CN113769161A - 一种用于骨组织再生的近红外光响应性仿生血管支架及其制备方法 - Google Patents
一种用于骨组织再生的近红外光响应性仿生血管支架及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种用于骨组织再生的近红外光响应性仿生血管支架及其制备方法,该方法基于微流控湿法纺丝技术,生成尺寸均一的仿生血管中空结构的可降解水凝胶纤维,结合3D打印技术,使得中空纤维基元在指定位置挤出,再通过层层堆积的方式,制备出三维仿生血管水凝胶支架。本发明将具有近红外光响应性和骨组织再生活性的黑磷纳米材料和热敏感水凝胶相结合,赋予该仿生血管支架具备可控收缩/膨胀的动态性质,并能提高中空支架的矿化能力,有效诱导骨组织再生。本发明的微流控芯片和3D打印技术便于实现个性化定制,纤维材料内部组成能够轻松实现精确调节,实现对三维支架的宏观形状、通道尺寸、仿生动态响应及骨组织再生活性的有效调控。
Description
技术领域
本发明涉及骨组织缺损修复的治疗方法,特别涉及一种用于骨组织再生的近红外光响应性仿生血管支架及其制备方法。
背景技术
由于骨骼疾病、创伤、感染和手术切除引起的骨组织缺损的修复一直是骨科领域的难题和研究热点。传统修复骨缺损的治疗方法是使用自体移植物、同种异体移植物或异种移植物,这些方法存在以伤补伤、传染疾病和宿主免疫排异反应等不足。骨组织工程支架在治疗骨缺损方面具有广阔的前景,无需移植组织,通过刺激机体内源性再生活性有望实现缺损部位解剖结构和生理功能的再现。目前,三维(3D)打印技术在构建仿生结构骨工程支架方面备受关注。通过3D打印的方式,可以实现精确设计和控制支架的尺寸、整体形状以及孔道的大小、形状、连通性,满足个性化医疗需求。然而传统的3D打印支架绝大部分是有实心的基元层层堆积而成,不利于手术中营养成分和细胞向支架内部的传输,进而限制了新生血管和骨组织的长入。最近,同轴喷嘴改进的3D打印技术已被用于制造具有通道结构的骨组织工程支架,以促进细胞生长和血管化进入支架。但是,该方法所制备支架的通道尺寸受限于打印头喷嘴的尺寸(数百微米),难以仿造天然毛细血管的微血管尺寸和结构。此外,中空通道没有动态响应性,短时间内组织和血管是很难迁移到通道内部的。因此,如何实现支架结构的高度仿生及加速缺损部位的血管化组织形成,仍然是科研人员未来需要继续深入研究和解决的问题。
微流控技术是一种通过微通道精确操控微量流体的技术,应用于多级结构材料制备具有明显的优势,通过微流控方式构建三维组织和器官的技术在组织工程和再生医学等领域备受关注。在制备功能性微纤维方面,微流控技术通过改变微管道的结构设计、微流体的流动状态、多相层流间的剪切关系等,可以实现多种不同结构微纤维的可控制备。
因此,在本发明中,我们从构建仿生血管中空结构的水凝胶纤维材料具有入手,依托三维打印技术和微流控技术,设计发明了一种新型仿生血管水凝胶支架的制备方法,将具有近红外光响应性和骨组织再生活性的黑磷纳米材料和热敏感水凝胶相结合,赋予该仿生血管支架具备可控收缩/膨胀的动态性质,加速新生血管长入支架通道内部。同时,黑磷纳米片具有诱导羟基磷灰石晶体形成的性能,可提高中空支架的矿化能力,更加有效诱导骨组织再生,为开发用于骨组织再生的新型智能生物材料提供新思路和方法。
发明内容
本发明所要解决的技术问题是针对上述现有技术的不足,提供一种用于骨组织再生的近红外光响应性仿生血管支架及其制备方法。
为实现上述技术目的,本发明采取的技术方案为:
一种用于骨组织再生的近红外光响应性仿生血管支架的制备方法,包括如下步骤:
(1)生成一维仿生血管水凝胶纤维基元:设计和构建嵌套式入射通道微流控装置,选择合适浓度交联剂的水相溶液作为内相,选择不同组成配比的黑磷复合温敏性预聚物溶液作为外相,选择合适浓度交联剂的水相溶液作为收集液,同时经过紫外激光照射进行二重交联固化,制得尺寸均一、连续稳定的仿生热响应中空水凝胶纤维材料;
(2)制备三维仿生血管水凝胶支架:将步骤(1)制备的中空纤维基元通过3D打印的方式,层层堆积有序排列,制备出具有三维连通多孔结构的黑磷复合温敏性中空水凝胶纤维支架,利用紫外激光照射进行二重交联固化,随后将支架浸泡在含有离子交联剂的水溶液一段时间,进一步加强固化成型;
通过调整微流控通道直径以及各相流体流速,能够对所得纤维的中空通道尺寸进行调控;通过改变黑磷复合温敏性预聚物溶液的组成配比能够制备出成分可控的生物活性纤维支架;通过改变三维打印程序能够得到不同三维连通多孔结构、不同宏观外形或不同尺寸的纤维支架。
步骤(1)中,所述嵌套式入射通道微流控装置的微流控芯片由玻璃毛细管、载玻片、盖玻片、点样针头和速干胶组装而成;其中,玻璃毛细管由外相毛细管和内相毛细管同轴嵌套组装而成。
进一步的,所述外相毛细管的管径为300~800μm,所述内相毛细管管径为20~200μm,通过改变内、外相流速或内、外相毛细管管径,能够调节仿生血管水凝胶纤维的中空通道内、外径。
步骤(1)中,黑磷复合温敏性预聚物溶液选择添加不同黒磷含量的海藻酸钠和N-异丙基丙烯酰胺NIPAM的混合分散液作为外相,所述内相为一定浓度的氯化钙水溶液;其中,海藻酸钠和NIPAM溶于水中的浓度分别为2%w/v和15%v/v,黒磷相对于预聚物总体积浓度为0~0.5%w/v;通过在0~0.5%范围内改变外相中黒磷的含量,能够调节纤维基元的光热响应性能和骨组织再生活性。
步骤(1)中,内相和收集液的聚合物交联剂选择氯化钙水溶液;其中,氯化钙水溶液浓度为0.2~2%w/v,通过氯化钙固体粉末溶于水溶液中配制而成。
步骤(2)中,通过3D打印的方式将一维仿生血管水凝胶纤维基元层层堆积、有序排列制备出中空纤维支架;所述中空纤维支架的组成中空圆柱状结构的纤维基元,内径为20~200μm,外径为300~800μm;各中空纤维支架层层堆积形成具有三维连通多孔结构的纤维支架,尺寸为100~1000μm。
进一步的,所述具有三维连通多孔结构的纤维支架的基元堆积方式、结构和尺寸能够通过调整三维打印程序而改变,整体结构可为圆柱体、立方体或复合多面体,基元堆积方式为正交、斜交或平行堆积,以仿生体内血管交错网络结构。
步骤(2)中,3D打印成型后的纤维支架在紫外激光照射下进行二重交联固化后再将支架浸泡在含有离子交联剂的水溶液中维持6~24h加强固化成型,从而得到稳定多孔结构的三维仿生血管中空通道支架。
本发明还提供了采用上述方法制备得到的用于骨组织再生的近红外光响应性仿生血管支架。
与现有技术相比,本发明的有益效果在于:
1)相对于传统3D打印制备出的静态实心基元结构,本发明的制备方法通过结合微流控制备出具有仿生血管动态响应中空结构的纤维支架,制备工艺简单可控,反应条件要求低;
2)本发明依托微流控技术,采用嵌套式微流控芯片进行仿生血管纤维制备,构造简单、搭建步骤少,不需要复杂的机械加工过程,工艺简单,操作方便;通过调整微流控芯片中毛细管管径以及各相流体流速,可以实现对所得纤维的仿生血管结构的调控;通过改变各组分的配比可以制备出多种组成的生物活性纤维支架。
3)本发明通过结合3D打印技术,制备出3D打印仿生血管水凝胶支架,支架的尺寸、整体形状以及孔道的大小、形状、连通性可以实现精确设计和控制,满足个性化医疗需求;支架的三维孔道结构能提供一个有利于细胞黏附、增殖、分化以及生长的三维支架式外环境,有利于氧气、营养物质的输运,进而促进新生组织长入;此外,三维打印技术可实现高效、快速、可重复性制备,避免人为误差。
4)本发明提出将具有近红外光响应性和骨组织再生活性的黑磷纳米材料和热敏感水凝胶相结合,赋予该仿生血管支架具备可控收缩/膨胀的动态性质,加速新生血管长入支架通道内部;同时,黑磷纳米片具有诱导羟基磷灰石晶体形成的性能,可提高中空支架的矿化能力,更加有效诱导骨组织再生,为开发用于骨组织再生的新型智能生物材料提供新思路和方法。
附图说明
图1为本发明采用微流控3D打印方式制备具有近红外光响应性的仿生动态血管支架的示意图。
图2本发明的黑磷复合水凝胶支架与纯水凝胶支架近红外光响应的可逆体积转变性能比较图。
图3通过增加近红外光照次数增加细胞在支架中空通道内部富集的测定图;其中,图(a)为细胞在中空通道内的荧光照片,图(b)为采用CCK8法对不同光照次数下通道内细胞进行定量分析的结果。
图4为光热响应的动态仿生血管支架植入大鼠颅骨缺损部位6周之后的Micro-CT成像结果。
具体实施方式
为了使本领域技术领域人员更好地理解本发明的技术方案,下面结合附图对本发明的实施例作进一步详细描述。
下述实施例中所使用的实验方法,如无特殊说明,均为常规方法,所用的试剂、方法和设备,如无特殊说明,均为本技术领域常规试剂、方法和设备。
实施例1
微流控3D打印黑磷复合NIPAM基水凝胶支架的制备,如图1所示,具体制备流程如下:
(1)配制内、外相溶液和收集液:
1.1)内相溶液:由氯化钙水溶液组,称取一定量氯化钙粉体,溶于超纯水,形成浓度为0.2%(w/v)的氯化钙水溶液,分别作为内相溶液。
1.2)外相溶液:黒磷分散在浓度2%(w/v)和15%(v/v)的海藻酸钠和NIPAM混合预聚物溶液中;首先将黑磷晶体粉末分散在超纯水中,连续超声1小时后,低速离心去掉沉淀,真空冷冻干燥得到黑磷纳米片。称取一定量的黑磷纳米片,超声分散在超纯水中,获得黑磷分散液;称取一定质量的海藻酸钠和NIPAM固体,溶于超纯水,获得浓度分别为2%(w/v)和15%(w/v)的海藻酸钠和NIPAM混合预聚物溶液;待溶液完全溶解后,加入一定质量的光引发剂苯基-2,4,6-三甲基苯甲酰亚膦酸锂(LAP),其最终浓度为0.5%(w/v)。
1.3)收集液:浓度为2%(w/v)的氯化钙水溶液。
(2)组装多通道嵌套式微流控芯片:利用微电极拉制仪或乙炔喷灯拉制两种不同尺寸的玻璃毛细管,外相毛细管管径为300~800μm,内相毛细管管径为20~200μm;随后利用含5%(v/v)的3-氨丙基三乙氧基硅烷(APTES)的乙醇溶液进行亲水处理;微流控芯片由玻璃毛细管、载玻片、盖玻片、点样针头和速干胶组装而成,其中,玻璃毛细管由外相锥形毛细管和内相纺锤形出口毛细管同轴嵌套组装而成。
(3)制备具有中空结构的黑磷复合海藻酸钙微纤维:
将内及外相溶液抽取到相应规格的医用一次性针筒注射器中并将其分别安放在两台蠕动泵上,注射器和微流控芯片通过聚乙烯管连接,设定各相流速,启动蠕动泵工作;在微流控通道内,当内相离子交联液和中间相聚合物溶液相遇时,由于钙离子和海藻酸迅速交联固化,具有中空结构的黑磷复合海藻酸钙纤维由外相玻璃毛细管挤出。
(4)制备具有仿生血管结构的黑磷复合NIPAM基水凝胶支架:
将微流控芯片整合到3D打印平台,利用计算机程序操控微流控喷头的移动位置,调整喷头的移动速度为3~10mm/s,匹配纤维的挤出速度,逐层堆积连续挤出的微流控纤维材料,可制备出三维连通多孔结构的中空纤维支架;待打印结束后,将支架暴露在紫外激光照射下5~10min,进行二重交联固化,随后再将支架长时间浸泡在浓度为2%的氯化钙水溶液中24h,进一步加强固化成型,从而得到具有稳定三维连通多孔结构的中空纤维支架。
实施例2
黑磷复合NIPAM基水凝胶支架的近红外光响应实验:
(1)近红外光响应的可逆体积相变性能:
利用808nm近红外光照射纯水凝胶支架和黑磷复合支架,记录支架体积变化,同时利用热成像仪实时监控温度变化,如图2所示;结果表明,黑磷复合支架在近红外光照射下迅速收缩,当近红外光关闭后支架逐渐恢复成原始尺寸,而不含黑磷的支架不具备这种可逆体积相变性能。
(2)细胞在支架仿生中空通道内的富集实验:
将具有仿生血管中空通道的黑磷复合NIPAM基水凝胶支架置于密度为100万/mL的细胞悬液中,利用近红外光照射支架使其收缩,随后关闭激光让支架慢慢恢复原始尺寸,该过程中,仿生血管通道逐渐扩张,将周围的细胞吸入到通道内部。如图3所示,细胞在通道内的数量随着近红外激光的开关次数的增加而增加,表现出显著的近红外光响应性细胞富集行为。
实施例3
近红外光响应性的仿生血管水凝胶支架的体外和体内成骨活性评估实验:
(1)体外成骨活性评估实验包括细胞增殖、粘附和碱性磷酸酶活性检测:
1.1)细胞增殖:首先将实例2中制备的不同通道数目的中空纤维支架浸泡在75%乙醇溶液进行灭菌后备用;采用大鼠骨髓间充质干细胞以及含10%的FBS的完全低糖细胞培养基MEMα培养基进行实验;首先,将支架放入48孔板后。然后向每个孔内支架上种入1万个细胞,将培养板放入含有5%CO2的培养箱中,温度维持37℃恒定;分别培养1、3、5天后,利用CCK8法,通过测450nm处的吸光度,评估大鼠骨髓间充质干细胞增殖情况。
1.2)细胞粘附:将2万个细胞接种到黑磷复合水凝胶纤维支架商,培养三天后,经过固定,染色等操作后,通过荧光共聚焦显微镜进行观察拍照。
1.3)碱性磷酸酶活性:将纤维支架灭菌后,分别放入6孔板中;向每个孔板中加入5万个兔子骨髓间充质干细胞,放入细胞培养箱中培养,并隔天换培养基;在培养了7天和14天后,进行细胞碱性磷酸酶活性检测;具体实验流程为,在检测时间点时,吸出培养基,用PBS轻轻洗三次,然后加入200μL辛基酚聚氧乙烯醚(Triton X-100),用移液枪吸取TritonX-100充分吹到培养板上的每个角落,充分裂解细胞,然后吸出50μL细胞裂解液与150μL碱性磷酸酶试剂混合,利用酶标仪检测其在405nm处的吸光度值。然后进行蛋白检测,先吸取25μL细胞裂解液与200μL的蛋白定量试剂混合,在37℃下反应30min,然后再利用酶标仪检测其在562nm处的吸光度值;通过蛋白的标准曲线,吸光度值被转化为蛋白浓度。然后将数据归一,得到细胞内的总蛋白量。相对的碱性磷酸酶活性即为吸光度数值(405nm处)与100μL细胞裂解上清液中的总蛋白量的比值。
(2)体内成骨活性评估实验:选用12只雄性大鼠(180~220g),利用电钻在大鼠颅骨左右两边各制造一个直径为6mm的圆形缺损,然后将纤维支架植入到缺损中,随后缝合伤口;对于光照组,在支架植入前5天,每天进行近红外激光照射。在手术6周时对大鼠做Micro-CT活体分析,如图4所示,并通过图像分析系统对新形成的骨的面积进行量化分析;随后将大鼠处死,然后获得组织样品,脱水并用石蜡包埋,将样品切片并进行Masson染色和CD31免疫组化染色,评估缺损部位胶原沉积和血管生成的情况。
以上仅是本发明的优选实施方式,本发明的保护范围并不仅局限于上述实施例,凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理前提下的若干改进和润饰,应视为本发明的保护范围。
Claims (9)
1.一种用于骨组织再生的近红外光响应性仿生血管支架的制备方法,其特征在于,包括如下步骤:
(1)生成一维仿生血管水凝胶纤维基元:设计和构建嵌套式入射通道微流控装置,选择合适浓度交联剂的水相溶液作为内相,选择不同组成配比的黑磷复合温敏性预聚物溶液作为外相,选择合适浓度交联剂的水相溶液作为收集液,同时经过紫外激光照射进行二重交联固化,制得尺寸均一、连续稳定的仿生热响应中空水凝胶纤维材料;
(2)制备三维仿生血管水凝胶支架:将步骤(1)制备的中空纤维基元通过3D打印的方式,层层堆积有序排列,制备出具有三维连通多孔结构的黑磷复合温敏性中空水凝胶纤维支架,利用紫外激光照射进行二重交联固化,随后将支架浸泡在含有离子交联剂的水溶液一段时间,进一步加强固化成型;
通过调整微流控通道直径以及各相流体流速,能够对所得纤维的中空通道尺寸进行调控;通过改变黑磷复合温敏性预聚物溶液的组成配比能够制备出成分可控的生物活性纤维支架;通过改变三维打印程序能够得到不同三维连通多孔结构、不同宏观外形或不同尺寸的纤维支架。
2.根据权利要求1所述的用于骨组织再生的近红外光响应性仿生血管支架的制备方法,其特征在于:步骤(1)中,所述嵌套式入射通道微流控装置的微流控芯片由玻璃毛细管、载玻片、盖玻片、点样针头和速干胶组装而成;其中,玻璃毛细管由外相毛细管和内相毛细管同轴嵌套组装而成。
3.根据权利要求2所述的用于骨组织再生的近红外光响应性仿生血管支架的制备方法,其特征在于:所述外相毛细管的管径为300~800μm,所述内相毛细管管径为20~200μm,通过改变内、外相流速或内、外相毛细管管径,能够调节仿生血管水凝胶纤维的中空通道内、外径。
4.根据权利要求3所述的用于骨组织再生的近红外光响应性仿生血管支架的制备方法,其特征在于:步骤(1)中,黑磷复合温敏性预聚物溶液选择添加不同黒磷含量的海藻酸钠和N-异丙基丙烯酰胺NIPAM的混合分散液作为外相,所述内相为一定浓度的氯化钙水溶液;其中,海藻酸钠和NIPAM溶于水中的浓度分别为2%w/v和15%v/v,黒磷相对于预聚物总体积浓度为0~0.5%w/v;通过在0~0.5%范围内改变外相中黒磷的含量,能够调节纤维基元的光热响应性能和骨组织再生活性。
5.根据权利要求4所述的用于骨组织再生的近红外光响应性仿生血管支架的制备方法,其特征在于:步骤(1)中,内相和收集液的聚合物交联剂选择氯化钙水溶液;其中,氯化钙水溶液浓度为0.2~2%w/v,通过氯化钙固体粉末溶于水溶液中配制而成。
6.根据权利要求1所述的用于骨组织再生的近红外光响应性仿生血管支架的制备方法,其特征在于:步骤(2)中,通过3D打印的方式将一维仿生血管水凝胶纤维基元层层堆积、有序排列制备出中空纤维支架;所述中空纤维支架的组成中空圆柱状结构的纤维基元,内径为20~200μm,外径为300~800μm;各中空纤维支架层层堆积形成具有三维连通多孔结构的纤维支架,尺寸为100~1000μm。
7.根据权利要求6所述的用于骨组织再生的近红外光响应性仿生血管支架的制备方法,其特征在于:所述具有三维连通多孔结构的纤维支架的基元堆积方式、结构和尺寸能够通过调整三维打印程序而改变,整体结构可为圆柱体、立方体或复合多面体,基元堆积方式为正交、斜交或平行堆积,以仿生体内血管交错网络结构。
8.根据权利要求7所述的用于骨组织再生的近红外光响应性仿生血管支架的制备方法,其特征在于:步骤(2)中,3D打印成型后的纤维支架在紫外激光照射下进行二重交联固化后再将支架浸泡在含有离子交联剂的水溶液中维持6~24h加强固化成型,从而得到稳定多孔结构的三维仿生血管中空通道支架。
9.一种用于骨组织再生的近红外光响应性仿生血管支架,其特征在于,采用权利要求1~8任一项所述的制备方法制备得到。
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