Melbourne Medical School Collected Works - Research Publications
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ItemEndothelial Response to the Combined Biomechanics of Vessel Stiffness and Shear Stress Is Regulated via Piezo1(AMER CHEMICAL SOC, 2023-12-11)How endothelial cells sense and respond to dynamic changes in their biophysical surroundings as we age is not fully understood. Vascular stiffness is clearly a contributing factor not only in several cardiovascular diseases but also in physiological processes such as aging and vascular dementia. To address this gap, we utilized a microfluidic model to explore how substrate stiffness in the presence of shear stress affects endothelial morphology, senescence, proliferation, and inflammation. We also studied the role of mechanosensitive ion channel Piezo1 in endothelial responses under the combined effect of shear stress and substrate stiffness. To do so, we cultured endothelial cells inside microfluidic channels covered with fibronectin-coated elastomer with elastic moduli of 40 and 200 kPa, respectively, mimicking the stiffness of the vessel walls in young and aged arteries. The endothelial cells were exposed to atheroprotective and atherogenic shear stress levels of 10 and 2 dyn/cm2, respectively. Our findings show that substrate stiffness affects senescence under atheroprotective flow conditions and cytoskeleton remodeling, senescence, and inflammation under atherogenic flow conditions. Additionally, we found that the expression of Piezo1 plays a crucial role in endothelial adaptation to flow and regulation of inflammation under both atheroprotective and atherogenic shear stress levels. However, Piezo1 contribution to endothelial senescence was limited to the soft substrate and atheroprotective shear stress level. Overall, our study characterizes the response of endothelial cells to the combined effect of shear stress and substrate stiffness and reveals a previously unidentified role of Piezo1 in endothelial response to vessel stiffening, which potentially can be therapeutically targeted to alleviate endothelial dysfunction in aging adults.
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ItemNo Preview AvailableBioengineered Vascular Model of Foam Cell Formation(AMER CHEMICAL SOC, 2023-11-29)Foam cell formation is a complex blood vessel pathology, which is characterized by a series of events, including endothelium dysfunction, inflammation, and accumulation of immune cells underneath the blood vessel walls. Novel bioengineered models capable of recapitulating these events are required to better understand the complex pathological processes underlying the development of foam cell formation and, consequently, advanced bioengineered platforms for screening drugs. Here, we generated a microfluidic blood vessel model, incorporating a three-dimensional (3D) extracellular matrix coated with an endothelial layer. This system enables us to perform experiments under a dynamic microenvironment that recapitulates the complexities of the native vascular regions. Using this model, we studied the effectors that regulate monocyte adhesion and migration, as well as foam cell formation inside vessel walls. We found that monocyte adhesion and migration are regulated by both the endothelium and monocytes themselves. Monocytes migrated into the extracellular matrix only when endothelial cells were cultured in the vessel model. In addition, the exposure of an endothelial layer to tumor necrosis factor α (TNF-α) and low shear stress both increased monocyte migration into the subendothelial space toward the matrix. Furthermore, we demonstrated the process of foam cell formation, 3 days after transmigration of peripheral blood mononuclear cells (PBMCs) into the vessel wall. We showed that pre-exposure of PBMCs to high shear rates increases their adhesion and migration through the TNF-α-treated endothelium but does not affect their capacity to form foam cells. The versatility of our model allows for mechanistic studies on foam cell formation under customized pathological conditions.
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ItemNo Preview AvailableAn Ultrasound‐Responsive Theranostic Cyclodextrin‐Loaded Nanoparticle for Multimodal Imaging and Therapy for Atherosclerosis (Small 31/2022)(Wiley, 2022-08)In article number 2200967, Xiaowei Wang, Karlheinz Peter, and co-workers show that theranostic nanoparticles made of air can deliver a near-infrared fluorescence dye, cyclodextrin, to be used as a contrast agent for ultrasound and fluorescence imaging and as ultrasound-responsive anti-atherosclerotic drug, achieving reduction of cholesterol in plaques after ingestion of nanoparticle by monocytes/macrophages.
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ItemNo Preview Available3D‐Printed Micro Lens‐in‐Lens for In Vivo Multimodal Microendoscopy (Small 17/2022)(Wiley, 2022-04)In article number 2107032, Jiawen Li and co-workers use two-photon 3D printing to develop a 330 micron diameter lens optimized for both fluorescence imaging and optical coherence tomography. This lens-in-lens design is incorporated in an intravascular imaging catheter offering improved performance for heart disease detection.
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ItemNo Preview AvailableStudying the Synergistic Effect of Substrate Stiffness and Cyclic Stretch Level on Endothelial Cells Using an Elastomeric Cell Culture Chamber(AMER CHEMICAL SOC, 2023-02-01)Endothelial cells lining blood vessels are continuously exposed to biophysical cues that regulate their function in health and disease. As we age, blood vessels lose their elasticity and become stiffer. Vessel stiffness alters the mechanical forces that endothelial cells experience. Despite ample evidence on the contribution of endothelial cells to vessel stiffness, less is known about how vessel stiffness affects endothelial cells. In this study, we developed a versatile model to study the cooperative effect of substrate stiffness and cyclic stretch on human aortic endothelial cells. We cultured endothelial cells on elastomeric wells covered with fibronectin-coated polyacrylamide gel. Varying the concentrations of acrylamide and bis-acrylamide enabled us to produce soft and stiff substrates with elastic modules of 40 and 200 kPa, respectively. Using a customized three-dimensional (3D) printed cam-driven system, the cells were exposed to 5 and 10% cyclic stretch levels. This enabled us to mimic the stiffness and stretch levels that endothelial cells experience in young and aged arteries. Using this model, we found that endothelial cells cultured on a soft substrate had minimal cytoskeletal alignment to the direction of the stretch compared to the ones cultured on the stiff substrate. We also observed an increase in the cellular area and aspect ratio in cells cultured on the stiff substrate, both of which are positively regulated by cyclic stretch. However, neither cyclic stretch nor substrate stiffness significantly affected the nuclear circularity. Additionally, we found that the accumulation of NF-κB in the nucleus, endothelial proliferation, tube formation, and expression of IL1β depends on the stretch level and substrate stiffness. Our model can be further used to investigate the complex signaling pathways associated with vessel stiffening that govern the endothelial responses to mechanical forces.
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ItemNo Preview AvailableDynamic Vortex Generation, Pulsed Injection, and Rapid Mixing of Blood Samples in Microfluidics Using the Tube Oscillation Mechanism(AMER CHEMICAL SOC, 2023-02-07)Here, we describe the generation of dynamic vortices in micro-scale cavities at low flow rates. The system utilizes a computer-controlled audio speaker to axially oscillate the inlet tube of the microfluidic system at desired frequencies and amplitudes. The oscillation of the tube induces transiently high flow rates in the system, which facilitates the generation of dynamic vortices inside the cavity. The size of the vortices can be modulated by varying the tube oscillation frequency or amplitude. The vortices can be generated in single or serial cavities and in a wide range of cavity sizes. We demonstrate the suitability of the tube oscillation mechanism for the pulsed injection of water-based solutions or whole blood into the cavity. The injection rate can be controlled by the oscillation characteristics of the tube, enabling the injection of liquids at ultralow flow rates. The dynamic vortices facilitate the rapid mixing of the injected liquid with the main flow. The controllability and versatility of this technology allow for the development of programmable inertial microfluidic systems for performing multistep biological assays.
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ItemNo Preview AvailableImpact of prehospital opioid dose on angiographic and clinical outcomes in acute coronary syndromes(BMJ PUBLISHING GROUP, 2023-02)BACKGROUND: An adverse interaction whereby opioids impair and delay the gastrointestinal absorption of oral P2Y12 inhibitors has been established, however the clinical significance of this in acute coronary syndrome (ACS) is uncertain. We sought to characterise the relationship between prehospital opioid dose and clinical outcomes in patients with ACS. METHODS: Patients given opioid treatment by emergency medical services (EMS) with ACS who underwent percutaneous coronary intervention (PCI) between 1 January 2014 and 31 December 2018 were included in this retrospective cohort analysis using data linkage between the Ambulance Victoria, Victorian Cardiac Outcomes Registry and Melbourne Interventional Group databases. Patients with cardiogenic shock, out-of-hospital cardiac arrest and fibrinolysis were excluded. The primary end point was the risk-adjusted odds of 30-day major adverse cardiac events (MACE) between patients who received opioids and those that did not. RESULTS: 10 531 patients were included in the primary analysis. There was no significant difference in 30-day MACE between patients receiving opioids and those who did not after adjusting for key patient and clinical factors. Among patients with ST-elevation myocardial infarction (STEMI), there were significantly more patients with thrombolysis in myocardial infarction (TIMI) 0 or 1 flow pre-PCI in a subset of patients with high opioid dose versus no opioids (56% vs 25%, p<0.001). This remained significant after adjusting for known confounders with a higher predicted probability of TIMI 0/1 flow in the high versus no opioid groups (33% vs 11%, p<0.001). CONCLUSIONS: Opioid use was not associated with 30-day MACE. There were higher rates of TIMI 0/1 flow pre-PCI in patients with STEMI prescribed opioids. Future prospective research is required to verify these findings and investigate alternative analgesia for ischaemic chest pain.
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ItemAssociation between frailty, delirium, and mortality in older critically ill patients: a binational registry study(SPRINGER, 2022-11-17)BACKGROUND: Frailty and delirium are prevalent among older adults admitted to the intensive care unit (ICU) and associated with adverse outcomes; however, their relationships have not been extensively explored. This study examined the association between frailty and mortality and length of hospital stay (LOS) in ICU patients, and whether the associations are mediated or modified by an episode of delirium. METHODS: Retrospective analysis of data from the Australian New Zealand Intensive Care Society Adult Patient Database. A total of 149,320 patients aged 65 years or older admitted to 203 participating ICUs between 1 January 2017 and 31 December 2020 who had data for frailty and delirium were included in the analysis. RESULTS: A total of 41,719 (27.9%) older ICU patients were frail on admission, and 9,179 patients (6.1%) developed delirium during ICU admission. Frail patients had significantly higher odds of in-hospital mortality (OR: 2.15, 95% CI 2.05-2.25), episodes of delirium (OR: 1.86, 95% CI 1.77-1.95), and longer LOS (log-transformed mean difference (MD): 0.24, 95% CI 0.23-0.25). Acute delirium was associated with 32% increased odds of in-hospital mortality (OR: 1.32, 95% CI 1.23-1.43) and longer LOS (MD: 0.54, 95% CI 0.50-0.54). The odds ratios (95% CI) for in-hospital mortality were 1.37 (1.23-1.52), 2.14 (2.04-2.24) and 2.77 (2.51-3.05) for non-frail who developed delirium, frail without delirium, and frail and developed delirium during ICU admission, respectively. There was very small but statistically significant effect of frailty on in-hospital mortality (b for indirect effect: 0.00037, P < 0.001) and LOS (b for indirect effect: 0.019, P < 0.001) mediated through delirium. CONCLUSION: Both frailty and delirium independently increase the risk of in-hospital mortality and LOS. Acute delirium is more common in frail patients; however, it does not mediate or modify a clinically meaningful amount of the association between frailty and in-hospital mortality and LOS.
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ItemIn vivo fluorescence imaging: success in preclinical imaging paves the way for clinical applications(BMC, 2022-10-15)Advances in diagnostic imaging have provided unprecedented opportunities to detect diseases at early stages and with high reliability. Diagnostic imaging is also crucial to monitoring the progress or remission of disease and thus is often the central basis of therapeutic decision-making. Currently, several diagnostic imaging modalities (computed tomography, magnetic resonance imaging, and positron emission tomography, among others) are routinely used in clinics and present their own advantages and limitations. In vivo near-infrared (NIR) fluorescence imaging has recently emerged as an attractive imaging modality combining low cost, high sensitivity, and relative safety. As a preclinical tool, it can be used to investigate disease mechanisms and for testing novel diagnostics and therapeutics prior to their clinical use. However, the limited depth of tissue penetration is a major challenge to efficient clinical use. Therefore, the current clinical use of fluorescence imaging is limited to a few applications such as image-guided surgery on tumors and retinal angiography, using FDA-approved dyes. Progress in fluorophore development and NIR imaging technologies holds promise to extend their clinical application to oncology, cardiovascular diseases, plastic surgery, and brain imaging, among others. Nanotechnology is expected to revolutionize diagnostic in vivo fluorescence imaging through targeted delivery of NIR fluorescent probes using antibody conjugation. In this review, we discuss the latest advances in in vivo fluorescence imaging technologies, NIR fluorescent probes, and current and future clinical applications.