Bioactive glasses—structure and applications

Bioactive glasses—structure and applications

17

Imran Farooq1, Saqib Ali1, Shehriar Husain2, Erum Khan3,4 and Robert G. Hill5 1 Department of Biomedical Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia, 2Department of Dental Materials Science, Jinnah Sindh Medical University, Karachi, Pakistan, 3Bhitai Dental and Medical College, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan, 4Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia, 5Dental Physical Sciences, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom

Chapter Outline 17.1 Introduction 454 17.2 Bioactivity of glasses

454

17.2.1 Mechanism of action 455 17.2.2 Solubility 455

17.3 Factors affecting apatite formation 456 17.4 Composition of different bioactive glasses

456

17.4.1 Silicate-based bioactive glasses 457 17.4.2 Borate-based bioactive glasses 458

17.5 Methods of synthesis 460 17.6 Clinical applications of bioactive glasses 17.6.1 17.6.2 17.6.3 17.6.4 17.6.5 17.6.6 17.6.7 17.6.8 17.6.9

460

Bone graft substitute 461 Bone regeneration 461 Drug delivery system 462 Coating of implants 463 Use in toothpastes 463 Antibacterial activity 465 Role in minimal invasive dentistry 465 Bioactive glass scaffolds 465 Particle size of bioactive glasses and its effect on various clinical applications 468

17.7 Future of bioactive glasses 17.8 Conclusion 470 References 470 Further reading 476

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Advanced Dental Biomaterials. DOI: https://doi.org/10.1016/B978-0-08-102476-8.00017-7 Copyright © 2019 Elsevier Ltd. All rights reserved.

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17.1

Advanced Dental Biomaterials

Introduction

“A material is said to be bioactive, if it gives an appropriate biological response and results in the formation of a bond between material and the tissue” (Farooq et al., 2012). Bioactive glass (BG) is a biomaterial that was introduced by Prof. Larry Hench in 1969 (Hench, 2006), with the intent of developing a biocompatible material that forms an intimate bond with the bone. The first glass discovered is known as 45S5 (Bioglass), having a glass composition of 46.1 mol.% SiO2, 24.4 mol.% Na2O, 26.9 mol.% CaO, and 2.6 mol.% P2O5 (Kobayashi et al., 2010). BG has the capability to interact with the body tissues to form a resilient bond, and its controlled degradation over time is useful in releasing therapeutic ions, which can help the bone regeneration (Fuchs et al., 2015; Ali et al., 2014). Safety of these glasses was a concern, so various studies were performed, and these glasses were graded safe to be used by US Food and Drug Administration (FDA) (Paolinelis et al., 2008). BGs are synthetic and osteoconductive materials that form a hydroxycarbonate apatite (HCA) layer at the site, after the dissolution of the glass (Jones, 2013). This HCA is comparable to the bone mineral, and it interacts with collagen fibers of the bone to form an adherent interface between the material and the tissue (Jones, 2013; Nejatain et al., 2017). Recently, BGs have been used for different dental applications such as in toothpaste to enhance enamel remineralization and occlude open dentinal tubules (Farooq et al., 2012). Recent modifications in the structure of BG have resulted in various formulations being available, such as high phosphate-based glasses, borate-based glasses, and fluoride-containing BGs (Khalid et al., 2017), and these glasses are different from the conventional 45S5 glass. Borate and phosphate glasses have rapid solubility (which can be altered from several hours to several months based on the end application) (Fu et al., 2010a), whereas fluoride-containing glasses can form fluorapatite (FAP) layer, on the surface, which promotes remineralization and is more durable in the mouth (Farooq et al., 2013). This chapter focuses on the structure of different BGs and their clinical applications. Apart from these objectives, this chapter also reviews the methods of their synthesis and gives an overview of bioactivity of these glasses.

17.2

Bioactivity of glasses

The BGs are highly bioactive and a previous in vitro study has demonstrated the formation of apatite by the new composition of glasses in Tris-buffer solution, in as little as 6 hours (Farooq et al., 2013). These glasses stimulate cell cycling in vitro, which results in stimulation of osteoblasts, as a result of which more mineralized tissue is formed in a shorter time (Xynos et al., 2000). Due to ion exchange, BGs can raise the pH of the solution in which they are present, thus exhibiting antibacterial effects (Gubler et al., 2008). Some groups of these glasses, such as silvercontaining BGs (Newby et al., 2011), release important ions, such as silver, which

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can augment these antibacterial effects (Kwakye-Awuah et al., 2008). In vivo studies are important as they help in predicting the clinical performance of a material. An in vivo survey carried out in rabbits showed better performance of 45S5 as compared to the synthetic hydroxyapatite (HAP) regarding bone regeneration (Oonishi et al., 2000).

17.2.1 Mechanism of action The bioactivity of these glasses is dependent on their mechanism and speed of action. Briefly, the reactions to form HAP involve ion exchange of Ca21 and Na1 ions for H1 ions from the solution, a consequent increase in the pH of the solution, the formation of silanol (Si-OH) bonds on the surface of the glass, and the resulting formation of a silica-rich layer, degradation of silica (due to increased pH), and then then the development of a layer of amorphous CaO P2O5 on the silica-rich layer, which then crystallizes as HAP due to the absorption of hydroxyl and carbonate ions (Jones, 2013).

17.2.2 Solubility The glass composition plays a vital role in determining the solubility and bioactivity of BGs. At this point, understanding some other terms such as glass transition temperature (Tg) and network connectivity (NC) becomes essential. The Tg is defined as a range of transformation when an amorphous solid is converted into a supercooled liquid on heating (Dudowicz et al., 2005). The degradation rate of the glass and its strength can be assessed through Tg (O’Donnell, 2011). There is a presence of a significant processing window between the Tg and peak crystallization temperature of glass warrants that the glass will not crystallize during quenching (Dimarzio and Gibbs, 1959). The presence of crystalline phases reduces the exchange of ions, and thus bioactivity is reduced (Ali et al., 2014). The NC can be defined as the mean number of bridging oxygen bonds per silicon atom (Hill and Brauer, 2011). It can be used to analyze the solubility and bioactivity of a glass, as a low NC implies that the glass has lower Tg, but a high solubility and bioactivity (Hill, 1996). The silica in the glass is considered a network former, which can hold the glass structure together (Srivastava et al., 2012). Therefore a lower content of silica can ensure faster dissolution and more rapid bioactivity (Jones, 2013). Fluoride is an essential ion when it comes to dentistry as it remineralizes tooth structure and prevents demineralization (Featherstone, 2000). The inclusion of fluoride in the BG composition decreases its Tg, which means that the glass will have a reduced hardness, but it will be more bioactive (Farooq et al., 2012). Sodium oxide (Na2O) can also affect the properties of BGs. The Na2O is regarded as a network disrupter as its addition expands the glass network; therefore it reduces Tg and the glass becomes more bioactive (Wallace et al., 1999). In the fluoride-containing BG compositions, when phosphate content is increased, it results in maintenance of the NC and formation of FAP (Brauer et al., 2010). In an in vitro study, it was reported that

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high phosphate-containing BGs were able to form apatite more rapidly in Trisbuffer solution and within 6 hours, as compared with low phosphate-containing BGs (which formed apatite after 3 days) (Mneimne et al., 2011). This means that by controlling the amount of phosphate in the BG composition, reactivity, and apatite-forming ability of the BGs can be controlled (Mneimne et al., 2011).

17.3

Factors affecting apatite formation

Many factors, such as different ions, can accelerate or hinder apatite formation ability of BGs. As described in the previous section, phosphate content can significantly increase apatite formation capabilities of BGs (when NC is maintained) (O’Donnell et al., 2009). Similarly, controlled addition of fluoride (Brauer et al., 2010) and substitution of calcium by strontium can positively favor the apatite formation process (Brauer, 2015). On the other hand, magnesium ions have been shown to delay or inhibit apatite formation (Diba et al., 2012), probably due to the obstruction of active growth sites on the apatite crystal surfaces (Kanzaki et al., 2000). Generally, for dental applications, faster apatite formation is required, whereas for some other medical applications, such as cartilage repair, a slower apatite formation is desirable (Brauer, 2015). Therefore the addition of different ions into BG composition can be carefully planned according to the desired outcome.

17.4

Composition of different bioactive glasses

The affinity of a biomaterial to bond to mineralized biological tissue is dependent upon its composition. A range of such glass systems has been developed over the years, which include compositional modifications with certain elemental additives and variations in synthesis techniques. The compositions of 45S5 and a few essential variants are shown in Table 17.1. Table 17.1 Composition of different bioactive glasses (Khalid et al., 2017).

45S5 13 93 6P53B 58S 70S30C 13 93B1 13 93B1 P50C35N15

Na2O

K2O

MgO

CaO

SiO2

P2O5

B2O3

24.5 6.0 10.3 0 0 5.8 5.5 9.3

0 12.0 2.8 0 0 11.7 11.1 0

0 5.0 10.2 0 0 4.9 4.6 0

24.5 20.0 18.0 32.6 28.6 19.5 18.5 19.7

45.0 53.0 52.7 58.2 71.4 34.4 0 0

6.0 4.0 6.0 9.2 0 3.8 3.7 71.0

0 0 0 0 0 19.9 56.6 0

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17.4.1 Silicate-based bioactive glasses Silicate glasses are considered as a reliable material when considering the design of novel medical devices boasting specific properties. A large surface area, a high degree of purity index, and porosity within the bulk of the material contribute significantly toward the high level of reactivity exhibited when employing this material for research purposes and as a component of a biomaterial (Aguiar et al., 2009). The open-ended structure of these BGs enables the manifestation of free space within the bulk of the material. This allows for the addition of Na1, K1, Ca21, and Mg21 cations into the glass matrix. These cationic species are termed as network modifiers. Network modifiers are known to induce network disruption—a crucial preliminary step if realization of nonbridging oxygen (NBO) groups is to occur within the glass structure (Gonza´lez et al., 2003; Sen and Youngman, 2003). The presence of NBOs has a strong influence on the connectivity of the material as a whole. The commercial variant 45S5 (based on silicate glass) has been the focus of multiple studies pertaining to biomedical applications (Hench, 2006). The inherent properties of this version of 45S5 allow for it to bond to mineralized bone tissue—a phenomenon which has been the subject of numerous investigations for the better part of four decades and counting. The silicate glass 45S5 structure can be best visualized as a three-dimensional (3D) SiO2 network with a central silicon ion surrounded by four coordinating oxygen ions arranged in a tetrahedron configuration. The SiO2 content in silicate BG compositions is in direct relation to their chemical stability. Moreover, glass network modifiers in variable ratios are the primary structural and compositional determinants of the bioactive nature of this material. Common glass network modifiers include Na2O and CaO, whereas magnesium (Mg21) and zinc (Zn21) fall on the border of modifiers and intermediate ions (which increase the processing window to avoid crystallization) (Dietzel, 1941). The role of these modifiers is to break some part of the Si O bonds, thereby creating NBOs and disturbing the tetrahedral silicate network (Benoit et al., 2001). In other words, these network modifiers are responsible for considerably lowering the connectivity value of the SiO2 network attributed to the formation of nonbridging silicon oxygen bonds. The resulting enhanced dissolution index translates into an increased probability of ionic exchange events at the surface of the material that would eventually contribute to the formation of a biomimetic HAP layer on the surface of the implanted material (Vichery and Nedelec, 2016; Hench, 1991). Phosphate ions can increase the bioactivity of the glass (Mercier et al., 2011), and a linear relationship in terms of increased bioactivity can be observed with the addition of phosphate in BG, owing to the inherent ability of phosphate to influence the formation of apatite in living mineralized tissues (Hill and Brauer, 2011). Some studies have aimed to decipher the bonding configurations and the presence of NBO groups by utilizing spectroscopic techniques such as infrared (IR) spectroscopy and X-ray photoelectron spectroscopy (Serra et al., 2003). The results from these analyses were found to be in agreement with one another. The inclusion of network modifiers to the silica network has a direct effect on electron density of the

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bonding states of the silicon and oxygen atomic structure (Serra et al., 2003). Moreover, by carrying out these analyses, the investigators were able to demonstrate a rise in the proportion of alkali-earth elements in the silica network, which leads to a concurrent cleavage of Si O Si (bridging oxygen) by Si O NBO groups (nonbridging silicon oxygen groups). This has far-reaching implications in terms of eliciting a reproducible and robust biological response at the material interface when submerged in body fluids (Peitl et al., 2001). The role of NBO groups during the initial stages of bioactivity of BGs is of much importance. IR spectroscopy has emerged as a powerful tool that yields useful information in terms of developing a quantifiable database pertaining to the concentration of Si O NBO groups and ultimately their bond strength, which may be ascertained from the relative intensity of the respective IR absorption bands. The ideal ratio between the Si O NBO and the Si O groups, estimated to be at $ 1 as derived from IR absorption band intensity, is critical for realization of an effective ion exchange and subsequent dissolution of the silica—ultimately contributing to the formation of an SiO2-rich layer on the material surface (Serra et al., 2002). Therefore a definite correlation exists between the nature and type of NBO functional groups and the formation of calcium phosphate rich layers. Hence spectroscopic techniques have established themselves as reliable techniques for gaining a deeper understanding of the pivotal role of network modifiers through alteration of the BG structure and subsequently their bioactive behavior. When the 45S5 BG is implanted, a chemical degradation reaction process releasing cationic species such as Na1 and Ca21 ensues. This paves the way for the formation of a carbonate-substituted HAP-like material. This leads to a subsequent release of silicon in the guise of silicic acid (Si(OH)4) (Lai et al., 2002). The low SiO2 and high Na2O and CaO content are important compositional features determining the bioactivity of 45S5 (Huang et al., 2006a). Many investigators still consider the original 45S5 version as the gold standard in the realm of BG for hard mineralized tissue regeneration. However, issues pertaining to the impact of time-dependent release of degradation products especially during the initial stages, when there is an uptake in the alkaline earth metal sourced cationic species concentrations of Na1 and Ca21 from the bulk of the material with accompanying pH changes (Tahriri et al., 2017), have yet to be fully elucidated in light of their biological niche, toxicity, and subsequent dispersion from the site of implantation. Another limitation of 45S5 glass is its incredible performance in high load-bearing applications such as bone scaffolds (Hench and Jones, 2015). Research is still going on to achieve tougher scaffolds that can serve as an appropriate scaffolding material.

17.4.2 Borate-based bioactive glasses The trace element boron is essential for maintaining bone health. The first borosilicate glass formulation to be considered for biomedical applications was conceived in 1990 (Brink, 1997). These glasses are considered as a reactive species, which accounts for their low chemical stability index. This translates to a more

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rapid conversion rate into HAP for this group of BG as compared to their silicabased counterparts (Yao et al., 2007). The substitution of SiO2 with B2O3 allowed a significant escalation in the conversion rate of borate glass to HAP postimmersion in aqueous phosphate solutions (Huang et al., 2006b). Although the mechanism by which borate-based BG undergoes conversion to a layer of apatite is similar to its silica-based equivalent, in that a borate-rich layer ensues in place of a silicate-rich layer, borate-based BGs are more amenable to precise tinkering with the degradation profile and sintering behavior, which can be achieved over a range of time lines in contrast to silicate-based BGs (Yang et al., 2012). Spanning the course of a few decades, a significant amount of research has been conducted, and consequently, key data have been generated from studies pertaining to the behavior and properties of the original formulation of 45S5 BG. On the other hand, probing research questions exploring borate-based compositions are only just beginning to surface in the literature (Rahaman et al., 2011; Kaur et al., 2014) An innovative take on developing BG powders was the development of sphericalshaped borate-based BG powders for replacement of bone tissue using spray pyrolysis (Cho and Kang, 2009). Evidence for the resulting crystalline structure of the powders prepared in this way was gathered using X-ray diffraction (XRD) analysis. The preparation technique had a profound influence on the phase transitions observed in the glass powder. Powders synthesized (using pyrolysis) below a temperature range of 1400 C predominantly exhibited a crystalline phase that dominated the composition. A low rate of turnover to the glass phase was attributed, in this instance, to a shorter “stay” time within the confines of the alumina reactor. The opposite is true in the case of increased preparation temperatures of 1500 C, in that the amorphous phase enjoyed a majority throughout the glass substructure summed up by a reduction in sharpness of the XRD peaks. In this way ideal temperature parameters for preparing spherical bioactive borate-based glass powders with a dense inner core were identified to stand at 1200 C. A standing criticism leveled against silicate-based BG stems from an incomplete conversion process for yielding a calcium phosphate material postimplantation in vivo. Indeed corresponding XRD patterns between different glass samples have in fact revealed the strongest intensity hydroxyapatite (HA) peaks, an indication of enhanced bioactive potential, in glass samples with increasing B2O3:SiO2 molar ratio postimmersion in a phosphate solution (Fu et al., 2007). These findings were in agreement with pH and weight loss studies—solutions containing glass samples having increased B2O3 content consistently showing increased pH values and more significant weight loss with immersion time compared to neat borate- and silicate-based glass samples (Huang et al., 2006b). The significant disparity in the reactivity, pH, and observable weight change rate between silicate and boratebased glass is primarily attributed to their overall network structure. The BO3 trihedron chains possess a threefold coordination number that hinders the formation of a 3D network structure when compared to their silicon-based counterpart (Cheng et al., 2009). This has a profound impact in lowering the chemical durability of the borate glass network structure translating to an accelerated dissolution rate.

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Moreover, in line with the suggestion put forth by prominently featured works, formation of a layer of HA on the surface of a biomaterial under certain parameters in vitro can be extrapolated as its bioactive potential in vivo (Hench, 1998; Zadpoor, 2014). The formation of a dense microstructured HAP as evidenced by scanning electron microscopy (SEM)-based surface morphological analysis on borate-based BG samples as reported previously (Yao et al., 2007) can be evaluated as evidence for bioactive potential in the same light. It is important to mention at this point the deviations in the mechanism that allows for the conversion of boratebased BG and silicate-based BG to carbonate-substituted HAP. Even though a large part of the dissolution precipitation reaction process for both glasses is similar for the most part, pure borate-based BG conversion to carbonate-substituted HAP differs considerably in that it does not involve the formation of the SiO2-rich layer at any point of the conversion and dissolution sequence when assessed postimmersion in a phosphate-rich solution (Huang et al., 2006b). Rather a complete ionic dissolution of the borate-based glass into the solution ensues due to a simultaneous infiltration and breakdown of the B O glass network structure by the phosphate solution. The process continues until the full conversion of the borate glass to carbonatesubstituted HAP postleaching and reaction of the Ca21 ions with the PO432 in solution. The rate at which borate-based BG undergoes conversion to carbonatedsubstituted HAP, a reliable scale for a measure of its degree of bioactivity, is heavily predicated on the B2O3:SiO2 ratio of the glass, with a higher B2O3 level translating to a higher borate glass conversion rate to HAP in this case.

17.5

Methods of synthesis

The BGs require a high standard of raw material purity prior to their preparation. This is mainly because the quality of the materials heavily influences the quality of the end product at the starting point. Pure silica sand (quartz), reactive grade carbonates of sodium and/or potassium, etc. are some of the common ingredients required in weighted amounts. BGs are usually of a soft nature. This usually allows for their easy shaping and sizing. Two common methods of preparing BGs include melt quenching (at temperatures exceeding 1200 C) and sol gel method (converting the system from a liquid “sol” into a solid “gel”) (O’Donnell, 2012). However, going into the details of these methods is beyond the scope of this chapter.

17.6

Clinical applications of bioactive glasses

The BGs are different from conventional glasses as they possess numerous features which ensure their wide-ranging clinical applications. These glasses are biocompatible, osteoconductive, and can bond firmly to the tissue (Toosi and Behravan, 2017). The conventional silicate-based glasses are composed of phosphate and calcium in somewhat similar proportion to that of the bone HAP. Due to these abilities, they

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can be utilized in a broad range of medical and dental applications. The BGs can be divided into different families having different compositions, which can be used for a specific function or to achieve a desired clinical outcome (Rao and Ravindranadh, 2016). These glasses can be effectively used for replacement, repair, or reconstruction of different body parts such as bone and teeth (Baino et al., 2014). Some of the most important applications of BGs are discussed in the following subsections.

17.6.1 Bone graft substitute When bone is lost due to an infection, disease process, or trauma, the bone can be replaced with a bone graft. Clinically, BG has been in use for more than a decade as a synthetic bone graft. In orthopedics, it is as a product called Novabone (Elshahat, 2006) and in maxillofacial surgeries as PerioGlas (Fetner et al., 1994). A very common BG which has been used as a bone graft is 45S5 (Rao and Ravindranadh, 2016). The FDA in 2005 permitted the use of 45S5 for osteostimulation (Hench, 1998). In another study it was reported that BGs have an osteostimulatory effect along with an osteoconductive function (Boccaccini et al., 2010), which other osteoconductive bioceramics usually lack (Gerhardt and Boccaccini, 2010). Also, their ability to bond to osseous tissues is much superior as compared with other alloplastic materials (Wilson et al., 1993). It is a reality that BGs do not have ideal mechanical properties, but the addition of Na2O into SiO2 CaO BG composition improves its biological absorbability and mechanical capability (Chen et al., 2010). A previous study reported that BG scaffolds can totally resorb in 6 months with little inflammatory response (Moimas et al., 2006), demonstrating their superiority over other bone graft materials which can cause adverse reactions as well (Wang and Yeung, 2017). An earlier study that was conducted on animal models where properties of BG and HAP were compared concluded that it is very easy to manipulate the composition of BG for specific uses, and BG takes less time in response generation as compared to HAP (Oonishi et al., 1997). The BGs when used as a bone graft have also shown admirable bone healing properties in numerous follow-ups of long-term studies (Khalid et al., 2017; Van-Gestel et al., 2015).

17.6.2 Bone regeneration Bone regeneration is another important clinical application, and BGs have a greater filler effect than that of an autogenous bone (Heikkil¨a et al., 1995). In a previous study by Macedo et al. (2004) two different compositions of BGs were used to study bone formation in tibiae of rats, and it was reported that both compositions of BGs promoted bone formation. It has been reported earlier that significant bone regeneration can be promoted by BGs in vitro as they have osteostimulatory effects (Hench, 2013). The presence of BGs in the treatment of large bony defects can result in infection-free bone regeneration (Stoor et al., 2017). In an animal study, periodontal defects were treated with particles of BG, which triggered bone mineralization (Felipe et al., 2009).

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One of the advancements in BG research is control of its degradation rate with the manipulation of its composition. Borate-based BGs are very useful in bone regeneration because of the variation of controlled degradations rates along with the ease of their fabrication. The compositional flexibility and easy manipulation of the glass composition can make it a source of different elements such as copper, fluoride, or boron which can encourage growth of the bone (Toosi and Behravan, 2017).

17.6.3 Drug delivery system Researchers have always been looking for an innovative drug delivery system to have superior medication control with a prolonged action. Assuming that a certain medication or molecule will reach a specific site without any secondary reactions and will perform the desired reaction, the drug delivery system becomes supremely important to the researchers. These glasses show larger flexibility in terms of compositional manipulation, making them independent of any specific stoichiometry. Thus ions of various concentrations having different therapeutic properties can be incorporated in conventional compositions. These ions can be released during the process of dissolution, and they can execute their desired therapeutic function in the human body (Hoppe et al., 2011). In a study on pulp capping agents containing BG, there was a greater occurrence of development of a properly positioned dentin bridge (Stanley et al., 2001). As discussed earlier, borate-based BGs are used in bone regeneration and can also be used in the treatment of infection of bone, where they act as a drugreleasing substrate (Liu et al., 2010; Jia et al., 2010). An earlier in vitro study comparing borate-based BGs with 45S5 reported that higher content of B2O3 improved the conversion rate to HAP, as compared to 45S5 particles, which stopped after only partial conversion of particles to HAP (Brown et al., 2009). Another study has also revealed that teicoplanin-loaded borate BG implants could be helpful in treating chronic osteomyelitis in animals (Zhang et al., 2010), so it can be predicted that they will be equally useful in humans as well. In a previous study conducted on animal models, BG porous blocks were used for delivering antibiotics in treating osteomyelitis (Kundu et al., 2011). After 2 years of treatment of infected arthroplasty, some outstanding results were witnessed, and osteogenesis was triggered by the implant material, which was evident on radiography where complete radiological replacement of the osseous defects was seen (Kawanabe et al., 1998). Excellent bone integration and biocompatibility were seen in BG implants infused with gentamicin sulfate, which released gentamicin into local osseous tissues, and during the resorption process, these implants also promoted the growth of the bone (Meseguer-Olmo et al., 2006; Arcos et al., 2001). In another study BG combined with tetracycline and BG combined with tetracycline:beta-cyclodextrin were able to demonstrate considerable bacteriostatic activity with little effect on the bioactivity of the glass itself (Domingues et al., 2004).

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17.6.4 Coating of implants The success of dental implants is dependent on several factors, of which the implant material is of utmost importance (Najeeb et al., 2015). Over time, the use of metallic materials has grown significantly due to their ideal mechanical properties (Roessler et al., 2002). Metals such as titanium, cobalt, and stainless steel (SS) grade 316L are used in the preparation of implants (Garcia et al., 2004). SS has been the choice in orthopedic implants as it is quite economical (Fathi et al., 2003). But this material, in long-term use, is very much prone to unwanted biological reactions, thus leading to failure of the implant mechanically. Titanium (Ti) and Ti-alloys have good mechanical and physical properties which makes them the material of choice for implant applications, and currently, they are the most widely used implant material (Najeeb et al., 2017). It is a challenge to get a perfect interface between the dental/orthopedic implant and the bone, because the development and preservation of viable bone opposing the biomaterial surfaces are very essential for the success and the stability of noncemented dental/orthopedic implants (Moimas et al., 2006). There has been the initiation of extensive research into coatings of metallic implants with BGs as BGs offer worthy bone bonding ability with controlled surface reactivity (Greenspan, 1999; Hench and Andersson, 1993; Ferraris et al., 1996). It was reported earlier that a bond is formed between implanted bioceramics and natural tissues as a result of an active biological layer that is formed on the surface of the implant by bioactive materials (Rahaman et al., 2011). In another study performed on the human jaw bone, there was a comparison of Ti-alloy dental implants coated with BG and HAP, and it was concluded that both materials were nontoxic and biocompatible, and BG demonstrated good osseointegration properties, comparable to that of HAP (Mistry et al., 2011). It is a common practice nowadays to use implants coated with BGs for achieving good osseointegration with the alveolar bone. Using BG in dental implants as coating material shows superior bone regeneration along with better adherence to the metal surface of the implant (Koller et al., 2007).

17.6.5 Use in toothpastes The use of BGs in toothpaste has been increased in the last two decades. They have been incorporated in various toothpastes because of their potential to treat dentin hypersensitivity and to remineralize tooth structure (Abbasi et al., 2015). BGs’ first commercial use in oral health was to treat dentin hypersensitivity, keeping in mind that they have the capability to occlude by a HAP layer the uncovered dentinal tubules that are the main cause of the pain and sensitivity (Burwell et al., 2009; Dababneh et al., 1999). The BG-based dentifrice has showed superior tubule occlusion properties on dentin discs of extracted human teeth when compared with a standard fluoride-based dentifrice, before and after a citric acid challenge, in an in vitro SEM study (Fig. 17.1) (Farooq et al., 2015).

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Figure 17.1 Scanning electron microscopy micrograph of a dentin disc that was brushed with bioactive glass containing toothpaste, post citric acid challenge at 6000 3 , scale bar: 20 mm. Source: Adapted from Farooq, I., Moheet, I.A., AlShwaimi, E., 2015. In vitro dentin tubule occlusion and remineralization competence of various toothpastes. Arch. Oral. Biol. 60 (9), 1246 1253.

Lynch et al. (2012) also reported admirable capability of fluoride-containing BGs in occluding open dentinal tubules in an in vitro study. In recent times it has also been established that BGs can act as a remineralizing agent (Mehta et al., 2014; Reynolds, 2008). The role of fluoride in prevention and its application is of interest in dentistry. The addition of fluoride to BGs not only enhances remineralization, but it also prevents demineralization of enamel and dentin (O’Donnell, 2011). Farooq et al. (2018) performed a study to analyze remineralization potential of a novel dentifrice consisting of fluoride-containing BG (BiominF) with that of a dentifrice containing only BG (Novamin). Enamel blocks were demineralized with citric acid and then remineralized using toothpaste slurries (a mixture of toothpaste with artificial saliva). After 5 minutes and 24 hours, mean enamel volume changes were evaluated by microcomputed tomography, and mean surface loss or gain was investigated using a profilometer. It was demonstrated through the results of this study that BiominF specimens showed better remineralization potential, especially after 5 minutes. The possible reason for the better performance of BiominF could be that it contains fluoride in its BG composition with high PO432 content, which could serve as a source of the delivery of all essential ions (Ca21, PO432, and F2) together to form FAP, rather than fluorite (CaF2) (Mneimne et al., 2011). Another difference between Novamin and BiominF is the difference between their particle size (BiominF being smaller than Novamin), which can result in better tubule occlusion. The difference between the particle size of these two materials is shown in Table 17.2.

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Table 17.2 Showing particle size difference between Novamin and BiominF (http://www.biomin.co.uk/science/bioactive-glasses/biomintm-vs-novaminr). Particle size

Novamin (µm)

BiominF (µm)

D10 D50 D90

0.177 14.47 45.55

0.62 5.92 0.62

17.6.6 Antibacterial activity Besides remineralization, these glasses can show antibacterial activity as well by raising the pH of an aqueous solution. It is very common to use antimicrobials in certain dental procedures used in the fields of periodontics and endodontics (Khalid et al., 2017). In a previous study the insertion of BG in periodontal defects has shown inhibition of bacterial colonization due to the rise in the pH and possibly because it provided calcium ions to the defective site (Allan et al., 2001).

17.6.7 Role in minimal invasive dentistry BGs have a shown significant potential in minimally invasive dentistry. BG powder can also be utilized in cutting cavities with air abrasion, causing less damage to tooth enamel as compared to conventional cavity preparation performed by a highspeed handpiece. Alumina powder is commonly used in air abrasion machines, as it has coarse particles (Fig. 17.2) (Hassan et al., 2017), but it is an inert material having no benefit other than quick cutting. Alumina can be replaced with BGs, as they possess apatite-forming ability, and also have coarse angular particles with sharp edges (Fig. 17.3) for efficient cutting. Farooq et al. (2013) synthesized a few new, different compositions of BGs with fluoride and reported the formation of apatite in vitro within 6 hours (which was quicker than traditional 45S5) and with comparable cutting efficiency to that of alumina (Fig. 17.4).

17.6.8 Bioactive glass scaffolds Tissue engineering has developed extensively in the past two decades as an approach for the repair and regeneration of tissues and organs which are lost or damaged due to traumatic injuries, diseases, or the aging process (Nerem, 1991). Autografts, bone allografts, synthetic biomaterials, and metallic implants have been reported in the literature for the rejuvenation of tissue and bony defects. The limitations of current treatments and the higher costs have encouraged interest in the engineering of new bone substitutes. The target of scaffold-based bone tissue engineering is to repair and regenerate bony defects with minimum side effects (Hutmacher et al., 2007). A scaffold is a porous structure which, preferably, should direct new tissue formation by providing a matrix with interconnected porosity and

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Figure 17.2 Scanning electron microscopy micrograph of alumina particles at 500 3 , scale bar 300 μm. Source: Adapted from Hassan, U., Farooq, I., Moheet, I.A., AlShwaimi, E., 2017. Cutting efficiency of different dental materials utilized in an air abrasion system. Int. J. Health. Sci. (Qassim) 11 (4), 23 27.

Figure 17.3 Scanning electron microscopy micrograph of 45S5 at 1000 3 , scale bar 100 μm.

tailored surface chemistry for the cell growth and proliferation and the transport of nutrients and metabolic waste (Hansbrough et al., 1994). Ideally a scaffold should mimic the bone morphologically, structurally, and functionally in order to augment integration with its surrounding tissues (Johnson and Herschler, 2011; Karageorgiou and Kaplan, 2005).

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Figure 17.4 FTIR spectra for a BG batch which shows formation of apatite at 6 h. BG, Bioactive glass; FTIR, Fourier-transform infrared spectroscopy. Source: Adapted from Farooq, I., Tylkowski, M., Mu¨ller, S., Janicki, T., Brauer, D.S., Hill, R.G., 2013. Influence of sodium content on the properties of bioactive glasses for use in air abrasion. Biomed. Mater. 8 (6), 065008.

BGs have etching characteristics as a scaffold material for bone tissue engineering. These glasses undergo specific reactions that lead to the formation of amorphous calcium phosphate or crystalline HAP phase on the glass surface, which results in a stable bonding with the surrounding tissue (Jones et al., 2006). The activation of expression of osteogenic genes (Xynos et al., 2001) and stimulation of angiogenesis have been reported by BGs (Gorustovich et al., 2009). Although the low mechanical strength of BG scaffolds limits their usage for the repair of defects in load-bearing bones (Yunos et al., 2008), researchers have tried to overcome this issue by optimizing the composition, sintering conditions, and processing, and now BG scaffolds can be created with predesigned pore architecture and with strength comparable to human trabecular and cortical bones (Liu et al., 2011). In addition to strength and elastic modulus other mechanical properties such as reliability and fracture toughness are also of decisive importance for scaffolds implanted in loadbearing bone defects. As mentioned earlier, BG scaffolds can be created with the preferred compressive strength for the restoration of load-bearing bone defects. Still their practice in these applications may be restricted due to their intrinsic brittleness, which is also called fracture toughness. Adding a biocompatible polymer coating is suggested to improve the toughness of BG scaffolds by providing a crack bridging mechanism through the polymer layer for energy dissipation. Regardless of its innate brittleness, BG has numerous appealing characteristics to be used as a scaffold material in bone tissue engineering, especially novel innovative BGs

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established on borosilicate and borate compositions that have displayed the capability to develop new bone formation (Rahaman et al., 2011) with the least side effects. Literature reports various methods for the fabrication of BG scaffolds, which include sol gel, freeze casting, thermal bonding of particles, polymer foam replication, fibers or spheres, and solid free-form fabrication. The capability of BG scaffolds to support cell function and proliferation in laboratories and clinical tissue ingrowth has been publicized in many studies (Fu et al., 2010a; Goodridge et al., 2007; Fu et al., 2010b; Zhao et al., 2008). Regardless of brittleness, BGs have a distinctive set of properties such as formation of HAP layer, intimate bond formation with hard tissues, and release of ions during the degradation process, which are favorable for osteogenesis, angiogenesis, and chondrogenesis (Rahaman et al., 2011). Prospective research is expanding on the favorable properties of BGs, considering brittleness through innovative scaffold design and processing, predominantly when used for the repair of load-bearing bones.

17.6.9 Particle size of bioactive glasses and its effect on various clinical applications Before concluding this section, another key area to discuss is the importance of particle size of BGs and its impact on various clinical applications. In general, a smaller sized BG particle is preferred as it can produce better results. A few common BG-based materials along with their particle sizes and uses are summarized in Table 17.3. In dentistry an increased particle size of the glass in toothpaste can cause more abrasion of the enamel (Mahmood et al., 2014). Therefore one solution is to use smaller sized particles in dentifrices. To comminute the glass frit, percussion milling (ball milling) is usually performed (Mahmood et al., 2014). But grinding the particles to a smaller size (after milling) usually involves higher costs; therefore another alternative is to reduce the abrasivity of the existing glass by incorporating

Table 17.3 Showing particle size of different bioactive glass based products used for various clinical application. Product

Particle size

Uses

Novamin PerioGlas

(D50 value) of 18 μm 90 710 μm

Biogran

300 360 μm

Used in toothpaste to treat hypersensitivity by blocking open dentinal tubules Used for bone regeneration around the tooth or bone repair in the jaw for anchoring implants Used as a bone graft in jaw defects

Source: Values adapted from Jones, J.R., 2013. Review of bioactive glass: from Hench to hybrids. Acta Biomater. 9 (1), 4457 4486.

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ions such as fluoride, which can produce a softer glass that will form FAP (Mneimne et al., 2011). Wilson and Low (1992) reported the effect of different sizes of 45S5 particulates on the regeneration of bone in periodontal defects produced in a monkey model. The study demonstrated the ideal rate of bone repair when a range of 45S5 particle sizes were used. In another study Ajita et al. (2015) studied the effect of the size of nanostructured BG particles on mouse mesenchymal stem cell (MSC) proliferation. It was concluded from this study that smaller sized nano-BG particles were able to increase proliferation of MSCs, thus implicating that they could produce desirable results in various clinical applications.

17.7

Future of bioactive glasses

The development of composite materials combining biodegradable polymers (synthetic and natural) with nanoscale BG particles or fibers is emerging as a robust approach toward third-generation bioactive materials. The biomedical applications of these novel materials are bound to expand, for example, as bone filler materials, temporary orthopedic implants, as 3D biocompatible scaffolds in the field of tissue engineering (Guarino et al., 2007), and in the dental industry for tooth remineralization, dentin regeneration, and reconstruction of bony defects. Composite materials add strength and bioactivity through an inorganic bioactive filler while polymers enhance flexibility and capacity to distort under loads (Boccaccini et al., 2010). The 45S5 particulate has been used in many oral care products for the treatment of tooth hypersensitivity as 45S5 particles stick to the dentin by forming a HAP layer that is comparable in composition to tooth enamel, and it blocks the dentinal tubules, thus relieving the pain for extended periods (Gillam et al., 2002). Dental care with 45S5 is not limited to toothpaste only. Sodium bicarbonate abrasives are used to remove stains by dentists, but the use of 45S5 through air polishing can stimulate remineralization; thus it reduces dentin hypersensitivity along with better stain removal and results in much whiter teeth (Banerjee et al., 2010). The use of BG, as or in a restorative material, is a debatable topic, as it is meant to degrade in an aqueous solution (saliva in case of the oral cavity). However, a recent study by Khvostenko et al. (2016) reported that the use of BG as filler for resin-based composite restorations could decrease biofilm penetration into marginal gaps of simulated tooth restorations, thus implicating that composite restorations containing BG can reduce the development and propagation of secondary tooth decay at the margins of the restoration. Another potential area (related to dentistry) for the BG is their use as pits and fissure sealant. Previously, Yang et al. (2016) reported in an in vitro study that BGcontaining sealants can inhibit the demineralization of the enamel surface within microgaps between the material and the tooth when disclosed to a cariogenic environment.

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Conclusion

BGs make a firm bond with the host and have the ability to degrade and form apatite in physiological solutions. The easy manipulation of their composition makes them the material of choice for extensive clinical applications. With their current use in different medical and dental applications, an optimistic future for these glasses can easily be anticipated.

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Further reading Hench, L.L., 1981. Bioceramics. J. Am. Ceram. Soc. 81 (7), 1705 1728. Owens, G.J., Singh, R.K., Forouton, F., et al., 2016. Sol gel based materials for biomedical applications. Prog. Mater. Sci. 77, 1 79.