Table 2: 45S5 Bioglass® reaction stages. Table adapted from Baino et al. [22].
2.3.1.3 Influence of the Ionic Dissolution Products
Key mechanisms inducing new bone growth are related to the controlled release of ionic dissolution products from the degrading bioactive glass, principally critical concentrations of biologically active, soluble silica and calcium ions [10], [26].
Recently, it has been demonstrated that bioactive glasses, along with ionic dissolution products, improve osteogenesis by regulating osteoblast proliferation, differentiation, and gene expression.
In order to regenerate bone, it is crucial that osteoprogenitor cells undergo cell division (mitosis) and receive the right chemical stimuli from their local environment that orient them to enter the active segments of the cell cycle [26].
Sun et al. [27] have found that 45S5 Bioglass® triggers human osteoblast proliferation by reducing the growth cycle to pass through G1 (first growth phase including amino acid synthesis) and S (synthesis) and then enter G2 (second growth phase, including the mitosis) quickly. In the presence of critical concentrations of Si and Ca ions, in 48 h, the osteoblasts that are able to differentiate into a mature osteocyte phenotype, start to proliferate and regenerate new bone. Furthermore, osteoblasts, that are not in the correct phase of the cell cycle and are not able to differentiate, are led to apoptosis by the ionic dissolution products [27], [28].
Besides, recent studies have shown that controlled release of low concentrations of ionic dissolution products from BGs can promote also angiogenesis [17].
2.4.1 Silicate Bioactive Glasses
Silica is the main component of silicate BGs. SiO4 basic units are connected to each other at the oxygen centres. The presence of non-bridging oxygen ions connected with silicon makes the silica structure open. Furthermore, the opening of silica network structure is also caused by the addition of network modifiers such as Na+, K+, Ca2+, which substitute bridging oxygens of the network with non-bridging oxygens. It has been shown that the properties of bioactive glass also depend on the amount of modifier ion-oxygen bonds and non-bridging oxygen bonds [13].
Na2O, CaO, P2O5 are the basics oxides required for a silicate glass to achieve bioactivity. Moreover, it should have the following characteristics: the quantity of SiO2 must be between 45 wt% and 60 wt%, and the amount of CaO and Na2O should be high, as well as the CaO/P2O5 ratio. In fact, a quantity of silica higher than recommended reduces the dissolution rate of the glass ions from the surface causing a dramatic reduction in bioactivity. While a lower content of silica leads to completely dissolvable basic SiO4 units. The quantity of silica affects the formation of hydroxyapatite carbonate (HCA) when the bioactive glass comes into contact with the physiological fluid, favouring the bond with living tissues. As a result, the strength of the bond between bone and soft/hard tissue increases.
The high CaO/P2O5 ratio favours the release of ions from the surface of the glass, when immersed in the body fluid, quickly leading to the formation of a surface layer of HCA [13].
Finally, silicate bioactive glasses support the proliferation and differentiated function of osteoblastic cells [1].
As already mentioned, BioglassÒ is a silicate bioactive glass [24].
2.4.2 Borate Bioactive Glasses
It has been recently discovered that specific compositions in other glass-forming systems, such as borate glasses, are bioactive too [24].
Borate glasses are highly reactive and have low chemical durability. Accordingly, they totally convert to HA faster than the silicate glasses [1]. Huang et al. [30] gradually replaced SiO2 with B2O3 and have demonstrated a considerable increment in glass conversion to HA in aqueous phosphate solutions [30]. However, borate glasses convert to apatite with a mechanism which is similar to that of silicate glasses, with the development of a borate-rich layer similar to the silicate-rich layer of the previous ones [1].
The remarkable difference in the degradation rate between borate and silicate BGs may be explained considering the glass network structure. Due to its coordination number, indeed, boron is not able to completely form 3D structures, creating less resistant network interconnections [31].
The derived advantage is that the degradation rate can be designed by acting on the glass composition [22]. Therefore, by adjusting the glass composition, it should be possible to match the degradation rate of borate BG with the bone regeneration rate [24].
For the first time in 2005, scaffolds using borate BG were developed by means of soft pressing and sintering treatment [1].
In addition, the fast and controllable reaction of borate BGs has play a key role in soft tissue regeneration, blood vessel formation (angiogenesis) and wound healing [32].
Boron is a trace element, required for bone health. Borate glass leads to higher pH value of the culture medium. In vitro, borate BGs stimulate cell proliferation and differentiation, whereas in vivo they
improve tissue infiltration [1]. Borate BGs were also used as a substrate for drug release in the treatment of bone infection [24].
The downside of these glasses is the toxicity of boron released into the solution as borate ions, (BO3)3- [33]. It has been noted that under conventional static in vitro culture conditions, some borate glasses are toxic to cells, but toxicity is much lower under dynamic culture conditions [33].
2.4.3 Phosphate Bioactive Glasses
Phosphate bioactive glasses based on the P2O5 as glass network former, and CaO and Na2O as modifiers were developed for biomedical purpose by several research groups [34], [35], [36], [37], [38].
These glasses present chemical affinity with bone because their constituent ions are present in the organic mineral phase of bone [24].
Phosphate BGs are characterized by the presence of phosphate (PO4) tetrahedron structural unit, which is highly asymmetric in nature. Due to this asymmetry these glasses have low durability and easy hydration of P-O-P bonds [1].
Since phosphate BGs show an excellent tendency to dissolve spontaneously in aqueous media, they are optimal materials to construct temporary implants [29].
In addition, these glasses were deeply studied as vehicles to release, in a controlled manner, antibacterial ions such as silver, copper, zinc, and gallium [1].
Furthermore, phosphate glass fibres which are obtained from phosphate glasses through the spinning process, are suitable to be used as guides for muscle or nerve repair in soft tissue engineering [1].
As concerns hard tissue engineering, the phosphate BGs are considered as bone tissue regenerative materials in the form of either bulk or powders combined with polymers in composite materials [1].
2.4.4 Black Glasses
Black glasses are based on silicon oxycarbide (Si-O-C) [39]. They form by partial replacement of oxygen ions by carbon ions in an amorphous silica structure [40].
The simplest and the most reliable method to obtain black glasses is the sol-gel route using opportune precursors containing Si-C bonds in their polymeric chains [41].
The Si-C bond is highly durable and remains intact during the entire glass synthesis [41]. Therefore, Si-O and Si-C are the only bonds present in stochiometric silicon oxycarbide glasses [42].
It could be expected that with the increasing amount of carbon ions in the glass network the properties of the glass will also improve. Therefore, one prefers to design glasses with high contents of carbon.
However, the maximum amount of carbon atoms that can be introduced into the silica network is 45% [42].
Black glasses, in addition to Si-C and Si-O bonds, generally contain also the so-called free carbon, which confers them black colour [43], [44].
Functional parameters of black glasses can vary within a wide range, according to the amount of free carbon and isomorphous substitution in the glass structure [45], [46].
2.4.5 Doped Bioactive Glasses
Incorporating different ions into the BGs compositions could improve their physical-chemical properties while conferring specific therapeutic action [47].
This incorporation of particular ions in the composition of glass is called doping process and it was widely employed for the production of BG-based multifunctional products for various clinical applications [47].
A doping element, by definition, is an additional incorporation in the main composition at a very low concentration compared to the main components, ranging from a few ppm to a few percent [47].
Recent studies showed that, in some cases, the controlled introduction of doping elements can lead to increased efficiency in performing a specific therapeutic action (e.g., antibacterial properties, angiogenesis) [48], [49]. In other cases, doping may enhance surface structure of the material or the physical characteristics of it [47].
There is no specific date marking the start of the doping, but around late 1985 incorporating different ions into the bioactive glasses became very common [50].
At the beginning, the dopants were selected according to their similarity in valence with the elements already present, whereas later, the choice of the dopants was made on the basis of the literature about the essential trace elements required in human body and their action [51], [52].
Since metal ions, by acting as an enzyme cofactors, affect signalling pathways and encourage tissue formation, they are considered interesting doping materials in the field of hard and soft tissue engineering [52], [53].
Some ions, such as Sr, Zn, Cu, Mg and B are believed to be promising in improving the bioactivity of implant materials by monitoring the release of specific ions during in vivo dissolution.
Bioactive glasses doped with iron and bioactive glasses doped with rare-earth elements, such as yttrium, samarium, holmium and rhenium captured the attention of many researchers, since the doping element make them respectively suited for hyperthermia treatment and brachytherapy. These glasses and their applications will be discussed more thoroughly afterwards.