The relevance of biomaterials to the prevention and treatment of osteoporosis

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Osteoporosis is a worldwide disease with a very high prevalence in humans older than 50. The main clinical consequences are bone fractures, which often lead to patient disability or even death. A number of commercial biomaterials are currently used to treat osteoporotic bone fractures, but most of these have not been specifically designed for that purpose. Many drug- or cell-loaded biomaterials have been proposed in research laboratories, but very few have received approval for commercial use. In order to analyze this scenario and propose alternatives to overcome it, the Spanish and European Network of Excellence for the Prevention and Treatment of Osteoporotic Fractures, ‘‘Ageing’’, was created. This network integrates three communities, e.g. clinicians, materials scientists and industrial advisors, tackling the same problem from three different points of view. Keeping in mind the premise ‘‘living longer, living better’’, this commentary is the result of the thoughts, proposals and conclusions obtained after one year working in the framework of this network.
RESEARCHER ID M-3378-2014 (María Vallet Regí) ORCID 0000-0002-6104-4889 (María Vallet Regí)
[1] Planell JA, Navarro M. Challenges of bone repair. In: Planell, Best, Lacroix, Merolli, editors. Bone repair biomaterials. Cambridge: CRC Press; 2009. [2] Streubel PN, Ricci WM, Wong A, Gardner MJ. Mortality after distal femur fractures in elderly patients. Clin Orthop Relat Res 2011;469:1188–96. [3] National Osteoporosis Foundation. [4] Hoerger TJ, Downs KE, Lakshmanan MC, Lindrooth RC, Plouffe Jr L, Wendling B, et al. Healthcare use among U.S. women aged 45 and older: total costs and costs for selected postmenopausal health risks. J Womens Health Gend Based Med 2007;8:1077–89. [5] Rissanen P, Aro S, Sintonen H, Asikainen K, Slätis P, Paavolainen P. Costs and cost-effectiveness in hip and knee replacements: a prospective study. Int J Technol Assess Health Care 1997;13:574–88. [6] Day JC. Population projections of the United States by age, sex, race and Hispanic origin: 1995 to 2050. Washington, DC: US Government Printing Office; 1996. [7] Ray NF, Chan JK, Thamer M, Melton III LJ. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res 1997;12:24–35. [8] Chrischilles E, Shireman T, Wallace R. Costs and health effects of osteoporotic fractures. Bone 1994;15:377–86. [9] Melton LJ. Hip fractures: a worldwide problem today and tomorrow. Bone 1993;14:1–8. [10] Kanis JA, Johnell O. Requirements for DXA for the management of osteoporosis in Europe. Osteoporos Int 2005;16:229–38. [11] Manton KG, Gu X. Changes in the prevalence of chronic disability in the United States black and nonblack population above age 65 from 1982 to 1999. Proc Natl Acad Sci USA 2001;98:6354–9. [12] Boyd CM, Landefeld CS, Counsell SR, Palmer RM, Fortinsky RH, Kresevic D, et al. Recovery of activities of daily living in older adults after hospitalization for acute medical illness. J Am Geriatr Soc. 2008;56:2171–9. [13] Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013;381:752–62. [14] Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146–56. [15] Rodríguez-Mañas L, Féart C, Mann G, Viña J, Chatterji S, Chodzko-Zajko W, et al. Searching for an operational definition of frailty: a Delphi method based consensus statement: the frailty operative definition-consensus conference project. J Gerontol A Biol Sci Med Sci 2013;68:62–7. [16] Espeland MA, Gill TM, Guralnik J, Miller ME, Fielding R, Newman AB, et al. Designing clinical trials of interventions for mobility disability: results from 1802 D. Arcos et al. / Acta Biomaterialia 10 (2014) 1793–1805 Author's personal copy the lifestyle interventions and independence for elders pilot (LIFE-P) trial. J Gerontol A Biol Sci Med Sci 2007;62:1237–43. [17] Felsenberg D, Silman AJ, Lunt M, Armbrecht G, Ismail AA, Finn JD, et al. Incidence of vertebral fracture in europe: results from the European Prospective Osteoporosis Study (EPOS). J Bone Miner Res 2002;17:716–24. [18] Gauthier A, Kanis JA, Jiang Y, Martin M, Compston JE, Borgstrom F, et al. Epidemiological burden of postmenopausal osteoporosis in the UK from 2010 to 2021: estimations from a disease model. Arch Osteoporos 2011;6:179–88. [19] Seeman E, Delmas PD. Bone quality—the material and structural basis of bone strength and fragility. N Engl J Med 2006;354:2250–61. [20] Consensus conference. Osteoporosis. JAMA 1984;252:799–802. [21] Ismail AA, Cooper C, Felsenberg D, Varlow J, Kanis JA, Silman AJ, et al. Number and type of vertebral deformities: epidemiological characteristics and relation to back pain and height loss. European Vertebral Osteoporosis Study Group. Osteoporos Int 1999;9:206–13. [22] Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. J Am Med Assoc 1999;282:637–45. [23] Lewiecki EM, Compston JE, Miller PD, Adachi JD, Adams JE, Leslie WD, et al. Official positions for FRAX(R) bone mineral density and FRAX(R) simplification from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX(R). J Clin Densitom 2011;14:226–36. [24] Gonzalez-Macias J, Marin F, Vila J, Diez-Perez A. Probability of fractures predicted by FRAX(R) and observed incidence in the Spanish ECOSAP Study cohort. Bone 2012;50:373–7. [25] Dennison EM, Compston JE, Flahive J, Siris ES, Gehlbach SH, Adachi JD, et al. Effect of co-morbidities on fracture risk: findings from the Global Longitudinal Study of Osteoporosis in Women (GLOW). Bone 2012;50:1288–93. [26] Hans DB, Kanis JA, Baim S, Bilezikian JP, Binkley N, Cauley JA, et al. Joint official positions of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX�. Executive summary of the 2010 Position Development Conference on Interpretation and use of FRAX� in clinical practice. J Clin Densitom 2011;14:171–80. [27] Zioupos P, Hansen U, Currey JD. Microcracking damage and the fracture process in relation to strain rate in human cortical bone tensile failure. J Biomech 2008;41:2932–9. [28] Diez-Perez A, Guerri R, Nogues X, Caceres E, Pena MJ, Mellibovsky L, et al. Microindentation for in vivo measurement of bone tissue mechanical properties in humans. J Bone Miner Res 2010;25:1877–85. [29] Guerri-Fernandez RC, Nogues X, Quesada Gomez JM, Torres Del Pliego E, Puig L, Garcia-Giralt N, et al. Microindentation for in vivo measurement of bone tissue material properties in atypical femoral fracture patients and controls. J Bone Miner Res 2013;28:162–8. [30] Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res 2000;15:1526–36. [31] Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P, Griesmacher A, et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 2011;22:391–420. [32] Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2013;24:23–57. [33] Lekamwasam S, Adachi JD, Agnusdei D, Bilezikian J, Boonen S, Borgstrom F, et al. A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos Int 2012;23:2257–76. [34] Rizzoli R, Adachi JD, Cooper C, Dere W, Devogelaer JP, Diez-Perez A, et al. Management of glucocorticoid-induced osteoporosis. Calcif Tiss Int 2012;91:225–43. [35] Kaufman JM, Reginster JY, Boonen S, Brandi ML, Cooper C, Dere W, et al. Treatment of osteoporosis in men. Bone 2013;53:134–44. [36] Diez-Perez A, Hooven FH, Adachi JD, Adami S, Anderson FA, Boonen S, et al. Regional differences in treatment for osteoporosis. The Global Longitudinal Study of Osteoporosis in Women (GLOW). Bone 2011;49:493–8. [37] Diez-Perez A, Olmos JM, Nogues X, Sosa M, Diaz-Curiel M, Perez-Castrillon JL, et al. Risk factors for prediction of inadequate response to antiresorptives. J Bone Miner Res 2012;27:817–24. [38] Diez-Perez A, Adachi JD, Agnusdei D, Bilezikian JP, Compston JE, Cummings SR, et al. Treatment failure in osteoporosis. Osteoporos Int 2012;23:2769–74. [39] Rizzoli R, Reginster JY, Boonen S, Breart G, Diez-Perez A, Felsenberg D, et al. Adverse reactions and drug–drug interactions in the management of women with postmenopausal osteoporosis. Calcif Tiss Int 2011;89:91–104. [40] Pazianas M, Abrahamsen B, Eiken PA, Eastell R, Russell RG. Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate—Danish National Register Based Cohort Study. Osteoporos Int 2012;23:2693–701. [41] Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Eng J Med 2007;357:1799–809. [42] Kwong FN, Harris MB. Recent developments in the biology of fracture repair. J Am Acad Orthop Surg 2008;16:619–25. [43] Diaz-Garcia RJ, Oda T, Shauver MJ, Chung KC. A systematic review of outcomes and complications of treating unstable distal radius fractures in the elderly. J Hand Surg Am 2011 May;36(5):824–35. [44] Papanastassiou ID, Phillips FM, Van Meirhaeghe J, Berenson JR, Andersson GB, Chung G, et al. Comparing effects of kyphoplasty, vertebroplasty, and nonsurgical management in a systematic review of randomized and nonrandomized controlled studies. Eur Spine J 2012;21:1826–43. [45] Edidin AA, Ong KL, Lau E, Kurtz SM. Mortality risk for operated and nonoperated vertebral fracture patients in the Medicare population. J Bone Miner Res 2011;26:1617–26. [46] Gao H, Liu Z, Xing D, Gong M. Which is the best alternative for displaced femoral neck fractures in the elderly? A meta-analysis. Clin Orthop Relat Res 2012;470:1782–91. [47] Keating JF, Grant A, Masson M, Scott NW, Forbes JF. Randomized comparison of reduction and fixation, bipolar hemiarthroplasty, and total hip arthroplasty. Treatment of displaced intracapsular hip fractures in healthy older patients. J Bone Joint Surg Am 2006;88:249–60. [48] Morshed S, Bozic KJ, Ries MD, Malchau H, Colford Jr JM. Comparison of cemented and uncemented fixation in total hip replacement: a meta-analysis. Acta Orthop 2007;78:315–26. [49] Yamada H, Yoshihara Y, Henmi O, Morita M, Shiromoto Y, Kawano T, et al. Cementless total hip replacement: past, present, and future. J Orthop Sci 2009;14:228–41. [50] Parker MJ, Gurusamy KS, Azegami S. Arthroplasties (with and without bone cement) for proximal femoral fractures in adults. Cochrane Database Syst Rev. 2010;16:CD001706. [51] Abdulkarim A, Ellanti P, Motterlini N, Fahey T, O’Byrne JM. Cemented versus uncemented fixation in total hip replacement: a systematic review and metaanalysis of randomized controlled trials. Orthop Rev (Pavia) 2013;5:e8. [52] Lorich DG, Geller DS, Nielson JH. Osteoporotic pertrochanteric hip fractures. Management and current controversies. J Bone Joint Surg Am 2004;86:398–410. [53] Fini M, Giavaresi G, Torricelli P, Krajewski A, Ravaglioli A, Mattioli Belmonte M, et al. Biocompatibility and osteointergration in osteoporotic bone. J Bone Joint Surg Br 2001;83:139–43. [54] Heini PF, Berlemann U, Kaufman M, Lippuner K, Fankhauser C, Van Landuyt P. Augmentation of mechanical properties in osteoporotic vertebral bones – a biomechanical investigation of vertebroplasty efficacy with different bone cements. Eur Spine J 2001;10:164–71. [55] Yu L, Li Y, Zhao K, Tang Y, Cheng Z, Chen J, et al. A novel injectable calcium phosphate cement-bioactive glass composite for boneregeneration. PLOS One 2013. [56] Hoekstra JWM, van den Beucken JJJP, Leeuwenburgh SCG, Bronkhorst EM, Meijer GJ, Jansen JA. Tantalum oxide and barium sulfate as radiopacifiers in injectable calcium phosphate-poly(lactic-co-glycolic acid) cements for monitoring in vivo degradation. J Biomed Mater Res 2014;A102:141–9. [57] Chen W, Zhou H, Weir MD, Tang M, Bao C, Xu HHK. Human embryonic stem cell-derived mesenchymal stem cell seeding on calcium phosphate cementchitosan- RGD scaffold for bone repair. Tiss Eng A 2013;19:915–27. [58] Vorndran E, Geffers M, Ewald A, Lemm M, Nies B, Gbureck U. Ready-to-use injectable calcium phosphate bone cement paste as drug carrier. Acta Biomater 2013;9:9558–67. [59] Franchi M, Fini M, Giavaresi G, Ottani V. Peri-implant osteogenesis in health and osteoporosis. Micron 2005;36:630–44. [60] Fini M, Giavaresis G, Torricelli P, Borsari V, Giardino R, Nicolini A, et al. Osteoporosis and biomaterial osteointegration. Biomed Pharmacother 2004;58:487–93. [61] Verron E, Gauthier O, Janvier P, Pilet P, Lesouer J, Bujoli B, et al. In vivo bone augmentation in an osteoporotic environment using bisphosphonate-loaded calcium deficient apatite. Biomaterials 2010;31:7776–84. [62] Manzano M, Lozano D, Arcos D, Portal-Nuñez S, López C, Esbrit P, et al. Comparison of the osteoblastic activity conferred to si-doped hydroxyapatite scaffolds by different osteostatin coating. Acta Biomater 2011;7:3555–62. [63] Arcos D, Vallet-Regi M. Bioceramics for drug delivery. Acta Mater 2013;61:890–911. [64] Verron E, Bouler JM, Guicheux J. Controlling the biological function of calcium phosphate bone substitutes with drugs. Acta Biomater 2012;8:3541–51. [65] Trejo CG, Lozano D, Manzano M, Doadrio JC, Salinas AJ, Dapia S, et al. The osteoinductive properties of mesoporous silicate coated with osteostatin in a rabbit femur cavity defect model. Biomaterials 2010;31:8564–73. [66] Manzano M, Vallet-Regí M. Revisiting bioceramics: bone regenerative and local drug delivery systems. Prog. Solid State Ch 2012;40:17–30. [67] Chapman JR, Harrington RM, Lee KM, Anderson PA, Tencer AF, Kowalski D. Factors affecting the pullout strength of cancellous bone screws. J Biomech Eng 1996;118:391–8. [68] Frigg R, Frenk A, Wagner M. Biomechanics of plate osteosynthesis. Tech Orthop 2007;22:203–8. [69] McKoy BE, An YH. An injectable cementing screw for fixation in osteoporotic bone. J Biomed Mater Res 2000;53:216–20. [70] Hu MH, Wu HT, Chang MC, Yu WK, Wang ST, Liu CL. Polymethylmethacrylate augmentation of the pedicle screw: the cement distribution in the vertebral body. Eur Spine J 2011;20:1281–8. [71] Choma TJ, Pfeiffer FM, Swope RW, Hirner JP. Pedicle screw design and cement augmentation in osteoporotic vertebrae: effects of fenestrations and cement viscosity on fixation and extraction. Spine (Phila Pa 1976) 2012;37:E1628–32. D. Arcos et al. / Acta Biomaterialia 10 (2014) 1793–1805 1803 Author's personal copy [72] Gittens RA, Olivares-Navarrete R, Cheng A, Anderson DM, McLachlan T, Stephan I, et al. The roles of titanium surface micro/nanotopography and wettability on the differential response of human osteoblast lineage cells. Acta Biomater 2013;9:6268–77. [73] Buser D, Schenk RK, Steinemann S, Fiorellini JP, Fox CH, Stich H. Influence of surface characteristics on bone integration of titanium implants – a histomorphometric study in miniature pigs. J Biomed Mater Res 1991;25:889–902. [74] Cocharan DL, Jackson JM, Bernard JP, ten Bruggenkate CM, Buser D, Taylor TD, et al. A 5-year prospective multicenter study of early loaded titanium implants with a sandblasted and acid-etched surface. Int Oral Maxillofac Implants 2011;26:1324–32. [75] Orsini G, Piattelli M, Scarano A, Petrone G, Kenealy J, Piattelli A, et al. Randomized, controlled histologic and histomorphometric evaluation of implants with nanometer-scale calcium phosphate added to the dual acidetched surace in the human posterior maxilla. J Periodontol 2007;78:209–18. [76] Collaert B, Wijnen L, De Bruyn H. A 2-year prospective study on immediate loading with fluoride-modified implants in the edentulous mandible. Clin Oral Implants Res 2011;22:1111–6. [77] Park JH, Wasilewski CE, Almodovar N, Olivares-Navarrete R, Boyan BD, Tannenbaum R, et al. The responses to surface wettability gradientes induced by chitosan nanofilms on microtextured titanium mediated by specific integrin receptors. Biomaterials 2012;33:7386–93. [78] Bornstein MM, Wittneben JG, Bragger U, Buser D. Early loading at 21 days of non-submerged titanium implants with a chemically modified sandblasted and acid-etched surface. 3-year results of a prospective study in the posterior mandible. J Periodontol 2010;81:809–18. [79] Nguyen HQ, Deporter DA, Pilliar RM, Valiquette N, Yakubovich R. The effect of sol–gel-formed calcium phosphate coatings on bone in growth and osteoconductivity of porous-surfaced Ti alloy implants. Biomaterials 2004;25:865–76. [80] Yang Y, Kim KH, Ong JL. A review on calcium phosphate coatings produced using a sputtering process—an alternative to plasma spraying. Biomaterials 2005;26:327–37. [81] Surmenev RA. A review of plasma-assisted methods for calcium phosphatebased coatings fabrication. Surf Coat Technol 2012;206:2035–56. [82] Heimann RB. Thermal spraying of biomaterials. Surface Coatings Technol 2006;201:2012–9. [83] Surmenev RA, Surmeneva MA, Ivanova AA. Significance of calcium phosphate coatings for the enhancement of new bone osteogenesis – A review. Acta Biomater 2014;10:557–79. [84] Bright DS, Clark HG, McCollum DE. Serum analysis and toxic effects of methylmethacrylate. Surg Forum 1972;23:455–7. [85] Leeson MC, Lippitt SB. Thermal aspects of the use of polymethylmethacrylate in large metaphyseal defects in bone: A clinical review and laboratory study. Clin Orthop Relat Res 1993:239–45. [86] Topoleski LDT, Ducheyne P, Cuckler JM. A fractographic analysis of in vivo poly(methyl methalcrylate) bone cement failure mechanisms. J Biomed Mater Res 1990;24:135–54. [87] Berlemann U, Ferguson SJ, Nolte LP, Hein PF. Adjacent vertebral failure after vertebroplasty—a biomechanical investigation. J Bone Joint Surg Br 2002;84B:748–52. [88] Lewis G. Injectable bone cements for use in vertebroplasty and kyphoplasty: state-of-the-art review. J Biomed Mater Res B Appl Biomater 2006;76:456–68. [89] Urlings TAJ, Van Der Linden E. Elastoplasty: first experience in 12 patients. Cardiovasc Intervent Radiol 2013;36:479–83. [90] Blattert TR, Jestaedt L, Weckbach A. Suitability of a calcium phosphate cement in osteoporotic vertebral body fracture augmentation: a controlled, randomized, clinical trial of balloon kyphoplasty comparing calcium phosphate versus polymethylmethacrylate. Spine 2009;34:108–14. [91] Piazzolla A, De Giorgi G, Solarino G. Vertebral body recollapse without trauma after kyphoplasty with calcium phosphate cement. Musculoskelet Surg 2011;95:141–5. [92] Boszczyk B. Prospective study of standalone balloon kyphoplasty with calcium phosphate cement augmentation in traumatic fractures (G. Maestretti et al.). Eur Spine J 2007;16:611. [93] Maestretti G, Cremer C, Otten P, Jakob RP. Prospective study of standalone balloon kyphoplasty with calcium phosphate cement augmentation in traumatic fractures. Eur Spine J 2007;16:601–10. [94] Bernards CM, Chapman JR, Mirza SK. Lethality of embolizednorian bone cement varies with the time between mixing and embolization. In: 50th Annual Meeting of the Orthopaedic Research Society, San Fransisco; 2004. p. 0254. [95] Krebs J, Aebli N, Goss BG, Sugiyama S, Bardyn T, Boecken I, et al. Cardiovascular changes after pulmonary embolism from injecting calcium phosphate cement. J Biomed Mater Res B Appl Biomater 2007;82:526–32. [96] Dressel S, Jarvers JSG, Josten C, Blattert TR. Percutaneous balloon kyphoplasty in osteoporotic vertebral body fracture with a calcium aluminate ceramic (Xeraspine�). Eur Musculoskelet Rev 2012;7:209–12. [97] Rauschmann M, Vogl T, Verheyden A, Pflugmacher R, Werba T, Schmidt S, et al. Bioceramic vertebral augmentation with a calcium sulphate/ hydroxyapatite composite (Cerament™ SpineSupport) in vertebral compression fractures due to osteoporosis. Eur Spine J 2010;19:887–92. [98] Masala S, Nano G, Marcia S, Muto M, Fucci FPM, Simonetti G. Osteoporotic vertebral compression fractures augmentation by injectable partly resorbable ceramic bone substitute (Cerament™|SPINE SUPPORT): A prospective nonrandomized study. Neuroradiology 2012;54:589–96. [99] Bai B, Kummer FJ, Spivak J. Augmentation of anterior vertebral body screw fixation by an injectable, biodegradable calcium phosphate bone substitute. Spine 2001;26:2679–83. [100] Bohner M, Lemaitre J, Cordey J, Gogolewski S, Ring TA, Perren SM. Potential use of biodegradable bone cement in bone surgery: holding strength of screws in reinforced osteoporotic bone. Orthop Trans 1992;16:401–2. [101] Mermelstein LE, Chow LC, Friedman C. Crisco Iii JJ. The reinforcement of cancellous bone screws with calcium phosphate cement. J Orthop Trauma 1996;10:15–20. [102] Stankewich CJ, Swiontkowski MF, Tencer AF, Yetkinler DN, Poser RD. Augmentation of femoral neck fracture fixation with an injectable calciumphosphate bone mineral cement. J Orthop Res 1996;14:786–93. [103] Larsson S, Stadelmann VA, Arnoldi J, Behrens M, Hess B, Procter P, et al. Injectable calcium phosphate cement for augmentation around cancellous bone screws. In vivo biomechanical studies. J Biomech 2012;45:1156–60. [104] Stadelmann VA, Bretton E, Terrier A, Procter P, Pioletti DP. Calcium phosphate cement augmentation of cancellous bone screws can compensate for the absence of cortical fixation. J Biomech 2010;43:2869–74. [105] Vallet-Regí M, Colilla M, Izquierdo-Barba I. Bioactive mesoporoussilicas as controlled delivery systems: Application in bonetissue regeneration. J Biomed Nanotechnol 2008;4:1–15. [106] Hutmacher DW. Scaffolds in tissue engineering bone and cartilage. Biomaterials 2000:2529–43. [107] Stevens MM, George J. Exploring and engineering the cell surface interface. Science 2005;310:1135–8. [108] Schieker M, Seitz H, Drosse I, Seitz S, Mutschler W. Biomaterials as scaffolds for bone tissue engineering. Eur J Trauma 2006;32:114–24. [109] Kruyt MC, de Bruijn JD, Wilson CE, et al. Viable osteogenic cells are obligatory for tissue-engineered ectopic bone formation in goats. Tissue Eng 2003;9:327–36. [110] Dorozhkin SV, Epple M. Biological and medical significance of calcium phosphates. Angew Chem Int Ed 2002;41:3130–46. [111] Vallet-Regí M, González-Calbet JM. Calcium phosphates as substitution of bone tissues. Progr Solid State Chem 2004;32:1–31. [112] Bohner M. Resorbable biomaterials as bone graft substitutes. Mater Today 2010;13:24–30. [113] Weiner S, Wagner HD. The material bone: structure–mechanical function relations. Annu Rev Mater Sci 1998;28:271–9. [114] Tadic D, Epple M. A thorough physicochemical characterisation of 14 calcium phosphate-based bone substitution materials in comparison to natural bone. Biomaterials 2004;25:987–94. [115] Weiss P, Obadia L, Magne D, Bourges X, Rau C, Weitkamp T, et al. Synchrotron X-ray microtomography (on a micron scale) provides three-dimensional imaging representation of bone ingrowth in calcium phosphate biomaterials. Biomaterials 2003;24:4591–601. [116] Schilling AF, Linhart W, Filke S, Gebauer M, Schinke T, Rueger JM, et al. Resorbability of bone substitute biomaterials by human osteoclasts. Biomaterials 2004;25:3963–72. [117] Detsch R, Hagmeyer D, Neumann M, Schaefer S, Vortkamp A, Wuelling M, et al. The resorption of nanocrystalline calcium phosphates by osteoclast-like cells. Acta Biomater 2010;6:3223–33. [118] Xynos ID, Hukkanen MVJ, Batten JJ, Buttery LD, Hench LL, Polak JM. Bioglass (R) 45S5 stimulates osteoblast turnover and enhances bone formation in vitro: implications and applications for bone tissue engineering. Calcif Tiss Int 2000;67:321–9. [119] Han P, Wu C, Xiao Y. The effect of silicate ions on proliferation, osteogenic differentiation and cell signaling pathways (WNT and SHH) of bone marrow stromal cells. Biomater Sci 2013;1:379–92. [120] Aguirre A, González A, Planell JA, Engel E. Extracellular calcium modulates in vitro bone marrow-derived Flk-1+ CD34+ progenitor cell chemotaxis and differentiation through a calcium-sensing receptor. Biochem Biophys Res Commun 2010;393:156–61. [121] Hench LL. Genetic design of bioactive glass. J. Eur Ceram Soc 2009;29:1257–65. [122] Rahaman MN, Day DE, Bal BS, Fu Q, Jung SB, Bonewald LF, et al. Bioactive glass in tissue engineering. Acta Biomater 2011;7:2355–73. [123] Xynos ID, Edgar AJ, Buttery LDK, Hench LL, Polak JM. Gene-expression profiling of human osteoblasts following treatment with the ionic products of Bioglass� 45S5 dissolution. J Biomed Mater Res 2001;55:151–7. [124] Gorustovich AA, Roether JA, Boccaccini AR. Effect of bioactive glasses on angiogenesis: in-vitro and in-vivo evidence. A review. Tiss Eng B 2010;16:199–207. [125] Navarro M, Ginebra MP, Planell JA. Cellular response to calcium phosphate glasses with controlled solubility. J Biomed Mater Res 2003;67A:1009–15. [126] Charles-Harris M, Koch M, Navarro M, Lacroix D, Engel E, Planell JA. A PLA/ calcium phosphate degradable composite material for bone tissue engineering: an in vitro study. J Mater Sci Mater Med 2008;19:1503–13. [127] Navarro M, Sanzana ES, Planell JA, Ginebra MP, Torres PA. In vivo behavior of calcium phosphate glasses with controlled solubility. Key Eng Mater 2005;284–286:893–6. [128] Gentleman E, Fredholm YC, Jell G, Lotfibakhshaiesh N, O’Donnell MD, Hill RG, et al. The effects of strontium-substituted bioactive glasses on osteoblasts and osteoclasts in vitro. Biomaterials 2010;31:3949–56. 1804 D. Arcos et al. / Acta Biomaterialia 10 (2014) 1793–1805 Author's personal copy [129] Teofilo JM, Brentegani LG, Lamano-Carvalho TL. Bone healing in osteoporotic female rats following intra-alveolar grafting of bioactive glass. Arch Oral Biol 2004;49:755–62. [130] Vallet-Regí M, Balas F, Arcos D. Mesoporous materials for drug delivery. Angew Chem Int Ed 2007;46:7548–58. [131] Schliephake H, Weich HA, Dullin C, Gruber R, Frahse S. Mandibular bone repair by implantation of rhBMP-2 in a slow release carrier or polylactic acid—an experimental study in rats. Biomaterials 2008;29:103–10. [132] Devescovi V, Leonardi E, Ciapetti G, Cenni E. Growth factors in bone repair. Chir Organi Mov 2008;92:161–8. [133] Lissenberg-Thunnissen SN, de Gorter DJJ, Sier CFM, Schipper IB. Use and efficacy of bone morphogenetic proteins in fracture healing. Int Orthop 2011;35:1271–80. [134] Wernike E, Montjovent MO, Liu Y, Wismeijer D, Hunziker EB, Siebenrock KA, et al. VEGF incorporated into calcium phosphate ceramics promotes vascularisation and bone formation in vivo. Eur Cells Mater 2010;19:30–40. [135] Lode A, Wolf-Brandstetter C, Reinstorf A, Bernhardt A, Koenig U, Pompe W, et al. Calcium phosphate bone cements, functionalized with VEGF: release kinetics and biological activity. J Biomed Mater Res 2007;81A:474–83. [136] Evans CH. Gene therapy for bone healing. Exp Rev Mol Med 2010;23(12):e18. [137] Bushman FD. Retroviral integration and human gene therapy. J Clin Invest 2007;117:2083–6. [138] Yi Y, Hahm SH, Lee KH. Retroviral gene therapy: safety issues and possible solutions. Curr Gene Ther 2005;5:25–35. [139] Sokolova V, Epple M. Inorganic nanoparticles as carriers of nucleic acids into cells. Angew Chem Int Ed 2008;47:1382–95. [140] Guo X, Huang L. Recent advances in nonviral vectors for gene delivery. Acc Chem Res 2012;45:971–9. [141] Wegman F, Bijenhof A, Schuijff L, Oner FC, Dhert WJA, Alblas J. Osteogenic differentiation as a result of BMP-2 plasmid DNA based gene therapy in vitro and in vivo. Eur Cell Mater 2011;21:230–42. [142] Zhang C, Wang KZ, Qiang H, Tang YL, Li QA, Li MA, et al. Angiopoiesis and bone regeneration via co-expression of the hVEGF and hBMP genes from an adeno-associated viral vector in vitro and in vivo. Acta Pharmacol Sin 2010;31:821–30. [143] Krebs MD, Salter E, Chen E, Sutter KA, Alsberg E. Calcium phosphate-DNA nanoparticle gene delivery from alginate hydrogels induces in vivo osteogenesis. J Biomed Mater Res A 2010;92A:1131–8. [144] Keeney M, van den Beucken JJJP, van der Kraan PM, Jansen JA, Pandit A. The ability of a collagen/calcium phosphate scaffold to act as its own vector for gene delivery and to promote bone formation via transfection with VEGF165. Biomaterials 2010;31:2893–902. [145] Cheang TY, Wang SM, Hu ZJ, Xing ZH, Chang GQ, Yao C, et al. Calcium carbonate/CaIP6 nanocomposite particles as gene delivery vehicles for human vascular smooth muscle cells. J Mater Chem 2010;20:8050–5. [146] Chernousova S, Klesing J, Soklakova N, Epple M. A genetically active nanocalcium phosphate paste for bone substitution, encoding the formation of BMP-7 and VEGF-A. RSC Adv 2013;3:11155–61. [147] Liu H, Webster TJ. Mechanical properties of dispersed ceramic nanoparticles in polymer composites for orthopedic applications. Int J Nanomed 2010;5:299–313. [148] Dunlop JWC, Fratzl P. Biological composites. Ann Rev Mater Res 2010;40:1–24. [149] Weiner S, Wagner HD. The material bone: structure-mechanical function relations. Annu Rev Mater Sci 1998;28:271–98. [150] Nikolov S, Petrov M, Lymperakis L, Friak M, Sachs C, Fabritius HO, et al. Revealing the design principles of high-performance biological composites using ab initio and multiscale simulations: The example of lobster cuticle. Adv Mater 2010;22:519. [151] Kurreck J. RNA Interference: from basic research to therapeutic applications. Angew Chem Int Ed 2009;48:1378–98. [152] Kesharwani P, Gajbhiye V, Jain NK. A review of nanocarriers for the delivery of small interfering RNA. Biomaterials 2012;33:7138–50. [153] Reischl D, Zimmer A. Drug delivery of siRNA therapeutics: potentials and limits of nanosystems. Nanomedicine 2009;5:8–20. [154] Ghildiyal M, Zamore PD. Small silencing RNAs: an expanding universe. Nat Rev Genet 2009;10(2):94–108. [155] Laroui H, Theiss AL, Yan Y, Dalmasso G, Nguyen HTT, Sitaraman SV, et al. Functional TNF-a gene silencing mediated by polyethyleneimine/TNF-a siRNAnanocomplexes in inflamed colon. Biomaterials 2011;32:1218–28. [156] Zhang X, Kovtun A, Mendoza-Palomares C, Oulad-Abdelghani M, Facca S, Fioretti F, et al. SiRNA-loaded multi-shell nanoparticles incorporated into a multilayered film as a reservoir for gene silencing. Biomaterials 2010;31:6013–8. [157] NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;14(285):785–95. [158] Arvidson K, Abdallah BM, Applegate LA, Nicola Baldini N, Cenni E, Gomez- Barrena E, et al. Bone regeneration and stem cells. J Cell Mol Med 2011;15:718–46. [159] Gómez-Barrena E, Rosset P, Muller I, Giordano R, Bunu C, Laroylle P, et al. Bone regeneration: stem cell therapies and clinical studies in orthopaedics and traumatology. J Cell Mol Med 2011;15:1266–86. [160] Hernigou P, Poignard A, Beaujean F, Rouard H. Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am 2005;87:1430–7. [161] Jakob F, Ebert R, Ignatius A, Matsushita T, Watanabe Y, Groll J, et al. Bone tissue engineering in osteoporosis. Maturitas 2013;75:118–24. [162] Bohner M, Lemaitre J. Can bioactivity be tested in vitro with SBF solution? Biomaterials 2009;30:2175–9. [163] Pan H, Zhao X, Darvell BW, Lu WW. Apatite-formation ability – predictor of ‘‘bioactivity’’? Acta Biomater 2010;6:4181–8. [164] Kallmes DF, Comstock BA, Heagerty PJ, Turner JA, Wilson DJ, Diamond TH, et al. A randomized controlled trial of vertebroplasty for osteoporotic spine fractures. N Engl J Med 2009;361:69–579. [165] Buchbinder R, Osborne RH, Ebeling PR, Wark JD, Mitchell P, Wriedt C, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med 2009;361:557–68. [166]