摘要
我国50岁以上人群中有骨质疏松(Osteoporosis, OP)患者近7000万,每年新发脊柱压缩骨折约181万例。微创椎体成形术(Vertebroplasty, VP)或球囊扩张椎体后凸成形术(Balloon kphoplasty, BKP)是脊柱压缩骨折(Vertebral compression fractures, VCF)的主要外科治疗手段。VP或BKP中所采用的材料大多数为聚甲基丙烯酸甲酯(Polymethylmethacrylate, PMMA)。该材料存在明显缺陷:不可吸收、无生物活性(骨传导、诱导作用等),固化过程中发热明显等。因此,寻找一种能够具有良好流动性、骨传导、骨诱导作用,兼具良好的力学支撑性能及一定降解率的骨修复材料已经成为骨科亟待解决的难题。
磷酸钙骨水泥(Calcium phosphate cement, CPC)因其自固化,无类似PMMA的产热效应,可任意塑形,良好的生物相容性、骨传导性及可降解被新生骨替代等特点,具有广阔的临床应用价值。然而,CPC在体内降解缓慢。另外,在一些供血不足区域及伴代谢紊乱的老年病患中,CPC的骨传导作用并不足以达到完全的骨修复效果,因此赋予CPC更高的传导性或诱导性可进一步改善其生物学性能。
生物玻璃(Bioactive glass, BG)由于其良好的生物活性和生物相容性倍受关注,生物玻璃与软组织或骨之间存在密切的离子交换,可直接参与人体骨组织的代谢和修复过程,最终可在材料表面形成与人体骨相同的无机矿物成分——碳酸羟基磷灰石,诱导新生骨组织的生长。将其作为可注射型材料组成成分与CPC复合应用于椎体成形或球囊成形术及不规则骨缺损如口腔及颅面部等处的骨缺损填充修复的研究鲜见文献报道。
目的:
优选最佳的CPC与BG材料复合比,研发出一种体内可吸收、具有良好生物相容性及成骨活性的新型可注射生物复合材料。
方法:
1.将CPC与BG以不同质量比混合后,比较其固化时间及可注射性能,筛选出合适的材料复合比;
2.将CPC与BG以选定的材料复合比及固液比混合后,分析其组成成分,微观结构,固化时间,可注射性能,力学强度及体外生物活性特性和降解性等材料学特性;
3.将大鼠成骨细胞(osteoblasts, OB)接种于材料试件表面,观察OB在试件表面粘附、增殖和分化能力;
4.将CPC-BG复合生物材料植入新西兰白兔体内4,12周后,行大体、显微CT(Micro-computed tomography,Micro-CT)分析和组织学观察。
结果:
1.随着BG加入的比例增加(10%,20%,30%,40%),CPC-BG复合生物材料的固化时间延长,可注射性能提高。较单纯CPC,CPC-BG组固化时间延长(21min到44min),同时可注射性能显著提高(P <0.05);
2. CPC-BG复合生物材料的材料学研究中,X射线衍射分析(X-ray diffraction,XRD)结果显示CPC及CPC-BG复合生物材料组主要的衍射峰为沉积的羟基磷灰石(Hydroxyapatite, HAp),随着BG含量从10%升至20%,可出现Ca2SiO4及Ca3SiO5衍射峰,电镜观察发现加入BG后,材料结构更紧密。力学性能方面,固化1天及7天后的材料CPC+20%BG组明显高于单纯CPC组(P <0.05)。体外生物活性实验结果发现,浸泡模拟体液(Simulated body fluid, SBF)后,CPC-BG组表面HA沉积量明显多于CPC。能谱结果(Energy dispersive spectroscopy, EDS)表明,CPC-BG复合材料表面沉积的HA主要由Ca, P及Si组成,而CPC仅含Ca及P元素。体外降解实验发现,加入BG后可提高材料降解性;
3.细胞学实验结果表明,加入BG后,可提高成骨细胞的粘附,增殖及分化。MTT结果显示,8h后,CPC-BG复合材料组与单纯CPC组有统计学差异(P<0.05)。随着时间的延长,细胞进一步增殖,在1d,4d及7d时MTT结果显示,CPC-BG组优于CPC组,其中在4d及7d时,CPC-BG组与CPC组有统计学差异(P <0.05)。碱性磷酸酶活性(Alkaline phosphatase, ALP)检测发现,7d时,CPC-BG组与CPC组有统计学差异(P <0.05);
4.新西兰白兔体内植入实验中,大体,Micro-CT和组织学检测显示,在4周和12周,所有材料组的体内降解率和新生骨生成量随着时间的延长而增加,其中CPC-BG组材料的体内降解率和新生骨生成量均明显高于CPC组(P <0.05)。
结论:
1.CPC-BG(10%,20%)复合生物材料的固化时间及可注射性符合外科手术要求,随着BG的增加,复合生物材料的成分、微观结构发生了改变,可注射性,力学性能进一步提高,同时,体外生物活性及降解率也有了明显的改善;
2.将BG引入CPC中,有利于成骨细胞的粘附、增殖和分化;
3.CPC-BG复合生物材料具有优秀的生物相容性,更高的生物活性、体内降解率和骨生成率,更有利于骨缺损的修复。
In China, there are70million people over the age of50suffering from osteoporosis(OP) and1.81million cases of vertebral compression fractures (VCF) occurred annually.Currently, percutaneous vertebroplasty (VP) and balloon kyphoplasty (BKP) have becomethe main surgical treatment of VCF. Polymethylmethacrylate (PMMA) is the mostcommonly used cement in VP and KP. However, there are several disadvantages ofPMMA: nonbiodegradable, no osteoconductive, osteoinductive and osteogenic activityand the high-polymerization isotherm leading to thermal necrosis of the soft tissues at theaugmentation site. Therefore, to design a novel biomaterial with good flowability,osteoconductive, osteoinductive and osteogenic activity as well as good mechanicalproperty and certain degradation rate for bone regeneration has become the urgentproblem in the field of orthopedics.
Calcium phosphate cements (CPC) have been widely used as bone substitutematerials in clinic applications because of their self-setting properties, no thermogeniceffect, high biocompatibility and osteoconduction as well as bone replacement capability.However, the currently used CPC has some limitations due to its poor mechanicalproperties and low biodegradation rate. Furthermore, the osteoconductive properties ofCPC are not sufficient to achieve complete bone repairment under critical conditions, suchas poorly vascularized sites and elderly patients with metabolic disorders. Consequently,the enrichment of CPC with osteopromotive or osteoinductive factors is necessary toimprove its biological performance.
As a surface active bone substitute, bioactive glass (BG) has recently attracted moreattention due to their good biocompatibility and bioactivity both in bone and in soft tissues.Studies have shown that close ion exchange between BG and soft issue or bone can bedirectly involved in the metabolism of human bone tissue and repair process. Bioactiveglass such as45S5BG bonds strongly to bone and promotes bone growth with formationof a hydroxycarbonate apatite (HCA) layer and the release of Ca, P and Si ions. As far aswe know, it is not until recently, there were a few relevant literatures available regardingCPC-BG applicably in minimally invasive injectable graft.
Objective:
The aim of this study is to develop a new injectable biocomposite with excellentbiocompatibility, improved bioactivity and biodegradability by adding BG into CPC.
Methods:
1. Prepare the CPC-BG composite by adding different proportions of BG45S5powder(10wt%,20wt%,30wt%,40wt%) into CPC powder and mixed with potassiumphosphate buffers (pH7.0) at a given P/L ratio of2.0g/ml. Optimize the compositionratio by comparing setting time and injectability among different groups;
2. Fabricate the CPC-BG composite with the selected composition ratio and P/L ratio andinvestigate the composition, morphology/microstructure, setting time, injectability,compressive strength, surface reaction layer formation and degradation of CPC-BG;
3. The osteoblasts (OB) were seeded onto the CPC-BG composite disks and the adhesion,proliferation, morphology and differentiation abilities of the OB were observed;
4. The CPC-BG and CPC specimens were implanted into femoral condyle defects ofrabbits. After4and12weeks implantation, macroscopic evaluation, histologicalevaluation, and micro-CT analysis were performed.
Results:
1. The setting times of CPC-BG were prolonged as the content of BG increased,increased from21min to44min, with the weight ratio of BG varied from10%to40%at P/L ratio of2.0g/ml. The injectability of CPC-BG composite paste was significantlyimproved compared with injectability of CPC paste (p <0.05);
2. XRD showed that main peaks for HA of hardened CPC-BG composite, were notobviously altered and peaks for Ca2SiO4and Ca3SiO5could be seen in the XRDpatterns of CPC-BG composite with10%and20%BG. The SEM micrographs for thecross section of the CPC and CPC-BG composite specimens (10%,20%) showed thatthe CPC-BG composite specimens closely combined with each other which showedmore compact microstructure than CPC. The compressive strength of CPC-BGcomposites rose with an increase in the weight ratio of BG and there were significantdifferences between CPC and CPC-20%BG composite specimens at day1and day7(p<0.05). After immersing in simulated body fluid (SBF) for7and14days, the amountof apatite aggregates on CPC-BG composite surface were larger and apatite layersgrew more densely on CPC-BG composite surface than amount on CPC surface. EDSindicated that the surface of CPC-BG composite (10%,20%) consisted of a calciumphosphate with a Ca/P ratio of about1.56and1.53and contained Si, while the surfaceof CPC consisted of a calcium phosphate with a Ca/P ratio of about1.67, contained noSi. The degradation rates of all CPC-BG composite specimens were significantlyhigher than degradation rates of CPC specimens (p <0.05);
3. The degree of cell attachment, proliferation and differentiation was increased byadding BG into CPC. The MTT assay showed that the OD values of CPC-BG composite specimens (20%) were significantly higher than OD values of CPCspecimens (p <0.05) in a period of8h. OD values of CPC-BG composite specimens(20%) were significantly higher than OD values of CPC specimens at4and7days (p<0.05), indicating that CPC-BG composite specimens promoted cell growth andfacilitated proliferation with no cytotoxic effect on cells compared with CPCspecimens. The ALP activity of cells cultured on CPC-BG composite (20%) wassignificantly higher than ALP activity on CPC and TCPS control (p <0.05) at4and7days;
4. With the prolonged implantation period from4to12weeks, the in vivo degradationrate and the amount of newly formed bone of CPC-BG composites and CPC wereincreased. Moreover, the in vivo degradation rate and the amount of newly formedbone of CPC-BG composites were significantly higher that of CPC specimens (p <0.05).
Conclusions:
1. The setting time and injectablity of CPC-BG composite (10%,20%) conform to thesurgical requirement. CPC-BG(10%,20%) possessed a retarded setting time andmarkedly better injectability and mechanical properties than CPC. Meanwhile,CPC-BG samples showed significantly improved in vitro degradability and bioactivitycompared to CPC in SBF.
2. Adding BG into CPC is benefit for OB to adhere, proliferate and differentiate.
3. CPC-BG with excellent biocompatibility, improved bioactivity and in vivodegradability enhanced the efficiency of new bone formation in comparison with CPC,which exhibits promising prospects for bone regeneration.
引文
[1]胥少汀。实用骨科学(第三版)。人民军医出版社,2005,1198-1199.
[2]中国老年学学会骨质疏松委员会骨质疏松诊断标准学科组。中国人原发性骨质疏松症诊断标准(试行)。中国骨质疏松杂志,1999,5(7): l-3.
[3] World Health Organization. Prevention and management of osteoporosis. World Health OrganTech Rep Ser,2003,921:1-164.
[4] Kanis JA, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. JBMB.1994,9:1137-1141.
[5] Mithal A, Dhingra V, Lau E. The Asian audit: Epidemiology, costs and burden of osteoporosis inAsia. Beizing, China: An International Osteoporosis Foundation (IOF) publication;2009
[6] Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence andeconomic burden of osteoporosis-related fractures in the United States,2005-2025. J BoneMiner Res,2007,22(3):465-475.
[7] Kanis JA, Delmas P, Burckhardt P, et al. Guidelines for diagnosis and management ofosteoporosis. The European Foundation for Osteoporosis and Bone Disease. Osteoporos Int,1997;7:390-406.
[8] Bonura F. Prevention, screening, and management of osteoporosis: an overview of the currentstrategies. Postgrad Med.2009,121(4):5-17.
[9] He Y. The investigation present condition and progresion of bone density determinationtechnique. Foreign Medical Seiences-Section of Radimion Medicine and Nuclear Medicine,2001,25(4):161-162(inChinese).
[10] Cameron JR, Sorenson JA. Measurement of bone mineral in vivo: an improved method. Science196311,142:230-232.
[11] Cullum ID, Ell PJ, Ryder JP. X-ray dual-photon absorptiometry: a new method for themeasurement of bone density. Br J Radiol1989,62(739):587–592.
[12] Genant HK, Block JE, Steiger P, Glueer CC, Smith R. Quantitative computed tomography inassessment of osteoporosis. Semin Nucl Med1987,17(4):316-333.
[13] Guglielmi G, Lang TF. Quantitative computed tomography. Semin usculoskelet Radiol2002,6(3):219-227
[14] Kanis JA, Gluer CC, Committee fo Scientific Advisors, International Osteoporosis Foundation,An update on the diagnosis and assessment of osteoporosis with densitometry. Osteoporos Int2000,11:192-202.
[15] Marshll D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral densitypredict occurrence of osteoporotic fractures. BMJ1996,312:1254-1259.
[16] Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk offracture in women with existing vertebral fractures. Lancet.1996,348:1535–1541.
[17] Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture inwomen with low bone density but without vertebral fractures: results from the FractureIntervention Trial. JAMA.1998,280:2077–82.
[18] McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture inelderly women. Hip Intervention Program Study Group.N Engl J Med.2001,344:333–40.
[19] Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Effects of risedronatetreatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: arandomized controlled trial. JAMA.1999,282:1344–52.
[20] Chesnut III CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily orintermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res.2004,19:1241–49.
[21] Black DM, Delmas PD, Eastell R, et al. Once–yearly zoledronic acid for treatment ofpostmenopausal osteoporosis. N Engl J Med.2007,356:1809–22.
[22] Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture riskreduction in postmenopausal women with osteoporosis: four-year results from a randomizedclinical trial. J Clin Endocrinol Metab.2002,87:3609–17.
[23] Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the risk ofnonvertebral fractures in postmenopausal women with osteoporosis: Treatment of PeripheralOsteoporosis (TROPOS) study. J Clin Endocrinol Metab.2005,90:2816–22.
[24] Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebralfracture in women with postmenopausal osteoporosis. N Engl J Med.2004,350:459–68.
[25] Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1–34) on fracturesand bone mineral density in postmenopausal women with osteoporosis. N Engl J Med.2001,344:1434–41.
[26] Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone(1–84) on vertebral fracture and bone mineral density in postmenopausal women withosteoporosis: a randomized trial. Ann Intern Med.2007,146:326–39.
[27] Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin inhealthy postmenopausal women: principal results From the Women's Health Initiativerandomized controlled trial. JAMA.2002,288(3):321–333.
[28] The Writing Group for the PEPI. Effects of hormone therapy on bone mineral density: resultsfrom the postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA.1996,276(17):1389–1396.
[29] Komm BS, Lyttle CR. Developing a stringent preclinical selection criteria leading to anacceptable candidate for clinical evaluation. Ann NY Acad Sci2001,949:3172–326.
[30] Maria LR, Cristina C, Marta C, et al. Risk factors for osteoporosis and fractures inpostmenopausal women bet ween50and65years of age in a primary care setting in s pain: aquestionnaire. The Open Rheumatology Journal,2008,2:582–63.
[31] Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausalwomen with osteoporosis treated with raloxifene: results from a3-year randomized clinical trial.JAMA.1992,82(7):637–645.
[32] Silverman SL, Christiansen C, Genant HK, et al. Efficacy of bazedoxifene in reducing newvertebral fracture risk in postmenopausal women with osteoporosis: results from a3-year,randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res.2008,23(12):1923–1934.
[33] Cummings SR, Ensrud K, Delmas PD, et al. PEARL study investigators. Lasofoxifene inpostmenopausal women with osteoporosis. N Engl J Med.2010,362(8):686–696.
[34] Iwamoto J, Takeda T, Sato Y. Efficacy and safety of a lendronate and risedronate forpostmenopausal osteoporosis. Curr Med Res Opin2006,22(5):919-928.
[35] Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk offracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group.Lancet.1996,348(9041):1535–1541.
[36] Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture inwomen with low bone density but without vertebral fractures. Results from the fractureintervention trial. JAMA.1998,280:2077-2090.
[37] Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral andnon-vertebral fractures in women with postmenopausal osteoporosis: a randomized controlledtrial. JAMA.1999,282:1344-1350.
[38] McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture inelderly women. N Engl J Med.2001,344:333-350.
[39] Harris ST, Reginster JY, Harley C, et al. Risk of fracture in women treated with monthly oralibandronate or weekly bisphosphonates: the evaluation of IBandronate Efficacy. Bone.2009,44(5):758–765.
[40] Black DM, Delmas PD, Eastell R, et al.Once-yearly zolendronic acid for treatment ofpostmenopausal osteoporosis. N Engl J Med.2007,356:1809-1815.
[41] Wysowski DK. Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med.2009,360(1):89–90.
[42] Cardwell CR, Abnet CC, Cantwell MM, et al. Exposure to oral bisphosphonates and risk ofesophageal cancer.2010. JAMA.304(6):657–663.
[43] Karsdal MA, Henriksen K, Arnold M, et al. Calcitonin-A drug of the past or for the future?Physicologic inhibition of bone resorption while sustaining osteoclast numbers improves bonequality. Bio Drugs2008,22(3):137-144.
[44] Chesnut CH, Azria M, Silverman S, et al. Salmon calcitonin: a review of current and futuretherapeutic indication. Osteoporos Int2008,19(4):479-491.
[45] Jadhav SB, Jain GK. Statins and osteoporosis: new role for old drugs. J Pharmacol,2006,58(1):3.
[46] Deborah TG, Ivy MA, Mark PE. How can osteoporosis patients benefit more from their therapy?Adherence issues with bisphosphonate therapy. Ann Pham acother,2006,40(6):1143-1145.
[47] Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardialinfarction and cardiovascular events: meta-analysis. BMJ.2010,341: c3691.
[48] Kung AW, Pasion EG, Sofiyan M, et al. A comparison of teriparatide and calcitonin therapy inpostmenopausal Asian women with osteoporosis: a6-month study. Curr Med Res Opin,2006,22(5):929-937.
[49] Vahle JL, Sato M, Long GG, et al. Skeletal changes in rats given daily subcutaneous injections ofrecombinant human parathyroid hormone (1-34) for2years and relevance to human safety.Toxicol Pathol.2002,30:312-320.
[50] Black DM, Bilezikian JP, Ensrud KE, et al. One year of alendronate after one year of parathyroidhormone (PTH1-84) for osteoporosis. N Engl J Med.2005,353:555-560.
[51] Rejnmark L, Vestergaard P, Mosekilde L. Statin but not non-statin lipid-lowering drugs decreasefracture risk: a nation-wide case-control study. Calcif Tissue Int2006,79(1):27-36.
[52] Hsia J, Heiss G, Ren H, et al. Women’s Health Initiative Investigators. Calcium/vitamin Dsupplementation and cardiovascular events.Circulation.2007,115:846–54.
[53] Bischoff-Ferrari HA, Dietrich T, Orav E, et al. Positive association between25-hydroxy vitaminD levels and bone mineral density: a population-based study of younger and older adults. Am JMed.2004,116:634-649.
[54] Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the riskof fractures. N Engl J Med.2006,354:669-680.
[55] Dawson-Hughes B, Harris SS, Krall EA, et al. Effect of calcium and vitamin D supplementationon bone density in men and women65years of age or older. N Engl J Med.1997,337:670-684.
[56] Holick MF. Optimal vitamin D status for the prevention and treatment of osteoporosis. DrugsAging.2007,24(12):1017–1029.
[57] Dawson-Hughes B, Bischoff-Ferrari HA, Mayer J. Therapy of osteoporosis with calcium andvitamin D. J Bone Miner Res.2007,22[Suppl2]:V59–V63.
[58] Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebralfracture in women with postmenopausal osteoporosis (SOTI). N Engl J Med.2004,350(5):459–468.
[59] Seeman E, De Vernejoul MC, Adami S, et al. Strontium ranelate reduces the risk of nonvertebralfractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis(TROPOS) study. J Clin Endocrinol Metab.2005,90(5):2816–2822.
[60] Reginster JY, Bruyère O, Sawicki A, et al. Long-term treatment of postmenopausal osteoporosiswith strontium ranelate: results at8years. Bone.2009,45(6):1059–1064.
[61] Breart G, Cooper C, Meyer O, et al. Osteoporosis and venous thromboembolism: a retrospectivecohort study in the UK General Practice Research Database. Osteoporos Int.2010,21(7):1181–1187.
[62] Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausalosteoporosis. Biologics.2008,2(4):645–653.
[63] McClung MR, Lewiecki EM, Cohen SB, et al. AMG162Bone Loss Study Group. Denosumabin postmenopausal women with low bone mineral density. N Engl J Med.2006,354(8):821–831.
[64] Lewiecki EM, Miller PD, McClung MR, et al. Two year treatment with denosumab (AMG162)in a randomized phase2study of postmenopausal women with low BMD. J Bone Miner Res.2007,22(12):1832–1841.
[65] Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density andturnover in postmenopausal women with low bone mass after long-term continued, discontinued,and restarting of therapy: a randomised blinded phase2clinical trial. Bone.2008,43(2):222–229.
[66] Cummings SR, San Martin J, Mc Clung MR, et al. FREEDOM Trial. Denosumab for preventionof fractures in postmenopausal women with osteoporosis. N Engl J Med.2009,361(8):756–765.
[67] Aghaloo T, Felsenfeld A, Tetradis S. Osteonecrosis of the jaw in a patient on denosumab. J OralMaxillofac Surg.2010,68(5):959–963.
[68] Taylor KH, Middlefell LS, Mizen KD. Osteonecrosis of the jaws induced by anti-RANK ligandtherapy. Br J Oral Maxillofac Surg.2010,48(3):221–223.
[69] Gauthier JY, Chauret N, Cromlish W, et al. The discovery of odanacatib (MK-0822), a selectiveinhibitor of cathepsin K. Bioorg Med Chem Lett.2008,18(3):923–928.
[70] Stoch SA, Zajic S, Stone J, et al. Effect of the cathepsin K inhibitor odanacatib on boneresorption biomarkers in healthy postmenopausal women: two double-blind, randomized,placebocontrolled phase I studies. Clin Pharmacol Ther.2009,86(2):175–182.
[71] Bone HG, McClung MR, Roux C. Odanacatib, a cathepsin-K inhibitor for osteoporosis: atwo-year study in postmenopausal women with low bone density. J Bone Miner Res.2010,25(5):937–947.
[72] Henriksen DB, Alexandersen P, Hartmann B, et al. Disassociation of bone resorption andformation by GLP-2. A14day study in healthy postmenopausal women. Bone.2007,40(3):723.
[73] Jarvik JG, Deyo RA. Vertebroplasty for osteoporotic compression fracture: effective treatmentfor a neglected disease. AJNR Am J Neuroradiol.2001;22(3):594–595.
[74] Silvernam SL: The clinical consequences of vertebral compression fracture. Bone.1992,13:S27-S31.
[75] Weill A, Chiras J, Simon JM, et al: Spinal metastases: Indications for and results of percutaneousinjection of acrylic surgical cement.1996, Radiology.199:241-247.
[76] Kim AK, Jensen ME, Dion JE, et al. Unilateral transpedicular percutaneous vertebroplasty:Initial experience. Radiology.2002,222:737-741.
[77] Garfin SR, Yuan HA, Reiley MA. New technologies in spine: kyphoplasty and vertebroplasty forthe treatment of painful osteoporotic compression fractures. Spine.2001;26:1511–1515.
[78] Lieberman IH, Dudeney S, Reinhardt MK, Bell G. Initial outcome and efficacy of “kyphoplasty”in the treatment of painful osteoporotic vertebral compression fractures. Spine.2001;26:1631–1638.
[79] Phillips FM, Ho E, Campbell-Hupp M, McNally T, Todd Wetzel F, Gupta P. Early radiographicand clinical results of balloon kyphoplasty for the treatment of osteoporotic vertebralcompression fractures. Spine.2003;28(19):2260–2265; discussion2265–2267.
[80] Jensen ME, McGraw JK, Cardella JF, et al. Position statement on percutaneous vertebralaugmentation: a consensus statement developed by the American Society of Interventional andTherapeutic Neuroradiology, Society of Interventional Radiology, American Association ofNeurological Surgeons/Congress of Neurological Surgeons, and American Society of SpineRadiology. J Vasc Interv Radiol.2007,18:325-330.
[81] Peh WC, Munk PL, Bilula LA. Percutaneous vertebral augmentation: vertebroplasty,kyphoplasty and skyphoplasty. Radiol Clin North Am.2008,46:611-635.
[82] Garfin SR, Reilley MA. Minimally invasive treatment of osteoporotic vertebral bodycompression fractures. Spine J.2002,2(1):76–80.
[83] Garfin SR, Yuan H, Lieberman IH. Early outcomes in the minimally-invasive reductions andfixation of compression fractures. Proceedings of the NASS.2000:184–185.
[84] Lieberman I, Reinhardt MK. Vertebroplasty and kyphoplasty for osteolytic vertebral collapse.Clin Orthop Relat Res.2003,415(Suppl):S176–S186.
[85] Takemasa R, Yamamoto H. Repair of osteoporotic vertebral compression fracture bytranspedicular injection of bioactive calcium phosphate cement into the vertebral body. Spine J.2002,2:96-102.
[86] Cortet B, Cotten A, Boutry N, et al. Percutaneous vertebroplasty in patients with osteolyticmetastases or multiple myeloma. Rev Rhum Engl Ed.1997,64(3):177–183.
[87] Sauter D, Goldfrank L, Charash BD. Cardiopulmonary arrest following an infusion of calcium2-amino ethanol phosphate. J Emerg Med.1990,8:717–20.
[88] Henschel A, Dannenberg L, Gobel U, et al. Disseminated ischemic necrosis and livedo racemosain a chronic dialysis patient with calciphylaxis. Hautarzt.1999,50:439–44.
[89] Charnley J. The bonding of prostheses to bone by cement. J Bone Joint Surg Br.1964,46:518–29.
[90] Kuhn KD. Bone cements: up-to-date comparison of physical and chemical properties ofcommercial materials. Springer,2000, p:21–34.
[91] Lewis G. Fatigue testing and performance of acrylic bone-cement materials: state-of-the-artreview. J Biomed Mater Res.2003,66B:457–86.
[92] Jasper LE, Deramond H, Mathis JM, et al. Material properties of various cements for use withvertebroplasty. J Mater Sci Mater Med.2002,13:1–5.
[93] Lewis G. Injectable bone cements for use in vertebroplasty and kyphoplasty: state of the artreview. J BiomedMater Res B Appl Biomater.2006,76B:456–468.
[94] Jasper LE, Deramond H, Mathis JM, Belkoff SM. The effect of monomer to powder ratio on thematerial properties of cranioplastic. Bone.1999,25:27S–29S.
[95] Belkoff SM, Sanders JC, Jasper LE. The effect of the monomer to powder ratio on the materialproperties of acrylic cement. J Biomed Mater Res.2002,63:369–399.
[96] Carrodeguas RG, Lasa BV, del Barrio JSN. Injectable acrylic bone cements for vertebroplastywith improved properties. J Biomed Mater Res B Appl Biomater.2004,68:B94–B104.
[97] Ward E, Munk PL, Rashid F, et al. Musculoskeletal interventional radiology: radiofrequencyablation. Radiol Clin North Am.2008,46:599–610.
[98] Ledlie JT, Renfro M. Balloon kyphoplasty: one-year outcomes in vertebral body heightrestoration, chronic pain, and activity levels. J Neurosurg.2003,98:36–42.
[99] Coumans JV, Reinhardt MK, Lieberman IH. Kyphoplasty for vertebral compression fractures:1-year clinical outcomes from a prospective study. J Neurosurg.2003;99:44–50.
[100] Fessl R, Roemer FW, Bohndorf K. Percutaneous vertebroplasty for osteoporotic vertebralcompression fractures: experiences and prospective clinical outcomes in26consecutive patientswith50vertebral fractures. Rofo.2005,177(6):884–892.
[101] Togawa D, Reid J, Bauer TW, et al. Histological evaluation of calcium sulfate HA/TCPcomposites using a canine metaphyseal defect model. Trans50th Annual Meeting ofOrthopaedic Research Society.2004,10:40-50.
[102] Rohmiller MT, Schwalm D, Glattes RC, et al. Evaluation of calcium sulfate paste foraugmentation of lumbar pedicle screw pullout strength. Spine J.2002,2:255–60.
[103] Glazer PA, Spencer UM, Alkalay RN, et al. In vivo evaluation of calcium sulfate as a bone graftsubstitute for lumbar spinal fusion. Spine J.2001,1:395–401.
[104] Stubbs D, Deakin M, Chapman-Sheath P, et al. In vivo evaluation of resorbable bone graftsubstitutes in a rabbit tibial defect model. Biomaterials.2004,25:5037–44.
[105] Verlaan JJ, Oner FC, Slootweg PJ, et al. Histologic changes after vertebroplasty. J Bone JointSurg Am.2004,86-A:1230–8.
[106] Fulmer MT, Ison IC, Hankermayer CR, et al. Measurements of the solubilities and dissolutionrates of several hydroxyapatites. Biomaterials.2002,23:751–5.
[107] Friedman CD, Costantino PD, Takagi S, et al. BoneSource hydroxyapatite cement: a novelbiomaterial for craniofacial skeletal tissue engineering and reconstruction. J Biomed MaterRes.1998,43:428–32.
[108] Chow LC, Hirayama S, Takagi S, et al. Diametral tensile strength and compressive strength of acalcium phosphate cement: effect of applied pressure. J Biomed Mater Res.2000,53:511–7.
[109] Lee DD, Tofighi A, Aiolova M, et al. Alpha-BSM: a biomimetic bone substitute and drugdelivery vehicle. Clin Orthop.1999,7:S396–405.
[110] Yetkinler DN, Goodman SB, Reindel ES, Carter D, Poser RD, Constantz BR. Mechanicalevaluation of a carbonated apatite cement in the fixation of unstable intertrochanteric fractures.Acta Orthop Scand2002,73:157–64.
[111] Christian Ryf, Sabine Goldhah MD, Marek R, Michael B, Beate H. A new injectable brushitecement: first results in distal radius and proximal tibia fractures. Euro J Trauma and EmergencySurg2009,35:389-396.
[112] Keating JF, Hajducka CL. Minimal internal fixation and calcium phosphate cement in thetreatment of fractures of the tibial plateau: A pilot study. J Bone Joint Surg2003,85B:68-73.
[113] Thordarson DB, Bollinger M. SRS cancellous bone cement augmentation of calcaneal fracturefixation, Foot Ankle Int2005,26:347-352.
[114] Schildhauer TA, Bauer TW, Josten C, Muhr G. Open reduction and augmentation of internalfixation with an injectable skeletal cement for the treatment of complex calcaneal fractures. JOrthop Trauma2000,14:309-317.
[115] Stankewich CJ, Swiontkowski MF, Tencer AF, Yetkinler DN, Poser RD. Augmentation offemoral neck fracture fixation with an injectable calcium-phosphate bone mineral cement. JOrthop Res1996,14:786-793.
[116] Elder S, Frankenburg EP, Goulet J. Biomechanical evaluation of calcium phosphatecement-augmented fixation of unstable intertrochanteric fractures. J Orthop Trauma2000,14:386-393.
[117] Schildhauer TA, Bauer TW, Josten C, et al. Open reduction and augmentation of internal fixationwith an injectable skeletal cement for the treatment of complex calcaneal fractures. J OrthopTrauma.2000,14:309–17.
[118] Verlaan JJ, van Helden WH, Oner FC, et al. Balloon vertebroplasty with calcium phosphatecement augmentation for direct restoration of traumatic thoracolumbar vertebral fractures. Spine.2002,27:543–8.
[119] Turner TM, Urban RM, Lim TH, et al. Vertebroplasty using injectable calcium phosphate cementcompared to polymethylmethacrylate in a unique canine vertebral body large defect model.Trans49th Annual Meeting of Orthopaedic Research Society.2003,8:267-290.
[120] Takikawa S, Bauer TW, Turner AS, et al. Comparison of injectable calcium phosphate cementand polymethylmethacrylate for use in vertebroplasty: in-vivo evaluation using an osteopenicsheep model. Presented at the28th Annual Meeting of the Society of Biomaterials.Tampa.2002,April:231-236.
[121] Nakano M, Hirano N, Matsuura K, et al. Percutaneous transpedicular vertebroplasty withcalcium phosphate cement in the treatment of osteoporotic vertebral compression and burstfractures. J Neurosurg.2002,97:287–93.
[122] Takemasa R, Yamamoto H. Repair of osteoporotic vertebral compression fracture bytranspedicular injection of bioactive calcium phosphate cement into the vertebral body. Spine J.2002,2:96-102.
[123] Belkoff SM, Mathis JM, Erbe EM, et al. Biomechanical evaluation of a new bone cement for usein vertebroplasty. Spine.2000,25:1061–4.
[124] Heini PF, Berlemann U, Kaufmann M, et al. Augmentation of mechanical properties inosteoporotic vertebral bones: a biomechanical investigation of vertebroplasty efficacy withdifferent bone cements. Eur Spine J.2001,10:164–71.
[125] Belkoff SM, Mathis JM, Deramond H, et al. An ex vivo biomechanical evaluation of ahydroxyapatite cement for use with kyphoplasty. AJNR Am J Neuroradiol.2001,22:1212–6.
[126] Otsuka M, Matsuda Y, Fox JL, et al. A Novel Skeletal Drug Delivery System Using Sel-f settingCalcium Phosphate Cement9: Effects of the Mixing Solution Volume on Anticancer DrugRelease from Homogenous Drug-load Cement. J Pharm Sci,1995,84(6):733-736.
[127] Sasaki S, Ishii Y. Apatite Cement Containing Antibiotics: Efficacy in Treating ExperimentalOsteomyelitis. J Orthop Sci,1999,4:361-369.
[128] Kamegai A, Shimamurs N, Naitou K, et al. Bone Formation Under the Influence of BoneMorphogenetic Protein/Self-setting Apatite Cement Composite as a Delivery System. BiomedMater Eng,1994,4(4):291-307.
[129] Meraw S J, Reeve CM, Lohes CM, et al. Treatment of Per-implant Defects with CombinationGrowth Factor Cement. J Periodontrol,2000,71(1):8-13.
[130] Bai B, Jazrawi LM, Kummer FJ, Spivak JM. The use of an injectable, biodegradable calciumphosphate bone substitute for the prophylactic augmentation of osteoporotic vertebrae and themanagement of vertebral compression fractures. Spine1999,24(15):1521–1526.
[131] Schildhauer TA, Bennett AP, Wright TM, Lane JM, O’Leary PF. In travertebral bodyreconstruction with an injectable in situ-setting carbonated apatite: biomechanical evaluation ofa minimally invasive technique. J Bone Joint Surg1999,17:67–72.
[132] Mermelstein LE, McLain RF, Yerby SA. Reinforcement of thoracolumbar burst fractures withcalcium phosphate cement. Spine1998,23(6):664–671
[133] Moore DC, Maitra RS, Farjo LA, Graziano GP, Goldstein SA. Restoration of pedicle screwfixation with an in situ setting calcium phosphate cement. Spine1997,22(15):1696–1705.
[134] Renner SM, Lim TH, Kim WJ, Katolik L, An HS, Andersson GB. Augmentation of pediclescrew fixation strength using an injectable calcium phosphate cement as a function of injectiontiming and method. Spine,2004,29(11): E212-216.
[135] Leung KS, Siu WS, Li SF, Qin L, Cheung WH, Tam KF, Lui PP. An in vitro optimized injectablecalcium phosphate cement for augmenting screw fixation in osteopenic goats. J Biomed MasterRes B Appl Biomaster,2006,78(1):153-160.
[136] Hashemi A, Bednar D, Ziada S. Pullout strength of pedicle screws augmented with particulatecalcium phosphate: an experimental study. Spine J,2009,9(5):404-410.
[137] Brown WE, Chow LC (1985) Dental restorative cement pastes. US Patent no.4518430.
[138] Xu HHK, Zhao L, Detamore MS, Takagi S, Chow LC. Umbilical cord stem cell seeding onfast-resorbable calcium phosphate bone cement. Tissue engineering: Part A2010,16:2743-2753.
[139] Moreau JL, Xu HHK Mesenchymal stem cell proliferation and differentiation on an injectablecalcium phosphate-Chitosan composite scaffold, Biomaterials2009,30:2675-2682.
[140] Bohnera M, Baroudb G. Injectability of calcium phosphatepastes. Biomaterials2005,26:1553
[141] Pina S,Torres P M C, Ferreira J M F.Injectability of brushite-forming Mg-substituted andSr-substituted a-TCP bone cements.J Mater Sci:Mater Med2010,21:431
[142] Qi X P,Ye J D,Wang Y J.Improved injectability and in vitro degradation of a calcium phosphatecement containing poly (lactide-co-glycolide) microspheres. Acta Biomater2008,4:1837
[143] Huan ZG, Chang J Calcium-phosphate-silicate composite bone cement: self-setting propertiesand in vitro bioactivity. J Mater Sci: Mater Med200920:833-841.
[144] Becker T A, Kipke D R.Flow properties of liquid calcium alginate polymer injected throughmedical microcatheters for endovascular embolization. J Biomed Mater Res2002,61(4):533
[145] Burguera EF, Xu HHK, Sun L.Injectable calcium phosphate cement: Effects of powder-to-liquidratio and needle size.J Biomed Mater Res B2008,84:493
[146] Ishikawa K. Effects of spherical tetracalcium phosphate on injectability and basic properties ofapatitic cement. Key Eng Mater2003,240-242:369
[147] Jack V, Buchanan FJ, Dunne NJ. Particle attrition of a-tri-calcium phosphate: Effect onmechanical, handling and injectability properties of calcium phosphate cements. Eng Medicine2008,222:19
[148]叶冬平,周子强,梁伟国.一种可注射自固化含锶复合胶原磷酸钙骨水泥的结构和性能.中国组织工程研究与临床康复2009,13(38):7411
[149] Klammer U, Reuther T, Blank M, Reske I, Barralet JE, et al. Phase composition, mechanicalperformance and in vitro biocompatibility of hydraulic setting calcium magnesium phosphatecement. Acta Biomater2010.6:1529-1535.
[150] Leroux L, Hatim Z, Freche M, Lacout JL. Effect of various adjuvants (lactic acid, glycerol, andchitosan) on injectability of a calcium phosphate cement. Bone1999,25:31S-34S.
[151] Gburecka U, Barraletb JE, Spatz K, et al.Ionic modification of calcium phosphate cementviscosity. PartⅠ: Hypodermic injection and strength improvement of apatite cement.Biomaterials2004,25:2187
[152] Kai D,Li D X,et al.Addition of sodium hyalu-ronate and the effect on performance of theinjectable calcium phosphate cement.J Mater Sci:Mater Med2009,20:1595
[153] Tao Y,et al.Synthesis and property of a novel calcium phosphate cement[J].J Biomed Mater ResB,2009,90(2):745
[154] Chen FP, Liu CS, Wei J, Chen XL. Physicochemical Properties and Biocompatibility of WhiteDextrin Modified Injectable Calcium–Magnesium Phosphate Cement. International J AppliedCeramic Technology2010,9:979-990.
[155] Liu CS, Shao H, Chen F, et al. Effects of the granularity of raw materials on the hydration andhardening process of calcium phosphate cement. Biomaterials2003,24:4103-4113.
[156] Dos Santos LA, Carrodeguas RG, et al. Dual-setting calcium phosphate cement modified withammonium ployacrylate. Artificial Organs2003,27:412-418.
[157] Ginebra MP, Canal C, Espanol M, Pastorino D, Montural EB. Calcium phosphate cements asdrug delivery materials. Advanced Drug Delivery Reviews.2012,64:1090-1110.
[158] Verron E, Khairoun I, Guicheux J, Bouler JM. Calcium phosphate biomaterials as bone drugdelivery systems: a review. Drug Discovery Today.2010,15:547-552.
[159]沈卫,刘昌胜,顾燕芳.磷酸钙骨水泥的水化反应、凝结时间及抗压强度.硅酸盐学报1998,26(2):129-135.
[160] Ishikawa K, Miyamoto Y, Kon M, et al. Non-decay type fast-setting calcium phosphate cement:composite with sodium alginate. Biomaterials1995,16:527-532.
[161] Chiang TY, Ho CC, Chen DCH, Lai MH, Ding SJ. Physicochemical properties andbiocompatibility of chitosan oligosaccharide/gelatin/calcium phosphate hybrid cements.Materials Chemistry and Physics.2010,120:282-288.
[162] Liu CS, Wang W, Shen W, et al. Evaluation of the biocompatibility of a nonceramichydroxyapatite. J Endon1997,23:490-493.
[163] Guo H, Su JC, Wei J, Kong H, Liu CS, Biocompatibility and osteogenicity of degradableCa-deficient hydroxyapatite scaffolds from calcium phosphate cement for bone tissueengineering. Acta Biomater2009,5:268-278.
[164]李峰,赵信义,吴军正,等.含银磷酸钙骨水泥生物相容性评价.牙体牙髓周病学杂志2006,16(5):264-268.
[165] Urist MR, Silverman BF, Buring K, et al. The bone induction principle. Clin Orthop Rel Res1967,53:243-283.
[166] Ooms EM, Wolke JGC, Van de Heuvel MT, et al.Histological evaluation of the bone response tocalcium phosphate cement implanted in cortical bone. Biomaterials2003,24:989-1000.
[167] Lanao RPF, Leeuwenburgh SCG, Wolke JGC, Jansen JA. In vitro degradation rate of apatitecalcium phosphate cement with incorporated PLGA microspheres. Acta Biomater2011,7:3459-3468.
[168] Habraken WJEM, Liao HB, Zhang Z, et al. In vivo degradation of calcium phosphate cementincorporated into biodegradable microspheres. Acta Biomater2010,6:2200-2211.
[169] Takahashi K, Fujishiro Y, Yin S, et al. Preparation and compressive strength of α-tricalciumphosphate based cement dispersed with ceramic particles. Ceramics International2004,30(2):199.
[170] Tieliewuhan Y, Hirata I, Sasaki A, et al. Osteoblast proliferation behavior and bone formationand in CO3apatite-collagen sponges with a porous hydroxyapatite frame. Dent Mater J,2004,3:258-264.
[171] Bigi A, Panzavolat S, Sturba L, et al. Normal and osteopenic bone-derived osteoblast response toa biomimetic gelatin-calcium phosphate bone cement. J Biomed Mater Res A2006,4:739-745.
[172] Hu YL, Li H, Li SJ, et al. Preparation and property of injectable calcium phosphate cementincorporated with rhBMP-2loaded chitosan microspheres. Orthopedic Journal of China2010,18:1723-1726.
[173] Bai B, Yin Z, Xu Q, et al. Histological changes of an injectable rhBMP-2/calcium phosphatecement in vertebroplasty of rhesus monkey. Spine,34:1887-1892.
[174] Blom EJ, Klein-Nulend J, Wolke JGC, et al. Transforming growth factor-β1incorporation in anα-tricalcium phosphate/dicalcium phosphate dihydrate/tetracalcium phosphate monoxide cement:release characteristics ans physicochemical properties. Biomaterials2002;23:1261-1268.
[175] Rojbani H, Nyan M, Ohka K, et al, Evaluation of the osteoconductivity of α-tricalciumphosphate, β-tricalcium phosphate, and hydroxyapatite combined with or without simvastatin inrat calvarial defect. J Biomed Mater Res Part A2011,98:488-498.
[176] Morris MS, Lee Y, Lavin MT, et al. Injectable simuvastatin in periodontal defects and alveolarridges: pilot studies. Journal of periodontology2008,1465-1473.
[177] Panzavolta S, Torricelli P, Bracci B, et al. Alendronate and Pamidronate calcium phosphate bonecements: setting properties and in vitro response of osteoblast and osteoclast cells, Journal ofinorganic biochemistry2009,103:101-106.
[178] Hench LL, Splinter RJ, Allen WC, et al. Bonding mechanisms at the interface of ceramicprosthetic materials. J Biomed Mater Res A,1971,5(6):117-141.
[179] Wilson J, Pigott GH, Schoen FJ, et al. Toxicology and biocompatibility of bioglasses. J BiomedMater Res,1981,15(6):805-817
[180] Hench LL. Bioceramics: from concept to clinic. J Am Ceram Soc,1991,74(7):1487-1510
[181] Hench LL. The story of bioglass. J Mater Sci Mater Med,2006,17(11):967-978
[182] Xynos ID,Edgar AJ,Buttery LD,et al. Gene-expression profiling of human osteoblastsfollowing treatment with the ionic products of Bioglass45S5dissolution. J Biomed Mater Res,2001,55(2):151-157
[183] Hoppe A, Guldal NS,Boccaccini AR. A review of the biological response to ionic dissolutionproducts from bioactive glasses and glass-ceramics. Biomaterials,2011,32(11):2757-2774
[184] Wheeler DL, Eschbach EJ, Hoellrich RG, et al. Assessment of resorbable bioactive material forgrafting of critical-size cancellous defects. J Orthop Res,2000,18(1):140-148
[185] Loty C, Sautier JM, Tan MT, et al. Bioactive glass stimulates in vitro osteoblast differentiationand creates a favorable template for bone tissue formation. J Bone Miner Res,2001,16(2):231-239
[186] Yuan H, Bruijn JD, Zhang X, et al. Bone induction by porous glass ceramic made fromBioglass(45S5). J Biomed Mater Res,2001,58(3):270-276
[187] Kirk JF, Ritter G, Waters C, et al. Osteoconductivity and osteoinductivity of NanoFUSE DBM.Cell Tissue Bank,2012,[Epub ahead of print]
[188] Gerhardt LC, Widdows KL, Erol MM, et al. The pro-angiogenic properties of multi-functionalbioactive glass composite scaffolds. Biomaterials,2011,32(17):4096-4108.
[189] Lin FH, Huang YY, Hon MH, et al. Fabrication and biocompatibility of a porous bioglassceramic in a Na2O-CaO-SiO2-P2O5system. J Biomed Eng,1991,13(4):328-334.
[190] Kim HW, Song JH, Kim HE. Bioactive glass nanofiber-collagen nanocomposite as a novel boneregeneration matrix. J Biomed Mater Res Part A2006,79:698-705.
[191] Hautamaki M, Meretoja VV, Mattila RH, et al. Osteoblast response to polymethyl methacrylatebioactive glass composite. J Mater Sci: Mater in Med2010,21:1685-1692.
[192] Hautamaki MP, Aho AJ, Alander P, et al. Repair of bone segment defects with surface porousfiber-reinforced polymethyl methacrylate (PMMA) composite prosthesis: histomorphometricincorporation model and characterization by SEM. Acta orthopaedica2008,79:555-564.
[193] He Q, Chen H, Huang L, Dong J, Guo D, et al. Porous surface modified bioactive bone cementfor enhanced bone bonding. PLoS One2012,7: e42525.
[194] Verrier S, Blaker JJ, Maquet V, et al. PDLLA/Bioglass composites for soft-tissue and hard-tissueengineering: an in vitro cell biology assessment. Biomaterials,2004,25(15):3013-3021
[195] Misra SK, Ansari TI, Valappil SP, et al. Poly(3-hydroxybutyrate) multifunctional compositescaffolds for tissue engineering applications. Biomaterials,2010,31(10):2806-2815
[196] Kim HW, Lee EJ, Kim HE, et al. Effect of fluoridation of hydroxyapatite inhydroxyapatite-polycaprolactone composites on osteoblast activity. Biomaterials,2005,26(21):4395-4404.
[197] Aldini NN, Fini M, Giavaresi G, et al. Osteointegration of bioactive glass-coated and uncoatedzirconia in osteopenic bone: an in vivo experimental study. J Biomed Mater Res A,2004,68(2):264-272.
[198] Fathi MH, Doostmohammadi A. Bioactive glass nanopowder and bioglass coating forbiocompatibility improvement of metallic implant. J Mater Process Technol,2009,209(3):1385-1391
[199] Mehdikhani-Nahrkhalaji M, Fathi MH, Mortazavi V, et al. Novel nanocomposite coating fordental implant applications in vitro and in vivo evaluation. J Mater Sci Mater Med,2012,23(2):485-495.
[200] Pantchev A, Nohlert E, Tegelberg A. Endodontic surgery with and without inserts of bioactiveglass PerioGlas: a clinical and radiographic follow-up. Oral Maxillofac Surg,2009,13(1):21-26
[201] Seddighi A, Seddighi AS, Zali AR, et al. Study of the role of nova bone as a filling material incervical cage in anterior fusion of cervical spine in patients with degenerative cervical discdisease. Glob J Health Sci,2011,3(1):155-160.
[202] Tsigkou O, Jones JR, Polak JM, Stevens MM. Differentiation of fetal osteoblasts and formationof mineralized bone nodules by45S5Bioglass conditioned medium in the absence ofosteogenic supplements. Biomaterials2009,30:3542-3550.
[203] Laurencin CT, Ambrosio AMA, Borden MD, Cooper JA. Tissue engineering: orthopedicapplications. Annu Rev Biomed Eng1999,1:19-46.
[204] Huan ZG, Chang J (2009) Novel bioactive composite bone cements based on the β-tricalciumphosphate-monocalcium phosphate monohydrate composite cement system. Acta Biomaterialia5:1253-1264.
[205] Leach JK, Kaigler D, Wang Z, Krebsbach PH, Mooney DJ. Coating of vegf-releasing scaffoldwith bioactive glass for angiogenesis and bone regeneration. Biomaterials2006,27:3249-3255.
[206] Hoppe A, Guldal NS, Boccaccini AR. A review of the biological response to ionic dissolutionproducts from bioactive glasses and glass-ceramics. Biomaterials201132:2757-2774.
[207] Lee MH, Ducheyne P, Lynch L, et al. Effect of biomaterial surface properties onfibronectin-alpha(5)beta(1) integrin interaction and cellular attachment. Biomaterials2006,27:1907-1916.
[208] Lee JY, Kang BS, Hicks B, Chancellor TF, Chu BH, Wang HT, et al.The control of cell adhesionand viability by zinc oxide nanorods. Biomaterials2008,29:3743-3749.
[209] Bosetti M, Cannas M The effect of bioactive glasses on bone marrow stromal cellsdifferentiation. Biomaterials2005,26:3873-3879.
[210] Reilly GC, Radin S, Chen AT, Ducheyne P. Differential alkaline phosphatase responses of ratand human bone marrow derived mesenchymal stem cells to45S5bioactive glass. Biomaterials2007,28:4091-4097.
[211] Pamula E, Kokoszka J, Cholewa-kowalska K, Laczka M, Kantor L, et la.Degradation,bioactivity, and osteogenic potential of composites made of PLGA and two different sol-gelbioactive glasses. Ann Biomed Eng2011,39:2114-2129.
[212] Hennessy KM, Clem WC, Phipps MC, Sawyer AA, Shaikh FM, et al.The effect of RGDpeptides on osseointegration of hydroxyapatite. Biomaterials2008,29:3075-3083.