An Additive to PMMA Bone Cement Enables Postimplantation Drug Refilling, Broadens Range of Compatible Antibiotics, and Prolongs Antimicrobial Therapy

Abstract

Poly(methyl methacrylate) (PMMA) bone cement is used in several biomedical applications including as antibiotic-filled beads, temporary skeletal spacers, and cement for orthopedic implant fixation. To mitigate infection following surgery, antibiotics are often mixed into bone cement to achieve local delivery. However, since implanted cement is often structural, incorporated antibiotics must not compromise mechanical properties; this limits the selection of compatible antibiotics. Furthermore, antibiotics cannot be added to resolve future infections once cement is implanted. Finally, delivery from cement is suboptimal as incorporated antibiotics exhibit early burst release with most of the drug remaining permanently trapped. This prolonged subtherapeutic dosage drives pathogen antibiotic resistance. To overcome these limitations of antibiotic-laden bone cement, insoluble cyclodextrin (CD) microparticles are incorporated into PMMA to provide more sustained delivery of a broader range of drugs, without impacting mechanics. PMMA formulations with and without CD microparticles are synthesized and filled with one of three antibiotics and evaluated using zone of inhibition, drug release, and compression studies. Additionally, the ability of PMMA with microparticles to serve as a refillable antibiotic delivery depot is explored. Findings suggest that addition of CD microparticles to cement promotes postimplantation antibiotic refilling and enables incorporation of previously incompatible antibiotics while preserving favorable mechanical properties.

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery

“…However this amount is similar to the amount of RM remaining in non‐templated polymers as determined by colorimetric spectroscopy (data not shown) and FTIR analysis (Figure ). Past work by our lab has shown that any drug remaining in the device was unavailable for further delivery even after extensive washing with organic solvents, so total drug loading was calculated from the maximum released amount, rather than maximum loaded amount …”

“…Past work by our lab has shown that any drug remaining in the device was unavailable for further delivery even after extensive washing with organic solvents, so total drug loading was calculated from the maximum released amount, rather than maximum loaded amount. [37,38]…”

Use of affinity allows anti‐inflammatory and anti‐microbial dual release that matches suture wound resolution

“…When CD is insolubilized by forming a high molecular weight polymer, we can take advantage of this molecular affinity to alter the rate of release beyond that capable of diffusion alone. Past work from our lab and others has shown that this affinity reduces the initial drug burst effect, retaining more drug to be delivered at later time points . Additionally, loading CD polymers is very straightforward, and can be done post‐polymerization, allowing drug incorporation for dual drug loading and release.…”

“…Past work from our lab and others has shown that this affinity reduces the initial drug burst effect, retaining more drug to be delivered at later time points. 41 Additionally, loading CD polymers is very straightforward, and can be done post-polymerization, allowing drug incorporation for dual drug loading and release.…”

Combination antibiotic PMMA composites provide sustained broad-spectrum antimicrobial activity and allow for post-implantation refilling

“…In order to locally deliver antibiotics in orthopedic procedures, such as knee or hip replacements, an antibiotic is often directly added to poly(methyl methacrylate) (PMMA) bone cement during the mixing process 13 . PMMA is used in a variety of orthopedic and non-orthopedic applications including as a temporary spacer in a two-part revision procedure 14 , as an anchor between the patient's bone and the metallic implant in arthroplasties 15 , and as antibiotic-filled beads [16][17] . In these applications, typically only one antibiotic, such as gentamicin or tobramycin, is used in an effort to provide antimicrobial coverage 18 .…”