Search

Antibiotic-loaded calcium phosphate cement (CPC) has emerged as a promising biomaterial for drug delivery in orthopedics. However, there are problems such as the burst release of antibiotics, low cumulative release ratio, inappropriate release cycle, inferior mechanical strength, and poor anti-collapse properties. In this research, montmorillonite-gentamicin (MMT-GS) was fabricated by solution intercalation method and served as the drug release pathways in CPC to avoid burst release of GS, achieving promoted cumulative release ratios and a release cycle matched the time of inflammatory response. The results indicated that the highest cumulative release ratio and release concentration of GS in CPC/MMT-GS was 94.1 ± 2.8 % and 1183.05 μg/mL, and the release cycle was up to 504 h. In addition, the hierarchical GS delivery system was divided into three stages, and the kinetics followed the Korsmeyer-Peppas model, the zero-order model, and the diffusion-dissolution model, respectively. Meanwhile, the compressive strength of CPC/MMT-GS was up to 51.33 ± 3.62 MPa. Antibacterial results demonstrated that CPC/MMT-GS exhibited excellent in vitro long-lasting antibacterial properties to E. coli and S. aureus. Furthermore, CPC/MMT-GS promoted osteoblast proliferation and exhibited excellent in vivo histocompatibility. Therefore, CPC/MMT-GS has favorable application prospects in the treatment of bone defects with bacterial infections and inflammatory reactions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The high incidence of osteomyelitis associated with critical-sized bone defects raises clinical challenges in fracture healing. Clinical use of antibiotic-loaded bone cement as an adjunct therapy is limited by incompatibility with many antimicrobials, sub-optimal release kinetics, and requirement of surgical removal. Furthermore, overuse of antibiotics can lead to bacterial modifications that increase efflux, decrease binding, or cause inactivation of the antibiotics. Herein, we compared the efficacy of gallium maltolate, a new metal-based antimicrobial, to gentamicin sulfate released from electrospun poly(lactic-co-glycolic) acid (PLGA) wraps in the treatment of osteomyelitis. In vitro evaluation demonstrated sustained release of each antimicrobial up to 14 days. A Kirby Bauer assay indicated that the gentamicin sulfate-loaded wrap inhibited the growth of osteomyelitis-derived isolates, comparable to the gentamicin sulfate powder control. In contrast, the gallium maltolate-loaded wrap did not inhibit bacteria growth. Subsequent microdilution assays indicated a lower than expected sensitivity of the osteomyelitis strain to the gallium maltolate with release concentrations below the threshold for bactericidal activity. A comparison of the selectivity indices indicated that gentamicin sulfate was less toxic and more efficacious than gallium maltolate. A pilot study in a contaminated femoral defect model confirmed that the sustained release of gentamicin sulfate from the electrospun wrap resulted in bacteria density reduction on the surrounding bone, muscle, and hardware below the threshold that impedes healing. Overall, these findings demonstrate the efficacy of a resorbable, antimicrobial wrap that can be used as an adjunct or stand-alone therapy for controlled release of antimicrobials in the treatment of osteomyelitis., (© 2021 Wiley Periodicals LLC.)

Treatment of postsurgical infections, associated with orthopedic surgeries, has been a major concern for orthopedics. Several strategies including systematic and local administration of antibiotics have been proposed to this regard. The present work focused on fabricating alginate (Alg) modified brushite (Bru) cements, which could address osteogeneration and local antibiotic demands. To find the proper method of drug incorporation, Gentamicin sulfate (Gen) was loaded into the samples in the form of solution or powder. Several characterization tests including compression test, morphology, cytotoxicity, and cell adhesion assays were carried out to determine the proper concentration of Alg as a modifier of the Bru cement. The results indicated that addition of 1 wt% Alg led to superior mechanical and biological properties of the cement. Moreover, Alg addition changed the morphology of the cement from plate and needle-like structures to petal-like structure. Fourier transform infrared spectroscopy results confirmed the successful loading of Gen on the cements, specifically when Gen solution was used, and X-Ray Diffractometer result indicated that Gen caused a decrease in crystalline size. Furthermore, thermal analysis revealed that Gen-loaded sample had more stable structure as the transformation temperature slightly shifted to a higher one. The stability study confirmed the chemical stability and adequate mechanical performance of the cements within 1 month of soaking time. Finally, the addition of Alg has a positive impact on the release behavior at low concentration of Gen solution so that 20% decrease within 2 weeks of release experiment was remarkably detected., (© 2019 Wiley Periodicals, Inc.)

Two-stage revision arthroplasty is the treatment of choice for periprosthetic infection, a serious complication after knee or hip arthroplasty. Our prospective clinical trial aimed to investigate the concentrations of gentamicin and vancomycin in wound exudate and tissue in two-stage revision arthroplasty. Wound exudate and periprosthetic membrane samples were collected from 18 patients (10 hip and eight knee patients), who were due for two-stage treatment after a periprosthetic joint infection. Samples were taken during insertion of antibiotic-impregnated spacers and after their removal. The concentrations of gentamicin and vancomycin in wound exudates and adjacent tissue were analyzed using high-performance liquid chromatography mass spectrometry. Average time period of spacer implantation was 13.6 weeks (9.3-22.6 weeks). The concentration of vancomycin in wound exudate decreased from a median of 43.28 μg/mL (0.28-261.22) after implantation to 0.46 μg/mL (0.13-37.47) after the removal of the spacer. In the adjacent tissue, vancomycin concentration was mainly undetectable prior to spacer implantation (0.003 μg/g [0.003-0.261]) and increased to 0.318 μg/g [0.024-484.16] at the time of spacer removal. This was also observed for gentamicin in the tissue of patients who previously had cement-free implants (0.008 μg/g [0.008-0.087] vs. 0.164 μg/g [0.048-71.75]) while in the tissue of patients with previously cemented prosthesis, baseline concentration was already high (8.451 μg/g [0.152-42.926]). Despite the rapid decrease in antibiotics release from spacer cement observed in vitro, in vivo antibiotics are much longer detectable, especially in the adjacent soft tissue. © 2018 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials Published By Wiley Periodicals, Inc. J Biomed Mater Res B Part B, 2019. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1587-1597, 2019., (© 2018 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals, Inc.)

Periprosthetic joint infections continues to be a common complication in total joint arthroplasty, resulting in significant morbidity, mortality, and additional cost. Trabecular metal implants with an internal cemented interface may be customizable drug delivery devices with an ingrowth interface. Thirty-six acetabular implants were assembled in vitro, half with a trabecular metal shell and half without. The antibiotic loaded bone cement was prepared via three different mixing techniques and at two different mixing times. Mixing time had a significant effect on the total amount of gentamicin eluted. The long mixing protocol eluted up to 126% (p = 0.001) more gentamicin than the short mixing protocol at 4 h and 192% (p < 0.001) more at 7 days. Hand or mechanical mixing technique had no significant effect on elution at 4 h. At 7 days, the mechanical mixing system under vacuum eluted over 50% (p = 0.031) more gentamicin than without a vacuum and nearly 60% (p = 0.040) more gentamicin than hand mixing. The use of a trabecular metal shell had no significant effect on the bulk elution of gentamicin at 4 h (p > 0.05) but significantly reduced total gentamicin elution under certain mixing protocols at 7 days. A possible optimization strategy to improve elution kinetics would be to use a long mixing time with a mechanical mixing system under vacuum. The establishment of trabecular metal as an effective delivery vehicle for antibiotics makes possible an entirely new class of drug eluting device designs. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Poly(methyl methacrylate) (PMMA) bone cement is used in several biomedical applications including as antibiotic-filled beads, temporary skeletal spacers, and cement for orthopedic implant fixation. To mitigate infection following surgery, antibiotics are often mixed into bone cement to achieve local delivery. However, since implanted cement is often structural, incorporated antibiotics must not compromise mechanical properties; this limits the selection of compatible antibiotics. Furthermore, antibiotics cannot be added to resolve future infections once cement is implanted. Finally, delivery from cement is suboptimal as incorporated antibiotics exhibit early burst release with most of  the drug remaining permanently trapped. This prolonged subtherapeutic dosage drives pathogen antibiotic resistance. To overcome these limitations of antibiotic-laden bone cement, insoluble cyclodextrin (CD) microparticles are incorporated into PMMA to provide more sustained delivery of a broader range of drugs, without impacting mechanics. PMMA formulations with and without CD microparticles are synthesized and filled with one of three antibiotics and evaluated using zone of inhibition, drug release, and compression studies. Additionally, the ability of PMMA with microparticles to serve as a refillable antibiotic delivery depot is explored. Findings suggest that addition of CD microparticles to cement promotes postimplantation antibiotic refilling and enables incorporation of previously incompatible antibiotics while preserving favorable mechanical properties., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Copal® spacem is a new PMMA bone cement for fabricating spacers. This study compares elution of gentamicin, elution of vancomycin, and compressive strength of Copal® spacem and of Palacos® R+G at different vancomycin loadings in the powder of the cements. We hypothesized that antibiotic elution of Copal® spacem is superior at comparable compressive strength., Methods: Compression test specimens were fabricated using Copal® spacem manually loaded with 0.5 g gentamicin and additionally 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (COP specimens) and using 0.5 g gentamicin premixed Palacos® R+G manually loaded with 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (PAL specimens). These specimens were used for determination of gentamicin and vancomycin elution (in fetal calf serum, at 22°C) and for determination of compressive strength both prior and following the elution tests., Results: Cumulative gentamicin concentrations (p < 0.005) and gentamicin concentration after 28 days (p ≤ 0.043) were significantly lower for COP specimens compared to PAL specimens. Cumulative vancomycin concentrations were significantly higher (p ≤ 0.043) for COP specimens after the second day. Vancomycin concentrations after 28 days were not significantly higher for the Copal specimens loaded with 2 g and 4 g of vancomycin. Compressive strength was not significantly different between COP specimens and PAL specimens before elution tests. Compressive strength after the elution tests was significantly lower (p = 0.005) for COP specimens loaded with 2 g of vancomycin., Conclusion: We could not demonstrate consistent superior antibiotic elution from Copal® spacem compared to Palacos® R+G for fabricating gentamicin and vancomycin loaded spacers. The results do not favor Copal® spacem over Palacos® R+G for the use as a gentamicin and vancomycin biantibiotic-loaded spacer.

Antibiotic loaded bone cements are used as drug delivery systems for the treatment of periprosthetic joint infections. They can be loaded with antibiotics during industrial component production (premixing) and during cement preparation (manually blending). Although double premixed antibiotic loaded bone cements are available, manually blending of a gentamicin premixed antibiotic loaded bone cement with vancomycin is still popular. We compared in vitro antibiotic elution and compressive strength of 0.5 g gentamicin premixed bone cement (PALACOS® R + G), 0.5 g gentamicin premixed bone cement (PALACOS® R + G) manually blended with 2.0 g vancomycin, 0.5 g gentamicin and 2.0 g vancomycin premixed bone cement (COPAL® G + V), 1 g gentamicin and clindamycin premixed bone cement (COPAL® G + C) and bone cement without an antibiotic (PALACOS® R) as control. Antibiotic concentration measurements were performed for 6 weeks and then compression strength was tested. Concentrations of gentamicin showed no significant differences between PALACOS® R + G, PALACOS® R + G with vancomycin and COPAL G® + V. After 48 h COPAL G® + C produced significantly higher gentamicin concentrations than the other formulations. After 12 h PALACOS® R + G with vancomycin produced significantly higher vancomycin concentrations, but had the lowest compression strength. We found no influence of vancomycin addition on gentamicin elution, irrespectively of the loading method. However, the manually vancomycin blended ALBC produced higher vancomycin concentrations. Compression strength after aging is reduced by loading with vancomycin.

Aims: Vancomycin is commonly added to acrylic bone cement during revision arthroplasty surgery. Proprietary cement preparations containing vancomycin are available, but are significantly more expensive. We investigated whether the elution of antibiotic from 'home-made' cement containing vancomycin was comparable with more expensive commercially available vancomycin impregnated cement., Materials and Methods: A total of 18 cement discs containing either proprietary CopalG+V; or 'home-made' CopalR+G with vancomycin added by hand, were made. Each disc contained the same amount of antibiotic (0.5 g gentamycin, 2 g vancomycin) and was immersed in ammonium acetate buffer in a sealed container. Fluid from each container was sampled at eight time points over a two-week period. The concentrations of gentamicin and vancomycin in the fluid were analysed using high performance liquid chromatography mass spectrometry., Results: The highest peak concentrations of antibiotic were observed from the 'home-made' cements containing vancomycin, added as in the operating theatre. The overall elution of antibiotic was, fivefold (vancomycin) and twofold (gentamicin) greater from the 'home-made' mix compared with the commercially mixed cement. The use of a vacuum during mixing had no significant effect on antibiotic elution in any of the samples., Conclusion: These findings suggest that the addition of 2 g vancomycin powder to gentamicin-impregnated bone cement by hand significantly increases the elution of both antibiotics compared with commercially prepared cements containing vancomycin. We found no significant advantages of using expensive commercially produced vancomycin-impregnated cement and recommend the addition of vancomycin powder by hand in the operating theatre. Cite this article: Bone Joint J 2017;99-B:73-7., (©2017 The British Editorial Society of Bone & Joint Surgery.)

Objectives: Numerous studies have examined the biomechanics of polymethyl methacrylate (PMMA) with added antibiotics, but direct comparison between studies is difficult. Our purpose was to evaluate the effects of the addition of antibiotic drugs and silver on compressive and bending strength of PMMA. Our null hypothesis was that there would be no significant difference in the compressive strength or bending strength of PMMA with the addition of silver or varying amounts of antibiotic drugs., Methods: Polymethyl methacrylate was mixed with cefazolin, gentamicin, vancomycin, or silver; the control was PMMA alone. Antibiotic groups contained 20 g PMMA and 0.5 g, 1 g, 2 g, or 3 g of antibiotic. Silver groups had 0.25 g silver powder alone added to 20 g PMMA or silver with PMMA and 0, 0.5 g or 1 g of antibiotic. Samples underwent four-point bending and compression testing in air at room temperature and prevailing humidity. Pairwise comparisons between groups and to the ASTM and ISO standards were performed., Results: Compression: All antibiotic and silver groups were weaker than the control. Samples with cefazolin tended to be stronger than other antibiotic groups with equivalent doses of antibiotic. All groups were above the ASTM standard, except 3 g vancomycin. Four-point bending: The addition of antibiotics did not significantly affect bending strength in groups with lower doses of antibiotics. The silver + PMMA group was weaker than the control. No groups were significantly below the ISO standard except the 3 g vancomycin group., Clinical Significance: The addition of antibiotic or silver decreased the biomechanical strength in all samples, but not below the ASTM or ISO standard for most groups. The addition of cefazolin appears to affect strength the least, while high doses of vancomycin alter strength the most.

Objective: To evaluate whether the addition of porogens to polymethyl methacrylate (PMMA) enhances the antibiotic elution rate from antibiotic-loaded bone cement., Methods: Two porogens, gelatin sponge (Spongostan, Ferrosan Medical Devices) and ceramic granules (Bicera, Wiltrom), were added to liquid gentamicin-loaded PMMA at increasing concentrations. Porosity was analyzed using Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy. Young's modulus and drug elution were also measured. The gentamicin content of the eluents was evaluated by o-phthaldialdehyde (OPA) assay on days 1, 2, 5, 7, 10, and 14., Results: After day 5, the drug-releasing rate of Spongostan was significantly higher than that of Bicera in the order G3 > G2 > T3 > G1 > T2 > T1 > bone cement, where G represents the concentration of Spongostan and T represents the concentration of Bicera. The addition of Bicera and Spongostan increased the drug-releasing efficiency of PMMA by 3.75-fold and 5.65-fold, respectively. Spongostan also resulted in larger pores (ie, 70 to approximately 200 μm) compared with Bicera (5 to 10 μm) but reduced biomechanical strength., Conclusion: Both gelatin sponge and ceramic granules improved the local antibiotic elution rate, although the drug-releasing rate of Spongostan was significantly higher than that of Bicera.

To improve antibiotic properties, poly(methyl methacrylate) (PMMA)-based bone cements are formulated with antibiotic and nanostructured materials, such as hydroxyapatite (HAP) nanorods, carbon nanotubes (CNT) and mesoporous silica nanoparticles (MSN) as drug carriers. For nonporous HAP nanorods, the release of gentamicin (GTMC) is not obviously improved when the content of HAP is below 10%; while the high content of HAP shows detrimental to mechanical properties although the release of GTMC can be substantially increased. As a comparison, low content of hollow nanostructured CNT and MSN can enhance drug delivery efficiency. The presence of 5.3% of CNT in formulation can facilitate the release of more than 75% of GTMC in 80 days, however, its mechanical strength is seriously impaired. Among nanostructured drug carriers, antibiotic/MSN formulation can effectively improve drug delivery and exhibit well preserved mechanical properties. The hollow nanostructured materials are believed to build up nano-networks for antibiotic to diffuse from the bone cement matrix to surface and achieve sustained drug release. Based on MSN drug carrier in formulated bone cement, a binary delivery system is also investigated to release GTMC together with other antibiotics., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Soluble particulate fillers can be incorporated into antibiotic-loaded acrylic bone cement in an effort to enhance antibiotic elution. Xylitol is a material that shows potential for use as a filler due to its high solubility and potential to inhibit biofilm formation. The objective of this work, therefore, was to investigate the usage of low concentrations of xylitol in a gentamicin-loaded cement. Five different cements were prepared with various xylitol loadings (0, 1, 2.5, 5 or 10 g) per cement unit, and the resulting impact on the mechanical properties, cumulative antibiotic release, biofilm inhibition, and thermal characteristics were quantified. Xylitol significantly increased cement porosity and a sustained increase in gentamicin elution was observed in all samples containing xylitol with a maximum cumulative release of 41.3%. Xylitol had no significant inhibitory effect on biofilm formation. All measured mechanical properties tended to decrease with increasing xylitol concentration; however, these effects were not always significant. Polymerization characteristics were consistent among all groups with no significant differences found. The results from this study indicate that xylitol-modified bone cement may not be appropriate for implant fixation but could be used in instances where sustained, increased antibiotic elution is warranted, such as in cement spacers or beads., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Previous experience has demonstrated the importance of testing new bone cement in vivo before widespread clinical use. We performed a consecutive, radiostereometric (RSA) study comparing Refobacin Bone Cement (RBC) to the well proven Palacos with Gentamicin (PWG). According to the manufacturer of RBC it has the equivalent characteristics as PWG, and in vitro tests show good results. The purpose of this study was to evaluate whether RBC is safe to use in clinical practice for total hip arthroplasty (THA). Two consecutive series of patients with primary osteoarthritis received a THA using a highly polished, collarless, tapered stem with a hollow centralizer. The study comprises 21 hips with RBC and 30 with PWG. The patients were followed up for two years with repeated RSA examinations and clinical outcome questionnaires SF-12 and WOMAC. There were no statistically significant migratory differences between the groups. The mean subsidence after two years was 1.28 mm and 1.40 mm, and the mean retroversion was 1.03° and 0.99°, for the RBC and the PWG groups respectively. Almost all migration occurred in the interface between the stem and the cement. The WOMAC and SF12 clinical scores did not reveal any clinical differences between the groups. We conclude that, as previous in vitro tests indicate, RBC performs as well as PWG and seems to be safe to use in clinical practice for THA.

The use of antibiotics as a supplement to bone cement for the purposes of providing a local release of antibiotics is common practice in arthroplasty surgery and the kinetics of elution of the antibiotics in such systems have been investigated previously. However, in these previous studies no account was taken of the potential effects that wear may have on the elution kinetics of the antibiotic. Here, we have modified an existing wear testing rig to allow the simultaneous study of the elution kinetics of bone cement samples containing antibiotics being subjected to immersion only and immersion and conjoint wear. The results show contrasting effects with two commonly used antibiotics. Bone cement containing daptomycin showed no substantial change in antibiotic elution due to wear, while cement containing gentamicin (the most commonly used antibiotic in this application) in contrast demonstrated a substantial reduction in the rate of antibiotic elution when wear was applied. Scanning electron microscopy revealed a possible explanation for these diverse results, due to wear-induced "sealing" of the surface in conjunction with the crystal morphology of the antibiotic.

Coloured bone cements have been introduced to make the removal of cement debris easier at the time of primary and revision joint replacement. We evaluated the physical, mechanical and pharmacological effects of adding methylene blue to bone cement with or without antibiotics (gentamicin, vancomycin or both). The addition of methylene blue to plain cement significantly decreased its mean setting time (570 seconds (SD 4) vs 775 seconds (SD 11), p = 0.01), mean compression strength (95.4 MPa (SD 3) vs 100.1 MPa (SD 6), p = 0.03), and mean bending strength (65.2 MPa (SD 5) vs 76.6 MPa (SD 4), p < 0.001) as well as its mean elastic modulus (2744 MPa (SD 97) vs 3281 MPa (SD 110), p < 0.001). The supplementation of the coloured cement with vancomycin and gentamicin decreased its mean bending resistance (55.7 MPa (SD 4) vs 65.2 MPa (SD 5), p < 0.001).The methylene blue significantly decreased the mean release of gentamicin alone (228.2 µg (SD 24) vs 385.5 µg (SD 26), p < 0.001) or in combination with vancomycin (498.5 µg (SD 70) vs 613 µg (SD 25), p = 0.018) from the bone cement. This study demonstrates several theoretical disadvantages of the antibiotic-loaded bone cement coloured with methylene blue.

Background: Liquid antimicrobial use for antimicrobial-loaded bone cement is limited because of decreased strength and small volume that can be loaded. Emulsifying the liquid antimicrobial into the monomer may address both issues., Questions/purposes: We determined the effect of using a surfactant-stabilized emulsion on antimicrobial release, compressive strength, and porosity., Methods: We made 144 standardized test cylinders from emulsified antimicrobial-loaded bone cement (three batches, 72 cylinders) and control antimicrobial-loaded bone cement made with antimicrobial powder (three batches, 72 cylinders). For each formulation, five specimens per batch (n = 15) were eluted in infinite sink conditions over 30 days for gentamicin delivery; five specimens per batch were axially compressed to failure after elution of 0, 1, and 30 days (n = 45); and two noneluted specimens and two gentamicin delivery specimens from each batch (n = 12) were examined under scanning electron microscopy for porosity. Antimicrobial release and compressive strength were compared across cement type and time using repeated-measures ANOVA., Results: Emulsified antimicrobial-loaded bone cement released four times more antimicrobial than control. Compressive strength of emulsified antimicrobial-loaded bone cement was less than control before elution (58.1 versus 81.3 MPa) but did not decrease over time in elution. Compressive strength of control antimicrobial-loaded bone cement decreased over 30 days in elution (81.3 versus 73.9 MPa) but remained stronger than emulsified antimicrobial-loaded bone cement. Porosity was homogeneous, with pores ranging around 50 μm., Conclusions: Emulsified antimicrobial-loaded bone cement has homogeneous porosity with increased drug release but a large loss of strength., Clinical Relevance: Liquid antimicrobials are released from emulsified antimicrobial-loaded bone cement, but increased strength is needed before this method can be used for implant fixation.

Poly(methyl methacrylate)-based bone cements are functionalized with mesoporous silica nanoparticles (MSN) to enable a highly efficient and sustained release of antibiotics to reduce the risk of post-operative joint infection. To overcome the limited drug release of 5% for only 1 day with the current commercial-grade bone cements, a 8 wt% MSN-formulated bone cement is able to increase the drug release efficiency by 14-fold and sustain the release for up to 80 days. The loaded MSN is suggested to build up an effective network of rod-shaped silica particles with uniformly arranged nanoporous channels, which is responsible for the effective drug diffusion and extend time-release to the external surfaces. MSN has no detrimental effect on the critical weight-bearing bending modulus and compression strength of bone cement. In vitro assay test results show a much sustained antibacterial effect and low cytotoxicity of MSN demonstrating the potential applicability of MSN-formulated bone cement.

Purpose: The purpose of this study is the evaluation of the differences and, eventually, of the advantages or disadvantages of manual formulations with respect to industrial ones., Methods: Medical-grade bone cements (Palacos R® and Palacos LV®), based on poly-methyl methacrylate (PMMA) and used clinically in several cemented prosthetic devices were manually enriched with gentamicin sulphate during preparation and then compared with a commercially-available, antibiotic-loaded cement (Palacos R+G®) by means of an in vitro antibacterial test (inhibition zone evaluation). The purpose of this study was to evaluate the differences and advantages or disadvantages, if any, of manual formulations compared to commercial ones. The use of a different antibiotic (vancomycin) alone or in addition to gentamicin-containing bone cements was also considered., Results and Conclusion: The commercial formulation produces an inhibition zone that is a bit larger and more regular than the manually mixed preparation. The vancomycin halo is smaller but clearer than the gentamicin halo. The addition of vancomycin to gentamicin-containing bone cements does not significantly increase the halo dimensions but could be an interesting strategy in the prevention of multiple and resistant infections.

The purpose of this study was to characterize a poly(methyl methacrylate) bone cement that was loaded with the antibiotic gentamicin sulphate (GS) and lactose, which served to modulate the release of GS from cement specimens. The release of GS when the cement specimens were immersed in phosphate-buffered saline at 37 degrees Celsius was determined spectrophotometrically. The microstructure, porosity, density, tensile properties and flexural properties of the cements were determined before and after release of GS. A kinetics model of the release of GS from the cement that involved a coupled mechanism based on dissolution/diffusion processes and an initial burst effect was proposed. Dissolution assay results showed that drug elution was controlled by a diffusion mechanism which can be modulated by lactose addition. Density values and mechanical properties (tensile strength, flexural strength, elastic modulus and fracture toughness) were reduced by the increased porosity resulting from lactose addition, but maintained acceptable values for the structural functions of bone cement. The present results suggest that lactose-modified, gentamicin-loaded acrylic bone cements are potential candidates for use in various orthopaedic and dental applications., (Copyright 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Aim: Two clinically established PMMA bone cements (Refobacin Palacos R and Palacos R + G) and two newer cements not yet in widespread clinical use (Refobacin Bone Cement R and SmartSet GHV) were tested in vitro for practically relevant differences., Methods: The tests included chemical analyses, handling properties and testing according to the ISO standard for PMMA bone cements., Results: The results obtained indicate clearly that the copolymers used in Refobacin Bone Cement R and SmartSet GHV differ from those used in the Palacos cements. There were also significant differences in viscosity behaviour and waiting time (p < 0.01 for Palacos cements versus Refobacin Bone Cement R) as an expression of different handling properties. The hardening times under ISO 5833 conditions also differed significantly (p < 0.01 and p < 0.05 for Palacos cements compared with Refobacin Bone Cement R and p < 0.01 for Refobacin Bone Cement R compared with SmartSet GHV)., Conclusion: In view of these differences in material properties, the clinical data from long-term use of the bone cements Refobacin Palacos R and Palacos R + G cannot be extrapolated to the newly developed PMMA cements Refobacin Bone Cement R and Smart GHV. Before broad clinical use of these cements, prospective clinical studies using RSA or DEXA and, as a second step, statistically powerful prospective comparative studies should be performed. Until these data are available, patients in whom Refobacin Bone Cement R and SmartSet GHV are used should be informed that the material employed deviates from the standard procedures for cemented joint replacement in the Scandinavian arthroplasty registers and that the long-term consequences cannot, in the final instance, be foreseen. This is essential in order to avoid later malpractice claims on the grounds of inadequate information.

Previously reported antibiotic-impregnated cement strengths have been based on uniaxial and fatigue testing methodologies. These methods may not provide an accurate characterization of bone cement's true load-bearing capacity in total joint replacement (TJR). The present study utilized biaxial testing to report on the properties of antibiotic-impregnated cement. Test groups included: PMMA mixed with Vancomycin, Gentamicin, Tobramycin, or no antibiotic (control). In comparison to the control group, PMMA samples mixed with powdered gentamicin resulted in an increase in the mean elastic modulus by 6.50% versus a drop noted with powdered vancomycin and tobramycin by 2.65 and 1.37% respectively. The mean elastic modulus in samples containing liquid gentamicin dropped by 11.6%. This study supports the continued use of powdered antibiotics when clinically indicated, but suggest caution in the use of liquid gentamicin in TJR.

Background: In some countries, commercially available antibiotic powder-loaded acrylic bone cement is routinely used in joint replacement, while, in others, "off-label" formulations are used in selected procedures (where the antibiotic powder is blended manually with the powder of a plain cement in the operating room/theater by either the surgeon or approved personnel). In the latter situation, an arbitrary rather than a rational approach is used for deciding on the amount of the antibiotic that is blended with the cement powder (herein referred to as "the antibiotic powder loading")., Methods and Results: The first objective of this study was to present two methods for estimating the optimum loading of gentamicin sulfate powder that may be blended manually with the powder of a commercially available acrylic bone cement, ABC (Wopt). The second objective was to define the challenges associated with each of these methods. The loading (W) was optimized with respect to two key properties of the cured cement that were obtained simultaneously, namely (1) fatigue life in phosphate-buffered saline solution (PBS) at 37 degrees C, and (2) the rate of elution of the gentamicin from the cement (E) in that medium. Three sets of specimens were used, containing 2.25, 4.25 and 11.50 wt/wt% of the gentamicin that was blended manually with the cement powder. The fatigue tests involved determining the number of cycles at which a specimen fractured (Nf) when subjected to fully-reversed tension-compression sinusoidal load, +/- 15 MPa at 2 Hz. E was determined from the concentration of gentamicin in the PBS solution when the specimen fractured, using fluorescence polarization immunoassay for the measurement. Consistent with a priori expectations, it was found that, with increase in W, Nf decreased while E increased. Two approaches for obtaining an estimate of Wopt are described, a mathematical method and an empirical one, that lead to Wopt values of 6.50 wt/wt% and 4.78 wt/wt%, respectively. Thus, this antibiotic loading ranges from about the same to about 92% greater than that in SmartSet GHV Gentamicin, which is a commercially available bone cement used clinically and which has the same composition as SmartSet HV except for the presence of gentamicin sulfate in its powder (blended in by the manufacturer)., Interpretation: We present and critically compare two rational methods of determining the optimum loading of an antibiotic powder in an acrylic bone cement, which should serve as a guide when using "off-label" antibiotic powder-loaded acrylic bone cements in cemented joint replacements.

The objective of this study was to investigate the release mechanism and kinetics of the antimicrobial peptide, Dhvar-5, both alone and in combination with gentamicin, from a standard commercial polymethyl methacrylate (PMMA) bone cement. Different amounts of Dhvar-5 were mixed with the bone cement powders of Osteopal and the gentamicin-containing Osteopal G bone cement and their release kinetics from the polymerized cement were investigated. Additionally, the internal structure of the bone cements were analysed by scanning electron microscopy (SEM) of the fracture surfaces. Secondly, porosity was investigated with the mercury intrusion method and related to the observed release profiles. In order to obtain an insight into the mechanical characteristics of the bone cement mixtures, the compressive strength of Osteopal and Osteopal G with Dhvar-5 was also investigated. The total Dhvar-5 release reached 96% in the 100 mg Dhvar-5/g Osteopal cement, whereas total gentamicin release from Osteopal G reached only 18%. Total gentamicin release increased significantly to 67% with the addition of 50mg Dhvar-5/g, but the Dhvar-5 release was not influenced. SEM showed an increase of dissolved gentamicin crystals with the addition of Dhvar-5. The mercury intrusion results suggested an increase of small pores (< 0.1 microm) with the addition of Dhvar-5. Compressive strength of Osteopal was reduced by the addition of Dhvar-5 and gentamicin, but still remained above the limit prescribed by the ISO standard for clinical bone cements. We therefore conclude that the antimicrobial peptide, Dhvar-5, was released in high amounts from PMMA bone cement. When used together with gentamicin sulphate, Dhvar-5 made the gentamicin crystals accessible for the release medium presumably through increased micro-porosity (< 0.1 microm) resulting in a fourfold increase of gentamicin release.

Two-solution bone cement consists of methyl methacrylate monomer and poly(methyl methacrylate) polymer dissolved together to yield a viscous solution. Two solutions are used such that the initiator, benzoyl peroxide (BPO), is placed in one solution and the activator, N,N, dimethyl-para-toluidine, is placed in the other. This approach to bone cement provides for a simplified use during surgery and eliminates some of the sources of porosity formation. However, the BPO-containing solution cement will spontaneously polymerize over time and will limit the useful shelf life of this component of the system. The activator-containing component is much more stable and is not as susceptible to spontaneous polymerization. In making two-solution cements, it is envisioned that antibiotics may be incorporated and that the polymer may be sterilized using gamma(gamma)-irradiation. Therefore, this study investigated the shelf life of the initiator-containing solution bone cement and studied the effects of initiator concentration, gamma-irradiation, gentamicin addition, and the role of storage temperature. Isothermal differential scanning calorimetry (Iso-DSC) techniques were used to monitor the polymerization of BPO-containing solutions. It was found that the shelf life was highly temperature dependent and followed an Arrhenius expression where refrigeration storage (4 degrees C) yielded approximately a 12-month storage time, while 70 degrees C storage results in setting in about 5-7 min. gamma-irradiation and gentamicin addition did not significantly affect the shelf life. Initiator concentration affected storage time with higher levels resulting in shorter shelf life.

Objective: To find out an effective technique to repair large segmental infected bony defect., Methods: Calcium phosphate cement (CPC) incorporated with bone morphogenetic protein and gentamycin was embedded in the massive reconstituted bovine xenograft (MRBX), then CPC-MRBX was obtained after CPC's solidification. In vivo test was applied to test the drug delivery capability of CPC-MRBX, in which it was implanted in the dorsal muscle pouch of 18 rabbits. The drug concentration of animal blood and surrounding soft tissue of the CPC-MRBX in the muscle pouch was measured 1, 2, 5, 10, 15, 20, 25, 30 and 35 d after operation, 2 rabbits each time. Large segmental infected femur defect in the rabbit model was created to test the repairing capability of CPC-MRBX. External fixation was done 1.5-2.0 cm above the knee, the most adjacent nail to fracture site was 0.5-0.8 cm away, and proper pressure was applied to the graft. In experimental group (n = 25), the bony defect was replaced by CPC-MRBX, while in the control group(n = 15) dissected bone block was re-implanted in original position. The animal was subjected to radiographic, histological examination at 4, 8, 16 and 24 weeks. The general condition was observed after the operation., Results: CPC-MRBX was easily made under normal temperature and pressure. In vivo drug delivery test showed that the drug concentration of the tissue remained above the minimal inhibitory concentration of staphylococcus 30 d after operation and no significant increase of blood drug concentration was observed. In experimental group, no adverse influence was observed. Four weeks after operation, the animal could bear load, bony callus around the graft was observed by X-ray, and abundant chondral tissues that grew into CPC-MRBX were observed by histological method. Eight weeks after operation, progressively increasing bony callus around the graft was observed, external fixation could be removed, normal function was restored, and CPC was degenerated dramatically while new bone tissues were growing. Sixteen weeks after the operation, more new bone tissues grew and CPC was degenerated further while marrow tissues were taking shape. Twenty-four weeks after the operation, femur healed completely and CPC was degenerated completely. In the control group, the autograft remained unhealed on X-ray at 4 weeks, and osteomyelitis manifestation such as inflammatory cells infiltration and osteolysis was detected at 4 weeks. All the animals in the control group died before the 8th week, 4 of which showed positive hemoculture., Conclusion: CPC-MRBX is readily available and can be applied to repairing large segmental infected bony defect.

Background: The aim of the present study was to establish an in vitro microbiologic monitoring system which measures the dynamics of antibiotic release from acrylic bone cement and its antibacterial efficacy., Methods: Palacos R and Orthofix R cements containing gentamicin sulfate were tested. The in vitro elution dynamics was analyzed by plate diffusion method during a 1-year period after mixing. High but rapidly decreasing antibiotic levels were detected within the 1st week, resulting in an almost steadily low concentration by the end of the 1st month. After 1 year, it was still possible to demonstrate the inhibitory effect of the drug from both cements. Comparison of the time-related release between the antibiotics failed to find any statistically significant differences., Conclusion: The method described is a useful and reproducible technique for the in vitro measurement of the inhibitory activity of antibiotic released from bone cements., (2004 S. Karger AG, Basel.)

The release of gentamicin as a function of time was measured for Palacos and two-solution bone cements by using a novel pH technique. The pH of an aqueous solution of gentamicin is a function of the gentamicin concentration and it decreases linearly over concentrations of 0.0-0.1 wt %. Therefore, a new, direct, and inexpensive in vitro technique was developed based on continuous readings of the pH in phosphate-buffered saline (PBS) at 37 degrees C to determine the release kinetics of gentamicin from poly(methyl methacrylate) (PMMA)-based bone cement. In addition, this method was used to compare the release profiles of Palacos R-40 bone cement with a two-solution bone cement developed in our laboratory and loaded with two different concentrations of gentamicin sulfate. Finally, the pH-based method was used to track the elution of gentamicin in both mixed and static conditions to determine the effect of mixing on the diffusion of gentamicin out of the cement. It was found that Palacos R-40 released 4.95 +/- 0.22 wt % of its gentamicin after 24 h in PBS solution. This data compares favorably with previously reported values of gentamicin elution from Palacos R-40, which ranged from 3 to 8 wt % of the total amount of incorporated gentamicin, depending on the size and the surface area of the samples. The results show that Palacos samples released 4.84 +/- 0.27 mg after 24 h, a two-solution cement loaded with an equivalent concentration of gentamicin sulfate released 3.81 +/- 0.52 mg, and two-solution cement loaded with twice the concentration of Palacos released 5.53 +/- 0.26 mg of gentamicin. A higher percentage of release was recorded from Palacos than from the two-solution bone cement, and the effect of PBS mixing conditions on the release kinetics was only significant in the early stages of release and not at 24 h. It was concluded that monitoring the pH is an effective technique to measure gentamicin release from PMMA-based bone cements in PBS solution., (Copyright 2004 Wiley Periodicals, Inc. J Biomed Mater Res 69A: 577-583, 2004)

Barium sulphate is added to polymethylmethacrylate (PMMA) bone cement as a radiopacifier. Gentamicin is an antibiotic added to bone cement to treat or prevent infection in arthroplasty. This study investigated the combined effect of barium sulphate and gentamicin sulphate on the fatigue strength of PMMA bone cement. Three different formulations were studied: pure PMMA, PMMA with barium sulphate added and PMMA with barium sulphate and gentamicin sulphate added. Before testing all specimens were stored in water at 37 degrees C for at least 15 days to season the PMMA and to elute the antibiotic. Fatigue tests were performed following a previously validated procedure. The slope part of the Wöhler diagram was obtained and a rough endurance limit was estimated for all three formulations. The experimental data showed that the addition of barium sulphate to PMMA bone cement affected the fatigue strength of the material, whereas addition of gentamicin sulphate to the radiopaque PMMA had no effect on the fatigue properties of the bone cement. While PMMA with barium sulphate added was confirmed to have a reduced fatigue strength when compared with plain PMMA, no detrimental effect was found for the addition of gentamicin sulphate to radiopaque PMMA.

The purpose of the present work was the study of the gentamicin sulphate (GS) release from a commercial acrylic bone cement CMW-1 with the aims of establishing the influence of the slabs preparation as well as the release mechanism and kinetics. The effect of the amount of GS on the release kinetic parameters has been also investigated. In vitro release studies were performed in a buffered saline solution at pH 7.4 and 37 degrees C. The GS concentration was determined using an indirect spectrophotometric method with an o-phthaldialdehyde as a derivatizing reagent. A commercial and three modified samples were tested. The free and fractured surfaces of the GS cement slabs before and after the release studies were observed by means of scanning electron microscopy (SEM). For low GS concentration loading the release was very incomplete because most of the GS beads were encapsulated by the hydrophobic PMMA matrix. A higher amount of antibiotic was released from cement that has a higher amount incorporated. A model and therefore a mechanism of release based on this model have been proposed. It has allowed us to explain the changes in dissolution kinetics of an acrylic matrix type controlled release system up to 12% GS loading. The cumulative amount of GS released M(t)/M(i), was fitted as a function of time. For lower amounts of GS, the regression analysis (R(2)>0.99) revealed that the release is most adequately represented by M(t)/M(i)=b+kt(n), where b represents a burst effect. The goodness of fit decreases as the amount of GS increases. The influence of some other type of release mechanism for higher amounts of GS must be taken into account and a second model for the release, M(t)/M(i)=b+k x [1-exp(-kt)], is proposed.

The influence of the (2-hydroxyethyl methacrylate) (HEMA) monomer addition as a comonomer to the cement liquid component and of a polymer, poly(N-vinyl-2-pyrrolidone) (PVP) to the solid component of a standard CMW-1 bone cement on gentamicin sulphate (GS) on its drug release properties have been studied. The addition of HEMA modifies the habit of the delivery curves. The incorporation of PVP into the cement matrix, apparently, did not very much modify the shape of the HEMA modified cement release curves, but led to a remarkable increase of the maximum amount of GS released. This effect was proportional to the PVP concentration incorporated. From the matrix composition and SEM data, a model based on the morphology of the matrix has been proposed. The cumulative amount of GS released by each slab Mt is most adequately fitted and represented by the equation Mt = c + at 1/2 + b[1 - exp(-nt)], which corroborates that the release occurs according to the model proposed. by means of three discrete mechanisms, namely: (i) a short-term initial elution due to the imperfections in the poly(methyl methacrylate) covering of the most external GS beads, burst effect by the buffer solution; (ii) followed by a fracture by stress cracking in an active media of the coated GS beads located on the external surface of the matrix where water molecules enter to dissolve GS molecules releasing them into the buffer solution by a diffusion-controlled process; and (iii) a third process in which the buffer solution penetrates into the internal voids and cracks creating a series of channels in a labyrinthic structure, which may facilitate the access of water molecules to the plastic-coated GS beads within the bulk matrix. This third process is enhanced by the incorporation of PVP beads as dissolved molecules within the matrix. This water-soluble additive is leachable, generating a highly porous structure in the cement. This HEMA and PVP modified cement may be used as a drug delivery system to modulate the GS release rate.

Due to the extended use of acrylic bone cements, its necessary to develop improved formulations in order to resolve their many drawbacks. The present work was conducted to make a physical-chemical characterisation of this kind of acrylic cement in order to introduce future changes in the formulations to: (1) improve or at least maintain their mechanical properties; (2) diminish their toxicity, and (3) control the drug release (rate and amount). From the dissolution method we can conclude that the preparation method (with or without pressure) of specimens is not responsible for the erratic release. The cumulative amount of gentamicin released was fitted to a semi-empirical equation to explain the possible release mechanism. The powder size, shape and distribution that could affect several properties of bone cement were studied with the aid of different techniques such as SEM, laser diffraction spectroscopy, and powder X-ray diffraction. From SEM micrographs, it was possible to observe that the surfaces of the specimens were very irregular with numerous small craters that may serve as conduits for eluting the antibiotic. An 'in vitro' drug diffusion model is proposed to elucidate the drug release mechanism. Finally an 'in vivo' study was performed to evaluate the antibiotic release to the neighbouring bone sites.

Antibiotic-loaded polymeric bone cement is used in orthopedic surgery to deliver local high concentrations of antibiotics to the tissues. The precise mechanism by which antibiotic is released from the polymeric matrix is still not very well known. This research was conducted to investigate the in vitro drug release behavior of antibiotic from acrylic bone cement. A spectrophotometric method for the quantitative analysis of gentamicin sulfate using o-phtaldialdehyde as a derivatizing reagent was thoroughly validated, in order to assure a minimum quality level of the measures. The method proved to be quick, reliable, less expensive than methods such as polarization fluorescence immunoassay and others, and therefore more convenient for the routine analysis of the numerous samples generated during in vitro liberation assays. The release of gentamicin from commercial CMW1 acrylic bone cement samples was investigated following proposed in vitro release experiments.

Objective: To determine whether different methods of sterilization of antibiotic vials or the heat of polymerization altered the antimicrobial activity or mechanical properties of antibiotic/polymethylmethacrylate (PMMA) composites when compared to antibiotic-free PMMA., Study Design: In vitro study., Methods: Steam-sterilized, gas-sterilized, and non-sterilized 1 gram vials of cefazolin and injectable gentamicin sulfate (high and low doses) were mixed with PMMA to prepare composites for antibiotic elution evaluation, compression, and elongation testing. Blocks of PMMA that contained antibiotic were assayed for antibacterial activity using an agar gel diffusion method or were placed in phosphate buffered saline (PBS) to assess elution of antibiotic. Phosphate buffered saline samples from steam-sterilized cefazolin and high-dose gentamicin groups were assayed on days 1, 2, 5, and 9 for cefazolin or gentamicin concentration by high-pressure liquid chromatography or fluorescent polarization immunoassay, respectively., Results: PMMA blocks containing antibiotic inhibited bacterial growth of Staphylococcus aureus 25923 for an average of 9 days. Cefazolin and gentamicin concentration in PBS decreased dramatically after the first 24 hours, but remained above minimum inhibitory concentration (MIC) throughout the experiment for all groups except low-dose gentamicin. Compressive strength of plugs made from plain cement and plugs made from PMMA mixed with untreated and steam-sterilized cefazolin was similar, but was significantly different from the other groups. There appeared to be an inverse relationship between compressive strength and elongation., Conclusion: PMMA/antibiotic composites inhibited bacterial growth for 7 to 10 days. Compressive strength was affected by different additions of antibiotic., Clinical Relevance: Bacteria introduced during a surgical procedure may be inhibited by elution of antibiotic from PMMA at the time of contamination.

Bone cement containing gentamicin may release antibiotic when fractured during revision operations. Tissue samples taken during surgery may be contaminated by gentamicin and give inaccurate microbiological assessment. We studied five patients in whom cement containing gentamicin had been used in the primary procedure. During revision hip replacement, samples of joint fluid, tissues and cement were taken both before and after disruption of the cement. With the exception of one sample of joint fluid, low concentrations of gentamicin were recorded in the samples taken before the cement was disrupted, but after disruption the specimens contained gentamicin at concentrations high enough to inhibit or prevent growth of sensitive organisms. The cement contained very high levels up to ten years after insertion. Our findings suggest that no reliance can be placed on the microbiological assessment of specimens taken once cement splitting has started and that specimens should therefore be taken as early as possible.

Poly(methylmethacrylate) (PMMA) is a widely used material with both dental and orthopaedic applications. The acrylic cement is produced by the combination of polymethylacrylate beads with methylmethacrylate monomer. After polymerisation, a heterogeneous and porous matrix is formed which can be used to deliver therapeutic agents. In this work, the release of antibiotic, growth hormone and serum albumin is demonstrated. The mechanism is similar for all agents; a rapid release followed by a slow continuous release. The quantity of drug released depends upon the formulation of both the PMMA and the drug. The polymer-to-monomer ratio can greatly affect the ratio of drug release; increased polymer-to-monomer ratio leads to increased release of antibiotic. Optimum release is achieved if a crystalline formulation of the drug is used rather than a fine powder. Experimental methods to improve the drug release performance of bone cements are presented.