The Role of Tissue Engineering in Orthodontic and Orthognathic Treatment: A Narrative Review

Abstract

Background: Orthodontics and orthognathic surgery present challenges such as extended treatment durations, patient discomfort, and complications like root resorption. Recent advancements in tissue engineering and nanotechnology offer promising solutions by improving bone regeneration, periodontal repair, and biomaterial integration. Objectives: This review explores the integration of scaffold-based tissue engineering and nanotechnology in orthodontics, focusing on their roles in accelerating bone regeneration, reducing treatment times, and minimizing adverse effects to enhance the predictability and success of orthodontic interventions. Methods: Relevant literature was selected from PubMed, Scopus, and Web of Science, focusing on studies related to scaffold technology, biomaterials, and nanotechnology in orthodontics. Keywords included “tissue engineering”, “orthodontics”, “biomaterials”, “scaffolds”, “nanotechnology”, and “bone regeneration”. Priority was given to peer-reviewed original studies, systematic reviews, and meta-analyses addressing innovative treatment approaches and clinical outcomes. Results: Findings indicate that scaffolds enhance bone regeneration and periodontal repair, while nanoparticles improve biomaterial integration and drug delivery efficiency. These advancements contribute to faster, more predictable orthodontic treatments with reduced complications. However, challenges such as high costs, regulatory hurdles, and the need for long-term clinical validation remain barriers to widespread adoption. Conclusions: Tissue engineering and nanotechnology offer minimally invasive, biologically driven solutions for orthodontic treatment. While significant progress has been made, further clinical studies, cost-effective strategies, and regulatory approvals are needed to integrate these innovations into routine practice.

1. Introduction

Orthodontics plays a crucial role in addressing dental malocclusions and skeletal deformities, but traditional methods face significant limitations [1]. Conventional treatments typically require lengthy durations, frequent clinical visits, and pose risks such as root resorption, relapse, and considerable patient discomfort. Moreover, these treatments may not fully account for the intricate biological processes of bone and tissue remodeling, which are essential during orthodontic tooth movement [2,3]. As patient demands shift toward faster, more efficient, and less invasive treatments, the field of orthodontics faces a pressing need for innovation.

Recent years have witnessed transformative advancements in tissue engineering, scaffold technology, and nanotechnology, reshaping the landscape of orthodontic solutions [4]. Tissue engineering, for instance, focuses on the regeneration of oral tissues, such as bone and periodontal ligaments, through biomimetic processes, which are essential for treatments that require rapid healing and lasting results [5]. A scaffold in tissue engineering is a three-dimensional structure that provides a temporary framework for supporting cell attachment, proliferation, and differentiation, ultimately facilitating new tissue formation. These scaffolds, made from natural or synthetic biomaterials, are designed to mimic the extracellular matrix and promote bone regeneration in orthodontic and orthognathic applications.

Orthodontic treatments exert mechanical forces on teeth and surrounding tissues, which can lead to various biological and clinical complications. Studies have shown that orthodontic tooth movement induces an increase in interleukin-1β (IL-1β), a pro-inflammatory cytokine in gingival crevicular fluid, contributing to periodontal tissue inflammation and destruction [6]. Furthermore, prolonged orthodontic treatments may cause white spot lesions—areas of demineralization on enamel surfaces—leading to esthetic and structural concerns [7]. Another well-documented risk is root resorption, where excessive force results in the loss of root structure, potentially compromising tooth stability [8]. Additionally, orthodontic treatments can alter soft tissue appearance in the lower third of the face, impacting facial aesthetics and patient satisfaction [9].

Tissue engineering presents a promising solution to mitigate these challenges by facilitating accelerated tissue repair, controlled inflammatory responses, and improved bone remodeling. By integrating bioactive scaffolds, nanotechnology, and biomimetic strategies, researchers are developing biologically adaptive materials that enhance healing, reduce unwanted side effects, and improve overall treatment outcomes.

Scaffold technology further enhances tissue engineering by incorporating biocompatible and bioresorbable materials that support tissue regeneration while maintaining structural integrity during the bone remodeling process under orthodontic forces [10]. These scaffolds, whether synthesized from natural or synthetic materials, are meticulously designed to stimulate tissue growth and serve as matrices for cell migration and differentiation, significantly reducing tissue stress and minimizing risks such as root resorption [11].

Additionally, nanotechnology introduces a remarkable level of precision in orthodontic care. By manipulating materials at the molecular scale, nanomaterials, such as nano-enhanced polymers and coatings, enhance the mechanical properties, durability, and biocompatibility of orthodontic appliances [10,11]. In contrast, nanoparticles—discrete nanoscale particles such as silver, zinc oxide, or hydroxyapatite—serve functional roles, including antimicrobial protection, osteogenic stimulation, and targeted drug delivery [12,13,14].

This distinction is crucial: nanomaterials contribute to the structural integrity of orthodontic devices, while nanoparticles interact with biological tissues at the cellular level, enhancing bone regeneration and minimizing complications [15].

Given these advancements, this review aims to explore the integration of scaffold-based tissue engineering and nanotechnology in orthodontic and orthognathic treatments. Specifically, we will examine recent developments in scaffold design, the role of bioactive molecules, and the impact of nanomaterials on tissue regeneration. Furthermore, we will highlight current challenges, clinical applications, and future directions to optimize patient outcomes through innovative biomaterials and personalized treatment approaches.

2. Methodology

This review provides a comprehensive overview of recent advancements in tissue engineering applications in orthodontics and orthognathic surgery. Relevant literature was selected from peer-reviewed journals, focusing on studies related to scaffold technologies, biomaterials, nanotechnology, and their clinical applications. Sources were identified through databases such as PubMed, Scopus, and Web of Science, prioritizing recent research published in the last decade. Emphasis was placed on original studies, review articles, systematic reviews, and meta-analyses that provide insights into innovative treatment approaches, challenges, and future perspectives.

3. Tissue Engineering in Orthodontics

Recent advancements in tissue engineering are set to revolutionize the field of orthodontics through the innovative applications of stem cell technology and bioprinting [16] Figure 1 and Figure 2. These technologies utilize undifferentiated stem cells, such as mesenchymal stem cells (MSCs) and adipose-derived stem cells (ASCs), along with precision bioprinting techniques to create scaffolds that closely mimic the natural extracellular matrix (ECM) of dental tissues. These scaffolds facilitate not only the structural and functional repair of craniofacial tissues but also enable customized treatments for dental malocclusions and other dentofacial anomalies [17,18]. For example, scaffolds seeded with ASCs demonstrated accelerated orthodontic tooth movement by stimulating PDL reorganization and enhancing bone remodeling in animal models [17,18].

Figure 3 illustrates the complex interaction between dental pulp stem cells (DPSCs), fibroblasts, and endothelial cells in promoting tissue regeneration and angiogenesis during orthodontic treatments. The integration of DPSCs into the bone remodeling process leads to the differentiation of osteoblast progenitors and osteocytes. Fibroblasts, under the influence of extracellular matrix components (e.g., CG1, CG3), proliferate and differentiate to repair tissues. Angiogenesis is facilitated by the activation and budding of endothelial cells, forming microvascular networks that enhance the healing process. The figure also emphasizes the role of microRNAs and signaling pathways, such as Akt and STAT3, in regulating cellular proliferation and differentiation, critical for tissue regeneration under orthodontic forces [19].

The strategic application of these advanced techniques promises to enhance regenerative capabilities within orthodontics, leading to more effective management of complex dental cases [5]. Additionally, bioprinted scaffolds integrated with extracellular vesicles from MSCs have shown improved bone density and healing in craniofacial defect models [17]. These findings underscore the potential of integrating stem cell therapies with advanced biomaterials to achieve predictable and efficient therapeutic outcomes.

In addition, the integration of smart biomaterials is reshaping treatment modalities in orthodontics. Engineered to respond adaptively to changes within the oral environment, such as pH and temperature fluctuations, these materials dynamically interact with biological tissues [22]. This interaction promotes faster and more predictable tooth movement while also reducing common orthodontic complications like root resorption and inadequate bone healing, thereby improving the overall treatment process [23]. Shape-memory alloys used in orthodontic wires adjust pressure based on intraoral conditions to optimize tooth movement without manual adjustments, and pH-responsive polymers release antimicrobial agents in response to bacterial activity, protecting against decay and infection near orthodontic fixtures [24,25]. For example, hydroxyapatite-tricalcium phosphate scaffolds loaded with VEGF have been shown to enhance angiogenesis and bone regeneration in craniofacial models, overcoming limitations like poor vascularization [18].

However, many challenges remain for the tissue engineering of dental, oral, and craniofacial structures. Considerations such as the high demand for aesthetics, appropriate vascularization, the complex environment, the need to accommodate multiple tissue phenotypes, and the overall integration into functional systems are major determinants [26,27]. For instance, scaffolds derived from natural extracellular matrices (ECMs), such as those produced by MSCs, have shown superior proliferation and osteogenic differentiation compared to synthetic scaffolds [17,18]. These approaches emphasize the need to incorporate signaling molecules like VEGF and fibroblast growth factors (FGFs) to promote angiogenesis and cellular integration in engineered tissues [28,29].

To address these challenges, recent studies have explored combining biomimetic scaffolds with advanced manufacturing techniques, such as 3D and 4D printing, to create personalized devices tailored to individual patient needs. For example, magnesium-doped bioceramic scaffolds were used to regenerate mandibular defects, demonstrating exceptional mechanical properties and osteogenic potential in preclinical trials [30]. Additionally, customized titanium implants fabricated using CBCT data reduced surgical time and improved osseointegration in alveolar ridge augmentation procedures [17].

These technological integrations into clinical orthodontics suggest a future where treatments are not only more efficient but also less invasive. This enhances patient comfort and satisfaction by minimizing treatment duration and improving aesthetic outcomes [31]. For example, bioengineered scaffolds seeded with MSCs demonstrated significant enhancements in bone density and accelerated orthodontic tooth movement in vivo, reducing relapse rates and treatment times [32]. Such findings highlight the potential of these approaches to revolutionize traditional orthodontic practices [18].

As these technologies continue to evolve, they hold the promise of transforming orthodontic practices into more adaptive, efficient, and patient-centered healthcare services. The ongoing development and clinical integration of bioprinted tissues, stem cell applications, and smart biomaterials are pushing the boundaries of what is possible in orthodontic care, marking a significant leap forward in the management and treatment of dental and facial irregularities [33].

4. Scaffold Systems in Orthodontics

4.1. Transforming Orthodontic Treatment Through Adaptive Technologies

Smart scaffolds signify a revolutionary step in orthodontic treatments, engineered to dynamically interact with the biological environment of the oral cavity [34]. These systems are not passive structures; they actively respond to changes in mechanical stresses and biochemical signals. This adaptability is critical in promoting effective tissue regeneration and mitigating complications such as inflammation or unwanted tissue growth [35]. For instance, smart scaffolds can detect increased pH levels indicative of inflammation and respond by releasing anti-inflammatory agents directly at the site, thereby improving the healing process and patient comfort [36]. Advanced materials such as hydrogels that exhibit stimuli-responsive properties are frequently used in these scaffolds. These materials can alter their behavior in response to temperature, pH, or mechanical forces, making them ideal for the fluctuating conditions within the oral cavity [16]. For example, a rise in local pH due to bacterial activity can trigger the scaffold to release encapsulated antimicrobial or anti-inflammatory agents directly at the site of infection or inflammation. This localized drug delivery system not only targets therapeutic actions more precisely but also reduces systemic side effects [37,38].

Moreover, the integration of nanotechnology plays a crucial role in enhancing the functional properties of these scaffolds. Nanoparticles can be engineered to provide improved scaffold strength, controlled degradation rates, and enhanced biocompatibility. They can also be used to create a more conducive microenvironment for osteointegration, crucial for the stability of orthodontic implants and appliances. For example, nanoparticles of bioactive glass or calcium phosphate can be incorporated into the scaffold matrix to enhance mineral deposition and bone growth. Figure 4 illustrates the integration of these technologies, emphasizing how scaffolds incorporating nanoparticles can accelerate orthodontic bone remodeling and reduce treatment duration [20]. By harnessing the potential of these adaptive technologies, orthodontic treatment is significantly advancing toward more personalized, effective, and less invasive therapies. This tailored approach not only ensures better alignment of the teeth and jaw but also supports the overall health of the oral tissues, promoting faster recovery times and improved long-term outcomes for patients [39,40,41,42].

4.2. Advanced Fabrication Techniques

4.2.1. Revolutionizing Scaffold Design with 3D Printing

Leveraging 3D printing technologies, modern orthodontics has seen a significant shift toward customized scaffold designs that enhance both treatment efficacy and patient comfort [43]. These advanced fabrication techniques employ a diverse array of biocompatible materials, such as polylactic acid (PLA), composite materials blending polymers with ceramic particles, and pure ceramic options such as hydroxyapatite and tricalcium phosphate. Each material is selected for its unique properties: polymers for their flexibility and ease of manipulation, composites for their enhanced mechanical strength and osteoconductivity, and ceramics for their biocompatibility and bone-bonding capabilities [44,45,46].

In orthodontics, 3D printing has enabled precise, patient-specific scaffold designs that are customized to the topographical and morphological features of the patient’s dental anatomy. This process begins with a detailed digital scan of the patient’s oral structures, which is converted into a sophisticated 3D model. The ability of 3D printers to layer materials with precision down to micrometers ensures that each scaffold fits perfectly, optimizing contact with existing bone and soft tissues to encourage better integration and reduce the risk of implant failure [47,48]. Recent innovations in additive manufacturing (3D printing) include the development of thermal stimulus-based hydroxyapatite-reinforced PLA scaffolds, which not only provide structural support but also exhibit shape-memory properties that adapt to environmental stimuli like temperature changes. This technology, known as bioprinting, constructs vital tissues that mimic the natural bone structure, allowing scaffolds to be bioactive, fostering more natural bone integration. Additionally, bioprinting with materials like collagen and bio-inks enables the development of more complex scaffolds that can support soft tissue regeneration alongside bone repair [49,50,51].

Stereolithography (SLA), fused deposition modeling (FDM), and digital light processing (DLP) are three primary 3D printing techniques used in orthodontics [52]. These methods differ in their precision and application. SLA produces highly accurate models with smooth surfaces, making it ideal for aligner molds and occlusal splints, though it requires post-processing. FDM, a more cost-effective method, extrudes thermoplastic layers but has lower precision and surface quality, making it suitable for study models rather than clinical use. DLP, like SLA, cures entire layers at once, offering high accuracy with faster printing times but still requiring post-processing. While SLA and DLP are preferred for precision appliances, FDM remains useful for educational models. As technology advances, improved materials and processes will further enhance 3D printing applications in orthodontics [53,54].

4.2.2. Functionally Enhanced Scaffold Design

The scaffolds produced through 3D printing are not only designed to fit the patient’s unique anatomy but can also be customized to include functional features such as micro-pores or channels to facilitate vascularization and nerve growth, which are critical for the long-term success of implants and bone regeneration. These structures may be impregnated with growth factors or anti-inflammatory agents that are gradually released to promote healing, prevent infection, and support rapid bone integration [55,56].

Moreover, the addition of nanoparticles into the scaffold matrix significantly enhances its functional properties. For instance, bioactive nanoparticles like calcium phosphate and bioactive glass improve mineral deposition and bone growth, while metal nanoparticles such as silver enhance the antimicrobial properties of orthodontic appliances. These nanoparticles can be embedded into the scaffold to promote osseointegration while minimizing the risk of bacterial infections during orthodontic treatment [57].

4.2.3. Precision and Customization in Clinical Practice

3D printing allows orthodontists to plan and simulate treatment with a high degree of precision. Software tools such as CAD (computer-aided design) and CAM (computer-aided manufacturing) facilitate the virtual planning of orthodontic treatments, allowing for the customization of appliances like clear aligners and retainers. This level of customization improves patient outcomes by reducing the treatment duration and enhancing overall comfort [58]. Orthodontic appliances like retainers, aligners, and even complex mini-implant-supported devices can be fabricated with greater accuracy and durability using 3D printing technologies. Appliances such as palatal expanders and customized mini-implants are created with biocompatible materials, ensuring that they offer mechanical strength and patient-specific functionality [59,60]. By leveraging these advanced fabrication techniques, orthodontic treatments are becoming more personalized, efficient, and less invasive. The ability to design and manufacture precise, patient-specific scaffolds and appliances reduces the duration of orthodontic therapy, minimizes complications, and improves prognostic outcomes, making the treatment journey more comfortable and efficient for patients.

4.2.4. Integration into Clinical Practice

The integration of smart scaffolds into everyday clinical practice requires a comprehensive approach involving multiple disciplines. Collaboration between orthodontists, material scientists, and bioengineers is essential to tailor scaffold designs that are both effective and safe for patient use [61]. This multidisciplinary effort ensures that each scaffold is not only functionally optimal but also customized to the individual’s specific clinical needs. Moreover, the introduction of these innovative materials into the market must navigate complex regulatory pathways to verify their safety and efficacy. Orthodontic professionals must also consider ethical aspects, including patient consent and the long-term implications of implanting new biotechnologies, ensuring that these advanced treatments align with the highest standards of patient care and regulatory compliance. Building on the comprehensive role of nanoparticles in orthodontics, it is crucial to delve deeper into how these tiny yet powerful agents are revolutionizing the field. Nanoparticles, due to their ultra-small size, interact at a cellular level, offering unprecedented opportunities to enhance the material properties of orthodontic appliances and contribute to tissue engineering and regenerative medicine within the oral cavity [62,63,64].

5. Role of Nanoparticles in Orthodontic Regeneration

The synthesis of new nanoparticle formulations involves manipulating materials at the molecular scale to improve their compatibility and functionality within biological systems. For orthodontic applications, this often means enhancing the mechanical properties and biocompatibility of appliances [65]. Techniques such as sol-gel processing, chemical vapor deposition, and controlled precipitation are employed to create nanoparticles that are consistently uniform in size and shape [66,67]. These nanoparticles can be metals, ceramics, or composites, depending on the desired properties. For instance, nanoparticles like silica or polymeric nanoparticles are synthesized to fill microvoids in orthodontic composites, enhancing their mechanical strength and durability under the constant stress of orthodontic adjustments [68].

Multifunctional nanoparticles are tailored to address multiple challenges in orthodontics simultaneously. These include improving the antimicrobial properties of orthodontic appliances to reduce the risk of plaque buildup and infection, and enhancing the mechanical properties to withstand the biomechanical forces exerted during dental correction procedures [69]. Silver nanoparticles, for example, are incorporated into the surfaces of brackets and wires, offering sustained antimicrobial activity due to their ability to release silver ions, which are lethal to bacteria [70]. On the mechanical front, nanoparticles like titanium dioxide can be added to ceramic brackets to improve their fracture toughness and wear resistance [69].

5.1. Specific Areas of Application

5.1.1. Brackets and Wires

Nanoparticles such as tungsten disulfide (WS₂), titanium nitride (TiN), and zinc oxide (ZnO) are incorporated into the manufacturing of orthodontic brackets and wires to significantly improve surface smoothness. By filling surface irregularities and forming lubricating layers, these nanoparticles reduce frictional resistance and wear between brackets and arch wires, which is critical for enhancing the efficiency of tooth movement during orthodontic treatment. For instance, WS₂ and ZnO coatings have demonstrated up to 50–64% friction reduction, facilitating smoother sliding mechanics. Additionally, coatings like silver nanoparticles (AgNPs) and TiN offer antimicrobial properties, reducing bacterial adhesion and inhibiting biofilm formation around orthodontic appliances. This dual benefit—friction reduction and antimicrobial action—not only improves patient oral hygiene but also minimizes complications like plaque-induced gingivitis and white spot lesions, ensuring safer and more effective orthodontic outcome [67,71].

5.1.2. Adhesives and Cements

Nanoparticles such as silver nanoparticles (AgNPs), zinc oxide (ZnO), and bioactive glass nanoparticles (BGNs) are incorporated into dental adhesives and cements to enhance bonding strength and introduce antibacterial properties. These nanoparticles interact at the adhesive-tooth interface to form stronger mechanical bonds, reducing the likelihood of bracket detachment during orthodontic treatment. For example, ZnO nanoparticles improve the microshear bond strength while simultaneously inhibiting the growth of cariogenic bacteria like Streptococcus mutans. AgNPs, due to their broad-spectrum antimicrobial activity, significantly reduce biofilm formation at the adhesive interface, minimizing the risk of white spot lesions and enamel demineralization. Additionally, the incorporation of nanohydroxyapatite (nHA) promotes remineralization of surrounding enamel, providing added protection against acidic environments. This combined enhancement in adhesion performance and antibacterial efficacy ensures more durable orthodontic outcomes and improved patient oral health throughout treatment [67,72].

5.1.3. Coatings on Appliances

Special nanoparticle-based coatings are applied to orthodontic appliances to enable the continuous release of therapeutic agents such as ions [e.g., silver (Ag⁺), fluoride (F⁻), and calcium (Ca²⁺)] or drugs. These coatings provide dual action; they help control demineralization and promoting remineralization of tooth enamel surrounding orthodontic brackets. For instance, coatings infused with fluoride-releasing nanoparticles create a sustained release mechanism that reinforces enamel integrity and inhibits acid-induced demineralization. Similarly, calcium phosphate nanoparticles or bioactive glass nanoparticles (BGNs) release essential ions to support enamel remineralization, restoring lost mineral content. In addition, silver nanoparticle (AgNP) coatings contribute antimicrobial properties, reducing bacterial biofilm formation and preventing conditions like white spot lesions and enamel decay. This continuous therapeutic delivery ensures long-term protection of the tooth surface, improving patient outcomes during orthodontic treatment [67,73].

The table below categorizes various scaffold materials used in orthodontic and orthognathic surgery, detailing their material type, roles in treatment, and significance (

Table 1. Scaffold materials in orthodontic and orthognathic surgery with roles, importance, and references.

No.	Scaffold Type	Material Type	Role in Orthodontics and Orthognathic Surgery	Importance in Orthodontic and Orthognathic Treatment	References
1	Polylactic Acid (PLA)	Polymer	Used for gradual tissue integration and scaffold stability in bone regeneration.	Ideal for controlled resorption in guided bone regeneration in orthognathic surgery	[11,74,75]
2	Polyglycolic Acid (PGA)	Polymer	Facilitates rapid cell integration and healing in post-surgical applications.	Beneficial for quick scaffold degradation in orthognathic surgery	[76,77]
3	Polycaprolactone (PCL)	Polymer	Serves as a framework for long-term tissue engineering in orthognathic surgeries.	Provides extended support for complex craniofacial reconstructions.	[78,79]
4	Poly(lactic-co-glycolic acid) (PLGA)	Polymer	Offers tailored degradation for scaffolds in alignment and bone defect corrections.	Customizable for patient-specific needs in orthodontics and orthognathic surgery.	[80,81]
5	Hydroxyapatite (HA)	Ceramic	Supports bone osseointegration and density improvement in surgical areas.	Essential for bone grafting and enhancing osteoconductivity in surgical repairs.	[82,83]
6	Tricalcium Phosphate (TCP)	Ceramic	Used in alveolar ridge augmentation and cleft palate repairs.	Promotes bone regeneration critical for orthodontic anchor points and device stability.	[84,85,86]
7	Bioactive Glass	Ceramic	Enhances bone bonding and supports soft tissue healing around implants.	Useful in complex craniofacial reconstructions and as a filler in bone defects.	[87,88]
8	Polymer–Ceramic Composites	Composite	Combines strength and bioactivity for load-bearing applications in orthodontics.	Provides durable and biocompatible options for long-term craniofacial scaffolding.	[89,90]
9	Fiber-Reinforced Composites	Composite	Utilized for reinforcing bone grafts and orthodontic appliances needing high strength.	Offers robust mechanical support where significant bite forces are involved.	[91,92]
10	Alginate	Natural	Used for impression making and as a carrier for bioactive molecules.	Important for creating precise dental molds and delivering therapeutic agents.	[93,94]
11	Chitosan	Natural	Facilitates hemostasis and has antimicrobial properties for wound healing.	Supports post-surgical recovery and is used in drug delivery systems in orthodontics.	[95,96,97]
12	Titanium Mesh	Metal	Provides rigid support for bone grafts in extensive reconstructive surgery.	Used for structural support in segmental osteotomies and large defect bridging.	[98,99]
13	Silver Nanoparticles (Ag NPs)	Metal Nanoparticle	Used in coatings on brackets and archwires to prevent microbial colonization and reduce dental plaque.	Provides broad-spectrum antimicrobial properties essential for reducing the risk of infection and improving oral hygiene during orthodontic treatment.	[100,101,102]
14	Zinc Oxide Nanoparticles (ZnO NPs)	Metal Oxide Nanoparticle	Incorporated into dental cements and adhesives to enhance antimicrobial properties against oral pathogens.	Helps in preventing decay and infection at critical application sites, improving the longevity and success of orthodontic treatments.	[103,104]
15	Titanium Dioxide Nanoparticles (TiO2 NPs)	Metal Oxide Nanoparticle	Utilized in composite materials for fixed appliances to improve antimicrobial activity and mechanical properties.	Enhances the durability and infection resistance of orthodontic appliances under varied oral conditions, beneficial for long-term treatment stability.	[64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105]
16	Hydroxyapatite Nanoparticles (nHAP)	Ceramic Nanoparticle	Applied in surface treatments of implants to enhance bone integration and regeneration.	Supports rapid osseointegration due to its similarity to natural bone mineral components, crucial for the stability of orthodontic implants.	[106,107]
17	Silica Nanoparticles (SiO2 NPs)	Ceramic Nanoparticle	Used to improve the physical properties of orthodontic acrylics and composites, making devices more durable and effective.	Enhances the mechanical strength and clarity of orthodontic appliances, important for maintaining appliance integrity and aesthetics during treatment.	[108,109]
18	Carbon Nanotubes	Carbon-based Nanoparticle	Reinforces orthodontic polymers to increase durability and reduce the risk of fractures in orthodontic appliances.	Provides structural integrity to polymers, significantly enhancing their mechanical properties and resistance to the mechanical forces during orthodontic treatment.	[110,111]

). It highlights both traditional and nanoparticle-enhanced materials, showcasing their applications and importance in improving treatment outcomes.

6. Growth Factors in Orthodontic Tissue Engineering: Enhancing Treatment and Recovery

Recent advancements in the field of orthodontics have highlighted the transformative role of growth factors in tissue engineering, which are essential for promoting the regenerative processes necessary for successful orthodontic treatments [112]. Growth factors such as Bone Morphogenetic Proteins (BMPs), Transforming Growth Factor-beta (TGF-β), fibroblast growth factors (FGFs), and Insulin-like Growth Factors (IGF) play pivotal roles in stimulating migration, proliferation, and differentiation of cells involved in bone and periodontal tissue regeneration [113,114] (Figure 4, Table 2).

The study by Radermacher et al. illustrates the sophisticated interplay between mechanical stimuli and biological agents. This research reveals that when mesenchymal stem cells are subjected to controlled compressive forces in the presence of specific growth factors, there is a marked enhancement in osteogenic differentiation and alignment. These insights are crucial for clinical orthodontics, where manipulating cellular behavior through mechanical and biochemical cues can optimize tissue remodeling and accelerate treatment processes [115].

Furthermore, the integration of growth factors into various delivery systems such as biocompatible scaffolds and slow-releasing matrices is critically discussed in the review presented by Montemurro et al. These systems are designed to address traditional challenges in orthodontic treatment by providing a localized, sustained release of growth factors, thus maintaining their stability and bioactivity over extended periods. Such innovative delivery mechanisms ensure that the therapeutic potential of growth factors is fully realized, promoting efficient and effective healing and regeneration [62].

Figure 4. A schematic representing the biological events of the Tooth biology of movement. Growth factors, when correctly applied, can significantly enhance the outcomes of orthodontic treatments by improving the regeneration capabilities of bone and periodontal tissues. This integration of growth factors into orthodontic practice not only promises more predictable clinical outcomes but also opens the door to novel therapeutic strategies that could redefine traditional treatment methodologies. As research continues to evolve, the potential for these biomolecules in clinical applications continues to expand, marking a new era in orthodontic tissue engineering that leverages the power of biological and mechanical sciences to treat complex dental and skeletal irregularities. Adopted from [114].

Figure 4. A schematic representing the biological events of the Tooth biology of movement. Growth factors, when correctly applied, can significantly enhance the outcomes of orthodontic treatments by improving the regeneration capabilities of bone and periodontal tissues. This integration of growth factors into orthodontic practice not only promises more predictable clinical outcomes but also opens the door to novel therapeutic strategies that could redefine traditional treatment methodologies. As research continues to evolve, the potential for these biomolecules in clinical applications continues to expand, marking a new era in orthodontic tissue engineering that leverages the power of biological and mechanical sciences to treat complex dental and skeletal irregularities. Adopted from [114].

Table 2. Growth factors and cytokines involved in orthodontic bone remodeling, detailing their roles, mechanisms, and significance in orthodontic treatments. References provide further context and evidence for their applications.

Growth Factor/Cytokine	Role in Orthodontic Bone Remodeling	Mechanism of Action	Significance in Orthodontics	Refs.
Transforming Growth Factor-β (TGF-β)	Influences cell differentiation and proliferation. Modulates bone remodeling.	Stimulates the production of matrix proteins and downregulates matrix degradation, affecting tissue structure.	Essential for the regulation of cellular activities during tooth movement and stabilization of the newly formed bone.	[116,117,118]
Vascular Endothelial Growth Factors (VEGFs)	Promotes angiogenesis and tissue regeneration.	Induces endothelial cell proliferation, promotes vessel permeability, and enhances the migration and formation of blood vessels.	Critical for ensuring adequate blood supply for bone healing and regeneration during mechanical stress in orthodontics.	[22,119,120]
Platelet-Derived Growth Factors (PDGFs)	Crucial for cell recruitment and proliferation necessary for bone regeneration and repair.	Attracts cells such as fibroblasts, smooth muscle cells, and monocytes to the site of injury, promoting remodeling of the periodontal ligament and alveolar bone.	Supports the movement of teeth and the repair of periodontal tissues, enhancing the response to orthodontic forces.	[118,119,120,121]
Fibroblast Growth Factor 2 (FGF2)	Supports proliferation and differentiation of various cells, aiding in angiogenesis and wound healing.	Stimulates endothelial cells, fibroblasts, and other cells, enhancing their proliferation and activities necessary for tissue repair and vascular growth.	Important for rapid tissue repair and regeneration, particularly in the dental pulp during and after orthodontic appliance activation.	[120,121,122]
Hepatocyte Growth Factor (HGF)	Supports wound healing and tissue regeneration, responsive to mechanical forces.	Acts on various cell types to promote cellular proliferation, movement, and survival; has anti-fibrotic effects.	Enhance tissue repair and regeneration around moving teeth, minimizing treatment time and improving outcomes.	[115,123,124]
Osteoprotegerin (OPG)	Inhibits osteoclast activation, preventing excessive bone resorption.	Functions as a decoy receptor for RANKL, inhibiting its ability to bind RANK on osteoclasts and thus preventing osteoclastogenesis.	Plays a crucial role in maintaining alveolar bone density and preventing unwanted bone loss during tooth movement.	[125,126]
Soluble Receptor Activator of Nuclear Factor Kappa-Β Ligand (sRANKL)	Promotes osteoclast differentiation and activity, influencing bone resorption.	Binds to RANK on osteoclast precursors, promoting their maturation and activity, essential for bone remodeling.	Vital for the controlled resorption of bone necessary to accommodate tooth realignment.	[127,128]
Bone Morphogenetic Proteins (BMPs)	Stimulates osteoblast differentiation, crucial for bone formation and healing.	Induces the transformation of stem cells into bone-forming osteoblast cells, also induces the production of other growth factors in the osteoblasts.	Plays a pivotal role in the regeneration of bone defects and enhances the stability of teeth post-orthodontic treatment.	[129,130,131]
Insulin-like Growth Factors (IGFs)	Enhances osteoblast proliferation, contributing to bone density and growth.	Mediates growth hormone effects, leading to cell proliferation and inhibition of apoptosis in osteoblastic cells.	Supports rapid remodeling required during tooth movement, ensuring timely adjustment to the desired positions.	[132,133,134]
Connective Tissue Growth Factor (CTGF)	Involved in connective tissue development and repair, significant for periodontal ligament adjustments.	Promotes extracellular matrix production in connective tissues, influencing fibroblast proliferation and angiogenesis.	Essential for the repair and regeneration of periodontal ligament and surrounding soft tissue during orthodontic treatment.	[135,136]
Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α)	Regulate inflammation and bone resorption processes; influence osteoclastic activity.	Pro-inflammatory cytokines that stimulate osteoclastogenesis and bone resorption while modulating immune response in periodontal tissues.	Their regulation is crucial for balancing bone formation and resorption, affecting the stability and duration of treatment.	[21,137,138]

Table 2. Growth factors and cytokines involved in orthodontic bone remodeling, detailing their roles, mechanisms, and significance in orthodontic treatments. References provide further context and evidence for their applications.

Growth Factor/Cytokine	Role in Orthodontic Bone Remodeling	Mechanism of Action	Significance in Orthodontics	Refs.
Transforming Growth Factor-β (TGF-β)	Influences cell differentiation and proliferation. Modulates bone remodeling.	Stimulates the production of matrix proteins and downregulates matrix degradation, affecting tissue structure.	Essential for the regulation of cellular activities during tooth movement and stabilization of the newly formed bone.	[116,117,118]
Vascular Endothelial Growth Factors (VEGFs)	Promotes angiogenesis and tissue regeneration.	Induces endothelial cell proliferation, promotes vessel permeability, and enhances the migration and formation of blood vessels.	Critical for ensuring adequate blood supply for bone healing and regeneration during mechanical stress in orthodontics.	[22,119,120]
Platelet-Derived Growth Factors (PDGFs)	Crucial for cell recruitment and proliferation necessary for bone regeneration and repair.	Attracts cells such as fibroblasts, smooth muscle cells, and monocytes to the site of injury, promoting remodeling of the periodontal ligament and alveolar bone.	Supports the movement of teeth and the repair of periodontal tissues, enhancing the response to orthodontic forces.	[118,119,120,121]
Fibroblast Growth Factor 2 (FGF2)	Supports proliferation and differentiation of various cells, aiding in angiogenesis and wound healing.	Stimulates endothelial cells, fibroblasts, and other cells, enhancing their proliferation and activities necessary for tissue repair and vascular growth.	Important for rapid tissue repair and regeneration, particularly in the dental pulp during and after orthodontic appliance activation.	[120,121,122]
Hepatocyte Growth Factor (HGF)	Supports wound healing and tissue regeneration, responsive to mechanical forces.	Acts on various cell types to promote cellular proliferation, movement, and survival; has anti-fibrotic effects.	Enhance tissue repair and regeneration around moving teeth, minimizing treatment time and improving outcomes.	[115,123,124]
Osteoprotegerin (OPG)	Inhibits osteoclast activation, preventing excessive bone resorption.	Functions as a decoy receptor for RANKL, inhibiting its ability to bind RANK on osteoclasts and thus preventing osteoclastogenesis.	Plays a crucial role in maintaining alveolar bone density and preventing unwanted bone loss during tooth movement.	[125,126]
Soluble Receptor Activator of Nuclear Factor Kappa-Β Ligand (sRANKL)	Promotes osteoclast differentiation and activity, influencing bone resorption.	Binds to RANK on osteoclast precursors, promoting their maturation and activity, essential for bone remodeling.	Vital for the controlled resorption of bone necessary to accommodate tooth realignment.	[127,128]
Bone Morphogenetic Proteins (BMPs)	Stimulates osteoblast differentiation, crucial for bone formation and healing.	Induces the transformation of stem cells into bone-forming osteoblast cells, also induces the production of other growth factors in the osteoblasts.	Plays a pivotal role in the regeneration of bone defects and enhances the stability of teeth post-orthodontic treatment.	[129,130,131]
Insulin-like Growth Factors (IGFs)	Enhances osteoblast proliferation, contributing to bone density and growth.	Mediates growth hormone effects, leading to cell proliferation and inhibition of apoptosis in osteoblastic cells.	Supports rapid remodeling required during tooth movement, ensuring timely adjustment to the desired positions.	[132,133,134]
Connective Tissue Growth Factor (CTGF)	Involved in connective tissue development and repair, significant for periodontal ligament adjustments.	Promotes extracellular matrix production in connective tissues, influencing fibroblast proliferation and angiogenesis.	Essential for the repair and regeneration of periodontal ligament and surrounding soft tissue during orthodontic treatment.	[135,136]
Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α)	Regulate inflammation and bone resorption processes; influence osteoclastic activity.	Pro-inflammatory cytokines that stimulate osteoclastogenesis and bone resorption while modulating immune response in periodontal tissues.	Their regulation is crucial for balancing bone formation and resorption, affecting the stability and duration of treatment.	[21,137,138]

7. Future Directions of Role of Artificial Inelligence (AI) and Machine Learning in Personalizing Orthodontic Treatment

7.1. AI in the Design of Tissue-Engineered Products and Nanoparticle-Enhanced Materials

AI and machine learning (ML) have the potential to transform the design and customization of tissue-engineered products and nanoparticles by making the process more data-driven and predictive [139]. In orthodontic tissue engineering, AI can analyze vast amounts of biological, mechanical, and chemical data to identify optimal designs for scaffolds used in tissue regeneration [140]. For example, AI models can simulate the behavior of various biocompatible materials, such as polycarbonates, and predict their success in promoting cell adhesion, proliferation, and osteogenic differentiation under different clinical conditions [141].

AI can also enhance the customization of nanoparticle-based therapies by predicting how these particles interact with tissues at the molecular level. For example, nanoparticles used for delivering osteogenic agents (like calcium or growth factors) can be optimized using AI algorithms that consider the particle size, shape, surface chemistry, and targeted release mechanisms. These predictions help in refining nanoparticle formulations that work best for individual patients’ specific tissue environments [142,143].

In practice, AI systems will learn from previous patient outcomes and continuously refine the design and effectiveness of tissue-engineered scaffolds and nanoparticles by using feedback loops. They could analyze patient data such as healing rates, bone density, and immune response, and then suggest adjustments to the scaffold design or nanoparticle delivery strategy to optimize recovery. This iterative improvement is a key advantage of AI over traditional trial-and-error approaches in material design [139,144].

7.2. AI-Driven Personalization: Genetic Profiles and Predictive Modeling

AI can truly personalize orthodontic treatments by incorporating genetic profiles and using predictive modeling to forecast how a specific patient will respond to treatment [145]. AI systems can process genetic data, such as single nucleotide polymorphisms (SNPs) and other genomic variations, to determine how likely a patient is to benefit from a specific orthodontic device or treatment protocol [146]. For example, patients with specific genetic markers may have different tissue regeneration capacities, which can be considered when designing tissue scaffolds or selecting nanoparticle-based interventions. In addition, AI-powered feedback loops play a crucial role in the continuous personalization of treatments. One of AI’s most powerful capabilities is its ability to learn from data and refine predictions over time [146,147]. In orthodontic treatment, AI can operate within feedback loops that continuously gather data from patients throughout the process. A patient’s healing progress can be monitored using wearable sensors or regular imaging, allowing AI systems to adjust the treatment plan in real time. This dynamic approach ensures that treatments are tailored to the patient’s evolving biological responses [144]. For instance, in tissue engineering, AI might monitor how quickly a scaffold integrates with surrounding tissue and suggest modifications to scaffold design or nanoparticle release profiles if healing is slower than expected [139]. In orthodontics, AI systems might adjust the forces applied by braces or aligners based on real-time data about tooth movement, thereby minimizing discomfort and improving outcomes [148]. Moreover, AI can analyze patient imaging, 3D scans, and treatment outcomes using machine learning algorithms to identify patterns that correlate with better treatment results for certain subpopulations [149]. This allows for the creation of highly customized treatment plans based not only on a patient’s biological characteristics but also on predictive outcomes derived from similar cases. As more data are collected, AI systems can continuously refine predictions, improving the personalization of treatments over time [150].

7.3. Multi-Modal Data Integration

AI’s ability to integrate multiple types of data (genetic, imaging, clinical history, and patient feedback) allows it to make comprehensive decisions. A personalized orthodontic treatment would not only consider the physical characteristics of a patient’s teeth and jaw structure (obtained from 3D imaging and CT scans) but also integrate genetic information to predict how fast the bone will regenerate and how tissues will respond to mechanical forces. Additionally, AI can assess lifestyle data, such as a patient’s diet, oral hygiene habits, and stress levels, which might influence the effectiveness of orthodontic interventions [151,152,153].

7.4. AI-Driven Predictive Models

Predictive models built using machine learning can anticipate treatment outcomes even before the intervention starts. For instance, in orthodontics, AI can predict the speed of tooth movement, and the response of bone and tissue based on a combination of factors, including genetic predispositions, the patient’s age, bone density, and treatment history [154]. These predictive models allow orthodontists to create more accurate treatment timelines and minimize the likelihood of adverse outcomes. By using advanced modeling techniques such as neural networks, AI can predict multiple complex interactions simultaneously, giving orthodontists tools to provide better-tailored treatments for each patient [155].

In orthodontics, AI is already being used in technologies such as customized 3D-printed aligners (e.g., Invisalign) [156]. AI algorithms analyze patient scans to create personalized aligners that are precisely shaped to guide teeth into their ideal positions [156]. This process ensures that each aligner is unique to the patient’s dental structure, and ML algorithms continuously adjust the aligners’ design as treatment progresses based on the rate of tooth movement. AI’s ability to predict how the teeth will shift over time ensures that the treatment is as efficient and comfortable as possible [157].

8. Discussion

Tissue engineering is shaping the future of orthodontic and orthognathic treatment, bringing solutions to challenges that have long frustrated both patients and clinicians—prolonged treatment times, root resorption, and unpredictable bone remodeling [2,16]. The use of biocompatible scaffolds, nanotechnology, and bioactive molecules is paving the way for treatments that work with the body rather than against it [158].

One of the biggest game changers in this field is scaffold technology. These structures do not just fill spaces; they guide tissue regeneration, helping bone and soft tissues grow where they are needed most. Thanks to 3D and 4D printing, these scaffolds can now be customized for each patient, offering a level of precision that was once impossible. But even with these advancements, we are still figuring out how to optimize their degradation rates and long-term stability to ensure they integrate seamlessly into the body [159].

Nanotechnology is another exciting area. Nanoparticles like hydroxyapatite, silver, and bioactive glass have been integrated into adhesives, cements, and brackets, helping to improve bone regeneration, antimicrobial properties, and material strength. However, while lab studies show promising results, we need more clinical trials to fully understand how these materials behave over time in the human body [65,160].

We are also seeing a growing role for growth factors, such as BMPs and VEGFs, which can accelerate bone remodeling and healing. While these biological molecules have the potential to shorten treatment time and reduce complications, delivering them in a controlled and sustained manner remains a challenge. They are too little, and they do not work. Too much, and they might trigger unwanted effects [113,114].

And then there’s AI—a tool that could personalize orthodontic treatments by predicting how different biomaterials interact with each patient’s bone structure. AI could optimize scaffold designs, adjust treatment plans in real time, and even suggest the best nanomaterial combinations. But we are still in the early stages, and before AI-driven orthodontics becomes the norm, we need more real-world data and regulatory approvals [141].

8.1. Limitations

Limited clinical evidence remains a major concern, as most studies are still in the preclinical stage, requiring long-term human trials to confirm safety and efficacy [161]. Variability in study methodologies makes it difficult to compare results, as different research groups use diverse biomaterials and testing approaches [162]. High costs and accessibility issues also limit widespread clinical adoption, with advanced technologies like bioprinting and AI-driven treatments requiring specialized expertise and equipment. Additionally, regulatory and ethical barriers pose challenges, particularly for stem cell-based therapies and gene-enhanced biomaterials [163,164]. Lastly, while this review focuses on emerging technologies, more comparative studies are needed to determine whether they truly outperform conventional orthodontic treatments.

8.2. Future Directions

Future research should prioritize large-scale clinical trials to validate biomaterials and scaffold-based therapies in real-world orthodontic applications. Standardizing biomaterial formulations will improve consistency and facilitate clinical translation. Advancements in 4D printing and smart biomaterials could lead to adaptive scaffolds that respond dynamically to oral conditions [165,166]. AI integration could enhance personalized treatment planning and material selection. Finally, efforts should focus on reducing costs and improving scalability to make these technologies more accessible for broader clinical use [167].

As we stand on the cusp of a new era in medical science, it is crucial for the orthodontic field to not only embrace these technological innovations but also ensure they are accessible and beneficial to all. The democratization of these advanced technologies is essential; they must not be available only to a select few but should reshape orthodontic care across diverse populations. Embracing this challenge is not just an opportunity but a responsibility, ensuring that the future of orthodontics remains as dynamic and effective as the technologies are driving its transformation.

9. Conclusions

The integration of nanotechnology, 3D printing, and bioengineered scaffolds is advancing orthodontic and orthognathic treatment by addressing key challenges such as prolonged treatment duration, inadequate bone regeneration, and biofilm-related complications [168,169]. Nanoparticles like silver, zinc oxide, and hydroxyapatite improve material strength, antimicrobial properties, and osteointegration, enhancing device longevity and treatment efficiency [103]. Meanwhile, 3D-printed scaffolds composed of hydroxyapatite, polylactic acid, and bioactive glass enable patient-specific bone regeneration, which is crucial for correcting severe malocclusions and supporting periodontal healing [170,171].

Beyond these material innovations, AI is transforming treatment by optimizing scaffold design, predicting tissue responses, and refining orthodontic force application [148]. The combination of nanotechnology, AI-driven simulations, and regenerative scaffolds ensures that emerging biomaterials meet clinical needs, improve patient outcomes, and gain regulatory approval [172].

However, long-term clinical validation remains a challenge. The biocompatibility, degradation kinetics, and mechanical stability of nano-enhanced materials and 3D-printed scaffolds require extensive vivo studies before widespread adoption. Additionally, regulatory hurdles and cost barriers limit accessibility [172,173]. Future research should focus on enhancing scaffold bioactivity with VEGF and BMPs, integrating AI-driven real-time treatment monitoring, and developing 4D-printed biomaterials that dynamically adapt to mechanical forces, improving tissue remodeling and reducing relapse risks [171].

By overcoming these challenges, nanotechnology, AI, and advanced biomaterials will enable more efficient, personalized, and accessible orthodontic treatments, marking a new era in orthodontic care.