1-s2.0-S0169409X12001111-main ANTIBIOTIOK TULANG PDF

ADR-12282; No of Pages 12
Advanced Drug Delivery Reviews xxx (2012) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr
1 Immobilized antibiotics to prevent orthopaedic implant infections☆

Q1 2 Noreen J. Hickok ⁎, Irving M. Shapiro
F
Q2 3 Department of Orthopaedic Surgery, Jefferson Medical College, Philadelphia, PA 19107, USA
4
O
a r t i c l e i n f o a b s t r a c t
O
5
6 Article history: Many surgical procedures require the placement of an inert or tissue-derived implant deep within the body 21
7 Received 22 September 2011 cavity. While the majority of these implants do not become colonized by bacteria, a small percentage de- 22
R
8 Accepted 20 March 2012 velops a biofilm layer that harbors invasive microorganisms. In orthopaedic surgery, unresolved peripros- 23
9 Available online xxxx
thetic infections can lead to implant loosening, arthrodeses, amputations and sometimes death. The focus 24
11
10
12
of this review is to describe development of an implant in which an antibiotic tethered to the metal surface 25
P
13 Keywords:
14 Antibiotics
is used to prevent bacterial colonization and biofilm formation. Building on well-established chemical syn- 26
15 Bacteria theses, studies show that antibiotics can be linked to titanium through a self-assembled monolayer of siloxy 27
16 Staphylococcal aureus amines. The stable metal–antibiotic construct resists bacterial colonization and biofilm formation while
D 28
17 Vancomycin remaining amenable to osteoblastic cell adhesion and maturation. In an animal model, the antibiotic modi- 29
18 Titanium fied implant resists challenges by bacteria that are commonly present in periprosthetic infections. While 30
19 Implants the long-term efficacy and stability is still to be established, ongoing studies support the view that this 31
E
20 Orthopaedic novel type of bioactive surface has a real potential to mitigate or prevent the devastating consequences of or- 32
thopaedic infection. 33
© 2012 Published by Elsevier B.V. 34
T
38 36
35
37
C
40
39 Contents
E
41 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
42 2. Orthopaedic infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
R
43 3. Implant colonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
44 4. Implant designs to minimize bacterial colonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
R
45 5. Treatment of surgical infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

46 6. Surface tethering of antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
47 7. Effects of tethered vancomycin on osteoblast-like cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
O
48 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
49 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
50 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
C
51
N
1. Introduction 52
U
Abbreviations: APTES, aminopropyltriethoxysilane; Cfu, colony forming units, refer-

ring to bacterial numbers; cpTi, commercially pure titanium; ECM, extracellular matrix; Infection continues to plague all medical disciplines that rely on 53
Fmoc-AEEA, Fmoc-[2-(2-amino-ethoxy)-ethoxy]-acetic acid; HATU, O-(7-azabenzo- implantation of a foreign object. In orthopaedics, while a diversity of 54
triazole-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate; MALDI-TOF MS, organisms are present in deep infection, the dominant bacteria are 55
Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectroscopy; MIC,
Gram-positive pathogens [1], with Staphylococcus aureus (S. aureus) 56
minimum inhibitory concentration; PBS, phosphate buffered saline; SAM, self-assembled
monolayer; SEM, scanning electron microscopy; TSB, BHL Tryptic Soy Broth; VAN-Ti, Ti and the coagulase-negative staphylococci especially prevalent [2–5]. 57
alloy displaying covalently-tethered vancomycin. Established treatments rely on controlled release of antibiotics 58
☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Targeted [6–10], or, more recently, the release of silver ions from the implant 59
delivery of therapeutics to bone and connective tissues". surface [11–19]. While both treatments have considerable strengths, 60
⁎ Corresponding author at: Department of Orthopaedic Surgery, Thomas Jefferson
limitations such as tissue toxicity have prompted a search for alterna- 61
University, 1015 Walnut St., Suite 501, Philadelphia, PA 19107, USA. Tel.: + 1 215
955 6979; fax: + 1 215 955 9159. tives that are antibacterial over the lifetime of the implant. The objec- 62
E-mail address: Noreen.Hickok@jefferson.edu (N.J. Hickok). tive of this review is to examine factors leading to orthopaedic 63
0169-409X/$ – see front matter © 2012 Published by Elsevier B.V.

doi:10.1016/j.addr.2012.03.015
Please cite this article as: N.J. Hickok, I.M. Shapiro, Immobilized antibiotics to prevent orthopaedic implant infections, Adv. Drug Deliv. Rev.
(2012), doi:10.1016/j.addr.2012.03.015
2 N.J. Hickok, I.M. Shapiro / Advanced Drug Delivery Reviews xxx (2012) xxx–xxx
64 infection and consider the efficacy of immobilized antibiotics for span. On the other hand, when cells first populate the surface, the 128
65 long-term prevention of implant-associated infections. numbers of adherent bacteria decrease as coverage from adherent 129
osteoblast-like cells increase. Overall, this in vitro model suggests 130
66 2. Orthopaedic infections that bacterial presence limits osteoblast-like cell population of the 131
implant whereas adhesion of osteoprogenitor cells to the implants 132
67 The incidence of infection depends on the surgical site and the limits bacterial adhesion. These studies provide an in vitro competi- 133
68 procedure. Transcutaneous fracture fixation pins have a 2–30% tion model for major non-immune events modulating implantation. 134
69 chance of infection [15,20–22], bone supplementation can be as In this “race for the surface,” the importance of fostering the initial 135
70 high as 13%[23,24], spinal infections are in the 2–5% range [25,26], bone ingrowth to counteract bacterial colonization was deemed to 136
71 and depending on the center, infection after arthroplasty can be sig- be of critical importance. Addition of macrophages to a bacterial-cell 137
72 nificantly less than 1–2%[27–31]. In cases of devastating trauma de- system allows an in vitro measure of a simplified integration of the ac- 138
73 spite aggressive antibiotic prophylaxis and delay of hardware tivated macrophage and its control of bacterial colonization, allowing 139
74 placement, infection occurs frequently [32–34]. the mammalian cells to have the advantage in the race to the surface. 140
75 Pathogen colonization of hardware is enhanced by the host re- Clinically, early contamination, especially during the initial im- 141
F
76 sponse to implantation. Specifically, the host rapidly coats implanted plantation period, is assumed to occur peri-operatively through intro- 142
77 materials with serum proteins that promote cell recruitment and tis- duction of the pathogen either on the implant or into the surgical site. 143
O
78 sue repair. Unfortunately, these same serum proteins are used by Under these conditions, microorganisms would be present at the sur- 144
79 pathogens for adhesion and virulence [35–37]. The problem is further face during the initial post-operative stages which include clot forma- 145
80 compounded by activation of an inflammatory response as well as the tion and dissolution prior to stem cell commitment and osteoblast 146
O
81 complement system upon presentation of these adsorbed proteins. colonization of the implant. This situation may be particularly devas- 147
82 These events, including attenuated activation of phagocytic cells, tating as the host cell response to implantation includes complement 148
83 blunt the local immune response creating an opportunity for patho- activation, recruitment of phagocytic cells whose activity quickly be- 149
R
84 gen colonization [38–40]. In addition, the proteins adsorbed onto comes attenuated in the presence of the large foreign object, and re- 150
85 the implant can promote bacterial adhesion to the implant lease of inflammatory cytokines [63]. Together, these events 151
P
86 [5,41,42]. Another complication is added as the bacteria use the increase the probability for successful bacterial propagation. To 152
87 adsorbed serum fibronectin and vitronectin to interact with adjacent mimic this situation, Schwarz and his colleagues set up a peripros- 153
88 cells. In some cases, these interactions lead to cellular internalization thetic infection model in which the implant was already populated
D 154
89 which can initiate a chronic infection [43–46] as antimicrobial pene- with bacteria at the time of surgery [64]. Infection ensues as the col- 155
90 tration into infected mammalian cells may be insufficient to eradicate onizing bacteria further activate (in addition to the foreign body reac- 156
91 the pathogen [47–50]. Internalization is not limited to professional tion) the immune system to result in tissue degradation, sinus 157
E
92 phagocytic cells — HeLa cervical carcinoma cells [51], aortic endothe- formation, and dissemination of bacteria into the surrounding tissues. 158
93 lial cells, fibroblasts and osteoblasts, among others harbor bacteria, in Later infections may arise due to persistence of an indolent infec- 159
T
94 vitro [52–57]. Finally, the presence of a bacterial biofilm (a communi- tion (seeded in the peri-operative period) or hematogenous seeding 160
95 ty of surface adherent bacteria encased in a polymeric complex) pro- of the implant by a low-level bacterial contamination such as tran- 161
C
96 tects microorganisms from antibiotic activity and from immune cell sient bacteremias experienced with urinary tract infections. 162
97 surveillance. The avidity with which these pathogens colonize im- With revision arthroplasty (replacement of the implant due to 163
98 plants, their recalcitrance to antibiotic treatment in an adherent aseptic loosening or infection), infection and re-infection are more 164
E
99 state, and the possibility that they can persist in the tissue despite im- prevalent. Because even low levels of bacterial colonization can in- 165
100 plant removal, make prevention rather than treatment of infection of duce implant loosening, some cases of aseptic loosening are now con- 166
R
101 paramount importance. sidered to be due to subclinical contamination of the site. Infection 167
102 Since surfaces that tend to be biocompatible often promote bacte- rates can be greater than 10% for revision of septic joints [65], even 168
103 rial colonization, it raises the question, how can infection be avoided? with aggressive antimicrobial treatment. One explanation is that ad- 169
R
104 Clearly, the first defense is rigid adherence to sterile techniques. Clean jacent tissues can harbor bacteria [66–68] so that removal of the im- 170
105 room environments have been shown to lower orthopaedic infection plant, debridement of the bone, and aggressive antimicrobial 171
O
106 rates to below 1% [58]. A robust host response is also required. Ap- treatment may be inadequate to remove all of the bacterial contami- 172
107 proximately 20 years ago, Gristina [59], suggested that there was a nation. In these cases, placement of an implant may become 173
108 “race to the surface” between the cells from the host tissue and the in- impossible. 174
C
109 vading pathogens. Conditions are optimum for the host when mam-
110 malian cells rapidly populate the implant prior to contamination by 3. Implant colonization 175
N
111 pathogens. In the process, the adhering mammalian cells remodel

112 the serum proteins adherent to the implant surface and initiate for- Except in cases of trauma where probable sources of infection are 176
113 mation of either a fibrous or osseous interface with the implant, to ul- obvious, there still is debate concerning the origin of the contaminat- 177
U
114 timately minimize the inflammation associated with the foreign body ing organisms. Implant colonization can occur peri-operatively as de- 178
115 reaction to the implant [38,40]. In concert with tissue formation, im- tailed above or hematogenously later in the lifetime of the implant. 179
116 mune cell surveillance, although attenuated in the peri-implant The hematogenous spread may occur when low numbers of bacteria 180
117 space, serves to protect the site from bacterial colonization. Such are transiently dispersed throughout the body, such as occurs during 181
118 events would be expected to promote host cell survival and prevent urinary tract infections or dental procedures. Under ideal circum- 182
119 bacterial biofilm formation, thereby providing a level of protection stances, these blood-borne bacteria are cleared by the host immune 183
120 that would be optimum for orthopaedic implants. system before they lodge in vulnerable sites. Unfortunately, transient 184
121 The tissue infection paradigm has been elegantly modeled in vitro bacteremias of 100 or fewer microorganisms are capable of success- 185
122 by Subbiahdoss et al. [60–62]. These researchers showed that when fully colonizing an implant surface [40,68,69]. From this perspective, 186
123 challenged with bacterial toxins, flow conditions promoted cell sur- the limiting factor is time not organism dose. 187
124 vival and allowed examination of the competition between bacteria Importantly, bacterial adherence to the implant initiates metabol- 188
125 and cell for surfaces. Using this flow system, pre-incubation of the ic and phenotypic changes that render the adherent pathogen resis- 189
126 surface with bacteria supports osteoblast-like cell adhesion, albeit tant to antibiotics as well as protecting it from immune surveillance 190
127 with a more rounded morphology and very limited proliferative [70]. As immune surveillance may already be compromised due to 191
(2012), doi:10.1016/j.addr.2012.03.015
N.J. Hickok, I.M. Shapiro / Advanced Drug Delivery Reviews xxx (2012) xxx–xxx 3
192 the presence of the implant, protection of the bacteria may be even common [94,95], with conflicting reports as to its efficacy in stabiliz- 256
193 more effective. With respect to antibiotics, even with antibiotic con- ing bone growth around the implant [94,96,97]. There is some debate 257
194 centrations that are 20–100× greater than the minimum inhibitory whether any of these textured surfaces or hydroxyapatite layers alter 258
195 concentration (MIC), some adherent bacteria can still persist on im- the frequency or extent of bacterial colonization [85,98–101]. Howev- 259
196 plants, in vitro [71,72]. Fortunately, some antibiotics, such as vanco- er, while hydroxyapatite coatings themselves may or may not be per- 260
197 mycin and daptomycin, appear to be somewhat effective against missive for bacterial colonization, they do serve as ready depots for 261
198 biofilms [73,74]. adsorption of antibiotics for in situ release [102–104]. In one applica- 262
199 This apparent antibiotic resistance is initiated upon adhesion to an tion, adsorption of gentamicin to hydroxyapatite resulted in sufficient 263
200 implant when bacteria change from a rapidly growing, non-adherent antibiotic release to allow short-term prophylaxis [105,106]. 264
201 planktonic state to a sessile organism. Generally, these adherent bac- At the other end of the size spectrum, nano-texturing is being in- 265
202 teria secrete and then become encased in a thick biofilm matrix that troduced to foster drug delivery and bone ingrowth. The effect of 266
203 serves to further protect them against host assault. Within this bio- nanotexture on bacterial colonization appears to depend on size, tex- 267
204 film, channels exist for nutrient exchange, and, as in any renewing ture, and spacing [107–109], which will also affect serum protein ad- 268
205 structure, there is both proliferation and death [41,75–77]. This latter sorption and mammalian cell adhesion. An interesting topography 269
F
206 event results in the biofilm being a rich repository of DNA. Exchange has been based on the natural diamond-like texturing of shark skin, 270
207 of biofilm-trapped DNA between bacterial species can cause transfer which shows a 50–80% decrease in colonization [110]. In vivo exper- 271
O
208 of traits, in particular those responsible for true antibiotic resistance iments will be required to determine if nano-texturing promotes tis- 272
209 [41,77]. sue formation and remodeling while decreasing bacterial adhesion 273
210 An important corollary to the presence of a mature biofilm on an and biofilm formation. 274
O
211 implant is the sloughing off of bacteria into the environment. These
212 bacteria can then colonize the surrounding tissue [66–68], adhering 5. Treatment of surgical infection 275
R
213 to ECM proteins present in the tissue as well as initiating cellular pro-
214 cesses that cause pathogen internalization [36,55,78–81]. Thus, once While low, the orthopaedic infection rate reflects the surgical 276
215 implant colonization has occurred, continuing infection is propagated technique, the health and age of the patient, the physical dimensions 277
P
216 not only through the bacteria disseminated from the biofilm on the and state of the surgical site and the implant material [111]. To min- 278
217 implant, but through adherence and colonization of contiguous imize infection, systematic antibiotics are administered 2 to 14 days 279
218 tissues. post-surgery with additional oral prophylaxis [111,112]. When
D 280
219 In summary, adhesion of bacteria to a surface and subsequent bio- there is severe trauma, implant placement may be delayed to allow 281
220 film formation promotes metabolic, phenotypic, and genotypic clearance of any contaminants introduced in the wound [113]. 282
221 changes that make their eradication extremely difficult. Moreover, When infection is present, it is often necessary to supplement an- 283
E
222 continuous seeding of surrounding tissues increases the probability tibiotic therapy with implant removal and elimination of infected 284
223 that infection will continue. For these reasons, the single most impor- bone [114–117]. For arthroplasties, optimum treatment includes re- 285
T
224 tant target for prevention of implant-associated infections is eradica- moval of the infected component and debridement of surrounding 286
225 tion of bacteria before they can populate the implant/tissue bone to remove additional sources of bacteria that have been 287
C
226 environment. detected in the tissue around orthopaedic implants, catheters, and 288
other implants [118,119]. When the two-stage procedure is used, an 289
227 4. Implant designs to minimize bacterial colonization antibiotic-eluting spacer is implanted, and, after treatment periods 290
E
of ~ 6 weeks, assuming a good outcome, a new implant can be 291

228 Depending on surgical requirements, orthopaedic implants can be inserted into the bone [65,120,121]. Even with these measures, re- 292
R
229 comprised of a single material, as in fracture fixation hardware and infection rates can be high, which again emphasizes the possibility 293
230 spinal hardware (metals or polymers such as polyethylarylketone), that contamination from the surrounding tissue can re-seed the im- 294
231 multiple materials, such as the combinations of plastics or ceramics plant and cause active infection. For the most difficult cases, arthrod- 295
R
232 and metals used for hip and knee implants (which are often accompa- esis or amputation may be the only options [114]. This propensity for 296
233 nied by cements or morselized bone to enhance implant fit) or com- re-infection underscores the importance of preventing the initial bac- 297
O
234 plex proteins and minerals as found in allograft bone. It is important terial colonization of the implant. 298
235 to note that all implants are not designed to be osseointegrated. Un- Because the higher antibiotic doses associated with the antibiotic- 299
236 fortunately, all implants are prone, to some degree, to bacterial colo- eluting spacers can eradicate most infections, systems have been pro- 300
C
237 nization. The propensity for bacterial colonization does, to some posed to deliver antimicrobials at high doses from the implant itself 301
238 extent, depend on the material. However the general rule of thumb to obviate the need for a two-stage procedure. Porous materials, 302
N
239 is that in accord with the “race for the surface” scenario, i.e., enhanced such as cancellous bone [122], collagen sponges and PMMA [123] 303
240 protein adsorption will ultimately result in increased [osseo]integra- have been loaded with antibiotics. In common with the antibiotic- 304
241 tion and resistance to infection; however during the early stages of bearing cements, the goal of these elution systems is to keep the im- 305
U
242 this process, these self-same properties predispose the implant to plant surface sterile while eradicating bacterial contamination of the 306
243 bacterial colonization. surrounding tissue [124–128]. Newer systems have used biodegrad- 307
244 At the material level, the composition of the implant has some im- able implant coatings to facilitate and control antibiotic release 308
245 pact on bacterial colonization. For instance, in vivo, stainless steel is [129–133]. A detailed synopsis of controlled release systems is out- 309
246 colonized more readily than titanium, perhaps due to differences in side the scope of this review. 310
247 osseointegration [82,83] which may reflect differences in protein ad- Controlled release systems are powerful therapeutic tools and ef- 311
248 sorption to the surface. Hydrophobicity/hydrophilicity, surface com- fectively eradicate bacterial contamination. However, they have a 312
249 position, and texturing all impact bone ingrowth and bacterial number of shortcomings. Firstly, high local antibiotic concentrations 313
250 adhesion [84–86]; of these, the most important is surface hydropho- are only achieved over the short term. Specifically, in an allograft sys- 314
251 bicity [87–89]. Texturing of surfaces at the micro level through pro- tem, independent of initial concentrations and time of impregnation, 315
252 cesses such as sand-blasting and at the macro level through ~75% of the adsorbed vancomycin and ~ 99% of netilmicin elutes with- 316
253 introduction of beads, sintering, etc., have improved osseointegration in 120 h [134]. Likewise within a six week time period, the concentra- 317
254 of the neck of joint replacement stems [90–93]. Additionally, application of antibiotics from spacers has significantly decreased [111,135]. 318
255 tion of calcium phosphate, especially sintered hydroxyapatite is While these levels may initially approach supratherapeutic levels, 319
(2012), doi:10.1016/j.addr.2012.03.015
320 bacteria may still be able to evade the antimicrobial agents by adop- original problem, i.e., that they are prone to bacterial contamination 386
321 tion of a metabolic state that allows them to “persist,” by biofilm for- and biofilm formation. Furthermore on the tethered surface, such 387
322 mation, and by dissemination into the surrounding tissues where scoring could cause increased instability of the otherwise stable 388
323 antibiotic penetrance will be low. Thus, while controlled release of SAM due to its disruption and subsequent hydrolysis. Again, exposure 389
324 antibiotics provide a highly effective modality for treatment of acute of the underlying surface would occur, giving rise to the same weak- 390
325 infection, at late treatment times, when antibiotics levels fall to sub- ness as the spent elution system. 391
326 therapeutic levels, surviving bacteria can slowly re-establish a biofilm An additional weakness is linked to the role of tissue-associated 392
327 which will again serve as a nidus for bacterial dissemination bacteria in the propagation of infection. By necessity, a tethered anti- 393
328 [66,67,136]. This high dissemination rate is in keeping with the rela- biotic is only active in the space immediately adjacent to the implant. 394
329 tively high re-infection rates after revision for an infected component. Thus, the antibiotic would not be able to interact with those bacteria 395
330 Secondly, the drop in antibiotic levels exposes the surviving bacteria that are but a few microns distant from the surface. For this reason, 396
331 to sub-inhibitory concentrations of antibiotics. This metabolic pres- the best use of such systems would be in combination treatments 397
332 sure increases the risk of fostering development of resistant strains that include systemic or locally delivered antibiotics. 398
333 of bacteria [77,137]. Resistant bacterial sub-populations with ex- Orthopaedic implants are highly engineered to display textures or 399
F
334 tremely high MICs were detected after use of gentamicin beads dur- surfaces that either foster bone ingrowth, or in the case of fracture fix- 400
335 ing two-stage exchange arthroplasty [137], supporting the need for ation nails, stability without osseointegration. While we have shown 401
O
336 integrated systems which ensure that conditions that foster resis- that we can tether antibiotics with retention of topography [175], 402
337 tance are not established. Thirdly, high levels of antibiotics can the addition of the SAM, linkers, and the antibiotic to the surface 403
338 cause local tissue toxicity, compromising bone regrowth, immune readily allows osteoblast adhesion and maturation. On the one 404
O
339 system surveillance and implant osseointegration. hand, such enhanced cell adhesion would support the osteoblast's 405
340 Silver-impregnated surfaces have enjoyed success as wound ability to win the race for the surface; on the other hand, application 406
341 healing dressings and appear to decrease levels of both adherent of these surfaces to components that need to be removed might prove 407
R
342 bacteria and bacteria adjacent to the implant [12–15,138]. Elution problematic. 408
343 times tend to be longer than conventional controlled release sys-
P
344 tems giving the surfaces an additional advantage. Questions remain 6. Surface tethering of antibiotics 409
345 as to implant efficacy, long-term tissue toxicity as well as acquisition
346 of silver-resistance. Based on the overall advantages of the surface-tethered implant,
D 410
347 In the search for complementary systems, we and others have ex- we developed a strategy to prevent bacterial colonization of im- 411
348 plored the possibility that antibiotics, and in a few cases antimicrobial plants with two key objectives: 1. Prevent bacterial adhesion and 412
349 peptides, covalently attached to an implant surface, may provide pro- biofilm formation. 2. Avoid therapies likely to foster pathogen resis- 413
E
350 tection long after controlled release of antibiotics has waned. The ad- tance. For this purpose, the most efficacious approach is to create 414
351 vantage of such a system is firstly, unlike elution systems, the surface an implant surface that integrates a controlled release system 415
T
352 could remain antibacterial over the lifetime of the coating. While this (days to weeks) with a permanent, covalently-tethered antibacter- 416
353 coating is present, the implant should display antimicrobials, unlike ial layer that resists colonization over the long-term (months to 417
C
354 controlled release systems where the antibiotic-depleted surface be- years). We reasoned that (1) non-adherent planktonic bacteria 418
355 comes susceptible to bacterial colonization [134,139–143]. The long- can be eradicated by local antibiotic release or by the immune sys- 419
356 term antibacterial coverage would have greatest impact in cases of tem and (2) that minimizing bacterial adhesion through implant 420
E
357 established infection where re-contamination of the implant from coating would prevent biofilm formation and effectively remove 421
358 the surrounding tissue is always a possibility. the implant as a reservoir of bacteria. Our research findings support 422
R
359 Secondly, because the antibiotics are tethered, no bulk tissue tox- the power of these hybrid antibacterial surfaces to combating bac- 423
360 icity would be anticipated. If toxicity were experience, it would be terial adhesion and colonization [147,148]. In this manuscript, the 424
361 expected to be limited to the sub-micron tissue–implant interface. remainder of the discussion is focused on the value of the antibac- 425
R
362 Thirdly, it is likely that the probability of fostering of antibiotic resis- terial surface. 426
363 tance with the use of these attachment systems would be low. Indeed, Bonding of molecules to surfaces has an extensive literature. The 427
O
364 the amounts of antibiotic or other tethered antimicrobial attached to cell adhesion peptide RGD has been immobilized to glass [149], 428
365 the surface is very low compared to either the MIC of the agent or to quartz [150–152], gold [153], silicone [154], silica [155] and titani- 429
366 controlled release systems. On metal surfaces, based on previous um [156–158]. Different linkages have been used on titanium sur- 430
C
367 measurements [144–146] we would expect quantities of antibiotic faces including diphosphonic acids [159,160], plasma amination 431
368 that are in the nanogram range, a million-fold less than the amounts [161], silanization to reveal active amines [145,156,162], surface 432
N
369 immobilized in the controlled release systems. At these concentra- photopolymerization of PEG-acrylamide groups [163], reaction 433
370 tions, even if catastrophic release were to occur, the amount of antibi- with p-nitrophenyl chloroformate to activate the surface [164] and 434
371 otic would be too low to foster resistance. Whether resistance will interestingly, titanium-binding peptides to allow PEGylation [165]. 435
U
372 occur and the frequency of its occurrence is, so far, outside the limits Antimicrobial peptides have also been grafted onto surfaces with 436
373 of our test. Our resistance experiments to date have been solely based successful bacterial killing for the cationic LL-37 on Ti [166], and 437
374 on metabolic pressure exerted by vancomycin-tethered Ti rods on S. the pore forming toxin maiganin I on thiol-gold [167]. Covalent 438
375 aureus under laboratory conditions [144]. Similarly, the strains isolat- modification of titanium surfaces with antibiotics has focused to date 439
376 ed from our animal experiments, based on limited testing, remain predominantly on vancomycin [163,168–170], with one report on 440
377 vancomycin sensitive. Thus, the question about the surface's effects daptomycin [171]. In our studies, we have tethered vancomycin to 441
378 on antibacterial resistance remains open. commercially pure titanium [169]; vancomycin [145,172] gentamicin, 442
379 Although there are very obvious advantages for non-eluting sys- ceftriaxone, kanamycin, tetracycline, and doxycycline (unpublished 443
380 tems, they also have their weaknesses. Coatings tend to be fragile — data) to titanium alloy (Ti90Al6V4); and vancomycin [173] and 444
381 a problem both with controlled release as well as tethered systems. doxycycline to bone allograft. These surfaces showed antibacterial 445
382 For all systems, the fragility is associated with the significant forces activity with retention of antibiotic specificity. 446
383 that are often applied to orthopaedic hardware during insertion — The immobilization strategy that we have used to facilitate chem- 447
384 forces that are sufficient to cause scraping of the metal which would ical coupling of linkers and antibiotics to metal surfaces relies on ini- 448
385 be certain to score the coating. Bare surfaces then re-acquire the tial formation of an amine-rich, reactive surface. Our strategy is to 449
(2012), doi:10.1016/j.addr.2012.03.015
450 generate and maintain the Ti–O linkage which can then be used to that is used for tethering of the vancomycin to the implant has been 491
451 form bonds with other agents, in particular aminopropyltriethoxy si- used to make other adducts of vancomycin with retention of activity 492
452 lane (APTES). APTES forms three siloxy bonds to the titanium oxide; [178]. The reversibility of the bonding allows the surface to be regen- 493
453 this layer is further stabilized by cross-linking to generate a self- erated after exposure to bacteria. Specifically, because vancomycin 494
454 assembled monolayer (SAM) [174]. In this reaction scheme, a fresh has a relatively low affinity for its substrate, bacterial fragments can 495
455 oxide layer is formed (i.e., passivation) through use of oxidizing solu- be released from the surface, even after they have interacted with 496
456 tions (e.g., chromic acid (H2SO4/HNO3) or piranha acid (H2O2/ the vancomycin. We have tested these surfaces in small (rat [148]) 497
457 H2SO4)[161]) that etch the metal or through use of hydrothermal and large (sheep (Schaer, Hickok, et al., unpublished data)) animal 498
458 aging [169,173,175]. An important consideration is retention of the models. If efficacy were lost due to the presence of either dead bacte- 499
459 topography of the highly engineered implant surface. Thus, while pi- ria or bacterial fragments on the surface, we would expect a small lag 500
460 ranha acid increased surface pitting, hydrothermal aging appeared to in the establishment of infection, i.e., the animals with coated im- 501
461 retain surface features (Fig. 1 [173]). plants would still establish infection after a lag period. However, we 502
462 The presence of the SAM that is covalently grafted on the surface have not observed establishment of a fulminating infection; indeed, 503
463 of the Ti metal and displays primary amines provides a convenient these VAN-tethered implants have been surprisingly successful. 504
F
464 first step for subsequent tethering reactions. We have confirmed the With respect to other antibiotics, especially those that contain the 505
465 formation of the amine-bearing SAM (1) through reaction with fluor- β-lactam ring, we would expect them to irreversibly bind to the cell 506
O
466 escamine and detection of fluorescence by confocal laser scanning wall of the bacterium. While these surfaces would be active initially, 507
467 microscopy [173,176] and (2) through colorimetric detection of pri- we would expect them to lose active antibiotic with repeated expo- 508
468 mary amines using the ninhydrin reaction [145,169]. sure, in keeping with our preliminary results (Hickok, et al., unpub- 509
O
469 To enhance the entry of the tethered antibiotic into the bacteri- lished data). 510
470 um, we sequentially coupled two membrane-soluble Fmoc-[2-(2- The vancomycin-tethered surface showed a time dependent in- 511
R
471 amino-ethoxy)-ethoxy]-acetic acid (Fmoc-AEEA) linkers to the hibition of bacterial colonization for the Gram-positive organisms 512
472 APTES surface in the presence of O-(7-azabenzo-triazole-1-yl)- S. aureus [145] and S. epidermidis [177]. The vancomycin surfaces 513
473 1,1,3,3-tetramethyluronium hexa-fluorophosphate (HATU). After clearly decreased bacterial colonization, but did not eradicate all 514
P
474 deprotection of the second linker, we coupled the Ti-APTES- adherent bacteria. Therefore in studies of vancomycin-tethered 515
475 (AEEA)2 product with vancomycin in the presence of HATU [169]. to bone allograft, we asked the utility of the surfaces against dif- 516
476 The predicted structure would give vancomycin an ~ 30–40 Å arm ferent starting bacterial inocula. At 10 3–10 4 cfu bacteria (6 h ex-
D 517
477 for inserting into the bacterium [172]. posure), the vancomycin–allograft surfaces were most effective, 518
478 Vancomycin coverage was visualized through indirect immuno- with increased colonization with inocula above 10 4 cfu [179]. In 519
479 fluorescence. Coverage was also estimated through recovery of fluo- keeping with the known activity of vancomycin against Gram- 520
E
480 rescent antibodies which suggested that ~ 29 ng of vancomycin was positive organisms and as a control, the Gram-negative organism 521
481 immobilized on a 1 × 10 mm pin [144,145,176,177]. Using acid cleav- Escherichia coli (E. coli) readily adhered to vancomycin-modified 522
T
482 age of the siloxy bonds, the cleaved material was analyzed with surfaces (Fig. 2, [177]). Importantly, the vancomycin-tethered sur- 523
483 MALDI-TOF mass spectroscopy (MALDI-TOF MS). The array of molec- face could inhibit biofilm formation by S. epidermidis (Fig. 3 524
C
484 ular ions detected were consistent with the predicted struc- [177]). While these studies addressed the short-term activity of 525
485 ture [169,172], confirming that the desired Ti-APTES-(AEEA)2- the surface, they did not assess conservation of biocidal activity 526
486 vancomycin product was formed. for a long time period (months, even year after implant placement). 527
E
487 Vancomycin, the antibiotic used in these studies, interferes with For these studies, vancomycin coverage was assayed in the presence 528
488 cell wall synthesis in two ways: inhibiting synthesis of the polymeric of S. aureus in tryptic soy broth. Both vancomycin coverage and activity 529
R
489 glycan molecules and blocking polymer cross-linking by reversible appeared to be maintained for dry pins or pins maintained in PBS 530
490 binding to the peptidoglycan Lys-D-Ala-D-Ala. The carboxylic acid for times out to 2 years [145,177]. A similar modification of native 531
R
O
C
N
U
Fig. 1. SEM imaging reveals preservation of topography. Microtopographical assessment of smooth and beaded surfaces was performed by scanning electron microscopy (SEM)
imaging (1000×). (A) Control titanium alloy surfaces showed normal, shallow machining lines across the surface. (B) Control, commercially pure titanium (cpTi) beaded surfaces
showed concentric shallow machining lines. (C) Hydrothermally-aged Ti alloy appeared similar to control surfaces (D) Hydrothermally-aged, beaded cpTi surfaces were also similar
to control surfaces. (E) The H2SO4:H2O2 treated Ti alloy surface disc showed obvious etching and deepening of the natural crevices of the metal. Dark areas indicate pitting. (F) Sim-
ilarly, the etched, beaded cpTi exhibited extensive pitting. (Magnification: 1000X, bar = 100 μm).
Figure reproduced from [176] with permission of Springer.
(2012), doi:10.1016/j.addr.2012.03.015
F
O
O
R
Fig. 2. Bacterial colonization of vancomycin-tethered Ti (Vanc-Ti) surfaces. A. Control or vancomycin-tethered surfaces were challenged (initial concentration ~ 1 × 104 cfu/ml) with
S. epidermidis (Gram-positive), which should be sensitive to vancomycin or E. coli (Gram-negative) which does not have vancomycin sensitivity. Colonization of control surfaces
P
was robust, as indicated by green fluorescence, for both S. epidermidis and E. coli. Only E. coli could show any significant colonization of the Vanc-Ti surface, in keeping with the
Gram-positive spectrum of activity of vancomycin. B. Numbers of adherent bacteria recovered at each time point for the two surfaces, expressed as a percent of the two hour con-
trols in the histograms and given as colony forming units (cfu) in the tables below the histograms. Values are shown as cfu ± SEM, where * denotes p b 0.5. Magnification:
bar = 200 μm. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
D
Figure reproduced from [177] with permission of Elsevier.
E
T
C
E
R
R
O
C
N
U
Fig. 3. A. Biofilm formation by S. epidermidis was assessed on control or vancomycin-tethered Ti (Vanc-Ti) surfaces by detection of crystal violet incorporation. Biofilm formation
was expressed relative to the absorbance of the 2 h control for both control and Vanc-Ti surfaces, with absorbance values presented in tabular form below the histogram. B, C.
The presence of S. epidermidis on control (B) and Vanc-Ti (C) surfaces was visualized by SEM. The characteristic clusters of grape-like S. epidermidis are apparent on control surfaces
whereas on the Vanc-Ti surface, few if any S. epidermidis are visible. Magnification: bar = 5 μm.
Figure reproduced from [177] with permission of Elsevier.
(2012), doi:10.1016/j.addr.2012.03.015
532 allograft bone was stable for at least 10 months by antibody staining [177]. Overall, however, the tethered vancomycin appeared to 557
533 and at least two months on the basis of activity determinations [173]. endow the implant with the ability to resist bacterial colonization, 558
534 The longevity of polymerized VAN on surfaces has not been published not only for the first bacterial assault, but for several subsequent 559
535 [163,170,180], nor is there information on the long-term activity of challenges. 560
536 the antimicrobial peptide surfaces. However, if these surfaces are Importantly, recovery of adherent bacteria from challenges such 561
537 indeed stable, then they too should be capable of preventing the as those described above and from challenges maintained for several 562
538 establishment of bacterial colonization over the long term — the months, indicated that there was no evidence of acquisition or foster- 563
539 major advantage over the controlled release systems. Longevity ing of resistance [144]. Of course, selection for resistance has only 564
540 and efficacy will need to be measured in vivo to assess their success. been measured under conditions of metabolic pressure. As the bulk 565
541 If the surfaces described above are to have clinical utility, they of the bacteria (i.e., those not in contact with the surface) will not 566
542 must retain their antibacterial character in a physiological envi- be experiencing a metabolic pressure, an incidental resistant organ- 567
543 ronment and withstand multiple challenges by bacteria. The ism, which is typically slow-growing [181,182], will not have a selec- 568
544 vancomycin-coupled surfaces were tested for activity in the pres- tive growth advantage and is likely to lose out in the struggle for 569
545 ence of serum proteins. Firstly, antibody binding and reactivity nutrients. In addition to metabolic pressure, resistance arises in 570
F
546 of the tethered vancomycin was retained in the presence of mixed populations of bacteria, especially in biofilms, where transfer 571
547 these proteins [145,177]. Secondly, the tethered vancomycin con- of plasmid elements can cause transfer of traits [181,182]. Important- 572
O
548 tinued to inhibit bacterial adhesion, even in the presence of ly, as biofilm formation appears to be retarded on these surfaces, the 573
549 serum proteins (Fig. 4 [177]). To determine if these surfaces with- ability to horizontally transfer plasmids is limited, which would min- 574
550 stand multiple bacterial challenges, the antibiotic tethered pins imize the possibility of resistance. Finally, acquisition of antibiotic re- 575
O
551 were repeatedly challenged for 24 h with S. epidermidis, followed sistance is rare. Thus, on an implant where the numbers of surface 576
552 by removal of the adherent bacteria, washing and re-challenge bacteria are limited, the probability of development of resistance is 577
[145]. By the fifth re-challenge, based on Live/Dead staining, some
R
553 small. While all of these predictions suggest that resistance due to 578
554 variability appeared not only in colonization of the vancomycin- surface-tethered antibiotics will be infrequent, only the simple condi- 579
555 tethered pin, but also in the ability of the bacteria to colonize the tions have been tested and further more detailed studies need to be 580
P
556 control pins probably due to the presence of residual detergent performed. 581
D
E
T
C
E
R
R
O
C
N
U
Fig. 4. Antimicrobial activity of the tethered vancomycin (Vanc-Ti) surface in the presence of serum. (A) Fibronectin adsorption and vancomycin fluorescence. (Left) Control or Vanc-
Ti rods were incubated with FBS for 24 h and fibronectin adsorption detected by immunofluorescence analysis. Both surfaces showed abundant fibronectin (red stain), compared to
the rods incubated in H2O. (Right) Following incubation with serum proteins, rods were incubated with an antibody against vancomycin and visualized by immunofluorescence.
Despite protein adsorption, vancomycin fluorescence (blue stain) was clearly detectable on the Vanc-Ti rods, with no staining on control surfaces. (B) Antimicrobial activity.
Vanc-Ti rods that had been treated with serum proteins were challenged with S. epidermidus (initial concentration = ~ 1 × 104 cfu/ml) for 24 h and live, adherent bacteria stained
with the Live/Dead kit (green). Fluorescence detected from the serum-treated Vanc-Ti rods was very low and similar to the fluorescence detected from the H2O-incubated Vanc-Ti
rods. In both cases, this fluorescence was much less intense than the fluorescent yield generated by bacteria that had colonized the control rods. Magnification: bar = 200 μm. (For
interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Reproduced from [177] with permission of Elsevier.
(2012), doi:10.1016/j.addr.2012.03.015
582 7. Effects of tethered vancomycin on osteoblast-like cells removal of VAN-Ti rods suggested bone ongrowth and osseointe- 606
gration. As assessed by microCT analysis, when control titanium 607
583 While the tethered antibiotic surfaces are promising with respect to alloy rods were present in infected femora, bone lysis was apparent; 608
584 inhibiting bacterial colonization, it is important to characterize them in those femora that contained VAN-Ti rods, bone structure 609
585 with respect to biocompatibility. As a first measure of this complex phe- remained close to normal (Fig. 6 [161]). This preliminary study 610
586 nomenon, which should ultimately address its effects on the immune thus supports the contention that removal of the implant as a 611
587 system as well as the surrounding bone tissue, we have focused on ef- nidus of infection allows the rat's robust immune system to clear 612
588 fects of the tethered vancomycin–Ti surface on osteoblast-like cells. As the infection. 613
589 discussed earlier, antibiotics can block osseointegration by down- Thus, these antibiotic-coupled surfaces, whether constrained to 614
590 regulating pre-osteoblast recruitment, proliferation, differentiation, classical antibiotics or embracing new antimicrobials and antimicro- 615
591 and maturation. Indeed, when osteoblast-like cells are cultured on ei- bial peptides, appear to overcome many of the problems associated 616
592 ther control or tethered vancomycin surfaces, we have found that with controlled release systems, i.e., finite lifespan, tissue toxicity, 617
593 there is little change in morphology, size and density of adherent cells and release of sub-therapeutic levels of antibiotics. Our in vitro 618
594 (Fig. 5 [144]). In other studies, we have found no significant differences and in vivo studies suggest that these antimicrobial-tethered im- 619
F
595 in number, viability, or levels of maturation markers associated with plants decrease bacterial colonization and biofilm formation [148]. 620
596 maintaining osteoblasts on vancomycin-modified allograft surfaces Based on the results of these studies and available knowledge con- 621
O
597 [173,179]. Based on these studies, we would predict that in vivo the sur- cerning organism adherence and biofilm organization, we are of the 622
598 faces would preserve cell commitment, differentiation and proliferative opinion that this antimicrobial implant surface is ready for pre- 623
599 status while maintaining the osseointegrative properties of the modi- clinical and clinical evaluation. Finally, the organometallic chemistry 624
O
600 fied implant. Fortunately, as the antibiotic surfaces limit bacterial adher- that has been employed to generate the hybrid surface can be 625
601 ence, biofilm formation and the deleterious effects of colonization in the adapted to couple a host of other agents to solid surfaces. These 626
602 “race for the surface” would be minimized. surface-bound agents can be tailored to maintain an implant that 627
R
603 We have performed preliminary testing of vancomycin-modified resists bacterial colonization. Importantly, these surfaces require 628
604 titanium alloy (VAN-Ti) rods in our rodent model of osteomyelitis long-term testing in animal and clinical models to determine if 629
P
605 [148]. After three weeks in uninfected femora, the difficulty of their activity is stable and to test if tissue healing and resistance 630
D
E
T
C
E
R
R
O
C
N
U
Fig. 5. Vancomycin-tethered titanium surfaces support normal cellular morphology. Preosteocyte-like MLO-A5 cells (initial inoculum: ~ 30,000 cells) were assessed for morphology
and cytoskeletal architecture on the different surfaces. (A) MLO-A5 cells readily adhered to smooth, control surfaces, with a number of cells exhibiting an array of actin stress fibers;
other cells showed cellular extensions that are characteristic of cells undergoing shape or size changes. (B) MLO-A5 cells readily colonized the VAN-hTi surface, with cell shapes
ranging from small to more trapezoidal shapes. Actin stress fibers were apparent throughout, as were cells bearing microspikes, presumably a sign of cell spreading. (C) Cells on
control, beaded surfaces appeared well-spread, with abundant actin staining. Some stress fibers were apparent as were short actin bundles. Morphology was within that normally
observed for the MLO-A5 cells. (D) Cells seeded on beaded surfaces VAN-hTi surfaces showed abundant cellular colonization, with a normal actin cytoskeletal network. Cell shape
appeared normal. (Stain: actin cytoskeleton: Alexafluor 488 conjugated phalloidin — red; nuclei: propidium iodide — blue; original magnification: 40×). (For interpretation of the
references to color in this figure legend, the reader is referred to the web version of this article.)
Figure reproduced from [176] with permission of Springer.
(2012), doi:10.1016/j.addr.2012.03.015
F
O
O
R
P
D
E
Fig. 6. MicroCT cross-sectional analysis of the control and vancomycin-modified titanium rods based on animals sacrificed at Day 14. (A) Cortical mid-shaft cross-sections from the
control infected side are compared to (B) sections from the side receiving the modified rod, where severe changes in bone anatomy are observed. (C) In the control femur of another
T
animal, aggressive remodeling with cortical bone penetration and destruction, abundance of cysts, severe periosteal reaction and reorganization, and enlargement of the entire fem-
oral bone are readily apparent in distal diaphyseal cross-sections when compared to (D) sections from the side receiving a vancomycin-modified titanium rod.
C
Figure reproduced from [148] with permission of Wolters Kluwer Health.
631 to infection leads to decreased pain, suffering, and disability due to [6] H. Anwar, M.K. Dasgupta, J.W. Costerton, Testing the susceptibility of bacteria in 657
E
biofilms to antibacterial agents, Antimicrob. Agents Chemother. 34 (1990) 658

632 orthopaedic infection. 2043–2046. 659
[7] C.P. Duncan, B.A. Masri, The role of antibiotic-loaded cement in the treatment of 660
R
an infection after a hip replacement, Instr. Course Lect. 44 (1995) 305–313. 661
633 Conflict of interest [8] D.N. Fish, H.M. Hoffman, L.H. Danziger, Antibiotic-impregnated cement use in 662
U.S. hospitals, Am. J. Hosp. Pharm. 49 (1992) 2469–2474. 663
664
R
634 Noreen J. Hickok is a founder of SmartTech, Inc., a commercial en- [9] K.L. Garvin, Two-stage reimplantation of the infected hip, Semin. Arthroplasty 5
(1994) 142–146. 665
635 tity that holds the license for this technology. [10] K. Steinbrink, The case for revision arthroplasty using antibiotic-loaded acrylic 666
cement, Clin. Orthop. Relat. Res. (1990) 19–22. 667
O
[11] L. Zhao, H. Wang, K. Huo, L. Cui, W. Zhang, H. Ni, Y. Zhang, Z. Wu, P.K. Chu, Anti- 668
636 Acknowledgements bacterial nano-structured titania coating incorporated with silver nanoparticles, 669
Biomaterials 32 (2011) 5706–5716. 670
C
637 The authors thank Christopher S. Adams, Valentin Antoci, Jr., [12] F.H. Furkert, J.H. Sorensen, J. Arnoldi, B. Robioneck, H. Steckel, Antimicrobial ef- 671
ficacy of surface-coated external fixation pins, Curr. Microbiol. 62 (2011) 672
638 Theresa A. Freeman, and Javad Parvizi, along with countless other
1743–1751. 673
639 colleagues who have been instrumental in furthering this work. [13] L. Juan, Z. Zhimin, M. Anchun, L. Lei, Z. Jingchao, Deposition of silver nanoparti- 674
N
640 The authors thank the NIH (grants DE-13319, DE-10875, AR-051303, cles on titanium surface for antibacterial effect, Int. J. Nanomedicine 5 (2010) 675
641 DE-019901, and HD-061053) and the Department of Defense (grant 261–267. 676
[14] E.M. Hetrick, M.H. Schoenfisch, Reducing implant-related infections: active re- 677
U
642 DAMD17-03-1-0713) for research support. Results presented are not lease strategies, Chem. Soc. Rev. 35 (2006) 780–789. 678
643 the statement or policy of the funding agencies. [15] A. Masse, A. Bruno, M. Bosetti, A. Biasibetti, M. Cannas, P. Gallinaro, Prevention of 679
pin track infection in external fixation with silver coated pins: clinical and mi- 680
crobiological results, J. Biomed. Mater. Res. 53 (2000) 600–604. 681
644 References [16] M. Mrksich, L.E. Dike, J. Tien, D.E. Ingber, G.M. Whitesides, Using microcontact 682
printing to pattern the attachment of mammalian cells to self-assembled mono- 683
645 [1] D.T. Tsukayama, R. Estrada, R.B. Gustilo, Infection after total hip arthroplasty. A layers of alkanethiolates on transparent films of gold and silver, Exp. Cell Res. 684
646 study of the treatment of one hundred and six infections, J. Bone Joint Surg. 235 (1997) 305–313. 685
647 Am. 78 (1996) 512–523. [17] S.P. Valappil, J.C. Knowles, M. Wilson, Effect of silver-doped phosphate-based 686
648 [2] G. Peersman, R. Laskin, J. Davis, M. Peterson, Infection in total knee replacement: glasses on bacterial biofilm growth, Appl. Environ. Microbiol. 74 (2008) 687
649 a retrospective review of 6489 total knee replacements, Clin. Orthop. Relat. Res. 5228–5230. 688
650 (2001) 15–23. [18] J. Kassler, J. Barnett, A rehabilitation hospital's experience with ionic silver Foley 689
651 [3] P.J. Sanderson, Infection in orthopaedic implants, J. Hosp. Infect. 18 (1991) catheters, Urol. Nurs. 28 (2008) 97–99. 690
652 367–375. [19] A. Coughlan, D. Boyd, C.W. Douglas, M.R. Towler, Antibacterial coatings for med- 691
653 [4] R.O. Darouiche, Antimicrobial approaches for preventing infections associated ical devices based on glass polyalkenoate cement chemistry, J. Mater. Sci. Mater. 692
654 with surgical implants, Clin. Infect. Dis. 36 (2003) 1284–1289. Med. 19 (2008) 3555–3560. 693
655 [5] L.G. Harris, R.G. Richards, Staphylococci and implant surfaces: a review, Injury [20] G. De Bastiani, R. Aldegheri, L. Renzi Brivio, Dynamic axial fixation. A rational al- 694
656 37 (2006) S3–S14. ternative for the external fixation of fractures, Int. Orthop. 10 (1986) 95–99. 695
(2012), doi:10.1016/j.addr.2012.03.015
696 [21] A.J. Thakur, J. Patankar, Open tibial fractures. Treatment by uniplanar external [53] K.L. Bost, W.K. Ramp, N.C. Nicholson, J.L. Bento, I. Marriott, M.C. Hudson, Staph- 782
697 fixation and early bone grafting, J. Bone Joint Surg. Br. 73 (1991) 448–451. ylococcus aureus infection of mouse or human osteoblasts induces high levels 783
698 [22] H.A. Schroder, H. Christoffersen, T.S. Sorensen, S. Lindequist, Fractures of the of interleukin-6 and interleukin-12 production, J. Infect. Dis. 180 (1999) 784
699 shaft of the tibia treated with Hoffmann external fixation, Arch. Orthop. Trauma 1912–1920. 785
700 Surg. 105 (1986) 28–30. [54] J.K. Ellington, M. Harris, L. Webb, B. Smith, T. Smith, K. Tan, M. Hudson, Intracel- 786
701 [23] H.J. Mankin, F.J. Hornicek, K.A. Raskin, Infection in massive bone allografts, Clin. lular Staphylococcus aureus. A mechanism for the indolence of osteomyelitis, 787
702 Orthop. Relat. Res. 432 (2005) 210–216. J. Bone Joint Surg. Br. 85 (2003) 918–921. 788
703 [24] C. Centers for Disease, Prevention, Update: allograft-associated bacterial infec- [55] J.K. Ellington, S.S. Reilly, W.K. Ramp, M.S. Smeltzer, J.F. Kellam, M.C. Hudson, 789
704 tions — United States, MMWR Morbid. Mortal, Weekly Report, 51, 2002, Mechanisms of Staphylococcus aureus invasion of cultured osteoblasts, Microb. 790
705 pp. 207–210. Pathog. 26 (1999) 317–323. 791
706 [25] I. Collins, J. Wilson-MacDonald, G. Chami, W. Burgoyne, P. Vineyakam, T. [56] C. Garzoni, W.L. Kelley, Staphylococcus aureus: new evidence for intracellular 792
707 Berendt, J. Fairbank, The diagnosis and management of infection following persistence, Trends Microbiol. 17 (2009) 59–65. 793
708 instrumented spinal fusion, Eur. Spine J. 17 (2008) 445–450. [57] O. Krut, H. Sommer, M. Kronke, Antibiotic-induced persistence of cytotoxic 794
709 [26] M.A. Weinstein, J.P. McCabe, F.P. Cammisa Jr., Postoperative spinal wound infec- Staphylococcus aureus in non-phagocytic cells, J. Antimicrob. Chemother. 53 795
710 tion: a review of 2,391 consecutive index procedures, J. Spinal Disord. 13 (2000) (2004) 167–173. 796
711 422–426. [58] P.E. Gosden, A.P. MacGowan, G.C. Bannister, Importance of air quality and relat- 797
712 [27] G. Cierny III, D. DiPasquale, Periprosthetic total joint infections: staging, treated factors in the prevention of infection in orthopaedic implant surgery, J. Hosp. 798
713 ment, and outcomes, Clin. Orthop. Relat. Res. 403 (2002) 23–28. Infect. 39 (1998) 173–180. 799
714 800
F
[28] J.M. Duggan, G.M. Georgiadis, J.F. Kleshinski, Management of prosthetic joint in- [59] A.G. Gristina, Biomaterial-centered infection: microbial adhesion versus tissue
715 fections, Inf. Med. 18 (2001) 534–541. integration, Science 237 (1987) 1588–1595. 801
716 [29] E.J. McPherson, C. Woodson, P. Holtom, N. Roidis, C. Shufelt, M.J. Patzakis, Peri- [60] G. Subbiahdoss, R. Kuijer, D. Grijpma, H. van der Mei, H. Busscher, Microbial bio- 802
O
717 prosthetic total hip infection: outcomes using a staging system, Clin. Orthop. film growth vs. tissue integration: “The race for the surface” experimentally 803
718 Relat. Res. 403 (2002) 8–15. studied, Acta Biomater. 5 (2009) 1399–1404. 804
719 [30] S.P. Nair, R.J. Williams, B. Henderson, Advances in our understanding of the bone [61] G. Subbiahdoss, D. Grijpma, H. van der Mei, H. Busscher, R. Kuijer, Microbial bio- 805
720 and joint pathology caused by Staphylococcus aureus infection, Rheumatology 39 film growth versus tissue integration on biomaterials with different wettabil- 806
O
721 (2000) 821–834. ities and a polymer-brush coating, J. Biomed. Mater. Res. A 94A (2010) 533–538. 807
722 [31] L. Pulido, E. Ghanem, A. Joshi, J.J. Purtill, J. Parvizi, Periprosthetic joint infection: [62] G. Subbiahdoss, R. Kiujer, H. Busscher, H. van der Mei, Mammalian cell growth 808
723 the incidence, timing, and predisposing factors, Clin. Orthop. Relat. Res. 466 versus biofilm formation on biomaterial surfaces in an in vitro post-operative 809
R
724 (2008) 1710–1715. contamination model, Microbiology 156 (2010) 3073–3078. 810
725 [32] S.E. Meadows, J.D. Zuckerman, K.J. Koval, Posttraumatic tibial osteomyelitis: di- [63] S. Franz, S. Rammelt, D. Scharnweber, J. Simon, Immune responses to implants — 811
726 agnosis, classification, and treatment, Bull. Hosp. Joint Dis. 52 (1993) 11–16. a review of the implications for the design of immunomodulatory biomaterials, 812
727 [33] R.M. Mody, M. Zapor, J.D. Hartzell, P.M. Robben, P. Waterman, R. Wood-Morris, Biomaterials 32 (2011) 6692–6709. 813
P
728 R. Trotta, R.C. Andersen, G. Wortmann, Infectious complications of damage con- [64] D. Li, K. Gromov, K. Soballe, J.E. Puzas, R.J. O'Keefe, H. Awad, H. Drissi, E.M. 814
729 trol orthopedics in war trauma, J. Trauma 67 (2009) 758–761. Schwarz, Quantitative mouse model of implant-associated osteomyelitis and 815
730 [34] T.F. Moriarty, U. Schlegel, S. Perren, R.G. Richards, Infection in fracture fixation: the kinetics of microbial growth, osteolysis, and humoral immunity, J. Orthop. 816
731 can we influence infection rates through implant design? J. Mater. Sci. Mater. D Res. 26 (2008) 96–105. 817
732 Med. 21 (2010) 1031–1035. [65] B. Fink, A. Grossmann, M. Fuerst, P. Schafer, L. Frommelt, Two-stage cementless 818
733 [35] S. Ahmed, S. Meghji, R.J. Williams, B. Henderson, J.H. Brock, S.P. Nair, Staphylo- revision of infected hip endoprostheses, Clin. Orthop. Relat. Res. 467 (2009) 819
734 coccus aureus fibronectin binding proteins are essential for internalization by os- 1848–1858. 820
E
735 teoblasts but do not account for differences in intracellular levels of bacteria, [66] C.A. Broekhuizen, M.J. Schultz, A.C. van der Wal, L. Boszhard, L. deBoer, C.M. 821
736 Infect. Immun. 69 (2001) 2872–2877. Vandenbroucke-Grauls, S.A. Zaat, Tissue around catheters is a niche for bacteria 822
737 [36] C.R. Hauck, K. Ohlsen, Sticky connections: extracellular matrix protein recogni- associated with medical device infection, Crit. Care Med. 36 (2008) 2395–2402. 823
T
738 tion and integrin-mediated cellular invasion by Staphylococcus aureus, Curr. [67] C.A. Broekhuizen, M. Sta, C.M. Vandenbroucke-Grauls, S.A. Zaat, Microscopic detec- 824
739 Opin. Microbiol. 9 (2006) 5–11. tion of viable Staphylococcus epidermidis in peri-implant tissue in experimental 825
740 [37] L. Piroth, Y.A. Que, E. Widmer, A. Panchaud, S. Piu, J.M. Entenza, P. Moreillon, The biomaterial-associated infection, identified by bromodeoxyuridine incorporation, 826
C
741 fibrinogen- and fibronectin-binding domains of Staphylococcus aureus fibronectin- Infect. Immun. 78 (2010) 954–962. 827
742 binding protein A synergistically promote endothelial invasion and experimental [68] S. Zaat, C. Broekhuizen, M. Riool, Host tissue as a niche for biomaterial- 828
743 endocarditis, Infect. Immun. 76 (2008) 3824–3831. associated infection, Future Microbiol. 5 (2010) 1149–1151. 829
744 830
E
[38] D. Higgins, R. Basaraba, A. Hohnbaum, E. Lee, D. Grainger, M. Gonzalez-Juarrero, [69] S.D. Elek, P.E. Conen, The virulence of Staphylococcus pyogenes for man: a study
745 Localized immunosuppressive environment in the foreign body response to of the problems of wound infection, Br. J. Exp. Pathol. 38 (1957) 573–586. 831
746 implanted biomaterials, Am. J. Pathol. 175 (2009) 161–170. [70] K. Lewis, Multidrug tolerance of biofilms and persister cells, Curr. Top. Microbiol. 832
747 833
R
[39] D. Holt, L. Chamberlain, D. Grainger, Cell–cell signaling in co-cultures of macro- Immunol. 322 (2008) 107–131.
748 phages and fibroblasts, Biomaterials 31 (2010) 9382–9394. [71] S. Aslam, Effect of antibacterials on biofilms, Am. J. Infect. Control. 36 (2008) 834
749 [40] W. Zimmerli, P. Sendi, Pathogenesis of implant-associated infection: the role of S175.e9-11. 835
750 the host, Semin. Immunopathol. 33 (2011) 295–306. [72] G.G. Anderson, G.A. O'Toole, Innate and induced resistance mechanisms of bac- 836
R
751 [41] J.W. Costerton, L. Montanaro, C.R. Arciola, Biofilm in implant infections: its pro- terial biofilms, Curr. Top. Microbiol. Immunol. 322 (2008) 85–105. 837
752 duction and regulation, Int. J. Artif. Organs 28 (2005) 1062–1068. [73] P.S. Stewart, W.M. Davison, J.N. Steenbergen, Daptomycin rapidly penetrates a 838
753 [42] M. Delmi, P. Vaudaux, D.P. Lew, H. Vasey, Role of fibronectin in staphylococcal Staphylococcus epidermidis biofilm, Antimicrob. Agents Chemother. 53 (2009) 839
O
754 adhesion to metallic surfaces used as models of orthopaedic devices, J. Orthop. 3505–3507. 840
755 Res. 12 (1994) 432–438. [74] K. Smith, A. Perez, G. Ramage, C.G. Gemmell, S. Lang, Comparison of biofilm- 841
756 [43] J.E. Wyatt, S.M. Poston, W.C. Noble, Adherence of Staphylococcus aureus to cell associated cell survival following in vitro exposure of meticillin-resistant Staph- 842
757 monolayers, J. Appl. Bacteriol. 69 (1990) 834–844. ylococcus aureus biofilms to the antibiotics clindamycin, daptomycin, linezolid, 843
C
758 [44] J. Pizarro-Cerda, P. Cossart, Bacterial adhesion and entry into host cells, Cell 124 tigecycline and vancomycin, Int. J. Antimicrob. Agents 33 (2009) 374–378. 844
759 (2006) 715–727. [75] A. Jain, Y. Gupta, R. Agrawal, P. Khare, S.K. Jain, Biofilms — a microbial life per- 845
760 [45] R.R. Isberg, Z. Hamburger, P. Dersch, Signaling and invasin-promoted uptake via spective: a critical review, Crit. Rev. Ther. Drug Carrier Syst. 24 (2007) 846
N
761 integrin receptors, Microbiol. Infect. 2 (2000) 793–801. 393–443. 847

762 [46] C.R. Hauck, Cell adhesion receptors — signaling capacity and exploitation by bac- [76] J. Palmer, S. Flint, J. Brooks, Bacterial cell attachment, the beginning of a biofilm, 848
763 terial pathogens, Med. Microbiol. Immunol. 191 (2002) 55–62. J. Ind. Microbiol. Biotechnol. 34 (2007) 577–588. 849
U
764 [47] J.K. Ellington, M. Harris, M.C. Hudson, S. Vishin, L.X. Webb, R. Sherertz, Intracel- [77] J.W. Costerton, Biofilm theory can guide the treatment of device-related ortho- 850
765 lular Staphylococcus aureus and antibiotic resistance: implications for treatment paedic infections, Clin. Orthop. Relat. Res. 437 (2005) 7–11. 851
766 of staphylococcal osteomyelitis, J. Orthop. Res. 24 (2006) 87–93. [78] M. Bonazzi, P. Cossart, Bacterial entry into cells: a role for the endocytic machin- 852
767 [48] B. Sinha, M. Herrmann, Mechanism and consequences of invasion of endothelial ery, FEBS Lett. 580 (2006) 2962–2967. 853
768 cells by Staphylococcus aureus, Thromb. Haemost. 94 (2005) 266–277. [79] H.S. Courtney, D.L. Hasty, J.B. Dale, Molecular mechanisms of adhesion, coloniza- 854
769 [49] A.L. Baltch, L.H. Bopp, R.P. Smith, P.B. Michelsen, W.J. Ritz, Antibacterial activities tion, and invasion of group A streptococci, Ann. Med. 34 (2002) 77–87. 855
770 of gemifloxacin, levofloxacin, gatifloxacin, moxifloxacin and erythromycin [80] M.C. Hudson, W.K. Ramp, N.C. Nicholson, A.S. Williams, M.T. Nousiainen, Inter- 856
771 against intracellular Legionella pneumophila and Legionella micdadei in human nalization of Staphylococcus aureus by cultured osteoblasts, Microb. Pathog. 19 857
772 monocytes, J. Antimicrob. Chemother. 56 (2005) 104–109. (1995) 409–419. 858
773 [50] E.L. Kaplan, G.S. Chhatwal, M. Rohde, Reduced ability of penicillin to eradicate [81] H. Khalil, R.J. Williams, G. Stenbeck, B. Henderson, S. Meghji, S.P. Nair, Invasion 859
774 ingested group A streptococci from epithelial cells: clinical and pathogenetic im- of bone cells by Staphylococcus epidermidis, Microbiol. Infect. 9 (2007) 460–465. 860
775 plications, Clin. Infect. Dis. 43 (2006) 1398–1406 [see comment]. [82] G.A. Melcher, B. Claudi, U. Schlegel, S.M. Perren, G. Printzen, J. Munzinger, Influ- 861
776 [51] A. Schnaith, H. Kashkar, S.A. Leggio, K. Addicks, M. Kronke, O. Krut, Staphylococ- ence of type of medullary nail on the development of local infection. An exper- 862
777 cus aureus subvert autophagy for induction of caspase-independent host cell imental study of solid and slotted nails in rabbits, J. Bone Joint Surg. Br. 76 863
778 death, J. Biol. Chem. 282 (2007) 2695–2706. (1994) 955–959. 864
779 [52] E.H. Alexander, M.C. Hudson, Factors influencing the internalization of Staphylo- [83] S. Arens, U. Schlegel, G. Printzen, W.J. Ziegler, S.M. Perren, M. Hansis, Influence of 865
780 coccus aureus and impacts on the course of infections in humans, Appl. Micro- materials for fixation implants on local infection. An experimental study of steel 866
781 biol. Biotechnol. 56 (2001) 361–366. versus titanium DCP in rabbits, J. Bone Joint Surg. Br. 78 (1996) 647–651. 867
(2012), doi:10.1016/j.addr.2012.03.015
868 [84] M. Yoshinari, Y. Oda, T. Kato, K. Okuda, A. Hirayama, Influence of surface modi- [113] M.A. Buttaro, A. Morandi, H.G. Rivello, F. Piccaluga, Histology of vancomycin- 954
869 fication to titanium on oral bacterial adhesion in vitro, J. Biomed. Mater. Res. 52 supplemented impacted bone allografts in revision total hip arthroplasty, 955
870 (2000) 388–394. J. Bone Joint Surg. Br. 87 (2005) 1684–1687. 956
871 [85] P.M. Duarte, A.F. Reis, P.M. DeFreitas, C. Ota-Tsuzuki, Bacterial adhesion on [114] K. Hilpert, M. Elliott, H. Jenssen, J. Kindrachuk, C.D. Fjell, J. Korner, D.F. Winkler, 957
872 smooth and rough titanium surfaces after treatment with different instruments, L.L. Weaver, P. Henklein, A.S. Ulrich, S.H. Chiang, S.W. Farmer, N. Pante, 958
873 J. Periodontol. 80 (2009) 1824–1832. R. Volkmer, R.E. Hancock, Screening and characterization of surface-tethered 959
874 [86] L.G. Harris, R.G. Richards, Staphylococcus aureus adhesion to different treated ti- cationic peptides for antimicrobial activity, Chem. Biol. 16 (2009) 58–69. 960
875 tanium surfaces, J. Mater. Sci. Mater. Med. 15 (2004) 311–314. [115] J.M. Spivak, A.M. Petrizzo, Revision of a lumbar disc arthroplasty following late 961
876 [87] B. Kouidhi, T. Zmantar, H. Hentati, A. Bakhrouf, Cell surface hydrophobicity, bio- infection, Eur. Spine J. 19 (2010) 677–681. 962
877 film formation, adhesives, properties and molecular detection of adhesins genes [116] M. Sierra-Hoffman, C. Jinadatha, J.L. Carpenter, M. Rahm, Postoperative instru- 963
878 in Staphylococcus aureus associated to dental caries, Microb. Pathog. 49 (2010) mented spine infections: a retrospective review, South. Med. J. 103 (2010) 964
879 14–22. 25–30. 965
880 [88] N.P. Boks, W. Norde, H.C. van der Mei, H.J. Bussher, Forces involved in bacterial [117] J.I. Kim, K.T. Suh, S.J. Kim, J.S. Lee, Implant removal for the management of in- 966
881 adhesion to hydrophilic and hydrophobic surfaces, Microbiology 154 (2008) fection after instrumented spinal fusion, J. Spinal Disord. Tech. 23 (2010) 967
882 3122–3133. 258–265. 968
883 [89] N.P. Boks, H.J. Kaper, W. Norde, H.C. Van der Mei, H.J. Busscher, Mobile and im- [118] B.Y. Betsch, S. Eggli, K.A. Siebenrock, M.G. Tauber, K. Muhlemann, Treatment of 969
884 mobile adhesion of staphylococcal strains to hydrophilic and hydrophobic sur- joint prosthesis infection in accordance with current recommendations im- 970
885 faes, J. Colloid Interface Sci. 331 (2009) 60–64. proves outcome, Clin. Infect. Dis. 46 (2008) 1221–1226. 971
886 972
F
[90] D. Buser, R.K. Schenk, S. Steinemann, J.P. Fiorellini, C.H. Fox, H. Stich, Influence of [119] A.D. Hanssen, Managing the infected knee: as good as it gets, J. Arthroplasty 17
887 surface characteristics on bone integration of titanium implants. A histomor- (2002) 98–101. 973
888 phometric study in miniature pigs, J. Biomed. Mater. Res. 25 (1991) 889–902. [120] m. Sukeik, F.S. Haddad, Two-stage procedure in the treatment of late chronic hip 974
O
889 [91] J.O. Galante, J. Jacobs, Clinical performances of ingrowth surfaces, Clin. Orthop. infections — spacer implantation, Int. J. Med. Sci. 6 (2009) 253–257. 975
890 Relat. Res. 276 (1992) 41–49. [121] J.Y. Lazennec, E. Fourniols, T. Lenoir, A. Aubry, M.L. Pissonnier, B. Issartel, 976
891 [92] J. Lincks, B.D. Boyan, C.R. Blanchard, C.H. Lohmann, Y. Liu, D.L. Cochran, D.D. M.A. Rousseau, Infections in the operated spine: update on risk management 977
892 Dean, Z. Schwartz, Response of MG63 osteoblast-like cells to titanium and tita- and therapeutic strategies, Orthop. Traumatol. Surg. Res. 97 (2011) 373–380. 978
O
893 nium alloy is dependent on surface roughness and composition, Biomaterials [122] M.P. De Grood, Pathology, diagnosis and treatment of subdural empyema, Arch. 979
894 19 (1998) 2219–2232. Chir. Neerl. 3 (1951) 128–138. 980
895 [93] D.A. Puleo, A. Nanci, Understanding and controlling the bone–implant interface, [123] M.A. Buttaro, R. Pusso, F. Piccaluga, Vancomycin-supplemented impacted bone 981
R
896 Biomaterials 20 (1999) 2311–2321. allografts in infected hip arthroplasty: two-stage revision results, J. Bone Joint 982
897 [94] P. Ducheyne, L.L. Hench, A. Kagan II, M. Martens, A. Bursens, J.C. Mulier, Effect Surg. Br. 87-B (2005) 314–319. 983
898 of hydroxyapatite impregnation on skeletal bonding of porous coated implants, [124] J.S. Humphrey, S. Mehta, A.V. Seaber, T.P. Vail, Pharmacokinetics of a degradable 984
899 985
P
J. Biomed. Mater. Res. 14 (1980) 225–237. drug delivery system in bone, Clin. Orthop. Relat. Res. 349 (1998) 218–224.
900 [95] P. Ducheyne, J. Beight, J. Cuckler, B. Evans, S. Radin, Effect of calcium phosphate [125] K. Kanellakopoulou, E.J. Giamarellos-Bourboulis, Carrier systems for the local de- 986
901 coating characteristics on early post-operative bone tissue ingrowth, Biomate- livery of antibiotics in bone infections, Drugs 59 (2000) 1223–1232. 987
902 rials 11 (1990) 531–540. [126] N. Rushton, Applications of local antibiotic therapy, Eur. J. Surg. Suppl. 578 988
903 [96] M.S. Block, I.M. Finger, M.G. Fontenot, J.N. Kent, Loaded hydroxylapatite-coated D (1997) 27–30. 989
904 and grit-blasted titanium implants in dogs, Int. J. Oral. Maxillofac. Implants 4 [127] H. Suh, S. Suh, B. Min, Anti-infection treatment of a transcutaneous device by a 990
905 (1989) 219–225. collagen–rifampicin composite, ASAIO J. 40 (1994) M406–M411. 991
906 [97] R.D. Bloebaum, D. Beeks, L.D. Dorr, C.G. Savory, J.A. DuPont, A.A. Hofmann, Com- [128] Z. Wachol-Drewek, M. Pfeiffer, E. Scholl, Comparative investigation of drug de- 992
E
907 plications with hydroxyapatite particulate separation in total hip arthroplasty, livery of collagen implants saturated in antibiotic solutions and a sponge con- 993
908 Clin. Orthop. Relat. Res. 298 (1994) 19–26. taining gentamicin, Biomaterials 17 (1996) 1733–1738. 994
909 [98] M. Raulio, M. Jarn, J. Ahola, J. Peltonen, J.B. Rosenholm, S. Tervakangas, [129] C.G. Ambrose, T.A. Clyburn, K. Louden, J. Joseph, J. Wright, P. Gulati, G.R. Gogola, 995
T
910 J. Kolehmainen, T. Ruokolainen, P. Narko, M. Salkinoja-Salonen, Microbe re- A.G. Mikos, Effective treatment of osteomyelitis with biodegradable micro- 996
911 pelling coated stainless steel analysed by field emission scanning electron mi- spheres in a rabbit model, Clin. Orthop. Relat. Res. 421 (2004) 293–299. 997
912 croscopy and physicochemical methods, J. Ind. Microbiol. Biotechnol. 35 [130] A. Billon, L. Chabaud, A. Gouyette, J.M. Bouler, C. Merle, Vancomycin biodegrad- 998
C
913 (2008) 751–760. able poly(lactide-co-glycolide) microparticles for bone implantation. Influence 999
914 [99] F. Riedewald, Bacterial adhesion to surfaces: the influence of surface roughness, of the formulation parameters on the size, morphology, drug loading and in 1000
915 PDA J. Pharm. Sci. Technol. 60 (2006) 164–171. vitro release, J. Microencapsul. 22 (2005) 841–852. 1001
E
916 [100] M. Oga, T. Arizono, Y. Sugioka, Bacterial adherence to bioinert and bioactive ma- [131] J.H. Calhoun, J.T. Mader, Treatment of osteomyelitis with a biodegradable antibi- 1002
917 terials studied in vitro, Acta Orthop. Scand. 64 (1993) 273–276. otic implant, Clin. Orthop. Relat. Res. 341 (1997) 206–214. 1003
918 [101] C.R. Arciola, L. Montanaro, A. Moroni, M. Giordano, A. Pizzoferrato, M.E. Donati, [132] T. Kalicke, J. Schierholz, U. Schlegel, T.M. Frangen, M. Koller, G. Printzen, D. Seybold, 1004
R
919 Hydroxyapatite-coated orthopaedic screws as infection resistant materials: in S. Klockner, G. Muhr, S. Arens, Effect on infection resistance of a local antiseptic 1005
920 vitro study, Biomaterials 20 (1999) 323–327. and antibiotic coating on osteosynthesis implants: an in vitro and in vivo study, 1006
921 [102] B. Buranapanitkit, V. Srinilta, N. Ingviga, K. Oungbho, A. Geater, C. Ovatlarnporn, J. Orthop. Res. 24 (2006) 1622–1640. 1007
922 The efficacy of a hydroxyapatite composite as a biodegradable antibiotic deliv- [133] S. Gitelis, G.T. Brebach, The treatment of chronic osteomyelitis with a biodegrad- 1008
R
923 ery system, Clin. Orthop. Relat. Res. 424 (2004) 244–252. able antibiotic-impregnated implant, J. Orthop. Surg. 10 (2002) 53–60. 1009
924 [103] M.A. Rauschmann, T.A. Wichelhaus, V. Stirnal, E. Dingeldein, L. Zichner, R. [134] E. Witsø, L. Persen, P. Benum, K. Bergh, Release of netilmicin and vancomycin 1010
925 Schnettler, V. Alt, Nanocrystalline hydroxyapatite and calcium sulphate as bio- from cancellous bone, Acta Orthop. Scand. 73 (2002) 199–205. 1011
O
926 degradable composite carrier material for local delivery of antibiotics in bone in- [135] W. Tomford, J. Thongphasuk, H. Mankin, M. Ferraro, Frozen musculoskeletal al- 1012
927 fections, Biomaterials 26 (2005) 2677–2684. lografts. A study of the clinical incidence and causes of infection associated with 1013
928 [104] M.E. Shirtliff, J.H. Calhoun, J.T. Mader, Experimental osteomyelitis treatment their use, J. Bone Joint Surg. Am. 72 (1990) 1137–1143. 1014
929 1015
C
with antibiotic-impregnated hydroxyapatite, Clin. Orthop. Relat. Res. 401 [136] A.J. Kuijpers, G.H. Engbers, P.B. van Wachem, J. Krijgsveld, S.A. Zaat, J. Dankert,
930 (2002) 239–247. J. Feijen, Controlled delivery of antibacterial proteins from biodegradable 1016
931 [105] C.L. Baldwin, R. Goenka, Host immune responses to the intracellular bacteria matrices, J. Control. Release. 53 (1998) 235–247. 1017
932 Brucella: does the bacteria instruct the host to facilitate chronic infection? Crit. [137] D. Neut, H. van de Belt, I. Stokroos, J.R. van Horn, H.C. van der Mei, H.J. Busscher, 1018
N
933 Rev. Immunol. 26 (2006) 407–442. Biomaterial-associated infection of gentamicin-loaded PMMA beads in ortho- 1019
934 [106] J.A. Anderson, P.K. Sculco, S. Heitkemper, D.J. Mayman, M.P. Bostrom, T.P. Sculco, paedic revision surgery, J. Antimicrob. Chemother. 47 (2001) 885–891. 1020
935 An articulating spacer to treat and mobilize patients with infected total knee [138] J. Fu, J. Ji, D. Fan, J. Shen, Construction of antibacterial multilayer films containing 1021
U
936 arthroplasty, J. Arthroplasty 24 (2009) 631–635. nanosilver via layer-by-layer assembly of heparin and chitosan-silver ions com- 1022
937 [107] S.D. Puckett, E. Taylor, T. Raimondo, T.J. Webster, The relationship between the plex, J. Biomed. Mater. Res. A 79 (2006) 665–674. 1023
938 nanostructure of titanium surfaces and bacterial attachment, Biomaterials 31 [139] V. Antoci Jr., C.S. Adams, N.J. Hickok, I.M. Shapiro, J. Parvizi, Antibiotics for local 1024
939 (2010) 706–713. delivery systems cause skeletal cell toxicity in vitro, Clin. Orthop. Relat. Res. 1025
940 [108] E.P. Ivanova, V.K. Truong, J.Y. Wang, C.C. Berndt, R.T. Jones, I.I. Yusuf, I. Peake, 462 (2007) 200–206. 1026
941 H.W. Schmidt, C. Fluke, D. Barnes, R.J. Crawford, Impact of nanoscale roughness [140] E. Witso, L. Persen, P. Benum, K. Bergh, Cortical allograft as a vehicle for antibi- 1027
942 of titanium thin film surfaces on bacterial retention, Langmuir 26 (2010) otic delivery, Acta Orthop. 76 (2005) 481–486. 1028
943 1973–1982. [141] J.C. Gray, M.W. Elves, Osteogenesis in bone grafts after short-term storage and 1029
944 [109] V.K. Truong, R. Lapovok, Y.S. Estrin, S. Rundell, J.Y. Wang, C.J. Fluke, R.J. Crawford, topical antibiotic treatment. An experimental study in rats, J. Bone Joint Surg. 1030
945 E.P. Ivanova, The influence of nano-scale surface roughness on bacterial adhe- Br. 63 (1981) 441–445. 1031
946 sion to ultrafine-grained titanium, Biomaterials 31 (2010) 3674–3683. [142] S. Isefuku, C.J. Joyner, A.H. Simpson, Toxic effect of rifampicin on human 1032
947 [110] K.K. Chung, J.F. Schumacher, E.M. Sampson, R.A. Burne, P.J. Antonelli, A.B. osteoblast-like cells, J. Orthop. Res. 19 (2001) 950–954. 1033
948 Brennan, Impact of engineered surface microtopography on biofilm formation [143] M.L. Edin, T. Miclau, G.E. Lester, R.W. Lindsey, L.E. Dahners, Effect of cefazolin 1034
949 of Staphylococcus aureus, Biointerphases 2 (2007) 89–94. and vancomycin on osteoblasts in vitro, Clin. Orthop. Relat. Res. 333 (1996) 1035
950 [111] C. Lord, M. Gebhardt, W. Tomford, H. Mankin, Infection in bone allografts. Inci- 245–251. 1036
951 dence, nature, and treatment, J. Bone Joint Surg. Am. 70 (1988) 369–376. [144] V. Antoci Jr., C.S. Adams, J. Parvizi, P. Ducheyne, I.M. Shapiro, N.J. Hickok, Cova- 1037
952 [112] H.J. Mankin, S. Doppelt, W.W. Tomford, Clinical experience with allograft im- lently attached vancomycin provides a nanoscale antibacterial surface, Clin. 1038
953 plantation. The first ten years, Clin. Orthop. Relat. Res. 174 (1983) 69–86. Orthop. Relat. Res. 461 (2007) 81–87. 1039
(2012), doi:10.1016/j.addr.2012.03.015
1040 [145] V. Antoci Jr., S.B. King, B. Jose, J. Parvizi, A.R. Zeiger, E. Wickstrom, T.A. Freeman, [163] M.C. Lawson, C.N. Bowman, K.S. Anseth, Vancomycin derivative photopolymer- 1099
1041 R.J. Composto, P. Ducheyne, I.M. Shapiro, N.J. Hickok, C.S. Adams, Vancomycin ized to titanium kills S. epidermidis, Clin. Orthop. Relat. Res. 461 (2007) 96–105. 1100
1042 covalently bonded to titanium alloy prevents bacterial colonization, J. Orthop. [164] L.J. Mikulec, D.A. Puleo, Use of p-nitrophenyl chloroformate chemistry to immo- 1101
1043 Res. 25 (2007) 858–866. bilize protein on orthopedic biomaterials, J. Biomed. Mater. Res. 32 (1996) 1102
1044 [146] S. Fiorilli, P. Rivolo, E. Descrovi, C. Riccardi, L. Pasquardisi, L. Lunelli, l. Vanzetto, 203–208. 1103
1045 C. Perzoolli, B. Onida, E. Garron, Vapor phase self-assembled monolayers of ami- [165] X. Khoo, P. Hamilton, G.A. O'Toole, B.D. Snyder, D.J. Kenan, M.W. Grinstaff, Di- 1104
1046 nosilane on plasma activated silicon substrate, J. Colloid Interface Sci. 321 rected assembly of PEGylated-peptide coatings for infection-resistant titanium 1105
1047 (2008) 235–241. metal, J. Am. Chem. Soc. 131 (2009) 10992–10997. 1106
1048 [147] C.S. Adams, V. Antoci Jr., G. Harrison, P. Patal, T.A. Freeman, I.M. Shapiro, J. [166] M. Gabriel, K. Nazmi, E.C. Veerman, A.V. Nieuw Amerongen, A. Zentner, Prepara- 1107
1049 Parvizi, N.J. Hickok, S. Radin, P. Ducheyne, Controlled release of vancomycin tion of LL-37-grafted titanium surfaces with bactericidal activity, Bioconjug. 1108
1050 from thin sol–gel films on implant surfaces successfully controls osteomyelitis, Chem. 17 (2006) 548–550. 1109
1051 J. Orthop. Res. 27 (2009) 701–709. [167] V. Humblot, J.F. Yala, P. Thebault, K. Boukerma, A. Hequet, J.M. Berjeaud, C.M. 1110
1052 [148] V. Antoci Jr., C.S. Adams, N.J. Hickok, I.M. Shapiro, J. Parvizi, Vancomycin bound Pradier, The antibacterial activity of Magainin I immobilized onto mixed thiols 1111
1053 to Ti rods reduces periprosthetic infection: preliminary study, Clin. Orthop. self-assembled monolayers, Biomaterials 30 (2009) 3503–3512. 1112
1054 Relat. Res. 461 (2007) 88–95. [168] J. Parvizi, E. Wickstrom, A.R. Zeiger, C.S. Adams, I.M. Shapiro, J.J. Purtill, P.F. 1113
1055 [149] S.P. Massia, J.A. Hubbell, Covalent surface immobilization of Arg-Gly-Asp- and Sharkey, W.J. Hozack, R.H. Rothman, N.J. Hickok, Frank Stinchfield Award. Titani- 1114
1056 Tyr-Ile-Gly-Ser-Arg-containing peptides to obtain well-defined cell-adhesive um surface with biologic activity against infection, Clin. Orthop. Relat. Res. 429 1115
1057 substrates, Anal. Biochem. 187 (1990) 292–301. (2004) 33–38. 1116
1058 1117
F
[150] A. Rezania, C.H. Thomas, A.B. Branger, C.M. Waters, K.E. Healy, The detachment [169] B. Jose, V. Antoci Jr., A.R. Zeiger, E. Wickstrom, N.J. Hickok, Vancomycin covalent-
1059 strength and morphology of bone cells contacting materials modified with a ly bonded to titanium beads kills Staphylococcus aureus, Chem. Biol. 12 (2005) 1118
1060 peptide sequence found within bone sialoprotein, J. Biomed. Mater. Res. 37 1041–1048. 1119
O
1061 (1997) 9–19. [170] M.C. Lawson, K.C. Hoth, C.A. Deforest, C.N. Bowman, K.S. Anseth, Inhibition of 1120
1062 [151] A. Rezania, K.E. Healy, Biomimetic peptide surfaces that regulate adhesion, Staphylococcus epidermidis biofilms using polymerizable vancomycin deriva- 1121
1063 spreading, cytoskeletal organization, and mineralization of the matrix deposited tives, Clin. Orthop. Relat. Res. 468 (2010) 2081–2091. 1122
1064 by osteoblast-like cells, Biotechnol. Prog. 15 (1999) 19–32. [171] C.P. Chen, E. Wickstrom, Self-protecting bactericidal titanium alloy surface 1123
O
1065 [152] A. Rezania, K.E. Healy, The effect of peptide surface density on mineralization of a formed by covalent bonding of daptomycin bisphosphonates, Bioconjug. 1124
1066 matrix deposited by osteogenic cells, J. Biomed. Mater. Res. 52 (2000) 595–600. Chem. 21 (2010) 1978–1986. 1125
1067 [153] R. Derda, D.J. Wherritt, L.L. Kiessling, Solid-phase synthesis of alkanethiols for the [172] O.P. Edupuganti, V. Antoci Jr., S.B. King, B. Jose, C.S. Adams, J. Parvizi, I.M. Shapiro, 1126
R
1068 preparation of self-assembled monolayers, Langmuir 23 (2007) 11164–11167. A.R. Zeiger, N.J. Hickok, E. Wickstrom, Covalent bonding of vancomycin to 1127
1069 [154] E.A. Cavalcanti-Adam, I.M. Shapiro, R.J. Composto, E.J. Macarak, C.S. Adams, RGD Ti6Al4V alloy pins provides long-term inhibition of Staphylococcus aureus colo- 1128
1070 peptides immobilized on a mechanically deformable surface promote osteoblast nization, Bioorg. Med. Chem. Lett. 17 (2007) 2692–2696. 1129
1071 differentiation, J. Bone Miner. Res. 17 (2002) 2130–2140. [173] C. Ketonis, C.S. Adams, S. Barr, A. Aiyer, I.M. Shapiro, J. Parvizi, N.J. Hickok, Anti- 1130
P
1072 [155] A.R. El-Ghannam, P. Ducheyne, M. Risbud, C.S. Adams, I.M. Shapiro, D. Castner, S. biotic modification of native grafts: improving upon nature's scaffolds, Tissue 1131
1073 Golledge, R.J. Composto, Model surfaces engineered with nanoscale roughness Eng. Part A 16 (2010) 2041–2049. 1132
1074 and RGD tripeptides promote osteoblast activity, J. Biomed. Mater. Res. A 68 [174] M.H. Lee, D.A. Brass, R. Morris, R.J. Composto, P. Ducheyne, The effect of non- 1133
1075 (2004) 615–627. Dspecific interactions on cellular adhesion using model surfaces, Biomaterials 1134
1076 [156] A.G. Secchi, V. Grigoriou, I.M. Shapiro, E.A. Cavalcanti-Adam, R.J. Composto, P. 26 (2005) 1721–1730. 1135
1077 Ducheyne, C.S. Adams, RGDS peptides immobilized on titanium alloy stimulate [175] D.A. Puleo, Retention of enzymatic activity immobilized on silanized Co–Cr–Mo 1136
1078 bone cell attachment, differentiation and confer resistance to apoptosis, and Ti–6Al–4V, J. Biomed. Mater. Res. 37 (1997) 222–228. 1137
E
1079 J. Biomed. Mater. Res. A 83 (2007) 577–584. [176] C. Ketonis, J. Parvizi, C.S. Adams, I.M. Shapiro, N.J. Hickok, Topographic features 1138
1080 [157] D.M. Ferris, G.D. Moodie, P.M. Dimond, C.W. Gioranni, M.G. Ehrlich, R.F. retained after antibiotic modification of Ti alloy surfaces, Clin. Orthop. Relat. 1139
1081 Valentini, RGD-coated titanium implants stimulate increased bone formation Res. 467 (2009) 1678–1687. 1140
T
1082 in vivo, Biomaterials 20 (1999) 2323–2331. [177] V. Antoci, C.S. Adams, J. Parvizi, H.M. Davidson, R.J. Composto, T.A. Freeman, E. 1141
1083 [158] K. Okamoto, T. Matsuura, R. Hosokawa, Y. Akagawa, RGD peptides regulate the Wickstrom, A.R. Zeiger, P. Ducheyne, D. Jungkind, I.M. Shapiro, N.J. Hickok, 1142
1084 specific adhesion scheme of osteoblasts to hydroxyapatite but not to titanium, Vancomycin-modified Ti alloy inhibits S. epidermidis biofilm formation: impli- 1143
C
1085 J. Dent. Res. 77 (1998) 481–487. cations for treatment of periprosthetic infection, Biomaterials 29 (2008) 1144
1086 [159] M.P. Danahy, M.J. Avaltroni, K.S. Midwood, J.E. Schwarbauer, J. Schwartz, 4684–4690. 1145
1087 Self-assembled monolayers of alpha, omega-diphosphonic acids on Ti enable [178] P.J. Loll, P.H. Axelsen, The structural biology of molecular recognition by vanco- 1146
1088 1147
E
complete or spatially controlled surface derivatization, Langmuir 20 (2004) mycin, Annu. Rev. Biophys. Biomol. Struct. 29 (2000) 265–289.
1089 5333–5337. [179] C. Ketonis, S. Barr, C.S. Adams, I.M. Shapiro, J. Parvizi, N.J. Hickok, Vancomycin 1148
1090 [160] A. Heijink, J. Schwartz, M.E. Zobitz, K. Nicole Crowder, G.E. Lutz, J.D. Sibonga, bonded to bone grafts prevents bacterial colonization, Antimicrob. Agents Che- 1149
1091 Self-assembled monolayer films of phosphonates for bonding RGD to titanium, 1150
R
mother. 55 (2011) 487–494.

1092 Clin. Orthop. Relat. Res. 466 (2008) 977–984. [180] M.C. Lawson, R. Shoemaker, K.B. Hoth, C.N. Bowman, K.S. Anseth, Polymerizable 1151
1093 [161] D.A. Puleo, R.A. Kissling, M.S. Sheu, A technique to immobilize bioactive proteins, vancomycin derivatives for bactericidal biomaterial surface modification: struc- 1152
1094 including bone morphogenetic protein-4 (BMP-4) on titanium alloy, Biomate- ture–function evaluation, Biomacromolecules 10 (2009) 2221–2234. 1153
R
1095 rials 23 (2002) 2079–2087. [181] R.B. Sykes, The 2009 Garrod lecture: the evolution of antimicrobial resistance: a 1154
1096 [162] S.M. Wojcik, D.A. Puleo, Biochemical surface modification of Ti–6Al–4V for the Darwinian perspective, J. Antimicrob. Chemother. 65 (2010) 1842–1852. 1155
1097 delivery of protein to the cell–biomaterial interface, Biomed. Sci. Instrum. 33 [182] J. Wimpenny, Microbial metropolis, Adv. Microb. Physiol. 56 (2009) 29–84. 1156
O
1098 (1997) 166–171. 1157

1158
C
N
U
(2012), doi:10.1016/j.addr.2012.03.015

1-s2.0-S0169409X12001111-main ANTIBIOTIOK TULANG PDF

Transféré par

Informations du document

Titre original

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

1-s2.0-S0169409X12001111-main ANTIBIOTIOK TULANG PDF

Transféré par

Droits d'auteur :

Formats disponibles

ADR-12282; No of Pages 12

Advanced Drug Delivery Reviews xxx (2012) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Advanced Drug Delivery Reviews

1 Immobilized antibiotics to prevent orthopaedic implant infections☆

45 5. Treatment of surgical infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Abbreviations: APTES, aminopropyltriethoxysilane; Cfu, colony forming units, refer-

0169-409X/$ – see front matter © 2012 Published by Elsevier B.V.

111 pathogens. In the process, the adhering mammalian cells remodel

of ~ 6 weeks, assuming a good outcome, a new implant can be 291

Figure reproduced from [148] with permission of Wolters Kluwer Health.

bioﬁlms to antibacterial agents, Antimicrob. Agents Chemother. 34 (1990) 658

761 integrin receptors, Microbiol. Infect. 2 (2000) 793–801. 393–443. 847

mother. 55 (2011) 487–494.

1098 (1997) 166–171. 1157

Vous aimerez peut-être aussi