National University of Science and Technology "MISIS", Leninsky prospect 4, Moscow 119049, Russia.
N.N. Blokhin Russian Cancer Research Centre of RAMS, Kashirskoe shosse 24, Moscow 115478, Russia.
Mater Sci Eng C Mater Biol Appl. 2018 Sep 1;90:289-299. doi: 10.1016/j.msec.2018.04.068. Epub 2018 Apr 24.
Implant-related bacterial infections remain a serious problem that is not solved yet. Herein we combined several antibacterial agents to achieve synergistic effects and broader protection of widely used metallic implants. Titanium samples with microcontainers for drug, produced by selective laser sintering, were coated with Ag-doped biocompatible and bioactive TiCaPCON film and loaded with an antibiotic (gentamicin or a mixture of gentamicin and amphotericin B). Bactericide release tests demonstrated that the release rate of one bactericide agent (Ag ions or gentamicin) depended on the presence of the other antibacterial component. The antibacterial activity of the biocide-doped samples was evaluated against clinically isolated Escherichia coli O78 (E. coli), Staphylococcus aureus (S. aureus) bacteria, and Neurospora crassa wt-987 (N. crassa) spores. It was found that samples loaded with low gentamicin concentration (0.2 and 0.02 mg/cm), i.e. 10 and 100 times less than the standard gentamicin concentration (2 mg/cm), demonstrated a superb antibacterial activity against E. coli bacteria. We showed that a crosslinking reaction between gentamicin and TiCaPCON film proceeded either through the formation of amide bonds or via the electrostatic interaction between amine groups of gentamicin and COOH groups of TiCaPCON and led to the formation of relatively stable drug/film conjugates that prevented a rapid dissolution of gentamicin and ensured its long-term (for 72 h) antibacterial protection. Leaching of silver ions provided an effective antibacterial protection after the depletion of the drug reservoirs. The obtained results clearly show a synergistic antibacterial action of Ag ions and gentamicin against S. aureus bacteria. In addition, in the presence of Ag ions, the antifungal activity of samples loaded with a mixture of gentamicin and amphotericin B against N. crassa fungus was observed to increase. Thus, it is demonstrated that silver can be successfully coupled with different types of antibiotics to provide innovative hybrid metal-ceramic bioconstructions that are able to deliver precise doses of bactericide agents within a certain period of time and are equally effective against Gram-negative E. coli bacteria, Gram-positive S. aureus, and N. crassa fungus.
植入物相关的细菌感染仍然是一个尚未解决的严重问题。在这里，我们将几种抗菌剂结合起来，以实现广泛使用的金属植入物的协同作用和更广泛的保护。通过选择性激光烧结生产的带有药物微容器的钛样品，涂有掺银的生物相容性和生物活性 TiCaPCON 薄膜，并负载抗生素（庆大霉素或庆大霉素和两性霉素 B 的混合物）。杀菌剂释放试验表明，一种杀菌剂（银离子或庆大霉素）的释放速率取决于另一种抗菌成分的存在。用杀生物剂掺杂的样品的抗菌活性针对临床分离的大肠杆菌 O78（大肠杆菌）、金黄色葡萄球菌（金黄色葡萄球菌）细菌和粗糙脉孢菌 wt-987（粗糙脉孢菌）孢子进行了评估。结果发现，负载低浓度庆大霉素（0.2 和 0.02 mg/cm）的样品，即低于标准庆大霉素浓度（2 mg/cm）的 10 和 100 倍，对大肠杆菌表现出极好的抗菌活性。我们表明，庆大霉素和 TiCaPCON 薄膜之间的交联反应可以通过形成酰胺键或通过庆大霉素的胺基与 TiCaPCON 的 COOH 基团之间的静电相互作用进行，从而导致形成相对稳定的药物/薄膜缀合物，防止庆大霉素快速溶解并确保其长期（72 小时）抗菌保护。银离子的浸出在药物储库耗尽后提供了有效的抗菌保护。所得结果清楚地表明银离子和庆大霉素对金黄色葡萄球菌具有协同的抗菌作用。此外，在存在银离子的情况下，负载庆大霉素和两性霉素 B 混合物的样品对粗糙脉孢菌真菌的抗真菌活性增加。因此，证明银可以成功与不同类型的抗生素结合，提供创新的混合金属陶瓷生物结构，能够在一定时间内精确输送杀菌剂剂量，并且对革兰氏阴性大肠杆菌、革兰氏阳性金黄色葡萄球菌和粗糙脉孢菌真菌同样有效。
