Embedding bioelectronics within a multi–functional characterisation platform for cellular interrogation and cardiac tissue deterministic regeneration
Creators: name: Cox-Pridmore, Dannielle
Publisher: name: University of Surrey
Year: 2023

description: Cardiovascular disorders are the leading cause of mortality worldwide, resulting in the deaths of over ~19 million people annually. A therapeutic option is cardiac tissue engineering (CTE), which is the creation of contractile cardiac muscle tissue in vitro. However, currently available CTE approaches struggle to engineer tissue that has a mature physical appearance and electrical properties suitable for research and clinical applications. <br>
description: <br>
description: This thesis focuses on the development of a multifunctional bioelectronic platform that can allow for the simultaneous creation and characterisation of cardiac tissue. A functional and mechanically stable, exceedingly thin biomimetic bioelectronic device has been designed and fabricated, composed of gold (Au) electrode ribbons passivated by biocompatible SU–8 mesh layers, that can be seamlessly integrated into a customised on–stage incubator chamber, combined with a fluorescence microscope, and stimulation/measurement system to allow for continuous and long–term monitoring and manipulation of cell behaviour, in turn, regulating tissue formation. <br>
description: <br>
description: The porous design of the encapsulating SU–8 provides a level of extracellular matrix–like geometric control over tissue creation, while resulting in ~85% of the device equating to empty space to encourage cell movement, and the efficient diffusion of oxygen, nutrients, and metabolic waste for more effective cardiac cell culture. In addition, the device contains 12 mm long electrodes to provide electrical stimulation (ES) that promote correct tissue assembly and formation by directing cell growth, alignment, maturation, and contraction. <br>
description: <br>
description: The presence of the bioelectronic mesh provided orientation of cells with narrow distribution of angles relative to the ribbon direction. On average, 39% of cardiomyocytes’ nuclei were aligned with the mesh ribbon (0o). Larger widths (60 µm) encouraged the greatest cell elongation and cell alignment, with 53% of cells growing within the device’s direction (0o). This is in stark contrast with the control 2D cell culture that showed no favourable directionality. The ability to control cellular alignment allows for improved functionality, due to the direction–dependent nature of cardiac muscle. In addition, the bioelectronic mesh was able to induce nuclei elongation both without (27%) and with (55%) electrical stimulation. Finally, the application of electrical stimulation from the mesh device tripled the beating rate of the cardiomyocytes from 24 bpm to 72 bpm, providing a contraction profile comparable to endogenous heart tissue. <br>
description: <br>
description: The bioelectronic platform described in this thesis has been demonstrated to be an improvement of already established CTE methods, to create and verify reliable cardiac tissue constructs in vitro. In time, this could be used to allow a greater understanding of the cardiovascular system, how tissues form, disease progression, pharmaceutical validation, or to be transplanted to repair and/or replace damaged heart tissue.<br>
description: <br>
description: The long–term aim of the work is for the bioinspired extracellular matrix–like bioelectronics embedded within human cardiac organoids to be used for multifunctional physiological interrogation and disease modelling. The device has been designed with integrated biosensor recording pads, with ongoing and future work demonstrating the potential to record local extracellular signals from cells in real–time. This can be applied to provide a greater understanding of the differences between healthy and disease cells in their presentation and progression, and the understanding of possible targets for future treatment. The work described in this thesis can expand and develop into many areas of cardiovascular research and medicine.<br>