Bioactive glass
Bioactive glass is a biocompatible, silicate-based material designed to interact positively with living tissues, particularly by dissolving in body fluids to form a strong bond with bone through the creation of a hydroxycarbonate apatite (HCA) layer that mimics natural bone mineral.[1] Typically composed of SiO₂, Na₂O, CaO, and P₂O₅ in varying ratios—such as the prototypical 45S5 Bioglass formulation (45 wt.% SiO₂, 24.5 wt.% Na₂O, 24.5 wt.% CaO, and 6 wt.% P₂O₅)—bioactive glasses exhibit tunable degradation rates and ion release profiles that promote biological responses like osteogenesis and angiogenesis.[2] Discovered in the late 1960s by Larry Hench during research into inert biomaterials for implants, the material marked a paradigm shift toward "third-generation" biomaterials that not only replace but actively stimulate tissue regeneration.[3] Key properties of bioactive glasses include their osteoconductive and osteoinductive capabilities, enabling them to guide bone growth and stimulate stem cell differentiation via released ions such as silicon, calcium, and phosphate, while also demonstrating inherent antibacterial effects against pathogens like Staphylococcus epidermidis.[1] These glasses can be processed through methods like melt-quenching, sol-gel synthesis, or advanced techniques such as 3D printing to create scaffolds, particulates, or coatings with mechanical strengths suitable for load-bearing applications, though challenges remain in achieving fracture toughness comparable to that of cortical bone, with dense forms exhibiting a compressive modulus of up to 60 GPa (vs. ~15 GPa for cortical bone).[2] Variations in composition, such as doping with ions like boron, magnesium, or copper, further enhance properties like vascularization or antimicrobial activity without compromising bioactivity.[3] In clinical applications, bioactive glasses are widely used for hard tissue regeneration, including bone grafts (e.g., NovaBone® and BonAlive® S53P4 for spinal fusion and osteomyelitis treatment, with success rates exceeding 88% in long-term studies), dental restorative materials to treat dentin hypersensitivity, periodontal defect repair, and coatings on titanium implants to improve osseointegration.[3] They have also found roles in middle ear prostheses and sinus augmentation, with the first FDA approval in 1985 for a middle ear prosthesis and for Perioglass™ in 1993 as a dental bone graft material.[4] Ongoing research frontiers focus on hybrid composites with polymers for soft tissue engineering and scalable manufacturing to address regulatory hurdles and expand use in regenerative medicine. As of 2025, expanded FDA approvals, such as for Bonalive® Orthopedics granules in 2023, and emerging uses in chronic wound healing further broaden their clinical scope.[2][5][6]Historical Development
Discovery and Early Research
In 1969, Larry Hench and his colleagues at the University of Florida developed the first bioactive glass as part of a U.S. Navy-funded research program aimed at creating implantable materials that could form a strong chemical bond with living bone, addressing the limitations of inert biomaterials that often led to fibrous encapsulation and implant loosening.[7] This breakthrough shifted the paradigm toward second-generation biomaterials designed for interfacial reactivity with host tissues.[7] The inaugural composition tested was 45S5 Bioglass, formulated with 46.1 mol% SiO₂, 24.4 mol% Na₂O, 26.9 mol% CaO, and 2.6 mol% P₂O₅, selected to mimic the ionic environment of bone while promoting surface reactivity.[8] Early in vitro experiments exposed these glasses to physiological solutions, revealing rapid ion exchange and the formation of a hydroxyapatite-like calcium phosphate layer on the surface, which mimicked the mineral phase of bone and laid the foundation for understanding bioactivity mechanisms.[9] Subsequent initial animal implantation studies in the early 1970s, including placements in rat femurs, demonstrated direct apposition of new bone to the glass surface without intervening fibrous tissue, achieving mechanical bond strengths comparable to cortical bone after several weeks.[9] These results validated the material's potential for orthopedic applications and spurred further investigation into its biocompatibility.[7] Seminal publications from this period include Hench et al.'s 1971 paper detailing the bonding mechanisms at the bone-implant interface based on in vitro and early in vivo data, which established the theoretical framework for bioactive materials.[9] Hench's 1980 review further synthesized these findings, emphasizing the role of surface reactions in achieving bioactivity and influencing subsequent research directions.[10]Clinical Translation and Commercialization
The transition of bioactive glass from laboratory research to clinical applications began in the 1980s with initial human trials evaluating 45S5 Bioglass particles for the treatment of periodontal disease, demonstrating its potential to support bone regeneration in dental defects.[11] These early studies paved the way for regulatory milestones, including U.S. Food and Drug Administration (FDA) clearance in 1985 for a 45S5-based middle ear prosthesis (MEP®) designed to replace ossicles damaged by chronic otitis media, marking the first approved bioactive glass implant for conductive hearing loss repair.[11] By 1993, the FDA approved particulate 45S5 Bioglass under the trade name PerioGlas® for dental applications, specifically to fill and augment jaw bone defects associated with periodontal osseous lesions.[12] Commercialization accelerated in the 1990s and 2000s, with NovaBone Products, LLC (USA) leading the development and marketing of 45S5-based synthetic bone grafts, including PerioGlas® and subsequent formulations like NovaBone Putty, which received FDA clearance in 2006 for orthopedic and dental void filling.[13] In Europe, Vivoxid Oy (Finland) commercialized S53P4 bioactive glass as BonAlive® granules, obtaining CE marking in 2006 as a Class III medical device for bone cavity filling and sinus augmentation procedures.[14] This product expanded in the 2010s with additional EU approvals for antimicrobial applications, leveraging S53P4's inherent antibacterial properties to treat chronic osteomyelitis by inhibiting growth of pathogens like methicillin-resistant Staphylococcus aureus.[15] Larry Hench, the pioneer of bioactive glass, passed away in 2015, but research and clinical applications have continued to advance under subsequent leaders in the field.[16] Ongoing advancements address formulation challenges, particularly the material's limited mechanical strength, which has historically restricted its use to particulate rather than bulk forms to avoid brittleness under load-bearing conditions.[3] As of 2024, clinical trials continue to explore injectable bioactive glass composites, such as those incorporating 45S5 or S53P4 variants in hydrogel matrices, for minimally invasive delivery in bone defect repair and infection management.[17] These efforts, including randomized controlled trials for diabetic foot osteomyelitis, aim to enhance versatility while maintaining bioactivity and regulatory compliance.[18]Material Properties
Atomic and Network Structure
Bioactive glasses exhibit an amorphous, non-crystalline structure, characterized by a disordered arrangement of atoms that lacks long-range periodicity, which is essential for their enhanced reactivity in physiological environments.[11] This structure is primarily formed by a silica-based tetrahedral network composed of SiO₄ units, where silicon atoms are coordinated with four oxygen atoms in a tetrahedral configuration, connected through corner-sharing to form a continuous but irregular framework.[19] Network modifiers such as Na⁺ and Ca²⁺ ions play a crucial role by disrupting the Si–O–Si bridging bonds within the silica network, thereby generating non-bridging oxygens (NBOs) that terminate the silicate chains and facilitate selective ion exchange during dissolution.[20] These modifiers lower the overall polymerization of the network, promoting the release of soluble species that contribute to the material's bioactivity.[19] Phosphate is incorporated into bioactive glasses primarily as orthophosphate (PO₄³⁻) groups, often existing in isolated Q⁰ environments within the silicate matrix, which supports the nucleation of apatite-like phases without significantly repolymerizing the network when present in low concentrations, such as in the classic 45S5 composition.[19] A key structural parameter governing the properties of bioactive glasses is the network connectivity (NC), defined as the average number of bridging oxygens per network-forming tetrahedron, which typically ranges from 1.7 to 2.2 in bioactive compositions to achieve a balance between sufficient solubility for ion release and structural stability to prevent premature degradation.[19] For instance, the 45S5 bioactive glass has an NC of approximately 1.9, dominated by Q² silicate species that form chain-like structures.[19] The atomic structure is commonly characterized using nuclear magnetic resonance (NMR) spectroscopy, which identifies Qⁿ species—where n represents the number of bridging oxygens connected to a central silicate tetrahedron—with Q² and Q³ species predominating in bioactive glasses to reflect their depolymerized nature.[20] Fourier-transform infrared (FTIR) spectroscopy complements this by detecting characteristic Si–O vibrations, such as those around 1000–1100 cm⁻¹ for Si–O–Si bridges and 900–950 cm⁻¹ for Si–O⁻ NBOs, providing insights into the degree of network disruption.[11] In contrast to inert glasses, which possess higher silica content (>60 mol% SiO₂) and greater network connectivity leading to chemical stability, bioactive glasses incorporate elevated levels of network modifiers (e.g., 20–30 mol% combined Na₂O and CaO), resulting in a lower melting point and increased surface reactivity that enables biological integration.[20]Key Compositions and Variants
Bioactive glasses are primarily classified by their network-forming oxides, with silicate-based compositions forming the foundational family due to their balance of bioactivity and mechanical stability. The archetypal 45S5 Bioglass, developed by Larry Hench in the early 1970s, has a composition of 45 wt% SiO₂, 24.5 wt% Na₂O, 24.5 wt% CaO, and 6 wt% P₂O₅, which enables rapid surface reactions leading to hydroxyapatite formation while maintaining structural integrity.[21] A variant, S53P4, adjusts this to 53 wt% SiO₂, 23 wt% Na₂O, 20 wt% CaO, and 4 wt% P₂O₅, increasing silica content to enhance chemical durability and impart inherent antibacterial properties through elevated sodium and calcium release that disrupts bacterial membranes.[22] Another silicate variant, 13-93, incorporates potassium and magnesium for improved processability, with a composition of 53 wt% SiO₂, 6 wt% Na₂O, 12 wt% K₂O, 5 wt% MgO, 20 wt% CaO, and 4 wt% P₂O₅, resulting in higher sinterability and controlled degradation rates suitable for load-bearing scaffolds.[23] Borate-based bioactive glasses replace silica with boron oxide to accelerate dissolution, addressing limitations in soft tissue applications where faster resorption is needed. The 13-93B3 composition exemplifies this, featuring 53 wt% B₂O₃, 20 wt% CaO, 12 wt% K₂O, 6 wt% Na₂O, 5 wt% MgO, and 4 wt% P₂O₅, which promotes quicker conversion to hydroxyapatite and supports angiogenesis due to boron's role in modulating ion release kinetics.[24] Phosphate-based bioactive glasses prioritize P₂O₅ as the primary network former, typically with SiO₂ below 40 mol% and elevated P₂O₅ (often 40-50 mol%) alongside CaO and Na₂O modifiers, enabling ultra-rapid dissolution tailored for transient dental fillers where complete resorption within weeks is desirable.[25] In the ternary SiO₂-Na₂O-CaO phase diagram (with ~6 wt% P₂O₅ fixed), bioactive behavior is confined to a specific window of 45-52 wt% SiO₂, where glasses exhibit class A reactivity—forming both hydroxyl-carbonate apatite and direct bonds to soft tissues—beyond which bioactivity diminishes due to either excessive stability or rapid breakdown.[21] Recent advancements in the 2020s have introduced doped variants, such as those incorporating copper (Cu) or silver (Ag) ions at 1-5 mol% levels into base compositions like 45S5 or 13-93, enhancing antimicrobial efficacy by generating reactive oxygen species that inhibit biofilm formation without compromising core bioactivity.[26] Mesoporous structures, featuring ordered pores of 2-50 nm, have also emerged in silicate and borate glasses, achieved through surfactant templating to increase surface area (up to 500 m²/g) and facilitate drug loading while tuning degradation via pore interconnectivity.[27]| Glass Family | Example Composition | Key Features Influencing Properties |
|---|---|---|
| Silicate-based | 45S5: 45 wt% SiO₂, 24.5 wt% Na₂O, 24.5 wt% CaO, 6 wt% P₂O₅ | Balanced bioactivity and durability for bone interfacing.[21] |
| Silicate-based | S53P4: 53 wt% SiO₂, 23 wt% Na₂O, 20 wt% CaO, 4 wt% P₂O₅ | Higher stability and antibacterial ion release.[22] |
| Silicate-based | 13-93: 53 wt% SiO₂, 6 wt% Na₂O, 12 wt% K₂O, 5 wt% MgO, 20 wt% CaO, 4 wt% P₂O₅ | Enhanced sinterability and controlled resorption.[23] |
| Borate-based | 13-93B3: 53 wt% B₂O₃, 20 wt% CaO, 12 wt% K₂O, 6 wt% Na₂O, 5 wt% MgO, 4 wt% P₂O₅ | Accelerated degradation for soft tissue compatibility.[24] |
| Phosphate-based | Typical: <40 mol% SiO₂, 40-50 mol% P₂O₅, balance CaO/Na₂O | Rapid dissolution for short-term dental uses.[25] |