The Mark Coventry Award: PhotothermAA Gel Combined With Debridement, Antibiotics, and Implant Retention Significantly Decreases Implant Biofilm Burden and Soft-Tissue Infection in a Rabbit Model of Knee Periprosthetic Joint Infection.

BACKGROUND: Chronic periprosthetic joint infection (PJI) is a major complication of total joint arthroplasty. The underlying pathogenesis often involves the formation of bacterial biofilm that protects the pathogen from both host immune responses and antibiotics. The gold standard treatment requires implant removal, a procedure that carries associated morbidity and mortality risks. Strategies to preserve the implant while treating PJI are desperately needed. Our group has developed an anti-biofilm treatment, PhotothermAA gel, which has shown complete eradication of 2-week-old mature biofilm in vitro. In this study, we tested the anti-biofilm efficacy and safety of PhotothermAA in vivo when combined with debridement, antibiotics and implant retention (DAIR) in a rabbit model of knee PJI. METHODS: New Zealand white rabbits (n = 21) underwent knee joint arthrotomy, titanium tibial implant insertion, and inoculation with Xen36 (bioluminescent Staphylococcus aureus) after capsule closure. At 2 weeks, rabbits underwent sham surgery (n = 6), DAIR (n = 6), or PhotothermAA with DAIR (n = 9) and were sacrificed 2 weeks later to measure implant biofilm burden, soft-tissue infection, and tissue necrosis. RESULTS: The combination of anti-biofilm PhotothermAA with DAIR significantly decreased implant biofilm coverage via scanning electron microscopy compared to DAIR alone (1.8 versus 81.0%; P < .0001). Periprosthetic soft-tissue cultures were significantly decreased in the PhotothermAA with DAIR treatment group (log reduction: Sham 1.6, DAIR 2.0, combination 5.6; P < .0001). Treatment-associated necrosis was absent via gross histology of tissue adjacent to the treatment area (P = .715). CONCLUSIONS: The addition of an anti-biofilm solution like PhotothermAA as a supplement to current treatments that allow implant retention may prove useful in PJI treatment.

Standardized quantification of biofilm in a novel rabbit model of periprosthetic joint infection.

Periprosthetic joint infection (PJI) is one of the most devastating complications of total joint arthroplasty. The underlying pathogenesis involves the formation of bacterial biofilm that protects the pathogen from the host immune response and antibiotics, making eradication difficult. The aim of this study was to develop a rabbit model of knee PJI that would allow reliable biofilm quantification and permit the study of treatments for PJI. In this work, New Zealand white rabbits ( n = 19 ) underwent knee joint arthrotomy, titanium tibial implant insertion, and inoculation with Xen36 (bioluminescent Staphylococcus aureus) or a saline control after capsule closure. Biofilm was quantified via scanning electron microscopy (SEM) of the tibial explant 14 d after inoculation ( n = 3 noninfected, n = 2 infected). Rabbits underwent debridement, antibiotics, and implant retention (DAIR) ( n = 6 ) or sham surgery ( n = 2 noninfected, n = 6 infected) 14 d after inoculation, and they were sacrificed 14 d post-treatment. Tibial explant and periprosthetic tissues were examined for infection. Laboratory assays supported bacterial infection in infected animals. No differences in weight or C-reactive protein (CRP) were detected after DAIR compared to sham treatment. Biofilm coverage was significantly decreased with DAIR treatment when compared with sham treatment (61.4 % vs. 90.1 %, p < 0 .0011) and was absent in noninfected control explants. In summary, we have developed an experimental rabbit hemiarthroplasty knee PJI model with bacterial infection that reliably produces quantifiable biofilm and provides an opportunity to introduce treatments at 14 d. This model may be used to better understand the pathogenesis of this condition and to measure treatment strategies for PJI.

Hyperthermia-mediated changes in the tumor immune microenvironment using iron oxide nanoparticles.

Iron oxide nanoparticles (IONPs) have often been investigated for tumor hyperthermia. IONPs act as heating foci in the presence of an alternating magnetic field (AMF). It has been shown that hyperthermia can significantly alter the tumor immune microenvironment. Typically, mild hyperthermia invokes morphological changes within the tumor, which elicits a secretion of inflammatory cytokines and tumor neoantigens. Here, we focused on the direct effect of IONP-induced hyperthermia on the various tumor-resident immune cell subpopulations. We compared direct intratumoral injection to systemic administration of IONPs followed by application of an external AMF. We used the orthotopic 4T1 mouse model, which represents aggressive and metastatic breast cancer with a highly immunosuppressive microenvironment. A non-inflamed and 'cold' microenvironment inhibits peripheral effector lymphocytes from effectively trafficking into the tumor. Using intratumoral or systemic injection, IONP-induced hyperthermia achieved a significant reduction of all the immune cell subpopulations in the tumor. However, the systemic delivery approach achieved superior outcomes, resulting in substantial reductions in the populations of both innate and adaptive immune cells. Upon depletion of the existing dysfunctional tumor-resident immune cells, subsequent treatment with clinically approved immune checkpoint inhibitors encouraged the repopulation of the tumor with 'fresh' infiltrating innate and adaptive immune cells, resulting in a significant decrease of the tumor cell population.

Uncovering the Magnetic Particle Imaging and Magnetic Resonance Imaging Features of Iron Oxide Nanocube Clusters.

Multifunctional imaging nanoprobes continue to garner strong interest for their great potential in the detection and monitoring of cancer. In this study, we investigate a series of spatially arranged iron oxide nanocube-based clusters (i.e., chain-like dimer/trimer, centrosymmetric clusters, and enzymatically cleavable two-dimensional clusters) as magnetic particle imaging and magnetic resonance imaging probes. Our findings demonstrate that the short nanocube chain assemblies exhibit remarkable magnetic particle imaging signal enhancement with respect to the individually dispersed or the centrosymmetric cluster analogues. This result can be attributed to the beneficial uniaxial magnetic dipolar coupling occurring in the chain-like nanocube assembly. Moreover, we could effectively synthesize enzymatically cleavable two-dimensional nanocube clusters, which upon exposure to a lytic enzyme, exhibit a progressive increase in magnetic particle imaging signal at well-defined incubation time points. The increase in magnetic particle imaging signal can be used to trace the disassembly of the large planar clusters into smaller nanocube chains by enzymatic polymer degradation. These studies demonstrate that chain-like assemblies of iron oxide nanocubes offer the best spatial arrangement to improve magnetic particle imaging signals. In addition, the nanocube clusters synthesized in this study also show remarkable transverse magnetic resonance imaging relaxation signals. These nanoprobes, previously showcased for their outstanding heat performance in magnetic hyperthermia applications, have great potential as dual imaging probes and could be employed to improve the tumor thermo-therapeutic efficacy, while offering a readable magnetic signal for image mapping of material disassemblies at tumor sites.

Exploring the chelation-based plant strategy for iron oxide nanoparticle uptake in garden cress (Lepidium sativum) using magnetic particle spectrometry.

Although iron is one of Earth's most abundant elements, its availability to plants remains an agricultural challenge, particularly in high pH environments. At high pH, iron forms insoluble ferric oxide-hydroxides that makes it inaccessible to plants. It is estimated that 30% of the world's cropland is too alkaline for optimal plant growth. Staple crops, like rice, are particularly susceptible to iron deficiency, thereby, necessitating the need for continued research in developing iron-based fertilizers. Recent studies have demonstrated the potential of using iron oxide nanoparticles (IONPs) as fertilizers to address iron deficiency in plants, but some studies have generated conflicting results. One of the major challenges associated in investigating IONP plant uptake and translocation is the inability to distinguish between intact IONPs versus leached iron ions. In this study, we utilized a new approach based on magnetic particle spectrometry (MPS) to monitor the uptake and distribution of different sized (10 and 20 nm) chelated IONPs in plants. We exposed garden cress (Lepidium sativum) plants to EDTA-capped IONPs and observed an 8-fold enhancement in total biomass and 1.4 times increase in chlorophyll production compared to plants treated with a commercial chelated iron fertilizer (Fe-EDTA). Moreover, we demonstrated that the uptake and tissue distribution of IONPs can be quantitatively monitored using MPS, and the results of the analysis were validated by atomic absorption spectroscopy, which is the conventional method used to study IONP plant uptake. Our study demonstrates that MPS is a reliable, sensitive, and effective analytical tool for the development of IONP-based fertilizers.

A novel synthetic route for high-index faceted iron oxide concave nanocubes with high T2 relaxivity for in vivo MRI applications.

Iron oxide nanoparticles (IONPs) with high-index facets have shown great potential as high performance T2 contrast agents for MRI. Previous synthetic approaches focused mainly on ion-directed or oxidative etching methods. Herein, we report a new synthetic route for preparing high-index faceted iron oxide concave nanocubes using a bulky coordinating solvent. Through the systematic replacement of a non-coordinating solvent, 1-octadecene, with trioctylamine, the solvent interaction with the nanoparticle surface is modified, thereby, promoting the growth evolution of the IONPs from spherical to concave cubic morphology. The presence of the bulky trioctylamine solvent results in particle size increase and the formation of nanoparticles with enhanced shape anisotropy. A well-defined concave nanocube structure was evident from the early stages of particle growth, further confirming the important role of bulky coordinating solvents in nanoparticle structural development. The unique concave nanocube morphology has a direct influence on the magnetic properties of the IONPs, ultimately leading to an ultra-high T2 relaxivity (862.2 mM-1 s-1), and a 2-fold enhancement in T2*-weighted in vivo MRI contrast compared to spherical IONP analogs.

High-performance iron oxide nanoparticles for magnetic particle imaging - guided hyperthermia (hMPI).

Magnetic particle imaging (MPI) is an emerging imaging modality that allows the direct and quantitative mapping of iron oxide nanoparticles. In MPI, the development of tailored iron oxide nanoparticle tracers is paramount to achieving high sensitivity and good spatial resolution. To date, most MPI tracers being developed for potential clinical applications are based on spherical undoped magnetite nanoparticles. For the first time, we report on the systematic investigation of the effects of changes in chemical composition and shape anisotropy on the MPI performance of iron oxide nanoparticle tracers. We observed a 2-fold enhancement in MPI signal through selective doping of magnetite nanoparticles with zinc. Moreover, we demonstrated focused magnetic hyperthermia heating by adapting the field gradient used in MPI. By saturating the iron oxide nanoparticles outside of a field free region (FFR) with an external static field, we can selectively heat a target region in our test sample. By comparing zinc-doped magnetite cubic nanoparticles with undoped spherical nanoparticles, we could show a 5-fold improvement in the specific absorption rate (SAR) in magnetic hyperthermia while providing good MPI signal, thereby demonstrating the potential for high-performance focused hyperthermia therapy through an MPI-guided approach (hMPI).

Iron Oxide and Titanium Dioxide Nanoparticle Effects on Plant Performance and Root Associated Microbes.

In this study, we investigated the effect of positively and negatively charged Fe3O4 and TiO2 nanoparticles (NPs) on the growth of soybean plants (Glycine max.) and their root associated soil microbes. Soybean plants were grown in a greenhouse for six weeks after application of different amounts of NPs, and plant growth and nutrient content were examined. Roots were analyzed for colonization by arbuscular mycorrhizal (AM) fungi and nodule-forming nitrogen fixing bacteria using DNA-based techniques. We found that plant growth was significantly lower with the application of TiO2 as compared to Fe3O4 NPs. The leaf carbon was also marginally significant lower in plants treated with TiO2 NPs; however, leaf phosphorus was reduced in plants treated with Fe3O4. We found no effects of NP type, concentration, or charge on the community structure of either rhizobia or AM fungi colonizing plant roots. However, the charge of the Fe3O4 NPs affected both colonization of the root system by rhizobia as well as leaf phosphorus content. Our results indicate that the type of NP can affect plant growth and nutrient content in an agriculturally important crop species, and that the charge of these particles influences the colonization of the root system by nitrogen-fixing bacteria.

Highly efficient antibacterial iron oxide@carbon nanochains from wüstite precursor nanoparticles.

A new hydrothermal synthesis approach involving the carbonization of glucose in the presence of wüstite (FeO) nanoparticles is presented, which leads to the fabrication of rapidly acting and potent antibacterial agents based on iron oxide@carbon (IO@C) nanochains. By using nonmagnetic FeO precursor nanoparticles that slowly oxidize into the magnetic Fe3O4 crystal structure under hydrothermal conditions, we were able to prepare well-defined and short-length IO@C nanochains that are highly dispersed in aqueous media and readily interact with bacterial cells, leading to a complete loss in bacterial cell viability within short incubation times at minimal dosage. The smaller IO@C nanochains synthesized using the FeO precursor nanoparticles can reach above 2-fold enhancement in microbe-killing activity when compared to the larger nanochains fabricated directly from Fe3O4 nanoparticles. In addition, the synthesized IO@C nanochains can be easily isolated using an external magnet and be subsequently recycled to effectively eradicate Escherichia coli cells even after five separate treatment cycles.

Iron oxide-loaded hollow mesoporous silica nanocapsules for controlled drug release and hyperthermia.

Magnetic field-responsive iron oxide-loaded hollow mesoporous silica nanocapsules that exhibit high drug loading capacity were synthesized using polymer nanospheres as sacrificial templates. Due to their magnetic field induced heating and remotely triggered drug release capabilities, these hybrid nanomaterials provide an excellent platform for the combination of hyperthermia and chemotherapy.

Adsorption of Cd2+ on carboxyl-terminated superparamagnetic iron oxide nanoparticles.

The affinity of Cd(2+) toward carboxyl-terminated species covalently bound to monodisperse superparamagnetic iron oxide nanoparticles, Fe(3)O(4)(np)-COOH, was investigated in situ in aqueous electrolytes using rotating disk electrode techniques. Strong evidence that the presence of dispersed Fe(3)O(4)(np)-COOH does not affect the diffusion limiting currents was obtained using negatively and positively charged redox active species in buffered aqueous media (pH = 7) devoid of Cd(2+). This finding made it possible to determine the concentration of unbound Cd(2+) in solutions containing dispersed Fe(3)O(4)(np)-COOH, 8 and 17 nm in diameter, directly from the Levich equation. The results obtained yielded Cd(2+) adsorption efficiencies of ~20 µg of Cd/mg of Fe(3)O(4)(np)-COOH, which are among the highest reported in the literature employing ex situ methods. Desorption of Cd(2+) from Fe(3)O(4)(np)-COOH, as monitored by the same forced convection method, could be accomplished by lowering the pH, a process found to be highly reversible.