CN1725988A - 具有多孔层的医用装置及其制造方法 - Google Patents

具有多孔层的医用装置及其制造方法 Download PDF

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CN1725988A
CN1725988A CNA2003801030682A CN200380103068A CN1725988A CN 1725988 A CN1725988 A CN 1725988A CN A2003801030682 A CNA2003801030682 A CN A2003801030682A CN 200380103068 A CN200380103068 A CN 200380103068A CN 1725988 A CN1725988 A CN 1725988A
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medical apparatus
alloy
implantable medical
medicine
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怀耶-凯·利耶
卡雷恩·洛伊
迈克尔·L·里德
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Setagon Inc
University of Virginia Patent Foundation
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University of Virginia Patent Foundation
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Abstract

本发明提供了一种用于制造具有至少一个多孔层的医用装置的方法,包括提供具有至少一种合金的医用装置,以及除去至少一种合金成分用以形成多孔层。虽然可以使用这些方法来制造具有多孔层的支架装置,但使用这些方法可制造具有一个或多个多孔层的任何其它适宜的医用装置。合金可以包括任何适宜的金属组合,有时还包括金属和非金属的组合。在某些实施例中,通过溶解(或“脱合金成分腐蚀”)过程来除去一种或多种电化学活性最强的合金成分,以便留下多孔基质。然后可以用一种或多种治疗药物浸渍多孔基质层以便改善对患者的治疗。

Description

具有多孔层的医用装置及其制造方法
技术领域
本发明一般而言涉及医用装置及其制造方法。更具体而言,本发明涉及具有至少一个多孔层的可植入医用装置、以及制造这类装置的方法。
背景技术
可植入医用装置正越来越广泛地被用来将一种或多种治疗药物递送到体内的部位。这类药物可能本身有益于治疗和/或可以提高可植入装置的功效。例如,对用于经皮腔内冠状动脉成形术(PTCA)过程的药物洗脱支架的使用已经进行了许多研究。虽然某些可植入装置只是简单地用一种或多种治疗药物进行涂布,但是其它的装置包括用于容纳、附着或另外的保持治疗药物的装置,以便在更长时间间隔内以受控释放的方式或类似方式在治疗部位提供药物。
例如多孔材料,通常用于医用植入物作为用于保留治疗药物的基质。已经用于该用途的材料包括陶瓷制品,例如羟磷灰石和多孔氧化铝、以及烧结金属粉。聚合材料,例如聚乙二醇/聚(L-乳酸)(PLGA)也已经用于该用途。这些材料通常用作医用植入物的涂层,这就对涂层附着力、机械性能和材料的生物相容性提出了问题。
此外,这些涂层的应用给制造过程带来了额外的复杂性,并增加了总生产成本。
因此,具有改良的带有多孔层的可植入医用装置和用于制造这些装置的方法是很有益的。这类方法在对装置的制造进行简化的同时,将会理想地产生一种附着力更强而且机械上更坚固的多孔层。这些方法还可以理想地提供具有所需要的孔径尺寸和密度的多孔层。通过本发明至少会实现这些目的中的一些。
发明内容
本发明的方法提供了用于制造具有至少一个多孔层的可植入医用装置的方法。在一个方面,制造具有一个多孔层(用于可释放地含有至少一种治疗药物)的可植入医用装置的方法包括提供包含至少一种合金的可植入医用装置,以及除去该合金的至少一种成分以便形成多孔层。在一些实施例中,将该成分除去用以形成多孔层作为一种生物相容性材料,例如金。在一些实施例中,该医用装置包括具有外表面和内表面的管状支架装置。例如,该支架装置可以包括在经皮腔内冠状动脉成形术(PTCA)过程中使用的冠状动脉支架。在这些实施例其中的一些中,合金是沿着支架装置的外表面设置(disposed)的。
可选地,提供的可植入医用装置也可以包括在医用装置的至少一个表面上沉积的合金。在多个实施例中,都可以沿着可植入医用装置的外表面来沉积合金,以使溶解步骤在该装置的外表面上形成多孔层。在一些实施例中,该合金包括一种或多种金属,例如但不限于金、银、镍钛金属互化物、钢、铬、铁、镍、铜、铝、钛、钽、钴、钨、钯、钒、铂和/或铌。在其它实施例中,该合金包括至少一种金属和至少一种非金属。可选地,在溶解步骤之前,可以在合金中嵌入至少一种物质。例如,可以在合金中嵌入一种盐或一种氧化物颗粒用以在溶解过程中增加孔隙的形成。
溶解一种或多种合金成分可以涉及将合金暴露于溶解性物质中。例如,在一个实施例中,可以将不锈钢合金暴露于氢氧化钠中。
通常,将合金的一种或多种电化学活性最强的成分溶解。在溶解步骤之后,可以进行另外的加工处理。例如,在溶解步骤之后,可以用钛、金和/或铂对装置进行涂布。一些实施例进一步包括将至少一种治疗药物引入到多孔层中。例如,在不同的实施例中,可以通过液体浸渍、真空干燥、高压灌注或蒸气装载来引入治疗药物。治疗药物可以是任何适宜的药物或药物组合,例如但不限于抗再狭窄药或抗炎药,如雷帕霉素、西罗莫司、紫杉醇、泼尼松和/或同类药物。
在其它实施例中,可以通过多孔层来封装活细胞,从而实现所选择分子的运输,例如进入细胞中和从细胞中出来的氧、葡萄糖或胰岛素,同时对来自于患者免疫系统的细胞进行屏蔽。一些实施例可选地包括具有不同孔隙率和原子组成的多个多孔层。
在另一个方面,使用一种具有用于可释放地含有至少一种治疗药物的多孔层的可植入医用装置来治疗血管的方法包括:提供至少一个可植入支架,其具有用于可释放地含有至少一种治疗药物的多孔层;以及将该支架放置在血管内所需要的位置,其中在放置之后该支架从多孔层中释放至少一种治疗药物。例如,在一个实施例中,所需要的位置可以包括血管中的一个狭窄区域,并且该至少一种治疗药物可以抑制血管的再狭窄。此外,一些实施例中的治疗药物可以是一种或多种抗再狭窄药、抗炎药、或两者的组合。在一个实施例中,血管可以是冠状动脉。在这样的一些实施例中,放置步骤可以包括放置支架以便多孔层与在血管中的狭窄斑块和血管内壁的至少之一相接触。
在又一个方面,可植入医用装置具有至少一个多孔层,其包括至少一种剩余的合金成分和填隙空间(interstitial spaces),其中填隙空间包括合金的至少一种除去的合金成分的空间,该合金包括至少一种剩余的合金成分和至少一种除去的合金成分。在一些实施例中,该多孔层包括基质。同样在一些实施例中,可植入医用装置包括具有外表面和内表面的可植入支架装置,并且多孔层是沿着外表面加以布置的。例如,支架装置可以包括用于经皮腔内冠状动脉成形术过程的冠状动脉支架。如上所述,合金可以包括一种或多种金属,其选自由金、银、镍钛金属互化物、钢、铬、铁、镍、铜、铝、钛、钽、钴、钨、钯、钒、铂和/或铌组成的组。例如,合金可以包括不锈钢而多孔层可以包括铁和镍。
在一些实施例中,被溶解的一种成分(或多种成分)包括合金的电化学活性最强的成分。通常,所述装置进一步包括至少一种放置在至少一个多孔层内的治疗药物。可以预期使用任何这样的药物或药物组合。最后,所述装置可以包括在该装置外表面上的钛或铂涂层。
附图说明
图1是根据本发明一个实施例的具有一个多孔层的可植入支架装置的透视图。
图2A-2B是根据本发明一个实施例通过将金银合金中的银溶解而形成的多孔层的电子显微照片。
图3A-3C是侧面剖视图,其示出了根据本发明一个实施例的制作具有一个多孔层的可植入支架装置的方法。
具体实施方式
本发明提供了用于制造具有至少一个多孔层的可植入医用装置的方法。通常,这些方法包括提供含有合金的可植入医用装置并除去至少一种合金成分用以形成多孔层。在一些实施例中,可以首先在可植入装置上沉积合金,然后可以将一种或多种合金成分除去以便形成多孔层。经常将这类方法称为“脱合金成分腐蚀(dealloying)”。对于脱合金成分腐蚀方法的一般描述,可以参考Jonah Erlebacher等人的“Evolution of nanoporosity in dealloying,”Nature410,pp.450-452,March 2001,将其全部内容合并于此作为参考。对可植入装置的一层进行脱合金成分腐蚀提供了一个多孔层,然后可以用一种或多种治疗药物浸渍该多孔层,以便通过该装置将药物递送给患者。脱合金成分腐蚀方法的使用通常会在可植入医用装置上提供比目前可获得的附着力更强和机械上更坚固的多孔层,同时还简化了装置的制造。
虽然下面的描述通常集中于PTCA过程中使用的可植入支架装置的实例,但是可以用本发明的方法制造任何适宜的可植入医用装置。其它装置可以包括但不限于其它的支架、支架-移植物、可植入导管、输液泵、脉管通路装置如可植入端口(port)、矫形植入物、可植入电极等等。类似地,通过本发明的方法制造的装置可以用来在患者护理情况下、在兽医情况下、在研究装置(setting)或类似情况下,提供任何适宜的治疗或联合治疗。治疗药物可以包括,例如,药品、基因、抗再狭窄药、抗血栓形成药、抗生素、抗凝固药、抗炎药、癌症治疗药物和/或类似物。因此,以下特定实施例的描述仅是示例性的,而不是用来限制如在所附权利要求中阐明的本发明的范围。
现参照图1,根据本发明的方法制造的可植入医用装置可以包括一种细长的支架装置10,其具有二层或多层12、14和内腔16。
在一个实施例中,支架装置10包括外部的多孔层12和内部的非多孔层14。其它实施例可以适应性地包括内部的多孔层12和外部的非多孔层14,多重多孔层12,多重非多孔层14,医用装置整个表面之上的多孔涂层,或者多孔和非多孔表面、层、区域、或诸如此类的任意组合,从而提供想要的效果。在一个实施例中,例如,多重多孔层可以彼此形成层次,其中每一层具有不同的孔隙率和原子组成。多孔层12和非多孔层14在不同的实施例中可以具有任意适宜的厚度。例如,在某些实施例中,可能需要非常薄的多孔层12,如用于递送相对少量的治疗药物。在另一实施例中,可以使用较厚的多孔层12来递送更大量的治疗药物和/或获得更长的药物递送持续时间。可以预期使用任意适宜组合和结构的多孔层12和非多孔层14。在一个实施例中,多孔层12可以包括支架装置10的整个厚度,以至于该装置完全是多孔的。此外,支架装置10只是可以使用的具有多孔层的装置的一个实例。其它装置,例如,可能没有内腔,但仍然对本发明的应用是适合的。
如上所述,根据本发明的实施例可以制造具有一个或多个多孔层12的任何医用装置。在该装置是可植入支架装置10的情况下,可以制造具有一个或多个多孔层12的任何适当类型、大小和结构的支架装置。在一个实施例中,支架装置10包括可膨胀支架,用于在PTCA过程中植入在冠状动脉中。采用任何适宜材料或材料组合都可以制造这样的支架装置10。在一个实施例中,支架装置10包括不锈钢非多孔层14和铁与镍的多孔层12。在某些实施例中,多孔层12可以由生物相容性材料组成,例如金。在其它实施例中,多孔层12可以由钴-铬合金如L605组成。可以预期使用任何其它适宜的材料或材料组合。此外,支架装置10可以包括包含生物相容性材料如钛、金或铂的层或涂层,其可以提供生物相容性、耐腐蚀性、或两者兼而有之。
现参照图2A和2B,其更详细地示出了多孔层12。这些图中的多孔层12是通过从金-银合金中选择性地将银溶解而制成的。如可以从扫描电子显微照片上看到的,多孔层12包括多孔基质和结构元素。在任意给出的实施例中,这类孔的尺寸和密度可以随制造该装置和形成多孔层12的方法中的一种或多种元素的变化而变化。例如,在将合金暴露于溶解性物质等的持续时间间隔内可以使用一种物质来选择性地溶解合金,将合金的一种或多种成分选择性地溶解,从而选择性地给予多孔层12某些所需要的特征。也可以在进行脱合金成分腐蚀过程之前或之后进行热退火,从而改变孔径的大小和密度。在本发明范围内可以预期利用多孔层厚度、孔径大小、孔密度等的任意适当组合。
虽然在图1和图2中未示出,但本发明的任何可植入医用装置可以包括放置在一个或多个多孔层12内的一种或多种治疗药物。
如上所述,可以包括任何药物或者药物组合。另外,如下面要描述的,任何适宜的用于将药剂引入到多孔层中的方法都可以使用。
现参照图3A到图3C,用于制造具有多孔层的可植入医用装置20的方法可适应性地包括:提供包括至少一种合金的可植入装置;以及除去至少一种合金成分用以形成多孔层。如在剖视图3A中所示,医用装置20,如支架,可以包括前体合金层(precursor alloy layer)22、基质层24和内腔。可以通过各种方法将前体合金层22沉积在基质层24上,这些方法包括但不限于物理气相沉积、离子植入、溅射沉积、热或电子束蒸发、化学气相沉积、脉冲激光沉积或类似方法。使用这类技术,前体合金层22可以由如上所述的各种材料进行原位合成,以致暴露于脱合金成分腐蚀过程将除去前体合金层22的牺牲成分,而留下多孔基质。在另一实施例中,可以由相同材料制成前体合金层22和基质层24。如前所述,医用装置20可以包括任何适宜的支架或其它装置,并且前体合金层22、基质层24和/或其它层可以具有任何适当的结构、厚度等。在某些实施例中,前体合金层22是沿着装置20的外表面设置的,而在其他实施例中,前体合金层22可以沿着内表面、内表面和外表面、或类似方式加以设置。用来形成前体合金层22的合金可以包括任何适宜的合金,并且可以是金属-金属合金或金属-非金属合金。在多个实施例中,例如,前体合金层22的成分可以包括钢、镍钛金属互化物、铬、黄铜、铜、铁、镍、铝、钛、金、银、钽、钴、钨、钯、钒、铂和/或铌。在某些实施例中,在前体合金层22中可以嵌入一种或多种另外的物质,从而在制造过程中导致或者增加孔的形成。例如,可以在前体合金层22中加入盐、氧化物颗粒或类似物来增加孔的形成。
如图3B所示,通常将可植入医用装置20暴露于一种物质(箭头)中来进行溶解,或者换句话说(or otherwise)除去至少一种合金成分,以便由前体合金层22形成多孔层。在不同的实施例中,任何适宜的物质都可以用来除去至少一种合金成分。例如,在一个实施例中,合金包含不锈钢,如316L不锈钢,而溶解钢的至少一种成分包括将钢暴露于热氢氧化钠中来溶解铬并且保留铁和镍作为多孔层。在另一实施例中,可以将银-金合金暴露于硝酸中来溶解银并保留金作为多孔层(如图2A和图2B所示)。在另一实施例中,通过加入牺牲物质如银、铜或铝来改变钴-铬合金,如L605,随后通过在适宜的溶剂如硝酸、硫酸或磷酸中进行处理,以除去该牺牲物质,从而保留原钴-铬合金的多孔膜。在另一实施例中,在有硫酸的情况下,腐蚀铂-铜合金用以产生多孔铂。在某些实施例中,可以通过适当的溶解物质来溶解镍钛金属互化物,从而保留多孔层。溶解过程可以包括使用电化学电池以对溶液中的装置20施加偏压(bias),从而促进脱合金成分腐蚀过程。可以预期使用任何其它合适的合金与溶解或除去成分的物质的组合。此外,可以预期使用任何将医用装置20暴露于溶解物质的方法。例如,可以用任何适当的物质或物质的组合来对医用装置20进行浸渍、喷涂、涂布等等。
如图3C所示,一种或多种前体合金层22的成分被选择性地除去以便形成多孔层23。在某些实施例中,除去至少一种合金成分包括将一种或多种电化学活性最强的合金成分溶解。例如,可以将钢合金中的铬成分溶解,留下铁和镍成分。对医用装置20的附加处理可以包括将一种或多种治疗药物引入到多孔层23中。可以将任何适当的药物引入并且可以通过任意所希望的方法将它们引入。例如,用于引入治疗药物的方法包括但不限于液体浸渍、真空干燥、高压灌注、蒸气装载等等。
在另一实施例中,可以将多种治疗药物引入到由多个多孔层23组成的多孔基质中。如前所述,多个多孔层可以在原子组成、以及在孔径大小和密度方面有差异。成分差异可以便于在治疗药物和涂层之间发生优先结合,从而改变药物的洗脱动力学。孔径大小和密度也将影响来自各层和穿过各层的治疗药物的运输动力学。因而多个多孔层的使用可以便于控制多种治疗药物的洗脱动力学。在又一实施例中,可以将活细胞封装在装置20的内腔26中。在一个这样的实施例中,可以将整个装置制成多孔的(从而可以通过多孔层将装置的内腔和装置的外部分开)。可以将活细胞(例如胰岛细胞)封装在内腔中,并且可以对层的孔隙率加以调节以允许运输所选择的分子(例如氧、葡萄糖;以及治疗性的细胞产物,如胰岛素、干扰素),同时防止抗体和其它免疫系统药物进入,否则它们可能会攻击或危害被封装的细胞。在某些实施例中,在医用装置20上可以形成或加入保护层或涂层,如钛层、金层或铂层或者涂层。如果担心多孔层23可能不是生物相容性的,可以在多孔层23中沉积钝化层用以提高生物相容性。例如,可以在脱合金成分的多孔层23中电镀非常薄的金层。也可以使用无电沉积来达到同样的效果。取决于多孔层23的组成,多孔涂层还可以进行化学钝化或者在反应离子等离子体中进行钝化。
虽然所涉及的各种示例性实施例已对本发明进行了充分地描述,但在本发明的范围内可以设想各种另外的实施例和对已描述的实施例的改变。因此,前述的任何部分都不应看作是对在权利要求中阐明的本发明范围的限制。

Claims (41)

1.一种制造具有至少一个多孔层的可植入医用装置的方法,所述多孔层用来可释放地包括至少一种治疗药物,所述方法包括:提供包括至少一种合金的可植入医用装置;以及除去所述合金的至少一种成分用以形成所述至少一个多孔层。
2.根据权利要求1所述的方法,其中进行所述除去步骤以便形成所述多孔层作为生物相容性材料。
3.根据权利要求2所述的方法,其中所述生物相容性材料包括金。
4.根据权利要求1所述的方法,其中提供所述可植入医用装置包括提供具有外表面和内表面的管状支架装置。
5.根据权利要求4所述的方法,其中所述支架装置包括用于经皮腔内冠状动脉成形术过程的冠状动脉支架。
6.根据权利要求4所述的方法,其中所述至少一种合金是沿着所述支架装置的外表面设置的。
7.根据权利要求1所述的方法,其中提供所述可植入医用装置包括在所述医用装置的至少一个表面上沉积所述至少一种合金。
8.根据权利要求1所述的方法,其中所述合金是沿着所述可植入医用装置的外表面设置的,以便通过所述除去步骤在所述装置的外表面上形成所述多孔层。
9.根据权利要求1所述的方法,其中所述合金包括至少一种金属,选自由金、银、镍钛金属互化物、钢、铬、铁、镍、铜、铝、钛、钽、钴、钨、钯、钒、铂和铌组成的组。
10.根据权利要求1所述的方法,其中所述合金包括至少一种金属和至少一种非金属。
11.根据权利要求1所述的方法,进一步包括在所述除去步骤前在所述合金中嵌入至少一种物质。
12.根据权利要求11所述的方法,其中所述至少一种物质选自由盐和氧化银颗粒组成的组。
13.根据权利要求1所述的方法,其中除去所述至少一种成分包括将不锈钢合金暴露于氢氧化钠中。
14.根据权利要求1所述的方法,其中除去所述至少一种成分包括将所述合金的电化学活性最高的成分溶解。
15.根据权利要求1所述的方法,进一步包括在所述除去步骤之后在所述装置上涂布钛、金和铂中的至少一种。
16.根据权利要求1所述的方法,进一步包括将所述至少一种治疗药物引入到所述多孔层中。
17.根据权利要求16所述的方法,其中引入所述至少一种治疗药物包括通过液体浸渍、真空干燥、高压灌注以及蒸气装载中的至少之一来进行引入。
18.根据权利要求16所述的方法,其中所述至少一种治疗药物包括至少一种抗再狭窄药或抗炎药用于抑制冠状动脉的再狭窄。
19.根据权利要求1所述的方法,其中所述装置设置有多层合金,并且将多种成分除去以便提供具有多重多孔层的装置。
20.根据权利要求19所述的方法,其中所述多重多孔层具有不同的孔隙率和不同的原子组成。
21.根据权利要求1所述的方法,进一步包括在所述装置的内腔形成多孔层。
22.根据权利要求21所述的方法,进一步包括将活细胞放置在所述内腔的多孔层内部,所述多孔层具有一定的孔隙率以允许将至少一些分子运输给所述活细胞,同时避免至少一些免疫系统药物接近所述细胞。
23.一种使用具有至少一个多孔层的可植入医用装置用于治疗血管的方法,所述多孔层用于可释放地含有至少一种治疗药物,该方法包括:
提供具有至少一个多孔层的至少一种可植入支架,所述多孔层用于可释放地含有至少一种治疗药物;以及
将所述支架放置在所述血管内所需要的位置,其中所述支架在放置之后从所述至少一个多孔层释放所述至少一种治疗药物。
24.根据权利要求23所述的方法,其中所述所需要的位置包括所述血管中的狭窄区域,以及,其中所述至少一种治疗药物包括至少一种抗再狭窄药或抗炎药用于抑制冠状动脉的再狭窄。
25.根据权利要求23所述的方法,其中所述装置设置有多层合金,并且将多种成分除去用以提供具有多重多孔层的装置。
26.根据权利要求25所述的方法,其中所述多重多孔层具有不同的孔隙率和不同的原子组成。
27.根据权利要求23所述的方法,其中所述血管包括冠状动脉。
28.根据权利要求23所述的方法,其中所述放置步骤包括放置所述支架以便所述多孔层与所述血管中的狭窄斑块和所述血管的内壁的至少之一相接触。
29.一种具有至少一个多孔层的可植入医用装置,所述至少一个多孔层的每一层包括:
至少一种剩余的合金成分;以及
填隙空间,其中所述填隙空间包括合金的至少一种除去的合金成分的空间,所述合金包括所述至少一种剩余的合金成分和所述至少一种除去的合金成分。
30.根据权利要求29所述的可植入医用装置,其中所述至少一个多孔层的每一层包括基质。
31.根据权利要求29所述的可植入医用装置,其中所述至少一个多孔层的每一层包括至少一种生物相容性材料。
32.根据权利要求31所述的可植入医用装置,其中所述生物相容性材料包括金。
33.根据权利要求29所述的可植入医用装置,其中所述可植入医用装置包括具有外表面和内表面的可植入支架装置,并且其中所述至少一个多孔层是沿着所述外表面设置的。
34.根据权利要求33所述的可植入医用装置,其中所述支架装置包括用于经皮腔内冠状动脉成形术过程的冠状动脉支架。
35.根据权利要求29所述的可植入医用装置,其中所述合金包括至少一种金属,其选自由金、银、镍钛金属互化物、钢、铬、铁、镍、铜、铝、钛、钽、钴、钨、钯、钒、铂和铌组成的组。
36.根据权利要求35所述的可植入医用装置,其中,所述合金包括不锈钢,所述至少一种剩余的合金成分包括铁和镍,并且所述至少一种除去的合金成分包括铬。
37.根据权利要求29所述的可植入医用装置,其中所述至少一种除去的成分包括所述合金的电化学活性最高的成分。
38.根据权利要求29所述的可植入医用装置,进一步包括放置在所述至少一个多孔层中的至少一种治疗药物。
39.根据权利要求38所述的可植入医用装置,其中所述至少一种治疗药物包括至少一种用于抑制冠状动脉再狭窄的药物。
40.根据权利要求29所述的可植入医用装置,进一步包括在所述装置的外表面上的涂层,所述涂层包括钛、金和铂中的至少一种。
41.根据权利要求29所述的可植入医用装置,其中所述装置包括多重多孔层,每一层具有不同的孔隙率和原子组成。
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WO (1) WO2004043292A2 (zh)

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EP1572032B1 (en) 2008-07-30
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KR20050065643A (ko) 2005-06-29
AU2003295535A1 (en) 2004-06-03
DE60322581D1 (de) 2008-09-11
US20040148015A1 (en) 2004-07-29
WO2004043292A3 (en) 2005-02-10
EP1572032A4 (en) 2006-01-04
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WO2004043292A2 (en) 2004-05-27

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