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The development of new drugs for musculoskeletal regeneration purposes has attracted much attention in the last decades. In this work, we present three novel vitamin B9 (folic acid)-derivatives bearing divalent cations (ZnFO, MgFO and MnFO), providing their synthesis mechanism and physicochemical characterization. In addition, a strong emphasis has been placed on evaluating their biological properties (along with our previously reported SrFO) using human mesenchymal stem cells (hMSC). In all the cases, pure folate derivatives (MFOs) with a bidentate coordination mode between the metal and the folate anion, and a 1:1 stoichiometry, were obtained in high yields. A non-cytotoxic dose of all the MFOs (50 ¿g/mL) was demonstrated to modulate by their own the mRNA profiles towards osteogenic-like or fibrocartilaginous-like phenotypes in basal conditions. Moreover, ZnFO increased the alkaline phosphatase activity in basal conditions, while both ZnFO and MnFO increased the matrix mineralization degree in osteoinductive conditions. Thus, we have demonstrated the bioactivity of these novel compounds and the suitability to further studied them in vivo for musculoskeletal regeneration applications., This work has been funded by the Spanish MICINN(MAT201573656-JIN, RTI2018-095159-B-I00), ISCIII-FEDER-MINECO-AES (PI15/00752, PI15/01118, PI18/00643) CAM (IND2018/BMD-9485) and ERASMUSþTraineeship Programmes. D.F.-V. isfinancially supported by a predoctoral program MICINN FPU18/04683. L.S is financially supported by a Miguel Servet contract(CPII16/00038) from ISCIII- FEDER-MINECO-AES- FSE. N.V is financially supported by Program I2 from CAM. B. V. and L. R. are members of the SusPlast platform from the Spanish National Research Council (CSIC)

The aim of this paper is to achieve in situ photochemical synthesis of silver nanoclusters (AgNCs) stabilized by the multiple-amine groups of chitosan (Ch@AgNCs) with luminescent and photothermal properties. Ch@AgNCs were obtained by applying a fast and simple methodology previously described by our group. Direct functionalization of AgNCs with chitosan template provided new nanohybrids directly in water solution, both in the presence or absence of oxygen. The formation of hybrid AgNCs could be monitored by the rapid increase of the absorption and emission maximum band with light irradiation time. New Ch@AgNCs not only present photoluminescent properties but also photothermal properties when irradiated with near infrared light (NIR), transducing efficiently NIR into heat and increasing the temperature of the medium up to 23 °C. The chitosan polymeric shell associated to AgNCs works as a protective support stabilizing the metal cores, facilitating the storage of nanohybrids and preserving luminescent, photothermal and bactericide properties., The authors are thankful for the financial support from Ministerio de Economía y Competitividad (MINECO) through the project MAT2017- 84277-R and MAT2014-57429-R and Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigaciónn (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, UE) through the projects: PGC2018-095364-B-I00 and RTI2018-095159-B-10

Achievement of spatiotemporal control of growth factors production remains a main goal in tissue engineering. In the present work, we combined inducible transgene expression and near infrared (NIR)-responsive hydrogels technologies to develop a therapeutic platform for bone regeneration. A heat-activated and dimerizer-dependent transgene expression system was incorporated into mesenchymal stem cells to conditionally control the production of bone morphogenetic protein 2 (BMP-2). Genetically engineered cells were entrapped in hydrogels based on fibrin and plasmonic gold nanoparticles that transduced incident energy of an NIR laser into heat. In the presence of dimerizer, photoinduced mild hyperthermia induced the release of bioactive BMP-2 from NIR-responsive cell constructs. A critical size bone defect, created in calvaria of immunocompetent mice, was filled with NIR-responsive hydrogels entrapping cells that expressed BMP-2 under the control of the heat-activated and dimerizer-dependent gene circuit. In animals that were treated with dimerizer, NIR irradiation of implants induced BMP-2 production in the bone lesion. Induction of NIR-responsive cell constructs conditionally expressing BMP-2 in bone defects resulted in the formation of new mineralized tissue, thus indicating the therapeutic potential of the technological platform., This work was supported by grant PI15/01118 from ISCIII-Fondos FEDER, Ministerio de Economía y Competitividad (MINECO), Spain, grant RTI2018-095159-B-I00 from Ministerio de Ciencia, Innovación y Universidades (MICINN), Spain, grant Roche-IdiPAZ from the intramural funding program of Foundation for Biomedical Research of Hospital Universitario La Paz-IdiPAZ, grant ERC-2013-CoG-614715 (NANOHEDONISM) from ERC Consolidator Grant program, grant R21AR072336 from NIH, United States, and by HSF Pharmaceuticals S.A. C.E-D. was the recipient of predoctoral grant FI14/00447 from ISCIII-Fondos FEDER, Ministerio de Economía y Competitividad (MINECO). N.V. is supported by Program I2 from Comunidad Autónoma de Madrid.

This article focuses on the electrochemical study of two titanium alloys employed in the manufacture of orthopedic implants – Ti-6Al-4V and Ti-6Al-7Nb – both of them obtained through powder metallurgy (PM). For comparative purposes, Ti-6Al-4V fabricated conventionally has also been investigated. Samples were immersed in a simulated body fluid (SBF) and incubated at 37 °C for different immersion time. Under these experimental conditions, we compared the influence of the processing method of alloys (PM or conventional) and their composition in the corrosion resistance. The corrosion resistance of these alloys in contact with SBF was evaluated with electrochemical impedance spectroscopy (EIS). The resulting impedance plots of all of them showed good reproducibility. For the lowest frequency tested (10 mHz) all of the samples showed high impedance modulus value approximately on the order of 106 Ω. This behavior is usually ascribed to a high corrosion protection performance. Although no significant differences in the evolution of the corrosion behavior for different immersion times has been found; the Ti-6Al-7Nb alloy processed by PM delivers a steady growth of corrosion resistance from day one until twelve weeks immersion. This sample showed the best performance between the two studied compositions. The resulting impedance plots show how powder metallurgy allows obtaining materials with similar or superior corrosion resistance in physiological conditions, than alloys obtained conventionally. Alloys characterization by scanning electron microscopy revealed no evidence of pitting corrosion phenomenon. Authors acknowledge funds provided by Spanish Government (programme MINECO, Ref. MAT2012-38650-C02-01) and regional government of Madrid (programme MULTIMAT-CHALLENGE, Ref. S2013/MIT-2862).

316LVM austenitic stainless steel is often the material of choice on temporal musculoskeletal implants and surgical tools as it combines good mechanical properties and acceptable corrosion resistance to the physiologic media, being additionally relatively inexpensive. This study has aimed at improving the resistance to bacterial colonization of this surgical stainless steel, without compromising its biocompatibility and resistance. To achieve this aim, the effect of Si ion implantation on 316LVM has been studied. First, the effect of the ion implantation parameters (50 keV; fluence: 2.5-5 × 1016 ions/cm2; angle of incidence: 45-90°) has been assessed in terms of depth profiling of chemical composition by XPS and nano-topography evaluation by AFM. The in vitro biocompatibility of the alloy has been evaluated with human mesenchymal stem cells. Finally, bacterial adhesion of Staphylococcus epidermidis and Staphylococcus aureus on these surfaces has been assessed. Reduction of bacterial adhesion on Si implanted 316LVM is dependent on the implantation conditions as well as the features of the bacterial strains, offering a promising implantable biomaterial in terms of biocompatibility, mechanical properties and resistance to bacterial colonization. The effects of surface composition and nano-topography on bacterial adhesion, directly related to ion implantation conditions, are also discussed. © 2014 Elsevier B.V., The work was supported by the Spanish Ministry for Science and Innovation Grants CIT-420000-2008-17, MAT2009-14695-C04-01-02-03 and grants from Fundación Mutua Madrileña (Spain), and the Junta de Extremadura-FEDER (Grant GR10149). NV is supported by Program I2 from Comunidad de Madrid (Spain).

We investigated whether near-infrared (NIR) light could be employed for patterning transgene expression in plasmonic cell constructs. Hollow gold nanoparticles with a plasmon surface band absorption peaking at ~750 nm, a wavelength within the so called >tissue optical window>, were used as fillers in fibrin-based hydrogels. These composites, which efficiently transduce NIR photon energy into heat, were loaded with genetically-modified cells that harbor a heat-activated and ligand-dependent gene switch for regulating transgene expression. NIR laser irradiation in the presence of ligand triggered 3-dimensional patterns of transgene expression faithfully matching the illuminated areas of plasmonic cell constructs. This non-invasive technology was proven useful for remotely controlling in vivo the spatiotemporal bioavailability of transgenic vascular endothelial growth factor. The combination of spatial control by means of NIR irradiation along with safe and timed transgene induction presents a high application potential for engineering tissues in regenerative medicine scenarios. © 2014 Elsevier Ltd.

Advanced nanomechanical testing has been used to evaluate mechanical properties of Ni-free Al12(Fe,Cr)3Si2 intermetallic coatings grown on the 316 LVM steel by hot dipping in a Al-12.6 at.% Si liquid alloy for various immersion times. Despite the ultrafine-grained structure of the coating (∼200 nm), the indentation size effect is more pronounced for the intermetallic coating than for the steel, which is explained by the higher geometrical necessary dislocation (GND) density of the intermetallic coating. To determine the true hardness of the coatings, the model of Nix and Gao was used. It has been shown that the hardness of the coating decreases from 6.2 GPa for the shortest time of immersion (60 s), to 3.36 GPa for the highest immersion time (600 s), which is always much higher than that for the substrate (1.82 GPa). The decrease in both hardness and GND with increasing immersion time is related to the relaxation of residual stresses, which act as a hardening factor. The net effect is an increase of the plasticity index of the coating. Young's modulus for the intermetallic phase (146 GPa) is lower than that for the austenitic steel 316 LVM (220 GPa), which will favour the load transfer at the bone/metal interface, weakening the so-called >stress shielding effect>. Hence, the nanomechanical properties of this novel Ni-free intermetallic coating, tightly adhered to the substrate, offer a window of opportunity for orthopaedic applications. © 2010 Elsevier Ltd. All rights reserved.

Titanium and its alloys are widely used as implant materials for dental and orthopaedic applications due to their advantageous bulk mechanical properties and biocompatibility, compared to other metallic biomaterials. In order to improve their wear and corrosion resistance, several surface modifications that give rise to an outer ceramic layer of rutile have been developed. The ability of rutile wear debris to stimulate the release of inflammatory cytokines from macrophages has not been addressed to date. We have compared the in vitro biocompatibility of sub-cytotoxic doses of rutile and titanium particles in THP-1 cells driven to the monocyte/macrophage differentiation pathway as well as in primary cultures of human macrophages. Confocal microscopy experiments indicated that differentiated THP-1 cells and primary macrophages efficiently internalised rutile and titanium particles. Treatment of THP-1 cells with rutile particles stimulated the release of TNF-α, IL-6 and IL-1β to a lesser extent than titanium. The influence of osteoblasts on the particle-induced stimulation of TNF-α and IL-1β was analysed by co-culturing differentiated THP-1 cells with human primary osteoblasts. Under these conditions, secretion levels of both cytokines after treatment of THP-1 cells with rutile particles were lower than after exposure to titanium. Finally, we observed that primary macrophages released higher amounts of TNF-α, IL-6 and IL-1β after incubation with titanium particles than with rutile. Taken together, these data indicate that rutile particles are less bioreactive than titanium particles and, therefore, a higher biocompatibility of titanium-based implants modified with an outer surface layer of rutile is expected. © 2006 Elsevier Ltd. All rights reserved.