Periprosthetic joint infection (PJI) is a catastrophic adverse complication of joint arthroplasty. Both local and systemic antibiotic delivery are required for treatment of this refractory infection. Bone cement, a polymer named polymethyl methacrylate (PMMA), has been used for prothesis fixation of cemented joint arthroplasty since 1960. The cement fills gaps between the joint prosthesis and bone but has no antimicrobial capacity, and thus, the concept of antibiotic-loaded bone cement (ALBC) was introduced in 1970 by Buchholz and Engelbrecht to address this limitation. Although ALBC has been used for decades, recent studies have cast a shadow on its actual effectiveness. A retrospective study showed no decrease in infection rates with ALBC in primary total knee arthroplasty (TKA), while a similar study found that ALBC was associated with a significantly lower rate of revision caused by infection. Meta-analysis indicated that ALBC might be related to an increase in PJI risk in the early post-operative period of TKA, and the risk was lower in ALBC total hip arthroplasty (THA).[6,7] With the aging of the population, more patients receiving joint arthroplasty have high infection risk factors, such as obesity and diabetes. As a result of natural selection, highly resistant microbes, such as methicillin-resistant Staphylococcus aureus (MRSA), began to appear in PJI. All of the above factors call for a modified, more powerful ALBC. Based on associated papers in recent years, the purpose of this review was to introduce the latest progress in the antibiotic capacity, drug-elution properties, and mechanical performance of ALBC. New ideas for clinical application of ALBC will also be discussed.
Antimicrobial Capacities of Antibiotics in ALBC
According to a retrospective study based on 278 monomicrobial PJI cases from 2003 to 2017, the most frequent pathogens were Staphylococcus epidermidis (35%) and S. aureus (21%). So antibiotics against Staphylococcus are the most urgent need. Although simulation on dissolvable alginate beads still proved gentamycin's eradication ability towards Staphylococcus biofilm, this common choice in ALBC was being challenged by drug resistant microbes. An in vitro test of 93 Staphylococcus species obtained from PJI patients found a resistant percentage of 66%. Combination with other antibiotics was a possible choice. In double antibiotic beads containing gentamycin and daptomycin, vancomycin or ciprofloxacin, the minimal biofilm eradication concentration (MBEC) decreased, indicating enhancement of bioactivity. In contrast, the MBEC decreased when gentamycin was applied with rifampin, clindamycin, or linezolid. In another test, it was found that 40 g PMMA with 1.5 g daptomycin and 0.5 g gentamycin was the optimal choice for treatment of PJI caused by gram-positive bacteria. Changing of drug could be another ideal choice. As another classical antibiotic choice in ALBC, vancomycin was still effective towards some updated pathogen. During an in vitro comparative research towards MRSA, vancomycin group maintained the inhibition zone for 4 weeks. When compensated with vancomycin, daptomycin exhibited better resistance towards S. aureus in ALBC than vancomycin-linezolid group. Teicoplanin, an alternative for vancomycin, also scored an eradication rate of 96% (24/25) in a cohort study mainly composed by Staphylococcus PJIs. There are still other candidates. The combination of 4 g ceftazidime and 40 g PMMA showed antimicrobial effect to Staphylococcus in laboratory. When compensated with 3 wt% (weight percent) of ceftaroline (1.2 g drug in 40 g cement powder), a successor of ceftazidime, extraneous ALBC elution fluid can keep the drug dose above the MIC for MRSA for 6 weeks.
Fungi are rare but intractable pathogens of PJI. Brown et al found 31 fungal PJIs from 3525 PJI cases treated in their institution from 1996 to 2014. The survivorship of reinfection in 2 years was only 38% in hips and 76% in knees. Because of the inability of normal antibiotics, antifungal agent became a unique member of ALBC family. Plain amphotericin B showed strong mechanical performance when added in ALBC, but the drug elution was too low for clinical use. The elution characteristics were significantly improved when the ALBC was made of liposomal amphotericin B. Plain amphotericin with the help of a sodium deoxycholate or N-methyl-D-glucamine/palmitate carrier led to the same outcome. Both of the modified ALBCs showed resistance against Candida spp., with an insignificant influence on mechanical performance. Econazole and fluconazole also showed in vitro bioactivity towards Candida spp., while mechanical performance was also insufficient for weight-bearing use.[17,22]
Antibiotic Elution Kinetics of ALBC
Based on a systematic review of the current literature, there is sufficient elution of antibiotics after ALBC spacer implantation and at spacer removal. The exact mechanism of antibiotic elution from ALBC remains uncertain. Based on in vitro elution measurements, there is a hypothesis describing it as a bi-phasic process.[15,25,26] Antibiotics are usually premixed with the cement powder. After mixing with monomer liquid, a condensed cement layer forms with uniform distribution of the antibiotic particles. Particles distributed on the surface directly dissolve in body fluid, resulting in a short “burst elution” phase. Many more particles are present inside the matrix but have difficulty penetrating the hardened PMMA structure and thus are released in a slower “continuous elution” phase. The following factors may influence elution kinetics.
- (1) Kind of antibiotic: It is believed that total antibiotic release may be related to the chemical nature of the antibiotic, such as molecular size, electrical charge, and hydrophobic/hydrophilic character. When added at the same dose and incubated in the same in vitro environment, the antibiotics are released in the burst phase, and total elution ranks in the order of vancomycin < linezolid < daptomycin. Synergism between daptomycin and vancomycin can enhance the burst and total elution.In vitro tests found a synergistic effect with combinations of different types of drugs. For vancomycin, tobramycin, and gentamycin, the more antibiotic types that were added into PMMA, the higher the elution rate and amount were.
- (2) Dosage of antibiotic: Higher drug dosage in ALBC can promote drug elution. A significant enhancement of elution velocity and total amount were seen in vancomycin-loaded cement when the drug dose increased from 1 g per 40 g PMMA to 4 g. The similar phenomenon was observed in multi-drug ALBCs. In an in vitro test, the total release of each kind of drugs increased in both ciprofloxacin/meropenem and ciprofloxacin/ceftazidime ALBC. Another study about vancomycin and tobramycin combination showed that incorporation of 1 g vancomycin resulted in an approximately 38% increase of tobramycin elution. However, too much antibiotic could worse mechanical performance of cement and limit its application, which would be discussed below.
- (3) Methods of mixing: Various preparations may affect the elution of antibiotics from ALBC. In Frew's experiments, vancomycin-loaded ALBC was prepared using three procedures: “commercially prepared” (by the manufacturer), “manufacturer mixed” (homemade in accordance with the manufacturer's instructions), and “homemade” (all the drugs added into the cement powder at once). Then, the three cement groups were mixed and tested. In vitro experiments recorded the highest elution in the “homemade” group, likely the result of an increase in the porosity caused by clumping of vancomycin embedded in the cement. A long mixing time (mixing 90 s, doughing 30 s) significantly enhanced drug elution compared with a short mixing time (mixing 30 s, doughing 90 s) in gentamycin-loaded ALBC, and an obvious increase in total drug elution of 7 days was detected in the vacuum mixing group.
- (4) Environment temperature: Lower temperature extends the polymerization reaction, causing an increase of air pore collected in cement matrix. So, it will be easier for antibiotic particles to penetrate the cement. Tai et al found a higher proportion of vancomycin release from ALBC cured at 0°C than samples cured at 50°C. A relatively higher temperature could also benefit drug elution, Sundblad et al reported increase of drug elution in tobramycin/vancomycin loaded ALBC at both high (37°C) and low (8°C) polymerization temperature than room temperature. Frozen storage affected drug elution of ALBC. Compared with ALBC spacers stored in room temperature, the frozen stored sample showed no effect in drug elution and antimicrobial ability. On the contrary, low temperature was an optical environment for the preservation of prefabricated ALBC spacer. The degradation of drug was less than 1% after 3-month’ storage at −80°C in such spacer.
- (5) Thermogenesis of polymerization: The polymerization of PMMA is an exothermic reaction, and thus, it is believed that only “heat-stable” antibiotics could tolerate the partial high temperature caused by polymerization. An in vitro test for 38 frequently used antibiotic agents found aminoglycoside, glycopeptide, tetracycline, and quinolone as “heat-stable” and β-lactam as “heat-sensitive.” Carli et al conducted thorough research in this field. They measured temperatures of PMMA cured inside silicone molds of the distal femur and proximal tibia and then incubated vancomycin (representing “heat-stable”) and ceftazidime (representing “heat-sensitive”) in accordance with the temperature curves collected from molds. Finally, the MICs were tested in both groups. The results indicated that the MIC of ceftazidime increased by only two-fold and the bioactivity was reserved. Whether more “heat-sensitive” antibiotics could be utilized clinically should be further discussed.
- (6) Ultrasound sonication: Antibiotic remaining in cement can be released during sonication. Ultrasound sonication is a common way to promote solute dissolution in chemistry. A 6-week in vitro simulation test was performed with ALBC spacers produced with formulations used in clinical practice. The sonication was performed at 2, 4, and 6 weeks for 5 min at a frequency of 40 kHz. Antibiotic concentrations were determined every week. Compared with the control group, with sonication, there was an increase in elution of the antibiotics. Another study using different sonication times and frequencies demonstrated that a lower frequency and longer sonication time could benefit antibiotic elution, with a clinically acceptable mechanical performance.
Mechanical Performance of ALBC
Chemical bonds are formed during PMMA polymerization, determining the mechanical performance. However, antibiotic molecules do not generally take part in this reaction. For instance, in econazole-loaded ALBC, no compound except PMMA and econazole was detected via magnetic resonance spectroscopy. Due to the absence of strengthened bonds, antibiotics diminish the internal strength of cement, thus decreasing mechanical performance. In vitro tests showed a significant decline in the yield strength of ALBCs loaded with cefazolin, cefuroxime, ceftazidime, meropenem, vancomycin, gentamycin, and clindamycin at ratios used in clinical practice. Among them, gentamycin and clindamycin led to substantial decreases, resulting in failure to meet the threshold for weight-bearing use. With drug particles gradually leaving the cement, the remaining gaps become weak points in the structure and lead to initiation of cracks. After 2 weeks of incubation at 37°C in natural saline, the impact strength of gentamycin/vancomycin-loaded ALBC decreased by nearly 40%. An in vitro fatigue test to investigate gentamycin-loaded ALBC and plain PMMA found a difference in their fatigue crack propagation. Cracks began to propagate in ALBC specimens before its failure, showing slow growth with fatigue cycles. In contrast, cracks either did not appear to propagate or propagated extremely slowly in plain specimens until close to failure, ending with rapid crack propagation.
The following factors may influence mechanical performance.
- (1) Kind of antibiotic: Differences in chemical nature among various antibiotics influence changes in mechanical performances. The yield strength of 5wt% cefazolin-loaded ALBC was 85.43 MPa compared with 92.30 MPa in 5wt% ceftazidime-loaded cement. It is noteworthy that antibiotic molecules are radical scavengers, which inhibit polymerization. The most prominent example is hydroquinone in the rifampin structure. When rifampin is added, PMMA showed a serious reduction in compressive strength, with a prolonged setting time, decreased exothermic output in the curing process, and an increase in toxicity due to MMA monomer release, indicating incomplete polymerization.
- (2) Dosage of antibiotic: As a destroyer of cement structure, the more antibiotic molecules that are embedded, the worse the mechanical performance of ALBC is. An in vitro test of vancomycin showed a negative correlation between bending strength and antibiotic dose. In tobramycin, gentamycin, and vancomycin systems, an increase in both type and quantity significantly decreased the compressive and bending strength. Another study using tobramycin and vancomycin demonstrated the same phenomenon, along with a decrease in cement porosity, confirming degradation of the structure.
- (3) Physical state of the drug: In general, antibiotics are added into PMMA powder in the solid state, but some are added in the liquid state. The impact strength was reduced under the weight-bearing threshold with a mixture of 240 mg gentamycin solution and 40 g plain PMMA, while the strength was above the threshold with a mixture of 1 g gentamycin powder and 40 g PMMA.
ALBC Modification Additives
The inclusion of porogens to generate open porosity is considered an effective way to improve the elution behavior of cement. Carboxymethylcellulose successfully enhanced the porosity and bioactivity of econazole-loaded ALBC. Unfortunately, the compression strength was significantly decreased under the threshold necessary for weight-bearing applications. Hollow titanium dioxide nanotubes are also in this family and showed the same effect in gentamycin-loaded cement, retaining sufficient strength for use at weight-bearing sites.
Sustained drug release systems
Sustained drug release systems mediate slow but continuous drug elution via a changing elution profile. Daptomycin-loaded cement with poly D, L-lactic-co-glycolic acid copolymer (PLGA) exhibited altered elution profiles. In the initial stage, a moderate burst (close to 10%) was still observed in the first 3 h. Then, a progressive elution in the next 35 days was observed, followed by a sudden elution increase, which was prolonged in the following 20 days. This change might be ascribed to biodegradation of the inner PLGA microparticles. Overall, PLGA obviously enhanced release of the drug.[15,47] Silicon dioxide nanoparticles can also act as drug carriers. In vitro experiments investigating this additive showed an increase in the drug release rate, total elution, and antimicrobial activity, with no significant changes in mechanical performance or biocompatibility.[48–50] Calcium polyphosphate, an analog of bone tissue, extended the elution time, with a significant decrease in the initial elution and maintenance of bioactivity. When coated on PMMA in combination with alginate-chitosan nanoparticles, vancomycin prolonged drug elution for 60 days. Rifampin-filled β-cyclodextrin particles achieved a longer effect time but no longer met the weight-bearing standard. To modify the characteristics, microcapsules of rifampicin containing alginate, polyhydroxybutyratehydroxyvalerate, ethyl cellulose and stearic acid were introduced. They relieved the mechanical antimicrobial activity of ALBC and improved the compression strength. Personalized drug release systems are designed for particular conditions. According to Ikeda design, a vancomycin-loaded calcium phosphate cement core was embedded in a PMMA shell with prefabricated holes. In vitro experiments verified its superiority in antibiotic elution time and bioactivity compared with conventional ALBC spacers.
Inorganic antimicrobial agents
The history of inorganic antimicrobial agent was even longer than antibiotics. Some of them were still ideal candidates for cement additive. Silver is the most famous antibacterial metal. The development of nanotechnology made it possible to apply silver into PMMA without severe damage of physical properties. When incorporated with silver nanoparticles, this complex cement demonstrated substantially no difference in mechanical and material properties. In test against S. epidermidis, the cement showed significant ability of biofilm eradication. NanoSilver, PMMA loaded with metallic silver nanoparticles, showed high-antibacterial activity against MRSA and methicillin-resistant S. epidermidis with no significant cytotoxicity towards osteoblast. Silver nanoparticles capped with tiopronin showed similar characters when encapsulated in bone cement. Copper is another type of antibacterial material. Copper-doped bioactive glass powder appeared well distribution in PMMA. The copper-doped cement showed good bioactivity, released a significant amount of copper in simulated body fluid.
Although many researches illustrated a promising future of inorganic antibacterial material, there were also some studies reporting negative results. During in vivo tests on S. aureus contaminated rabbit femur model, bone cement with 0.6% or 1% silver did not show better bioactivity than tobramycin-loaded ALBC, because silver could only kill pathogens on cement surface and was useless for pathogens in surrounding tissues. The toxicity of heavy metal element could be another potential danger for metallic antimicrobial agents like copper.
Organic antimicrobial agents
Despite antibiotics, some organic antimicrobial materials were also suitable for bone cement. Quaternary ammonium monomers with N-alkyl chain lengths varying from 6 to 18, namely, MEIM-x (x = 6–18), have shown significant antibacterial activity. Under laboratory conditions, x ≥ 10 was recognized as a prerequisite for adequate bioactivity, and at that time, 2wt% was enough for bioactivity. This compound inhibits polymerization and endures through the hardening time. However, a minor effect on mechanical performance and biocompatibility was seen in tests. An antimicrobial quaternary ammonium dendrimer containing iodine was found to have an in vitro antimicrobial effect towards gram-positive bacteria within 30 days at a dose of 10%. When added in osteomyelitis models generated through damage to the femoral head, bone cement with short, linear, α-helical antimicrobial peptides added showed inhibitory activity against biofilm formation. The elution fluid of ozonized sunflower oil-loaded PMMA collected in the first 24 h inhibited the growth of Pseudomonas aeruginosa for 20 h. Nature organics, such as blood and synovial fluid, were also applied into bone cement. In vitro tests showed inhibition of drug release from cement beads coated with heparin coagulative blood or synovial fluid, but the total release was not influenced.
Clinical Applications of ALBC
Application of multiple antibiotics broadens the antimicrobial spectrum but leads to defects in mechanical performance, and thus, this type of ALBC is usually used as beads or spacers. Hsu et al produced bone cement specimens loaded with 4 g of either vancomycin or teicoplanin and 4 g of ceftazidime, imipenem or aztreonam and then measured the in vitro elution characteristics and antibacterial capacities of the specimens. The most effective combination was implanted into eight chronic PJI patients to assess in vivo drug dose and bioactivity. Vancomycin and ceftazidime, the elected best choice, exhibited good capacities in both the laboratory and clinical practice. In another prospective study investigating gentamycin-clindamycin loaded cement, 32 subjects were divided into two groups: PJI patients underwent a one-stage exchange, and aseptic loosening patients underwent revision or primary arthroplasty but were considered at high risk for infection. At the end of a 5-year follow-up, no reinfection was found. A retrospective study on daptomycin- and tobramycin-loaded cement reported a cure rate of 92% (11/12) for patients who had any MRSA infection during the evaluation period compared with 62% (13/21) for patients with MSSA. The difference might stem from systemic use of antibiotics that could not be balanced in this type of trial. An improvement in daptomycin release in joint fluid was also seen with the presence of tobramycin.
ALBC spacers play an important role in revision of PJI. As mentioned above, antibiotics primarily decrease the mechanical performance of cement, which could lead to mechanical failures, such as spacer dislocation, spacer fracture, and femoral fracture. According to a retrospective study, 45% (14/31) of patients suffered at least one spacer-related mechanical complication in the interim period, and patients who had mechanical complications were younger than those without mechanical complications. Chronic infection and utilization of the posterior approach were risk factors for the development of spacer-related complications according to univariate analysis. Various methods have been applied to improve the performance of spacers. Commercial gentamycin-loaded cement spacers fixed with vancomycin-gentamycin ALBC were tried in revision TKA in one cohort study. Within a mean follow-up time of 74.1 months, the average time from spacer implantation to prosthesis reimplantation was 9.1 months (range of 3–27 months). The mean American Knee Society Score improved from 68.4 pre-operatively (range of 34–108) to 112.7 at the final follow-up examination (range of 49–180). The average range of motion improved from 40.1 degrees (range of 6–90 degrees) to 79.3 degrees (range of 45–125 degrees). There are some studies on personal spacer designs. Stainless intramedullary rods were implanted to enforce spacers in infected TKA cases with extensive bone loss. The rate of success for the first reimplantation was 77% (75/97). Pathogen cultures of the spacer rods were positive in two cases, but none of them failed. A custom-made spacer template was created by applying dental silicone on the surface of a bipolar femoral prothesis with the proper size, and then, ALBC was used to fill the template to complete the spacer. No recurrence was detected among patients receiving the spacer. Another retrospective study comparing the outcomes of commercial spacers, hand-made spacers and a hand-made tibial spacer with reimplantation of a sterile femoral component in infectious revisions of TKA resulted in no significant differences among the three groups, and the lowest financial cost was recorded for the hand-made spacer group. A new spacer technique called “ENDO technique” was introduced by Lausmann et al The technique involves a dual mobility liner and a downsized stainless cemented straight stem fixed with ALBC in a “deliberately poor cementing technique” (covering only the proximal 4/5 of the stem). Data from a retrospective study of 30 cases showed a mean spacer duration time of 53.6 days (ranging from 14 to 288 days). The incidence of spacer-related complications was 6.7% (2/30), and the Harris hip score was significantly improved from 34.0 (ranging from 3 to 62) to 48.1 (ranging from 11 to 73) (P = 0.0008).
Partial revision simplifies some steps of the conventional two-stage revision and retains the original uninfected prosthesis components; thus, more bone resource can be restored with less time of operation. There are two surgical techniques for partial revision.
The first is retainment of an ALBC spacer as a prosthesis in a one-stage operation. A simulation test demonstrated the wear-resistance of an ALBC spacer after a cyclic test on a knee wear simulator for 500,000 walking cycles. Examinations of prolonged implanted vancomycin-PMMA intramedullary rods (117 days) and beads (210 days) found them effective for P. aeruginosa and S. aureus. The ALBC spacer was found to be an optional successor for an infected prosthesis. Beaupre et al measured the health-related quality of life (HRQL) of patients who received a revision THA. It was found that improvements in the HRQL appeared 3 to 6 months after spacer implantation. Patients desiring better motion capacity (7 of 22 patients) received a second-stage operation after 24 months, while others kept the spacer. A 24-month follow-up found no significant difference between the two groups (P > 0.32), and thus, one-stage revision using ALBC showed the same effect in low-activity need patients. In Lee's retrospective study, the eradication rate for one-stage revision (92.3%) was slightly lower than that for the two-stage revision (94.9%). Similar differences were found in Visual Analogue Score (VAS) and Harris scores. However, motion abilities showed no difference between the two groups. Researchers concluded that a two-stage revision was still a standard option but a one-stage revision is suitable for patients of advanced age or who were unable to receive the standard revision.
The second is preservation of some prosthesis components. Chen et al conducted a prospective study of partial revision in chronic PJI patients of biotype THA. During the first surgical stage, they retained the stem or cup that was unable to be removed and replaced others with ALBC spacers. The second stage was conducted when infection was controlled. At a mean follow-up time of 5 years, the infection cure rate was 81.3% (13/16), and two of the remaining three patients received further prosthesis-removing surgery due to detection of high-virulence organisms. This type of operation is only recommended for those who are not immunocompromised and are infected with a low-virulence organism. Crawford et al applied hand-made or commercial ALBC acetabular spacers in patients with chronic PJI and failed to remove the femoral component. A retrospective review reported that 95% (39/41) of patients received implantation of a new acetabular component in an average period of 9.2 weeks, and two cases received a two-stage revision. If the failure was defined as infection recurrence, Kaplan-Meier survival was 77% at a mean follow-up time of 5.5 years.
Although partial revision can benefit subjects with severe complications (ie, advanced aged or osteoporosis) by minimizing surgical trauma and accelerating post-operative recovery, special attention should be paid during the treatment. (1) ALBC can never take the place of systemic antimicrobial treatment. Animal experiments confirmed the effect of ALBC only within the joint space, and the placement of a spacer without the auxiliary step could not eradicate pathogens in a murine osteomyelitis model. A prospective study in humans measured a serum drug dose lower than the effective threshold in the first 6 months after implantation of vancomycin-loaded ALBC, regardless of the prevention or treatment dose used. Based on these discoveries, it is necessary for ALBC to be applied in conjunction with systemic antibiotic treatment. (2) The risk of hepatic or renal defection should be considered. Edelstein et al conducted prospective studies in primary revisions using ALBC spacers containing vancomycin, gentamycin, or tobramycin. The results suggested a detectable serum dose of drugs 8 weeks after implantation. The risk factors for an increased vancomycin dose include diabetes, high blood urea nitrogen, a high amount of ALBC, and systemic drug delivery. In another group of 37 patients, during the 8 weeks after ALBC spacer implantation, ten patients (27%) fitted risk, injury, failure, loss, end-stage kidney disease (RIFLE) criteria for kidney injury, and two patients (5%) fitted the criteria for kidney failure.[83,84]
In conclusion, the application of antibiotics in bone cement has been broadly regarded as a simple and economic cure for PJI and other orthopedic infections. As a classical filler and fixture, ALBC is continuously being used for new applications. Meropenem or ceftazidime ALBCs have been used to treat melioidosis of the musculoskeletal system. Multi-antibiotic-loaded cement played an essential role in application of a total femur spacer and filling.[86,87] New bone defect filling and cement fixation techniques are still being designed.[88–91] Some questions have developed in the process and remain unsolved. For instance, one prospective study found an increase in immunological factors (ie, soluble interleukin-6 [SIL-6] and C-reactive protein [CRP]) in gentamycin-loaded cement implant patients, which may indicate that unknown immunomodulatory pathways are altered by ALBC. In response to the increasing achievements in medical and material science, further researches should be conducted to investigate the antimicrobial bioactivity, pharmaceutical elution, and mechanical enhancement activity of ALBC. Therefore, more options will be provided to surgeons, which will contribute to the lifespan of joint prostheses and improve post-operative quality of life.
This study was supported by a grant from the Beijing Municipal Science and Technology Project (No. Z171100000417024).
Conflicts of interest
1. Otto-Lambertz C, Yagdiran A, Wallscheid F, Eysel P, Jung N. Periprosthetic Infection in Joint Replacement. Dtsch Arztebl Int
2017; 114:347–353. doi: 10.3238/arztebl.2017.0347.
2. Charnley J. The bonding of prostheses to bone by cement. J Bone Joint Surg Br
1964; 46-B:518–529. doi: 10.1302/0301-620X.46B3.518.
3. Buchholz HW, Engelbrecht H. Uber die Depotwirkung einiger Antibiotica bei Vermischung mit dem Kunstharz Palacos. Chirurg
4. Anis HK, Sodhi N, Faour M, Klika AK, Mont MA, Barsoum WK, et al. Effect of antibiotic
-impregnated bone cement
in primary total knee arthroplasty. J Arthroplasty
2019; 34:2091–2095. doi: 10.1016/j.arth.2019.04.033.
5. Jameson SS, Asaad A, Diament M, Kasim A, Bigirumurame T, Baker P, et al. Antibiotic
-loaded bone cement
is associated with a lower risk of revision following primary cemented total knee arthroplasty: an analysis of 731 214 cases using national joint registry data. Bone Joint J
2019; 101B:1331–1347. doi: 10.1302/0301-620x.101b11.Bjj-2019-0196.R1.
6. Kunutsor SK, Beswick AD, Whitehouse MR, Blom AW, Lenguerrand E. Implant fixation and risk of prosthetic joint infection following primary total hip replacement: meta-analysis of observational cohort and randomised intervention studies. J Clin Med
2019; 8:722–737. doi: 10.3390/jcm8050722.
7. Kunutsor SK, Wylde V, Whitehouse MR, Beswick AD, Lenguerrand E, Blom AW. Influence of fixation methods on prosthetic joint infection following primary total knee replacement: meta-analysis of observational cohort and randomised intervention studies. J Clin Med
2019; 8:828–843. doi: 10.3390/jcm8060828.
8. Blanco JF, Diaz A, Melchor FR, da Casa C, Pescador D. Risk factors for periprosthetic joint infection after total knee arthroplasty. Arch Orthop Trauma Surg
2020; 140:239–245. doi: 10.1007/s00402-019-03304-6.
9. Rosteius T, Jansen O, Fehmer T, Baecker H, Citak M, Schildhauer TA, et al. Evaluating the microbial pattern of periprosthetic joint infections of the hip and knee. J Med Microbiol
2018; 67:1608–1613. doi: 10.1099/jmm.0.000835.
10. Flurin L, Greenwood-Quaintance KE, Patel R. Microbiology of polymicrobial prosthetic joint infection. Diagn Microbiol Infect Dis
2019; 94:255–259. doi: 10.1016/j.diagmicrobio.2019.01.006.
11. Dall GF, Tsang STJ, Gwynne PJ, MacKenzie SP, Simpson A, Breusch SJ, et al. Unexpected synergistic and antagonistic antibiotic
activity against Staphylococcus biofilms. J Antimicrob Chemother
2018; 73:1830–1840. doi: 10.1093/jac/dky087.
12. Anguita-Alonso P, Hanssen AD, Osmon DR, Trampuz A, Steckelberg JM, Patel R. High rate of aminoglycoside resistance among staphylococci causing prosthetic joint infection. Clin Orthop Relat Res
2005; 439:43–47. doi: 10.1097/01.blo.0000182394.39601.9d.
13. Eick S, Hofpeter K, Sculean A, Ender C, Klimas S, Vogt S, et al. Activity of fosfomycin- and daptomycin-containing bone cement
on selected bacterial species being associated with orthopedic infections. Biomed Res Int
2017; 2017:2318174doi: 10.1155/2017/2318174.
14. Yuenyongviwat V, Ingviya N, Pathaburee P, Tangtrakulwanich B. Inhibitory effects of vancomycin and fosfomycin on methicillin-resistant Staphylococcus aureus
-impregnated articulating cement spacers. Bone Joint Res
2017; 6:132–136. doi: 10.1302/2046-3758.63.2000639.
15. Parra-Ruiz FJ, Gonzalez-Gomez A, Fernandez-Gutierrez M, Parra J, Garcia-Garcia J, Azuara G, et al. Development of advanced biantibiotic loaded bone cement
spacers for arthroplasty associated infections. Int J Pharm
2017; 522:11–20. doi: 10.1016/j.ijpharm.2017.02.066.
16. Buyuk AF, Sofu H, Camurcu IY, Ucpunar H, Kaygusuz MA, Sahin V. Can teicoplanin be an effective choice for antibiotic
-impregnated cement spacer in two-stage revision total knee arthroplasty? J Knee Surg
2017; 30:283–288. doi: 10.1055/s-0036-1584535.
17. Martinez-Moreno J, Merino V, Nacher A, Rodrigo JL, Yuste BBB, Merino-Sanjuan M. Bioactivity of ceftazidime and fluconazole included in polymethyl methacrylate bone cement
for use in arthroplasty. J Arthroplasty
2017; 32:3126–3133. doi: 10.1016/j.arth.2017.04.057.
18. Haseeb A, Ajit Singh V, Teh CSJ, Loke MF. Addition of ceftaroline fosamil or vancomycin to PMMA: an in vitro comparison of biomechanical properties and anti-MRSA efficacy. J Orthop Surg (Hong Kong)
2019; 27:1–9. doi: 10.1177/2309499019850324.
19. Brown TS, Petis SM, Osmon DR, Mabry TM, Berry DJ, Hanssen AD, et al. Periprosthetic joint infection with fungal pathogens. J Arthroplasty
2018; 33:2605–2612. doi: 10.1016/j.arth.2018.03.003.
20. Goss B, Lutton C, Weinrauch P, Jabur M, Gillett G, Crawford R. Elution and mechanical properties of antifungal bone cement
. J Arthroplasty
2007; 22:902–908. doi: 10.1016/j.arth.2006.09.013.
21. Czuban M, Wulsten D, Wang L, Di Luca M, Trampuz A. Release of different amphotericin B formulations from PMMA bone cements and their activity against Candida biofilm. Colloids Surf B Biointerfaces
2019; 183:110406doi: 10.1016/j.colsurfb.2019.110406.
22. Tatara AM, Rozich AJ, Kontoyiannis PD, Watson E, Albert ND, Bennett GN, et al. Econazole-releasing porous space maintainers for fungal periprosthetic joint infection. JMSMM
2018; 29:70–80. doi: 10.1007/s10856-018-6073-1.
23. Anagnostakos K, Meyer C. Antibiotic
elution from hip and knee acrylic bone cement
spacers: a systematic review. Biomed Res Int
2017; 2017:4657874doi: 10.1155/2017/4657874.
24. Atici T, Sahin N, Cavun S, Ozakin C, Kaleli T. Antibiotic
release and antibacterial efficacy in cement spacers and cement beads impregnated with different techniques: in vitro study. Eklem Hastalik Cerrahisi
2018; 29:71–78. doi: 10.5606/ehc.2018.59021.
25. Kummer A, Tafin UF, Borens O. Effect of sonication on the elution of antibiotics from polymethyl methacrylate
(PMMA). J Bone Joint Infect
2017; 2:208–212. doi: 10.7150/jbji.22443.
26. Alonso LM, Ruiz APM, Flores JAM, Herrera DLR, Garcia OR, Lozano OEL, et al. Evaluation of acrylic bone cements with single and combined antibiotics: release behavior and in vitro antibacterial effectiveness. Int J Polym Mater Po
2018; 67:830–838. doi: 10.1080/00914037.2017.1383250.
27. Cacciola G, De Meo F, Cavaliere P. Mechanical and elution properties of G3 low viscosity bone cement
loaded up to three antibiotics. J Orthop
2018; 15:1004–1007. doi: 10.1016/j.jor.2018.08.035.
28. Lee SH, Tai CL, Chen SY, Chang CH, Chang YH, Hsieh PH. Elution and mechanical strength of vancomycin-loaded bone cement
: in vitro study of the influence of brand combination. PLoS One
2016; 11:e0166545doi: 10.1371/journal.pone.0166545.
29. Slane J, Gietman B, Squire M. Antibiotic
elution from acrylic bone cement
loaded with high doses of tobramycin and vancomycin. J Orth Res
2018; 36:1078–1085. doi: 10.1002/jor.23722.
30. Frew NM, Cannon T, Nichol T, Smith TJ, Stockley I. Comparison of the elution properties of commercially available gentamicin and bone cement
containing vancomycin with ’homemade’ preparations. Bone Joint J
2017; 99-B:73–77. doi: 10.1302/0301-620X.99B1.BJJ-2016-0566.R1.
31. Mooney JA, Manasherob R, Smeriglio P, Bhutani N, Amanatullah DF. Effect of trabecular metal on the elution of gentamicin from Palacos cement. J Orth Res
2019; 37:1018–1024. doi: 10.1002/jor.24274.
32. Tai CL, Tsai SL, Chang YH, Hsieh PH. Study the effect of polymerization temperature in the release of antibiotic
from bone cement
. Biomed Mater Eng
2011; 21:341–346. doi: 10.3233/bme-2012-0681.
33. Sundblad J, Nixon M, Jackson N, Vaidya R, Markel D. Altering polymerization temperature of antibiotic
-laden cement can increase porosity and subsequent antibiotic
elution. Int Orthop
2018; 42:2627–2632. doi: 10.1007/s00264-018-4135-0.
34. Chen DW, Chang Y, Hsieh PH, Ueng SW, Lee MS. The influence of storage temperature on the antibiotic
release of vancomycin-loaded polymethylmethacrylate. ScientificWorldJournal
2013; 2013:573526doi: 10.1155/2013/573526.
35. Chang Y, Chen WC, Hsieh PH, Chen DW, Lee MS, Shih HN, et al. In vitro activities of daptomycin-, vancomycin-, and teicoplanin-loaded polymethylmethacrylate against methicillin-susceptible, methicillin-resistant, and vancomycin-intermediate strains of Staphylococcus aureus
. Antimicrob Agents Chemother
2011; 55:5480–5484. doi: 10.1128/aac.05312-11.
36. Kurata K, Matsushita J, Furuno A, Fujino J, Takamatsu H. Assessment of thermal damage in total knee arthroplasty using an osteocyte injury model. J Orth Res
2017; 35:2799–2807. doi: 10.1002/jor.23600.
37. Samara E, Moriarty TF, Decosterd LA, Richards RG, Gautier E, Wahl P. Antibiotic
stability over six weeks in aqueous solution at body temperature with and without heat treatment that mimics the curing of bone cement
. Bone Joint Res
2017; 6:296–306. doi: 10.1302/2046-3758.65.Bjr-2017-0276.R1.
38. Carli AV, Sethuraman AS, Bhimani SJ, Ross FP, Bostrom MPG. Selected heat-sensitive antibiotics are not inactivated during polymethylmethacrylate curing and can be used in cement spacers for periprosthetic joint infection. J Arthroplasty
2018; 33:1930–1935. doi: 10.1016/j.arth.2018.01.034.
39. Clauss M, Laschkolnig E, Graf S, Kuhn KD. Influence of sonication on bacterial regrowth from antibiotic
loaded PMMA scaffolds - an in-vitro study. J Bone Joint Infect
2017; 2:213–217. doi: 10.7150/jbji.22382.
40. Wendling AC, Mar DE, Burkes JC, McIff TE. Effect of ultrasound frequency and treatment duration on antibiotic
elution from polymethylmethacrylate bone cement
. Kans J Med
2019; 12:45–49. doi: 10.17161/kjm.v12i2.11703.
41. Fleaca R, Mitariu SIC, Oleksik V, Oleksik M, Roman M. Mechanical behaviour of orthopaedic cement loaded with antibiotics in the operation room. Mater Plast
2017; 54:402–407. doi: 10.1155/2013/573526.
42. Kalantari M, Hashemi A. Effect of antibiotics augmentation and storage condition on impact resistance of orthopedic bone cement
. J Mech Med Biol
2017; 17:1750019doi: 10.1142/s0219519417500191.
43. Sheafi EM, Tanner KE. Relationship between fatigue parameters and fatigue crack growth in PMMA bone cement
2019; 120:319–328. doi: 10.1016/j.ijfatigue.2018.11.013.
44. Funk GA, Menuey EM, Cole KA, Schuman TP, Kilway KV, McIff TE. Radical scavenging of poly (methyl methacrylate) bone cement
by rifampin and clinically relevant properties of the rifampin-loaded cement. Bone Joint Res
2019; 8:81–89. doi: 10.1302/2046-3758.82.Bjr-2018-0170.R2.
45. Singh VA, Haw BC, Haseeb A, Teh CSJ. Hand-mixed vancomycin versus commercial tobramycin cement revisited: a study on mechanical and antibacterial properties. J Orthop Surg (Hong Kong)
2019; 27:1–9. doi: 10.1177/2309499019839616.
46. Shen SC, Letchmanan K, Chow PS, Tan RBH. Antibiotic
elution and mechanical property of TiO2 nanotubes functionalized PMMA-based bone cements. J Mech Behav Biomed Mater
2019; 91:91–98. doi: 10.1016/j.jmbbm.2018.11.020.
47. Chen KH, Tsai SW, Wu PK, Chen CF, Wang HY, Chen WM. Partial component-retained two-stage reconstruction for chronic infection after uncemented total hip arthroplasty: results of sixteen cases after five years of follow-up. Int Orthop
2017; 41:2479–2486. doi: 10.1007/s00264-017-3505-3.
48. Letchmanan K, Shen SC, Ng WK, Kingshuk P, Shi ZL, Wang W, et al. Mechanical properties and antibiotic
release characteristics of poly (methyl methacrylate)-based bone cement
formulated with mesoporous silica nanoparticles. J Mech Behav Biomed Mater
2017; 72:163–170. doi: 10.1016/j.jmbbm.2017.05.003.
49. Al Thaher Y, Yang LR, Jones SA, Perni S, Prokopovich P. LbL-assembled gentamicin delivery system for PMMA bone cements to prolong antimicrobial activity. PLoS One
2018; 13:e0207753doi: 10.1371/journal.pone.0207753.
50. Perni S, Caserta S, Pasquino R, Jones SA, Prokopovich P. Prolonged antimicrobial activity of PMMA bone cement
with embedded gentamicin-releasing silica nanocarriers. ACS Appl Bio Mater
2019; 2:1850–1861. doi: 10.1021/acsabm.8b00752.
51. Zhou ZB, Seta J, Markel DC, Song W, Yurgelevic SM, Yu XW, et al. Release of vancomycin and tobramycin from polymethylmethacrylate cements impregnated with calcium polyphosphate hydrogel. J Biomed Mater Res B Appl Biomater
2018; 106:2827–2840. doi: 10.1002/jbm.b.34063.
52. Asik MD, Kaplan M, Yalinay M, Guven EO, Bozkurt M. Development of a sequential antibiotic
releasing system for two-stage total joint replacement surgery. J Biomed Nanotechnol
2019; 15:2193–2201. doi: 10.1166/jbn.2019.2850.
53. Cyphert EL, Lu CY, Marques DW, Learn GD, Von Recum HA. Combination antibiotic
delivery in PMMA provides sustained broad-spectrum antimicrobial activity and allows for postimplantation refilling. Biomacromolecules
2020; 21:854–866. doi: 10.1021/acs.biomac.9b01523.
54. Sanz-Ruiz P, Carbó-Laso E, Del Real-Romero JC, Arán-Ais F, Ballesteros-Iglesias Y, Paz-Jiménez E, et al. Microencapsulation of rifampicin: a technique to preserve the mechanical properties of bone cement
. J Orthop Res
2018; 36:459–466. doi: 10.1002/jor.23614.
55. Ikeda S, Uchiyama K, Minegishi Y, Ohno K, Nakamura M, Yoshida K, et al. Double-layered antibiotic
-loaded cement spacer as a novel alternative for managing periprosthetic joint infection: an in vitro study. J Orthop Surg Res
2018; 13:322–330. doi: 10.1186/s13018-018-1033-5.
56. Slane J, Vivanco J, Rose W, Ploeg HL, Squire M. Mechanical, material, and antimicrobial properties of acrylic bone cement
impregnated with silver nanoparticles. Mater Sci Eng C Mater Biol Appl
2015; 48:188–196. doi: 10.1016/j.msec.2014.11.068.
57. Alt V, Rupp M, Lemberger K, Bechert T, Konradt T, Steinrücke P, et al. Safety assessment of microsilver-loaded poly (methyl methacrylate) (pMMA) cement spacers in patients with prosthetic hip infections: results of a prospective cohort study. Bone Joint Res
2019; 8:387–396. doi: 10.1302/2046-3758.88.BJR-2018-0270.R1.
58. Prokopovich P, Leech R, Carmalt CJ, Parkin IP, Perni S. A novel bone cement
impregnated with silver-tiopronin nanoparticles: its antimicrobial, cytotoxic, and mechanical properties. Int J Nanomedicine
2013; 8:2227–2237. doi: 10.2147/ijn.S42822.
59. Miola M, Cochis A, Kumar A, Arciola CR, Rimondini L, Verne E. Copper-doped bioactive glass as filler for PMMA-based bone cements: morphological, mechanical, reactivity, and preliminary antibacterial characterization. Materials
2018; 11:961doi: 10.3390/ma11060961.
60. Moojen DJ, Vogely HC, Fleer A, Verbout AJ, Castelein RM, Dhert WJ. No efficacy of silver bone cement
in the prevention of methicillin-sensitive Staphylococcal infections in a rabbit contaminated implant bed model. J Orthop Res
2009; 27:1002–1007. doi: 10.1002/jor.20854.
61. Zhu WB, Liu F, He JW. Effect of polymerizable quaternary ammonium monomer MEIM-x's alkyl chain length and content on bone cement
's antibacterial activity and Cheek for physicochemical properties. J Mech Behav Biomed Mater
2018; 87:279–287. doi: 10.1016/j.jmbbm.2018.08.004.
62. Abid CK, Jain S, Jackeray R, Chattopadhyay S, Singh H. Formulation and characterization of antimicrobial quaternary ammonium dendrimer in poly (methyl methcarylate) bone cement
. J Biomed Mater Res B Appl Biomater
2017; 105:521–530. doi: 10.1002/jbm.b.33553.
63. Melicherčík P, Nešuta O, Čeřovský V. Antimicrobial peptides for topical treatment of osteomyelitis and implant-related infections: study in the spongy bone. Pharmaceuticals (Basel)
2018; 11:E20doi: 10.3390/ph11010020.
64. Alonso LM, Torres IF, Tamayo ÁMZ, Lozano OEL, Ramos ID, García-Menocal JÁD, et al. Antibacterial effect of acrylic bone cements loaded with drugs of different action's mechanism. J Infect Dev Ctries
2019; 13:487–495. doi: 10.3855/jidc.10716.
65. Dusane DH, Diamond SM, Knecht CS, Farrar NR, Peters C, Howlin RP, et al. Effects of loading concentration, blood and synovial fluid on antibiotic
release and anti-biofilm activity of bone cement
beads. J Controlled Release
2017; 248:24–32. doi: 10.1016/j.jconrel.2017.01.005.
66. Hsu YH, Hu CC, Hsieh PH, Shih HN, Ueng SWN, Chang YH. Vancomycin and ceftazidime in bone cement
as a potentially effective treatment for knee periprosthetic joint infection. J Bone Joint Surg Am
2017; 99:223–231. doi: 10.2106/jbjs.16.00290.
67. Abdelaziz H, von Förster G, Kühn KD, Gehrke T, Citak M. Minimum 5 years’ follow-up after gentamicin- and clindamycinloaded PMMA cement in total joint arthroplasty. J Med Microbiol
2019; 68:475–479. doi: 10.1099/jmm.0.000895.
68. Jagadale V, Achilike R, Nord KM. Daptomycin-tobramycin cement beads have lethal local antibacterial effect in resistant periprosthetic joint infections. Curēus
2019; 11:e5726doi: 10.7759/cureus.5726.
69. Yang FS, Lu YD, Wu CT, Blevins K, Lee MS, Kuo FC. Mechanical failure of articulating polymethylmethacrylate (PMMA) spacers in two-stage revision hip arthroplasty: the risk factors and the impact on interim function. BMC Musculoskel Disord
2019; 20:372–382. doi: 10.1186/s12891-019-2759-x.
70. Vecchini E, Micheloni GM, Perusi F, Scaglia M, Maluta T, Lavini F, et al. Antibiotic
-loaded spacer for two-stage revision of infected total knee arthroplasty. J Knee Surg
2017; 30:231–237. doi: 10.1055/s-0036-1584190.
71. Hipfl C, Winkler T, Janz V, Perka C, Müller M. Management of chronically infected total knee arthroplasty with severe bone loss using static spacers with intramedullary rods. J Arthroplasty
2019; 34:1462–1469. doi: 10.1016/j.arth.2019.03.053.
72. Ohtsuru T, Morita Y, Murata Y, Munakata Y, Itoh M, Kato Y, et al. Custom-made, antibiotic
-loaded, acrylic cement spacers using a dental silicone template for treatment of infected hip prostheses. Eur J Orthop Surg Traumatol
2018; 28:615–620. doi: 10.1007/s00590-017-2117-3.
73. Nodzo SR, Boyle KK, Spiro S, Nocon AA, Miller AO, Westrich GH. Success rates, characteristics, and costs of articulating antibiotic
spacers for total knee periprosthetic joint infection. Knee
2017; 24:1175–1181. doi: 10.1016/j.knee.2017.05.016.
74. Lausmann C, Citak M, Hessling U, Wolff M, Gehrke T, Suero EM, et al. Preliminary results of a novel spacer technique in the management of septic revision hip arthroplasty. Arch Orthop Trauma Surg
2018; 138:1617–1622. doi: 10.1007/s00402-018-3038-2.
75. Affatato S, Foroni F, Merola M, Baldacci F. Preliminary results of the tribological performance of new modular temporary knee spacer antibiotic
-impregnated. J Mech Behav Biomed Mater
2019; 95:205–209. doi: 10.1016/j.jmbbm.2019.04.009.
76. Swearingen MC, Granger JF, Sullivan A, Stoodley P. Elution of antibiotics from poly (methyl methacrylate) bone cement
after extended implantation does not necessarily clear the infection despite susceptibility of the clinical isolates. Pathog Dis
2018; 74:ftv103doi: 10.1093/femspd/ftv103.
77. Beaupre LA, Stampe K, Masson E, O’connor G, Clark M, Joffe AM, et al. Health-related quality of life with long-term retention of the PROSthesis of antibiotic
loaded acrylic cement system following infection resolution in low demand patients. J Orthop Surg (Hong Kong)
2017; 25:1–7. doi: 10.1177/2309499017716257.
78. Lee WY, Hwang DS, Kang C, Shin BK, Zheng L. Usefulness of prosthesis made of antibiotic
-loaded acrylic cement as an alternative implant in older patients with medical problems and periprosthetic hip infections: a 2- to 10-year follow-up study. J Arthroplasty
2017; 32:228–233. doi: 10.1016/j.arth.2016.06.011.
79. Crawford DA, Adams JB, Morris MJ, Berend KR, Lombardi AV. Partial 2-stage exchange for infected total hip arthroplasty: an updated report. J Arthroplasty
2019; 34:3048–3053. doi: 10.1016/j.arth.2019.07.001.
80. Carli AV, Bhimani S, Yang X, de Mesy Bentley KL, Ross FP, Bostrom MPG. Vancomycin-loaded polymethylmethacrylate spacers fail to eradicate periprosthetic joint infection in a clinically representative mouse model. J Bone Joint Surg Am
2018; 100:e76doi: 10.2106/JBJS.17.01100.
81. Trombetta RP, Bentley KLD, Schwarz EM, Kates SL, Awad HA. A murine femoral osteotomy model with hardware exchange to access antibiotic
-impregnated spacers for implant-associated osteomyelitis. Eur Cell Mater
2019; 37:431–443. doi: 10.22203/eCM.v037a26.
82. Oe K, Iida H, Ueda N, Nakamura T, Okamoto N, Ueda Y. In vivo serum concentration of vancomycin in antibiotic
-loaded acrylic cement for the treatment and prevention of periprosthetic hip infection. J Orthop Sci
2017; 22:710–714. doi: 10.1016/j.jos.2017.03.003.
83. Edelstein AI, Okroj KT, Rogers T, Della Valle CJ, Sporer SM. Systemic absorption of antibiotics from antibiotic
-loaded cement spacers for the treatment of periprosthetic joint infection. J Arthroplasty
2018; 33:835–839. doi: 10.1016/j.arth.2017.09.043.
84. Edelstein AI, Okroj KT, Rogers T, Della Valle CJ, Sporer SM. Nephrotoxicity after the treatment of periprosthetic joint infection with antibiotic
-loaded cement spacers. J Arthroplasty
2018; 33:2225–2229. doi: 10.1016/j.arth.2018.02.012.
85. Perumal R, Abel L, Samuel S, Govindaraju S. Melioidosis of the musculoskeletal system. Med Princ Pract
2020; 29:121–127. doi: 10.1159/000503021.
86. Canham CD, Walsh CP, Incavo SJ. Antibiotic
impregnated total femur spacers: a technical tip. Arthroplast Today
2018; 4:65–70. doi: 10.1016/j.artd.2017.06.001.
87. Sanz-Ruiz P, Calvo-Haro JA, Villanueva-Martinez M, Matas-Diez JA, Vaquero-Martín J. Biarticular total femur spacer for massive femoral bone loss: the mobile solution for a big problem. Arthroplast Today
2018; 4:58–64. doi: 10.1016/j.artd.2017.02.007.
88. Vermesan D, Prejbeanu R, Haragus H, Dema A, Oprea MD, Andrei D, et al. Case series of patients with pathological dyaphiseal fractures from metastatic bone disease. Int Orthop
2017; 41:2199–2203. doi: 10.1007/s00264-017-3582-3.
89. Elmarsafi T, Steinberg JS, Kim PJ, Attinger CE, Evans KK. Viability of permanent PMMA spacer with combined free fasciocutaneous tissue transfer for failed charcot reconstruction: a 38 month prospective case report. Int J Surg Case Rep
2017; 41:174–179. doi: 10.1016/j.ijscr.2017.08.066.
90. Çelik T, Kişioğlu Y. Evaluation of new hip prosthesis design with finite element analysis. Australas Phys Eng Sci Med
2019; 42:1033–1038. doi: 10.1007/s13246-019-00802-0.
91. Kutzner KP, Freitag T, Bieger R, Reichel H, Pfeil J, Ignatius A, et al. Biomechanics of a cemented short stem: standard vs. line-to-line cementation techniques. A biomechanical in-vitro study involving six osteoporotic pairs of human cadaver femurs. Clin Biomech
2018; 52:86–94. doi: 10.1016/j.clinbiomech.2018.01.004.
92. Wilairatana V, Sinlapavilawan P, Honsawek S, Limpaphayom N. Alteration of inflammatory cytokine production in primary total knee arthroplasty using antibiotic
-loaded bone cement
. J Orthop Traumatol
2017; 18:51–57. doi: 10.1007/s10195-016-0432-9.