CN102380126B - 一种新型的纳米银骨水泥 - Google Patents
一种新型的纳米银骨水泥 Download PDFInfo
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- CN102380126B CN102380126B CN201110333770.4A CN201110333770A CN102380126B CN 102380126 B CN102380126 B CN 102380126B CN 201110333770 A CN201110333770 A CN 201110333770A CN 102380126 B CN102380126 B CN 102380126B
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- Prior art keywords
- bone cement
- strontium
- silver
- nanometer silver
- bone
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Abstract
本发明公开了一种新型的纳米银骨水泥，主要成分为含锶磷酸钙晶须、聚甲基丙烯酸甲酯以及纳米银。含锶磷酸钙晶须直径在0.3-2μm之间，占骨水泥的含量为5％-20％；锶与钙的摩尔之比为1∶30-1∶5，锶和钙摩尔数之和与磷的摩尔数之比为1.5-2.0。本发明所述的新型骨水泥含有纳米银，含量为0.1％-2％，其直径在5-50nm之间。本发明描述了新型纳米银骨水泥的制作方法，详细公开了含锶磷酸钙晶须的制备方法。本发明还公开了上述纳米银骨水泥的应用。
Description
技术领域
本发明涉及一种新型骨水泥。具体而言，本发明通过对聚甲基丙烯酸甲酯骨水泥与磷酸钙骨水泥进行改造，结合锶盐的生物活性与纳米银技术，制备了具有良好应用前景的新型骨水泥。
背景技术
研究证明，锶盐具有抗骨吸收和增加骨形成的作用。在小鼠颅盖骨培养系统中，对钙释放进行测定，发现锶盐可使骨吸收减低大约30％。对长骨细胞培养系统中培养的小鼠牙本质细胞，通过相同的测量方法，发现锶盐可以抑制破骨细胞的活性。在大鼠颅骨和颅盖骨培养系统中，锶盐起初表现了可以增进成骨前细胞的增殖，从而增进了功能细胞的活性与骨基质的合成，这种作用是钙试剂所不具备的。锶可以活化某些类型细胞的钙感受器，导致三磷酸肌醇的产生和丝裂原信号的激活。一些锶敏感受体有可能对骨细胞产生作用。锶通过激活成骨细胞的胞外激酶调节信号可以诱导环氧化酶2和前列腺素E2的产生，锶盐这些作用有可能对骨形成产生作用。在成年大鼠，锶盐可以增加腰椎骨与股骨的骨量，通过对松质骨容量的测定得以证实。对于正常成年小鼠，锶盐口服给药可以增加椎体骨的形成，减少骨的吸收，最终使骨量增加。这些作用导致骨强度增加，可以使腰椎轴与附件骨的机械性能增加。实验动物的血清碱性磷酸酶活性增高，这正与锶盐使骨形成作用增强一致。锶盐治疗四周性骨质疏松治疗试验中，5091名年龄在74岁左右绝经后确诊为骨质疏松的妇女，通过3年的治疗比较，锶盐治疗组中病人的非椎体骨折率比安慰剂组病人下降了16％，这种化合物也使大部分的脆性骨折相对危险性减少了19％。锶也应用在骨科学中，含锶的磷酸钙骨水泥(Sr-CPC)是典型的例子。
20世纪80年代以来，磷酸钙骨水泥(Calcium Phosphate Cement，CPC)因其具有良好的生物相容性和骨传导性，并能在体内降解等优点而倍受关注[Brown WE，Chow LC.A new calcium phosphate water-setting cement.AmericanCeramic Society，OH：Westerville，1987：352]。已有研究表明，Sr-CPC的理化性能与其掺锶量有重要关系[Guo DG，Xu KW，Han Yong，et al.Development of astrontium-containing hydroxyapatite bone cement.Biomaterials，2005，26(19)：4073-4083.赵晓云，郭大刚，憨勇，等.含锶磷酸钙骨水泥的制备及性能研究.无机材料学报，2005，20(5)：1167-1173.]。在掺锶磷灰石(Sr-HA)陶瓷的研究工作中，也发现其力学性能、降解性能与其掺锶量密切相关[Christoffersen J，Christoffersen MR，Kolthoff N.Effects of strontium ions on growth and dissolutionof hydroxtapatite and on bone mineral detection.Bone，1997，20(1)：47-52.陈德敏，傅远飞，顾国珍等.掺锶羟磷灰石固溶体的制备及离解度测定.中国生物医学工程学报，2001，20(3)：278-280.]。
实验研究表明，Sr-CPC无明显体外细胞毒性与急性全身毒性。Sr-CPC热原性、溶血性、体外细胞毒性以及ALP值均与掺锶量有紧密联系。其中，Sr-CPC的热原性、溶血性以及ALP值与掺锶量呈非线性关系：掺锶组的热原性、溶血性以及ALP值均优于未掺锶组。综合分析幼兔成骨细胞在掺锶磷酸钙骨水泥表面的黏附、增殖与表达实验结果可知：成骨细胞在不同骨水泥材料表面均有黏附、增殖及表达，但程度有所不同。Sr-CPC表面成骨细胞黏附较少，增殖不活跃。电镜照片显示Sr-CPC材料表面较多的细胞、小颗粒，提示细胞黏附数量多，材料溶解、破坏重，提示加入适量(5％-10％)Sr可以改善CPC的溶解动力学，提高其生物降解性。掺锶量不仅是调控Sr-CPC理化性能的关键因素，而且也是影响其体外细胞生物学性能的重要因素。
常用骨水泥是聚甲基丙烯酸甲酯(Polymethylmethacrylate，PMMA)，PMMA聚合效果好，并且强度较高；此外，PMMA具细胞毒性，对活体肿瘤细胞具有一定的杀伤作用。但是PMMA也存在很多的缺点[Belkoff SM，Molloy S.Temperature measurement during polymerization of polymethylmethacrylate cementused for vertebroplasty.Spine，2003；28：1555-1559]：单体具有一定的生物毒性；PMMA骨水泥发生聚合时为产热反应，从而引起相应的神经功能损伤[Cortet B，Cotton A，Boutry N，et al.Percutaneous vertebroplasty in patients with osteolyticmetastases or multiple myeloma.Rev Rhum Engl Ed，1997，64(3)：177-83.]；PMMA生物组织相容性差，注入体内后不能吸收降解；同时其无成骨作用，不能诱导新骨生成[Bartucci EJ，Gonzalez MH，Cooperman DR，et al.The effect of adjunctivemethylmethacrylate on failures of fixation and function in patients withintertrochanteric fractures and osteoporosis.J Bone Joint Surg(Am)，1985，67(7)：1094-107.McAfee PC，Bohlman HH，Ducker T，et al.Failure of stabilization of thespine with methylmethacrylate：a retrospective analysis of twenty-four cases.J BoneJoint Surg(Am)，1986，68(8)：1145-1157.]。这些缺点导致了PMMA在临床应用时常常会发生一些严重的并发症。
CPC聚合时不产热，无生物毒性，同时还具有良好的组织相容性及成骨作用。国外学者对其用于人体后的组织病理学进行研究，未发现有炎症及异物排斥反应，因此近几年来被有些学者推荐作为PMMA骨水泥的替代品，已越来越多的用于临床。CPC以多种磷酸盐为主要成份，是一种生理条件下具有自固化能力及降解活性、成骨活性的无机材料。CPC的其他优点包括高度的生物相容性，可任意塑型，固化过程温性等特点。CPC可分为磷酸三钙和磷酸四钙系统，不同的磷酸盐发生水化反应后，其最终产物都是羟基磷灰石(HAP)。固液相二者按适当比例调和后发生一系列等温反应，先形成一种可任意塑型的能用于注射的糊状物，在体内环境下自行固化，结晶反应后，最后形成羟基磷灰石晶体，并可自行调节酸碱平衡维持中性水平。CPC良好的生物相容性和生物学安全性是其作为骨修复材料必备的基本条件。Costantino等证实CPC不具有诱导成骨活性，而是通过骨传导作用成骨[Costantino PD，Friedman CD，Jones K，etal.Experimental hydroxyapatite cement dranioplasty.Plast Reconstrr Surg，1992，90：174-185.]。CPC修复骨缺损时，新骨从材料的表面开始生长，逐渐向深层推进，与自体骨或异体骨的替代过程基本一致。新骨对CPC的替代过程类似于骨的再塑形，新骨长入材料所占有的空间内，虽然植入的CPC被新骨部分或全部取代，但是材料植入时的容积和外形并没有改变，只是由新生的有机组织取代了原来的无机材料，CPC这一特点在骨缺损修复临床应用有十分重要的意义。CPC具有良好的生物力学性能，完全凝固的CPC具有介于松质骨与皮质骨的抗压强度[Larsson S，Thomas WB.Use of injectable cacium phosphate cement for fracturefixation：a review.Clin Orthop，2002，395(1)：23-32.]。研究表明，将CPC植入动物与周围组织良好共存，未见明显炎症反应，无排斥反应出现，不引起组织的变性坏死[Constantz BR，Barr BM，Ison IC，et al.Histological chemical andcrystallographic analysis of four calcium phosphate cements in different rabbitosseous sites.J Biomed Mater Res，1998，43：451-461.Higashi S，Ohsumi T，OzumiK，et al.Evaluation of cytotoxicity of calcium phosphate cement consisting ofalpha-tricalcium phosphate and dicalcium phosphate dehydrate.Dent Mater J，1998，17：186-194.]。戴红莲等试验证明了CPC不会产生全身或局部毒性反应，对肌肉无刺激，不致溶血、凝血，不引起炎症和排斥反应等[戴红莲闫玉华等.a-TCP/TTCP骨水泥的降解性能研究.硅酸盐通报2001.4：9-13.]。也有研究表明。CPC无细胞毒性反应，无致癌以及基因突变作用。
CPC也存在很多缺点：CPC在生理环境中的抗疲劳与破坏强度低，尤其是在湿环境下断裂韧性非常低，是典型的脆性材料[Xu HH，Simon CG Jr.Fastsetting calcium phosphate-chitosan scaffold：mechanical properties andbiocompatibility.Biomaterials，2005；26：1337-1348]，并且CPC存在固化时间长，粘结性差的缺点，并且CPC不具备PMMA的肿瘤杀伤作用。CPC本身强度和脆性问题解决的关键是研制一种有机无机复合人工骨[Liu H，Li H，Cheng W，etal.Novel injectable calcium phosphate/chitosan composites for bone substitutematerials.Acta Biomater，2006；2：557-565]，以可降解有机高分子材料来增强、增韧磷酸钙骨水泥，在保持良好的骨传导性的同时使其机械性能得到大幅度提高。
近年来多份报道骨水泥负载抗生素及添加剂的研究。抗生素可以被加入PMMA骨水泥中从而减少感染的机会[Belkoff SM，Mathis JM，Erbe EM，etal.Biomechanical evaluation of a new bone cement for use in vertebroplasty.Spine，2000，25(9)：1061-1064.Jensen ME，Evans AJ，Mathis JM，et al.Percutaneouspolymethylmethacrylate vertebmplasty in the treatment of osteoporotic vertebralbody compressionfractures；technical aspects.AJNR Am J Neuroradiol，1997；18：1897-1904.]，同时这些抗生素也影响到骨水泥的机械性能。研究表明在骨水泥中加入不同种类的抗生素，抗生素较少时不会对骨水泥的机械性能造成很坏的影响，然而抗生素较多时则明显破坏骨水泥的机械性能[Murphy KJ，Deramond H.Percutaneous vertebmplasty in benign and malignant disease.Neumimaging Clin NAm，2000；10(3)：535-545.]；这被向PMMA中加入0.5g红霉素和0.24g多黏菌素时没有破坏骨水泥的疲劳寿命所证实[Davis JP，OConnor DO，Burke DW，et al.Influence of antibiotic impregnation on the fatigue lift of Simplex P and Palacos Racrylic bone cement，with and without centrifugation.J Biomed Mater Res，1989；23：379-97.]。学者们也研究了CPC骨水泥及抗生素以达到更好的临床治疗效果。Hamanishi等利用磷酸四钙(TTCP)和磷酸氢钙(DCPD)形成的CPC负载万古霉素治疗耐甲氧西林金黄色葡萄球菌(MRSA)导致的骨髓炎，效果良好[Hamanishi C，Kitamoto K，Tanaka S，et al.A self-setting TTCP-DCPD apatite cenment for rebaseof vancomycin.J Bomted Mater Res，1996；33(3)：139-143.]。Takechi等研究认为，加入硫酸庆大霉素粉末或溶液的CPC固化时间和机械强度增加均有增加[Takeyhi M，Miyamoto Y，Ishikawa K，et al.Initial histological evaluation ofanti-washout type fast-setting calcium phosphate cement following subcutaneousimplantation.Biomate-rials，1998；19(22)：2057-2063.]。Takechi等在CPC中掺人海藻酸钠或壳聚糖，结果显示在抗生素释放第一阶段，实验组释药稍慢于对照组，且实验组释药浓度维持在一个较对照组稍高的水平[Takechi M MiyamotoY.Momota Y.et al.The in vitro antibiotic release from antiwashout apatite cementusing chitosan.J Mater Sci Mater Med，2002；13(10)：973-978]。这表明将一些高分子物质掺人CPC，是一种延缓抗生素释放时问的策略。
骨水泥中也可以添加纳米银作为抗菌剂。Alt等研制了一种新型纳米银骨水泥材料，在体外实验中发现，纳米银含量为1％的骨水泥可抑制耐药性极强的MRSA和MRSE菌株，而对照的2％庆大霉素组及普通骨水泥组却没有显示任何抗菌效果，并且在细胞毒性试验中，各组之间无统计学差异，认为纳米银骨水泥在关节成形术中是不错的选择[Alt V，Bechert T，Steinrucke P，et al.Nanoparticulate silver.A new antimicrobial substance for bone cement.Orthopade.2004；33(8)：885-892.]。
纳米银是一种尺寸小于100nm的金属粒子。金属银达到了纳米级别，其物理、化学以及生物学特征表现出与原来不同的特性[Chen X，Schluesener H J.Nanosilver：A nanoproduct in medical application.Toxicol Lett，2008，176：1-12]。纳米银的抗菌作用机制与银离子很接近，但应用纳米银的有效杀菌浓度却明显低于应用金属银[Elechiguerra J L，Burte J L，Morones J R，et al.Interaction of silvernanoparticles with HIV-1.J Nanobiotechnol，2005，3：6.Kong H，Jang J.Antibacterial properties of novel poly(methyl methacrylate)nanofiber containingsilver nanoparticles.Langmuir，2008，24：2051-2056]。纳米银具有较大的比表面积，例如，1克球状银表面积为10.6cm2，而1克直径为10nm的银纳米粒子的表面直径达到6×105cm2，大大增加了持续释放银离子所需的表面积。存在更多的处于活性状态的银原子，其随时可与接触的细菌或病毒作用，起到杀灭作用。Morones等应用原子分辨率的高角环形暗场显像技术和透射显微镜研究1～100nm的纳米银对抗大肠杆菌性能，结果显示在纳米银可以明显抑制的细菌生长。通过扫描透射电子显微镜，研究者还发现大部分的银出现在细菌细胞内，只有少量的银黏附在细菌表面。应用原子分辨率的高角环形暗场显像技术对不同尺寸纳米银的抗菌性进行比较，显示小于5nm的纳米银表现出了更好的抗菌能力。这表明纳米银的抗菌性能还具有尺寸依赖性[Morones J R，Elechiguerra J L，Camacho A，et al.The bactericidal effect of silver nanoparticles.Nanotechnol，2005，16：2346-2353.Lok C N，Ho C M，Chen R，et al.Proteomic analysis of the mode ofantibacterial action of silver nanoparticles.J Proteome Res，2006，5：916-924]。纳米银得杀菌除释放银离子的作用机制外，还可以与细菌细胞膜结合，并与膜上含硫蛋白作用使其失活。纳米银进入细胞中心后与含硫的有机物质反应，包括蛋白与DNA，从而影响细菌细胞功能[Song H Y，Ko K K，Oh I H，et al.Fabrication ofsilver nanoparticles and their antimicrobial mechanisms.Eur Cells Mater，2006，11：58.Sondi I，Salopek-Sondi B.Silver nanoparticles as antimicrobial agent：A casestudy on E.coli as a model for gram-negative bacteria.J Colloid Interface Sci，2004，275：177-182]。
纳米银的抗感染性能优良[Hu B，Wang S B，Wang K，et al.Microwave-assisted rapid facile“green”synthesis of uniform silver nanoparticles：self-assembly into multilayered films and their optical properties.J Phys Chem C，2008，112：11169-11174.Zhang W Z，Qiao X L，Chen J G.Synthesis of nanosilvercolloidal particles in water/oil microemulsion.Colloids Surfaces A：Physico-chemEng Aspects，2007，299：22-28]。Li等首次研究了纳米银涂层口罩的抗菌性能，结果显示纳米银涂层口罩对金黄色葡萄球菌及大肠埃希菌具有很好的杀灭能力，并且佩戴口罩的志愿者没有出现局部过敏及皮肤发痒的情况[Li Y，Leung P，YaoL，et al.Antimicrobial effect of surgical masks coated with nanoparticles.J HospInfect，2006，62：58-63]。Tian等建立动物创伤模型，应用纳米银进行治疗，并对结果进行定量PCR、免疫组化等分析，结果显示银纳米颗粒可减少创口炎症反应，调节纤维化因子，从而起到加速创面愈合及减少疤痕形成的作用[Tian J，Wong K K，Ho C M，et al.Topical delivery of silver nanoparticles promotes woundhealing.Chem Med Chem，2007，2：129-136]。
骨水泥是骨科手术的重要医用材料，改进骨水泥的强度、韧性，增加骨水泥的生物学功能以及抗菌功能具有重要的现实意义。
发明内容
本发明公开了一种新型的纳米银骨水泥。所述骨水泥包括固相和液相两部分。
所述的纳米银骨水泥的固相主要成分为含锶磷酸钙晶须、聚甲基丙烯酸甲酯以及纳米银。
所述的含锶磷酸钙晶须中锶与钙的摩尔之比为1∶30-1∶5，其直径在0.3-2μm之间。所述的含锶磷酸钙晶须在骨水泥的含量为5％-20％，其中锶和钙摩尔数之和与磷的摩尔数之比为1.5-2.0。本发明所述的新型骨水泥含有纳米银，所述的纳米银含量为0.1％-2％，其直径在5-50nm之间。
所述的液相部分包括：90％-95％的甲基丙烯酸甲酯单体、0.5％-1.5％的N，N-二甲基对甲苯胺、0.02-0.05％的阻聚剂对苯二酚。
本发明公开了一种新型的纳米银骨水泥的制作方法，包括：
1)制备含锶磷酸钙晶须；
2)制备纳米银；
3)制备聚甲基丙烯酸甲酯粉末；
4)将上述三种物质研磨混匀。
5)将固相与液相以质量比2∶1搅拌混匀，即制得所述的新型的纳米银骨水泥。所述的固相为含锶磷酸钙晶须、聚甲基丙烯酸甲酯以及纳米银混合物，液相成份为90％-95％的甲基丙烯酸甲酯单体、0.5％-1.5％的N，N-二甲基对甲苯胺、0.02-0.05％的阻聚剂对苯二酚。
其中，制备含锶磷酸钙晶须的方法包括以下步骤：
1)将磷酸氢二氨、十二烷基硫酸钠以及山梨醇在pH值条件至2-3反应，制备磷溶液；
2)将硝酸钙、硝酸锶以及尿素混合搅拌使药品充分溶解，得到锶钙溶液；
3)用锶钙溶液滴定磷溶液，在90℃-100℃进行恒温反应，反应15h-19h后停止加热，将反应后的溶液自然冷却到室温，在室温条件下陈化20h-30h。
4)将陈化结束后的溶液真空抽滤，加入蒸馏水进行过滤，抽滤至pH值为7，再加入无水乙醇，继续过滤，消除残余的离子。在45-70℃温度下，恒温干燥。即可得到含锶磷酸钙晶须。
本发明还公开了所述新型的纳米银骨水泥的主要用途，所述的纳米银骨水泥可以用作骨科手术材料，也可以用作治疗骨质疏松的医药材料。
附图说明
图1新型骨水泥制备流程图。固相为含锶磷酸钙晶须、聚甲基丙烯酸甲酯以及纳米银混合物，液相为90％-95％的甲基丙烯酸甲酯单体、0.5％-1.5％的N，N-二甲基对甲苯胺、0.02-0.05％的阻聚剂对苯二酚。
图2各组骨水泥对大肠杆菌的杀菌率。第一组为PMMA骨水泥，第二组为本发明所述的新型纳米银骨水泥。
图3各组骨水泥对金黄色葡萄球菌的杀菌率。第一组为PMMA骨水泥，第二组为本发明所述的新型纳米银骨水泥。
图4各组骨水泥对大肠杆菌的长效杀菌率。第一组为PMMA骨水泥，第二组为本发明所述的新型纳米银骨水泥。
图5各组骨水泥对金黄色葡萄球菌的长效杀菌率。第一组为PMMA骨水泥，第二组为本发明所述的新型纳米银骨水泥。
图6新型纳米银骨水泥的力学强度。A组为CPC骨水泥，B组为20％含锶磷酸钙新型纳米银骨水泥，C组为10％含锶磷酸钙新型纳米银骨水泥，D组为5％含锶磷酸钙新型纳米银骨水泥。
实施例一新型纳米银骨水泥的制备
1、含锶磷酸钙晶须制备
1)将磷酸氢二氨、十二烷基硫酸钠以及山梨醇在pH值条件至2-3反应，制备磷溶液；
2)将硝酸钙、硝酸锶以及尿素混合搅拌使药品充分溶解，得到锶钙溶液；
3)用锶锶钙溶液滴定磷溶液，在90-100℃进行恒温反应，反应15h-19h后停止加热，将反应后的溶液自然冷却到室温，在室温条件下陈化20h-30h；
4)将陈化结束后的溶液真空抽滤，加入蒸馏水进行过滤，抽滤至pH值为7，再加入无水乙醇，继续过滤，消除残余的离子。在45-70℃温度下，恒温干燥20h。即可得到含锶磷酸钙晶须。
2、纳米银的制备
本发明采用氧化还原法制备纳米银，实验材料包括：硝酸银、28％浓氨水、30％过氧化氢。制备步骤如下：
1)配制100ml 0.1mol/L的硝酸银溶液，滴入适量28％浓氨水搅拌至澄清；
2)在冰浴条件下缓慢滴加200ml 30％H2O2于溶液中，剧烈搅拌至无气体放出，即得纳米银混悬液；
3)将上述的纳米银混悬液于340×g离心30min，得到的沉淀于50℃真空干燥箱中干燥12h，即得纳米银粉。
3、制备聚甲基丙烯酸甲酯粉末
本发明采用悬浮聚合法制备聚甲基丙烯酸甲酯(PMMA)，实验材料包括：甲基丙烯酸甲酯(MMA)，丙烯酸甲酯(MA)，过氧化二苯甲酰(BPO)，聚乙烯醇(PVA)。制备步骤如下：
1)在三颈烧瓶中加入蒸馏水267.5ml，在搅拌下加入适量PVA，10min后加适量的BPO和70.8ml的MMA单体，9.45ml的MA单体。在10-20min内升至70℃，继续升温，在20-30min内，升至80℃，再在70-80min内升至98℃，持续30min。
2)将上步所得混合物倒入烧杯中静置，抽去上层母版，用蒸馏水(80℃)洗涤过滤，重复三次。然后将洗涤过滤后的产物置于40℃的烘箱中干燥，干燥后研磨过筛得到PMMA白色细粉颗粒。
4、纳米银骨水泥固相的制备
取含锶磷酸钙晶须20g、纳米银1g、聚甲基丙烯酸甲酯粉末69.5g、硫酸钡10g、引发剂过氧化二苯甲酰0.5g，至于球磨机中相互研磨均匀。
5、取70g纳米银骨水泥固相与35ml骨水泥液相，真空下混合搅拌，混合物由稀浆状逐渐变成粘糊状。即制得所述新型纳米银骨水泥。
实施例二新型纳米银骨水泥的抗菌作用
实验采用的抗菌对象为：标准菌株大肠埃希氏菌(ATCC8099)、金黄色葡萄球菌(ATCC6538)。
采用国家薄膜密着法进行抗菌性实验。抗菌试件片为50mmX50mmX2mm，试件用蒸馏水冲洗干净，紫外线照射后备用在各阴性及对照抗菌试片上加菌悬液，覆盖消毒PE薄膜，37℃恒温箱中培养24h，计数菌落数，试验重复3次，结果取平均值。平均值将用于计算抗菌率，抗菌率的计算公式为：
R(％)＝(A-B)/AX100％
其中R为抗菌率(％)，A为阴性对照组平均回收残留菌数(CFU/片)，B为实验组样品平均回收残留菌数(CFU/片)。
实验分两组，第一组为PMMA骨水泥，第二组为本发明的新型纳米银骨水泥。实验结果显示本发明的新型纳米银骨水泥对大肠埃希氏菌、金黄色葡萄球菌具有明显的杀菌作用。实验结果见图2和图3。
实施例三新型纳米银骨水泥的长效杀菌作用
实验采用的抗菌对象为：标准菌株大肠埃希氏菌(ATCC8099)、金黄色葡萄球菌(ATCC6538)。
制备与实施例二中相同的实验样品，经紫外照射消毒后，置于50ml无菌生理盐水中，每周换一次新的无菌生理盐水。4周后取出，按照实施例二的方法检测各样品对大肠埃希氏菌和金黄色葡萄球菌的杀伤。
实验分两组，第一组为PMMA骨水泥，第二组为本发明的新型纳米银骨水泥。实验结果显示本发明的新型纳米银骨水泥，在28天后，对大肠埃希氏菌、金黄色葡萄球菌依然具有明显的杀菌作用，所以本发明的骨水泥，具有长效杀菌作用。实验结果见图4和图5。
实施例四新型纳米银骨水泥力学强度测试
20％含锶磷酸钙新型纳米银骨水泥的制备：取含锶磷酸钙晶须20g、纳米银1g、聚甲基丙烯酸甲酯粉末69.5g、硫酸钡10g、引发剂过氧化二苯甲酰0.5g，至于球磨机中相互研磨均匀。将70g纳米银骨水泥固相与35ml骨水泥液相，真空下混合搅拌，混合物由稀浆状逐渐变成粘糊状。
10％含锶磷酸钙新型纳米银骨水泥的制备：取含锶磷酸钙晶须10g、纳米银1g、聚甲基丙烯酸甲酯粉末79.5g、硫酸钡10g、引发剂过氧化二苯甲酰0.5g，至于球磨机中相互研磨均匀。将70g纳米银骨水泥固相与35ml骨水泥液相，真空下混合搅拌，混合物由稀浆状逐渐变成粘糊状。
5％含锶磷酸钙新型纳米银骨水泥的制备：取含锶磷酸钙晶须10g、纳米银1g、聚甲基丙烯酸甲酯粉末79.5g、硫酸钡10g、引发剂过氧化二苯甲酰0.5g，至于球磨机中相互研磨均匀。将70g纳米银骨水泥固相与35ml骨水泥液相，真空下混合搅拌，混合物由稀浆状逐渐变成粘糊状。
CPC骨水泥由上海瑞邦生物材料有限公司生产制造，将粉末同固化液按已配好的比例(一包粉末配一支固化液)调和混匀。
将上述四种混合物迅速填入模具中，用砝码压实，两端用玻璃封住两端模具，至于37℃恒温箱，保持100％湿度，30min后脱模，得到Φ6mm×12mm的圆柱状试样，并将其至于模拟体液中，3天后用CSS-44100型电子拉力测试机对试样进行抗压强度的测试，加载2000kgf，压缩速率为1mm/min，试样的上下面垫上滤纸。结果见图6，结果显示新型纳米银骨水泥的力学强度明显优于CPC骨水泥。
实施例五新型纳米银骨水泥骨内植入实验
实验分为四组：A组为PMMA组，B组为5％含锶新型纳米银骨水泥组，C组为10％含锶新型纳米银骨水泥组，D组为20％含锶新型纳米银骨水泥组。实验前一天，将骨水泥试样经60Co照射消毒备用。
取健康成年新西兰兔4只，雌雄均有，用速眠新以0.12ml/kg兔耳缘静脉注射麻醉后，实验动物取俯卧位，术前1d脱毛。手术切开股骨外侧肌肉，分离暴露股骨中段，用消毒好的低速牙科电钻在股骨骨面上钻孔，至髓腔，孔径为2×2mm，每侧股骨上钻2个孔，将准备好的骨水泥试样放入孔内，骨蜡止血，封闭试样与孔之间的缝隙。分层缝合切口，放回笼内单独饲养。于术后24周各处死4只动物，取出股骨全段，金刚砂片切割，系列脱水，树脂包埋，HE染色制作骨切片标本。
初步实验结果显示，B、C、D组的材料与骨组织间无间隙，骨水泥材料内部有大量的骨组织长入，可见丰富的哈佛氏小管。而A组与骨质有一层较厚的纤维结缔组织，骨水泥材料内部未发现骨组织。所以本发明的骨水泥较PMMA骨水泥能够更好被骨组织吸收，进行骨重建。
Claims (2)
1.一种纳米银骨水泥的制作方法，包括：
(1)含锶磷酸钙晶须制备
1)将磷酸氢二氨、十二烷基硫酸钠以及山梨醇在pH值条件至2-3反应，制备磷溶液；
2)将硝酸钙、硝酸锶以及尿素混合搅拌使药品充分溶解，得到锶钙溶液；
3)用锶钙溶液滴定磷溶液，在90-100℃进行恒温反应，反应15h-19h后停止加热，将反应后的溶液自然冷却到室温，在室温条件下陈化20h-30h；
4)将陈化结束后的溶液真空抽滤，加入蒸馏水进行过滤，抽滤至pH值为7，再加入无水乙醇，继续过滤，消除残余的离子，在45-70℃温度下，恒温干燥20h，即可得到含锶磷酸钙晶须；
(2)纳米银的制备
采用氧化还原法制备纳米银，实验材料包括：硝酸银、28％浓氨水、30％过氧化氢，制备步骤如下：
1)配制100ml0.1mol/L的硝酸银溶液，滴入适量28％浓氨水搅拌至澄清；
2)在冰浴条件下缓慢滴加200ml30％H2O2于溶液中，剧烈搅拌至无气体放出，即得纳米银混悬液；
3)将上述的纳米银混悬液于340×g离心30min，得到的沉淀于50℃真空干燥箱中干燥12h，即得纳米银粉；
(3)制备聚甲基丙烯酸甲酯粉末
采用悬浮聚合法制备聚甲基丙烯酸甲酯(PMMA)，实验材料包括：甲基丙烯酸甲酯(MMA)，丙烯酸甲酯(MA)，过氧化二苯甲酰(BPO)，聚乙烯醇(PVA)，制备步骤如下：
1)在三颈烧瓶中加入蒸馏水267.5ml，在搅拌下加入适量PVA，10min后加适量的BP0和70.8ml的MMA单体，9.45ml的MA单体，在10-20min内升至70℃，继续升温，在20-30min内，升至80℃，再在70-80min内升至98℃，持续30min；
2)将上步所得混合物倒入烧杯中静置，抽去上层母版，用蒸馏水80℃洗涤过滤，重复三次；然后将洗涤过滤后的产物置于40℃的烘箱中干燥，干燥后研磨过筛得到PMMA白色细粉颗粒；
(4)纳米银骨水泥固相的制备
取含锶磷酸钙晶须20g、纳米银1g、聚甲基丙烯酸甲酯粉末69.5g、硫酸钡10g、引发剂过氧化二苯甲酰0.5g，至于球磨机中相互研磨均匀；
(5)取70g纳米银骨水泥固相与35ml骨水泥液相，真空下混合搅拌，混合物由稀浆状逐渐变成粘糊状，即制得所述新型纳米银骨水泥。
2.一种由权利要求1所述的方法制备的纳米银骨水泥。
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| CN108946690A (zh) * | 2018-07-02 | 2018-12-07 | 昆明理工大学 | 一种抗菌改性羟基磷灰石材料的制备方法 |
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| 储新宏.多孔磷酸钙骨水泥生物复合材料的研究.《中国优秀硕士学位论文全文数据库 医药卫生科技辑》.2011,(第04期),第E080-33页. |
| 多孔磷酸钙骨水泥生物复合材料的研究;储新宏;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20110415(第04期);第E080-33页 * |
| 掺锶羟基磷灰石固溶体的制备及解离度测定;陈德敏等;《中国生物医学工程学报》;20010630;第278-280页 * |
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