CHAPTER 1: Unique Nature of Phosphate and Borate Bioactive Glasses

Phosphate glasses have structural features that are significantly different from those of silicate glasses. Phosphate glasses typically consist of a layered or chain structure in which PO₄ units are connected and, with a few exceptions, do not form a three-dimensional PO₄ network. This is because P is pentavalent and can form a 4-coordinated structure with oxygen by forming a dπ–pπ-type bond with one of the four coordinating oxygens. Therefore, non-bridging oxygens (NBOs) are naturally present in phosphate glasses, eliminating the requirement of introducing modifier components such as alkali oxides. The introduction of modifiers leads to the formation of various phosphate groups such as orthophosphate units, Q⁰, pyrophosphate units, Q¹, metaphosphate (intermediate) units, Q², and branching units, Q³. The difference in π-bonding and σ-bonding properties of each group influences the chemical properties of the phosphate glasses. Q³ is chemically unstable because the double bond moiety is localised to a single P–O bond, and it easily reacts with water to convert to Q² delocalised to two P–O bonds. This is called the “anti-branching rule”.¹  This delocalisation of the double bond can be verified through X-ray photoelectron spectroscopy (XPS) by using the O 1s spectra²  and via electron spin resonance (ESR) spectroscopy.³  In M₂O–P₂O₅ (M = alkali metal cation) glasses, upon increasing the M₂O content to a composition at which Q³ groups disappear, such glasses become more chemically stable, in contrast to conventional silicate glasses. When glasses with an ultraphosphate composition are melted, moisture in the raw materials and in the atmosphere is taken up. The (M₂O + H₂O)/P₂O₅ ratio tends to approach unity, following the “anti-branching rule”, to eliminate Q³ branching groups. As a result, phosphate glasses include a larger number of OH groups than silicate or borate glasses do.⁴ 

Because phosphate glasses have lower electron densities on oxygen than silicate glasses and are more acidic, they can be used as good solvents for basic oxides and serve as hosts with weaker ligand fields. Moreover, it is considered that these structural features also contribute to the good glassification ability, even when the P₂O₅ amount is 40% or less, and to the dissolution of oxide compounds, such as Ag₂O, at high concentrations. The chemical durability of phosphate glasses can be considerably improved by incorporating B₂O₃ and/or Al₂O₃ to improve the symmetry around tetrahedral PO₄, and various practical glasses such as ultraviolet transparent glasses or sulfur-resistant glasses have been developed. The detailed structure and properties of phosphate glasses for biological use are described by Delia Brauer in Chapter 2.

The structure of phosphate glasses has been described in many reviews,^5–8  including Van Wazer⁹  and Abe¹⁰  et al. Therefore, in this chapter, the author will introduce recently reported phosphate glasses with interesting specific structures and properties.

Unlike silicate and borate glasses, phosphate glasses can be vitrified even when their composition comprises a small amount of so-called “network former” (NWF) ions. When appropriate compositions are chosen, phosphate glasses consisting of Q⁰ and/or Q¹ units can be obtained without polymerisation of PO₄ tetrahedra.^8,10  Glass “networks” are formed by PO₄ tetrahedra being ionically connected via metal cations. In other words, it is difficult to form a glassy state only with the Q⁰ and/or Q¹ units; however, phosphate glasses can be vitrified by incorporating other components that play the role of a network former. These glasses are examples of systems in which Zachariasen's “random network model” cannot be applied, and are classified as “invert glasses”, as proposed by Trap and Stevels.¹¹  Here, independent anionic groups are linked by cations that were originally network modifier (NWM) components; the anionic groups act as NWM-like groups and the cations are functionally considered to be NWF. For biomedical application, 60CaO–30P₂O₅–10TiO₂ (in mol%) glass¹²  has been reported as one of the ideal glasses. This glass exhibits in vitro bioactivity (apatite-forming ability in a simulated body fluid). This glass and its glass-ceramic with a modified composition have been reported to adhere directly to bone in animal experiments.¹³ 

Maeda et al.¹⁴  have clarified the effect of TiO₂ in a calcium phosphate invert glass on the local structure by using spectroscopic methods and simulations based on molecular dynamics (MD). From ³¹P magic angle spinning nuclear magnetic resonance (MAS-NMR) spectra, Q¹ and Q² peaks were observed in the 60CaO–40P₂O₅ glass, whereas Q⁰ and Q¹ peaks were observed in the 60CaO–30P₂O₅–10TiO₂ glass. Malavasi et al.¹⁵  reported the network connectivities for 60CaO–40P₂O₅ and 60CaO–30P₂O₅–10TiO₂ glasses to be 1.42 and 0.77, respectively. The shortening of the phosphate chain structure by incorporating TiO₂ was considered to cause a decrease in network connectivity. In the Raman spectrum of the 60CaO–30P₂O₅–10TiO₂ glass, peaks attributed to the TiO₄ and TiO₆ units were observed.

In the XPS O1s spectrum of the 60CaO–40P₂O₅ glass, peaks attributed to P–O–P and P–O–Ca bonds were observed, while in that of the 60CaO–30P₂O₅–10TiO₂ glass, the P–O–Ti peak was observed in addition to the P–O–P and P–O–Ca peaks. These results suggest that in the 60CaO–30P₂O₅–10TiO₂ glass, 4- and 6-fold coordinated titanium ions exist and form P–O–Ti bonds with the phosphate species.

Figure 1.1 shows the structural model of the glasses obtained using the MD method. In this figure, the structures wherein P, Ti and O are contributing to the glass network structure are extracted. The network connectivities for 60CaO–40P₂O₅ and 60CaO–30P₂O₅–10TiO₂ glasses were 1.53 and 0.67, respectively, which are close to the spectroscopy results. Because the formation of the P–O–Ti bond is considered in the XPS measurement, TiO₂ also acts as an NWF. Assuming that P₂O₅ and TiO₂ work to form the network structure of the 60CaO–30P₂O₅–10TiO₂ glass, its connectivity is 1.81, which is higher than that for the 60CaO–40P₂O₅ glass.

Water wettability, which is a functional indicator for biomaterials, of 60CaO–40P₂O₅ and 60CaO–30P₂O₅–10TiO₂ glasses was evaluated to be 75.0° ± 4.4° and 54.0° ± 4.9°, respectively. The incorporation of TiO₂ increases the network connectivity of the glass, resulting in an increase in the bond strength of the entire glass. This increases the surface tension, which contributes to the improvement of hydrophilicity. The elucidation of the local structure of phosphate glasses has allowed its correlation with their biological functions.

The development of this invert glass has led to the investigation of new biomedical glasses, which are described in detail by Sungho Lee in Chapter 5.

It has been reported that the incorporation of TiO₂ and CaO improves the chemical durability of phosphate glasses, thus widening their scope for biomedical application.^16,17  Recently, silicate ions have been recognised as therapeutic ions that effectively promote bone formation.^18,19  In some phosphate glasses, chemical durability may be improved by incorporating SiO₂ into the composition. If silicate and/or Ca²⁺ ions can be released slowly, silicophosphate glasses are expected to be useful as biomedical glasses.

The oxygen coordination number of silicon in oxide glasses is usually 4; that is, a tetrahedral SiO₄ structure is formed. However, Dupree et al.²⁰  revealed that in phosphate glasses with a certain composition (P₂O₅ > 40 mol%), part of silicon forms an octahedral 6-fold coordinated structure even under atmospheric pressure. Such structure formation was promoted by the decrease in the electron-donating property (optical basicity) of O atoms in the glasses due to the presence of a large amount of P₂O₅ with high acidity.²¹  When a monovalent element such as lithium or sodium and/or a divalent element such as magnesium or calcium are incorporated in some silicophosphate glasses, the negative charge of the 6-fold coordinated silicate structure, SiO₆, is compensated. Therefore, this structure tends to form.²² 

The formation of the SiO₆ structure in silicophosphate glasses has been reported to affect their thermomechanical properties²³  and optical properties²⁴  and improve their durability in water;²⁵  the structure may be effective in controlling various properties. The improvement of properties is attributed to the bridging of the phosphate chains in the glasses by the SiO₆ structure. In contrast, the SiO₄ structure in the glasses incorporates the phosphate chain structure and breaks the chain, for example, resulting in reduced chemical stability. Consequently, the durability of the glasses in water deteriorates.

A structural analysis of the phosphate glasses containing SiO₆ units has been performed by MAS-NMR^26,27  and/or X-ray absorption fine structure (XAFS)²⁸  methods. Theoretical calculations of SiO₆ structures in phosphate glasses using a density functional theory (DFT) method have revealed the presence of atomic clusters around silicon at a scale of approximately a dozen atoms.²²  Recently, the author of this chapter reported a glass model analysed by MD simulation.²⁹ 

Figure 1.2 shows an example of the calculation results for the P₂O₅–SiO₂–Na₂O glass. It was found that the SiO₆ structure contributes to glass network formation and converts the Q_P² unit into an energetically stable Q_P³ unit; this is favoured because the Si–O bond in the SiO₆ structure has higher ionicity than the Si–O bond in SiO₄ and the P–O bonds. It was also confirmed that the Q_P³ unit is likely to be preferentially coordinated to the SiO₆ structure, and Na⁺ ions with high coordination numbers are easily coordinated in the vicinity by the interaction with O of the Si–O–P bond. The formation of a SiO₆ structure may lead to better control of the hydrolysis reaction of Q_P³ units and the diffusion of Na⁺ ions. The effective incorporation of SiO₆ and SiO₄ structures in phosphate glasses is likely to be a critical step in the development of new biomaterials.

Borate glasses are known to have various groups of medium-range structures (borate superstructural units). As a particularly specific and well-known property, the so-called “boron oxide anomaly” phenomenon has been extensively investigated.^30,31  For example, by increasing the content of an alkali oxide (M₂O; M = Li, Na, K, Rb, Cs) in M₂O–B₂O₃ glasses, their thermal expansion coefficients decrease and reach a minimum value at 16 mol%. Krogh-Moe³²  considered that a B₂O₃ glass consists only of a 3-membered ring (boroxol ring) of 3-fold coordinated boron and proposed a model in which the boroxol ring changes to a ring with a 4- or more membered ring when an alkali oxide is incorporated. The boron oxide anomaly of borate glasses consisting of these rings can be clearly explained. In an MD study before a report by Yamamoto et al.,³³  the number of the boroxol rings was less than or almost zero compared with that determined by the experimental results.^34,35  However, they clarified the high reproducibility of the boron oxide anomaly and the relationship between the ring structures and the change in their thermal expansion coefficients by performing an MD simulation on the basis of the interatomic interaction estimated from the first-principles calculation.

One of the attractive properties of borate glasses as a biomaterial is their variation of chemical durability. Borosilicate glasses are chemically durable, while typical borate glasses exhibit rapid dissolution in aqueous solutions.

Many aspects of the structure of borate glasses remain unknown, and to the best of our knowledge, such glasses have few practical applications. Nevertheless, borate, borosilicate, and borophosphate glasses have been developed and evaluated to obtain properties that are difficult to acquire with silicate and phosphate glasses. Boron oxide plays an important role in adjusting the solubility of ion-releasing-type multi-component glasses.

Boron has been reported to influence the activity of osteoblasts and promote angiogenesis.^36,37  Boron deficiency sometimes adversely affects bone formation;³⁸  boron deficiency in rats has been reported to reduce bone volume and thickness and to impair the regeneration of the alveolar bone.³⁹  Therefore, some studies have been conducted to investigate the application scope of boron-based glasses in biological functions. Unary borate glass exhibits extremely low chemical durability. However, its durability improves drastically by incorporating SrO in its composition, for example.⁴⁰  This is because the ionic radius of Sr²⁺ is larger than that of Ca²⁺. Elements with large ionic radii require more space in the glass network, thus controlling the mobility of other ions. The Sr²⁺ ion is known as a therapeutic ion that contributes to bone formation.

For widening the application scope of borate-based biomaterials, suppression of their solubility is essential. However, their high solubility can promote some applications. The use of borate glass corresponding to Bioglass® 45S5 (46.1B₂O₃–26.9CaO–24.4Na₂O–2.6P₂O₅ (mol%); wherein SiO₂ is completely replaced by B₂O₃) leads to the formation of a larger amount of hydroxyapatite (HA) in simulated body fluid (in vitro bioactivity) than that when original silicate-based Bioglass® 45S5 is used.⁴¹  When the borate glass was soaked in a simulated body fluid, Ca²⁺, PO₄³⁻, Na⁺, and BO₃³⁻ ions from the glass were released, and PO₄³⁻ ions in the solution reacted with Ca²⁺ ions to form HA on the glass surface. The starting point that induces HA nucleation is an attack on the B–O network structure in an aqueous solution. It is considered that this is because the BO₃ structure cannot completely form a strong three-dimensional network, unlike the SiO₄ structure, thus inducing the continuous dissolution of the glass. In animal experiments in which 45S5-based glass particles containing B₂O₃ were implanted in the tibia and contralateral tibia of male Wistar rats, a statistically significant increase in bone tissue formation around the particles was observed.⁴² 

Borate glasses, as well as phosphate-based glasses, are excellent solvents/matrices and can be used for the release of therapeutic ions.¹⁹  The use of borate glasses containing several therapeutic ions to heal bone defects has been investigated for promoting bone regeneration. For example, when borate glasses containing divalent cations such as Mg²⁺, Ca²⁺, and Sr²⁺ ions were used, vigorous cell adhesion and growth were observed along with high solubility in water.⁴³  Borate glasses may stimulate bone marrow mesenchymal stem cells to form bone.

It has also been reported that boron is involved in promoting wound healing⁴⁴  and releasing growth factors and cytokines.⁴⁵  The dissolution of a large amount of Ca²⁺ ions from borate glasses supported the migration of epidermal cells to wounds and contributed to the regeneration of skin and soft tissues.⁴⁶  Therefore, one of the most important current applications of borate glasses is as a wound healing system.

Phosphate-based and borate-based glasses are interesting biomaterials that exhibit unique behaviour because of their structures and physical properties. While silicate glasses tend to have a three-dimensional network structure composed of SiO₄ units, phosphate glasses often have chain structures composed of PO₄ units. Recently, a “mixed alkaline metaphosphate glass”⁴⁷  showing entropic elasticity, which mimics the organic chain polymer structure, has been reported. When this glass is stretched unidirectionally while being heated and then cooled, the –P–O–P– chains are linearly arranged along the stretching direction; therefore, the glass shows a large anisotropy. When reheating this glass at the stretching temperature, the glass shrinks. Even oxide glasses, which are hard and fragile at room temperature, can exhibit the property of expanding and contracting like rubber at a high temperature if the internal structure at atomic and molecular scales is controlled well. As described above, phosphate glasses have intermediate properties between inorganic and organic matter, and there is still significant potential for discovering new phenomena and functions.

One of the unique properties of borate glasses is their high solubility in aqueous solutions. Many studies have been conducted to utilise this property to explore their potential for promoting cell adhesion, proliferation, and differentiation. Modifying biomaterials to allow functions such as angiogenesis and soft tissue infiltration and exploring new mechanisms for promoting bone formation are challenging and require further investigation.

The structural analysis of silicate-based glasses has been widely conducted for promoting their application as biomedical glasses. While groups are conducting the necessary analyses of phosphate-based and borate-based glasses, further advances are expected in the future. Slow progress on finding new functions by using computational-chemistry-based approaches, such as simulation of the interface between the living tissue and material, has been made. Finally, digital transformation of biomedical glasses is a critical future research topic.