CN1958082A - 一种用于骨修复的矿化多肽材料及其制备方法 - Google Patents
一种用于骨修复的矿化多肽材料及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种用于骨修复的矿化多肽材料，属于生物工程技术领域。其微结构为附着钙磷盐晶体的多肽纤维的三维网络，其中的纤维由包裹着纳米钙磷盐晶体的多肽组成。其中多肽的氨基酸序列具有重复的Gly－X－Y结构，其中Gly代表甘氨酸，X、Y分别为甘氨酸之外的任何一种氨基酸，其中纳米钙磷盐晶体可以为羟基磷灰石、二水合磷酸氢钙等。本发明的矿化多肽材料，成份和结构接近天然骨，其钙磷盐晶体为纳米尺寸，具有良好的生物活性、生物相容性和生物降解性，可促进骨再生，并随新骨的生成最终降解。本发明解决了以往骨材料存在病毒隐患和免疫反应，在治疗骨缺损和骨折等骨修复中可达到自体骨的效果，具有优异的骨诱导性能。
Description
技术领域
本发明涉及一种用于骨修复的矿化多肽材料及其制备方法，属于生物工程技术领域。
背景技术
目前临床骨修复所用到的自体骨和异体骨存在来源短缺、免疫排斥和感染疾病的危险。生物骨组织的主要成分是胶原和羟基磷灰石。纯的羟基磷灰石具有优异的生物相容性、骨传导性和生物活性，已被广泛用于整形外科手术和齿科手术。但是纯的羟基磷灰石脆性大，韧性差，并且易从植入部位脱落，在临床上限制了它的使用。在已有技术中，本申请人曾经提出了名称为“纳米相钙磷盐/胶原/聚乳酸骨复合多孔材料的制备方法”、申请号为00107493.8、公开号为CN 1272383A的专利申请，该多孔材料对骨缺陷和骨折有良好的医疗效果。但由于目前所用胶原主要来源于动物，存在病毒隐患和免疫反应的风险。
与动物源胶原相比，多肽不仅具有胶原的固有特性，如：生物相容性、生物降解性、生物粘附性、促新细胞形成和促上皮细胞形成，而且具有无病毒隐患、可加工性和低排异反应等特点，可被广泛应用于医学、美容、保健品和化妆品等多个行业。所以采用基因工程方法生产的多肽制备骨修复材料可以解决以往骨修复材料的病毒隐患和免疫排斥反应问题。
发明内容
本发明的目的是提出一种用于骨修复的矿化多肽材料及其制备方法，用人工合成的多肽材料替代已有技术中的胶原，以避免病毒隐患和免疫反应。
本发明提出的用于骨修复的矿化多肽材料，其微结构为附着钙磷盐晶体的多肽纤维的三维网络，其中的纤维由包裹着纳米钙磷盐晶体的多肽组成。
上述矿化多肽材料中的多肽的氨基酸序列具有重复的Gly-X-Y结构，其中Gly代表甘氨酸，X、Y分别为甘氨酸之外的任何一种氨基酸。
上述矿化多肽材料中的纳米钙磷盐晶体可以为羟基磷灰石、二水合磷酸氢钙、磷酸氢钙或磷酸八钙中的任何一种。
本发明提出的制备上述用于骨修复的矿化多肽材料的方法，包括以下步骤：
(1)在浓度为1.5×10-4-1.5×10-2g/ml的多肽的酸溶液或水溶液中边搅拌边滴加含有钙离子的溶液，滴加量为每克多肽滴加钙离子0.003～0.053mol，其中酸为盐酸、乙酸、硝酸中的一种；
(2)在步骤(1)的溶液中边搅拌边缓慢滴加含有磷酸根离子的水溶液，加入的磷酸根离子与钙离子的摩尔比为Ca∶P＝1-2∶1；
(3)在步骤(2)的溶液中边搅拌边滴加碱液，调节pH值为7.4-10；
(4)将步骤(3)的溶液搅拌后静置，待沉淀与上清分层后，除去上清，离心分离出沉淀，用去离子水洗涤去除其中的可溶性盐分，使洗涤液呈中性；
(5)将沉淀物放入冻干机内冷冻干燥，随后将干燥物研磨，即得所述的矿化多肽材料。
本发明提出的用于骨修复的矿化多肽材料，含有多肽和纳米钙磷盐，其中的多肽可以替代以往广泛用于骨修复材料的胶原，由于多肽由人工合成，因此可以大大减小病毒隐患和免疫排斥反应。本发明的矿化多肽材料，成份和结构接近天然骨，其钙磷盐晶体为纳米尺寸，具有良好的生物活性、生物相容性和生物降解性，可促进骨再生，并随新骨的生成最终降解。而且本发明解决了以往骨材料存在病毒隐患和免疫反应的问题，在治疗骨缺损和骨折等骨修复中可达到自体骨的效果，是一种具有优异的骨诱导性能和广泛应用前景的新型骨材料。
附图说明
图1为本发明方法制备的矿化多肽材料的扫描电镜(SEM)照片。
图2为图1所示的矿化多肽材料的透射电镜(TEM)和选区电子衍射(SAED)图。
具体实施方式
本发明提出的用于骨修复的矿化多肽材料，其微结构为附着钙磷盐晶体的多肽纤维的三维网络，其中的纤维由包裹着纳米钙磷盐晶体的多肽组成。其中的多肽的氨基酸序列具有重复的Gly-X-Y结构，其中Gly代表甘氨酸，X、Y分别为甘氨酸之外的任何一种氨基酸。其中的纳米钙磷盐晶体可以为羟基磷灰石(HA)、二水合磷酸氢钙(DCPD)、磷酸氢钙(DCP)、磷酸八钙(OCP)和其他存在于天然骨中的矿物。
本发明提出的制备上述用于骨修复的矿化多肽材料的方法，包括以下步骤：
(1)在浓度为1.5×10-4-1.5×10-2g/ml的多肽的酸溶液或水溶液中边搅拌边滴加含有钙离子的溶液，滴加量为每克多肽滴加钙离子0.003～0.053mol，其中酸为盐酸、乙酸、硝酸中的一种；
(2)在步骤(1)的溶液中边搅拌边缓慢滴加含有磷酸根离子的水溶液，加入的磷酸根离子与钙离子的摩尔比为Ca∶P＝1-2∶1；
(3)在步骤(2)的溶液中边搅拌边滴加碱液，调节pH值为7.4-10；
(4)将步骤(3)的溶液搅拌后静置，待沉淀与上清分层后，除去上清，离心分离出沉淀，用去离子水洗涤去除其中的可溶性盐分，使洗涤液呈中性；
(5)将沉淀物放入冻干机内冷冻干燥，随后将干燥物研磨，即得所述的矿化多肽材料。
在上述制备方法中，步骤(1)所述的含钙离子的溶液为氢氧化钙和钙盐中的任何一种，钙盐优选为硝酸钙、氯化钙；
在上述制备方法中，步骤(2)所述的含磷酸根离子的溶液为磷酸和磷酸盐的任何一种，磷酸盐优选为磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、磷酸氢二氨、磷酸二氢氨。
本发明中用到的多肽首选合成多肽，如利用重组DNA技术，通过适合的表达宿主如细菌(例如大肠杆菌)获得的多肽。
本发明的实施例中所用的多肽为发酵的大肠杆菌中获得的多肽，这种水溶性的多肽是西安巨子生物技术股份有限公司生产的，其氨基酸序列为：
HDP VVL QRR DWE NPG VTQ LNR HLA HAH PPF ASD HPM GAP
GPA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA
GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP
GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP
GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP
GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA
GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GAH GPA GAL GAH
GPA GPL GPA GPP GSA GAP GAH GPA GPL GAH GPA GPL GAH
GPA GPL GAH GPA GPL GAP GPA GPP GSA GAP GPP GAP GPA
GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA
GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP
GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP
GAH GPA GPL GAH GPA GPL GAH GPA GPL GAH GPA GPL GAP
GPA GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA
GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP
GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP
GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP
GPA GPP GSA GAP GPP GAH GPA GPL GAH GPA GPL GAH GPA
GPL GAH GPA GPL GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA
GAP GPP GAP GPA GPP GSA GAP GPP GSA GAP GPP GAP GPA
GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA
GAP GPP GAH GPA GPL GAH GPA GPL GAH GPA GPL GAM GAP
GAT GLS AGA THG LVT CGL
以下介绍本发明的实施例：
实施例1：
1)将60g固含量1％的液态多肽溶于300ml去离子水中，滴加40ml浓度为0.5mol/L的CaCl2溶液后，继续缓慢加入浓度为0.5mol/L的H3PO4溶液24ml，滴加的同时用磁力搅拌器混合均匀。
2)在上述第一步的溶液中边搅拌边缓慢滴加NaOH溶液，直至pH值稳定为7.4。
3)将上述体系搅拌、静置，除去上清，离心分离出沉淀，用去离子水反复洗涤去掉其中的盐分并达到中性后，放入冻干机内冷冻干燥，随后将干燥物研磨制得干粉。
实施例2
1)将70g固含量1％的液态多肽溶于4500ml去离子水中，加入10ml浓度为0.2mol/L的Ca(NO3)2溶液后，继续缓慢滴加浓度为0.2mol/L的Na2HPO4溶液10ml，滴加的同时用磁力搅拌器混合均匀。
2)在上述第一步的溶液中边搅拌边缓慢滴加NaOH溶液，直至pH值稳定为10.0。
3)将上述体系搅拌、静置，除去上清，离心分离出沉淀，用去离子水反复洗涤去掉其中的盐分并达到中性后，放入冻干机内冷冻干燥，随后将干燥物研磨制得干粉。
实施例3
1)将1.5g固态多肽溶于100ml去离子水中，加入浓度为2mol/L的Ca(NO)3溶液40ml，继续缓慢滴加40ml浓度为1mol/L的KH2PO4溶液后，滴加的同时用磁力搅拌器混合均匀。
2)在上述第一步的溶液中边搅拌边缓慢滴加KOH溶液，直至pH值为8.0。
3)将上述体系搅拌、静置，除去上清，离心分离出沉淀，用去离子水反复洗涤去掉其中的盐分并达到中性后，放入冻干机内冷冻干燥，随后将干燥物研磨制得干粉。
图1为由本发明方法的实施例1制备的矿化多肽材料的扫描电镜(SEM)照片。图中的标尺为1微米(1μm，图中显示为“um”)。这些纤维大约为30nm宽、500nm长，由覆盖着纳米羟基磷灰石的多肽构成。
图2显示了图1所示的矿化多肽骨材料的透射电镜(TEM)和选区电子衍射(SAED)图。从图中可以看出，矿化的多肽纤维由直径约6nm长度不等的纳米棒组成，这些纳米棒排列起来形成图1所示的纤维。
在选区电子衍射花样中，环形衍射对应羟基磷灰石的211晶面。两对弧形衍射分别对应羟基磷灰石的002和004晶面，意味着羟基磷灰石的c轴为择优取向。矿化多肽的这个特点与天然骨类似。在骨中，羟基磷灰石的c轴大致平行于胶原纤维长轴。
这些图片证明该材料中的多肽是矿物形核和生长的模板，本发明确实对天然骨的微结构进行了仿生。
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530 535 540
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820 825 830
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835 840 845
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Claims (4)
1、一种用于骨修复的矿化多肽材料，其特征在于该多肽材料的微结构为附着钙磷盐晶体的多肽纤维的三维网络，其中的纤维由包裹着纳米钙磷盐晶体的多肽组成。
2、如权利要求1所述的矿化多肽材料，其特征在于其中所述的多肽的氨基酸序列具有重复的Gly-X-Y结构，其中Gly代表甘氨酸，X、Y分别为甘氨酸之外的任何一种氨基酸。
3、如权利要求1所述的矿化多肽材料，其特征在于其中所述的纳米钙磷盐晶体为羟基磷灰石、二水合磷酸氢钙或磷酸八钙中的任何一种。
4、一种制备如权利要求1所述的用于骨修复的矿化多肽材料的方法，其特征在于该方法包括以下步骤：
(1)在浓度为1.5×10-4-1.5×10-2g/ml的多肽的酸溶液或水溶液中边搅拌边滴加含有钙离子的溶液，滴加量为每克多肽滴加钙离子0.003～0.053mol，其中酸为盐酸、乙酸、硝酸中的一种；
(2)在步骤(1)的溶液中边搅拌边缓慢滴加含有磷酸根离子的水溶液，加入的磷酸根离子与钙离子的摩尔比为Ca∶P＝1-2∶1；
(3)在步骤(2)的溶液中边搅拌边滴加碱液，调节pH值为7.4-10；
(4)将步骤(3)的溶液搅拌后静置，待沉淀与上清分层后，除去上清，离心分离出沉淀，用去离子水洗涤去除其中的可溶性盐分，使洗涤液呈中性；
(5)将沉淀物放入冻干机内冷冻干燥，随后将干燥物研磨，即得所述的矿化多肽材料。
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| GB0717716A GB2441876A (en) | 2006-09-14 | 2007-09-11 | A mineralized poly-peptide material used in bone remodeling and corresponding preparation method |
| DE102007043859A DE102007043859A1 (de) | 2006-09-14 | 2007-09-14 | Mineralisierte Polypeptidsubstanz für den Knochenaufbau und deren Herstellung |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102154786A (zh) * | 2011-04-25 | 2011-08-17 | 东南大学 | 矿化玉米蛋白纤维膜及其制备方法 |
| CN102505462A (zh) * | 2011-10-31 | 2012-06-20 | 中国科学院苏州纳米技术与纳米仿生研究所 | 一维纳米复合材料的制备方法 |
| CN102504530A (zh) * | 2011-11-23 | 2012-06-20 | 广东省微生物研究所 | 一种新型γ-聚谷氨酸/羟基磷灰石复合材料及其制备方法 |
| CN101698117B (zh) * | 2009-10-27 | 2012-11-07 | 张为鹏 | 骨修复复合材料及其制备方法 |
| CN101417149B (zh) * | 2008-10-22 | 2012-11-21 | 四川大学 | 含钙的磷酸盐成分的可降解生物活性复合材料及制备方法 |
| CN114209880A (zh) * | 2021-11-25 | 2022-03-22 | 浙江大学 | 一种有序矿化多肽的生物复合材料的制备方法及其产品和应用 |
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| EP1859818B1 (en) * | 2005-03-15 | 2013-05-29 | National University Corporation Nara Institute of Science and Technology | Composite for biocompatible material and process for production thereof |
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| DE19812713A1 (de) * | 1998-03-24 | 1999-09-30 | Merck Patent Gmbh | Verfahren zur Herstellung von mineralisierten Kollagenfibrillen und deren Verwendung als Knochenersatzwerkstoff |
| US6300315B1 (en) * | 1999-08-28 | 2001-10-09 | Ceramedical, Inc. | Mineralized collagen membrane and method of making same |
| CN1106861C (zh) | 2000-05-19 | 2003-04-30 | 清华大学 | 纳米相钙磷盐/胶原/聚乳酸骨复合多孔材料的制备方法 |
| US6911425B2 (en) * | 2000-08-16 | 2005-06-28 | Acologix, Inc. | Integrin binding motif containing peptides and methods of treating skeletal diseases |
| CN1196712C (zh) | 2001-02-21 | 2005-04-13 | 范代娣 | 一种类人胶原蛋白及其生产方法 |
| WO2003054146A2 (en) * | 2001-11-14 | 2003-07-03 | Northwestern University | Self-assembly and mineralization of peptide-amphiphile nanofibers |
| AU2003228587A1 (en) * | 2002-04-18 | 2003-11-03 | University Of Florida | Biomimetic organic/inorganic composites, processes for their production, and methods of use |
| EP2295089B1 (en) * | 2002-07-31 | 2018-05-09 | DENTSPLY SIRONA Inc. | Bone repair putty comprising porous particulate and carrier gel |
| CN1446590A (zh) * | 2003-01-21 | 2003-10-08 | 华东理工大学 | 新型聚肽/磷酸钙复合骨水泥 |
| WO2006062776A2 (en) * | 2004-11-29 | 2006-06-15 | The Regents Of The University Of California | Hydroxyapatite-binding peptides for bone growth and inhibition |
| EP1859818B1 (en) * | 2005-03-15 | 2013-05-29 | National University Corporation Nara Institute of Science and Technology | Composite for biocompatible material and process for production thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101417149B (zh) * | 2008-10-22 | 2012-11-21 | 四川大学 | 含钙的磷酸盐成分的可降解生物活性复合材料及制备方法 |
| CN101698117B (zh) * | 2009-10-27 | 2012-11-07 | 张为鹏 | 骨修复复合材料及其制备方法 |
| CN102154786A (zh) * | 2011-04-25 | 2011-08-17 | 东南大学 | 矿化玉米蛋白纤维膜及其制备方法 |
| CN102505462A (zh) * | 2011-10-31 | 2012-06-20 | 中国科学院苏州纳米技术与纳米仿生研究所 | 一维纳米复合材料的制备方法 |
| CN102505462B (zh) * | 2011-10-31 | 2013-10-30 | 中国科学院苏州纳米技术与纳米仿生研究所 | 一维纳米复合材料的制备方法 |
| CN102504530A (zh) * | 2011-11-23 | 2012-06-20 | 广东省微生物研究所 | 一种新型γ-聚谷氨酸/羟基磷灰石复合材料及其制备方法 |
| CN114209880A (zh) * | 2021-11-25 | 2022-03-22 | 浙江大学 | 一种有序矿化多肽的生物复合材料的制备方法及其产品和应用 |
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| Publication number | Publication date |
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| CN100366302C (zh) | 2008-02-06 |
| GB0717716D0 (en) | 2007-10-17 |
| GB2441876A (en) | 2008-03-19 |
| DE102007043859A1 (de) | 2008-07-10 |
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