**Abstract**

Increasing popularities of bioactive-glasses and their potential medical applications have led to countless studies into improving their material characteristics and overall performance. Some scientists hope to create new bioactive-glass compositions, while others seek to merely modify existing ones such as the novel 45S5 bioactive-glass composition; created by Dr. Larry Hench. These modifications aim to address potential complications that may arise at a site following implantation such as bacterial infections. In other cases, the incorporation of a selected element or compound may aim to improve the implant functioning by increasing cell proliferation. Although possibilities are plentiful, researchers avoid compromising the typical bioactive glass characteristics when doping with elements such as silver, or gold to achieve additional properties. This chapter elaborates on the incorporation of popular elements by doping bioactive-glass compositions to introduce desired properties based on the implant application.

**Keywords:** doping, bioactive glass, hydroxyapatite, angiogenesis, osteogenesis, osteoconductive, biocompatibility, cell proliferation

## **1. Introduction**

A bioactive material is one that is able to elicit a specific biological response at the interface of a material that results in bond formation between the body tissues and the material that they surround [1]. Common bioactive materials include bioactive glasses, and from that derived bioactive glass-ceramics and bioactive ceramics.

Bioactive glass was first introduced in the late 1960's by Dr. Larry Hench after an enlightening conversation with an army officer while attending a scientific conference. During their discussion, they connected on the common tragic injuries that the soldiers were experiencing during the Vietnam War that was occurring at that time. These types of injuries involved those to the limbs, and during that time, the treatment quite often involved amputation due to the absence of a material capable of effectively supporting the hands or the feet. Over the next few years, Hench and his students developed a soda-calcia-phosphate-silicate based glass composition, which was proven to stimulate bone [2]. The result of this development in 1969 was the well-known and copyrighted 45S5 Bioglass. This discovery was the beginning of a new generation of materials, acting as temporary substrates for supporting damaged tissues [3], and since then launched products formed from variations of bioactive glasses and glass-cermaics such as calcium phosphates and synthetic hydroxyapatite [4–7].

The main purpose of such substrates was to create implants that react to the body's process unlike the implants that were in use at that time which were inert or unreactive. His continued study focused on revealing the mechanism on why his novel glass composition, 45S5, was able to interact with the body as a result of by-products from the dissolution of the glass components in the body [8, 9].

When a glass is designed to function as a potential implant and possess bioactive features, its behavior is monitored as certain criteria must be achieved before confirming bioactivity. This can be done by determining its surface type. There are five surface type characteristics of silica-based glasses. Type I surfaces undergo only a thin surface layer hydration when exposed to the bodily aqueous environment. In a case like that, the bulk composition is similar to that of the surface composition. Type II surfaces consists of a silica-rich protective film that occurs as a result of selective alkali ion removal. Type III surfaces are known for their ability to form dual surface layers, known to contribute to durability in both acidic and alkali solutions. Type III surface interactions are characteristic of an ideal bioactive glass. Type IV surfaces have the ability to form a silica-rich layer, however, the silica concentration is not high enough to protect the glass from further attack by network dissolution. Therefore, they are known to have poor durability. Glasses that undergo congruent dissolution with equivalent loss of alkali and silica exhibit that of a Type V glass surface [10].

## **2. What constitutes an effective bioactive glass?**

The original purpose for creating a bioactive glass was to form a chemical bond with bone, and this was achieved by Dr. Larry Hench as stated prior. It is important to understand the mechanism of how this interaction became possible. According to Hench, further thermodynamic studies allowed us to understand that there is a formation of an organic structure being derived from an inorganic one. He was able to determine that the stability of Bioglass® came as a direct result of the formation of a Type III surface [10]. This usually occurs as the result of the presence of phosphorus pentoxide P2O5 in its composition or in some cases, aluminum(III) oxide Al2O3, forming an additional surface layer of either alumina-silicate or calcium-phosphate species on the surface of the silica-rich layer. This comes as a result of dealkalization, surface structural modifications or precipitation from solution [9, 10]. Glasses like these tend to be very durable in both acidic and alkaline solutions, which contribute to the formation of a hydroxyapatite layer capable of creating a bond with tissue.

Hench, his students, and his second wife, June Wilson, a clinical biologist, also noted that this mechanism contributed to 45S5 creating strong bonds to living tissue because of the expression of bone-growth genes [2, 11] in the body that was stimulated by the chemical byproducts of the glass components in the body due to Type III surface interaction [10].

## **2.1 Mechanism of bioactive glass as an implant and hydroxyapatite (HA) formation**

The chemical mechanism that occurs once a bioactive glass is successfully introduced into the body as an implant involves a series of ion transfer reactions, as shown *Incorporation of Novel Elements in Bioactive Glass Compositions to Enhance Implant Performance DOI: http://dx.doi.org/10.5772/intechopen.99430*

#### **Figure 1.**

*Illustration of series of ion exchanges involved in the formation of HA [12].*

in **Figure 1**, that result in the formation of hydroxyapatite (HA). The HA formation is required for the conformation of bioactivity. When a bioactive glass comes into contact with the bodily environment, a series of reactions occur to confirm bioactivity according to **Figure 1** in a 5-stage process:


Following the confirmation of bioactivity in stage 5, adsorption and desorption of growth factors, produced by the surrounding cells, are enhanced by the HA layers. Thereafter, macrophages prepare the implant site for tissue repair by the elimination of dead cells, followed by the attachment of osteoblast stem cells. The following stage involves the differentiation and proliferation of the osteoblast stem cells toward the mature osteoblast phenotype. This typically occurs within hours to weeks depending on the class of the bioactive material. Thereafter, generation of an extracellular matrix occurs as growth factors stimulate cell division and mitosis and the proteins required for the matrix development. The extracellular matrix becomes mineralized followed by the encasement of mature osteocytes in a collagen-HCA matrix, resulting in bone growth [13].

#### **2.2 The original Bioglass® composition**

The novel glass composition Bioglass 45S5 was of the Na2O-CaO-SiO2-P2O5 glass system and was known to possess a high calcium concentration with its composition close to a eutectic in the Na2O-CaO-SiO2 phase diagram [4, 5, 14]. Hench's novel discovery included this glass system in the following mol% concentration: 46.1%SiO2, 24.4%Na2O, 26.9%CaO, 2.6%P2O5. This glass composition was trademarked Bioglass® and since then has only been used in Ref. to the 45S5 composition and not for any other general bioactive glasses [14]. Its ability to create a bond to bone so strong that it could only be removed once the bone was broken.

#### **2.3 Characterization and measurement of bioactivity**

**Figure 2** illustrates a ternary plot in increments of 10 wt% of the three base compounds with the addition on P2O5 for the formation of the novel Bioglass® composition, and for the design of other potential bioactive glasses and glass ceramics based on

#### **Figure 2.**

*Compositional dependence (wt%) of bone bonding and soft tissue bonding of bioactive glass and glass-ceramics. The compositions within region a have a constant 6%P2O5 apart from AW glass ceramic which consists of concentration of P2O5 greater than 6%. Regions S and E both have the ability to interact with and bond to soft tissue and within region E specifically lies the novel bioglass® composition reprinted with permission from [15].*

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

#### **Figure 3.**

*(a) XRD analysis and identification of HA formation through starred peaks after glass composition S4-Z1 is immersed in SBF solution for 3,7, 14 and 21 days respectively. (b) FTIR analysis of S4-Z1 after immersion in SBF for 3. 7, 14, and 21 days respectively. (c) HA formation identified via SEM analysis after immersion in SBF solution for 21 days. Reprinted with permission [19].*

the wt% of each component. Within it identifies regions of bonding type as it relates to the ability to bond to hard or soft tissue. This is a good tool to predict the bioactive behavior of glass compositions within the SiO2-Na2O-CaO series and other potential series depending on the compounds involved in the desired composition.

The index of bioactivity, IB, is used to indicate the measurement of the bioactivity of any material. Introduced by Hench, IB =100/*t*0.5*bb*, where t0.5bb is the time for more than 50% of the implant interface to be bonded to bone [16]. Bioactivity increases as the IB increases.

Since 1994, bioactive materials were classified into Class A and Class B types. Class A bioactive materials were determined to be osteoproductive materials which elicit both intracellular and extracellular responses at its interface. Therefore, Class A bioactive glasses have the ability to bond with both bone and soft tissue. Class B materials are known as osterconductive materials which elicit only an extracellular response at its interface. Therefore, osteoconductive implants provide a biocompatible interface along which bone migrates. Bioglass® is both osteoproductive and osteoconductive and has an IB of 10 [17]. Region D in **Figure 2** has an IB of 0 while there is an IB of 2 at region A, and it increases as the composition becomes more central on the ternary plot [18].

Experimental processes known to test for bioactivity include *in vivo* or *in vitro* studies. However, many scientists have performed *in vitro* studies such as Simulated Body Fluid (SBF) testing followed by Fourier Transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), and X-ray diffraction (XRD). FTIR analysis is performed to detect the presence of HA formation by identifying and

evaluating bond bending and stretching inherent to particular functional groups. XRD analysis is possible through the evaluation of phase analysis and identification of peaks absorbed at certain wavelengths, while SEM analysis is used to evaluate the morphology and microstructure of the HA formation. These are indicated in the following **Figure 3** for the analysis of a bioactive glass composition S4-Z1 after submersion in SBF solution at room temperature for 3, 7, 14, and 21 days respectively.
