Cardiovascular diseases (CVD) are the leading cause of death around the world, being responsible for 31.8% of all deaths in 2017. The leading cause of CVD is Ischemic heart disease (IHD), which caused 8.1 million deaths in 2013. IHD occurs when coronary arteries in the heart are narrowed or blocked, preventing the flow of oxygen and blood into the cardiac muscle, which could provoke acute myocardial infarction (AMI) and ultimately lead to heart failure and death. Cardiac regenerative therapy aims to repair and refunctionalize damaged heart tissue through the application of (1) intramyocardial cell delivery, (2) epicardial cardiac patch, and (3) acellular biomaterials. These approaches have provided benefit of cell localization and tissue structure respectively. However, to improve cell retention and integration, there is a need for the intramyocardial delivery of functional tissues while preserving anisotropic muscle alignment. Here, we developed a biodegradable z-wire scaffold that supports the scalable gel-free production of an array of functional cardiac tissues in a 384-well plate format. The z-wire scaffold design supports cellular alignment, provides tunable mechanical support, and allows for hallmark tissue contraction. When the scaffold is imparted with magnetic properties, individual tissues can be assembled with macroscopic alignment under magnetic guidance. When used in combination with a customized surgical delivery tool, z-wire tissues can be injected directly into the myocardial wall, with controlled tissue orientation according to the injection path. This modular tissue engineering approach, in combination with the use of smart scaffolds, could expand opportunity in functional tissue delivery. / Thesis / Master of Science in Chemical Engineering (MSChE)

L'objectif de cette thèse était d'explorer de nouvelles applications cardiaques pour l'histotripsie et de développer les outils permettant leur mise en place non-invasive. La thérapie ultrasonore cardiaque est en effet encore assez peu développée aujourd’hui, à cause de la difficulté à traiter un organe en mouvement permanent, et très bien protégé derrière la cage thoracique.Nous avons d'abord montré in vivo, sur un modèle ovin, que l’on pouvait sectionner les cordages mitraux de manière non-invasive ainsi que traiter la sténose aortique calcifiée. Engendrer de la cavitation sur les feuillets valvulaires permet effectivement d’agir à distance sur les calcifications, et de globalement assouplir la valve.Simultanément, nous avons développé un dispositif pour la thérapie cardiaque non invasive, fondé sur le concept de cavité à retournement temporel. Ce dispositif permet l'émission d'impulsions ultrasonores de haute intensité dans un très grand volume d’intérêt. L’on peut ainsi déplacer le point de thérapie en 3 dimensions de manière entièrement électronique, et sans déplacer mécaniquement l’appareil. Après optimisation, ce dispositif a permis de créer des lésions mécaniques bien contrôlées dans une région d'intérêt de 2 000 cm3.Pour faire face au défi que représente la cage thoracique, nous avons développé une méthode de focalisation adaptative et l'avons mise en œuvre dans un prototype 2D du dispositif. Avec cette méthode, nous pouvons non seulement construire un front d'onde ultrasonore adaptatif qui se propage de manière préférentielle à travers les espaces intercostaux, mais grâce aux propriétés des cavités à retournement temporel, nous pouvons également augmenter la pression focale obtenue sur la cible de thérapie.Enfin, pour approfondir ce travail sur la focalisation adaptative, et nous avons considéré le cas de l'imagerie transcrânienne. Pour cette application, nous avons choisi d’utiliser la focalisation par retournement temporel dans le bruit de speckle, pour corriger les aberrations induites par le crâne. En simulations numériques, nous avons pu calculer les modulations de phase et d'amplitude induites par les os et améliorer le contraste et la résolution d'une image B-mode. / The objective of this thesis was to explore new applications for cardiac histotripsy, and to develop the tools making it possible non-invasively. Cardiac ultrasound therapy indeed still remains limited due to the tremendous challenge of treating a constantly and rapidly moving organ, well protected behind the ribcage.We first showed in vivo, on a large animal model, that histotripsy could be used non-invasively to cut mitral chordae, and to treat calcified aortic stenosis in a beating heart. Cavitation on the valve leaflets can indeed locally and remotely act on the calcifications, and globally soften the valve. Simultaneously, we developed a therapeutic device allowing completely non-invasive cardiac shock-wave therapy based on the time reversal cavity concept. In particular, this device allows the emission of high intensity ultrasound pulses, and provides 3D electronical steering of the therapy focal spot in a large volume. After a thorough optimisation process, this device was capable of creating well controlled mechanical lesions over a 2 000 cm3 region of interest. To tackle the challenge of ultrasound propagation through the rib cage, we developed an adaptive focusing method (DORT method through a time reversal cavity), and implemented it in a 2D prototype of the device. With this method, we not only could build an adaptive ultrasonic wavefront propagating preferentially through the intercostal spaces, but due to time reversal cavities properties, we could also increase the peak pressure obtained on target.Finally, we pushed our work on adaptive focusing further, and considered the case of transcranial imaging. For this application, we chose to use the time reversal of speckle noise technique, to correct the aberrations induced by the skull. In numerical simulations, we were able to derive the phase and amplitude modulations induced by the bones, and could improve the contrast and resolution of a B-mode image.