CN114767937B - 胶原外脱矿的牙骨材料 - Google Patents
胶原外脱矿的牙骨材料 Download PDFInfo
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- CN114767937B CN114767937B CN202210404652.6A CN202210404652A CN114767937B CN 114767937 B CN114767937 B CN 114767937B CN 202210404652 A CN202210404652 A CN 202210404652A CN 114767937 B CN114767937 B CN 114767937B
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- A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
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Abstract
本申请公开了胶原外脱矿的牙骨材料。该牙骨材料是基于胶原纤维的尺寸排阻效应,通过大分子螯合剂与牙本质胶原纤维外的钙结合,脱去胶原纤维外矿物质晶体,得到具有独特纳米结构和高机械强度的外脱矿牙骨材料。纤维外脱矿牙骨材料展现出由内矿化胶原纤维构成的独特纳米结构,具有优良的机械强度和生物相容性,可以有效促进细胞的粘附与增殖,支撑细胞生长,促进干细胞成骨向分化,且纤维外矿物质脱去后留下的孔隙有益于组织血管化及营养物质运输。因此,胶原外脱矿牙骨材料可以作为组织工程支架材料应用于骨组织再生,具有良好的生物医学应用前景。
Description
技术领域
本申请涉及生物医学工程的技术领域,尤其涉及胶原外脱矿的牙骨移植材料。
背景技术
骨移植材料的选择多种多样,其中,自体骨移植不存在免疫反应,具有更短的愈合时间和更快的骨整合速率,是骨移植手术的金标准(Piattelli,A.;Degidi,M.;DiStefano,D.A.;Rubini,C.;Fioroni,M.;Strocchi,R.,Microvessel density in alveolarridge regeneration with autologous and alloplastic bone.Implant Dent 2002,11(4),370-5)。然而,自体骨移植由于需要开辟第二术区,存在并发症多、患者自我汇报疼痛率高、费用高昂等问题(Chavda,S.;Levin,L.,Human Studies of Vertical andHorizontal Alveolar Ridge Augmentation Comparing Different Types of BoneGraft Materials:A Systematic Review.J Oral Implantol 2018,44(1),74-84)。牙本质基质由离体牙制备而成。既往研究发现,牙本质和颌面骨在胚胎学上都起源于神经嵴,具有相同的起源(Yoshida,T.;Vivatbutsiri,P.;Morriss-Kay,G.;Saga,Y.;Iseki,S.,Celllineage in mammalian craniofacial mesenchyme.Mech Dev 2008,125(9-10),797-808)。牙本质由磷酸钙盐为主的无机矿物质和胶原蛋白为主的有机物层层组装而成,与骨组织具有相似的组成与结构[1]。相比于其他骨移植材料,牙本质基质更易获取、生物相容性良好,同时具有良好的骨诱导性、骨传导性,是一种极具潜力的骨移植材料(Avery,S.J.;Sadaghiani,L.;Sloan,A.J.;Waddington,R.J.,Analysing the bioactive makeup ofdemineralised dentine matrix on bone marrow mesenchymal stem cells forenhanced bone repair.Eur Cell Mater 2017,34,1-14)。
相关技术中,对于牙本质基质的脱矿处理均采用EDTA、盐酸等小分子脱矿剂进行无选择性的脱矿处理,同时脱去胶原纤维内外的矿物质,因此存在机械强度低的技术缺陷。
发明内容
有鉴于此,本申请提供胶原外脱矿的牙骨材料,能够提高机械强度。
已为普遍意识到的是,相关技术中,对于牙本质基质的脱矿处理均采用EDTA、盐酸等小分子脱矿剂进行无选择性的脱矿处理。
由于骨组织的再生是动态过程,伴随着破骨细胞的吸收和成骨细胞形成新骨,随着矿物质被脱去,牙本质基质在体内的吸收速率变快,若快于新骨形成的速率,则不利于骨再生效果。此外,干细胞存在“机械记忆”,细胞外基质的机械强度影响着干细胞分化的方向,与骨组织机械强度相似的基底诱导干细胞成骨向分化,支架基底机械强度不足可能影响细胞的成骨向分化。
本发明人意外地发现,基于胶原尺寸排阻效应,分子量大于40kDa的钙离子螯合剂由于无法进入牙本质胶原纤维内间隙,会选择性脱去胶原纤维外矿物质,保留纤维内矿物质,实现了胶原外脱矿。本发明人构建的胶原外脱矿牙骨材料展现出由内矿化胶原纤维构成的独特纳米结构,具有优良的机械强度和生物相容性,可以有效促进细胞的粘附与增殖,支撑细胞生长,促进干细胞成骨向分化。基于此,创立了本发明创造。
<牙骨材料>
该胶原外脱矿的牙骨材料,采用分子量大于40kDa的金属离子螯合剂对牙本质材料进行脱矿处理所得到。
这里,术语“牙骨材料”依据机械粉碎形式的不同可以为粉末、颗粒、片状或块状等不同形状。
<金属离子螯合剂>
本文所用“金属离子螯合剂”是指能够与常见的钙等配位金属离子形成配位作用的配体。这些配位金属离子可以示例性地为具有惰性气体结构的阳离子,或者亚层d轨道已充满的金属离子,或者具有不完全亚层的过渡金属离子等。
合适但非限制性的金属离子螯合剂选自聚丙烯酸盐、羧甲基纤维素盐、羧甲基壳聚糖、壳聚糖、聚天冬氨酸盐中的一种或至少二种以上。
合适但非限制性的金属离子螯合剂的pH为中性或碱性。
<脱矿处理>
脱矿处理的过程包括:
使牙本质材料进行超声清洗,得到材料C;
使所述材料C在含有所述金属离子螯合剂的浸渍液进行浸渍处理,得到材料D;
将所述材料D进行冷冻干燥,得到所述牙骨材料。
合适但非限制性的,所述浸渍处理的时间为0.1~48小时。
合适但非限制性的,所述冷冻干燥的温度为-80℃,冷冻时间为1~10小时。
合适但非限制性的,所述超声清洗在无菌磷酸盐缓冲液中实施。
合格但非限制性的,所述牙骨材料为粉末、颗粒、片状或块状等不同形状。
本申请具有以下有益效果:
①本申请胶原外脱矿牙骨材料制备工艺简便,制备条件宽松,处理时间短。
②本申请胶原外脱矿牙骨材料具有胶原内矿化、外脱矿的独特理化性质,保留矿化胶原纤维网络,具有良好的机械强度和纳米形貌,有利于支撑细胞生长,促进细胞粘附、增殖。
③本申请胶原外脱矿牙骨材料保留了牙本质的生物活性物质,且脱去了胶原纤维外矿物质,具有大量孔隙,有利于营养物质和代谢产物的运输以及组织血管化发生,是优良的组织工程支架。
附图说明
下面结合附图,通过对本申请的具体实施方式详细描述,将使本申请的技术方案及其它有益效果显而易见。
图1为本申请实施例1、比较例1、比较例2所涉及相关材料的扫描电镜图像。
图2为本申请实施例1、比较例1、比较例2所涉及相关材料的超薄切片透射电镜图像。
图3为本申请实施例1、比较例1、比较例2所涉及相关材料的原子力显微镜图像。
图4为本申请实施例1、比较例1、比较例2所涉及相关材料的弹性模量测定结果。
图5为本申请实施例1、比较例1、比较例2所涉及相关材料的细胞骨架染色图像。
图6为本申请实施例1、比较例1、比较例2所涉及相关材料的PCR检测结果。
图7为本申请实施例1、比较例1、比较例2所涉及相关材料的Micro CT三维重建图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
<实施例的过程>
实施例1
S1、取新鲜的人类离体牙,去离子水超声清洗3次,滤干水分,加入消毒液(75%乙醇),常温下浸泡15分钟,滤去溶液后,无菌去离子水浸泡1小时,超声清洗5分钟,反复上述浸泡超声清洗3次;
S2、利用机械方法去除牙齿的牙釉质,开髓,拔除牙髓组织后,得到牙本质基质为主的材料A;
S3、利用电动研磨机粉碎材料A,收集粒径0.2-0.8mm的牙本质粉,得到材料B;
S4、将材料B浸泡在无菌磷酸盐缓冲液(PBS)中进行超声清洗,每10分钟更换一次液体,共清洗30分钟,去除清洗液得到材料C;
S5、将材料C加入至15%wt PAAN(Mw=225kDa)聚丙烯酸钠水溶液中,搅拌12小时后,去除溶液,然后注入无菌PBS超声清洗,每10min更换一次液体,共清洗30min,离心取沉淀得到材料D;
S6、将S5制备好的材料D进行冷冻干燥,在-80℃持续10小时,得到冻干胶原外脱矿牙骨粉;
S7、将冻干胶原外脱矿牙骨粉进行真空密封包装,进行辐照灭菌,得到胶原外脱矿牙骨粉材料。
实施例2
S1、取新鲜的人类离体牙,去离子水超声清洗3次,滤干水分,加入消毒液(75%乙醇),常温下浸泡15分钟,滤去溶液后,无菌去离子水浸泡1小时,超声清洗5分钟,反复上述浸泡超声清洗3次;
S2、利用机械方法去除牙齿的牙釉质,开髓,拔除牙髓组织后,得到牙本质基质为主的材料A;
S3、利用慢速锯切割材料A,得到2×2×1mm立方状的牙本质片材料B;
S4、将材料B浸泡在无菌磷酸盐缓冲液(PBS)中进行超声清洗,每10分钟更换一次液体,共清洗30分钟,去除清洗液得到材料C;
S5、将材料C加入至15%wt PAAN(Mw=225kDa)聚丙烯酸钠水溶液中,搅拌24小时后,去除溶液,然后注入无菌PBS超声清洗,每10min更换一次液体,共清洗30min,离心取沉淀得到材料D;
S6、将S5制备好的材料D进行冷冻干燥,在-80℃持续10小时,得到冻干胶原外脱矿牙骨片;
S7、将冻干胶原外脱矿牙骨片进行真空密封包装,进行辐照灭菌,得到胶原外脱矿牙骨片材料。
实施例3
将实施例1中S5所涉及的聚丙烯酸钠替换成羧甲基壳聚糖,其它同实施例1。
实施例4
将实施例1中S5所涉及的聚丙烯酸钠替换成聚天冬氨酸盐,其它同实施例1。
实施例5
将实施例1中S5所涉及的聚丙烯酸钠替换成羧甲基纤维素盐,其它同实施例1。
比较例1
未经处理的牙骨材料。
比较例2
与实施例唯一不同的是,S5中所涉及的聚丙烯酸钠水溶液处理过程替换为EDTA梯度处理过程:材料C分别浸入17%(5分钟),10%(5分钟),5%(10分钟)EDTA溶液中脱矿处理,其它均同实施例1。
<评价>
1、评价过程
A、将由实施例1、比较例1、比较例2所得的牙骨材料进行SEM图,具体测试过程如下:
将牙骨材料浸入2.5%戊二醛中室温固定1小时,4℃固定24小时,在室温下依次使用50%、70%、80%、90%、100%酒精梯度处理脱水,每个梯度处理时长5min,浸入HDMS浸泡30分钟,室温下真空干燥1小时,30mA电流喷金120秒后,利用场发射扫描电子显微镜(ZeissSIGMA)观察。
B、将由实施例1、比较例1、比较例2所得的牙骨材料进行超薄切片透射电镜图像,具体测试过程如下:
(1)将牙骨材料在室温下依次使用梯度浓度的乙醇溶液处理脱水(70%,80%,95%,100%×3),每个梯度处理时长1小时,在100%乙醇溶液中过夜;
(2)将牙骨材料在室温下置于100%环氧丙烷中3小时,每小时换液;
(3)按体积比1:1的比例将环氧丙烷与包埋树脂混合均匀,将牙骨材料浸泡其中,4小时后换新的混合液并过夜;
(4)按体积比1:3的比例将环氧丙烷与包埋树脂混合均匀,将牙骨材料浸泡其中,真空干燥8小时;
(5)将样品置于环氧树脂包埋模具中,使用纯树脂包埋,然后将模具放入60℃烘箱干燥固化48小时;
(6)将包埋完成的树脂块使用显微镜超薄切片机(UC7,Leica)切成50nm厚度的超薄切片,使用单槽碳膜透射电镜铜网打捞后干燥,利用透射显微镜(HT7700,Hitachi)观察。
C、将由实施例1、比较例1、比较例2所得的牙骨材料进行原子力显微镜图像,具体测试过程如下:
将牙骨材料包埋入环氧树脂中,依次用600、1200、2000目砂纸抛光,然后依次用9、3、1、0.25、0.05微米的抛光液在自动抛光机(MetaDi,Buehler)中进一步抛光。利用原子力显微镜(MultiMode8,Bruker)的PeakForce QNM模式进行检测。每个扫描区域尺寸为20×20μm2。
D、将由实施例1、比较例1、比较例2所得的牙骨材料进行弹性模量测定结果,具体测试过程如下:
将牙骨材料包埋入环氧树脂中,依次用600、1200、2000目砂纸抛光,然后依次用9、3、1、0.25、0.05微米的抛光液在自动抛光机(MetaDi,Buehler)中进一步抛光。利用原子力显微镜(MultiMode8,Bruker)的PeakForce QNM模式进行检测。每个扫描区域尺寸为20×20μm2,每个样品中随机选择6个尺寸为2×2的兴趣区域统计其弹性模量。
E、将由实施例1、比较例1、比较例2所得的牙骨材料进行细胞骨架染色图像,具体测试过程如下:
将牙骨材料浸泡入细胞培养基中,以2×104个/cm2的密度接种大鼠骨髓间充质干细胞(第三代),置于37℃,5%CO2环境培养1天后,用PBS漂洗3次,4%多聚甲醛固定15分钟,0.1%Triton-100通透15分钟,4%牛血清白蛋白(BSA)封闭30分钟,利用FITC标记的鬼笔环肽染色孵育30分钟,最后用Dapi染液孵育5分钟,使用抗荧光淬灭封片液进行封片,上述每个步骤间均采用PBS漂洗5分钟×3次。将制备完成的样本置于共聚焦显微镜(sp8,Leica)下进行观察。
F、将由实施例1、比较例1、比较例2所得的牙骨材料进行PCR检测结果,具体测试过程如下:
将牙骨材料浸泡入细胞培养基中,以1×105个/cm2的密度接种大鼠骨髓间充质干细胞(第三代),置于37℃,5%CO2环境培养1天后,更换成骨诱导培养基,分别进行成骨诱导培养7天,利用RNA提取试剂盒(CWBIO)提取RNA,利用逆转录试剂盒(TAKARA)对提取出的RNA进行逆转合成cDNA,采用实时荧光定量PCR技术SYBR Green法检测成骨分化特异性基因ALP,Col1a1,BSP的表达水平。
G、实施例1、比较例1、比较例2所得的牙骨材料植入大鼠颅骨缺损处修复8周后进行micro CT检测结果,具体测试过程如下:
将8周龄大鼠利用异氟烷吸入麻醉后,利用手持电磨机配备直径5mm的环切钻制备大鼠颅骨缺损模型,并将实施例1、比较例1、比较例2所得的牙骨材料植入大鼠颅骨缺损区域并缝合,8周后处死大鼠,取颅骨组织,浸泡入4%多聚甲醛固定24h,之后流水冲洗24小时,进行Micro CT(Bruker)扫描重建。
2、评价结果
如图1所示,该图中a、b代表未处理牙骨材料(比较例1),该图中c、d代表EDTA脱矿牙骨材料(比较例2),该图中e-g代表胶原外脱矿牙骨材料(实施例1)。
由图1可看出,EDTA处理的牙骨材料由疏松的胶原网构成,外脱矿处理的牙骨材料胶原纤维外的矿物质被选择性脱去,可以清晰看到仅包含纤维内矿物质的矿化胶原纤维(箭头所指)。
如图2所示,图中a代表未处理牙骨材料(比较例1),图b代表EDTA脱矿牙骨材料(比较例2),图中c代表胶原外脱矿牙骨材料(实施例1)。
由图2可以看出,EDTA脱矿牙骨材料表面由完全脱矿的胶原网构成,而胶原外脱矿牙骨材料表面胶原内矿物质保留,可见单根矿化胶原纤维(黄色箭头),胶原外矿物质被选择性去除。
如图3所示,该图中a、b、c分别为未处理牙骨材料(比较例1)、EDTA处理的脱矿牙骨材料(比较例2)和胶原外脱矿牙骨材料(实施例1)的形貌图。
由图3可以看出,外脱矿牙骨材料表面的小管塞去除,呈纤维外脱矿后独特的纳米级形貌,而EDTA脱矿处理后的牙本质基质表面由于胶原塌陷,成微米级起伏形貌。
如图4所示,该图中UDM、PDM、EDM分别为未处理牙骨材料(比较例1)、EDTA处理的脱矿牙骨材料(比较例2)和胶原外脱矿牙骨材料(实施例1)。
由图4的结果显示,外脱矿牙骨材料的机械强度与未处理牙骨材料相似,明显高于EDTA处理的脱矿牙骨材料。
如图5所示,该图中a、b、c分别为未处理牙骨材料(比较例1)、EDTA处理的脱矿牙骨材料(比较例2)和胶原外脱矿牙骨材料(实施例1)。
图5的结果显示,胶原外脱矿牙骨材料明显促进细胞粘附、增殖。
如图6所示,该图中UDM、PDM、EDM分别为未处理牙骨材料(比较例1)、EDTA处理的脱矿牙骨材料(比较例2)和胶原外脱矿牙骨材料(实施例1)。
图6结果显示,共培养7天后,胶原外脱矿牙骨材料诱导BMSC成骨向分化效果最佳。
如图7所示,该图中UDM、PDM、EDM分别为未处理牙骨材料(比较例1)、EDTA处理的脱矿牙骨材料(比较例2)和胶原外脱矿牙骨材料(实施例1)。
图7结果显示了不同牙骨材料植入大鼠颅骨缺损模型8周后,骨缺损修复效果Micro CT三维重建图。结果显示,胶原外脱矿牙骨材料的骨缺损修复效果最佳。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。
Claims (3)
1.一种胶原外脱矿的牙骨材料的应用,其特征在于,胶原外脱矿的牙骨材料采用分子量大于40kDa的金属离子螯合剂对牙本质材料进行脱矿处理所得到;
胶原外脱矿的牙骨材料为纳米级,且应用于诱导BMSC成骨向分化的材料上;
所述金属离子螯合剂选自聚丙烯酸盐、羧甲基纤维素盐、羧甲基壳聚糖、壳聚糖、聚天冬氨酸盐中的一种或至少二种以上;
所述金属离子螯合剂的pH为中性或碱性;
所述脱矿处理的过程包括:
使牙本质材料进行超声清洗,得到材料C;
使所述材料C在含有所述金属离子螯合剂的浸渍液进行浸渍处理,得到材料D;
将所述材料D进行冷冻干燥,得到所述牙骨材料;
所述浸渍处理的时间为0.1~48小时。
2.根据权利要求1所述牙骨材料的应用,其特征在于,所述冷冻干燥的温度为-80℃,冷冻时间为1~10小时。
3.根据权利要求1所述牙骨材料的应用,其特征在于,所述超声清洗在无菌磷酸盐缓冲液中实施。
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