Various Biomaterials and Techniques for Improving Antibacterial

May 30, 2018 - The present article reviews various techniques such as modification in surface chemistry/composition and tailored structures (micro to ...
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Various Biomaterials and Techniques for Improving Antibacterial Response Angaraj Singh, and ASHUTOSH KUMAR DUBEY ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.8b00033 • Publication Date (Web): 30 May 2018 Downloaded from http://pubs.acs.org on May 30, 2018

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Various Biomaterials and Techniques for Improving Antibacterial Response Angaraj Singh and Ashutosh Kumar Dubey* Department of Ceramic Engineering, Indian Institute of Technology (BHU), Varanasi-221005, Uttar Pradesh, India Abstract Majority of failures in prosthetic implants and devices are caused by infections. Microbial infections are one of the major causes of these failures. The present article reviews various techniques such as, modification in surface chemistry/composition and tailored structures (micro to nano) for improving the antibacterial response of prosthetic implants. In addition, the application of external stimulants such as magnetic and electric fields, as well as polarization is recently realized as a fairly appealing approach to diminish the bacterial population. A comprehensive response of surface modifications as well as external stimuli in inducing the antibacterial response in prosthetic implants has also been summarized. The mechanisms for the antibacterial response due to these modifications, such as generation of toxic metal ions by dissolution of their respective oxides, and production of reactive oxygen species (ROS) such as, singlet oxygen, hydroxyl radicals (OH-), hydrogen peroxide (H2O2), superoxide’s, peroxides (O2-2), etc., have been elaborately discussed. Key words: Hydroxyapatite, Polarization, Magnetic field, Electric filed, Antibacterial response.

*Corresponding author: A. K. Dubey ([email protected])

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Table of contents

1. Introduction 2. Antibacterial response of tailored bio-materials 2.1

Antibacterial Response of HA- Ag Bio-composites

2.2

Antibacterial Response of TiO2 based Bio-composites

2.3

Antibacterial Response of ZnO based Bio-composites

2.4

Antibacterial Response due to Metal Ions

3. Effect of Nanostructured Materials on Antibacterial Response 3.1

Antibacterial Response of Zinc Oxide (ZnO) Nanoparticles

3.2

Antibacterial Response of Silver (Ag) Nanoparticles

3.3

Antibacterial Response of Copper and Copper oxide Nanoparticles

3.4

Antibacterial Response of Iron Oxide Nanoparticles

3.5

Antibacterial Response of Magnesium Oxide (MgO) Nanoparticles

3.6

Antibacterial Response of Gold (Au) Nanoparticles

4. Effect of External Stimuli on Antibacterial Response 4.1

Effect of Magnetic Field

4.2

Effect of Electrical Stimuli

4.3

Effect of Surface Charge (Polarization)

5. Challenges and Future Perspectives 6. Closure 7. References

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1. Introduction Bacteria are recognized as one of the major causes of serious infectious diseases since early 1800s.1 In recent years, bacterial infections in biomedical implants and devices are one of the growing problems that lead to the failure of implants and promote the chances of revision surgery.2,3 These bacterial infections initiate on the material surfaces with the growth of biofilm. Although, both gram positive and gram negative bacteria are responsible for the microbial infection, maximum infection (~ 65%) is caused due to gram-positive cocci.4 Gram-positive cocci include coagulase-negative staphylococci, staphylococcus aureus, streptococcus species and enterococcus species. However, aerobic gram-negative cocci include enterobacteriaceae and pseudomonas aerugenosa. Fig. 1 summarizes the microbes that cause infections in hip and knee prosthetic implants.5 Commonly used orthopedic implant materials such as, stainless steel, cobalt-chromium, gold, silver, titanium and its alloys, zinc oxide, magnesium oxide, hydroxyapatite, bio-glass, tricalcium phosphate, polyethylene, polyamide polymethylmethacrylate etc., are susceptible towards microbial infections.6,7 In 20th century, application of antibiotics started that provides temporary relief at the infected site.8,9 Few naturally occurring materials such as silver, gold etc., oxides such as zinc oxide, titanium oxide, magnesium oxide etc., are used as additives in bio-composites that shows antibacterial response.10 To overcome these infections effectively, various techniques such as, modifications in surface chemistry, the compositional variation of prosthetic implants as well as the application of external stimulants are in continuous thrust. The adhesion of bacteria with biomaterial surfaces can take place via hydrophobic and electrostatic interaction as well as Vander Waals forces.11 Bacterial cells acquire charge (usually negative) on their surface due to the ionization of proton-active functional groups such as, carboxyl, phosphate, amino and hydroxyl groups. Gram-negative bacteria possess more negative charge as

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compared to gram-positive bacteria.12 Basically, there are three methods to determine the surface charge in bacterial cells: (1) Particulate micro-electrophoresis, (2) Proton Tritation and (3) Dielectric Spectroscopy. The particulate micro-electrophoresis method is frequently used to determine the electrokinetic potential (zeta potential) and charge on bacterial cells.13 Nanotechnology is one of the prospective approaches which can be effectively utilized to address this issue.14,15 In recent years, applications of magnetic and electric fields are evolved as potentially appealing techniques for reducing the bacterial population without affecting the surface chemistry of implants.16 The external stimuli induced antibacterial response depends upon the field parameters such as, intensity, exposure time, and frequency/ pulse duration etc.17,18 The combined effect of both, surface modifications as well as external stimuli on antibacterial response has also been evaluated.19,20 The antibacterial agents target bacterial cell genome, cell respiration, cell division, metabolic pathways and membrane disruptors to kill the bacteria.21 Fig. 2 summarizes various mechanisms that lead to death of bacterial cells.21 This article summarizes the recent advancements, made for improving antibacterial response of prosthetic implant materials, which includes, compositional modifications, surface chemistry alteration as well as the application of properly tuned external stimuli (electric and magnetic fields).Further, the fundamental mechanisms, inducing antibacterial response due to these treatments have been summarized. As a step ahead, the recent addition to address the issue of microbial infections by electrical polarization of biomaterial surfaces has also been presented. 2. Antimicrobial Response of Tailored Bio-composites In last few decades, bio-ceramic composites are widely used for orthopedic implant applications, among which hydroxyapatite (HA) and HA-based composites are the appealing choices due to their reasonable bioactivity as well as chemical resemblance with natural bone.22,23,24 Despite of having excellent biocompatibility, HA allows bacterial growth on it’s surface, which increases

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the possible risk of infection during/after implantation. 25 The number of antibacterial agents, such as Au, ZnO, Ag, TiO2 etc. have been suggested to incorporate in HA matrix to develop HAbased antibacterial implants.26,27 The antibacterial response for both gram-positive as well as gram-negative bacteria can be realized in terms of colony forming unit (CFU),28 diameter of inhibition zone (area around biomaterial substrate that allows no bacterial growth29) and cell viability etc. 2.1 Antibacterial Response of HA-Ag Bio-composites Silver possesses an inherent antibacterial property which is being used as an antibacterial agent in form of ions and compounds etc., since archaic time.30,31 The antibacterial response of HA–Ag bio-composites depends on Ag content in the composite against both, gram-positive and gramnegative bacteria.32,33 Ag concentration of 10, 50, and 100 µg/cm3 in HA have demonstrated to inhibit the growth of E.coli bacteria by 62 %, 88 %, and 100 % for, respectively, after 24 hours of incubation. 34 Table 1 summarizes the antibacterial response of various HA-based biocomposites against both, gram-positive and gram-negative bacteria.26,34,35,36,37,38,39,40,41,42,62 There are two main mechanisms, responsible for the antibacterial activity of Ag. One of them is the formation of Ag+ ions by its oxidation, which is considered to be highly reactive with bacteria. These ions can bind to DNA, RNA and proteins in bacterial cells and inhibit their growth. Ag+ ions also lead to structural changes in bacteria and consequently, the cell distortion.43 The other mechanism, responsible for antibacterial activity of silver-based composite is the formation of reactive oxygen species (ROS), which includes free radicals such as superoxide’s, hydroxyl radicals, hydrogen peroxide radicals etc.44 Fig. 3 demonstrates consequences of the interaction of silver ions with the cell wall.

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2.2 Antibacterial Response of TiO2 based Bio-composites TiO2 is a non-toxic metal oxide, primarily used as photo catalyst.45 TiO2 based bio-composites are also used in biomedical implants due to their reasonable biocompatibility and chemical stability.46 In presence of visible light, TiO2 oxidizes to produce free radicals [hydrogen peroxide (H2O2), superoxide’s, peroxides (O2-2), hydroxyl radicals(OH-)] which demonstrate antibacterial response.47 Due to this effect, TiO2 based bio-composites are used as antibacterial agent. The coating of chitosan and carbon nano tubes (CNTs) on Ti implant has been reported to improve the antibacterial response by 8 % and 39 % against E.coli and S.aureus bacteria, respectively, after incubation of 12 hours. CNTs also increase the oxidative stresses which inhibit the bacterial response.48 The addition of 60 wt. % TiO2 in HA makes the composite antibacterial against both, grampositive and gram-negative bacteria, where the diameter of inhibition zone has been obtained to be 21 and 14.5 mm for S. aureus and E. coli bacteria, respectively after incubation of 24 hours in growth medium.49 Azimzadehirani et al.50 reported that AgCl/TiO2 composite reduces CFU/ml by 99.97 % for B. subtilis bacteria on exposure to visible light for 3 hours. However, no reduction in cell viability against P. aerugenosa bacteria was reported, rather biofilm formation has been reduced by 57% for the same substrate and similar exposure conditions (Table 1). The antibacterial response of TiO2 based bio-composites is due to the formation of free radicals (superoxide’s, hydroxyl radicals, hydrogen peroxide radicals etc.)51 In general, TiO2 shows photo-catalytic behavior under UV light, however, surface modification of TiO2 (with iodine, dopamine, and chitosan etc.) improves it’s visible absorbance as well as antibacterial response.52,53,54 In presence of visible light, TiO2 surface, irradiated by photon energy, produces electron (e-) and hole (h+) pairs at conduction and valence bands, respectively [eq. (1)]. The generated electrons and holes have strong oxidizing power.

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These electrons and holes can recombine and produce ROS (superoxide radicals, hydroxyl radicals, and hydrogen peroxide), as shown in equations (2) and (3), that kill bacterial cells.55

TiO2 + hν → e− + h+

O2 + e− → O− 2

(1)

(2)

H2 O + h+ → (OH)− + h+

(3)

Ti generates singlet oxygen molecules in the absence of visible light which is one of the possible mechanisms for antibacterial response.56 Fig. 4 schematically represents the mechanisms responsible for the antibacterial activity of TiO2 based bio-composites.57 2.3 Antibacterial Response of ZnO based Bio-composites In general, few of the metal oxides such as, ZnO, MgO, TiO2 and iron oxide illustrate antibacterial effect.58 There are number of reports suggesting that the antibacterial response of ZnO based bio-composites depends on ZnO content in the composite and exposure period against both, gram-positive and gram-negative bacteria.59,60, 61 It has been demonstrated that the number of bacterial colonies reduced by 13 % to 50.45 % for ZnO content of 1.5 % to 30 wt. % in HA-ZnO bio-composite against E. coli bacteria after incubation of 4 hours in growth medium. However, the incubation of 24 hours leads to the reduction in bacterial colonies by 26 % to 60 % for similar material composition and bacteria.62 Grenho et al.63 reported that the biofilm formation for HA- 25 wt. % ZnO composite reduces by 98 % and 99 % for S. aureus and E. coli bacteria, respectively. The antibacterial response of carboxymethyl chitosan (CMCh) super molecular hydrogels cross-linked by zinc ions (Zn2+) increases with increasing the Zn2+content in the hydrogel against S.aureus and E.coli bacteria. The diameter of inhibition zone for CMCh-Zn2+ super mo-

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lecular hydrogel has been demonstrated to increase by 118 % and 120 % for S. aureus and E. coli bacteria, respectively, when Zn2+ content increases from 0.65 mg/ml to 3.90 mg/ml.64 The antimicrobial response of ZnO based bio-composites are due to the formation of reactive oxygen species (ROS), and release of Zn2+ ions.65 ROS are more toxic to gram-negative bacteria while Zn2+ ions are responsible for the killing of gram-positive bacteria.66 Distortion of the bacterial cell wall is a toxic phenomenon which occurs for two reasons. One of them is due to the reaction of ROS with the lipid layer of the cell wall (for gram-negative bacteria), which destroy cell wall structure and consequently, the death of bacterial cells.67 Another reason for cell wall distortion is due to the release of Zn+2 ions in the growth media, as mentioned above. These Zn2+ions diffuse in the cell walls (for gram-positive bacteria) and disrupt the amino acid metabolism and enzymes which leads to cell death.68,69,70 Fig.5 illustrate schematically the mechanisms, responsible for the antibacterial response of ZnO bio-composites.71 2.4 Antibacterial Response due to Metal Ions Number of metallic elements (e.g., Au, Ag, Zn etc.) have been used as an antibacterial agent since ancient time.72,73 These antibacterial metallic elements/ions are being used as additives in the ceramic and polymeric matrix to improve the antibacterial activity of developed biocomposites.74 It has been demonstrated that the antibacterial response of composites, containing these metals depends on the concentration of metal ions.75,76 Ag ion at a concentration of 0.2 ppm in the growth media decreases CFU/ml by 99.96 % for S. aureus bacteria after 30 minutes of incubation.77 The minimum bactericidal concentrations (MBCs) of Ag+, Zn2+ ions for killing 99 % of S. aureus and E. coli bacteria were reported to be 0.25 µM, 10 µM, respectively. However, for similar killing efficiency, the MBCs of Cu2+ ions have been reported to 10 µM and 25 µM for

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S.aureus and E.coli bacteria, respectively.78 The mechanisms of membrane damage by metal ions are illustrated schematically in Fig. 6.79 Metal ions (e.g., Cu2+, Mg2+, Zn2+, Ag+, and Fe2+ etc.) are released by dissolution of metals in growth media.80 It has been reported that Cu

2+

shows nontoxic nature under controlled condi-

tions and highly effective for bacteria killing.81 These metal ions interact with the bacterial cell membrane and penetrate the cell wall which damages it by creating pits and holes.82 These pits and holes stop the transport of electron chain which helps in regulating the proteins, carbohydrates, fat and energy metabolisms. This results in the loss of proteins and DNA and consequently, leads to the bacterial cell death.83 In another study, it has been reported that Ag+, Zn2+ and Cu2+ ions produce ROS (by fanton reaction) which increases the oxidative stress and damage the cell membranes.84,85 3. Effect of Nanostructured Materials on Antibacterial Response Nanoparticles have different properties than their respective counter bulk materials, such as, higher surface area, catalytic activity, dissolution rate etc.86 The antibacterial response of Fe, TiO2, and ZnO etc. nanoparticles improves with the reduction in their respective particle sizes due to increase in specific surface area.87 For example, iron oxide nanoparticles show antibacterial activity whereas such response in its bulk counterpart is not observed.88 It has been reported that generation of H2O2 depends upon the specific surface area, that increases the oxidative stresses which kill the bacterial cells.58 In fact, nanoscale size reduction of inherent antibacterial materials, such as Ag, also increases antibacterial response significantly as compared to their bulk counterpart.89

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3.1 Antibacterial Response of Zinc Oxide (ZnO) Nanoparticles Zinc (Zn), as well as its alloys, composites, and oxides, have been used in biomedical fields for bio-sensing, imaging, drug delivery and bio-implant applications.90 Zn containing nano-materials exhibits excellent antibacterial properties.91 The antibacterial activity of ZnO nanoparticles is suggested to be majorly influenced by the particle sizes, even in nano-size range. In addition to particle size, exposure duration, as well as concentration of ZnO in the solution is crucial factor for its antibacterial response (Table 2). Raghupati et al.92 reported that antibacterial activity of S.aureus depends upon the size of nanoparticles. It has been demonstrated that the exposure of E. coli with ZnO nanoparticles (~40 nm) for 24 hours with a concentration of 0.8 µl/ml reduces the bacterial colony by 86 %.93 However, the decrease in bacterial colonies for K. pneumonia has been reported to be 75.38 % at the concentration of 0.75 mM for similar material and incubation period.94 The antibacterial efficiency of Ti-ZnO nanorodes against S. aureus and E. coli bacteria has been reported to be 65.5 % and 55.4 %, respectively after incubation of 12 hours. However, for hybrid ZnO/polydopamine (PDA) / arginine-glycine-aspartic acid crystine (RGDC) nanorodes, it has been reported to be 72.2 % and 74.7 %, respectively, against similar bacteria and incubation condition.95 The release of zinc ions, owing to the dissolution of ZnO as well as and formation of ROS are the suggested mechanisms, responsible for the antibacterial activity of ZnO nanoparticles. 96 Nanosized ZnO particulates penetrate the cell wall easily and produce comparatively higher amount of ROS than that of bulk-sized ZnO.97 Fig. 7 (a) summarizes the possible means for improving the antibacterial response due to ZnO nanoparticles and Fig. 7 (b) illustrates the mechanisms, responsible for the antibacterial response of ZnO nanoparticles.98 Sirelkhatim et al.98 reported that defects present in nanoparticles are also responsible for increasing the antibacterial response. Point defects in nanoparticles increase the abrasive nature of its

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surface that injured the bacterial cells/membranes. However, surface defects, produced by the partial dissolution of nanosized ZnO in water, results in an uneven surface texture that damage the bacterial cells.99 In another study, it has been demonstrated that physical interaction of ZnO nanoparticles with the bacterial cells also play an important role in bactericidal effects. The strong electrostatic interaction takes place between bacterial cell surface (negative charge) and Zn2+ ions. As a result, ZnO nanoparticles (≤ 10 nm) collect at the outer layer of plasma membranes and neutralize the surface charge of bacterial cells.68 This leads to increase in surface tension, membrane permeability, change in membrane texture, morphology, and generation of oxidative stress which results in bacterial cell death.68 ZnO nanoparticles (≤ 10 nm) passage through the cytoplasm membrane and accumulate inside bacterial cells (via particle internalization) which damages the intercellular constituents, including nucleic acids etc.100,101 3.2 Antibacterial Response of Silver (Ag) Nanoparticles Silver is used as an antibacterial agent since ancient time due to its inherent antibiotic properties.9 In recent years, silver nanoparticles have been reintroduced as a quite appealing choice for the development of new generation bactericidal material.102 The nano-structured form of silver improves the antibacterial properties as compared to its bulk counterpart.103 In addition to particle size, the antibacterial response of Ag nanoparticles depends upon the shaped as well as the concentration of Ag in the growth medium and exposure time.104,105 Triangular shaped Ag nanoparticles show the better antibacterial response (as compared to other shapes) even at low concentrations.106 The growth of E. coli bacteria has been suggested to inhibit by 70 % and 100 %, respectively, after 24 hours of exposure to Ag nanoparticles (~12nm) with the concentration of 10µg/cm3 and 60µg/cm3 in Luria-Bertina growth media.107 However, the growth of S. aueus bacteria is restricted completely for Ag nanoparticles with concentration of 100 µg/ml.108 It has also been demon-

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strated that few composites of silver nanoparticles (graphene oxide/silver nanoparticles, and AgCl/ZnO) shows antibacterial response due to photodynamic effect. The antibacterial efficiency of graphene oxide and silver nanoparticles composite has been reported to be 96.3 % and 99.4 % against E.coli and S.aureus bacteria, respectively, when exposed to visible light of wavelength 660 nm.109 The antibacterial responses of nanoparticles against various pathogens are summarized in Table 2.66,88,107,,110,111,112,113,114,115,116,117,118,119,120,140 The mechanism for the antibacterial response of Ag nanoparticles is very complicated. Catalina et al.121 proposed three mechanisms, for the antibacterial response of Ag nanoparticles. (i) The release of silver ions that disrupts ATP production and DNA replication. (ii) Formation of reactive oxygen species (ROS), and (iii) Direct damage of cell membrane by silver nanoparticles due to its inherent antibacterial property. Silver nanoparticles interact with bacterial cells and penetrate inside (particle internalization) through pits and holes which disrupt the cell walls [Fig. 8 (a and b)].98 It has been hypothesized that Ag+ ions are released by dissolving silver nanoparticles in growth media.122

Choi et al.123 reported that silver nanoparticles oxidize in presence of oxygen and release silver ions as well as produce hydroxyl radicals. These silver ions interact with peptidoglycan layer in the bacterial membrane and consequently, disrupt the cell metabolic processes. This mechanism is dominated in case of gram-positive bacteria, owing to their thick peptidoglycan layers as compared to gram-negative bacteria.124 In addition, the formation of ROS is also lead to the death of bacterial cells.125 Fig. 8 (c and d) represents the schematic diagrams of mechanisms, responsible for the generation of Ag ions and ROS that produces bactericidal effect.98

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3.3 Antibacterial Response of Copper and Copper oxide Nanoparticles Copper and its oxides have also been used as antibacterial materials since ancient time.126 Nanosized Cu and CuO attracted attention in last few decades due to better antibacterial response as compared to it's bulk counterpart. However, the application of Cu nanoparticles is limited due to its rapid oxidation during air exposure.127 It has been suggested that the size of inhibition zone depends on the concentration of Cu in growth media for both, gram-positive and gram-negative bacteria.128 The diameter of inhibition zone has been obtained to be 23 mm and 18 mm for Cu nanoparticles (~20 nm) with concentrations of 0.22 mg/L and 0.29 mg/L against E. coli and S. aureus bacteria, respectively, after incubation of 24 hours.129 Similarly, the diameter of inhibition zone for Cu nanoparticles (~ 20 nm) increases by 48 % against E.coli bacteria after incubation of 12 hours.130 Lu et al.131 demonstrated in vivo that Cu containing carboxyl methyl chitosan (CMC) alginate (Alg) scaffolds (i.e., CMC/Alg/Cu) shows better antibacterial response against S.aureus bacteria as compared to mere carboxyl methyl chitosan alginate (CMC/Alg). Table 2 summarizes the antibacterial response of CuO nanoparticles against various pathogens. It is assumed that Cu ions produced by Cu nanoparticles interact with sulfydryl groups that destroy the bacterial cells, enzymes and proteins. The interaction of bacterial cells with Cu nanoparticles affects the membrane integrity due to decrease in transmembrane potential.132 Nanostructured CuO produces more Cu+ ions and ROS as compared to its bulk form. Generally, metal-based nanoparticles generate metal ions via dissolution. Produced Cu ions come into contact with the bacterial cell membrane and produce oxidative stresses which damage the cell membrane and proteins.133 The antibacterial response of CuO nanoparticles depends upon the concentration of CuO nano crystals.134 ROS production starts with the reduction of O2 and synthesis of sulphoxide anion. ROS interact with the cellular membranes that lead to the damage of DNA,

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enzymes and other proteins.135,136 Aruoja et al.137 suggested that CuO nanoparticles are more toxic than bulk CuO due to the solubility of CuO nanoparticles and release of Cu ions. Fig. 9 demonstrates the mechanisms responsible for antibacterial response of Cu nanoparticles.132 3.4 Antibacterial Response of Iron Oxide Nanoparticles Iron oxide has attracted attention in biomedical field due to its antibacterial properties.138 The antibacterial response of iron oxide nanoparticles also depends upon the particle size, concentration of iron oxide in growth media as well as exposure time.139 It has been demonstrated that the size of inhibition zone increased by 61.53 %, 60.17 % and 55.17 % for E. coli, P. aerugenosa, and S. aureus bacteria, respectively while increasing the concentration of iron oxidenanoparticles (~10 nm) from 0.01 to 0.15 mg/ml in growth media, after incubation of 24 hours.140 However, the size of inhibition zone has increased by 21.42 % and 29.41% against E.coli and S. Aureus bacteria, respectively when standard antibiotics neomycin (30 µg/disc) was used with iron oxide nanoparticles (~66 nm and concentration 50 mg/ml) and incubated for 24 hours.141 The CFU of S. aureus bacteria for porous iron-carboxylate metal-organic framework [MOF-53(Fe)] nanoparticles decreases by 16.26 % for concentration of [MOF-53(Fe)] Fe ions of 87.5 % and incubation for 24 hours. 142 The antibacterial response of iron-oxide nanoparticles with various pathogens are summarized in Table 2. The mechanisms responsible for the antibacterial response of iron oxide nanoparticles are similar to other metal oxides such as ZnO, TiO2 and CuO etc.143 However, the primary cause of antibacterial response of iron oxide is oxidative stresses, produces via the formation of ROS which includes superoxide’s, hydroxyl radicals, hydrogen peroxide and singlet oxygen molecules. ROS can be generated by Fenton reaction.144

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Produced ROS is toxic in nature which damages the proteins and DNA in bacteria.145 Fig. 10 demonstrates the mechanisms, for the antibacterial response of iron oxide.146 3.5 Antibacterial Response of Magnesium Oxide (MgO) Nanoparticles Magnesium (Mg) is a quite appealing biodegradable implant.147 Magnesium oxide has been used as catalyst for ceramic synthesis.148 However, nano-structured MgO exhibit anti-oxidative and anti-inflammatory properties, due to which, it is potentially used as antibacterial agent. 149 In general, nano-sized inorganic metal oxides have potential to kill bacteria because they react with intracellular oxygen and produce ROS.150 The antibacterial response of MgO nanoparticles depends upon the annealing temperature, concentration of MgO and incubation time.151 It has been reported that viability of E. coli bacteria decreases by 83 % and 95 % with the exposure of MgO nanoparticles (~8 nm) for 1 and 4 hours, respectively. Similarly, for S. aureus bacteria, it has been reduced by 82 % and 99.9 %, respectively for the similar particles and exposure conditions.152 The antibacterial efficiency of Mg alloy (AZ 31) doped with Silver nanoparticles and polymethyltrimethoxysilane (PMTMS) against S. aureus bacteria increases by 85%, after incubation of 16 hours. However, it is increased by 98.40 % for silver nanoparticles dipped in Polyethylenimine (PEI) solution for similar bacteria and incubation condition.153 Sundrarajan et al.154 reported that diameter of inhibition zone for nano-structured MgO samples decreases with increasing the annealing temperature. The maximum size of inhibition zone has been found to be 23 and 21 mm against S. aureus and E.coli bacteria, respectively, when MgO nanoparticles (~4.6 nm) were annealed at 300 °C. However, annealing of MgO nanoparticles (~ 13.3 nm) at 700 °C results in the size of inhibition zone to be 19 and 17 mm, respectively, against similar bacteria (Table 2). Despite of a number of proposed mechanisms, the exact mechanism responsible for the antibacterial response of MgO nanoparticles is still unclear.155 It has been hypothesized that oxidation

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and reduction reactions occur at the surface of MgO nanoparticles which produce ROS.156 Peter et al.157 suggested that antibacterial response of MgO nanoparticles is due to the presence of defects (oxygen vacancies) on the surface of nanoparticles. MgO nanoparticles hydrated to form Mg(OH)2 at the surface that leads to the generation of electrons and holes. The oxygen molecules present on the surface react with electrons and produce superoxide’s which leads to the destruction of cells. Due to hygroscopic nature, MgO nanoparticles absorb moisture and form a thin water layer around it. The local pH of this thin layer is higher than its equilibrium value in the growth media. When nanoparticles come in contact with bacterial cells, the higher value of pH damage the membrane which results in cell death.158,159 Therefore, MgO nanoparticles induced pH variation of the growth media is also one of the possible reasons for the antibacterial response of MgO. Fig. 11(a and b) illustrates the proposed mechanisms responsible for the antibacterial response of MgO nanoparticles.160 3.6 Antibacterial Response of Gold (Au) Nanoparticles Gold nanoparticles have widely applied in biomedical applications such as imaging, gene therapy, water remediation, and drug delivery etc. Au nanoparticles are also used as an antibacterial agent due to its photo thermal and optical properties.161 The size of inhibition zone increases by 33.33 %, and 29.31 % against S. aureus and E. coli bacteria, respectively, for Au nanoparticles with the concentration of 50 µg/ml in media after incubation of 24 hours. However, size of inhibition zone decreases by 29.41 % against Basilus subtilus bacteria with the concentration of 75 µg/ml for similar particles and exposure time.162 Table 2 summarizes the antibacterial response of gold nanoparticles with various bacterial cells. There are basically two mechanisms, which are responsible for the antibacterial activity of Au nanoparticles. One of them is by collapsing the membrane potential that inhibits ATPase activity and secondly by inhibiting the subunit of ribosome for tRNA binding.163 In contrast to the earlier

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discussed antibacterial agents, Au nanoparticles showed ROS independent antibacterial response.164 Fig. 12 represents the mechanisms for antibacterial response of Au nanoparticles.163 The ATP level decreases by down-regulation of subunits of F-Type ATP synthesis, which disrupts the metabolic activities of bacteria and consequently, diminishes bacterial growth.165 Au nanoparticles interact with the ribosomal proteins and prevent the subunit of the ribosome to bind with tRNA that leads to the collapse of the biological system by releasing the 4, 6diaminopyrimidine thiol which affects the synthesis of protein.166 4. Effect of External Stimuli on Antibacterial Response In recent years, electric and magnetic fields are being recognized as potential means for controlling the bacterial infection in prosthetic implants.167 The external stimuli improve the antibacterial properties of bio-materials e.g. HA, etc., which is restricted for direct use in prosthetic implants due to lack of antibacterial properties.168 The external stimuli also reduce the use of antibiotics.169 Recently application of electric current pulsed electric field, magnetic field and as well as polarization is recognizes for controlling the biofilm formations and bacterial adhesion to the implant surfaces.170 4.1 Effect of Magnetic Field In biomedical field, the influence of magnetic field on various processes such as, cancer therapy, drug delivery, antimicrobial agent etc., has been studied. 171 The growth rate of both grampositive and gram-negative bacteria depends upon the magnetic field intensity as well as exposure time.172 It has been demonstrated that low-intensity DC magnetic field (2.7-10mT) is not bacteriostatic on gram-negative E. coli bacteria.172 However, the growth of S.aureus bacteria decreases with the exposure to low-intensity DC magnetic field (0.1-0.3 mT).173 In case of E. coli bacteria, the number of CFU decreases by 57 %, 68 %, and 76 % for 24 hours exposure to static magnetic field strengths of 30, 50 and 80 mT, respectively. However, similar treatment (magnet-

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ic field and exposure time) for S.aureus bacteria reduces the CFU by 18 %, 32.47 %, and 61.73 %, respectively. In contrast, the growth rate of Bacillus subtilis bacteria increases by 72 %, 75%, and 81%, respectively, after exposure to similar magnetic field intensity and time duration.174 Table 3 summarizes the antibacterial activity for both, gram positive and gram negative bacterial cells under the exposure of magnetic field with varying intensity and exposure period.172,175,176,177,178,179,180,181 It has been reported that inhomogeneous (5.2~6.0 T and 3.2~6.7 T) magnetic field is more effective than homogeneous (7 T) magnetic field, as for as the viability of E.coli cells in the magnetic field is concerned.182 The viability of bacterial cells decreases by 60 % and 70 % for S.aureus and E.coli bacteria, respectively after exposure to the pulsed magnetic field of 4 T for 30 mS.183 Almost similar effect has been reported for exposure to the static magnetic field on antibacterial response while both, gram-positive and gram-negative bacteria were cultured on various bioceramics surfaces. The viability of both, gram positive and gram negative bacteria, adhered on the surfaces of HA and HA-Fe3O4 composites, decreases with increasing the duration of exposure (0.5-4 hours) in the magnetic field (100 mT) as well as the Fe3O4 content in the biocomposites.184 Table 4 summarizes the antibacterial response of external stimulant, while bacteria are adhered on various biomaterial substrates.184,185,19,205,220,222 There are basically two mechanisms, which are responsible for antibacterial activity due to the application of external magnetic field. Electromagnetic field affects the permeability of the ionic channels in the cell membrane. The other possible effect is the formation of free radicals such as hydroxyl radicals, superoxide's etc., due to magnetic field exposure that increases the production of reactive oxygen species (ROS) which is bactericidal.186,187,188,189,190 Fig. 13 schematically represents the mechanism of antibacterial response in the magnetic field.183

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4.2 Effect of Electrical Stimuli In last few decades, the potentiality of electrical stimuli, such as, electric field and electric current has been realized in controlling the microbial population on bio-composite surfaces.191,192,193 The external electric field induced antibacterial response depends on the intensity of electric field, exposure time and pulse duration (in case of pulsed electric field) etc.194,195 The number of CFU for E. coli and S.aureus bacteria decreases by 33 % and 31 %, respectively, after exposure to the static electric field of 4.5 kV/cm for the duration of 30 minutes. However, CFU decreases by 56 and 54 %, respectively, for similar bacteria and electric field, after exposure for 2.5 hours. The antibacterial response also depends upon the frequency of the applied electric field. Mirzaii et al.196 reported that the number of CFU decreases by 3 % and 47.17 % against S. aureus bacteria upon exposure to an electric field with strength of 6 V/cm2 and frequencies of 1 MHz and 20 MHz, respectively, for 6 hours. However, the similar treatment (electric field and frequency) leads to the reduction of CFU by 10 % and 27 % for P. aerugenosa bacteria, when exposed for 4 hours. Table 3 summarizes the antibacterial activity for both, grampositive and gram- negative bacterial cells under the exposure to the electric field. The mechanism, responsible for electric field induced antibacterial activity is electrolysis of molecules on the surface of bacterial cells that produce the toxic substances, like, H2O2, oxidizing radicals, and chlorine molecule.197,198 Fig. 14 demonstrating the mechanisms, suggested for antimicrobial response in electric field. The following reactions occur at cathode and anode.199 Production of H2O2 at cathode,

Production of Cl2 at anode,

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Pulsed electric field (PEF) is used for killing the bacteria in food preservation. Malicki et al.200 reported that the maximum reduction (4.7 log unit) in CFU/ml against E.coli bacteria is obtained after the exposure of pulsed electric field (32.89 kV/cm) with 180 pulses for the duration of 30 µs. However, CFU/ml decreasesby 1.2 log unit against Bacillus cereus bacteria, through exposure of 16.7 kV/cm PEF for 2 mS (50 pulses).201 The application of electric field induces a potential across the cell membrane for short duration which causes the loss of membrane resistance.202,203 The strength of the applied electric field is also an important parameter for pulsed electric stimulation induced the bactericidal effect. Usually, the electric field strength of 20-80 kV/cm range is applied for a short duration (generally in microseconds) for killing the bacterial cells.204 External electrical stimuli induced antimicrobial response has been observed in both, gram positive and gram negative bacteria, while cultured on various bio-composite surfaces. It has been demonstrated that the viability of S.aureus bacteria, decreases by 60 % on the application of DC electric field (1V/cm) for 24 hours, cultured on HA surface. However, 10 wt. % ZnO addition to HA increases the viability reduction from 60 to 70 % under the exposure of similar electric field.205 The bacterial killing efficiency of hybrid hydrogel prepared with layered black phosphorus nano sheets against S.aureus and E.coli bacteria were reported to be 99.51 % and 98.90 % respectively, under the electrostatic interaction in visible light for 10 minutes.206

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Production of metal ions and formation of ROS are the main mechanisms, responsible for the antibacterial activity of bio-composites (e.g., HA-ZnO) due to an additional effect of electric field (Fig. 15205). Dissolution of ZnO produces Zn+2 ions that destruct the cell wall and disintegrates the biofilm formed on the surface. ROS (OH- and H2O2) can be generated at the surface due to electrolysis of ZnO molecules, which diminishes bacterial growth.205 In addition to the electric field, alternating current (AC) and direct current (DC) within some physiological limit can be used as an antibacterial agent. Petrofsky et al.207 reported that the bacterial growth decreases by 9.8 % and 3.8 % against E. coli and S.aureus bacteria, respectively, under the application of 20 mA DC current for 24 hours. However, bacterial growth reduces by 38% against P. aerugenosa bacteria, after exposure to an AC current of 20 mA for 24 hours. Few other studies suggested that application of DC current (1, 5 and 10 mA) show bacteriostatic effect, whereas AC current does not show any remarkable antibacterial effect.208 Table 3 presents the summary of the antibacterial response of biocomposites against both, gram-positive and gramnegative bacterial cells due to exposure of external electrical stimuli. The mechanism, responsible for antibacterial response due to the application of electric current is the generation of chemical oxidant as well as the hydrophobicity of suspension medium.209,210,211Application of electric current to bacterial suspension generates few chemical oxidants, such as, chloride on electrodes due to electrolysis, which is bactericidal.212Oxidative stress develops in the solution due to ions which cause the significant reduction in hydrophobicity i.e., reduction in biofilm formation.213A high-intensity electric current can alter the orientation of membrane lipids and also oxidize the cellular constituents, which destruct the cell membrane.214

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4.3 Effect of Surface Charge (Polarization) The bacterial cell surface is complex, heterogeneous structure which carries the negative charge, develops from dissociation of carboxyl, phosphate and amino groups.13The outer layer of bacterial cells contains pores, formed by proteins which transport charge species through the membrane. The interaction of bacterial cells with substrate depends on its chemistry and surface charge.13 In recent past, the number of techniques such as exposure of implants to electric and magnetic fields, have been suggested to obtain the bacteriostatic effect in prosthetic implants.215,216,217,218 Surface charge is one of the modern technique for minimizing bacterial adhesion and inhibition of biofilm formation.21,219 The surface charge can be developed by the treatment of implant with very high-intensity DC electric field at elevated temperature. For example, HA can be polarized by DC electric field of 3 kV/cm at 400˚C for 2 hours. The bacterial cells for polarized HA have been decreased by 42.10 % (positively charged surface) against S. aureus bacteria, after incubation of 72 hours. However, for negatively charged HA surface, it is increased by 28 % for similar bacteria and incubation conditions.220 Gottenbos et al.221 reported that positively charged surface of polymethacrylate (PMMA)- trimethylaminoethyl methacrylate chloride (TMAEMA-Cl) composite revealed better antibacterial response as compared to the negatively charged surface after incubation of 2 hours against S. aureus bacteria. It has been demonstrated that polarized (DC electric field of 0.1-1 kV/cm in the air at 250 ˚C for 1 hour) glass ceramic (Cerec Blocs S3-M14) shows antibacterial response against S. mutans bacteria. 222 Table 4 summarizes the electrical stimulation induced the antibacterial response of various bio-composites cultured against different bacteria. The mechanisms, responsible for the antibacterial response of polarized surface is hydrophilicity of the poled surface. Hydrophilicity of charged surfaces increases, irrespective of their polar

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character. The increased hydrophilicity results in the detachment of bacteria from the surface.223,224 Fig. 16 schematically illustrate the mechanisms for the antibacterial response of polarized surfaces. 5. Challenges and Future Perspectives The possibility of bacterial infections in orthopeadic implants are becoming very serious concern as over one millions of prosthetic surgeries are presently being performed every year across the global. However, there is a lifelong risk of such kind of infections. The uses of antibiotics provide temporary solution. The development of biomaterials with bactericidal properties is anticipated as better choice to antibiotics. Over the past few decades, the doping of various antibacterial agents, such as Ag, Ti, Au, etc., in existing implant materials has been explored as one of the possible solutions. However, the potential toxicity of worn/leached metallic particulates/ions raises a serious concern. Further, the exposures with external electric and magnetic stimuli have been realized as the potential choice to overcome the above issues. The application of electric and magnetic fields are also quite challenging as it depends on the number of properly tuned parameters such as, field intensity, exposure duration, frequency etc. In case of high intensity of applied external magnetic stimulus, there is a possible risk of variation in hormonal concentration and gene expression that can produce critical adverse effects. Similarly, for direct exposure of bacterial cells to electric field has been reported to produce some toxic substances such as Cl2 and H2O2 that can damage the other cells as well. Despite of enormous amount of technological advancement in this direction, bacterial infection in biomedical implants are still a serious concern. Since the bacterial membrane contains charge, the electrical polarization of prosthetic implants to produce like charges could be a potential technique to improve the antibacterial response without addition of any antibacterial agents as well as exposure to electrical or magnetic fields.

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6. Closure Owing to the fact that bacterial infections cause serious complications during/after implantation, the present study summarizes the possible ways to address this issue by means of compositional modifications, surface chemistry alterations as well as electric and magnetic fields exposure.The compositional modification includes incorporation of naturally existing antibiotic agents such as Ag, Au, etc. as well as metal oxides such as, ZnO, TiO2, MgO etc. in base biomaterial matrix. Modifications in surface chemistry include, nanosized tailored biomaterials in particulate or in bulk form. Such bio-composites illustrate size, composition and time dependent antibacterial response. In addition, externally applied electrical and magnetic stimuli potentially induce the antibacterial response on biomaterial surfaces. However, such effect is observed within a particular window of applied stimulation parameters. Owing to electric charge on bacterial cell membrane, the polarization of biomaterial substrate has also been recently realized as potential candidate for offering antibacterial response. The polarization induced antibacterial response is strong function of poling parameters (polarizing field and duration of poling) as well as bacterial cell type. Furthermore, the mechanisms, responsible for antibacterial effect of these agents such as generation of metal ions (Ag+, Zn2+, Cu+, etc.,), free radicals (hydrogen peroxide, singlet oxygen, hydroxyl group etc.,) surface wettability; electrolysis and oxidative stress have been elaborately discussed. 6. Acknowledgments AKD gratefully acknowledge SERB, Department of Science and Technology (DST), Government of India for financial support.

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List of Tables Table 1: Effect of various material compositions on antibacterial response

S. N.

1.

2.

Material Composition Base material

HA

HA

Secondary phase

Ag

1000 ppm of Ag

Pathogen (Incubation Time :12 hours)

Effects

S. mutans

Diameter of inhibition zone 6.33 mm (for 5 wt.% Ag in HA) 8.66 mm (for 10 wt.% Ag in HA)

S. anguinis

7.66 mm (for 5 wt.% Ag in HA) 9.66 mm ( for 10 wt.% Ag in HA)

L. acidophilus

5.66 mm (for 5 wt.% Ag in HA) 7.66 mm ( for 10 wt.% Ag in HA)

S. aureus

17 mm

Pneumococcus

HA

Fluro Hydroxy apatite (FHA) ZnO

Cr

HA 4.

5.

E. coli

14.7 mm

S. epidermidis

10 mm

S. aureus (72 hours)

21.07 mm

S. aureus

42 mm

E. coli

10-13 mm

collagen/poly lactic acid with antibiotic vancomycin (VCM/nHAC/P LA) FHA -40 Zr-20 Ce composite. (Compositions are in wt. %)

26

34

18 mm

E. coli

3.

17.5 mm

References

35

15-17 mm

S. aureus

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6-9 mm

S. aureus ZnO

-

No inhibition zone found

E. coli 6.

HA

ZnO (1.5-30 wt. %)

E. coli E. coli for 3 hours

7.

HA

AgCl/ TiO2

8.

FHA

Zr-Ce (40 wt.% Zr & 20 % Ce)

9.

10.

11.

HA

HA

HA

0.2 wt. %Zn, 0.25 wt. % Ag, and 0.025 wt. % Au TiO2 (10-60 wt. %) ZnO (1.5-30 wt. %)

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Bacterial colonies decreased by 35% (for 10 wt.% ZnO) 60 % (for 30 wt. % ZnO) Colony forming unit (CFU) decreases by 99.10 % when exposed to visible light irradiation Diameter of inhibition zone 37 mm

E. coli S. aureus

42 mm

E. coli S. aureus

15 mm 16 mm

Bacillus cereus E. coli

14 mm 14 mm (60 wt.% TiO2 )

38

39

40

41

42 S. aureus

21 mm (60 wt.% TiO2 ) Bacterial colonies decreased by 13 % ( for 1.5 wt. % ZnO) 50.45 % ( for 30 wt.% ZnO)

E. coli

Table 2. Antibacterial response of nanoparticles against various pathogens

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S. N.

1.

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Nonmaterials ZnO nanoparticles

Average Particle Size 6.8 nm

Pathogens (Incubation Time: 12 hours)

Concentration in growth medium

E. coli

0.1 mg/mL

S. aureus

0.1 mg/mL Fe3O4 concentration

2.

3.

Iron oxide nanoparticles

Silver nanoparticles

66 nm

12 nm

E. coli S. Epidermidis S. aureus Bacillus subtilis

12

16

50 mg/mL

20

16

E. coli

10 µg/cm3 60 µg/cm3

S. aureus B. subtilis E.coli S.aureus E.coli S.aureus

E. coli

20-100 µg/mL

Ag-ZnO nanocomposites

64 nm

E.coli P. aerugenosa S. aureus

7.

50 mg/mL

25 nm

5.

Iron oxide nanoparticles TiO2 nanoparticles

15

E. coli S.aureus

48 nm

Bacterial cell death 99.8 % 98 % Diameter of inhibition zone (mm) With slanWithout andered antibiotic tibiotic 11 14 14

35 nm

ZnO nanoparticles

Ref.

50 mg/mL

100 µg/cm3 10 ppm 1000 ppm 0.1 mg/mL 550 µg/mL 60 µg/mL 0.01-0.15 mg/mL 0.01-0.15 mg/mL 0.01-0.15 mg/mL 10-50 mg/mL 10-50 mg/mL

4.

6.

50 mg/mL

Effects

bacterial growth inhibited by 70 % 100 % 100 % 90 % 48 % 98 % 100 % 100 %

66

88

107

110

61 % 111 60 % 55.17 % 30 % 25 %

112

41.17 %

113

Diameter of inhibition zone (mm) 8.

TiO2 nanoparticles

100 mg/mL

E. coli 22.41 nm

12 15

S. epidermidis

27

144 mg/mL

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9.

CuO nanoparticles

E. coli S. aureus E. coli S. aureus S. aureus P. aerugenosa E. coli S. aureus

103 µg/mL 120 µg/mL 103 µg/mL 120 µg/mL 1 mg/mL

15.8 13.2 16.8 15 27

1 mg/mL

24

1 mg/mL 1 mg/mL

16 nm

E. coli

60 µg/mL

35.8 42.8 Completely inhibit the CFU

14 nm

B. subtilis

13.5 µg/mL

E. coli

31.25 µg/mL

S. aureus

125 µg/mL

P. aerugenosa

62.5 µg/mL

7.8 nm 4.8 nm

10.

MgO nanoparticles

43-91 nm

11.

MnFe2O4/ Ag

216 nm

12 13

14.

Table 3: Effect of external stimulant on anti-

15.

Silver nanoparticles Silver nanoparticles

CuO nanoparticles

Iron oxide nanoparticles

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23.17 nm

E. coli 10 nm

P. aerugenosa S. aureus

76 % reduction in CFU Completely inhibit the bacterial growth Completely inhibit the bacterial growth Completely inhibit the bacterial growth Diameter of inhibition zone increased by

0.01-0.15 mg/mL 0.01-0.15 mg/mL 0.01-0.15 mg/mL

1.

External stimulant

Low-intensity magnetic field 2.7-10 mT

Types of pathogens and exposure duration E. coli for 12 minutes L. adecarboxylata for 12 minutes S. aureus for 12 minutes S. aureus (Exposure duration 30-150 minutes for each) E. coli for1 hour

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1

1

1

1

1 60 % 55.17 %

References

The exponential decrease in CFU with increasing the exposure time. 31% (exposure time 30 min.) 54% (exposure time 150 min.) Not bacteriostatic.

1

61 %

bacterial response

S.N.

1

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2.

Static magnetic field (4 mT-16 mT)

S. aureus (2-20 hours)

CFU reduced by 17 % (exposure time 2 hours and variation of magnetic field from 4mT – 16 mT) 62% (exposure time 20 hours and variation of magnetic field from 4 mT – 16 mT)

176

67% (at 4 mT exposure time increases from 2 20 hours) 85% (at 160 mT exposure time increases from 2 -20 hours)

3.

4.

5.

Low intensity DC current (0.2-1.0 mA)

DC current of 2,000 µA

Static electric field (2.5V/cm, )

Candida albicans for (2-18 hours)

S. epidermidis for 48 hours S. aureus for 48 hours

E. coli

29

CFU/cm2 reduced to 42 % (exposure time 2 hours and variation of DC current from 0.2-1.0 mA) 69% (exposure time 18 hours and variation of DC current from 0.2-1.0 mA) 34% (at 0.2 mA DC current and exposure time increases from 2 -18 hours) 65% (at 0.2 mA DC current and exposure time increases from 2 -18 hours) CFU reduces by 6log10 CFU/cm2 4-5log10 -CFU/cm2 CFU / cm2 decreased by 35.48% (exposure duration 15 minutes) 88% (exposure duration 120 minutes)

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178

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S. aureus

E. coli 6.

Static magnetic field (10mT)

7.

Low-frequency electric field (6.849V/cm)

S. aureus (Exposure duration 24 hours for each)

E. coli for 50 minutes

8.

CFU / cm2 decreased by 30.76% (exposure duration 15 minutes) No more decrement when exposed for 120 minutes. The maximum reduction in cell viability is detected

180

Minimum reduction in cell viability is detected Bacterial death by 42.41% at frequency of 10 Hz

181

30.76% at frequency of 100 Hz S. aureus

Magnetic field (30100mT) (Applied in aerobic as well as anaerobic conditions).

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S. mutans

Maximum bacterial growth detected for S. aureus and S. mutans under aerobic condition. No bacterial growth for E. coli bacteria under aerobic condition.

182

E. coli (Exposure duration 48 hours for each)

Table 4: Effect of external stimulant on antibacterial response, while bacteria are being adhered on various biomaterial substrates

Material composition S.N.

1.

Base material

HA

Secondary phase

-

External stimulant (Magnetic field/ electric field/ surface charge) Static Magnetic field of 100 mT

Types of pathogens and exposure time E. coli for 4 hours S. epidermidis for 30

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Effects

Cell viability decrease by 60 % 17 %

References

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4 hours Fe3O4 (10-40 wt. %)

Static Magnetic field of 100 mT

S. aureus for 4 hours S. aureus for 4 hours S. epidermidis 4 hours

2.

HA

3.

Glass substrate

-

Low-intensity electric field (1.5-30 V/cm)

4.

HA

ZnO (10 wt. %)

DC electric field of intensity 1 V/cm

S. aureus for 24 hours

Positively charged surface

S. aureus for 72 hours

Negatively charged surface

S. aureus for 72 hours S. epidermidis 4 hours

5..

6.

HA

Glass ceramic (Cerec Blocs S3-M14)

-

-

Polarized surface (DC electric field of 0.1 -1 kV/cm in air at 250 ˚C for 1 hours)

Streptococcus mutans for 24 hours

List of Figures

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Bacterial adhesion is reduced by 8 % ( HA) 25% (HA-40 wt.% Fe3O4) Bacterial adherence Recesses to 98 % No effect on bacterial adhesion %Viability reduction 60 % (pure HA) 70 % (10wt.% ZnO in HA)

184

185

205

Bacterial cells per colony decreases by 42.10 % 28 %

220

No effect on bacterial adhesion Reduction in bacterial adhesion.

222

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Fig. 1 Contribution of microbes that causes the prosthetic joint infections.

Fig.2 Mechanisms of killing bacteria by any antibacterial agents [Reproduced with permission from ref. (21): Open access].

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Fig. 3. Schematic illustrating the mechanism of antibacterial response of silver ions and their composites.

Fig. 4. Schematic diagram of proposed mechanisms for antibacterial response of TiO2. [Reproduced with permission from ref. (57): Copyright [2014], Royal society of chemistry].

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Fig.5. Schematic presentation of mechanisms for antibacterial response of ZnO based bio- composites. [Reproduced with permission from ref. (71): Open access].

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Fig.6. Schematic illustration representing the mechanism behind the antimicrobial behaviour due to metal ions. Metal ions can be released by dissolution of metal oxides and free radicals are formed by endocytosis process. [Reproduced with permission from ref (79): Open access].

Fig. 7: Schematic illustration represents (a) various modes of antibacterial response due to ZnO nanoparticles and (b) the possible mechanisms for ZnO nanoparticles mediated antibacterial response. [Reproduced with permission from ref. (98): Open access].

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Fig.8. Schematic illustrating (a) nanoparticles internalization into the cell wall, (b) disruption of cell wall and release of intracellular materials, (c) thickenings of cell wall and release of cytoplasm and (d) mechanisms of dissolution of nanoparticles in the bacterial membrane, release of metal ions, ROS and disruption of DNA [Reproduced with permission from ref. (98): Open access].

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Fig. 9. Schematic illustration of antibacterial response due to Cu nanoparticles. [Reproduce with permission from ref. (132): Open access].

Fig.10. Schematic demonstration of mechanisms, responsible for antibacterial activity of iron oxide nanoparticles [Reproduced with permission from ref. (146): Open access].

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Fig. 11: Schematic diagram representing the (a) interaction of bacterial cells with MgO and generation of ROS and (b) protein disruption with pH variation. [Reproduced with permission from ref (160): Open access].

Fig.12: Schematic illustrating the possible mechanism for antibacterial response of gold nanoparticles. [Reproduced with permission from ref. (163): Copyright (2015) Springer nature].

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Fig. 13: Schematic representation of mechanism for antibacterial activity due to production of free radicals in magnetic field [Reproduced with permission from ref. (183): Copyright (2015) Springer nature].

Fig. 14: Schematic representation for the mechanisms of antibacterial response due to electric field.

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Fig. 15: Schematic illustrates the antibacterial activity of HA-ZnO biocomposite due to Electric field. [Reproduced with permission from ref (205): Copyright (2015) Wiley Periodicals].

Fig.16: Representing the schematic illustration of mechanism for antibacterial response of charged surfaces (polarization). 40

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