Combination Antibiotic Delivery in PMMA Provides Sustained Broad-Spectrum Antimicrobial Activity and Allows for Postimplantation Refilling

Abstract

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).

Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes

“…Remarkably, a steady release of resveratrol from the pCD disks was observed up to seven days in vivo. This agrees with existing in vitro pCD work from the von Recum lab, in which multiple drug types have been delivered at a fairly steady release rate over the course of days/weeks [50,52,78]. Resveratrol metabolites, monosulfate, mono-glucuronide, dihydro monosulfate, dihydro and disulfate, were all evaluated through mass spectrometry as they have been thought to contribute similar physiological benefits as resveratrol [79][80][81].…”

“…The insolubilization of CD can be achieved by forming a high molecular weight polymer, in which the inclusion complexes can be exploited to alter the rate of release beyond the rate of diffusion alone. The von Recum lab has shown the affinity within the inclusion complex can reduce the initial drug burst release, allowing the release of the drug to be delivered over a long period of time [36,[48][49][50][51][52]. This time scale is dependent on a number of factors, but when loaded with antibiotic drugs, such as rifampicin, release from pCD disks has been recorded at antimicrobial levels for as long as 8 months [36].…”

A PMMA bone cement composite that functions as a drug-refillable depot for localized, multi-window chemotherapeutic treatment of bone cancer

“…To determine the porosities of PMMA samples with DOX and DOX-filled γ -CD microparticles, micro-computed tomography (micro-CT) was used. Settings for the micro-CT scans were based upon a published methodology [55], [56], [58]. Specifically, PMMA cylinders were scanned inside of polypropylene tubes using a Siemens Inveon PET-CT scanner (Siemens Medical Solutions, Malvern, PA) controlled by Siemens Inveon Acquisition Workplace software on a PC.…”

“…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 [55]- [58]. Incorporation of 10wt% CD microparticles in the PMMA did not negatively impact its ultimate compressive strength relative to clinically-used controls [55], [56], [58]. 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) [59].…”

Progress of antibiotic-loaded bone cement in joint arthroplasty

“…[ 52 ] Rifampin-filled β-cyclodextrin particles achieved a longer effect time but no longer met the weight-bearing standard. [ 53 ] To modify the characteristics, microcapsules of rifampicin containing alginate, polyhydroxybutyratehydroxyvalerate, ethyl cellulose and stearic acid were introduced. They relieved the mechanical antimicrobial activity of ALBC and improved the compression strength.…”