Gentamycin delivered from a PDLLA coating of metallic implants: In vivo and in vitro characterisation for local prophylaxis of implant-related osteomyelitis
Introduction
Implant-related infection is a strongly feared complication in orthopaedic and trauma surgery as it may result in implant failure, poor functional outcome, chronic osteomyelitis or even sepsis and death. Removal of the implant and multiple debridements often become necessary to eradicate infection from affected bone tissue. Besides the considerable costs of treatment, this certainly means a horrible ordeal for both patient and physician [7]. Regarding the over ageing of Western societies [21], there is a significant increase of patients in need of orthopaedic implants or fracture fixation devices. Therefore, a seemingly low risk of infection, estimated to a range of 0.5–5%, has to be considered more than relevant for its serious consequences [4].
Therefore, methods for prevention of perioperative infections have been improved within the past few decades [4]. In addition, effective protocols of systemically administered antibiotics have been established for prophylaxis [2], [13], [17], [18].
However, current concepts of infection prophylaxis also focus on the interface of implant surface and the surrounding tissue. Accidental contamination can result in bacterial colonisation and, subsequently, into clinically relevant infection [4]. In this process, bacterial adhesion and anchorage on the surface of biomaterials represent the initial crucial step. Therefore, much effort has been spent to modify the properties of implants’ surfaces [8], [9], [12], [24], [26], [27].
In the present study, we investigate a previously described poly(d,l-lactide) (PDLLA) coating of titanium implants that serves as a local drug delivery system [33]. This biodegradable, thin and robust implant coating provides good mechanical properties and shows only up to 5% of abrasion during intramedullary implantation of the coated implant [33]. Using a cold coating technique, gentamicin is incorporated into the PDLLA (10% (w/w)) and titanium wires are coated.
The in vitro release profile of the antibiotic from coated implants is analysed and compared to the release profile in the tibia of rats. Furthermore, considering that biofilm formation of bacteria after adhesion to the implant surface is critical for infection development, the adhesion of bacteria to coated versus uncoated implants is investigated. Finally, the possible influence of released gentamicin on the viability and proliferation of osteoblast-like cells is investigated, as this can be an indicator of potential inhibition of fracture healing in the presence of a coated implant.
Section snippets
PDLLA coating
PDLLA (Resomer 203, Boehringer®, Germany) with a molecular weight of 30 kDa was dissolved in volatile solvent ethyl acetate according to a ratio of 1 g/15 ml. The solution was sterile filtered (Minisart, 0.2 μm, Sartorius®, Germany).
A total of 166.65 mg lyophilised gentamicin sulphate (Synopharm®, Germany) per gram PDLLA was added, yielding a concentration of 10% gentamicin base w/w of the polymer. The suspension was vortexed for 30 min.
For in vitro investigations, 10 titanium implants (IM-nails,
Gentamicin release in vitro
Gentamicin was released with an initial burst. After 1 min, 60% of the incorporated antibiotic was discharged from the coating into PBS. This rapid liberation was followed by a slow and constant further release. After 3 weeks, an additional 10% was eluted and after 6 weeks, a total of about 85% of the antibiotic was eluted from the coating (Fig. 2).
Antibacterial efficacy of gentamicin after release from the coating
All tested samples revealed adequate zones of inhibition on agar discs, which had been incubated with B. subtilis. The diameters determined ranged
Discussion
Antibiotic therapy represents a significant step in the prophylaxis of implant-related infections. However, application form, time point and chosen antibiotic still remain a frequently discussed issue in orthopaedic surgery [2], [13], [17], [18], [28]. The need for bone-efficient antibiotics, such as aminoglycosides, is in contrast to their severe toxicity when applied systemically. In view of these toxic side effects, effective local drug levels can hardly be achieved at the target site.
Funding
This study was supported by a grant from the Charité-Universitätsmedizin Berlin.
Conflict of interest statement
None of the authors has any financial or personal relationship with other people, or organisations, that could inappropriately influence (bias) the work.
Acknowledgements
The authors would like to thank Andrea Montali, Synthes GmbH, Switzerland, for proofreading the manuscript and for helpful discussions and Marc Lübberstedt for his help with the cell-culture experiment.
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