BioMEMS for cardiac tissue monitoring and maturation
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Diseases of the heart have been the most common cause of death in the United States since the middle of the 20th century. The development of engineered cardiac tissue over the last three decades has yielded human induced pluripotent stem cell-derived (hiPSC) cardiomyocytes (CMs), microscale “heart-on-a-chip” platforms, optical interrogation techniques, and more. Having spawned its own scientific field, ongoing research promises lofty goals to address the heart disease burden around the world, such as patient-specific disease models, and clinical trials on chip-based platforms. The greatest academic pursuit for engineered cardiac tissues is to increase their maturity, thereby increasing relevance to native adult tissue. Investigation of cardiomyocyte maturity necessitates the development of 3D-tissue compatible techniques for measuring and perturbing cardiac biology with enhanced precision. This dissertation focuses on the development of biological microelectromechanical systems (BioMEMS) for precision measurement and perturbation of cardiac tissue. We discuss three unique approaches to interfacing MEMS-based tools with cardiac biology. The first is a high resolution magnetic sensor, which directly measures the spatial gradient of a magnetic field. This has an ideal application in magnetocardiography (MCG), as the flux of ions during cardiac contractions produces measurable magnetic signals around the tissue and can be leveraged for noncontact diagnosis. The second is a highly functionalized heart-on-a-chip platform, wherein the mechanical contractions of cardiac microtissues can be simultaneously recorded and actuated. Contractile dynamics are leading indicators of maturity in engineered cardiac tissue and mechanical conditioning has shown recent promise as a critical component of cardiac maturation. The third is the imaging of contractile nanostructures in engineered cardiomyocytes at depth in a 3D microtissue. We use small angle X-ray scattering (SAXS) to discern the periodic arrangement of myofilaments in their native 3D environment. We enable a significant structural analysis to provide insight for functional maturation. Enabling these three thrusts required developing two supporting technologies. The first is the engineered control of dynamic second order systems, a foundational element of all our MEMS and magnetic techniques. We demonstrate numerous algorithms to improve settling time or decrease dead-time such that samples with fast temporal effects can be measured. The second is a microscale gluing technique for integrating myriad of materials with MEMS devices, yielding unique sensors and actuators.
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