Controlled release of gentamicin from polyelectrolyte multilayers to treat implant-related infection

Abstract

Polyelectrolyte multilayered (PEM) coatings were fabricated to incorporate and release the small, hydrophilic antibiotic gentamicin from implant surfaces for infection control. The use of a cationic hydrolytically cleavable poly(p-amino ester) rendered these films biodegradable, yielding both diffusion-based and surface-erosion based release of this therapeutic. The Layer-by- Layer (LbL) assembly platform was used to create conformal, micron scale reservoirs with highly tunable drug release. Film release profiles were engineered through film architecture design and post-processing crosslinking techniques. Delivery of gentamicin was sustained for weeks, which is a significant improvement from previous gentamicin-releasing LbL systems. To gain better insight on the mechanisms of release and aid in rational film design, a theoretical treatment of the physical system was performed. These results include an analytical mathematical model describing the release of drug per surface area of film as a function of time as well as a computational model that simulates the time-dependent concentration profiles in these LbL systems. These erodible, antibiotic coatings were demonstrated to be bactericidal against Staphylococcus aureus, an infectious microorganism that is highly relevant to implant-related infections. Film degradation products were generally nontoxic toward MC3T3-E1 osteoprogenitor cells. A reproducible in vivo rabbit bone infection model was developed to test the PEM coatings against sterile, uncoated placebos; subsequent in vivo experimentation demonstrated the proof-of-principle that an antibiotic-eluting LbL film can efficaciously treat a pre-existing implant-related infection. One further application was studied which combined the release-based mechanism of these erodible films with a permanent, contact-killing LbL film. This combination has the treatment benefit of an initial burst release of antibiotic, prevents biofilm formation, and reduces the probability of developing antibiotic resistance due to the prolonged presence of sublethal concentrations of gentamicin.