Skip to main content

Advertisement

AMB Express
AMB Express Cover Image
Download PDF

Antibacterial potential associated with drug-delivery built TiO2 nanotubes in biomedical implants

AMB Express volume 9, Article number: 51 (2019) Cite this article

Abstract

The fast evolution of surface treatments for biomedical implants and the concern with their contact with cells and microorganisms at early phases of bone healing has boosted the development of surface topographies presenting drug delivery potential for, among other features, bacterial growth inhibition without impairing cell adhesion. A diverse set of metal ions and nanoparticles (NPs) present antibacterial properties of their own, which can be applied to improve the implant local response to contamination. Considering the promising combination of nanostructured surfaces with antibacterial materials, this critical review describes a variety of antibacterial effects attributed to specific metals, ions and their combinations. Also, it explains the TiO2 nanotubes (TNTs) surface creation, in which the possibility of aggregation of an active drug delivery system is applicable. Also, we discuss the pertinent literature related to the state of the art of drug incorporation of NPs with antibacterial properties inside TNTs, along with the promising future perspectives of in situ drug delivery systems aggregated to biomedical implants.

Introduction

Biomedical implants have their most critical moment of integration to living tissues when their biomaterial first contacts the human cells and local microorganisms (Yue et al. 2015). Researchers and clinicians expect the best biomaterial performance during this first contact, and enhance it by changing surface properties and morphology to boost the speed and quality of the healing process (Kunrath and Hubler 2018). However, implant surface contamination by bacterial agents might pose a significant threat, jeopardizing implant healing and/or affecting significantly its long-term survival (Sridhar et al. 2015; Raphel et al. 2016).

Nanoscale changes in implant surfaces have been the focus of several currently reported studies. The possibilities involved in surface nanotexturization are diverse, and studies show that these surfaces might offer substantial advantages regarding bacterial adhesion, bacterial proliferation and bone healing (Coelho et al. 2014; Truong et al. 2015; Kunrath and Hubler 2018). Following this idea, a nanotexturization method using electrochemical anodizing allows the formation of TiO2 nanotubes (TNTs), which substantially alter the physico-chemical properties of the implant surface making it friendlier to human bone cells and promoting potential antibacterial properties (Huang et al. 2017; Zhukova et al. 2017).

TNTs allow properties changes in terms of surface roughness, energy, wettability, tube diameter and possibly its greatest advantage, the alternative of incorporation of components as antibiotic drugs and other materials with similar potential, along with organic chemicals such as specific proteins, cytokines and growth factors (Hemeg 2017; Awad et al. 2017). The incorporating of such characteristics might allow the concept of a drug delivery system incorporated to those biomedical implants, as numerous drugs might be integrated to the tubes and released in situ through the activation of specific trigger mechanisms, which might be activated for local infection control as needed. (Wang et al. 2017a, b, c; Kunrath et al. 2018).

Infections contracted during the surgical act and/or after the healing process represent one of the potential risks to induce failure of a biomedical implant. Therefore, studies have been proposed aiming the development of drug incorporation systems like nanomaterials with antimicrobial properties to minimize those associated risks (Truong et al. 2015). Many ions and metal particles have been described to present antibacterial properties, which can be used in TNTs (Hemeg 2017). Nonetheless, biocompatibility and citotoxicity are features to be carefully evaluated before their safe indication as applicable tools in vivo (Lewinski et al. 2008). Innovative studies are nowadays testing these possibilities regarding drug incorporation with nanomaterials, evaluating their responses against bacterial colonization and cell adhesion (Liu et al. 2016; Yao et al. 2018).

In addition, TNTs surfaces allow the development of resorbable coatings over their tubes, which could maintain these added drugs viable, including antibiotics and other potential antibacterial agents, as well as to promote their slow release to the surrounding tissues if needed (Chen et al. 2013a, b; Kumeria et al. 2015). Preliminary studies with biodegradable coatings show promising results of drug release systems up to 30 days after surgical implantation. This might provide the basis for the development of a long-term release system activated by a specific mechanism without favoring bacterial drug resistance (Gulati et al. 2012).

The present critical review aims to describe the currently available nanoscale metallic materials with potential antibacterial properties already reported in the literature, detailing the TNTs surface construction process for biomedical implants along with their specific properties that might influence the adhesion and proliferation of microorganisms. In order to do that, the present review illustrates the status quo of nanoparticles/drugs with antibacterial properties incorporated in the TNTs and their preliminary reported test results, including a summary of coating possibilities and alternatives of late drug release mechanisms.

Nanostructures and materials vs. antibacterial properties

Several materials and natural structures are studied searching for similarities in their intrinsic natural properties that could be adapted and used as biomaterials (Hasan et al. 2013). Some natural tissue surfaces have the ability to inhibit bacterial adhesion and proliferation, as well as alter their surface wettability. Natural-occurring examples are found in plant leaves, skin of aquatic animals, insect wings, among other structures that present antibacterial properties or some effect that might hinders bacterial proliferation (Bhadra et al. 2015; Jaggessar et al. 2017).

Currently, implants are produced using synthetic and non-synthetic materials with nanosurfaces, many of them through lithography, laser, or receiving chemical treatments (Zhang et al. 2006; Penha et al. 2018). Due to nanotopographical characteristics, the promotion of cellular interaction is substantial, since the extracellular matrix contact with the prepared surface occurs in nanoscale (Yim et al. 2010). Applied biomaterials are expected to provide faster tissue healing where they are inserted without any generated proinflammatory reactions, including degradation in vivo or corrosion. In addition, they might present properties to mitigate or even inhibit bacterial contamination (Bettinger et al. 2009; Neoh et al. 2012).

In this context, many metals have been studied in their natural atomic size, as well as fragmented to a condition of nanoparticles (NP), presenting potential properties (Kim and An 2012; Hemeg 2017). As already known, metals such as Zinc, Silver, Gold, Cobalt, Nickel and Lead have natural antibacterial characteristics, since their interaction with bacteria usually generates cellular structural damages, and complications in bacterial adhesion and proliferation (Dizaj et al. 2014; Hemeg 2017).

Therefore, many of these materials, when brought to NPs scale, have their antibacterial properties intensified, since they are able to interact more rapidly and effectively at nanoscale level (Hemeg 2017; Lee et al. 2018). Their main factor related to antibacterial action is associated with the production of hydrogen peroxide, superoxide anions and free hydroxyl radicals that induce countless damages to bacteria, such as membrane disruption, oxidative stress, changes in DNA, interference in the biofilm formation, among others (Oktar et al. 2015; Durán et al. 2016). The electrostatic interaction between the NPs and microorganisms affects its toxicity. Some NPs when connecting to bacterial cell surface release metal ions that bind and disrupt the cell membrane. Likewise, the metal adsorption results in oxidative stress due to ROS generation, which can lead to cell membrane damage. Furthermore, penetration of metal ions across the bacterial membrane results in damages to DNA by interaction with nitrogenous bases, which generate inhibition of DNA replication or lead to DNA degradation. In addition, metal ions can bind to ribosome subunits, inhibiting the protein synthesis (Hajipour et al. 2012; Hemeg 2017; Lee et al. 2018). Another important action of NPs is their interaction with biofilm. Biofilm is formed by microorganisms involved in a self-produced polymeric matrix that mediate the adhesion to a surface, acting as a physical barrier against antimicrobials (Kumar et al. 2017). However, NPs such as TiO2, Ag, ZnO, Cds, MgF2, Bi and YF3 can inhibit bacterial biofilm formation or disrupt formed biofilms (Hemeg 2017).

To clarify the antibacterial properties of metals, Table 1 shows the results of studies on different bacterial species and the generated effects in terms of their function and tissues, focusing mainly on the use of NPs derived from base metals. NPs are able to inhibit the adhesion, proliferation and to cause damage both in gram-positive and gram-negative bacteria, but some studies have demonstrated that NPs derived from NiO, Cu, Al2O3, SiO2 and Fe2O3 should be more effective against gram-positive bacterial strains (Baek and An 2011; Ruparelia et al. 2008; Jiang et al. 2009; Azam et al. 2012), suggesting a greater vulnerability of gram-positive bacteria to NPs. However, other studies indicated that Au and ZnO NPs are most effective against gram-negative pathogens, due to the higher thickness of the peptidoglycan layer in gram-positive bacteria (Shamaila et al. 2016; Sinha et al. 2011). In addition, Ruparelia et al. (2008) demonstrated that silver NPs should be more effective against E. coli (gram-negative bacteria) than B. subtilis (gram-positive bacteria). Conversely, Yoon et al. (2007) found a better efficiency of Ag NPs against B. subtilis than E. coli. Therefore, it should be considered that there are many variables among the studies, such as NP size and concentration, and the method used to evaluate the antimicrobial activity.

Table 1 Nanoparticles with antibacterial activity and the effects generated on bacterial species
Full size table

TiO2 nanotubes (TNTs)

Anodization process

Physical and chemical treatments for Ti have been proposed in order to obtain surfaces with better biocompatibility. Among these techniques, anodization has been recognized for improving wear and corrosion resistance, as well as increasing TiO2 surface roughness and surface porosity, with varying thicknesses (Liu et al. 2012). In addition, it is considered a methodology that easily reproduces results, being accessible and inexpensive, and also able to facilitate researchers to test their properties with different scientific bases (Awad et al. 2017).

Surface modification has been reported to be an effective tool to promote the integration between bone and biomaterials (Minagar et al. 2012). Anodizing is an effective electrochemical method that has been used successfully in orthopedic implants surface treatment (Liu et al. 2004). It can be performed in an electrochemical cell with two electrodes (usually titanium anode, platinum or titanium cathode). The oxidation and reduction reactions occur at the anode when a current or constant voltage is applied, thus establishing an electric field that guides ion diffusion present in the electrolyte, leading to oxide film formation on the surface of the anode.

The chemical and structural properties of anode oxides vary according to the different solutions used as electrolytes. The anodization electrochemical parameters significantly affect film growth behavior and properties. Such features include the type of solution used as electrolyte, reagent concentration, temperature, electrical parameters, anodizing time and solution stirring speed (Liu et al. 2004; Cui et al. 2009; Liu et al. 2012). The anode potential and the electric current can alter the anion transfer process during anodization, as well as determining thickness, surface morphology and microstructure of the anodic coatings (Awad et al. 2017; Kunrath et al. 2018).

From the control of this entire process and selection of the correct protocols, TNTs can be developed with dimensions and properties suitable for biomedical implants as shown in Fig. 1.

Fig. 1
figure1

Anodization process explanatory scheme (1). TiO2 nanotubes made through anodization (2)

Full size image

TiO2 nanotubes properties and advantages

Small changes in the anodization process directly influence the properties of TNTs, such as surface roughness, wettability, cellular interaction, drug loading capacity and chemical physical structure, as can be seen in Fig. 2 (Awad et al. 2017). Nanotubes surfaces with greater roughness and very low wettability angles have been described to allow expressive responses in adhesion and proliferation of mesenchymal or bone cells (Vasilev et al. 2010; Yu et al. 2018). On the other hand, some investigations have shown TNTs surfaces with hydrophobic properties might positively influence bacterial adhesion (Zhang et al. 2013).

Fig. 2
figure2

[Reprinted and adapted with permission from Elsevier, (Awad et al. 2017)]

Alteration in nanotube diameter and morphology only by variation of the solution used and voltage parameters. 1 M solution (NH4) 2SO4 + NH4 F at 20 V (1a, b) and NH4F + H2O + ethylene glycol at 60 V (1c, d). Adhesion of osteoblastic cells on machined surface (2a) and surface of TiO2 (2b) nanotubes

Full size image

Important biological properties associated with implant surfaces are hugely influenced by changes in tube morphological characteristics. A great number of studies applying cell culture techniques on TNTs presented better cell adhesion and proliferation on nanotubes of 70 nm in diameter (Awad et al. 2017; Yu et al. 2018), although expressive results were also reported when applying diameters ranging from 30 to 100 nm (Yu et al. 2018).

Antibacterial properties of TNT surfaces were evaluated in comparison with bacterial responses to microtextured surfaces (Miao et al. 2017). As most bacteria and/or viruses have their size compatible to a micrometric scale, the nanoscale topography presented in TNTs seemed to reject or even hinder their growth in culture (Jaggessar et al. 2017; Miao et al. 2017; Lee et al. 2018) Another observed advantage is that TNTs chemical–physical structure presents great resistance to corrosion and degradation in vivo, showing promising results considering application in biomedical implants (Alves et al. 2017).

Despite these numerous advantages, the greatest differential of the TNTs technology relies on the possibility of drug or NPs incorporation in the tubes. As described by some authors, this might allow even the creation of a “smart” drug transport system, allowing that a drug could be stored and late released in situ in an on-demand basis, not possible in any other surface treatment currently used in biomedical implants (Wang et al. 2017a, b, c; Awad et al. 2017).

Wettability and bacterial adhesion

One of the most influential properties regarding cell or bacterial adhesion to metallic implants is surface wettability. This property can be modified with consequent treatments of the nanotubes applying thermal, chemical, photofunctionalization, and coating treatments (Oliveira et al. 2017; Hasan et al. 2013; Lai et al. 2016).

Studies on hydrophobic surfaces showed important bacterial anti-adhesion properties and promotion of bone cells growth (Lai et al. 2016; Fadeeva et al. 2011; Gittens et al. 2014). These results might be extrapolated for nanotubes surface development aiming the promotion of bacterial repulsion, combined with high biocompatibility as depicted in Fig. 3 (Xu and Siedlecki 2014; Mei et al. 2014).

Fig. 3
figure3

SEM image showing (white arrows) a nanotube surface after adhesion assay with Staphylococcus epidermidis and fixation (1), and its previous characterization regarding wettability indicating hydrophobicity (2)

Full size image

Synthetic and/or non-synthetic coatings, which are used to keep added drugs in the internal parts of the nanotubes, or to protect the TNT system, usually present hydrophobic properties (Oliveira et al. 2017; Kumeria et al. 2015). The adsorption of bacterial extracellular matrix to these surfaces might be impaired, turning bacterial local proliferation and consequently biofilm formation unlikely (Xu and Siedlecki 2014).

However, other studies characterized hydrophilic surfaces as presenting better adhesion and proliferation conditions for bone-like and undifferentiated mesenchymal cells, as well as pre-osteoblasts (Lotz et al. 2018; Gittens et al. 2014). This may be a counterpoint compared to hydrophobic surfaces. Nonetheless, as described above, other studies showed better antibacterial performance on hydrophobic surfaces, and this surface wettability vs. bacterial/cell relation is still not fully clarified.

Drug delivery system

Traditional therapies to prevent or treat infection/inflammation in surrounding tissues of biomedical implants are usually administered systemically. However, systemic drug administration does not target a specific site and may not interact directly at the desired site. The possibility of having a localized and selective drug delivery system for biomedical implants acting as an aid or even replace a systemic drug administration becomes extremely promising (Lyndon et al. 2014; Hemeg 2017).

It has been stated that regarding implant surgery, osteoblasts and bacteria establish a marked competition for implant surface adhesion, and the alternative of loading TNTs with antibacterial drugs might be of great advantage (Miao et al. 2017). Other studies have also suggested that the successful loading of TNTs with antimicrobial peptides for later local release might positively contribute to raise levels of infection prevention, or the combination of an initial rapid release with an extended slow and gradual release (Li et al. 2017).

Investigations suggested that some bacteria such as Staphylococcus aureus, Staphylococcus epidermidis and Escherichia coli are often present in implant postoperative infections and negatively affect the healing process of bone. In order to combat this local cellular competition more emphatically, the alternative of improving surface properties with antibacterial characteristics becomes crucial (Anselme et al. 2010; Widaa et al. 2012). Alternatively to antibacterial drugs, application of specific metal particles might also be considered due to their specific bacteriostatic and bactericidal activities. Metallic elements such as ZnO-NPs presented excellent ability to control S. aureus when applied to TNTs (Yao et al. 2018). In this context, an investigation on loading of ZnO nanoparticles of irregular and regular shapes to the implant surface and later testing it against bacterial proliferation as well as macrophages viability was conducted. The results suggested a ZnO capacity to inhibit bacterial growth and macrophage adhesion, which might ultimately result in lower levels of local inflammation around implants (Yao et al. 2018).

Silver nanoparticles loaded onto TNTs showed a significant antibacterial effect against E. coli at both contact kill analysis and agent release killing effect, presenting promising results (Chen et al. 2013a, b). Copper nanocubes (20 nm) were also loaded onto TNTs and showed effective antibacterial action against S. aureus and E. coli, causing eradication of these bacteria in laboratorial cultures (Rosenbaum et al. 2017).

In addition to NPs derived from metals, studies showed also the possibility of TNTs loading with commonly used systemic antibiotics, especially those targeting bacterial cell wall and protein synthesis. Investigations have presented in vitro and in vivo results involving TNTs loaded with vancomycin (Zhang et al. 2013). Preliminary data suggested better in vitro antibacterial performance against S. aureus in the groups with nanotubes loaded with antibiotics compared with TNTs-only control group (Zhang et al. 2013), suggesting that the application of antibiotics in situ might be a viable alternative appropriate to this technology.

Different outcomes of antibiotic loaded TNTs where verified, and most often antibiotics might generate particularly interesting results. A pioneer study in TNTs antibiotic loading used doses of gentamicin against S. epidermidis in vitro (Popat et al. 2007). Their results showed complete TNTs filling, as well as reduction in bacterial surface adhesion and an increase in the proliferation rate of pre-osteoblasts where the antibiotic was used, revealing a double positive result without interfering with implant biocompatibility (Popat et al. 2007).

The most recent studies employing incorporation of drugs, specific agents and NPs as antibacterial agents into TNTs is summarized in Table 2, where their promising results are described, revealing also the “state of the art” of this technology.

Table 2 Antibacterial drugs and NPs loaded in TiO2 nanotubes
Full size table

Biomolecules and NPs immobilization through coatings

As the demand of active functionalization of different biomedical implant surfaces rises, the need to investigate how to properly seize/immobilize different types of drugs or NPs on the implant surface escalates. Thus, a series of investigations suggesting the use of ceramic, organic, or inorganic materials as implant coatings are being conducted with the objective of creating a protective stable but resorbable layer that can gradually release the drug once needed (Civantos et al. 2017).

The TNTs surfaces offer the possibility of chemical–physical coating adhesion on their surface along with drug incorporation to their tubes. When evaluated in vitro, biodegradable coatings showed excellent results on titanium surfaces, positively influencing their biocompatibility with expressive results of bone cell proliferation and adhesion (Goodman et al. 2013; Oliveira et al. 2017). In addition, progressive coating degradation has been characterized as a viable event that may allow the release of drugs or NPs aiming to potentiate bone healing or even prevent possible microbial infections (Oliveira et al. 2017). Figure 4 shows a schematic of how TNTs with coatings stabilize the drugs in their tubes and materials, which can be used to make these coatings.

Fig. 4
figure4

Schematics showing how coated TNTs may present stabilized drugs in their tubes and how some materials are applied to these coatings (a), reprinted with permission from Elsevier, (Oliveira et al. 2017). Scheme showing how the release of drugs influences the behavior of bacteria (b), reprinted with permission from Elsevier, (Ionita et al. 2017)

Full size image

Furthermore, some studies have even extrapolated the incorporation of drugs or growth factors (GFs) not only to their TNTs but into their coatings as well. Chitosan coatings incorporated with GFs presented better results in terms of cell adhesion, bone cell proliferation and increase in the expression of bone formation markers in vitro (Abarrategi et al. 2007). Also, Chitosan coatings were tested for antibiotic incorporation in vivo presenting promising results as well (Jennings et al. 2015; Lai et al. 2017).

The combination of loaded TNTs with a drug-incorporated surface coating might represent an attractive possibility for in loco treatment of a failing and/or compromised implanted device. However, studies investigating this possibility are scarce and, when available, still at early stages, and so far there is no single definition in terms of the best surface coating material or the ideal drug to be implemented for these purposes in vivo.

One attempt to investigate the possibilities involving surface coating association with TNTs drug delivery system was related to late local antibiotic-release activation (Wang et al. 2017a, b, c). In this investigation, nanotubes were firstly loaded with antibiotics and then sealed with coordination polymers through a metal ion bond, generating a hybrid system with potential antibacterial properties. Reported in vitro observations revealed that the antibiotic agent was kept inside the tubes until the surrounding environment had its pH altered. As the inflammatory process elicited by bacterial infection has the potential to change the local pH, this in vitro drug release system was activated, suggesting a possibility for long-term local drug maintenance prior to its late release (Wang et al. 2017a, b, c).

In conclusion, the present overview critically analyzed the significant diversity of drugs, metals and NPs presenting antibacterial properties and their functionalization on TNTs surfaces, depicting a wide range of these potential metals and drugs used in biomedical implants and related advanced research regarding their biocompatibility and potential antibacterial effects.

TiO2 nanotubes surfaces show a large energy area for immobilization and subsequent functionalization of nanoparticles, preserving its biocompatibility and mechanical stability. Many strategies to incorporate NPs and drugs to implant surfaces have been presenting promising preliminary results in combating bacteria that cause infections in the human, and especially where biomedical implants may be placed.

It has been suggested by some investigations that the drug delivery system applied to TNTs might be successful and has promising early results. Even though a large part of these reported studies represent in vitro evidence, the pathway for clinical trials involving concepts on the application of drug delivery TNTs has already been suggested, followed by more extensive cytotoxicity tests and in vivo observations to firstly ensure their biologic safety.

The possibility of decreasing the application of systemic antibiotics usually associated with side effects to patients for an in situ usage seems to be one of these drug-loaded TNTs most advantageous properties, since their association with surface coatings may keep a drug and/or NP active for a long-term gradual release once needed. Further investigation in vivo should be performed to establish the proper advantages and efficacy linked to the in situ application of antibiotics in biomedical implants compared to systemic drug administration.

Finally, the use of functionalized TNTs aiming a localized release of antibiotic drugs and bactericide NPs has presented promising early results and should be further explored aiming future medical applications. The possibilities related to local infection control may positively influence the outcome of a major biomedical problem related to implant loss and/or disfunction. With established protocols regarding adequate drug dose and production optimization, this technology can play an important role into further increase the clinical success of biomedical implants in the near future.

Abbreviations

DNA:

deoxyribonucleic acid

GFs:

growth factors

NPs:

nanoparticles

ROS:

reactive oxygen species

TNTs:

TiO2 nanotubes

References

  1. Abarrategi A, Civantos A, Ramos V, Sanz Casado JV, López-Lacomba JL (2007) Chitosan film as rhBMP2 carrier: delivery properties for bone tissue application. Biomacromol 9:711–718. https://doi.org/10.1021/bm701049g

  2. Ali Z, Raj B, Vishwas M, Athhar MA (2016) Synthesis, characterization and antimicrobial activity of Ce doped TiO2 nanoparticles. Int J Curr Microbiol Appl Sci 5:705–712. https://doi.org/10.20546/ijcmas.2016.504.081

  3. Alves SA, Rossi AL, Ribeiro AR, Toptan F, Pinto AM, Celis JP, Shokuhfar T, Rocha LA (2017) Tribo-electrochemical behavior of bio-functionalized TiO2 nanotubes in artificial saliva: understanding of degradation mechanisms. Wear 384:28–42. https://doi.org/10.1016/j.wear.2017.05.005

  4. Ansari MA, Khan HM, Khan AA, Cameotra SS, Saquib Q, Musarrat J (2014) Interaction of Al(2)O(3) nanoparticles with Escherichia coli and their cell envelope biomolecules. J Appl Microbiol 116:772–783. https://doi.org/10.1111/jam.12423

  5. Anselme K, Davidson P, Popa AM, Giazzon M, Liley M, Ploux L (2010) The interaction of cells and bacteria with surfaces structured at the nanometre scale. Acta Biomater 6:3824–3846. https://doi.org/10.1016/j.actbio.2010.04.001

  6. Awad NK, Edwards SL, Morsi YS (2017) A review of TiO2 NTs on Ti metal: electrochemical synthesis, functionalization and potential use as bone implants. Mater Sci Eng C 76:1401–1412. https://doi.org/10.1016/j.msec.2017.02.150

  7. Azam A, Ahmed AS, Oves M, Khan MS, Habib SS, Memic A (2012) Antimicrobial activity of metal oxide nanoparticles against Gram-positive and Gram-negative bacteria: a comparative study. Int J Nanomed 7:6003–6009. https://doi.org/10.2147/IJN.S35347

  8. Baek YW, An YJ (2011) Microbial toxicity of metal oxide nanoparticles (CuO, NiO, ZnO, and Sb2O3) to Escherichia coli, Bacillus subtilis, and Streptococcus aureus. Sci Total Environ 409:1603–1608. https://doi.org/10.1016/j.scitotenv.2011.01.014

  9. Bettinger CJ, Langer R, Borenstein JT (2009) Engineering substrate topography at the micro-and nanoscale to control cell function. Angew Chem Int Ed Engl 48(30):5406–5415. https://doi.org/10.1002/anie.200805179

  10. Bhadra CM, Truong VK, Pham VT, Al Kobaisi M, Seniutinas G, Wang JY, Juodkazis S, Crawford RJ, Ivanova EP (2015) Antibacterial titanium nano-patterned arrays inspired by dragonfly wings. Sci Rep 5:16817. https://doi.org/10.1038/srep16817

  11. Bogdanović U, Lazić V, Vodnik V, Budimir M, Marković Z, Dimitrijević S (2014) Copper nanoparticles with high antimicrobial activity. Mater Lett 128:75–78. https://doi.org/10.1016/j.matlet.2014.04.106

  12. Chatterjee AK, Chakraborty R, Basu T (2014) Mechanism of antibacterial activity of copper nanoparticles. Nanotechnology 25:135101. https://doi.org/10.1088/0957-4484/25/13/135101

  13. Chen X, Cai K, Fang J, Lai M, Li J, Hou Y, Luo Z, Hu Y, Tang L (2013a) Dual action antibacterial TiO2 nanotubes incorporated with silver nanoparticles and coated with a quaternary ammonium salt (QAS). Surf Coat Technol 216:158–165. https://doi.org/10.1016/j.surfcoat.2012.11.049

  14. Chen X, Cai K, Fang J, Lai M, Hou Y, Li J, Luo Z, Hu Y, Tang L (2013b) Fabrication of selenium-deposited and chitosan-coated titania nanotubes with anticancer and antibacterial properties. Colloids Surf B Biointerfaces 103:149–157. https://doi.org/10.1016/j.colsurfb.2012.10.022

  15. Chen Y, Gao A, Bai L, Wang Y, Wang X, Zhang X, Huang X, Hang R, Tang B, Chu P (2017) Antibacterial, osteogenic, and angiogenic activities of SrTiO3 nanotubes embedded with Ag2O nanoparticles. Mater Sci Eng C 75:1049–1058. https://doi.org/10.1016/j.msec.2017.03.014

  16. Cheng H, Xiong W, Fang Z, Guan H, Wu W, Li Y, Zhang Y, Alvarez A, Gao B, Huo K, Xu J, Xu N, Zhang C, Fu J, Khademhosseini A, Li F (2016) Strontium (Sr) and silver (Ag) loaded nanotubular structures with combined osteoinductive and antimicrobial activities. Acta Biomater 31:388–400. https://doi.org/10.1016/j.actbio.2015.11.046

  17. Civantos A, Martínez-Campos E, Ramos V, Elvira C, Gallardo A, Abarrategi A (2017) Titanium coatings and surface modifications: toward clinically useful bioactive implants. ACS Biomater Sci Eng 3:1245–1261. https://doi.org/10.1021/acsbiomaterials.6b00604

  18. Coelho PG, Takayama T, Yoo D, Jimbo R, Karunagaran S, Tovar N, Janal MN, Yamano S (2014) Nanometer-scale features on micrometer-scale surface texturing: a bone histological, gene expression, and nanomechanical study. Bone 65:25–32. https://doi.org/10.1016/j.bone.2014.05.004

  19. Cui X, Kim H-M, Kawashita ML, Wang L, Xiong T, Kokubo T, Nakamura T (2009) Preparation of bioactive titania films on titanium metal via anodic oxidation. Dent Mater J 25:80–86. https://doi.org/10.1016/j.dental.2008.04.012

  20. Cui Y, Zhao Y, Tian Y, Zhang W, Lü X, Jiang X (2012a) The molecular mechanism of action of bactericidal gold nanoparticles on Escherichia coli. Biomaterials 33:2327–2333. https://doi.org/10.1016/j.biomaterials.2011.11.057

  21. Cui C, Gao X, Qi Y, Liu S, Sun J (2012b) Microstructure and antibacterial property of in situ TiO2 nanotube layers/titanium biocomposites. J Mech Behav Biomed Mater 8:178–183. https://doi.org/10.1016/j.jmbbm.2012.01.004

  22. Dakal TC, Kumar A, Majumdar RS, Yadav V (2016) Mechanistic basis of antimicrobial actions of silver nanoparticles. Front Microbiol 7:1831. https://doi.org/10.3389/fmicb.2016.01831

  23. Dhanabalan K, Gurunathan K (2015) Microemulsion mediated synthesis and characterization of CdS nanoparticles and its anti-biofilm efficacy against Escherichia coli ATCC 25922. J Nanosci Nanotechnol 15:4200–4204. https://doi.org/10.1166/jnn.2015.9597

  24. Dizaj SM, Lotfipour F, Barzegar-Jalali M, Zarrintan MH, Adibkia K (2014) Antimicrobial activity of the metals and metal oxide nanoparticles. Mater Sci Eng C 44:278–284. https://doi.org/10.1016/j.msec.2014.08.031

  25. Durán N, Durán M, de Jesus MB, Seabra AB, Fávaro WJ, Nakazato G (2016) Silver nanoparticles: a new view on mechanistic aspects on antimicrobial activity. Nanomed Nanotechnol Biol Med 12:789–799. https://doi.org/10.1016/j.nano.2015.11.016

  26. Esfandiari N, Simchi A, Bagheri R (2014) Size tuning of Ag-decorated TiO nanotube arrays for improved 2 bactericidal capacity of orthopedic implants. J Biomed Mater Res Part A 102A:2625–2635. https://doi.org/10.1002/jbm.a.34934

  27. Esparza-Gonzalez SC, Sanchez-Valdes S, Ramirez-Barron SN, Loera-Arias MJ, Bernal J, Meléndez-Ortiz IH, Betancourt-Galindo R (2016) Effects of different surface modifying agents on the cytotoxic and antimicrobial properties of ZnO nanoparticles. Toxicol In Vitro 37:134–141. https://doi.org/10.1016/j.tiv.2016.09.020

  28. Fadeeva E, Truong VK, Stiesch M, Chichkov BN, Crawford RJ, Wang J, Ivanova EP (2011) Bacterial retention on superhydrophobic titanium surfaces fabricated by femtosecond laser ablation. Langmuir 27:3012–3019. https://doi.org/10.1021/la104607g

  29. Feng W, Geng Z, Li Z, Cui Z, Zhu S, Liang Y, Liu Y, Wang R, Yang X (2016) Controlled release behaviour and antibacterial effects of antibiotic-loaded titania nanotubes. Mater Sci Eng C 62:105–112. https://doi.org/10.1016/j.msec.2016.01.046

  30. Feris K, Otto C, Tinker J, Wingett D, Punnoose A, Thurber A, Kongara M, Sabetian M, Quinn B, Hanna C, Pink D (2010) Electrostatic interactions affect nanoparticle-mediated toxicity to gram-negative bacterium Pseudomonas aeruginosa PAO1. Langmuir 26:4429–4436. https://doi.org/10.1021/la903491z

  31. Franci G, Falanga A, Galdiero S, Palomba L, Rai M, Morelli G, Galdiero M (2015) Silver nanoparticles as potential antibacterial agents. Molecules 20:8856–8874. https://doi.org/10.3390/molecules20058856

  32. Gajjar P, Pettee B, Britt D, Huang W, Johnson W, Anderson A (2009) Antimicrobial activities of commercial nanoparticles against an environmental soil microbe, Pseudomonas putida KT2440. J Biol Eng 3:9. https://doi.org/10.1186/1754-1611-3-9

  33. Gao A, Hang R, Huang X, Zhao L, Zhang X, Wang L, Tang B, Ma S, Chu PK (2014) The effects of titania nanotubes with embedded silver oxide nanoparticles on bacteria and osteoblasts. Biomaterials 35:4223–4235. https://doi.org/10.1016/j.biomaterials.2014.01.058

  34. Gittens RA, Scheideler L, Rupp F, Hyzy SL, Geis-Gerstorfer J, Schwartz Z, Boyan BD (2014) A review on the wettability of dental implant surfaces II: biological and clinical aspects. Acta Biomater 10:2907–2918. https://doi.org/10.1016/j.actbio.2014.03.032

  35. Goodman SB, Yao Z, Keeney M, Yang F (2013) The future of biologic coatings for orthopaedic implants. Biomaterials 34(13):3174–3183. https://doi.org/10.1016/j.biomaterials.2013.01.074

  36. Guisbiers G, Wang Q, Khachatryan E, Mimun LC, Mendoza-Cruz R, Larese-Casanova P, Webster TJ, Nash KL (2016) Inhibition of E. coli and S. aureus with selenium nanoparticles synthesized by pulsed laser ablation in deionized water. Int J Nanomed 11:3731–3736. https://doi.org/10.2147/IJN.S106289

  37. Gulati K, Ramakrishnan S, Aw MS, Atkins GJ, Findlay DM, Losic D (2012) Biocompatible polymer coating of titania nanotube arrays for improved drug elution and osteoblast adhesion. Acta Biomater 8:449–456. https://doi.org/10.1016/j.actbio.2011.09.004

  38. Hajipour M, Fromm K, Ashkarran A, de Aberasturi D, de Larramendi I, Rojo T, Serpooshan V, Parak W, Mahmoud M (2012) Antibacterial properties of nanoparticles. Trends Biotechnol 30:499–511. https://doi.org/10.1016/j.tibtech.2012.06.004

  39. Hasan J, Crawford RJ, Ivanova EP (2013) Antibacterial surfaces: the quest for a new generation of biomaterials. Trends Biotechnol 31(5):295–304. https://doi.org/10.1016/j.tibtech.2013.01.017

  40. Hemeg HA (2017) Nanomaterials for alternative antibacterial therapy. Int J Nanomed 12:8211–8225. https://doi.org/10.2147/IJN.S132163

  41. Hernandez-Delgadillo R, Velasco-Arias D, Diaz D, Arevalo-Niño K, Gazrza-Enriquez M, De la Garza-Ramos MA, Cabral-Ramos C (2012) Zerovalent bismuth nanoparticles inhibit Streptococcus mutans growth and formation of biofilm. Int J Nanomed 7:2109–2113. https://doi.org/10.2147/IJN.S29854

  42. Huang Q, Yang Y, Zheng D, Song R, Zhang Y, Jiang P, Vogler EA, Lin C (2017) Effect of construction of TiO2 nanotubes on platelet behaviors: structure–property relationships. Acta Biomater 51:505–512. https://doi.org/10.1016/j.actbio.2017.01.044

  43. Huo S, Jiang Y, Gupta A, Jiang Z, Landis RF, Hou S, Liang XJ, Rotello VM (2016) Fully zwitterionic nanoparticle antimicrobial agents through tuning of core size and ligand structure. ACS Nano 10:8732–8737. https://doi.org/10.1021/acsnano.6b04207

  44. Ionita D, Bajenaru-Georgescu D, Totea G, Anca Mazare Schmuki P, Demetrescu I (2017) Activity of vancomycin release from bioinspired coatings of hydroxyapatite or TiO nanotube. Int J Pharm 517:296–302. https://doi.org/10.1016/j.ijpharm.2016.11.062

  45. Jaggessar A, Shahali H, Mathew A, Yarlagadda PK (2017) Bio-mimicking nano and micro-structured surface fabrication for antibacterial properties in medical implants. J Nanobiotechnol 15(1):64. https://doi.org/10.1186/s12951-017-0306-1

  46. Jennings JA, Wells CM, McGraw GS, Velasquez Pulgarin DA, Whitaker MD, Pruitt RL, Bumgardner JD (2015) Chitosan coatings to control release and target tissues for therapeutic delivery. Ther Deliv 6(7):855–871. https://doi.org/10.4155/tde.15.31

  47. Jiang W, Mashayekhi H, Xing B (2009) Bacterial toxicity comparison between nano- and micro-scaled oxide particles. Environ Pollut 157:1619–1625. https://doi.org/10.1016/j.envpol.2008.12.025

  48. Kannan S, Sundrarajan M (2015) Biosynthesis of Yttrium oxide nanoparticles using Acalypha indica leaf extract. Bull Mater Sci 38:945–950. https://doi.org/10.1007/s12034-015-0927-7

  49. Kazemzadeh-Narbat M, Lai BF, Ding C, Kizhakkedathu JN, Hancock RE, Wang R (2013) Multilayered coating on titanium for controlled release of antimicrobial peptides for the prevention of implant-associated infections. Biomaterials 34:5969–5977. https://doi.org/10.1016/j.biomaterials.2013.04.036

  50. Khashan KS, Sulaiman GM, Abdul Ameer FA, Napolitano G (2016) Synthesis, characterization and antibacterial activity of colloidal NiO nanoparticles. Pak J Pharm Sci 29:541–546

  51. Kim SW, An YJ (2012) Effect of ZnO and TiO2 nanoparticles preilluminated with UVA and UVB light on Escherichia coli and Bacillus subtilis. Appl Microbiol Biotechnol 95(1):243–253. https://doi.org/10.1007/s00253-012-4153-6

  52. Kumar A, Pandey A, Singh S, Shanker R, Dhawan A (2011a) Engineered ZnO and TiO nanoparticles induce oxidative stress and DNA damage 2 leading to reduced viability of Escherichia coli. Free Radic Biol Med 51:1872–1881. https://doi.org/10.1016/j.freeradbiomed.2011.08.025

  53. Kumar A, Pandey A, Singh S, Shanker R, Dhawan A (2011b) Cellular uptake and mutagenic potential of metal oxide nanoparticles in bacterial cells. Chemosphere 83:1124–1132. https://doi.org/10.1016/j.chemosphere.2011.01.025

  54. Kumar A, Alam A, Rani M, Ehtesham NZ, Hasnain SE (2017) Biofilms: survival and defense strategy for pathogens. Int J Med Microbiol 303:481–489. https://doi.org/10.1016/j.ijmm.2017.09.016

  55. Kumeria T, Mon H, Aw MS, Gulati K, Santos A, Griesser HJ, Losic D (2015) Advanced biopolymer-coated drug-releasing titania nanotubes (TNTs) implants with simultaneously enhanced osteoblast adhesion and antibacterial properties. Colloids Surf B Biointerfaces 130:255–263. https://doi.org/10.1016/j.colsurfb.2015.04.021

  56. Kunrath MF, Hubler R (2018) A bone preservation protocol that enables evaluation of osseointegration of implants with micro- and nanotextured surfaces. Biotech Histochem. https://doi.org/10.1080/10520295.2018.1552017

  57. Kunrath MF, Hubler R, Shinkai RS, Teixeira ER (2018) Application of TiO2 nanotubes as a drug delivery system for biomedical implants: a critical overview. ChemistrySelect 3(40):11180–11189. https://doi.org/10.1002/slct.201801459

  58. Lai Y, Huang J, Cui Z, Ge M, Zhang KQ, Chen Z, Chi L (2016) Recent advances in TiO2-based nanostructured surfaces with controllable wettability and adhesion. Small 12(16):2203–2224. https://doi.org/10.1002/smll.201501837

  59. Lai M, Jin Z, Yang X, Wang H, Xu K (2017) The controlled release of simvastatin from TiO2 nanotubes to promote osteoblast differentiation and inhibit osteoclast resorption. Appl Surf Sci 396:1741–1751. https://doi.org/10.1016/j.apsusc.2016.11.228

  60. Lee D, Seo Y, Khan M, Hwang J, Jo Y, Son J, Lee K, Park C, Chavan S, Gilad A, Choi J (2018) Use of nanoscale materials for the effective prevention and extermination of bacterial biofilms. Biotechnol Bioprocess Eng 23:1–10. https://doi.org/10.1007/s12257-017-0348-0

  61. Lellouche J, Friedman A, Lahmi R, Gedanken A, Banin E (2012a) Antibiofilm surface functionalization of catheters by magnesium fluoride nanoparticles. Int J Nanomed 7:1175–1188. https://doi.org/10.2147/IJN.S26770

  62. Lellouche J, Friedman A, Gedanken A, Banin E (2012b) Antibacterial and antibiofilm properties of yttrium fluoride nanoparticles. Int J Nanomed 7:5611–5624. https://doi.org/10.2147/IJN.S37075

  63. Lewinski N, Colvin V, Drezek R (2008) Cytotoxicity of nanoparticles. Small 4(1):26–49. https://doi.org/10.1002/smll.200700595

  64. Li J, Zhou H, Qian S, Liu Z, Feng J, Jin P, Liu X (2014) Plasmonic gold nanoparticles modified titania nanotubes for antibacterial application. Appl Phys Lett 104:261110. https://doi.org/10.1063/1.4885401

  65. Li B, Hao J, Min Y, Xin S, Guo L, He F, Liang C, Wang H, Li H (2015) Biological properties of nanostructured Ti incorporated with Ca, P and Ag by electrochemical method. Mater Sci Eng C 51:80–86. https://doi.org/10.1016/j.msec.2015.02.036

  66. Li T, Wang N, Chen S, Lu R, Li H, Zhang Z (2017) Antibacterial activity and cytocompatibility of an implant coating consisting of TiO2 nanotubes combined with a GL13K antimicrobial peptide. Int J Nanomed 12:2995–3007. https://doi.org/10.2147/IJN.S128775

  67. Liu X, Chu PK, Ding C (2004) Surface modification of titanium, titanium alloys, and related materials for biomedical applications. Mater Sci Eng R Rep 47(3–4):49–121. https://doi.org/10.1016/j.mser.2004.11.001

  68. Liu JH, Wu GL, Yu M, Wu L, Zhang Y, Li SM (2012) Influence of incremental rate of anodising current on roughness and electrochemical corrosion of oxide film on titanium alloy Ti–10V–2Fe–3Al. Surf Eng 28(6):406–411. https://doi.org/10.1179/1743294411Y.0000000091

  69. Liu W, Golshan NH, Deng X, Hickey DJ, Zeimer K, Li H, Webster TJ (2016) Selenium nanoparticles incorporated into titania nanotubes inhibit bacterial growth and macrophage proliferation. Nanoscale 8(34):15783–15794. https://doi.org/10.1039/C6NR04461A

  70. Lotz EM, Berger MB, Schwartz Z, Boyan BD (2018) Regulation of osteoclasts by osteoblast lineage cells depends on titanium implant surface properties. Acta Biomater 68:296–307. https://doi.org/10.1016/j.actbio.2017.12.039

  71. Lyndon JA, Boyd BJ, Birbilis N (2014) Metallic implant drug/device combinations for controlled drug release in orthopaedic applications. J Control Release 179:63–75. https://doi.org/10.1016/j.jconrel.2014.01.026

  72. Ma M, Kazemzadeh-Narbat M, Hui Y, Lu S, Ding C, Chen DDY, Hancock REW, Wang R (2012) Local delivery of antimicrobial peptides using self-organized TiO2 nanotube arrays for peri-implant infections. J Biomed Mater Res Part A 100A:278–285. https://doi.org/10.1002/jbm.a.33251

  73. Mei S, Wang H, Wang W, Tong L, Pan H, Ruan C, Ma Q, Liu M, Yang H, Zhang L, Cheng Y, Zhang Y, Zhao L, Chu PK (2014) Antibacterial effects and biocompatibility of titanium surfaces with graded silver incorporation in titania nanotubes. Biomaterials 35:4255–4265. https://doi.org/10.1016/j.biomaterials.2014.02.005

  74. Miao X, Wang D, Xu L, Wang J, Zeng D, Lin S, Huang C, Liu X, Jiang X (2017) The response of human osteoblasts, epithelial cells, fibroblasts, macrophages and oral bacteria to nanostructured titanium surfaces: a systematic study. Int J Nanomed 12:1415–1430. https://doi.org/10.2147/IJN.S126760

  75. Minagar S, Berndt CC, Wang J, Ivanova E, Wen C (2012) A review of the application of anodization for the fabrication of nanotubes on metal implant surfaces. Acta Biomater 8:2875–2888. https://doi.org/10.1016/j.actbio.2012.04.005

  76. Morones J, Elechiguerra J, Camacho A, Holt K, Kouri J, Ramírez J, Yacaman M (2005) The bactericidal effect of silver nanoparticles. Nanotechnology 16:2346–2353. https://doi.org/10.1088/0957-4484/16/10/059

  77. Nemati S, Hadjizadeh A (2017) Gentamicin-eluting titanium dioxide nanotubes grown on the ultrafine-grained titanium. AAPS Pharm Sci Tech 18:2180–2187. https://doi.org/10.1208/s12249-016-0679-8

  78. Neoh KG, Hu X, Zheng D, Kang ET (2012) Balancing osteoblast functions and bacterial adhesion on functionalized titanium surfaces. Biomaterials 33:2813–2822. https://doi.org/10.1016/j.biomaterials.2012.01.018

  79. Nour El Din S, El-Tayeb TA, Abou-Aisha K, El-Azizi M (2016) In vitro and in vivo antimicrobial activity of combined therapy of silver nanoparticles and visible blue light against Pseudomonas aeruginosa. Int J Nanomed 11:1749–1758. https://doi.org/10.2147/IJN.S102398

  80. Oktar FN, Yetmez M, Ficai D, Ficai A, Dumitru F, Pica A (2015) Molecular mechanism and targets of the antimicrobial activity of metal nanoparticles. Curr Top Med Chem 15(16):1583–1588

  81. Oliveira WF, Arruda IR, Silva GMM, Machado G, Coelho LCBB, Correia MTS (2017) Functionalization of titanium dioxide nanotubes with biomolecules for biomedical applications. Mater Sci Eng C 81:597–606. https://doi.org/10.1016/j.msec.2017.08.017

  82. Penha N, Groisman S, Ng J, Gonçalves OD, Kunrath MF (2018) Physical-chemical analyses of contaminations and internal holes in dental implants of pure commercial titanium. J Osseointegration 10(2):57–63. https://doi.org/10.23805/jo.2018.10.02.05

  83. Piszczek P, Lewandowska Z, Radtke A, Jedrzejewski T, Kozak W, Sadowska B, Szubka M, Talik E, Fiori F (2017) Biocompatibility of titania nanotube coatings enriched with silver nanograins by chemical vapor deposition. Nanomaterials 7:274. https://doi.org/10.3390/nano7090274

  84. Popat KC, Eltgroth M, LaTempa TJ, Grimes CA, Desai TA (2007) Decreased Staphylococcus epidermis adhesion and increased osteoblast functionality on antibiotic-loaded titania nanotubes. Biomaterials 28:4880–4888. https://doi.org/10.1016/j.biomaterials.2007.07.037

  85. Rai M, Deshmukh S, Ingle A, Gade A (2012) Silver nanoparticles: the powerful nanoweapon against multidrug-resistant bacteria. J Appl Microbiol 112:1364–5072. https://doi.org/10.1111/j.1365-2672.2012.05253.x

  86. Ramyadevi J, Jeyasubramanian K, Marikani A, Rajakumar G, Rahuman A (2012) Synthesis and antimicrobial activity of copper nanoparticles. Mater Lett 71:114–116. https://doi.org/10.1016/j.matlet.2011.12.055

  87. Raphel J, Holodniy M, Goodman SB, Heilshorn SC (2016) Multifunctional coatings to simultaneously promote osseointegration and prevent infection of orthopaedic implants. Biomaterials 84:301–314. https://doi.org/10.1016/j.biomaterials.2016.01.016

  88. Roguska A, Belzarz A, Zalewska J, Holdynski M, Andrzejczuk M, Pizarek M, Ginalska G (2018) Metal TiO2 nanotube layers for the treatment of dental implant infections. ACS Appl Mater Interfaces 10(20):17089–17099. https://doi.org/10.1021/acsami.8b04045

  89. Rosenbaum J, Versace DL, Abbad-Andallousi S, Pires R, Azevedo C, Cénédese P, Dubot P (2017) Antibacterial properties of nanostructured Cu–TiO2 surfaces for dental implants. Biomater Sci 5:455–462. https://doi.org/10.1039/c6bm00868b

  90. Ruparelia J, Chatterjee A, Duttagupta S, Mukherji S (2008) Strain specificity in antimicrobial activity of silver and copper nanoparticles. Acta Biomater 4:707–716. https://doi.org/10.1016/j.actbio.2007.11.006

  91. Seil J, Webster T (2012) Antimicrobial applications of nanotechnology: methods and literature. Int J Nanomed 7:2767–2781. https://doi.org/10.2147/IJN.S24805

  92. Shamaila S, Zafar N, Riaz S, Sharif R, Nazir J, Naseem S (2016) Gold nanoparticles: an efficient antimicrobial agent against enteric bacterial human pathogen. Nanomaterials 6:71. https://doi.org/10.3390/nano6040071

  93. Simon-Deckers A, Loo S, Mayne L'hermite M, Herlin-Boime N, Menguy N, Reynaud C, Gouget B, Carriere M (2009) Size-, composition- and shape-dependent toxicological impact of metal oxide nanoparticles and carbon nanotubes toward bacteria. Environ Sci Technol 43(21):8423–8429. https://doi.org/10.1021/es9016975

  94. Sinha R, Karan R, Sinha A, Khare S (2011) Interaction and nanotoxic effect of ZnO and Ag nanoparticles on mesophilic and halophilic bacterial cells. Bioresour Technol 102:1516–1520. https://doi.org/10.1016/j.biortech.2010.07.117

  95. Sirelkhatim A, Mahmud S, Seeni A, Kaus N, Ann L, Bakhori S, Hasan H, Mohamad D (2015) Review on zinc oxide nanoparticles: antibacterial activity and toxicity mechanism. Nanomicro Lett 7:219–242. https://doi.org/10.1007/s40820-015-0040-x

  96. Sridhar S, Wilson TG Jr, Palmer KL, Valderrama P, Mathew MT, Prasad S, Jacobs M, Gindri IM, Rodrigues DC (2015) In vitro investigation of the effect of oral bacteria in the surface oxidation of dental implants. Clin Implant Dent Relat Res 17:e562–e575. https://doi.org/10.1111/cid.12285

  97. Taylor EN, Webster TJ (2009) The use of superparamagnetic nanoparticles for prosthetic biofilm prevention. Int J Nanomedicine 4:145–152

  98. Truong VK, Pham VT, Medvedev A, Lapovok R, Estrin Y, Lowe TC, Baulin V, Boshkovikj V, Fluke CJ, Crawford RJ, Ivanova EP (2015) Self-organised nanoarchitecture of titanium surfaces influences the attachment of Staphylococcus aureus and Pseudomonas aeruginosa bacteria. Appl microbiol biotech 99(16):6831–6840. https://doi.org/10.1007/s00253-015-6572-7

  99. Tsuang Y-H, Sun J-S, Huang Y-C, Lu C-H, Chang W, Wang C-C (2008) Studies of photokilling of bacteria using titanium dioxide nanoparticles. Artif Organs 32:167–174. https://doi.org/10.1111/j.1525-1594.2007.00530.x

  100. Uhm S-H, Song D-H, Kwon J-S, Lee S-B, Han J-G, Kim K-N (2014) Tailoring of antibacterial Ag nano-structures on TiO2 nanotube layers by magnetron sputtering. J Biomed Mater Res Part B 102B:592–603. https://doi.org/10.1002/jbm.b.33038

  101. Vasilev K, Poh Z, Kant K, Chan J, Michelmore A, Losic D (2010) Tailoring the surface functionalities of titania nanotube arrays. Biomaterials 31:532–540. https://doi.org/10.1016/j.biomaterials.2009.09.074

  102. Wang G, Feng H, Gao A, Hao Q, Jin W, Peng X, Li W, Wu G, Chu PK (2016) Extracellular electron transfer from aerobic bacteria to Au-loaded TiO2 semiconductor without light: a new bacteria-killing mechanism other than localized surface plasmon resonance or microbial fuel cells. ACS Appl Mater Interfaces 8:24509–24516. https://doi.org/10.1021/acsami.6b10052

  103. Wang T, Liu X, Zhu Y, Cui ZD, Yang XJ, Pan H, Yeung KWK, Wu S (2017a) Metal ion coordination polymer-capped pH-triggered drug release system on titania nanotubes for enhancing self-antibacterial capability of Ti implants. ACS Biomater Sci Eng 3:816–825. https://doi.org/10.1021/acsbiomaterials.7b00103

  104. Wang Q, Huang JY, Li HQ, Zhao AZJ, Wang Y, Zhang KQ, Sun HT, Lai YK (2017b) Recent advances on smart TiO2 nanotube platforms for sustainable drug delivery applications. Int J Nanomed 12:151. https://doi.org/10.2147/IJN.S117498

  105. Wang G, Feng H, Jin W, Gao A, Peng X, Li W, Wu H, Li Z, Chu PK (2017c) Long-term antibacterial characteristics and cytocompatibility of titania nanotubes loaded with Au nanoparticles without photocatalytic effects. Appl Surf Sci 414:230–237. https://doi.org/10.1016/j.apsusc.2017.04.053

  106. Wang G, Feng H, Hu L, Jin W, Hao Q, Gao A, Peng X, Li W, Wong K-Y, Wang H, Li Z, Chu PK (2018) An antibacterial platform based on capacitive carbon-doped TiO2 nanotubes after direct or alternating current charging. Nat Commun 9(1):2055. https://doi.org/10.1038/s41467-018-04317-2

  107. Widaa A, Claro T, Foster TJ, O’Brien FJ, Kerrigan SW (2012) Staphylococcus aureus protein A plays a critical role in mediating bone destruction and bone loss in osteomyelitis. PLoS ONE 7:e40586. https://doi.org/10.1371/journal.pone.0040586

  108. Xu LC, Siedlecki CA (2014) Staphylococcus epidermidis adhesion on hydrophobic and hydrophilic textured biomaterial surfaces. Biomed Mater 9(3):035003

  109. Yang T, Qian S, Qiao Y, Liu X (2016) Cytocompatibility and antibacterial activity of titania nanotubes incorporated with gold nanoparticles. Colloids Surf B Biointerfaces 145:597–606. https://doi.org/10.1016/j.colsurfb.2016.05.073

  110. Yao C, Webster TJ (2009) Prolonged antibiotic delivery from anodized nanotubular titanium using a co-precipitation drug loading method. J Biomed Mater Res B Appl Biomater 91:587–595. https://doi.org/10.1002/jbm.b.31433

  111. Yao S, Feng X, Lu J, Zheng Y, Wang X, Volinsky A, Wang L-N (2018) Antibacterial activity and inflammation inhibition of ZnO nanoparticles embedded TiO2 nanotubes. Nanotechnology 29:244003. https://doi.org/10.1088/1361-6528/aabac1

  112. Yim EK, Darling EM, Kulangara K, Guilak F, Leong KW (2010) Nanotopography-induced changes in focal adhesions, cytoskeletal organization, and mechanical properties of human mesenchymal stem cells. Biomaterials 31(6):1299–1306. https://doi.org/10.1016/j.biomaterials.2009.10.037

  113. Yoon KY, Byeon JH, Park J-H, Hwang J (2007) Susceptibility constants of Escherichia coli and Bacillus subtilis to silver and copper nanoparticles. Sci Total Environ 373:572–575. https://doi.org/10.1016/j.scitotenv.2006.11.007

  114. Yu Y, Shen X, Luo Z, Hu Y, Li M, Ma P, Ran Q, Dai L, He Y, Cai K (2018) Osteogenesis potential of different titania nanotubes in oxidative stress microenvironment. Biomaterials 167:44–57. https://doi.org/10.1016/j.biomaterials.2018.03.024

  115. Yue C, van der Mei HC, Kuijer R, Busscher HJ, Rochford ET (2015) Mechanism of cell integration on biomaterial implant surfaces in the presence of bacterial contamination. J Biomed Mater Res Part A 103(11):3590–3598. https://doi.org/10.1002/jbm.a.35502

  116. Zhang G, Zhang J, Xie G, Liu Z, Shao H (2006) Cicada wings: a stamp from nature for nanoimprint lithography. Small 2:1440–1443. https://doi.org/10.1002/smll.200600255

  117. Zhang H, Sun Y, Tian A, Xue XX, Wang L, Alquhali A, Bai X (2013) Improved antibacterial activity and biocompatibility on vancomycin-loaded TiO2 nanotubes: in vivo and in vitro studies. Int J Nanomed 8:4379. https://doi.org/10.2147/IJN.S53221

  118. Zhang Y, Zhang L, Li B, Han Y (2017) Enhancement in sustained release of antimicrobial peptide from dual-diameter-structured TiO2 nanotubes for long-lasting antibacterial activity and cytocompatibility. ACS Appl Mater Interfaces 9:9449–9461. https://doi.org/10.1021/acsami.7b00322

  119. Zhao L, Wang H, Huo K, Cui L, Zhang W, Ni H, Zhang Y, Wu Z, Chu PK (2011) Antibacterial nano-structured titania coating incorporated with silver nanoparticles. Biomaterials 32:5706–5716. https://doi.org/10.1016/j.biomaterials.2011.04.040

  120. Zhukova Y, Hiepen C, Knaus P, Osterland M, Prohaska S, Dunlop JW, Fratzl P, Skorb EV (2017) The role of titanium surface nanostructuring on preosteoblast morphology, adhesion, and migration. Adv Healthc Mater 6(15):1601244. https://doi.org/10.1002/adhm.201601244

Download references

Authors’ contributions

MFK, conception/design/creation/acquisition/interpretation/drafted the work. BFL, design/acquisition/interpretation/drafted the work. RH, conception/acquisition/drafted the work. SDO, design/acquisition/interpretation/drafted the work. ERT, conception/interpretation/drafted the work. All authors read and approved the final manuscript.

Acknowledgements

This study was partially supported by the Brazilian National Council of Research and Development (CNPq)—Research Grant Number: 140903/2016-0. SDO is thankful for the Research Career Award of the National Council for Scientific and Technological Development (CNPq).

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Not applicable.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Funding

Not applicable.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author information

Affiliations

  1. Dentistry University, School of Health Sciences, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, P.O. Box 6681, Porto Alegre, 90619-900, Brazil
    • Marcel Ferreira Kunrath
    •  & Eduardo Rolim Teixeira
  2. Immunology and Microbiology Laboratory, School of Sciences, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, P.O. Box 6681, Porto Alegre, 90619-900, Brazil
    • Bruna Ferreira Leal
    •  & Sílvia Dias de Oliveira
  3. Materials and Nanoscience Laboratory, Pontifical Catholic University of Rio Grande do Sul (PUCRS), P.O. Box 1429, Porto Alegre, 90619-900, Brazil
    • Marcel Ferreira Kunrath
    •  & Roberto Hubler
Authors
  1. Marcel Ferreira Kunrath
    View author publications
    You can also search for this author in
  2. Bruna Ferreira Leal
    View author publications
    You can also search for this author in
  3. Roberto Hubler
    View author publications
    You can also search for this author in
  4. Sílvia Dias de Oliveira
    View author publications
    You can also search for this author in
  5. Eduardo Rolim Teixeira
    View author publications
    You can also search for this author in

Corresponding author

Correspondence to Marcel Ferreira Kunrath.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kunrath, M.F., Leal, B.F., Hubler, R. et al. Antibacterial potential associated with drug-delivery built TiO2 nanotubes in biomedical implants. AMB Expr 9, 51 (2019). https://doi.org/10.1186/s13568-019-0777-6

Download citation

Keywords

  • Antibacterial surfaces
  • Biomedical implants
  • Drug delivery
  • Nanoparticles
  • Surfaces
  • TiO2 nanotubes