Professional Documents
Culture Documents
nanomedjournal.com
Abstract
The favorable biocompatibility of hydroxyapatite (HA) makes it a popular bone graft material as well as a coating layer on metallic
implant. To reduce implant-related infections, silver ions were either incorporated into the apatite during co-precipitation process
(AgHA-CP) or underwent ion-exchange with the calcium ions in the apatite (AgHA-IE). However, the distribution of silver ions in
AgHA-CP and AgHA-IE was different, thus affecting the antibacterial action. Several studies reported that nanosized AgHA-CP containing
0.5 wt.% of silver provided an optimal trade-off between antibacterial properties and cytotoxicity. Nevertheless, nanosized AgHA and
AgHA nanocoatings could not function ideally due to the compromise in the bone differentiation of mesenchymal stem cells, as evidenced
in the reduced alkaline phosphatase, type I collagen and osteocalcin. Preliminary studies showed that biological responses of nanosized
AgHA and AgHA nanocoatings could be improved with the addition of silicon. This review will discuss on nanosized AgHA and
AgHA nanocoatings.
From the Clinical Editor: In many patients needing bone graft material, hydroxyapatite (HA) has proven to be a popular choice. Nonetheless,
implant-related infections remain a major concern. Hence, effective preventive measures are needed. In this review article, the authors discussed the
application of incorporating silver nanoparticles in HA and its use as bone graft biomaterials together with the addition of silica.
2015 Elsevier Inc. All rights reserved.
Key words: Antibacterial; Apatite; Nanosized; Silver
http://dx.doi.org/10.1016/j.nano.2015.03.016
1549-9634/ 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Lim PN, et al, Development of nanosized silver-substituted apatite for biomedical applications: A review. Nanomedicine: NBM
2015;11:1331-1344, http://dx.doi.org/10.1016/j.nano.2015.03.016
1332
Table 1
Various proposed mechanism of antibacterial action by silver ions.
Proposed mechanism
Ref.
98
1, 35, 99-102
103
104
105
106-109
103, 110
1333
34
1334
Figure 3. Scanning electron microscope images of adherent E. coli treated by (A) HA, and (B) AgHA-CP particles. 63 Reprinted from material science
engineering: C, 31, Singh B., Dubey A. K., Kumar S., Saha N., Basu B., Gupta R., In vitro biocompatibility and antimicrobial activity of wet chemically
prepared Ca10 xAgx(PO4)6(OH)2 (0.0 b x b 0.5) hydroxyapatites, p. 1320, Copyright (2011), with permission from Elsevier.
1335
1336
Figure 6. Schematic diagram illustrating the antibacterial action of (A) AgHA-CP and (B) AgHA-IE.
silver. 39,63 However, it was noted that there was lesser adhesion
of cells on the surface of the nanosized AgHA-CP with greater
amount of silver (Figure 7). Through the examination of
hemolysis ratio, Oh et al, 30 Chen et al 39 and Stanic et al 28
reported that hemolysis ratio of nanosized AgHA-CP with a
silver content of less than 5 wt.% showed good blood
compatibility. Likewise, the cytotoxicity of nanosized AgHA-CP
also increased with increasing silver content, as indicated by the
increasing hemolysis ratio.
Recently, well-stretched human adipose-derived mesenchymal stem cell (hASCs) on nanosized AgHA-CP containing an
optimized amount of 0.5 wt.% silver was also demonstrated. In
addition, cell proliferation was observed on nanosized AgHA-CP
containing 0.5 wt.% of silver over a period of 7 days (Figure 8).
Furthermore, bone differentiation of nanosized AgHA-CP was
evaluated. It was observed that the bone differentiation markers
(Figure 9) such as alkaline phosphatase (ALP), type I collagen
(type I COL) and osteocalcin (OCN) were significantly lower on
nanosized AgHA-CP containing 0.5 wt.% of silver than
nanosized HA. Although the substitution of low silver content
(0.5 wt.%) did not affect the proliferation of hASCs, its bone
differentiation was affected.
In-vivo experiment was carried out at the periapical area of
both mandibular 1st molar of rats. 44 The wound implanted with
AgHA-IE generally healed in 1 week, and showed minimum
signs of inflammation in-vivo after 3 weeks. However, AgHA-IE
containing 4.3 wt.% of silver showed mild delayed in the
organization of fibrinoid materials in the center of defects, with
mild inflammatory reaction at the early healing phase as
compared to AgHA-IE containing 0.15 and 1.5 wt.% of silver.
Both in-vivo and in-vitro results demonstrated that the presence
of silver in apatite did not induce cytotoxicity, but affected
bone growth.
Despite the obvious antibacterial benefit, few studies have
reported on achieving antibacterial properties with excellent
biological responses in the nanosized AgHA-CP. Thus, there
was a compromise between the antibacterial properties and
favorable biological responses of nanosized AgHA-CP. In order
1337
Figure 7. SEM images of cell morphology on (A) tissue culture plate, (B) 0.5 wt.% AgHA, (C) 1 wt.% AgHA and (D) 1.5 wt.% AgHA pellets. 29 Adapted
from antibacterial nanosized silver substituted hydroxyapatite: Synthesis and characterization/Rameshbabu N., Kumar T. S. S., Prabhakar T. G., Sastry V. S.,
Murty K. V. G. K., Rao K. P./Journal of biomedical material research and 80A. Copyright (c) [2006] [John Wiley and Sons].
1338
Figure 8. Cell growth versus culture period. 64 Adapted from effect of silver
content on the antibacterial and bioactive properties of silver-substituted
hydroxyapatite/Lim P. N., Teo E. Y., Ho B., Tay B. Y., Thian E. S/Journal of
biomedical material research and 101A. Copyright (c) [2013] [John Wiley
and Sons].
1339
Table 2
Various coating technologies to deposit AgHA-IE nanocoatings and their characteristics.
Coating Techniques
Materials
Conc. of
Silver
One-step
Magnetron Co-Sputtering
2 wt.%
AgHA
Radio Frequency
Plasma Spraying
Thermal Spraying
HA, silver
HA, silver
5-100 ppm
Electrophoretic Deposition/
Solgel
20.87 wt.%
Process Description
Ref.
35
48
51, 52
37, 38, 53, 54
39, 57, 58
55, 56
1340
Table 3
Silver release of AgHA (-CP and -IE) nanocoatings produced by various coating techniques.
Coating Techniques
Conc. of Silver
Ref.
Electrophoretic Deposition/SolGel
20.87 wt.%
79, 84
Electrospraying
1 wt.%
1-5 wt.%
0.5-3 wt.%
Electrophoretic Deposition
0.4 wt.%
CoBlast Technology
0.6 at.%
2-6 wt.%
Thermal Spraying
3-50 wt.%
50% of the incorporated silver ions were released into SBF solution
within first 24 h.
Silver content of AgHA was reduced from 5.03 wt.% to 4.21 wt.%
after immersing in stimulated body fluid for 21 days.
Silver ions were released quickly in the few days and then slowed
down after day 14. After 49 days, 0.9 ppm silver ions were measurable.
Silver content was reduced from 0.63 wt.% to 0.15 wt.% after 28 days
in phosphate buffer saline solution. Silver ions were rapidly released
within the first few hours and the release rate decreased after 4 h in
ultrapure water.
Initial silver ions release was 56 ppb and accumulated to 1.704 ppm
up to 10 days in stimulated body fluid solution.
90% of incorporated silver was released into phosphate buffer saline
solution after 30 days, with 4% silver remained in coatings.
Silver release rate was slower over the first 12 h and reached near
steady-state afterwards till 168 h in phosphate buffer saline.
At 168 h, 373 ppb silver ions were measurable.
59
39, 57, 58
42, 55, 56
46, 47
50
51, 52
37, 38, 53, 54
Figure 10. Concentrations of silver in (I) body fluid and (II) stimulated body fluid after the immersion of the (A) AgHA-CP and (B) AgHA-IE coating for
different times. 57 Reprinted from surface and coatings technology, 205, Chen Y, Zheng X, Xie Y, Ji H, Ding C, Li H, Dai K., Silver release from
silver-containing hydroxyapatite coatings, p. 1892, Copyright (2010), with permission from Elsevier.
1341
Table 4
In-vitro antibacterial properties of AgHA (-CP and -IE) nanocoatings.
Coating Techniques
Bacterial Strain
Effects
Ref.
Micro-Arc Oxidation
Biomimetic Deposition/SolGel
Ion Beam Assisted
Deposition/SolGel
Electrophoretic Deposition/SolGel
SolGel
S. aureus, E. coli
S. aureus, E. coli
S. aureus, E. coli, S.
epidermidis, P. aeruginosa
E. coli
S. aureus, E. coli
77
80, 81
85
79
87
S. aureus, S. epidermidis
E. coli
S. aureus E. coli, P. aeruginosa
S. epidermidis, P. aeruginosa
B. subtilis, E. coli
S. aureus
CoBlast Technology
S. aureus
S. aureus
P. aeruginosa
Thermal Spraying
88, 89
74
35
76
39, 57, 58
42, 55, 56
36, 90
46, 47
50
61, 62
51, 52
37, 38, 53, 54
Table 5
Biological properties of AgHA (-CP and -IE) nanocoatings in in-vitro cell studies.
Cell Type
Coating Techniques
Conc. of Ag
Thermal Spraying
Pulsed Laser Deposition
3 wt.%
1.2/4.4 wt.%
Effects
No cytotoxicity.
Mild cytotoxic effect was observed on AgHA coatings
with cell morphology destruction and decolonization.
L929 fibroblast
Vacuum Plasma Spraying
1/3/5 wt.%
No cytotoxicity and hemolysis effects of AgHA
coatings when Ag content is less than 5 wt.%.
MG63
Electrophoretic Deposition/
20.87 wt.%
Cells didnt reach confluence on AgHA coatings after
SolGel
5 days. Osteogenic activity of MG63 was inhibited
on AgHA coatings.
SolGel
1.0, 1.5 wt.% Osteoconductivity of AgHA coatings was proved. A
Human embryonic palatal
mesenchyme (HEPM) cells
significant less ALP activity was observed on
1.5 wt.% AgHA.
HEPM cells
Magnetron Co-Sputtering
2 wt.%
No cytotoxicity.
Osteoblast
SolGel
0.3-1.6 wt.% Cell adhesion, spreading and ALP expression was
depressed on more concentrated AgHA coatings.
MC3T3 osteoblast
Ion Beam Assisted Deposition 1/3/6.6 wt.% Silver concentration within 1 to 3 wt.% gave good
biocompatibility and antibacterial properties.
Human osteoblast cell line (hFOB) Radio Frequency
0.7-1.6 wt.% Less cell proliferated on AgHA coatings as compared
Magnetron Sputtering
to HA coatings; poor cell attachment and almost no ALP
activity on AgHA coatings indicated cytotoxicity.
Adipose-derived stem cells
DoD Micro-Dispensing
0.5 wt.%
No cytotoxicity in cell proliferation and differentiation;
Technique
but was not superior to HA coatings in terms of
cellular response.
HEp2 cell line
Pulsed Laser Deposition
0.53 wt.%
No cytotoxicity.
Ref.
37, 38, 53, 54
36, 90
39, 57
79
40
35
88, 89
56
48
61
49, 60
1342
References
1. Darouiche RO. Anti-infective efficacy of silver-coated medical
prostheses. Clin Infect Dis 1999;29:1371-7.
2. Jarvis WR. Selected aspects of the socioeconomic impact of
nosocomial infections: Morbidity, mortality, cost, and prevention. Infect Control Hosp Epidemiol 1996;17:552-7.
3. Stamm WE. Infections related to medical devices. Ann Intern Med
1978;89:764-9.
4. Hetrick EM, Schoenfisch MH. Reducing implant-related infections:
Active release strategies. Cheminform 2006;37:780-9.
5. Darouiche RO. Treatment of infections associated with surgical
implants. N Engl J Med 2004;350:1422-9.
6. Capanna R, Morris H, Campanacci D, Del Ben M, Campanacci M.
Modular uncemented prosthetic reconstruction after resection of
tumours of the distal femur. J Bone Joint Surg Br 1994;76-B:178-86.
7. Gristina A. Biomaterial-centered infection: Microbial adhesion versus
tissue integration. Science 1987;237:1588-95.
8. Mack D, Becker P, Chatterjee I, Dobinsky S, Knobloch JKM, Peters G,
et al. Mechanisms of biofilm formation in Staphylococcus epidermidis
and Staphylococcus aureus: Functional molecules, regulatory circuits,
and adaptive responses. Int J Med Microbiol 2004;294:203-12.
9. Zimmerli W, Lew PD, Waldvogel FA. Pathogenesis of foreign body
infection. Evidence for a local granulocyte defect. J Clin Invest
1984;73:1191-200.
10. Zilberman M, Elsner JJ. Antibiotic-eluting medical devices for various
applications. J Control Release 2008;130:202-15.
11. Schnieders J, Gbureck U, Thull R, Kissel T. Controlled release of
gentamicin from calcium phosphatepoly(lactic acid-co-glycolic acid)
composite bone cement. Biomaterials 2006;27:4239-49.
12. Takechi M, Miyamoto Y, Ishikawa K, Nagayama M, Kon M, Asaoka K,
et al. Effects of added antibiotics on the basic properties of anti-washouttype fast-setting calcium phosphate cement. J Biomed Mater Res
1998;39:308-16.
13. van de Belt H, Neut D, Schenk W, van Horn JR, van der Mei HC,
Busscher HJ. Infection of orthopedic implants and the use of
antibiotic-loaded bone cements A review. Acta Orthop Scand
2001;72:557-71.
14. Ip M, Lui SL, Poon VKM, Lung I, Burd A. Antimicrobial activities of
silver dressings: An in vitro comparison. J Med Microbiol 2006;55:59-63.
15. Taylor PL, Ussher AL, Burrell RE. Impact of heat on nanocrystalline
silver dressings: Part I: Chemical and biological properties. Biomaterials 2005;26:7221-9.
16. Rupp ME, Fitzgerald T, Marion N, Helget V, Puumala S, Anderson JR, et al.
Effect of silver-coated urinary catheters: Efficacy, cost-effectiveness, and
antimicrobial resistance. Am J Infect Control 2004;32:445-50.
17. Campbell AA, Song L, Li XS, Nelson BJ, Bottoni C, Brooks DE, et al.
Development, characterization, and anti-microbial efficacy of hydroxyapatite-chlorhexidine coatings produced by surface-induced mineralization. J Biomed Mater Res 2000;53:400-7.
18. Melville A, Rodrguez-Lorenzo L, Forsythe J. Effects of calcination
temperature on the drug delivery behaviour of ibuprofen from
hydroxyapatite powders. J Mater Sci: Mater Med 2008;19:1187-95.
19. Martnez-Gutierrez F, Thi EP, Silverman JM, de Oliveira CC, Svensson SL,
Hoek AV, et al. Antibacterial activity, inflammatory response, coagulation
and cytotoxicity effects of silver nanoparticles. Nanomed: Nanotech Biol
Med 2012;8:328-36.
20. Guzman M, Dille J, Godet S. Synthesis and antibacterial activity of
silver nanoparticles against gram-positive and gram-negative bacteria.
Nanomed: Nanotech Biol Med 2012;8:37-45.
21. Brandt O, Mildner M, Egger AE, Groessl M, Rix U, Posch M, et al.
Nanoscalic silver possesses broad-spectrum antimicrobial activities and
exhibits fewer toxicological side effects than silver sulfadiazine. Nanomed: Nanotech Biol Med 2012;8:478-88.
22. Kim JS, Kuk E, Yu KN, Kim JH, Park SJ, Lee HJ, et al. Antimicrobial effects
of silver nanoparticles. Nanomed: Nanotech Biol Med 2007;3:95-101.
23. Gosheger G, Hardes J, Ahrens H, Streitburger A, Buerger H, Erren M,
et al. Silver-coated megaendoprostheses in a rabbit model An
analysis of the infection rate and toxicological side effects. Biomaterials 2004;25:5547-56.
24. Klasen HJ. Historical review of the use of silver in the treatment of
burns. I. Early uses. Burns 2000;26:117-30.
25. Lansdown A. Silver. II. Toxicity in mammals and how its products aid
wound repair. J Wound Care 2002;11:173-7.
26. Lansdown AB. Silver. I. Its antibacterial properties and mechanism of
action. J Wound Care 2002;11:125-30.
27. Schierholz JM, Lucas LJ, Rump A, Pulverer G. Efficacy of silvercoated medical devices. J Hosp Infect 1998;40:257-62.
28. Stanic V, Janackovic D, Dimitrijevic S, Tanaskovic SB, Mitric M,
Pavlovic MS, et al. Synthesis of antimicrobial monophase silver-doped
hydroxyapatite nanopowders for bone tissue engineering. Appl Surf Sci
2011;257:4510-8.
29. Rameshbabu N, Kumar TSS, Prabhakar TG, Sastry VS, Murty KVGK,
Rao KP. Antibacterial nanosized silver substituted hydroxyapatite:
Synthesis and characterization. J Biomed Mater Res 2007;80A:581-91.
30. Oh KS, Park SH, Jeong YK. Cytotoxicity and antimicrobial effect of
Ag doped hydroxyapatite. Key Eng Mater 2004;264268:2107-10.
31. Bellantone M, Williams HD, Hench LL. Broad-spectrum bactericidal
activity of Ag2O-doped bioactive glass. Antimicrob Agents Chemother
2002;46:1940-5.
32. Kawashita M, Tsuneyama S, Miyaji F, Kokubo T, Kozuka H,
Yamamoto K. Antibacterial silver-containing silica glass prepared by
solgel method. Biomaterials 2000;21:393-8.
33. Kim TN, Feng QL, Kim JO, Wu J, Wang H, Chen GC, et al.
Antimicrobial effects of metal ions (Ag +, Cu 2+, Zn 2+) in hydroxyapatite. J Mater Sci: Mater Med 1998;9:129-34.
34. Oh KS, Park SH, Jeong YK. Antimicrobial effects of Ag doped
hydroxyapatite synthesized from co-precipitation route. Key Eng
Mater; 2004;264268:2111-4.
35. Chen W, Liu Y, Courtney HS, Bettenga M, Agrawal CM, Bumgardner JD,
et al. In vitro anti-bacterial and biological properties of magnetron cosputtered silver-containing hydroxyapatite coating. Biomaterials
2006;27:5512-7.
36. Jelnek M, Weiserov M, Kocourek T, Zezulov M, Strnad J.
Biomedical properties of laser prepared silver-doped hydroxyapatite.
Laser Phys 2011;21:1265-9.
1343
55. Trujillo NA, Oldinski RA, Ma H, Bryers JD, Williams JD, Popat KC.
Antibacterial effects of silver-doped hydroxyapatite thin films sputter
deposited on titanium. Mater Sci Eng: C 2012;32:2135-44.
56. Sandukas S, Yamamoto A, Rabiei A. Osteoblast adhesion to
functionally graded hydroxyapatite coatings doped with silver. J
Biomed Mater Res 2011;97A:490-7.
57. Chen Y, Zheng X, Xie Y, Ji H, Ding C, Li H, et al. Silver release from
silver-containing hydroxyapatite coatings. Surf Coat Technol
2010;205:1892-6.
58. Ruan H, Fan C, Zheng X, Zhang Y, Chen Y. In vitro antibacterial and
osteogenic properties of plasma sprayed silver-containing hydroxyapatite coating. Chin Sci Bull 2009;54:4438-45.
59. Kose N, Otuzbir A, Kiremiti A, Doan A. A silver ion-doped calcium
phosphate-based ceramic nanopowder-coated prosthesis increased
infection resistance. Clin Orthop Relat Res 2013;47:1-8.
60. Erakovi S, Jankovi A, Ristoscu C, Duta L, Serban N, Visan A, et al.
Antifungal activity of Ag: Hydroxyapatite thin films synthesized by
pulsed laser deposition on Ti and Ti modified by TiO2 nanotubes
substrates. Appl Surf Sci 2014;293:37-45.
61. Chang L, Sun J, Fuh JYH, San Thian E. Deposition and characterization of a dual-layer silicon-and silver-containing hydroxyapatite
coating via a drop-on-demand technique. RSC Adv 2013;3:11162-8.
62. Thian ES, Chang L, Lim PN, Gurucharan B, Sun J, Fuh JYH, et al.
Chemically-modified calcium phosphate coatings via drop-on-demand
micro-dispensing technique. Surf Coat Technol 2013;231:29-33.
63. Singh B, Dubey AK, Kumar S, Saha N, Basu B, Gupta R. In vitro
biocompatibility and antimicrobial activity of wet chemically prepared
Ca10 xAgx(PO4)6(OH)2 (0.0 b x b 0.5) hydroxyapatites. Mater Sci
Eng: C 2011;31:1320-9.
64. Lim PN, Teo EY, Ho B, Tay BY, Thian ES. Effect of silver content on
the antibacterial and bioactive properties of silver-substituted hydroxyapatite. J Biomed Mater Res 2013;101A:2456-64.
65. Badrour L, Sadel A, Zahir M, Kimakh L, El Hajbi A. Synthesis and
physical and chemical characterization of Ca10-xAgx(PO4)6(OH)2-xx
apatites. Ann Chim Sci-Mat 1998;23:61-4.
66. Vik H, Andersen KJ, Julshamn K, Todnem K. Neuropathy caused by
silver absorption from arthroplasty cement. Lancet 1985;325:872.
67. Hidalgo E, Domnguez C. Study of cytotoxicity mechanisms of silver
nitrate in human dermal fibroblasts. Toxicol Lett 1998;98:169-79.
68. Leaper DL. Silver dressings: Their role in wound management. Int
Wound J 2006;3:282-94.
69. Oh KS, Park SH, Jeong YK. Durability in antimicrobial effects of silver
doped hydroxyapatite depending on the synthesis route. Mater Sci
Forum 2004;449452:1233-6.
70. Wu X, Li J, Wang L, Huang D, Zuo Y, Li Y. The release properties of
silver ions from Ag-nHA/TiO2/PA66 antimicrobial composite scaffolds. Biomed Mater 2010;5:044105.
71. Benger JR, Kelly AJ, Winson IG. Does early wound infection after
elective orthopaedic surgery lead on to chronic sepsis? J R Coll Surg
Edinb 1998;43:43-4.
72. Hu C, Guo J, Qu J, Hu X. Efficient destruction of bacteria with Ti(IV)
and antibacterial ions in co-substituted hydroxyapatite films. Appl
Catal B 2007;73:345-53.
73. Lim PN, Shi Z, Neoh KG, Ho B, Tay BY, Thian ES. The effects of
silver, silicon-containing apatite towards bacteria and cell responses.
Biomed Mater 2013;9:015010.
74. Chung RJ, Hsieh MF, Huang CW, Perng LH, Wen HW, Chin TS.
Antimicrobial effect and human gingival biocompatibility of
hydroxyapatite solgel coatings. J Biomed Mater Res
2006;76B:169-78.
75. Chung RJ, Hsieh MF, Huang KC, Perng LH, Chou FI, Chin TS. Antimicrobial hydroxyapatite particles synthesized by a solgel route. J
Solgel Sci Technol 2005;33:229-39.
76. Yanovska A, Stanislavov A, Sukhodub L, Kuznetsov V, Danilchenko S,
Sukhodub L. Silver-doped hydroxyapatite coatings formed on Ti-6Al-4V
substrates and their characterization. Mater Sci Eng: C 2014;36:215-20.
1344
77. Song WH, Ryu HS, Hong SH. Antibacterial properties of Ag (or Pt)
containing calcium phosphate coatings formed by microarc oxidation.
J Biomed Mater Res 2009;88:246-54.
78. Venkateswarlu K, Rameshbabu N, Chandra Bose A, Muthupandi V,
Subramanian S, MubarakAli D, et al. Fabrication of corrosion resistant,
bioactive and antibacterial silver substituted hydroxyapatite/titania
composite coating on Cp Ti. Ceram Int 2012;38:731-40.
79. Ionita D, Dilea M, Titorencu I, Demetrescu I. Merit and demerit effects
of silver nanoparticles in the bioperformance of an electrodeposited
hydroxyapatite: Nanosilver composite coating. J Nanopart Res
2012;14:1-10.
80. Ciobanu G, Ilisei S, Luca C. Hydroxyapatite-silver nanoparticles
coatings on porous polyurethane scaffold. Mater Sci Eng: C
2014;35:36-42.
81. Romana A. Ag-loaded hydroxyapatite coatings on polyurethane
surfaces by biomimetic deposition. Rev Roum Chim 2013;58:223-7.
82. Roguska A, Pisarek M, Andrzejczuk M, Lewandowska M, Kurzydlowski KJ, JanikCzachor M. Surface characterization of CaP/Ag/
TiO2 nanotube composite layers on Ti intended for biomedical
applications. J Biomed Mater Res 2012;100:1954-62.
83. Lee IS, Whang CN, Oh KS, Park JC, Lee KY, Lee GH, et al. Formation
of silver incorporated calcium phosphate film for medical applications.
Nucl Instrum Methods Phys Res B 2006;242:45-7.
84. Shirkhanzadeh M, Azadegan M, Liu G. Bioactive delivery systems for
the slow release of antibiotics: Incorporation of Ag + ions into microporous hydroxyapatite coatings. Mater Lett 1995;24:7-12.
85. Feng Q, Cui F, Kim T, Kim J. Ag-substituted hydroxyapatite coatings
with both antimicrobial effects and biocompatibility. J Mater Sci Lett
1999;18:559-61.
86. Ghani Y, Coathup MJ, Hing KA, Blunn GW. Development of a
hydroxyapatite coating containing silver for the prevention of peri
prosthetic infection. J Orthop Res 2012;30:356-63.
87. Iconaru SL, Chapon P, Le Coustumer P, Predoi D. Antimicrobial
activity of thin solid films of silver doped hydroxyapatite prepared by
solgel method. Sci World J 2014;2014:165351.
88. Qu J, Lu X, Li D, Ding Y, Leng Y, Weng J, et al. Silver/hydroxyapatite
composite coatings on porous titanium surfaces by solgel method. J
Biomed Mater Res 2011;97B:40-8.
89. Samani S, Hossainalipour S, Tamizifar M, Rezaie H. In vitro
antibacterial evaluation of solgelderived Zn , Ag , and (Zn + Ag)
doped hydroxyapatite coatings against methicillinresistant Staphylococcus aureus. J Biomed Mater Res 2013;101:222-30.
90. Jelnek M, Kocourek T, Jurek K, Remsa J, Mikovsk J, Weiserov M,
et al. Antibacterial properties of Ag-doped hydroxyapatite layers
prepared by PLD method. Appl Phys A 2010;101:615-20.
91. Surmenev RA. A review of plasma-assisted methods for calcium
phosphate-based coatings fabrication. Surf Coat Technol
2012;206:2035-56.
92. Pichugin V, Surmenev R, Shesterikov E, Ryabtseva M, Eshenko E,
Tverdokhlebov S, et al. The preparation of calcium phosphate coatings
on titanium and nickeltitanium by RF-magnetron-sputtered deposition: Composition, structure and micromechanical properties. Surf
Coat Technol 2008;202:3913-20.