Abstract
BackgroundIn orthopedics, the treatment of implant-associated infections represents a high challenge. Especially, potent antibacterial effects at implant surfaces can only be achieved by the use of high doses of antibiotics, and still often fail. Drug-loaded magnetic nanoparticles are very promising for local selective therapy, enabling lower systemic antibiotic doses and reducing adverse side effects. The idea of the following study was the local accumulation of such nanoparticles by an externally applied magnetic field combined with a magnetizable implant. The examination of the biodistribution of the nanoparticles, their effective accumulation at the implant and possible adverse side effects were the focus. In a BALB/c mouse model (n = 50) ferritic steel 1.4521 and Ti90Al6V4 (control) implants were inserted subcutaneously at the hindlimbs. Afterwards, magnetic nanoporous silica nanoparticles (MNPSNPs), modified with rhodamine B isothiocyanate and polyethylene glycol-silane (PEG), were administered intravenously. Directly/1/7/21/42 day(s) after subsequent application of a magnetic field gradient produced by an electromagnet, the nanoparticle biodistribution was evaluated by smear samples, histology and multiphoton microscopy of organs. Additionally, a pathohistological examination was performed. Accumulation on and around implants was evaluated by droplet samples and histology.ResultsClinical and histological examinations showed no MNPSNP-associated changes in mice at all investigated time points. Although PEGylated, MNPSNPs were mainly trapped in lung, liver, and spleen. Over time, they showed two distributional patterns: early significant drops in blood, lung, and kidney and slow decreases in liver and spleen. The accumulation of MNPSNPs on the magnetizable implant and in its area was very low with no significant differences towards the control.ConclusionDespite massive nanoparticle capture by the mononuclear phagocyte system, no significant pathomorphological alterations were found in affected organs. This shows good biocompatibility of MNPSNPs after intravenous administration. The organ uptake led to insufficient availability of MNPSNPs in the implant region. For that reason, among others, the nanoparticles did not achieve targeted accumulation in the desired way, manifesting future research need. However, with different conditions and dimensions in humans and further modifications of the nanoparticles, this principle should enable reaching magnetizable implant surfaces at any time in any body region for a therapeutic reason.
Highlights
In orthopedics, the treatment of implant-associated infections represents a high challenge
In vivo setup The in vivo experiments were authorized according to the German Animal Welfare Act and performed in 50 female BALB/cJHanZtm mice with an average body weight (BW) of 28 ± 2.4 g
Detection of targeted enrichment of magnetic nanoporous silica nanoparticles (MNPSNPs) on the implant surface The ferritic steel and titanium alloy explants were put into 100 μL A. dest., respectively, vortexed and treated in an ultrasonic bath to detach eventually accumulated MNPSNPs
Summary
The treatment of implant-associated infections represents a high challenge. Worldwide rising bacterial resistance against antibiotics [8,9,10,11] and further, the irreversible adhesion of bacteria and production of extracellular matrix in biofilm formation on the implant surface (infection cause) complicate a successful treatment [12,13,14]. This challenge is still accomplished by using high systemic doses of antibiotics for several months, accepting adverse side effects [1, 15, 16]. Different prevention methods were studied avoiding bacterial adhesion in combination with enhancing osseointegration [18, 19] like surface modifications or antimicrobial coatings of implants [20,21,22,23]
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