Antibiotic-loaded PMMA Research Articles

MID-TERM RESULTS OF THE NEW ENDO-SPACER TECHNIQUE IN TWO-STAGE SEPTIC EXCHANGE SURGERY FOR PERIPROSTHETIC JOINT INFECTION OF THE HIP

Mechanical failure due to dislocation, fracture and acetabular wear as well as persistence of infection are the main complications associated with the use of hip spacers in the treatment of periprosthetic joint infections (PJI).We have developed a novel, custom-made spacer as part of two-stage septic hip replacement and present the two- to five-year results after reimplantation.We prospectively examined a total of 73 patients over our study period in whom our new spacer technique was used. The technique includes a dual mobility inlay and a cemented straight stem in combination with antibiotic-loaded PMMA bone cement which allows full weight bearing meanwhile the interim period. The follow-up ranged between 24 and 60 months after reimplantation as second stage of a two-stage approach. The patients were contacted as part of the follow-up using a questionnaire concerning reoperation, reinfection as well as hip function by using the Harris Hip Score.72 patients (98,6%) could be reimplanted, one patient is still using the spacer prothesis for 45 months because of excellent functional results with a Harris Hip Score of 95, nevertheless reimplantation is planned. The reinfection rate was less than 7% after reimplantation. The dislocation rate was 5%, and in total there was an overall complication rate of less than 10%. The Harris Hip Score was significantly improved.The ENDO spacer surgical technique is a promising option in the treatment of periprosthetic joint infections (PJI) for two-stage septic exchange with a low dislocation rate and good infection control after reimplantation. In addition, it enables early mobilization with the possibility of full weight-bearing in the interval between spacer implantation and reimplantation.

Impact of Antibiotic-Loaded PMMA Spacers on the Osteogenic Potential of hMSCs.

Antibiotic-loaded PMMA bone cement is frequently used in modern trauma and orthopedic surgery. Although many of the antibiotics routinely applied are described to have cytotoxic effects in the literature, clinical experience shows no adverse effects for bone healing. To determine the effects of antibiotic-loaded PMMA spacers on osteogenesis in vitro, we cultivated human bone marrow mesenchymal stem cells (BM-hMSCs) in the presence of PMMA spacers containing Gentamicin, Vancomycin, Gentamicin + Clindamycin as well as Gentamicin + Vancomycin in addition to a blank control (agarose) and PMMA containing no antibiotics. The cell number was assessed with DAPI staining, and the osteogenic potential was evaluated by directly measuring the amount of hydroxyapatite synthesized using radioactive 99mTc-HDP labelling as well as measuring the concentration of calcium and phosphate in the cell culture medium supernatant. The results showed that Gentamicin and Vancomycin as well as their combination show a certain amount of cytotoxicity but no negative effect on osteogenic potential. The combination of Gentamicin and Clindamycin, on the other hand, led to a drastic reduction in both the cell count and the osteogenic potential.

A Customized Knee Antibiotic-Loaded PMMA Spacer: A Preliminary Design Analysis.

A preliminary design of customized antibiotic-loaded poly-methyl-methacrylate (ALPMMA) spacer characterized by an appropriate footprint according to the specific patient’s anatomy and a reliable mechanical response to severe functional loads (i.e., level walking and 45° bent knee) is reported. The targeted virtual prototyping process takes origin from a novel patented 3D geometrical conceptualization characterized by added customization features and it is validated by a preliminary FEM-based analysis. Mechanical and thermomechanical properties of the antibiotic-doped orthopedic PMMA cement, which will be used for the future prototype manufacturing, were measured experimentally by testing samples taken during a real day-running orthopedic surgery and manufactured according to the surgeon protocol. FEM analysis results indicate that small area is subjected to intensive stresses, validating the proposed geometry from the mechanical point of view, under the two loading scenarios, moreover the value of safety margins results positive, and this is representative of the lower stress magnitude compared to the critical material limits. The experimental data confirm that the presence of antibiotic will last during the surgeon period moreover, the temperature dependent modulus of the bone cement is slightly affected by the body range temperature whereas it will drastically drop for higher temperature out the range of interest. A complete customization, according to a patient anatomy, and the corresponding real prototype spacer will be manufactured by 3D printing techniques, and it will be validated by destructive testing during the second stage of this activity before commercialization.

An assessment of the C-reactive protein, erythrocyte sedimentation rate and white blood cell count, values during the post-operative period of infected tibial nonunions treated with antibiotic- loaded PMMA-coated nails

<p>In this study, our aim was to assess the changes in the serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood cell count (WBC) values during the follow-up period of infected tibial pseudoarthrosis treated using antibiotic-loaded nails. Three patients with infected femoral nonunions and 11 patients with infected tibial nonunions were included in the study. All patients were treated with intramedullary nails coated with antibiotic-loaded PMMA after local extensive debridement. Postoperatively, parenteral antibiotic therapy was administered. The CRP, ESR and WBC values were noted preoperatively and on the first day, and then on the second, sixth, and 12<sup>th</sup> weeks postoperatively. The changes in these values over time were analyzed comparatively. The preoperative CRP level was found to be significantly lower than the early postoperative period (1<sup>st</sup> day), while no significant differences were detected during the follow-up period. The CRP level constantly decreased between the first postoperative control (1<sup>st</sup> day) and the final follow-up time (12<sup>th</sup> week). The postoperative ESR showed a significant difference when compared to the preoperative value, and also showed a decreasing trend in the postoperative period, having its highest value on the first day. The WBC did not exhibit a significant difference when comparing the preoperative and postoperative values. C-reactive protein level and ESR can be used to monitor the adequacy of the treatment after antibiotic-loaded nail application, whereas WBC may be insufficient in the diagnosis and follow-up of osteomyelitis treated with antibiotic-loaded nails.</p>

The Role of Poly(Methyl Methacrylate) in Management of Bone Loss and Infection in Revision Total Knee Arthroplasty: A Review.

Poly(methyl methacrylate) (PMMA) is widely used in joint arthroplasty to secure an implant to the host bone. Complications including fracture, bone loss and infection might cause failure of total knee arthroplasty (TKA), resulting in the need for revision total knee arthroplasty (rTKA). The goals of this paper are: (1) to identify the most common complications, outside of sepsis, arising from the application of PMMA following rTKA, (2) to discuss the current applications and drawbacks of employing PMMA in managing bone loss, (3) to review the role of PMMA in addressing bone infection following complications in rTKA. Papers published between 1970 to 2018 have been considered through searching in Springer, Google Scholar, IEEE Xplore, Engineering village, PubMed and weblinks. This review considers the use of PMMA as both a bone void filler and as a spacer material in two-stage revision. To manage bone loss, PMMA is widely used to fill peripheral bone defects whose depth is less than 5 mm and covers less than 50% of the bone surface. Treatment of bone infections with PMMA is mainly for two-stage rTKA where antibiotic-loaded PMMA is inserted as a spacer. This review also shows that using antibiotic-loaded PMMA might cause complications such as toxicity to surrounding tissue, incomplete antibiotic agent release from the PMMA, roughness and bacterial colonization on the surface of PMMA. Although PMMA is the only commercial bone cement used in rTKA, there are concerns associated with using PMMA following rTKA. More research and clinical studies are needed to address these complications.

Comparative Influence of Two Compositional Modifications on Maximum Exotherm Temperature and Other Properties of an Antibiotic-Loaded PMMA Bone Cement

Comparative Influence of Two Compositional Modifications on Maximum Exotherm Temperature and Other Properties of an Antibiotic-Loaded PMMA Bone Cement

Preliminary results of a novel spacer technique in the management of septic revision hip arthroplasty.

Mechanical failure due to dislocation, fracture and acetabular wear is a major complication associated with the use of spacers in the management of periprosthetic joint infection (PJI). We have developed a novel custom-made spacer in the setting of two-stage septic revision hip arthroplasty and present the preliminary results of our technique. Between May 2015 and November 2017, 30 patients underwent hip revision using the ENDO spacer technique in the setting of a two-stage septic exchange arthroplasty. The technique involves the dual mobility liner and the downsized stainless cemented straight stem in combination with antibiotic-loaded PMMA bone cement. The primary outcome measure was the overall spacer complication rate, particularly spacer dislocation. Furthermore, functional outcome using the Harris Hip Score (HHS) before spacer implantation and prior re-implantation was evaluated. The mean age of the patients was 69.8years (range from 45 to 85; SD = 9.9years). No microorganisms were preoperatively found in 23 (76.7%) cases. Successful re-implantation was performed in all patients after a mean spacer duration time of 53.6days (range 14-288days; SD = 48.2). Spacer-related complications occurred in only two patients (6.7%). The HHS significantly improved from 34.0 (range 3-62; SD = 15.1) to 48.1 (range 11-73; SD = 15.7) (p = 0.0008). The ENDO spacer surgical technique is a feasible option in the treatment of periprosthetic joint infection (PJI), with a low dislocation rate. Furthermore, it allows early mobilization with the possibility of full-weight bearing.

Studies on the cytocompatibility, mechanical and antimicrobial properties of 3D printed poly(methyl methacrylate) beads

Osteomyelitis is typically a bacterial infection (usually from Staphylococcus) or, more rarely, a fungal infection of the bone. It can occur in any bone in the body, but it most often affects the long bones (leg and arm), vertebral (spine), and bones of the foot. Microbial success in osteomyelitis is due to their ability to form biofilms which inhibit the wound healing process and increases resistance to anti-infective agents. Also, biofilms do not allow easy penetration of antibiotics into their matrix making clinical treatment a challenge. The development of local antibiotic delivery systems that deliver high concentrations of antibiotics to the affected site is an emerging area of research with great potential. Standard treatment includes antibiotic therapy, either locally or systemically and refractory cases of osteomyelitis may lead to surgical intervention and a prolonged course of antibiotic treatment involving placement of antibiotic-doped beads or spacers within the wound site. There are disadvantages with this treatment modality including insufficient mixing of the antibiotic, lack of uniform bead size, resulting in lower antibiotic availability, and limitations on the antibiotics employed. Thus, a method is needed to address biofilm formations in the wound and on the surface of the surgical implants to prevent osteomyelitis. In this study, we show that all antibiotics studied were successfully doped into PMMA and antibiotic-doped 3D printed beads, disks, and filaments were easily printed. The growth inhibition capacity of the antibiotic-loaded PMMA 3D printed constructs was also demonstrated.

Diagnosis of spacer-associated infection using quantitative cultures from sonicated antibiotics-loaded spacers: implications for the clinical outcome.

Recent studies showed that a positive microbiological result from sonication of the PMMA spacer was associated with poor outcome of patients, but no quantitative analysis has yet been performed. For this purpose, a prospective analysis of 50 spacers (46 patients) was performed. All spacers were processed according to a previously described protocol, including centrifugation and quantitative culture. Clinical data and outcome were also analysed. A statistical relationship between the results of the cultures and the outcome of the patient was assessed. Sixteen patients were diagnosed with spacer-associated infection. Thirteen out of 50 spacers gave a positive culture. Nine of 13 presented with growth of an organism not isolated in the first-stage cultures, and in 7 out of 13 the organisms count was high (>10,000 CFU/ml). We have detected a significant statistical relationship between poor outcome and positive cultures, high colony counts, isolation of different organisms, positive periprosthetic cultures and spacer-associated infection. The detection in a sonicated, antibiotic-loaded PMMA spacer of organisms other than those isolated in the first surgical samples or high colony counts of any organisms is diagnostic with regard to spacer-associated infection.

Not all approved antibiotic-loaded PMMA bone cement brands are the same: ranking using the utility materials selection concept.

In the literature on in vitro characterization of approved antibiotic-loaded poly(methyl methacrylate) bone cement brands, there is no information on the basis for selection of a given brand for use in cemented arthroplasties. This shortcoming is addressed in the present study. It involved determining four key properties (fatigue limit, fracture toughness, polymerization rate, and phosphate buffered saline diffusion coefficient) for six brands and then using the mean property values, in conjunction with a materials selection methodology, called the utility concept, to rank the brands. It is emphasized that the present work is an illustration of a rational approach to selection of a cement brand and, as such, the study findings are not intended to be recommendations regarding clinical use or otherwise of a brand.

Activity of bone cement loaded with daptomycin alone or in combination with gentamicin or PEG600 against Staphylococcus epidermidis biofilms

Daptomycin is a promising candidate for local treatment of bone infection due to its activity against multi-resistant staphylococci. We investigated the activity of antibiotic-loaded PMMA against Staphylococcus epidermidis biofilms using an ultra-sensitive method bacterial heat detection method (microcalorimetry).PMMA cylinders loaded with daptomycin alone or in combination with gentamicin or PEG600, vancomycin and gentamicin were incubated with S. epidermidis-RP62A in tryptic soy broth (TSB) for 72h. Cylinders were thereafter washed and transferred in microcalorimetry ampoules pre-filled with TSB. Bacterial heat production, proportional to the quantity of biofilm on the PMMA, was measured by isothermal microcalorimetry at 37°C. Heat detection time was considered time to reach 20μW. Experiments were performed in duplicate.The heat detection time was 5.7–7.0h for PMMA without antibiotics. When loaded with 5% of daptomycin, vancomycin or gentamicin, detection times were 5.6–16.4h, 16.8–35.7h and 4.7–6.2h, respectively. No heat was detected when 5% gentamicin or 0.5% PEG600 was added to the daptomycin-loaded PMMA.The study showed that vancomycin was superior to daptomycin and gentamicin in inhbiting staphylococcal adherence in vitro. However, PMMA loaded with daptomycin combined with gentamicin or PEG600 completely inhibited S. epidermidis-biofilm formation.PMMA loaded with these combinations may represent effective strategies for local treatment in the presence of multi-resistant staphylococci.

Incidence of Deep Infection in Aseptic Revision THA using Vancomycin-Impregnated Impacted Bone Allograft

The addition of antibiotic to cement is a frequent practice in aseptic revision hip surgery There is concern about adding vancomycin to cement due to potential effects on mechanical properties and prolonged elution of subtherapeutic levels antibiotic. Bone allografts can store and provide high levels of vancomycin to surrounding tissues. We analyzed the incidence of infection after one-stage aseptic revision hip reconstruction utilizing acetabular and/or femoral vancomycin-impregnated impacted bone allograft and a THA fixed with cement containing no antibiotic. We hypothesized that the infection rate may be similar to that reported in the literature following traditional impaction grafting using antibiotic loaded cement. Seventy five consecutive patients (80 hips) with a preoperative Merle D'Aubigné and Postel functional score averaging 4.8 points were followed up for a mean of 36 months (range 24 - 59 months). The incidence of infection was 1.25% (CI 95%=96.26-100%). A deep infection (thought to be haematognous in origin) occurred in 1 patient 2 years after the index surgery. The average postoperative Merle D´Aubigne score was 16.2 points. The last radiographic evaluation demonstrated a less than 5 mm acetabular migration and a less than 5 mm femoral subsidence in all cases. Vancomycin-supplemented allografts restored bone stock and provided sound fixation with a low incidence of infection. This incidence of deep sepsis is similar to that reported with antibiotic-loaded PMMA but without the reported mechanical and pharmacological disadvantages.

Mechanical Properties and Drug Release Behavior of Bioactivated PMMA Cements

Septic loosening of cemented implants represents an unresolved long-term problem of total hip endoprostheses. Common treatments of infected prostheses involve the use of temporary antibiotic-loaded PMMA spacer-implants or antibiotic-loaded cements. The latter are either provided by a manufacturer or are obtained by simply mixing specific antibiotic powders according to a microbial sensitivity test with PMMA cement. This study is aimed to investigate the antibiotic release behavior and mechanical properties of novel modified PMMA cements, which were bioactivated by chemical modification of commercial cements with either 0.5% hydroxyethylmethacrylate-phosphate (HEMA-P) or 0.5% hydroxyethylmethacrylate-phosphate + calcium chloride and sodium carbonate as buffer. Tobramycin release experiments from the cements were performed statically by immersion of the drug-loaded samples in PBS buffer following liquid change after different periods of time or during cyclic mechanical loading of the cement samples. Cement modification did not significantly alter the mechanical properties of the cements, but affected the release rate from the matrix. While the unmodified cement released approximately 0.33 mg/cm(2) tobramycin after 48 h independent of the testing regime, modification with both HEMA-P and salt buffer increased the antibiotic release to 37-50 mg/cm(2) when tested under cyclical mechanical loading.

An aluminium mold for intraoperative production of antibiotic-loaded PMMA knee prostheses

For treatment of total knee prosthesis infections, a two-stage protocol with explantation of the infected components, antibiotic cement spacer implantation, and secondary reimplantation of the prosthesis after curing the infection is the accepted standard procedure (Wilde and Ruth 1988, Pitto and Spika 2004). The cement spacer is antibiotic-loaded, maintains the articular distance between femur and tibia, stabilizes the knee, and allows passive motion of the knee (Scott et al. 1993). Different techniques have been used for fabrication of this spacer, including intraoperative molding. The results of handcrafted spacers are unsatisfactory because such spacers have a rough surface and are not congruent. As a result, instability, limited range of motion, and excessive wear have been reported (Goksan and Freeman 1992, Hanssen et al. 1994). We have developed a tapered aluminium mold for production of a custom made PMMA spacer like prostheses (CLSP) during the intervention. We consider the use of the CSLP as a promising approach for the treatment of complicated deep TKA infections since this technique is time sparing, cheap and easy to apply in all surgical theatres. Construction of the spacer mold The 2 molds were produced in a computerized numerical-control sinking machine (DMU 70eV-process) based on the design of the balanSys knee system (size B; D) (Mathys AG, Bettlach, Switzerland). The mold for the femoral spacer consists of 3 parts and for the tibial spacer, of 2. It is made of high-strength aluminium (AA7075 T6 3.4365; density 2.8 kg/dm3 and tensile strength 520–560 Nm/mm2) and coated with Altef. In this process, the surface of the base material is converted into a ceramic coating in which Teflon is integrated. Half of the coating penetrates into the base material, which results in an increase of 25 µm, leading to a standard coating thickness of 50 µm. The mold can be cleaned and sterilized for re-use (Figure 1 and ​and22). Figure 3. Implantation of the intraoperative molded PMMA knee spacer. Figure 1. Femoral mold, composed of 3 parts. It can be filled through 2 channels with tubes. Figure 2. The 2 parts of the tibial mold. Surgical technique and postoperative protocol The first step includes explantation of the prosthetic components and removal of the cement mantle. An extensive debridement of the infected joint is performed. Biopsies are taken for microbiological culture and histology. The appropriate size for the components is assessed on conventional AP and lateral knee radiographs. The parts of the femoral mold component are mounted with 2 screws. If necessary, special antibiotics can be added to the cement, based on the cultures and antibiogram. The mold is filled through 2 channels on the upper side, using a 20-mL tube. After polymerization of the cement, the screws, which interlink the mold, are opened and the femoral spacer component can be easily removed from the mold. Since the cement expands during polymerization, pressure inside the closed mold rises and creates a smooth surface on the final cement spacer. The femoral component is implanted first with a small portion of additional cement. Then the distance between the tibia and the femur is measured in neutral position. The tibial mold is filled with PMMA cement according to the distance measured. After polymerization of the cement, the tibial part of the spacer is removed from the mold and the mounting cement on the posterior and lateral side of the spacer is removed with a Luer pincer. The tibial component is then implanted with a small portion of cement (Figure 3). The stability and range of motion is tested, and then the wound can be closed (Figures 4). Figure 4. After implantation of the PMMA spacer. Depending on the agent and the intraoperative findings, an individual protocol of intravenous and oral antibiotics is indicated. Continuous passive motion is started 24 h postoperatively, with no limitations. Ambulation is started (with two crutches and partial weight bearing of 20 kg) on the third day after surgery.

Treatment of proximal femur infections with antibiotic-loaded cement spacers

In case of periprosthetic hip infections the implantation of antibiotic-loaded PMMA spacers is accepted for an adequate treatment option. Although their indication for the treatment of destructive, bacterial infections of the proximal femur would make sense, literature data are scarce. Hence, the aim of this study was to evaluate the efficacy of antibiotic-impregnated spacers in the treatment of proximal femur infections. In 10 consecutive patients (5 M/ 5 F, mean age 66 y.) with bacterial proximal femur infections, a femoral head/neck resection was prospectively performed with a subsequent implantation of an antibiotic-loaded spacer. The joint-specific outcome was evaluated by the Merle d'Aubigne and the Mayo hip score, the general outcome by SF-36. The time periods were divided into "infection situation", "between stages" and meanly 1 year "after prosthesis implantation". The spacers were meanly implanted over 90 [155-744] days. In all cases an infection eradication could be achieved. After infection eradication, a prosthesis implantation was performed in 8 cases. The general scores showed significant increases at each time period. With regard to the dimension "pain", both scores demonstrated a significant increase between "infection situation" and "between stages", but no significance between "between stages" and "after prosthesis implantation". Spacers could be indicated in the treatment of proximal femur infections. Besides an infection eradication, a pain reduction is also possible.

Sucrose, Xylitol, and Erythritol Increase PMMA Permeability for Depot Antibiotics

Release of antibiotics from antibiotic-loaded PMMA is dependent on its permeability. Loading PMMA with soluble particulate filler has been proposed to increase permeability and antibiotic release for beads and spacers. We therefore assessed particulate sucrose, xylitol, and erythritol as fillers to increase the permeability and elution kinetics of filler-loaded PMMA. Based on lower solubility, we hypothesized that erythritol would not enhance permeability and elution as much as xylitol and sucrose. We made filler-loaded PMMA beads with each of the three fillers combined with phenolphthalein, and soaked in 0.1% NaOH solution. Permeability was assessed qualitatively by relative depth of phenolphthalein color change caused by penetration of NaOH solution into subsequently split beads. Elution was quantitatively assessed by spectrophotometric light absorption measurements of the eluent. Fluid penetration reached the center of 7-mm beads by day 15, similar for all three materials. Elution of phenolphthalein was greater for xylitol than for the other two materials. Particulate sucrose, xylitol, and erythritol fillers increase PMMA permeability and elution kinetics but relative solubility did not determine the relative degree of enhancement of permeability and elution by these materials.

The effect of mixing on gentamicin release from polymethylmethacrylate bone cements.

We compared the release of gentamicin from 6 different commercially available, antibiotic-loaded PMMA bone cements used for vacuum- and hand-mixed cement using a Cemvac vacuum mixing system. We also measured the release of gentamicin after manual addition of the antibiotic to different commercial, unloaded bone cements after hand-mixing. The porosity of cements was reduced in all vacuum-mixed cements, as compared with hand-mixed cements, concurrent with a statistically significant reduction (3 of 6) or increase (1 of 6) in the total amounts of gentamicin released. The total gentamicin release was studied in 3 of the brands after manual addition and mixing of the antibiotics. We found that the release of antibiotics was lower than in samples made from industrial mixing. In conclusion, the manual addition and mixing of gentamicin in PMMA bone cements leads to a lower release of antibiotics than that in corresponding commercially available antibiotic-loaded cements, while vacuum-mixing only leads to a minor reduction in antibiotic release, as compared to hand-mixing.