Bioactive glass (BG) interacts with cells and tissues, triggering cell signalling pathways that promote bone regeneration and other regenerative processes, including angiogenesis and wound healing. When BG comes into contact with body fluids, it undergoes ion exchange and dissolution processes, releasing ions such as calcium, phosphate, and silicate. These ions are bioactive, meaning they can influence cellular behaviour and promote tissue regeneration.
The release of ions like calcium can stimulate osteoblast (bone-forming cell) differentiation, supporting bone tissue regeneration. Silicate ions are particularly known for their role in promoting angiogenesis (the formation of new blood vessels), which is essential for the healing of both bone and soft tissues. These ions also activate various signalling pathways involved in cell adhesion, proliferation, and matrix production.
Bioactive Glass (BG) in VEGF expression and angiogenesis.
BG enhances the expression of Vascular Endothelial Growth Factor (VEGF) in Various cell types. This process involves the HIF-1α/VEGF cascade signalling pathway, which regulates the synthesis and secretion of VEGF in response to BG.
Activation of PI3K/Akt Pathway by Bioactive Glass:
Bioactive Glass (BG) has been shown to trigger the activation of the PI3K/Akt pathway in various cell types, including cardiomyocytes, osteocytes. When BG interacts with cells, it leads to the activation of Phosphoinositide 3-Kinase (PI3K), which in turn phosphorylates and activates Akt (also known as protein kinase B). This pathway is often initiated by surface interactions or the release of bioactive ions from BG (e.g., silicate ions), which can bind to receptors on the cell membrane, leading to PI3K activation.
Upregulation of VEGF via PI3K/Akt Pathway:
One of the key downstream effects of the PI3K/Akt pathway activation is the upregulation of VEGF (Vascular Endothelial Growth Factor). VEGF is crucial for angiogenesis and the communication between cardiomyocytesand endothelial cells, facilitating endothelial cell migration, survival, and capillary formation. The activation of Akt promotes transcriptional upregulation of VEGFin cardiomyocytes, Osteocytes. Akt can phosphorylate several downstream targets that regulate gene expression, including HIF-1α (Hypoxia-Inducible Factor 1-alpha), which plays a significant role in VEGF gene expression under low oxygen conditions.
VEGF, upregulated via PI3K/Akt signalling, promotes endothelial cell migration, survival, essential for angiogenesis. This is particularly important in the context of cardiac,Bone tissue repair where endothelial cell recruitment and capillary formation are needed to restore oxygen and nutrient supply to injured tissue.
Bioactive glass in Cytokine mediated signalling:
Bioactive glass (BG) is a class of materials that are known for their ability to interact with biological tissues, often used in medical applications like bone regeneration and wound healing. When it comes to the cytokine response, bioactive glass plays a crucial role in modulating inflammation, tissue repair, and regeneration.
Cytokines are signalling proteins that mediate immune responses and influence various aspects of cellular communication, including inflammation, wound healing, and tissue repair. The interaction between bioactive glass and cytokine production is of significant interest in research due to the potential to enhance healing and modulate immune responses in a controlled manner.
Activation of Cytokine mediated signalling:
The release of ions such as silicon (Si), calcium (Ca), and phosphate (P) from bioactive glasses has been shown to activate various signalling pathways. These ions stimulate immune cells such as macrophages and osteoblasts, influencing their cytokine production.BG can influence the behaviour of macrophages, which are essential cells in the immune system that produce cytokines during inflammation and tissue healing. For example, BG has been shown to promote pro-inflammatory cytokines (like TNF-α, IL-1β) initially to recruit cells involved in the immune response and then modulate anti-inflammatory cytokines (like IL-10) to promote tissue repair.
Cytokine Modulation for Bone Regeneration:
Bioactive glass not only interacts with the immune system but also supports bone regeneration through the regulation of cytokines. For instance, it has been reported that BG can influence the production of osteoinductive cytokines, such as bone morphogenetic proteins (BMPs), and growth factors that promote osteoblast differentiation and bone formation. Bioactive glass’s ability to shift the balance between pro-inflammatory and anti-inflammatory cytokines is important for controlling the immune response. Early in the healing process, a controlled inflammatory response is essential for proper tissue repair, while prolonged inflammation can lead to tissue damage. BG helps in maintaining this balance, thus contributing to both the initial inflammatory response and later anti-inflammatory resolution.
Activation of MAPK Pathways:
The MAPK signalling pathways are critical for controlling a wide range of cellular processes, including proliferation, differentiation, migration, and survival. Bioactive glass can activate several components of the MAPK family, particularly the ERK (Extracellular Signal-Regulated Kinase) pathway, which is commonly involved in regulating cell behaviour in response to extracellular signals, like ions released by bioactive glass. The MAPK family includes several sub-pathways, but the most relevant ones in the context of fibroblast cell signalling are:
- ERK (Extracellular Signal-Regulated Kinase): This pathway is crucial for fibroblast proliferation, migration, and differentiation. When bioactive glass dissolves and releases ions like calcium (Ca²⁺) or silicon (Si⁴⁺), these can act as secondary messengers that activate the ERK pathway, which then promotes the expression of genes involved in cell growth, ECM synthesis, and wound healing.
- JNK (c-Jun N-terminal kinase): JNK is activated in response to stress signals and can regulate inflammatory responses and cell apoptosis. Bioactive glass dissolution products can also activate this pathway, which might contribute to regulating the balance between cell survival and apoptosis in damaged tissues.
- p38 MAPK: The p38 pathway is activated by inflammatory cytokines and stress and plays a key role in regulating the production of pro-inflammatory cytokines and ECM components. Bioactive glass could activate the p38 MAPK pathway to regulate fibroblast function during tissue remodelling and inflammation.
Wnt/β-Catenin Pathway:
Bioactive Glass Activation: The bioactive glass-derived ions can modulate the Wnt/β-catenin pathway, promoting fibroblast differentiation and ECM synthesis. This pathway is also involved in regulating tissue remodelling, which is important for wound healing and regeneration. The Wnt/β-catenin signalling pathway plays a crucial role in regulating stem cell behaviour, cell differentiation, and tissue development. It is involved in regulating fibroblast differentiation and ECM production.
NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) Pathway:
NF-κB is a central regulator of the inflammatory response and plays a critical role in tissue repair and immune responses. It controls the expression of genes involved in inflammation, cell survival, and ECM production.
These pathways, once activated by bioactive glass, influence the transcription of various genes involved in cell division, differentiation, and ECM remodelling, thereby enhancing tissue repair.
Conclusion:
Bioactive Glass (BG) enhances Vascular Endothelial Growth Factor (VEGF) expression, promoting angiogenesis through the HIF-1α/VEGF signalling pathway. BG activates the PI3K/Akt pathway in various cells, such as cardiomyocytes and osteocytes. This pathway triggers VEGF upregulation, which is crucial for endothelial cell migration, survival, and capillary formation, aiding tissue repair in cardiac and bone tissues.
Additionally, BG influences cytokine-mediated signalling, modulating the immune response and tissue regeneration. BG releases ions (silicon, calcium, phosphate) that activate immune cells, promoting both pro-inflammatory cytokines for immune cell recruitment and anti-inflammatory cytokines for tissue repair.
BG also regulates bone regeneration by influencing osteoinductive cytokines like BMPs. It activates MAPK pathways, including ERK, JNK, and p38, which control cell proliferation, migration, and inflammation. BG can also modulate the Wnt/β-Catenin and NF-κB pathways, supporting fibroblast differentiation, ECM synthesis, and tissue remodelling, crucial for wound healing and regeneration.
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