Bioglass 45S5 belongs to the SiO₂-Na₂O-CaO-P₂O₅ quaternary system. Its precise weight-percentage composition is: 45% SiO₂, 24.5% Na₂O, 24.5% CaO and 6% P₂O₅ (7). The relatively low silica content, below the 60 mol% threshold Hench (2) identified as critical for bioactivity, yields a highly disrupted silicate network. Sodium and calcium ions serve as network modifiers, breaking Si-O-Si bridging bonds and creating non-bridging oxygen sites that allow rapid ionic exchange with biological fluids (8).

The network connectivity of 45S5 is ~2.11, placing it at the boundary of glass-forming stability and accounting for both its outstanding bioactivity and its susceptibility to dissolution, a double-edged feature with important clinical consequences (9).

Phosphorus in the composition exists predominantly as orthophosphate groups (PO₄^3-) rather than as a structural constituent of the silicate network. These groups are deemed to facilitate the formation of apatite-like phases early in the bioactive response, acting as nucleation sites for hydroxyapatite precipitation (10).

In its original melt-derived form, Bioglass 45S5 is optically transparent, with a glass transition temperature (Tg) near 520˚C and a crystallization temperature of ~610˚C. Its density is 2.7 g/cm³; its elastic modulus is ~35 GPa, lower than cortical bone (~20 GPa), but well above cancellous bone (~0.5-2 GPa). Compressive strength ranges from 500 to 1,000 MPa, yet the fracture toughness (Kᴵc ~0.7-0.9 MPa·m½) falls well short of cortical bone (~2-6 MPa· m½), which restricts use in load-bearing sites (11,12).

Particle size profoundly influences the biological response. Fine particles (90-710 µm) are standard for periodontal applications, whereas submicron- and nanosized 45S5 particles produced by sol-gel synthesis exhibit ~30-fold greater specific surface area than melt-derived equivalents, thereby accelerating bioactivity and enabling new application formats such as coatings, scaffolds, and toothpaste additives (13).

Hench [Hench (2) and Hench and Thompson (14)] introduced the ‘bioactivity index’ (I^ᴬ) as a quantitative measure of in vivo bond formation. Bioglass 45S5 ranks among the highest I^ᴬ values of any bioactive material, forming bonds with bone within hours of implantation in animal models, a property attributed to the rapid formation of a silica-rich gel layer followed by CHA precipitation (14).

The sequence of surface reactions leading to hydroxyapatite formation is well-characterized and proceeds through at least 11 stages, as first proposed by Hench [Hench (2), Hench and Polak (4) and Hench and Thompson (14)] and later refined (4,15). Stages 1-2 involve the rapid exchange of Na⁺ and Ca²⁺ from the glass for H⁺/H₃O⁺ from the solution, creating a silica-rich surface and raising local pH, followed by loss of soluble silica through hydrolysis of Si-O-Si bonds, generating Si-OH (silanol) groups. Stages 3-5 involve the condensation and repolymerization of the silica-rich layer into a hydrated silica gel. During stages 6-8, Ca²⁺ and PO₄^3- ions migrate to the surface and form an amorphous calcium phosphate layer. Finally, stages 9-11 involve crystallization of this amorphous layer into biologically equivalent CHA, incorporating carbonate, fluoride and magnesium from the surrounding medium.

The resulting CHA layer is chemically and structurally analogous to bone mineral, enabling adsorption of growth factors and extracellular matrix proteins and providing a scaffold for osteoblast attachment and differentiation (16) (Fig. 1).

At the cellular level, silicon ions released during glass dissolution upregulate osteocalcin, bone sialoprotein and collagen type I expression in osteoblasts, providing a molecular basis for the osteoinductive potential of 45S5(17). Calcium and phosphate ions sustain supersaturation at the implant-tissue interface, potentiating mineralization. Notably, the local alkaline shift triggered by Na⁺ and Ca²⁺ release creates conditions that favor osteogenic differentiation while inhibiting osteoclastic activity (18).

In soft-tissue contexts relevant to dentistry, including gingival fibroblasts and periodontal ligament (PDL) cells, 45S5 dissolution products stimulate proliferation and collagen synthesis. The study by Wilson and Low (6) demonstrated that 45S5 binds to both hard and soft connective tissues within days of implantation, an ability attributed to formation of a collagen-CHA composite at the implant-soft tissue interface.

An aspect of 45S5 bioactivity that has not received the sufficient attention is its intrinsic antibacterial effect, arising from the rapid elevation of local pH on dissolution. Studies have documented significant reductions in the viability of Streptococcus mutans, Porphyromonas gingivalis and Fusobacterium nucleatum on 45S5 surfaces at pH values reaching 9-11 (19,20). This property holds particular relevance for dental applications involving infected sites or materials that must resist microbial colonization, such as endodontic sealers, periodontal grafts and implant coatings.

The earliest dental application of Bioglass 45S5 in periodontal regeneration was reported by Wilson and Low (6), who used a Patus monkey model of periodontal defects to evaluate 45S5 particulate of various sizes. The results demonstrated new bone formation throughout the defect, with bone growth initiated at the surface of the bioactive glass particles forming a trabecular network that reproduced the architecture of the original alveolar bone (6). Subsequently, Low et al (21)) evaluated bioactive ceramic in the treatment of periodontal osseous defects in a clinical setting, reporting improvements in probing depth, attachment gain and radiographic bone fill. Subsequent research using standardized three-wall intrabony defects in dogs and non-human primates confirmed the osteoconductive capacity of 45S5 particulates, demonstrating radiographic bone fill comparable to autogenous grafts at 3-6 months (22).

PDL cells are a heterogeneous population of fibroblast-like cells located in the PDL, a specialized connective tissue that anchors the tooth root to the alveolar bone. These cells possess multi-lineage differentiation potential, they can adopt osteoblastic, cementoblastic and fibroblastic phenotypes, which renders them central to periodontal regeneration research. In vitro studies using human PDL cells have demonstrated that 45S5 ionic dissolution products promote cell proliferation, alkaline phosphatase activity and mineralized nodule formation. For example, Varanasi et al (23) reported that PDL cells cultured in 45S5-conditioned media exhibited the upregulation of cementoblastic markers, including cementum attachment protein and osteopontin, suggesting a role in cementogenesis (Table II).

Clinical evidence. PerioGlas^® (NovaBone Products), a commercially available 45S5 particulate developed for periodontal indications, has been evaluated in numerous clinical trials. Froum et al (24) conducted a controlled trial evaluating 59 defects in 16 healthy adults, reporting significantly greater probing depth (PD) reduction (4.26 vs. 3.44 mm) and clinical attachment level (CAL) gain (2.96 vs. 1.54 mm) in 45S5-treated sites compared to open-flap debridement alone at 12 months.

The 5-year clinical and radiological study by Mengel et al (25) comparing a bioabsorbable membrane with BG in 12 patients with generalized aggressive periodontitis, demonstrated that both treatments yielded significant improvements in CAL and PD, with a radiographically greater defect fill in the BG group. The systematic review of preclinical evidence by Sculean et al (26), which examined the biological rationale for combining barrier membranes with grafting materials, confirmed histological evidence of periodontal regeneration in animal models treated with bioactive materials.

Combination approaches using 45S5 with resorbable membranes (guided tissue regeneration) or platelet-rich fibrin (PRF) have shown additive benefits in more complex multi-wall defects. Bodhare et al (27) reported significantly greater CAL gain (4.1 vs. 2.9 mm) when 45S5 was combined with PRF compared to 45S5 alone, pointing towards synergistic promotion of tissue regeneration.

The overall quality of the periodontal evidence base for Bioglass 45S5 is, at best, moderate. The majority of the available clinical trials are characterized by small sample sizes (often <20 patients), short follow-up intervals (typically ≤12 months), heterogeneous outcome measures, and moderate risk of bias linked to incomplete blinding or inadequate randomization procedures. These methodological shortcomings hinder firm conclusions regarding long-term treatment stability and superiority over established grafting materials. Large-scale, multicenter randomized clinical trials with standardized primary outcomes, including radiographic defect fill, CAL gain and patient-reported outcomes measured over at least 24 months of follow-up, are therefore required to strengthen the evidence base for 45S5 in periodontal therapy.

Post-extraction alveolar bone resorption produces significant volumetric deficiencies that complicate implant placement. Bioglass 45S5 has been investigated as a socket grafting material to preserve ridge dimensions. Preclinical and early clinical data indicate that 45S5 particulates placed into extraction sockets can maintain alveolar width and bone volume relative to ungrafted controls, though high-quality randomized clinical trial data evaluating PerioGlas^® specifically for ridge preservation remain limited.

The use of 45S5 combined with collagen membranes for guided bone regeneration in horizontal and vertical bone augmentation has shown promising results in case series. Its gradual resorption, typically complete within 6-18 months depending on particle size, provides a temporary scaffold that is replaced by newly formed bone, histologically comparable to native bone in biopsies obtained at implant placement (28).

The biological compatibility of Bioglass 45S5 with dental pulp tissue has been evaluated in both direct and indirect pulp-capping settings. Animal studies have demonstrated that 45S5 placed in direct contact with exposed pulp tissue induces reparative dentinogenesis, with a dentinal bridge forming within 4-8 weeks, mediated by upregulation of transforming growth factor-β1 and bone morphogenetic protein-2 (BMP-2) in odontoblasts (29).

Relative to calcium hydroxide [Ca(OH)₂], long considered the gold standard for indirect pulp capping, 45S5 exhibits equivalent or superior dentinal bridge quality in animal models, with a more homogeneous, less porous bridge structure (30). The antibacterial effect of 45S5, attributable to its alkaline dissolution, may offer additional protection against residual bacteria at the capping interface. That said, evidence from human clinical trials remains limited, and further well-controlled studies are warranted before 45S5 can realistically challenge mineral trioxide aggregate or biodentine as a clinical standard of care.

Root-end filling and apico-exeresis. Several in vitro and ex vivo investigations have explored 45S5-based materials as root-end filling agents, taking advantage of their ability to form a CHA seal at the dentinal interface. Early findings suggest that 45S5 mixed with an appropriate vehicle may achieve marginal adaptation at the dentinal walls comparable to established root-end filling materials. The biocompatibility of the material with periapical tissues and its ability to promote cementogenesis render it theoretically attractive, although in vivo data from periapical surgery remain limited (4,5,15,31).

Root canal sealers. Novel 45S5-based endodontic sealers, typically incorporating 45S5 powder within a resin or calcium silicate matrix, have been evaluated for sealing ability, biocompatibility and apatite-forming potential. Trope et al (31) and subsequent investigators reported that 45S5-enriched sealers exhibit significantly lower cytotoxicity than epoxy resin-based sealers (AH Plus) in fibroblast cultures, and superior biocompatibility in subcutaneous implantation animal models. Their capacity to form CHA at the sealer-dentine interface may contribute to long-term marginal sealing and periapical healing (16-20).

DH affects 10-30% of adults and is characterized by a short, sharp pain response to thermal, evaporative, osmotic or tactile stimuli. According to the hydrodynamic theory, stimuli induce fluid movement within exposed dentinal tubules, activating pulpal nociceptors. Tubule occlusion therefore constitutes a primary therapeutic strategy (32-35).

Bioglass 45S5 entered desensitizing toothpastes following the seminal research by Greenspan et al (32) in the 1990s, who demonstrated that 45S5 particles mechanically and chemically occlude dentinal tubules through rapid deposition of a CHA plug. This mechanism differs from that of potassium nitrate (nerve depolarization) or strontium chloride (tubule occlusion via strontium apatite), and has been shown to be more durable in simulated oral abrasion challenges.

Clinical trials evaluating Sensodyne^® Repair & Protect (GlaxoSmithKline), which contains NovaMin^®, a commercialized 45S5 formulation, have demonstrated significant reductions in DH scores (Schiff sensitivity scale and visual analogue scale) compared to placebo toothpastes at 4, 8 and 12 weeks (33). An overview of the evidence by Gendreau et al (34) published in the Journal of Clinical Dentistry concluded that NovaMin-containing toothpaste was effective in reducing DH, although comparisons with other active agents (stannous fluoride, potassium oxalate) remained inconclusive owing to heterogeneity.

The addition of fluoride to 45S5 formulations, producing fluorapatite rather than hydroxyapatite in the tubular plug, has been shown to enhance acid resistance and provide additional caries-protective benefits, opening avenues for combined desensitizing and anti-caries products (35).

The capacity of 45S5 to release calcium, phosphate and silicate ions in supersaturating concentrations provides a physico-chemical basis for anti-caries activity. In vitro pH-cycling models simulating cariogenic challenge have demonstrated that 45S5-containing dentifrices significantly reduce enamel mineral loss and promote subsurface lesion remineralization compared to conventional sodium fluoride toothpastes (36).

Confocal Raman spectroscopy and transverse microradiography analyses performed in the study by Mneimne et al (35) demonstrated that 45S5 combined with fluoride produces fluorohydroxyapatite deposits within artificial carious lesions, with mineral recovery reaching 73% of the original mineral content after 20 pH cycles. These findings have stimulated interest in 45S5 as an active ingredient in professionally applied demineralizing varnishes and as a component of glass ionomer cements, where its incorporation accelerates early fluoride release and improves bioactivity.

Recent studies have explored nano-45S5 incorporated into resin composites to create intrinsically demineralizing restorative materials capable of counteracting secondary caries, a leading cause of restoration failure. Odermatt et al (37) demonstrated that nano-45S5-containing composites maintain CHA-forming ability in pH-cycling models without the significant compromise of mechanical properties.

Although Bioglass 45S5 is unsuitable as a bulk implant material in dentistry due to its insufficient fracture toughness, it has found widespread use as a surface coating on titanium or titanium alloy implants. Techniques including enameling, sol-gel deposition, electrophoretic deposition and magnetron sputtering have been used to deposit thin (2-50 µm) 45S5 films on implant surfaces (38).

These coatings accelerate early bone apposition at the implant surface. In rabbit and dog models, 45S5-coated implants have exhibited significantly greater bone-to-implant contact values, typically 70-85% vs. 50-65% for sand-blasted, acid-etched controls, at 4 weeks of healing (39). The mechanism involves the preferential adsorption of fibronectin and vitronectin onto the CHA-forming surface, facilitating integrin-mediated osteoblast attachment and early matrix mineralization.

Clinical evidence. The clinical literature on 45S5-coated dental implants remains limited relative to the abundant preclinical data. Early clinical reports have suggested favorable survival rates for BG-coated cylindrical implants, with peri-implant bone loss comparable to that reported for conventional titanium implants of the era. However, concerns over coating delamination under functional loading and difficulties in controlling film thickness uniformly across complex implant geometries have curtailed the commercial adoption of 45S5 coatings in mainstream implantology.

Beyond its regenerative and restorative roles, 45S5 has been investigated in orthodontic contexts, particularly for the prevention of white spot lesions, a common iatrogenic complication of fixed appliance therapy. Experimental bonding agents and bracket adhesives incorporating 45S5 particles or NovaMin^® exhibit ion-releasing profiles sufficient to maintain local supersaturation and inhibit subsurface enamel demineralization in pH-cycling models.

In vitro evidence also supports the use of 45S5 in dental sealant formulations for occlusal caries prevention in children, although clinical data are not yet available. The biocompatibility, low cytotoxicity and self-setting ion-releasing properties of the material render it a compelling candidate for preventive dental materials research.

Melt-derived Bioglass 45S5 is constrained in terms of porosity, specific surface area and formulation flexibility. Sol-gel synthesis, introduced by Li et al (40) in 1991, circumvents these limitations by enabling production of glass particles with controlled mesoporosity (2-50 nm pore diameter) and surface areas exceeding 200 m²/g, >30-fold higher than those of melt-derived 45S5. Mesoporous BG (MBG) of 45S5 composition exhibits accelerated ion-release kinetics, depositing CHA within hours rather than days in simulated body fluid, and has been explored as a drug delivery carrier for antibiotics, growth factors, and anti-inflammatory agents, thereby enabling combination therapy in infected bone defects (41). The recent comparative study by Pacheco-Vergara et al (42) demonstrated that 3D-printed MBG, BG 45S5 and β-tricalcium phosphate scaffolds all support osteogenic differentiation in vitro, with MBG exhibiting the most rapid mineral deposition kinetics.

The therapeutic profile of 45S5 can be modulated by the partial substitution of network-forming or modifying ions with biologically active elements. Strontium-substituted 45S5 (Sr-45S5), in which strontium replaces calcium, enhances osteoblastic differentiation and inhibits osteoclastogenesis via the calcium-sensing receptor pathway, offering potential benefits for osteopenic bone regeneration (43). Geng et al (44) demonstrated that the careful optimization of the strontium content on titanium surfaces balances apatite-forming ability with osteogenic activity, achieving ideal osseointegration conditions in vivo (44). Silver-doped 45S5 exhibits broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, without significant cytotoxicity at therapeutic concentrations (45).

Zinc-containing 45S5 formulations have been investigated for their dual osteogenic and anti-infective properties, while fluoride-doped variants (fluorobioglass) produce fluorapatite, more resistant to acid dissolution than hydroxyapatite, at the bioactive interface, potentially offering enhanced caries protection (46,47). Magnesium substitution has been shown to delay in vitro dissolution rates, allowing the finer control of the biodegradation profile for load-bearing scaffold applications.

To overcome the brittleness of monolithic 45S5, composite materials incorporating 45S5 particles within biodegradable polymer matrices, including polylactic acid, polyglycolic acid, polycaprolactone and natural polymers, such as chitosan, collagen and silk fibroin, have been extensively studied (48). These composites exhibit compressive strengths of 100-250 MPa with fracture toughnesses approaching 2-3 MPa·m½ while retaining the ion-releasing bioactivity of the glass phase. 3D printing techniques, including fused deposition modelling and stereolithography, have been applied to produce patient-specific 45S5/polymer scaffolds for complex alveolar bone defect reconstruction (49). Notably, McWilliam et al recently described a novel biofabrication method combining nanosecond laser micromachining with electrospun nanofiber meshes, enabling the creation of intricately designed scaffolds at anatomically relevant dimensions that could be adapted to craniofacial and dentoalveolar applications (50).