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Tesi amb menció de Doctorat Industrial (Generalitat de Catalunya), Tesi amb continguts retallats per motius de confidencialitat, (English) Bone defects pose a major clinical and socio-economic burden and there is a clear need for new bone grafting strategies that take into account the physical-chemical properties of the native bone, to help treat bone defects in a time- and cost-effective way. Autografts are considered the gold standard due to their biological performance, however, additional surgical procedures for bone harvesting poses drawbacks. For this reason, the industrial- and scientific communities have focused on the development of synthetic bone grafting solutions. The present PhD thesis advances in the development of biomimetic personalised bone grafting solutions, including the clinical validation and the development of new material formulations with improved mechanical performance. Chapter 1: Gives an insight into the general context of bone regeneration and the materials used as bone substitutes, emphasising the need for innovative personalised synthetic bone grafts. This chapter offers an overview of additive manufacturing techniques and frequently employed ceramics in bone tissue engineering and their consolidation strategies. Further, a global presentation is given on their clinical translation, especially emphasising calcium phosphates and MimetikOss® 3D. Chapter 2: Focuses on evaluating the clinical performance of the 3D-printed bone graft MimetikOss® 3D in a horizontal vestibular augmentation. The ridge in the anterior maxilla is reconstructed with a synthetic patient-specific bone graft with a staged approach for dental implant placement. 3D-printed bone grafts permit a perfect fit in the surgical site without any additional shaping, which reduces surgery time compared with other bone augmentation techniques (e.g., guided bone regeneration, standard blocks). The bone graft is completely osseointegrated and its macropores colonised by newly formed bone at 10-months post-surgery without signs of encapsulation. A stable bone gain is achieved, resulting in a fully restored b, (Català) Els defectes ossis suposen una càrrega assistencial i una despesa socioeconòmica important i, per tant, hi ha una clara necessitat de desenvolupar noves estratègies d'empelt ossi que tinguin en compte les propietats fisicoquímiques de l'os autòleg per aconseguir tractar els defectes ossis d'una manera més eficaç. Els autoempelts són considerats la opció de referència pel seu excel·lent rendiment biològic. Malgrat això, presenta greus inconvenients ja que requereixen d’una cirurgia addicional per a obtenir- los. Per aquest motiu, les comunitats industrial i científica s'han centrat en el desenvolupament de d'empelts ossis sintètics, aprofitant la facilitat de control químic, estructural i geomètric. La present tesi doctoral es centra en el desenvolupament d'empelts ossis biomimètics personalitzats, incloent la validació clínica i el desenvolupament de noves formulacions de materials amb un millor comportament mecànic. El capítol 1 dóna una visió global de l’estat de l’art de la regeneració òssia i els materials utilitzats com a substituts ossis, posant èmfasi en la necessitat de desenvolupar empelts ossis sintètics personalitzats innovadors. Aquest capítol ofereix una revisió de les tècniques de fabricació additiva i els materials ceràmics utilitzats més freqüentment en l'enginyeria de teixits ossis i les seves estratègies de consolidació. Es presenta la seva transferència a l’entorn clínic, focalitzant-se en els fosfats de calci i en MimetikOss® 3D. El capítol 2 es centra en avaluar el comportament clínic de l'empelt ossi ceràmic imprès en 3D MimetikOss® 3D en un augment vestibular horitzontal. Aquests empelts ossis permeten un encaix perfecte en el lloc quirúrgic sense cap necessitat de fresat addicional, la qual cosa redueix el temps de cirurgia en comparació amb altres tècniques de regeneració òssia (regeneració òssia guiada, blocs estandarditzats). L'empelt ossi està completament osteointegrat i els seus macropors són colonitzats per l'os 10 mesos despr, (Español) Los defectos óseos suponen una carga asistencial y un gasto socioeconómico importante y, por eso, existe una necesidad de desarrollar nuevas estrategias de injerto óseo que tengan en cuenta las propiedades fisicoquímicas del hueso autólogo, para conseguir tratar los defectos óseos de una manera más eficaz. Los autoinjertos se consideran el estándar de referencia debido a su excelente comportamiento biológico. No obstante, presentan graves inconvenientes, requerido de una cirugía adicional para su obtención. Por este motivo, las comunidades industrial y científica se han centrado en el desarrollo de injertos óseos sintéticos, aprovechando su capacidad de control químico, estructural y geométrico. La presente tesis doctoral se centra en el desarrollo de injertos óseos biomiméticos y personalizados, incluyendo la validación clínica y el desarrollo de nuevas formulaciones de materiales con comportamiento mecánico mejorado. En el capítulo 1 se presenta el estado del arte en el campo de la regeneración ósea y los materiales utilizados como sustitutos óseos, enfatizando la necesidad de injertos óseos sintéticos personalizados innovadores. Este capítulo describe las técnicas de fabricación aditiva y los cerámicos frecuentemente empleados en la ingeniería de tejido óseo y sus estrategias de consolidación. Se presenta su transferencia al mundo clínico, haciendo hincapié en el fosfato de cálcico y MimetikOss® 3D. El capítulo 2 se centra en evaluar el comportamiento clínico del injerto óseo cerámico personalizado MimetikOss® 3D en un aumento vestibular horizontal. Los injertos óseos impresos en 3D permiten un ajuste perfecto en el lecho quirúrgico sin necesidad de fresado adicional, lo que reduce el tiempo de la cirugía en comparación con otras técnicas de reconstrucción ósea (regeneración ósea guiada, bloques estándar). El injerto óseo está completamente osteointegrado y sus macroporos son colonizados por hueso 10 meses después de la cirugía sin signos de encapsulaci, Postprint (published version)

The application of 3D printing to calcium phosphates has opened unprecedented possibilities for the fabrication of personalized bone grafts. However, their biocompatibility and bioactivity are counterbalanced by their high brittleness. In this work we aim at overcoming this problem by developing a self-hardening ink containing reactive ceramic particles in a polycaprolactone solution instead of the traditional approach that use hydrogels as binders. The presence of polycaprolactone preserved the printability of the ink and was compatible with the hydrolysis-based hardening process, despite the absence of water in the ink and its hydrophobicity. The microstructure evolved from a continuous polymeric phase with loose ceramic particles to a continuous network of hydroxyapatite nanocrystals intertwined with the polymer, in a configuration radically different from the polymer/ceramic composites obtained by fused deposition modelling. This resulted in the evolution from a ductile behavior, dominated by the polymer, to a stiffer behavior as the ceramic phase reacted. The polycaprolactone binder provides two highly relevant benefits compared to hydrogel-based inks. First, the handleability and elasticity of the as-printed scaffolds, together with the proven possibility of eliminating the solvent, opens the door to implanting the scaffolds freshly printed once lyophilized, while in a ductile state, and the hardening process to take place inside the body, as in the case of calcium phosphate cements. Second, even with a hydroxyapatite content of more than 92%, the flexural strength and toughness of the scaffolds after hardening are twice and five times those of the all-ceramic scaffolds obtained with the hydrogel-based inks, respectively., Peer Reviewed, Postprint (published version)

Three-dimensional printing has opened up new perspectives in bone substitution, facilitating the production of customized scaffolds. The advances of the last few years have placed this technology at the forefront of personalized medicine and virtual surgical planning. This article presents an overview of additive manufacturing of bioceramics for bone regeneration, covering both the additive manufacturing methods and the consolidation strategies that can be applied. We highlight the main progress made in recent years, with an insight into drug delivery applications and the advances in the translation of this technology to the biomedical industry and the clinics. Furthermore, the main challenges and future trends of this new medical technology are identified and discussed., Peer Reviewed, Postprint (author's final draft)

Bone is a hard tissue which is remodelled throughout life and possesses the ability to heal small injuries and ruptures, meanwhile larger fractures, or voids generated after a tumour removal, are more difficult or even impossible for the bone to heal by itself. Thus, bone substitutes are required and natural bone substitutes from the patient itself, from a human cadaver donor or from an animal are nowadays current options for bone repair. The main problem when using natural bone substitutes is the risk for disease transmission or rejection, the limited amount of the bone substitute in autografts and some ethical considerations. For these reasons, new synthetic bone substitutes have been developed the past years. One class among the many biomaterials applied for synthetic bone substitution are Calcium Phosphate Cements (CPCs). This report focuses on the development of Calcium Phosphate Cement (CPC) microspheresfrom alpha Tricalcium Phosphate (α-TCP) as synthetic bone substitution and drug carrier of the chemotherapeutic drug doxorubicin. Once the microspheres synthesized and loaded with the antitumoral drug, the main goal is to study the impact on the doxorubicin release kinetics from polymer-coated microspheres to a physiological receptor medium (PBS). In order to avoid loss of the incorporated doxorubicin by using a chemical wet process, polymer coating of the microspheres was carried out by low-pressure plasma polymerization. Leaning on their biocompatible properties, poly(ethylene glycol) (PEG) and poly(εcaprolactone) (PCL) layers were selected for coating the doxorubicin-loaded microspheres, using the monomers Diethylene Glycol Dimethyl Ether (DIGLYME) and ε-Caprolactone (ε-CL), respectively, as precursors for plasma polymerization. By performing a sieving of the microspheres after their synthesis, the doxorubicin loading capacity was evaluated for microspheres with different size distribution and it was revealed that microspheres of the size 100 < ∅ < 150 μm ha