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Magnetic hyperthermia holds significant therapeutic potential, yet its clinical adoption faces challenges. One obstacle is the large-scale synthesis of high-quality superparamagnetic iron oxide nanoparticles (SPIONs) required for inducing hyperthermia. Robust and scalable manufacturing would ensure control over the key quality attributes of SPIONs, and facilitate clinical translation and regulatory approval. Therefore, we implemented a risk-based pharmaceutical quality by design (QbD) approach for SPION production using flame spray pyrolysis (FSP), a scalable technique with excellent batch-to-batch consistency. A design of experiments method enabled precise size control during manufacturing. Subsequent modeling linked the SPION size (6–30 nm) and composition to intrinsic loss power (ILP), a measure of hyperthermia performance. FSP successfully fine-tuned the SPION composition with dopants (Zn, Mn, Mg), at various concentrations. Hyperthermia performance showed a strong nonlinear relationship with SPION size and composition. Moreover, the ILP demonstrated a stronger correlation to coercivity and remanence than to the saturation magnetization of SPIONs. The optimal operating space identified the midsized (15–18 nm) Mn_0.25Fe_2.75O₄ as the most promising nanoparticle for hyperthermia. The production of these nanoparticles on a pilot scale showed the feasibility of large-scale manufacturing, and cytotoxicity investigations in multiple cell lines confirmed their biocompatibility. In vitro hyperthermia studies with Caco-2 cells revealed that Mn_0.25Fe_2.75O₄ nanoparticles induced 80% greater cell death than undoped SPIONs. The systematic QbD approach developed here incorporates process robustness, scalability, and predictability, thus, supporting the clinical translation of high-performance SPIONs for magnetic hyperthermia.

Injectable poly (methyl methacrylate) (PMMA) bone cements are widely used in orthopaedics to stabilize fractures and for implant fixation. However, bacterial attachment to bone cements leads to significant complications that can create a need for implant revision. Common attempts at reducing bacterial attachment are through the addition of antibiotics or antibacterial nanometals to the bone cements. However, clinical data is inconclusive on the effectiveness of antibiotic-loaded bone cements and a negative osteoblastic response has been reported for certain additive concentrations. There is therefore a need for an additive that can positively affect osteoblastic behaviour while inhibiting bacterial attachment. Silicon nitride (Si3N4) could be such an additive, with initial studies showing promise in achieving antipathogenic properties. The aim of this study was hence to investigate the possibility of creating a bone cement that can support osteoblast growth while reducing bacterial attachment by introducing silicon nitride powders into an injectable PMMA cement. To this end, commercially available bone cements were doped with 5%, 10% and 20% weight/weight (w/w) of Si3N4. Their mechanical properties were examined through compression testing and their radiopacity was evaluated through fluoroscopy imaging. The samples that fulfilled compressive strength requirements had their biological properties tested using Staphylococcus epidermidis bacteria for antibacterial properties and MC3T3-E1 preosteoblasts for the examination of cytotoxicity. Bone cements that were doped with up to 20% w/w Si3N4 were radiopaque (only 13% reduction in optical density compared to radiopaque controls) and retained their compressive strength (85.35 ± 2.1 MPa compared to 83.4 ± 1.9 MPa for the commercial cements), while significantly reducing bacterial attachment by more than 90% compared to commercial cements and achieving a similar level of preosteoblast metabolic activity. This study supports further evaluation of Si3N4 as an additive to injectable bone cements as a way to create mechanically stable, radiopaque, bacteriostatic bone cements that could improve osteointegration.

Surface nitriding has been widely used to improve the surface physicochemical properties of Ti alloys. However, the currently utilized surface nitriding methods, such as laser nitriding, typically require expensive and complicated instruments, which makes surface nitriding a less cost-effective process. Meanwhile, the antibacterial properties of surface-nitrided Ti alloy implants have not been evaluated. Thereafter, in this study, we were aiming to develop an effective, simple, and cost-effective surface nitriding strategy to enhance the antimicrobial properties of Ti alloy implants. The surface nitriding strategy was realized by wet-chemical etching and thermal treatment at controlled conditions. Results showed that the above surface modification treatments exerted significant effects on the phase composition and morphology of the newly formed phases on the surface of Ti samples. Crystalline TiN and TiO2 formed after treatments. Meanwhile, amorphous nitrides and oxynitride were also presented on the sample surfaces. The surface-modified Ti samples showed a bacterial inhibition effect compared with the non-treated Ti ones, and the bacterial inhibition effect was attributed to the released ammonia species from the surface of Ti samples. The surface modification strategy shows promise to improve the bacteriostatic property of Ti implants in dental and orthopedic fields.

Silicon nitride (Si₃N₄) is a ceramic material that is well-established in industrial applications due to its stability in demanding environments. The mechanical properties and biocompatibility of the material have led to its approval for clinical use in spinal implants. The unique surface chemistry of Si₃N₄ has been shown to create a chemical environment that is supportive to bone regeneration while simultaneously reducing bacterial viability, both in vitro and in animal models in vivo. Thus, Si₃N₄ can be used in the spine to reduce patient recovery times while protecting the implant site from damaging and costly infections. However, results from clinical studies have not shown significant differences between silicon nitride and other spinal implant materials in terms of patient outcomes.   

Thus, the first aim of this thesis was to find ways to optimise the biological properties of the material and in turn create spinal implants that would exhibit significantly higher osteointegration while reducing the incidence of infections. To this end, a thermochemical surface modification was developed that changed the surface chemistry and roughness of the material resulting in increased in vitro bioactivity without affecting its antibacterial behaviour. Furthermore, the possibility of creating an osteoconductive, antibacterial bone cement to be used in vertebroplasties in the spine was explored. By adding up to 20%wt of a Si₃N₄ powder to poly methyl methacrylate (PMMA) cements, a significant (>90%) reduction of bacterial biofilm formation was achieved without affecting the compressive strength or biocompatibility of the modified bone cements in a negative way.

A secondary objective of the study was to explore the antipathogenic properties of the material, fulfilling the growing need for a world where the spread of dangerous pathogens will be limited. The efficiency of the material against one of the most resilient DNA-viruses, the human adenovirus, was tested. It was found that contact with Si₃N₄ in both powder and bulk form rapidly reduced infectivity (>98% and >73%, respectively). Based on these results, a thermal modification of silicon nitride powders was developed, that would enhance their antiviral efficiency against SARS-CoV-2 and thus the applicability of the material. It was found that 10%wt modified-Si₃N₄ slurries rendered the coronavirus non-infectious after less than a minute of contact. The results of these studies proved that silicon nitride can also be used as an antipathogenic agent in environmental applications.

Overall, in this thesis, steps were taken towards the development of Si₃N₄-based materials that can lead to faster healing, lower infection rates and that can be used to limit the spread of disease.

Silicon nitride (Si3N4) is a promising biomaterial, currently used in spinal fusion implants. Such implants should result in high vertebral union rates without major complications. However, pseudarthrosis remains an important complication that could lead to a need for implant replacement. Making silicon nitride implants more bioactive could lead to higher fusion rates, and reduce the incidence of pseudarthrosis. In this study, it was hypothesized that creating a highly negatively charged Si3N4 surface would enhance its bioactivity without affecting the antibacterial nature of the material. To this end, samples were thermally, chemically, and thermochemically treated. Apatite formation was examined for a 21-day immersion period as an in-vitro estimate of bioactivity. Staphylococcus aureus bacteria were inoculated on the surface of the samples, and their viability was investigated. It was found that the thermochemically and chemically treated samples exhibited enhanced bioactivity, as demonstrated by the increased spontaneous formation of apatite on their surface. All modified samples showed a reduction in the bacterial population; however, no statistically significant differences were noticed between groups. This study successfully demonstrated a simple method to improve the in vitro bioactivity of Si3N4 implants while maintaining the bacteriostatic properties.

The spread of SARS-CoV-2 led to a global pandemic that caused several million deaths. The severity of this pandemic created challenges for scientists worldwide regarding the prevention of the spread of COVID-19, the disease the virus causes. While the use of personal protective equipment and social distancing limited the spread of the virus, high transmission rates were noted. A solution to the issue of viral spread can be partially given by the utilization of antiviral materials for long-term protection against pathogens on environmental surfaces. To this end, nitrides are materials of high interest due to their proven efficiency in inactivating bacteria and viruses. Silicon nitride (Si3N4) is a ceramic material that possesses an inactivation mechanism termed ‘catch and kill’. In this study we hypothesized that a surface-modified Si3N4 material whose hydrophilicity has been increased through a heat treatment could lead to high attachment and inactivation of SARS-CoV-2 virions. Si3N4 powders were oxidized, characterized and the inactivation of SARS-CoV-2 by them was tested. The results showed that oxidized Si3N4 was highly effective in binding and inactivating SARS-CoV-2 after as little as one minute of contact and can be used to inhibit the spread of COVID-19 under certain circumstances.

Containing the spread of pathogens and treating the diseases they cause have become topics of high importance and urgency for researchers. Recent epidemics and pandemics, key amongst them being the pandemic caused by the coronavirus disease (COVID-19), have highlighted the devastating results virus infections can have on our society. Uncovering and utilising materials for the protection from and treatment of virus-induced diseases can considerably alleviate the load imposed on healthcare systems worldwide. Silicon nitride is a biocompatible ceramic material used in orthopedic implants that is effective in the inactivation of single-stranded RNA viruses. However, the effect of the material on the more resilient DNA viruses remains unknown. This study aimed to investigate the antiviral behaviour of the material, in powder and bulk form, against DNA viruses, and more specifically the human adenovirus. The results of the study indicated that silicon nitride dramatically reduces adenoviral infectivity in powder (>98% reduction in infective virus compared to untreated samples) and bulk form (>73% reduction in infective virus compared to negative control). In both cases, inactivation was achieved rapidly, in one minute for powders and 10 minutes for bulk surfaces. The findings of this study strengthen the potential of silicon nitride to be used as an antiviral agent, aiding the fight against the spread of both DNA and RNA virus diseases.