Elsevier

Injury

Volume 41, Issue 10, October 2010, Pages 1053-1059
Injury

Gentamycin delivered from a PDLLA coating of metallic implants: In vivo and in vitro characterisation for local prophylaxis of implant-related osteomyelitis

https://doi.org/10.1016/j.injury.2010.05.010Get rights and content

Abstract

Locally applied antibiotics support prophylaxis of highly feared implant associated infections. Implant coatings with poly(d,l-lactide) (PDLLA)/gentamicin seem to be a promising approach. Aims of this study were to analyse the release kinetics of gentamicin in vivo, in vitro, to analyse the antibacterial efficacy, the resistance development and its impact on osteoblasts. For the in vitro release experiments titanium implants were coated with PDLLA/gentamicin and the antibiotic release in aqueous solution was analysed at 20 time points (from 10 s to 110 days). For the in vivo experiments PDLLA/gentamicin-coated kirschner wires were implanted in the tibiae of 18 rats. Gentamicin concentration in the bone was analysed at several time points (n = 3 each, 1 h to 7 days). Bactericidal efficacy, bacterial adhesion on the implants and resistance development were tested. AP activity, cell count and CICP expression of osteoblasts were analysed. Gentamicin was released rapidly with an initial burst in aqueous solution and followed by a slow release. Similarly, in vivo gentamicin concentration reached a high peak initially followed by a decrease to a low level. No development of resistance was observed in the investigated setting, the antibacterial efficacy was not affected by the coating process and significantly fewer bacteria were attached to the implant. Osteoblasts were not negatively affected by the gentamicin released from the coating. PDLLA/gentamicin coating resulted in a desired antibiotic peak concentration within the bone. Bacterial adhesion was successfully prevented. No bacterial resistances were developed. This coating seems to be a suitable supplement for prophylaxis of implant-associated infections.

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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