Dual‐analgesic loadedUHMWPEexhibits synergistic antibacterial effects againstStaphylococci

Abstract

Total joint arthroplasty is one of the most common surgeries in the United States, with almost a million procedures performed annually. Periprosthetic joint infections (PJI) remain the most devastating complications associated with total joint replacement. Effective antibacterial prophylaxis after primary arthroplasty could substantially reduce incidence rate of PJI. In the present study we propose to provide post‐arthroplasty prophylaxis via dual‐analgesic loaded ultra‐high molecular weight polyethylene (UHMWPE). Our approach is based on previous studies that showed pronounced antibacterial activity of analgesic‐ and NSAID‐loaded UHMWPE against Staphylococci. Here, we prepared bupivacaine/tolfenamic acid‐loaded UHMWPE and assessed its antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis. Dual‐drug loaded UHMWPE yielded an additional 1–2 log reduction of bacteria, when compared with single‐drug loaded UHMWPE. Analysis of the drug elution kinetics suggested that the observed increase in antibacterial activity is due to the increased tolfenamic acid elution from dual‐drug loaded UHMWPE. We showed that the increased fractal dimension of the drug domains in UHMWPE could be associated with increased drug elution, leading to higher antibacterial activity. Dual‐analgesic loaded UHMWPE proposed here can be used as part of multi‐modal antibacterial prophylaxis and promises substantial reduction in post‐arthroplasty mortality and morbidity.

Irradiation Behavior of Analgesic and Nonsteroidal Anti-Inflammatory Drug-Loaded UHMWPE for Joint Replacement

“…The small but significant improvement (p < 0.05) in the wear rate found for virgin UHMWPE after low-dose gamma irradiation was consistent with previous results. 67 The wear rates of the therapeutic loaded UHMWPEs studied here were not significantly affected by the presence of these molecules (in line with what was previously published for 5% BP/5% TA 24 ) except for 10% bupivacaine loading, for which there was a significant decrease. The clinically relevant wear behavior of UHMWPE is known to be governed by asperity contacts and adhesive/abrasive wear and is not under hydrodynamic lubrication.…”

“…A limitation of this study is tolfenamic acid which has not been used in humans as a part of postoperative analgesia. Previous results on cell viability (osteoblast-like cell line MG-63) showed no cytotoxic potential for UHMWPE eluting bupivacaine and/or tolfenamic acid . Tolfenamic acid has an excellent safety profile in animals and humans and can possibly be explored to leverage the release and antimicrobial activity of prophylactic implants.…”

“…Previous results on cell viability (osteoblast-like cell line MG-63) showed no cytotoxic potential for UHMWPE eluting bupivacaine and/or tolfenamic acid. 24 Tolfenamic acid has an excellent safety profile in animals and humans and can possibly be explored to leverage the release and antimicrobial activity of prophylactic implants. Another important limitation is the lack of in vivo testing of the sterilized materials.…”

“…4,23 It was shown that tolfenamic acid, an NSAID, could also be incorporated into UHMWPE together with bupivacaine. 24 Although tolfenamic acid is not commonly prescribed in orthopedic applications, it has been shown to significantly reduce pain in patients with arthritis. 25,26 Based on these studies, there is a need to further explore the feasibility of using analgesic/NSAID-eluting implants as part of multimodal analgesia to treat postoperative pain.…”

“…Clinically, intraarticular bupivacaine is widely used as a bolus injection and in a sustained-delivery formulation (Exparel, Pacira Pharmaceuticals, CA) to effectively manage postoperative pain associated with total joint replacement . Peri-articular drug cocktails often also incorporate NSAIDs and vasoconstrictor agents such as epinephrine to increase the residence time for the pain medication. , It was shown that tolfenamic acid, an NSAID, could also be incorporated into UHMWPE together with bupivacaine . Although tolfenamic acid is not commonly prescribed in orthopedic applications, it has been shown to significantly reduce pain in patients with arthritis. , Based on these studies, there is a need to further explore the feasibility of using analgesic/NSAID-eluting implants as part of multimodal analgesia to treat postoperative pain.…”