Poly(methyl methacrylate) Bone Cement Composite Can Be Refilled with Antibiotics after Implantation in Femur or Soft Tissue

Abstract

While periprosthetic joint infections (PJIs) result in a small percentage of patients following arthroplasties, they are challenging to treat if they spread into bone and soft tissue. Treatment involves delivering antibiotics using poly(methyl methacrylate) (PMMA) bone cement. However, antibiotic release is insufficient for prolonged infections. Previous work demonstrated efficacy of incorporating insoluble cyclodextrin (CD) microparticles into PMMA to improve antibiotic release and allow for post-implantation drug refilling to occur in a tissue-mimicking model. To simulate how antibiotic refilling may be possible in more physiologically relevant models, this work investigated development of bone and muscle refilling models. The bone refilling model involved embedding PMMA-CD into rabbit femur and administering antibiotic via intraosseous infusion. Muscle tissue refilling model involved implanting PMMA-CD beads in bovine muscle tissue and administering antibiotic via tissue injection. Duration of antimicrobial activity of refilled PMMA-CD was evaluated. PMMA-CD composite in bone and muscle tissue models was capable of being refilled with antibiotics and resulted in prolonged antimicrobial activity. PMMA-CD provided sustained and on-demand antimicrobial activity without removal of implant if infection develops. Intraosseous infusion appeared to be a viable technique to enable refilling of PMMA-CD after implantation in bone, reporting for the first time the ability to refill PMMA in bone.

PMMA Bone Cement Composite Functions as an Adjuvant Chemotherapeutic Platform for Localized and Multi‐Window Release during Bone Reconstruction

“…Loading CD Microparticles with DOX: 20 mg samples of dried 𝛾-CD microparticles were placed in 1 mL of dimethyl sulfoxide (DMSO) containing DOX dissolved at 5 mg mL −1 , covered in foil, and placed on a rotisserie shaker for 72 h. [25][26][27][28] DOX-filled 𝛾-CD microparticles were washed 5 times with MilliQ water, frozen, lyophilized, and stored in a desiccator until further use.…”

“…PMMA Fabrication (Beads and Cylinders): PMMA fabrication was carried out in small batches, and in accordance with manufacturer instructions. [25][26][27][28] For each batch, 2 g of Simplex HV surgical-grade bone cement powder was mixed with desired additives (i.e., DOX, 𝛾-CD microparticles, or DOX-filled 𝛾-CD microparticles) until homogeneous, and combined with 1 mL of methyl methacrylate liquid monomer. For DOX control samples (without 𝛾-CD microparticles), batches containing free 25 mg (1.25% wt/wt DOX/PMMA) were prepared.…”

“…Agarose gels were prepared as previously described. [25][26][27][28]69] 5 mL of hot agarose dissolved in phosphate-buffered saline (PBS) (0.075% wt/vol) was added into each well of a 6-well plate. Next, a small PMMA bead (plain: without drug or 𝛾-CD; PMMA/10wt%CD, or PMMA/15wt%CD: without drug) was placed on top of the solidified agarose (centered near the bottom of the well) and an additional 5 mL of hot agarose was placed on top to embed the PMMA bead.…”

“…[ 23,24 ] We have previously incorporated polymerized insoluble CD microparticles into PMMA bone cement, and the composite system has demonstrated its capacity to be repeatedly refilled with antibiotics after implantation and to release the drugs in a controlled and consistent manner. [ 25–28 ] Incorporation of 10 wt% CD microparticles in the PMMA did not negatively impact its ultimate compressive strength relative to clinically‐used controls. [ 25,26,28 ] While α ‐CD is most frequently utilized to solubilize different small molecules, here, we incorporated γ ‐CD microparticles into PMMA for the delivery of DOX due to the strong affinity between DOX and γ ‐CD (−5.98 kcal).…”

Mini Review Therapeutic Strategies Targeting for Biofilm and Bone Infections

“…This infection treatment pattern is available to eliminate biofilm persisting bacteria, such as SCVs ( Huiras et al, 2012 ). Conventional polymethylmethacrylate (PMMA) is often utilized for the delivery of antibiotics, such as gentamicin and vancomycin, in the form of beads, which can be embedded into the surroundings of musculoskeletal infections ( Cyphert et al, 2021 ). Due to the recurrence of S. aureus SCVs following local application of gentamicin in osteomyelitis, gentamicin is not recommended as a single-application treatment ( Miller et al, 1978 ; von Eiff et al, 1997 ; Wright and Nair, 2010 ).…”