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Bacterial infection remains a significant problem associated with orthopaedic surgeries leading to surgical site infection (SSI). This unmet medical need can become an even greater complication when surgery is due to malignant bone tumor. In the present study, we evaluated in vitro titanium (Ti) implants subjected to gallium (Ga) and silver (Ag)-doped thermochemical treatment as strategy to prevent SSI and improve osteointegration in bone defects caused by diseases such as osteoporosis, bone tumor, or bone metastasis. Firstly, as Ga has been reported to be an osteoinductive and anti-resorptive agent, its performance in the mixture was proved by studying human mesenchymal stem cells (hMSC) and pre-osteoclasts (RAW264.7) behaviour. Then, the antibacterial potential provided by Ag was assessed by resembling “The Race for the Surface” between hMSC and Pseudomonas aeruginosa in two co-culture methods. Moreover, the presence of quorum sensing molecules in the co-culture was evaluated. The results highlighted the suitability of the mixture to induce osteodifferentiation and reduce osteoclastogenesis in vitro. Furthermore, the GaAg surface promoted strong survival rate and retained osteoinduction potential of hMSCs even after bacterial inoculation. Therefore, GaAg-modified titanium may be an ideal candidate to repair bone defects caused by excessive bone resorption, in addition to preventing SSI., Peer Reviewed, Postprint (published version)

The Boston keratoprosthesis (BKPro) is a medical device used to restore vision in complicated cases of corneal blindness. This device is composed by a front plate of polymethylmethacrylate (PMMA) and a backplate usually made of titanium (Ti). Ti is an excellent biomaterial with numerous applications, although there are not many studies that address its interaction with ocular cells. In this regard, despite the good retention rates of the BKPro, two main complications compromise patients' vision and the viability of the prosthesis: imperfect adhesion of the corneal tissue to the upside of the backplate and infections. Thus, in this work, two topographies (smooth and rough) were generated on Ti samples and tested with or without functionalization with a dual peptide platform. This molecule consists of a branched structure that links two peptide moieties to address the main complications associated with BKPro: the well-known RGD peptide in its cyclic version (cRGD) as cell pro-adherent motif and the first 11 residues of lactoferrin (LF1–11) as antibacterial motif. Samples were physicochemically characterized, and their biological response was evaluated in vitro with human corneal keratocytes (HCKs) and against the gram-negative bacterial strain Pseudomonas aeruginosa. The physicochemical characterization allowed to verify the functionalization in a qualitative and quantitative manner. A higher amount of peptide was anchored to the rough surfaces. The studies performed using HCKs showed increased long-term proliferation on the functionalized samples. Gene expression was affected by topography and peptide functionalization. Roughness promoted a-smooth muscle actin (a-SMA) overexpression, and the coating notably increased the expression of extracellular matrix components (ECM). Such changes may favour the development of unwanted fibrosis, and thus, corneal haze. In contrast, the combination of the coating with a rough topography decreased the expression of a-SMA and ECM c, Peer Reviewed, Postprint (published version)

The rapid integration in the bone tissue and the prevention of bacterial infection are key for the success of the implant. In this regard, a silver (Ag)-doped thermochemical treatment that generate an Ag-doped calcium titanate layer on titanium (Ti) implants was previously developed by our group to improve the bone-bonding ability and provide antibacterial activity. In the present study, the biological and antibacterial potential of this coating has been further studied. In order to prove that the Ag-doped layer has an antibacterial effect with no detrimental effect on the bone cells, the behavior of osteoblast-like cells in terms of cell adhesion, morphology, proliferation and differentiation was evaluated, and the biofilm inhibition capacity was assessed. Moreover, the competition by the surface between cell and bacteria was carried out in two different co-culture methods. Finally, the treatment was applied to porous Ti implants to study in vivo osteointegration. The results show that the incorporation of Ag inhibits the biofilm formation and has no effect on the performance of osteoblast-like cells. Therefore, it can be concluded that the Ag-doped surface is capable of preventing bone bacterial infection and providing suitable osseointegration., Postprint (published version)

Additive manufacturing (AM) enables fully dense biomimetic implants in the designed geometries from preferred materials such as titanium and its alloys. Titanium aluminum vanadium (Ti6Al4V) is one of the pioneer metal alloys for bone implant applications, however, the reasons for eliminating the toxic effects of Ti6Al4V and maintaining adequate mechanical strength have increased the potential of commercially pure titanium (cp-Ti) to be used in bone implants. This literature review aims to evaluate the production of cp-Ti and Ti6Al4V biomedical implants with laser powder bed fusion (L-PBF) technology, which has a very high level of technological matureness and industrialization level. The optimization of L-PBF manufacturing parameters and post-processing techniques affect the obtained microstructure leading to various mechanical, corrosion and biological behaviors of the manufactured titanium. All of the features are considered in the light of specifications and needs of bone implant applications. The most critical disadvantages of the L-PBF technology, such as residual stresses and leading deformations are introduced and the potential solutions are discussed. Moreover, the manufacturability of porous bone implants that causes benefit and harm in L-PBF applications are assessed., Peer Reviewed, Objectius de Desenvolupament Sostenible::3 - Salut i Benestar, Postprint (published version)

The performance and properties of Titanium (Ti) and its alloys can be fully exploited for biomedical applications such as orthopedic and dental implants, when porous structures are used. Such Ti structures can matched the bone mechanical properties, providing a solution to the stress-shielding effect problem and facilitating implant biointegration. Powder metallurgy (PM) combined with space holder (SH) technology is an appealing process to produce porous implants. This article briefly discusses the suitability of the PM with SH technology to produce porous structures from the perspectives of both design and manufacture for the production of medical devices., Peer Reviewed, Postprint (published version)

One of the major problems faced by metallic implants is the high probability of bacterial infections, with significant consequences for the patient. In this work, a thermochemical treatment is proposed to obtain silver-doped calcium titanate coatings on the Ti surface to improve the bioactivity of porous 3D-printed Ti structures and simultaneously provide them with antibacterial properties. A complete characterization of the new coating, the study of the ion release and the analysis of its cytotoxicity were carried out together with evaluation of the natural apatite forming in simulated body fluid (SBF). Moreover, the antibacterial properties of the coatings were assessed against Pseudomona aeruginosa and Escherichia coli as gram-negative and Staphylococcus aureus and Staphylococcus epidermidis as gram-positive bacterial strains. Ag ions were integrated into the Ca titanate layer and Ag nanoparticles were formed within the entire 3D Ti surface. Ca and Ag ions were released from both porous and solid samples into the Hanks' solution for 48 h. The treated surfaces showed no cytotoxicity and an apatite layer precipitated on the entire porous surface when the samples were immersed in SBF. The release of Ag from the surface had a strong antibacterial effect and prevented bacterial adhesion and proliferation on the surface. Moreover, the nanostructured topography of the coating resulted also in a reduction of bacterial adhesion and proliferation, even in absence of Ag. In conclusion, the cost-effective approach here reported provided protection against the most predominant bacterial colonizers to the Ti porous implants, while maintaining their bioactivity., 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)

type:Journal Article, Ti metal treated with NaOH, NH4OH, and heat and then soaked in simulated body fluid (SBF) showed in vitro apatite formation whereas that treated with NaOH, HNO3, and heat and then soaked in SBF did not. The anatase TiO2 precipitate and/or the fine network structure formed on the surface of the Ti metal treated with NaOH, NH4OH, and heat and then soaked in SBF might be responsible for the formation of apatite on the surface of the metal. The NaOH, NH4OH, and heat treatments might produce nitrogen-doped TiO2 on the surface of the Ti metal, and the concentration of methylene blue (MB) in the Ti metal sample treated with NaOH, NH4OH, and heat decreased more than in the untreated and NaOH- and heat-treated ones. This preliminary result suggests that Ti metal treated with NaOH, NH4OH, and heat has the potential to show photocatalytic activity under visible light.

Three methods for the production of Polyethylene glycol (PEG) coatings on titanium are compared, i.e. plasma polymerization, electrodeposition and silanization. The compared deposition methods presented similar wettability (hydrophilic coatings), chemical composition assessed by XPS and thickness around 1 nm. The coatings lowered albumin adsorption and presented a decreased fibroblast, Streptococcus sanguinis and Lactobacillus salivarius adhesion. Immobilization of a cell adhesion peptide (RGD) presented a higher fibroblast adhesion and no alteration of the bacterial adhesion, giving three methods for the biofunctionalization of titanium for dental implants. The feasibility of each methodology is compared in terms of the process parameters in order to provide a guide for the election of the methodology., Peer Reviewed, Postprint (author's final draft)