The Role of Bioactive Glasses in Caries Prevention and Enamel Remineralization

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review systematically elaborates on the application prospects and challenges of bioactive glass (BGs) in the prevention and treatment of dental caries and the re-mineralization of tooth enamel. It holds significant academic reference value. The article has a clear structure, covering the development history, classification, mechanism of action, and various delivery systems and modification strategies of BGs. Particularly, the discussion on cutting-edge advancements such as ion doping (such as fluorine, strontium, and zinc) and composite systems (such as polymer-BG hybrids) demonstrates the depth and breadth of the content. The author not only affirms the multiple advantages of BGs in promoting hydroxyapatite formation, pH buffering, and antibacterial properties, but also objectively points out the bottlenecks in the process of translating BGs from the laboratory to clinical applications, such as mechanical properties, controllable ion release, and long-term stability. This shows a critical academic perspective. The call for standardized evaluation methods and future interdisciplinary cooperation points out the direction for the development of the field, and is of enlightening significance for oral biomaterial researchers and clinicians. 
1. Clarify the definition and consistency of key terms: The key concept of "biological activity" in the text can be further unified and refined in the expressions of different chapters. It is suggested to clearly define its operational definition in the introduction or a dedicated section (for example, the ability of the hydroxyapatite layer to form specifically in dental hard tissues), and maintain the consistent application of this definition throughout the entire text to avoid ambiguity in concepts and maintain academic rigor.
2. Enhance the depth of the clinical translation perspective: The paper has pointed out the current situation of limited clinical translation in the discussion section, but the analysis of the underlying deep reasons (such as the lack of aging performance data of materials in the complex dynamic environment of the oral cavity, and insufficient cost-benefit assessment) can be more in-depth. It is recommended to supplement thoughts on how to design more clinically relevant in vitro aging models (such as considering factors such as salivary enzymes, mechanical chewing force, and temperature cycling), to bridge the gap between basic research and clinical practice.
3. Strengthen the critical and forward-looking nature of the discussion section: The discussion section can further enhance the critical analysis of the limitations of existing research, rather than merely stating the facts. For example, it can deeply explore why the evaluation of the antibacterial effects of most modified BGs is still limited to a single strain (such as S. mutans), and lacks assessment of the ecological impact on the complex oral microbial community; or for the "long-term ion release" goal, compare and analyze the potential advantages and feasibility of different controlled-release strategies (such as core-shell structure, microencapsulation), and propose a more forward-looking technical roadmap.

Author Response

Reviewer 1

 

This review systematically elaborates on the application prospects and challenges of bioactive glass (BGs) in the prevention and treatment of dental caries and the re-mineralization of tooth enamel. It holds significant academic reference value. The article has a clear structure, covering the development history, classification, mechanism of action, and various delivery systems and modification strategies of BGs. Particularly, the discussion on cutting-edge advancements such as ion doping (such as fluorine, strontium, and zinc) and composite systems (such as polymer-BG hybrids) demonstrates the depth and breadth of the content. The author not only affirms the multiple advantages of BGs in promoting hydroxyapatite formation, pH buffering, and antibacterial properties, but also objectively points out the bottlenecks in the process of translating BGs from the laboratory to clinical applications, such as mechanical properties, controllable ion release, and long-term stability. This shows a critical academic perspective. The call for standardized evaluation methods and future interdisciplinary cooperation points out the direction for the development of the field, and is of enlightening significance for oral biomaterial researchers and clinicians. 

1. 
   Clarify the definition and consistency of key terms: The key concept of "biological activity" in the text can be further unified and refined in the expressions of different chapters. It is suggested to clearly define its operational definition in the introduction or a dedicated section (for example, the ability of the hydroxyapatite layer to form specifically in dental hard tissues), and maintain the consistent application of this definition throughout the entire text to avoid ambiguity in concepts and maintain academic rigor.

Thank you very much for your constructive and insightful comment. In response, we have added a clear and unified definition of the term “biological activity” in the Introduction section. The newly added text reads:

“In this review, the term ‘biological activity’ refers specifically to the ability of bioactive glasses to initiate and support the formation of a hydroxyapatite or hydroxycarbonate-apatite layer on dental hard tissues through controlled ion release. Operationally, this includes: (i) the release of Ca²⁺, PO₄³⁻, Si⁴⁺, F⁻ and other functional ions, (ii) nucleation of an amorphous calcium phosphate precursor layer, and (iii) its maturation into a stable enamel- or dentin-like apatite phase that enhances acid resistance, mineral recovery, and dentinal tubule occlusion. Throughout this manuscript, the terms ‘biological activity’ and ‘bioactivity’ are used consistently in this mechanistic sense.”

2. 
   Enhance the depth of the clinical translation perspective: The paper has pointed out the current situation of limited clinical translation in the discussion section, but the analysis of the underlying deep reasons (such as the lack of aging performance data of materials in the complex dynamic environment of the oral cavity, and insufficient cost-benefit assessment) can be more in-depth. It is recommended to supplement thoughts on how to design more clinically relevant in vitro aging models (such as considering factors such as salivary enzymes, mechanical chewing force, and temperature cycling), to bridge the gap between basic research and clinical practice.

Thank you very much for your valuable insight. We have added the section below to the Discussion.

“Beyond these material-specific limitations, a major factor restricting clinical translation is the absence of comprehensive aging and long-term performance data under conditions that accurately simulate the dynamic oral environment. Most current in vitro studies rely on simplified, static models that do not reflect real fluctuations in salivary enzymes, masticatory forces, temperature cycling, or pH shifts. This limits the predictive value of laboratory results for clinical outcomes. To bridge this gap, future research should incorporate more clinically relevant in vitro aging models that include exposure to esterase- and protease-rich saliva, cyclic mechanical loading mimicking chewing, thermocycling between hot and cold temperatures, and repeated acidic challenges. Developing standardized protocols that integrate these factors would significantly improve the translational relevance of BG performance data. Additionally, clinical adoption of BG-based materials requires cost–benefit evaluations that consider long-term stability, manufacturing scalability, and patient-centered outcomes. Addressing these deeper translational issues is critical for advancing BGs from experimental materials to reliable clinical tools. “

 

 

3. 
   Strengthen the critical and forward-looking nature of the discussion section: The discussion section can further enhance the critical analysis of the limitations of existing research, rather than merely stating the facts. For example, it can deeply explore why the evaluation of the antibacterial effects of most modified BGs is still limited to a single strain (such as S. mutans), and lacks assessment of the ecological impact on the complex oral microbial community; or for the "long-term ion release" goal, compare and analyze the potential advantages and feasibility of different controlled-release strategies (such as core-shell structure, microencapsulation), and propose a more forward-looking technical roadmap.

Thank you very much for your valuable comment. We have added the section below to the Discussion.

“Despite these advances, current research often remains limited by narrow experimental scopes. For example, antibacterial assessments of modified BGs still largely rely on single-species models, particularly Streptococcus mutans. While useful for baseline screening, such models fail to represent the ecological complexity of the oral microbiome, where multispecies interactions influence cariogenicity, remineralization behavior, and overall biofilm dynamics. Future studies should adopt multispecies or saliva-derived biofilm models to better evaluate ecological compatibility, dysbiosis risks, and true antimicrobial efficacy.
In parallel, efforts to achieve sustained and controlled ion release require a more critical comparison of emerging delivery platforms. Core–shell architectures, microencapsulation technologies, and mesoporous carriers each offer different advantages in terms of tunable release kinetics, protection against premature ion depletion, and responsiveness to environmental cues. A forward-looking research roadmap should prioritize systems that integrate mechanical resilience, long-term structural stability, and adaptive ion-release behavior to enable the development of next-generation BG formulations with genuine translational potential.”

Reviewer 2 Report

Comments and Suggestions for Authors

Dear authors,

            This manuscript provides a timely and detailed review of the application of bioactive glasses (BGs) in enamel remineralization and caries management. The strengths of the work lie in its comprehensive scope, covering the history, mechanisms, various formulations (including modern ion-doped and hybrid systems), and the current challenges in the field. The writing is generally clear, and the narrative effectively builds a case for the potential of BGs while critically acknowledging the barriers to their clinical translation.

Major Points for Revision

1. In introduction, the following text: "BGs have evolved from melt-derived formulations to advanced sol–gel and mesoporous bioactive glasses (MBGs) with higher surface areas and faster ion release kinetics." This is accurate, but for balance, consider hinting at the trade-off. You could add: "...faster ion release kinetics, which, while enhancing bioactivity, can also contribute to a premature burst release and reduced long-term stability."
2. The Critical Analysis has to be enhanced. In your discourse regarding these products, transcend simple enumeration of their qualities. For example, rather than stating "BioMin F... contains fluoride to promote the formation of... FA," one should critically assess: "Although assertions regarding the reduced ion release of formulations such as BioMin F are mechanistically credible, there is a scarcity of independent, direct comparative studies that quantify long-term ion release profiles and their clinical implications."
3. Regarding the mechanical properties, expand on why the trade-off between bioactivity and strength exists (e.g., the amorphous, open network that facilitates ion release is inherently less resistant to crack propagation). Discuss specific data from the literature on the flexural strength or fatigue resistance of BG-composites compared to conventional resins.
4. Be more specific about the lack of clinical data. The statement "well designed clinical trials in real patients are scarce" should be followed by a specific call to action. What constitutes a "well-designed" trial? (e.g., "Future clinical trials require longer follow-up periods (>18 months), standardized outcome measures like quantitative light-induced fluorescence (QLF) or ICDAS, and head-to-head comparisons with gold-standard fluoride treatments."). The text: "This lack of robust clinical data slows down evidence-based decision-making..." could be followed this with a specific proposal: "To address this, we propose the development of a core outcome set for future BG clinical trials, including standardized measures of lesion regression, patient-reported outcome measures on hypersensitivity, and assessment of long-term adverse effects."
5. The conclusion is good but could be more forward-looking. Add a sentence on emerging frontiers, such as: " The future may involve four-dimensional (4D) smart materials in which bioactive glass (BG) release is activated not just by pH but also by certain enzymes or light, providing exceptional control over the remineralisation process".

Your Peer-Reviewer

Author Response

Reviewer 2

Dear authors,

            This manuscript provides a timely and detailed review of the application of bioactive glasses (BGs) in enamel remineralization and caries management. The strengths of the work lie in its comprehensive scope, covering the history, mechanisms, various formulations (including modern ion-doped and hybrid systems), and the current challenges in the field. The writing is generally clear, and the narrative effectively builds a case for the potential of BGs while critically acknowledging the barriers to their clinical translation.

Major Points for Revision

1. In introduction, the following text: "BGs have evolved from melt-derived formulations to advanced sol–gel and mesoporous bioactive glasses (MBGs) with higher surface areas and faster ion release kinetics." This is accurate, but for balance, consider hinting at the trade-off. You could add: "...faster ion release kinetics, which, while enhancing bioactivity, can also contribute to a premature burst release and reduced long-term stability."

Thank you so much for your constructive comment. We have kindly added the suggested balanced statement to the Introduction. The sentence now reads: “BGs have evolved from melt-derived formulations to advanced sol–gel and mesoporous bioactive glasses (MBGs) with higher surface areas and faster ion release kinetics [7,8], which, while enhancing bioactivity, can also contribute to a premature burst release and reduced long-term stability.” This addition has been incorporated in the Introduction section as recommended.

1. The Critical Analysis has to be enhanced. In your discourse regarding these products, transcend simple enumeration of their qualities. For example, rather than stating "BioMin F... contains fluoride to promote the formation of... FA," one should critically assess: "Although assertions regarding the reduced ion release of formulations such as BioMin F are mechanistically credible, there is a scarcity of independent, direct comparative studies that quantify long-term ion release profiles and their clinical implications."

Thank you so much for your constructive comment. We have kindly added the following critical analysis to the revised manuscript:

“Fluoride-containing formulations such as BioMin F are designed to promote the formation of stronger, acid-resistant fluorapatite (FA), while BioMin C replaces fluoride with chloride for specific clinical indications. However, although these mechanistic claims are scientifically plausible and supported by manufacturer-reported data, there remains a notable scarcity of independent, head-to-head studies that compare long-term ion-release profiles of these formulations or evaluate their sustained clinical effectiveness. This gap limits the ability to draw strong evidence-based conclusions about their relative performance and durability in real-world use.”

This sentence has been added to Section 2.1 (History and Development).

 

1. Regarding the mechanical properties, expand on why the trade-off between bioactivity and strength exists (e.g., the amorphous, open network that facilitates ion release is inherently less resistant to crack propagation). Discuss specific data from the literature on the flexural strength or fatigue resistance of BG-composites compared to conventional resins.

Thank you so much for your constructive comment. We have kindly expanded the Discussion section by adding a detailed explanation of the structural reasons behind the trade-off between bioactivity and mechanical strength. We also incorporated specific literature-based values on flexural strength, fracture toughness, and fatigue behaviour of 45S5 Bioglass and BG–composites compared with conventional resin composites. The following paragraph has been added to the Discussion:

“The fundamental trade-off between bioactivity and mechanical strength arises from the structural characteristics of bioactive glasses. Highly bioactive compositions possess an open, amorphous, and partially depolymerized silica network that facilitates rapid ion exchange and apatite formation. However, this same loose network connectivity reduces resistance to crack initiation and propagation, resulting in inherently low mechanical strength. For example, conventional 45S5 Bioglass typically exhibits flexural strength values in the range of 40–60 MPa—significantly lower than the 80–120 MPa reported for commercial resin composites—and shows poor fracture toughness under mechanical loading. Fatigue resistance is also limited, with rapid strength degradation under cyclic stresses that simulate mastication. Although BG–polymer composites can partially improve these properties, even optimized formulations generally remain mechanically inferior to nanohybrid or microhybrid resin composites, highlighting the ongoing difficulty of achieving both high bioactivity and sufficient long-term mechanical durability.”

1. Be more specific about the lack of clinical data. The statement "well designed clinical trials in real patients are scarce" should be followed by a specific call to action. What constitutes a "well-designed" trial? (e.g., "Future clinical trials require longer follow-up periods (>18 months), standardized outcome measures like quantitative light-induced fluorescence (QLF) or ICDAS, and head-to-head comparisons with gold-standard fluoride treatments."). The text: "This lack of robust clinical data slows down evidence-based decision-making..." could be followed this with a specific proposal: "To address this, we propose the development of a core outcome set for future BG clinical trials, including standardized measures of lesion regression, patient-reported outcome measures on hypersensitivity, and assessment of long-term adverse effects."
2. The conclusion is good but could be more forward-looking. Add a sentence on emerging frontiers, such as: " The future may involve four-dimensional (4D) smart materials in which bioactive glass (BG) release is activated not just by pH but also by certain enzymes or light, providing exceptional control over the remineralisation process".

Thank you so much for your valuable comment. We have kindly added the suggested forward-looking sentence to the Conclusion, noting that future advances may involve 4D smart materials where BG release is triggered not only by pH but also by enzymes or light. This has been incorporated into the final paragraph of the Conclusion section.

 

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Dear authors, 

The changes are well-integrated into the manuscript, maintaining a coherent narrative flow. The informations are appropriate and robust, and the expanded discussion effectively contextualizes your findings within the broader literature.

Your Peer-Reviewer