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(2021) Fu, LuThesisAngiogenesis is a vital step of cancer growth and metastasis and has become a promising target for cancer therapy. Due to the abnormal vascularisation and poor blood supply, tumours are usually hypoxic and lack nutrients, which triggers tumour aggressiveness and hampers efficient drug delivery. The success of traditional anti-angiogenic strategies, which focuses on decreasing the vascular supply to tumours, is limited by insufficient drug delivery or tumour resistance. Thus, vascular promotion therapy based on promoting angiogenesis is emerging as a complementary cancer therapy. Heparin is a linear negatively charged polysaccharide that, in addition to its anticoagulant action, can promote angiogenesis by potentiating angiogenic growth factors. Thus, heparin is a promising bioactive for cancer drug delivery applications. Cerium oxide nanoparticles (CNPs), a cytocompatible redox biomaterial, has gained attention as it actively scavenges reactive oxygen species (ROS) in biological systems which are related to cancer aggressiveness and tumour hypoxia. In this thesis, CNPs were functionalised with heparin with different chain lengths and density, aiming to investigate their mechanisms of interaction with the vasculature as blood vessel-targeting cancer therapeutics. CNPs were synthesised via precipitation and then functionalised with different amounts of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) via an organosilane linker. CNPs and heparin-CNPs were approximately 12 nm in crystal size, exhibited face-centred cubic phase structure in morphology and as determined by high-resolution transmission electron microscopy (HRTEM) and X-ray diffraction (XRD), respectively. The successful functionalisation of CNPs with heparin was qualitatively verified by attenuated total reflectance-Fourier transform infra-red spectroscopy (ATR-FTIR) and X-ray photoelectron spectroscopy (XPS). Additionally, thermogravimetric analysis (TGA) demonstrated the conjugation of heparin onto the surface of CNPs with approximately 1.5 μmol UFH, and either 1.8 μmol or 5.7 μmol LMWH conjugated per gram of CNPs. In addition, CNPs and heparin-CNPs showed a dose-dependent cytotoxicity in human umbilical vein endothelial cells (HUVECs), indicating that concentrations of heparin-CNPs above 5 μg/mL can act as anti-angiogenic agents. Heparin-CNPs at a dose of 1.5 μg/mL had limited redox activity which correlated with their limited effect on vascular endothelial growth factor receptor 2 (VEGFR2) expression, a key receptor in angiogenesis regulated via redox. However, the heparin-CNPs signalled fibroblast growth factor 2 (FGF-2) in vitro and in vivo, a key growth factor in angiogenesis, indicating their potential to support angiogenesis. In vivo analyses of the heparin-CNPs indicated that they dose-dependently promoted angiogenesis in the CAM assay at doses up to 1 mg/mL. Moreover, compared to CNPs, heparin-CNPs reduced intracellular ROS level in melanoma cells (MM200), reducing the hypoxic level of tumour cells, which indicated their potential as an anti-cancer agent. A human tumour model in the CAM was developed in this thesis to investigate the effects of nanoparticles on tumour angiogenesis and their interactions with the tumour vasculature. It was found that heparin-CNPs, compared to CNPs, dose-dependently promoted angiogenesis in the human tumour model in the CAM and exhibited a higher level of penetration into the tumour mass via light sheet microscopy and histological analysis. Overall, heparin-CNPs dose-dependently promoted angiogenesis by modulating key processes in angiogenesis and address tumour aggressiveness, showing their potential application in cancer therapeutics.
(2021) Li, BitongThesisIn the past decade, the discovery of the CRISPR/Cas system launched a new era of genome editing and has rapidly become a universal research tool. The specific recognition between guide RNA and target nucleic acids enables CRISPR/Cas systems to exhibit high specificity compared to gene editing systems such as zinc finger or transcription activator-like effector nucleases. In this thesis, the CRISPR/Cas12a and CRISPR/Cas13a systems were designed to modify DNA or RNA associated with the HSPG2 gene which encodes perlecan, the major extracellular heparan sulphate (HS) proteoglycan in basement membranes. Perlecan has essential roles in organ development and contributes angiogenesis in pathological processes including cancer. The Cas12a and Cas13a nucleases were expressed in transformed E. coli and purified via His-tag affinity followed by size exclusion chromatography. The purified Cas12a nuclease exhibited high activity and specificity in a collateral activity assay in which the reporter sequence was only cleaved in the presence of the Cas12a protein and target ssDNA. Similarly, Cas13a nuclease exhibited high activity and specificity in a collateral activity assay with target ssRNA. A CRISPR/Cas12a gRNA was designed to target exon 2 of HSPG2 and was able to cleave amplified genomic DNA extracted from human melanoma cell line, MM200. Additionally, the collateral activity assay revealed that Cas12a nuclease dose-dependently cleaved the reporter ssDNA when used with target HSPG2 DNA. Similarly, a CRISPR/Cas13a gRNA was designed to target exon 2 of HSPG2 RNA and was able to cleave the target RNA extracted from MM200 cells and was active in the collateral activity assay when used with target HSPG2 RNA. Modification of HSPG2 nucleic acids in both MM200 cells and human umbilical vein endothelial cells (HUVECs) was also established. The CRISPR/Cas12a system resulted in up to 39 and 24 % reduction in HSPG2 gene expression in MM200 and HUVECs, respectively. Moreover, the CRISPR/Cas13a system achieved up to 69 and 99% reduction in HSPG2 RNA in MM200 and HUVECs, respectively. The HSPG2 mRNA modification in both MM200 and HUVECs resulted in decreased expression of FGF2 and VEGF-A, genes involved in the perlecan signalling pathway networks and associated with angiogenesis. The established CRISPR/Cas12a and CRISPR/Cas13a systems provide novel and efficient nucleic acid editing tools to further study the functions of perlecan in vitro and potentially in vivo. In addition, the LbCas12a or LwCas13a-based collateral cleavage assay enabled efficient and specific detection of the HSPG2 genome or transcripts, suggestive of its potential in perlecan-related disease diagnoses, such as cancer or genetic disorders.
Measurement of factors affecting fit at the prosthetic socket-residual limb interface in people with transtibial amputation(2020) Armitage, LucyThesisMany people with transtibial amputation rate the fit between their residual limb and prosthetic socket as the most important factor in the use of their prosthesis. Current research suggests that poor fit between the residual limb and the prosthetic socket can cause pain, skin breakdown or alteration of gait. This thesis focused on measurement methods to assess residual limb – prosthetic socket fit in people with transtibial amputation. Three aspects of fit were examined and new measurement methods for each aspect were explored. Fit affects the amount of relative movement that occurs between the residual limb and prosthetic socket. A method to measure this movement was proposed using motion capture analysis. The development and attempted validation of the method were outlined. Results were unpredictable and subject to confounding factors such as marker movement artefact. Therefore, the method was deemed not to be appropriate as a fit measurement tool in its current form. Based on these findings it was deemed necessary to investigate other measures of fit Fluctuation in residual limb volume can also affect fit. The reliability and validity of current residual limb volume measurement techniques were examined in a systematic review. Results demonstrated that circumferential measurements are the most reliable and valid tool currently available. The results from this review informed a study investigating the use of a low-cost optical scanner as a clinical volume measurement tool. Results found that the scanner was reliable when used by the same assessor but was not valid. The loading state at the prosthetic socket-residual limb interface is also an important factor in assessment of fit. The effect of pressure feedback to the prosthetist on the design of prosthetic sockets was assessed. It found that feedback resulted in reduction in pressure over anatomical regions of concern, and improved consistency between prosthetists. A new sensor to measure pressure and shear at the socket-limb interface was developed and benchtop testing was performed. These methods have the potential to aid in an improved understanding of the mechanisms that affect fit at the socket-limb interface of people with transtibial amputation. It is hoped that this can lead to improved fit and comfort for prosthetic users.
(2020) Leong, Chin NengThesisMyocardial infarction (MI) is one of the diseases with the highest mortality rate. Following MI, myocardium experiences abrupt changes in its loading condition due to the presence of infarct. In response to such changes, myocytes undergo adaptations to maintain homeostasis. However, maladaptation can happen and lead to remodelling, in which the left ventricle (LV) gradually loses its function and eventually turns into heart failure. Nevertheless, the mechanisms underlying LV remodelling are still poorly understood. In this study, a generic LV model was developed, incorporating realistic fibre orientation and excitable contracting myocardium. It was demonstrated that the developed model is capable of reproducing physiological LV functions, including action potential propagation, LV pressure and cavity volume, LV twisting and wall thickening. Subsequently, the generic LV model was utilised to investigate the effects of the infarct state on LV regional mechanics, including the interaction between non-contractile infarct and contractile myocardium. It was found that infarct transmural extent (TME) is more important than infarct size in determining LV regional mechanics impairments. Neighbouring contractile myocardium and non-contractile infarct induce a mechanical tethering effect, which elevates with infarct TME, at the border zone (BZ). Such mechanical tethering causes the BZ to have high systolic fibre stress, elevated energy expenditure and reduced myocardial energy efficiency, which are believed to give rise to infarct extension. The generic LV model was then modified into a patient-specific model, incorporating patient-specific infarcted LV geometry and optimised regional material properties, to study the correlation between infarct extension and myocardial mechanics impairments, including the underlying mechanisms responsible for the impairments. Among the observed myocardial mechanics impairments, only the depressed myocardial energy efficiency was found to be correlated with infarct extension. The depressed myocardial energy efficiency was due to inadequate generation of contraction force, which, at least in part, owing to inadequate stretching of myocardium at end-diastole (the Frank-Starling law). Although a stiff infarct can prevent infarct expansion, results of this study showed that it can also cause the neighbouring myocardium to be under-stretched at end-diastole, thereby depressing the generated contraction force and energy efficiency during systole, which were found to be correlated with infarct extension of the neighbouring myocardium.
(2022) Tang, JunmaThesisConverting natural resources or greenhouse gases into value-added species with low carbon footprint, is essential for the development and sustainability of modern society. However, the goal for sustainable and cost-effective conversion by using many current technologies, including photo-, electro- and thermal-based catalytic reaction systems, has been largely underachieved. Hence, it is a necessity to explore and develop new approaches to fulfill this objective. In this thesis, three hybrid catalytic systems, containing liquid gallium (Ga) and solid materials as co-catalysts, are demonstrated, which realize the gaseous and liquid feedstocks conversion through nano-tribo-electrochemical reaction pathways. In the first stage of this PhD thesis, the author reports a green carbon capture and conversion technology for mitigating CO2 emissions. The technology uses suspensions of Ga liquid metal to reduce CO2 into solid carbonaceous products and O2 at near room temperature. The solid co-contributor of silver-Ga rods ensures a cyclic sustainable process. The overall process relies on mechanical energy as the input, which drives nano dimensional triboelectrochemical reactions. In the next stage, for the gaseous feedstock conversion, the author demonstrates an approach based on Ga liquid metal droplets and Ni(OH)2 co-catalysts for CH4 conversion into H2 and carbon. Mainly driven by the triboelectric voltage, originating from the joint contributions of the co-catalysts during agitation, CH4 is converted at the Ga and Ni(OH)2 interfaces. The efficiency of the system is enhanced when the reaction is performed at an increased pressure. The dehydrogenation of other non-gaseous hydrocarbons using this approach is also demonstrated. In the final stage, the author explores and realizes the liquid biofuels conversion, including canola oil and other liquid hydrocarbons, with H2 and C2H4 as the main products by employing Ga and nickel particles as the co-catalysts and mechanical energy as the stimulus. Altogether, the work of this PhD research offers novel pathways for low energy and green conversion of gaseous and liquid feedstocks that can be implemented in large scale conversion systems of the future.
(2022) Zhang, ChengchenThesisLiquid metals (LMs) are a class of metals and their alloys which have low melting points near or below room temperature, and they are mainly composed of post-transition elements. The low melting points of LMs make them easily stay in a liquid state and readily be broken into tens or hundreds of nanometers, which are called LM nanoparticles (LMNPs). In this thesis, the author investigates LMNPs for three exciting applications of creating conductive polymer-LMNPs compositions and explores the potential utilization of LMNPs in biological applications. In the first phase of this research, the author develops nanocomposites of Ga-based LMNPs (EGaIn NPs) with conductive polymer polyaniline (PANI). This work reports a method of growing PANI nanofibers on the EGaIn NPs by firstly providing initial functionalization sites at the interfaces for the formation of PANI nanofibrous network. The nanocomposites provide synergistic effects of PANI nanofibers and EGaIn NPs for the applications of environmental sensing and molecular separation. In the second phase of the research, the author focused on the exploration of LMNPs for their anti-inflammatory applications. Considering that Ga ions (Ga3+), have been historically utilized as anti-inflammatory agents by interfering with the Fe homeostasis of immune cells. The study presents the anti-inflammatory effects of Ga by delivering Ga nanoparticles (Ga NPs) into lipopolysaccharide-induced macrophages. The Ga NPs show a selective anti-inflammatory effect by modulating nitric oxide production without disturbing other pro-inflammatory mediators. This work reveals the different anti-inflammatory effects between Ga NPs and Ga3+ come from their different endocytic pathways: transferrin receptor independent and dependent endocytosis for Ga NPs and Ga3+, respectively. In the final phase, the author studies the interactions between LMNPs and macrophages at a light microscopic level. The mechanistic responses of macrophages to LMNPs with different densities were observed, in comparison to some other commonly studied nanoparticles. This work discovers the mobility of macrophages is very much density-dependent. This thesis comprehensively studies the interactions between LMNPs and polymeric and biological systems, at both molecular and microscopic levels, which provides a basis and road map for utilizing LMNPs in various fields such as electronics and biomedical engineering.
Sensory mechanisms involved in obtaining frictional information for perception and grip force adjustment during object manipulation(2023) Afzal, HafizThesisSensory signals informing about frictional properties of a surface are used both for perception to experience material properties and for motor control to be able to handle objects using adequate manipulative forces. There are fundamental differences between these two purposes and scenarios, how sensory information typically is obtained. This thesis aims to explore the mechanisms involved in the perception of frictional properties of the touched surfaces under conditions relevant for object manipulation. Firstly, I show that in the passive touch condition, when the surface is brought in contact with immobilised finger, humans are unable to use existing friction-related mechanical cues and perceptually associate them with frictional properties. However, a submillimeter range lateral movement significantly improved the subject's ability to evaluate the frictional properties of two otherwise identical surfaces. It is demonstrated that partial slips within the contact area and fingertip tissue deformation create very potent sensory stimuli, enabling tactile afferents to signal friction-dependent mechanical effects translating into slipperiness (friction) perception. Further, I demonstrate that natural movement kinematics facilitate the development of such small skin displacements within the contact area and may play a central role in enabling the perception of surface slipperiness and adjusting grip force to friction when manipulating objects. This demonstrates intimate interdependence between the motor and sensory systems. This work significantly extends our understanding of fundamental tactile sensory processes involved in friction signaling in the context of motor control and dexterous object manipulation tasks. This knowledge and discovered friction sensing principles may assist in designing haptic rendering devices and artificial tactile sensors as well as associated control algorithms to be used in robotic grippers and hand prostheses.
(2021) Deng, FeiThesisCytokines are a large, diverse family of small soluble proteins (4-60 kDa) expressed by immune and nonimmune cells. They play significant roles in cellular signalling, activation, growth and differentiation, resulting in a wealth of information related to health and disease. Defects in the regulatory networks may cause fluctuation of cytokine levels and accompany in inflammation or diverse diseases, indicating that cytokine measurement could be an effective approach for characterizing the function of immune system, diagnosing and predicting disease, and evaluating the effects of treatment. However, detection of cytokines is challenging because of their low biological concentration (pg/mL), complicated interacting networks, and inhomogeneous distribution. The current methods for detection of cytokines are mainly based on immunoassay techniques. Among them, enzyme-linked immunosorbent assay (ELISA) and Meso Scale Discovery (MSD) have become the most common cytokine quantification tools due to the simple protocols and relatively high sensitivity (pg/mL). However, all these approaches were limited on multiplex monitoring of in vivo cytokines with ultralow concentration (fg/mL) and superb spatial resolution. In this project, four novel biosensors have developed for sensitive, multiplex and in vivo monitoring of cytokines, which include three published papers and two revised manuscripts. Optical fibre and stainless steel were applied as the substrates for the development of the deployable biosensors with the capability of in vivo application. Sandwich structure was designed with capture module (antibody) immobilized on the surface of substrates and detection module (antibody or aptamer) conjugated with fluorescent reporter for signal amplification and readout. We first tested the sandwich-based biosensors in in vitro experiments by assessing and optimising their performance in PBS buffer, serum, plasma, saliva, perspiration, and whole blood. After validation of in vitro work, we applied the biosensors for in vivo monitoring of cytokines in rat brain or spine cord for the study of chronic pain or the development of diseases. The findings indicated that the designed sensing devices have the potential to be used for sensitive and multiplex monitoring of analytes (such as cytokines) in clinical practice and help with the better understanding of various disease conditions.
(2022) Wei, YuanThesisBrain machine interfaces, or brain computer interfaces, are attracting ever increasing research interests for their promising application prospects. A number of methods and devices were proposed on this topic, but all have inherent limits particularly concerning spatial density and signal resolution. An optical-electrode is hereby proposed to overcome these limitations by transducing the electrical signal into an optical signal using liquid crystal cells. In addition, photovoltaic stimulation capabilities were added to form an integrated bidirectional interface. A recording subsystem and a stimulating subsystem were proposed for driving the sensing and stimulation parts respectively, and their benchtop characterisations were carried out. Noise performances in the recording subsystem were analysed and optimised. To provide initial validation, animal studies were conducted on rabbit sciatic nerves (in vivo and ex vivo) and on cardiac tissues (ex vivo). The recorded signals and stimulated responses were compared with those made by commonly used traditional electrical systems under the same experimental conditions. Compound action potentials, although showing differences on delays and morphology over traditional methods, were successfully recorded and evoked. The charge balance ability was also demonstrated in the experiments. Finally, a 'zero mode' photodetector is introduced, which is specifically suitable for the recording subsystem and can potentially improve the noise performance. The works in this thesis will contribute to the next iteration of the technology, i.e. help the creation of high density arrays in the form of integrated chips.
(2023) Baharfar, MahrooThesisLow melting point post-transition metals and alloys, dubbed as liquid metals (LMs), have emerged as group of soft yet conductive materials with remarkable physical and chemical properties. The enigmatic features of LMs originate from their deformable and electron-rich core as well as their atomically smooth and chemically active interface. These features can offer opportunities for designing novel electrochemical systems with improved performance and applicability. Despite the great potential, LM-based electrochemical modules are at nascent stage and the fundamental knowledge regarding electric field-induced events at LMs/electrolyte interfaces is still elusive. The present thesis focuses on the incorporation of LMs and LM-based materials in different electrochemical set-ups. The outcomes showcase the capability of LMs for materials synthesis, biosensing, and alloy processing via electrochemical routes. In chapter 3 of this thesis, the author focuses on the exploitation of autogenous interfacial potential generated on gallium and indium eutectic alloy, EGaIn, to drive a galvanic reduction reaction (GRR). It is revealed that EGaIn could effectively reduce graphene oxide (GO) in different configurations to produce monolayers and thick membranes of reduced GO (rGO) as well as LM droplets covered with a shell of rGO flakes. In chapter 4, the core-shell structures of LM-rGO, synthesized via GRR, were electrochemically characterized through their incorporation as a modifier to electrochemical interfaces. The author revealed that incorporation of the LM-based modifier results in improved charge transfer kinetics, higher electroactive surface area, and lower resistance. The remarkable electrochemical performance of LM-rGO particles were exploited for selective biosensing of dopamine using both paper-based devices and conventional electrochemical set-ups. In chapter 5, droplets of a gallium- and an indium-based LM eutectic alloys were electrochemically diagnosed to explore interfacial events occurring at LM/electrolyte interface. The author showed that upon surface perturbation by a cathodic voltage, solute elements tend to segregate at the interface according to their energy levels. The electrolyte solution was observed to have a substantial effect on the composition of segregated domains. Collectively, this PhD research demonstrates opportunities for designing novel electrochemical systems based on LMs and provides valuable insights into voltage-dependent behaviour of LMs, which can potentially contribute to the advancement of scientific fields such as materials processing, energy, and sensors.
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