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  • Keratin-Based Biomaterials for Enamel Repair: Current Advances and Future Perspectives in Toothpaste Formulations

  • Photo Snehal Mishra* Photo AMAN PRASAD

  • G H Raisoni University, Saikheda, Pandhurna, Madhya Pradesh, India

Abstract

Dental enamel demineralization is a primary factor in the development of dental caries and enamel erosion, which continue to be major global oral health concerns. Traditional remineralization strategies, including fluoride-based toothpastes and calcium-phosphate systems, are widely used to strengthen enamel and reduce mineral loss. Although effective in enhancing enamel resistance to acid attack, these approaches often have limitations in completely restoring the structural integrity of natural enamel. Consequently, there is increasing interest in biomimetic materials that can better support enamel repair and regeneration. Among these, keratin-based biomaterials have emerged as promising candidates for next-generation oral care formulations. Keratin is a naturally occurring fibrous protein rich in cysteine residues that provide strong structural stability and excellent biocompatibility. Derived from natural sources such as wool, hair, and feathers, keratin can be processed into various biomaterial forms suitable for dental applications. Its ability to form bioadhesive films and act as a scaffold for mineral deposition makes it particularly useful in enamel remineralization strategies. When incorporated into toothpaste formulations, keratin may bind to demineralized enamel surfaces, facilitate the nucleation of calcium and phosphate ions, and support the formation of mineral layers that mimic natural enamel structure. Recent studies suggest that keratin-based toothpaste formulations can enhance enamel surface hardness, reduce sensitivity, and provide protective barriers against acid-induced demineralization. This review discusses recent advances in keratin-based biomaterials for enamel repair, their mechanisms of action, and their potential integration into modern toothpaste systems. It also highlights future prospects, including formulation optimization, synergistic combinations with established remineralizing agents, and the need for clinical validation to support their broader application in preventive dentistry.

Keywords

Keratin-based biomaterials, enamel remineralization, toothpaste formulations, dental caries prevention, biomimetic dental materials, oral care innovations.

Introduction

Dental enamel is the hardest and most highly mineralized tissue in the human body, composed of approximately 96% inorganic minerals, primarily hydroxyapatite crystals, with the remaining fraction consisting of water and a small amount of organic matrix. Despite its remarkable hardness and resistance to mechanical stress, enamel is unable to regenerate once it is damaged because it lacks living cells after tooth eruption. Consequently, enamel is particularly vulnerable to demineralization caused by acidic conditions generated from bacterial metabolism, dietary acids, and environmental factors[1]. The progressive loss of mineral content leads to dental caries and enamel erosion, which remain among the most prevalent oral health problems worldwide. As a result, significant research has focused on developing biomimetic approaches that can restore or remineralize enamel structure and function[2].

Traditional strategies for enamel remineralization have primarily relied on fluoride-based formulations. Fluoride enhances enamel resistance to acid attack by promoting the formation of fluorapatite and facilitating the deposition of calcium and phosphate ions on the tooth surface. Although fluoride-containing toothpastes are widely used and clinically effective, concerns related to dental fluorosis and the limited ability of fluoride to fully restore the complex hierarchical structure of enamel have encouraged the exploration of alternative and complementary remineralization strategies[3,4]. Recent advances in biomaterials and nanotechnology have led to the development of innovative materials such as nano-hydroxyapatite, calcium phosphate nanomaterials, casein phosphopeptide–amorphous calcium phosphate (CPP-ACP), and bioactive glasses, which aim to mimic natural enamel mineralization processes.

Table 1.Mechanisms and Evidence of Biomimetic Agents Mimicking Enamel Mineralization

Agent

How it Mimics Enamel Mineralization

Evidence / Performance

Citations

Nano-hydroxyapatite (nHAp)

Chemically similar to natural enamel apatite. The nano-sized particles (≈20–80 nm) can penetrate surface nanodefects, adhere to enamel lesions, fill micropores, and act as a reservoir of calcium and phosphate ions, often described as “liquid enamel.”

Demonstrates formation of enamel-like mineral layers and increases surface microhardness in vitro and ex vivo. In some studies, remineralization performance is comparable or superior to CPP-ACP and occasionally fluoride; however, results vary and many findings are laboratory-based.

5, 6, 7, 8, 9, 10, 11, 12

Calcium phosphate nanoparticles (ACP, NACP, DCPA)

Provide a highly soluble source of calcium and phosphate ions. Amorphous calcium phosphate (ACP) acts as a transient precursor phase that converts into hydroxyapatite, mimicking natural non-classical crystallization pathways during enamel formation.

Various formulations including toothpastes, mousses, and dental adhesives promote epitaxial growth of hydroxyapatite layers and dentinal tubule occlusion. Doping with ions such as CO?²?, F?, Mg²?, and Sr²? enhances nucleation efficiency and crystal stability.

13-15

CPP-ACP

Casein phosphopeptides stabilize amorphous calcium phosphate nanocomplexes and localize supersaturated calcium and phosphate ions on the enamel surface, promoting subsurface ion diffusion and remineralization.

Demonstrates clear remineralization of early enamel lesions compared with no treatment. Some in vitro studies report CPP-ACP performing equal to or better than fluoride, whereas others show no significant advantage. Meta-analyses indicate low to moderate quality evidence with considerable heterogeneity.

3, 5, 9, 11

Bioactive glass (BAG, nBG)

Releases sodium, calcium, and phosphate ions, increasing local pH and inducing precipitation of a carbonated calcium-deficient hydroxyapatite layer similar to natural enamel or bone mineral.

Toothpastes containing BAG increase enamel microhardness and promote apatite layer formation. Several in vitro studies report performance comparable to or better than CPP-ACP and occasionally nano-hydroxyapatite in treating eroded enamel.

14, 7, 15,

Among emerging biomimetic materials, protein-based systems have gained increasing attention due to their ability to guide organized crystal nucleation and growth. Proteins such as amelogenin-derived peptides, elastin-like recombinamer matrices, and keratin have demonstrated significant potential in directing enamel-like mineral formation. These biomolecules can function as scaffolds or templates for hydroxyapatite crystal deposition, promoting the formation of structured mineral layers that closely resemble the natural architecture of enamel[16].

Keratin, a fibrous structural protein naturally present in hair, wool, and feathers, has recently emerged as a promising candidate for enamel repair applications. Interestingly, keratin is also found in the small organic fraction of dental enamel[1]. Studies have shown that specific hair keratins are expressed by ameloblasts during enamel development and become incorporated into the mature enamel matrix. Mutations in keratin genes, particularly KRT75, have been associated with altered enamel structure, reduced mechanical strength, and increased susceptibility to dental caries. These findings suggest that keratin plays a functional role in maintaining enamel toughness and resistance to acid attack, positioning it as more than just a passive structural component[17].

Recent research has demonstrated that water-based keratin films can self-assemble into fibrous networks rich in β-sheet structures capable of templating the ordered growth of apatite nanocrystals. This biomimetic process enables the formation of enamel-like hierarchical structures and has been shown to restore both the optical and mechanical properties of early enamel lesions. In vitro studies have further reported that keratin-based coatings applied to eroded human enamel can produce significant improvements in surface microhardness and protective mineral layer formation. Notably, a 10% keratin coating demonstrated remineralization performance comparable to conventional fluoride treatments following acid rechallenge, indicating its potential as a protective and regenerative material for enamel surfaces[18-19].

Given the inability of enamel to naturally regenerate, the development of biomimetic remineralization strategies that closely replicate natural enamel formation remains a major focus in dental materials research. Protein-based systems, particularly keratin-derived materials, offer promising opportunities for designing advanced oral care formulations capable of promoting enamel repair and protection. In this context, keratin-based biomaterials are being explored for integration into various dental products, including surface coatings, remineralization agents, and toothpaste formulations.

Therefore, this review aims to summarize current knowledge on enamel structure and remineralization mechanisms, discuss the emerging role of keratin as a biomimetic material for enamel repair, and explore the potential application of keratin-based systems in toothpaste formulations designed for enamel restoration and protection.

Composition of Tooth Enamel

Natural tooth enamel is considered an almost completely mineralized bioceramic and represents the hardest tissue in the human body. It is primarily composed of inorganic mineral crystals, with only small fractions of organic material and water. Despite the extremely low organic content, each component plays an important role in determining the mechanical strength, structural organization, and protective function of enamel. The three principal components of mature enamel are described below.

  1. Hydroxyapatite crystals (≈95–96 wt%)

The dominant component of mature enamel is carbonated hydroxyapatite, accounting for approximately 95–96% of the total weight of enamel 6,18,19. These hydroxyapatite crystals are arranged in a highly ordered hierarchical structure that provides enamel with exceptional hardness and resistance to mechanical wear. The crystals are nano-sized, typically measuring around 20–50 nm in thickness and 70–170 nm in width, while extending several micrometers in length [20,21].

These elongated crystals are tightly packed together and organized into enamel rods (prisms) and interrod enamel, forming bundles that extend from the dentinoenamel junction to the outer enamel surface. This hierarchical organization contributes significantly to enamel’s high compressive strength and resistance to mechanical stress [22,23].

Figure 1 : Microstructural Organization of Enamel Showing Hydroxyapatite Crystals and Enamel Rods

  1. Organic matrix (proteins, <1 wt%)

Although mature enamel contains less than 1% organic matter, this small fraction plays an essential role in the mechanical and structural behavior of enamel. The organic matrix mainly consists of short peptide fragments derived from enamel matrix proteins, particularly amelogenin, which are remnants of proteins involved in enamel formation [24,25]. Even in very small amounts, these organic components significantly influence hardness, fracture toughness, and crack propagation behavior in enamel. They are also believed to regulate crystal growth and orientation during enamel development, contributing to the stability of the mineral structure.

  1. Water (≈3–5 wt%)

Water accounts for approximately 3–5% of the total weight of human enamel. It is present both within hydroxyapatite crystals and in the spaces between them. Together with residual organic components and trace ions, water forms an amorphous intergranular phase that plays an important role in enamel’s mechanical and physicochemical properties.This intergranular phase facilitates ion diffusion, which is essential for processes such as demineralization and remineralization, and contributes to the overall mechanical behavior of enamel by enabling limited movement between crystals under stress [26-27].

Mechanism of Enamel Demineralization

Enamel demineralization is a dynamic process driven primarily by acids produced within dental plaque biofilms. These acids dissolve the calcium-phosphate mineral phase of enamel, disrupting the balance between demineralization and remineralization. When acid exposure becomes frequent or prolonged, mineral loss exceeds repair, leading to the initiation and progression of dental caries.

Acid Production by Oral Bacteria

Dental caries begins when bacteria present in dental plaque metabolize dietary sugars and produce organic acids, mainly lactic acid [29,30]. These acids diffuse into the enamel surface and lower the local pH at the tooth–biofilm interface. When sugar consumption is frequent, the plaque pH repeatedly drops below the critical threshold of approximately 5.5, at which enamel hydroxyapatite begins to dissolve[31]. This shift disrupts the natural balance between mineral loss and mineral gain, favoring net demineralization.

Metagenomic and microbiological studies have demonstrated that carious lesions contain high abundances of acidogenic and aciduric microorganisms, emphasizing their central role in the initiation and progression of enamel demineralization[33].

Figure 2 : Role of Biofilm Acids in Enamel Demineralization and Subsurface Lesion Development

Role of Streptococcus mutans

Streptococcus mutans is considered one of the most important cariogenic bacteria because of several biological characteristics that promote enamel demineralization. First, it exhibits strong acidogenicity, meaning it efficiently ferments sucrose and other dietary carbohydrates to produce organic acids [34-35]. Second, S. mutans demonstrates aciduricity, allowing it to survive and proliferate in acidic environments where many other oral microorganisms cannot persist [36]. As the biofilm becomes increasingly acidic, this property enables S. mutans to dominate the microbial community.

Additionally, S. mutans contributes to robust biofilm formation by synthesizing extracellular polysaccharides, particularly glucans, through the activity of glucosyltransferase enzymes[36]. These glucans create a sticky extracellular matrix that enhances bacterial adhesion to tooth surfaces and traps acids close to the enamel, prolonging mineral dissolution. Caries development is not caused by a single microorganism but rather involves polymicrobial interactions within the biofilm. Studies have shown that co-colonization with organisms such as Candida albicans can further enhance acid production and biofilm virulence, accelerating enamel demineralization[37].

Loss of Calcium and Phosphate Ions

When the pH in dental plaque falls below the critical level, hydrogen ions attack the hydroxyapatite crystals of enamel. This chemical reaction leads to dissolution of the mineral lattice and release of calcium and phosphate ions into the surrounding environment . Chemical and spectroscopic analyses, including X-ray fluorescence studies, have demonstrated that phosphate ions are often released first during early enamel erosion, followed by calcium ions. This process results in measurable changes in the Ca/P ratio of enamel mineral, reflecting preferential phosphate loss during initial stages of demineralization[38].

Similar patterns of mineral loss are observed when enamel is exposed to bacterial acids, acidic beverages, or certain chemical agents. These conditions lead to surface softening, increased roughness, and progressive weakening of the enamel structure[38].

Formation of White Spot Lesions

The earliest clinically detectable stage of dental caries is the formation of a white spot lesion. During this stage, acids produced by plaque bacteria diffuse into the enamel subsurface and dissolve mineral beneath a relatively intact outer surface layer. This process creates subsurface porosity within the enamel structure. Because the porous enamel scatters light differently from sound enamel, the affected area appears as a chalky, opaque white region on the tooth surface[38]. These lesions are often observed around orthodontic brackets, near gingival margins, or in areas where plaque accumulates easily. Experimental studies using in vitro biofilm models have shown that sustained exposure to acidic environments produced by Streptococcus mutans biofilms can induce visible white spot lesions and early cavitation on enamel specimens[38,33]. White spot lesions therefore represent the earliest visible manifestation of dental caries. In this stage, acids produced by S. mutans-dominated biofilms drive the loss of calcium and phosphate ions from enamel, leading to subsurface mineral dissolution and the formation of characteristic opaque lesions.

Current Remineralization Strategies:

Fluoride and Calcium Phosphate Systems

Remineralization aims to restore lost mineral content in demineralized enamel by supplying calcium and phosphate ions and enhancing the enamel’s resistance to acidic challenges. Conventional fluoride toothpastes remain the gold standard for caries prevention and remineralization. However, in recent years, biomimetic calcium-phosphate systems such as nano-hydroxyapatite, casein phosphopeptide–amorphous calcium phosphate (CPP-ACP), and bioactive glass have been developed to more closely replicate the natural mineralization process of enamel.

Fluoride-Based Toothpastes

Mechanism: Fluorapatite Formation and Acid Resistance

Fluoride accumulates on the enamel surface and reacts with calcium and phosphate ions present in saliva to form fluorapatite or fluorohydroxyapatite. These minerals have lower solubility than native hydroxyapatite, thereby increasing enamel resistance to acid dissolution and improving remineralization efficiency [10,40]. Fluoride-containing toothpastes have demonstrated a clear dose–response effect, where concentrations of at least 1000 ppm fluoride significantly enhance enamel remineralization and protect against erosive challenges when compared with non-fluoride formulations [41],.

Figure 3 : Schematic Illustration of Caries Initiation and White Spot Lesion Development

Limitations: Fluorosis Risk

Although fluoride is highly effective in preventing dental caries, excessive fluoride exposure during tooth development may lead to dental fluorosis. This condition occurs when children, particularly those under six years of age, ingest large amounts of fluoride toothpaste or other fluoride-containing products [13,14,15,18].

Systematic reviews, including Cochrane analyses, indicate that the risk of fluorosis increases when young children regularly use toothpaste containing ≥1000 ppm fluoride from early childhood. Therefore, careful control of toothpaste concentration, amount used, and swallowing behavior is recommended when fluoride products are used by children.

Calcium Phosphate Technologies

Calcium phosphate-based technologies aim to mimic the natural mineral composition of enamel by delivering bioavailable calcium and phosphate ions to demineralized surfaces. These systems promote nucleation and growth of hydroxyapatite crystals, thereby supporting enamel repair and strengthening[42]

Biomimetic Strategies for Enamel Remineralization

Biomimicry in dentistry refers to the design and application of materials and therapeutic strategies that imitate the natural structure, composition, and functional mechanisms of biological tissues, particularly dental enamel[43]. Enamel is a highly mineralized tissue composed predominantly of organized hydroxyapatite crystals arranged in a hierarchical architecture, which provides exceptional mechanical strength and resistance to wear. However, unlike other tissues, enamel lacks regenerative capacity once damaged. Therefore, biomimetic approaches aim to replicate the natural processes of enamel formation (amelogenesis) to restore its structure and function[44].

In the context of enamel remineralization, biomimetic strategies focus on recreating the physicochemical environment necessary for the nucleation, growth, and organization of hydroxyapatite crystals. These approaches often involve the use of analogs of enamel matrix proteins, ion-delivery systems, and nanostructured materials that can guide mineral deposition in a controlled manner. By mimicking the role of proteins such as amelogenin, these systems facilitate the formation of organized mineral phases rather than random precipitation, thereby improving the quality of remineralization[45].

Modern biomimetic agents—including nano-hydroxyapatite, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), and bioactive glass—function by supplying bioavailable calcium and phosphate ions, stabilizing precursor phases, and promoting crystal growth on demineralized enamel surfaces. These materials not only enhance mineral deposition but also help restore surface microhardness and reduce sensitivity. Emerging biomaterials, such as keratin-based systems, further extend this concept by acting as organic scaffolds that support mineral nucleation and mimic natural extracellular matrices[46-47].

Agents for Biomimetic Strategies for Enamel Remineralization

Nano-hydroxyapatite (nHAp)

Nano-hydroxyapatite (nHAp) is one of the most extensively studied biomimetic agents for enamel remineralization due to its close chemical and structural similarity to natural enamel apatite. Recent studies have further strengthened its role as a promising alternative or adjunct to fluoride-based systems. The nano-sized particles (20–80 nm) enable deep penetration into enamel microporosities, where they act as nucleation centers and a reservoir of calcium and phosphate ions, facilitating the formation of enamel-like mineral layers.

Significant advancements in nHAp-based formulations. A 2025 in vitro study demonstrated that nHAp-containing toothpaste and serum effectively reduced enamel demineralization and significantly improved surface microhardness around orthodontic brackets, showing comparable performance to conventional fluoride toothpaste[48] Similarly, a 2025 comparative study reported that hydroxyapatite-based toothpastes can remineralize early enamel lesions effectively and may serve as a viable alternative to fluoride formulations[49].

Figure 4 : Schematic Representation of Enamel Remineralization Pathways Including Keratin-Based Systems

Systematic reviews and clinical evidence published in 2024–2025 further support that hydroxyapatite-based oral care products are capable of preventing caries progression and promoting enamel remineralization, with comparable efficacy to fluoride and improved biocompatibility . Additionally, studies combining nHAp with fluoride or other agents have shown synergistic effects, enhancing remineralization outcomes and improving enamel surface properties[50].

Casein Phosphopeptide–Amorphous Calcium Phosphate (CPP-ACP)

Casein phosphopeptide–amorphous calcium phosphate (CPP-ACP) is a widely studied biomimetic remineralizing agent that stabilizes calcium and phosphate ions in an amorphous, bioavailable form, thereby maintaining a state of supersaturation at the enamel surface. The casein phosphopeptides bind to dental biofilms, enamel, and soft tissues, enabling localized delivery of calcium and phosphate ions and facilitating subsurface remineralization. This mechanism closely mimics natural enamel mineralization by promoting ion diffusion into early carious lesions and inhibiting further demineralization[51,52].

CPP-ACP has demonstrated significant potential in the management of early enamel lesions, particularly white spot lesions. Clinical and in vitro studies have reported its ability to enhance enamel surface microhardness and promote mineral gain compared to untreated controls. In some cases, CPP-ACP has shown comparable or superior performance to fluoride-based systems, especially when used in combination with fluoride (CPP-ACPF), which enhances ion availability and remineralization efficiency[53].

Furthermore, novel delivery systems such as CPP-ACP-containing lozenges and varnishes have shown promising results in improving remineralization outcomes and patient compliance.

Despite these encouraging findings, evidence from systematic reviews and meta-analyses indicates variability in outcomes due to differences in study design, application protocols, and lesion characteristics. Some studies report no statistically significant advantage over fluoride alone, highlighting the need for standardized methodologies and long-term clinical validation Overall, CPP-ACP remains a key biomimetic agent with substantial potential for incorporation into advanced toothpaste formulations aimed at enamel repair and caries prevention[53,54].

Bioactive Glass (BAG)

Bioactive glass (BAG) is a well-established biomimetic material widely used in enamel remineralization due to its ability to release essential ions and promote the formation of hydroxyapatite. Typically composed of calcium sodium phosphosilicate, BAG interacts with saliva and aqueous media to release calcium, phosphate, and sodium ions, resulting in an increase in local pH. This alkaline environment facilitates the precipitation of a carbonated, calcium-deficient hydroxyapatite layer on the enamel surface, closely resembling the mineral phase of natural enamel[55].

The mechanism of BAG closely mimics natural biomineralization processes by inducing rapid nucleation and growth of apatite crystals. Upon application, BAG particles adhere to the enamel surface and gradually dissolve, forming a silica-rich layer that acts as a template for calcium-phosphate deposition. This leads to the formation of a protective mineralized layer that not only restores enamel surface integrity but also occludes dentinal tubules, thereby reducing hypersensitivity[56].

Numerous in vitro and in situ studies have demonstrated that BAG-containing toothpastes significantly enhance enamel surface microhardness and promote remineralization of early carious lesions[57]. Comparative studies indicate that BAG performs similarly or, in some cases, more effectively than CPP-ACP and nano-hydroxyapatite in restoring mineral loss and protecting against acid erosion. Additionally, the incorporation of nano-sized bioactive glass (nBG) has shown improved reactivity, greater surface area, and enhanced ion release, leading to superior remineralization outcomes[58].

Despite its strong biomimetic potential, challenges such as formulation stability, particle size optimization, and long-term clinical validation remain. Nevertheless, bioactive glass continues to be a promising component in advanced toothpaste formulations aimed at effective enamel repair and caries prevention.

Limitations and Research Gaps

Despite significant progress in biomimetic remineralization, several limitations remain. Most evidence for agents such as nano-hydroxyapatite, CPP-ACP, and bioactive glass is derived from in vitro or short-term studies, with limited long-term clinical validation. Variability in study design, formulation composition, and application protocols leads to inconsistent outcomes, making direct comparisons difficult[6,59-61]. Additionally, the depth and durability of remineralization achieved by these agents are not always sufficient to fully restore natural enamel structure[62]. Challenges related to formulation stability, standardization, and scalability further hinder their widespread clinical adoption. Therefore, well-designed, long-term clinical trials and standardized evaluation methods are needed to establish their efficacy and optimize their use in toothpaste formulations[63].

Keratin: Structure, Sources, and Properties

Molecular Structure (α-keratin and β-keratin)

Keratin is a fibrous, intermediate filament protein broadly classified into α-keratin and β-keratin. α-keratin, predominantly found in mammals, is composed of coiled α-helical polypeptide chains stabilized by hydrogen bonding and extensive disulfide cross-linking, imparting elasticity and tensile strength. In contrast, β-keratin, mainly present in avian sources such as feathers, exhibits a β-sheet structure that confers higher rigidity and structural order. The high cysteine content in keratin enables strong intermolecular disulfide bonding, which is critical for its stability and functional performance as a biomaterial[64].

Sources

Keratin is derived from abundant and renewable biological sources, including wool, human hair, and poultry feathers. These sources are considered sustainable and economically viable, making keratin an attractive candidate for large-scale biomedical and dental applications. Feather-derived keratin, in particular, has gained attention due to its high availability and ease of processing[65].

Extraction and Purification Techniques

Keratin extraction involves the cleavage of disulfide bonds to solubilize the protein. Common methods include reductive extraction using thiol agents (e.g., β-mercaptoethanol), oxidative methods, and environmentally friendly enzymatic hydrolysis[66]. Advanced techniques such as ionic liquid extraction and microwave-assisted processes have also been explored to improve yield and preserve functional integrity. Purification is typically achieved through dialysis, centrifugation, and lyophilization to obtain keratin with controlled molecular weight and high purity[67].

 Properties Relevant to Enamel Repair[68-69]

  • Biocompatibility: Keratin is non-immunogenic and well-tolerated in biological systems, supporting its safe use in oral care formulations.
  • Biodegradability: It undergoes controlled degradation into amino acids, minimizing toxicity and environmental impact.
  • Mechanical Strength: Strong intermolecular interactions and cross-linking provide structural integrity, aiding in the formation of durable coatings on enamel.
  • Sulfur-rich Composition (Cysteine): The abundance of cysteine residues facilitates disulfide bond formation and enhances adhesion to tooth surfaces and interaction with calcium ions.
  • Film-forming Ability: Keratin can form uniform, bioadhesive films that act as protective barriers and scaffolds for mineral deposition.
  • Mineralization Potential: Functional groups such as –COOH, –NH?, and –SH promote nucleation and growth of hydroxyapatite, supporting biomimetic remineralization.

Overall, these properties make keratin a promising biomaterial for developing advanced toothpaste formulations aimed at effective enamel repair and regeneration.

Keratin-Based Biomaterials in Biomedical Applications

Keratin-based biomaterials have gained significant attention in biomedical research due to their excellent biocompatibility, biodegradability, and structural versatility. In tissue engineering and wound healing, keratin scaffolds and hydrogels have been widely utilized to support cell adhesion, proliferation, and differentiation. Their intrinsic bioactivity, along with the presence of cell-binding motifs, facilitates rapid tissue regeneration and enhances healing processes, particularly in skin repair and chronic wound management[70].

In the field of drug delivery, keratin has been explored as a carrier for controlled and targeted release systems. Its ability to form nanoparticles, films, and hydrogels allows encapsulation of therapeutic agents, improving drug stability and sustained release profiles[71]. The presence of functional groups such as amino, carboxyl, and thiol groups enables efficient drug binding and responsiveness to environmental conditions, making keratin-based systems suitable for advanced delivery applications[72].

Keratin has also shown promising applications in bone and skin regeneration. In bone tissue engineering, keratin scaffolds promote mineral deposition and support osteogenic activity due to their affinity for calcium ions and ability to act as a template for hydroxyapatite formation. Similarly, in skin regeneration, keratin-based matrices mimic the natural extracellular environment, accelerating tissue repair and restoring structural integrity[73].

These biomedical properties are highly relevant to dental applications, particularly in enamel remineralization. The ability of keratin to form bioadhesive films, support mineral nucleation, and interact with calcium and phosphate ions makes it an ideal candidate for biomimetic enamel repair. Its scaffold-forming capability can facilitate organized mineral deposition on demineralized enamel surfaces, while its compatibility with oral tissues supports its integration into toothpaste formulations aimed at regenerative and preventive dentistry[74].

Formulation Strategies of Keratin-Based Toothpastes

Keratin-based toothpaste formulations are designed to exploit the protein’s bioadhesive and mineralization-promoting properties while ensuring stability and user acceptability. Various formulation approaches have been developed to optimize its performance in enamel repair.

Types of Formulations

  • Keratin Nanoparticles: Keratin can be engineered into nanoparticles to enhance surface area, penetration into enamel microporosities, and interaction with calcium and phosphate ions. These systems improve bioavailability and enable uniform deposition on demineralized enamel[75].
  • Keratin Hydrogels: Hydrogels provide a hydrated, three-dimensional network that allows sustained release of active ions. They enhance retention time on the tooth surface and create a favorable microenvironment for remineralization[76].
  • Keratin Coatings/Films: Film-forming keratin can create a thin, protective layer over enamel, acting as a barrier against acid attack while serving as a scaffold for mineral deposition[77].

Combination Approaches

  • Keratin + Fluoride: Combines the remineralizing effect of fluoride (fluorapatite formation) with keratin’s scaffold and adhesion properties, potentially enhancing mineral deposition and acid resistance.
  • Keratin + Nano-hydroxyapatite (nHAp): Provides synergistic effects where keratin supports nucleation and nHAp supplies direct mineral content, improving enamel surface repair and microhardness.
  • Keratin + Bioactive Glass (BAG): Enhances ion release (Ca²?, PO?³?) and increases local pH, while keratin aids in adhesion and organized mineral growth, leading to improved remineralization outcomes.

Stability and Compatibility Issues

Keratin formulations may face challenges related to protein denaturation, aggregation, and pH sensitivity. Compatibility with other toothpaste ingredients such as surfactants, abrasives, and preservatives must be carefully optimized to maintain functional integrity and efficacy[79].

Manufacturing Considerations

Large-scale production requires standardized extraction and purification of keratin with consistent quality. Formulation processes must ensure uniform dispersion, stability during storage, and acceptable texture and shelf life. Additionally, cost-effectiveness, scalability, and regulatory compliance are important factors for successful commercialization[80].

Evaluation of Keratin-Based Toothpaste Systems

The efficacy of keratin-based toothpaste formulations is assessed through a combination of laboratory, in situ, and clinical approaches to determine their remineralization potential and practical applicability.

In vitro Studies

  • Surface Microhardness: Measurement of enamel microhardness (e.g., Vickers or Knoop hardness tests) is commonly used to evaluate remineralization. Keratin-based systems have shown improvements in surface hardness, indicating mineral gain and structural recovery of demineralized enamel[82].
  • SEM/AFM Analysis: Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) provide detailed insights into surface morphology and topographical changes. These techniques reveal the formation of mineralized layers, reduction in surface porosity, and improved enamel smoothness after treatment[82].
  • Mineral Deposition Assays: Techniques such as energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR) are used to confirm calcium-phosphate deposition and hydroxyapatite formation on enamel surfaces[83].

In situ and Ex vivo Studies

In situ and ex vivo models simulate oral conditions more closely by incorporating factors such as saliva, pH fluctuations, and biofilm presence. These studies help evaluate the real-time remineralization potential, retention, and durability of keratin-based formulations under dynamic conditions.

Challenges and Limitations

Despite the promising potential of keratin-based biomaterials, several challenges hinder their widespread application in toothpaste formulations. One major limitation is the variability in keratin sources and extraction methods, which can lead to inconsistencies in molecular weight, purity, and functional properties. This variability affects reproducibility and performance across formulations[83].

Scale-up and standardization remain significant hurdles, as laboratory extraction techniques may not be easily translated to industrial production while maintaining quality and cost-effectiveness. Additionally, stability issues such as protein denaturation, aggregation, and sensitivity to pH and temperature can compromise the effectiveness of keratin in complex toothpaste systems containing surfactants and abrasives[84].

Another critical limitation is the limited availability of clinical evidence, with most studies confined to in vitro or short-term evaluations, making it difficult to establish long-term efficacy and safety[85]. Furthermore, regulatory and safety concerns, including biocompatibility validation, source traceability, and compliance with cosmetic and pharmaceutical guidelines, must be addressed before commercialization.

Future Perspectives

Future research on keratin-based toothpaste formulations is expected to focus on enhancing functionality and clinical applicability. The development of advanced nanostructured keratin systems may improve penetration, surface interaction, and controlled mineral delivery. The integration of smart and stimuli-responsive formulations, capable of releasing active components in response to pH or environmental changes, represents a promising direction for targeted enamel repair. Advances in computational tools and material science may enable AI-driven formulation design, optimizing composition, stability, and performance more efficiently. Additionally, the emergence of personalized oral care products, tailored to individual risk factors and oral conditions, could further enhance treatment outcomes. Finally, the incorporation of keratin into broader regenerative dentistry approaches, including tissue engineering and biomimetic restoration strategies, may pave the way for next-generation solutions in enamel repair and preventive oral healthcare.

CONCLUSION

Keratin-based biomaterials represent a promising and emerging approach in the field of biomimetic enamel remineralization. Owing to their unique structural characteristics, biocompatibility, and ability to interact with calcium and phosphate ions, keratin systems offer significant potential for restoring enamel integrity through mechanisms that closely mimic natural biomineralization. Unlike conventional agents that primarily focus on mineral supplementation, keratin provides an organic scaffold that supports organized crystal growth and enhances adhesion to demineralized enamel surfaces. Current evidence suggests that keratin-based formulations, particularly when combined with established remineralizing agents such as fluoride, nano-hydroxyapatite, and bioactive glass, may provide synergistic effects, leading to improved remineralization outcomes and enhanced protection against acid-induced damage. However, despite encouraging in vitro and preliminary in situ findings, the transition from laboratory research to clinical application remains limited.Key challenges, including variability in raw materials, formulation stability, scalability, and regulatory considerations, must be addressed to ensure consistency and safety. Furthermore, the lack of robust long-term clinical data highlights the need for well-designed trials to validate efficacy and support commercialization.

In conclusion, keratin-based biomaterials hold strong potential as next-generation ingredients in toothpaste formulations aimed at enamel repair and caries prevention. Continued advancements in material engineering, formulation strategies, and clinical research are essential to fully realize their role in advancing preventive and regenerative dentistry.

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Snehal Mishra
Corresponding author

G H Raisoni University, Saikheda, Pandhurna, Madhya Pradesh, India

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AMAN PRASAD
Co-author

G H Raisoni University, Saikheda, Pandhurna, Madhya Pradesh, India

Aman Prasad, Snehal Mishra, Keratin-Based Biomaterials for Enamel Repair: Current Advances and Future Perspectives in Toothpaste Formulations, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 4, 4168-4189. https://doi.org/10.5281/zenodo.19752639

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