CN110128679B - 一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法 - Google Patents
一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法 Download PDFInfo
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Abstract
本发明公开了一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,包括以下步骤:步骤1:将导电粒子和多巴胺单体分散在水中形成悬浮液,加入氢氧化钙溶液调节悬浮液为弱碱性,充分反应生成多巴胺修饰的导电粒子的氢氧化钙溶液A;步骤2:制备聚乙烯醇溶液B,加入溶液A中,得混合溶液C;步骤3:向混合溶液C中滴加磷酸反应后成型,经过冻融循环即可得到下层水凝胶;步骤4:将聚乙烯醇、天然高分子和多巴胺溶于去离子水形成混合溶液,在弱碱性条件下完全反应后得到溶液D;步骤5:将溶液D置于下层水凝胶上方,冻融循环后即可得到所需双层水凝胶;本发明得到的双层水凝胶组织粘附性和电刺激响应能力好。
Description
技术领域
本发明涉及生物材料制备技术领域,具体涉及一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法。
背景技术
骨和软骨相关疾病是人类最常见的疾病,它们影响到全世界数百万人。而骨软骨一体化修复的主要困难之一是必须考虑三个方面:骨、软骨和骨-软骨界面。其中骨软骨(骨-软骨)界面是透明软骨和软骨下骨的固定点,因此起着关键连接作用。此外,它还提供了支持生物力学运动从关节到骨骼的能量传递的机械结构。由于透明软骨再生能力差、受损的骨软骨组织难以治疗。从软骨表面到软骨下骨的复杂生物和化学梯度的存在也很难从损伤中恢复。
水凝胶正成为一种有潜力的骨软骨一体化修复材料。传统的骨软骨一体化修复水凝胶多采用分层结构,上下两层通过缝合线或粘接剂连接,使得上下层接触不紧密。水凝胶与宿主组织整合度差,不能进行梯度修复。然而,传统的骨软骨一体化修复水凝胶的主要组成为天然高分子,其存在的缺点是力学性能差,不能承受骨软骨损伤部位的复杂应力。最终导致修复效果不佳。
发明内容
本发明针对现有技术存在的问题提供一种具有组织粘附性、良好的电刺激响应能力的用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法。
本发明采用的技术方案是:一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,包括以下步骤:
步骤1:按照设定质量比将导电粒子和多巴胺单体分散在水中形成悬浮液,加入氢氧化钙溶液调节悬浮液为弱碱性,充分反应生成多巴胺修饰的导电粒子的氢氧化钙溶液A;
步骤2:制备聚乙烯醇溶液B,将其加入步骤1得到的溶液A中,混合均匀得混合溶液C;
步骤3:向混合溶液C中滴加磷酸溶液,在弱碱性条件下完全反应后成型,经过冻融循环即可得到下层水凝胶;
步骤4:将按照设定比例将聚乙烯醇、天然高分子和多巴胺溶于去离子水形成混合溶液,在弱碱性条件下完全反应后得到溶液D;
步骤5:将溶液D置于步骤3制备得到的下层水凝胶上方,冻融循环后即可得到所需双层水凝胶。
进一步的,所述步骤1中悬浮液中导电粒子和多巴胺单体总浓度为1~20mg/L,多巴胺单体和导电粒子的质量比为0.25~4:1。
进一步的,步骤1在50~90℃条件下搅拌反应2~10小时。
进一步的,所述步骤2中聚乙烯醇溶液浓度为200~500mg/L,溶液A和溶液B按照体积比为1:1混合。
进一步的,所述步骤3中滴加磷酸溶液按照溶液C中的钙离子和磷酸中磷离子摩尔比为1.67:1的比例滴加。
进一步的,所述步骤3中冻融循环温度为-20℃~-80℃,经4~6小时完成。
进一步的,所述步骤4中混合溶液中聚乙烯醇浓度为100~200 mg/L,天然高分子浓度为10~30 mg/L,多巴胺浓度为2~10 mg/L。
进一步的,所述步骤5中双层水凝胶中,制备上层水凝胶所需溶液与制备下层水凝胶所需溶液的体积比为1:10~20。
进一步的,所述步骤1中所需氢氧化钙溶液浓度为30~60 mg/mL,调节pH为8~9;步骤3和步骤4中采用氢氧化钠调节pH,弱碱性为pH为8~9。
进一步的,所述天然高分子为丝素蛋白、壳聚糖、明胶、胶原纤维、硫酸软骨素中的一种;导电粒子为石墨烯、单壁碳纳米管、多壁碳纳米管、聚吡咯颗粒、聚苯胺颗粒、聚3,4-乙烯二氧噻吩颗粒、金纳米颗粒及纳米线、银纳米颗粒及纳米线中的一种。
本发明的有益效果是:
(1)本发明中导电粒子经多巴胺修饰可更好的被固定在水凝胶网络中;同时多巴胺上的酚羟基可以与Ca离子螯合,作为羟基磷灰石原位形成的位点,在水凝胶网络内部均匀形成具有骨活性的羟基磷灰石纳米颗粒和导电网络;
(2)本发明采用生物可降解聚合物作为基体,降解产物无毒,采用冻融交联法与天然高分子共混避免了有毒交联剂的使用;改善了天然高分子力学性能不足的问题,通过调整可降解聚合物的浓度和冻融时间和次数可得到不同力学性能的水凝胶;
(3)本发明采用冻融物理交联制备得到的双层水凝胶不存在界面应力,界面能通过氢键交联紧密结合为一体,水凝胶中大量的酚羟基能有较好的组织粘附性,改善植入水凝胶与宿主的结合。
附图说明
图1为本发明实施例1中下层水凝胶SEM图。
图2为本发明实施例1制备得到的双层水凝胶截面的SEM图。
图3为本发明实施例1制备得到的下层水凝胶的XRD和羟基磷灰石的XRD对比结果示意图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明。
一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,包括以下步骤:
步骤1:将导电粒子和多巴胺单体分散在水中形成悬浮液,多巴胺和导电粒子在悬浮液中总浓度为1~20 mg/L,多巴胺和导电粒子的质量比为0.25~4:1。将溶液用浓度为30~60 mg/L的氢氧化钙调节pH至8~9,在50~90 ℃条件下搅拌2~10小时,反应完成后得到含有多巴胺修饰的导电粒子的氢氧化钙溶液A。
步骤2:将聚乙烯醇溶解于去离子水中,制备浓度为200~500 mg/L的聚乙烯醇溶液B;完全溶解后向其中加入含有多巴胺修饰的导电粒子的氢氧化钙溶液A,其中,溶液A和溶液B体积比为1:1,均匀分散后得到混合溶液C。
步骤3:向混合溶液C中按照钙磷摩尔比为1.67:1的比例滴加磷酸溶液,滴加完成后用氢氧化钠调节溶液pH为8~9,搅拌反应完成后倒入模具成型;经冻融循环(-20℃~-80℃)4~6小时制备出用于骨修复的下层水凝胶。
步骤4:将聚乙烯醇、天然高分子和多巴胺溶于去离子水中,完全溶解后混合溶液中聚乙烯醇的浓度为100~200 mg/mL,天然高分子的浓度为10~30 mg/mL,多巴胺的浓度为2~10 mg/mL。完全溶解后氢氧化钠调节pH为8~9,反应完成后得到溶液D。
步骤5:将溶液D倒入模具中下层水凝胶的上方,上下凝胶所用溶液体积比为1:10~20,冻融循环制备出双层水凝胶。
天然高分子为丝素蛋白、壳聚糖、明胶、胶原纤维、硫酸软骨素中的一种;导电粒子为石墨烯、单壁碳纳米管、多壁碳纳米管、聚吡咯颗粒、聚苯胺颗粒、聚3,4-乙烯二氧噻吩颗粒、金纳米颗粒及纳米线、银纳米颗粒及纳米线中的一种。
实施例1
一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,包括以下步骤:
步骤1:将石墨烯和多巴胺单体分散在水中形成悬浮液,多巴胺和石墨烯在悬浮液中总浓度为1 mg/L,多巴胺和石墨烯的质量比为0.25~4:1。将溶液用浓度为30~60 mg/L的氢氧化钙调节pH至8,在50 ℃条件下搅拌2小时,反应完成后得到含有多巴胺修饰的石墨烯的氢氧化钙溶液A。
步骤2:将聚乙烯醇溶解于去离子水中,制备浓度为200 mg/L的聚乙烯醇溶液B;完全溶解后向其中加入含有多巴胺修饰的石墨烯的氢氧化钙溶液A,其中,溶液A和溶液B体积比为1:1,均匀分散后得到混合溶液C。
步骤3:向混合溶液C中按照钙磷摩尔比为1.67:1的比例滴加磷酸溶液,滴加完成后用氢氧化钠调节溶液pH为8,搅拌反应完成后倒入模具成型;经冻融循环(-20℃)4~6小时制备出用于骨修复的下层水凝胶。
步骤4:将聚乙烯醇、丝素蛋白和多巴胺溶于去离子水中,完全溶解后混合溶液中聚乙烯醇的浓度为100 mg/mL,天然高分子的浓度为10 mg/mL,多巴胺的浓度为2 mg/mL。完全溶解后氢氧化钠调节pH为8,反应完成后得到溶液D。
步骤5:将溶液D倒入模具中下层水凝胶的上方,上下凝胶所用溶液体积比为1:10,冻融循环制备出双层水凝胶。
图1为本发明通过多巴胺诱导原位矿化制备得到的下层水凝胶的SEM图,图2为本发明制备的到双层水凝胶的截面SEM图;从图1中可以看出羟基磷灰石纳米颗粒均匀分散在导电水凝胶基体中。从图2可以看出双层水凝胶的界面清晰但紧密结合无缝隙。
图3为多巴胺诱导原位矿化制备得到的下层水凝胶(曲线A)和羟基磷灰石(曲线B)的XRD图谱,从图中可以看出,水凝胶网络内部的纳米颗粒为羟基磷灰石。
实施例2
一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,包括以下步骤:
步骤1:将单壁碳纳米管和多巴胺单体分散在水中形成悬浮液,多巴胺和单壁碳纳米管在悬浮液中总浓度为5 mg/L,多巴胺和单壁碳纳米管的质量比为1:1。将溶液用浓度为40 mg/L的氢氧化钙调节pH至8.5,在60 ℃条件下搅拌3小时,反应完成后得到含有多巴胺修饰的单壁碳纳米管的氢氧化钙溶液A。
步骤2:将聚乙烯醇溶解于去离子水中,制备浓度为300 mg/L的聚乙烯醇溶液B;完全溶解后向其中加入含有多巴胺修饰的单壁碳纳米管的氢氧化钙溶液A,其中,溶液A和溶液B体积比为1:1,均匀分散后得到混合溶液C。
步骤3:向混合溶液C中按照钙磷摩尔比为1.67:1的比例滴加磷酸溶液,滴加完成后用氢氧化钠调节溶液pH为8.5,搅拌反应完成后倒入模具成型;经冻融循环(-30℃)5小时制备出用于骨修复的下层水凝胶。
步骤4:将聚乙烯醇、壳聚糖和多巴胺溶于去离子水中,完全溶解后混合溶液中聚乙烯醇的浓度为120 mg/mL,壳聚糖的浓度为15 mg/mL,多巴胺的浓度为3 mg/mL。完全溶解后氢氧化钠调节pH为8.5,反应完成后得到溶液D。
步骤5:将溶液D倒入模具中下层水凝胶的上方,上下凝胶所用溶液体积比为1:15,冻融循环制备出双层水凝胶。
实施例3
一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,包括以下步骤:
步骤1:将聚吡咯颗粒和多巴胺单体分散在水中形成悬浮液,多巴胺和聚吡咯颗粒在悬浮液中总浓度为10 mg/L,多巴胺和石墨烯的质量比为2:1。将溶液用浓度为50 mg/L的氢氧化钙调节pH至8.7,在70 ℃条件下搅拌4小时,反应完成后得到含有多巴胺修饰的聚吡咯颗粒的氢氧化钙溶液A。
步骤2:将聚乙烯醇溶解于去离子水中,制备浓度为400 mg/L的聚乙烯醇溶液B;完全溶解后向其中加入含有多巴胺修饰的聚吡咯颗粒的氢氧化钙溶液A,其中,溶液A和溶液B体积比为1:1,均匀分散后得到混合溶液C。
步骤3:向混合溶液C中按照钙磷摩尔比为1.67:1的比例滴加磷酸溶液,滴加完成后用氢氧化钠调节溶液pH为8.2,搅拌反应完成后倒入模具成型;经冻融循环(-40℃)5.5小时制备出用于骨修复的下层水凝胶。
步骤4:将聚乙烯醇、明胶和多巴胺溶于去离子水中,完全溶解后混合溶液中聚乙烯醇的浓度为160 mg/mL,明胶的浓度为25 mg/mL,多巴胺的浓度为5 mg/mL。完全溶解后氢氧化钠调节pH为8.2,反应完成后得到溶液D。
步骤5:将溶液D倒入模具中下层水凝胶的上方,上下凝胶所用溶液体积比为1:14,冻融循环制备出双层水凝胶。
本发明中的导电微粒经多巴胺修饰后可更好的被固定在水凝胶网络中;同时多巴胺上的酚羟基可以鳌合Ca离子作为羟基磷灰石原位形成的位点,能在水凝胶网络内部均匀形成具有成骨活性的羟基磷灰石纳米颗粒和导电网络;采用生物可降解聚合物作为基体,降解产物无毒,采用冻融交联法与天然高分子共混避免了有毒交联剂的使用,改善了天然高分子力学性能不足的问题,通过调整可降解聚合物的浓度和冻融的时间和次数可得到不同力学性能的水凝胶;使用的冻融物理交联制备的双层水凝胶不存在界面应力,界面能通过氢键交联紧密结合为一体,水凝胶中大量的酚羟基能有较好的组织粘附性,改善植入水凝胶与宿主的结合。
Claims (9)
1.一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,其特征在于,包括以下步骤:
步骤1:按照设定质量比将导电粒子和多巴胺单体分散在水中形成悬浮液,加入氢氧化钙溶液调节悬浮液为弱碱性,充分反应生成多巴胺修饰的导电粒子的氢氧化钙溶液A;
步骤2:制备聚乙烯醇溶液B,将其加入步骤1得到的溶液A中,混合均匀得混合溶液C;
步骤3:向混合溶液C中滴加磷酸溶液,在弱碱性条件下完全反应后成型,经过冻融循环即可得到下层水凝胶;
步骤4:将按照设定比例将聚乙烯醇、天然高分子和多巴胺溶于去离子水形成混合溶液,在弱碱性条件下完全反应后得到溶液D;
步骤5:将溶液D置于步骤3制备得到的下层水凝胶上方,冻融循环后即可得到所需双层水凝胶;所述步骤3中滴加磷酸溶液按照混合溶液C中的钙离子和磷酸中磷离子摩尔比为1.67:1的比例滴加。
2.根据权利要求1所述的一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,其特征在于,所述步骤1中悬浮液中导电粒子和多巴胺单体总浓度为1~20mg/L,多巴胺单体和导电粒子的质量比为0.25~4:1。
3.根据权利要求1所述的一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,其特征在于,步骤1在50~90℃条件下搅拌反应2~10小时。
4.根据权利要求1所述的一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,其特征在于,所述步骤2中聚乙烯醇溶液浓度为200~500mg/L,溶液A和溶液B按照体积比为1:1混合。
5.根据权利要求1所述的一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,其特征在于,所述步骤3中冻融循环温度为-20℃~-80℃,经4~6小时完成。
6.根据权利要求1所述的一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,其特征在于,所述步骤4中混合溶液中聚乙烯醇浓度为100~200mg/L,天然高分子浓度为10~30mg/L,多巴胺浓度为2~10mg/L。
7.根据权利要求1所述的一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,其特征在于,所述步骤5中双层水凝胶中,制备上层水凝胶所需溶液与制备下层水凝胶所需溶液的体积比为1:10~20。
8.根据权利要求1所述的一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,其特征在于,所述步骤1中所需氢氧化钙溶液浓度为30~60mg/mL,调节pH为8~9;步骤3和步骤4中采用氢氧化钠调节pH,弱碱性为pH为8~9。
9.根据权利要求1所述的一种用于电刺激骨软骨一体再生的导电双层水凝胶的制备方法,其特征在于,所述天然高分子为丝素蛋白、壳聚糖、明胶、胶原纤维、硫酸软骨素中的一种;导电粒子为石墨烯、单壁碳纳米管、多壁碳纳米管、聚吡咯颗粒、聚苯胺颗粒、聚3,4-乙烯二氧噻吩颗粒、金纳米颗粒及纳米线、银纳米颗粒及纳米线中的一种。
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CF01 | Termination of patent right due to non-payment of annual fee |