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  • (2022) Bhattacharjee, Shovon
    Thesis
    There is an ongoing global threat of highly transmissible infectious disease outbreaks such as the COVID-19 pandemic. Consequently, the demand for effective, sustainable, and reusable personal protective equipment (PPE) is high for the protection of the frontline workers and community, especially with possible vaccine-resistant variants emerging. However, the commonly used PPE, especially protective clothing, and face masks, has several drawbacks and improvement areas. In this thesis, three state-of-the-art reviews (Chapters 2A, 2B, and 2C) identified the challenges and limitations of commonly used protective clothing and face masks. Potential new materials, technologies, and strategies were also addressed to overcome the limitations and challenges. Lastresort strategies were outlined to help people navigate their choices during mask shortages. In addition, it was revealed that the multifunctional performance of PPE could be significantly enhanced with the application of advanced materials such as graphene and metal nanoparticles (NPs). Accordingly, in Chapters 3 and 4, reduced graphene oxide (RGO) and copper (Cu)/silver (Ag) NPs incorporated cotton and silk fabrics were developed by a facile dip and dry method using a silane crosslinking agent followed by chemical reduction and vacuum heat treatment. The developed fabrics demonstrated excellent multifunctional activities such as hydrophobicity, electroconductivity, Joule heating capacity, heat dissipation, thermal stability, mechanical stability, UV shielding, and washing durability. Especially, the RGO- and Cu-NPs-embedded cotton and silk fabrics exhibited the best multifunctional performances with high washing durability among all other fabric samples. To further assess the potential of protective clothing, antimicrobial activity and biocompatibility of the developed fabrics were investigated in Chapter 5. The graphene and Cu/Ag NPs incorporated fabrics showed excellent activity against bacteria (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus) and fungus (Candida albicans). On top of the antimicrobial activity, the developed fabrics showed low cytotoxicity, making them a potential candidate for application in next-generation PPE. During COVID-19, due to the massive global shortage of disposable masks/respirators, cloth masks became a mainstay and showed hope of being a sustainable alternative to medical masks. Chapter 6 provides a comprehensive study using violent respiratory events (sneeze) and evaluating all dimensions of protection (respiratory droplet blocking efficiency, water resistance, and breathing resistance) to develop a blueprint for the optimal design of a high-performing reusable cloth mask that can outperform a disposable surgical mask. The results reveal that droplet blocking efficiency increases by ∼20 times per additional fabric layer. A minimum of 3 layers with a combination of cotton/linen (hydrophilic) for the inner layer, blends for the middle–layer, and polyester/nylon (hydrophobic) for the outer–layer is required to resemble the performance of surgical masks. The fabrics' average thread count and porosity should be greater than 200 and less than 2 %, respectively. Overall, the developed graphene/NPs incorporated multifunctional fabrics, and face mask design proved to be a breakthrough to prevail over the limitations of the conventional PPE materials. They hold great promise to be applied to a broader range of PPE and could provide a sustainable PPE solution globally.

  • (2022) Khosravanihaghighi, Ayda
    Thesis
    The two leading causes of failure of orthopaedic implants are aseptic loosening and periprosthetic joint infection. Since the numbers of primary and revision joint replacement surgeries are increasing, strategies to mitigate these failure modes have become increasingly important. However, most recent work has focused on the design of coatings to prevent infection or to enhance bone mineralisation. However, long-term success of the implants is contingent on addressing both of these issues. Consequently, the present work focussed on multifunctional orthopaedic coatings that inhibit microbial cells while still promoting osseointegration. Nanoceria has considerable potential to be used in biomedical applications owing to its unique bio-responsive redox switching and its capacity to be doped with different therapeutic ions of varying functionalities. Therefore, the effect of different cations incorporated in ceria on cellular behaviour in vitro as well as the anti-bacterial performance were investigated. The two main foci were: (1) characterisation of the bioceramic materials and (2) biological response to undoped and doped ceria ceramics in vitro using bacteria colonies forming unit (CFU) and cytotoxicity Ceria (CeO2) thin films (~820 nm thickness) doped with 0-9 mol% Ga or Mn were fabricated by spin coating on 3D-printed Ti6Al4V followed by heat treatment at 650°C for 2 h, and these were characterised by transmission electron microscopy (TEM) and field emission scanning electron microscopy (FESEM) (microstructure), 3D laser scanning confocal microscopy (topography), glancing angle X-ray diffraction (GAXRD) (structure and mineralogy), and X-ray photoelectron spectroscopy (XPS) (surface chemistry). In vitro testing was conducted, including inhibition of bacterial growth, simulated body fluid (SBF) testing, and cell attachment and proliferation studies. The data are interpreted in terms of the following: (1) The roles of the sol-gel precursor viscosity, which affected pore filling and surface coverage, (2) Lattice contraction, which contradicted the XPS data, (3) Intervalence charge transfer, which increased the Ce3+ concentration but was a minor effect, (4) Substitutional solid solubility, which is consistent with Hume-Rothery’s rules and the GAXRD data, (5) Redox charge compensation, where the defect equilibria highlight the key role of this mechanism, which decreased the Ce3+ concentration and provided the majority effect, (6) Electronegativity, which plays a small, if any, role in affecting the ion valences but is important in initiating intervalence charge transfer, (7) Multivalence charge transfer, which combined the electron exchanges between film matrix, dopants, and Ti substrate. The most significant outcome was that the bioactivity of ceria derives directly from the Ce3+ concentration, which itself results from solid solubility (substitutional and interstitial) and charge compensation and redox. This challenges the common assumption of the dominance of oxygen vacancies in the performance of ceria. The antibacterial activity was dependent on the type, amount, and valence of the dopant, where opposite trends were observed for gram-positive S. aureus and gram-negative E. coli bacteria. All of the doped samples resulted in enhanced cell proliferation, although this was greatest at the lowest dopant concentration. Surface hydroxyapatite formation on the samples was achieved by soaking in SBF at 2 weeks and 1 month.

  • (2022) Joshi, Nidhi
    Thesis
    RNA interference (RNAi) has emerged as a promising tool to silence any kind of gene expression from viral infection to genetic disease, especially in the field of cancer treatment. siRNA-based therapeutics offer an efficient and specific targeting of disease-causing genes. An aberrant expression of Wnt pathways and ROR receptors which are the transmembrane protein of tyrosine kinase family, have been reported in many cancers, including ovarian cancer. The upregulation of Wnt pathways and ROR receptors are known to be potential contributors in ovarian cancer progression and metastasis. Therefore, targeting these receptors could be a powerful approach towards designing and developing new therapeutic materials. In that regard, siRNA-based therapeutics offer an efficient and specific targeting of overexpressed disease-causing genes. However, the challenge remains for the effective and safe delivery of siRNA therapeutics while maintaining its efficacy and therapeutic integrity. Polymeric nanostructures hold great promise towards designing a compatible delivery vector for nucleic acid therapeutics, especially for siRNA drugs. Among polymeric systems, polycationic carriers based on PDMAEMA are widely explored as nucleic acid delivery vectors. The low toxicity and high transfection efficiency make them an excellent candidate for targeted siRNA therapy. There is an immense scope to study PDMAEMA based vectors as cancer therapeutic carriers for siRNA drugs in platinum-resistant and high-grade ovarian cancer. Therefore, this study aims to develop well-defined biocompatible polymeric nanocarriers for targeted siRNA (ROR2 siRNA) therapy in cisplatin resistance (A2780) and high grade serous ovarian cancer (HGSOC) cells. Polymeric systems containing PDMAEMA as siRNA condensing core have been employed with various structural modifications to investigate the delivery efficiency and therapeutic potential of siRNA drugs. The ability of polymeric nano-vector either generated from PEGylation or BSA modification of PDMAEMA to efficiently bind and release ROR2 siRNA in both 2D and 3D ovarian cancer cell model have been investigated. It was observed that the inhibitory effect of ROR2- siRNA encapsulated in the core of polyion complex (PIC) is strongly dependent on the polyPEGMEMA block length. Reduction of ROR2 expression in both transcription and translation levels was observed in A2780 cells. Alternatively, the BSA modified PDMAEMA nanoparticles present a biocompatible approach for targeted siRNA delivery in HGSOC cells. BSA decorated nanoparticles have shown potential to deliver ROR2-siRNA efficiently in the cytoplasm and hence displayed a significant reduction in migration and invasive features of HGSOC cells.

  • (2022) Amaldoss, Maria John Newton
    Thesis
    Nanocatalytic tumor therapies involve established strategies to increase the concentration of endogenous oxygen species (ROS) H2O2 to cytotoxic levels. These strategies are based on increasing the ROS levels through stimuli from drugs, the action of ROS-producing agents, and nanoparticulate catalysis. However, these techniques frequently are indiscriminatory, being cytotoxic to diseased cells and normal cells alike, leading to significant unwanted side-effects. The present work reports a new paradigm strategy based upon the catalytic action of a cell-discriminative, ROS-mediating, autophagy-suppressive nanoparticle, which is CePO4·H2O (rhabdophane). CePO4·H2O nanoparticles were synthesised using CeNO3·6H2O precipitated in an aqueous solution of sodium tripolyphosphate (STPP) at room temperature. The nanoparticles were well crystallised, equiaxed (~10-35 nm), of positive surface charge, and of general valence ratio 〖"Ce" 〗_"0.8" ^"3+" 〖"Ce" 〗_"0.2" ^"4+" 〖"PO" 〗_"4.1" . Materials characterisation involved particuological (hydrodynamic particle size, surface area, zeta potential), mineralogical (X-ray diffraction, laser Raman microspectroscopy), chemical (X-ray photoelectron spectroscopy), structural (Fourier transform infrared spectroscopy), and microstructural (transmission electron microscopy) analyses. Biological characterisation involved examination of the effects on HT-1080 fibrosarcoma cells and MRC-5 normal fibroblasts in terms of cellular interactions (cell viability by MTT assay), cellular uptake and trafficking (confocal laser scanning microscopy, biological transmission electron microscopy, flow cytometry), ROS generation (confocal laser scanning microscopy, flow cytometry), apoptosis (annexin V-FITC assay), gene expression (q-RT-PRC), and protein expression (western blot analyses). The key observations and conclusions from the biological evaluation are as follows: Discriminative Cytotoxicity: CePO4·H2O nanoparticles are the first to exhibit discriminative cytotoxicity: At 24 h, fibrosarcoma HT-1080 cell viability is ~10% but MRC-5 normal cell viability is ~45%. Discriminative Uptake: CePO4·H2O nanoparticles are the first, without the use of a targeting ligand, to be internalized readily by cancer cells but scarcely by normal cells. Self-Targeting: CePO4·H2O nanoparticles are trafficked toward the mitochondrial environment and possibly the converse trafficking. Mitochondrial Starvation: The preceding proximity between CePO4·H2O nanoparticles and cancer cell leads to increased phosphate concentration in the cellular environment, the concentration gradient of which effectively starves the mitochondria, leading to mitochondrial stress and dysfunction. Discriminative ROS Generation: CePO4·H2O nanoparticles are the first to demonstrate elevated cellular ROS in cancer cells by multiple mechanisms while normal cells exhibit only a low level of such elevation. Autophagy Suppression: CePO4·H2O nanoparticles suppress autophagy, thereby increasing cellular stress and suppressing cancer cell survival, thus offering a complement to mitochondrial starvation. Redox Switching: CePO4·H2O nanoparticles are the first nonmetallic nanoparticles to balance redox switching through simple electronic charge compensation rather than more complex ionic charge compensation. Biocompatibility: As hydrated phosphates, CePO4·H2O nanoparticles are more biocompatible than metals or oxides, suggesting greater feasibility of renal clearance. These advantages derive from the key role of the redox and defect equilibria arising from the oxidation reaction Ce3+ → Ce4+ + e′, which is induced by the acidic pH environment of the cancer call versus the stability of the Ce3+ valence in the basic pH environment of the normal cell. The former both elevates the ROS level and disrupts the electron transfer chain. Ultimately, the suppression of the proliferation of cancer cells derives from the cross-talk involving cellular ROS elevation, autophagy suppression, and their mitochondrial control.

  • (2023) Ireland, Jake
    Thesis
    Pluripotent stem cell-derived cardiomyocytes (hPSC–CM) have great importance for predicting safety parameters for pharmaceutical compounds and models of healthy versus disease states of the human heart. In recent years, there has been an insistence that all new pharmaceutical products are tested on in vitro models for potential proarrhythmic effects and the increased demand for improved biomimetic hPSC-CM in pharmaceutical safety assays such as the Comprehensive in vitro Proarrhythmic Assay (CiPA). In addition, hPSC-CM are being utilised in cell therapies to treat and reverse the effects of ischaemic heart disease, offering potential cures for cardiovascular diseases instead of treatments for delaying progressive heart failure. In the first part of this thesis, I will examine how purified extracellular matrix proteins (ECMPs) can influence pluripotent stem cell (PSC) behaviour and how we may use this to precondition cardiac progenitor lineage specifications. I use array-based techniques to investigate how protein combinations affect proliferation, pluripotency, germ layer, and cardiac progenitors. This method allows us to visualise how individual proteins can affect cells' behaviour in a larger array whilst highlighting how specific combinations can precondition pluripotent cells towards a cardiomyocyte lineage. This combinatorial approach led to the identification of several unique matrices that promote differentiation, which will aid efforts at producing therapeutically useful cell types with greater efficiency. In the second part of this thesis, I demonstrate a novel bioreactor that attenuates a magnetic field to dynamically modulate the stiffness of magnetoactive hydrogel to look at how biomimetic dynamic stiffening of a substrate can influence cardiomyocyte lineage specification. We investigate how biomimetic in vivo mechanics may influence cell fate by following the expression profiles of cells in different dynamic environments. Non-invasive electromagnetic signals affect substrate stiffness when combined with magnetic particles and magnetic fibres and how this can help direct cell orientation and accompanying lineage specification Finally, I investigate how variability in cell phenotypes and expression patterns are influenced by biomimetic cues and how these variabilities could be utilised in future safety assessment protocols and cell therapy treatments for cardiovascular disease.