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The 3D printing of titanium (Ti) offers countless possibilities for the development of personalized implants with suitable mechanical properties for different medical applications. However, the poor bioactivity of Ti is still a challenge that needs to be addressed to promote scaffold osseointegration. The aim of the present study was to functionalize Ti scaffolds with genetically modified elastin-like recombinamers (ELRs), synthetic polymeric proteins containing the elastin epitopes responsible for their mechanical properties and for promoting mesenchymal stem cell (MSC) recruitment, proliferation, and differentiation to ultimately increase scaffold osseointegration. To this end, ELRs containing specific cell-adhesive (RGD) and/or osteoinductive (SNA15) moieties were covalently attached to Ti scaffolds. Cell adhesion, proliferation, and colonization were enhanced on those scaffolds functionalized with RGD-ELR, while differentiation was promoted on those with SNA15-ELR. The combination of both RGD and SNA15 into the same ELR stimulated cell adhesion, proliferation, and differentiation, although at lower levels than those for every single moiety. These results suggest that biofunctionalization with SNA15-ELRs could modulate the cellular response to improve the osseointegration of Ti implants. Further investigation on the amount and distribution of RGD and SNA15 moieties in ELRs could improve cell adhesion, proliferation, and differentiation compared to the present study., Peer Reviewed, Postprint (published version)

Tesi per compendi de publicacions, Titanium (Ti) and Ti alloys have been used for decades for bone implants and prostheses due to its mechanical reliability and good biocompatibility. However, implant-related infections, lack of osseointegration with the surrounding bone, and the mismatch of mechanical properties between implant and bone, remain among the leading reasons for implant failure. In the present PhD thesis, two strategies have been studied to increase implant viability: fabrication of porous Ti structures and surface functionalization. The stiffness mismatch between titanium implant and bone can cause significant bone resorption, which can lead to serious complications such as periprosthetic fracture during or after revision surgery. Titanium surface plays a major role in the bone prosthesis interactions, not only to promote initial cell adhesion but also to avoid bacterial adhesion. One strategy studied in the thesis has been the development and manufacturing of porous Ti structures. A scaffold with a porosity of 75% has been prepared by direct ink writing, with the objective of reducing the apparent modulus elasticity of Ti prostheses. In this work, porous Ti structures with a stiffness and compressive strength of 2.6 GPa and 64.5 MPa respectively has been manufactured. To this end, a new ink formulation was designed based on the mixture of a thermosensitive hydrogel with Ti irregular powder particles with a mean particle size of 22.45 μm. A thermal treatment was optimized to ensure the complete elimination of the binder before the sintering process, in order to avoid contamination of the titanium structures. The understanding of infections is closely linked to the concept of the “race for the surface”. The winner of this race (cell versus bacteria) decides if a solid anchoring between implant and bone will be achieved or if bacterial growth will lead to a periprosthetic infection. Another strategy studied on this thesis focuses on the functionalization of the Ti surface. First, surface, El titani (Ti) i els seus aliatges s'han emprat durant dècades per a implants i pròtesis òssies a causa de la seva fiabilitat mecànica i bona biocompatibilítat. Tanmateix, les infeccions relacionades amb els implants, la manca d'osteointegració amb l'os circumdant i el desajust de les propietats mecàniques entre l'implant i l'os, continuen sent els principals motius de fallida de l'implant En la present tesi doctoral, s'han estudiat dues estratègies per augmentar la viabilitat de l'implant fabricació d'estructures poroses de Ti i funcionalització superficial. El desajust de la rigidesa entre l'implant de titani i l'os pot causar una reabsorció òssia important, que pot provocar complicacions greus com la fractura periprotètica durant o després de la cirurgia de revisió . La superfície del titani té un paper important en les interaccions os-pròtesi, no només per promoure l'adhesió inicial de les cèl·lules, sinó també per evitar l'adhesió bacteriana. Una estratègia estudiada a la tesi ha estat el desenvolupament i fabricació d'estructures poroses de Ti. S'ha preparat un andamiatge amb una porositat del 75% mitjançant Direct lnk Writing, amb l'objectiu de reduir l'elasticitat del mòdul aparent de les pròtesis de Ti. En aquest treball, s'han fabricat estructures poroses de Ti amb una rigidesa i resistència a la compressió de 2,6 GPa i 64,5 MPa respectivament. Per això, es va dissenyar una nova formulació de tinta basada en la barreja d'un hidrogel termosensible amb partícules de pols irregulars de Ti amb una mida mitjana de partícula de 22,45 µm. Es va optimitzar un tractament tèrmic per assegurar l’eliminació completa de l'aglutinant abans del procés de sinterització, per evitar la contaminació de les estructures de titani. La lluita contra les infeccions està estretament lligada al concepte de "carrera per la superfície". El guanyador d'aquesta carrera (cèl·lula contra bacteris) decideix si s'aconseguirà un ancoratge sòlid entre l'implant i l'os o si el creixement bact, Postprint (published version)

Implants for orthopedic applications need to be biocompatible and bioactive, with mechanical properties similar to those of surrounding natural bone. Given this scenario titanium (Ti) scaffolds obtained by Direct Ink Writing technique offer the opportunity to manufacture customized structures with controlled porosity and mechanical properties. Considering that 3D Ti scaffolds have a significant surface area, it is necessary to develop strategies against the initial bacterial adhesion in order to prevent infection in the early stages of the implantation, while promoting cell adhesion to the scaffold. The challenge is not only achieving a balance between antibacterial activity and osseointegration, it is also to develop a homogeneous coating on the inner and outer surface of the scaffold. The purpose of this work was the development of a single-step electrodeposition process in order to uniformly cover Ti scaffolds with a layer of calcium phosphate (CaP) loaded with chlorhexidine digluconate (CHX). Scaffold characterization was assessed by scanning electron microscopy, Energy dispersive X-ray spectroscopy, X-ray diffraction, micro-Raman microscopy and compressive strength tests. Results determined that the surface of scaffolds was covered by plate-like and whisker-like calcium phosphate crystals, which main phases were octacalcium phosphate and brushite. Biological tests showed that the as-coated scaffolds reduced bacteria adhesion (73 ± 3% for Staphylococcus aureus and 70 ± 2% for Escherichia coli). In vitro cell studies and confocal analysis revealed the adhesion and spreading of osteoblast-like SaOS-2 on coated surfaces. Therefore, the proposed strategy can be a potential candidate in bone replacing surgeries., Peer Reviewed, Postprint (author's final draft)

Titanium (Ti) and Ti alloys have been used for decades for bone prostheses due to its mechanical reliability and good biocompatibility. However, the high stiffness of Ti implants and the lack of bioactivity are pending issues that should be improved to minimize implant failure. The stress shielding e ect, a result of the stiffness mismatch between titanium and bone, can be reduced by introducing a tailored structural porosity in the implant. In this work, porous titanium structures were produced by direct ink writing (DIW), using a new Ti ink formulation containing a thermosensitive hydrogel. A thermal treatment was optimized to ensure the complete elimination of the binder before the sintering process, in order to avoid contamination of the titanium structures. The samples were sintered in argon atmosphere at 1200 ºC, 1300 ºC or 1400 ºC, resulting in total porosities ranging between 72.3% and 77.7%. A correlation was found between the total porosity and the elastic modulus of the sca olds. The stiffness and yield strength were similar to those of cancellous bone. The functionalization of the sca old surface with a cell adhesion fibronectin recombinant fragment resulted in enhanced adhesion and spreading of osteoblastic-like cells, together with increased alkaline phosphatase expression and mineralization., Peer Reviewed, Postprint (published version)

Metallic implants have some limitations related to bioactivity and bacteria colonization leading to infections. In this regard, calcium phosphate coatings can be used as carrier for drug delivery in order to improve the mentioned drawbacks. The present work proposes the introduction of an antibacterial agent in the course of a pulsed and reverse pulsed electrodeposition. Calcium phosphate coatings were prepared in 30¿min using different pulse waveforms (unipolar-bipolar), current densities (2–5¿mA/cm2) and temperatures (40–60¿°C). Mechanical stability of the as-coated surfaces was studied in order to select the optimal electrodeposition conditions. Subsequently, selected coatings were loaded with an antiseptic agent, chlorhexidine digluconate (CHX), via a single-step co-deposition procedure. CHX concentration added to the electrolyte was adjusted to 3¿mM based on the antibacterial efficacy of the loaded coatings evaluated in vitro with Staphylococcus aureus and Escherichia coli bacteria strains. Whereas the same chlorhexidine concentration was added to the electrolyte, results showed that the amount of CHX loaded was different for each condition while release kinetics was maintained. The results of this work demonstrate that a pulsed co-deposition strategy has great potential to modulate local delivery of antibacterial agents such as chlorhexidine digluconate, which may prevent early phase infections of metallic implants after insertion., Postprint (author's final draft)

El titanio y sus aleaciones son biomateriales usados frecuentemente en implantes y prótesis. Sin embargo, estos biomateriales metálicos tienen limitaciones relacionadas con la bioactividad.Una vía para aumentar la bioactividad del titanio es añadir un recubrimiento de fosfato de calcio (CaP) a la superficie mediante deposición electroquímica. Esta técnica tiene como ventajas la baja temperatura del proceso y un buen control del espesor y la composición química de la capa depositada. Durante el proceso, sin embargo, se producen burbujas de hidrógeno en las proximidades del cátodo, que dificultan la obtención de capas uniformes.El presente estudio propone usar corriente pulsada para la electrodeposición como mecanismo para reducir la producción de burbujas de hidrógeno y mejorar el equilibrio de la concentración de iones en la solución, permitiendo la formación de capas de fosfato de calcio más uniformes., Peer Reviewed

El titanio y sus aleaciones son biomateriales usados frecuentemente en implantes y prótesis. Sin embargo, estos biomateriales metálicos tienen limitaciones relacionadas con la bioactividad. Una vía para aumentar la bioactividad del titanio es añadir un recubrimiento de fosfato de calcio (CaP) a la superficie mediante deposición electroquímica. Esta técnica tiene como ventajas la baja temperatura del proceso y un buen control del espesor y la composición química de la capa depositada. Durante el proceso, sin embargo, se producen burbujas de hidrógeno en las proximidades del cátodo, que dificultan la obtención de capas uniformes. El presente estudio propone usar corriente pulsada para la electrodeposición como mecanismo para reducir la producción de burbujas de hidrógeno y mejorar el equilibrio de la concentración de iones en la solución, permitiendo la formación de capas de fosfato de calcio más uniformes, Postprint (published version)

En aquest projecte es desenvolupa un recobriment de hidroxiapatita mitjançant electrodeposició per polsos, i a la vegada aquest recobriment es fa servir com a transport per l’alliberació d'un agent antibacterià, en concret el digluconat de Clorhexidina. La primera part del projecte s’optimitzen els paràmetres del procés d'electrodeposició. L'interès es centra sobretot en la millora de l’adherència i la uniformitat de la capa. Els factors sobre els que s’ha actuat són: el sistema de subjecció de la mostra, la densitat de corrent, la temperatura de treball, el pretractament de la mostra i el temps del polsos. El control de l’adherència s’ha dut a terme per ultrasons i la caracterització dels recobriments obtinguts s’ha realitzat mitjançant SEM, difracció de raigs X i la rugositat per microscòpia interferomètrica. Els millors resultats s’han obtingut treballant a 40ºC, amb una densitat de corrent de 2mA/cm2, time on=1s i toff=2s, amb un pretractament previ de la mostra amb hidròxid de sodi. Sota aquestes condicions s’observa també que creixen cristalls de hidroxiapatita sobre el recobriment després de ser immers en SBF, el que suggereix un possible comportament bioactiu in vivo. La segona part es centra en la incorporació de digluconat de clorhexidina al recobriment per dues vies: per co-diposició i per absorció, afegint una quantitat controlada de digluconat de clorhexidina sobre el recobriment. Per comprovar que l’agent antibacterià no modifica la morfologia de la superfície del recobriment, es caracteritzen les mostres per SEM. La morfologia obtinguda és la mateixa, només en el cas de la co-deposició, la capa obtinguda és més gruixuda i més cohesionada, el digluconat de clorhexidina actua com agent de nucleació. Finalment es realitzen proves de citotoxicitat per comprovar la biocompatibilitat del recobriment. Es detecta que les mostres amb Digluconat de Clorhexidina amb dilucions 1:10 i superiors no son citotòxiques. L’assaig de difusió en Agar es realitza amb Strep