Sage Journals: Discover world-class research

Abstract

Advances in biomaterials and drug delivery systems are redefining modern dentistry, moving beyond traditional restorative approaches toward biologically guided regeneration. This review highlights the development of smart, multifunctional platforms such as nanoparticles, hydrogels, scaffolds, and additive manufacturing (AM) technologies that enable localized, controlled therapeutic delivery while promoting tissue repair. These innovations are transforming treatments across periodontics, oral oncology, endodontics, and pediatric care by offering site-specific action and enhanced biocompatibility. Stimuli-responsive materials and dual-function scaffolds are engineered to respond to environmental cues such as pH or enzymatic activity, providing on-demand drug release and supporting healing in dynamic oral environments. AM technologies further allow for the fabrication of patient-specific constructs with optimized architecture and mechanical properties.

Despite promising preclinical and early clinical outcomes, several challenges persist, including concerns regarding long-term safety, biocompatibility, and regulatory complexities, particularly for nano-enabled and multifunctional systems. Standardized toxicity assessments and harmonized approval pathways are needed to facilitate clinical translation. This review critically examines current material strategies, technological platforms, and their therapeutic applications in dental medicine and addresses emerging safety considerations and regulatory frameworks. Collectively, these innovations represent a shift toward more personalized, regenerative, and minimally invasive oral healthcare solutions.

Keywords

Dental biomaterials drug delivery systems regenerative dentistry tissue engineering oral drug delivery

Graphical Abstract

Introduction

The landscape of dentistry is being reshaped by the rapid evolution of biomaterials and drug delivery technologies. Traditionally focused on mechanical restorations, the field now increasingly embraces regenerative strategies, shifting the paradigm from repair to regeneration.¹ In this transformation, biomaterials are no longer passive structural components but functional tools that actively guide healing, control infections, and modulate immune responses. Bone regeneration plays a central role in this shift, particularly in addressing conditions like infections, tumors, and trauma.² However, natural healing is often hindered by large defects, poor vascularization, and systemic diseases. While autografts are still considered the gold standard due to their biocompatibility and osteoinductive potential, they come with drawbacks such as limited availability and donor site morbidity. Synthetic grafts, though structurally supportive, often lack the biological signaling needed for effective regeneration.² These challenges have fueled the development of tissue engineering approaches that integrate biodegradable scaffolds with cell recruitment and bioactive cues to enhance bone repair and regeneration.³ Recent advances in bioengineering have enabled the development of smart, multifunctional materials that respond to environmental stimuli, support tissue regeneration, and deliver therapeutic agents with precision. These include nanoparticles, hydrogels, composite scaffolds, and stimuli-responsive systems that release drugs in a controlled and site-specific manner. Such innovations are particularly crucial in the oral cavity, where complex anatomical structures, constant mechanical stress, and a dynamic microbial environment present unique challenges for both treatment efficacy and patient compliance.⁴ In parallel, the application of advanced therapy medicinal products, including cell-based and gene therapies, has opened new frontiers in regenerative dentistry. Stem cells sourced from dental pulp, periodontal ligaments, and apical papilla are now being explored for their potential to regenerate complex oral tissues such as dentin-pulp complexes, periodontal structures, and even entire teeth. However, while preclinical results are promising, clinical translation remains hindered by safety, regulatory, and cost-related challenges.⁵

The integration of biocompatible materials into drug delivery systems offers several advantages over conventional therapeutic strategies. Natural polymers like chitosan and alginate, and synthetic polymers such as PLGA and polycaprolactone (PCL), have demonstrated the ability to prolong drug release, enhance bioavailability, and minimize systemic side effects. These materials can be formulated into hydrogels, microspheres, or nanocarriers tailored for the unique demands of oral and dental applications, including infection control, pain management, cancer therapy, and post-surgical healing.⁶

Moreover, additive manufacturing (AM) (3D printing) and biofabrication technologies are facilitating the design of patient-specific scaffolds with biomimetic architecture, paving the way for personalized regenerative therapies. Incorporating drug-loaded nanoparticles into these constructs enables dual functionality, simultaneous structural support and therapeutic delivery.^{7, 8}

The aim of this review is to explore and critically evaluate recent innovations in biomaterials and drug delivery systems tailored for dental applications, with a particular focus on regenerative medicine. By examining a wide range of platforms, including nanoparticles, hydrogels, scaffolds, and AM approaches, the study seeks to highlight how these technologies are transforming traditional dental treatments into more personalized, site-specific, and biologically integrated solutions. Special attention is given to the dual functionality of these materials in promoting tissue regeneration while providing therapeutic delivery, as well as the regulatory and safety considerations that accompany their clinical translation.

Methods and Materials

A narrative literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar, covering publications from 2009 to 2024. Key search terms included “dental biomaterials,” “drug delivery systems,” “oral tissue engineering,” “regenerative dentistry,” “nanoparticles,” “hydrogels,” “scaffolds,” “additive manufacturing,” and “oral drug delivery.” Peer-reviewed articles, including one relevant systematic review, were included based on their relevance to dental and oral applications. This review synthesizes current evidence and emerging trends but does not follow a systematic review protocol.

Smart Drug Delivery Platforms in Dentistry

Modern drug delivery platforms in dentistry are rapidly evolving to incorporate “smart” or stimulus-responsive materials that react to local environmental conditions such as pH, oxidative stress, or enzymatic activity.⁹ These adaptive systems enable precise, on-demand release of therapeutics, especially important in infected or inflamed periodontal and endodontic sites, where traditional systems often fail to maintain effective concentrations.¹⁰

For instance, MMP-sensitive hydrogels and reactive oxygen species (ROS)-responsive polymer matrixes have demonstrated success in selectively releasing antimicrobials like chlorhexidine or ciprofloxacin when triggered by inflammation-associated enzymes or oxidative stress. These approaches reduce unnecessary drug exposure and improve treatment outcomes.¹¹

Functional Scaffolds for Regeneration and Targeted Therapy

Scaffolds used in oral tissue regeneration are no longer passive structures. They are now engineered as multifunctional systems capable of supporting tissue architecture, delivering drugs, and promoting biological healing.

Composite scaffolds made from PLGA, β-tricalcium phosphate (β-TCP), HA, and silk fibroin have been widely explored as carriers for osteogenic agents like bone morphogenetic proteins (BMPs) and simvastatin. These bioactive constructs stimulate angiogenesis, osteogenesis, and control infection simultaneously. Notably, PLGA scaffolds loaded with simvastatin enhanced BMP-2 expression and vascularization in periodontal defects, while remaining biodegradable and biocompatible.¹²

Natural Compounds and Nanoformulations

Natural therapeutic agents such as curcumin, known for its antioxidant and anti-inflammatory properties, have been successfully encapsulated in chitosan hydrogels, HA-polylactic acid (PLA) nanoparticles, or PLGA nanospheres to improve their stability and bioavailability. These nanoformulations enable sustained drug release and deeper tissue penetration, making them suitable for post-extraction socket healing, periodontitis, and oral mucositis (OM) treatment.¹³

Multifunctional Scaffolds for Cancer and Regeneration

Recent innovations have yielded dual drug-loaded nanofibrous scaffolds that provide both anticancer activity and support for tissue regeneration. For instance, electrospun polyhydroxybutyrate/gelatin nanofibers co-loaded with chemotherapeutics enabled spatiotemporal drug delivery in oral squamous cell carcinoma (OSCC), followed by scaffold degradation and tissue repair.^{14, 15}

Treatment of cancers such as OSCC often results in significant hard and soft tissue loss, challenging both function and aesthetics. To address this, dual-function scaffolds are emerging as powerful tools that combine localized cancer therapy with regenerative healing, tailored to the unique anatomical and physiological demands of the oral cavity.¹⁴

One of the most promising platforms is the injectable, self-assembling peptide-based hydrogel, which allows for the localized, prolonged release of anticancer agents directly within the oral lesion.¹⁶ These systems offer enhanced mucosal retention, reduced systemic toxicity, and are engineered to degrade into bioactive matrixes that support the healing of surrounding oral tissues, such as gingiva, alveolar bone, and mucosa.¹⁷ From recent studies, multifunctional scaffolds have been developed that simultaneously release chemotherapeutics and osteogenic or angiogenic factors, such as BMP-2 or VEGF, enabling both tumor suppression and periodontal or alveolar bone regeneration.¹⁸ This is particularly beneficial in cases of post-surgical defects or in peri-implant sites compromised by malignancy.

Moreover, scaffold surfaces functionalized with immune-modulatory or cell-adhesive peptides (e.g., RGD) help shift the microenvironment from an inflammatory, tumor-supportive state to one that promotes Mesenchymal Stem Cells (MSC) recruitment, angiogenesis, and tissue regeneration. These smart systems can also be stimuli-responsive, designed to release anticancer agents in acidic or enzyme-rich tumor environments, and subsequently support regenerative processes as the local conditions stabilize.

In the context of oral cancers and post-excisional wound management, such dual-function materials represent a crucial advancement offering a single-stage approach to both eradicate residual malignancy and guide tissue repair, especially in functionally critical zones like the mandible, palate, or gingiva.^{2, 19}

Surface-functionalized Biomaterials for Enhanced Bioactivity

Surface functionalization is a cornerstone strategy for improving scaffold performance in dental and periodontal regeneration. By modifying material surfaces with bioactive molecules, these systems enhance cell–material interactions and promote superior regenerative outcomes.²⁰

Incorporation of short bioactive peptides such as RGD (Arg-Gly-Asp) facilitates cell adhesion, migration, and differentiation. When combined with osteogenic or angiogenic growth factors like VEGF and BMP-2, these surfaces accelerate tissue healing, especially in periodontal and peri-implant regions.²¹

Nanoparticle coatings of gold, silver, or calcium-based on titanium implants further amplify bioactivity. These nanoscale modifications enhance osseointegration, stimulate angiogenesis and osteogenesis, and modulate immune responses toward a regenerative phenotype by promoting M2 macrophage polarization.^{22, 23}

Electrospun membranes functionalized with antimicrobial, anti-inflammatory, and osteoinductive agents closely mimic the extracellular matrix (ECM), acting as localized drug delivery systems for controlled release at defect sites.²⁴ Advanced approaches such as VEGF-loaded nanoparticles and siRNA-modified coatings have demonstrated improved vascularization and periodontal ligament formation.^{25, 26}

As illustrated in Figure 1, nanoparticles embedded on implant surfaces enable localized release of osteogenic and angiogenic factors, promoting cell adhesion, stem cell recruitment, and bone regeneration at the implant–bone interface, hallmarks of successful osseointegration.²⁷

Collectively, these surface-engineering strategies are redefining regenerative dentistry by creating site-specific, biologically responsive scaffolds that integrate structural stability with cellular signaling, ultimately enhancing clinical predictability and success.

Figure 1.

Schematic Illustration of Drug- and Bioactive Molecule-loaded Nanoparticles Integrated on the Surface of a Dental Implant. These Surface-functionalized Platforms Enable Localized, Controlled Release of Osteogenic and Angiogenic Factors, Enhancing Cell Recruitment, Osseointegration, and Bone Regeneration at the Implant–Bone Interface. Adopted From Ref. 27.

Photodynamic and Mucoadhesive Therapies

Photodynamic therapy (PDT) is a promising non-invasive strategy for treating oral mucosal tumors. It employs nanoparticle carriers loaded with light-sensitive agents such as methylene blue or porphyrins, which generate ROS upon light activation to induce tumor cell apoptosis. Methylene blue-loaded PLGA nanoparticles have shown strong antibacterial effects in root canals and notable potential for oral cancer therapy.^28–30

Complementary to PDT, mucoadhesive drug delivery systems extend the residence time of therapeutics on mucosal surfaces. Liposomal films containing chemotherapeutics like methotrexate enable sustained, localized release with minimal systemic exposure, ideal for superficial oral lesions and precancerous conditions. These systems adhere to moist oral tissues, maintaining effective local concentrations and improving bioavailability and patient compliance.³¹

Together, photodynamic and mucoadhesive therapies exemplify site-specific, minimally invasive, and patient-friendly approaches that integrate nanoparticle technology with precision drug delivery, advancing personalized and regenerative dental care.

AM and Scaffold Design for Personalized Regeneration

AM, widely known as 3D printing, has transformed scaffold fabrication in oral regenerative medicine. By using imaging data from CT or MRI, patient-specific constructs can be designed in CAD software and printed layer by layer through technologies such as fused deposition modeling (FDM), stereolithography (SLA), or selective laser sintering (SLS). This enables the production of scaffolds with high spatial accuracy, controlled porosity, and mechanical properties tailored to mimic native tissues.^{7, 8, 32}

Biocompatible materials such as PCL, PLGA, and hydroxyapatite (HA) composites are commonly used in AM to fabricate scaffolds with adjustable degradation rates and mechanical strength. These scaffolds can incorporate advanced features like pore channels, microgrooves, and gradient stiffness zones to guide cell orientation and differentiation, particularly useful for complex interfaces like the periodontal ligament or alveolar ridge (Figure 2).³²

Figure 2.

Paradigm Shift in Scaffold Production. Scaffold Fabrication Has Shifted From Standardized Manufacturing to Patient-specific Design Through AM. Traditional Methods Limit Complexity and Customization, Whereas AM Uses CAD/CAM and Patient Imaging to Create Personalized Scaffolds for Bone Regeneration. This Patient-centered Approach Enhances Precision and Accessibility in Clinical Dentistry. Adopted From Ref. 32.

Mechanical cues embedded within the scaffolds, such as stiffness and viscoelasticity, also influence stem cell behavior, enhancing osteogenesis and matrix deposition. AM’s capability to fabricate multiphasic or biphasic scaffolds supports both soft and hard tissue regeneration in a single construct. Furthermore, these scaffolds can be loaded with bioactive agents such as antibiotics (e.g., doxycycline), growth factors (e.g., BMP-2, VEGF), or gene vectors to enable simultaneous regeneration and therapeutic delivery.^{19, 33}

Clinical prototypes have already shown success in alveolar ridge reconstruction and complex periodontal defects. While reproducibility, bioresorption timing, and in vivo integration remain as challenges, AM-based scaffolds are quickly advancing toward clinical application in large bone defects, trauma care, and post-cancer reconstruction.³⁴

Material Considerations for Dental Scaffolds

The success of scaffold-based dental regeneration relies heavily on selecting suitable biomaterials, particularly polymers, that meet both biological and engineering requirements. These materials must balance biocompatibility, printability, mechanical stability, and degradation behavior to ensure safe and effective performance in the complex oral environment.^{32, 35}

Polycaprolactone

PCL is one of the most used polymers in dental scaffold fabrication due to its mechanical flexibility, slow degradation rate, and compatibility with FDM-based 3D printing. Its low melting point preserves the activity of temperature-sensitive biofactors, making it ideal for bioactive, cell-laden constructions. PCL is particularly well-suited for long-term support in load-bearing or large defects.^{32, 36}

PLA and PLGA

PLA and PLGA offer faster degradation rates and robust mechanical strength. PLGA is widely used in both scaffolds and drug delivery due to its tunability and biocompatibility. However, its acidic degradation products may cause local irritation, especially in larger volumes. These polymers are ideal for applications requiring short-term scaffolds, such as microspheres in endodontic or periodontal therapies.^{37, 38}

Composite Polymers

To address the limitations of single-polymer systems, composite scaffolds blend polymers like PCL or PLGA with bioactive ceramics such as HA, β-TCP, or bioactive glass. These composites enhance osteoconductivity, mechanical strength, and mimic the hybrid structure of native bone. They are especially effective in distributing mechanical stress under complex oral loads.³⁹

Tailoring Polymer Properties for Clinical Success

Optimizing scaffold properties for specific clinical needs involves tuning factors like pore size, elasticity, degradation rate, and viscoelasticity. For example, softer scaffolds may be used for gingival regeneration, while stiffer ones better support bone growth. Surface modifications, such as peptide conjugation or nanoparticle coating, enhance cell adhesion, immune response modulation, and overall clinical performance.²⁰

Innovations in Drug Delivery Systems for Oral Applications

Innovations in biomaterials have opened exciting possibilities for targeted therapy across a wide range of dental challenges, from managing peri-implant infections and oral cancers to promoting bone regeneration and pediatric care. These advanced systems are not just about delivering drugs; they are designed to do so intelligently, responding to local conditions, staying put where needed, and minimizing systemic side effects.^40–42 Table 1 summarizes some of the most promising platforms currently under investigation or in clinical use. It highlights how nanoparticles, hydrogels, mucoadhesive films, and other delivery vehicles are tailored to specific dental needs, each selected for its material type, therapeutic goal, and clinical benefit.

Table 1.

Innovations in Drug Delivery and Regenerative Medicine in Dentistry.

Application	Drug Delivery Platform	Material Type	Therapeutic Goal	Advantages	Ref.
Bone tissue regeneration	Nanoparticles (e.g., PLGA, HA, β-TCP, lipid-based NPs, magnetic NPs)	Bioceramics, bioactive glass, PLGA, polymer blends, simvastatin-loaded carriers	Promote osteogenesis and angiogenesis, treat critical defects	Enhanced targeting, improved healing, osteoinduction, reduced dose	^{2, 43}
Oral cancer therapy	Targeted drug carriers (e.g., polymeric/inorganic NPs, exosomes, hydrogels)	Liposomes, core-shell nanospheres, and biodegradable polymers	Tumor targeting, minimal toxicity, and immune modulation	Bioavailability boost, precision delivery, reduced side effects	^{44, 45}
Pediatric dentistry	Polysaccharide-based microspheres and nanogels	Chitosan, alginate, dextran, pectin	Safe delivery for caries, pulp infections, and gingivitis	Biodegradable, mucosal adhesion, low immunogenicity	^{46, 47}
Temporomandibular joint disorders (TMJ)	Metallic/polymeric NPs and liposome formulations	Silver, chitosan, and hyaluronic acid carriers	Reduce inflammation, cartilage protection	Targeted anti-inflammatory, reduced systemic load	⁴⁸
Oral infection control	Smart hydrogels, core-shell NPs, metal-polymer hybrid carriers	Ciprofloxacin-loaded hydrogels, AgNPs, ZnO NPs	Eradicate biofilms, local antibiotic release	Localized action, biofilm penetration, extended release	^{49, 50}
Antifungal and antiviral therapy	Nanoformulations with amphotericin B, acyclovir, etc.	Polymeric nanogels, micelles, lipid nanoparticles	Treat candidiasis, herpes, and COVID-19-related oral lesions	High solubility, mucosal targeting, prolonged activity	^{48, 51}
Gene and protein delivery	Polyplexes, dendrimers, DNA nanostructures	Biodegradable synthetic polymers, lipid-based vectors	Regeneration via BMPs, VEGF, and immune modulation	Controlled gene release, reduced degradation	^{52, 53}
Periodontal therapy	Growth factor-loaded hydrogels, antimicrobial nanogels	PLGA, chitosan, fibrin, electrospun nanofibers	Promote tissue and bone regeneration, combat periodontitis	Enhanced osteogenesis, reduced inflammation, and local release	^{54, 55}
Peri-implantitis treatment	Antibiotic-loaded hydrogels, nanoparticles, and injectable microspheres	Chitosan, collagen, HA, simvastatin-loaded systems	Reduce inflammation and bacterial colonization around implants	Sustained local delivery, infection control, and preserve osseointegration	^{56, 57}
Implant dentistry (drug-eluting implants)	Surface-functionalized nanoparticles, drug-loaded coatings	Titanium implants coated with bioactive ceramics or polymers	Promote osseointegration, prevent infection and early failure	Prevents early implant failure, enhances initial integration, supports long-term stability	^{58, 59}
Orthodontics and orthognathic treatment	Smart scaffolds, nanoparticle-based coatings, 3D-printed scaffolds, growth factor systems	PLA, PLGA, PCL, HA, TCP, bioactive glass, AgNPs, ZnO, VEGF/BMP-loaded matrixes	Accelerate bone remodeling, reduce root resorption, enhance periodontal regeneration, minimize treatment duration	Custom-fit scaffolds, sustained local delivery, enhanced osteointegration, antimicrobial action, biocompatibility, reduced relapse	⁶⁰

Local Therapeutics for Site-specific Challenges in Dentistry

The oral cavity’s dynamic environment, including salivary enzymes and chewing forces significant obstacles to localized drug delivery.⁴⁰ Traditional approaches, such as mouthwashes and gels, while convenient, are often rapidly cleared and fail to maintain therapeutic concentration at the target site. This has led to the development of local drug delivery systems that provide prolonged, site-specific action while minimizing systemic exposure.⁴¹

Mucoadhesive formulations, such as tablets, films, and in situ gelling systems, enhance drug residence by adhering to the mucosal surface.⁶¹ For instance, thermoresponsive chitosan/β-glycerophosphate gels have been engineered to transition from liquid to semi-solid at body temperature, enabling sustained drug retention within periodontal pockets.⁴² In “Zhao et al.” study showed that minocycline-loaded chitosan gel significantly reduced probing depth (PD) and gingival index in rats with induced periodontitis compared to untreated controls showed that minocycline-loaded chitosan gel significantly reduced PD and gingival index in rats with induced periodontitis compared to untreated controls.⁶²

Beyond gels, biodegradable polymer-based inserts, such as PLGA strips impregnated with tetracycline, have shown excellent results in clinical trials.⁶³ Maze et al. demonstrated that these films released antibiotics over a 10-day period and led to significant reductions in bleeding on probing and microbial load in patients with persistent periodontitis.⁶⁴

Table 2 summarizes representative examples of LDDS technologies applied in dental therapy, including microparticles, nanoparticles, and scaffolds across endodontic and regenerative contexts and in Figure 3, we present the most recent advancements in biomaterials used for dental drug delivery and regenerative medicine. These include a diverse range of systems from nanoparticles and hydrogels to electrospun scaffolds and mucoadhesive films designed to target everything from pediatric caries to oral cancers and peri-implant infections. Together, these innovations represent the foundation for a new era in dental care, one that is more personalized, predictive, and regenerative.

Table 2.

Summary of Local Drug Delivery Systems in Dentistry.

LDDS Type	Formulation	Target Application	Outcomes	Ref.
Microparticles	HA/PLGA coated with β-TCP microparticles	Endodontic disinfection	Neutral pH, antibiotic release, strong antibacterial activity, good cell biocompatibility	^{70, 71}
	Zein/PLGA microparticles with amoxicillin	Endodontic disinfection & regeneration	Inhibited Enterococcus faecalis growth; sustained AMX release over 6 days; suitable for intracanal dressing; sponge-like structure enhanced removal	⁷²
	Simvastatin-loaded PLGA microparticles	Periodontal regeneration	BMP-2 expression, neovascularization, osteoblastic activity	⁷³
Nanoparticles	Chitosan nanoparticles	Endodontic disinfection	Lower MIC and MBC (0.31 mg/mL) than calcium hydroxide; significantly reduced E. faecalis viability and biofilm; superior anti-biofilm activity under CLSM	⁷⁴
	PLGA nanoparticles with methylene blue	Endodontic PDT	Accumulated on microbial walls; reduced E. faecalis by ~2 log₁₀ in suspension and ~1 log₁₀ in root canals with light; enhanced antibacterial efficacy	⁷⁵
	AgNPs synthesized on graphene oxide (Ag-GO)	Endodontic disinfection	Enhanced biofilm disruption in main and lateral canals; superior efficacy with ultrasonic activation (UAI); significant reduction in microbial counts and biovolume	⁷⁶
	Gold NPs with PRF	Endodontic regeneration	Sustained growth factor release; promoted canal sterility and regeneration	⁷⁷
	Chitosan–gelatin scaffolds loaded with augmentin and mTAP (1 mg/mL)	Periodontal and endodontic disinfection and regeneration	Biocompatible; sustained antibiotic release; promoted hMSC attachment and proliferation; significantly reduced E. faecalis biofilm; enhanced cell viability and biofilm disruption	⁷⁸
	Ellagic acid (EA)-loaded chitosan nanoparticles	human oral cancer cell line (KB)	Sustained release; enhanced cytotoxicity with lower IC₅₀; induced apoptosis and DNA fragmentation	⁷⁹
	Anti-EGFR antibody-conjugated microbubbles MBs (EGFR-MBs)	HNSCC, OSCC	Boosted immunotherapy effectiveness through targeted DDS	⁸⁰
	Thermosensitive hydrogel with chitosan-coated curcumin lipid-core nanocapsules	OSCC therapy	Enhanced mucoadhesion and sustained release; reduced SCC-25 cell viability; non-irritant; suitable for buccal administration	⁸¹
Liposomes (mucoadhesive film)	Methotrexate-loaded liposomes in chitosan-HPMC-PVA buccal patch	OSCC therapy	Sustained release; reduced IC50; increased apoptosis via mitochondrial depolarization and ROS; enhanced site-specific cytotoxicity	⁸²
Nanofibers/Scaffolds	PVA/chitosan nanofibers loaded with ciprofloxacin and IDR-1002	Endodontic regenerative	Anti-biofilm, immunomodulatory, and regenerative properties; promoted pulp-like tissue formation; non-toxic to human cells	⁷²
Electrospun nanofibers	Clindamycin-modified TAP (metronidazole, ciprofloxacin, clindamycin) in nanofiber scaffolds	Intracanal disinfection	Safe, stain-free alternative to traditional TAP; effective antimicrobial activity; preserves dental pulp stem cell viability and avoids discoloration	⁸³
Hydrogels	Double antibiotic-loaded chitosan–fibrin hydrogel (metronidazole + ciprofloxacin)	Endodontic regeneration	Promoted significantly greater apical closure, root lengthening, and dentinal wall thickening than PRF in immature necrotic teeth; enabled sustained antibiotic release; validated in a 12-month randomized controlled trial	⁸⁴
	Gelatin hydrogel sponge incorporating PRP (rich in BMP-2, TGF-β1, PDGF-BB)	Guided bone/periodontal regeneration	Sustained release of growth factors; enhanced osteoblast and PDL cell activity; significantly improved alveolar bone regeneration in vivo	⁸⁵
	MMP-responsive GelMA hydrogel with CHX-loaded halloysite nanotubes	Endodontic and periodontal disinfection	Sustained CHX release triggered by MMPs; effective against E. faecalis biofilm; biocompatible with dental stem cells; reduced degradation and inflammation in vivo	⁸⁶
	CHX-loaded GelMA hydrogel	Endodontic disinfection	Broad-spectrum antibacterial and anti-biofilm activity at low CHX concentrations; preserved hydrogel structure and mechanical properties; non-cytotoxic to SHEDs; promising for cell-friendly disinfection in regenerative endodontics	⁸⁷
Nanoparticle–hydrogel complex	Heparin-functionalized PLGA nanoparticles loaded with BMP-2 in fibrin gel	Periodontal bone regeneration	Significantly enhanced bone regeneration and mineralization; increased ALP activity and osteocalcin expression; sustained BMP-2 release; induced mature bone formation in rat calvarial defect model	⁸⁸
Sponges	Collagen sponges loaded with amoxicillin–clavulanate and CHX	Endodontic disinfection	Sustained antimicrobial effect against biofilms; completely eliminated E. faecalis and S. aureus in root canals; sponge gradually degraded, supporting cell adhesion and eliminating the need for removal	⁸⁹
Submicron Particles	PLGA submicron particles loaded with quaternary ammonium silane (K21), calcium, and phosphorus	Endodontic disinfection	Sustained release; strong antibacterial activity against E. faecalis; effective dentinal tubule infiltration; promoted mineralization; biocompatible in vitro and in vivo	⁹⁰
3D Drug Constructs	Tubular 3D constructs with polydioxanone (PDS) and triple antibiotic paste (metronidazole, ciprofloxacin, minocycline)	Intracanal disinfection and regeneration	Strong antimicrobial activity against A. naeslundii biofilm; eliminated bacteria inside dentinal tubules; supported apical closure and osteodentin-like tissue formation in vivo; biocompatible alternative to TAP	⁹¹
Sealers/Coatings	Root canal sealer with DMAHDM, nanosilver (NAg), and amorphous calcium phosphate (NACP)	Endodontics & peri-implant disinfection	Raised pH and promoted remineralization; reduced E. faecalis biofilm by nearly 3 logs; maintained physical properties like flow and thickness	⁹²
Electrospun Scaffolds	Electrospun PDS nanofibers loaded with triple antibiotic paste (TAP: metronidazole, ciprofloxacin, minocycline)	Periodontics and pulp therapy	Completely eliminated P. gingivalis biofilm on dentin; sustained antibiotic release; biocompatible, low concentration TAP alternative supporting regenerative potential	⁹³
	PDS-based nanofibers loaded with ciprofloxacin (1–2.5 wt.%)	Antimicrobial regeneration in periodontium	Sustained antibacterial effect against E. faecalis; reduced cytotoxicity at low drug concentrations; preserved stem cell viability and proliferation; potential for regenerative endodontic applications	⁹⁴
Mucoadhesive Systems	Buccal/sublingual films using chitosan and polyacrylic acid	Pediatric drug delivery (pain/sedation/systemic)	Rapid onset of action via oral mucosa; avoids hepatic first-pass metabolism and injections; enhances compliance in children; ideal for emergency and non-invasive care	⁹⁵

Figure 3.

Models of Different Material Forms Used in Dental Drug Delivery and Regenerative Applications. (1) Hydrogels, Composed of 3D Polymer Networks, Are Capable of Carrying Drugs or Nanoparticles. (2) Nanoparticles, Which Can Be Inorganic or Organic, Are Exemplified Here as Mesoporous Structures. (3) Scaffolds, Typically Loaded with Growth Factors, Are Primarily Used for Supporting Tissue Regeneration. (4) Films Are Commonly Applied for Oral Mucosal Drug Delivery. (5) Nanofibers, Approximately 100 nm in Diameter, Serve as Drug Carriers.

Among the commercially available LDDS, Periochip, a gelatin-based matrix releasing chlorhexidine gluconate, remains a gold standard.⁶⁵ Likewise, Arestin, a PLGA microsphere formulation containing minocycline, provides sustained antibacterial activity and has received FDA approval for use in periodontal therapy.⁶⁶

More recently, polymeric and metallic nanoparticles have emerged as advanced delivery platforms capable of penetrating periodontal biofilms and releasing antimicrobials in response to environmental triggers.⁶⁷ In the study by Lecio et al., doxycycline-loaded nanoparticles achieved drug release for up to 21 days and effectively suppressed Porphyromonas gingivalis, significantly improving clinical parameters in beagle dogs.⁶⁸ Similarly, liposomal delivery systems have demonstrated improved antimicrobial retention and reduced osteoclast activity in rat models of bone loss.⁵⁴

Importantly, LDDS are also being explored for immunomodulatory purposes. For example, chitosan nanoparticles loaded with statins or N-phenacylthiazolium bromide have shown the ability to reduce inflammation and promote bone formation in periodontal defects, highlighting a dual role in both infection control and tissue regeneration.⁶⁹

These innovations mark a shift toward personalized, non-invasive therapies, where drug–biomaterial composites are customized to the anatomical site, disease condition, and patient profile. This precision-targeted approach, especially beneficial for older or immunocompromised patients, enhances outcomes while minimizing systemic effects. Nanofiber scaffolds, bioresorbable hydrogels, and polymer-based carriers have proven effective for localized delivery in periodontal and craniofacial applications, particularly within complex areas such as periodontal pockets and alveolar bone defects.³

Targeted Endodontics: Microsphere-based Delivery Systems

The root canal’s complex structure and persistent infections make drug delivery challenging. Microsphere-based systems have emerged to support both disinfection and regenerative endodontic therapy.⁹⁶ A novel approach uses PLGA-coated biphasic ceramic microparticles loaded with a modified antibiotic mix of penicillin G, metronidazole, and ciprofloxacin chosen to be effective against key pathogens while avoiding tooth discoloration. These particles show ideal size for canal navigation, high drug loading efficiency, and a sustained release over 21 days while maintaining a neutral pH.⁷⁰ They exhibit strong antibacterial effects, low cytotoxicity to human gingival fibroblasts, and offer an added osteoconductive benefit from the HA/β-TCP core, making them promising for dual-function endodontic treatments.⁹⁷ Moreover, calcium hydroxide-loaded PLGA microspheres have demonstrated sustained Ca²⁺ ion release for up to 30 days, improving outcomes in apexification and pulp capping by stimulating mineralization.⁹⁸ Additional studies have successfully incorporated amoxicillin, minocycline, and ciprofloxacin into microsphere matrixes for targeted root canal disinfection, maintaining both antimicrobial potency and the mechanical integrity of sealing materials.⁹⁹

Beyond antimicrobial action, microspheres fabricated from PLGA, PLLA, and PCL are increasingly used as injectable scaffolds for stem cell support and tissue engineering.¹⁰⁰ For instance, PLGA microspheres loaded with VEGF have significantly improved angiogenic responses, essential for pulp revascularization.¹⁰¹ Nanofibrous PLLA microspheres that mimic the ECM have enhanced odontogenic differentiation of dental pulp stem cells (DPSCs), especially when combined with BMP-2. Meanwhile, GelMA-based microspheres have enabled both cryopreservation of DPSCs and enhanced cell spreading, ECM formation, and in vivo integration when compared to bulk hydrogel scaffolds.¹⁰²

Crucially, the injectability and moldability of these microspheres allow for minimally invasive delivery, making them especially effective in treating irregular, curved, or narrow canal spaces that are difficult to access with bulk materials.¹⁰³ Their surface functionalization with biomolecules such as RGD peptides, collagen, and fibronectin has also been shown to promote cell adhesion, migration, and signal transduction, which are pivotal for initiating and sustaining regenerative processes within the root canal environment.¹⁰⁴

Altogether, microsphere-based delivery systems represent a dual-function platform in endodontics, combining localized, sustained antimicrobial therapy with a biomimetic scaffold that fosters tissue regeneration. These systems address the unmet need for targeted, biologically active therapies in endodontics and are poised to redefine clinical strategies in both infection management and regenerative treatment.

Nanotechnology and Nanosizing in Dental Applications

The complexity of periodontal pockets inflamed mucosal tissues, and cancerous lesions in the oral cavity demand nanocarrier systems capable of deep tissue penetration and targeted payload release in response to specific stimuli such as acidic pH, enzymatic activity, or oxidative stress.¹⁰⁵

Nanoparticles for Periodontitis and Endodontics

In periodontitis treatment, nanoparticles formulated with antimicrobial agents like doxycycline, chlorhexidine, or augmentin have been embedded into injectable gels or directly applied to periodontal pockets.¹⁰⁶ These systems provide sustained antimicrobial activity along with a supportive matrix for healing. For instance, chitosan/gelatin nanoparticles loaded with augmentin and modified triple antibiotic paste (mTAP) exhibited strong antibacterial effects while promoting fibroblast adhesion and viability, both essential for effective endodontic disinfection and tissue repair.⁷⁸ Similarly, simvastatin-loaded PLGA microparticles have been shown to promote BMP-2 expression and angiogenesis in periodontal defects, linking infection control with regenerative outcomes.¹⁰⁷

Nanoparticle-based Strategies for Mucositis

OM, a common and debilitating side effect of cancer therapies, has been targeted using gold nanoparticles (AuNPs) due to their anti-inflammatory and antioxidant properties.¹⁰⁸ In a 5-FU-induced hamster model of OM, PVP-stabilized AuNPs significantly reduced ulceration and inflammatory mediators such as NF-κB and COX-2, while enhancing Nrf2-mediated antioxidant responses, including HO-1 and GSH. These findings highlight the potential of AuNPs to both prevent and manage OM by modulating oxidative and inflammatory pathways.¹⁰⁹

Advanced Nanocarriers in Oral Cancer Therapy

In OSCC, nanoparticles such as liposomes, polymeric nanoparticles (e.g., PLGA, PEGylated systems), and core-shell nanospheres are being developed for tumor-targeted chemotherapeutic delivery, minimizing damage to healthy tissues and enhancing co-delivery of immune modulators.¹¹⁰ These platforms can be fine-tuned with targeting ligands or stimuli-responsive coatings to improve tumor specificity. For example, AuNPs conjugated with cetuximab and cisplatin have been shown to significantly reduce the survival of radioresistant oral cancer cell colonies compared to conventional radiotherapy protocols.¹¹¹ In another approach, PLGA-based nanocarriers modified with anti-PD-L1 antibodies and loaded with all-trans retinoic acid (ATRA) demonstrated improved targeting capabilities and therapeutic outcomes in both CAL-27 cell lines and SCC-7 xenograft mouse models.¹¹²

Controlled Drug Delivery: Localized and Targeted Strategies

Scaffolds fabricated through AM are increasingly being used as localized drug delivery systems, allowing for both structural regeneration and targeted therapeutic action. By incorporating antibiotics such as doxycycline or metronidazole directly into biodegradable polymers like PCL or PLGA, these scaffolds can achieve sustained release over weeks, reducing infection risk while supporting tissue healing.^{6, 100} For instance, doxycycline-loaded PCL scaffolds not only promote osteogenesis but also inhibit osteoclast activity and collagenase production.¹¹³

Newer approaches include nanofiber delivery systems and nanocoatings, which enable the delivery of anti-inflammatory agents, antibiotics, and even gene vectors.¹¹⁴ However, high processing temperatures can degrade certain drugs, highlighting the importance of post-printing drug loading strategies or using nanofiber surface modifications.¹¹⁵ To minimize cytotoxicity, precise dosing and release control are critical, particularly in sensitive oral environments. Additionally, anti-fouling coatings like zwitterionic polymers and antimicrobial peptides are being investigated to prevent microbial colonization of scaffolds, ensuring better integration and regenerative success.¹¹⁶

Toxicity and Regulatory Considerations of Nanocarriers

Although nanocarriers are transforming dental therapeutics, their nanoscale properties pose potential risks requiring precise evaluation. NPs smaller than 100 nm can cross the blood–brain barrier and olfactory pathways, accumulating in the brain and other organs with unpredictable biodistribution.¹¹⁷ For instance, cationic gold and polystyrene NPs can induce hemolysis and coagulation, while carbon nanotubes promote platelet aggregation and ROS generation.¹¹⁸

Toxicity depends on factors such as particle size, shape, surface charge, aggregation, and coating. Both cationic and anionic NPs may disrupt the blood–brain barrier at high concentrations, and dendrimers, despite their potential for drug conjugation—raise immunological safety concerns.¹¹⁹ In the oral cavity, TiO₂, ZnO, and AgNPs found in toothpastes and restoratives interact with salivary proteins (e.g., lactoferrin, lysozyme), forming a protein corona that can alter antimicrobial activity and trigger immune responses. Incorporating nanosilver into non-degradable scaffolds may cause tissue accumulation and persistent inflammation.^{120, 121} Importantly, these risks are further influenced by oral-specific exposures, including constant saliva flow, biofilm interactions, and dynamic protein corona formation unique to the oral environment. Standardized, context-specific testing frameworks are emerging, but they remain fragmented and not yet harmonized across regulatory bodies.^{122, 123}

Toxicity testing remains limited, as most studies rely on immortalized cell lines that fail to mimic the complex oral environment (saliva, mucosa, biofilms).¹²² Artifacts, such as nonspecific binding of fluorescent dyes used in NP tracking, further confound results.¹²³ Occupational exposure is another concern for dental professionals who may inhale or contact airborne NPs during implant polishing, milling, or laser ablation. Long-term effects depend on exposure route, duration, and health status, yet these factors are inconsistently assessed.^{124, 125}

Regulatory gaps add complexity. Nanomedicine lacks a unified global classification, leading to inconsistencies in toxicity thresholds and testing standards.¹²⁶ The BIORIMA Decision Support System, based on Integrated Approaches to Testing and Assessment (IATA), provides a life cycle–oriented framework for risk evaluation, integrating material-specific testing, exposure modeling, and scenario simulations to guide safe design and occupational risk management.¹²⁷

Ensuring the safe use of nanocarriers in clinical dentistry requires a multifaceted approach: developing realistic in vivo models that replicate the oral environment, assessing protein corona formation and its immunogenic effects, conducting comprehensive hazard and exposure analyses, and adopting globally harmonized regulations. Protective measures for dental professionals are equally crucial.¹²³

In summary, while nano biomaterials hold great promise for targeted drug delivery and regenerative care, their complex toxicity profiles demand robust, standardized, and context-specific safety evaluation to protect both patients and practitioners.

Discussion

Advances in biomaterials have accelerated the transition from traditional restorative approaches toward biologically driven and regenerative therapies.¹²⁸ Current innovations in scaffolds, nanocarriers, and smart delivery systems enable localized and controlled therapeutic effects, improving outcomes for conditions such as periodontitis, pulp disease, and oral cancers.^{114, 129, 130} Biodegradable polymers, nanocomposites, and hydrogels provide structural support while simultaneously acting as delivery platforms that modulate cellular activity and promote tissue healing.^131–133

In regenerative dentistry, bioengineered scaffolds composed of PCL, PLA, chitosan, and HA have demonstrated significant potential in enhancing osteogenesis and periodontal regeneration.^{6, 131} Coupling these materials with bioactive molecules or growth factors further improves integration and accelerates functional recovery.¹³² Recent interest in natural-derived cargoes such as curcumin-loaded nanoparticles illustrates the shift toward multifunctional systems that combine mechanical reinforcement with immunomodulatory and antimicrobial activity.¹³⁴

Smart drug delivery systems represent another important advance. Stimuli-responsive carriers activated by changes in pH, temperature, or magnetic fields are designed to respond dynamically to the oral microenvironment, enabling precise spatiotemporal drug release.^{133, 135, 136} Complementary developments in mucoadhesive polymers and injectable hydrogels improve retention, penetration, and controlled release of therapeutics in the oral cavity.¹³⁷

Digital fabrication and AM technologies, including 3D printing and bioprinting, further expand personalization and functionality. These platforms allow precise control of scaffold architecture and enable fabrication of patient-specific constructs and drug-loaded devices.¹³⁸ Emerging bioprinting strategies are increasingly capable of generating complex dental tissues such as pulp-dentin interfaces by co-delivering cells, biomaterials, and bioactive factors in spatially organized patterns.¹³⁹

Despite notable progress, significant translational barriers remain. Material biocompatibility, degradation kinetics, and mechanical stability must be optimized to balance safe degradation with adequate support during tissue regeneration.^{140, 141} Moreover, multifunctional biomaterials combining structural scaffolds with active drug delivery pose regulatory complexities that are not yet fully harmonized across agencies.¹ Cost-effective manufacturing, long-term in vivo validation, and standardization of testing frameworks will be essential for clinical translation.¹⁴²

A particularly innovative direction involves biomaterial-guided organoid development. Recent work by Zhang et al. (2024) demonstrated that bio-orthogonally cross-linked gelatin hydrogels can support epithelial-mesenchymal interactions required for tooth organoid formation, emphasizing how the physico-mechanical environment influences stem cell behavior and morphogenesis.¹⁴³ This highlights a future in which engineered biomaterials may enable complete dental organ regeneration rather than repair alone.

Conclusion

The convergence of advanced biomaterials, nanotechnology, and precision drug-delivery platforms is redefining the future of dentistry, shifting the field from mechanical repair toward biologically guided regeneration.¹⁴⁴ Smart scaffolds, injectable hydrogels, bioactive nanoparticles, and AM strategies now offer targeted, site-specific interventions that integrate structural support with controlled therapeutic release. Among these, polymers such as PLGA, PCL, and chitosan combined with growth factors or antimicrobial agents serve as versatile, multifunctional systems improving clinical outcomes across periodontics, endodontics, implantology, and oral oncology. Over the next decade, technologies with the strongest translational potential include stimuli-responsive hydrogels, personalized 3D-printed constructs incorporating biological cues, immunomodulatory nanomaterials, and emerging gene-activated scaffolds. These innovations align with global trends toward patient-specific, minimally invasive, and biologically informed treatment modalities. Despite notable progress, key challenges persist, including the complexity of the oral environment, inter-patient variability, long-term safety considerations, and regulatory uncertainty. Continued interdisciplinary collaboration supported by standardized testing frameworks and harmonized clinical evaluation pathways will be essential to translate these emerging biomaterial technologies into predictable and widely applicable clinical solutions, ultimately advancing dentistry toward a fully regenerative and patient-centered paradigm.

Footnotes

Authors’ Contributions

The authors contributed equally.

Data Availability Statement

No datasets were generated or analyzed during the current study.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval Institutional Statement

Not applicable.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Informed Consent

Not applicable.

ORCID iD

Rosana Farjaminejad

References

Saberian

, Jen

, Zafari

, . The regeneration in dentistry with scaffolds application . BoD–Books on Demand, 2024 Jul 24. DOI: 10.5772/intechopen.115062

Farjaminejad

, Farjaminejad

and Garcia-Godoy

Nanoparticles in bone regeneration: A narrative review of current advances and future directions in tissue engineering. J Funct Biomater 2024; 15(9): 241. DOI: 10.3390/oral5010021

Farjaminejad

, Farjaminejad

, Sotoudehbagha

, . Non-invasive medical imaging in the evaluation of composite scaffolds in tissue engineering: Methods, challenges and future directions. J Compos Sci 2025; 9(8): 400. DOI: 10.3390/jcs9080400

Percival

, Paul

and Husseini

GA.

Recent advancements in bone tissue engineering: Integrating smart scaffold technologies and bio-responsive systems for enhanced regeneration. Int J Mol Sci 2024; 25(11): 6012. DOI: 10.3390/ijms25116012

Bakopoulou

Prospects of advanced therapy medicinal products–based therapies in regenerative dentistry: Current status, comparison with global trends in medicine and future perspectives. J Endod 2020; 46(9): S175–S188. DOI: 10.1016/j.joen.2020.06.026

, Munguia-Lopez

, Cho

, . Polymeric scaffolds for dental, oral and craniofacial regenerative medicine. Molecules 2021; 26(22): 7043. DOI: 10.3390/molecules26227043

Pathak

, Saikia

, Das

, . 3D printing in biomedicine: Advancing personalized care through additive manufacturing. Explor Med 2023; 4(6): 1135–1167. DOI: 10.37349/emed.2023.00200

Farjaminejad

, Farjaminejad

, Nucci

, . 3D printing approach in maxillofacial surgery in Iran: An evaluation using the NASS framework. Appl Sci 2024; 14(7): 3075. DOI: 10.3390/app14073075

Fugolin

, Huynh

and Rajasekaran

SP.

Innovations in the design and application of stimuli-responsive restorative dental polymers. Polymers 2023; 15(16): 3346. DOI: 10.3390/polym15163346

10.

D’Amico

, Aceto

, Petrini

, . How will nanomedicine revolutionize future dentistry and periodontal therapy? Int J Mol Sci 2025; 26(2): 592. DOI: 10.3390/ijms26020592

11.

, Li

, Shi

, . New advances in periodontal functional materials based on antibacterial, anti-inflammatory and tissue regeneration strategies. Adv Healthc Mater 2025; 14(9): 2403206. DOI: 10.1002/adhm.202403206

12.

Sharma

, Sudhakara

, Singh

, . Critical review of biodegradable and bioactive polymer composites for bone tissue engineering and drug delivery applications. Polymers 2021; 13(16): 2623. DOI: 10.3390/polym13162623

13.

Sharifianjazi

, Khaksar

, Esmaeilkhanian

, . Advancements in fabrication and application of chitosan composites in implants and dentistry: A review. Biomolecules 2022; 12(2): 155. DOI: 10.3390/biom12020155

14.

Saberian

, Jenča

, Petrášová

, . Application of scaffold-based drug delivery in oral cancer treatment: A novel approach. Pharmaceutics 2024; 16(6): 802. DOI: 10.3390/pharmaceutics16060802

15.

Ramanathan

, Thangavelu

, Felciya

, . Dual drug loaded polyhydroxy butyric acid/gelatin nanofibrous scaffold for possible post-surgery cancer treatment. Mater Lett 2022; 323: 132597. DOI: 10.1016/j.matlet.2022.132597

16.

Huang

, Huang

, Liu

, . Hydrogels for the treatment of oral and maxillofacial diseases: Current research, challenges and future directions. Biomater Sci 2022; 10(22): 6413–6446.

17.

Chen

, Deng

, Lai

, . Hydrogels for oral tissue engineering: Challenges and opportunities. Molecules 2023; 28(9): 3946. DOI: 10.3390/molecules28093946

18.

Ding

, Kang

, Li

, . An in situ tissue engineering scaffold with growth factors combining angiogenesis and osteoimmunomodulatory functions for advanced periodontal bone regeneration. J Nanobiotechnol 2021; 19(1): 247. DOI: 10.1186/s12951-021-00992-4

19.

Muzzio

, Moya

and Romero

Multifunctional scaffolds and synergistic strategies in tissue engineering and regenerative medicine. Pharmaceutics 2021; 13(6): 792. DOI: 10.3390/pharmaceutics13060792

20.

Chen

, Song

, Xu

, . Biomaterial scaffolds for periodontal tissue engineering. J Funct Biomater 2024; 15(8): 233. DOI: 10.3390/jfb15080233

21.

De Leon

and Romanos

GE.

The use of bioactive proteins and peptides to promote osseointegration and success of dental implants: A narrative review. Front Oral Maxillofac Med 2025; 7.

22.

Hakim

, Yari

, Nikparto

, . The current applications of nano and biomaterials in drug delivery of dental implant. BMC Oral Health 2024; 24(1): 126. DOI: 10.1186/s12903-024-03911-9

23.

Zhang

, Su

, Zhou

, . Toward a better regeneration through implant-mediated immunomodulation: Harnessing the immune responses. Adv Sci 2021; 8(16): 2100446.

24.

Epicoco

, Pellegrino

, Madaghiele

, . Recent advances in functionalized electrospun membranes for periodontal regeneration. Pharmaceutics 2023; 15(12): 2725. DOI: 10.3390/pharmaceutics15122725

25.

Liu

, Yang

, Ni

, . Enhanced bacteriostasis and osseointegrative properties of siRNA-modified polyetheretherketone surface for implant applications. PLoS One 2024; 19(12): e0314091. DOI: 10.1371/journal.pone.0314091

26.

Wang

, Song

, Cui

, . Calcium-siRNA nanocomplexes optimized by bovine serum albumin coating can achieve convenient and efficient siRNA delivery for periodontitis therapy. Int J Nanomedicine 2020; 15: 9241–9253. DOI: 10.2147/IJN.S278103

27.

Soe

, Wahyudi

, Mattheos

, . Application of nanoparticles as surface modifiers of dental implants for revascularization and regeneration of bone. BMC Oral Health 2024; 24(1): 1175. DOI: 10.1186/s12903-024-04966-4

28.

Keshaw

Photodynamic therapy: An overview of fundamentals, functioning and clinical application in the treatment of periodontal disease .

29.

Alaqeel

, Moussa

, Altinawi

, . Antibacterial effectiveness of photo-sonodynamic treatment by methylene blue-incorporated poly(D,L-lactide-co-glycolide) acid nanoparticles to disinfect root canals. Photodiagn Photodyn Ther 2023; 43: 103692.

30.

Yang

, Li

, Liu

, . Photodynamic therapy empowered by nanotechnology for oral and dental science: Progress and perspectives. Nanotechnol Rev 2023; 12(1): 20230163. DOI: 10.1515/ntrev-2023-0163

31.

Jin

, Dong

, Xu

, . Development and in vitro evaluation of mucoadhesive patches of methotrexate for targeted delivery in oral cancer. Oncol Lett 2018; 15(2): 2541–2549.

32.

Latimer

, Maekawa

, Yao

, . Regenerative medicine technologies to treat dental, oral and craniofacial defects. Front Bioeng Biotechnol 2021; 9: 704048. DOI: 10.3389/fbioe.2021.704048

33.

Xue

, Yuan

, Yao

, . Bioactive factors-imprinted scaffold vehicles for promoting bone healing: The potential strategies and the confronted challenges for clinical production. BIO Integration 2020; 1(1): 37–54.

34.

Ramieri

, Vellone

and Cascone

Hemifacial microsomia treated by total joint reconstruction and orthognathic surgery: All-in-one approach. Minerva Stomatol 2016; 65(Suppl 1): 15–.

35.

Lesko

, Jungova

, Culenova

, . Polymer-based scaffolds as an implantable material in regenerative dentistry: A review. J Funct Biomater 2025; 16(3): 80. DOI: 10.3390/jfb16030080

36.

Farjaminejad

, Shojaei

, Goodarzi

, . Tuning properties of bio-rubbers and its nanocomposites with addition of succinic acid and ε-caprolactone monomers to poly(glycerol sebacic acid) as main platform for application in tissue engineering. Eur Polym J 2021; 159: 110711. DOI: 10.1016/j.eurpolymj.2021.110711

37.

Özcan

, Hotza

, Fredel

, . Materials and manufacturing techniques for polymeric and ceramic scaffolds used in implant dentistry. J Compos Sci 2021; 5(3): 78. DOI: 10.3390/jcs5030078

38.

Leong

, Setzer

, Trope

, . Biocompatibility of two experimental scaffolds for regenerative endodontics. Restor Dent Endod 2016; 41(2): 98–105. DOI: 10.5395/rde.2016.41.2.98

39.

Hajiali

, Tajbakhsh

and Shojaei

Fabrication and properties of polycaprolactone composites containing calcium phosphate-based ceramics and bioactive glasses in bone tissue engineering: A review. Polym Rev 2018; 58(1): 164–207. DOI: 10.1080/15583724.2017.1332640

40.

Bhati

and Nagrajan

RK.

A detailed review on oral mucosal drug delivery system. Int J Pharm Sci Res 2012; 3(3): 659.

41.

Hearnden

, Sankar

, Hull

, . New developments and opportunities in oral mucosal drug delivery for local and systemic disease. Adv Drug Deliv Rev 2012; 64(1): 16–28. DOI: 10.1016/j.addr.2011.02.008

42.

Daghrery

and Bottino

MC.

Smart injectable hydrogels for craniomaxillofacial bone regeneration 2024. DOI: 10.1039/BK9781837673070-00348

43.

Kumar

, Kumar

, Saini

, . Comprehensive survey on nanobiomaterials for bone tissue engineering applications. Nanomaterials 2020; 10(10): 2019. DOI: 10.3390/nano10102019

44.

Ketabat

, Pundir

, Mohabatpour

, . Controlled drug delivery systems for oral cancer treatment—current status and future perspectives. Pharmaceutics 2019; 11(7): 302. DOI: 10.3390/pharmaceutics11070302

45.

Zhao

, Li

, Wu

, . Research progress and prospect of nanoplatforms for treatment of oral cancer. Front Pharmacol 2020; 11: 616101. DOI: 10.3389/fphar.2020.616101

46.

Katsarov

, Shindova

, Lukova

, . Polysaccharide-based micro- and nanosized drug delivery systems for potential application in pediatric dentistry. Polymers 2021; 13(19): 3342. DOI: 10.3390/polym13193342

47.

Wrzyszcz-Kowalczyk

, Dobrzynski

, Grzesiak-Gasek

, . Application of selected biomaterials and stem cells in the regeneration of hard dental tissue in paediatric dentistry—based on the current literature. Nanomaterials 2021; 11(12): 3374. DOI: 10.3390/nano11123374

48.

Lal

, Alam

, Ahmed

, . Nano drug delivery platforms for dental application: Infection control and TMJ management—a review. Polymers 2021; 13(23): 4175. DOI: 10.3390/polym13234175

49.

Wang

, Li

, Tang

, . Smart stimuli-responsive hydrogels for drug delivery in periodontitis treatment. Biomed Pharmacother 2023; 162: 114688. DOI: 10.1016/j.biopha.2023.114688

50.

Jiao

, Tay

, Niu

, . Advancing antimicrobial strategies for managing oral biofilm infections. Int J Oral Sci 2019; 11(3): 28. DOI: 10.1038/s41368-019-0062-1

51.

Şenel

, Özdoğan

and Akca

Current status and future of delivery systems for prevention and treatment of infections in the oral cavity. Drug Deliv Transl Res 2021; 11(4): 1703–1734. DOI: 10.1007/s13346-021-00961-2

52.

Plonka

, Khorsand

, Yu

, . Effect of sustained PDGF nonviral gene delivery on repair of tooth-supporting bone defects. Gene Ther 2017; 24(1): 31–39. DOI: 10.1038/gt.2016.73

53.

Jiang

, Su

, Li

, . Research progress on nanomaterials for tissue engineering in oral diseases. J Funct Biomater 2023; 14(8): 404. DOI: 10.3390/jfb14080404

54.

Kumaar

and Nair

SC.

Nanomaterials: An intra-periodontal pocket drug-delivery system for periodontitis. Ther Deliv 2023; 14(3): 227–249. DOI: 10.4155/tde-2023-0001

55.

Zhuang

, Lin

and Yu

Advance of nano-composite electrospun fibers in periodontal regeneration. Front Chem 2019; 7: 495. DOI: 10.3389/fchem.2019.00495

56.

Chen

, Feng

, Xia

, . Progress in surface modification of titanium implants by hydrogel coatings. Gels 2023; 9(5): 423. DOI: 10.3390/gels9050423

57.

Norowski

Jr and Bumgardner

JD.

Biomaterial and antibiotic strategies for peri-implantitis: A review. J Biomed Mater Res B Appl Biomater 2009; 88(2): 530–543. DOI: 10.1002/jbm.b.31152

58.

Kaliaraj

, Siva

and Ramadoss

Surface functionalized bioceramics coated on metallic implants for biomedical and anticorrosion performance–a review. J Mater Chem B 2021; 9(46): 9433–9460. DOI: 10.1039/D1TB01301G

59.

Alshimaysawee

, Fadhel Obaid

, Al-Gazally

, . Recent advancements in metallic drug-eluting implants. Pharmaceutics 2023; 15(1): 223. DOI: 10.3390/pharmaceutics15010223

60.

Farjaminejad

, Farjaminejad

, Hasani

, . The role of tissue engineering in orthodontic and orthognathic treatment: a narrative review. Oral 2025; 5(1): 21. DOI: 10.3390/oral5010021

61.

Zahir-Jouzdani

, Wolf

, Atyabi

, . In situ gelling and mucoadhesive polymers: Why do they need each other? Expert Opin Drug Deliv 2018; 15(10): 1007–1019. DOI: 10.1080/17425247.2018.1517741

62.

Zhao

, Wei

, Xiong

, . A multiple controlled-release hydrophilicity minocycline hydrochloride delivery system for the efficient treatment of periodontitis. Int J Pharm 2023; 636: 122802. DOI: 10.1016/j.ijpharm.2023.122802

63.

Liu

, Li

and Liang

Current research progress of local drug delivery systems based on biodegradable polymers in treating chronic osteomyelitis. Front Bioeng Biotechnol 2022; 10: 1042128. DOI: 10.3389/fbioe.2022.1042128

64.

Steinberg

and Friedman

Sustained-release delivery of antimicrobial drugs for the treatment of periodontal diseases: Fantasy or already reality?

Periodontol 2000 2020; 84(1): 176–187. DOI: 10.1111/prd.12341

65.

Park

, Um

, Chang

, . Controlled releasing properties of gelatin nanofabric device containing chlorhexidine. Oral Biol Res 2021; 45(2): 90–98. DOI: 10.21851/obr.45.02.202106.90

66.

Patel

, Greene

, Desai

, . Biorelevant and screening dissolution methods for minocycline hydrochloride microspheres intended for periodontal administration. Int J Pharm 2021; 596: 120261. DOI: 10.1016/j.ijpharm.2021.120261

67.

Fayazi

, Rostami

, Amiri Moghaddam

, . A state-of-the-art review of the recent advances in drug delivery systems for different therapeutic agents in periodontitis. J Drug Target 2025; 33(5): 612–647. DOI: 10.1080/1061186X.2024.2445051

68.

Lecio

, Ribeiro

, Pimentel

, . Novel 20% doxycycline-loaded PLGA nanospheres as adjunctive therapy in chronic periodontitis in type-2 diabetics: randomized clinical, immune and microbiological trial. Clin Oral Investig 2020; 24(3): 1269–1279. DOI: 10.1007/s00784-019-03005-9

69.

Zhang

, Jiang

, Lei

, . Drug delivery systems for oral disease applications. J Appl Oral Sci 2022; 30: e20210349. DOI: 10.1590/1678-7757-2021-0349

70.

Parhizkar

, Nojehdehian

, Tabatabaei

, . An innovative drug delivery system loaded with a modified combination of triple antibiotics for use in endodontic applications. Int J Dent 2020; 2020(1): 8859566. DOI: 10.1155/2020/8859566

71.

Santos

, Dos Santos

and Carvalho

MS.

New insights in hydrogels for periodontal regeneration. J Funct Biomater 2023; 14(11): 545. DOI: 10.3390/jfb14110545

72.

Sousa

, Luzardo-Alvarez

, Pérez-Estévéz

, . Development of a novel AMX-loaded PLGA/zein microsphere for root canal disinfection. Biomed Mater 2010; 5(5): 055008. http://iopscience.iop.org/1748-605X/5/5/055008

73.

Kheirallah

and Almeshaly

Present strategies for critical bone defects regeneration. Oral Health Case Rep 2016; 2(3): 127.

74.

Pandey

, Bhushan

, Joshi

, . Comparative evaluation of antimicrobial efficacy of chitosan nanoparticles and calcium hydroxide against endodontic biofilm of Enterococcus faecalis: An in vitro study. J Conserv Dent Endod 2024; 27(7): 750–754.

75.

Pagonis

, Chen

, Fontana

, . Nanoparticle-based endodontic antimicrobial photodynamic therapy. J Endod 2010; 36(2): 322–328. DOI: 10.4103/JCDE.JCDE_219_24

76.

Ioannidis

, Niazi

, Mylonas

, . The synthesis of nano silver–graphene oxide system and its efficacy against endodontic biofilms using a novel tooth model. Dent Mater 2019; 35(11): 1614–1629. DOI: 10.1016/j.dental.2019.08.105

77.

Saud

and Narayana

IH.

Enriched advanced platelet-rich fibrin plus gold nanoparticles against Enterococcus faecalis for its potential use in revascularization for necrotic immature permanent teeth. J Conserv Dent Endod 2024; 27(7): 701–705. DOI: 10.4103/JCDE.JCDE_213_24

78.

Alghofaily

, Almana

, Alrayes

, . Chitosan–gelatin scaffolds loaded with different antibiotic formulations for regenerative endodontic procedures promote biocompatibility and antibacterial activity. J Funct Biomater 2024; 15(7): 186. DOI: 10.3390/jfb15070186

79.

Arulmozhi

, Pandian

and Mirunalini

Ellagic acid encapsulated chitosan nanoparticles for drug delivery system in human oral cancer cell line (KB). Colloids Surf B Biointerfaces 2013; 110: 313–320. DOI: 10.1016/j.colsurfb.2013.03.039

80.

Hirabayashi

, Iwanaga

, Okinaga

, . Epidermal growth factor receptor-targeted sonoporation with microbubbles enhances therapeutic efficacy in a squamous cell carcinoma model. PLoS One 2017; 12(9): e0185293. DOI: 10.1371/journal.pone.0185293

81.

Ortega

, da Silva

, da Costa

, . Thermosensitive and mucoadhesive hydrogel containing curcumin-loaded lipid-core nanocapsules coated with chitosan for the treatment of oral squamous cell carcinoma. Drug Deliv Transl Res 2023; 13(2): 642–657. DOI: 10.1007/s13346-022-01227-1

82.

Jin

, Dong

, Xu

, . Development and in vitro evaluation of mucoadhesive patches of methotrexate for targeted delivery in oral cancer. Oncol Lett 2018; 15(2): 2541–2549. DOI: 10.3892/ol.2017.7613

83.

Montero-Miralles

, Martín-González

, Alonso-Ezpeleta

, . Effectiveness and clinical implications of the use of topical antibiotics in regenerative endodontic procedures: A review. Int Endod J 2018; 51(9): 981–988. DOI: 10.1111/iej.12913

84.

Mittal

, Baranwal

, Aggarwal

, . Comparison of double antibiotic chitosan hydrogel scaffold with platelet-rich fibrin in regeneration in immature necrotic permanent teeth: Randomized controlled trial. J Conserv Dent Endod 2024; 27(12): 1251–1260. DOI: 10.4103/JCDE.JCDE_609_24

85.

Nakajima

, Tabata

and Sato

Periodontal tissue regeneration with PRP incorporated gelatin hydrogel sponges. Biomed Mater 2015; 10(5): 055016.

86.

Ribeiro

, Sanz

, Münchow

, . Photocrosslinkable methacrylated gelatin hydrogel as a cell-friendly injectable delivery system for chlorhexidine in regenerative endodontics. Dent Mater 2022; 38(9): 1507–1517. DOI: 10.1016/j.dental.2022.07.002

87.

Ribeiro

, Münchow

, Bordini

, . Engineering of injectable antibiotic-laden fibrous microparticles gelatin methacryloyl hydrogel for endodontic infection ablation. Int J Mol Sci 2022; 23(2): 971. DOI: 10.3390/ijms23020971

88.

Chung

, Ahn

, Jeon

, . Enhanced bone regeneration with BMP-2 loaded functional nanoparticle–hydrogel complex. J Control Release 2007; 121(1–2): 91–99. DOI: 10.1016/j.jconrel.2007.05.029

89.

Manuel

, Tania

, Rafael

, . In vitro development of a new sponge-based delivery system for intracanal antimicrobial administration in endodontic treatment. J Clin Med 2021; 10(12): 2725. DOI: 10.3390/jcm10122725

90.

Fan

, Li

, Sun

, . Quaternary ammonium silane, calcium and phosphorus-loaded PLGA submicron particles against Enterococcus faecalis infection of teeth. Mater Sci Eng C 2020; 111: 110856. DOI: 10.1016/j.msec.2020.110856

91.

Bottino

, Albuquerque

, Azabi

, . A novel patient-specific three-dimensional drug delivery construct for regenerative endodontics. J Biomed Mater Res B Appl Biomater 2019; 107(5): 1576–1586. DOI: 10.1002/jbm.b.34250

92.

Baras

, Sun

, Melo

, . Novel root canal sealer with dimethylaminohexadecyl methacrylate, nano-silver and nano-calcium phosphate. Dent Mater 2019; 35(10): 1479–1489. DOI: 10.1016/j.dental.2019.07.014

93.

Albuquerque

, Evans

, Gregory

, . Antibacterial TAP-mimic electrospun polymer scaffold: Effects on P. gingivalis-infected dentin biofilm. Clin Oral Investig 2016; 20(2): 387–393. DOI: 10.1007/s00784-015-1577-2

94.

Kamocki

, Nör

and Bottino

MC.

Effects of ciprofloxacin-containing antimicrobial scaffolds on dental pulp stem cell viability: In vitro studies. Arch Oral Biol 2015; 60(8): 1131–1137. DOI: 10.1016/j.archoralbio.2015.05.002

95.

Lam

, Xu

, Worsley

, . Oral transmucosal drug delivery for pediatric use. Adv Drug Deliv Rev 2014; 73: 50–62. DOI: 10.1016/j.addr.2013.08.011

96.

Farjaminejad

, Farjaminejad

and Garcia-Godoy

Regenerative endodontic therapies: Harnessing stem cells, scaffolds and growth factors. Polymers 2025; 17(11): 1475. DOI: 10.3390/polym17111475

97.

Parsaee

, Alizadeh

, Rezaee

, . Evaluation of the osteoconductive properties of scaffold containing platelet-enriched fibrin with tricalcium phosphate in alveolar socket repair after tooth extraction: An animal study. J Biomater Appl 2023; 37(10): 1789–1800. DOI: 10.1177/08853282231170346

98.

Chaiyosang

, Mahatnirunkul

and Leelapornpisid

The effects of calcium hydroxide-loaded poly(lactic-co-glycolic acid) biodegradable nanoparticles in the ex vivo external inflammatory root resorption model. J Contemp Dent Pract 2023; 24(6): 351–356.

99.

Tahmasebi

, Ardestani

, Hassani

, . The current novel drug delivery system (natural and chemical composites) in dental infections for antibiotics resistance: A narrative review. Cell Mol Biol 2022; 68(10): 141–160. DOI: 10.14715/cmb/2022.68.10.23

100.

Atila

and Kumaravel

Advances in antimicrobial hydrogels for dental tissue engineering: Regenerative strategies for endodontics and periodontics. Biomater Sci 2023; 11(20): 6711–6747.

101.

Limjeerajarus

, Sonntana

, Pajaree

, . Prolonged release of iloprost enhances pulpal blood flow and dentin bridge formation in a rat model of mechanical tooth pulp exposure. J Oral Sci 2019; 61(1): 73–81. DOI: 10.2334/josnusd.17-0368

102.

Zein

, Harmouch

, Lutz

, . Polymer-based instructive scaffolds for endodontic regeneration. Materials 2019; 12(15): 2347. DOI: 10.3390/ma12152347

103.

Yang

, Li

, Zhang

, . Microspheres and their potential in endodontic regeneration application. Chin J Dent Res 2022; 25(1): 29–36.

104.

Casanova

, Reis

, Martins

, . Surface biofunctionalization to improve the efficacy of biomaterial substrates to be used in regenerative medicine. Mater Horiz 2020; 7(9): 2258–2275. DOI: 10.1039/D0MH00542H

105.

Zięba

, Chaber

, Duale

, . Polymeric carriers for delivery systems in the treatment of chronic periodontal disease. Polymers 2020; 12(7): 1574. DOI: 10.3390/polym12071574

106.

Aggarwal

, Verma

, Gupta

, . Local drug delivery based treatment approaches for effective management of periodontitis. Curr Drug Ther 2019; 14(2): 135–152. DOI: 10.2174/1574885514666190103112855

107.

Kheirallah

and Almeshaly

Simvastatin, dosage and delivery system for supporting bone regeneration: An update review. J Oral Maxillofac Surg Med Pathol 2016; 28(3): 205–209. DOI: 10.1016/j.ajoms.2015.10.005

108.

Choudhury

, Brunton

, Dias

, . Gold nanoparticles as innovative therapeutics for oral mucositis: A review of current evidence. Drug Deliv Transl Res 2025; 15(7): 2323–2353. DOI: 10.1007/s13346-024-01748-x

109.

Choudhury

, Brunton

, Schwass

, . Effectiveness of gold nanoparticles in prevention and treatment of oral mucositis in animal models. Syst Rev 2024; 13(1): 39. DOI: 10.1186/s13643-023-02425-9

110.

Niu

, Sun

, Bai

, . Progress of nanomaterials-based photothermal therapy for oral squamous cell carcinoma. Int J Mol Sci 2022; 23(18): 10428. DOI: 10.3390/ijms231810428

111.

Ahmed

, Mohsen

, Sharaky

, . Effect of cisplatin/gold chitosan nanocomposite on oral squamous cell carcinoma and oral epithelial cells. Cancer Nanotechnol 2025; 16(1): 4. DOI: 10.1186/s12645-025-00306-5

112.

Zhang

, Wu

, Du

, . Nano-drug delivery systems in oral cancer therapy: Recent developments and prospective. Pharmaceutics 2023; 16(1): 7. DOI: 10.3390/pharmaceutics16010007

113.

Mirzaeei

, Pourfarzi

, Saeedi

, . Development of a PVA/PCL/CS-based nanofibrous membrane for guided tissue regeneration and controlled delivery of doxycycline hydrochloride. AAPS PharmSciTech 2024; 25(1): 27. DOI: 10.1208/s12249-024-02735-8

114.

Makvandi

, Josic

, Delfi

, . Drug delivery (nano) platforms for oral and dental applications. Adv Sci 2021; 8(8): 2004014. DOI: 10.1002/advs.202004014

115.

Tortorella

, Vetri Buratti

, Maturi

, . Surface-modified nanocellulose for application in biomedical engineering and nanomedicine. Int J Nanomedicine 2020; 15: 9909–9937. DOI: 10.2147/IJN.S266103

116.

Mitwalli

, Alsahafi

, Balhaddad

, . Emerging contact-killing antibacterial strategies for developing anti-biofilm dental polymeric restorative materials. Bioengineering 2020; 7(3): 83. DOI: 10.3390/bioengineering7030083

117.

Wang

, Wang

, Yin

, . Long-term application of silver nanoparticles in dental restoration materials: Potential toxic injury to the CNS. J Mater Sci Mater Med 2023; 34(11): 52. DOI: 10.1007/s10856-023-06753-z

118.

Umapathi

, Kumawat

and Daima

HK.

Engineered nanomaterials for biomedical applications and their toxicity: A review. Environ Chem Lett 2022; 20(1): 445–468. DOI: 10.1007/s10311-021-01307-7

119.

Eker

, Duman

, Akdaşçi

, . A comprehensive review of nanoparticles: From classification to application and toxicity. Molecules 2024; 29(15): 3482. DOI: 10.3390/molecules29153482

120.

Elmarsafy

SM.

A comprehensive narrative review of nanomaterial applications in restorative dentistry. Cureus 2024; 16(4): e58544. DOI: 10.7759/cureus.58544

121.

Gronwald

, Kozłowska

, Kijak

, . Nanoparticles in dentistry—current literature review. Coatings 2023; 13(1): 102. DOI: 10.3390/coatings13010102

122.

Jităreanu

, Agoroaei

, Caba

I-C

, . The evolution of in vitro toxicity assessment methods for oral cavity tissues. Toxics 2025; 13(3): 195.

123.

Besinis

, De Peralta

, Tredwin

, . Review of nanomaterials in dentistry. ACS Nano 2015; 9(3): 2255–2289. DOI: 10.1021/nn505015e

124.

Schmalz

, Hickel

, van Landuyt

, . Nanoparticles in dentistry. Dent Mater 2017; 33(11): 1298–1314. DOI: 10.1016/j.dental.2017.08.193

125.

Peres

, Peres

, Araujo

, . Social and dental status along the life course and oral health impacts in adolescents. Health Qual Life Outcomes 2009; 7(1): 95. DOI: 10.1186/1477-7525-7-95

126.

Abdellatif

, Mohammed

, Khan

, . Nanoscale delivery: A comprehensive review of nano-structured devices, preparative techniques, site-specificity designs, biomedical applications, commercial products, and references to safety, cellular uptake, and organ toxicity. Nanotechnol Rev 2021; 10(1): 1493–1559. DOI: 10.1515/ntrev-2021-0096

127.

Cazzagon

, Giubilato

, Pizzol

, . Occupational risk of nano-biomaterials. NanoImpact 2022; 25: 100373. DOI: 10.1016/j.impact.2021.100373

128.

Amrollahi

, Shah

, Seifi

, . Recent advancements in regenerative dentistry. Mater Sci Eng C 2016; 69: 1383–1390. DOI: 10.1016/j.msec.2016.08.045

129.

Ogay

, Mun

, Kudaibergen

, . Progress and prospects of polymer-based drug delivery systems for bone tissue regeneration. Polymers 2020; 12(12): 2881. DOI: 10.3390/polym12122881

130.

Farjaminejad

, Farjaminejad

, Hasani

, . Advances and challenges in polymer-based scaffolds for bone tissue engineering. Polymers 2024; 16(23): 3303. DOI: 10.3390/polym16233303

131.

Farjaminejad

, Hasani

, Farjaminejad

, . The critical role of nano-hydroxyapatites as an advanced scaffold in drug delivery. Carbohydr Polym Technol Appl 2025; 6: 100692. DOI: 10.1016/j.carpta.2025.100692

132.

Huang

, Chen

, Suo

, . Unlocking the future of periodontal regeneration. Biomedicines 2024; 12(5): 1090. DOI: 10.3390/biomedicines12051090

133.

Liu

, Yang

, Xiong

, . The smart drug delivery system and its clinical potential. Theranostics 2016; 6(9): 1306. DOI: 10.7150/thno.14858

134.

Cota Quintero

, Ramos-Payán

, Romero-Quintana

, . Hydrogel-based scaffolds: Advancing bone regeneration. Gels 2025; 11(3): 175. DOI: 10.3390/gels11030175

135.

and Li

Current application of magnetic materials in the dental field. Magnetochemistry 2024; 10(7): 46. DOI: 10.3390/magnetochemistry10070046

136.

Municoy

, Alvarez Echazu

, Antezana

, . Stimuli-responsive materials for tissue engineering and drug delivery. Int J Mol Sci 2020; 21(13): 4724. DOI: 10.3390/ijms21134724

137.

Gujjala

, Manasa

, Rajini

, . Current technological advances in mucoadhesive buccal drug delivery systems. J Pharma Insights Res 2024; 2(6): 71–80. DOI: 10.69613/kwpvgk70

138.

Kouhi

, de Souza Araújo

, Asa’ad

, . Recent advances in additive manufacturing of patient-specific devices. Dent Mater 2024; 40(4): 700–715. DOI: 10.1016/j.dental.2024.02.006

139.

Shopova

, Mihaylova

, Yaneva

, . Advancing dentistry through bioprinting. J Funct Biomater 2023; 14(10): 530.

140.

Han

, Kim

, Jang

, . Bioprinting of three-dimensional dentin–pulp complex. J Tissue Eng 2019; 10: 2041731419845849. DOI: 10.1177/2041731419845849

141.

Yazdanian

, Rahmani

, Tahmasebi

, . Current and advanced nanomaterials in dentistry as regeneration agents. Mini Rev Med Chem 2021; 21(7): 899–918. DOI: 10.2174/1389557520666201124143449

142.

Tiozzo-Lyon

, Andrade

, Leiva-Sabadini

, . Microfabrication approaches for oral research and clinical dentistry. Front Dent Med 2023; 4: 1120394. DOI: 10.3389/fdmed.2023.1120394

143.

Zhang

, Contessi Negrini

, Correia

, . Generating tooth organoids using defined bioorthogonally cross-linked hydrogels. ACS Macro Lett 2024; 13(12): 1620–1626. DOI: 10.1021/acsmacrolett.4c00520

144.

Farjaminejad

, Farjaminejad

, Hasani

, . Innovative drug delivery systems in bone regeneration. J Bionic Eng 2025; 22: 1–22. DOI: 10.1007/s42235-025-00739-z

The Future of Biomaterials in Dentistry: Innovations in Drug Delivery and Regenerative Medicine

Abstract

Keywords

Introduction

Methods and Materials

Smart Drug Delivery Platforms in Dentistry

Functional Scaffolds for Regeneration and Targeted Therapy

Natural Compounds and Nanoformulations

Multifunctional Scaffolds for Cancer and Regeneration

Surface-functionalized Biomaterials for Enhanced Bioactivity

Photodynamic and Mucoadhesive Therapies

AM and Scaffold Design for Personalized Regeneration

Material Considerations for Dental Scaffolds

Polycaprolactone

PLA and PLGA

Composite Polymers

Tailoring Polymer Properties for Clinical Success

Innovations in Drug Delivery Systems for Oral Applications

Innovations in Drug Delivery and Regenerative Medicine in Dentistry.

Local Therapeutics for Site-specific Challenges in Dentistry

Summary of Local Drug Delivery Systems in Dentistry.

Targeted Endodontics: Microsphere-based Delivery Systems

Nanotechnology and Nanosizing in Dental Applications

Nanoparticles for Periodontitis and Endodontics

Nanoparticle-based Strategies for Mucositis

Advanced Nanocarriers in Oral Cancer Therapy

Controlled Drug Delivery: Localized and Targeted Strategies

Toxicity and Regulatory Considerations of Nanocarriers

Discussion

Conclusion

Footnotes

Authors’ Contributions

Data Availability Statement

Declaration of Conflicting Interests

Ethical Approval Institutional Statement

Funding

Informed Consent

ORCID iD

References