Bioactive materials, including bioactive glasses [1–3] and glass-ceramics [4–6], are special compositions made typically from the Na₂O-CaO-MgO-P₂O₅-SiO₂ system (Table 3.1). All of the compositions in Table 3.1 form a mechanically strong bond with bone within weeks or months. Details are described in references [7–15]. The rate of bone bonding depends upon composition of the material. Glass compositions with lower contents of SiO₂ (<52 % by weight) have the fastest rates of bone bonding and also bond to soft tissues [16]. Compositions such as 45S5 Bioglass with high rates of bioactivity produce rapid regeneration of trabecular bone with an amount, architecture, and biomechanical quality of bone that match that originally present in the site [14, 17–19]. The rapid regeneration of bone is due to a combination of processes called osteostimulation and osteoconduction [16–19]. Large differences in rates of in vivo bone regeneration and extent of bone repair indicate that there are two classes of bioactive materials (Table 3.1) [16–19].

Class A bioactivity leads to osteoconduction, growth of new bone along the bioactive interface, and osteostimulation, growth of new bone throughout the defect to regenerate the architecture of bone natural to the site, as a consequence of rapid reactions on the bioactive glass surface [16–19]. The surface reactions involve dissolution of critical concentrations of soluble Si and Ca ions that give rise to both intracellular and extracellular responses at the interface of the glass with its physiological environment. The intracellular and extracellular response of osteoprogenitor cells results in rapid formation of osteoid bridges between particles, followed by mineralization to produce mature bone structures. This process is termed osteostimulation or osteoproduction. Rates of osteostimulation of various types of bioactive particulates have been quantified by Oonishi et al. that provide the fundamental in vivo comparisons of Class A versus Class B bioactive materials [14–19].

The original discovery of bioactive glasses and emphasis of research were on the mechanisms of interfacial bonding of bone to bioactive glasses [1–3, 7–22]. The seminal step to shift thinking from bioactive bonding to bone regeneration was the reporting by June Wilson et al. for the first time that new bone had colonized the surface of an array of 45S5 Bioglass particulate placed in a surgically created site in the jaw of monkeys that mimicked the loss of bone from periodontal disease [31]. New bone formed around the particles and created a regenerated architecture of bone that bridged the bioactive glass particles (Fig. 3.2). The new phenomenon was designated as osteoproduction, now generally called osteostimulation. The concept of osteostimulation was quantified by Oonishi et al. a few years later [14, 32]. The second key finding to develop a genetic basis for bone regeneration was the finding of Xynos et al. that it was not only the glass but it was the ionic dissolution products released from 45S5 Bioglass that influenced and controlled the cell cycle of osteogenic precursor cells and ultimately controlled the differentiated cell population [26, 27]. Cells that were not capable of achieving a fully differentiated phenotype characteristic of mature osteocytes were eliminated from the in vitro cultures by programmed cell death, apoptosis. The shift in cell population towards mature osteoblasts occurred rapidly, in hours, and led to mineralized bone nodules in culture, without addition of organic bone growth factors, such as bone morphogenetic proteins (BMP). Another key finding from the work of Xynos et al. was that the effective ionic dissolution products released at slow rates from 45S5 Bioglass were biologically active soluble Si and Ca ions. Both ions are necessary for osteostimulation. Osteostimulation occurs only when the ions are present at a particular ratio of ions and at a particular concentration range of 15–30 ppm Si and 60–90 ppm Ca.

These findings provide an understanding of the clinical success of use of 45S5 Bioglass particles, NovaBone and PerioGlas, in a wide range of dental and orthopedic applications in use for nearly 20 years, as discussed in [17–19]. When used as a synthetic bone graft, the bioactive glass particles dissolve slowly and release the critical concentrations of Si and Ca over many weeks, as needed for progressive regeneration of bone to fill the defect. The initial effect is proliferation of osteogenic precursor cells at the periphery of the particles. These cells undergo mitosis and lead to an expanded population of mature osteoblasts that generate extracellular matrix proteins, especially Type I collagen that mineralizes to form regenerated bone (Fig. 3.3).

Oonishi et al. used a critical size defect model in a rabbit femoral condyle model to quantify the histological sequence of osteostimulation by 45S5 Bioglass particulate [14, 32]. The studies show that there is both more rapid bone formation in the presence of the osteostimulation particles and regeneration of a more highly mineralized quality of bone in the defect, in comparison with synthetic hydroxyapatite (HA) particles or bioactive A/W glass-ceramic particles. The rate of bone regeneration in the Oonishi model is related to the rate of release of the soluble Si and Ca ions from the particulates tested. A rapid rate of release, as depicted in Fig. 3.1 Stages 1–5, is necessary for rapid bone regeneration and optimal fill of the defect by regenerated trabecular bone.

The third critical step in developing a genetic basis for tissue regeneration was the discovery that critical concentrations of ionic dissolution products (soluble Si and Ca ions) activate or upregulate seven families of genes in osteogenic precursor cells [27–30]. The genes encode transcription of numerous proteins that control the cell cycle, proliferation, and ultimately the differentiation of the cells towards the mature osteoblastic phenotype. The seminal paper leading to identification of the genetic response to bioactive dissolution products was published by Xynos et al. in 2001 resulting from a collaboration at Imperial College London of biomaterials investigators (the author’s group) and the cell and molecular biology groups of Professor Dame Julia Polak [27].