Changes in extracellular matrix in failing human non-ischemic and ischemic hearts with mechanical unloading

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Elastomeric droplet generation of vascularized cardiac spheroids for the use of high-throughput drugs screening

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Pretext Training Algorithms for Event Sequence Data

Pretext training followed by task-specific fine-tuning has been a successful approach in vision and language domains. This paper proposes a self-supervised pretext training framework tailored to event sequence data. We introduce a novel alignment verification task that is specialized to event sequences, building on good practices in masked reconstruction and contrastive learning. Our pretext tasks unlock foundational representations that are generalizable across different down-stream tasks, including next-event prediction for temporal point process models, event sequence classification, and missing event interpolation. Experiments on popular public benchmarks demonstrate the potential of the proposed method across different tasks and data domains

Mapping signalling perturbations in myocardial fibrosis via the integrative phosphoproteomic profiling of tissue from diverse sources

Study of the molecular basis of myocardial fibrosis is hampered by limited access to tissues from human patients and by confounding variables associated with sample accessibility, collection, processing and storage. Here, we report an integrative strategy based on mass spectrometry for the phosphoproteomic profiling of normal and fibrotic cardiac tissue obtained from surgical explants from patients with hypertrophic cardiomyopathy, from a transaortic-constriction mouse model of cardiac hypertrophy and fibrosis, and from a heart-on-a-chip model of cardiac fibrosis. We used the integrative approach to map the relative abundance of thousands of proteins, phosphoproteins and phosphorylation sites specific to each tissue source, to identify key signalling pathways driving fibrosis and to screen for anti-fibrotic compounds targeting glycogen synthase kinase 3, which has a consistent role as a key mediator of fibrosis in all three types of tissue specimen. The integrative disease-modelling strategy may reveal new insights into mechanisms of cardiac disease and serve as a test bed for drug screening

Biowire II Platform: High Fidelity Heart-on-a-chip for Drug Screening and Disease Modeling

Cardiotoxicity is a major cause of drug failure at the late stages of clinical trials and it is linked to unqualified candidates as early as possible is key for reducing the costs of drug discovery and preventing the patient fatality. Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to tissue maturation, cardiac chamber specification and platform versatility can be overcome. The plastic-based platform developed in this thesis, Biowire II, facilitates the scalable, miniaturized 3D tissue cultivation with multiple cell sources in a low absorption environment. The platform deploys two fluorescent, elastic polymer wires to serve as tissue anchors and force sensors, and enables on-line, non-invasive, recording of passive tension, active force, contractile dynamics, Ca2+ transients, endpoint assessments of action potentials and conduction velocity. The conditions of cardiac tissue formation, including cell seeding density, non-myocyte populations and hydrogels, were characterized in detail to ensure the consistent production of functional tissues with hallmarks of adult myocardium. The temporary electrical pacing and long-term electrical conditioning were incorporated and optimized for the platform to facilitate standardized drug testing and chamber-specific cardiac tissue maturation. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. This study is the first to report the engineering of the heteropolar cardiac tissues, which contain well-separated atrial and ventricular ends, and demonstrate their spatially confined responses to serotonin and ranolazine. More importantly, Biowire II platform enabled modeling of polygenic left ventricular hypertrophy with induced pluripotent stem cell derived cardiomyocytes from six different patients, using uniquely designed 8-months-long electrical conditioning protocol. The platform was scaled up into a 96 well-plate format with all the key features, such as plastic culture environment, elastic force sensors and embedded carbon electrodes. An innovative fabrication method was developed to rapidly cast suspended force sensors on top of a patterned surface. This advanced version of platform eliminates adhesives, standardizes and further increases the throughput of tissue production and drug testing.Ph.D.2021-12-02 00:00:0

A Multi-Hook Control Strategy for a Semi-Active Device Combining an Adjustable Inerter and Damper

Neither the separate skyhook damping nor the skyhook inertance control strategy can adapt to the variations of both road and load conditions simultaneously. To address this issue, this work proposed a novel ideal multi-hook system by combining the skyhook inerter and hybrid damper, with both of their coefficients optimized. The proposed system can achieve road holding without sacrificing ride comfort. Depending on whether the inerter and damper were adjusted independently or together, this ideal multi-hook was realized semi-actively in two different control models with three different control strategies, i.e., independent, inertance-based and damping-based control. The effects of these strategies were compared and analyzed. The simulation results show that compared with passive suspension, the root mean square value of body acceleration of the three kinds of multi-hook suspension decreases by more than 40% under different loads and by more than 28% on the roads of Classes A, B and C. Compared with the skyhook damping suspension, the dynamic wheel load of the multi-hook suspensions is reduced by more than 27.5%, proving that the semi-active suspension system with multi-hook control guarantees handling stability under various road and load conditions while ensuring ride comfort

A Multi-Hook Control Strategy for a Semi-Active Device Combining an Adjustable Inerter and Damper

Neither the separate skyhook damping nor the skyhook inertance control strategy can adapt to the variations of both road and load conditions simultaneously. To address this issue, this work proposed a novel ideal multi-hook system by combining the skyhook inerter and hybrid damper, with both of their coefficients optimized. The proposed system can achieve road holding without sacrificing ride comfort. Depending on whether the inerter and damper were adjusted independently or together, this ideal multi-hook was realized semi-actively in two different control models with three different control strategies, i.e., independent, inertance-based and damping-based control. The effects of these strategies were compared and analyzed. The simulation results show that compared with passive suspension, the root mean square value of body acceleration of the three kinds of multi-hook suspension decreases by more than 40% under different loads and by more than 28% on the roads of Classes A, B and C. Compared with the skyhook damping suspension, the dynamic wheel load of the multi-hook suspensions is reduced by more than 27.5%, proving that the semi-active suspension system with multi-hook control guarantees handling stability under various road and load conditions while ensuring ride comfort

The Role of Tissue Engineering and Biomaterials in Cardiac Regenerative Medicine

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