CN112604029A - 用于牙槽骨修复的“三明治式”可降解支架的制备及产品和应用 - Google Patents
用于牙槽骨修复的“三明治式”可降解支架的制备及产品和应用 Download PDFInfo
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Abstract
本发明涉及一种用于牙槽骨修复的“三明治式”可降解支架的制备方法及其产品和应用,通过双喷头3D打印制备自固化羟基磷灰石和PLGA双层支架;之后,进行聚酯表面的氨基化,利用EDC/NHS偶联反应化学固定负载促内皮生长药物的丝素蛋白涂层。本发明制备与骨创伤相匹配的羟基磷灰石支架,生物活性涂层改性的PLGA为骨创面外固定提供匹配的基座,与骨胶、骨钉、缝合线配合使用达到固定的效果,实现精准植骨。所有材料均可生物降解,材料的降解速率适合新骨生长,负载VEGF的丝素蛋白涂层提高了PLGA与黏膜的相容性,克服传统钛网支架提前黏膜外暴露、体内不可降解等缺陷,满足临床应用的需求。
Description
技术领域
本发明涉及一种生物医用材料技术领域的方法,具体是一种用于牙槽骨修复的“三明治式”可降解支架的制备及其产品和应用,通过3D打印技术和表面涂层改性技术制备。
背景技术
口腔种植技术广泛应用于牙列缺损和牙齿缺失的修复治疗,但牙槽骨缺失导致种植区缺少足量的骨组织为植入物提供稳定的支撑,进而增大了手术难度和限制了种植义齿的适用范围 [Lekovic V.,et al, J. Periodontol., 1998]。口腔种植学的引导骨再生技术能够有效的扩增骨量,恢复牙槽骨的高度和丰满度。在目前的临床操作中,该技术主要以天然骨粉或人工骨粉为填充、辅以金属外固定材料包覆为主,该方法面对较大骨组织缺损时,骨增量效果并不理想,主要原因在于,一方面,粉末填充物受软组织挤压和自身溶解过程不平均,形状上易发生塌陷,致使修复牙槽骨厚度和牙槽嵴高度方面效果不稳定;另一方面,由于需要满足骨粉的固定需求,金属固定物多为网状包覆式设计,而传统的钛网表面不适合组织粘附,导致钛网植入后,粘骨膜瓣无法实现完整覆盖,术后黏膜下的钛网暴露率高;其次,金属固定物不可降解,在术后取出过程中可能造成二次创伤,增加手术风险。
本发明拟开发一种新颖的适用于CAD/CAM技术的常温下3D打印制备全羟基磷灰石支架技术,制备与缺损区形状匹配、同时具有一定力学强度和药物负载能力的骨修复支架,作为骨粉类无定型填充物的替代。为了解决目前临床中常用的钛网固定物存在的如不可降解、黏膜粘附能力差、提前暴露等问题,可降解聚酯类聚合物作为钛网的替代材料得到了广泛的研究,其中,PLGA具有足够的机械强度和良好的生物相容性,其体内降解能力较快,适用于作为固定支架使用。丝素蛋白是一种天然的大分子材料,含有一种与细胞粘附密切相关的特殊三肽结构,即精-甘-天冬氨酸肽结构,能促进上皮细胞在材料表面迁移、粘附和增殖[Unger R. E., Biomaterials, 2004]。以丝素蛋白涂层改性PLGA,可以促进其与黏膜组织的快速融合。
基于以上背景,本项目拟在常温3D打印载药羟基磷灰石支架的基础上,结合CAD/CAM技术,开发一种三明治式可降解支架的制备技术,支架由三部分组成,即具有良好增骨能力的羟基磷灰石支架、可降解的自固定PLGA支架以及促进黏膜与支架快速融合的载药丝素蛋白涂层。该支架可以改善传统牙槽骨修复技术的缺陷,实现个性化精确增骨,同时降低由固定材料黏膜外暴露和二次手术取出引起手术并发症的风险,为解决以上临床难题提供新的途径。
发明内容
为改善传统牙槽骨修复技术的缺陷,实现个性化精确增骨,同时降低由固定材料黏膜外暴露和二次手术取出引起手术并发症的风险,本发明目的在于提供一种用于牙槽骨修复的“三明治式”可降解支架的制备方法。
本发明的再一目的在于:提供一种上述方法制备的用于牙槽骨修复的“三明治式”可降解支架产品。
本发明的又一目的在于:提供一种上述产品的应用。
本发明目的通过下述方案实现:一种用于牙槽骨修复的“三明治式”可降解支架的制备方法,其特征在于通过双喷头3D打印制备自固化羟基磷灰石和PLGA双层支架;之后,进行聚酯表面的氨基化,利用EDC/NHS偶联反应化学固定负载促内皮生长药物的丝素蛋白涂层,包括以下步骤:
(1)将磷酸氢钙与碳酸钙按摩尔比2:1混合均匀,在1250-1400℃炉中锻烧2-4h后取出,在鼓风环境下急速冷却,之后采用氧化锆球磨罐湿法球磨的方式得到粒径均一的α-TCP粉末;
(2)配制浓度为5-10%(w/v)的明胶溶液,与甘油、1wt%戊二醛溶液按体积比100:20:1进行混合,将上述α-TCP粉末按固液比0.6-1g/mL加入混合溶液,得到自固化羟基磷灰石3D打印“墨水”;
(3)将上述“墨水”装入低温打印喷头,出料针头选用0.3-0.5mm;将PLGA颗粒装入高温打印喷头,出料针头选用0.17-0.5mm,打印温度为180-200℃。3D打印机采用双喷头打印模式,依次打印两种材料,打印完毕后,材料在室温下静置24h,使磷酸钙部分自然固化;
(4)将支架浸泡在50%(v/v)的乙醇水溶液中超声2小时,然后用大量水冲洗,将清洗过的支架置于1 ,6-己二胺和异丙醇的混合溶液中于45℃下反应5 min,去离子水清洗12h,真空干燥24h,使PLGA表面氨基化;
(5)配制EDC/NHS/MES交联剂水溶液,浓度为20mM/10mM/10mM,再配制VEGF和羟基磷灰石的混合溶液;交联溶液与混合溶液按1:9混合后,立即将表面氨基化的打印支架浸泡其中,在37℃反应4h。反应结束后,水洗支架表面,进行冷冻干燥,即得到“三明治”式可降解支架。
步骤(1)所述的磷酸氢钙与碳酸钙的混合方式为无水乙醇介质中湿法球磨,球磨速度为400rpm,球磨时间为2-4h;干燥方式为通过旋转蒸发除去乙醇,置于60℃烘箱中干燥24h。
步骤(2)所述明胶溶液的配制方式为50℃恒温水浴中磁力搅拌溶解;α-TCP粉末与混合溶液的混合方式为37℃水浴下磁力搅拌混合10min。
步骤(3)所述PLGA分子量为10万-40万,LA/GA为75/25-90/10,分子链两端可为酯基、羟基或羧基封端。
步骤(3)所述的SF/VEGF混合溶液,丝素蛋白溶度为0.1-0.5mg/mL、羟基磷灰石浓度为0.1-10μg/mL。
本发明提供一种用于牙槽骨修复的“三明治式”可降解支架,根据上述任一所述方法制备得到,支架由三部分组成,即具有良好增骨能力的羟基磷灰石支架、可降解的自固定PLGA支架以及促进黏膜与支架快速融合的载药丝素蛋白涂层。
本发明提供一种“三明治式”可降解支架在制备用于牙槽骨修复材料中的应用。
制备以α-TCP为主体的自固化羟基磷灰石打印墨水,采用低温喷头常温下打印;制备以PLGA为主体的打印墨水,采用高温喷头在180-200℃进行熔融打印;采用双喷头3D打印模式,按模型设计将两种材料打印形成双层支架,室温静置24h使磷酸钙部分自然固化;之后,进行聚酯表面的氨基化,利用EDC/NHS偶联反应化学固定负载促内皮生长药物的丝素蛋白涂层。
本发明制备与骨创伤相匹配的羟基磷灰石支架,生物活性涂层改性的PLGA为骨创面外固定提供匹配的基座,与骨胶、骨钉、缝合线配合使用达到固定的效果,实现精准植骨。所有材料均可生物降解,材料的降解速率适合新骨生长,负载VEGF的丝素蛋白涂层提高了PLGA与黏膜的相容性,克服传统钛网支架提前黏膜外暴露、体内不可降解等缺陷,满足临床应用的需求。
附图说明
图1是所制备“三明治”式可降解支架示意图;
图2是羟基磷灰石和PLGA结合界面的SEM图。
具体实施方式
以下实施例以发明技术方案为前提进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围并不限于下述的实施例。
实施例1
一种用于牙槽骨修复的“三明治式”可降解支架,通过双喷头3D打印制备自固化羟基磷灰石和PLGA双层支架;之后,进行聚酯表面的氨基化,利用EDC/NHS偶联反应化学固定负载促内皮生长药物的丝素蛋白涂层,按以下步骤制备:
(1)α-TCP的制备:
按摩尔比2:1称量磷酸氢钙粉末和碳酸钙粉末,使用适量无水乙醇为介质湿法球磨,转速400rpm,球磨时间4h,球磨珠与粉末质量比为2:1。原料混合液通过旋转蒸发除去乙醇,置于60℃烘箱中干燥24h;将干燥后的粉末置于马弗炉中,1400℃煅烧2h后取出,在鼓风环境下急速冷却;将冷却后的粉末以无水乙醇为介质湿法球磨,转速450rpm,用氧化锆球磨罐球磨6h,球磨珠与粉末质量比为4:1。粉末悬浊液置于80℃烘箱中充分干燥,制备得到α-TCP粉末;
(2)称取明胶5g加入50mL超纯水中,在50℃水浴中磁力搅拌溶解,配制浓度为10%(w/v)的明胶溶液;取5mL上述明胶溶液,加入0.5mL甘油及0.05mL质量分数为1%的戊二醛溶液,于37℃水浴中搅拌均匀后,加入3g 步骤(1)中制备的α-TCP粉末,磁力搅拌10min,得到的混合液即为自固化羟基磷灰石3D打印“墨水”;之后,
(3)将上述“墨水”装入低温打印喷头,出料针头选用0.3-0.5mm;将PLGA颗粒装入高温打印喷头,出料针头选用0.17-0.5mm,打印温度为180-200℃。3D打印机采用双喷头打印模式,依次打印两种材料,打印完毕后,材料在室温下静置24h,使磷酸钙部分自然固化;
(4)将支架浸泡在50%(v/v)的乙醇水溶液中超声2小时,然后用大量水冲洗,将清洗过的支架置于1 ,6-己二胺和异丙醇的混合溶液中于45℃下反应5 min,去离子水清洗12h,真空干燥24h,使PLGA表面氨基化,得到表面氨基化的支架;
(5)配制EDC/NHS/MES交联剂水溶液,浓度为20mM/10mM/10mM,再配制0.2g/mL丝素蛋白和5μg/mL VEGF的混合溶液;交联剂水溶液与混合溶液按1:9混合后,立即将表面氨基化的打印支架浸泡其中,在37℃反应4h;反应结束后,水洗支架表面,进行冷冻干燥,即得到图1所示的“三明治”式可降解支架。
羟基磷灰石和PLGA结合界面的SEM图见图2。
实施例2
一种用于牙槽骨修复的“三明治式”可降解支架,按实施例1步骤(1)、(2)制备3D打印支架,将打印支架浸泡在50%(v/v)的乙醇水溶液中超声2小时,然后用大量水冲洗,将清洗过的支架置于1 ,6-己二胺和异丙醇的混合溶液中于45℃下反应5 min,去离子水清洗12h,真空干燥24h,得到表面氨基化的支架。配制EDC/NHS/MES交联剂水溶液,浓度为20mM/10mM/10mM,再配制0.1g/mL丝素蛋白和2μg/mL VEGF的混合溶液;交联溶液与混合溶液按体积比1:9混合后,立即将PLGA氨基化的支架浸泡其中,在37℃反应4h。反应结束后,水洗支架表面,进行冷冻干燥,即得到三明治式可降解支架。
实施例3
一种用于牙槽骨修复的“三明治式”可降解支架,按实施例1(1)、(2)制备3D打印支架,将打印支架浸泡在50%(v/v)的乙醇水溶液中超声2小时,然后用大量水冲洗,将清洗过的支架置于1 ,6-己二胺和异丙醇的混合溶液中于45℃下反应5 min,去离子水清洗12h,真空干燥24h,得到表面氨基化的支架。配制EDC/NHS/MES交联剂水溶液,浓度为20mM/10mM/10mM,再配制0.1g/mL丝素蛋白和5μg/mL VEGF的混合溶液;交联溶液与混合溶液按体积比1:9混合后,立即将PLGA氨基化的支架浸泡其中,在37℃反应4h。反应结束后,水洗支架表面,进行冷冻干燥,即得到三明治式可降解支架。
Claims (7)
1.一种用于牙槽骨修复的“三明治式”可降解支架的制备方法,其特征在于,通过双喷头3D打印制备自固化羟基磷灰石和PLGA双层支架;之后,进行聚酯表面的氨基化,利用EDC/NHS偶联反应化学固定负载促内皮生长药物的丝素蛋白涂层,包括以下步骤:
(1)将磷酸氢钙与碳酸钙按摩尔比2:1混合均匀,在1250-1400℃炉中锻烧2-4h后取出,在鼓风环境下急速冷却,之后采用氧化锆球磨罐湿法球磨的方式得到粒径均一的α-TCP粉末;
(2)配制浓度为5-10%(w/v)的明胶溶液,与甘油、1wt%戊二醛溶液按体积比100:20:1进行混合,将上述α-TCP粉末按固液比0.6-1g/mL加入混合溶液,得到自固化羟基磷灰石3D打印“墨水”;
(3)将上述“墨水”装入低温打印喷头,出料针头选用0.3-0.5mm;将PLGA颗粒装入高温打印喷头,出料针头选用0.17-0.5mm,打印温度为180-200℃。3D打印机采用双喷头打印模式,依次打印两种材料,打印完毕后,材料在室温下静置24h,使磷酸钙部分自然固化;
(4)将支架浸泡在50%(v/v)的乙醇水溶液中超声2小时,然后用大量水冲洗,将清洗过的支架置于1 ,6-己二胺和异丙醇的混合溶液中于45℃下反应5 min,去离子水清洗12h,真空干燥24h,使PLGA表面氨基化;
(5)配制EDC/NHS/MES交联剂水溶液,浓度为20mM/10mM/10mM,再配制VEGF和羟基磷灰石的混合溶液;交联溶液与混合溶液按1:9混合后,立即将表面氨基化的打印支架浸泡其中,在37℃反应4h。反应结束后,水洗支架表面,进行冷冻干燥,即得到“三明治”式可降解支架。
2.根据权利要求1所述的一种用于牙槽骨修复的“三明治式”可降解支架的制备方法,其特征在于,步骤(1)所述的磷酸氢钙与碳酸钙的混合方式为无水乙醇介质中湿法球磨,球磨速度为400rpm,球磨时间为2-4h;干燥方式为通过旋转蒸发除去乙醇,置于60℃烘箱中干燥24h。
3.根据权利要求1所述的一种用于牙槽骨修复的“三明治式”可降解支架的制备方法,其特征在于,步骤(2)所述明胶溶液的配制方式为50℃恒温水浴中磁力搅拌溶解;α-TCP粉末与混合溶液的混合方式为37℃水浴下磁力搅拌混合10min。
4.根据权利要求1所述的一种用于牙槽骨修复的“三明治式”可降解支架的制备方法,其特征在于,步骤(3)所述PLGA分子量为10万-40万,LA/GA为75/25-90/10,分子链两端可为酯基、羟基或羧基封端。
5.根据权利要求1所述的一种用于牙槽骨修复的“三明治式”可降解支架的制备方法,其特征在于,步骤(3)所述的SF/VEGF混合溶液,丝素蛋白溶度为0.1-0.5mg/mL、羟基磷灰石浓度为0.1-10μg/mL。
6.一种用于牙槽骨修复的“三明治式”可降解支架,其特征在于,根据权利要求1-5任一所述方法制备得到,支架由三部分组成,即具有良好增骨能力的羟基磷灰石支架、可降解的自固定PLGA支架以及促进黏膜与支架快速融合的载药丝素蛋白涂层。
7.根据权利要求6所述“三明治式”可降解支架在制备用于牙槽骨修复材料中的应用。
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