Development of a Personalised Device for Systemic Magnetic Drug Targeting to Brain Tumours.

Delivering therapies to deeply seated brain tumours (BT) is a major clinical challenge. Magnetic drug targeting (MDT) could overcome this by rapidly transporting magnetised drugs directly into BT. We have developed a magnetic device for application in murine BT models using an array of neodymium magnets with a combined strength of 0.7T. In a closed fluidic system, the magnetic device trapped magnetic nanoparticles (MNP) up to distances of 0.8cm. In mice, the magnetic device guided intravenously administered MNP (<50nm) from the circulation into the brain where they localised within mouse BT. Furthermore, MDT of magnetised Temozolomide (TMZmag+) significantly reduced tumour growth and extended mouse survival to 48 days compared to the other treatment groups. Using the same principles, we built a proof of principle scalable magnetic device for human use with a strength of 1.1T. This magnetic device demonstrated trapping of MNP undergoing flow at distances up to 5cm. MDT using our magnetic device provides an opportunity for targeted delivery of magnetised drugs to human BT.

Surface Characteristics and Adhesion of Veneering Composite Resin to PAEK-Based Substructure Restorative Materials.

PURPOSE: To evaluate and compare the shear bond strength (SBS) of composite veneering material to polyetherketoneketone (PEKK), polyetheretherketone (PEEK), zirconia (YZ), and nickel-chromium alloy (NiCr) substructure restorative materials. MATERIALS AND METHODS: Forty samples (12 × 2 mm) were prepared from four materials: PEKK, PEEK, zirconia, and NiCr alloy (n = 10). The Vickers hardness was evaluated before preparing the surface for bonding by shot-blasting using 110 µm Al2 O3 particles. The surface roughness (Ra) of each sample was determined using a noncontact optical profilometer. The veneering resin was bonded onto each sample following primer application. The prepared samples were then subjected to an SBS test using a universal testing machine at 0.5 mm/min crosshead speed. Failure modes and surface topography following debonding were assessed. The data were statistically analyzed using ANOVA and Tukey's post-hoc comparison test (p < 0.05).  RESULTS: The highest and lowest mean surface roughness was observed in PEEK (3.45 ±0.13 µm) and NiCr (1.87 ±0.07 µm) materials, respectively. A significant difference in roughness values was observed between the materials except for NiCr and YZ (p = 0.547). Concerning SBS, PEEK and NiCr exhibited the highest (16.23 ±0.96 MPa) and lowest (10.1 ±0.63 MPa) values. The mean difference in SBS indicated a statistically significant difference between the material groups (p < 0.01). CONCLUSIONS: PEKK materials demonstrated significantly lower SBS than PEEK and significantly higher SBS values than conventional zirconia and alloy materials. A positive and significant correlation between mean roughness and SBS was observed, but the causality could be either intrinsic to the material or the roughness.

Demonstrating the Potential of Using Bio-Based Sustainable Polyester Blends for Bone Tissue Engineering Applications.

Healthcare applications are known to have a considerable environmental impact and the use of bio-based polymers has emerged as a powerful approach to reduce the carbon footprint in the sector. This research aims to explore the suitability of using a new sustainable polyester blend (Floreon™) as a scaffold directed to aid in musculoskeletal applications. Musculoskeletal problems arise from a wide range of diseases and injuries related to bones and joints. Specifically, bone injuries may result from trauma, cancer, or long-term infections and they are currently considered a major global problem in both developed and developing countries. In this work we have manufactured a series of 3D-printed constructs from a novel biopolymer blend using fused deposition modelling (FDM), and we have modified these materials using a bioceramic (wollastonite, 15% w/w). We have evaluated their performance in vitro using human dermal fibroblasts and rat mesenchymal stromal cells. The new sustainable blend is biocompatible, showing no differences in cell metabolic activity when compared to PLA controls for periods 1-18 days. FloreonTM blend has proven to be a promising material to be used in bone tissue regeneration as it shows an impact strength in the same range of that shown by native bone (just under 10 kJ/m2) and supports an improvement in osteogenic activity when modified with wollastonite.

Effect of Demineralizing Agents on Organic and Inorganic Components of Dentine.

There is a requirement to ensure that in vitro studies that use demineralized human dentine models are reliable and clinically relevant. The literature reports several strategies for these studies with a lack of consensus on the mode of action of the different demineralizing acids on human dentine. This in vitro study aims to characterize the effect of clinically relevant acids on human dentine, using standardized substrates and complementary analytical techniques. The study focuses on an analysis of the mineral content and the integrity of the collagen following partial demineralization. Samples of human dentine were exposed to a range of acids commonly encountered in the oral cavity. Characterization of the mineral content used Vickers micro-hardness, energy-dispersive spectroscopy, and X-ray fluorescence. Characterization of the collagen integrity was undertaken by means of scanning electron microscopy and hydroxyproline assay. The following conclusions were reached: (i) each demineralizing agent tested had a unique effect on the mineral levels; (ii) chelating agents, strong acids, and weak acids affect the mineral and organic phases of dentine in significantly different ways with no correlation between them; and (iii) the demineralizing agents caused some degree of collagen denaturation, citric acid causing the most damage. Overall, there is no clear link between the type of demineralizing agent and the effect on the organic and inorganic dentine. The choice of demineralizing agent should be aligned to the experiment objectives so that the selected dentine (caries or erosion) model is fit for the purpose.

TopoStats - A program for automated tracing of biomolecules from AFM images.

We present TopoStats, a Python toolkit for automated editing and analysis of Atomic Force Microscopy images. The program automates identification and tracing of individual molecules in circular and linear conformations without user input. TopoStats was able to identify and trace a range of molecules within AFM images, finding, on average, ~90% of all individual molecules and molecular assemblies within a wide field of view, and without the need for prior processing. DNA minicircles of varying size, DNA origami rings and pore forming proteins were identified and accurately traced with contour lengths of traces typically within 10 nm of the predicted contour length. TopoStats was also able to reliably identify and trace linear and enclosed circular molecules within a mixed population. The program is freely available via GitHub (https://github.com/afm-spm/TopoStats) and is intended to be modified and adapted for use if required.

In vitro Candida albicans biofilm formation on different titanium surface topographies.

OBJECTIVES: To investigate if differences in titanium implant surface topography influence Candida albicans biofilm formation. MATERIALS AND METHODS: Titanium discs were prepared and characterized using a profilometer: Group A (R a 0.15 µm, smooth), Group B (R a 0.64 µm, minimally rough) and Group C (R a 1.3 µm, moderately rough). Contact angle and surface free energy (SFE) were determined for each group. Non-preconditioned titanium discs were incubated with C. albicans for 24 h. In additional experiments, the titanium discs were initially coated with human saliva, bovine serum albumin or phosphate-buffered saline for 2 h before incubation with C. albicans for 24 h. The amount of fungal biofilm formation was quantified using a colorimetric assay. RESULTS: C. albicans biofilm formation was significantly lower (p < 0.05) on the minimally rough titanium surface compared to smooth and moderately rough surfaces. The titanium surface displaying the lowest SFE (Group B) was associated with significantly lower (p < 0.05) C. albicans biofilm formation than the other two groups. Salivary coating resulted in greater adherence of C. albicans with increased surface roughness. CONCLUSIONS: The minimally rough titanium discs displayed lowest SFE compared to smooth and moderately rough surfaces and showed the least C. albicans biofilm formation. This study demonstrated that C. albicans biofilm formation increased in a SFE-dependent manner. These findings suggest that SFE might be a more explanatory factor for C. albicans biofilm formation on titanium surfaces than roughness. The presence of a pellicle coating may negate the impact of SFE on C. albicans biofilm formation on titanium surfaces.

Characterization of a composite polylactic acid-hydroxyapatite 3D-printing filament for bone-regeneration.

Autologous cancellous-bone grafts are the current gold standard for therapeutic interventions in which bone-regeneration is desired. The main limitations of these implants are the need for a secondary surgical site, creating a wound on the patient, the limited availability of harvest-safe bone, and the lack of structural integrity of the grafts. Synthetic, resorbable, bone-regeneration materials could pose a viable treatment alternative, that could be implemented through 3D-printing. We present here the development of a polylactic acid-hydroxyapatite (PLA-HAp) composite that can be processed through a commercial-grade 3D-printer. We have shown that this material could be a viable option for the development of therapeutic implants for bone regeneration. Biocompatibility in vitro was demonstrated through cell viability studies using the osteoblastic MG63 cell-line, and we have also provided evidence that the presence of HAp in the polymer matrix enhances cell attachment and osteogenicity of the material. We have also provided guidelines for the optimal PLA-HAp ratio for this application, as well as further characterisation of the mechanical and thermal properties of the composite. This study encompasses the base for further research on the possibilities and safety of 3D-printable, polymer-based, resorbable composites for bone regeneration.

Evaluation of reproducibility of the chemical solubility of dental ceramics using ISO 6872:2015.

STATEMENT OF PROBLEM: The current chemical solubility method in the International Standards Organization (ISO) 6872 (2015) specifies only the total surface area of specimens for testing (≥30 cm2) but does not describe the morphology or geometry. This could impact the reproducibility of the test outcomes. PURPOSE: The purpose of this in vitro study was to investigate the factors influencing the reliability of the ISO 6872:2015 "Dentistry-Ceramic materials" test for chemical solubility. MATERIAL AND METHODS: Chemical solubility analysis of a range of materials and specimen geometries was performed in accordance with ISO 6872:2015. Yttria-stabilized tetragonal zirconia polycrystal (Y-TZP), VITABLOCS Mark II, IPS e.max Press, and IPS e.max ZirPress materials were formed into a range of cubic and spherical geometries to comply with the 30-cm2 minimum surface area requirement. The surface microstructure of the specimens was analyzed using a scanning electron microscope, inductively coupled plasma optical emission spectrometry (ICP-OES) was used to analyze the solutes, and surface hardness of the specimens was measured by using a Vickers hardness tester before and after testing. An optimized solubility test was devised, which eliminated specimen handling once the specimens had been ground and polished. This modified test was performed on VITABLOCS Mark II and Y-TZP. RESULTS: The results of the original chemical solubility method of ISO 6872:2015 showed significantly variable findings for each tested material, with a predictable relationship between geometry and chemical solubility. The hardness values decreased significantly after the solubility testing. The optimized method showed significantly improved reproducibility of the chemical solubility measurement compared with the original ISO 6872:2015 test. CONCLUSIONS: The results of the current chemical solubility standard method can be manipulated while still complying with the ISO 6872:2015 standard.

Biomodification of a Class-V Restorative Material by Incorporation of Bioactive Agents.

Restoring subgingival class-V cavities successfully, demand special biological properties from a restorative material. This study aimed to assess the effects of incorporating bioactive materials to glass ionomer cement (GIC) on its mechanical and biological properties. Hydroxyapatite, chitosan, chondroitin sulphate, bioglass, gelatine and processed bovine dentin were incorporated into a GIC restorative material. Compressive strength, biaxial flexural strength (BFS), hardness, setting and working time measurements were investigated. Biocompatibility of the new materials was assessed using both monolayer cell cultures of normal oral fibroblasts (NOF) and TR146 keratinocytes, and a 3D-tissue engineered human oral mucosa model (3D-OMM) using presto-blue tissue viability assay and histological examination. Significant reduction in the compressive strength and BFS of gelatine-modified discs was observed, while chondroitin sulphate-modified discs had reduced BFS only (p value > 0.05). For hardness, working and setting times, only bioglass caused significant increase in the working time. NOF viability was significantly increased when exposed to GIC-modified with bovine dentine, bioglass and chitosan. Histological examination showed curling and growth of the epithelial layer toward the disc space, except for the GIC modified with gelatine. This study has highlighted the potential for clinical application of the modified GICs with hydroxyapatite, chitosan, bioglass and bovine dentine in subgingival class-V restorations.

Factors controlling crystallization of miserite glass-ceramic.

OBJECTIVE: The purpose of this study was to investigate a range of variables affecting the synthesis of a miserite glass-ceramic (GC). METHODS: Miserite glass was synthesized by the melt quench technique. The crystallization kinetics of the glass were determined using Differential Thermal Analysis (DTA). The glasses were ground with dry ball-milling and then sieved to different particle sizes prior to sintering. These particle sizes were submitted to heat treatment regimes in a high temperature furnace to form the GC. The crystal phases of the GC were analyzed by X-ray diffraction (XRD). Scanning electron microscopy (SEM) was used to examine the microstructure of the cerammed glass. RESULTS: XRD analysis confirmed that the predominant crystalline phase of the GC was miserite along with a minor crystalline phase of cristobalite only when the particle size is <20 µm and the heat treatment at 1000°C was carried out for 4h and slowly cooled at the furnace rate. For larger particle sizes and faster cooling rates, a pseudowollastonite crystalline phase was produced. Short sintering times produced either a pseudowollastonite or xonotolite crystalline phase. SIGNIFICANCE: The current study has shown that particle size and heat treatment schedules are major factors in controlling the synthesis of miserite GC.

Evaluation of a novel multiple phase veneering ceramic.

OBJECTIVES: To produce a new veneering ceramic based on the production of a multiple phase glass-ceramic with improved performance in terms of strength and toughness. METHODS: A composition of 60% leucite, 20% diopside and 20% feldspathic glass was prepared, blended and a heat treatment schedule of 930°C for 5 min was derived from differential thermal analysis (DTA) of the glasses. X-ray diffraction (XRD) and SEM analysis determined the crystalline phases and microstructure. Chemical solubility, biaxial flexural strength (BFS), fracture toughness, hardness, total transmittance and coefficient of thermal expansion (CTE) were all measured in comparison to a commercial veneering ceramic (VITA VM9). Thermal shock resistance of the leucite-diopside and VITA VM9 veneered onto a commercial high strength zirconia (Vita In-Ceram YZ) was also assessed. Statistical analysis was undertaken using Independent Samples t-test. Weibull analysis was employed to examine the reliability of the strength data. RESULTS: The mean chemical solubility was 6 µg/cm(2) for both ceramics (P=1.00). The mean BFS was 109 ± 8 MPa for leucite-diopside ceramic and 79 ± 11 MPa for VITA VM9 ceramic (P=0.01). Similarly, the leucite-diopside ceramic demonstrated a significantly higher fracture toughness and hardness. The average total transmittance was 46.3% for leucite-diopside ceramic and 39.8% for VITA VM9 (P=0.01). The leucite-diopside outperformed the VITA VM9 in terms of thermal shock resistance. Significance This novel veneering ceramic exhibits significant improvements in terms of mechanical properties, yet retains a high translucency and is the most appropriate choice as a veneering ceramic for a zirconia base core material.