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Effects of Vancomycin, Cefazolin and Test Conditions on the Wear Behavior of Bone Cement
The Journal of Arthroplasty xxx (2013) xxx–xxx
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Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement Pablo Sanz-Ruiz PhD, MD a, Eva Paz b, Juana Abenojar Ph.D c, Juan Carlos del Real Ph.D b, Javier Vaquero PhD, MD a, Francisco Forriol PhD, MD d a
Department of Traumatology and Orthopaedic Surgery, General University Hospital Gregorio Marañón, Madrid, Spain Institute for Research in Technology/Mechanical Engineering Dept., Universidad, Pontificia Comillas, Madrid, Spain Materials Performance Group, Materials Science and Engineering Dept., Universidad, Carlos III de Madrid, Spain d Faculty of Medicine, Universidad San Pablo CEU, Madrid, Spain b c
a r t i c l e
i n f o
Article history: Received 12 February 2013 Accepted 11 April 2013 Available online xxxx Keywords: polymethylmethacrylate (PMMA) bone cement friction arthroplasty infection antibiotic-loaded cement
a b s t r a c t Antibiotic cement has been recommended in the treatment of prosthetic infections. The purpose of this study was to investigate the mechanical behavioral changes in cement loaded with two antibiotics, vancomycin and cefazolin, in dry and liquid medium. Six groups and four study conditions were established according to the doses of antibiotic used and the ageing (immersion in phosphate buffered saline) of the samples. Properties evaluated were friction coefficient and wear. Samples in dry medium showed higher wears than in liquid. Antibiotic selection did not influence wear properties tested in dry conditions, however, in liquid medium, there were higher frictional coefficients and wear for cefazolin loaded cement after one week and for vancomycin and cefazolin after one month. The results suggest that antibiotic cements behave differently in liquid and that the molecular characteristics of antibiotics are essential for determining this influence. © 2013 Elsevier Inc. All rights reserved.
The treatment of prosthetic infections remains controversial since it depends on multiple variables such as the function of the affected joint, the elapsed time since implantation and the medical condition of the patient. It has been widely documented that the two-stage revision using a bone cement spacer (polymethylmethacrylate, PMMA) mixed with various antibiotics obtain the highest success rates [1–4]. The addition of antibiotics to PMMA, particularly in liquid form, adversely affects its mechanical strength [5–7]; therefore, it is necessary to consider an antibiotic’s microbiological profile, its influence on the cement and its spreading capacity, among other features. The most commonly antibiotics used are tobramycin, gentamicin, vancomycin, clindamycin and cephalosporins [2,8]. Since the introduction in the market of cement with gentamicin for infection prophylaxis in primary arthroplasty, various microorganisms with acquired resistance to gentamicin [9] have been described. This necessitates the search for new antibiotics and combinations thereof to increase the antimicrobial spectrum without compromising the characteristics of PMMA. There are multiple studies that assess and compare the effect of different antibiotics on the resistance of PMMA to bending and
compression. Most of these studies have been performed in vitro, based on ISO and ASTM standards for testing acrylic cements [10,11]. The extrapolation of in vitro results to clinical practice is controversial since these studies disregard the changes undergone by antibioticmixed PMMA with the liquid medium of the physiological environment. It is also important to note that the influence of these antibiotics in the breakdown of bone cement has not been well defined; this wear is closely related to the osteolysis observed in medium/long term in patients undergoing joint replacements that occasionally leads to an aseptic loosening of the implant [12,13]. The aim of this study is to investigate the mechanical behavior changes of two antibiotics with different biochemical properties on the process of in vitro wear of commercial acrylic bone cement preloaded with gentamicin. Therefore, this study will determine if the results are similar in relation to test condition and if they are maintained after being immersed in physiological saline solution for a period of 7 and 30 days, thus simulating physiological conditions. Material and Experimental Method Preparation of the Antibiotic-Loaded Bone Cement
The Conflict of Interest statement associated with this article can be found at http:// dx.doi.org/10.1016/j.arth.2013.04.008. Reprint requests: Pablo Sanz-Ruiz, PhD, MD, C/ Padre Claret nº 3, 5ª A, Madrid, 28002. Spain.
The cement under study was Palacos R + G (Heraeus Medical GmbH, Wehrheim, Germany) containing 0.5 g of gentamicin. The selected antibiotics were Normon EFG vancomycin (Normon,
0883-5403/0000-0000$36.00/0 – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.arth.2013.04.008
Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008
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Table 1 The Study Groups and the Amount of the Antibiotic Relative to the Mass of the Cement Powder (in w/w).
Group Group Group Group Group Group
1 (Control) 2 3 4 5 6
Cefazolin
Vancomycin
2.5% 2.5% -
2.5% 5% 5% 10%
Table 2 The Test Type and Aging Conducted for Each of the Tested Conditions.
Condition Condition Condition Condition
1 2 3 4
Test
Ageing
Dry Immersed in saline solution Immersed in saline solution Immersed in saline solution
Without ageing Without ageing 1 week in saline solution at 37 °C 1 month in saline solution at 37 °C
Madrid, Spain), an antibiotic with a high molecular weight (1449.3 g/mol) and low water solubility, and cefazolin Normon EFG (Normon, Madrid, Spain), an antibiotic with a low molecular weight (454.51 g/mol) and high water solubility. Depending on the antibiotic selected and the dose used, 6 study groups were established. The amounts and combinations of the tested antibiotics are shown in Table 1. The antibiotic was added manually by adding the same amount of polymer powder as antibiotic to obtain a homogeneous sample, as recommended by Frommelt et al [14]. The cements were prepared by manually mixing the powdered PMMA with the liquid monomer methylmethacrylate in a bowl with a spatula according to the manufacturers' instructions. The resulting mix of liquid cement was then poured into a silicon mold that contained six holes of 30 mm in diameter and 4 mm in height. The mold with the samples was pressurized on a metal foil for 30 minutes with a load of 100 N. After the cement hardened, the cement discs were removed from the mold and stored under dark, at room temperature. Each disc had a total surface area of 7.07 cm 2 and a weight of 3.5 ± 0.3 g. During the preparation of the samples, the temperature and relative humidity were kept constant at 23 ± 2°C and at 35 ± 5%, respectively. In all
cases, the samples were mixed in air (without vacuum) and stored for 24 hours prior to testing or conditioning Sample Conditioning Four different test conditions were established (Table 2). Condition 1 specimens were tested in dry condition. Condition 2 was tested in the liquid medium (phosphate-buffered saline; PBS) without ageing. Samples from conditions 3 and 4 were tested in the liquid medium after ageing. Exposure to ageing environment was achieved by immersion of antibiotic-loaded cement discs in 250 ml of PBS at a constant temperature of 37°C. Wear Study (Mechanical Wear Tests) The mechanical wear tests were carried out in a Pin on Disk Tribometer from Microtest (Madrid, Spain), with a 6 mm diameter AISI 304 stainless steel pin. The wear tests were performed according to the ASTM G99-05 [15] on cylindrical specimens. The tests were conducted a speed at of 0.1 m/s with an applied load of 15 N, and the sliding distance was 1000 m. Three samples from each group were tested at each condition (18 samples per condition), yielding a total of 72 tested samples. For the samples tested in the liquid medium, a circular beaker (50 mm radius × 30 mm height) was fixed to the tribometer with 100 ml PBS for direct testing in the liquid medium. For each group and ageing condition, the coefficient of friction and wear was evaluated. The average friction coefficient was obtained by the tribometer, whereas the lost volume and the wear of each sample were obtained by a geometric relationship [15] using a Nikon Profile Projector V profilometer −20 (Nikon Instruments Inc, Melville, NY), defined in (mm 3/nm)·10 −4. Scanning electron microscope After the mechanical wear test, the wear tracks were studied using a XL-30 Scanning Electron Microscope (SEM) from Philips (Eindhoven, Holland), to determine the mechanism of wear. The samples were prepared using gold coating in a high-resolution Polaron SC7610 sputter coater from VG Microtech (Uakfield, United Kingdom) to
Fig. 1. The friction coefficients of each groups under each test condition.
Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008
P. Sanz-Ruiz et al. / The Journal of Arthroplasty xxx (2013) xxx–xxx
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provide a conducting medium for the electrons and enough contrast in the SEM micrographs. The energy of the electron beam was 10 kV. Statistical Analysis The values were expressed as the mean ± the standard deviation. The results for each test were statistically analyzed using an analysis of variance (ANOVA) and t Dunnett test as post-hot analysis by using SPSS 15.0 for Windows from IBM SPSS (Chicago, IL). A P value b .05 was assumed to be statistically significant. Results In the tests performed under dry conditions, the friction coefficient values are higher than for those conducted in the liquid medium. In some groups, this decrease in friction was approximately 30% but only groups 1, 3 and 5 showed statistically significant differences (P = .025; P = .035; P = .026, respectively) (Fig. 1). In the tests carried out under dry conditions, no significant differences were observed among the friction coefficients for the different groups, although the friction coefficients were slightly lower for the control group (Group 1) and slightly higher in the group containing the largest amount of antibiotics (Group 6) (Table 3 A). In the tests conducted with samples immersed in PBS, especially for those aged for one month, the groups with cefazolin (Group 2 and group 4) had significantly higher friction coefficients than the control group under the same conditions (P b .001 condition 2; P = .016 condition 3; P b .001 condition 4). Vancomycin did not significantly increase the friction coefficient except when added in dosages above 10% w/w (Group 6) (P = .012). In general terms, the coefficient friction changes with the ageing time, but it does not follow a fixed pattern. The condition 2 samples (without ageing but tested in liquid medium) show a reduction in relation to dry samples and there are statistically significant differences between them (P b .05). Although the group 2 (containing only cefazolin) presents higher value (Fig. 1), the differences in the evolution path of the friction coefficient during the test between the samples tested in liquid and dry medium can be seen in the graphs of Fig. 2. The friction coefficient of dry samples reaches quickly a stable trend. However, in liquid medium the friction coefficient continues growing along the test time. Also the difference between maximum and minimum are different, these fluctuations are large in the samples tested in dry condition (from 0.6 to 1) and small the samples tested in liquid medium. After ageing, the group 2 samples show the higher values of friction coefficient. This value grows significantly with the ageing time (P = .027) (Fig. 1) (Fig. 3). Also this effect could be observed in the group 4 (cefazolin and vancomycin), but no statistical significance was observed. The presence of vancomycin seems to lead a reduction
Fig. 2. The evolution of the friction coefficient during the wear test of Group 2 testing (A) under dry conditions and (B) in saline solution after 1 month of ageing in saline solution at 37 °C.
in the values of the friction coefficient when compared with those that contain cefazolin only. The wear, expressed in (mm 3/nm)·10 −4, gives an idea of the volume of material lost during the test. The wear was significantly higher in the dry samples than in the samples tested in liquid medium (P b .001). After 1 week of ageing process, only our cefazolin group showed a significantly higher wear than the samples tested in liquid medium (P = .016), but after 1 month of ageing, the cefazolin and high-dose vancomycin groups had higher wears (P = .005; P = .01) (Fig. 4). A significant increment of wear was observed on 2.5% cefazolin samples (group 2) when compared with the same amount of vancomycin (group 3) after an ageing time of 1 week (P b .001) and 1 month (P b .001) (Fig. 4). The analysis of the SEM images showed a large wear track in those samples tested in dry condition. High abrasive wear is observed when the samples are studied with a higher magnification (Fig. 5). In liquid medium condition the wear was smaller due to a less abrasive wear. In addition, adhesion of wear debris was also observed in this condition (Fig. 6) (Fig. 7). In the samples tested in dry condition the abrasive particles are observed in the wear track (Fig. 8)
Table 3 The Friction Coefficient (A) and the Average Wear (B) obtained in the Test. Group Condition Average Friction Coefficient Dry medium Liquid medium Liquid medium + ageing 1 week Liquid medium + ageing 1 month Average wear (mm3/N ± m) ± 10-4 Dry medium Liquid medium Liquid medium + ageing 1 week Liquid medium + ageing 1 month
1 0.61 0.42 0.47 0.29
0.2564 0.1203 0.0579 0.1110
± 0.04 ± 0.06 ± 0.06 ± 0.11
± 0.0666 ± 0.0074 ± 0.0116 ± 0.0217
2 0.69 0.51 0.57 0.67
0.2332 0.0529 0.1366 0.1028
± 0.07 ± 0.00 ± 0.01 ± 0.08
± 0.0959 ± 0.0363 ± 0.0006 ± 0.0145
3 0.07 ± 0.08 0.39 ± 0.11 0.45 ± 0.06 0.8 ± 0.11
0.1734 0.0675 0.0727 0.0416
± 0.0183 ± 0.0092 ± 0.0077 ± 0.0022
4 0.70 0.29 0.37 0.5
0.5081 0.1896 0.1506 0.0965
± 0.00 ± 0.02 ± 0.08 ± 0.11
± 0.0639 ± 0.0171 ± 0.0253 ± 0.0081
5 0.70 0.42 0.60 0.34
0.3144 0.1177 0.0475 0.0567
± 0.07 ± 0.07 ± 0.00 ± 0.13
± 0.0005 ± 0.0586 ± 0.0083 ± 0.0074
6 0.80 0.41 0.49 0.59
0.2460 0.1352 0.0436 0.0762
± 0.04 ± 0.03 ± 0.21 ± 0.054
± 0.1006 ± 0.0317 ± 0.0020 ± 0.0176
Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008
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Fig. 3. Variation in the friction coefficient in the groups containing cefazolin (Groups 2 and 4) with ageing time.
Discussion The results of this study were influenced by the choice of bone cement, environmental conditions and the antibiotics used. In this study, Palacos R + G bone cement (Heraeus Medical GmbH, Wehrheim, Germany) was used, since it is one of the most widespread commercial cements and it has superior elution of antibiotics than other commercial cements [16,17]. The use of cement preloaded with gentamicin is widespread in the treatment of prosthetic infection, and there is evidence that adding it on an industrial scale does not affect the mechanical properties of the PMMA [18]. The environmental conditions used were similar to the ideal conditions for using bone cement in surgery [19,20] The antibiotics were selected based on their widespread distribution, frequent use in prosthetic infections, low price and their biochemical profiles with different molecular weights and solubilities [3,21]. The samples were mixed manually because there is no current agreement on the mixing method that least affects the mechanical properties and elution of PMMA with antibiotics [22–26]. The effect of immersing PMMA in a liquid medium has been described previously [27–30] and the plasticizing effect of water and its effect in mechanical properties have been widely studied [28,30– 34]. The wear observed in this study was low, although there was considerably greater wear in the dry samples than any conditioned sample. The zirconium oxide functioned as third body increasing the wear in the dry condition (Fig. 8). Differences in wear, as a function of ageing time, were observed in cefazolin samples. Nottrott et al. [35] suggested that the effect of the liquid medium is partly offset by the
Fig. 5. The wear track of Group 6 under dry conditions (A) and solution conditions after 1 month (B) Note the abrasive wear in dry condition. There is a less abrasive wear and increased adhesive wear in liquid medium.
slow polymerization of the remaining monomer. They studied the compression resistance of different PMMAs after different conditioning processes in a liquid medium. This study did not have enough data
Fig. 4. The wear of each groups under each test condition.
Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008
P. Sanz-Ruiz et al. / The Journal of Arthroplasty xxx (2013) xxx–xxx
Fig. 6. A SEM micrograph (800×) of a cross section of the wear track testing in liquid medium and after ageing for one week. The image was taken in SE (A) and BSE (B).
to support this affirmation, since the samples were tested after 24 h, and therefore the bone cement was not fully polymerized. If the influence that the mixed antibiotic has on the wear is observed, it can be deduced that both antibiotics increase the friction coefficients and that the friction coefficients is greater at higher doses of antibiotic in dry test condition. In a liquid medium, although the friction coefficients and wear decreased as they were influenced by the effect of the water, the cefazolin samples showed higher values of wear and friction coefficients than the samples with same amount of vancomycin (Fig. 4). This could be explained by the different hydrophilic properties of the antibiotics, which resulted in an increased release of cefazolin compared to vancomycin giving rise to a material and volume loss, thus favoring wear. The observed influence of the introduction of PMMA in a liquid medium in this study is consistent with published data in other studies, although we did not find any studies that compare wear in this medium. Several authors have compared the different resistances of cements prepared with different doses of vancomycin in a dry medium, the addition of the antibiotic resulted in a very small decrease in the mechanical strength and was not dose dependent, it did increase the fatigue of the cement itself [36]. Pelletier et al.[6] obtained the same results by simultaneously adding different doses of vancomycin and flucloxacillin. Currently, no studies have compared the influence of different antibiotics on the mechanical properties of bone cement in a liquid medium. In this study, it was not possible to measure directly the antibiotic elution in the different cement samples. The addition of
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Fig. 7. A BSE micrograph of Group 4 under dry (A) and aging conditions after 1 month (B). The image A showed a uniform material except zirconium oxide (black arrows). Different deposits from PMMA, salts and pin oxides (white arrows) ware observed in the B image.
cefazolin could increase the elution of vancomycin. This finding is supported by studies that show increased elution of vancomycin by adding gentamicin to Palacos [37,38]. Carretani et al. [39] studied the elution of different cements with vancomycin alone and with
Fig. 8. The abrasive effect of zirconium oxide. Particles of Zirconium oxide on the cement (black arrow).
Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008
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vancomycin and imipenem, observing that the mixture of both increased the elution by almost 50%. Although imipenem is not chemically or molecularly the same as cefazolin, until new studies are performed, it can assume a similar behavior due to their similarity from a biochemical point of view because both belong to the group of B-lactams and have similar molecular weights. Unlike the previous studies in the literature, we used the wear of PMMA to observe the effect of antibiotics on PMMA. Saleh et al. [40] and Goodman et al. [41] considered that one of the factors involved in periprosthetic osteolysis are bone cement wear particles. Unlike previous studies in the literature, we studied the influence of the addition of antibiotics to bone cement on PMMA wear. Currently, the use of articulated spacers in the treatment of prosthetic infections has outperformed statics both in function and cure rates [42–45]. These spacers are subjected to shear forces on their surfaces, and studies are required to determine how the behavior of different cements against these forces depends on their composition. This study is a first step in trying to understand what happens on the surface of dynamic spacers. There are a number of potential limitations in our study. Prior to mechanical testing we discarded any samples with obvious voids. This may have biased our results, although the same protocol was followed for all cement types. We have attempted to mimic the environmental conditions in a joint by using a study medium with a PBS. A healthy joint contains synovial fluid, which, besides having a similar ionic composition, also has various substances such as proteins, cells, glucose, etc., that confer properties which are very different from those of the solution. It is therefore important to keep this in mind when extrapolating these results to the clinic. In the study, the samples were immersed in a sealed container. In joints, there is a flow between absorption/production in addition to the movement itself, which may influence the wear particles that are deposited on the cement itself, altering the wear figures obtained in this study. One of the objectives of this study was to compare the wear characteristics of various antibiotics mixed with cement in an environment similar to a physiological environment, so that the difference in composition compared to the joint fluid should not pose a weakness on the extrapolation of the results. Nevertheless, it would be desirable to conduct further studies with synovial fluid to corroborate that assertion. This study measured the wear of PMMA mixed with antibiotics in liquid medium for the first time, showing that bone cement behaves differently under dry conditions compared to a liquid medium, and its wear properties are strongly influenced not only by the addition of an antibiotic, but also by the type of antibiotic used. The type of antibiotic and ageing also exert an influence over PMMA wear. Moreover, the antibiotic mixture produces synergistic effects to be taken into account. Based on our findings, we believe that wear tests on PMMA bone cements should be included in future studies due to the biological relevance of PMMA wear. In addition, future testing conditions should be used for opening new horizons for obtaining study mediums emulating physiological conditions.
Conclusion The results suggest that cements with antibiotic behave differently in liquid mediums and that the molecular characteristics of the antibiotic are essential in determining its influence on the wear properties of the cement.
Acknowledgments The authors acknowledge the support from Fundación Mapfre for grant funding. The authors also thank Mr. Fernando Perez for his help in this research and Dr. Rojo for his help in review this paper.
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Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008
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Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement Pablo Sanz-Ruiz PhD, MD a, Eva Paz b, Juana Abenojar Ph.D c, Juan Carlos del Real Ph.D b, Javier Vaquero PhD, MD a, Francisco Forriol PhD, MD d a
Department of Traumatology and Orthopaedic Surgery, General University Hospital Gregorio Marañón, Madrid, Spain Institute for Research in Technology/Mechanical Engineering Dept., Universidad, Pontificia Comillas, Madrid, Spain Materials Performance Group, Materials Science and Engineering Dept., Universidad, Carlos III de Madrid, Spain d Faculty of Medicine, Universidad San Pablo CEU, Madrid, Spain b c
a r t i c l e
i n f o
Article history: Received 12 February 2013 Accepted 11 April 2013 Available online xxxx Keywords: polymethylmethacrylate (PMMA) bone cement friction arthroplasty infection antibiotic-loaded cement
a b s t r a c t Antibiotic cement has been recommended in the treatment of prosthetic infections. The purpose of this study was to investigate the mechanical behavioral changes in cement loaded with two antibiotics, vancomycin and cefazolin, in dry and liquid medium. Six groups and four study conditions were established according to the doses of antibiotic used and the ageing (immersion in phosphate buffered saline) of the samples. Properties evaluated were friction coefficient and wear. Samples in dry medium showed higher wears than in liquid. Antibiotic selection did not influence wear properties tested in dry conditions, however, in liquid medium, there were higher frictional coefficients and wear for cefazolin loaded cement after one week and for vancomycin and cefazolin after one month. The results suggest that antibiotic cements behave differently in liquid and that the molecular characteristics of antibiotics are essential for determining this influence. © 2013 Elsevier Inc. All rights reserved.
The treatment of prosthetic infections remains controversial since it depends on multiple variables such as the function of the affected joint, the elapsed time since implantation and the medical condition of the patient. It has been widely documented that the two-stage revision using a bone cement spacer (polymethylmethacrylate, PMMA) mixed with various antibiotics obtain the highest success rates [1–4]. The addition of antibiotics to PMMA, particularly in liquid form, adversely affects its mechanical strength [5–7]; therefore, it is necessary to consider an antibiotic’s microbiological profile, its influence on the cement and its spreading capacity, among other features. The most commonly antibiotics used are tobramycin, gentamicin, vancomycin, clindamycin and cephalosporins [2,8]. Since the introduction in the market of cement with gentamicin for infection prophylaxis in primary arthroplasty, various microorganisms with acquired resistance to gentamicin [9] have been described. This necessitates the search for new antibiotics and combinations thereof to increase the antimicrobial spectrum without compromising the characteristics of PMMA. There are multiple studies that assess and compare the effect of different antibiotics on the resistance of PMMA to bending and
compression. Most of these studies have been performed in vitro, based on ISO and ASTM standards for testing acrylic cements [10,11]. The extrapolation of in vitro results to clinical practice is controversial since these studies disregard the changes undergone by antibioticmixed PMMA with the liquid medium of the physiological environment. It is also important to note that the influence of these antibiotics in the breakdown of bone cement has not been well defined; this wear is closely related to the osteolysis observed in medium/long term in patients undergoing joint replacements that occasionally leads to an aseptic loosening of the implant [12,13]. The aim of this study is to investigate the mechanical behavior changes of two antibiotics with different biochemical properties on the process of in vitro wear of commercial acrylic bone cement preloaded with gentamicin. Therefore, this study will determine if the results are similar in relation to test condition and if they are maintained after being immersed in physiological saline solution for a period of 7 and 30 days, thus simulating physiological conditions. Material and Experimental Method Preparation of the Antibiotic-Loaded Bone Cement
The Conflict of Interest statement associated with this article can be found at http:// dx.doi.org/10.1016/j.arth.2013.04.008. Reprint requests: Pablo Sanz-Ruiz, PhD, MD, C/ Padre Claret nº 3, 5ª A, Madrid, 28002. Spain.
The cement under study was Palacos R + G (Heraeus Medical GmbH, Wehrheim, Germany) containing 0.5 g of gentamicin. The selected antibiotics were Normon EFG vancomycin (Normon,
0883-5403/0000-0000$36.00/0 – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.arth.2013.04.008
Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008
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Table 1 The Study Groups and the Amount of the Antibiotic Relative to the Mass of the Cement Powder (in w/w).
Group Group Group Group Group Group
1 (Control) 2 3 4 5 6
Cefazolin
Vancomycin
2.5% 2.5% -
2.5% 5% 5% 10%
Table 2 The Test Type and Aging Conducted for Each of the Tested Conditions.
Condition Condition Condition Condition
1 2 3 4
Test
Ageing
Dry Immersed in saline solution Immersed in saline solution Immersed in saline solution
Without ageing Without ageing 1 week in saline solution at 37 °C 1 month in saline solution at 37 °C
Madrid, Spain), an antibiotic with a high molecular weight (1449.3 g/mol) and low water solubility, and cefazolin Normon EFG (Normon, Madrid, Spain), an antibiotic with a low molecular weight (454.51 g/mol) and high water solubility. Depending on the antibiotic selected and the dose used, 6 study groups were established. The amounts and combinations of the tested antibiotics are shown in Table 1. The antibiotic was added manually by adding the same amount of polymer powder as antibiotic to obtain a homogeneous sample, as recommended by Frommelt et al [14]. The cements were prepared by manually mixing the powdered PMMA with the liquid monomer methylmethacrylate in a bowl with a spatula according to the manufacturers' instructions. The resulting mix of liquid cement was then poured into a silicon mold that contained six holes of 30 mm in diameter and 4 mm in height. The mold with the samples was pressurized on a metal foil for 30 minutes with a load of 100 N. After the cement hardened, the cement discs were removed from the mold and stored under dark, at room temperature. Each disc had a total surface area of 7.07 cm 2 and a weight of 3.5 ± 0.3 g. During the preparation of the samples, the temperature and relative humidity were kept constant at 23 ± 2°C and at 35 ± 5%, respectively. In all
cases, the samples were mixed in air (without vacuum) and stored for 24 hours prior to testing or conditioning Sample Conditioning Four different test conditions were established (Table 2). Condition 1 specimens were tested in dry condition. Condition 2 was tested in the liquid medium (phosphate-buffered saline; PBS) without ageing. Samples from conditions 3 and 4 were tested in the liquid medium after ageing. Exposure to ageing environment was achieved by immersion of antibiotic-loaded cement discs in 250 ml of PBS at a constant temperature of 37°C. Wear Study (Mechanical Wear Tests) The mechanical wear tests were carried out in a Pin on Disk Tribometer from Microtest (Madrid, Spain), with a 6 mm diameter AISI 304 stainless steel pin. The wear tests were performed according to the ASTM G99-05 [15] on cylindrical specimens. The tests were conducted a speed at of 0.1 m/s with an applied load of 15 N, and the sliding distance was 1000 m. Three samples from each group were tested at each condition (18 samples per condition), yielding a total of 72 tested samples. For the samples tested in the liquid medium, a circular beaker (50 mm radius × 30 mm height) was fixed to the tribometer with 100 ml PBS for direct testing in the liquid medium. For each group and ageing condition, the coefficient of friction and wear was evaluated. The average friction coefficient was obtained by the tribometer, whereas the lost volume and the wear of each sample were obtained by a geometric relationship [15] using a Nikon Profile Projector V profilometer −20 (Nikon Instruments Inc, Melville, NY), defined in (mm 3/nm)·10 −4. Scanning electron microscope After the mechanical wear test, the wear tracks were studied using a XL-30 Scanning Electron Microscope (SEM) from Philips (Eindhoven, Holland), to determine the mechanism of wear. The samples were prepared using gold coating in a high-resolution Polaron SC7610 sputter coater from VG Microtech (Uakfield, United Kingdom) to
Fig. 1. The friction coefficients of each groups under each test condition.
Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008
P. Sanz-Ruiz et al. / The Journal of Arthroplasty xxx (2013) xxx–xxx
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provide a conducting medium for the electrons and enough contrast in the SEM micrographs. The energy of the electron beam was 10 kV. Statistical Analysis The values were expressed as the mean ± the standard deviation. The results for each test were statistically analyzed using an analysis of variance (ANOVA) and t Dunnett test as post-hot analysis by using SPSS 15.0 for Windows from IBM SPSS (Chicago, IL). A P value b .05 was assumed to be statistically significant. Results In the tests performed under dry conditions, the friction coefficient values are higher than for those conducted in the liquid medium. In some groups, this decrease in friction was approximately 30% but only groups 1, 3 and 5 showed statistically significant differences (P = .025; P = .035; P = .026, respectively) (Fig. 1). In the tests carried out under dry conditions, no significant differences were observed among the friction coefficients for the different groups, although the friction coefficients were slightly lower for the control group (Group 1) and slightly higher in the group containing the largest amount of antibiotics (Group 6) (Table 3 A). In the tests conducted with samples immersed in PBS, especially for those aged for one month, the groups with cefazolin (Group 2 and group 4) had significantly higher friction coefficients than the control group under the same conditions (P b .001 condition 2; P = .016 condition 3; P b .001 condition 4). Vancomycin did not significantly increase the friction coefficient except when added in dosages above 10% w/w (Group 6) (P = .012). In general terms, the coefficient friction changes with the ageing time, but it does not follow a fixed pattern. The condition 2 samples (without ageing but tested in liquid medium) show a reduction in relation to dry samples and there are statistically significant differences between them (P b .05). Although the group 2 (containing only cefazolin) presents higher value (Fig. 1), the differences in the evolution path of the friction coefficient during the test between the samples tested in liquid and dry medium can be seen in the graphs of Fig. 2. The friction coefficient of dry samples reaches quickly a stable trend. However, in liquid medium the friction coefficient continues growing along the test time. Also the difference between maximum and minimum are different, these fluctuations are large in the samples tested in dry condition (from 0.6 to 1) and small the samples tested in liquid medium. After ageing, the group 2 samples show the higher values of friction coefficient. This value grows significantly with the ageing time (P = .027) (Fig. 1) (Fig. 3). Also this effect could be observed in the group 4 (cefazolin and vancomycin), but no statistical significance was observed. The presence of vancomycin seems to lead a reduction
Fig. 2. The evolution of the friction coefficient during the wear test of Group 2 testing (A) under dry conditions and (B) in saline solution after 1 month of ageing in saline solution at 37 °C.
in the values of the friction coefficient when compared with those that contain cefazolin only. The wear, expressed in (mm 3/nm)·10 −4, gives an idea of the volume of material lost during the test. The wear was significantly higher in the dry samples than in the samples tested in liquid medium (P b .001). After 1 week of ageing process, only our cefazolin group showed a significantly higher wear than the samples tested in liquid medium (P = .016), but after 1 month of ageing, the cefazolin and high-dose vancomycin groups had higher wears (P = .005; P = .01) (Fig. 4). A significant increment of wear was observed on 2.5% cefazolin samples (group 2) when compared with the same amount of vancomycin (group 3) after an ageing time of 1 week (P b .001) and 1 month (P b .001) (Fig. 4). The analysis of the SEM images showed a large wear track in those samples tested in dry condition. High abrasive wear is observed when the samples are studied with a higher magnification (Fig. 5). In liquid medium condition the wear was smaller due to a less abrasive wear. In addition, adhesion of wear debris was also observed in this condition (Fig. 6) (Fig. 7). In the samples tested in dry condition the abrasive particles are observed in the wear track (Fig. 8)
Table 3 The Friction Coefficient (A) and the Average Wear (B) obtained in the Test. Group Condition Average Friction Coefficient Dry medium Liquid medium Liquid medium + ageing 1 week Liquid medium + ageing 1 month Average wear (mm3/N ± m) ± 10-4 Dry medium Liquid medium Liquid medium + ageing 1 week Liquid medium + ageing 1 month
1 0.61 0.42 0.47 0.29
0.2564 0.1203 0.0579 0.1110
± 0.04 ± 0.06 ± 0.06 ± 0.11
± 0.0666 ± 0.0074 ± 0.0116 ± 0.0217
2 0.69 0.51 0.57 0.67
0.2332 0.0529 0.1366 0.1028
± 0.07 ± 0.00 ± 0.01 ± 0.08
± 0.0959 ± 0.0363 ± 0.0006 ± 0.0145
3 0.07 ± 0.08 0.39 ± 0.11 0.45 ± 0.06 0.8 ± 0.11
0.1734 0.0675 0.0727 0.0416
± 0.0183 ± 0.0092 ± 0.0077 ± 0.0022
4 0.70 0.29 0.37 0.5
0.5081 0.1896 0.1506 0.0965
± 0.00 ± 0.02 ± 0.08 ± 0.11
± 0.0639 ± 0.0171 ± 0.0253 ± 0.0081
5 0.70 0.42 0.60 0.34
0.3144 0.1177 0.0475 0.0567
± 0.07 ± 0.07 ± 0.00 ± 0.13
± 0.0005 ± 0.0586 ± 0.0083 ± 0.0074
6 0.80 0.41 0.49 0.59
0.2460 0.1352 0.0436 0.0762
± 0.04 ± 0.03 ± 0.21 ± 0.054
± 0.1006 ± 0.0317 ± 0.0020 ± 0.0176
Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008
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Fig. 3. Variation in the friction coefficient in the groups containing cefazolin (Groups 2 and 4) with ageing time.
Discussion The results of this study were influenced by the choice of bone cement, environmental conditions and the antibiotics used. In this study, Palacos R + G bone cement (Heraeus Medical GmbH, Wehrheim, Germany) was used, since it is one of the most widespread commercial cements and it has superior elution of antibiotics than other commercial cements [16,17]. The use of cement preloaded with gentamicin is widespread in the treatment of prosthetic infection, and there is evidence that adding it on an industrial scale does not affect the mechanical properties of the PMMA [18]. The environmental conditions used were similar to the ideal conditions for using bone cement in surgery [19,20] The antibiotics were selected based on their widespread distribution, frequent use in prosthetic infections, low price and their biochemical profiles with different molecular weights and solubilities [3,21]. The samples were mixed manually because there is no current agreement on the mixing method that least affects the mechanical properties and elution of PMMA with antibiotics [22–26]. The effect of immersing PMMA in a liquid medium has been described previously [27–30] and the plasticizing effect of water and its effect in mechanical properties have been widely studied [28,30– 34]. The wear observed in this study was low, although there was considerably greater wear in the dry samples than any conditioned sample. The zirconium oxide functioned as third body increasing the wear in the dry condition (Fig. 8). Differences in wear, as a function of ageing time, were observed in cefazolin samples. Nottrott et al. [35] suggested that the effect of the liquid medium is partly offset by the
Fig. 5. The wear track of Group 6 under dry conditions (A) and solution conditions after 1 month (B) Note the abrasive wear in dry condition. There is a less abrasive wear and increased adhesive wear in liquid medium.
slow polymerization of the remaining monomer. They studied the compression resistance of different PMMAs after different conditioning processes in a liquid medium. This study did not have enough data
Fig. 4. The wear of each groups under each test condition.
Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008
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Fig. 6. A SEM micrograph (800×) of a cross section of the wear track testing in liquid medium and after ageing for one week. The image was taken in SE (A) and BSE (B).
to support this affirmation, since the samples were tested after 24 h, and therefore the bone cement was not fully polymerized. If the influence that the mixed antibiotic has on the wear is observed, it can be deduced that both antibiotics increase the friction coefficients and that the friction coefficients is greater at higher doses of antibiotic in dry test condition. In a liquid medium, although the friction coefficients and wear decreased as they were influenced by the effect of the water, the cefazolin samples showed higher values of wear and friction coefficients than the samples with same amount of vancomycin (Fig. 4). This could be explained by the different hydrophilic properties of the antibiotics, which resulted in an increased release of cefazolin compared to vancomycin giving rise to a material and volume loss, thus favoring wear. The observed influence of the introduction of PMMA in a liquid medium in this study is consistent with published data in other studies, although we did not find any studies that compare wear in this medium. Several authors have compared the different resistances of cements prepared with different doses of vancomycin in a dry medium, the addition of the antibiotic resulted in a very small decrease in the mechanical strength and was not dose dependent, it did increase the fatigue of the cement itself [36]. Pelletier et al.[6] obtained the same results by simultaneously adding different doses of vancomycin and flucloxacillin. Currently, no studies have compared the influence of different antibiotics on the mechanical properties of bone cement in a liquid medium. In this study, it was not possible to measure directly the antibiotic elution in the different cement samples. The addition of
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Fig. 7. A BSE micrograph of Group 4 under dry (A) and aging conditions after 1 month (B). The image A showed a uniform material except zirconium oxide (black arrows). Different deposits from PMMA, salts and pin oxides (white arrows) ware observed in the B image.
cefazolin could increase the elution of vancomycin. This finding is supported by studies that show increased elution of vancomycin by adding gentamicin to Palacos [37,38]. Carretani et al. [39] studied the elution of different cements with vancomycin alone and with
Fig. 8. The abrasive effect of zirconium oxide. Particles of Zirconium oxide on the cement (black arrow).
Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008
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vancomycin and imipenem, observing that the mixture of both increased the elution by almost 50%. Although imipenem is not chemically or molecularly the same as cefazolin, until new studies are performed, it can assume a similar behavior due to their similarity from a biochemical point of view because both belong to the group of B-lactams and have similar molecular weights. Unlike the previous studies in the literature, we used the wear of PMMA to observe the effect of antibiotics on PMMA. Saleh et al. [40] and Goodman et al. [41] considered that one of the factors involved in periprosthetic osteolysis are bone cement wear particles. Unlike previous studies in the literature, we studied the influence of the addition of antibiotics to bone cement on PMMA wear. Currently, the use of articulated spacers in the treatment of prosthetic infections has outperformed statics both in function and cure rates [42–45]. These spacers are subjected to shear forces on their surfaces, and studies are required to determine how the behavior of different cements against these forces depends on their composition. This study is a first step in trying to understand what happens on the surface of dynamic spacers. There are a number of potential limitations in our study. Prior to mechanical testing we discarded any samples with obvious voids. This may have biased our results, although the same protocol was followed for all cement types. We have attempted to mimic the environmental conditions in a joint by using a study medium with a PBS. A healthy joint contains synovial fluid, which, besides having a similar ionic composition, also has various substances such as proteins, cells, glucose, etc., that confer properties which are very different from those of the solution. It is therefore important to keep this in mind when extrapolating these results to the clinic. In the study, the samples were immersed in a sealed container. In joints, there is a flow between absorption/production in addition to the movement itself, which may influence the wear particles that are deposited on the cement itself, altering the wear figures obtained in this study. One of the objectives of this study was to compare the wear characteristics of various antibiotics mixed with cement in an environment similar to a physiological environment, so that the difference in composition compared to the joint fluid should not pose a weakness on the extrapolation of the results. Nevertheless, it would be desirable to conduct further studies with synovial fluid to corroborate that assertion. This study measured the wear of PMMA mixed with antibiotics in liquid medium for the first time, showing that bone cement behaves differently under dry conditions compared to a liquid medium, and its wear properties are strongly influenced not only by the addition of an antibiotic, but also by the type of antibiotic used. The type of antibiotic and ageing also exert an influence over PMMA wear. Moreover, the antibiotic mixture produces synergistic effects to be taken into account. Based on our findings, we believe that wear tests on PMMA bone cements should be included in future studies due to the biological relevance of PMMA wear. In addition, future testing conditions should be used for opening new horizons for obtaining study mediums emulating physiological conditions.
Conclusion The results suggest that cements with antibiotic behave differently in liquid mediums and that the molecular characteristics of the antibiotic are essential in determining its influence on the wear properties of the cement.
Acknowledgments The authors acknowledge the support from Fundación Mapfre for grant funding. The authors also thank Mr. Fernando Perez for his help in this research and Dr. Rojo for his help in review this paper.
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Please cite this article as: Sanz-Ruiz P, et al, Effects of Vancomycin, Cefazolin and test Conditions on the Wear Behavior of Bone Cement, J Arthroplasty (2013), http://dx.doi.org/10.1016/j.arth.2013.04.008