Deb S (ed): Biomaterials for Oral and Craniomaxillofacial Applications.
Front Oral Biol. Basel, Karger, 2015, vol 17, pp 22-32 (DOI: 10.1159/000381690)
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Biological Impact of Bioactive Glasses and Their Dissolution Products
Alexander Hoppe · Aldo R. Boccaccini
Institute of Biomaterials, Department of Materials Science and Engineering, University of Erlangen-Nuremberg, Erlangen, Germany
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Abstract
For many years, bioactive glasses (BGs) have been widely considered for bone tissue engineering applications due to their ability to bond to hard as well as soft tissue (a property termed bioactivity) and for their stimulating effects on bone formation. Ionic dissolution products released during the degradation of the BG matrix induce osteogenic gene expression leading to enhanced bone regeneration. Recently, adding bioactive metallic ions (e.g. boron, copper, cobalt, silver, zinc and strontium) to silicate (or phosphate and borate) glasses has emerged as a promising route for developing novel BG formulations with specific therapeutic functionalities, including antibacterial, angiogenic and osteogenic properties. The degradation behaviour of BGs can be tailored by adjusting the glass chemistry making these glass matrices potential carrier systems for controlled therapeutic ion release. This book chapter summarises the fundamental aspects of the effect of ionic dissolution products from BGs on osteogenesis and angiogenesis, whilst discussing novel BG compositions with controlled therapeutic ion release.
© 2015 S. Karger AG, Basel
Bioactive glasses (BGs) are widely considered for bone tissue engineering applications due to their ability to strongly bond to bone (bioactivity), which is mediated through the formation of a surface layer of carbonated hydroxyapatite [1-3]. Furthermore, the ionic dissolution products from BGs can stimulate gene expression in stem cells regulating their osteogenic differentiation. There is also evidence that BGs are able to stimulate angiogenesis in vitro as well as in vivo [4-6], and in some cases BGs show antibacterial [7-13] and anti-inflammatory [14] properties. The impact of ionic dissolution products from BGs and their role in the interaction between BGs and cells has been emphasised by Hench [15], who summarised the evidence supporting the hypothesis that âionic dissolution products released from BGs stimulate the genes of cells towards a path of regeneration and self-repairâ. However, the exact mechanism behind the interaction of BGs (and their dissolution products) is still not fully understood, which has generated a large amount of research work investigating the specific effects of metallic ions (also termed bio-inorganics) on cell attachment, proliferation and differentiation in the last decade. Indeed, it is apparent that deciphering the role of inorganic ions on cell behaviour is key to understand the in vitro and in vivo behaviour of biomaterials. Beyond that, in order to improve the biological properties of BGs towards a specific host response, doping BGs with metallic (therapeutic) ions has emerged as a promising approach [16-18]. Relevant ions with therapeutic functions include essential trace elements such as Sr, Cu, Zn or Mg, which are also known to have anabolic effects in bone metabolism [19-21] and angiogenesis, and to exhibit antibacterial properties. However, it is a question of dose whether these ions are therapeutic or potentially toxic [22]. Hence, a controlled release mechanism of these ions from a suitable (inorganic) carrier is required [17]. Since BGs are biodegradable, they can be used as carriers for therapeutic metallic ions whereby the release kinetics can be controlled by tailoring BG chemistry and in some cases by crystallisation of the glass. The controlled release of these ions after degradation of the BG matrix under physiological conditions (in vivo or in vitro in biological fluids) provides stimuli to human cells leading to an enhanced biological impact of BGs related to both osteogenesis and angiogenesis. This approach has led to the development of a novel group of inorganic materials with specific functionalities for regenerative medicine. In the last decade, a wide variety of novel BG compositions containing therapeutic ions has been developed using glass melting techniques, sol-gel methods and ion-exchange processes [16].
In this chapter, the biological responses to ionic dissolution products of BGs and glass ceramics are summarised and discussed. Key reports on basic silicate systems are presented and recent developments in novel glass compositions are highlighted.
Bio-Inorganics and Metallic Ions for Biomedical Applications
Trace elements are essential in human metabolism and are also known to play a role in physiological processes [20, 23]. For example, Ca [24-27], P [28], Si [29-31], Sr [32-37], Zn [38, 39], B [40, 41], Co [42-45], Cu [46-48] and Mg [49-53] are known to activate mechanisms related to bone mineralisation, bone remodelling and angiogenesis. Metallic ions thus represent promising therapeutic agents to be used in biomedicine [54]. For example, bio-inorganic therapy has been suggested as an alternative to gene therapy and the application of growth factors as they are cost effective and can be easily processed at high temperatures using conventional ceramic and glass processing routes [55]. Table 1 gives an overview of selected bio-inorganics and metallic ions with therapeutic effects on bone formation and angiogenesis; the advantages and applications of inorganic ions as stimulating agents for osteogenesis and angiogenesis have been comprehensively highlighted in the literature [16, 18, 23, 55]. However, the balance between therapeutic effects and toxicity is dose dependent, and hence controlled release is required in order to avoid overdosing. Therefore, the use of an inorganic carrier system based on BGs is highly promising since the degradation profile of BGs (silicate- as well as phosphate- and borate-based glasses) can be tailored by adjusting the glass chemistry and in some cases the crystallisation of the glass. The potential benefit of metallic ions incorporated in a silicate glass system has been widely investigated, and relevant studies on the biological performance of metal ion-containing BGs are highlighted separately.
Biological Response to Ionic Dissolution Products from Bioactive Glasses and Glass Ceramics
Ions from Standard Silicate Glasses
Osteogenic Properties
One key property of BGs is the ability to stimulate bone cells via the up-regulation of osteogenic and angiogenic genes, which results in enhanced bone regeneration [15, 70]. These effects have been investigated since 2001 [70-72] and the research has led to the development of âgenetically designedâ BGs, the so-called third-generation biomaterials. Accordingly, one main aspect is that the dissolution products from BGs, particularly the 45S5 composition (in weight %: 45SiO2-25CaO-25Na2O-6P2O5), are able to regulate gene expression in human osteoblastic cells, whereby several genes known to play a role in osteoblast metabolism, proliferation, and cell-cell and matrix-cell adhesion were 5-fold up-regulated when human osteoblastic cells were cultured in 45S5 BG-conditioned medium [72]. These findings were confirmed by Jell et al. [73],...