Antibiotics are commonly added to poly(methyl methacrylate) (PMMA) by surgeons to locally treat infections such as in bone cement for joint replacement surgeries, but also as implantable antimicrobial "beads". However, this strategy is of limited value in high risk patients where infections can be recurrent or chronic and otherwise hard to treat. Also when only one drug is incorporated and applied toward poly-microbial infections (multiple bacterial species), there is a high risk that bacteria can develop antibiotic resistance. To combat these limitations, we developed a combination-antibiotic PMMA composite system comprised of rifampicin-filled β cyclodextrin (β-CD) microparticles added into PMMA filled with a second drug. Different formulations were evaluated through Zone-of-Inhibition, drug activity, antibiotic release and refilling, as well as mechanical studies. Our combination-antibiotic PMMA composite system achieved up to an eight-fold increase in duration of antimicrobial activity in comparison to clinically used antibiotic-filled PMMA. Inclusion of CD microparticles also allowed for refilling of additional antibiotics after simulated implantation, resulting in additional windows of therapeutic efficacy. Mechanical testing showed that our tested formulations did have a small, but significant decrease in mechanical properties when compared to unmodified controls. While further studies are needed to determine whether the tested formulations are still suitable for loadbearing applications (e.g. bone cement), our composites are certainly amenable for a variety of non-load bearing applications (e.g. antimicrobial "beads" and temporary spacer in two-stage arthroscopic revisions).

Antibiotic-laden poly­(methyl methacrylate) (PMMA) bone cement is used in a variety of applications including temporary spacers for load-bearing arthroplasties and non-load bearing orthopedic revision procedures and antibiotic beads to treat infections. Depending upon the surgical preparation technique, properties of PMMA can widely vary. The primary objective of this work was to perform an in-depth structure–function analysis regarding how processing of PMMA impacted material and structural properties (i.e., porosity) and downstream functional properties (i.e., drug refilling and strength). PMMA with cyclodextrin (CD) microparticles was generated via hand- or vacuum-mixing and characterized for material and structural properties including porosity and internal morphology and functional properties of drug refilling, compressive strength, and antimicrobial activity. CD microparticles were incorporated into PMMA to enable functional refilling properties and to determine new information on drug distribution and distance or depth of PMMA which the refilled drug was able to penetrate. Vacuum-mixing of PMMA resulted in improved mechanical strength and allowed for incorporation of greater amounts of CD microparticles but less homogeneity relative to hand-mixing. Refilling studies showed shallow penetration of the drug into PMMA samples without CD. However, PMMA with CD microparticles showed increased depth of drug penetration, indicating that the drug could be delivered deeper within the device, resulting in more drug being available for delivery and more opportunity for later antibiotic refilling on a patient-specific basis. Knowledge of structure–function relationships can assist and provide valuable information in design and optimization of PMMA–CD for specific load-bearing or non-load-bearing applications.

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.