metals Review Silver-Deposited Nanoparticles on the Titanium Nanotubes Surface as a Promising Antibacterial Material into Implants Alina Năstaca Coman 1,†, Anca Mare 2,†, Corneliu Tanase 3,* , Eugen Bud 4,* and Aura Rusu 5 1 Medicine and Pharmacy Doctoral School, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, , 540142 Târgu Mures, , Romania; [email protected] 2 Department of Microbiology, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, , 540142 Târgu Mures, , Romania; [email protected] 3 Pharmaceutical Botany Department, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, , 540142 Târgu Mures, , Romania 4 Department of Orthodontics, Faculty of Dentistry, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, , 540142 Târgu Mures, , Romania 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, , 540142 Târgu Mures, , Romania; [email protected] * Correspondence: [email protected] (C.T.); [email protected] (E.B.); Tel.: +40-744215543 (C.T.); +40-744437661 (E.B.) † These authors share the first authorship. Abstract: The main disadvantage of the implants is the associated infections. Therefore, in the long term, the possibility of improving the antibacterial capacity of different types of implants (dental, orthopedic) is being researched. The severity of the problem lies in the increasing bacterial resistance and finding appropriate alternative treatments for infectious diseases, which is an important research field nowadays. The purpose of this review is to draw a parallel between different studies analyzing the antibacterial activity and mechanism of silver nanoparticles (NP Ag) deposited on the titanium nanotubes (NTT), as well as the analysis of the NP Ag toxicity. This review also provides an overview of the synthesis and characterization of TiO2-derived nanotubes (NT). Thus, the analysis aims Citation: Coman, A.N.; Mare, A.; to present the existing knowledge to better understand the NP Ag implants benefits and their Tanase, C.; Bud, E.; Rusu, A. antibacterial activity. Silver-Deposited Nanoparticles on the Titanium Nanotubes Surface as a Keywords: titanium nanotubes; silver nanoparticles; titan oxide; antibacterial activity Promising Antibacterial Material into Implants. Metals 2021, 11, 92. https://doi.org/10.3390/met11010092 1. Introduction Received: 16 December 2020 Accepted: 31 December 2020 Titanium, together with its alloys, is one of the most used elements in orthopedic Published: 5 January 2021 and dental applications due to its biocompatibility, mechanical properties, and corrosion resistance [1]. It is known that titanium-based alloys are used to manufacture medical Publisher’s Note: MDPI stays neu- appliances, such as artificial blood vessels and orthopedic/dental implants [2]. The causes tral with regard to jurisdictional clai- of implant rejection may still be unknown and impossible to predict preoperatively. Usually, ms in published maps and institutio- it is not due to the body’s intolerance to titanium but rather because of a local cause. One of nal affiliations. the leading causes of implant rejection is an immune system imbalance and a combination of bacterial infection with adverse reactions of the immune system [3,4]. Some of the situations that can lead to infections are non-compliance after surgery, prolonged operation time and post-surgical tissue contamination. Therefore, because of the increasing bacterial Copyright: © 2021 by the authors. Li- resistance to antimicrobial agents, infections are often difficult to treat even with specific censee MDPI, Basel, Switzerland. antibiotics, thus increasing the risk of mortality and morbidity [5]. However, several types This article is an open access article of microorganisms (bacteria, viruses, parasites, and fungi) can cause bone infections [6]. distributed under the terms and con- Staphylococ- ditions of the Creative Commons At- Osteomyelitis is a bone infection induced by microorganisms such as tribution (CC BY) license (https:// cus spp., which leads to progressive bone loss and tissue damage [7]. Because Staphylo- creativecommons.org/licenses/by/ coccus spp., are ubiquity bacteria, they can contaminate medical devices. Out of all the 4.0/). cases of pyogenic osteomyelitis, 80–90% are caused by Staphylococcus aureus. Although it is Metals 2021, 11, 92. https://doi.org/10.3390/met11010092 https://www.mdpi.com/journal/metals Metals 2021, 11, 92 2 of 16 part of human skin flora, Staphylococcus epidermidis can colonize medical devices, including orthopedic implants and catheters [6]. One method of preventing these infections is to add antimicrobial agents to the surface of titanium implants [8]. During infection, respectively, colonization can create biofilms, where bacteria are protected from the immune system and antibacterial agents. [9]. While forming these biofilms, bacteria are rigidly attached to the medical devices’ active or inert surface. Bacterial colonies can reproduce, differenti- ate, and secretion of extracellular polymeric substances such as proteins, polysaccharides, and lipids [10]. Thus, when biofilms are formed on medical devices (catheters or implants), the patients can develop complications such as chronic, difficult to treat infections [11]. However, biofilms on human surfaces are not always harmful, such as dental plaque composition that can determine the presence or absence of disease [12]. A promising approach to restrict the microbial adhesion and the colonization of medical devices is coating implant surfaces with thin antimicrobial bioactive films [2]. Previous studies demonstrated that Ag ions could infiltrate the microbial cell wall and bind to cellular DNA, interrupting the bacterial replication, exhibiting antimicrobial and antifungal properties [1,2,8]. In this review, the perspectives related to the characterization and synthesis of nan- otubes (NT) derived from TiO2 are followed. Moreover, the activity and antibacterial mechanism of silver nanoparticles (NP Ag) incorporated in titanium nanotubes (NTT) are presented and the toxicological aspects of NP Ag. 2. Methodology This review’s content is based on data obtained by PubMed, Science Direct, MDPI, Springer, and other databases. The most relevant studies regarding NP Ag and NTT were selected. Search terms were: “silver nanoparticles” (title) and “silver” (topic), “titanium dioxide” (title) and “nanotubes” (topic), in different combinations (topic) with “biological”, “implants”, “dentistry”, “orthopedics”, and “antibacterial” (MeSH browser keywords). Depending on the references obtained, other associations of keywords were used. 3. Characterization of NT Derived from TiO2 To use nanostructured materials for medical purposes, they must meet specific re- quirements. The first requirement is biocompatibility; this is the capacity of the material to induce an appropriate host response, in the case of a particular application [13], accepted definition by International Standards Organization (ISO), Food and Drug Administration (FDA) and American Society for Testing and Materials (ASTM). Titanium (Ti) surfaces modified with TiO2 nanotubes (TNT) are material with excellent biocompatibility and integrate well into bone tissue. Ti surfaces have chemical/thermal stability, controllable size, generous contact surface, and pores with adjustable sizes, surface chemistry, and good surface/volume ratio, due to their long and well-aligned structure. These features support the differentiation and proliferation of bone cells [14]. The bioactivity (the ability to interact with body tissue) is another mandatory requirement that nanostructures must meet [13]. Antibacterial studies focused on the manufacture of TiO2 nanotubes, acting as carriers for Ag, which has a proven and well-known antibacterial effect. Various methods can be used to attach Ag particles to the surface of TiO2 nanotubes: Ultrasonication [15], soaking in AgNO3 solution [16], electrodeposition [17], or sputter deposition techniques [18]. There are three polymorphic forms of TiO2 known in nature: Anatase (tetragonal), brookite (orthorhombic), and rutile (tetragonal) [12]. Anatase has a pyramidal crystalline structure (used as a photocatalyst under UV irradiation), rutile has a tetragonal structure with a prismatic habit, and brookite has an orthorhombic crystalline structure. The most common forms used to manufacture Ti nanotubes are anatase and rutile because brookite is less stable [19]. TiO2 is also a monoclinic mineral and is relatively new to the TiO2 family [20]. Of all, rutile is the most abundant in nature. It constitutes almost two-thirds of the available and known pigments. It is also considered to play a crucial role as a catalyst, mainly due to its high refractive index [21]. Metals 2021, 11, 92 3 of 16 4. Synthesis of NT Derived from TiO2 The physicochemical properties (size, shape, morphology, and composition of titanium oxide) are essential for photocatalytic control and performance. A synthetic procedure is necessary for the development of desired properties for photocatalytic activity [22]. There are numerous methods to synthesize NT derived from TiO2, the most important of which are: (a) deposition (by physical or chemical processes) in templates of nanoporous materials, (b) directed growth, starting