CN112870436A - 一种具有药物微球的4d打印多孔支架及其制备方法 - Google Patents
一种具有药物微球的4d打印多孔支架及其制备方法 Download PDFInfo
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Abstract
本发明介绍一种具有药物微球的4D打印多孔支架及其制备方法,涉及材料医学制造技术领域,4D打印多孔支架包括支架本体与载药微球,支架本体具有空腔和两端折叠盖结构,支架本体由形状记忆聚合物制备,载药微球位于所述支架空腔内,载药微球被两端折叠盖物理封锁在支架空腔,无需额外处理,可以保护载药微球的活性;支架本体为多孔结构。本发明所述的4D打印多孔支架具有良好的形状记忆性能,通过外界刺激使支架升温至形状记忆聚合物的转变温度,支架快速地恢复初始形状,折叠盖打开,使体液能够进入支架内部,加快药物溶出,实现调控药物微球释放速度。
Description
技术领域
本申请属于材料医学制造技术领域,具体而言,涉及一种具有药物微球的4D打印多孔支架及其制备方法。
背景技术
研究表明:骨组织是最坚硬的一种结缔组织,作为人体的支撑材料,承担着生命活动的重要职责。但是,由于创伤、先天畸形、骨关节炎、骨质疏松和癌症等导致的大段骨缺损是临床常见病种,其完整修复也一直是临床治疗的难点。随着我国人口老龄化国情加剧,临床骨缺损治疗需求将与日俱增。传统骨修复方法(自体骨移植、异体骨移植等)受困于各自的不足,难以满足临床需求。人工骨修复支架是指可以替代人体骨或者修复骨缺损的生物材料结构体,其来源广泛、可设计性强,是解决庞大临床需求的必然选择。4D打印作为一种先进的工艺技术,突破了传统支架制备方法的局限性,4D打印技术与3D打印相比特点在于可以实现自我组装,可变形材料会在指定时间之内变形为所需的形状。因此,采用4D打印技术加工形状记忆骨支架,使其植入人体后在外场激励下发生弯曲、扭曲、膨胀等自我变形最终达到预设三维空间构型,并通过形状记忆折叠盖来控制内部药物微球释放。其中,制备仿生可降解高分子支架,可在人体中吸收降解,避免二次手术及置入物的副作用,并且具有骨传导性和骨诱导作用,促进骨组织再生,促进骨的愈合,呈现出很好的应用前景。
受损骨组织的愈合过程需要多种因子共同调控成骨细胞的功能活动,单纯的人工骨支架无法快速的修复受损骨组织,为了达到满意的治疗效率和效果,支架外加的药物刺激是必要的,在人工骨支架领域,药物的负载方式主要有两种:一种是将药物或其它活性物质包埋在聚合物材料中,利用3D打印制成的骨支架能随着其在体内的逐渐降解,释放出其中包载的药物,实现缓慢释药,达到长效给药的目的,但这种方式往往需要经过高温、煅烧等苛刻的成型环境,限制了药物的负载方式;另一种是将药物吸附或者涂层实现支架的释药功能,但存在药物缓释性不强、操作复杂等问题。
在支架内包埋药物微球这种初级的结合方式会影响支架的多孔结构,而且影响药物活性并伴有微球降解脱落的风险。骨支架植入人体后,前三天注重受损部位控制出血和渗出,减轻肿胀疼痛炎症等症状,三天后损伤部位形成较好的骨细胞修复环境,此时释放药物更利于骨细胞生长。因此,需要开发一种具有良好的形状记忆性能骨修复用支架,能更有效地负载药物微球,从而可以既不影响支架的多孔结构,又赋予支架在适合的时机药物可控释放的功能。
发明内容
为了解决目前骨修复支架药物负载方式受限,并且支架植入人体后,无法根据患者恢复情况进行药物可控释放的技术问题。本发明提供一种具有药物微球的4D打印多孔支架及其制备方法,无需额外处理,可以保护载药微球的活性,还可以通过调控温度来控制给药速度。本发明保留了原有骨组织的天然多孔微结构,其能够提供适宜的微环境,进而促进细胞增殖和迁移;支架能够显著提高骨缺损所损失的力学强度,并具有局部药物缓释功能,同时将药物的全身副作用限制到最低限度。
为了实现以上目的,本发明的一方面提供了一种具有药物微球的4D打印多孔支架,包括:支架本体与载药微球,支架本体具有空腔和两端折叠盖结构,载药微球位于所述支架空腔内,载药微球被两端折叠盖物理封锁在支架空腔;所述4D打印多孔支架为多孔结构。
优选地,所述4D打印多孔支架由生物降解且生物相容性形状记忆材料制成。
优选地,所述4D打印多孔支架制备包括熔融沉积技术、立体光固化成型技术、聚合物喷射技术和直写技术中的至少一种。
优选地,所述载药微球的粒径大于所述4D打印多孔支架的纤维间孔隙的孔径;载药微球的粒径为400-1000μm;通过生物打印机制备所述4D打印多孔支架时,设定参数纤维直径为200-300μm,纤维间距为400-600μm。
优选地,形成所述多孔支架的形状记忆聚合物为选自聚乳酸、聚乙烯醇、聚氨酯、聚己内酯、壳聚糖、环氧化丙烯酸酯、交联聚乙烯、聚降冰片烯、反式聚异戊二烯和苯乙烯-丁二烯共聚物中的至少一种。
优选地,所述载药微球的药物选用粘液排促剂、抗生素、抗炎镇痛药物、抗真菌药物、抗感染药物、抗肿瘤药物、抗病毒药物与免疫增强剂中的至少一种。
本发明的另一方面提供一种具有药物微球的4D打印多孔支架的制备方法,所述方法包括如下步骤:
(a)设定打印编码程序;
(b)三维模型构建:根据建模软件进行目标物图像三维建模;
(c)三维建模的分层处理:选定适合的层截面间隔,将步骤b的三维模型离散成一系列有序的二维层片;
(d)制备形状记忆聚合物,准备4D打印浆料;
(e)将所述4D打印浆料装载到生物打印机设备的料筒中,加热熔融;
(f)截面加工:打印机的打印头由数控系统控制,在计算机控制下,根据输入的层片信息控制打印头的扫描和挤压,得到对应的一层截面;
(g)截面叠加:步骤f一层截面形成后,下一层的截面叠加打印成型,与前一层相粘结,从而各层的截面逐步叠合在一起,最终得到具有空腔和两端折叠盖结构的4D打印多孔支架;
(h)将载药微球置于所述的4D打印多孔支架空腔中;
(i)通过外场刺激进行形状记忆功能训练,将支架两端折叠盖闭合得到成型后的具有药物微球的4D打印多孔支架。
所述步骤i中,外场刺激采用热激励、电激励、磁激励、光激励或溶液激励中的至少一种。
上述所述4D打印多孔支架的玻璃化温度为40-60℃。
与现有技术相比,本申请的有益效果为:
本发明所述的一种具有药物微球的4D打印多孔支架,包括支架本体与载药微球,支架本体具有空腔和两端折叠盖结构,支架本体由形状记忆聚合物制备,载药微球位于所述支架空腔内,微球被两端折叠盖物理封锁在支架空腔,无需额外处理,可以保护载药微球的活性;支架本体为多孔结构,可以通过调控温度来控制给药速度。支架本体由形状记忆聚合物制成,具有良好的形状记忆性能,生物相容性能且能够生物降解,具有一定的硬度和机械应力,在植入人体后不会发生排异反应,在释放药物的同时,骨修复支架逐渐被生物降解,在被降解的同时,骨组织细胞在支架表面附着生长并不断增殖与支架融为一体,逐层降解且形成新的骨组织,本发明保留了原有骨组织的天然多孔微结构,其能够提供适宜的微环境,进而促进细胞增殖和迁移;支架能够显著提高骨缺损所损失的力学强度,并具有局部药物缓释功能,同时将药物的全身副作用限制到最低限度。
上述制备方法,利用形状记忆复合材料4D打印多孔支架,打印得到的形状记忆多孔支架为一体化结构,稳定性强、力学性能好,为骨组织细胞的修复提供了支撑结构,通过升温驱动所述的形状记忆多孔支架变形,快速回复支架的初始形状,形成折叠盖结构,实现调控药物释放速度,能够诱导骨组织细胞沿所述多孔支架结构生长,实现了骨缺损的修复,使骨细胞生长更加严密。同时,在骨组织细胞培养的后期,形状记忆聚合物发生大部分降解后,微球载体之间依然能保持相互连接堆砌,仍然可以维持细胞生长的空间,二者的复合可以互相弥补其缺点,具有一定的协同作用,对于一些培养条件要求严格的细胞生长更为有利。可以根据患者的需求来调整支架形状以及负载的药物微球种类、数目,为实现个性化订制提供了可能。
附图说明
以下附图仅对本发明作示意性的说明和解释,并不用于限定本发明的范围,其中:
图1示出了多孔支架的初始形状;
图2示出了载药微球装入多孔支架的空腔;
图3示出了多孔支架在外场激励下施加外力将两端折叠盖结构闭合,封锁住空腔中的药物微球;
图4示出了多孔支架再次在外场激励后,两端折叠盖自行打开,释放出内部的载药微球;
图中,1-多孔结构支架,2-折叠盖结构,3-支撑结构,4-药物微球。
具体实施方式
为了使本发明的目的、技术方案、设计方法及优点更加清楚明了,以下结合附图通过具体实施例对本发明进一步详细说明。应当理解,此处所描述的具体实施例仅用于解释本发明,并不用于限定本发明。
在下文中,将参考附图对本申请的具体实施例进行详细地描述,依照这些详细的描述,所属领域技术人员能够清楚地理解本申请,并能够实施本申请。在不违背本申请原理的情况下,各个不同的实施例中的特征可以进行组合以获得新的实施方式,或者替代某些实施例中的某些特征,获得其它优选的实施方式。
本发明提供一种具有药物微球的4D打印多孔支架,包括支架本体与载药微球,支架本体具有空腔和两端折叠盖结构,支架本体由形状记忆聚合物制备,载药微球位于所述支架空腔内,微球被两端折叠盖物理封锁在支架空腔,如图1-图4所示,4D打印多孔支架是由纤维形成多孔结构,优选地,所述支架本体由形状记忆聚合物制备,载药微球的粒径大于所述4D打印多孔支架的纤维间孔隙的孔径;载药微球的粒径为400-1000μm;通过生物打印机制备所述4D打印多孔支架时,设定参数纤维直径为200-300μm,纤维间距为400-600μm,从而更有效的封锁住药物微球,实现良好的药物控释功能。可以根据患者的需求来调整支架形状以及负载的药物微球种类、数目,为实现个性化订制提供了可能,更方便地应用于不同领域。
优选地,所述4D打印多孔支架制备包括熔融沉积技术、立体光固化成型技术、聚合物喷射技术和直写技术中的至少一种。4D打印技术具有高度可设计性和可精确构造的优势,可以通过软件设定模型和时间做出精确的调控,形状记忆材料会在设定的时间内变形为所需的形状,不需要连接任何复杂的机电设备,就能按照程序设计自动变形成相应的形状。
所述4D打印多孔支架可以使用常规用于生物打印机的粉体材料或溶液形成。优选地,形状记忆聚合物由生物降解且生物相容性形状记忆材料制成,一方面,能够生物降解且生物相容的形状记忆聚合物在植入人体后不会发生排异反应,有效减轻患者病痛;另一方面,骨修复支架会逐渐被生物降解,自身细胞修复完全替代骨支架,患者体内不会长期留有骨支架,对患者更安全,形成所述支架的形状记忆聚合物为选自聚乳酸、聚乙烯醇、聚氨酯、聚己内酯、壳聚糖、环氧化丙烯酸酯、交联聚乙烯、聚降冰片烯、反式聚异戊二烯和苯乙烯-丁二烯共聚物中的至少一种。同时,基于这些材料构建的复合多孔支架尤其适合用于骨修复领域。
本发明的另一方面提供一种具有药物微球的4D打印多孔支架的制备方法,所述方法包括如下步骤:
(a)设定打印编码程序;
(b)三维模型构建:根据建模软件进行目标物图像三维建模;
(c)三维建模的分层处理:选定适合的层截面间隔,将步骤b的三维模型离散成一系列有序的二维层片;
(d)制备形状记忆聚合物,准备4D打印浆料,所述4D打印浆料可以为适用于进行4D打印的任何形状记忆聚合物,优选地,例如所述4D打印形状记忆浆料可以为适用于4D打印的粉体或液体材料的浆料,例如可以聚乳酸、聚乙烯醇、聚氨酯、聚己内酯、壳聚糖、环氧化丙烯酸酯、交联聚乙烯、聚降冰片烯、反式聚异戊二烯和苯乙烯-丁二烯共聚物中的至少一种;更具体地,例如,可以通过将磷酸三钙粉末逐步加入到聚乳酸中,利用高速匀化机进行混合,得到均匀的浆料。进行4D打印之前,可以通过例如超声和真空处理,去除浆料中的气泡。
(e)将所述4D打印浆料装载到生物打印机设备的料筒中,加热熔融;按照预定的打印程序打印,得到具有空腔和两端折叠盖结构的4D打印多孔支架。具体地,可以将4D打印浆料例如聚乳酸浆料装载到生物打印机设备的料筒中,设计好4D打印多孔支架的打印程序,设定气压0.3-4MPa,层高200-300μm,纤维间距400-600μm打印支架,同时,根据需要设定好打印纹路,优选地设计成十字交叉型,也可以根据实际情况决定是否需要支撑结构,优选地设计成不需要支撑结构,以利于后续处理。
(f)截面加工:打印机的打印头由数控系统控制,在计算机控制下,根据输入的层片信息控制打印头的扫描和挤压,得到对应的一层截面;
(g)截面叠加:步骤f一层截面形成后,下一层的截面叠加打印成型,与前一层相粘结,从而各层的截面逐步叠合在一起,最终得到具有空腔和两端折叠盖结构的4D打印多孔支架;
(h)将载药微球置于所述的4D打印多孔支架空腔中;所述载药微球的粒径大于所述4D打印多孔支架的纤维间孔隙的孔径。优选地,所述载药微球的粒径为400-1000um。
(i)通过外场刺激进行形状记忆功能训练,将支架两端折叠盖闭合得到成型后的具有药物微球的4D打印多孔支架。
外场激励驱动方式优选热激励驱动、电激励驱动、磁激励驱动、光激励驱动和溶液激励驱动中的至少一种。
进一步地,热激励驱动条件为玻璃态转变温度小于热敷温度而大于人体骨组织温度,热敷温度指的是通过对外耳道外部进行热敷对形状记忆聚合物骨支架进行热驱动的温度,热敷温度应当考虑人体能够承受的温度,以及传递到骨组织内部的温度变化程度;例如当形状记忆聚合物为聚乳酸时,热敷温度不小于45℃;而当形状记忆聚合物外耳道支架的转变温度为体温时无需热敷。较好地,形状记忆聚合物外耳道支架的转变温度在42度至55度之间,防止人体体温的改变对形状记忆聚合物外耳道支架进行不可控的热驱动,同时在通过热敷进行热驱动时人体能够承受。
上述制备方法,利用形状记忆复合材料4D打印多孔支架,打印得到的形状记忆多孔支架为一体化结构,稳定性强、力学性能好,为骨组织细胞的修复提供了支撑结构,通过升温驱动所述的形状记忆多孔支架变形,快速回复支架的初始形状,形成折叠盖结构,实现调控药物释放速度,能够诱导骨组织细胞沿所述多孔支架结构生长,实现了骨缺损的修复,使骨细胞生长更加严密。同时,在骨组织细胞培养的后期,形状记忆聚合物发生大部分降解后,微球载体之间依然能保持相互连接堆砌,仍然可以维持细胞生长的空间,二者的复合可以互相弥补其缺点,具有一定的协同作用,对于一些培养条件要求严格的细胞生长更为有利。可以根据患者的需求来调整支架形状以及负载的药物微球种类、数目,为实现个性化订制提供了可能。
为了对本发明进一步了解,现对其做进一步说明。
形状记忆支架的成型方式选自熔融层积成型(FDM),熔融层积成型(FDM)是将将丝状材料加热融化后,通过3D打印机喷头喷出,沉积在前层已经固化的材料上,逐层成型骨支架实体造型。该技术优点是:结构简单、制造、加工成本较低、应用范围最广。
本发明采用4D打印成型原理,形状记忆支架的初始构型不受制造工艺的限制,按照病理需求,通过与医生充分交流,设计具有不同结构形式的适合个性需求的形状记忆支架创新结构,优选的人工骨支架为多孔结构。图1示出了多孔支架的初始形状,折叠盖的初始形状与支撑结构具有一定的角度(非90°),此时折叠盖的边缘与支架的空腔具有孔隙;1为具有空腔的多孔结构支架,空腔与支架外形形状优选为圆柱形、矩形、三角形等,多孔结构的网格形式优选菱形、三角形、正(余)弦和矩形结构,2为两端的折叠盖结构,折叠盖形状优选为圆形、扇形、矩形、菱形等,3为支架内部支撑结构。如图2所示,4为支架空腔中的药物微球,成型后的多孔支架在外场激励下施加外力将两端折叠盖结构闭合,封锁住空腔中的药物微球,图3示出了多孔支架在外场激励下施加外力将两端折叠盖结构闭合,封锁住空腔中的药物微球,此时折叠盖与支撑结构为90°折叠盖边缘与支架的空腔没有孔隙;图4示出了多孔支架再次在外场激励后,两端折叠盖自行打开,此时折叠盖与支撑结构为非90°折叠盖边缘与支架的空腔具有孔隙;释放出内部的载药微球。
尽管在上文中参考特定的实施例对本申请进行了描述,但是所属领域技术人员应当理解,在本申请公开的原理和范围内,可以针对本申请公开的配置和细节做出许多修改。本申请的保护范围由所附的权利要求来确定,并且权利要求意在涵盖权利要求中技术特征的等同物文字意义或范围所包含的全部修改。
需要说明的是,虽然上文按照特定顺序描述了各个步骤,但是并不意味着必须按照上述特定顺序来执行各个步骤,实际上,这些步骤中的一些可以并发执行,甚至改变顺序,只要能够实现所需要的功能即可。
以上已经描述了本发明的各实施例,上述说明是示例性的,并非穷尽性的,并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下,对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。本文中所用术语的选择,旨在最好地解释各实施例的原理、实际应用或对市场中的技术改进,或者使本技术领域的其它普通技术人员能理解本文披露的各实施例。
Claims (8)
1.一种具有药物微球的4D打印多孔支架,其特征在于,所述多孔支架包括支架本体与载药微球,支架本体具有空腔和两端折叠盖结构,载药微球位于所述支架空腔内,载药微球被两端折叠盖物理封锁在支架空腔;所述4D打印多孔支架为多孔结构。
2.根据权利要求1所述的一种具有药物微球的4D打印多孔支架,其特征在于,所述4D打印多孔支架由生物降解且生物相容性形状记忆材料制成。
3.根据权利要求2所述的一种具有药物微球的4D打印多孔支架,其特征在于,所述4D打印多孔支架制备包括熔融沉积技术、立体光固化成型技术、聚合物喷射技术和直写技术中的至少一种。
4.根据权利要求3所述的一种具有药物微球的4D打印多孔支架,其特征在于,所述载药微球的粒径大于所述4D打印多孔支架的纤维间孔隙的孔径;载药微球的粒径为400-1000μm;通过生物打印机制备所述4D打印多孔支架时,设定参数纤维直径为200-300μm,纤维间距为400-600μm。
5.根据权利要求1所述的一种具有药物微球的4D打印多孔支架,其特征在于,形成所述多孔支架的形状记忆聚合物为选自聚乳酸、聚乙烯醇、聚氨酯、聚己内酯、壳聚糖、环氧化丙烯酸酯、交联聚乙烯、聚降冰片烯、反式聚异戊二烯和苯乙烯-丁二烯共聚物中的至少一种。
6.根据权利要求1所述的具有药物微球的4D打印多孔支架,其特征在于,所述载药微球的药物选用粘液排促剂、抗生素、抗炎镇痛药物、抗真菌药物、抗感染药物、抗肿瘤药物、抗病毒药物与免疫增强剂中的至少一种。
7.一种具有药物微球的4D打印多孔支架的制备方法,其特征在于,所述方法包括如下步骤:
(a)设定打印编码程序;
(b)三维模型构建:根据建模软件进行目标物图像三维建模;
(c)三维建模的分层处理:选定适合的层截面间隔,将步骤b的三维模型离散成一系列有序的二维层片;
(d)制备形状记忆聚合物,准备4D打印浆料;
(e)将所述4D打印浆料装载到生物打印机设备的料筒中,加热熔融;
(f)截面加工:打印机的打印头由数控系统控制,在计算机控制下,根据输入的层片信息控制打印头的扫描和挤压,得到对应的一层截面;
(g)截面叠加:步骤f一层截面形成后,下一层的截面叠加打印成型,与前一层相粘结,从而各层的截面逐步叠合在一起,最终得到具有空腔和两端折叠盖结构的4D打印多孔支架;
(h)将载药微球置于所述的4D打印多孔支架空腔中;
(i)通过外场刺激进行形状记忆功能训练,将支架两端折叠盖闭合得到成型后的具有药物微球的4D打印多孔支架。
8.根据权利要求7所述的一种具有药物微球的4D打印多孔支架的制备方法,其特征在于,所述步骤i中,外场刺激采用热激励、电激励、磁激励、光激励或溶液激励中的至少一种。
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