂中溶解抗菌化合物和/或抗真菌化合物,所述溶剂例如N-甲基吡咯烷酮、C1-12羧酸的烷基酯等。第三,将硅烷溶液和抗菌和/或抗真菌溶液混合在一起。第四,将医疗植入物浸没在混合的溶液中,随后将包覆的植入物移除并进行风干,然后在约90℃进行烘干最长至1小时来形成涂层并将溶剂完全蒸发掉。据说,所述医疗植入物在植入后一旦与组织接触后,这种抗生素包覆的植入物会释放抗菌和/或抗真菌化合物。
另一常规方法是在植入的制备过程中,将抗菌化合物和/或药物混合入包含聚合物材料的植入物中从而使抗菌化合物从植入物中洗脱出来进入环境中。这些类型的植入物通常被称为药物洗脱植入物。通过将抗菌化合物溶解在一种或多种用于溶解所选择的聚合物材料的溶剂中来制备某些这样的植入物。将溶解的聚合物材料和抗菌化合物混合在一起然后将其倒入或分散至其中它们固化的形式中,之后被加工成最终的植入物。其它的方案涉及首先制备植入物,然后在外表面上所选择的位置中制成一个或多个凹槽和/或裂缝,然后在凹槽和/或裂缝中充满药物递送基质使之至少半固化。然后历经一定时间将药物从基质中洗脱出来。在某些植入物组合中,例如“球”和“孔窝”组合用于完全的髋关节置换或完全的膝关节置换套装,所述套装含有股骨组件、胫骨托架,胫骨打入器和髌骨组件,所述药物递送基质可混合入一种或多种组件的承重表面中从而使药物通过摩擦力进行释放,所述摩擦力是当两个或多个组件在它们正常的关节功能过程中相互摩擦而产生的。其它植入物药物洗脱方案具有形成在植入物的内部结构中的储存槽。在患者安装植入物之前,将所述储存槽充满药物溶液。某些植入物被设置成与含有药物溶液的外部储存槽相通并协作,在预防计划中或者当探测到感染时所述药物溶液从外部被抽入植入物中和/或植入物的周围。常规实践使用负载抗生素的粘合剂,例如(PROSTALAC是DepuyOrthopaedic Inc.的注册商标,Warsaw,IN,USA)和(SIMPLEX是HowmedicaOsteonics Corp.的注册商标,Mahwah,NJ,USA)用于整形外科植入物的安装。虽然这些粘合剂对于安装整形外科植入物之后马上减少术后感染的发生具有相当大的价值,但其长期效益是有限的,这是由于抗生素一旦暴露于哺乳动物组织就会从粘合剂表面迅速地消散。
对于常用的植入物和在常规使用中的植入物,仍然存在许多感染易感性相关的问题。有人担心某些抗菌化合物和/或药物的疗效会被用于溶解它们的溶剂和/或用于溶解聚合物材料的溶剂改变或损害,所述聚合物材料用于铸造植入物。此外,已知药物洗脱植入物的疗效随时间越来越减弱并且受限于植入物制备过程中药物负荷极限。带有负载药物的凹槽/裂缝的植入物可在一段时间内避免裂缝周围的感染,但是很容易受到远离凹槽/裂缝位置的它们表面区域上的微生物定植和生物膜形成的影响。综合这些问题,移除感染的植入物,研磨周围感染的骨骼结构,切除周围的感染组织并安装置换植入物是外科手术的挑战。
发明简述
本发明涉及具有抗菌化合物的可植入抗菌医疗设备,所述抗菌化合物被均匀地隔离遍及它们的结构基质并分布在它们的表面。在将医疗设备植入哺乳动物对象中后,所述抗菌化合物可从所述表面和结构基质中洗脱。本发明还涉及用于制备包含可洗脱的抗菌化合物的可植入医疗设备的方法,所述抗菌化合物被隔离在它们的结构基质中并分布在它们的表面。
发明详述
本发明涉及用于制备可植入的抗生素洗脱的聚合物医疗设备的方法,所述设备具有均匀分布并被隔离遍及它们结构基质且分布在它们表面的抗菌化合物和/或杀菌化合物。本发明还涉及通过本文所公开的示例性方法制备的可植入的抗生素隔离并洗脱的医疗设备。
特别地,本发明的示例性方法用于制备适于外科手术植入哺乳动物体内的基本上刚性的制品,所述哺乳动物例如人、灵长类动物、家畜、反刍动物、马科动物、犬科动物、猫科动物等。
所述示例性方法也用于制备可植入设备的外部硬壳,可植入设备例如心脏起搏器、脊髓刺激器、神经刺激***、用于将药物递送至脑脊液中的鞘内给药泵、用于递送化疗和/或解痉药的输液泵、胰岛素泵、渗透泵、肝素泵等。所述示例性方法还用于制备牙科假体、包含一个或多个置换牙齿组件的牙科植入物等。所述示例性方法还可用于制备经皮皮肤表面处理设备,例如用于提供经皮电神经刺激的设备和用于提供长期经皮穿刺途径的设备。所述示例性方法还可用于制备受伤处理表面设备,例如矫形钉和缝合线等。所述示例性方法特别用于制备三维复杂的矫形骨骼组件,包括但不限于关节置换物、髋关节垫片、膝关节垫片、肩关节垫片等。所述三维复杂的矫形骨骼组件可以是临时结构或者永久结构。
使用增材制造技术,所述示例性方法通常混合在加工过程中,一种或多种抗菌和/或杀菌组合物与基础原料同时沉积以形成包含本发明的可植入的抗菌制品的三维物理结构。所述制品可形成实体并致密的无孔三维结构。或者,所述结构可形成包含实体区域和多孔区域的非均匀三维结构。或者,所述结构可包含具有非均匀三维结构的内核,所述非均匀三维结构被包含一个或多个实体致密层的外壳覆盖。一种或多种所选择的抗生素组合物可混合入内核和/或外壳中。或者,所述结构可包含被一个或多个具有第二孔隙度的第二非均匀三维结构的层覆盖的内核,所述内核含有具有第一孔隙度的第一非均匀三维结构。一种或多种所选择的杀菌组合物可混合入内核和/或外层中。如果需要,所述制品能够形成具有从内核至外表面超过三个的多孔区域。
合适的增材制造技术包括熔融聚合物沉积技术,例如选择性激光烧结、选择性激光熔化、选择性热烧结、电子束熔化等。一种或多种抗生素组合物与聚合物材料同时沉积使抗生素组合物封存在聚合物材料所形成的基质内或其周围。以本发明制品中提供的比率来沉积所述抗生素,所述比率为基于抗菌制品的总重量,约0.01%w/w至约25%w/w的抗生素活性成分。例如,约0.01%w/w、约0.05%w/w、约0.1%w/w、约0.2%w/w、约0.3%w/w、约0.4%w/w、约0.5%w/w、约0.75%w/w、约1.0%w/w、约1.25%w/w、约1.5%w/w、约1.75%w/w、约2.0%w/w、约2.25%w/w、约2.5%w/w、约2.75%w/w、约3.0%w/w、约3.25%w/w、约3.5%w/w、约3.75%w/w、约4.0%w/w、约4.25%w/w、约4.5%w/w、约4.75%w/w、约5.0%w/w、约5.25%w/w、约5.5%w/w、约5.75%w/w、约6.0%w/w、约7.0%w/w、约8.0%w/w、约9.0%w/w、约10.0%w/w、约15.0%w/w、约20.0%w/w、约25.0%w/w,以及这些数值之间的中间数值。
本文所使用的术语“抗菌剂”是指抗生素、杀菌剂(antiseptic)和消毒剂。在本发明方法中所使用的用于制备抗菌可植入医疗设备的抗生素组合物的类型包括氨基糖苷类,例如妥布霉素、庆大霉素、新霉素、链霉素等;唑类,例如氟康唑、伊曲康唑等;β-内酰胺类抗生素,例如青霉烷类、头孢类、碳青霉烯类、单环β-内酰胺类、β-内酰胺酶抑制剂等;头孢菌素类,例如头孢乙腈、头孢羟氨苄、头孢氨苄、头孢唑啉、头孢罗奇、头孢拉宗等;氯霉素;克林霉素;夫西地酸;糖肽类,例如万古霉素、替考拉宁、雷莫拉宁等;大环内酯类,例如阿奇霉素、克拉霉素、地红霉素、红霉素、螺旋霉素、泰乐菌素等;甲硝唑;莫匹罗星;青霉素类,例如青霉素、普鲁卡因青霉素、苄星青霉素、青霉素V等;多烯类化合物,例如两性霉素B、制霉菌素、纳他霉素等;喹诺酮类,环丙沙星、氧氟沙星、达氟沙星等;利福霉素类,例如利福平、利福布丁、利福喷丁、利福昔明等;磺酰胺(sufonamide),例如磺胺醋酰、磺胺多辛等;四环素类,例如多西环素、米诺环素、替加环素等;甲氧苄啶等等。期望的是,妥布霉素和/或庆大霉素和/或新霉素和/或万古霉素特别适于与用于本发明抗菌医疗设备的增材制造的聚合物材料同时沉积。
各种热塑性聚合物和/或自由基聚合物和/或交联聚合物可用来与抗生素组合物同时沉积。例如聚甲基丙烯酸甲酯、丙烯腈-丁二烯-苯乙烯共聚物、聚碳酸酯、丙烯腈-丁二烯-苯乙烯共聚物与聚碳酸酯的共混物、聚醚醚酮、聚乙烯、聚酰胺、聚乳酸、聚亚苯基砜、聚苯乙烯、尼龙,特别是尼龙12等等。还可以使用甲基丙烯酸甲酯、聚乳酸、聚乙交酯、聚己内酯、聚酸酐、聚胺、聚氨酯、聚酯酰胺、聚原酸酯、聚二氧杂环己酮、聚缩醛、聚缩酮、聚碳酸酯、聚原碳酸酯(polyorthocarbonates)、聚磷腈、琥珀酸酯、聚苹果酸、聚氨基酸、聚乙烯吡咯烷酮、聚乙二醇、聚羟基纤维素(polyhydroxycellulose)、聚糖、甲壳素、壳聚糖,及它们的共聚物、嵌段共聚物、多嵌段共聚物、与聚乙二醇(PEG)的多嵌段共聚物、多元醇、三元共聚物,以及它们的混合物。还可以在所选择的聚合物和抗生素组合物沉积的过程中混入玻璃纤维。
如果需要的话,对于制备本文所公开的三维复杂的矫形骨骼组件,一种或多种骨生长促进组合物可与聚合物材料和抗生素组合物同时沉积使抗生素组合物和骨生长促进组合物封存在聚合物材料所形成的基质内或其周围。合适的骨生长促进组合物例如透明质酸、β-TCP组合物、用于调节Wnt信号通路的SOST(骨硬化蛋白)拮抗剂、用于调节Wnt信号通路的Wise拮抗剂、用于调节Wnt信号通路的LRP拮抗剂、(3-(((4-叔丁基-苄基)-(吡啶-3-磺酰基)-氨基)-甲基)-苯氧基)-乙酸及其类似物、7-[(4-丁基-苄基)-甲磺酰基-氨基]-庚酸及其类似物、7-{[2-(3,5-二氯-苯氧基)-乙基]-甲磺酰基-氨基}-庚酸及其类似物、3-苯并硫杂卓衍生物等。
颗粒材料结合过程例如选择性激光烧结、选择性激光液化、选择性热烧结和电子束液化(本文中均被称为“SLS”),包括选择性熔融颗粒床中的打印介质。在这类方法中,使用高功率的激光将小颗粒的塑料、金属、陶瓷或玻璃粉末熔融成具有期望的三维形状的块。所述激光通过扫描粉末床表面上该零件的横截面来选择性地熔融粉末状材料,所述横截面来源于三维数字描述(例如来源于CAD文件或扫描数据)。扫描每个横截面以后,粉末床被降低了一层厚度,新的材料层被施用在上面,并且重复这个过程直至该零件完成。由于成品零件密度取决于激光功率的峰值而不是激光的持续时间,因此SLS机器通常使用脉冲激光。合适的SLS机器在略低于本体粉末材料熔点将粉末床中的本体粉末材料预热从而在剩下的过程中使激光更容易升高所选区域的温度至熔点。
因此,也可通过提供一种或多种所选择的颗粒聚合物与一种或多种所选择的抗生素组合物和/或一种或多种骨生长促进组合物的粉末共混物,由SLS 3D打印机来制备本文所公开的示例性的可植入的聚合物抗菌设备。合适的SLS 3D打印机由EOS GmbH(Munich,Fed.Rep.德国)生产并在北美可以从EOS ofNorth America Inc.(Novi,MI,USA)购买到。合适的EOS SLS 3D打印机包括他们的P 110、P 395、P760和P 800设备(FORMIGA和EOSINT是EOS GmbH Electro Optical SystemsCo.的注册商标,Krailling,Fed.Rep.德国)。合适的SLS 3D打印机还由3D Systems Inc.(Rock Hill,SC,USA)生产并提供,例如他们的设备线(SPRO是3D Systems Inc.的注册商标)。合适的电子束熔融(也称为EBM)3D打印机由Arcam AB(Molndal,瑞典)生产并在北美可从他们芝加哥的办公室购买到。合适的Arcam EBM 3D打印机包括他们的Q10和A2设备。
用于SLS 3D打印的合适的示例性的粉末抗生素/聚合物组合物可包含一种或多种聚甲基丙烯酸甲酯、丙烯腈-丁二烯-苯乙烯共聚物、聚碳酸酯、丙烯腈-丁二烯-苯乙烯共聚物与聚碳酸酯的共混物、聚醚醚酮、聚乙烯、聚酰胺、聚乳酸、聚亚苯基砜、聚苯乙烯、尼龙特别是尼龙12等的颗粒。还可以使用甲基丙烯酸甲酯、聚乳酸、聚乙交酯、聚己内酯、聚酸酐、聚胺、聚氨酯、聚酯酰胺、聚原酸酯、聚二氧杂环己酮、聚缩醛、聚缩酮、聚碳酸酯、聚原碳酸酯、聚磷腈、琥珀酸酯、聚苹果酸、聚氨基酸、聚乙烯吡咯烷酮、聚乙二醇、聚羟基纤维素、聚糖、甲壳素、壳聚糖,及它们的共聚物、嵌段共聚物、多嵌段共聚物、与聚乙二醇(PEG)的多嵌段共聚物、多元醇、三元共聚物,以及它们的混合物
用于SLS 3D打印的合适的粉末抗生素/聚合物组合物可包含一种或多种氨基糖苷类,例如妥布霉素、庆大霉素、新霉素、链霉素等;唑类,例如氟康唑、伊曲康唑等;β-内酰胺类抗生素,例如青霉烷类、头孢类、碳青霉烯类、单环β-内酰胺类、β-内酰胺酶抑制剂等;头孢菌素类,例如头孢乙腈、头孢羟氨苄、头孢氨苄、头孢唑啉、头孢罗奇、头孢拉宗等;氯霉素;克林霉素;夫西地酸;糖肽类,例如万古霉素、替考拉宁、雷莫拉宁等;大环内酯类,例如阿奇霉素、克拉霉素、地红霉素、红霉素、螺旋霉素、泰乐菌素等;甲硝唑;莫匹罗星;青霉素类,例如青霉素、普鲁卡因青霉素、苄星青霉素、青霉素V等;多烯类化合物,例如两性霉素B、制霉菌素、纳他霉素等;喹诺酮类,环丙沙星、氧氟沙星、达氟沙星等;利福霉素类,例如利福平、利福布丁、利福喷丁、利福昔明等;磺酰胺,例如磺胺醋酰、磺胺多辛等;四环素类,例如多西环素、米诺环素、替加环素等;甲氧苄啶等等。用于SLS 3D打印的示例性的粉末抗生素/聚合物组合物中抗生素的含量可为约0.01%w/w、约0.05%w/w、约0.1%w/w、约0.2%w/w、约0.3%w/w、约0.4%w/w、约0.5%w/w、约0.75%w/w、约1.0%w/w、约1.25%w/w、约1.5%w/w、约1.75%w/w、约2.0%w/w、约2.25%w/w、约2.5%w/w、约2.75%w/w、约3.0%w/w、约3.25%w/w、约3.5%w/w、约3.75%w/w、约4.0%w/w、约4.25%w/w、约4.5%w/w、约4.75%w/w、约5.0%w/w、约5.25%w/w、约5.5%w/w、约5.75%w/w、约6.0%w/w、约7.0%w/w、约8.0%w/w、约9.0%w/w、约10.0%w/w、约15.0%w/w、约20.0%w/w、约25.0%w/w,以及这些数值之间的中间数值。
用于SLS 3D打印的合适的粉末抗生素/聚合物组合物可包含一种或多种透明质酸、β-TCP组合物、用于调节Wnt信号通路的SOST(骨硬化蛋白)拮抗剂、用于调节Wnt信号通路的Wise拮抗剂、用于调节Wnt信号通路的LRP拮抗剂、(3-(((4-叔丁基-苄基)-(吡啶-3-磺酰基)-氨基)-甲基)-苯氧基)-乙酸及其类似物、7-[(4-丁基-苄基)-甲磺酰基-氨基]-庚酸及其类似物、7-{[2-(3,5-二氯-苯氧基)-乙基]-甲磺酰基-氨基}-庚酸及其类似物、3-苯并硫杂卓衍生物等。用于SLS 3D打印的示例性的粉末抗生素/聚合物组合物中骨生长促进组合物的含量可为约0.01%w/w、约0.05%w/w、约0.1%w/w、约0.2%w/w、约0.3%w/w、约0.4%w/w、约0.5%w/w、约0.75%w/w、约1.0%w/w、约1.25%w/w、约1.5%w/w、约1.75%w/w、约2.0%w/w、约2.25%w/w、约2.5%w/w、约2.75%w/w、约3.0%w/w、约3.25%w/w、约3.5%w/w、约3.75%w/w、约4.0%w/w、约4.25%w/w、约4.5%w/w、约4.75%w/w、约5.0%w/w、约5.25%w/w、约5.5%w/w、约5.75%w/w、约6.0%w/w、约7.0%w/w、约8.0%w/w、约9.0%w/w、约10.0%w/w、约15.0%w/w、约20.0%w/w、约25.0%w/w,以及这些数值之间的中间数值。
本发明的3D打印方法可还包括或者包括步骤:抗生素组合物和/或第一骨生长促进组合物的第一抗生素组合物或混合物与所选择的聚合物材料在数个层中同时沉积以形成三维抗菌制品的核,随后抗生素组合物和/或第二骨生长促进组合物的第二抗生素组合物或混合物与所选择的聚合物材料同时沉积以形成抗菌制品的外部区域和表面。如果需要的话,所述方法还可包括抗生素组合物和/或第三骨生长促进组合物的第三抗生素组合物或混合物的附加层同时沉积。任选提供添加了杀菌组合物的最终的外表面层,所述杀菌组合物例如银纳米粒子、吡啶硫酮锌、阳离子聚合物杀菌剂等。任选提供添加了骨生长促进组合物的最终的外表面层,所述骨生长促进组合物例如透明质酸、β-TCP组合物、3-苯并硫杂卓衍生物等。
还任选提供添加了杀菌组合物与骨生长促进组合物的混合物的最终的外表面层。可使用用来制备所述三维抗菌制品的核结构基质的相同的增材制造方法来施加包含杀菌涂层和/或骨生长促进组合物的所述外表面层。或者可以三维抗菌制品的核结构基质上面的涂层形式来施加所述外表面层。外涂层可通过以下方法来施加:浸渍、喷淋、浸泡、浸渍、粉末涂层、溅射涂层,电弧沉积等。
本发明的抗生素洗脱制品例如矫形骨骼组件、矫形关节置换组件和骨垫片。还包括短期植入的临时矫形组件同时永久置换矫形组件正在制备中。本文所用的术语“短期”是指三百六十五(365)天或更短。本发明的抗生素洗脱制品的示例还有用于可植入设备的外部硬壳,可植入设备例如心脏起搏器、脊髓刺激器、神经刺激***、用于将药物递送至脑脊液中的鞘内给药泵、用于递送化疗和/或解痉药的输液泵、胰岛素泵、渗透泵、肝素泵等。本发明的抗生素洗脱制品的示例还有可植入的牙科假体、包含一个或多个置换牙齿组件的牙科植入物等。本发明的抗生素洗脱制品的示例还有用于提供经皮电神经刺激的经皮皮肤表面处理设备和用于提供长期经皮穿刺途径的设备。本发明的抗生素洗脱制品的示例还有受伤处理表面设备,例如矫形钉和缝合线等。
实施例
实施例1:
聚乳酸(PLA)颗粒来自于NatureWorks LLC(Blair,NE,USA)。聚己内酯(PCL)颗粒(CAPATM 6500)来自于Plastics Systems Inc.(Lakewood,WA,USA)。万古霉素和庆大霉素来自于Gold Biotechnology(St.Louis,MO,USA)。将0.28kg的万古霉素与5.8Kg的一批PLA颗粒一起干燥共混来制备包含约5%万古霉素的PLA共混物。将0.122kg的万古霉素与5.8Kg的一批PLA颗粒一起干燥共混来制备包含约2%万古霉素的PLA共混物。将0.125Kg的庆大霉素与2.5Kg的一批PCL颗粒一起干燥共混来制备包含约5%庆大霉素的PCL共混物。通过将包含约5%庆大霉素的PCL共混物与另外的PCL干燥共混以调节庆大霉素的含量至约2%来制备包含约2%庆大霉素的PCL共混物。
使用HiQ***(SINTERSTATION和SLS是3D SystemsInc.的注册商标,Valencia,CA,USA),由每个批次的聚合物/抗生素共混物来打印直径约1英寸(2.54cm)及厚度约0.125英寸(0.3175cm)的圆盘。由纯的PLA颗粒和PCL颗粒打印对照圆盘。将约4英寸的聚合物/抗生素共混物放入机器进料缸,然后通过在零件缸上沉积粉末来形成粉末床。然后,使用预热循环来加热进料缸和零件缸,之后,根据在3D System’s“Build Setup”Version 3.602软件中下载的STL CAD软件文件来打印圆盘。每种聚合物/抗生素共混物的一部分用于圆盘的SLS印刷以用来评价它们的抗生素洗脱性能,所述聚合物/抗生素共混物的剩下部分用于打印IV型哑铃形试验样品以用于拉伸试验。
用于PCL/万古霉素共混物和PCL/庆大霉素共混物的圆盘和IV型哑铃形样品的SLS打印的***操作条件:
粒子床温度:48℃
进料温度:环境温度
智能进料增重(Smart feed gain):1.3
填充激光功率(Fill laser power)(W):49
填充扫描速率(Fill scan speed)(英寸/秒):500
填充扫描间距(Fill scan spacing)(英寸):0.01
轮廓激光功率(Outline laser power)(W):14
轮廓扫描速度(Outline scan speed)(英寸/秒):70
用于来源于PLA/万古霉素共混物和PLA/庆大霉素共混物的圆盘的SLS打印的***操作条件:
粒子床温度:75℃
进料温度:40℃
智能进料增重:1.3
填充激光功率(W):67
填充扫描速率(英寸/秒):500
填充扫描间距(英寸):0.01
轮廓激光功率(W):14
轮廓扫描速度(英寸/秒):70
实施例2:
根据题目为“Standard Test Method for Tensile Properties of Plastics(塑料拉伸性能的标准试验方法)”的ASTM D638-08文件中提出的试验方法来测定含有抗生素的塑料IV型哑铃形试验样品的所选择的物理性能,所述试验方法由ASTM International(国际材料试验协会)出版,并可以从它们的网址http://www.astm.org/Standards/D638.htm公开获得。SLS打印的含有抗生素的塑料圆盘的物理性能列于表1-4中。
表1:用PCL/庆大霉素干燥共混物打印的IV型哑铃形样品的物理性能*
*数据为三次重复的平均值±SD
表2:用PCL/万古霉素干燥共混物打印的IV型哑铃形样品的物理性能*
*数据为三次重复的平均值±SD
表3:用PLA/庆大霉素干燥共混物打印的IV型哑铃形样品的物理性质*
*数据为三次重复的平均值±SD
**对照PLA颗粒没有被烧结好而且没有保持其结构
表4:用PLA/万古霉素干燥共混物打印的IV型哑铃形样品的物理性能*
*数据为三次重复率的平均值±SD
**对照PLA颗粒没有被烧结好并且对照IV型哑铃形样品没有保持它们的结构
实施例2:
通过其上放置测试取样片的培养皿中含有的Meuller Hinton琼脂表面上的金黄色葡萄球菌(Staphylococcus aureus)生长的抑制来评价实施例1制备的来自圆盘中的抗生素的洗脱。金黄色葡萄球菌(S.aureus)培养物在用5%绵羊血改进的TSA上进行生长。足够量的金黄色葡萄球菌培养物从TSA培养盘转移至0.85%无菌生理盐水溶液中来提供落在0.5-2.0马克法兰氏浊度标准内的均一悬浮液。之后,将等分的金黄色葡萄球菌培养物覆盖在培养皿中的Meuller Hinton琼脂上,将两个试验取样片(或者可选的,对照取样片)放置在琼脂上;一个是光泽面朝上,另一个是磨砂面朝上。然后将含有Meuller Hinton琼脂的培养皿在约35℃至约37℃的温度范围孵化约72小时。之后测量每个取样片周围抑制的区域并记录(mm)。试验取样片周围清晰的区域表明金黄色葡萄球菌生长的抑制。PLA/抗生素共混物取样片的直径是25mm,PCL/抗生素取样片的直径是26mm。PLA对照取样片的直径分别为25mm和26mm,并且被认为是“0”点。如果没有抑制发生,则记录值“25”并且表明没有发生微生物生长的抑制。表5中的数据确定抗生素从由每种聚合物/抗生素共混物打印的制品中洗脱出来。
表5:抗生素从包含PCL或PLA的3d打印制品中的洗脱*
*数据为三次重复的平均值±SD
Claims (29)
1.用于植入哺乳动物对象中的抗生素洗脱制品,通过选择性激光烧结方法、选择性激光熔化方法、选择性热烧结方法或电子束熔化方法中的一种来制备所述抗生素洗脱制品,其中将聚合物材料与所选择的抗生素组合物同时沉积。
2.如权利要求1所述的抗生素洗脱制品,其中所述聚合物材料选自聚甲基丙烯酸甲酯、丙烯腈-丁二烯-苯乙烯共聚物、聚碳酸酯、丙烯腈-丁二烯-苯乙烯共聚物与聚碳酸酯的共混物、聚醚醚酮、聚乙烯、聚酰胺、聚乳酸、聚亚苯基砜、聚苯乙烯、尼龙、甲基丙烯酸甲酯、聚乳酸、聚乙交酯、聚己内酯、聚酸酐、聚胺、聚氨酯、聚酯酰胺、聚原酸酯、聚二氧杂环己酮、聚缩醛、聚缩酮、聚碳酸酯、聚原碳酸酯、聚磷腈、琥珀酸酯、聚苹果酸、聚氨基酸、聚乙烯吡咯烷酮、聚乙二醇、聚羟基纤维素、聚糖、甲壳素、壳聚糖,及它们的共聚物、嵌段共聚物、多嵌段共聚物、与聚乙二醇(PEG)的多嵌段共聚物、多元醇、三元共聚物,以及它们的混合物。
3.如权利要求1所述的抗生素洗脱制品,其中所述抗生素组合物为一种或多种氨基糖苷类;唑类;β-内酰胺类抗生素;β-内酰胺酶抑制剂;头孢菌素类;氯霉素;克林霉素;夫西地酸;糖肽类;大环内酯类;甲硝唑;莫匹罗星;青霉素类;多烯类化合物;喹诺酮类;利福霉素;磺酰胺;诸如多西环素、米诺环素、替加环素等的四环素类;甲氧苄啶;以及它们的组合。
4.如权利要求1所述的抗生素洗脱制品,其中所述抗生素组合物为妥布霉素和/或庆大霉素和/或万古霉素。
5.如权利要求1所述的抗生素洗脱制品,其中对所述抗生素洗脱制品提供包含杀菌组合物的外涂层。
6.如权利要求5所述的抗生素洗脱制品,其中所述杀菌涂层包含一种或多种银纳米粒子、吡啶硫酮锌和阳离子聚合物杀菌剂。
7.如权利要求1所述的抗生素洗脱制品,其中所述制品为矫形骨骼组件。
8.如权利要求7所述的抗生素洗脱制品,其中骨生长促进组合物与所述聚合物材料和所述抗生素组合物同时沉积。
9.如权利要求8所述的抗生素洗脱制品,其中所述骨生长促进组合物选自透明质酸、β-TCP组合物、用于调节Wnt信号通路的SOST(骨硬化蛋白)拮抗剂、用于调节Wnt信号通路的Wise拮抗剂、用于调节Wnt信号通路的LRP拮抗剂、(3-(((4-叔丁基-苄基)-(吡啶-3-磺酰基)-氨基)-甲基)-苯氧基)-乙酸及其类似物、7-[(4-丁基-苄基)-甲磺酰基-氨基]-庚酸及其类似物、7-{[2-(3,5-二氯-苯氧基)-乙基]-甲磺酰基-氨基}-庚酸及其类似物和3-苯并硫杂卓衍生物。
10.如权利要求7所述的抗生素洗脱制品,其中对所述抗生素洗脱制品提供包含骨生长促进组合物的外涂层。
11.如权利要求10所述的抗生素洗脱制品,其中所述骨生长促进组合物选自透明质酸、β-TCP组合物、用于调节Wnt信号通路的SOST(骨硬化蛋白)拮抗剂、用于调节Wnt信号通路的Wise拮抗剂、用于调节Wnt信号通路的LRP拮抗剂、(3-(((4-叔丁基-苄基)-(吡啶-3-磺酰基)-氨基)-甲基)-苯氧基)-乙酸及其类似物、7-[(4-丁基-苄基)-甲磺酰基-氨基]-庚酸及其类似物、7-{[2-(3,5-二氯-苯氧基)-乙基]-甲磺酰基-氨基}-庚酸及其类似物和3-苯并硫杂卓衍生物。
12.如权利要求7所述的抗生素洗脱制品,其中所述制品为矫形关节置换组件。
13.如权利要求7所述的抗生素洗脱制品,其中所述制品为矫形骨置换组件。
14.如权利要求1所述的抗生素洗脱制品,其中所述制品为用于可植入设备的外部硬壳。
15.如权利要求14所述的抗生素洗脱制品,其中所述制品为心脏起搏器、脊髓刺激器、神经刺激***、用于将药物递送至脑脊液中的鞘内给药泵、用于递送化疗和/或解痉药的输液泵、胰岛素泵、渗透泵和肝素泵中的一种。
16.如权利要求1所述的抗生素洗脱制品,其中所述制品为可植入的牙科假体或口服设备或置换牙齿组件。
17.如权利要求1所述的抗生素洗脱制品,其中所述制品为经皮皮肤表面处理设备。
18.如权利要求1所述的抗生素洗脱制品,其中所述制品为受伤处理设备。
19.制备用于植入哺乳动物对象中的抗生素洗脱制品的方法,所述方法包括选择性激光烧结方法、选择性激光熔化方法、选择性热烧结方法或电子束熔化方法中的一种来制备所述抗生素洗脱制品,其中将聚合物材料与所选择的抗生素组合物同时沉积。
20.如权利要求18所述的方法,其中骨生长促进组合物与所述聚合物材料和所述抗生素组合物同时沉积。
21.含有抗生素的聚合物颗粒粉末,使用选择性激光烧结机、选择性激光液化机、选择性热烧结机和电子束液化机中的任意方法将其打印成三维抗生素洗脱制品。
22.如权利要求21所述的含有抗生素的聚合物颗粒粉末,其中所述聚合物选自聚甲基丙烯酸甲酯、丙烯腈-丁二烯-苯乙烯共聚物、聚碳酸酯、丙烯腈-丁二烯-苯乙烯共聚物与聚碳酸酯的共混物、聚醚醚酮、聚乙烯、聚酰胺、聚乳酸、聚亚苯基砜、聚苯乙烯、尼龙、甲基丙烯酸甲酯、聚乳酸、聚乙交酯、聚己内酯、聚酸酐、聚胺、聚氨酯、聚酯酰胺、聚原酸酯、聚二氧杂环己酮、聚缩醛、聚缩酮、聚碳酸酯、聚原碳酸酯、聚磷腈、琥珀酸酯、聚苹果酸、聚氨基酸、聚乙烯吡咯烷酮、聚乙二醇、聚羟基纤维素、聚糖、甲壳素、壳聚糖,及它们的共聚物、嵌段共聚物、多嵌段共聚物、与聚乙二醇(PEG)的多嵌段共聚物、多元醇、三元共聚物,以及它们的混合物。
23.如权利要求21所述的含有抗生素的聚合物颗粒粉末,其中所述聚合物选自聚乳酸、聚己内酯、尼龙和高密度聚乙烯。
24.如权利要求21所述的含有抗生素的聚合物颗粒粉末,其包含至少0.1%w/w的至少一种抗生素。
25.如权利要求21所述的含有抗生素的聚合物颗粒粉末,其中所述抗生素选自氨基糖苷类;唑类;β-内酰胺类抗生素;β-内酰胺酶抑制剂;头孢菌素类;氯霉素;克林霉素;夫西地酸;糖肽类;大环内酯类;甲硝唑;莫匹罗星;青霉素类;多烯类化合物;喹诺酮类;利福霉素;磺酰胺;诸如多西环素、米诺环素、替加环素等的四环素类;甲氧苄啶;以及它们的组合。
26.如权利要求21所述的含有抗生素的聚合物颗粒粉末,其中至少一种抗生素的浓度选自约0.1%w/w至约25.0%w/w的范围。
27.如权利要求21所述的含有抗生素的聚合物颗粒粉末,其中至少一种抗生素的浓度选自约0.5%w/w至约10.0%w/w的范围。
28.如权利要求21所述的含有抗生素的聚合物颗粒粉末,其中至少一种抗生素的浓度选自约0.75%w/w至约5.0%w/w的范围。
29.如权利要求21所述的含有抗生素的聚合物颗粒粉末,其还包含骨生长促进组合物,所述骨生长促进组合物选自透明质酸、β-TCP组合物、用于调节Wnt信号通路的SOST(骨硬化蛋白)拮抗剂、用于调节Wnt信号通路的Wise拮抗剂、用于调节Wnt信号通路的LRP拮抗剂、(3-(((4-叔丁基-苄基)-(吡啶-3-磺酰基)-氨基)-甲基)-苯氧基)-乙酸及其类似物、7-[(4-丁基-苄基)-甲磺酰基-氨基]-庚酸及其类似物、7-{[2-(3,5-二氯-苯氧基)-乙基]-甲磺酰基-氨基}-庚酸及其类似物和3-苯并硫杂卓衍生物。
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