The Use of Bioactive Glasses in Periodontology

Chapter 9

The Use of Bioactive Glasses in Periodontology John Nicholson Bluefield Centre for Biomaterials Ltd, London; Dental Materials Unit, Institute of Dentistry, Queen Mary University of London, United Kingdom

9.1 INTRODUCTION Periodontology is the branch of dentistry that is concerned with the supporting structures of the teeth. As such, it focuses on maintaining these structures in good health and free from disease and damage (Lindhe, 1983). Teeth in humans are supported by a complex biological structure known as the periodontium. This structure is embedded in alveolar bone of either the maxilla or the mandible, and it includes a layer of cementum and the periodontal ligament. The latter has some flexibility and also toughness, and these f­ eatures allow it to cushion the teeth to an extent, so that they are able to perform their biological functions. These are typically those of biting, tearing, and chewing. Covering the alveolar bone is the gingiva (gums), a soft tissue well supplied with blood vessels and which, in healthy patients, is pink in color. The structure of the periodontium is susceptible to attack by bacteria and this leads to the occurrence of specific periodontal diseases. These are gingivitis (early stage disease) and periodontitis (later stage disease) (see Table 9.1). The latter is especially damaging, since it results in destruction of the alveolar bone that supports the teeth. When this occurs, the teeth become loose and are ­eventually lost completely. In this way, periodontitis is the leading cause of tooth loss in adults throughout the world. The early stage disease, gingivitis, is the result of attack on the soft ­supporting tissue by bacteria naturally present in the mouth (Lindhe, 1983; Fermin and Carranza, 1996). These include Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola. Attack by these organisms causes the gums to become inflamed and red in color. In this condition, they bleed readily. This condition represents only a mild infection, and it can be reversed by improved oral hygiene, specifically brushing the teeth and gums at least twice a day and cleaning between the teeth with dental floss. Additional regular cleaning by a Biomedical, Therapeutic and Clinical Applications of Bioactive Glasses https://doi.org/10.1016/B978-0-08-102196-5.00009-4 © 2019 Elsevier Ltd. All rights reserved.

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TABLE 9.1  Stages of Periodontal Disease Stage

Diagnosis

Signs and Symptoms

Treatment

1

Gingivitis

Some swelling and redness of gums. Bleeding. Possible halitosis

Good oral hygiene (brushing and flossing) plus treatment by dental hygienist

2

Slight to moderate periodontitis

Increased redness. Bleeding. Halitosis

Professional scaling and root planning

3

Advanced periodontitis

Redness, swelling and oozing gums. Pain when chewing. Severe halitosis. Tooth loosening

Periodontal surgery plus extensive disinfection of deeper pockets

dental hygienist is also beneficial, particularly where this includes removal of the hardened plaque substance known as tartar or calculus. This latter substance builds up on certain tooth surfaces and acts as a location for bacteria to reside and thus become the focus for continued gingival infection. Gingivitis is considered mild partly because it can be reversed so readily, and also because it does not result in tooth loss (Fermin and Carranza, 1996). This is due to the fact that it infects only the soft tissue of the gingiva, rather than the alveolar bone. However, if gingivitis is not treated, it may develop further into the condition known as periodontitis. At this stage, the soft tissue of the gingiva retreats from the base of the tooth to leave spaces known as pockets. Bacteria from the oral plaque can enter these pockets, from where they are difficult to dislodge. Their continued presence in the pockets leads to infection. Once infection occurs, the body’s immune system becomes involved, and this is partly responsible for the breakdown of bone and connective tissue below the gumline. This natural response to infection is augmented by toxins produced by the infecting bacteria, and these all accelerate the loss of bone and connective tissue. If left untreated, this will eventually lead to the destruction of the supporting alveolar bone, resulting in the teeth becoming so loose that they are eventually lost altogether. Periodontal diseases are rare in young children and teenagers, and in general do not develop until patients are at least in their thirties (Lindhe, 1983). It has been estimated that some 48% of adults in the United States have chronic periodontitis and other countries appear to have similar prevalence of the disease (Albandar, 2005). Men appear to be more susceptible to periodontal disease than women for reasons that are not entirely clear. There are a number of risk factors that increase the chances of developing periodontal diseases, some of which arise from the lifestyle choices of the patient.

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Poor maintenance of oral hygiene is clearly one such risk factor, as is smoking. Other risk factors are: (i) Hormonal changes in females; (ii) Diabetes; (iii) Other diseases and their treatments; (iv) Medications; (v) Genetic susceptibility. The most obvious sign of the onset of periodontal diseases is the ­development of red and swollen gums, which bleed readily. Other signs and symptoms can ­include halitosis, pain during chewing, and receding gums (Fermin and Carranza, 1996).

9.2  TREATMENT FOR PERIODONTAL DISEASE The conventional treatments for periodontal disease have, for many years, been combined scaling and root planning or open flap debridement (Shue et  al., 2012). Scaling and root planning is an effective method of deep cleaning below the gumline which is carried out to remove plaque and tartar from the pockets around the teeth. The treatment has two parts. Scaling is the first step, and in this step, hand instruments are employed to remove plaque and tartar from the subgingival region by scraping. This step is followed by planning, a step in which the roots of the teeth are smoothed and contoured in order to encourage the soft tissue of the gingiva to reattach. Such treatment should be followed up with an improved regime of oral hygiene, with twice-daily toothbrushing and the regular use of dental floss. Medication such as treatment with doxycycline may also be used to ensure that the newly cleaned pockets do not become re-infected. Open flap debridement is a more invasive technique which aims to achieve much the same thing in terms of pocket cleanliness and gingival reattachment, but which allows the operator to have visual access to the region being treated. In contemporary clinical practice, it is typically carried out prior to placing implants or other materials with the potential to regenerate the alveolar bone. Both processes have a long history of clinical effectiveness (Shue et  al., 2012). Above all, they lead to removal of the infection and reductions in the size of the periodontal pockets. They also make subsequent cleaning easier. However, they are not the only treatments that can be applied. Modern periodontology makes use of a number of additional procedures, all of which involve surgery. The simplest is to implant a finely divided bioactive ceramic to promote regrowth of the alveolar bone. Of greater complexity is the provision of implants to replace teeth lost as a result of periodontal disease. In this case, a number of factors need to be considered. Since periodontal diseases arise from poor oral health, it is essential that this be addressed and improved if the placing of implants is to be successful. In addition, where there has been any significant loss of alveolar bone, this must be addressed prior to the provision of implants.

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A number of bioactive materials have been considered for use in these procedures. The present chapter concentrates on bioactive glass for these roles, but it should be noted in passing that other materials (hydroxyapatite and other synthetic calcium phosphate ceramics) have also been used with some success. However, bioactive glass is a key material in these applications and its versatility and ease of use has led to considerable clinical success. This will be explored in the remainder of the present chapter. A further potential complication in periodontology is the occurrence of furcation defects. These are the result of periodontal disease developing in multirooted teeth at the points where the roots of the tooth branch (Waerhaug, 1980). If left untreated, such furcation defects lead to the loss of alveolar bone at the branching point of the tooth root. Once this has begun, there typically follows considerable destruction of the bone as plaque, tartar, and bacteria occupy the space created at the furcation. Eliminating or reducing plaque in this region becomes impossible, so that the infection remains in place, causing the disease to progress and substantial bone loss to occur. These furcation defects can occur in various teeth of an adult, but are most common in the first molar of the mandible (Larato, 1970). Treatment can be difficult, not only because access to the diseased area is difficult for the dentist to achieve, but also because the anatomy makes it problematic to gain visual access to the affected region. Specially shaped scalers can be used to scrape clean root surfaces around furcation defects. Ultrasonic scalers can also be used to loosen debris and biofilm components, which can then be flushed away by a jet of water. Antimicrobial compounds can be employed to maintain sterile conditions in the area in question, while the furcations stabilize. Further treatment can then involve bioactive materials, such as Bioglass, which can be applied to the affected region in an appropriate carrier to stimulate bone deposition around the affected tooth.

9.3  NONGLASS MATERIALS USED IN PERIODONTAL THERAPY Before going on to describe the role of bioactive glasses in periodontology, it is appropriate to consider the alternatives that are available to clinicians. In all cases, these materials need to have the ability to promote regeneration of the periodontal tissues that have been affected by periodontal disease. In this way, the various materials are helpful in correcting defects caused by this disease. The term regeneration means the complete reestablishment of the tissues supporting the teeth, including the alveolar bone, periodontal ligament, and cementum (Cortellini and Tonetti, 2000). Indeed, it can be stated that the main goal of periodontal regeneration is to develop the complete structure of new cementum with fibers of periodontal ligament connected to fully formed alveolar bone (Polimeni et al., 2008; Sculean et al., 2008). The newly formed periodontal ligament fibers should be correctly oriented with respect to the

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TABLE 9.2  Materials Other Than Bioactive Glass Used in Periodontal Therapy Material

Comments

Hydroxyapatite

Similar composition to bone. Mixed clinical results

Tri‑calcium phosphate, αβ

Good resorbability, good clinical outcomes

Biphasic calcium phosphate

Biodegradable. Useful for bone defects

Calcium sulphate

Used as a barrier. Properties improved by mixing with bone allograft

Degradable polymer systems

Includes chitosan, polylactic acid, lactic acid/ glycolic acid copolymer. Used as delivery vehicles (drugs, growth factors) to affected sites

cementum and alveolar bone, a process which may involve so-called guided tissue regeneration (Shue et al., 2012). Some of the most frequently used materials for periodontal therapy are shown in Table 9.2. Their features will be considered briefly in the rest of this section of the chapter, but full details of the use and clinical outcomes are not included. For these, the reader is directed to the references cited. Natural polymers such as chitosan have mainly been used as delivery vehicles for biologically important molecules. For example, chitosan has been used to deliver DNA (Akncbay et al., 2007) and growth factors (Zhang et al., 2006; Akman et al., 2010). Synthetic polymers (polylactic acid or lactic acid-glycolic acid copolymers) have been used to create artificial membranes capable of being resorbed (Hou et  al., 2004; da Silva Periera et  al., 2000). The use of such resorbable membranes allows the natural periodontal ligament to regenerate and does not then need further surgery to remove the synthetic materials (Hou et al., 2004). As Table  9.2 shows, a variety of calcium phosphate materials have been used, and these typically have good properties. Their composition resembles that of bone mineral, and they are bioactive. This allows them to promote cellular function that leads to the healing of bone defects. Results vary somewhat between materials and also depend on their state of division and/or porosity of the material as applied. Hydroxyapatite, both natural and artificial, has been used extensively in various clinical fields where bone augmentation and regeneration are required (Shue et al., 2012). It has a similar composition and structure to the natural hydroxyapatite found in bones (Wang et al., 2007) and is known to bond directly to bone on implantation (Bagambisa et al., 1993). Despite its widespread use, applications of hydroxyapatite are limited because its surface properties are variable and this leads to inconsistent reactions by cells (Deligianni et al., 2001). This, in turn, can lead to only limited bone regeneration (Shue et al., 2012).

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In recent years, an alternative to hydroxyapatite, tricalcium phosphate, TCP, has been studied extensively as a potential bone substitute. TCP exists in two possible phases, α and β, of which β-TCP has been found to display particularly good biocompatibility and osteoconductivity in both animal and human studies (Shue et al., 2012). The latter property is defined as the ability to allow bone to form on a surface by serving as a scaffold or as a template (Hench and Wilson, 1993), and is an important feature of these materials when they are used in periodontology. For example, clinical studies using granular βTCP to repair periodontal defects have shown significant reductions in pocket depth and increases in gingival cell attachment within 6 months (Chawla et al., 2011). However, despite these successful features, β-TCP did not appear to stimulate regeneration of cementum, periodontal ligament, or alveolar bone (Stavropoulos et al., 2010). Calcium sulfate has been used with some success in periodontal therapy, mainly to act as a barrier for use with other graft materials (Moore et al., 2001; Sukumar et al., 2010). Used in this way, it can assist the process of periodontal regeneration (Pecora et al., 1997). However, in order to obtain the best clinical outcomes, calcium sulfate has to be mixed with another material, such as demineralised bone matrix (Orsini et al., 2008, 2001). This improves its bioactivity, and allows it to function to actively promote bone regeneration.

9.4  BIOACTIVE GLASS The field of bioceramics was effectively launched by the discovery of the glass later termed 45S5 and Bioglass, the composition of which is given in Table 9.3 (Jones, 2013), and the properties of which are given in Table 9.4 (Jones, 2013). It had been designed deliberately by Hench to be degradable (Hench, 2006), but was subsequently found to form a strong attachment with bone by direct bonding (Jones, 2013). This was in distinct contrast with the implantable materials known at the time, which were designed to be biologically inert. For such bio-inert materials, implantation caused a fibrous capsule to be formed and to completely encapsulate them. This prevented the formation of a stable interface capable of bonding directly with the tissues. TABLE 9.3  Composition of Bioglass Component

Proportion (mol%)

SiO2

46.1

Na2O

24.4

CaO

26.9

P2O5

2.6

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TABLE 9.4  Properties of Bioglass (Jones, 2013) Property

Value

Density

2.7 g cm−3

Network connectivity

2.12

Glass transition temperature

538°C

Onset of crystallization

677°C

Coefficient of thermal expansion

15.1 × 10−8°C−1

Young’s modulus

35 MPa

Bioglass not only bonds rapidly to bone, it also stimulates bone growth in the region adjacent to the bone-glass interface (Jones, 2013; Jones et al., 2016). The mechanism for this has been elucidated and the process appears to occur by initial dissolution of the upper layers of the glass followed by the formation of a layer of carbonated hydroxyapatite (hydroxycarbonate apatite, HCA) on the surface of the glass. This latter step is attributed to the presence of elevated levels of calcium ions and soluble silica species in the region around the implant caused by the initial dissolution. These soluble species stimulate osteogenic cells to produce bone matrix, the inorganic component of which is HCA (Hench and Polak, 2002). The bioactivity of this glass arises from the rapid rate of dissolution and consequent speed of deposition of the HCA layer. These steps then stimulate regeneration of the adjacent bone. Although there has been a huge amount of research since the original bioactive glass formulation was reported, including further work on conventional silicate glasses of varying composition, and also on phosphate and borate glasses, the biological properties of 45S5 (Bioglass) have not been improved upon (Jones, 2013). The first commercial product that employed particulate Bioglass was a granular substance for use in periodontology, known as PerioGlas. This product, which is now sold by NovaBone Products LLC of Alachua, Florida, came onto the market in 1993 (see Fig. 9.1). It received FDA approval in this year and the CE mark in 1997, and was designed for the clinician to press it into place within periodontal defects during surgery. The particles in this product have sizes in the range 90–710 μm and when used in this way the material has had considerable clinical success. It has been found to stimulate regrowth of bone to such an extent that an affected tooth can be readily saved. PeroGlas particles can also be used to prepare compromised alveolar bone to receive titanium implants, where the resulting

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FIG. 9.1  Commercial products for periodontology based on Bioglass. (Reproduced with permission from Fermin, A., Carranza, J., 1996. Classification of diseases of the periodontium. In: Carranza, F.A., Newman, M.G. (Eds.), Clinical Periodontology, eighth ed. W.B. Saunders, Philadelphia, p. 58.)

anchorage is capable of successfully maintaining support for the implants for long periods of time (Norton and Wilson, 2002).

9.5  BONE-BONDING BY BIOACTIVE GLASS Bioactive glass is appropriate for use in the treatment of periodontal diseases because of its ability to stimulate the growth of new bone. This is able to replace the bone destroyed by the progression of the periodontal disease. In this way, the teeth cease to be loose, and they are no longer in danger of being lost. The mechanism of this bone-bonding will now be considered in detail. Not surprisingly, given its biological complexity, the full details of the processes underlying bone regeneration and bone bonding are not fully understood (Jones, 2013). However, some aspects are well known, particularly those associated with the early part of the process. The strong bond formed between bone and bioactive glass is attributed to the formation of an HCA layer, a layer that is able to interact with collagen fibrils of the diseased bone to form a bonded structure (Hench and Paschall, 1973). Following the formation of this HCA layer, bone bonding occurs. The latter process is thought to involve protein adsorption, followed by incorporation of collagen fibrils. After this, bone progenitor cells become attached, cell differentiation occurs, and this leads to excretion of bone extracellular matrix and subsequent mineralization (Hench and Polak, 2002). Although the details of these later steps are not clear, it is apparent that the HCA layer that forms initially is able to act as an appropriate surface for the attachment and subsequent proliferation of osteogenic cells. The formation of HCA itself is a multistep process, and appears to involve five distinct steps, which apply in both natural body fluids in  vivo and in

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simulated body fluid in vitro (Clark et al., 1976; Hench, 1991). These are as follows: (i) Formation of silanol groups on the surface of the glass particles via a cation exchange process: ] Si ] O - Na + + H +  ] Si ] OH + Na + As a result of the removal of protons from solution in this way, the surrounding pH increases. (ii) This high local pH leads to an excess of OH− ions in the solution around the glass particles. These ions attack the SiOSi units in the surface of the glass, forming Si(OH)4, which is lost into the solution. (iii) The SiOH groups at the surface undergo a condensation process to create SiOSi units in a prepolymerization reaction. (iv) Ca2+ and PO 4 3- groups within the glass migrate to the surface and contribute an amorphous calcium phosphate component at the surface layer, nucleating onto the SiOH groups on the glass surface (Li and Zhang, 1990; Doostmohammadi et al., 2011). (v) Hydroxide and carbonate ions present in solution become incorporated into the surface layer, and these interact with the calcium and phosphate ions to form HCA (Fitzgerald et al., 2009). Having formed HCA by this well-defined process, there are further steps that lead to the attachment of bone. These steps are less well understood, but some aspects are known (Jones, 2013). Specifically, these are: (i) Proteins adsorb on the HCA surface. (ii) Cells are able to attach to the resulting deposited protein layer, and they do so, going on to differentiate. (iii) Differentiated cells produce a bone matrix and eventually fully formed bone, bonded strongly to the glass surface. These glass surfaces can thus be seen to have substantial biological activity. Human osteoblasts grown on bioactive glass have been found to produce an extracellular matrix, ECM, which mineralizes to form nodules of bone (Gough et al., 2004; Kaufmann et al., 2006; Bosetti and Cannas, 2005). The calcium ions and the soluble silica species dissolved from the surface of the bioactive glass stimulate cell division in osteoblasts, and also cause these cells to produce growth factors and ECM proteins (Jones, 2013). The rate of dissolution of the various species from the bioactive glass surface is critical for these processes to occur. Dissolution must be fast enough to create concentrations able to stimulate osteoblasts cells but not so fast that toxic levels build up (Jones, 2013). This dissolution behavior is controlled by the composition and structure of the glass, and in turn its dissolution behavior controls the bioactivity of the glass and its ability to stimulate cellular level

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bone regeneration. The particular feature that controls this dissolution behavior is the ratio of CaO to P2O5, which is relatively high in Bioglass, and leads to ready dissolution in physiological fluids. This, in turn, creates critical concentrations of biologically active species at locations where they can promote proliferation and differentiation of cells (Profeta and Prucher, 2015). A parameter that is important in determining dissolution behavior is the network connectivity of the glass in question. The connectivity is controlled by the composition of the silica network and the method of glass fabrication. Glasses with high silica content have high connectivity, due to the large proportion of oxygen atoms that form bridging units between the silica tetrahedral. This results in slow or negligible rates of dissolution and a corresponding lack of bioactivity. Introducing network-modifying cations, such as sodium or calcium, increases the proportion of nonbridging oxygens in the structure. This is because units of the type SiO−Na+ are created in place of SiOSi bridges, thereby lowering the connectivity of the glass. The lack of connectivity, as well as the charged nature of the species involved, creates a structure that is capable of dissolving in water or body fluids. Network connectivity can be quantified in terms of the number of bridging oxygens per silicon atom, Nc, and this in turn can be used to predict the bioactivity of the glass (Hill and Brauer, 2011; Hill, 1996). Glasses with Nc values above 2.6 are unlikely to show any useful degree of bioactivity because they are resistant to dissolution (Eden, 2011). By contrast, melt-derived Bioglass (45S5) has a calculated Nc of 2.12, a value which is consistent with its ideal rate of dissolution and exceptional level of bioactivity (Jones, 2013). The high rate of dissolution of bioactive glasses is responsible for another biologically useful effect, namely, the raising of the pH around the implanted glass, with resulting antimicrobial effects (Stoor et  al., 1998). This has been shown to be effective against the bacteria that cause periodontal disease, as well as those that cause caries (Allan et al., 2001). Owing to of this, bioactive glasses tend to be associated with reduced incidence of postoperative infections, a further advantage of these materials in bone reconstruction and related surgery.

9.6  PERIODONTAL APPLICATIONS OF BIOACTIVE GLASSES (a) Granular fillers for bone augmentation The structures supporting the teeth are complex. They include hard tissues in the form of trabecular and cortical bone, and also soft tissues, such as bone marrow and the periodontal ligament (Abbasi et al., 2015). As we have seen, periodontal disease affects all of these tissues, and treatment has involved a variety of approaches, of which the use of granular bioactive glass has been shown to be particularly effective.

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The loss of bone from the alveolar region is considered to be the defining outcome of periodontal disease, and results from the progression of periodontal disease due to bacterial infection. Other tissues of the periodontium are also affected adversely, but it is the destruction of the bone that is the most serious. This is because it is loss of bone that ultimately results in loosening and eventual loss of the teeth (Papapanou and Tonetti, 2000). The extent of bone loss is generally assessed clinically by the use of radiographs. The result of such assessment is used to assist in the diagnosis of the condition and in treatment planning aimed at rectifying the damage done by the disease (Papapanou and Tonetti, 2000). Bone augmentation with bioactive glass is widely used because this material is capable of causing specific responses in the remaining healthy cells of the periodontium. In particular, it promotes osteogenesis, thus stimulating new bone to form rapidly (Lovelace et al., 1998). It may also act as a barrier to epithelial cells, preventing them from growing downward, and thereby guiding tissue growth in the correct biological orientation. The high pH that it generates in the fluids surrounding it provides an antimicrobial environment that has been demonstrated in vivo (Allan et al., 2001). Bioactive glass particles stimulate the full development of bone, not just deposition of the mineral phase. Using porous particles of bioactive glass provides a space in which vascularization can occur to an optimal extent. These particles are also easy to manipulate under clinical conditions and have a hemostatic effect, that is, they arrest bleeding. This maintains a clear working area for the clinician and also improves ease of use (Schepers et al., 1998). Bioactive glass has proved to be very successful in the treatment of damage caused by periodontal disease. Three clinical outcomes are sought for effective treatment of this disease, namely, reduction in pocket depths, increase in the clinical attachment of the gingival tissue to the supporting bone, and improvement in the quantity and quality of the alveolar bone adjacent to the tooth socket. Bioactive glass has been shown to provide all three (Lovelace et  al., 1998; Froum et al., 1998; Ong et al., 1998). Over the years, a number of clinical studies have been published that demonstrate how bioactive glass, typically PerioGlas, provides all three of these desirable outcomes (Ioannou et al., 2015). For example, in a typical study, Nevins et al. (2000) reported on the treatment of intrabony defects around five teeth treated with bioactive glass. They determined the response to the implantation of this material using clinical radiographic measurements. Six months after treatment, the probing depth of the periodontal pockets had decreased by a mean of 2.7 mm. At the same time, the attachment of the gingiva to the alveolar bone around the socket had increased by a mean of 2.2 mm. Further histological study showed that, in one case, there was new cementum and new connective tissue formed in the region of the implant (Nevins et al., 2000). In the other four cases, healing involved bone bonding and formation of a new junctional epithelium. The type of repair examined in this study was of small infrabony defects, and bioactive glass has been found to be particularly suitable for use in lesions of this type (Sohrabi et al., 2012).

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This type of reduction in pocket depth within a few months has been widely confirmed (Chacko et al., 2014; Zamet et al., 1997; Park et al., 1998; Froum et al., 1998). At the same time, there is usually a significant increase in clinical attachment of the gingival tissue reported. However, the latter has been found to be somewhat variable, and may range from the minimal that is possibly not statistically significant (Chacko et  al., 2014; Froum et  al., 1998) to the very substantial (Zamet et  al., 1997). These differences may be related to the extent to which the disease had progressed at the time of treatment, and in cases where the disease is more advanced and gingival detachment greater, repair at the treatment site may progress more quickly than at sites with less detachment and a correspondingly less advanced disease state (Chacko et al., 2014). Ideally, periodontal therapy should result in the bone regenerating and the observed defects becoming filled with new bone. This has been widely observed with bioactive glass granules, such as PerioGlas (Ong et al., 1998; Chacko et al., 2014; Froum et al., 1998). There are other benefits of using PerioGlas in this way. The material is well tolerated by the body and shows exceptional biocompatibility with the bone of the alveolar ridge. No adverse clinical effects have been reported (Chacko et al., 2014). Moreover, postoperative healing is rapid and leads to highly satisfactory clinical outcomes (Ong et al., 1998; Chacko et al., 2014; Turunen et al., 1997; Karatzas et al., 1999). Systematic literature reviews confirm that bioactive glass particles give the best clinical results in the treatment of periodontal disease (Ioannou et al., 2015; Sohrabi et al., 2012; Rai and Kalantharakath, 2014), and that they reliably reduce the probing depth of periodontal pockets and increase the clinical attachment levels of gingival tissues. In addition to using bioactive glass alone to promote bone growth on the periodontium, it has been used in conjunction with resorbable and nonresorbable membranes (Bottino et al., 2012). The aim of these membranes is to prevent epithelial cells migrating into the underlying graft site. This allows other cell types to become attached at the graft site and these repopulate the defect and allow active bone growth to occur. This approach is known as guided tissue regeneration (Bottino et al., 2012), a process that is potentially enhanced by the additional use of growth factors blended with the glass particles (Ivanovski, 2009). However, in clinical use, the outcomes with such additional biomolecules have proved to be highly variable. Success depends inter alia on the specific tooth involved, the overall health of the bone at the defect site, surgical factors, and the oral health status of the patient. The potential use of blends of bioactive glass and biomolecules is currently the subject of research, and the aim is to create blends that are reliable and provide superior regenerative outcomes to the use of bioactive glass alone. However, we are some way from achieving this state of affairs. (b) Putties containing bioactive glass particles An alternative method of presentation of bioactive glass for periodontal treatment is as a putty (Grover et al., 2013). The commercial name of this ­material

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is NovaBone Putty (see Fig. 9.1) and it consists of bioactive glass granules premixed with a binder comprising polyethylene glycol and glycerine. This blend requires no preparation prior to being placed directly at the site of bone loss. It does not undergo any sort of hardening process, though the binder is capable of being resorbed to leave behind the bioactive glass particles. This material received approval for clinical use in the United States in 2006 and in Europe in 2007, and has many advantages as a means of presenting bioactive glass over simply using the unblended glass granules. The ultimate goal of deploying a bioactive glass putty is the same as that for using the particulate glass material, namely, to restore the periodontal structures lost as a result of the disease (Villar and Cochran, 2010), either to augment the alveolar ridge to receive implants or to treat defects caused by periodontal disease. It has the advantage over particulate bioactive glass of being easier to press into place, and more likely to remain in its location, due to the viscosity of the binder. Clinical studies have shown that this putty material is able to provide reliable and acceptable results (Grover et al., 2013). For instance, one study showed that 6  months after placement, the probing depth of the periodontal pockets had declined by a mean of 4.2 mm. Soft and hard tissues had each responded positively to the presence of the bioactive glass putty, and the inflammation due to periodontal disease had completely resolved at this time period. Results were similar to those obtained for particulate bioactive glass alone (Lovelace et al., 1998; Froum et al., 1998; Mengel et al., 2003), even down to the extent of decrease in size of periodontal pockets. Overall, the putty was well tolerated by patients, with none showing adverse effects such as abscesses, inflammation, or allergic reaction at the surgical sites. Hence, it has been shown that the putty is an acceptable way of presenting bioactive glass under clinical conditions, and that its use leads to successful regenerative outcomes. (c) Treatments for furcation defects The occurrence of periodontitis-affected furcations in multirooted teeth and its treatment is a very important problem in clinical periodontology (Muller and Eger, 1999; Karring and Cortinelli, 1999). As we have seen, defects develop in the region of these furcations as a result of infection, followed by inflammation, leading to bone resorption. Such defects are likely to result in loss of the tooth, and clinical findings have shown that such tooth loss is more frequent in teeth with furcation defects than in similar teeth without furcation defects and associated bone loss (El-Haddad et al., 2014). Clinically, treatment of these furcation defects is aimed at the regeneration of tissues at these sites. Such regeneration can be achieved by a variety of methods, including bone grafting and the use of bioactive glasses in a broader tissue engineering approach (Anderegg et al., 1999). The use of bioactive glasses arises from their ability to promote osteogenesis and cementogenesis, as well as their potential to stimulate the formation of a functional periodontal ligament (Nasr et al., 1999).

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Studies have shown that bioactive glass is easy to place and remains in place in the furcation defect even with suctioning adjacent to the site (El-Haddad et al., 2014). This is due to its ability to form a cohesive mass with saline or even blood. This mass does not flow, even during the time for which bleeding continues. Since bioactive glass is hemostatic, it rapidly forms a blood clot at the site of the furcation defect, and this is where the overall healing process originates (El-Haddad et al., 2014). In one study of treatment of furcation defects with bioactive glass particles, follow-up examinations ten days after surgery showed that the glass particles had remained in place (El-Haddad et al., 2014). For most patients, the overlying mucoperiosteal flaps were healthy and the whole site had begun to heal well. The success rate was 94%, and the relatively uncommon failures were all associated with infection and inflammation. These outcomes were attributed to poor oral hygiene by the patients concerned, coupled with a failure to maintain proper healing conditions (El-Haddad et al., 2014). This shows that these procedures using bioactive glass depend to a significant extent for their success on patient compliance, a feature that needs to be factored in when selecting patients for this particular treatment. In the majority of cases, the use of bioactive glass was successful, and results showed that the overlying gingival tissues were well able to tolerate the presence of the glass particles. The soft tissue generally healed well and resulted in stable wounds and excellent regeneration of the local periodontal structures (El-Haddad et al., 2014). Radiological examination after 6 months showed that there had been significant replacement of the lost bone at the former defect site and that the new bone was of good density (El-Haddad et  al., 2014). Data from other studies of bioactive glass in contact with bone in humans suggest that the glass particles begin to disappear at about 4 months and have become completely resorbed at 16 months (Tadjoen et al., 2000). Results of the clinical study of repair of furcation defects are consistent with these findings and show that bioactive glass is an excellent material for promoting bone regeneration at defect sites. This procedure allows teeth with furcation defects to be saved in a fully functioning periodontium, whereas in the past such teeth would have been lost. (d) Coatings for implants Another important use for bioactive glass is to coat implants used in dentistry (Lopez-Estebana et al., 2003). Implants are typically made of the alloy Ti-6Al-4V and are used to support ceramic crowns or a group of mainly ceramic prosthetic teeth. In this approach to dental treatment, it is critical that patients have high standards of oral hygiene and are nonsmokers. Patients need to comply carefully with clinical instructions following the placement of such implants because of the long healing times needed for full integration of the implant. These are typically between 3 and 6 months for both the maxilla and the mandible (Wennerberg et al., 2013).

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An important current trend in dental implantology is to modify titanium alloy surfaces with the aim of improving their osseointegration. This includes methods of increasing the overall surface area of the implant by processes such as grit-blasting and acid-etching, as well as coating the surface with a bioactive material. Synthetic hydroxyapatite has been used for such coatings, but success rates with them have been lower than expected (Xuereb et al., 2015; Ong and Chan, 2000). Failures of hydroxyapatite are associated with gap formation in the interfacial zone between the implant and natural bone (Albrektsson, 1998). This gap is formed as a result of bone loss arising from the loss of integrity of the coatings with time, resulting in local concentrations of mineralizing ions that are not conducive to bone repair. Hence, the gap appears between the implant and the healthy bone. Bioactive glass has also been used in this way to coat metallic dental implants (Moritz et al., 2004). It has the biological advantages that we have previously discussed, namely, a high degree of bioactivity that leads to the formation of a strong chemical bond to living bone (Xuereb et al., 2015). Its bioactivity is such that it causes bone to grow in the interfacial region more rapidly than hydroxyapatite, with no problems of bone resorption. The result is that the implant rapidly becomes stabilized, and bone that is formed is strongly attached to the metal implant surface. There are problems associated with the glassy nature of bioactive glass, notably that stresses arise at the coating-implant interface due to differences in the thermal properties of the glass and the titanium alloy substrate (VitaleBrovarone, 2005). This makes the glass coatings susceptible to cracking and debonding (Carrado, 2010) unless fabrication conditions are carefully chosen (Xuereb et  al., 2015). The composition can be altered to change the thermal expansion properties of the glass, specifically using MgO in place of CaO and K2O in place of Na2O. This gives a glass with a coefficient of thermal expansion that more closely matches that of the substrate alloy (Verne, 2012). The whole topic of fabrication of glass and applying it at appropriate thicknesses to dental implants is complicated and has received considerable attention in recent years (Xuereb et al., 2015; Vitale-Brovarone, 2005; Verne, 2012; Mistry et  al., 2011). Animal studies have shown that such implants perform well in living bone. Implants become strongly integrated into the host bone with no sign of fibrous capsule formation and with bone density at significantly greater levels than with uncoated control implants (Moritz et al., 2004; Wheeler et al., 2001). A critical issue with dental implants is that they need to penetrate the soft tissues and, on the exposed part, reside in an environment that contains numerous microorganisms (Hill and Brauer, 2011). Consequently, there is the potential for infections to develop at the penetration site. Where the soft tissues regrow to form healthy zones adjacent to the emerging implant, an attachment that has been described as a biological seal forms (Marchetti et  al., 2002). This seal

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isolates the bone from the oral cavity and substantially improves the chances of success for the implant. Bioactive glass is active against potentially infectious bacteria (Allan et al., 2001), which is an additional advantage of this material as a coating for implant surfaces. To date, there have been few detailed clinical studies of implants coated with bioactive glasses. One study, though, has confirmed that these implants perform as well as expected (Mistry et al., 2011), and that after 12 months, in the majority of cases, had sound bone growing right up against the implant surface, resulting in strong biological fixation. However, further long-term clinical studies are needed to confirm these findings and to indicate whether or not bioactive glass coating materials significantly improve the in vivo performance of metal implants (Xuereb et al., 2015). (e) Bone augmentation prior to the use of implants In view of the effectiveness with which bioactive glass promotes regeneration, there is the potential to use it to provide support for metal implants in patients who have lost teeth due to severe periodontitis. As mentioned when describing the use of bioactive glass coatings, this is not straightforward, as periodontitis is associated with poor oral hygiene and also possibly smoking by patients. Most clinicians consider that the use of implants in such patients is contraindicated (Lekolm et al., 1999). However, despite these concerns, bioactive glass has been used in this way and with reasonably successful outcomes (Gatti et  al., 2006). In a particular study, three patients received the granular bioactive glass PerioGlas to treat extraction sites prior to placing a titanium alloy dental implant. The aim was to generate new bone that was capable of providing sound early fixation to the implant. This was duly achieved, and at 6 months bone biopsies were performed and showed that new bone had formed successfully. In addition, the glass granules had substantially degraded. At a 2-year follow-up, all of the implants were loaded successfully and were stable, indicating that a satisfactory repair had been made (Gatti et al., 2006). Clinical success under such unpromising circumstances is further testimony to the remarkable biological activity of this type of glass material.

9.7 CONCLUSIONS Following this discovery of the bone-bonding properties of formulation 4S5S in 1969, its first practical application was as the material PerioGlas in periodontal therapy. This therapy is needed in the treatment of periodontitis, an infectious condition that leads to loss of bone and damage to the soft tissues that support the teeth. Application of bioactive glass particles stimulates bone repair, and also local soft tissue regeneration, and clinically results in the retention of teeth that would otherwise loosen and be lost completely. Typically, patients treated with this type of bioactive glass particles experience a significant reduction in the depth of their periodontal pockets, which are the source of the

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periodontitis infection. In many cases, too, there is a substantial increase in the level of attachment of gingival tissue to the underlying bone. Bioactive glass has also been used for repair of furcation defects. These also represent an important source of infection in patients, and can lead to tooth loss in much the same way as in those patients suffering from periodontitis. Bioactive glass particles formulated into a nonsetting paste are able to remain in place at the defect site, and to stimulate bone deposition. This creates a repair for the defect and results in increases in bone dentistry at the site of the furcation. Implants can be used to replace teeth lost by periodontal disease and it has been found that coating the part of implants that contact directly with the bone causes local bone regeneration. This leads to high bone density in the region of the implant and results in firm anchorage of the implant. There has been some work done on using bioactive glass particles instead of coatings to improve local bone density prior to placing a titanium alloy implant. This requires careful selection of the patient, and also patient compliance with oral hygiene measures, but can lead to successful outcomes, with metal implants being held secure in newly deposited bone. In this way, the implant can provide sound function for considerable periods of time after placement. Overall, this chapter demonstrates the effectiveness of bioactive glasses in a variety of repairs in the periodontal region. These glasses can stimulate sufficient bone regeneration to firmly anchor teeth and to reverse the damage caused by periodontal disease or can enhance bone repair adjacent to a metallic implant, thereby contributing to a successful clinical outcome. As such, these materials are highly valuable and have made a substantial contribution to oral health in many hundreds of individuals throughout the world.

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The Use of Bioactive Glasses in Periodontology  Chapter | 9  271 Sukumar, S., Drizhal, I., Paulusova, V., Bukac, J., 2010. Surgical treatment of periodontal intrabony defects with calcium sulphate in combination with beta tricalcium phosphate—a 12-month retrospective clinical evaluation. Acta Med. (Hradec Kralove) 53, 229. Tadjoen, E.S., de Lange, G.L., Holzmann, P.J., Kulper, L., Burger, E.H., 2000. Histological observations on biopsies harvested following sinus floor elevation using a bioactive glass materials of narrow size range. Clin. Oral Implants Res. 11, 334. Turunen, T., Peltola, J., Helenius, H., Yli-Urpo, A., Happonen, R.P., 1997. Bioactive glass and calcium carbonate granules as filler material around titanium and bioactive glass implants in the medullar space of the rabbit tibea. Clin. Oral Implants Res. 8, 96. Verne, E., 2012. Bioactive glass and glass-ceramic coatings. In: Jones, J.R., Clare, A.G. (Eds.), Bioglasses: An Introduction. John Wiley & Sons Ltd, Chichester. Villar, C.C., Cochran, D.L., 2010. Regeneration of periodontal tissues: Guided tissue regeneration. Dent. Clin. N. Am. 54, 73. Vitale-Brovarone, E.V., 2005. SiO2-CaO-K2O coatings on alumina and Ti6Al4V substrates for biomedical applications. J. Mater. Sci. Mater. Med. 16, 863. Waerhaug, J., 1980. The furcation problem, etiology, pathogenesis, diagnosis, therapy and prognosis. J. Clin. Periodontol. 7, 73. Wang, H., Li, Y., Zuo, Y., Li, J., Ma, S., Cheng, L., 2007. Biocompatibility and osteogenesis of biomimetic nano-hydroxyapatite/polyamide composite scaffolds for bone tissue engineering. Biomaterials 28, 3338. Wennerberg, A., Bougas, K., Jimbo, R., Albrektsson, T., 2013. Implant coatings: New modalities for increased osseointegration. Am. J. Dent. 26, 105. Wheeler, D.L., Montfort, M.J., McLoughlin, S.W., 2001. Differential healing response of bone adjacent to porous implants coated with hydroxyapatite and 45S5 bioactive glass. J. Biomed. Mater. Res. 55, 603. Xuereb, M., Camilleri, J., Attard, N.J., 2015. Systematic review of current dental implant coating materials and novel coating techniques. Quintessence Int. 28, 51. Zamet, J.S., Darbar, U.R., Griffiths, G.S., Bulman, J.S., Bragger, U., Burgin, W., Newman, H.N., 1997. Particulate bioglass as a grafting material in the treatment of periodontal infrabony defects. J. Clin. Periodontol. 24, 410. Zhang, Y., Cheng, X., Wang, J., Wang, Y., Shi, B., Huang, C., Yang, X., Lui, T., 2006. Novel ­chitosan/collagen scaffold containing transforming growth factor-beta 1 for periodontal tissue engineering. Biochem. Biophys. Res. Commun. 344, 362.