key: cord-1014697-r5j4abux
authors: Kumaravel, Vignesh; Nair, Keerthi M.; Mathew, Snehamol; Bartlett, John; Kennedy, James E.; Manning, Hugh G.; Whelan, Barry J.; Leyland, Nigel S.; Pillai, Suresh C.
title: Antimicrobial TiO(2) nanocomposite coatings for surfaces, dental and orthopaedic implants
date: 2021-02-23
journal: Chem Eng J
DOI: 10.1016/j.cej.2021.129071
sha: a3e761acefeed826a8ba20f6df1a63dfe781342c
doc_id: 1014697
cord_uid: r5j4abux

Engineering of self-disinfecting surfaces to constrain the spread of SARS-CoV-2 is a challenging task for the scientific community, because the human coronavirus spreads through respiratory droplets. Titania (TiO(2)) nanocomposite antimicrobial coatings is one of the ideal remedies to disinfect pathogens (virus, bacteria, fungi) from common surfaces under light illumination. The photocatalytic disinfection efficiency of recent TiO(2) nanocomposite antimicrobial coatings for surfaces, dental and orthopaedic implants are emphasized in this review. Mostly, inorganic metals (e.g. copper (Cu), silver (Ag), manganese (Mn), etc), non-metals (e.g. fluorine (F), calcium (Ca), phosphorus (P)) and two-dimensional materials (e.g. MXenes, MOF, graphdiyne) were incorporated with TiO(2) to regulate the charge transfer mechanism, surface porosity, crystallinity, and the microbial disinfection efficiency. The antimicrobial activity of TiO(2) coatings was evaluated against the most crucial pathogenic microbes such as Escherichia coli, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Legionella pneumophila, Staphylococcus aureus, Streptococcus mutans, T2 bacteriophage, H1N1, HCoV-NL63, vesicular stomatitis virus, bovine coronavirus. Silane functionalizing agents and polymers were used to coat the titanium (Ti) metal implants to introduce superhydrophobic features to avoid the microbial adhesion. TiO(2) nanocomposite coatings in dental and orthopaedic metal implants disclosed an exceptional bio-corrosion resistance, durability, biocompatibility, bone-formation capability, and long-term antimicrobial efficiency. Moreover, the commercial trend, techno-economics, challenges, and prospects of antimicrobial nanocomposite coatings are also discussed briefly.

The outbreak of various infectious diseases such as SARS-CoV, H1N1, and Ebola has resulted in a significant impact on the global economy and health systems [1, 2] . SARS-CoV-2 is the most recent pandemic, caused by the human coronavirus [3] [4] [5] . The global mortality rate of SARS-CoV-2 is increasing everyday owing to its extremely contagious characteristics.

At this stage, the world is fighting against an invisible enemy to control rampant infections and save the lives. Studies are in progress on various aspects such as rapid detection, development of vaccines, medication, therapy, etc [6] [7] [8] . There is an urgent need to develop self-disinfecting surfaces to control the spread of this disease. Photocatalytic surface coatings would be considered one of the best solutions to disinfect pathogens from the most commonly touched surfaces, such as commercial touch screens, mobile phones, ceramics, etc [9, 10] . Non-toxic metal oxides are commonly used for photocatalytic coatings, which could respond to light and moisture to generate the reactive oxygen species (ROSs), to destroy the microbes. Compared to the normal sanitation procedures, durable photocatalytic coatings could hinder the reactivation of microbes and destroy them completely. The mobility of ROSs in air is normally higher and so it could effectively destroy airborne microbes [1] . Titanium dioxide or titania (TiO 2 ) is one of the best photocatalysts for commercial antimicrobial coatings owing to its lowcost, reactivity, stability, reusability, durability, biocompatibility, crystallinity, high surface area and corrosion resistance. Very recently, the inactivation of a human coronavirus (HCoV-NL63) using TiO 2 nanoparticles coated glass coverslips has been studied at various humid environments under UV radiation [11] . In another study, the photocatalytic activity of TiO 2 coated films has been investigated against the bovine coronavirus under visible light irradiation of 500 lux [12] . Sandia National Laboratory, USA also reported the efficacy of Ag-TiO 2 coated surfaces against the vesicular stomatitis virus (the biosafety level-2 safe surrogate virus for SARS-CoV-2) under visible light irradiation [13] . All these recent studies clearly suggest that TiO 2 coatings are effective to disinfect the coronavirus and the related viral genomic RNA. The photocatalytic disinfection mechanism of coronavirus on a TiO 2 coated mobile phone touch screen through the attack of ROSs is schematically illustrated in Figure 1 . [14] . TiO 2 is one of the broad-spectrum bactericides with self-sterilizing effects and it could reduce the number of adhered microbes through increasing the electron donor surface 4 energy of the coating [15] [16] [17] [18] . In most of the recent studies, TiO 2 has been doped with metals/non-metals or other chemical modifiers to extend the light absorption into the visible region and improve the photo-generated charge transfer process [19] [20] [21] [22] . Imani et al. reported the effectivity of inorganic (such as copper (Cu), silver (Ag), zinc (Zn), silica, etc.) and organic (such as polyethylenimine, porphyrin, quaternary ammonium compounds, C 60 , etc.) coatings to prevent the spread of viral infections through contaminated surfaces [23] . Nevertheless, the bare metal or polymer coatings could fail to deliver long-term antimicrobial efficiency and could be easily corroded under certain circumstances [14, [24] [25] [26] .

Environmentally benign TiO 2 photocatalytic coatings with active ingredients are one of the best options to address the long-term antimicrobial efficiency with anti-corrosion surface features. There are no comprehensive reviews on the applications of TiO 2 nanocomposite photocatalytic coatings for antimicrobial applications. Coatings of TiO 2 with active inorganic metals /organic polymers /2D materials could demonstrate the maximum microbial disinfection efficacy compared to bare metals or TiO 2 [23] . This review focuses on the application of various TiO 2 nanocomposite antimicrobial coatings for surfaces and medical (dental and orthopaedic) implants.

Biofilm formation, proliferation, and the efficacy of ROSs on the microbes are briefly discussed in this section. The surface interaction of microbes is crucial as they establish alterations in the gene expression of cells, which influences the behaviour, morphology and the surface adhesion of the cells [27] . Understanding these mechanisms can guide the engineering of novel materials or technologies to inhibit microbial growth and proliferation. 5 

Bacteria are unicellular organisms, but in nature they are attached to inert or active surfaces to form well-structured three-dimensional (3D) communities known as 'biofilms' [28] . Biofilms can be form from either a single or multiple specie and it can protect the microbes from antibiotic treatments and stress conditions. The cycle of biofilm formation can be generally described through 5 steps (Figure 2 ). Step 1: In response to a specific environmental signal in a free-living cell, they attach to the surface using Van der Walls force and form an organic monolayer of polysaccharides or glycol proteins.

Step 2: Once the biofilm layer is formed, the cells move along using twitching motility that involves the extinction of specific pilin monomer (PilA). This could facilitate an irreversible cell attachment to the surface.

Step 3: Microcolonies are formed once more cells are attached to the surface. When the biofilm matures, it communicates between the colonies by sending and receiving autoinducer signals (AI), this communication is called quorum sensing (QS) [29] . QS is favourable to promote the development of biofilms into a 3D structure.

Step 4: In response to environmental changes, there can be metabolic features and genetic expressions of the cell.

They tend to uptake foreign DNA and result in expressing exogenous proteins. This step supports the cells in adapting to the surrounding conditions, such as the formation of antibioticresistant strains. Once it reaches a specific concentration, the genetic changes in the cells will be triggered, which causes the cells to bind to a substrate and each other.

Step 5: This stage is called dispersion, the matured sessile cells are released by shedding the biofilm and moving to new places, forming other colonies by repeating this cycle [28] . 6 

Photo-generated ROSs exhibited hormone effects on the biofilm formation [30] . The changing trends of AI (such as c-di-GMP) and QS signals (such as AHL and AI-2) during the development of biofilm stages could be disturbed by the ROSs attack [30] . The processes (suppress the production of AI, degradation of AI, inhibition of AI binding to the respective receptors, and prevention of biofilm gene expression and transcription) involved in the inactivation of QS signals (called quorum quenching) is shown in Figure S1 [31] . The key steps of QS and the communication between the colonies in biofilm could be blocked by the photocatalytic coatings.

Schematic of ROSs formation through semiconductor photocatalysis is displayed in [32, 33] .

Amongst these ROSs, O 2 •─ and H 2 O 2 are formed by the reduction of O 2 , which then further 7 dissociates to form • OH [34] . The anatase and rutile phases of TiO 2 have distinct reactivity towards • OH and O 2 •─ formation [35] . It could be ascribed to the differences in their adsorption towards H 2 O 2 and the alignment of band edges. The lifetime of ROSs in TiO 2 anatase phase is longer than that of rutile [36] . Compared to the individual polymorphs of TiO 2 , a mixture of anatase and rutile phases showed the maximum photocatalytic activity. This could be attributed to the heterojunction formation through the close contact of valance and conduction band edges [37] . ROSs could damage the cells, affect the microbial growth and migration of cells either by direct interaction with the cell membrane or diffusion of H 2 O 2 into the cells [38] . Reproduced with permission from [39] . Copyrights (2017), American Chemical Society. 8 The attack of ROSs on Gram-positive and Gram-negative bacteria is schematically illustrated in Figure 4 [40] . The attack of ROSs on the cytoplasm is the most significant mechanism to influence the metabolism, enzymatic, respiratory, and defence process of the microbe. However, the peptidoglycan (PGN) layers are the main barriers for the ROSs before entering the cytoplasmic membrane. Lipopolysacharide and lipid layers of Gram-negative bacteria could be easily destroyed through the photocatalysis mechanism. PGN layer of Grampositive bacteria is much thicker and more resistant to the ROSs. Nevertheless, the ROSs could be easily diffused through the pores in the PGN layers without the PGN degradation. Once the ROSs reach the cytoplasmic membrane, it could easily affect the key enzymatic and respiratory activities of microbes. [40] . Reproduced with permission from ref. [40] . Copyrights (2020), American Chemical Society.

Recently, the activity of TiO 2 on Pseudomonas aeruginosa (P. aeruginosa) biofilm formation was investigated under UVA irradiation [41] . The effect of ROSs attack in the lipase, 9 protein expression and biofilm formation were analysed. The rod-shaped morphology of the cells was faded with respect to the irradiation time, suggesting the degradation of cells. After 60 min of treatment, there was a drastic increase in the number of damaged cells (Log 4 reduction), as the viability of bacterial cells was greatly reduced due to the ROSs attack.

Furthermore, the motility of planktonic cells was also reduced, this could avoid further colony formation. Under extreme stress environments, the bacteria undergo resistant strategies like viable but non-culturable (VBNC) state to increase the tolerance to ROSs attack and to maintain intact membrane and genetic material. Under photocatalytic reaction, P. aeruginosa in planktonic form lost the ability to form a biofilm, as well as undergo disruption of the bacterial cell membrane. For the cells already under biofilm production, the rigidity of the εpoly(L-lysine) became weak, thus affecting the cell stability. Thus, the photocatalytic treatment of cells with TiO 2 could reduce the bacterial cell density including VBNC and inhibit the biofilm formation.

ROS attack is the principal mechanism for the destruction of biofilms under light illumination of TiO 2 . Nevertheless, the electrostatic interaction of the coating materials with the microbial cell wall could cause the leakage of intracellular contents under dark conditions [42] . Moreover, the key metabolic processes, ATP production, and protein synthesis could be inhibited by the interaction of metal ions in the photocatalytic coating with the amino acids of the microbes [43] .

Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) are commonly employed to investigate the changes in cell morphology and the destruction of cell integrity during the microbial disinfection process [44, 45] .

10 Bacteria: The photocatalytic disinfection mechanism of bacteria is shown in Figure 5 (a) [46] . At first, the shape of the cell becomes abnormal and then the cell membrane is damaged by the attack of ROSs. This could facilitate the entry of ROSs into the interior of the cells. Afterwards, the cells could be ruptured into small fragments during the prolonged light irradiation [47] . Potassium (K + ) is one of the key elements for the synthesis of proteins and polysomes inside the cells. K + ions are released during the cell membrane rupture and therefore cell permeability is commonly analysed through the detection of K + concentration [48, 49] . The concentrations of key elements such as adenosine triphosphate (ATP, vital for the bacteria metabolism), and antioxidant enzymes (superoxide dismutase (SOD) and catalase (CAT)) could also be reduced through the repetitive attack of ROSs. The bacteria could potentially repair and regrow through self-defence mechanisms [50] . However, the repair or regrowth of cells is not viable, as the leakage or damage of genome DNA/cytoplasm is severe during the constant photocatalytic treatment.

The photocatalytic disinfection mechanism of viruses is shown in Figure 5 (b) [46] . Viruses do not have any cell membrane, cytoplasm, and energy metabolism.

Consequently, the photocatalytic disinfection of viruses is usually examined via analysing the damage of major building blocks such as nucleic acids and proteins. ROSs could interact with the outer layer of surface proteins, which leads to the oxidation of the protein layer and the leakage of enveloped RNA [51] . The important protein side chains such as threonine, lysine, and arginine could be oxidized by the ROSs attack [52, 53] . Electrophoresis is used to explore the decline or disappearance of protein band intensities during the photocatalytic treatment.

11 Figure. 5. Photocatalytic disinfection mechanism of (a) bacteria, and (b) virus [46] .

Reproduced with permission from ref. [46] . Copyrights (2019), Elsevier

The photocatalytic activity of TiO 2 under a real-life scenario was tested to provide a basic understanding on the durability of coatings [54] . 1 wt % TiO 2 (42 % anatase, and 38 % rutile) was dispersed in water and coated on the limestone surfaces. The coatings were exposed in a real urban site for one year. The photocatalytic experiments were carried out for coated and uncoated limestone surfaces before and after light exposure (UV irradiance varied from 6.7 W/m 2 to 27 W/m 2 ). It was found that the photocatalytic efficiency was reduced by 20 % after the second term of exposure and was reduced to almost negligible after one year.

Additionally, the surface colour of limestone, which was retained by the TiO 2 coating was also 12 lost by the end of the term of exposure. These results revealed the enormous influence of environmental factors on the stability of photocatalytic coatings. Factors such as humidity, temperature, and concentration of pollutants in the microstructure of the coating could influence the photocatalytic activity of TiO 2 . The decrease in efficiency of the coating could be attributed to the blocking of active sites by the degradation intermediates or products. The presence of a higher concentration of Cl ─ , which could act as the oxidising radical scavenger in the environment was an additional factor for this adverse effect. However, by washing the coated surface with water, the photocatalytic activity was regained up to 85 %. The increase in humidity of the environment reduces the photocatalytic efficiency as the water molecule tends to occupy the active site on the surface rather than the pollutant. This enables the coatings to exhibit a hydrophilic surface effect instead of an oxidising effect. Furthermore, at low temperatures, the photocatalytic activity was reduced, while at increased temperatures the activity was regained as the TiO 2 sites were available due to evaporation of adsorbed water molecules. The deficiency of nanoparticles from the coating surface was also confirmed by Xray fluorescence (XRF) analysis, where the existence of Ti was reduced over the period. These results suggest that the influence of environmental factors on the activity of TiO 2 must be addressed for the sustainability of coatings in real-life applications [55] [56] [57] .

The development of efficient strategies against microbial infections, both in-vitro and in-vivo, is still quite challenging. Although TiO 2 antimicrobial surfaces are widely employed in various sectors, the rapid recombination of the generated holes and electrons limits its practical applications. Strategies such as loading of antibiotics, metal nanoparticles, and other 2D materials could lead to improved microbial disinfection via an enhanced ROSs generation.

Recent advances on the antimicrobial activity of TiO 2 for the surfaces and medical implants 13 are highlighted in this section. The key findings of TiO 2 nanocomposites for the disinfection of various microbes are given in Table S1 .

Sol-gel and hydrothermal techniques are commonly utilised for the synthesis of TiO 2 nanocomposites. The general flow chart for the fabrication of TiO 2 films and nanoparticles is shown in Figure S2 . Numerous methods such as deposition (e.g., spray/dip/spin coating), sputtering, functionalization, and implantation (e.g., electrospinning, electrodeposition, MAO, physical/chemical vapour deposition, and layer by layer assembly) could be used to coat the antimicrobial nanocomposites.

Recently, the in-situ anti-biofilm activity of phosphorus (P) and fluorine (F) doped TiO 2 coatings was investigated in three microbes, Escherichia coli (E. coli, SCC1), Staphylococcus epidermidis (S. epidermidis, ATCC 35983), and Pseudomonas fluorescens (P. fluorescens, ATCC 13525) under UVA light irradiation [40] . The influence of P/F-TiO 2 coating on the intracellular enzymatic functions and the respiratory process of the microbes, were also examined through the fluorescence staining. P/F-TiO 2 was synthesised via a sol-gel method, and the molar ratio of F/Ti and P/Ti was fixed at 0.03. To prepare the coatings, the required quantity of P/F-TiO 2 powders was dispersed in ethanol under ultrasonication. The photocatalytic suspension was then drop-casted on a 22 x 22 mm glass substrate with a surface coating density of 1 mg/cm 2 . The live and dead microbial population was assessed using a confocal laser scanning microscope (CLSM) after the light irradiation. The efficiency of P/F-TiO 2 coated glass substrate was also compared with the commercial TiO 2 P25. Fluorescence microscopy images (before and after light illumination), and the surface fraction coverage of live/damaged cells are displayed in Figure. S3. Experiments were also performed in the absence 14 of light or catalyst to demonstrate the impact of antimicrobial photocatalysis mechanism.

Almost all the E. coli were destroyed on P/F-TiO 2 coated glass after 10 min treatment. In the case of commercial TiO 2 P25 coated glass, only 50 % microbial reduction was measured during 10 min treatment. After 45 min of treatment, the average damaged to live E. coli ratio for P/F-TiO 2 and TiO 2 P25 was 1.15 (with a 80 % reduction in the enzymatic process) and 0.84 (with a 60 % reduction in the enzymatic process), respectively.

The physico-chemical properties of P/F-TiO 2 were superior (such as isoelectric point (3.4 ± 0.2), average particle size (10 nm), high specific surface area (130 m 2 /g)) than that of the commercial photocatalyst Degussa (Evonik) P25 TiO 2 (5.6 ± 0.5, 22 nm, and 55 m 2 /g).

Atomic force microscopy (AFM) results revealed that P/F-TiO 2 coated surface was smoother with small grain sizes (42 ± 16 nm). TiO 2 P25 coated surface was comprised of a huge grainlike morphology with large particle sizes (180 ± 35 nm). Topography results showed that the number of contact points for the microbial adhesion in P/F-TiO 2 was higher than that of TiO 2 P25. Therefore, the ROSs formed in P/F-TiO 2 coated surface could easily enter the microbial cell wall. The long-term efficiency of the light irradiated photocatalyst surface was assessed to examine the survival of microbes under favourable growth conditions for 16 h. Bacterial regrowth was restricted to ~60 % by the photocatalyst coated surface. The rate of microbial inactivation for P/F-TiO 2 coated surface was in the following order: E. coli > S. epidermidis > P. fluorescens.

The difference in antimicrobial activity was mainly ascribed to a discrepancy in the surface characteristics (e.g., electrostatic interaction, pH, topology, etc.) of the microbe and the coating material. Moreover, anti-oxidant enzymes such as CAT and SOD are available in the three microbes. The ability of anti-oxidative enzymes to defend against the ROSs may vary with respect to the bacterial species [58] . Anaerobic microbes (E. coli and S. epidermidis) are more sensitive towards O 2 exposure compared to aerobic P. fluorescens [59] . Aerobic P. 15 fluorescens strains could survive under ROSs attack through generating NADPH, ATP and glyoxylate [60] . The influence of O 2 on the photocatalytic inactivation of E. coli was tested.

The results revealed that efficiency was reduced under poor O 2 conditions, and that the colour of the coatings changed from white to blue. This was ascribed to the formation of reduced TiO 2 (Ti 3+ ) with O 2 vacancies [61, 62]. In the poor O 2 conditions, the photo-generated electrons could accumulate in the TiO 2 and thus reduce the Ti 4+ species into Ti 3+ .

A potential three-in-one antimicrobial platform was developed on a gallium (Ga)carbenicillin (Car) framework coated with oxygen-deficient hollow TiO 2 nano-shells (H-TiO 2-

x @MOF) to fight against methicillin-resistant Staphylococcus aureus (MRSA) and

Pseudomonas aeruginosa (PA) under visible light irradiation [63] . The oxygen vacancies have proved to narrow the bandgap of TiO 2 , improving its optical absorption range towards visible and near-infrared (IR) regions. Antibacterial properties were studied through in-vitro and invivo wound healing. In-vitro studies showed that H-TiO 2-x @MOF exhibited a higher antibacterial efficacy towards both MRSA and PA at pH 5.5 compared to that of pH 7.4. This could be attributed to the gradual degradation of Ga-MOF at low external pH similar to the wound microenvironment [64] . The antimicrobial experiments were also carried out under dark conditions. The results showed that the bacterial viability on the coatings with light irradiation was lower than the dark samples, indicating the visible light driven ROSs generation. The schematic of wound healing experiments is shown in Figure 6 [63] . Reproduced with permission from [63] .

Studies also shown the significance of nanostructures in upgrading ROSs generation and antimicrobial efficiency. The effect of optical and geometrical parameters on the photocatalytic efficiency of TiO 2 were comprehensively studied by Sen and co-workers [67] .

A silicon surface with nanostructured grass-like pillars known as black-silicon was coated on the TiO 2 via atomic layer deposition (AT_B-Si) [68] [69] [70] . The commonly accepted "contact killing" mechanism and the significance of pillar structures over flat surfaces (AT_Si) on ROSs generation were further investigated [71, 72] . The reflection of incident light, photogeneration of charge carriers, and the electron-hole recombination process on TiO 2 are schematically displayed in Figure 7 Reproduced with permission from [67] . Copyrights (2020), American Chemical Society 21 TiO 2 -SiO 2 nanopillars exhibited 73 % bactericidal efficiency (E. coli ATCC 25922) compared to TiO 2 -Si. In-vitro studies revealed that AT_B-Si caused the bacteria to lose their smoothness by both oxidative stress and an increased ROSs production disrupting the cell wall integrity. Finite element method (FEM) simulations indicated that with an increase in the height of nanopillars, the absorption on TiO 2 surface was also increased. However, there is a particular diffusion length associated with the ROSs beyond which the absorption does not lead to an increased ROSs generation. It was concluded that after 5 µm of pillar height, there was no further ROSs production even though the absorption of light increases. This work illustrated a basic design rule for optically activated nanostructured photocatalysts with an improved ROSs generation and antibacterial efficacy.

A specialized reusable filter surface with photocatalytic TiO 2 nanowires (TiO 2 NWs) was developed to inactive the airborne pathogens [1] . TiO 2 NWs offered an improved photocatalytic efficiency owing to the high surface to volume ratio for ROSs generation [73] .

The schematic of ROSs generation on TiO 2 NWs filter is displayed in Figure. The different timescales for ESR and antibacterial studies could be attributed to the importance of a mutual distance between TiO 2 NWs and the species in contact. Moreover, TiO 2 NWs could be reused more than 1000 times, which could further address the environmental pollution caused by disposable masks. 23 In a recent study, a hybrid of monolayer MXene (Ti 3 C 2 T x ) incorporated TiO 2 with (001) facets was investigated for the inactivation of airborne microbes [2] . Theoretical and experimental studies reveal that the (001) facet of TiO 2 is more reactive and stable owing to its high surface energy [77] . Besides, the photocatalytic activity of anatase TiO 2 with exposing (001) facets is exceptional to that of commercial P25 [78] . The hybridisation of (001)TiO 2 with monolayer Ti 3 C 2 T x two-dimensional (2D) nanosheets could further upgrade the photocatalytic activity through an improved electron-hole separation [79, 80] . (001) The microbial inactivation was studied in E. coli, Bacillus subtilis (B. subtilis) and its spore (bacteria in a dormant state). The microbial bio-aerosol was produced using an aerosol generator with a particle size of ~1-5 μm. The average particle size of (001)TiO 2 /Ti 3 C 2 T x was 20-30 nm, and the lattice spacing of (001) facet was ~0.23 nm. UV-visible light absorption intensities of bare TiO 2 and (001)TiO 2 /Ti 3 C 2 T x samples were almost identical. Compared to bare TiO 2 (3.2 eV), the band gap energy of (001)TiO 2 /Ti 3 C 2 T x was slightly increased (3.5 ~ 3.65 eV). Nonetheless, the PL intensity of (001)TiO 2 /Ti 3 C 2 T x was lower than that of bare TiO 2 , suggesting that an increased electron-hole separation was achieved on the hybrid catalyst surface. E. coli inactivation efficiency was in the following order ( Figure S4 (a) ): PU foam with UV < photolysis (UV-365 nm alone) < photolysis (UV-254 nm alone) < (001)TiO 2 /Ti 3 C 2 T x on PU foam at 365 nm < (001)TiO 2 /Ti 3 C 2 T x on PU foam at 254 nm. The microbial disinfection was not observed on the coatings at dark conditions ( Figure S4 (a) ). The hybrid photocatalyst with 3.4 % of Ti 3 C 2 T x showed the highest antimicrobial efficiency compared to others. 24 Electrical efficiency (EE) per Log order of microbial inactivation was studied to investigate the electricity consumption during the photocatalysis and photolysis ( Figure S4 (b)). Compared to various metal-doped TiO 2 photocatalysts (Cu-TiO 2 , Ag-TiO 2 , TiO 2 P25, MOF, etc) and UV photolysis, the electricity consumption for (001)TiO 2 /Ti 3 C 2 T x on PU foam under UV light irradiation was much smaller. In the case of different microbial species, the photocatalytic efficiency of (001)TiO 2 /Ti 3 C 2 T x was in the following order: E. coli > B. subtilis subtilis and its spore could protect them from the attack of ROSs during photocatalysis. The Log inactivation efficiency of the photocatalyst was increased with respect to the humidity from 30 to 95 %, indicating that the high humid conditions stimulate the photo-generation of ROSs [81, 82] . The reactivation of microbes was tested after the treatment of photolysis and photocatalysis. The reactivation of microbes was not observed for the photocatalysis condition whereas the reactivation was noted for dark and photolysis conditions. Bacteria were inactivated through the damage of DNA in the photolysis condition which could be repaired under certain cases. Microbes could enter the VBNC state in response to the light irradiation treatment [83] . However, the photocatalytic microbial inactivation was achieved via physical damage of the outer cell membrane by the ROSs attack [84] . The microbe could not repair its membrane after the photocatalysis without sufficient nutrition.

In another study, a ternary nanocomposite (TiO 2 /SiO 2 /Ag) coating was developed for medical devices using a magnetron co-sputtering technique [85] . Mesoporous SiO 2 was used 25 as a seed layer for the homogeneous immobilization of Ag nanoparticles on TiO 2 [86, 87] . E. coli (ATCC 10536) was selected to evaluate the antimicrobial activity because it is one of the common microbes for urinary tract infection in medical devices [88] . In vivo biofilm formation on coatings under urine flow was evaluated using artificial urine medium (AUM) under simulated urinary tract conditions. Silicone was also tested as a substrate in this study because it is widely used in urinary catheters and stents [89] . Compared to the bare glass, TiO 2 /SiO 2 /Ag coated substrates showed an outstanding efficiency to inhibit the biofilm formation under the simulated urine flow conditions after 24 and 48 h. The antimicrobial efficiency of the coatings was ascribed to cell membrane damage, leakage of cellular components, changes in cell shape/size, and an increase of cell surface roughness [90] .

Also, the Ag nanoparticles were able to bind the microbial proteins to inactive the electron transport chain, inhibit the respiratory process and growth of the cells [91, 92] . 26 In recent decades, TiO 2 photocatalysis has also been proven to be effective against viruses [93] . The key findings of recent antiviral TiO 2 nanocomposite coatings are shown in Table S2 .

The human influenza virus strain of A/PR8/H1N1 was treated with TiO 2 under UV light irradiation, and the efficiency of viral disinfection process was relied on the intensity of the light radiation [94] . Later, a photocatalytic air cleanser was developed using a TiO 2 -coated aluminium plate system [95] . It showed maximum efficiency against aerosol-associated influenza virus, indicating the competence of photocatalysis technology to detoxify the indoor air. LED light-driven TiO 2 / β-SiC solid alveolar photocatalytic foams were developed for the disinfection of T2 bacteriophage [96] . The overall antiviral efficiency of this nanocomposite was associated with the passive filtration effect of the foams. Further, Cu-TiO 2 nanofibers were designed to inactivate the bacteriophage f2 as well as E.coli 285, where the free ROSs in the bulk phase of the photocatalyst played a significant role in the virus inactivation process [97] .

Recently, various studies have also been conducted to inactivate the SARS-CoV-2 using TiO 2 nanocomposite coatings [12] . TiO 2 -Ag coatings with an anatase phase of TiO 2 was engineered through an ion-assisted deposition technique [13] . The exposure of UV light over 9 h showed the complete elimination of SARS-CoV-2 compared to the dark conditions. TiO 2 nanoparticles also displayed high efficiency against the human coronavirus type NL63. The cell infectivity assay demonstrated that the virus strains were disinfected within one minute of UV exposure [11] . Although TiO 2 holds several advantages such as non-toxic, highly economical, and chemical stability, utilization of more sustainable resources including visible/solar light for microbial disinfection is highly desirable in the future [98] . More selective viral inactivation techniques, especially towards the disinfection of SARS-CoV-2 should be further established. 27 Ti metal implants are commonly employed in dentistry (e.g., dental implants, dentures) and orthopaedics (e.g., artificial bone, plates, joints, screws, etc.) owing to its outstanding biocorrosion resistance, mechanical strength, and biocompatibility [99] [100] [101] . Globally, more than 200 million people are using orthopaedic metal implants for various bone-related diseases [102, 103] . However, the biomaterial centred infection (BCI) and the lack of bioactive/antimicrobial ingredients are the most common rationales for implant failures in several patients [104, 105] .

BCI is usually instigated through the formation, adhesion, and proliferation of biofilm on the implants. Antibiotic treatments are generally recommended to alleviate the minor infections after implant surgery. However, the dead cells on the implant surfaces from this bactericidal effect could act as binding sites for other live pathogens [106] . In some cases, the wound In a recent study, a two-step micro-arc oxidation (MAO) technique was used to fabricate the TiO 2 nanotubes coating loaded with bioactive (calcium (Ca), phosphorus (P)) and antimicrobial (Ag) materials [107] . The antimicrobial property of Ca-P-Ag/TiO 2 coating was investigated against Staphylococcus aureus (ATCC 6538) by the plate count method. MAO could introduce porous features on the Ti implant surface to enhance its adhesion and growth of osteoblasts [107] . At first, Ag-doped TiO 2 nanotubes were fabricated on the Ti surface by anodic oxidation under UV light treatment. Then, the as-synthesized Ag/TiO 2 nanotubes were subjected to MAO oxidation for 10 min in a solution containing Ag, Ca, and P precursors. SEM 28 images of bare and Ag/TiO 2 coated nanotubes are shown in Figure S5 . Nanotubes were formed with a diameter of 100-150 nm and ~20 tubes were noted in 4 μm x 3 μm area ( Figure S5 (a) ).

Spherical shaped Ag particles were attached to the TiO 2 nanotube orifice after 3 h of UV treatment ( Figure S5 (b) ). After the MAO treatment, the Ca-P-Ag/TiO 2 coating was gully shaped with micro-holes and nanopores on the surface. The spherical shaped Ag particles were evenly distributed, and the surface smoothness of the coating was increased with respect to the MAO voltage (from 320 V to 380 V). The Ag content of Ca-P-Ag/TiO 2 at 380 V was lower than the same at 320 and 350 V. This was attributed to the intense oxidation reaction of Ag at high voltages. At the same time, the Ca and P contents of Ca-P-Ag/TiO 2 were increased as the MAO voltage was increased from 320 (~ 5 wt % of Ca and P) to 380 V (~ 10 wt % of Ca and P). The molar ratio of Ca/P at 350 V was ~ 1.77, which was closer to the Ca/P ratio in bioactive hydroxyapatite (~ 1.67). Moreover, the microporous surface features of the coating were also maintained well at 350 V.

The growth of Staphylococcus aureus at different incubation times on the coating is shown in Figure S6 Microporous surface features could also enhance the hydrophilicity of the coating material.

The fine pores on the surface could act as a barrier to delay the contact of body fluids with the antimicrobial Ag. Consequently, Ag content inside the coating material could be gradually 29 released as it contacts with body fluids for long-term efficiency. The antimicrobial activity of the coating without Ag content was only 48.63 % after 1 day. The antimicrobial action of twosteps Ca-P-Ag/TiO 2 was mainly attributed to coulomb force adsorption of Ag, steady state release mechanism of antimicrobial agents, degradation of protein and photocatalytic reactions.

In a similar study, manganese (Mn) doped Ca-P/TiO 2 (Mn-Ca-P/TiO 2 ) was fabricated through a one-step MAO technique to evaluate the antimicrobial efficiency against Staphylococcus aureus [108] . Mn is one of the significant elements needed for bone growth, bone metabolism, synthesis of essential enzymes, and cellular homeostasis [109] . The ionic radius of Mn and Ca is analogous and hence it could be easily substituted in hydroxyapatite [110] . formation. The amount of hydroxyapatite crystals on Ti-Mn-EDTA was slightly higher than that of Ti-EDTA. The doping of Mn could endorse the glycosaminoglycans synthesis [111] and bone-related marker gene expression [112] in osteoblasts to assist the bone formation.

In another study, an anti-biofilm, biocompatible and superhydrophobic coating on Ti dental implants was engineered by a one-step non-thermal technique [113] . A low-pressure glow discharge plasma method was employed to minimize the polymicrobial bio-film adhesion on the Ti surface without influencing the fibroblast growth and proliferation. [114] . Therefore, the anti-biofilm activity of the Ti discs was also studied in Streptococcus mutans (UA 159) with 1 % sucrose supplementation for 4 h. Lastly, the biofilm polymicrobial composition on the coating was examined to estimate around 40 bacteria species associated with periodontitis (a chronic infectious inflammation in the teeth) by checkerboard DNA-DNA hybridisation [115] .

The surface of bare Ti disc was smoother whereas micrometre sized non-uniform aggregates (like cauliflower shape) were observed for superhydrophobic Ti disc. WCA of the superhydrophobic coating was higher than 150 °, suggesting an influence from HDMSO and Ar/O 2 plasma treatment. Surface roughness parameters (such as average roughness (R a ), root mean square average (R q ), average maximum height (R z ), and maximum height (R t )) of the 32 superhydrophobic Ti disc were higher than that of the bare Ti disc. CLSM results revealed the higher surface area and increased number of peaks for the superhydrophobic Ti disc (coating thickness of ~ 18 nm with ~ 2. 5 μm peak height).

The superior corrosion resistance of the coating was shown via open circuit potential (-0.10 V ± 0.05 for the superhydrophobic Ti disc and -0.32 V ± 0.01) and impedance. The corrosion potential of superhydrophobic and bare Ti disc was -0.09 V ± 0.03 and -0.52 V ± 0.03, respectively. A total of 26 adsorbed proteins from saliva on both Ti discs were distinguished by the proteomic analysis. Among them, 7 proteins were shared by both Ti discs.

The bare Ti disc displayed a total of 18 proteins whereas the superhydrophobic Ti disc showed a total of 15 proteins, suggesting the differences in surface properties for protein adsorption.

Fibroblast cell proliferation results at 1, 3 and 4 days suggested that the cell viability was not affected by both Ti discs, indicating the biocompatibility of the superhydrophobic Ti disc. Invitro microbiological assay results (polymicrobial, fungal and S. mutans adhesion) and the CLSM images of biofilm on the Ti discs are showed in Figure 9 . CLSM images revealed that a dense polymicrobial biofilm adhesion was noted on the bare Ti disc, whereas very rare and thin microbial colonies were detected on the superhydrophobic Ti disc. Moreover, the biofilm formed on the superhydrophobic Ti disc was more susceptible to the antimicrobial agent chlorhexidine (0.5 %) for 3 h. Total DNA levels of the 40 species on bare and superhydrophobic Ti discs were 130.4 ± 20.3 and 97 ± 68.7, respectively. Particularly, the level of Campylobacter gracilis pathogen (related to peri-implantitis and peri-implant bone loss in human) in the bare Ti disc was ~7-fold higher than the superhydrophobic Ti disc [116] . Reproduced with permission from [113] . Copyrights (2020), American Chemical Society Recently, a 2D graphdiyne assembled TiO 2 nanofibers (TiO 2 /GDY) was coated on Ti implants for bone tissue engineering [117] . GDY, owing to the presence of both sp and sp 2 hybridized carbon atoms, exhibits a large specific surface area with unique electrical conductivity and hole mobility. GDY was also reported for the visible light-driven antimicrobial activity [118] . The antimicrobial (against MRSA biofilm formation) and osteogenic property of TiO 2 /GDY were studied under in-vitro and in-vivo conditions. Plate counting results showed that ~ 98 % MRSA colonies were disinfected by TiO 2 /GDY under UV light irradiation ( Figure S9 (a), and (b) ). The microbial disinfection was not detected for the samples under dark conditions. The ratio of dead to live cells was four times higher for TiO 2 /GDY compared to bare TiO 2 ( Figure S9 (c), and (d)). SEM images revealed that biofilm formation was inhibited by the TiO 2 /GDY + UV, and an intracellular ROSs generation was observed for the TiO 2 /GDY treated bacteria ( Figure S9 (e) ). Fluorescence microscopy results revealed that the ROSs generation was increased with respect to irradiation time ( Figure S9 ROSs generation through extending the lifetime of charge carriers. At the same time, the existence of GDY in the nanocomposite could promote bone tissue regeneration. Hence, the TiO 2 /GDY composite could successfully be used for implant infections due to its sterilization effects and excellent biocompatibility. GDY was also reported for its free radical scavenging effect from long-term radiation-induced damage [119] . However, a significant amount of ROSs was generated by TiO 2 /GDY for the disinfection of microbes. The authors suggested that a small amount of GDY was used in the nanocomposite (around 10 mg of GDY for 200 mg of TiO 2 ) and hence the impact of its free radical scavenging effect was negligible under a short irradiation time. Conversely, the free radical scavenging ability of TiO 2 /GDY could be beneficial for long-term metal implantation with less cytotoxic effects compared to pure TiO 2 .

ROSs formation mechanism and biocompatibility [117] . Reproduced with permission from ref. [117] . Copyrights (2020), Springer Nature

Coating manufacturers have been covering their end-products with industrial coatings for many years, increasing the value of the end-product by conferring them numerous properties (antiscratch, anti-corrosion, anti-fouling, durability, etc). But today manufacturers are facing a major challenge in the form of superbugs, viruses, and multi-drug resistant microbes. Superbugs are developing resistance to the antimicrobials, outpacing the ability of the drug industry to develop new compounds. Thus, strategies are focusing on preventing the deposition and spread of these pathogens in society. Besides threatening health, these pathogens also damage production and infrastructure. Outlined below are some of the global challenges, problems and needs identified:

Antimicrobial resistance refers to the ability of microbes (bacteria, viruses, fungi, parasites) to survive antimicrobial drugs and additives. Although this is a natural phenomenon, modern practices have accelerated it. Antimicrobial resistance is a major constraint and cost for healthcare systems worldwide. 37 

The main foodborne pathogens such as Salmonella, Campylobacter and Escherichia coli already showed resistance in pigs, cattle, and poultry. These superbugs are a threat to our health, the food industry, and our food supply.

 Antimicrobial alternatives to tackle the super-bugs are needed. The pharma industry is overwhelmed as it cannot keep pace with antimicrobial resistance. Microbes always manage to develop resistance.

 Prevention is the best option to address infectious diseases, since treatment is much more expensive.

 Infections need to be caught and fought early. Microbes create biofilms and colonize the surfaces of our infrastructure. These become dense colonies that display x1,000 times more resistance to antibiotics [120] .

The field needs innovative biocidal mechanisms. Most antibiotic drugs or additives target biological traits in the bacteria, which manage to overcome these agents which can result in mutation.

The market requires antimicrobial coatings to protect surfaces from the spread of infections and the ability to mutate.

Contaminated surfaces contribute to the transmission of pathogens such as MRSA,

Escherichia coli, Clostridium difficile, and clinically relevant viruses have been shown to survive on surfaces from hours to over a year [121] . The perpetrator of the most recent pandemic, SARS-CoV-2 has also been reported to survive for up to 28 days at 20 °C on common surfaces such as glass, stainless steel and both paper and polymer banknotes [122] . The impact caused by antimicrobial-resistant (AMR) pathogens is an international health epidemic. Globally it was estimated that 700,000 deaths could be attributed to AMR per annum and the annual toll will climb to 10 million in the next 30 years unless action is taken [123] . From an EU perspective, the death of 33,000 citizens is associated with AMR, resulting in €1.5 billion in healthcare and productivity losses, and equating to losses of US$ 100 trillion in global GDP by 2050 if nothing is done to reverse the trend [124] . However, the recent COVID-19 pandemic is a wakeup call, highlighting the wide-ranging socio-economic impact of such an outbreak [125] .

According to market analysis, the global antimicrobial additives market size was valued at USD 2.6 billion in 2020 and is expected to grow at a compound annual growth rate (CAGR) of 8.4 % to USD 4.3 billion in 2027 [please refer reference S1 in supporting info]. Rapidly expanding end-use sectors due to a growing population and increased urbanisation are likely to escalate the demand for antimicrobial additives over the forecast period. Moreover, continuously rising demand for healthcare and products to tackle the COVID-19 pandemic will positively impact market growth. Asia Pacific is expected to dominate the market as the region has some of the major healthcare product manufacturers.

Despite government and public guidelines, measures such as social distancing, facemasks, and strict hygiene advice, it is extremely challenging to keep every surface continuously sanitized.

Hence, there is a strong global requirement for self-sanitising properties that would neutralize the surface from contaminant pathogens and reduce the risk of possible spread. In 2020, the outbreak of COVID-19 has deeply impacted the global economy, however, the pandemic has a positive impact on the antimicrobial additives and products market. The development, application and use of anti-microbial coatings have quickly become hot topics, with more widespread adoption and The manufacturing sector has an urgent need for visible light activate non-silver containing antimicrobial coatings. This is driven by the highest regulatory standards in healthcare, food industry, construction, electronics, med-tech, pharma, public infrastructure, and home environments. There is a crucial need to prevent the spread of pathogen infections, which are a major concern due to the emergence of resistance and the threat of future pandemics.

TiO 2 antimicrobial agents can be applied through standard dipping, spinning and spraying techniques or applied by chemical vapour deposition, sputtering, and thermal oxidation [38, 126] .

Each technique has advantages and drawbacks in terms of cost, manufacturability, and coating quality. TiO 2 can be applied in the amorphous phase and converted to other polymorphs on the substrate through heating, or it can be deposited in the already photocatalytic phase. The choice of TiO 2 -based antimicrobial formulations will be dependent on the substrates of intended use i.e., hard, or soft surfaces, and whether they are applied at a manufacturing stage, or as an aftermarket 41 solution. The choice between binding agents, and physically sintering the TiO 2 crystals into a surface, such as glass or ceramic, could dramatically affect the durability of the coating.

Commercially pure Ti and Ti-6Al-4V or grade 5 Ti are the most widely used biomedical metal implant. According to the recent data, more than 1000 tonnes of Ti metal have been used for implants in patients every year [127] . Owing to the excellent biocompatibility, more than Raton, Florida, USA)), hydroxyapatite (e.g. TSV-HA ® (Zimmer Biomet, Carlsbad, California, USA)), calcium nanoparticles, and calcium phosphate with discrete crystalline deposition (e.g.

Nanotite ® (Zimmer Biomet, Palm Beach Gardens, Florida, USA)) have been used as ceramic coatings on the Ti dental implants to promote the early bone healing [129] .

Techno-economy on the large-scale production of TiO 2 nanoparticles by the liquidphase synthesis method has been recently analysed [130] . The feasibility was assessed through the engineering analysis (to assess the feasibility of large-scale production using the available technology and inexpensive apparatus) and economic evaluation (to estimate the profitability using the parameters like the payback period, profitability index, gross profit margin, cumulative net-present value, internal rate return, and break-even point). The project estimation was calculated with various parameters such as utilities, sales, raw materials, labour, taxes, and subsidiaries. The results showed the potential profitability of the project for the large-scale production of TiO 2 . Nevertheless, further developments are required to attract investors and to increase the profit in developing countries. Moreover, the studies should also be focused on the synthesis of TiO 2 using bio-degradable raw materials to minimize waste and environmental burden.

Life cycle assessment (LCA) of TiO 2 coatings on residential window glass was examined using the Building of Environmental and Economic Sustainability (BEES) model [131] . The potential impact of TiO 2 on the environmental and economic aspects in a life cycle perspective (raw materials to final disposal) was evaluated [132] . Anatase TiO 2 was synthesised using a sol-gel technology, and the spray coating method was considered for the analysis. The indoor air quality, acidification potential, and smog formation potential of window glass were improved by the TiO 2 coating. The overall environmental score of TiO 2 coated glass was 0.44 43 (with economic score 0.52), whereas that of bare glass was 0.56 (with economic score 0.48),

indicating negative impact of TiO 2 coatings to the environment. In a similar study, the environmental impact of TiO 2 nanoparticles on recycled mortars was examined [133] . Life cycle assessment was focused on the production of materials to evaluate the sustainability of TiO 2 nanoparticles. The findings demonstrated that the addition of 0.5 % of TiO 2 showed a significant reduction in global warming potential (GWP), suggesting the negative impact of TiO 2 to the environment. The incorporation of TiO 2 nanoparticles with recycled aggregates in concretes could also promote the CO 2 uptake [133] . These studies suggest that the utilisation of TiO 2 coatings is beneficial during the whole life cycle.

TiO 2 antimicrobial coatings are one of the promising remedies to disinfect or control the spread of potentially life-threatening pathogens from high-touch, shared surfaces as well as medical devices. Owing to the high surface to volume ratio of TiO 2 as well as the multitude of surface coating techniques, it could be easily applied as a surface coating to destroy the toxic pathogens for the long-term. The technical challenges in antimicrobial surface coatings may offer a plethora of opportunities for the innovation and development in medical devices [134] , sensors [135] [136] [137] , membranes [138] , food packaging [139] , etc.

Stability/durability: The lifespan of TiO 2 antimicrobial coatings entirely relies on the type of application. For instance, the antimicrobial features of high touch surfaces should be considered for at least a year. In the case of surgical or medical devices, the antimicrobial property should be confined to a few hours, whereas for the medical implant the efficacy of TiO 2 must be limited to the necessary period of the body to accept the implant. The stability and durability of the photocatalytic coatings should be regularly monitored to guarantee their efficacy against the pathogens.

Coating methods: Spraying techniques have been primarily utilised to coat TiO 2 on various surfaces. Nevertheless, inkjet printing, and hydrothermal synthesis and liquid phase deposition would be some of the most convenient methods in the future to coat or print TiO 2 materials, as TiO 2 could then be incorporated into bioprinting or onto 3-D printed components, which is gaining popularity as additively manufactured implantable become more commonplace [140] .

Most of the photocatalytic coatings are biocompatible at a particular concentration with a specific coating method, however in-depth cytotoxic analysis should be required to evaluate the safety features of antimicrobial nanomaterials. A recent study suggested that most of the commercially available Ti implants with antimicrobial features have been limited only to orthopaedics. The mechanical durability and antimicrobial property of dental implants may vary as compared to that of orthopaedic 46 implants. Therefore, extensive research efforts should be taken in dental implantology to improve the long-term antimicrobial features of titanium dental implants. should be compared to enrich the activity of coatings. Besides the antioxidative enzymes, the capsular epoxy polysaccharides (EPS) could also safeguard the microbes from the ROSs attack [149] . Extensive studies are required for the in-depth knowledge of microbial disinfection mechanism using cytobiology and genetic technology.

The mechanism for the genotoxicity and cytotoxicity of non-bound TiO 2 particles should be comprehensively studied on various cell lines to investigate any potential toxic effects. Cytotoxicity could be influenced by the shape, size, and crystal structure of TiO 2 .

Reliable toxicokinetic models should be developed to assess the viability of antimicrobial photocatalytic coatings. To validate the safety features of the antimicrobial coatings, the toxic effects of TiO 2 nanoparticles interacting with other compounds should be studied. Compared to chemical approaches, green chemistry would be favourable for the synthesis of metal oxide nanoparticles with low cytotoxicity for long-term antimicrobial applications.

Some of the Ti metal implants might cause allergic symptoms such as irritation, erythema, and inflammation, leading to reactions such as yellow nail syndrome [150] . The release of metal ions into human blood after several months of implant placement has been observed and the binding of these metal ions to biomolecules might cause a severe toxic effect.

The toxicity, bioavailability, and environmental impact of Ti/TiO 2 have been recently reviewed [151] . The report suggested that TiO 2 rarely cause health and environmental problems.

However, the influence of TiO 2 on biodiversity, terrestrial and aquatic ecosystems should be investigated in detail in the future.

There are no comprehensive reports on the antimicrobial efficacy of surgical or laboratory gloves, indicating the negative impact of nanoparticles on the physio-chemical properties of latex. Antimicrobial gloves would be considered as one significant area to explore in the future. In the coming decades, a lot of innovations could ensue on the antimicrobial features of 2D materials such as graphene, MXenes, layered double hydroxides, and graphiticcarbon nitride.

effective technologies to deactivate infectious pathogens with superior efficiency on various surfaces. Herein, the recent advances of the antimicrobial TiO 2 nanocomposite coatings for surfaces, and medical implants have been reviewed.

Cell membrane rupture, leakage of K + ions, the decline of antioxidative enzymes/ATP concentration, and the damage of genome DNA/cytoplasm are the significant steps for the bacteria-killing mechanism. The photocatalytic disinfection of viruses is usually explored via analysing the damage of major building blocks such as RNA and surface proteins. The antimicrobial efficiency of the coatings could be mainly influenced by humidity, temperature, light illumination, and the accessibility of O 2 .

In most of the cases, TiO 2 is doped with metals (e.g., P, F, Cu, Ag, etc) or hybridised with 2D materials (e.g., MXenes, MOFs) to enrich the electron-hole separation process to achieve the maximum disinfection. The antimicrobial activity is mainly influenced through the discrepancy of microbe and coating material surface characteristics (e.g., electrostatic interaction, pH, topology, etc). The reactivation or regrowth of microbes was not spotted on the TiO 2 coatings after the light illumination. The crystalline features of TiO 2 such as facets and oxygen vacancies could be able to impact the yield of ROSs generation during the photocatalysis.

TiO 2 antimicrobial coatings could be utilised in dental and orthopaedic implants owing to its outstanding characteristics. TiO The COVID-19 pandemic situation has created an extra burden on the global health systems to determine the antimicrobial strategies to curtail the spread of coronavirus and other emerging pathogens. TiO 2 surface coating is an impressive technology to deal with health issues caused by life-threatening pathogen infections. TiO 2 surface coatings might be used to prevent the spread of pathogens in high-risk public areas with shared contact surfaces such as train stations, bus stations, airport, schools, colleges, stadiums, hospitals, religious places, supermarkets, theatres, museums, malls, libraries, hotels, bars, swimming pools, etc.

Photocatalytic Nanowires-Based Air Filter: Towards Reusable Protective Masks

Photocatalytic inactivation of airborne bacteria in a polyurethane foam reactor loaded with a hybrid of MXene and anatase TiO 2 exposing {0 0 1} facets

The proximal origin of SARS-CoV-2

SARS-CoV-2 infection in children

Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody

The COVID-19 vaccine development landscape

Developing Covid-19 vaccines at pandemic speed

COVID-19 vaccine development and a potential nanomaterial path forward

Photocatalytic and antifouling properties of electrospun TiO 2 polyacrylonitrile composite nanofibers under visible light

Antimicrobial films of poly (2-aminoethyl methacrylate) and its copolymers doped with TiO 2 and CaCO 3

Inactivation of Human Coronavirus by Titania Nanoparticle Coatings and UVC Radiation: Throwing Light on SARS-CoV-2

Application of a Photocatalyst as an Inactivator of Bovine Coronavirus

Photocatalytic Material Surfaces for SARS

SAND2020-9861. Sandia National Lab.(SNL-CA)

SNL-NM)

Advanced titanium dioxidepolytetrafluorethylene (TiO 2 -PTFE) nanocomposite coatings on stainless steel surfaces with antibacterial and anti-corrosion properties

Antibacterial characteristics of electroless plating Ni-P-TiO 2 coatings

Mechanisms of the enhanced antibacterial effect of Ag-TiO 2 coatings

Reduction of bacterial adhesion on Ag-TiO 2 coatings

Subsurface treatment of TiO 2 nanoparticles for limestone: Prolonged surface photocatalytic biocidal activities

TiO 2 codoped with nitrogen and bismuth: new perspectives to control implant-biofilm-related diseases

Synergistic Antimicrobial Titanium Carbide (MXene) Conjugated with Gold Nanoclusters

Gallium-Carbenicillin Framework Coated Defect-Rich Hollow TiO 2 as a Photocatalyzed Oxidative Stress Amplifier against Complex Infections

Synthesis and application of Ce-doped TiO 2 nanoparticles loaded on activated carbon for ultrasound-assisted adsorption of Basic Red 46 dye

Antimicrobial Nanomaterials and Coatings: Current Mechanisms and Future Perspectives to Control the Spread of Viruses Including SARS-CoV-2

Antimicrobial peptide melimine coating for titanium and its in vivo antibacterial activity in rodent subcutaneous infection models

Percutaneous external fixator pins with bactericidal micron-thin sol-gel films for the prevention of pin tract infection

Molecular toxicity mechanism of nanosilver

Bacteria-surface interactions

A review on basic biology of bacterial biofilm infections and their treatments by nanotechnology-based approaches

Bacterial quorum sensing: its role in virulence and possibilities for its control

Responses of freshwater biofilm formation processes (from colonization to maturity) to anatase and rutile TiO 2 nanoparticles: Effects of nanoparticles aging and transformation

Metal-based nanomaterials in biomedical applications: Antimicrobial activity and cytotoxicity aspects

Efficacy of the reactive oxygen species generated by immobilized TiO 2 in the photocatalytic degradation of diclofenac

Visible-light activation of TiO 2 photocatalysts: Advances in theory and experiments

Mechanism of the OH radical generation in photocatalysis with TiO 2 of different crystalline types

Synthesis of high-temperature stable anatase TiO 2 photocatalyst

Review of the anatase to rutile phase transformation

Enhanced photoelectrochemical performance from rationally designed anatase/rutile TiO 2 heterostructures

Highly efficient F, Cu doped TiO 2 anti-bacterial visible light active photocatalytic coatings to combat hospital-acquired infections

Generation and detection of reactive oxygen species in photocatalysis

Antibacterial and biofilm-preventive photocatalytic activity and mechanisms on P/F-modified TiO 2 coatings

Effect of photocatalysis (TiO 2 /UVA) on the inactivation and inhibition of Pseudomonas aeruginosa virulence factors expression

Bacteriostatic Activity of LLDPE Nanocomposite Embedded with Sol-Gel Synthesized TiO 2 /ZnO Coupled Oxides at Various Ratios

Engineered nanomaterials for antimicrobial applications: A review

Analysis in Rapid Microbial Detection and Identification at the Single Cell Level

Construction of an efficient nonleaching graphene nanocomposites with enhanced contact antibacterial performance

Graphitic carbon nitride (g-C 3 N 4 )-based photocatalysts for water disinfection and microbial control: A review

Fabrication of atomic single layer graphitic-C 3 N 4 and its high performance of photocatalytic disinfection under visible light irradiation

Enhanced visible-light-driven photocatalytic inactivation of Escherichia coli using g-C 3 N 4 /TiO 2 hybrid photocatalyst synthesized using a hydrothermal-calcination approach

Enhanced visible-light-driven photocatalytic bacteria disinfection by g-C 3 N 4 -AgBr

Photocatalytic enhancement for solar disinfection of water: a review

Sunlight-mediated inactivation of health-relevant microorganisms in water: a review of mechanisms and modeling approaches

Red phosphorus: an earthabundant elemental photocatalyst for "green" bacterial inactivation under visible light

Visible-light-driven photocatalytic inactivation of MS2 by metal-free g-C 3 N 4 : Virucidal performance and mechanism

Field performances of nanosized TiO 2 coated limestone for a self-cleaning building surface in an urban environment

Superior disinfection effect of Escherichia coli by hydrothermal synthesized TiO 2 -based composite photocatalyst under LED irradiation: Influence of environmental factors and disinfection mechanism

Photocatalytic activity of N-TiO 2 /O-doped N vacancy g-C 3 N 4 and the intermediates toxicity evaluation under tetracycline hydrochloride and Cr (VI) coexistence environment

Effects of environmental factors on the growth and microcystin production of Microcystis aeruginosa under TiO 2 nanoparticles stress

Detoxification of hydrogen peroxide and expression of catalase genes in Rhodobacter

Adaptation to oxidative stress by Gram-positive bacteria: the redox sensing system HbpS-SenS-SenR from Streptomyces reticuli

Glycine metabolism and anti-oxidative defence mechanisms in Pseudomonas fluorescens

Hydrogenation synthesis of blue TiO 2 for high-performance lithium-ion batteries

Reduced and n-type doped TiO 2 : nature of Ti 3+ species

Gallium-Carbenicillin Framework Coated Defect-Rich Hollow TiO 2 as a Photocatalyzed Oxidative Stress Amplifier against Complex Infections

Sequential release of drugs form a dual-delivery system based on pH-responsive nanofibrous mats towards wound care

Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections

Dual Inhibition of Klebsiella pneumoniae and Pseudomonas aeruginosa Iron Metabolism Using Gallium Porphyrin and Gallium Nitrate

Designing Photocatalytic Nanostructured Antibacterial Surfaces: Why Is Black Silica Better than Black Silicon?

Bactericidal activity of black silicon

Nano-fabrication methods and novel applications of black silicon

Bactericidal Characteristics of Bioinspired Nontoxic and Chemically Stable Disordered Silicon Nanopyramids

High Aspect Ratio Nanostructures Kill Bacteria via Storage and Release of Mechanical Energy

Contact Killing of Gram-Positive and Gram-Negative Bacteria on PDMS Provided with Immobilized Hyperbranched Antibacterial Coatings

The influence of the morphology of 1D TiO 2 nanostructures on photogeneration of reactive oxygen species and enhanced photocatalytic activity

One-step reductive synthesis of Ti3+ self-doped elongated anatase TiO 2 nanowires combined with reduced graphene oxide for adsorbing and degrading waste engine oil

Superhydrophilic and Underwater Superoleophobic Poly(propylene) Nonwoven Coated with TiO 2 by Atomic Layer Deposition

Fabrication of meshes with inverse wettability based on the TiO 2 nanowires for continuous oil/water separation

Effects of Ag doping on the photocatalytic disinfection of E. coli in bioaerosol by Ag-TiO 2 /GF under visible light

One-step preparation of graphenesupported anatase TiO 2 with exposed {001} facets and mechanism of enhanced photocatalytic properties

Preparation and photocatalytic activity of TiO 2 -loaded Ti

C 2 with small interlayer spacing

2D MXenes as co-catalysts in photocatalysis: synthetic methods

Absorption and photocatalytic degradation of VOCs by perfluorinated ionomeric coating with TiO 2 nanopowders for air purification

TiO 2 photocatalyst for removal of volatile organic compounds in gas phase-A review

UV disinfection induces a VBNC state in

Induction of Escherichia coli into a VBNC state through chlorination/chloramination and differences in characteristics of the bacterium between states

Magnetron co-sputtered TiO 2 /SiO 2 /Ag nanocomposite thin coatings inhibiting bacterial adhesion and biofilm formation

Biomimetic hierarchical walnut kernel-like and erythrocytelike mesoporous silica nanomaterials: controllable synthesis and versatile applications

The effect of TiO 2 -SiO 2 nanocomposite on the performance characteristics of leather

Observations of bacterial biofilm on ureteral stent and studies on the distribution of pathogenic bacteria and drug resistance

Self-sterilizing and self-cleaning of silicone catheters coated with TiO 2 photocatalyst thin films: A preclinical work

Plasma membrane is the target of rapid antibacterial action of silver nanoparticles in Escherichia coli and Pseudomonas aeruginosa

The effects of bacteria-nanoparticles interface on the antibacterial activity of green synthesized silver nanoparticles

Evaluation of E. coli inhibition by plain and polymer-coated silver nanoparticles

Interaction of titanium dioxide nanoparticles with influenza virus

Photocatalytic inactivation of influenza virus by titanium dioxide thin film

Improved Photocatalytic Air Cleaner with Decomposition of Aldehyde and Aerosol-Associated Influenza Virus Infectivity in Indoor Air

Photocatalytic decontamination of airborne T2 bacteriophage viruses in a small-size TiO 2 /β-SiC alveolar foam LED reactor

Photocatalytic disinfection performance in virus and virus/bacteria system by Cu-TiO 2 nanofibers under visible light

Review on heterogeneous photocatalytic disinfection of waterborne, airborne, and foodborne viruses: Can we win against pathogenic viruses?

Review on titanium and titanium based alloys as biomaterials for orthopaedic applications

Additive manufacturing of low-cost porous titanium-based composites for biomedical applications: Advantages, challenges and opinion for future development

Scalable fabrication of tunable titanium nanotubes via sonoelectrochemical process for biomedical applications

Three-dimensional printing of metals for biomedical applications

Antibacterial activities and biocompatibilities of Ti-Ag alloys prepared by spark plasma sintering and acid etching

Debridement, antibiotics and implant retention (DAIR) in patients with suspected acute infection after hip or knee arthroplasty-safe, effective and without negative functional impact

Engineered probiotics biofilm enhances osseointegration via immunoregulation and anti-infection

Targeting microbial biofilms: current and prospective therapeutic strategies

Enhancing antibacterial performance and biocompatibility of pure titanium by a two-step electrochemical surface coating

Synthesis, microstructure, anti-corrosion property and biological performances of Mn-incorporated Ca

TiO 2 composite coating fabricated via micro-arc oxidation

Mn-containing titanium surface with favorable osteogenic and antimicrobial functions synthesized by PIII&D

Improving the bioactivity and corrosion resistance properties of electrodeposited hydroxyapatite coating by dual doping of bivalent strontium and manganese ion

Multifunctional Mn-containing titania coatings with enhanced corrosion resistance, osteogenesis and antibacterial activity

Enhancing biological properties of porous coatings through the incorporation of manganese

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

Nanomechanical properties of glucans and associated cell-surface adhesion of Streptococcus mutans probed by atomic force microscopy under in situ conditions

Short-term benefits of the adjunctive use of metronidazole plus amoxicillin in the microbial profile and in the clinical parameters of subjects with generalized aggressive periodontitis

Mechanical non-surgical treatment of peri-implantitis: a single-blinded randomized longitudinal clinical study. II. Microbiological results

Graphdiyne-modified TiO 2 nanofibers with osteoinductive and enhanced photocatalytic antibacterial activities to prevent implant infection

2D graphdiyne oxide serves as a superior new generation of antibacterial agents

Graphdiyne nanoparticles with high free radical scavenging activity for radiation protection

Inhibiting bacterial cooperation is an evolutionarily robust antibiofilm strategy

How long do nosocomial pathogens persist on inanimate surfaces? A systematic review

The effect of temperature on persistence of SARS-CoV-2 on common surfaces

United Nations meeting on antimicrobial resistance, World Health Organization

Fact sheets on sustainable development goals: health targets

The socio-economic implications of the coronavirus pandemic (COVID-19): A review

Thick titanium dioxide films for semiconductor photocatalysis

Titanium for medical and dental applications-An introduction, Titanium in Medical and Dental Applications

Antimicrobial coated implants in trauma and orthopaedics-A clinical review and risk-benefit analysis

Achievements in the topographic design of commercial titanium dental implants: towards anti-peri-implantitis surfaces

Techno-Economic Analysis for The Production of Titanium Dioxide Nanoparticle Produced by Liquid-Phase Synthesis Method

Life cycle assessment of nano-sized titanium dioxide coating on residential windows

Development of comparative toxicity potentials of TiO 2 nanoparticles for use in life cycle assessment

TiO 2 nanoparticles influence on the environmental performance of natural and recycled mortars: A life cycle assessment

Effect of Anodized TiO 2 -Nb 2 O 5 -ZrO 2

Nanotubes with Different Nanoscale Dimensions on the Biocompatibility of a Ti35Zr28Nb Alloy

A novel antimicrobial electrochemical glucose biosensor based on silver-Prussian blue-modified TiO 2 nanotube arrays

Nanostructured titanium oxide hybrids-based electrochemical biosensors for healthcare applications

Sensors based on ruthenium-doped TiO 2 nanoparticles loaded into multi-walled carbon nanotubes for the detection of flufenamic acid and mefenamic acid

Photocatalytic and antimicrobial multifunctional nanocomposite membranes for emerging pollutants water treatment applications

nanoparticle/Cymbopogon citratus essential oil film as food packaging material: Physico-mechanical properties and its effects on microbial, chemical, and organoleptic quality of minced meat during refrigeration

Low-temperature fabrication of titania layer on 3D-printed 316L stainless steel for enhancing biocompatibility

High frequency of silver resistance genes in invasive isolates of Enterobacter and Klebsiella species

Will coronavirus disease (COVID-19) have an impact on antimicrobial resistance?

The Novel Coronavirus COVID-19 Outbreak: Global Implications for Antimicrobial Resistance

SARS-CoV-2, bacterial co-infections, and AMR: the deadly trio in COVID-19?

A nosocomial cluster of vancomycin resistant enterococci among COVID-19 patients in an intensive care unit

Emerging co-pathogens: New Delhi Metallo-betalactamase producing Enterobacterales infections in New York City COVID-19 patients

Antimicrobial Stewardship Program, COVID-19, and Infection Control: Spread of Carbapenem-Resistant Klebsiella Pneumoniae Colonization in ICU COVID-19 Patients. What Did Not Work?

Fouling and inactivation of titanium dioxide-based photocatalytic systems

Dual roles of capsular extracellular polymeric substances in photocatalytic inactivation of Escherichia coli: comparison of E. coli BW25113 and isogenic mutants

General review of titanium toxicity

Are Titania Photocatalysts and Titanium Implants Safe? Review on the Toxicity of Titanium Compounds

The authors (VK, SM, JB and SCP) would like to thank the European Union