The Impact of Incorporating Antimicrobials into Implant Surfaces

Abstract

With the increase in numbers of joint replacements, spinal surgeries, and dental implantations, there is an urgent need to combat implant-associated infection. In addition to stringent sterile techniques, an efficacious way to prevent this destructive complication is to create new implants with antimicrobial properties. Specifically, these implants must be active in the dental implant environment where the implant is bathed in the glycoprotein-rich salivary fluids that enhance bacterial adhesion, and propagation, and biofilm formation. However, in designing an antimicrobial surface, a balance must be struck between antimicrobial activity and the need for the implant to interact with the bone environment. Three types of surfaces have been designed to combat biofilm formation, while attempting to maintain osseous interactions: 1) structured surfaces where topography, usually at the nanoscale, decreases bacterial adhesion sufficiently to retard establishment of infection; 2) surfaces that actively elute antimicrobials to avert bacterial adhesion and promote killing; and 3) surfaces containing permanently bonded agents that generate antimicrobial surfaces that prevent long-term bacterial adhesion. Both topographical and elution surfaces exhibit varying, albeit limited, antimicrobial activity in vitro. With respect to covalent coupling, we present studies on the ability of the permanent antimicrobial surfaces to kill organisms while fostering osseointegration. All approaches have significant drawbacks with respect to stability and efficacy, but the permanent surfaces may have an edge in creating a long-term antibacterial environment.

Keywords: antibacterial surfaces; antibiotics; biofilm; dental implants; implant-associated infection; osseointegration.

Figure 1.

Stages in colonization of implants that interface with bone. Bacteria are always present in the oral environment. In a physiologic fluid, the organisms propagate, and some cluster together to form floating biofilms. Bacteria then either adhere to the protein-coated implants, with biofilm formation proceeding in a relatively protected niche, or localize to the bone around the implant. Nonadherent bacteria continue to be sloughed off from the surface-bound biofilms, seeding additional sites distant from the initial site of contamination.

Figure 2.

Elution profile of antibiotics in most controlled release systems. The therapeutic window usually has a rapid onset but may be maintained for up to a week. While antibiotic elution may continue for some time, antibiotic levels eventually fall below the minimal inhibitory concentration (MIC) and introduce the risk of allowing bacterial overgrowth in low to subinhibitory concentrations of antibiotics that may foster resistance.

Figure 3.

Synthetic steps in preparing antimicrobial surfaces. (A) Surface preparation of metal and tissues. Metal surfaces are passivated to create a fresh, abundant oxide layer. This oxide layer is allowed to couple with aminopropyltriethoxy silane (APTES), which will form a self-assembled monolayer on the surface of the metal. This silanization exposes primary amines, which are used for coupling of antibiotics. Similarly, tissues such as bone are partially demineralized, which allows retention of some mechanical properties while exposing more of the charged amino acids. In the synthesis here, these amines will be used to tether antibiotics. (B) Synthesis of permanent antimicrobial surfaces. Using the exposed amines, 2 to 4 aminoethoxyethoxy acetic acid (AEEA) linkers are sequentially coupled to bring the coupling site away from the surface. Antibiotics such as doxycycline or vancomycin are then coupled using reactions similar to those in peptide synthesis to form a covalently tethered antibiotic surface (Antoci, King, et al. 2007).

Figure 4.

Osteotomies repaired with vancomycin-tethered plates (A, B) and untreated, control plates (C, D). The representative craniocaudal digital radiograph of the site with the vancomycin-tethered plate made 90 d after osteotomy (A) is consistent with normal bone healing and callus formation at the osteotomy site (arrow), but the site with the control plate (C) shows progressive signs of cortical thinning, periosteal disruption, and osteolysis consistent with septic osteomyelitis at the osteotomy site (arrows). Three-dimensional reconstructed microcomputed tomography views of the same osteotomy sites in the vancomycin-tethered (B) and control animals (D) show persistence of the osteotomy gap (arrows) in the control, with a poorly organized lytic callus, enlarged medullary canal, and cortical thinning. Reproduced by permission from Stewart et al. (2012).