Antimicrobial efficacy, cytotoxicity, and ion release of mixed metal (Ag, Cu, Zn, Mg) nanoparticle polymer composite implant material

Abstract

Medical devices made of polymers are often protected against infection-relevant biofilm formation by embedding nanoparticles as a source of bioactive metal ion release. Safe application of such nanocomposites requires finding the optimal ion dose and identifying the cross-effects caused by material mixtures. This study investigated the safety and antimicrobial efficacy of thermoplastic polyurethane (TPU), which is widely used for medical devices, e.g., catheters containing zinc, silver, copper and magnesium nanoparticles, respectively, and combinations thereof. Nanoparticles were generated by using pulsed laser ablation in polymer solution. We found that the composites embedded with nanosilver were noncytotoxic to cells but toxic to bacteria, with an optimal effect at 0.5 wt%. In contrast, zinc, copper, and magnesium nanoparticle composites did not inhibit bacteria growth. Interestingly, by combining the antibacterial metals (Ag, Cu) with nanoparticles made of elements required in biological systems (Zn, Mg), we observed an altered ion release and corresponding changes to their antibacterial efficacy and biocompatibility. The combination of silver with magnesium in the nanocomposites did increase both the amount and rate of silver ion release, and resulted in an increased antimicrobial effect of this Ag-Mg-TPU composite material. The therapeutic window of silver could not be changed quantitatively by the Ag-Mg combination, but less wt% silver was required for achieving antimicrobial efficacy because of faster ion release in the clinically relevant, critical initial phase of immersion. According to our observations, the mechanism of Mg increasing the mass-specific bio-effectivity of silver is possibly nonelectrochemical but volumetric. A fine-tuning of the Mg to Ag ratio and the overall load would be required to test whether a larger therapeutic window compared with Ag composites can be gained by the mixed Mg-Ag nanocomposites. Overall, the addition of Mg to Ag reduces the lag phase of bioactivity by increasing the Ag ion release in the critical first days after application of the medical device.

Process Chain for the Fabrication of Nanoparticle Polymer Composites by Laser Ablation Synthesis

“…When the productivities obtained for this pilot-scale nanoparticle synthesis are transferred to composite materials, the potential of this method becomes visible. Doping a polymer with 1 wt % of metal nanoparticles, as done by Sowa-Söhle et al [56], with the amount of nanoparticles synthesized after 1 h of laser ablation can lead to composite yields of up to 410 g. In case lower concentrations like 0.1 wt % are doped, composite yields within the kilogram range can readily be obtained (Fig. 4 a).…”

“…However, the biocompatibility of both the matrix and the nanoparticle is crucial [51,72] and the safety of the product has to be ensured. In general, the polymer matrix needs to be nontoxic, and the nanoparticles have to be immobilized within the matrix [56,72]. The immobilization is necessary since direct contact of nanoparticles with biological tissues and cells, i.e., when using functionalized wound dressings or implants, can be toxic [51] or the nanoparticles can enter the body through a wound [72].…”

“…Here, it is important to find the suitable therapeutic window [73] for a particular application, the materials used, and the cells and biological tissues involved [56]. For example, when Cu and Ag nanoparticles are embedded into silicon to inhibit the growth of one kind of cell while it does not impair the function of other cells [73], there will be a different concentration needed than of Ag nanoparticles which are used to prevent biofilm formation on medical equipment [51,56]. Besides Ag and Cu, particles which are often applied for antimicrobial effects, ZnO is also an interesting material for nanointegration into polymers.…”

“…For example, noble metals like Ag can be mixed with less noble metals like Cu to control the ion release from a composite material electrochemically [81]. This way, nanoparticles of antibacterial materials like Ag or Cu can be mixed with nanoparticles made of elements required in biological systems like Zn or Mg, altering the antibacterial efficiency (by decreasing the Ag ion release induction period) and adjusting the biocompatibility [56]. Therefore, using a nanocomposite cocktail allows the design of bioactive nanocomposites with controlled ion release time and rate.…”

Synthesis, Physical, Mechanical and Antibacterial Properties of Nanocomposites Based on Poly(vinyl alcohol)/Graphene Oxide–Silver Nanoparticles

“…On the other hand, silver nanoparticles embedded in polymer matrices show less cytotoxicity than bared ones. Sowa-Söhle et al [76] found that thermoplastic polyurethane-silver nanoparticle composites with nanosilver concentrations from 0.01 to 1.0 wt % were non-cytotoxic to mouse fibroblass cells but toxic to bacteria. Oliveira et al [77] reported the preparation of PVA-Ag hydrogel samples with 0.25 and 0.50 wt % silver precursor.…”