Boosting Titanium Surfaces with Positive Charges: Newly Developed Cationic Coating Combines Anticorrosive and Bactericidal Properties for Implant Application.

Along with poor implant-bone integration, peri-implant diseases are the major causes of implant failure. Although such diseases are primarily triggered by biofilm accumulation, a complex inflammatory process in response to corrosive-related metallic ions/debris has also been recognized as a risk factor. In this regard, by boosting the titanium (Ti) surface with silane-based positive charges, cationic coatings have gained increasing attention due to their ability to kill pathogens and may be favorable for corrosion resistance. Nevertheless, the development of a cationic coating that combines such properties in addition to having a favorable topography for implant osseointegration is lacking. Because introducing hydroxyl (-OH) groups to Ti is essential to increase chemical bonds with silane, Ti pretreatment is of utmost importance to achieve such polarization. In this study, plasma electrolytic oxidation (PEO) was investigated as a new route to pretreat Ti with OH groups while providing favorable properties for implant application compared with traditional hydrothermal treatment (HT). To produce bactericidal and corrosion-resistant cationic coatings, after pretreatment with PEO or HT (Step 1), surface silanization was subsequently performed via immersion-based functionalization with 3-aminopropyltriethoxysilane (APTES) (Step 2). In the end, five groups were assessed: untreated Ti (Ti), HT, PEO, HT+APTES, and PEO+APTES. PEO created a porous surface with increased roughness and better mechanical and tribological properties compared with HT and Ti. The introduction of -OH groups by HT and PEO was confirmed by Fourier transform infrared spectroscopy and the increase in wettability producing superhydrophilic surfaces. After silanization, the surfaces were polarized to hydrophobic ones, and an increase in the amine functional group was observed by X-ray photoelectron spectroscopy, demonstrating a considerable amount of positive ions. Such protonation may explain the enhanced corrosion resistance and dead bacteria (Streptococcus aureus and Escherichia coli) found for PEO+APTES. All groups presented noncytotoxic properties with similar blood plasma protein adsorption capacity vs the Ti control. Our findings provide new insights into developing next-generation cationic coatings by suggesting that a tailorable porous and oxide coating produced by PEO has promise in designing enhanced cationic surfaces targeting biomedical and dental implant applications.

Biomaterial engineering surface to control polymicrobial dental implant-related infections: focusing on disease modulating factors and coatings development.

INTRODUCTION: Peri-implantitis is the leading cause of dental implant loss and is initiated by a polymicrobial dysbiotic biofilm formation on the implant surface. The destruction of peri-implant tissue by the host immune response and the low effectiveness of surgical or non-surgical treatments highlight the need for new strategies to prevent, modulate and/or eliminate biofilm formation on the implant surface. Currently, several surface modifications have been proposed using biomolecules, ions, antimicrobial agents, and topography alterations. AREAS COVERED: Initially, this review provides an overview of the etiopathogenesis and host- and material-dependent modulating factors of peri-implant disease. In addition, a critical discussion about the antimicrobial surface modification mechanisms and techniques employed to modify the titanium implant material is provided. Finally, we also considered the future perspectives on the development of antimicrobial surfaces to narrow the bridge between idea and product and favor the clinical application possibility. EXPERT OPINION: Antimicrobial surface modifications have demonstrated effective results; however, there is no consensus about the best modification strategy and in-depth information on the safety and longevity of the antimicrobial effect. Modified surfaces display recurring challenges such as short-term effectiveness, the burst release of drugs, cytotoxicity, and lack of reusability. Stimulus-responsive surfaces seem to be a promising strategy for a controlled and precise antimicrobial effect, and future research should focus on this technology and study it from models that better mimic clinical conditions.

Recent advances of polypyrrole conducting polymer film for biomedical application: Toward a viable platform for cell-microbial interactions.

Polypyrrole (PPy) is one of the most studied conductive polymers due to its electrical conductivity and biological properties, which drive the possibility of numerous applications in the biomedical area. The physical-chemical features of PPy allow the manufacture of biocompatible devices, enhancing cell adhesion and proliferation. Furthermore, owing to the electrostatic interactions between the negatively charged bacterial cell wall and the positive charges in the polymer structure, PPy films can perform an effective antimicrobial activity. PPy is also frequently associated with biocompatible agents and antimicrobial compounds to improve the biological response. Thus, this comprehensive review appraised the available evidence regarding the PPy-based films deposited on metallic implanted devices for biomedical applications. We focus on understanding key concepts that could influence PPy attributes regarding antimicrobial effect and cell behavior under in vitro and in vivo settings. Furthermore, we unravel the several agents incorporated into the PPy film and strategies to improve its functionality. Our findings suggest that incorporating other elements into the PPy films, such as antimicrobial agents, biomolecules, and other biocompatible polymers, may improve the biological responses. Overall, the basic properties of PPy, when combined with other composites, electrostimulation techniques, or surface treatment methods, offer great potential in biocompatibility and/or antimicrobial activities. However, challenges in synthesis standardization and potential limitations such as low adhesion and mechanical strength of the film must be overcome to improve and broaden the application of PPy film in biomedical devices.

The race for the optimal antimicrobial surface: perspectives and challenges related to plasma electrolytic oxidation coating for titanium-based implants.

Plasma electrolytic oxidation (PEO) is a low-cost, structurally reliable, and environmentally friendly surface modification method for orthopedic and dental implants. This technique is successful for the formation of porous, corrosion-resistant, and bioactive coatings, besides introducing antimicrobial compounds easily. Given the increase in implant-related infections, antimicrobial PEO-treated surfaces have been widely proposed to surmount this public health concern. This review comprehensively discusses antimicrobial implant surfaces currently produced by PEO in terms of their in vitro and in vivo microbiological and biological properties. We present a critical [part I] and evidence-based [part II] review about the plethora of antimicrobial PEO-treated surfaces. The mechanism of microbial accumulation on implanted devices and the principles of PEO technology to ensure antimicrobial functionalization by one- or multi-step processes are outlined. Our systematic literature search showed that particular focus has been placed on the metallic and semi-metallic elements incorporated into PEO surfaces to facilitate antimicrobial properties, which are often dose-dependent, without leading to cytotoxicity in vitro. Meanwhile, there are concerns over the biocompatibility of PEO and its long-term antimicrobial effects in animal models. We clearly highlight the importance of using clinically relevant infection models and in vivo long-term assessments to guarantee the rational design of antimicrobial PEO-treated surfaces to identify the 'finish line' in the race for antimicrobial implant surfaces.

Polymicrobial biofilms related to dental implant diseases: unravelling the critical role of extracellular biofilm matrix.

Biofilms are complex tri-dimensional structures that encase microbial cells in an extracellular matrix comprising self-produced polymeric substances. The matrix rich in extracellular polymeric substance (EPS) contributes to the unique features of biofilm lifestyle and structure, enhancing microbial accretion, biofilm virulence, and antimicrobial resistance. The role of the EPS matrix of biofilms growing on biotic surfaces, especially dental surfaces, is largely unravelled. To date, there is a lack of a broad overview of existing literature concerning the relationship between the EPS matrix and the dental implant environment and its role in implant-related infections. Here, we discuss recent advances in the critical role of the EPS matrix on biofilm growth and virulence on the dental implant surface and its effect on the etiopathogenesis and progression of implant-related infections. Similar to other biofilms associated with human diseases/conditions, EPS-enriched biofilms on implant surfaces promote microbial accumulation, microbiological shift, cross-kingdom interaction, antimicrobial resistance, biofilm virulence, and, consequently, peri-implant tissue damage. But intriguingly, the protagonism of EPS role on implant-related infections and the development of matrix-target therapeutic strategies has been neglected. Finally, we highlight the need for more in-depth analyses of polymicrobial interactions within EPS matrix and EPS-targeting technologies' rationale for disrupting the complex biofilm microenvironment with more outstanding translation to implant applications in the near future.

Race for Applicable Antimicrobial Dental Implant Surfaces to Fight Biofilm-Related Disease: Advancing in Laboratorial Studies vs Stagnation in Clinical Application.

Across years, potential strategies to fight peri-implantitis have been notoriously explored through the antimicrobial coating implant surfaces capable of interfering with the bacterial adhesion process. However, although experimental studies have significantly advanced, no product has been marketed so far. For science to reach the society, the commercialization of research outcomes is necessary to provide real advancement in the biomedical field. Therefore, the aim of this study was to investigate the challenges involved in the development of antimicrobial dental implant surfaces to fight peri-implantitis, through a systematic search. Research articles reporting antimicrobial dental implant surfaces were identified by searching PubMed, Scopus, Web of Science, The Cochrane Library, Embase, and System of Information on Grey Literature in Europe, between 2008 and 2020. A total of 1778 studies were included for quality assessment and the review. An impressive number of 1655 articles (93,1%) comprised in vitro studies, whereas 123 articles refer to in vivo investigations. From those 123, 102 refer to animal studies and only 21 articles were published on the clinical performance of antibacterial dental implant surfaces. The purpose of animal studies is to test how safe and effective new treatments are before they are tested in people. Therefore, the discrepancy between the number of published studies clearly reveals that preclinical investigations still come up against several challenges to overcome before moving forward to a clinical setting. Additionally, researchers need to recognize that the complex journey from lab to market requires more than a great idea and resources to develop a commercial invention; research teams must possess the skills necessary to commercialize an invention.

Copper source determines chemistry and topography of implant coatings to optimally couple cellular responses and antibacterial activity.

Implant-related infections at the early healing period are considered one of the main risk factors in implant failure. Designing coatings that control bacterial adhesion and have cell stimulatory behavior remains a challenging strategy for dental implants. Here, we used plasma electrolytic oxidation (PEO) to produce antimicrobial coatings on commercially pure titanium (cpTi) using bioactive elements (calcium and phosphorus) and different copper (Cu) sources: copper acetate (CuAc), copper sulfate (CuS), and copper oxide (CuO); coatings containing only Ca and P (CaP) served as controls. Cu sources drove differential physical and chemical surface features of PEO coatings, resulting in tailorable release kinetics with a sustained Cu ion release over 10 weeks. The antibacterial effects of Cu-containing coatings were roughness-dependent. CuAc coating exhibited optimal properties in terms of its hydrophilicity, pores density, and limited surface roughness, which provided the most robust antibacterial activity combined with appropriate responses of human primary stem cells and angiogenic cells. Our data indicate that Cu source selection largely determines the functionality of Cu-containing PEO coatings regarding their antibacterial efficacy and cytocompatibility.

Surface Engineering for Dental Implantology: Favoring Tissue Responses Along the Implant.

Dental implants represent an illustrative example of successful medical devices used in increasing numbers to aid (partly) edentulous patients. Particularly in spite of the percutaneous nature of dental implant systems, their clinical success is remarkable. This clinical success is at least partly related to the effective surface treatment of the artificial dental root, providing appropriate physicochemical properties to achieve osseointegration. The demographic changes in the world, however, with a rapidly increasing life expectancy and an increase in patients suffering from comorbidities that affect wound healing and bone metabolism, make that the performance of dental implants requires continuous improvement. An additional factor endangering the clinical success of dental implants is peri-implantitis, which affects both the soft and hard tissue interactions with dental implants. In this study, we shed light on the optimization of dental implant surfaces through surface engineering. Depending on the region along the artificial dental root, different properties of the surface are required to optimize prevailing tissue response to facilitate osseointegration, improve soft tissue attachment, and exert antibacterial efficacy. As such, surface engineering represents an important tool for assuring the continued future success of dental implants. Impact Statement Dental implants represent a common treatment modality nowadays for the replacement of lost teeth or fixation of prosthetic devices. This review provides a detailed overview of the role of surface engineering for dental implants and their components to optimize tissue responses at the different regions along the artificial dental root. The surface properties steering immunomodulatory processes, facilitating osseointegration, and rendering antibacterial efficacy (at both artificial root and abutment region) are described. The review finally concludes that surface engineering provides a tool to warrant that dental implants will remain future proof in more challenging applications, including an aging patient population and comorbidities that affect bone metabolism and wound healing.

Cross-kingdom microbial interactions in dental implant-related infections: is Candida albicans a new villain?

Candida albicans, an oral fungal opportunistic pathogen, has shown the ability to colonize implant surfaces and has been frequently isolated from biofilms associated with dental implant-related infections, possibly due to its synergistic interactions with certain oral bacteria. Moreover, evidence suggests that this cross-kingdom interaction on implant can encourage bacterial growth, leading to increased fungal virulence and mucosal damage. However, the role of Candida in implant-related infections has been overlooked and not widely explored or even considered by most microbiological analyses and therapeutic approaches. Thus, we summarized the scientific evidence regarding the ability of C. albicans to colonize implant surfaces, interact in implant-related polymicrobial biofilms, and its possible role in peri-implant infections as far as biologic plausibility. Next, a systematic review of preclinical and clinical studies was conducted to identify the relevance and the gap in the existing literature regarding the role of C. albicans in the pathogenesis of peri-implant infections.

Insight Into Corrosion of Dental Implants: From Biochemical Mechanisms to Designing Corrosion-Resistant Materials.

Purpose of Review: Despite advanced technologies to avoid corrosion of dental implants, the mechanisms toward the release of metals and their role in the onset of peri-implant diseases are still under-investigated. Effective knowledge on the etiopathogenesis of corrosive products and preventive strategies mitigating the risks for surface degradation are thus in dire need. This review aimed to summarize evidence toward biocorrosion in the oral environment and discuss the current strategies targeting the improvement of dental implants and focusing on the methodological and electrochemical aspects of surface treatments and titanium-based alloys. Recent Findings: Recent studies suggest the existence of wear/corrosion products may correlate with peri-implantitis progress by triggering microbial dysbiosis, the release of pro-inflammatory cytokines, and animal bone resorption. Furthermore, current clinical evidence demonstrating the presence of metal-like particles in diseased tissues supports their possible role as a risk factor for peri-implantitis. For instance, to overcome the drawback of titanium corrosion, researchers are primarily focusing on developing corrosion-resistant alloys and coatings for dental implants by changing their physicochemical features. Summary: The current state-of-art discussed in this review found corrosion products effective in affecting biofilm virulence and inflammatory factors in vitro. Controversial and unstandardized data are limitations, making the premise of corrosion products being essential for peri-implantitis onset. On the other hand, when it comes to the strategies toward reducing implant corrosion rate, it is evident that the chemical and physical properties are crucial for the in vitro electrochemical behavior of the implant material. For instance, it is foreseeable that the formation of films/coatings and the incorporation of some functional compounds into the substrate may enhance the material's corrosion resistance and biological response. Nevertheless, the utmost challenge of research in this field is to achieve adequate stimulation of the biological tissues without weakening its protective behavior against corrosion. In addition, the translatability from in vitro findings to clinical studies is still in its infancy. Therefore, further accumulation of high-level evidence on the role of corrosion products on peri-implant tissues is expected to confirm the findings of the present review besides the development of better methods to improve the corrosion resistance of dental implants. Furthermore, such knowledge could further develop safe and long-term implant rehabilitation therapy.

Fitting pieces into the puzzle: The impact of titanium-based dental implant surface modifications on bacterial accumulation and polymicrobial infections.

Polymicrobial infection is the main cause of dental implant failure. Although numerous studies have reported the ability of titanium (Ti) surface modifications to inhibit microbial adhesion and biofilm accumulation, the majority of solutions for the utilization of Ti antibacterial surfaces have been testedin in vitro and animal models, with only a few developed surfaces progressing into clinical research. Motivated by this huge gap, we critically reviewed the scientific literature on the existing antibacterial Ti surfaces to help understand these surfaces' impact on the "puzzle" of undesirable dental implant-related infections. This manuscript comprises three main sections: (i) a narrative review on topics related to oral biofilm formation, bacterial-implant surface interactions, and on how implant-surface modifications can influence microbial accumulation; (ii) a critical evidence-based review to summarize pre-clinical and clinical studies in an attempt to "fit pieces into the puzzle" to unveil the best way to reduce microbial loads and control polymicrobial infection around dental implants showed by the current in vivo evidence; and (iii) discussion and recommendations for future research testing emerging antibacterial implant surfaces, connecting basic science and the requirements for future clinical translation. The findings of the present review suggest no consensus regarding the best available Ti surface to reduce bacterial colonization on dental implants. Smart release or on-demand activation surface coatings are a "new piece of the puzzle", which may be the most effective alternative for reducing microbial colonization on Ti surfaces, and future studies should focus on these technologies.

UV-photofunctionalization of a biomimetic coating for dental implants application.

Photofunctionalization mediated by ultraviolet (UV) rays changes the physico-chemical characteristics of titanium (Ti) and improves the biological activity of dental implants. However, the role of UV-mediated photofunctionalization of biofunctional Ti surfaces on the antimicrobial and photocatalytic activity remains unknown and was investigated in this study. Commercially pure titanium (cpTi) discs were divided into four groups: (1) machined samples without UV light application [cpTi UV-]; (2) plasma electrolytic oxidation (PEO) treated samples without UV light application [PEO UV-]; (3) machined samples with UV light application [cpTi UV+]; and (4) PEO-treated samples with UV light application [PEO UV+]. The surfaces were characterized according to their morphology, roughness, crystalline phase, chemical composition and wettability. The photocatalytic activity and proteins adsorption were measured. For the microbiological assay, Streptococcus sanguinis was grown on the disc surfaces for 1 h and 6 h, and the colony forming units and bacterial organization were evaluated. In addition, to confirm the non-cytotoxic effect of PEO UV +, human gingival fibroblast (HGF) cells were cultured in a monolayer onto each material surface and the cells viability and proliferation evaluated by a fluorescent cell staining method. PEO treatment increased the Ti surface roughness and wettability (p < 0.05). Photofunctionalization reduced the hydrocarbon concentration and enhanced human blood plasma proteins and albumin adsorption mainly for the PEO-treated surface (p < 0.05). PEO UV+ also maintained higher wettability values for a longer period and provided microbial reduction at 1 h of bacterial adhesion (p = 0.012 vs. PEO UV-). Photofunctionalization did not increase the photocatalytic activity of Ti (p > 0.05). Confocal microscopy analyses demonstrated that PEO UV+ had no cell damage effect on HGF cells growth even after 24 h of incubation. The photofunctionalization of a biofunctional PEO coating seems to be a promising alternative for dental implants as it increases blood plasma proteins adsorption, reduces initial bacterial adhesion and presents no cytotoxicity effect.

Targeting Pathogenic Biofilms: Newly Developed Superhydrophobic Coating Favors a Host-Compatible Microbial Profile on the Titanium Surface.

Polymicrobial infections are one of the most common reasons for inflammation of surrounding tissues and failure of implanted biomaterials. Because microorganism adhesion is the first step for biofilm formation, physical-chemical modifications of biomaterials have been proposed to reduce the initial microbial attachment. Thus, the use of superhydrophobic coatings has emerged because of their anti-biofilm properties. However, these coatings on the titanium (Ti) surface have been developed mainly by dual-step surface modification techniques and have not been tested using polymicrobial biofilms. Therefore, we developed a one-step superhydrophobic coating on the Ti surface by using a low-pressure plasma technology to create a biocompatible coating that reduces polymicrobial biofilm adhesion and formation. The superhydrophobic coating on Ti was created by the glow discharge plasma using Ar, O2, and hexamethyldisiloxane gases, and after full physical, chemical, and biological characterizations, we evaluated its properties regarding oral biofilm inhibition. The newly developed coating presented an increased surface roughness and, consequently, superhydrophobicity (contact angle over 150°) and enhanced corrosion resistance (p < 0.05) of the Ti surface. Furthermore, proteomic analysis showed a unique pattern of protein adsorption on the superhydrophobic coating without drastically changing the biologic processes mediated by proteins. Additionally, superhydrophobic treatment did not present a cytotoxic effect on fibroblasts or reduction of proliferation; however, it significantly reduced (≈8-fold change) polymicrobial adhesion (bacterial and fungal) and biofilm formation in vitro. Interestingly, superhydrophobic coating shifted the microbiological profile of biofilms formed in situ in the oral cavity, reducing by up to ≈7 fold pathogens associated with the peri-implant disease. Thus, this new superhydrophobic coating developed by a one-step glow discharge plasma technique is a promising biocompatible strategy to drastically reduce microbial adhesion and biofilm formation on Ti-based biomedical implants.

Visible-Light-Induced Photocatalytic and Antibacterial Activity of TiO2 Codoped with Nitrogen and Bismuth: New Perspectives to Control Implant-Biofilm-Related Diseases.

Biofilm-associated diseases are one of the main causes of implant failure. Currently, the development of implant surface treatment goes beyond the osseointegration process and focuses on the creation of surfaces with antimicrobial action and with the possibility to be re-activated (i.e., light source activation). Titanium dioxide (TiO2), an excellent photocatalyst used for photocatalytic antibacterial applications, could be a great alternative, but its efficiency is limited to the ultraviolet (UV) range of the electromagnetic spectrum. Since UV radiation has carcinogenic potential, we created a functional TiO2 coating codoped with nitrogen and bismuth via the plasma electrolytic oxidation (PEO) of titanium to achieve an antibacterial effect under visible light with re-activation potential. A complex surface topography was demonstrated by scanning electron microscopy and three-dimensional confocal laser scanning microscopy. Additionally, PEO-treated surfaces showed greater hydrophilicity and albumin adsorption compared to control, untreated titanium. Bismuth incorporation shifted the band gap of TiO2 to the visible region and facilitated higher degradation of methyl orange (MO) in the dark, with a greater reduction in the concentration of MO after visible-light irradiation even after 72 h of aging. These results were consistent with the in vitro antibacterial effect, where samples with nitrogen and bismuth in their composition showed the greatest bacterial reduction after 24 h of dual-species biofilm formation ( Streptococcus sanguinis and Actinomyces naeslundii) in darkness with a superior effect at 30 min of visible-light irradiation. In addition, such a coating presents reusable photocatalytic potential and good biocompatibility by presenting a noncytotoxicity effect on human gingival fibroblast cells. Therefore, nitrogen and bismuth incorporation into TiO2 via PEO can be considered a promising alternative for dental implant application with antibacterial properties in darkness, with a stronger effect after visible-light application.