Analysis of the Biological Implications of the Mechanical Environment Within the Growth Plate During Bone Development in Physiological and Pathological Scenarios

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Analysis of the Biological Implications of the Mechanical Environment Within the Growth Plate During Bone Development in Physiological and Pathological Scenarios ANALYSIS OF THE BIOLOGICAL IMPLICATIONS OF THE MECHANICAL ENVIRONMENT WITHIN THE GROWTH PLATE DURING BONE DEVELOPMENT IN PHYSIOLOGICAL AND PATHOLOGICAL SCENARIOS. Presented by: JOHANA MARÍA GUEVARA MORALES A thesis submitted in conformity with the requirements to obtain the degree of: Ph.D in Biological Sciences Director: Luis Alejandro Barrera Avellaneda. Ph.D. Facultad de Ciencias – Pontificia Universidad Javeriana Co-Director: Diego Alexander Garzón Alvarado. Ph.D. Facultad de Ingeniería – Universidad Nacional de Colombia PONTIFICIA UNIVERSIDAD JAVERIANA FACULTAD DE CIENCIAS PROGRAMA DE DOCTORADO EN CIENCIAS BIOLÓGICAS BOGOTA – COLOMBIA 2016 ARTICULO 23 DE LA RESOLUCION No. 13 DE JULIO DE 1946 “La universidad no se hace responsable por los conceptos emitidos por sus alumnos en sus trabajos de tesis. Solo velará porque no se publique nada contrario al dogma y a la moral católica y porque la tesis no contenga ataques personales contra persona alguna, antes bien sea en ellas el anhelo de buscar la verdad y justicia” ANALYSIS OF THE BIOLOGICAL IMPLICATIONS OF THE MECHANICAL ENVIRONMENT WITHIN THE GROWTH PLATE DURING BONE DEVELOPMENT IN PHYSIOLOGICAL AND PATHOLOGICAL SCENARIOS. Johana María Guevara Morales __________________________________________ DANIEL SUAREZ. PhD. Evaluator 4 ANALYSIS OF THE BIOLOGICAL IMPLICATIONS OF THE MECHANICAL ENVIRONMENT WITHIN THE GROWTH PLATE DURING BONE DEVELOPMENT IN PHYSIOLOGICAL AND PATHOLOGICAL SCENARIOS. Johana María Guevara Morales __________________________________________ SHUNJI TOMATSU. MD. PhD. Evaluator 5 ANALYSIS OF THE MECHANICAL ENVIRONMENT WITHIN THE GROWTH PLATE DURING BONE DEVELOPMENT: PHYSIOLOGICAL AND PATHOLOGICAL IMPLICATIONS Johana María Guevara Morales ________________________________ ____________________________________ CONCEPCIÓN J. PUERTA B. PhD. ALBA ALICIA TRESPALACIOS R. PhD. Decana Facultad de Ciencias Directora Programa Posgrado Thesis done in Institute for the Study of Inborn Errors of Metabolism Pontificia Universidad Javeriana Bogotá, Colombia Biomimetics Lab and Group of Numerical Methods Universidad Nacional de Colombia Bogotá, Colombia And Schuchman’s Lab – Genetics and Genomics Deparment Mount Sinai School of Medicine New York, USA To all those who made possible this work and contributed to make of this a very enriching episode of my personal and academic life. 7 ACKNOWLEDGMENTS I apologize but I was unable to do this in English. Primero quisiera agradecer a Dios por esta enriquecedora experiencia, por todo lo que he aprendido como persona y como investigadora, por todas las oportunidades, las lecciones, pero sobre todo por todas esas maravillosas personas que puso en mi camino de quienes he recibido mucho apoyo, muchas lecciones y con quienes he pasado muchos momentos inolvidables. Y a mi familia, porque sin su apoyo y voz de aliento este logro no habría sido posible. Por ayudarme a levantarme cuando caí, por celebrar conmigo cada logro, por su amor incondicional. Especialmente quiero dar gracias a mis papás, las personas más importantes en mi vida, por todos sus concejos y todo el cariño que me brindan a diario. A mi tía Eliza que siempre ha sido mi ángel de la guarda, no creo poder pagar todo lo que has hecho por mí. Muchas gracias al Dr. Barrera por acompañarme en este proceso y darme su apoyo para emprender cada aventura académica. Muchas gracias por ser quien me dio la oportunidad de formar parte del maravilloso grupo de errores innatos y permitirme llegar a ser el profesional que soy hoy en día. Gracias por guiarme y darme su apoyo no solo en lo académico sino también en lo personal. Muchas gracias doc. Al Ing. Diego Garzón por darme la oportunidad de trabajar con él y ser parte del grupo. Gracias por toda la paciencia, por todo el tiempo y la dedicación. A OYEP porque siempre estuvo a mi lado dándome su consejo y su apoyo. Regañándome cuando era necesario y también escuchándome en esos momentos de estrés. Gracias por ser mi amiga y mi sensei. A mi compañera de batalla, Jokito, porque ¿qué habría sido de este camino sin tu valiosa compañía?. Gracias por los consejos, los regaños, las risas, los momentos de charlas profundas y los perros monstruo de la 45. A Juanito por ser mi compañero, mi compinche, mi amigo y hasta mi maestro en muchos aspectos. Muchas gracias por hacer de este doctorado una de las etapas más bonitas y memorables de mi vida. Gracias por enseñarme a pensar diferente y a ver la vida con otros ojos. Gracias por ayudarme a crecer como investigador y como persona. A Miguelito por aguantarme en las buenas y en las malas. Por hacer de este un viaje divertido y por ser siempre tan especial. A Hector porque creo que no hubiera terminado sin tu ayuda. Gracias por que a pesar de todo siempre estás ahí. Por ser mi compinche, mi par académico, mi revisor de estilo, pero sobre todo por ser un amigo incondicional. A mis compañeros y amigos del Instituto de Errores Innatos del Metabolismo por ser mi familia académica y estar siempre ahí cuando los necesite. A todos mis compañeros y amigos del laboratorio de biomiméticos y el grupo de métodos numéricos. Muchas gracias por recibirme y acogerme, ha sido muy grato tener la oportunidad de estar en la universidad nacional de Colombia y compartir con todos ustedes. Al Dr. Edward Schuchmann y la Dra. Calogera Simonaro por brindarme la oportunidad de trabajar con ellos y por todo su apoyo. A Mike por su ser mi guía y por toda su colaboración. Creo que ningún espacio será suficiente para agradecerle a todas las personas que han hecho posible este logro. A todos los que con sus conocimientos, su talento, su trabajo, sus concejos, su sonrisa, su cariño, etc, etc, han hecho parte de esta aventura académica. Son muchas muchas personas y aunque tal los nombres no estén en estos párrafos si están escritos en mi mente y en mi corazón …. Muchas gracias a todos. ANALYSIS OF THE MECHANICAL ENVIRONMENT WITHIN THE GROWTH PLATE DURING BONE DEVELOPMENT: PHYSIOLOGICAL AND PATHOLOGICAL IMPLICATIONS CONTENT ABSTRACT ____________________________________________________________ 14 INTRODUCTORY REMARKS _________________________________________ 15 1.1 INTRODUCTION _____________________________________________________ 15 1.2 OBJECTIVES ________________________________________________________ 17 1.2.1 General Aim _______________________________________________________________ 17 1.2.2 Specific Aims ______________________________________________________________ 17 1.3 THESIS OUTLINE ____________________________________________________ 17 2 CONCEPTUAL FRAMEWORK ________________________________________ 19 2.1 SKELETAL SYSTEM __________________________________________________ 19 2.2 LONG BONE ANATOMY AND DEVELOPMENT _________________________ 20 2.3 THE GROWTH PLATE ________________________________________________ 22 2.3.1 Hyaline Cartilage ____________________________________________________________ 24 2.4 ENDOCHONDRAL OSSIFICATION _____________________________________ 33 2.4.1 Chondrocyte Differentiation ___________________________________________________ 34 2.5 BIOCHEMICAL REGULATION OF LONG BONE GROWTH ______________ 39 2.5.1 Local Factors _______________________________________________________________ 39 2.5.2 Systemic Factors ____________________________________________________________ 44 2.6 MECHANICAL INFLUENCES ON LONG BONE GROWTH AND GROWTH PLATE ____________________________________________________________________ 45 2.6.1 Mechanical Effects on Chondrocytes Behavior _____________________________________ 46 2.6.2 Mechanotransduction _________________________________________________________ 49 2.7 IN SILICO APPROXIMATIONS TO BONE GROWTH AND MORPHOGENESIS. THE ROLE OF STRAINS AND PRESSURES. ___________________________________ 50 2.7.1 Computational Models _______________________________________________________ 50 2.8 ABNORMALITIES IN LONG BONE DEVELOPMENT _____________________ 52 2.8.1 Chondrodysplasias ___________________________________________________________ 53 7 3 GROWTH PLATE STRESS DISTRIBUTION DURING BONE DEVELOPMENT 56 3.1 INTRODUCTION _____________________________________________________ 56 3.2 MATERIALS AND METHODS __________________________________________ 58 3.2.1 Model _____________________________________________________________________ 58 3.2.2 Loading conditions and constrains ______________________________________________ 61 3.2.3 Data Analysis _______________________________________________________________ 62 3.3 RESULTS ____________________________________________________________ 63 3.3.1 Stress distribution during development ___________________________________________ 63 3.3.2 Growth plate effect on epiphyseal OI distribution ___________________________________ 66 3.3.3 SOC effect on epiphyseal stress distribution _______________________________________ 66 3.3.4 Growth plate OI distribution ___________________________________________________ 67 3.4 DISCUSSION AND CONCLUSIONS _____________________________________ 69 4 ANALYSIS OF THE ASSOCIATION BETWEEN MECHANICAL ENVIRONMENT AND GROWTH PLATE MORPHOLOGICAL EVOLUTION DURING PROXIMAL FEMUR DEVELOPMENT. ____________________________ 73 4.1 INTRODUCTION _____________________________________________________ 73 4.2 MATERIALS AND METHODS __________________________________________ 75 4.2.1 Geometric Model ____________________________________________________________ 75 4.2.2 Mechanical Stimuli __________________________________________________________ 76 4.2.3 Part 1: Influence of Growth Plate Shape on Stimuli Behavior _________________________ 77 4.2.4 Part 2:
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