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INTRODUCTION: Joint arthroplasty, while a successful procedure at improving the musculoskeletal function of patients, is associated with significant pain in the peri- and post-operative periods. The current standard of care includes nerve blocks and/or local injections of anesthetics/analgesics to control pain peri-operatively and oral opioids to manage pain post-operatively. The use of opioids is associated with significant adverse effects such as nausea, vomiting, opioid tolerance, and addiction. Thus, there is a drive to discover new methods to manage pain in the post-operative period using non-opioid medications. Recently, two extended-release formulations of bupivacaine have been developed: Exparel® (Pacira Pharmaceuticals) and HTX-011 (Heron Therapeutics), which are targeted at releasing bupivacaine over the first three days after injection. Most total joint arthroplasties in the US incorporate ultra-high molecular weight polyethylene (UHMWPE) as a bearing surface for the articulation of the joint. Previously, we have shown that antibiotic drug can be incorporated into compression-molded UHMWPE and eluted out after molding to help control and prevent infections.1 In this study, we extend our approach by incorporating bupivacaine into compression-molded UHMWPE, and we describe how a joint implant can be designed to incorporate pain medication and release it over an extended period of time, potentially enabling pain management for up to several weeks. METHODS: Bupivacaine hydrochloride monohydrate was blended with GUR 1020 UHMWPE (Celanese, Irving, TX) resin at the desired total bupivacaine content and compression molded to produce consolidated bupivacaine/UHMWPE materials. The obtained bupivacaine-loaded samples were cut into strips with dimensions of 3x5x20 mm and placed in 1.7 ml of deionized water. At pre-determined time-points, the water was replaced and the concentration of the released bupivacaine was measured by high-performance liquid chromatography. We used a two-compartment pharmacokinetic model for a bupivacaine-loaded UHMWPE component of a knee replacement to predict the concentration of bupivacaine both in the knee and system-wide based on literature.2,3 RESULTS: We tested the bupivacaine release kinetics of UHMWPE samples molded with 5.4%, 8%, 10%, 15%, and 20% bupivacaine by weight. Cross-sectional microscopy revealed a two-phase microstructure, with clear phase separation between the UHMWPE and bupivacaine domains (Figure 1). At lower bupivacaine concentrations, the bupivacaine domains were isolated from one another, while at higher bupivacaine loading, the bupivacaine domains became interconnected. Bupivacaine-loaded UHMWPE samples released bupivacaine at a rate proportional to their bupivacaine content. The release kinetics of bupivacaine can be described by a power law over the time frame of at least one week and up to 6 months; the power law exponent ranges between 0.03 – 0.35 and depends strongly on the bupivacaine concentration, with lower-concentration samples having lower power-law exponents (Figure 2). We used a pharmacokinetic model to project how much bupivacaine a bupivacaine-containing knee implant would release in vivo relative to the current standard of intra-articular or peri-articular injections and to predict the concentration of bupivacaine both locally and systemically. At short time periods, the concentration of bupivacaine local to the knee was higher than a bupivacaine-containing knee implant, but the knee implant sustained a higher local bupivacaine concentration at times > 100 minutes. Crucially, the bolus injection always had a higher peak systemic bupivacaine concentration, which means that the bolus injection is potentially more toxic than the extended-release implant (Figure 3). DISCUSSION: In this study, we showed that bupivacaine can be incorporated into UHMWPE implants and released over an extended period, in some cases up to 6 months. The phase-separated microstructure we observed suggests that bupivacaine releases through the pore network created by previously-released bupivacaine, and therefore we hypothesize that higher connectivity between bupivacaine clusters increases the rate of bupivacaine release. Notably, the power law exponent is always less than 0.5, indicating non-Fickian diffusion of bupivacaine. Nevertheless, the elution kinetics are sufficient such that even implants partially composed of bupivacaine-loaded UHMWPE can deliver clinically-relevant doses and sustain that release over extended periods of time while avoiding systemically-toxic bupivacaine levels. SIGNIFICANCE/CLINICAL RELEVANCE: We showed for the first time that incorporating pain medication into UHMWPE is feasible in managing post-arthroplasty pain by delivering non-opioid pain medication from the joint bearing surface. If successful, it is likely to address peri- and post-operative pain efficiently and reduce the use of systemic opioids for patients. ACKNOWLEDGEMENT: This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Medical Research Program under Award No. W81XWH-17-1-0614. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. REFERENCES: (1) Suhardi VJ, Bichara DA, Kwok SJJ, et al. 2017. Nat. Biomed. Eng. 1(6):0080. (2) Kaeding CC, Hill JA, Katz J, Benson L. 1990. Arthrosc. J. Arthrosc. Relat. Surg. 6(1):33–39. (3) Barry SL, Martinez SA, Davies NM, et al. 2015. J. Vet. Pharmacol. Ther. 38(1):97–100.
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