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A Systematic Investigation of Cellular Interactions with Lipid-Based Lyotropic Liquid Crystalline Nanoparticles
No full textThe clinical implementation of lipid nanoparticles (LNPs) in the first successful nucleic acid-based vaccines marks a milestone in drug delivery, demonstrating the transformative potential of these nanocarriers in life-changing therapeutics. A major challenge in drug delivery lies in overcoming biological and transport barriers that limit the efficacy of therapeutics. For example, many drugs fail to surpass biological barriers such as the plasma membrane or the blood-brain barrier. Furthermore, hydrophobic drugs suffer from poor water solubility, reducing their bioavailability in the bloodstream. Similarly, fragile cargoes like nucleic acids are rapidly degraded by enzymatic activity in the body before reaching their intended targets. Even when bioactive molecules reach their cellular targets and undergo internalization, intracellular barriers present a further obstacle to their therapeutic efficacy. Endosomal entrapment, lysosomal degradation, and cellular recycling pathways often prevent therapeutics from reaching their subcellular targets. These challenges significantly reduce the efficiency of drug delivery systems, necessitating novel strategies to improve intracellular cargo transport.LNPs have emerged as a promising solution due to their ability to encapsulate hydrophobic, hydrophilic, and amphiphilic compounds, effectively improving drug solubility, stability, and cellular uptake. By facilitating the transport of bioactive cargoes across the plasma membrane, LNPs function as a "Trojan horse" for intracellular delivery. Despite this advancement, endosomal entrapment and degradation remain a major limitation to their therapeutic efficacy. Studies estimate that less than 5% of nucleic acids successfully escape the endosome post-LNP endocytosis, highlighting the need for improved delivery strategies to enhance therapeutic outcomes.Non-lamellar lyotropic liquid crystalline nanoparticles (LLCNPs), including cubosomes, hexosomes, and micellar cubosomes, have emerged as a promising subclass of LNPs due to their highly ordered internal nanostructures and unique physicochemical properties. These nanoparticles exhibit high surface-to-volume ratios for efficient drug encapsulation, biocompatibility, sustained drug release properties, and importantly, the ability to fuse with cellular membranes, offering a potential strategy to circumvent endosomal entrapment and degradation. Despite extensive research on their design and physicochemical properties, the biological interactions of LLCNPs that govern intracellular delivery—particularly how their nanostructures affect cellular uptake, internalization pathways, intracellular fate, endosomal escape, and membrane fusion—remain largely unexplored. Understanding these interactions is crucial for elucidating their mechanism of action and their subsequent therapeutic efficacy.This thesis systematically investigates how LLCNP nanostructure influences cellular uptake, internalization mechanisms, and intracellular fate, providing critical insights into their potential as effective nanocarriers for drug delivery. Chapter 3 explores the cellular uptake efficiencies of LLCNPs with varying internal nanostructures (liposomes, cubosomes, hexosomes, and micellar cubosomes) in epithelial cells, using flow cytometry and confocal microscopy. This study revealed that non-lamellar LLCNPs exhibit significantly higher and more sustained cellular interactions than conventional liposomes, which are widely used in clinical applications. By optimizing LLCNP formulations to control size, surface charge, and surface stabilizer, this study isolated the effect of nanostructure on cellular interactions, highlighting non-lamellar structures as particularly effective for their enhanced cellular uptake.Chapter 4 investigated the internalization pathways governing these interactions, using pharmacological inhibitors and endocytic markers (analyzed via flow cytometry and confocal microscopy). This study revealed that liposomes primarily rely on endocytic pathways, whereas non-lamellar LLCNPs relied heavily on a passive non-endocytic mechanism for their internalization, likely membrane fusion. Interestingly, macropinocytosis emerged as the dominant endocytic pathway for non-lamellar LLCNPs, suggesting their potential for targeting immune cells and Ras-activated cancer cells, where macropinocytosis is highly active. Furthermore, the ability of non-lamellar LLCNPs to bypass endocytic pathways highlights their potential for therapeutic delivery in diseases characterized by impaired endocytosis, such as Type A Niemann-Pick disease and Alzheimer’s disease, and their potential in circumventing the endosomal pathways altogether. Given these findings and the enhanced cellular interactions observed in Chapter 3, it is likely that membrane fusion plays a critical role in the uptake of non-lamellar LLCNPs, particularly cubosomes, which exhibited the highest levels of cellular uptake. Despite the potential of LNP-mediated membrane fusion to circumvent endosomal entrapment and enable direct cytosolic delivery, this dynamic process remains underexplored, with previous studies limited to model membranes or inferred from FRET-based fusion assays. Direct visualization of this phenomenon in mammalian cells has remained elusive due to the nanoscale dimensions of LNPs. Chapter 5 addresses this critical gap by using a suite of advanced microscopy techniques, including electron microscopy (TEM, SEM, Cryo-SEM), fluorescence-based assays, and live cell fluorescence imaging. This study provides the first direct evidence of cubosome-mediated membrane fusion with mammalian plasma and endosomal membranes, demonstrating their ability to circumvent endosomal degradation and deliver cargo directly into the cytosol. Cubosomes were selected as a model system due to their demonstrated fusogenic properties, their enhanced cellular uptake, and their preferential utilization of non-endocytic pathways observed in Chapters 3 and 4. This study also highlighted the unique fusogenic properties of cubosomes driven by their physical properties and nanostructure, distinguishing them from other LNPs.To refine the nanoscale imaging of cubosome-membrane fusion, Chapter 6 develops an optimized Cryo-Electron Tomography (Cryo-ET) workflow, designed to enable high-resolution 3D imaging of membrane fusion events in a frozen-hydrated state. A major barrier to successful Cryo-ET imaging lies in sample preparation, as conventional workflows require highly complex techniques such as cryogenic fluorescence light microscopy (cryo-fLM) and cryogenic focused ion beam (cryo-FIB) milling, limiting accessibility for directly visualizing key biological processes such as membrane fusion. This chapter presents an optimized and accessible cryo-ET workflow, incorporating pre-optimized LNP-cell conditions, ultrathin cell lines (negating the need for cryo-FIB), fixation protocols, and fluorescence-based targeting for region selection (negating the need for cryo-fLM). This methodology streamlines Cryo-ET sample preparation, making the high-resolution imaging of LNP-membrane fusion more feasible, and providing a powerful tool for future investigations into the spatio-temporal dynamics of LNP-mediated fusion and intracellular delivery.Collectively, this thesis advances our understanding of LLCNP cellular interactions, internalization mechanisms, and intracellular fate, establishing nanostructure as a key design principle for enhanced intracellular drug delivery. The presented findings provide a framework for optimizing LLCNP formulations for targeted applications, such as the delivery of nucleic acids for cell transfection (leveraging cubosomes’ membrane fusion capabilities) or cancer therapeutics utilizing macropinocytosis-mediated uptake. By bridging fundamental biophysical insights with translational applications, this research lays the groundwork for next-generation LLCNP-based drug delivery technologies that harness nanostructure-driven intracellular delivery mechanisms.</p
Examining the Link between Coordination Mechanisms and Innovation Capability in Banks: A Resource-Based View Perspective
No full textThis study aimed to examine the impact of formal hierarchical structure, including the centralization of decision-making and formalization, as well as informal social relations, such as connectedness, on the innovation capability of banks in Bangladesh. To achieve the research objectives, a survey method was adopted, and a close-ended questionnaire was distributed to the bank managers in Bangladesh. The study received a total of 253 responses, which were analyzed utilizing a variance-based procedure called Partial Least Squares by using SmartPLS 3.0 software. The results revealed an interesting and significant finding, which was the centralization of decision-making leads to improved innovation speed and quality. The study emphasized the relevance of the centralization of decision-making for promoting innovation in the banking industry and made some recommendations for future research to extend the study. The significant contribution of this research lies in its examination of the link between coordination mechanisms and innovation capability using the resource-based view theory.</p
Tectonic Accentuations: Transformations from a Digital Design Framework to Material Articulation
No full textTectonic Accentuations provides insights into my creative practice and the tools I use by examining the transitions from a digital design framework to the unique circumstances in which projects materialise. It explores the relationships between design and technology, where architecture translates knowledge from other domains. I navigate between digital design tools and hands-on material work, combining traditional craftsmanship with advanced manufacturing methods. The practice-based research focuses on how production processes and the various stakeholders are imprinted in the accentuations of artefacts and buildings. The work in my design practice challenges fabrication methods and investigates new shapes and forms through a profound comprehension and transformation of materials. I critically reflect on selected projects through the lens of tectonic accentuations, exploring the different phases of my practice: the contingencies in its formative years, the transformations through impactful speculative concepts, and the specific articulations of designs that have emerged during the research. Simplicity and sustainability are key drivers, expressed by focusing on renewable materials, lightweight structures and reconfigurable building systems. Many of my projects experiment with hybrid renewable and synthetic materials. They are driven by a curiosity in fibre orientations in wood and how its properties can be combined with synthetic fibres and concrete.The research has expanded the concept of tectonics beyond the classical parameters of topography, climate, and environment to reveal how social, cultural, and economic observations translate into designs. It unveils the impact of different stakeholders in the materialisation processes and examines emerging accentuations. Design intent leads to knowledge transfer and generates novel solutions at the intersections of domains, where the hybridisation of digital and material practices and the combination of different materials cross their established boundaries.</p
Reclaiming Chinese Indonesian history through non-fiction animation
No full textI created this video for the Visualise Your Thesis 2025 competition, based on my PhD research project, titled "Reclaiming Chinese Indonesian History through Non-fiction Animation." In this short video, I aim to explain my research project through storytelling, as a way to simplify the complexity of my PhD research. In this creative practice research, I explore Chinese Indonesians' personal and collective stories through non-fiction animation, with the hope of presenting a more authentic representation of Chinese Indonesian identity. My intention is to spark curiosity within the Chinese Indonesian community to explore their cultural heritage, and to foster greater cultural understanding among the broader public.</p
Designing neighbourhoods to support early childhood development: Built environment features associated with early childhood development
No full textPositive and stimulating environments in the first eight years help children develop well physically, socially, emotionally, and cognitively. Analysing data from 47,000 five-year-olds, we examined neighbourhood features that were associated with early childhood development in different areas, including established suburbs and rapidly growing neighbourhoods on Melbourne's urban fringe.</p
Elucidating The Mechanisms Underlying Neurocognitive Dysfunction in Chronic Obstructive Pulmonary Disease
No full textChronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disorder characterized by persistent airflow limitation and both lung and systemic inflammation. In Australia, 2021, an approximate $832 million was spent on COPD associated costs and the fast-growing disease accounted for approximately 4% of all deaths. The primary cause of COPD in developing countries is primarily due to air pollution, but in developed countries, cigarette smoking (CS) takes the lead. COPD is often accompanied by multiple comorbidities that can significantly impact disease progression, quality of life, and overall prognosis. These comorbidities may be arising due to shared risk factors, systemic inflammation, and oxidative stress. The chronic systemic inflammation seen in COPD is hypothesised to contribute to extrapulmonary conditions including osteoporosis, kidney failure, diabetes mellitus, metabolic disease, musculoskeletal dysfunction, cardiovascular dysfunction, endothelial dysfunction and atherosclerosis, increasing the risk of heart attacks and strokes. Patients with COPD also frequently experience neurocognitive decline, affecting memory, attention, executive function, and processing speed. This impairment is theorised to result from chronic hypoxia, systemic inflammation, vascular damage, and/or oxidative stress, all of which contribute to structural and functional changes in the brain. While emerging evidence suggests a significant link between COPD and neurocognitive impairment, the molecular mechanisms underlying the comorbidity is unknown. Chronic inflammation and oxidative stress are hallmarks of COPD and may be contributing to neurocognitive decline by affecting neuroinflammation, neurogenesis, and synaptogenesis. Persistent low-grade inflammation, characterized by elevated levels of cytokines such as tumour necrosis factoralpha (TNF-α) and interleukin-6 (IL-6), has been linked to neuronal injury and neurocognitive decline. Inflammation contributes to vascular dysfunction, increasing the risk of cerebrovascular diseases such as small vessel disease and stroke, which further exacerbate neurocognitive deficits. Additionally, oxidative stress resulting from chronic inflammation and environmental exposures, such as smoking, accelerates neuronal damage and brain aging. Structural brain changes have also been observed in COPD patients using neuroimaging techniques. Studies have shown reductions in grey matter volume, particularly in areas related to neurocognition, such as the hippocampus, prefrontal cortex, and temporal lobes. These brain alterations correlate with poorer performance on neurocognitive tests assessing memory, problem-solving, and attention. White matter abnormalities, including lesions and decreased connectivity between brain regions, have also been reported, further contributing to neurocognitive dysfunction. The presence of these brain changes suggests that COPD-related neurocognitive impairment is not merely a transient phenomenon but may be part of a progressive neurodegenerative process. The clinical implications of neurocognitive dysfunction in COPD are profound. Neurocognitive decline may contribute to social withdrawal, depression, and reduced quality of life, further compounding the burden of COPD. Patients with more severe neurocognitive impairment may also struggle with decision-making and self-care, increasing their dependence on caregivers and healthcare resources. Additionally, neurocognitive impairment can reduce a patient’s ability to adhere to complex treatment regimens, including medication management, inhaler techniques, and pulmonary rehabilitation programs. This can lead to worsening disease control, increased hospitalizations, and higher mortality rates. Apocynin and ebselen are two compounds with significant antioxidant and antiinflammatory properties, making them promising candidates for various disease treatments, particularly those involving oxidative stress-related pathologies. Both compounds target different mechanisms of oxidative damage, with apocynin primarily acting as an NADPH oxidase (NOX) inhibitor and ebselen functioning as a glutathione peroxidase (GPx) mimetic. Due to their unique pharmacological properties, these compounds have been investigated for potential therapeutic applications in conditions such as COPD, neurodegenerative disorders, cardiovascular diseases, and cancer. The therapeutic applications of both apocynin and ebselen continue to be a subject of extensive research. In COPD, apocynin’s ability to reduce airway inflammation and oxidative damage offers a potential strategy to alleviate disease progression. Similarly, ebselen’s neuroprotective properties have gained attention in treating neurological disorders linked to oxidative stress and inflammation. However, despite their promising pharmacological profiles, challenges remain regarding bioavailability, long-term safety, and clinical efficacy in humans. Future studies focusing on optimizing their formulations, delivery methods, and understanding their precise mechanisms of action could pave the way for their inclusion in mainstream medical therapies. In summary, this thesis explored the mechanisms underlying COPD-related neurocognitive dysfunction, with a focus on inflammation and oxidative stress. CS induced- COPD in mice exhibited a phenotype closely resembling clinical quantitative traits following 8 weeks and 24 weeks of full body CS exposure. This phenotype included pulmonary and systemic inflammation, along with inflammatory gene expression. This model also presented with translatable neurocognitive dysfunction in the form of spatial, recognition, and social memory deficits. Impacts of CS were also seen on neuroinflammation, neurogenesis, and synaptogenesis in specific brain regions. Apocynin was administered prophylactically to determine molecular mechanisms underlying COPD associated neurocognitive dysfunction and to understand its preventative potential. Ebselen was administered therapeutically once disease was established to determine its curative potential. Both treatments revealed insights into the mechanisms at play and suggest promise in targeting the oxidative stress pathway to alleviate the neurocognitive health burden associated with COPD.</p
Creature Effects as Posthuman Practice
No full textWith the ultimate aim of contributing to positive change in human-animal relations, this paper examines how creature effects (CFX) reflects and shapes contemporary attitudes towards animals. Drawing on biologist Jacob von Uexkull’s concept of “umwelt”, the paper analyses four of the author’s recent animation projects and explores the diverse perspectives, or lifeworlds, elicited by contemporary CFX practices. The paper describes how different aspects of creature FX production (including modelling, rigging, texturing, and animation) elicit umwelts loosely aligned to the lifeworlds of naturalists, trackers, mathematicians, and painters. Through this description, the paper fosters a deeper understanding of the socio-cultural forces shaping CFX and suggests how these forces can be disrupted. The paper finds that CFX can be considered a “posthuman practice” when it rejects the notion of human mastery over technology and positions the artist/animator as an integral part of a complex assemblage. Approached as posthuman practice, CFX challenges human exceptionalism and explores the entangled relationship between humans, technology, and animals. In conclusion, the paper reflects on the future trajectory of CFX and briefly contemplates the potential impact of AI-based methods.</p
Australian Children’s Television Cultures Summary Report 2021-2024
No full textOver four years (2021–2024) the Australian Children’s Television Cultures research group comprehensively investigated the diverse roles, cultural significance, and production contexts of Australian children’s television and screen content during a time of profound disruption in the sector. This report provides a summary of key findings from across all streams of this unprecedented research project on Aussie kids’ television.</p
Parents’ Perspectives on Australian Children’s Television in the Streaming Era – 3
No full textThis report presents findings from surveys and interviews carried out with parents and guardians of children aged 14 years and younger that took place over four years (2021-2024). Topics included screen viewing practices, the role of local children’s television, and valued SVOD features and functionality. 756 surveys were completed by parents and guardians and 27 interviews were conducted.</p
Smart Structural Monitoring: Real-Time Bridge Response Using Digital Twins and Inverse Analysis
No full textContinuous monitoring is significant to ensure the safe operation of infrastructure systems despite the high costs of traditional methods. The current study presents the development of a real-time digital twin of a laboratory-scaled bridge that can assist in the infrastructure monitoring process. Initially, the bridge model was instrumented with strain gauges, and a script was developed to conduct an inverse structural analysis and subsequently, run a finite element analysis to visualize the overall structural response. Three main loading scenarios were tested, and observations highlighted that the digital twin model emulated the actual structural behavior with a high accuracy. Also, the magnitude and the location of the applied loads on the real structure were correctly identified and a linear elastic behavior was identified in the digital model as expected from the actual structure. Further, the rates of change in the strain values and deflections were also evaluated while discussing the significance of digital twin development.</p