Silver-substituted hydroxyapatite

Silver-substituted hydroxyapatite 1

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Zohaib Khurshid , Muhammad Sohail Zafar , Shehriar Hussain , Amber Fareed 4 , Safiyya Yousaf 5 , Farshid Sefat 6 1 Department of Prosthodontics and Dental Implantology, College of Dentistry, King Faisal University, Saudi Arabia; 2Department of Restorative Dentistry, College of Dentistry, Taibah University, Saudi Arabia; 3Department of Dental Materials, College of Dentistry, Jinnah Sindh Medical University, Karachi, Pakistan; 4Department of Preventive Dentistry, Oman Dental College, Muscat, Oman; 5Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford, United Kingdom; 6Interdisciplinary Research Center in Polymer Science & Technology (IRC Polymer), University of Bradford, Bradford, United Kingdom

10.1

Introduction

This chapter describes the rationale of synthesis and characterization of sliversubstituted apatite in terms of their physical, chemical, and biological characteristic for bone ingrowth. There are three main constituents of bones and teeth, which are living cells, extracellular collagenous matrix, and the calcium phosphate mineral part also known as hydroxyapatite (HA) or Ca5(PO4)3OH. Therefore, the ideal replacement of bone and teeth would be any combination of the above components. Currently, the best materials for these replacements are titanium alloys and calcium phosphate ceramics (Bir et al., 2012; Khurshid et al., 2016). Titanium alloys are widely used due to their strength, biocompatibility, and corrosion resistance (Najeeb et al., 2016), whereas calcium phosphates have shown excellent compatibility with bone due to the favorable biological responses and improved boneeimplant adhesion, and they can also be a scaffold for bone growth. Nanosized silver particles contain more active surface sites and are chemically durable, which are prepared by the chemical reduction of silver salts by sodium citrate or sodium borohydride, and utilize silver nitrate as the source for Ag (Russell and Hugo, 1994). Previously, AgNPs were used as antibacterial agents in the food and food storage (Chowdhury et al., 2016; Kumar et al., 2018), health sector (Sodagar et al., 2016), cosmetics (Domeradzka-Gajda et al., 2017) textile industry, and in environmental applications (Syafiuddin et al., 2017).

10.2

The rationale of silver in apatite

Apatite is one of the main constituents of a teeth and bones; therefore, a significant amount of research on the synthetic preparations of apatite as a bone replacement biomaterial, implant coatings, and drug delivery is reported in the literature

Handbook of Ionic Substituted Hydroxyapatites. https://doi.org/10.1016/B978-0-08-102834-6.00010-0 Copyright © 2020 Elsevier Ltd. All rights reserved.

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e (Owens et al., 2019; Palazzo et al., 2007). Apatite is formed by Caþ2, PO3 4 , and OH ions, and these ions are required in the correct orientation and in enough numbers to form the stable apatite crystal. Synthetic biological apatite is characterized by the presence of several foreign ions, which play an important metabolic role. Moreover, HA has the ability of anionic substitution (carbonate, fluoride, and silicate, or cationic) and cationic substitution (magnesium, strontium, zinc, iron, and silver) to enhance the therapeutic bone formation. Therefore, apatite substituted with relevant ions is regarded as attractive biomaterials for hard tissue substitution/repair (Sefat et al., 2019; Sheikh et al., 2015, 2014; Zafar et al., 2019, 2015) (see Fig. 10.1). Silver (Ag), in this regard, is of particular interest as it has been long recognized for inhibitory effect toward several pathogenic bacteria and microorganisms (Alexander, 2009). For centuries, it is known that silver ions exhibit strong inhibitory effects toward a broad spectrum of bacterial strains (Clement and Jarrett, 1994). Ag in its many oxidation states (Ag0, Agþ, Ag2þ, and Ag3þ) had been incorporated in many biomaterials including HA. It is desirable for the implants to have antibacterial properties to reduce the treatment duration by providing localized antibacterial effect, thus decreasing the need and the side effects of systemic therapies thereby improving its efficacy. Silver, an inorganic antibacterial agent, is historically known for its broad-spectrum antimicrobial activities against bacteria, viruses, algae, and fungi (Gosheger et al., 2004;

Repair and reconstruction surgery

Conservative dentistry

Pharmacy

Biomedical applications of hydroxyapatite (HA) Bone defect filling materials

Orthopedics materials

Implant surface coatings

Figure 10.1 Application of hydroxyapatite (HA) in the human body.

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Martínez-Gutierrez et al., 2012). Table 10.1 shows the several mechanisms of action by silver ions to interfere the cellular growth. Additionally, silver has the potential for the development of novel antimicrobial agents, formulations of drug delivery, biomaterial coatings, regeneration materials, and improved therapeutics. (Khurshid et al., 2017; Zafar et al., 2019, 2017; Zhao et al., 2009). The antibacterial mechanism of silver is related to the release of Agþ ions from Ag nanoparticles (AgNPs) to disrupt membrane permeability or by direct contact with bacterial result in microbial death (Agnihotri et al., 2013; Fu et al., 2016). The oxidation and release of Agþ in Ag-HA coating is essential for antibacterial activity; therefore, a mild heat treatment (170 C in air for 8 h) process of Ag-HA coating enhanced the consistent antimicrobial action of AgNP (Zhang et al., 2017). Recent studies suggested that the biological responses of silver-substituted hydroxyapatite (Ag-HA) may be improved with the addition of silicon (Si) because presence of Si in the HA structure is related to the rate of dissolution, precipitation, and biomineralization mechanisms (Zhang et al., 2017). The excellent bioactivity of sliver particles was experimentally evaluated against bacteria, fungi, viruses, and yeast. To achieve the therapeutic effects, incorporation of silver into the apatite is done by several methods that will be discussed later including coprecipitation process and ion exchange with the calcium ions in the apatite, wet precipitation reaction between calcium phosphate and orthophosphoric acid, and hydrothermal method (Kometani and Teranishi, 2010; Li et al., 2015). It is possible that the bioactivity and controlled release of ions from the HA is influenced by silver dispersion. Mostafa et al. (2010) reported the physical characteristics of Ag-HA composite using AgNPs and claimed that the release of Ca and P in Ag-HA composite can be controlled in presence of silver. More recently, Ruiz-Baltazar reported the green synthesis of AgNPs from biosynthesis on Melissa officinalis extract to develop Ag-HA nanocomposite. The results of this study showed that the impregnation process of AgNP was successful, and greater interaction of AgNPs with the HA matrix in Ag-HA composite was observed (see Fig. 10.2) (Ruíz-Baltazar et al., 2018). Lim et al. discussed the incorporation of silver ions in the apatite structure during the coprecipitation process (Ag-HA-CP) or underwent ion exchange with calcium ions in the apatite (Ag-HA-IE) and reported the chemical, physical, antibacterial properties, and biological responses of Ag-HA-CP and Ag-HA-IE (Lim et al., 2015). They claimed that the antibacterial action of Ag-HA-IE was related to the released silver ions, whereas in Ag-HA-CP, it was dependent on the surface-bound silver ions as shown in Fig. 10.3. Therefore, antibacterial efficacy of Ag-HA-CP is possibly achieved for a longer time compared with Ag-HA-IE, and a silver content between 0.5e2 wt.% in Ag-HA-CP may achieve effective antibacterial effect (Lim et al., 2015).

10.3

Substitution in hydroxyapatite

HA, (Ca10(PO4)6(OH)2), generally used for compensating bone defects and dental complications, is one of the basic material constituents of metallic

(a)

(b)

1.00kV-D 3.8mm x90.0k SE(T)

500 nm

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1.00kV-D 3.8mm x350k SE(T)

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(d)

1.00 µm

SU8230 3.0kV 3.4mm x35.0k SE(U)

SU8230 3.0kV 3.4mm x35.0k HA(T)F0

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Figure 10.2 (a and b) Hydroxyapatite (HA) scanning electron microscopy (SEM) micrographs obtained by the secondary electrons detector, (c and d) SEM images of the Ag-HA nanocomposite.
Adapted from Ruíz-Baltazar, A.J., Reyes-L
opez, S.Y., Silva-Holguin, P.N., Larra~ naga, D., Estévez, M., Pérez, R., 2018a. Novel biosynthesis of Ag-hydroxyapatite: structural and spectroscopic characterization. Results Phys. 9, 593e597. https://doi.org/10.1016/J.RINP.2018. 03.016, with permission.

AgHA-CP

AgHA-IE Released Ag+ ions damage cell wall

Surface-bound Ag+ ions damage cell wall

Bacteria

Bacteria Crystal surface

Crystal surface Ag+ ions diffusion

Crystal structure of AgHA-CP

Crystal structure of AgHA-IE

Figure 10.3 Graphical representation of substitution of silver into nanosized silver-substituted hydroxyapatite (nAg-HA) is employed to create antibacterial properties. Silver ions were either incorporated during the coprecipitation process (Ag-HA-CP) or underwent ion exchange with calcium ions in the apatite (Ag-HA-IE). Adapted with permission from Lim, P.N., Chang, L., Thian, E.S., 2015. Development of nanosized silver-substituted apatite for biomedical applications: a review. Nanomed. Nanotechnol. Biol. Med. 11, 1331e1344. https://doi.org/10.1016/j.nano.2015.03.016.

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SeO3 substituted HA

Ag+ substituted HA

Cu2+ substituted HA Substitution of HA with different biomaterials for antibacterial property

Zn2+ substituted HA

Sr2+ substituted HA

Ce3+ and Eu3+ substituted HA

Figure 10.4 Different materials substitution in the hydroxyapatite (HA) to enhance the antibacterial activity and strengthen it.

implants (Lyasnikova et al., 2016). Since the 1980s, the relative newness of HA layers remains a topic of substantial interest, especially with the ease of atomic doping or substitution. Thereby, when substituted with ions such as carbonate ion or magnesium, nanocrystalline HA develops similar characteristics to biological apatite, the dominating element of vertebrate tissues (Kolmas et al., 2017) (see Fig. 10.4). With wide-ranging biomedical applications, HA can be used as a microbial agent (Swetha et al., 2012), drug delivery system (Lin et al., 2011), and biomarker for potential nanomedical platforms (Zuo et al., 2012). Possessing excellent biocompatibility, HA exhibits a surface chemistry that supports bone ingrowth. However, when modified (in particular, with Ag-HA), high levels can be toxic, leading to damage of human biological tissues and argyrosis (Manshian et al., 2015).

10.4

Methods of Preparations

Special attention is paid to synthetic HA precursors by various ceramic processing routes including wet precipitation, coprecipitation, hydrothermal processing, solegel, etc. Production of these HA powders have stimulated academic and industrial research for several heterogeneous catalysis applications. Within each division, there are multiple variations that are dependent on the conditions of synthesis and reagents used (Fihri et al., 2017).

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10.4.1

Handbook of Ionic Substituted Hydroxyapatites

Wet precipitation

The most extensively used technique for the formation of HA power is the wet chemical method by either simple precipitation or hydrolysis. Wet precipitation can be performed at ambient or elevated temperatures using water or inorganic solvents. Highly dependent on the nucleationeaggregationeagglomerationegrowth mechanism, the technique releases harmless by-products (water) and is established for its clinical simplicity (Yelten-Yilmaz and Yilmaz, 2018). Reactions are conducted under atmospheric or high pressures offering control over the morphology and texture, thereby leading to a high yield of HA. Beginning with precipitation, the procedure is followed by aging, filtration, drying, and lastly heat treatment. The potential to apply diverse reagents, auxiliary additives, and apparatus enables tailorable properties on the synthesis method. For instance, these are determined by the Ca/P ratio, pH, and ripening time. To achieve reproducible HA powders, process parameters such as reactant addition rate, concentration, drying, and heat treatment conditions are essential for producing similar features of particle shape, particle size, and stoichiometry (Gentile et al., 2015; Mostafa, 2005). A lower addition rate of acid would promote larger sized particles (Ramesh et al., 2015). Being easily modified, the wet precipitation technique synthesizes HA/Ag and is usually prepared from Ca(NO3)2$4H2O, AgNO3, NH4OH and (NH4)2HPO4 (Badrour et al., 1998; Chen et al., 2010; Singh et al., 2011) or Ca(OH)2, AgNO3, and H3PO4 (Kim et al., 1998; Lim et al., 2013; Rameshbabu et al., 2007). Although wet chemical precipitation serves an economical benefit for use on an industrial scale (Abidi and Murtaza, 2014), a major drawback to this approach includes the presence of potential impurities due to various ions manifested in aqueous solution; therefore, it is incorporated into the crystal structure. Additionally, this can give rise to structures that are not crystallographically pure (Fihri et al., 2017).

10.4.2

Coprecipitation

Coprecipitation is a chemical process employed to prepare HA powders using low operating temperatures to generate high yields of pure products (Fihri et al., 2017; Ikoma et al., 1999). This simplicity of experimental methods has drawn attention to the field of biomedical applications (Kong et al., 2002). First proposed by Hayek and Newesely in 1963, coprecipitation is generally conducted by pH values ranging from 3 to 12 with the ability to perform in the presence of templates (Hayek et al., 2007). Considering the technique is variable dependant, various reagent and additives can be used (Fihri et al., 2017).

10.4.3

Hydrothermal

The hydrothermal process is a rather mature technique for developing complex oxide powders with high crystallinity in a confined environment (Zhang et al., 2011). The procedure requires a high temperature and pressure superior to that of the ambient pressure inside a pressure vessel (or autoclave). These determine the medium used,

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such as subcritical or supercritical. Chemical bonds are formed through the effect of condensation and reactivity, thus generating nuclei that ensure stoichiometric and highly crystalline synthesis of HA, respectively (Fihri et al., 2017). Morphology and porosity are controlled with high pressure creating microsized crystallites, thereby serving to modulate interactions between the solid and solvent. Commonly, this method is combined with conventional methods, coprecipitation protocols, etc (Abdel-Aal et al., 2008; Fihri et al., 2017; Zhu et al., 2009).

10.4.4 Solegel The solegel synthesis method involves mineralization from precursors in a solution to create colloidal sol, which eventually forms a gel-like compound (Kara et al., 2005). This exemplary process requires no energy conditions (Ramesh et al., 2015) though it entails strict control parameters and is highly reliant on (1) temperature and pH; (2) the nature of the solvent; and (3) the chemical nature of reagents used (Fihri et al., 2017). A process comprising a nonalkoxide solegel for HA synthesis has been established only for the conventional sources of calcium and phosphate, without performing adjustments to the pH (Kim and Kumta, 2004; Rajabi-Zamani et al., 2008). Additionally, an intimate contact is required at molecular level to produce nanocrystalline powders with homogenous composition, high purity, and overall a sophisticated nanomaterial suitable for tailoring various applications (Kalaiselvi, 2017; Uskokovi
c and Uskokovi
c, 2011). The protocol involves generating micelles around templates in either an aqueous or organic phase to hydrolyze the precursors, followed by polycondensation via the formation of a 3D inorganic network (Chen et al., 2011; Velu and Gopal, 2009). The synthesis of these ceramic materials are generally conducted at room temperature, while the solegel films, according to Lim et al. (2001), are more homogenous and smooth at 300 C. Ultimately, the low-temperature nature of the solegel technique (including heat treatment for drying, calcining, etc.) offers major advantages to restrain effectively the formation of the amorphous phase. Being easily applicable, the process does not require a high vacuum or refined equipment (Wang et al., 2008). Despite gaining considerable popularity, there are potential limitations that hinder the technique’s expansion on an industrial scale including high cost and scarcity of solegel methods (alkoxide-based precursors) as well as time-consuming process control (Fihri et al., 2017).

10.4.5 Microwave Because of enormous progress in offering alternatives to heating techniques, a continued interest remains widespread among microwave-assisted synthesis. The method generates an increased field of perfectly crystalline powder, particularly homogenous in terms of size, morphology, and porosity (Fihri et al., 2017; Tang et al., 2009). Recent studies have presented surfactants such as cetyltrimethylammonium bromide (CTAB), ethylenediaminetetraacetic acid, and sodium dodecyl sulfate to control parameters of HA nanostructures (Arami et al., 2009; Luk and Abbott, 2002). Molecular agitation is initiated by a purely thermal origin that is caused

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by the inversion of dipole with alternations in the electric field, whereas in an electrostatic origin, interactions such as dipoleedipole between polar molecules and the electric field are performed. These are considered as contributing factors of microwave-assisted preparation that encounter a direct effect on the kinetics and activation energy (Fihri et al., 2017). Overall, this approach has evidently presented to be simple and economical to prepare nanosized materials with narrow particle size distribution (Guha et al., 2010).

10.4.6

Other methods

Among the different synthesizing techniques for HA, the study of its properties and ability to mimic biological systems remains on the economic front for adopting efficient functionality. Preparation, shape selectivity, and characterization are vital for a good understanding of solid catalysts, as well as morphology and kinetics. Other techniques include hydrolysis (Sturgeon and Brown, 2009) and alternate energy input methods to obtain HA powder (Han et al., 2004).

10.5

Use of surfactants during preparation

To obtain control over Ag-HA morphology, several macromolecules, monosaccharides, and related molecules are explored (Ruíz-Baltazar et al., 2018). For example, CTAB is extensively used in many aqueous synthetic methods (Wang et al., 2006). The X-ray diffraction (XRD) is a powerful nondestructive technique used to determine crystal and molecular structures. Characterization of crystal orientations (texture) and other structural parameters, such as average grain size, strain, and crystal defects, can be observed to identify various diffraction patterns (Poralan et al., 2015). Fouriertransform infrared spectroscopy (FTIR) is an analytical measurement technology that is routinely applied to the characterization of biomaterials (Rehman and Bonfield, 1997). FTIR analyzer functions by simultaneously collecting data from the entire infrared spectrum, which remains a current interest especially for examining tissue sections as an alternative to conventional histopathology. Preparing samples is often a tedious process and problematic for solid materials that are too opaque in their normal form; therefore, they require a reduced optical density using various sampling techniques (Gadaleta et al., 1996). Additionally, Raman spectroscopy is a valuable tool in the field of vibrational spectroscopy as it gathers important information on the nature of chemical bonding in material. Ionita (2009) used this method to study the changes in HA composition obtained from dental hard tissues in various pathological processes (Tavaf et al., 2017). At work with the complexity of HA, it is necessary to evaluate individual compositions for maintaining physicochemical properties and implementing appropriate methods accordingly.

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10.6

245

Structure of silver-substituted hydroxyapatite

Brittle in nature, HA belongs to a large family of isomorphic compounds and is substituted with metals (silver) to enhance its load-bearing capacity (Fihri et al., 2017; Shepherd et al., 2012). Substituting silver into HA has displayed considerable promise as numerous studies have observed and concluded a reduction in thermal stability while detecting an increase in the solubility of the generated apatite. Crystal lizing in the hexagonal system, the unit cell contains Ca2þ, PO2 4 , and OH groups  closely packed together, while OH groups serve as a backbone for HA (Poralan et al., 2015). HA can be defined as a compact assemblage of tetrahedral PO4 groups, where P5þ ions are present in the center of the tetrahedrons, thus occupied by four oxygen atoms. Moreover, each PO4 tetrahedron delimits two types of unconnected channels (Fihri et al., 2017). The substitution of AgNPs with HA through precipitation method with various Ca/P ratios resulted in the distribution of Ag in b-TCP homogeneously after sintering with higher solubility of Ag exhibited by b-TCP than HA and b-CPP (Gokcekaya et al., 2015).

10.7

Effect on bioactivity of hydroxyapatite

Bone can be amicably visualized as a dynamic composite material, boasting a crossstriated pattern of collagen fibrils interspersed with recurring amorphous zones (Glimcher and Muir, 1984; Mahamid et al., 2010). These are apatite crystal nucleation points, a prelude to crystal growth. Collagen is deemed an important synergistic regulator of inhibitors of the apatite nucleation process and subsequently exerts an active control over mineralization (Landis and Silver, 2009; Nudelman et al., 2010). The use of surface functionalized implantable fixtures for enhancing biomimetic capabilities in vivo is predicated on achieving balance between optimal mechanical function and a localized mass transport delivery system facilitating biological nutrient payload delivery and subsequent tissue regeneration capabilities at the implantation site (Hollister et al., 2002). The coating of load-bearing implants with HA has been a mainstay mode of surface activation of metallic fixtures destined for bone tissue for a variety of applications [6]. A chemical composition similar to bone, osteoconductivity, and good biocompatibility (Ogilvie et al., 1987; Park et al., 2010) are some prominent features characteristic of HA. Implant coating features deployed for this purpose include dipping (Zhang et al., 2006), plasma spraying (Sun et al., 2001), precipitation, and, the most commonly used, electrochemical deposition (Yan et al., 2014). The electrochemical deposition technique delivers good control coupled with a simple performance but lends itself to drawbacks such as weak bonding at the coatingemetal interface. Plasma electrolyte processing techniques have also been investigated to develop silver-substituted HA for coating on the surface of commercially pure titanium (Cp Ti) (Venkateswarlu et al., 2012). The coprecipitation technique allows for adsorption from solution and subsequent incorporation at the calcium sites in HA. This ion-exchange process can be achieved through various

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techniques, which include microwave processing (Rameshbabu et al., 2007), electrostatic spraying (Hwang et al., 2008), and HA nucleation (coprecipitation) (Oh et al., 2004). A slow diffusion index of Ag from within the Ag-HA crystal lattice appears to provide the most significant effect in terms of bioactivity as determined by soaking studies of samples and XPS of media determining Ag release profile from the lattice. This inevitably led to enhanced osteoblast-mediated activity when utilizing Ag-HA. Enhanced cell spreading, proliferation, and mineralization coupled with increased enzymatic activity of alkaline phosphatase indicative of elevated bone matrix deposition were some of the observable changes. Analyses conducted using TEM, FTIR, and XRD confirmed the close association of chemical makeup, morphology, and dimensions of Ag-HA particles with mineralized bone tissue. Moreover, the bioactive properties of silver-substituted HA have also been promising in terms of conducive proliferation of human mesenchymal stem cells on sterilized Ag-HA discs (Lim et al., 2015).

10.8

Use of micro- and/or nanosilver particles in hydroxyapatite for implant coatings

The use of HA for developing bone grafts and as a coating layer on the surface of an implant is a commonly employed tactic. However, this does not lend HA any exemption from assaults meted out by the host immune response in vivo. Medical implanterelated infections accounted for approximately 50% of infectious patients acquired in the hospital setting (Stamm, 1978). With an increase in the use of medical implants particularly in the elderly and the immune-compromized segments of the population, an accompanying incidence of implant-related infections is also predicted to surge even higher, leading to pain and suffering coupled with a significant rise in medical expenditures (Hetrick and Schoenfisch, 2006). Therefore, active strategies need to be harnessed for improving the period of service of the implant by reducing instances of bacterial contamination. The biological acceptance of an implant is predicated on a complex interplay between bacterial contamination on the implant surface and integration into the surrounding tissues (Gottenbos et al., 2002; Lin et al., 2017). For the implantation process to be predictably successful, the competition must lean in the favor of tissue integration before any appreciable level of bacterial contamination of the implant surface (before tissue integration) ensues. This is especially significant in subjects who are immune-compromized, have underlying systemic conditions, and/or the elderly. Adhesion of bacteria followed by the formation of a biofilm lies at the heart of implant failure owing to infective process (Zimmerli et al., 1998). The bacterial agents residing within the biofilm are extremely resistant to attack by (i) antibacterial agents, thereby rendering them, for the most part, ineffective and (ii) host defences, as the biofilm assumes the properties of a very effective shield dampening assaults on these fronts (Hetrick and Schoenfisch, 2006; Zimmerli et al., 1984). Recently, Tian et al. reported

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the deposition of 10e30 nm sized AgNPs on the surface of HA scaffold coating on Ti6Al4V to enhance Ag load efficiency and antibacterial activity (Tan et al., 2019). Considering this, the incorporation of HA-coated bone grafts with antibacterial properties will help in lowering the incidence of implant-related infections. However, to mitigate issues pertaining to infection in HA, a functional ion substitution in the guise of silver has gained significant traction (Rameshbabu et al., 2007; Venkateswarlu et al., 2012). Silver ions have a propensity for binding to enzymes and proteins within bacterial cells and disrupting its integrity, which plays havoc with basic cellular processes such as respiration, oxidation, and enzyme signaling, ultimately leading to bacterial cell death.

10.9

Antibacterial effect of silver-substituted hydroxyapatite

Even though HA is an integral component of the chemical composition of bone, it does not display any prowess as an antibacterial agent. Hence, in spite of their glaring merits, neat HA coatings for metallic implants lack effective antibacterial properties. A yearning for a better sterile environment at this interface persists. The ray of opportunity to be capitalized here lies in the trait of convenient substitution of Ca2þ in HA substructure by more effective metallic ion species, yielding enhanced osseointegration. The incorporation of silver ions (Agþ) into the HA substructure via Ca2þ substitution has shown to provide enhanced protection against the colonization of pathogenic microbial species at the site of implantation in vivo (Balamurugan et al., 2008). Silversubstituted HA has been the subject of a great deal of attention in contrast to other metallic ions for displaying strong antibacterial effects with a statistically significant broad-spectrum inhibitory range. To that end, a number of approaches have been put forward, which focus on Agþ ion recruitment in the HA substructure. These deliver a Ag-HA composite elaborating a combination of osseointegration and antibacterial component against organisms such as Escherichia coli (Iqbal et al., 2012). The introduction of 2.5 wt.% Ag in HA showed a significantly high index of antibacterial activity (Gopi et al., 2014). Another promising technique was conducted on surface of stainless steel substrates coated with Agþ doped fluorohydroxyapatite (Bir et al., 2012). Other investigators proposed the use of nanosilver particle doped HA, which demonstrated significant antibacterial activity. The spectrum of activity covered important Gram-positive and Gram-negative species. These included Pseudomonas species and E. coli in the Gram-negative category and Gram-positive Staphylococcus aureus (Iqbal et al., 2012). An interesting utilization of the antibacterial properties of silver was investigated (Yan et al., 2014). They used silverdoped HA/TiO2 nanotube coating via electrochemical deposition technique. When applied on a Ti-based substrate, the resulting material showed an improved level of interaction with host cells along with enhanced antibacterial capabilities against E. coli.

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Hence, by combining the biocompatible nature of HA with the antibacterial properties of Ag, these approaches offer suitable substitutes and convenient ways to design HA-based biomaterials with superior antibacterial properties and biocompatibility.

10.10

Drug-loaded silver-substituted hydroxyapatite

Nanoparticles have received great attention regarding selective and specific drug actions to improve healthcare due to enhanced drug delivery systems. There have been significant scientific contribution and improvements in boneeimplant interface and in the antibacterial activity by utilizing Ag-HA combination. In this regard, incorporation of AgNPs as a drug deliver carrier for cancer therapy, as antiinflammatory agent in local anesthesia, and to control antioxidant and antimicrobial activates is well established. Similarly, Saravanan et al. studied the antibacterial effects after the addition of AgNPs (80-120 nm) in a scaffold of chitosan and HA. However, silversubstituted HA exhibits better osteoblast adherence, and antibacterial activity in lower silver (0.5%) is considered suitable for drug delivery in implant applications. Nonetheless, surface modification and ion substitution in apatite and HA systems are based on silver as specific, selective, and versatile candidates for potential predictable drug delivery applications. The long-term silver ion release from functionalized silverdoped HA as local drug delivery agent was reported by Dubnika et al. The results of this study suggested that the Ag-HA scaffolds possess the antibacterial activity up to 1 year (Dubnika et al., 2014).

10.11

Other biomedical applications

HA, defined as a major member of bioceramic materials, is widely functional in clinical applications to recompense for defects of various etiology and size, i.e., the musculoskeletal system. Serving excellent osteoconductive and osteointegrative properties, HA uses in dental implants and orthopedic components have appeared to gain much research attention, owing practicality to modern medicine, chemistry, and biology (Gibson et al., 1999). According to literature, the incorporation of silver can enhance the toughness and strength of doped materials with the ability to promote porous material development, therefore contributing to the fulfillment of desirable properties (Nath et al., 2010). The sintering temperatures, the selected material preparation, and its phase composition among other parameters can be altered to fit various applications (Dubnika et al., 2014). Silver has been generally used for medical equipment and wound dressings, as it possesses a broad spectrum of activity against Gram-positive and Gram-negative bacteria, fungi, viruses, and protozoa. By inhibiting the electron transport chain of microorganisms, binding of Ag ions with enzymes, nucleic acids, and membranes helps to promote bioimplant surface modification

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such as implant-associated infection (Funao et al., 2016). Other applications for Ag-HA include periodontal treatment, maxillofacial surgery, alveolar ridge augmentation, and otolaryngology (Hench, 1991).

10.12

Dental applications

Although silver has been used efficiently and effectively in dentistry, it is controversial for this specific area of research, due to its variable toxicity in biological systems. However, silver is a major component in dental amalgam restoratives, the materials for dental barrier membranes used for efficient alveolar bone reconstruction, caries prophylaxis in the form of silver diamine fluoride, dental prostheses, restorative and endodontics, and implantology. Antibacterial Ag-HA could be used in clinical dental applications, both in orthodontics and restorative dentistry (Kolmas et al., 2014; Sivolella et al., 2012). Akhavan et al. studied the effect of Ag-HA nanoparticles on shear bond strength of dental adhesive and reported that 5% increase of Ag-HA shear bond strength offers appropriate antimicrobial and mechanical properties for orthodontic adhesive (Akhavan et al., 2013). Similarly, Sodagar et al. tested antimicrobial properties of Ag-HA incorporation in adhesives used for orthodontic application and showed that the experimental adhesive containing 5% Ag-HA is the superior most antimicrobial action against tests bacteria, while increasing the amount Ag-HA particles by more than 5% had an undesirable effect when compared with the control group (Sodagar et al., 2016). The addition of AgNPs and HA nanoparticles to dental porcelain was an effective method to decreasing the colonizing bacterial growth activity. However, Mohsen et al. (2015) claimed that there was decrease in the fracture strength and the color of dental ceramic after incorporation of silver HA nanoparticles in dental ceramics. Several agents were added to dental composites to control the secondary caries around resin composite fillings such as fluoride-releasing fillers (strontium fluoride and ytterbium trifluoride), quaternary ammonium, and silver-containing fillers (Itota et al., 2004; Nejatian et al., 2017; Syed et al., 2019). AgNPs were loaded in polydopamine (PDA)-coated hydroxyapatite (HAePDA) nanowires to form AgNPladen HA (HAePDAeAg) nanowires to achieve reinforcement and antibacterial effect in dental resin composites (Ai et al., 2017).

10.13

Conclusion

To sum up the above discussion, silver is playing a key role in the biomedical sciences as an active ingredient or we can say antibacterial agent. Its substitution with HA brings drastic changes in combating the microbes. We highlighted the different synthesis methods and applications in biomedical field.

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