Nanotechnology for treating osteoporotic vertebral fractures

International Journal of Nanomedicine

Volumn 10, Issue , 2015, Pages 5139-5157

  Gao, Chunxia ^a   Wei, Donglei ^a   Yang, Huilin ^a   Chen, Tao ^b   Yang, Lei ^a,c  

^a First Affiliated Hospital   (China)

^b SOOCHOW UNIVERSITY   (China)

^c INSTITUTE OF MECHANICS   (China)

Author keywords

Bone cement; Kyphoplasty; Nanomaterials; Osteoporosis; Pedicle screw; Radiopacifier; Vertebral fracture

Indexed keywords

BIOMATERIAL; BONE CEMENT; CALCIUM PHOSPHATE CEMENT; CALCIUM SULFATE CEMENT; NANOMATERIAL; POLY(METHYL METHACRYLATE); POLYETHERETHERKETONE; SILVER NANOPARTICLE; UNCLASSIFIED DRUG;

ARTICLE; BALLOON CATHETER; BIOCOMPATIBILITY; BONE REGENERATION; CLINICAL EFFECTIVENESS; DRUG DELIVERY SYSTEM; FRAGILITY FRACTURE; HUMAN; HYDROGEL; KYPHOPLASTY; MATERIAL COATING; MECHANICAL STRESS; MORPHOMETRICS; NANOTECHNOLOGY; NONHUMAN; ORTHOPEDIC SURGICAL EQUIPMENT; PATIENT SAFETY; PEDICLE SCREW; PERCUTANEOUS VERTEBROPLASTY; SPINE FRACTURE; SPINE IMPLANT; TREATMENT OUTCOME; NANOMEDICINE; OSTEOPOROSIS; SPINAL FRACTURES;

BIOCOMPATIBLE MATERIALS; BONE CEMENTS; HUMANS; NANOMEDICINE; NANOSTRUCTURES; OSTEOPOROSIS; SPINAL FRACTURES;

EID: 84939606128     PISSN: 11769114     EISSN: 11782013     Source Type: Journal    
DOI: 10.2147/IJN.S85037     Document Type: Article

References (116)

1. Cummings SR, Black DM, Rubin SM. Lifetime risks of hip, Colles, or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med. 1989;149:2445–2448.
2. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser. 1994; 843:1–129.
3. Messina C, Bandirali M, Sconfienza LM. Prevalence and type of errors in dual-energy x-ray absorptiometry. Eur Radiol. 2015;25:1504–1511.
4. Pisani P, Renna MD, Conversano F. Screening and early diagnosis of osteoporosis through X-ray and ultrasound based techniques. World J Radiol. 2013;5:398–410.
5. Conversano F, Franchini R, Greco A. A Novel ultrasound methodology for estimating spine mineral density. Ultrasound Med Biol. 2015;41: 281–300.
6. Sunyecz JA. The use of calcium and vitamin D in the management of osteoporosis. Ther Clin Risk Manag. 2008;4:827–836.
7. Hernlund E, Svedbom A, Ivergård M, et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. Arch Osteoporos. 2013;8:136.
8. Boughton B, Odle T. Osteoporosis. In: Longe JL. The Gale Encyclopedia of Medicine. 3rd ed. Farmington Hills, MI, USA: Thompson Gale; 2006.
9. International Osteoporosis Foundation. Invest in your bones. Osteoporosis in the workplace. Available from: http://www.bbcbonehealth.org/documents/workplacereportEN.pdf. Accessed June 6, 2015.
10. Liao RX, Yu M, Jiang Y, Xia WB. Management of osteoporosis with calcitriol in elderly Chinese patients: a systematic review. Clin Interv Aging. 2014;9:515–526.
11. Kenneth GS, Piet G. Progress in osteoporosis and fracture prevention: focus on postmenopausal women. Arthritis Res Ther. 2009;11:251.
12. Kenneth ES, Jonathan RP, Elizabeth AW. Falls, fractures, and osteoporosis after stroke – time to think about protection? Stroke. 2002;33: 1432–1436.
13. Eastell R, Cedel SL, Wahner HW, et al. Classification of vertebral fractures. J Bone Miner Res. 1991;6:207–215.
14. He ZW, Zhai QP, Hu ML, et al. Bone cements for percutaneous vertebroplasty and balloon kyphoplasty: current status and future developments. J Orthop Translation. 2015;3:1–11.
15. Cosman F, Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25:2359–2381.
16. Ulmar B, Brunner A, Gühring M, Schmälzle T, Weise K, Badke A. Inter- and intraobserver reliability of the vertebral, local and segmental kyphosis in 120 traumatic lumbar and thoracic burst fractures: evaluation in lateral X-rays and sagittal computed tomographies. Eur Spine J. 2010;19:558–566.
17. Freedman BA, Potter BK, Nesti LJ, Giuliani JR, Hampton C, Kuklo TR. Osteoporosis and vertebral compression fractures – continued missed opportunities. Spine J. 2008;8:756–762.
18. Prather H, Watson JO, Gilula LA. Nonoperative management of osteoporotic vertebral compression fractures. Injury. 2007;38:S40–S48.
19. Nakashima H, Yukawa Y, Ito K, Machino M, Ishiguro N, Kato F. Combined posterior-anterior surgery for osteoporotic delayed vertebral fracture with neurologic deficit. Nagoya J Med Sci. 2014;76:307–314.
20. Koes BW, Tulder MW, Peul WC. Diagnosis and treatment of sciatica. BMJ. 2007;23:1313–1317.
21. Marcucci G, Brandi ML. Kyphoplasty and vertebroplasty in the management of osteoporosis with subsequent vertebral compression fractures. Clin Cases Miner Bone Metab. 2010;7:51–60.
22. Galibert P, Deramond H, Rosat P, Le Gars D. Note préliminaire sur le traitement des angiomes vertébraux par vertébroplastie acrylique percutanée [Preliminary note on the treatment of vertebral angioma by percutaneous acrylic vertebroplasty]. Neurochirurgie. 1987;33:166–168. French.
23. Cloft HJ, Jensen ME. Kyphoplasty: an assessment of a new technology. Am J Neuroradiol. 2007;28:200–203.
24. Spivak JM, Johnson MG. Percutaneous treatment of vertebral body pathology. J Am Acad Orthop Surg. 2005;13:16–17.
25. Hadjipavlou AG, Tzermiadianos MN, Katonis PG, Szpalski M. Percutaneous vertebroplasty and balloon kyphoplasty for the treatment of osteoporotic vertebral compression fractures and osteolytic tumours. J Bone Joint Surg Br. 2005;87:1595–1604.
26. Mathis JM, Ortiz AO, Zoarski GH. Vertebroplasty versus kyphoplasty: a comparison and contrast. AJNR Am J Neuroradiol. 2004; 25:840–845.
27. Bouza C, López-Cuadrado T, Cediel P, Saz-Parkinson Z, Amate JM. Balloon kyphoplasty in malignant spinal fractures: a systematic review and meta-analysis. BMC Palliat Care. 2009;8:12–21.
28. Van Meirhaeghe J, Bastian L, Boonen S, Ranstam J, Tillman JB, Wardlaw D. A randomized trial of balloon kyphoplasty and nonsurgical management for treating acute vertebral compression fractures: vertebral body kyphosis correction and surgical parameters. Spine (Phila Pa 1976). 2013;38:971–983.
29. Rotter R, Martin H, Fuerderer S, et al. Vertebral body stenting: a new method for vertebral augmentation versus kyphoplasty. Eur Spine J. 2010; 19:916–923.
30. David B, Laurie AK. Disadvantages of infection surveillance by medical record chart review. Am J Infect Control. 1981;9:15–17.
31. Engel E, Michiardi A, Navarro M, Lacroix D, Planell JA. Nanotechnology in regenerative medicine: the materials side. Trends Biotechnol. 2008;26:39–47.
32. Liu H, Webster TJ. Nanomedicine for implants: a review of studies and necessary experimental tools. Biomaterials. 2007;28:354–369.
33. Zhang LJ, Webster TJ. Nanotechnology and nanomaterials: promises for improved tissue regeneration. Nano Today. 2009;4:66–80.
34. Hassim A, Rachmawati H. Preparation and characterization of calcium carbonate nanoparticles. The third nanoscience and nanotechnology symposium 2010. AIP Publishing. 2010;1284(1):195–198.
35. Larsson S. Cement augmentation in fracture treatment. Scand J Surg. 2006;95:111–118.
36. Arora M, Chan EK, Gupta S, Diwan AD. Polymethylmethacrylate bone cements and additives: a review of the literature. World J Orthop. 2013; 4:67–74.
37. Barinov SM, Komlev VS. Calcium phosphate bone cements. Inorg Mater. 2011;47:1470–1485.
38. Nelson CL, McLaren SG, Skinner RA, Smeltzer MS, Thomas JR, Olsen KM. The treatment of experimental osteomyelitis by surgical debridement and the implantation of calcium sulfate tobramycin pellets. J Orthop Res. 2002;20:643–647.
39. No YJ, Roohani-Esfahani SI, Zreiqat H. Nanomaterials: the next step in injectable bone cements. Nanomedicine (Lond). 2014;9:1745–1764.
40. Rodriguez LC, Chari J, Aghyarian S, Gindri IM, Kosmopoulos V, Rodrigues DC. Preparation and characterization of injectable brushite filled-poly (methyl methacrylate) bone cement. Materials. 2014;7:6779–6795.
41. Harper EJ. Bioactive bone cements. Proc Inst Mech Eng H. 1998; 212:113–120.
42. Glimcher MJ. PMMA. Instr Course Lect. 1987;36:49.
43. Ricker A, Liu-Snyder P, Webster TJ. The influence of nano MgO and BaSO4 particle size additives on properties of PMMA bone cement. Int J Nanomedicine. 2008;3:125–132.
44. Boger A, Bohner M, Heini P. Properties of an injectable low modulus PMMA bone cement for osteoporotic bone. J Biomed Mater Res B Appl Biomater. 2008;86:474–482.
45. Alt V, Bechert T, Steinrücke P. An in vitro assessment of the antibacterial properties and cytotoxicity of nanoparticulate silver bone cement. Biomaterials. 2004;25:4383–4391.
46. Brown WE, Chow LC. A new calcium phosphate setting cement. J Dent Res. 1983;62:672–679.
47. Chow LC, Eanes ED. Calcium phosphate cement. Monogr Oral Sci. 2001;18:148–163.
48. Nakano M, Hirano N, Matsuura K, et al. Percutaneous transpedicular vertebroplasty with calcium phosphate cement in the treatment of osteoporotic vertebral compression and burst fractures. J Neurosurg. 2002;97(3 Suppl):287–293.
49. Oner FC, Verlaan JJ, Verbout AJ, Dhert WJ. Cement augmentation techniques in traumatic thoracolumbar spine fracture. Spine (Phila Pa 1976). 2006;31(11 Suppl):S89–S95.
50. Verlaan JJ, Dhert WJ, Verbout AJ, Oner FC. Balloon vertebroplasty in combination with pedicle screw instrumentation: a novel technique to treat thoracic and lumbar burst fractures. Spine (Phila Pa 1976). 2005;30:E73–E79.
51. Low KL, Tan SH, Zein SHS, McPhail DS, Boccaccini AR. Optimization of the mechanical properties of calcium phosphate/multi-walled carbon nanotubes/bovine serum albumin composites using response surface methodology. Mater Des. 2011;32:3312–3319.
52. Perez RA, Patel KD, Kim HW. Novel magnetic nanocomposite injectables: calcium phosphate cements impregnated with ultrafine magnetic nanoparticles for bone regeneration. RSC Adv. 2015;5:13411–13419.
53. El-Fiqi A, Kim J-H, Perez RA, Kim H-W. Novel bioactive nanocomposite cement formulations with potential properties: incorporation of the nanoparticle form of mesoporous bioactive glass into calcium phosphate cements. J Mater Chem B. 2015;3:1321–1334.
54. Ginebra MP, Espanol M, Montufar EB, Perez RA, Mestres G. New processing approaches in calcium phosphate cements and their applications in regenerative medicine. Acta Biomater. 2010;6:2863–2873.
55. Canal C, Ginebra MP. Fibre-reinforced calcium phosphate cements: a review. J Mech Behav Biomed Mater. 2011;4:1658–1671.
56. Wang X, Ye J, Wang Y, Chen L. Reinforcement of calcium phosphate cement by bio-mineralized carbon nanotube. J Am Ceram Soc. 2007;90: 962–964.
57. Chew KK, Low KL, Sharif Zein SH, et al. Reinforcement of calcium phosphate cement with multi-walled carbon nanotubes and bovine serum albumin for injectable bone substitute applications. J Mech Behav Biomed Mater. 2011;4:331–339.
58. Peltier LF. The use of plaster of Paris to fill defects in bone. Clin Orthop Res. 1961;21:1–29.
59. Zhou W, Xue YD, Ji XB, Yin GY, Zhang N, Ren YX. A novel injectable and degradable calcium phosphate/calcium sulfate bone cement. Afr J Biotechnol. 2011;10:19449–19457.
60. Raki LL, Beaudoin JL, Alizadeh RL, Makar J, Sato TJ. Cement and concrete nanoscience and nanotechnology. Materials. 2010;3:918–942.
61. Hesaraki S, Moztarzadeh F, Nemati R, Nezafati N. Preparation and characterization of calcium sulfate–biomimetic apatite nanocomposites for controlled release of antibiotics. J Biomed Mater Res B Appl Biomater. 2009;91:651–661.
62. Liu X, Wang XM, Chen Z, et al. Injectable bone cement based on mineralized collagen. J Biomed Mater Res B Appl Biomater. 2010;94: 72–79.
63. Li H, Xiao, HG Yuan J, Ou JP. Microstructure of cement mortar with nanoparticles. Compos Part B Eng. 2004;35:185–189.
64. Peng Q, Sun X, Gong T, et al. Injectable and biodegradable thermosensitive hydrogels loaded with PHBHHx nanoparticles for the sustained and controlled release of insulin. Acta Biomater. 2013;9:5063–5069.
65. Abdel-Bar HM, Abdel-Reheem AY, Osman R. Optimized formulation of vancomycin loaded thermoreversible hydrogel for treatment of orthopedic infections. J Pharm Sci. 2014;5:2936–2946.
66. Campbell SB, Patenaude M, Hoare T. Injectable superparamagnets: highly elastic and degradable poly(N-isopropylacrylamide)-superparamagnetic iron oxide nanoparticle (SPION) composite hydrogels. Biomacromolecules. 2013;14:644–653.
67. Cao L, Werkmeuster JA, Wang J, Glattauer V, McLean KM, Liu C. Bone regeneration using photocrosslinked hydrogel incorporating rhBMP-2 loaded 2-N, 6-O-sulfated chitosan nanoparticles. Biomaterials. 2014;35:2730–2742.
68. Kim HH, Park JB, Kang MJ, Park YH. Surface-modified silk hydrogel containing hydroxyapatite nanoparticle with hyaluronic acid-dopamine conjugate. Int J Biol Macromol. 2014;70:516–522.
69. Reddy NN, Varaprasad K, Ravindra S, et al. Evaluation of blood compatibility and drug release studies of gelatin based magnetic hydrogel nanocomposites. Colloids Surf A Physicochem Eng Asp. 2011; 385(1):20–27.
70. Heo DN, Ko WK, Bae MS. Enhanced bone regeneration with a gold nanoparticle–hydrogel complex. J Mater Chem B. 2014;2:1584–1593.
71. Kolambkar YM, Dupont KM, Boerckel JD. An alginate-based hybrid system for growth factor delivery in the functional repair of large bone defects. Biomaterials. 2011;32:65–74.
72. Luhmann T, Germershaus O, Groll J. Bone targeting for the treatment of osteoporosis. J Control Release. 2012;161:198–213.
73. Valente JFA, Gaspar VM, Antunes BP, Countinho P, Correia IJ. Microencapsulated chitosan-dextran sulfate nanoparticles for controlled delivery of bioactive molecules and cells in bone regeneration. Polymer. 2013; 54:5–15.
74. Ignjatović NL, Ninkov P, Sabetrasekh R, Uskoković DP. A novel nano drug delivery system based on tigecycline-loaded calcium phosphate coated with poly-DL-lactide-co-glycolide. J Mater Sci Mater Med. 2010;21:231–239.
75. Nguyen MK, Jeon O, Krebs MD, Schapira D, Alsberg E. Sustained localized presentation of RNA interfering molecules from in situ forming hydrogels to guide stem cell osteogenic differentiation. Biomaterials. 2014;35:6278–6286.
76. Peng KT, Chen CF, Chu IM. Treatment of osteomyelitis with teicoplaninencapsulated biodegradable thermosensitive hydrogel nanoparticles. Biomaterials. 2010;31:5227–5236.
77. Hamdan SA, Ruggero B, Sanne KB, et al. Synergistic effects of bisphosphonate and calcium phosphate nanoparticles on peri-implant bone responses in osteoporotic rats. Biomaterials. 2014;35: 5482–5490.
78. Alghamdi HS, Bosco R, Both SK. Synergistic effects of bisphosphonate and calcium phosphate nanoparticles on peri-implant bone responses in osteoporotic rats. Biomaterials. 2014;35:5482–5490.
79. Gillani R, Ercan B, Qiao A, Webster TJ. Nanofunctionalized zirconia and barium sulfate particles as bone cement additives. Int J Nanomedicine. 2010;5:1–11.
80. Gomoll AH, Fitz W, Scott RD, Thornhill TS, Bellare A. Nanoparticulate fillers improve the mechanical strength of bone cement. Acta Orthop. 2008;79:421–427.
81. Ajeesh M, Francis BF, Annie J, Harikrishna Varma PR. Nano iron oxide–hydroxyapatite composite ceramics with enhanced radiopacity. J Mater Sci Mater Med. 2010;21:1427–1434.
82. Abboud M, Casaubieilh L, Morvan F, Fontanille M, Duguet E. PMMA-based composite materials with reactive ceramic fillers: IV. Radiopacifying particles embedded in PMMA beads for acrylic bone cements. J Biomed Mater Res. 2000;53:728–736.
83. Khaled SM, Charpentier PA, Rizkalla AS. Synthesis and characterization of poly (methyl methacrylate)-based experimental bone cements reinforced with TiO2-SrO nanotubes. Acta Biomater. 2010;6:3178–3186.
84. Hoekstra JW, van den Beucken JJ, Leeuwenburgh SC, Meijer GJ, Jansen JA. Tantalumpentoxide as a radiopacifier in injectable calcium phosphate cements for bone substitution. Tissue Eng C. 2011;17:907–913.
85. Wardlaw D, Cummings SR, Meirhaeghe JV, Bastian L, Rabstam J, Eastell R. Efficacy and safety of balloon kyphoplasty compared with non-surgical care for vertebral compression fracture (FREE): a randomised controlled trial. Lancet. 2009;373:1016–1024.
86. Padovani B, Kasriel O, Brunner P, Peretti-Viton P. Pulmonary embolism caused by acrylic cement: a rare complication of percutaneous vertebroplasty. Am J Neuroradiol. 1999;20:375–377.
87. Mathis JM. Percutaneous vertebroplasty: complication avoidance and technique optimization. Am J Neuroradiol. 2003;24:1697–1706.
88. Antonio K, Ludwig O, Jens F, et al. Height restoration of osteoporotic vertebral compression fractures using different intravertebral reduction devices: a cadaveric study. Spine J. 2015;15:1092–1098.
89. Zheng Z, Luk KD, Kuang G, et al. Vertebral augmentation with a novel vessel-X bone void filling container system and bioactive bone cement. Spine. 2007;32:2076–2082.
90. Heini PF, Orler R. Vertebroplasty in severe osteoporosis. Technique and experience with multi-segment injection. Orthopade. 2004; 33(1):22–30.
91. Sun G, Wei D, Liu X, et al. Novel biodegradable electrospun nanofibrous P(DLLA-CL) balloons for the treatment of vertebral compression fractures. Nanomedicine. 2013;9:829–838.
92. Gautschi OP, Schatlo B, Schaller KS, Tessitore E. Clinically relevant complications related to pedicle screw placement in thoracolumbar surgery and their management: a literature review of 35,630 pedicle screws. Neurosurg Focus. 2011;31:E8.
93. Becker S, Chavanne A, Spitaler R. Assessment of different screw augmentation techniques and screw designs in osteoporotic spines. Eur Spine J. 2008;17:1462–1469.
94. Aksakal B, Kom M, Tosun HB, Demirel M. Influence of micro- and nano-hydroxyapatite coatings on the osteointegration of metallic (Ti6Al4V) and bioabsorbable interference screws: an in vivo study. Eur J Orthop Surg Traumatol. 2014;24:813–819.
95. Olerud C, Petrén-Mallmin M, Larsson S. Hydroxyapatite coating improves fixation of pedicle screws: a clinical study. J Bone Joint Surg Br. 2002;84:387–391.
96. Kim HS, Yang Y, Koh JT, et al. Fabrication and characterization of functionally graded nano-micro porous titanium surface by anodizing. J Biomed Mater Res B. 2009;88:427–435.
97. Rodriguez R, Kim K, Ong JL. In vitro osteoblast response to anodized titanium and anodized titanium followed by hydrothermal treatment. J Biomed Mater Res A. 2002;65A:352–358.
98. Yao C, Perla V, McKenzie J, Slamovich EB, Webster TJ. Anodized Ti and Ti6Al4V possessing nanometer surface features enhances osteoblast adhesion. J Biomed Nano. 2005;1:68–73.
99. Ercana B, Webster TJ. The effect of biphasic electrical stimulation on osteoblast function at anodized nanotubular titanium surfaces. Biomaterials. 2010;31(13):3684–3693.
100. Oha S, Brammera KS, Lib YS, et al. Stem cell fate dictated solely by altered nanotube dimension. Proc Natl Acad Sci U S A. 2009; 106:2130–2135.
101. Webster TJ, Ejiofor JU. Increased osteoblast adhesion on nanophase metals: Ti, Ti6Al4V, and CoCrMo. Biomaterials. 2004;25: 4731–4739.
102. Webster TJ, Siegel RW, Bizios R. Osteoblast adhesion on nanophase ceramics. Biomaterials. 1999;20:1221–1227.
103. Webster TJ, Ergun C, Doremus RH, Siegel RW, Bizios R. Enhanced functions of osteoblasts on nanophase ceramics. Biomaterials. 2000;21: 1803–1810.
104. Puckett S, Taylor E, Raimondo T, Webster TJ. The relationship between the nanostructure of titanium surfaces and bacterial attachment. Biomaterials. 2010;31:706–713.
105. Kurtz SM, Devine JN. PEEK biomaterials in trauma, orthopedic, and spinal implants. Biomaterials. 2007;28:4845–4869.
106. Toth JM, Wang M, Estes BT, Scifert JL, Seim HB III, Turner AS. Polyetheretherketone as a biomaterial for spinal applications. Biomaterials. 2006;27:324–334.
107. Cho DY, Liau WR, Lee WY, Liu JT, Chiu CL, Sheu PC. Preliminary experience using a polyetheretherketone (PEEK) cage in the treatment of cervical disc disease. Neurosurgery. 2002;51:1343–1349.
108. Wang L, Weng LQ, Song SH, Zhang ZG, Tian SL, Ma R. Characterization of polyetheretherketone–hydroxyapatite nanocomposite materials. Mater Sci Eng A. 2011;528(10–11):3689–3696.
109. Wang L, Weng L, Song S, Zhang Z, Tian S, Ma R. Characterization of polyetheretherketone-hydroxyapatite nanocomposite materials. Mater Sci Eng A. 2011;528:689–696.
110. Ma R, Weng L, Fang L, Luo Z, Song S. Structure and mechanical performance of in situ synthesized hydroxyapatite/polyetheretherketone nanocomposite materials. J Solgel Sci Technol. 2012;62:52–56.
111. Wu X, Liu X, Wei J, Ma J, Deng F, Wei S. Nano-TiO2/PEEK bioactive composite as a bone substitute material: in vitro and in vivo studies. Int J Nanomedicine. 2012;7:1215–1225.
112. Li K, Yeung CY, Yeung KWK, Tjong SC. Sintered hydroxyapatite/polyetheretherketone nanocomposites: mechanical behavior and biocompatibility. Adv Eng Mater. 2012;14:B155–B165.
113. Shortkroff S, Turell MB, Rice K, et al. Cellular response to nanoparticles. In: MRS Proceedings. Cambridge, UK: Cambridge University Press; 2001.
114. Dimitriou R, Jones E, McGonagle D, et al. Bone regeneration: current concepts and future directions. BMC Med. 2011;9:66.
115. Lubick N. Nanosilver toxicity: ions, nanoparticles or both? Environ Sci Technol. 2008;42:8617.
116. Rae T. Tolerance of mouse macrophages in vitro to barium sulfate used in orthopedic bone cement. J Biomed Mater Res. 1977;11:839–846.