Melbourne Medical School Collected Works - Research Publications
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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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ItemSodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes-Induced Atherosclerotic Plaque Instability(WILEY, 2022-01-04)Background Diabetes is known to accelerate atherosclerosis and increase plaque instability. However, there has been a lack of suitable animal models to study the effect of diabetes on plaque instability. We hypothesized that the tandem stenosis mouse model, which reflects plaque instability/rupture as seen in patients, can be applied to study the effects of diabetes and respective therapeutics on plaque instability/rupture. Methods and Results ApoE-/- mice at 7 weeks of age were rendered diabetic with streptozotocin and 5 weeks later were surgically subjected to tandem stenosis in the right carotid artery and fed with a high-fat diet for 7 weeks. As a promising new antidiabetic drug class, a sodium glucose co-transporter 2 inhibitor was tested in this new model. Diabetic mice showed an increase in the size of unstable atherosclerotic plaques and in the plaque instability markers MCP-1, CD68, and necrotic core size. Mice treated with dapagliflozin demonstrated attenuated glucose and triglyceride levels. Importantly, these mice demonstrated plaque stabilization with enhanced collagen accumulation, increased fibrosis, increased cap-to-lesion height ratios, and significant upregulation of the vasculoprotective NADPH oxidase 4 expression. Conclusions The tandem stenosis mouse model in combination with the application of streptozotocin represents a highly suitable and unique mouse model for studying plaque destabilization under diabetic conditions. Furthermore, for the first time, we provide evidence of plaque-stabilizing effects of sodium-glucose co-transporter 2 inhibitor. Our data also suggest that this newly developed mouse model is an attractive preclinical tool for testing antidiabetic drugs for the highly sought-after potential to stabilize atherosclerotic plaques.
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ItemPharmacological Inhibition of Factor XIIa Attenuates Abdominal Aortic Aneurysm, Reduces Atherosclerosis, and Stabilizes Atherosclerotic Plaques(GEORG THIEME VERLAG KG, 2022-02)BACKGROUND: 3F7 is a monoclonal antibody targeting the enzymatic pocket of activated factor XII (FXIIa), thereby inhibiting its catalytic activity. Given the emerging role of FXIIa in promoting thromboinflammation, along with its apparent redundancy for hemostasis, the selective inhibition of FXIIa represents a novel and highly attractive approach targeting pathogenic processes that cause thromboinflammation-driven cardiovascular diseases. METHODS: The effects of FXIIa inhibition were investigated using three distinct mouse models of cardiovascular disease-angiotensin II-induced abdominal aortic aneurysm (AAA), an ApoE-/- model of atherosclerosis, and a tandem stenosis model of atherosclerotic plaque instability. 3F7 or its isotype control, BM4, was administered to mice (10 mg/kg) on alternate days for 4 to 8 weeks, depending on the experimental model. Mice were examined for the development and size of AAAs, or the burden and instability of atherosclerosis and associated markers of inflammation. RESULTS: Inhibition of FXIIa resulted in a reduced incidence of larger AAAs, with less acute aortic ruptures and an associated fibro-protective phenotype. FXIIa inhibition also decreased stable atherosclerotic plaque burden and achieved plaque stabilization associated with increased deposition of fibrous structures, a >2-fold thicker fibrous cap, increased cap-to-core ratio, and reduction in localized and systemic inflammatory markers. CONCLUSION: Inhibition of FXIIa attenuates disease severity across three mouse models of thromboinflammation-driven cardiovascular diseases. Specifically, the FXIIa-inhibiting monoclonal antibody 3F7 reduces AAA severity, inhibits the development of atherosclerosis, and stabilizes vulnerable plaques. Ultimately, clinical trials in patients with cardiovascular diseases such as AAA and atherosclerosis are warranted to demonstrate the therapeutic potential of FXIIa inhibition.
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Item3D-Printed Micro Lens-in-Lens for In Vivo Multimodal Microendoscopy(WILEY-V C H VERLAG GMBH, 2022-04)Multimodal microendoscopes enable co-located structural and molecular measurements in vivo, thus providing useful insights into the pathological changes associated with disease. However, different optical imaging modalities often have conflicting optical requirements for optimal lens design. For example, a high numerical aperture (NA) lens is needed to realize high-sensitivity fluorescence measurements. In contrast, optical coherence tomography (OCT) demands a low NA to achieve a large depth of focus. These competing requirements present a significant challenge in the design and fabrication of miniaturized imaging probes that are capable of supporting high-quality multiple modalities simultaneously. An optical design is demonstrated which uses two-photon 3D printing to create a miniaturized lens that is simultaneously optimized for these conflicting imaging modalities. The lens-in-lens design contains distinct but connected optical surfaces that separately address the needs of both fluorescence and OCT imaging within a lens of 330 µm diameter. This design shows an improvement in fluorescence sensitivity of >10x in contrast to more conventional fiber-optic design approaches. This lens-in-lens is then integrated into an intravascular catheter probe with a diameter of 520 µm. The first simultaneous intravascular OCT and fluorescence imaging of a mouse artery in vivo is reported.
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ItemAnalyzing the shear-induced sensitization of mechanosensitive ion channel Piezo-1 in human aortic endothelial cells(WILEY, 2021-04)Mechanosensitive ion channels mediate endothelial responses to blood flow and orchestrate their physiological function in response to hemodynamic forces. In this study, we utilized microfluidic technologies to study the shear-induced sensitization of endothelial Piezo-1 to its selective agonist, Yoda-1. We demonstrated that shear stress-induced sensitization is brief and can be impaired when exposing aortic endothelial cells to low and proatherogenic levels of shear stress. Our results suggest that shear stress-induced sensitization of Piezo-1 to Yoda-1 is independent of cell-cell adhesion and is mediated by the PI3K-AKT signaling pathway. We also found that shear stress increases the membrane density of Piezo-1 channels in endothelial cells. To further confirm our findings, we performed experiments using a carotid artery ligation mouse model and demonstrated that transient changes in blood-flow pattern, resulting from a high-degree ligation of the mouse carotid artery alters the distribution of Piezo-1 channels across the endothelial layer. These results suggest that shear stress influences the function of Piezo-1 channels via changes in membrane density, providing a new model of shear-stress sensitivity for Piezo-1 ion channel.