CN115581813A - 压电水凝胶作为骨胶水的应用 - Google Patents
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Abstract
本发明公开了压电水凝胶作为骨胶水的应用,属于生物复合材料技术领域。该压电水凝胶由氧化硫酸软骨素、明胶与氨基化钛酸钡四方晶相颗粒原位交联而成;其中,氧化硫酸软骨素与明胶通过席夫碱动态键交联,氨基化钛酸钡四方晶相颗粒与氧化硫酸软骨素通过席夫碱动态键及氢键结合。通过将该压电水凝胶注射到复杂形态骨缺损部位,其能很好地适配缺损形态,并在超声精准加载下产生持续力‑电响应微环境,实现骨缺损部位的再生性修复,为临床发展具有力‑电响应功能的新型骨修复材料奠定科学基础,具有重大的临床意义与社会效益。
Description
技术领域
本发明属于生物复合材料技术领域,具体涉及压电水凝胶作为骨胶水的应用。
背景技术
因先天或后天原因,包括创伤、感染、肿瘤等引起的骨缺损是临床上一种常见的、多发的疾病。骨组织具有一定的修复能力,但当缺损较大超过其修复能力,则需要行骨移植术修复缺损。尽管目前羟基磷灰石、磷酸三钙、高分子支架材料等可协助新骨形成,实现骨缺损区的功能性修复。但这些材料只是对骨化学成分钙、磷、氧等元素进行仿生,缺乏针对包括硬度、粗糙度、表面电势、微纳多级结构等骨的物理特性仿生,因此普遍缺乏信号转导能力和骨感知能力。与此同时,大多数骨缺损形态不规则,而当前材料缺乏与复杂形态骨缺损适配的能力。因此,如何仿生骨的固有物理特性实现复杂形态骨缺损区的再生性修复成为临床亟待解决的问题。
骨组织是一类具有力-电响应特性的功能材料,即在受力情况下骨组织通过感应力的刺激作用而持续产生电信号形成电学微环境,进而调控骨的再生与重建。采用压电陶瓷来仿生骨组织的压电性,通过高电压极化的方式以及外界超声的作用下在压电陶瓷表面产生静态及动态的压电势,实现对骨的电学微环境仿生,从而促进材料与骨组织的骨整合和骨再生。但其缺乏与早期修复骨组织相匹配的弹性模量及针对复杂形态缺损的适配能力;对于高度粉碎性骨折,其难以固定并利用剩余骨片;且其不降解性限制了再生骨组织向内生长,这些都限制了其临床应用。因此,人们希望能开发一种可注射适配复杂骨缺损并产生内源性电信号促进骨修复的生物相容性骨黏附压电电活性材料。
发明内容
为解决现有技术的缺点和不足之处,本发明的目的在于提供一种压电水凝胶作为骨胶水的应用,该压电水凝胶在不规则骨缺损修复中的应用。
本发明的目的通过以下技术方案实现。
压电水凝胶作为骨胶水的应用,所述压电水凝胶由氧化硫酸软骨素、明胶与氨基化钛酸钡四方晶相颗粒原位交联而成;其中,氧化硫酸软骨素与明胶通过席夫碱动态键交联,氨基化钛酸钡四方晶相颗粒与氧化硫酸软骨素通过席夫碱动态键及氢键结合。
所述骨胶水是能够促进骨修复的生物胶水。
优选的,所述压电水凝胶中明胶、氧化硫酸软骨素、氨基化钛酸钡四方晶相颗粒的质量比为10:5:0.1~5。
进一步优选的,所述压电水凝胶中明胶、氧化硫酸软骨素、氨基化钛酸钡四方晶相颗粒的质量比为10:5:0.1~0.5。
更优选的,所述压电水凝胶中明胶、氧化硫酸软骨素、氨基化钛酸钡四方晶相颗粒的质量比为10:5:0.1。
优选的,所述氧化硫酸软骨素的氧化度为60%±2%;所述氨基化钛酸钡四方晶相颗粒中氨基的接枝率为4.5%-6.8%。
优选的,所述氨基化钛酸钡四方晶相颗粒的粒径为120~170nm。
优选的,所述压电水凝胶的制备方法包括以下步骤:
将氧化硫酸软骨素溶解于含有硼砂的PBS溶液中,得到氧化硫酸软骨素溶液;将氨基化钛酸钡四方晶相颗粒均匀混入氧化硫酸软骨素溶液中,最后加入明胶混合均匀,得到混合溶液,25~45℃原位交联30~120min形成水凝胶。
进一步优选的,所述混合溶液中明胶、氧化硫酸软骨素、氨基化钛酸钡四方晶相颗粒、硼砂、PBS的质量体积比为10g:5g:0.1~5g:2g:100ml,更优选为10g:5g:0.1~0.5g:2g:100ml。。
进一步优选的,所述氨基化钛酸钡四方晶相颗粒是钛酸钡四方晶相颗粒与硅烷偶联剂按照3g:15ml的比例混入100ml有机溶剂中,65℃避光反应5~6小时制得;所述硅烷偶联剂为3-氨丙基三乙氧基硅烷;所述有机溶剂为正己烷。
进一步优选的,所述将氨基化钛酸钡四方晶相颗粒均匀混入氧化硫酸软骨素溶液中是指加入颗粒后于超声下分散5min使其分布均匀。
进一步优选的,所述含有硼砂的PBS溶液是将硼砂按照2~3g/100ml的质量体积比加入pH值为7.2~7.4的PBS溶液中,40~50℃搅拌溶解制得。
进一步优选的,所述交联条件为35~40℃反应60~90min。
优选的,所述压电水凝胶在超声加载作用下产生的电信号能够促进早期及晚期成骨相关基因的表达。
优选的,所述超声的功率为0.5-2W/cm2。
进一步优选的,所述超声的功率为1.5W/cm2。
与现有技术相比,本发明具有以下优点及有益效果:
(1)本发明骨胶水的制备工艺简单、可控、成本低、重复性高,可实现批量化生产,降低以往骨修复材料的成本,减轻患者的经济负担,提高患者生活质量。
(2)本发明的骨胶水生物相容性好,通过注射到复杂形态骨缺损部位,其能很好地适配缺损形态,并在超声精准加载下产生持续力-电响应微环境,实现骨缺损部位的再生性修复,为临床发展具有力-电响应功能的新型骨修复材料奠定科学基础,具有重大的临床意义与社会效益。
附图说明
图1是本发明实施例1所得氨基化钛酸钡颗粒的扫描电镜图及傅立叶红外光谱。
图2是本发明实施例2所得压电电活性骨胶水的扫描电镜图。
图3是本发明实施例3所得压电电活性骨胶水在不同超声功率下的电压输出图。
图4是本发明实施例4所得压电电活性骨胶水的自愈合及骨黏合实物图。
图5是本发明实施例5所得压电电活性骨胶水诱导BMSCs成骨相关基因表达统计图;其中,ALP:碱性磷酸酶,Runx2:Runt相关转录因子2,BMP2:骨形成蛋白2,OPN:骨桥蛋白,OCN:骨钙素,COL-1:Ⅰ型胶原。
具体实施方式
下面结合具体的实施例和附图对本发明做进一步详细的说明,但本发明具体实施方式不限于此。
本发明实施例中未注明具体条件者,按照常规条件或者制造商建议的条件进行。所用未注明生产厂商的原料、试剂等,均为可以通过市售购买获得的常规产品。
以下所用氧化硫酸软骨素的氧化度为60%±2%。
对比例1
将5%w/v的氧化硫酸软骨素混入2g/100ml的硼砂PBS溶液中,搅拌5min溶解均匀获得氧化硫酸软骨素溶液;将10%w/v的明胶加入氧化硫酸软骨素溶液中,搅拌溶解均匀;将混合后所得明胶、氧化硫酸软骨素、硼砂、PBS的质量体积比为10g:5g:2g:100ml的混合液在37℃下交联90min得到可注射明胶/氧化硫酸软骨素水凝胶。
实施例1
为了制备氨基化的钛酸钡纳米颗粒,首先在避光条件下,将正己烷与3-氨丙基三乙氧基硅烷以20:3的体积比混合均匀,随后加入2.6%w/v粒径为150~200nm具有钙钛矿结构的四方晶相钛酸钡颗粒,65℃水浴反应6h,得到氨基化钛酸钡颗粒。钛酸钡颗粒、3-氨丙基三乙氧基硅烷、正己烷的质量体积比为3g:15ml:100ml。
实施例1所得氨基化钛酸钡颗粒的扫描电镜图和傅立叶红外光谱如图1所示。由图1结果可看出制得的氨基化钛酸钡颗粒为平均粒径120~170nm的四方相纳米颗粒,并具有典型的氨基基团。
实施例2
按实施例1的方法制得氨基化钛酸钡颗粒;将5%w/v的氧化硫酸软骨素混入2g/100ml的硼砂PBS溶液中,搅拌5min溶解均匀获得氧化硫酸软骨素溶液;将0.1%w/v或0.5%w/v氨基化钛酸钡颗粒加入氧化硫酸软骨素溶液中,超声分散5min;然后加入10%w/v明胶至混合溶液中,搅拌溶解均匀;最终混合液中明胶、氧化硫酸软骨素、氨基化钛酸钡颗粒、硼砂、PBS的质量体积比为10g:5g:0.1g:2g:100ml(命名0.1BGO)或10g:5g:0.5g:2g:100ml(命名0.5BGO),37℃下交联90min得到可注射压电电活性骨胶水。
对比例1所得水凝胶及实施例2所得压电电活性骨胶水的扫描电镜图如图2所示。由图2的结果可以看出随着氨基化钛酸钡颗粒掺杂比例的增加,骨胶水的孔径逐渐增大。
实施例3
为了获得压电电活性骨胶水的电信号,采用实施例1方法制得氨基化钛酸钡颗粒;按照实施例2方法制得明胶、氧化硫酸软骨素、氨基化钛酸钡颗粒、硼砂、PBS的质量体积比为10g:5g:0.1g:2g:100ml的压电电活性骨胶水(命名0.1BGO);使用0,0.5,1,1.5及2W/cm2的超声功率分别对0.1BGO加载,数字万用表记录骨胶水的电压输出。
实施例3所得压电电活性骨胶水在不同超声功率下的电压输出图如图3所示。由图3结果可以看出没有超声加载时压电电活性骨胶水的电压输出几乎为0,随着超声功率的增大其电压输出逐渐增大,在1.5W/cm2下的电压输出约为60mV,符合有利于成骨的电压。
实施例4
为了证明压电电活性骨胶水的自愈合性能和骨粘附性能,按照实施例1方法制得氨基化钛酸钡颗粒;按照实施例2方法制得明胶、氧化硫酸软骨素、氨基化钛酸钡颗粒、硼砂、PBS质量体积比为10g:5g:0.1g:2g:100ml的圆柱形压电电活性骨胶水(命名0.1BGO);将样品切成两半后放在一起,37℃下放置1h,评估骨胶水的宏观自愈合能力;将所述制得的压电电活性骨胶水以端-端和搭接剪切方式粘合新鲜的猪股骨松质骨片,研究骨胶水的粘合强度和柔韧性。
实施例4所得压电电活性骨胶水体外自愈合及体外骨黏合能力如图4所示。从图4可看出制得的骨胶水具有良好的自愈合能力和骨黏合能力。
实施例5
为了证明压电电活性骨胶水的成骨性能,按照对比例1方法制得明胶、氧化硫酸软骨素、硼砂、PBS的质量体积比为10g:5g:2g:100ml的可注射明胶/氧化硫酸软骨素水凝胶(命名GO);按照实施例1方法制得氨基化钛酸钡颗粒;按照实施例2方法制得明胶、氧化硫酸软骨素、氨基化钛酸钡颗粒、硼砂、PBS的质量体积比分别为10g:5g:0.1g:2g:100ml(命名0.1BGO)和10g:5g:0.5g:2g:100ml(命名0.5BGO)的骨胶水。将所制得的GO、0.1BGO及0.5BGO骨胶水与骨髓间充质干细胞(Bone marrow derived stroma cells,BMSCs)共培养7天,通过实时荧光定量PCR(qPCR)检测在超声(声强为1.5W/cm2;组别分别命名为GO+US,0.1BGO+US,0.5BGO+US)和不超声(组别分别命名为GO,0.1BGO,0.5BGO)作用下早期及晚期成骨相关基因的变化,评估该骨胶水的体外成骨性能。
实施例5所得骨胶水的体外成骨qPCR检测如图5所示。由图5的qPCR定量分析结果可以看出压电电活性骨胶水在超声加载作用下产生的电信号能够促进早期及晚期成骨相关基因的表达,可用于骨缺损再生性修复的治疗。
Claims (10)
1.压电水凝胶作为骨胶水的应用,其特征在于,所述压电水凝胶由氧化硫酸软骨素、明胶与氨基化钛酸钡四方晶相颗粒原位交联而成;其中,氧化硫酸软骨素与明胶通过席夫碱动态键交联,氨基化钛酸钡四方晶相颗粒与氧化硫酸软骨素通过席夫碱动态键及氢键结合。
2.根据权利要求1所述的压电水凝胶作为骨胶水的应用,其特征在于,所述压电水凝胶中明胶、氧化硫酸软骨素、氨基化钛酸钡四方晶相颗粒的质量比为10:5:0.1~5。
3.根据权利要求2所述的压电水凝胶作为骨胶水的应用,其特征在于,所述压电水凝胶中明胶、氧化硫酸软骨素、氨基化钛酸钡四方晶相颗粒的质量比为10:5:0.1~0.5。
4.根据权利要求3所述的压电水凝胶作为骨胶水的应用,其特征在于,所述水凝胶中明胶、氧化硫酸软骨素、氨基化钛酸钡四方晶相颗粒的质量比为10:5:0.1。
5.根据权利要求1-4任一项所述的压电水凝胶作为骨胶水的应用,其特征在于,所述氧化硫酸软骨素的氧化度为60%±2%;所述氨基化钛酸钡四方晶相颗粒中氨基的接枝率为4.5%-6.8%。
6.根据权利要求1-4任一项所述的压电水凝胶作为骨胶水的应用,其特征在于,所述氨基化钛酸钡四方晶相颗粒的粒径为120~170nm。
7.根据权利要求1-4任一项所述的压电水凝胶作为骨胶水的应用,其特征在于,所述压电水凝胶的制备方法包括以下步骤:
将氧化硫酸软骨素溶解于含有硼砂的PBS溶液中,得到氧化硫酸软骨素溶液;将氨基化钛酸钡四方晶相颗粒均匀混入氧化硫酸软骨素溶液中,最后加入明胶混合均匀,得到混合溶液,25~45℃原位交联30~120min形成水凝胶。
8.根据权利要求1-4任一项所述的压电水凝胶作为骨胶水的应用,其特征在于,所述压电水凝胶在超声加载作用下产生的电信号能够促进早期及晚期成骨相关基因的表达。
9.根据权利要求8所述的压电水凝胶作为骨胶水的应用,其特征在于,所述超声的功率为0.5-2W/cm2。
10.根据权利要求9所述的压电水凝胶作为骨胶水的应用,其特征在于,所述超声的功率为1.5W/cm2。
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