Peri-implant infections have been reported as one of the major complications that lead to the failure of orthopedic implants. An ideal solution to the peri-implant infection is to locally deliver antimicrobial agents through the implant surface. The rising problem of infections caused by multiple antibiotic-resistant bacteria makes traditional antibiotics less desirable for the prevention of peri-implant infections. One of the promising alternatives is the family of antimicrobial peptides (AMPs). In this study, we report the local delivery of AMPs through the nanotubular structure processed on titanium surface. Self-organized and vertically oriented TiO2 nanotubes, about 80 nm in diameter and 7 μm thick, were prepared by the anodization technique. HHC-36 (KRWWKWWRR), one of the most potent broad-spectrum AMPs, was loaded onto the TiO2 nanotubes via a simple vacuum-assisted physical adsorption method. Antimicrobial activity testing against Gram-positive bacterium, Staphylococcus aureus, demonstrated that this AMP-loaded nanotubular surface could effectively kill the bacteria (≈ 99.9% killing) and reduce the total bacterial number adhered to the surface after 4 h of culture. In vitro AMP elution from the nanotubes was investigated using liquid chromatography-mass spectrometry (LC-MS). The release profiles strongly depended on the crystallinity of the TiO2 nanotubes. Anatase TiO2 nanotubes released significantly higher amounts of AMP than amorphous nanotubes during the initial burst release stage. Both followed almost the same slow release profile from 4 h up to 7 days. Despite the differences in release kinetics, no significant difference was observed between these two groups in bactericidal efficiency.

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BackgroundMu opioid receptor (MOR) plays a crucial role in mediating analgesic effects of opioids and is closely associated with the pathologies of neuropathic pain. Previous studies have reported that peripheral nerve injury downregulates MOR expression, but the epigenetic mechanisms remain unknown.ObjectiveTherefore, we investigated DNA methyltransferase3a (DNMT3a) expression or methylation changes within MOR promoter in the spinal cord in a neuropathic pain induced by a chronic constriction injury (CCI) mouse model and further determined whether these injury-associated changes are reversible by pharmacological interventions.MethodsA CCI mouse model was established and tissue specimens of lumbar spinal cords were collected. The nociception threshold was evaluated by a Model Heated 400 Base. DNMT3a and MOR mRNA and protein level were detected by real-time-polymerase chain reaction and Western blot, respectively. Methylation of DNMT3a gene was measured by methylation-specific PCR.ResultsOur data showed that chronic nerve injury led to a significant upregulation of DNMT3a expression that was associated with increased methylation of MOR gene promoter and decreased MOR protein expression in the spinal cord. Inhibition of DNMT3a catalytic activity with DNMT inhibitor RG108 significantly blocked the increase in methylation of the MOR promoter, and then upregulated MOR expression and attenuated thermal hyperalgesia in neuropathic pain mice.ConclusionThis study demonstrates that an increase of DNMT3a expression and MOR methylation epigenetically play an important role in neuropathic pain. Targeting DNMT3a to the promoter of MOR gene by DNMT inhibitor may be a promising approach to the development of new neuropathic pain therapy.

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