**3. Development throughout the years**

As Hench's introduction of the novel 45S5 Bioglass® to the medical and engineering era became popular, it birthed future opportunities and advancements for bioactive glasses as researchers sought to make targeted improvements with it to further their knowledge about their applications. Additionally, toxicity of the glasses and environmental factors such as temperature, pressure, and pH must be considered when designing a particular bioactive glass for medical applications. Throughout the years, bioactive glasses have been used in the following areas: dental fillings and treatment, scaffold production, incorporation into other materials such as polymers and for hard and soft bone tissue engineering [20]. Further exploration and experimentation with bioactive glass compositions, led to the formation of many different compositions intended for specific purposes which were achieved by incorporating other compounds to customize them based of the desired characteristics. A few base compositions that have been created overtime is listed in the following **Table 1**.

Most of the bioactive glass compositions in **Table 1** consists of the following four compounds: SiO2, Na2O, CaO, and P2O5. The original 45S5 composition served to identify which combinations of compounds produced a glass with ideal bioactive properties. While the S53P4 composition comprised of a slight variation of Hench's original 45S5 composition, the 13-93 and 13-93B1 compositions include compounds not found in Hench's original composition. Although these deviations from the 45S5 composition reduces their bioactive potential, other benefits are gained. For example, S53P4 bioactive glass is more stable than the 45S5 composition and borate-based bioactive glasses stimulate faster hydroxyapatite (HA) formation rates. Magnesium ions have been shown to increase bioactive glass antibacterial properties and synergize well with host Mg ions in the body during the bone formation process. Furthermore, the "addition of borate ions into the glass matrix has been proven to increase apatite


#### **Table 1.**

*Composition of various silicate-based bioactive glasses [20].*

*Incorporation of Novel Elements in Bioactive Glass Compositions to Enhance Implant Performance DOI: http://dx.doi.org/10.5772/intechopen.99430*

formation rates" on bioactive glass surfaces. This in turn opens the potential for a faster bone remodeling process [21].

The continuous evolution of bioactive glasses is also revealed through their clinical applications. Silica-base bioactive glasses such as the nominal 45S5 and the S53P4 composition were the original accepted standard in the implantation industry. Their rapid surface reaction time and comparatively low softening temperatures allow for optimal conditions for bone remodeling. Recently, though, borate-based bioactive glasses have gained a foothold in the tissue engineering market. Having been approved in 2016 and 2018 respectively, the 13-93B3 and GL1605 compositions represent the newer borate bioactive glass compositions. Borate glasses on average have been shown to release Na and Ca ions at a faster rate than their silica-based counterparts [22]. They are also responsible for slower regional pH increases than silica glasses due to reduced concentrations of alkali ions and the presence of boron. Whether these features are improvements to silica-based glasses or not is up to researchers and their intended applications, but nevertheless, borate glasses have contributed to the expansion of the bioactive glass market.

#### **3.1 Limitations of bioactive glasses**

Like all materials, researchers are continuously testing and expanding the limitations of the base bioactive compositions. For example, some base compositions are more appropriate for environments under constant load while others for those of brief, high load amplitudes. Another factor to consider is the alkalinization of regions introduced to bioactive glasses. While this may not be significant at lower concentrations, it hinders the extent that base bioactive glass compositions can be incorporated into the body since large pH changes can be detrimental to human health. Researchers in response have to determine viable methods of retaining the beneficial effects bioactive glasses present while lessening their control over regional pH. Likewise, the intrinsic brittle nature of bioactive glasses has prompted researchers to consider alternative methods of incorporating them into the body that maintain their biological benefits while increasing their strain to failure nature [23–25]. Rather than diverting valuable resources toward synthesizing different base bioactive glass compositions for singular uses, researchers are now looking to expand base properties through a variety of methods. The goal is to synthesize inorganic bioactive glasses that feature similar properties to materials found within the human body (**Table 2**).


#### **Table 2.**

*Mechanical properties of various bioactive glasses, ceramics, and human bones [20].*

#### **3.2 Doping-glass performance and manipulation**

Customization and improvement of bioactive glasses can be achieved through doping. Doping involves the introduction of impurities or other elements into a base composition that would result in the enhancement in properties (mechanical, biological, structural, thermal, electrical, optical) of the particular product. Wetzel *et al* indicated a limitation of Bioglass® where it easily crystalized during high temperature processing. They deduced that the addition of Mg or Zn on the form of MgO or ZnO even at low concentrations improved the thermal behavior of Bioglass® [24]. Although doping is relatively simple to accomplish, the doping technique implemented can affect the extent of doping taking place. Likewise, there are various parameters one must consider when doping a material or bioglass in this instance. As previously stated, a doping technique must be selected under the assumption that some techniques are more applicable under certain conditions than others. For example, the standard melting technique is relatively straightforward, but the P2O5 within the bioactive glass has a much lower melting temperature than the other components [24–26]. A higher temperature processing can lead to the evaporation of a portion of the substance composition, therefore decreasing the overall bioactive potential of the glass along with other properties. Moreover, concentration of dopant material should be determined.

The CaO present in the Bioglass® composition increases its durability. Studies have shown that "when 10 mol% of CaO was substituted with 10 mol% SiO2 to form 20%Na2O-10%CaO-70%SiO2", it exhibited a slower Na+ dissolution, and a more stabilized SiO2-rich surface film when compared to the binary 20%Na2O-80%SiO2. This is due to the presence of CaO acts as a modifier that increases the coupling reactions between Si-O-Si and NS bonds, stabilizing the SiO2 rich film by filling the micro voids that form as a result of the Na dissolution, satisfies the bond in this film and prevents any further loss of Na ions [10]. The presence of P2O5 allows for the formation of a secondary calcium phosphate film that develops on the side that is in contact with the organic fluid environment.

In some bioactive glass and dopant compositions, low dopant concentrations may not produce the desired properties while high concentrations can. On the other hand, high dopant concentrations may have disadvantages associated with them such as cytotoxic and carcinogenic effects while low concentrations minimize them and provide protection from these drawbacks. Additionally, the application that a bioactive glass will be used for must also be taken into account when doping.

Other functional variables such as load, fatigue, temperature, and the substances that a bioactive glass will experience in its application are essential in the selection of a desired bioactive glass composition. While a doped bioactive glass may function well under minimal stress at room temperature, its properties may not be ideal in its environment of use. Therefore, it is important to consider the dopant material, concentration, and its application to ensure the promotion of ideal properties and the minimization of those that are not wanted.

Transition metals currently make up a large proportion of suitable dopants due to the medical benefits they provide. Elements like iron (Fe), copper (Cu), magnesium (Mg), and zinc (Zn) that already play vital roles within the human body are the focus of these studies [21, 26–30]. Similar interest has also been directed toward the rare earth elements. Various elements like Gadolinium (Gd), Erbium (Er), and Holmium (Ho) that are extensively used in a wide range of medical treatments are attractive avenues for researchers to explore [31–33]. While these make up most target dopant

*Incorporation of Novel Elements in Bioactive Glass Compositions to Enhance Implant Performance DOI: http://dx.doi.org/10.5772/intechopen.99430*

#### **Figure 4.**

*Cell viability of various transition metal oxides on A549 cells.* **Figure 1A** *and* **B** *Model the importance of researchers understanding the biological effects dopant compounds have on the human body. Cell viabilities below 70% are considered to be cytotoxic. While Cr2O3 and Fe2O3 caused little to no change in cellular viability, the same cannot be said for the oxides of Cu, Zn, Mn, and Ni. However, these ions are also key contributors to various vital functions in the human body [28].*

materials, much work is needed to understand the effects that doping a bioactive glass with one of these compounds will have and their extent. **Figure 4** reveals the cytotoxic effects that various transition element doping oxides have on cell lines. While some compounds may increase desired bioactive glass components, their biocompatibility should also be assessed before wide-spread usage.

#### *3.2.1 Boron oxide (B2O5)*

It has been experimentally revealed that borate glass systems exhibit greater hydroxyapatite (HA) formation and dissolution rates than their silicate-based relatives (ex: 45S5, 13-19, S53P4). Furthermore, borate glasses have been used for healing applications by medical professionals due to the borate ions possessing inherent antibacterial capabilities. When bioactive glasses are doped with borate ions, there was a "gradual increase in surface apatite formation rates" with increased concentration. [34] Additionally, the antibacterial properties of borate doped glass composition increased with greater doping concentrations. This trend is repeated microstructurally as the glass transition temperature, *T*g, decreases with increasing borate concentrations. Moreover, the glass stability factor and crystallization peak temperature, *T*p, gradually increased with increasing borate concentrations before decreasing once a concentration threshold is surpassed. This pattern is mirrored in cell proliferation studies and antibacterial tests concerning borate-doped bioactive glasses. Therefore, it is important for researchers to weigh the importance of enhanced HA formation

against decreased glass stability, cell proliferation, and antibacterial properties at greater borate concentrations. As with all materials, the conditions these bioactive glasses will be performing in will determine the importance researchers place on these material properties.

#### *3.2.2 Copper (Cu)*

Cu is another metallic ion that researchers have incorporated into bioactive glass matrices and scaffolds to increase biological performance. Researchers are drawn to it because of its positive effects on endothelial cells and blood vessel maturation. Cu is also an essential ion in the human body and plays a pivotal role in angiogenesis, so doping bioactive glasses with it serves to enhance these benefits [28, 29]. This is upheld in Cu-doped calcium phosphates and bioactive glass scaffolds that reveal enhanced angiogenesis and stimulated osteogenesis in Cu-doped bioactive glass scaffolds. The Cu2+ ion also possesses natural antibacterial properties and works in conjunction with the Ca2+ ions in BGs to increase this property. Cu-doped bioactive glasses and scaffolds have also been shown to increase the differentiation levels of mesenchymal stem cells (MSCs) and act as catalyzing agents in endothelial cell proliferation. On the other hand, bioactive glasses and scaffolds doped with Cu are less suitable at elevated temperatures than their non-doped base compositions. This is due to Cu weakening the BG matrix when it is doped which leads to a decreased glass transition temperature, *T*g. While this may not change the benefits doping bioactive glasses with Cu provides, it does limit the applications of Cu-doped bioactive glasses and scaffolds.

#### *3.2.3 Gold (Au)*

Bioactive glasses doped with gold nanoparticles (AuNPs) have also garnered interest among researchers. This is because AuNPs possess a wide range of biomedical applications like therapy, hygiene, diagnostics, and prevention. It is important to note that AuNPs with small diameters (1–2 nm) are toxic in the human body because they cause damage to cell structures when absorbed [35]. However, particle diameters from 3 to 100 nm appear to not have any toxic effect on cellular structures. Not only does doping with AuNPs increase a BG's biocompatibility, but they also increase the rate of the calcium phosphate layer on the surface, bettering its osteoconductive properties. Greater amplitudes in zeta potentials are also positively correlated with increasing dopant concentrations of AuNPs. In other words, increasing the dopant concentration of AuNP corresponds to greater long-term stability for the bioactive glasses. Interestingly, researchers have also discovered that AuNPs have the possibility of being released into nearby organs from the bioactive glasses they were doped with. This has led some to pursue methods of treatment delivery to specific regions of the body.

#### *3.2.4 Iron (Fe)*

Iron was one of the initial elements that were incorporated into bioactive glasses to increase their bioactivity and antibacterial properties [28]. Fe ions have been revealed to enhance the bone metabolism process which is why they were considered as potential doping candidates into bioactive glasses. Fe-doped bioactive glasses have characteristically lower crystallization temperatures than their non-doped counterparts and also have greater storage modulus values [27]. This is turn correlates to larger elastic modulus

#### *Incorporation of Novel Elements in Bioactive Glass Compositions to Enhance Implant Performance DOI: http://dx.doi.org/10.5772/intechopen.99430*

values for Fe-doped bioactive glasses, making them more suitable for implantation applications into the human body [25]. Likewise, scaffolds created from Fe-doped bioactive glasses have much greater degrees of formability than their base compositions. On the other hand, cytotoxic risks must be considered when doping with high concentrations of Fe which can have detrimental effects within patients and their environment. Interestingly, the magnetic properties present in Fe2+ ions are transferred into the base composition they are doped into. Researchers hope to take advantage of this magnetic behavior by expanding upon existing targeted therapeutic treatments.

#### *3.2.5 Magnesium (Mg)*

Magnesium is an important trace element in the human body, which is what makes it an excellent candidate for doping into bioactive glasses. The integral role Mg plays in bone development and maintenance drew researchers to include it among the first wave of transition metals to be considered as a suitable doping agent. Bioactive glasses doped with Mg have shown increased rates of HA formation on their surfaces and enhanced bioactive and antibacterial capabilities in comparison to their base concentrations [21]. Additionally, these bioactive glasses have exhibited superior long-term osteoconductive and biocompatibility properties. This is important because researchers are continuously seeking methods to increase biomedical implant lifespans since the percentage of individuals outliving their implants is increasing. Furthermore, Mg-doped bioactive glasses have promising applications in skeletal tissue regeneration due to their lower ionic release rates which do not affect the cellular environment to the extent of those with elevated rates.

#### *3.2.6 Rare earth elements (REE)*

Many REE ions have practical medical applications including but not limited to imaging techniques, cancer treatments, and pain relief [32]. Therefore, it is not surprising that some of these elements are viable options for therapeutic bioactive glasses. REE have been shown to promote bone repair and increase osteogenesis rates [31]. This is due to their ability to mimic calcium's role in the bone repair process and open the door to bone density disorder treatments. There are concerns about their cytotoxicity to both patients and the environment (**Table 3**), but that is for researchers to determine what level of risk is acceptable while achieving sought-after results [33]. Furthermore, the sustainability of REE's use as a whole is in question since demand for these naturally occurring elements will soon outweigh their supply. Solutions ranging from increased research into REE recycling and replacement are viable options to consider. However, one may also decide that the resources spent in developing a solution can be otherwise diverted to additional research into other dopant materials.

### *3.2.7 Silicon nitride (Si3N4)*

Greater quantities of bone tissue around bioactive glasses have been observed with Si3N4-doped BGs [23]. This compound's high strength, fracture toughness, low friction wear, and biocompatibility make it an ideal doping substance for bioactive glasses designed for load-bearing purposes. It is also important to note that Si3N4 is an osteoconductive biomaterial with the potential to catalyze osteogenesis. In other words, this compound increases the rate of bone formation by reducing the time it takes bone-forming cells to reach their target regions. Like other viable dopants,


#### **Table 3.**

*Cytotoxicity and Ecotoxicity of rare earth compounds [33].*

Si3N4 promotes MSC differentiation into osteoblasts and improves their adhesion to organic material. This in turn leads to an increased production of collagen and mineralization, enhancing the bone formation process. The increased bone formation also corresponds with an increase in environment pH. This is due to the Na+ and Ca2+ ions being released during bone formation that create hydroxides which contribute to an increase in regional pH. This phenomenon is shared among most bioactive glass compositions, and there are a multitude of methods to negate potential detrimental effects to patients.

*Incorporation of Novel Elements in Bioactive Glass Compositions to Enhance Implant Performance DOI: http://dx.doi.org/10.5772/intechopen.99430*

#### *3.2.8 Silver (Ag)*

Silver was one of the first transition metals that researchers attempted to dope bioactive glasses with. This is due to its inherent antibacterial capability that covers a wide array of diseases. Medical professionals have enjoyed its benefits in surgical applications and researchers sought to expand upon their success. It has been observed that Ag-doped bioactive glasses have greater bioactive and antibacterial capabilities than their non-doped bioactive glass counterparts [28]. Furthermore, Ag particles are able to diffuse uniformly throughout the bioactive glasses in which they are doped. The feature of not forming a separate Ag layer at the glass surface is important because some unintended and potentially dangerous cellular responses can occur [36]. Likewise, the antibacterial and bioactive benefits Ag particles present are countered by their possible cytotoxic effects in the human body at high concentrations. Therefore, researchers' margin of error and the specific application of these bioactive glasses play key roles in determining the extent they are doped with Ag particles.

#### *3.2.9 Zinc (Zn) and strontium (Sr)*

Zinc and Strontium have been doped separately and together into bioactive glass compositions to optimize their properties. Zn is responsible for promoting bone formation while Sr. has been found to limit bone resorption and promote bone remodeling [30]. Bioactive glasses, MSC proliferation and differentiation processes are also increased by the doping of Zn and Sr. When Zn is doped into the glass matrix, it is distributed uniformly, and the surface matrix experiences an accelerated growth of its apatite layer. This in turn corresponds to an overall increase in bioactivity. It is important to note that doping the bioactive glass with too much Zn will increase the potential of cytotoxic effects and a create a lower degradation profile. Additionally, solely doping a bioactive glass with Sr. has been found to limit the formation of the apatite layer on the glass surface. Furthermore, the Sr-glass network is looser than the base glass and Zn-glass networks due to Sr's ionic radius being larger than those of Ca, the element being substituted with the dopant material, and Zn. Although extensive research has been done regarding these differences in glass networks, there do not seem to be any significant effects in BG properties when low doping concentrations are used. Likewise, it has been experimentally determined that small molar concentrations of Zn (~2%) and Sr. (~5%) produce optimum cell proliferation and differentiation properties, minimizing negative effects associated with elevated doping concentrations. Co-doping the bioactive glass composition with both Zn and Sr. results in a combination of the two dopant effects. The (Zn + Sr)-glass network promotes cell proliferation and differentiation while also limiting the formation of the glass's surface apatite formation and bone resorption. These represent a few of the various elements and their effects that are considered throughout the glass doping process.

## **4. Conclusion**

Over the past few decades, since the discovery of Bioglass® in 1969, hundreds of other bioactive glass compositions have been derived or attempted, all with the hopes of either improving properties of existing applications such as metal implants, or to personalize a specific composition for a unique application. For instance, using a bioactive glass composition to coat a particular metal alloy for implantation. Over the years, researchers have introduced elements in the form of compounds into base compositions with the aim of achieving distinct properties such as increased bioactivity, anti-bacterial behavior, bone proliferation, etc. Therefore, they have since seen promising outcome when incorporating elements such as magnesium, copper, zinc, boron, and strontium, just to name a few. The evolution of bioactive glasses has already shown promising progress and is expected to be become a staple prat in medical devices and applications within the near future. However, this journey has yet to continue. It is important to evaluate the biological response to the newly developed bioactive glass compositions to fully understand their risks and benefits. We are curious to see where this field is leading us in the next years.
