Microbiological and physical properties of biofilm-active PMMA bone cements in arthroplasty

Abstract

Periprosthetic joint infection (PJI) remains one of the most serious complications in arthroplasty, associated with high morbidity, mortality, and substantial socioeconomic burden. Antibiotic‑loaded bone cements (ALBCs) play a central role in both the prevention and treatment of PJI. In primary arthroplasty, they enable high local antibiotic concentrations at the implant-tissue interface, reducing early bacterial adhesion and lowering infection risk. In revision surgery, especially for established infection, ALBCs facilitate targeted antimicrobial delivery as cement spacers, while simultaneously providing mechanical stability for temporary or definitive fixation. Despite decades of clinical experience with ALBCs, fundamental questions remain incompletely understood: the selection of the most appropriate antimicrobial drugs for admixing to acrylic bone cements, pharmacokinetic carrier elution aspects, cement matrix interactions, antibiotic admixing methodology, and antibiotic dose limitations. Furthermore, it is not clear to which extent laboratory experiences can be transferred to the clinical setting. These knowledge gaps are particularly relevant in the context of rising antimicrobial resistances, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin‑resistant enterococci (VRE), for which therapeutic options are increasingly restricted. This cumulative dissertation integrates material science, microbiology, and translational in-vivo modelling to advance the evidence-based use of ALBCs in arthroplasty and revision surgery. Across four studies, the work systematically examines (i) the feasibility of formulating novel daptomycin-loaded poly-methyl-methacrylate (PMMA) cements for PJIs caused by vancomycin-resistant bacteria, (ii) the mechanical, chemical, and kinetic consequences of manual antibiotic admixing, (iii) the impact of the cement matrix on antibiotic release and long-term antimicrobial activity, and (iv) the translational antimicrobial efficacy of commercial single antibiotic-loaded bone cements (SALBCs) and dual-antibiotic loaded bone cements (DALBCs) in a validated Galleria mellonella implant infection model. A fifth investigation, presented at the EBJIS (European Bone & Joint Infection Society) congress and published as abstract, proposes an optimal daptomycin dosage and suitable PMMA cement matrix for spacer applications using the Galleria mellonella biofilm model. The results demonstrate that acrylic bone cements are not interchangeable materials: the polymer composition and additives, hydrophilicity, viscosity, sterilisation method and manufacturing process collectively determine the antibiotic elution, antimicrobial efficacy and mechanical stability. DALBCs consistently outperformed SALBCs in infection prevention, achieving superior antibiofilm effects, and providing markedly increased survival in larvae infected with multi-drug-resistant Staphylococcus aureus and Enterococcus faecalis. High local antibiotic concentrations generated by antibiotic elution from acrylic bone cements were able to overcome resistance phenotypes, emphasising the unique pharmacodynamic environment of ALBC. Systematic evaluation of manual admixing revealed that dry mixing of the powder in cartridge mixing devices did neither improve mechanical stability nor antibiotic release. It generated abrasive plastic debris capable of embedding into the cement highlighting previously unrecognised risks. Fractionated bowl mixing was identified as the only safe and reproducible preparation method when manual admixing is unavoidable. Cement brand was found to be a dominant predictor of antibiotic release, with the polymer composition in Palacos® cements consistently outperforming the one in Simplex® cements across all antibiotics tested. Finally, integrating in-vitro release kinetics with the Galleria mellonella biofilm model enabled the identification of 1.5 g daptomycin per 40 g PMMA (Palacos® R+G and Simplex® T) as the optimal risk-benefit balance between antimicrobial efficacy and mechanical integrity for cement spacers in VRE caused infections. In summary, this thesis provides a comprehensive evidence base for the rational selection, mixing, and clinical application of ALBCs. It clarifies the material dependent performance and establishes best‑practice standards for manual admixing, validates an efficient in-vivo screening platform for cement performance, and supports the development of future daptomycin-loaded DALBC formulations capable of addressing the growing challenge of multi-drug-resistant PJI. These results are of high clinical relevance for surgeons who deal with these difficult-to-treat orthopaedic infections.