Controlled Release of Gentamicin from Polyelectrolyte Multilayers to Treat Implant-Related Infection

Most implanted devices are associated with orthopedics as over 800,000 joint replacements are performed in North America each year—reflecting a 200% increase between 1999 and 2002 alone [1, 2]. Primary joint replacements (also known as arthroplasties) are typically performed on patients with arthritis or major injury to alleviate pain and restore motion to the joint. These operations add up to an annual expenditure of $1.4 billion in the United States for total hip arthroplasty and $2.59 billion for total knees with 2/3 of these costs being offset by Medicare [3]. As expected, the number of revision surgeries is also on the rise at 17.5% for hips and 8.2% for knees [1]. Since revision surgeries require extended use of hospital resources and surgeon time, subtracting 1% from each of these values would have saved $112.6 million and $100 million for hips and knees respectively [1, 4].

In order to promote implant success, there has been rising interest in the design and implementation of combination devices. According to the United States Food and Drug Administration, a combination device is an apparatus that includes two or more regulated components (i.e. drugs, devices, or biologics) that are combined and produced as a single entity [5]. Drug-device combination products have garnered increasing attention from both pharmaceutical and medical device companies as a general strategy to address persisting complications in clinical practice. Coordinated design of such devices has the potential to greatly improve both device performance as well as the associated quality of life for the recipient. Since efficacy of a drug-device combination is generally not a linear combination of adding existing technologies together, these products can offer synergistic advantages over the case of administering both the drug and device separately in their conventional forms.

This thesis focuses on the incorporation of the small, hydrophilic antibiotic gentamicin into polyelectrolyted multilayered (PEM) surface coatings for tunable, local, and sustained delivery from implants based on Layer-by-Layer (LbL) assembly. These robust films are specifically designed to treat an existing implant-related infection. The critical advantage that places LbL on the cutting edge of existing technologies is its potential to release multiple therapeutics, simultaneously or sequentially, and thus allow for smart design of local therapeutic delivery from drug-device combinations for optimized treatment. For the stated case of orthopedic implants, the pertinent set of complications that could be addressed are pain, inflammation, infection, and long term loosening of the implant. The work presented in this thesis was conducted under a financial support parcel whose overarching aim was to develop a thin film solution to address this precise set of complications. Nevertheless, the end goal of a multi-therapeutic product necessitates design and optimization of individual therapeutic systems and this thesis specifically addresses the antibiotic delivery component for the treatment of infection.

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(β-amino ester) rendered these films biodegradable and thus yielded 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 for controlled release. Film release profiles were tuned through film architecture design and post-processing crosslinking techniques. Release 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, a theoretical treatment of the physical system was performed and yielded both an analytical mathematical model that describes the release of drug per area of film as a function of time as well as a computational model that simulates the time-dependent concentration profiles in these systems, thus laying a foundation for rational film design.

These erodible, antibiotic coatings were demonstrated to be bactericidal against Staphylococcus aureus, an infectious microorganism that is highly relevant to implant-related infections, and film degradation products were generally nontoxic towards 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 experimental efforts 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 efficacy of these erodible films with a permanent, contact-killing LbL film. This combination work yielded the treatment benefit of an initial burst release, while preventing both biofilm formation and reducing the possibility of development of antibiotic resistance that could have formed due to the presence of prolonged, sublethal concentrations of gentamicin.

Titanium rods coated with [Poly 1/PAA/GS/PAA]200 þ [Poly 1/PAA/GS]1 produced a baseline zone of inhibition of 25.6 mm (measured perpendicular to the long axis of the rod) against S. aureus after overnight incubation at 37^oC. As a control, the sample is referenced to a commercially available BD Sensi-Disc. The lighter color at the rod surface is a result of the ruptured agar and not the presence of bacteria. The scale bar is in centimeters [6].

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6. Moskowitz JS, Blaisse MR, Samuel RE, Hsu H.-P., Harris MB, Martin SD, Lee JC, Spector M, Hammond PT, The effectiveness of the controlled release of gentamicin from polyelectrolyte multilayers in the treatment of Staphylococcus aureus infection in a rabbit bone model. Biomaterials 2010; 31(23):6019-6030.