Implant-associated infections are highly challenging to treat, particularly with the emergence of multidrug-resistant microbials. Effective preventive action is desired to be at the implant site. Surface biofunctionalization of implants through Ag-doping has demonstrated potent antibacterial results. However, it may adversely affect bone regeneration at high doses. Benefiting from the potential synergistic effects, combining Ag with other antibacterial agents can substantially decrease the required Ag concentration. To date, no study has been performed on immobilizing both Ag and Fe nanoparticles (NPs) on the surface of additively manufactured porous titanium. We additively manufactured porous titanium and biofunctionalized its surface with plasma electrolytic oxidation using a Ca/P-based electrolyte containing Fe NPs, Ag NPs, and the combinations. The specimen’s surface morphology featured porous TiO2 bearing Ag and Fe NPs. During immersion, Ag and Fe ions were released for up to 28 days. Antibacterial assays against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa showed that the specimens containing Ag NPs and Ag/Fe NPs exhibit bactericidal activity. The Ag and Fe NPs worked synergistically, even when Ag was reduced by up to three times. The biofunctionalized scaffold reduced Ag and Fe NPs, improving preosteoblasts proliferation and Ca-sensing receptor activation. In conclusion, surface biofunctionalization of porous titanium with Ag and Fe NPs is a promising strategy to prevent implant-associated infections and allow bone regeneration and, therefore, should be developed for clinical application.@en

Patients receiving orthopedic implants are at risk of implant-associated infections (IAI). A growing number of antibiotic-resistant bacteria threaten to hamper the treatment of IAI. The focus has, therefore, shifted towards the development of implants with intrinsic antibacterial activity to prevent the occurrence of infection. The use of Ag, Cu, and Zn has gained momentum as these elements display strong antibacterial behavior and target a wide spectrum of bacteria. In order to incorporate these elements into the surface of titanium-based bone implants, plasma electrolytic oxidation (PEO) has been widely investigated as a single-step process that can biofunctionalize these (highly porous) implant surfaces. Here, we present a systematic review of the studies published between 2009 until 2020 on the biomaterial properties, antibacterial behavior, and biocompatibility of titanium implants biofunctionalized by PEO using Ag, Cu, and Zn. We observed that 100% of surfaces bearing Ag (Ag-surfaces), 93% of surfaces bearing Cu (Cu-surfaces), 73% of surfaces bearing Zn (Zn-surfaces), and 100% of surfaces combining Ag, Cu, and Zn resulted in a significant (i.e., >50%) reduction of bacterial load, while 13% of Ag-surfaces, 10% of Cu-surfaces, and none of Zn or combined Ag, Cu, and Zn surfaces reported cytotoxicity against osteoblasts, stem cells, and immune cells. A majority of the studies investigated the antibacterial activity against S. aureus. Important areas for future research include the biofunctionalization of additively manufactured porous implants and surfaces combining Ag, Cu, and Zn. Furthermore, the antibacterial activity of such implants should be determined in assays focused on prevention, rather than the treatment of IAIs. These implants should be tested using appropriate in vivo bone infection models capable of assessing whether titanium implants biofunctionalized by PEO with Ag, Cu, and Zn can contribute to protect patients against IAI. @en

The recently developed additively manufacturing techniques have enabled the fabrication of porous biomaterials that mimic the characteristics of the native bone, thereby avoiding stress shielding and facilitating bony ingrowth. However, aseptic loosening and bacterial infection, as the leading causes of implant failure, need to be further addressed through surface biofunctionalization. Here, we used a combination of (1) plasma electrolytic oxidation (PEO) using Ca-, P-, and silver nanoparticle-rich electrolytes and (2) post-PEO hydrothermal treatments (HT) to furnish additively manufactured Ti-6Al-4V porous implants with a multi-functional surface. The applied HT led to the formation of hydroxyapatite (HA) nanocrystals throughout the oxide layer. This process was controlled by the supersaturation of Ca²⁺ and PO₄³⁻ during the hydrothermal process. Initially, the high local supersaturation resulted in homogenous nucleation of spindle-like nanocrystals throughout the surface. As the process continued, the depletion of reactant ions in the outermost surface layer led to a remarkable decrease in the supersaturation degrees. High aspect-ratio nanorods and hexagonal nanopillars were, therefore, created. The unique hierarchical structure of the microporous PEO layer (pore size < 3 μm) and spindle-like HA nanocrystals (<150 nm) on the surface of macro-porous additively manufactured Ti-6Al-4V implants provided a favorable substrate for the anchorage of cytoplasmic extensions assisting cell attachment and migration on the surface. The results of our in vitro assays clearly showed the important benefits of the HT and the spindle-like HA nanocrystals including a significantly stronger and much more sustained antibacterial activity, significantly higher levels of pre-osteoblasts metabolic activity, and significantly higher levels of alkaline phosphatase activity as compared to similar PEO-treated implants lacking the HT.

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Prostate cancer is the most frequently diagnosed type of cancer among males. Brachytherapy has become a common treatment for this disease. In this form of radiotherapy, sealed radiation sources are placed through a implant catheters inside the prostate. This treatment affects the tumor cells locally and reduces damage to healthy tissues. However, accessing all relevant areas is met by difficulties. Innovating brachytherapy instruments can overcome these challenges. These new instruments need to be tested in a lab environment before patient testing is allowed. Phantom models provide a good validation model for testing new medical instruments. The goal of this study is to design and develop a cancerous prostate phantom model which can be used to test newly developed instruments for brachytherapy.
A material study was conducted to find the best mechanically tissue-mimicking materials. The effects of different concentrations, varying volumes, coolant additive and dimethyl-sulfoxide additive on the Young's modulus of poly-vinyl alcohol was tested. Unconfined compression tests were performed after each freeze-thaw cycle for a total of 7 cycles. These results showed that poly-vinyl alcohol can form material which, based on its Young's modulus, can mimic prostate tissue and adipose tissue. An increase in poly-vinyl alcohol concentration, volume, coolant additive, dimethyl-sulfoxide additive and the number of freeze-thaw cycles were each found to increase the Young's modulus of the material.
Three cancerous prostate phantom models were made of poly-vinyl material with each a different stiffness value achieved by varying the poly-vinyl alcohol concentrations. A low Young's modulus for model 1, medium for model 2 and high for model 3. The poly-vinyl alcohol was solved in a mixture of distilled water:DMSO (10:90 ratio) to produce a transparent material. Each model included a prostate, urethra and surrounding adipose tissue. The models were surrounded by a transparent casing which included an opening and template for needle insertion at the front. A pubic bone was added to model 2 and 3 to simulate prostate blockage by this tissue. Model 1 and 2 did not achieve the transparency that was required. The transparency was found to be sufficient in model 3.
A needle insertion experiment was conducted to validate the prostate phantom models. An 18Gauge brachytherapy needle was inserted 13, 10 and 20 times in model 1, 2 and 3 respectively with a velocity of 5 mm/s. Mean peak forces, describing the force upon puncture of the prostate material, for model 1 (0.57 N) and 2 (3.54 N) were lower than multiple peak forces found in literature. The median peak force of model 3 (6.17 N) came close to the peak force found during in patients with prostate cancer (6.28 N) in the study of Podder et al. (2006). Higher Young's moduli values produced higher peak forces. The insertion force in the adipose tissue of the models was lower than the results found in literature.
This study has shown that poly-vinyl alcohol can function as an easily controlled tissue mimicking material. The material study created an overview of the effects of concentration, volume, coolant, DMSO and freeze-thaw cycles on the Young's modulus of poly-vinyl alcohol. An easy to manufacture cancerous prostate phantom model was made of poly-vinyl alcohol and DMSO. Model 3 developed in this project can function as a test model for newly developed instruments meant for brachytherapy.

Purpose: Head-neck modularity was introduced into total hip arthroplasty to provide more intraoperative surgical options. However, modularity led to new problems, such as trunnionosis and fractures of the femoral prosthesis neck. The purpose of this study was to identify risk factors for hip neck fractures and to provide recommendations to prevent damage and fractures of the neck. Methods: A systematic review of the literature was performed according to the PRISMA guidelines. Results: Thirty-three case studies were included. Methodologically, most included studies were of moderate or good quality. The 80 neck fractures included in the review took place, on average, 7 years after stem placement. Male gender, high body weight, obesity, previous revision surgery, mixing components from different manufacturers, use of long skirted heads, cobalt-chromium (large size) heads were identified as potential risk factors. Conclusion: Hip neck fractures occur on average 7 years after stem placement. The etiology of hip neck fractures is multifactorial. This review revealed several preventable implant- and surgeon-related risk factors.

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Expanded Criteria Donor (ECD) organs are being used more often in clinical setting. The regenerative ability of the organs might be able to restore the organ to full functionality ex vivo. For long term kidney stabilization, optimization and monitoring an organ incubator is preferable. However, it is unclear which available parts would work best in synergy. A Normothermic Machine Perfusion (NMP) setup and a Mathematical Windkessel Model were created as a first step in a larger project of prolonged preservation of ECD organs. While the current NMP setup was found adequate for academic research, it can only be used for simple studies using water. Several fundamental improvements need to be made before the setup can be used as a fully functioning NMP setup for kidneys. Key improvements would be the addition of a Windkessel and a different cardiac pump.

When sawing in bone for medical or medico-legal procedures, fine, airborne dust is produced (aerosols) that can pose a health hazard when inhaled by practitioners. The goal of the current study was to find the influence of saw blade frequency and saw blade contact load, the degree of skeletonisation of the bone, the test environment with external air flows such as ventilation systems, and the type of saw blade used on the production of aerosol particles. A custom test setup was designed and manufactured to test the sawing parameters in 8 experiments, with 2 to 9 experimental conditions tested in each, where a particle counter was used to determine the production of aerosol particles while varying the 5 chosen parameters. Results showed that the number of counted particles was highest with higher saw blade frequencies, lower saw blade contact loads, in dry completely skeletonised bone compared to fresh bone, and using an electrical oscillating saw compared to hand-sawing. Under all conditions, the high amount of aerosol counted posed potential health risks. The tested external ventilation system was adequate in removing the produced number of particles, but these high-tech systems are not always available in developing countries or emergency situations. In conclusion, the production of aerosols can be reduced by optimising the sawing parameters. However, even the lowest number of aerosol particles counted during the current study was high enough to cause potential health risks to practitioners. Safety precautions should be taken, such as external ventilation, proper breathing gear, and adequate protocols, to truly minimise the risk in all bone sawing scenarios.

Development of synthetic bactericidal surfaces is a drug-free route to the prevention of implant-associated infections. Surface nanotopographies with specific dimensions have been shown to kill various types of bacterial strains through a mechanical mechanism, while regulating stem cell differentiation and tissue regeneration. The effective ranges of dimensions required to simultaneously achieve both aims are in the <200 nm range. Here, a nanoscale additive manufacturing (=3D printing) technique called electron beam induced deposition (EBID) is used to fabricate nanopillars with reproducible and precisely controlled dimensions and arrangements that are within those effective ranges (i.e. a height of 190 nm, a diameter of 80 nm, and an interspacing of 170 nm). When compared to the flat surface, the nanopatterned surfaces show a significant bactericidal activity against both Escherichia coli and Staphylococcus aureus (with respective killing efficiencies of 97 ± 1% and 36 ± 5%). Direct penetration of nanopatterns into the bacterial cell wall leads to the disruption of the cell wall and cell death. The more rigid cell wall of S. aureus is consistent with the decreased killing efficiency. These findings support the development of nanopatterns with precisely controlled dimensions that are capable of killing both Gram-negative and Gram-positive bacteria.@en

In recent years, more and more medical operations are done minimally invasive. Intervention radiology is a medical specialty which uses minimally invasive techniques to diagnose, or treat diseases. Instruments like needles and catheters are used by radiologists to enter the network of veins and arteries guided by image modalities. A complex treatment in the interventional radiology is the Transjugular Intrahepatic Portosystemic Shunt (TIPS) procedure. This treatment is developed for people who suffer from liver cirrhosis which are not eligible for liver transplantation. The problem which arise with a liver affected by cirrhosis is that it can not transmit enough blood. Without transplantation or a treatment this will eventually lead to death. During the TIPS procedure a connection is made between the right hepatic and the portal vein by a shunt. As a result, blood pressure reduction in the portal system since the blood can flow back to the right atrium of the heart, bypassing the liver.

The hardest part in a TIPS procedure is the intrahepatic puncture between the hepatic and portal vein. The interventional radiologist tries to enter the portal vein by puncturing a small stylet from the hepatic vein through the liver tissue. Due to cirrhosis the liver tissue is very stiff and stylet deflection will occur. To reduce the uncertainty of entering the portal vein, this thesis is focused on designing a stylet that is more stiff and able to steer. It is expected that the complexity of the procedure will be reduced and a higher hit rate to enter the portal vein will be achieved.\\
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The prototype of the steerable stylet has been evaluated through various experiments, a visibility test and with procedures in a test liver model. During these experiments the steering characteristics, the stiffness of the stylet, the maximum lateral forces exerted by the tip while steering, the influence of the stylet orientation and the visibility are obtained. Afterwards, an evaluation was done in a liver model, made of PVA, to determine whether the stylet is capable to reduce the complexity of the intrahepatic puncture step in the TIPS procedure.

With the prototype made in this graduation project, based on a steerable ablation needle, the complexity of the TIPS procedure is not reduced yet. The steerable stylet was not able to enter the portal vein. It was already hard to enter the right hepatic vein since the pre-bent stiffening cannula was adapted with a smaller angle which was necessary since the steerable stylet was too stiff to push through the pre-bent angle. According to this prototype, possibilities are shown to use a mechanical steering mechanism in instruments with a long thin shaft. The transmission in combination with the joint mechanisms fits within 1.3mm diameter, was able to bridge 60cm from distal end to proximal end and had only 4 components, the stylet, the rigid cannula, the key to fix the stylet to the rigid cannula and the transmission. By translating the stylet in a push or pull direction relative to the rigid cannula, steering angles could be achieved. With further research and development this steering mechanism must be able to steer the required amount of degrees without any extra components, is well visible with ultrasound, and is good resistant against lateral forces.

Atherosclerosis, the chronic inflammation of the arterial wall, is one of the leading causes of death in the western societies. Which is characterized by the accumulation of inflammatory macrophages and necrotic regions in the intima. Rupture of the plaque can lead to thrombosis, a blood clot in the blood vessel, blocking the natural flow of the blood. If left untreated the entire lumen can be blocked and the results can be fatal. Progression in atherosclerosis is mainly driven by the build up of macrophages. An important phenotype on these cells are cannabinoid receptors, important in the control of inflammatory pathways. By presenting inflammatory relieving cannabinoids to these receptors, the macrophages could become less inflammatory. A localized delivery would give the additional benefit of reducing systematic side effects. High density lipoprotein based nanoparticles have shown to be great carriers for drug molecules. Additionally, high density lipoproteins are able to relieve AS up to a certain extend. In this research we analyzed physical and physio-chemical properties of different nanoparticle formulations. Specifically, the size, morphology and ζ-potential. Next we investigated the cannabinoid receptor expression on different types of macrophages, which verified that macrophages in atherosclerotic conditions have an abundance of our target receptor. Finally we performed a small in vitro study showing both empty and cannabinoid loaded nanoparticles relieved pro-inflammatory signals.