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Novel Tissue Engineering Strategies for Cardiac Repair After a Myocardial Infarction

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Novel Tissue Engineering Strategies for Cardiac Repair After a Myocardial Infarction Departamento de Tecnología y Química Farmacéuticas Facultad de Farmacia y Nutrición TESIS DOCTORAL NOVEL TISSUE ENGINEERING STRATEGIES FOR CARDIAC REPAIR AFTER A MYOCARDIAL INFARCTION Laura Saludas Echauri Pamplona, 2020 Departamento de Tecnología y Química Farmacéuticas Facultad de Farmacia y Nutrición TESIS DOCTORAL NOVEL TISSUE ENGINEERING STRATEGIES FOR CARDIAC REPAIR AFTER A MYOCARDIAL INFARCTION Trabajo presentado por Laura Saludas Echauri para obtener el grado de Doctor en Farmacia Fdo. Laura Saludas Echauri Pamplona, 2020 UNIVERSIDAD DE NAVARRA FACULTAD DE FARMACIA Y NUTRICIÓN Departamento de Tecnología y Química Farmacéuticas DÑA. MARÍA BLANCO PRIETO, Catedrática de la Universidad de Navarra y Profesora Investigadora del Departamento de Tecnología y Química Farmacéuticas y D. FELIPE PRÓSPER CARDOSO, director del Área de Terapia Celular y codirector del Servicio de Hematología de la Cínica Universidad de Navarra Certifican: Que el presente trabajo, titulado “Novel tissue engineering strategies for cardiac repair after a myocardial infarction”, presentado por DÑA. LAURA SALUDAS ECHAURI para optar al grado de Doctor en Farmacia, ha sido realizado bajo su dirección en el Departamento de Tecnología y Química Farmacéuticas de la Universidad de Navarra y en el Área de Terapia Celular del Centro de Investigación Médica Aplicada (CIMA). Considerando finalizado el trabajo autorizan su presentación a fin de que pueda ser juzgado y calificado por el Tribunal correspondiente. Y para que así conste, firman la presente: Dra. María Blanco Prieto Dr. Felipe Prósper Cardoso Pamplona, 2020 Las investigaciones realizadas en el presente trabajo se han desarrollado gracias a la financiación recibida a través del Ministerio de Economía y Competitividad (SAF2013-42528-R y SAF2017-83734-R) y a través de la convocatoria del EuroNanoMed2 (proyecto: NanoHeart, ANR-16-ENM2–0005-01). Asimismo, agradezco a la Asociación de Amigos de la Universidad de Navarra y a Obra Social “la Caixa” por la beca para la formación de personal investigador proporcionada para la realización de esta tesis doctoral, y a Fundación Caja Navarra por la beca de movilidad. A mis padres, Joaquín y Tomy “Courage is like -it’s a habitus, a habit, a virtue: you get it by courageous acts. It is like you learn to swim by swimming. You learn courage by couraging.” Marie M. Daly (1921-2003) Bioquímica y primera mujer afroamericana en obtener el grado de Doctor en Química en Estados Unidos. Realizó importantes contribuciones acerca de las causas de un ataque al corazón. AGRADECIMIENTOS Seguramente esta tesis doctoral no hubiese sido posible sin el apoyo incondicional y la confianza depositada en mí de un gran número de personas que de una manera u otra me han guiado en este camino y me han empujado cada día a alcanzar la cima. No existe mejor manera de empezar que agradeciendo a todas ellas. En primer lugar, agradecer a la Universidad de Navarra. He tenido la gran suerte de poder pertenecer a esta universidad desde que empecé como estudiante de grado, más adelante como alumna de máster y finalmente, como estudiante de doctorado. Me siento enormemente agradecida por lo todo lo que he podido aprender y crecer en esta universidad y las oportunidades que siempre me ha brindado. En concreto, deseo extender este agradecimiento a todas las excepcionales personas que forman parte del Departamento de Tecnología y Química Farmacéuticas y del Área de Terapia Celular del Centro de Investigación Médica Aplicada (CIMA). A su vez, me gustaría expresar mi enorme gratitud a la Asociación de Amigos de la Universidad de Navarra, a la Obra Social “La Caixa” y a Fundación Caja Navarra por el apoyo económico prestado. Gracias a mis directores de tesis. A la Dra. María Blanco por haber confiado en mí para la realización de esta tesis doctoral y por acogerme en tu grupo. Por tu dedicación, compromiso y haberme guiado siempre con acierto en los momentos difíciles. Por todas las oportunidades que me has brindado durante estos años y que tanto me han ayudado a crecer profesional y personalmente. A mi codirector el Dr. Felipe Prósper, por haberme aportado siempre esa visión clínica tan necesaria e imprescindible para completar con éxito una investigación de este tipo. Por tu calidad investigadora y tu capacidad crítica. De la misma manera, agradecer el apoyo incondicional de la Dra. Elisa Garbayo. Me siento muy orgullosa de haber podido aprender tanto de ti estos años. Poder trabajar a tu lado ha sido muy gratificante y enriquecedor. Gracias por tus consejos y tu visión siempre tan optimista. Gracias a la directora del departamento, la Dra. Carmen Sanmartín, así como a todos los profesores por haber estado siempre dispuestos a ayudar: a la Dra. Carmen Dios, a la Dra. Conchita Tros, al Dr. Juan Manuel Irache y a la Dra. Socorro Espuelas. Quisiera agradecer enormemente a las excepcionales personas y profesionales del Área de Terapia Celular del CIMA y CUN. En especial al Dr. Manu Mazo por tu permanente buen humor, por lo sencillo que ha sido trabajar contigo y por tu larga experiencia, a la Dra. Bea Pelacho por tu predisposición a colaborar, a Gloria Abizanda y Elena Iglesias por vuestra ayuda en el trabajo con animales y por haber conseguido que las largas horas en el animalario fuesen mucho más cortas, y finalmente al Dr. Adrián Ruiz y la Dra. Silvia Hernández por vuestra entrega, dedicación y por haber tenido siempre palabras de ánimo para mi durante estos últimos meses. Ha sido realmente un honor poder colaborar y aprender de todos vosotros. Agradecimientos Gracias a todos los compañeros con los que he compartido esta experiencia y que con el tiempo se han ido convirtiendo en grandes amigos. A Simón, gracias por todo lo que me has ayudado pero sobre todo gracias por todos los momentos inolvidables que he vivido contigo dentro y fuera del laboratorio. A Carlos, por haber sido un compañero de viaje inigualable, por tu compañía, por escucharme cuando las cosas iban bien y cuando no. A Edurne y Pablo, por lo gratificante, sencillo y positivo que ha sido trabajar a vuestro lado. A Hugo, por tener siempre la solución a todos nuestros problemas, por tu paciencia y por no perder nunca el buen humor. Has sido indispensable estos años. Gracias a todos vosotros por haber hecho de la tesis una experiencia personal que nunca olvidaré. Estoy muy orgullosa de haberos conocido. Muchas gracias también al resto de personas con las que he tenido la oportunidad de coincidir cada día. A Alba, Cristina, Raquel, Esther, Cristian, Ana, Edu, Silvia y a todo el grupo de farmacocinética. En especial a Jorge, por haber sido mi confidente y amigo estos años. Ha sido un honor haber sido vuestra compañera y compartir con vosotros inquietudes y risas. Thanks to all the people involved in the NanoHeart project for the interesting discussions we had and the valuable advices provided. In addition, I would like to express my gratitude to Dr. Joost Sluijter, Dr. Pieter Vader and the whole group of Experimental Cardiology of the University Medical Centre Utrecht. Thanks for your support, your dedication and your help. Also thanks to all the amazing people that I had the chance to meet during those incredible months. Muchas gracias a mis amigas. Por haber creído en mi más que nadie, por apoyarme y por ser siempre luz. En especial a Blanca, por no haberme dejado sola ni un momento en este camino y haber conseguido que todo fuese más sencillo. Finalmente, el agradecimiento más especial me gustaría dedicárselo a mis padres. Todo esto es por y para vosotros. Nunca podré encontrar palabras suficientes para agradeceros todo lo que habéis hecho por mí. A todos los que habéis estado a mi lado incondicionalmente durante todo este tiempo, ¡GRACIAS! TABLE OF CONTENTS ABBREVIATIONS 1 FOREWORD 3 DRUG DELIVERY SYSTEMS FOR MENDING AN INFARCTED HEART .............................................. 5 INTRODUCTION 11 HEART TISSUE REPAIR AND CARDIOPROTECTION USING DRUG DELIVERY SYSTEMS ................. 13 Abstract ................................................................................................................................ 15 1. Introduction ...................................................................................................................... 17 2. Methods ............................................................................................................................ 18 3. Systemic administration of particles for treating myocardial infarction ............................... 18 3.1. Systemic administration of particles for cardiac repair ...................................................... 19 3.2. Systemic administration of particles for cardioprotection ................................................. 20 4. Local administration of particles for treating myocardial infarction ..................................... 23 4.1. Local administration of particles for cardiac repair ............................................................ 23 4.2. Local administration of particles for cardioprotection ....................................................... 27 5. Concluding remarks ........................................................................................................... 27 Acknowledgements ............................................................................................................... 29 References ............................................................................................................................ 29 HYDROGEL BASED APPROACHES FOR CARDIAC TISSUE ENGINEERING ....................................
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