CN104013993A - 一种具有诱导基因表达的骨生物修复制剂的制备方法 - Google Patents
一种具有诱导基因表达的骨生物修复制剂的制备方法 Download PDFInfo
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Abstract
本发明涉及一种具有诱导基因表达的骨生物修复制剂的制备方法。制得的生物材料可用于制造生物骨修复牙膏、组织工程再生、创伤修复医用材料等。特别是在:组织工程骨、周围神经、血管、肌腱、体外人工肝人工肾装置、组织工程口腔粘膜,骨修复材料,预防龋齿、牙齿松动、牙龈出血、牙齿修复,创伤修复等方面的有着重大的科学价值和意义,为人类组织再生工程作出重大贡献。
Description
技术领域
本发明涉及一种具有诱导基因表达的生物修复制剂的制备方法,特别涉及一种长期持续使用可解决骨修复等问题的生物活性制剂。本发明的产品可用于制造生物骨修复牙膏、组织工程再生、创伤修复医用材料等。可广泛的应用在:组织工程骨、周围神经、血管、肌腱、体外人工肝人工肾装置、组织工程口腔粘膜,骨修复材料,预防龋齿、牙齿松动、牙龈出血、牙齿修复,创伤修复等方面的广泛应用。
背景技术
一、牙膏市场:
当今中国牙膏市场中,每年我国共生产牙膏约80亿标准支(65克包装),实现总产值140亿元。我国牙膏的市场容量应在220亿元至240亿元之间,还有近1/3的功能性牙膏市场没开发。
牙膏的类型不外乎这四大类:脱敏牙膏,争对牙齿敏感的人群;第二类:防龋齿,儿童面临酸性饮食环境,对蛀牙的伤害。第三类:药物类牙膏,针对牙周炎等不同的病状;简单止血功能,无法修复受损牙齿部分。第四类:是美白、清新口气,只起到清洁作用。
中国人口老龄化严重,牙齿松动、牙龈出血等口腔疾病比较普遍;儿童防蛀,主要加入含氟牙膏,在地中海性质区域,造成大量氟斑牙。
二、组织工程应用:
目前组织工程应用主要出现:合成材料,高分子人工合成材料PLA PGAPLGA,钙磷类人工合成陶瓷材料TCP HAP CPC BGC,复合材料PLA+HAP/TCP/CPC等生物材料的研究。
创伤市场目前主要靠以猪皮为原料,制造人工植皮技术,有生物免疫原性的副作用。
骨修复材料,主要来源有同种异体骨,人工骨等材料。远远无法满足医学发展的需要。
发明内容
针对上述问题,本发明提供一种本发明涉及一种具有诱导基因表达的生物修复制剂的制备方法。该产品可用于制造生物骨修复牙膏、组织工程再生、创伤修复医用材料等。可广泛的应用在:组织工程骨、周围神经、血管、肌腱、体外人工肝人工肾装置、组织工程口腔粘膜,骨修复材料,预防龋齿、牙齿松动、牙龈出血、牙齿修复,创伤修复等方面的广泛应用。
本发明的制剂的制备方法包括如下步骤:
(1)制备氧化钙:取石灰石在铂金罐中密封,在1900℃的条件下高温煅烧,冷却后经粉碎成为10-20nm的CaO粉末;
(2)生成具有生物活性的羟基磷灰石:取规格为10-20nm的CaO和P2O5纳米粉末,按照质量比1∶1.67混合均匀(500g),在36-38℃的情况下,无光条件下陈化至少12小时;加入医用纯净水500g搅拌成糊状,随后加入Na2O2(3g)38℃下搅拌45分钟,过10-20目筛,得到粒径为10-20nm的羟基磷灰石Ca10(PO4)6(OH)2(HA);
(3)向步骤(2)所得羟基磷灰石中加入SiO2(5g)混合均匀后,在-15~-20℃下冻干机冷冻干燥成粉末,并加入医用甘油10g、医用聚乙二醇10g、医用级钛白粉3g、香精1g、卡波姆2-3g、AK糖3g和十二烷基硫酸钠2g,均匀混合;
(4)灭菌:将步骤(3)混合所得膏状体在10℃条件下,辐照灭菌2小时;
(5)干燥:将步骤(4)所得生物制剂,在-15℃条件下冻干成固体状;
(6)粉碎:将该固体粉碎成为20nm的粉末状。
(7)包装:将灭菌膏体灌装在无菌低密度聚乙烯管内,每管质量为60g。
其中,SiO2与Ca10(PO4)6(OH)2形成具有三维网状生物多孔结构的无机矿物质。SiO2与Ca10(PO4)6(OH)2与唾液中的H2O发生迅速的反应,PH值在7.5左右,合成具有诱导基因表达能力的羟基磷灰石。释放Ca离子和P离子,从而补充损伤骨结构矿物质,产生沉积在受损骨创面之上和之内的稳定的结晶状羟基磷酸盐灰石层(矿化),促使骨组织生长,抑制和杀灭细菌,诱导新的新生组织形成,同时杀菌等作用也能有效缓解创伤发炎肿胀等症状。
诱导基因表达能力:
普通的羟基磷灰石仅仅可以修复,不具有诱导基因表达能力,细胞组织不能有序排列。而本发明的材料形成无水无机矿物,该矿物质具有三维的网状多孔结构,其深入损伤部分深处的细胞和毛细血管沿着与人体骨骼和组织相一致的孔装结构中,有序生长,再生细胞爬行在三维网状结构中。让新生组织有序的排列,具有基因的表达的能力。
生物降解,爬行替代:
本发明的材料在组织再生后,原三维多孔结构无机矿物质。新生组织在30日内,逐步爬行替代原结晶矿物质,原结晶矿物质降解为二氧化碳和水,随毛细血管排出。其新生组织恢复为原有形状。
本发明的材料可用于制造生物骨修复牙膏、组织工程再生、创伤修复医用材料等。特别是在:组织工程骨、周围神经、血管、肌腱、体外人工肝人工肾装置、组织工程口腔粘膜,骨修复材料,预防龋齿、牙齿松动、牙龈出血、牙齿修复,创伤修复等方面的有着重大的科学价值和意义,为人类组织再生工程作出重大贡献。
附图说明
图1是X射线下的新生羟基磷灰石成像图。
图2是牙齿骨修复后的效果图。
图3是骨修复效果图。其形成的三维多孔网状结构,和人体结构基本一致。
图4是骨关节软组织的修复效果图。
图5是对软组织的修复作用。其中,诱导组为使用本发明的产品的结果图。
具体实施方式
以下实施方式仅用于阐述本发明,而本发明的保护范围并非仅仅局限于以下实施例。所述技术领域的普通技术人员依据本发明的公开内容,均可实现本发明的目的。
本发明的制剂的制备方法包括如下步骤:
(1)制备氧化钙:取石灰石在铂金罐中密封,在1900℃的条件下高温煅烧,冷却后经粉碎成为10-20nm的CaO粉末;
(2)生成具有生物活性的羟基磷灰石:取规格为10-20nm的CaO和P2O5纳米粉末,按照质量比1∶1.67混合均匀为500g的粉末,在36-38℃的情况下,无光条件下陈化至少12小时;加入医用纯净水500g搅拌成糊状,随后加入Na2O2(3g)38℃下搅拌45分钟,过10-20目筛,得到粒径为10-20nm的羟基磷灰石Ca10(PO4)6(OH)2(HA);
(3)向步骤(2)所得羟基磷灰石中加入SiO2(5g)混合均匀后,在-15~-20℃下冻干机冷冻干燥成粉末,并加入医用甘油10g、医用聚乙二醇10g、医用级钛白粉3g、香精1g、卡波姆2-3g、AK糖3g和十二烷基硫酸钠2g,均匀混合;
(4)灭菌:将步骤(3)混合所得膏状体在10℃条件下,辐照灭菌2小时;
(5)干燥:将步骤(4)所得生物制剂,在-15℃条件下冻干成固体状;
(6)粉碎:将该固体粉碎成为20nm的粉末状。
(7)包装:将灭菌膏体灌装在无菌低密度聚乙烯管内,每管质量为60g。
技术效果
临床试验研究报告:含本发明的骨修复生物制剂的牙膏与标准含氟牙膏对减轻牙龈炎症及菌斑效果的临床研究报告
研究人群和方法
本研究为随机、双盲、对照、平行的临床研究。试验牙膏为本发明实施方式的骨修复制剂制成的牙膏,阴性对照标准含氟牙膏。所有牙膏统一包装。所有受试用者使用同一厂家生产的同一型号牙刷。
受试者参加口腔软组织及硬组织检查,龈炎及菌斑检查,按照纳入和排除标准决定实验对象是否入选。
纳入标准:
(1)全身健康状况良好;
(2)年龄在18~70周岁;
(3)如果为女性,不得处于妊娠期和哺乳期内;
(4)改良Quigley-Hein菌斑指数≥1.5;
(5)Loe-Silness龈炎指数≥1.0;
(6)没有同时参加其他类似试验研究。
排除标准:
(1)至少20颗牙无活性龋、冠和V类型修复体;
(2)口腔有明显未治疗龋(肉眼观);
(3)无进展性牙周炎,如超过4mm的牙周袋不超过2个位置;
(4)怀孕或哺乳期;
(5)有全身疾病如中风、结核病、糖尿病、癫痫、传染性疾病(如肝炎)、滥用药物、对牙膏及其他口腔卫生产品过敏;
(6)长期食用抗生素治疗;
(7)戴正畸带环,部分或全口活动义齿,桥修复体超过4颗天然牙;
(8)有严重的牙龈炎和牙周病;
(9)有严重的牙科病变:龋。牙周病、癌前病变、口腔炎性状态;
(10)正在参加其他研究;
(11)对牙膏的成分发生过敏。
共100位研究对象参加了本发明产品的临床研究,将其随机分为试验组与对照组。给受试者统一发放各自相应的牙膏和软质牙刷,要求受试者按规定1日刷牙2次(早、晚),每次时间1min。要求试验过程中不使用任何其他口腔卫生用品,如其他种类的牙膏、牙刷、漱口液、牙线等。对饮食和抽烟不作限制。6周时补充试验的牙膏和牙刷。在使用药膏牙刷6周和12周时,对受试者牙菌斑和牙龈炎状况按照基线检查的程序进行再评估。
在基线、6周和12周评价前8小时不进行口腔清洁。采用改良的Q-H菌斑指数和牙龈指数(Silness&Plaque Index)评价牙周状况。
龈炎指数及检查方法:牙龈炎采用改良Loe-Silness龈炎指数测量,在测量菌斑指数之前测量牙龈情况。牙龈炎计数方法及标准如下:
0=无龈炎
1=轻度龈炎,牙龈色泽和质地略有变化,但探诊无出血
2=中度炎症,牙龈光亮。红、肿,增生、探诊出血
3=重度炎症,牙龈明显发红、增生、有自发性出血
检查每个牙颊面及舌面,除第三磨牙、假牙和有颈部修复体的牙,其余的牙均包括在计数之列。Loe-Silness龈炎指数的均数是指所有牙计数值的总和除以总的测量面数所得数值。
菌斑指数及检查方法:采用Quigley-Hein改良Turesky菌斑指数评价龈上菌斑。牙菌斑染色,首先滴5滴染色剂,用舌头将染色剂布满整个牙面(30秒),含一小口水,在嘱咐受试者含漱30秒,使染色剂充分与牙面接触,清水漱口。使用菌斑染色剂染色后根据下列标准记录:
0=无菌斑
1=牙颈部边缘存在散在的菌斑
2=牙颈边缘可见连续的薄菌斑带(达1mm宽)
3=牙颈部菌斑带大于1mm但少于牙面的1/3
4=菌斑覆盖牙面的1/3-2/3
5=菌斑覆盖牙面2/3以上,
检查每个牙齿的颊面和舌面。出第三磨牙、假牙和有颈部修复体的牙,其余的牙均在记数之列。每一受试者菌斑指数的均数由个人全部牙齿检查所得计数之和除以总的测量数得到。
统计方法:数据采用SPSS16.0统计软件的ANOVA及t检验进行统计分析,采用双侧检验,检验水准a为0.05.
结果:
100位受试者参加本研究,6周检查时随访98例,12周随访96例,失访率为4.0%。试验对象及检查者均没有牙膏副作用的报告,失访的主要原因是外出、生病,使用抗生素等,失访受试者退出本研究的原因与使用研究牙膏无关。试验结果如下:
表1完成研究人群的基线检查结果
*均数±标准差
临床检查结果见表2.
6周检查结果:使用本发明的试验牙膏与对照组比较,6周减少龈上菌斑(PI)和龈炎指数(GI)组间均显示统计学意义的差异(p<0.05)。
12周检查结果:使用本发明的试验牙膏与对照组比较,12周减少龈上菌斑(PI)和龈炎指数(GI)组间均显示统计学意义的差异(p<0.05)。
临床未见副作用报告。
表2菌斑指数(标准差)记分
表3牙龈出血指数(标准差)记分
结论
以上临床研究表明,使用含本发明的骨修复制剂的牙膏与使用对照牙膏相比,具有抑制牙菌斑的形成,减轻牙龈炎,改善牙龈健康的作用。在临床试验期间未观察到牙膏的副作用。
Claims (1)
1.一种具有诱导基因表达的骨生物修复制剂的制备方法,其特征在于所述方法包括如下步骤:
(1)制备氧化钙:取石灰石在铂金罐中密封,在1900℃的条件下高温煅烧,冷却后经粉碎成为10-20nm的CaO粉末;
(2)生成羟基磷灰石:取规格为10-20nm的CaO和P2O5纳米粉末,质量比1∶1.67混合均匀(500g),在36-38℃的情况下,无光条件下陈化至少12小时;加入医用纯净水500g搅拌成糊状,随后加入Na2O2(3g)38℃下搅拌45分钟,过10-20目筛,得到粒径为10-20nm的羟基磷灰石;
(3)向步骤(2)所得羟基磷灰石中加入SiO2(5g)混合均匀后,在-15~-20℃下冷冻干燥成粉末,并加入医用甘油10g、医用聚乙二醇10g、医用级钛白粉3g、香精1g、卡波姆2-3g、AK糖3g和十二烷基硫酸钠2g,均匀混合;
(4)灭菌:将步骤(3)混合所得膏状体在10℃条件下,辐照灭菌2小时;
(5)干燥:将步骤(4)所得的生物制剂,在-15℃条件下冻干成固体状;
(6)粉碎:将该固体粉碎成为20nm的粉末状;
(7)包装:将灭菌膏体灌装在无菌低密度聚乙烯管内,每管质量为60g。
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