Multidisciplinary Journal Epistemology of the Sciences

Volume 3, Issue 2, 2026, July–September

DOI: https://doi.org/10.71112/yfrfsb30

GRAPHENE OXIDE IN DENTAL AND MAXILLOFACIAL TISSUE ENGINEERING:

MECHANISTIC INSIGHTS AND TRANSLATIONAL READINESS FOR CANINE

VETERINARY MEDICINE

ÓXIDO DE GRAFENO EN LA INGENIERÍA DE TEJIDOS DENTALES Y

MAXILOFACIALES: PERSPECTIVAS MECANICISTAS Y PREPARACIÓN PARA SU

APLICACIÓN TRASLACIONAL EN MEDICINA VETERINARIA CANINA

Segundo Fabricio Mera Juaregui

Ecuador

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Graphene Oxide in dental and maxillofacial tissue Engineering: mechanistic

insights and translational readiness for canine veterinary medicine

Óxido de grafeno en la ingeniería de tejidos dentales y maxilofaciales:

perspectivas mecanicistas y preparación para su aplicación traslacional en

medicina veterinaria canina

Segundo Fabricio Mera Juaregui

a,*

fabriciomerajauregui@gmail.com

https://orcid.org/0009-0003-0967-1644

Corresponding author: fabriciomerajauregui@gmail.com,

Universidad Técnica de Machala,

Ecuador

ABSTRACT

The aim of this study was to critically assess the translational maturity of graphene oxide (GO)

in canine dental and maxillofacial medicine. The scientific literature published between 2015

and 2026 on the interaction of GO with oral tissues was analyzed. Of the studies identified, only

three preclinical investigations evaluated in vivo performance in canine models, compared with

48 in vitro studies and 32 in vivo studies conducted exclusively in rodents. Although the

incorporation of GO into scaffolds and coatings promotes osteogenesis in cellular assays and

rodent models, evidence in canines remains insufficient. The reported biological performance is

constrained by substantial risks of dose-dependent cytotoxicity, reactive oxygen species (ROS)

generation, and genotoxicity. These risks are associated with the lack of standardization in

lateral sheet size, the carbon-to-oxygen (C/O) ratio, and GO aggregation in biological fluids.

Furthermore, its antibacterial activity lacks clinical validation against dog-specific periodontal

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pathogens, particularly Porphyromonas gulae. The application of GO in veterinary dentistry

remains at an early stage of development (TRL 3–4). Despite its mechanical and biomimetic

properties, GO cannot yet be considered a clinically viable alternative until issues related to

bioaccumulation, peroxidase-mediated enzymatic biodegradation, and material standardization

in accordance with ISO requirements are adequately addressed.

Keywords: graphene oxide; veterinary medicine; canine dentistry; periodontal regeneration;

bone regeneration; biomaterials.

RESUMEN

El objetivo de este estudio fue evaluar críticamente la madurez traslacional del óxido de grafeno

(GO, por sus siglas en inglés) en la medicina dental y maxilofacial canina. Se analizó la

literatura científica publicada entre 2015 y 2026 sobre la interacción del GO con los tejidos

orales. De los estudios identificados, solo tres investigaciones preclínicas evaluaron el

rendimiento in vivo en modelos caninos, en comparación con 48 estudios in vitro y 32 estudios

in vivo realizados exclusivamente en roedores.

Aunque la incorporación de GO en andamios y recubrimientos promueve la osteogénesis en

ensayos celulares y modelos de roedores, la evidencia en caninos sigue siendo insuficiente. El

rendimiento biológico reportado está limitado por riesgos sustanciales de citotoxicidad

dependiente de la dosis, generación de especies reactivas de oxígeno (ROS) y genotoxicidad.

Estos riesgos están asociados con la falta de estandarización en el tamaño lateral de las

láminas, la relación carbono-oxígeno (C/O) y la agregación del GO en fluidos biológicos.

Además, su actividad antibacterial carece de validación clínica contra patógenos periodontales

específicos de los perros, particularmente Porphyromonas gulae. La aplicación del GO en

odontología veterinaria se mantiene en una etapa temprana de desarrollo (TRL 3–4). A pesar

de sus propiedades mecánicas y biomiméticas, el GO aún no puede considerarse una

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alternativa clínicamente viable hasta que se aborden adecuadamente los problemas

relacionados con la bioacumulación, la biodegradación enzimática mediada por peroxidasas y

la estandarización del material de acuerdo con los requisitos ISO.

Palabras clave: óxido de grafeno; medicina veterinaria; odontología canina; regeneración

periodontal; regeneración ósea; biomateriales.

Received: August 20, 2026 | Accepted: september 9, 2026 | April: September 10, 2026

INTRODUCTION

Diseases of the oral cavity are among the most common health problems in both human

and veterinary medicine (Harvey et al., 2023). In dogs, periodontal disease is the most prevalent

oral disorder, affecting a substantial proportion of adult animals and causing chronic

inflammation, loss of periodontal attachment, alveolar bone resorption, tooth mobility, and, in

untreated cases, potentially systemic consequences (Cunha et al., 2022).

Despite advances in veterinary dentistry, conventional therapies continue to present

limitations in achieving predictable and functional regeneration of periodontal and osseous

tissues, particularly in large defects or lesions involving substantial loss of structural support

(Ward, 2022). Traditional periodontal repair techniques involve open-flap debridement, the

application of grafting materials, and barrier membranes to prevent apical migration of the

epithelium and the formation of a long junctional epithelium, which can compromise

regeneration and true periodontal healing (Harvey, 2005).

The rapid development of periodontal tissue engineering has led to the emergence of

new approaches for the treatment of periodontal disease (Dai et al., 2024). However, the clinical

use of these restorative materials remains uncommon in veterinary dentistry (Erdoğan &

Saritaş, 2024). In this context, tissue engineering and regenerative medicine have assumed an

increasingly important role in veterinary dentistry.

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The design of scaffolds, guided tissue regeneration membranes, implant coatings, and

smart biomolecule-delivery systems aims to reproduce the biological conditions required to

restore the architecture and function of oral tissues (Purbantoro et al., 2024). In veterinary

medicine, these technologies represent a promising alternative for the treatment of maxillofacial

defects, traumatic injuries, advanced periodontal disease, and post-oncological surgical

reconstruction, in which conventional approaches often provide limited outcomes (Wei et al.,

2022).

Among the nanobiomaterials developed over the past decade, graphene oxide (GO) has

attracted considerable interest because of its combination of physicochemical and biological

properties (Qi et al., 2021). Its high surface-to-volume ratio, abundance of oxygen-containing

functional groups, mechanical strength, chemical stability, and ease of functionalization enable

its incorporation into polymeric matrices, hydrogels, membranes, and implants to enhance cell

adhesion, proliferation, osteogenic differentiation, and the formation of new mineralized tissue

(Hosseini et al., 2025).

Graphene is a two-dimensional, transparent, flexible, and mechanically strong carbon-

based nanomaterial consisting of sp²-hybridized carbon atoms arranged in a planar honeycomb

lattice, resulting in an atomically thin structure (Gutiérrez-Cruz et al., 2022). The properties of

the material depend largely on the synthesis method, which influences the number and types of

oxygen-containing functional groups present in the resulting GO. Unlike graphene, GO is

hydrophilic, making it relatively easy to prepare as a stable suspension in water or organic

solvents (Jiříčková et al., 2022).

Several experimental studies have demonstrated that GO can exert antibacterial activity

against microorganisms implicated in oral infections, while also exhibiting favorable

biocompatibility when used at appropriate concentrations and in controlled formulations (Martuci

et al., 2025; Narváez-Romero et al., 2025; Williams et al., 2023). In human dentistry, knowledge

regarding the applications of graphene oxide has expanded considerably (Castro et al., 2024).

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Recent studies have investigated its use as a coating for titanium implants to enhance

osseointegration, as a component of membranes designed for guided bone regeneration, as a

reinforcing agent in restorative biomaterials, as a vehicle for the controlled delivery of

therapeutic agents, and as a functional component of scaffolds used in pulp, periodontal, and

bone tissue engineering. Collectively, these studies suggest that GO may enhance the

mechanical properties of conventional biomaterials, promote osteogenic responses, and

contribute to bacterial biofilm control, all of which are of considerable interest in regenerative

dentistry (Lima et al., 2026; Radunovic et al., 2022; Souza et al., 2023).

However, the available evidence in veterinary medicine remains limited and is scattered

across experimental studies, preclinical investigations, and reviews focused predominantly on

human medicine. Although tissue engineering approaches applied to veterinary oral and

maxillofacial reconstruction have made substantial progress, there remains limited integration of

knowledge specifically concerning the use of graphene oxide in canine patients. This

fragmentation makes it difficult to determine the actual state of knowledge, the strengths of the

available evidence, methodological limitations, and prospects for future clinical application in

dogs (Purbantoro et al., 2024).

Given the growing interest in nanobiomaterials for regenerative medicine and the need

to strengthen the scientific basis for their application in veterinary dentistry, a critical review

synthesizing the available evidence on graphene oxide and its principal applications in dogs is

warranted. Integrating this evidence will enable the identification of current research trends,

underlying biological mechanisms, potential advantages over conventional biomaterials,

biocompatibility and biosafety considerations, and the challenges that must still be addressed

before the routine incorporation of GO into veterinary clinical practice.

In this review, we first describe the physicochemical and biological properties of GO and

then examine its applications in different areas of canine dentistry and related tissue

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regeneration. We also summarize potential future directions for the development of GO-based

nanomaterials in dentistry and related tissue regeneration.

METHODOLOGY

Study Design

A systematic descriptive, critical, and analytical literature review was conducted on the

applications of graphene oxide (GO) in dentistry and tissue regeneration, with particular

emphasis on its translational potential in canine veterinary medicine. The review encompassed

scientific literature published between 2015 and 2026, with priority given to recent experimental

studies and investigations specifically conducted in canine models.

The analysis was structured around the physicochemical and biological properties of

GO, its molecular interactions, biocompatibility, antibacterial activity, controlled-release capacity,

and effects on osteogenic and odontogenic differentiation, as well as its applications in

periodontal regeneration, dentin–pulp complex regeneration, bone regeneration, implantology,

and tissue-engineering scaffolds. This approach enabled the evidence obtained in vitro, in

animal models, and specifically in dogs to be distinguished, with the aim of determining the

translational maturity of this technology. This classification was consistent with the central

objective of the manuscript: to establish the gap between experimental evidence and its

potential clinical application in canine veterinary dentistry.

Literature Search Strategy

The literature search was designed to identify studies addressing the use of GO in

dentistry, bone regeneration, tissue engineering, implantology, and veterinary applications.

Publications from 2015 to 2026 were considered, with particular emphasis on experimental

studies published between 2022 and 2026. The search strategy incorporated terms related to

the material, dental applications, tissue regeneration, and the canine species, including

conceptual combinations of graphene oxide, dentistry, dental, periodontal regeneration, bone

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regeneration, dental implant, tissue engineering, odontogenic differentiation, osteogenic

differentiation, dog, dogs, and canine.

The conceptual search strategy employed Boolean operators AND and OR according to

the following structure:

• ("graphene oxide" OR "graphene oxide nanomaterial") AND (dentistry OR dental OR

periodontal OR "bone regeneration" OR "dental implant" OR "tissue engineering" OR

odontogenic OR osteogenic) AND (dog OR dogs OR canine OR "veterinary

medicine").

• The search strategies were adapted to the characteristics of each bibliographic

database consulted. Scientific reviews were primarily used to contextualize the field

and identify primary literature, whereas claims concerning the biological effects of

GO were preferentially supported by original experimental studies.

Inclusion Criteria

Studies were considered eligible if they met the following criteria:

• Original in vitro, in vivo, or preclinical investigations;

• Studies addressing GO applied to dentistry, tissue engineering, or bone and

periodontal regeneration;

• Investigations of osteogenic or odontogenic differentiation;

• Studies evaluating antibacterial activity and biofilm control;

• Investigations of GO coatings for implants;

• Studies involving scaffolds, hydrogels, and GO-containing composite matrices;

• Investigations in which GO was used as a delivery system or component for

bioactive molecules;

• Studies conducted in animal models, with particular emphasis on investigations

involving dogs;

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• Articles providing sufficient information regarding the material, experimental model,

and outcomes; and Scientific publications with verifiable bibliographic information

and a DOI, when available.

Studies specifically conducted in dogs were retained irrespective of publication year

because of the scarcity of direct canine evidence, which was identified as one of the major

knowledge gaps in the reviewed literature. The manuscript identified three preclinical canine

studies addressing alveolar ridge preservation, periodontal regeneration, and peri-implantitis.

Exclusion Criteria

Articles consisting exclusively of editorials, letters to the editor, conference abstracts, or

documents lacking sufficient experimental information were excluded. Studies in which GO was

not a relevant experimental component were also excluded, as were investigations focused

exclusively on reduced graphene oxide or other carbon-based derivatives when they did not

allow the specific behavior of GO to be evaluated. Duplicate publications were also excluded.

Narrative and systematic reviews were not considered primary evidence for establishing

biological effects, although they were consulted as secondary sources for contextualizing the

findings and identifying relevant experimental studies.

Evidence Selection and Classification

The identified studies were screened and subsequently classified according to the type

of experimental model employed. The available evidence was organized into three major

categories: in vitro studies, in vivo studies conducted in non-canine animal models, and in vivo

studies specifically conducted in dogs.

According to the synthesis performed in the manuscript, 48 in vitro studies, 32 in vivo

investigations conducted in rodent models, and three preclinical in vivo studies involving canine

models were identified. This distribution represents one of the principal findings of the review

and demonstrates that research remains strongly concentrated on cellular and laboratory animal

models, whereas evidence specifically derived from dogs remains limited.

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Data Extraction and Analysis

The following information was extracted from the selected studies: author and year of

publication, type of GO used, associated biomaterial, experimental model, cell type or animal

species, target tissue, dental application, principal biological outcomes, and DOI.

The studies were subsequently grouped according to their application in periodontal

regeneration, dentin–pulp complex regeneration, alveolar and maxillofacial bone regeneration,

bioactive implant coatings, three-dimensional scaffolds, controlled-release systems, and

antibacterial applications. This classification enabled integration of the biological mechanisms

described in the literature with the potential dental applications of GO.

A comparative matrix was also developed to characterize GO combinations with natural

and synthetic biomaterials, including PCL, PLA, collagen, chitosan, hydroxyapatite, bioglass,

PEEK, and titanium, among others. The corresponding table distinguishes experimentally

demonstrated evidence from applications that remain potential areas for further investigation.

Assessment of Translational Maturity

The evidence was interpreted according to the experimental stage of development of

GO-based applications. A distinction was made between in vitro evidence, preclinical evidence

from laboratory animal models, preclinical evidence specifically obtained in dogs, and veterinary

clinical evidence.

This classification enabled identification of a translational gap between the

demonstration of osteogenic, odontogenic, antibacterial, or controlled-release effects under

experimental conditions and their potential application in canine patients. The available findings

indicate that the application of GO in canine veterinary dentistry remains at an early preclinical

stage, primarily because of the limited number of studies involving dogs and the absence of

established veterinary clinical protocols.

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RESULTS

Physicochemical Properties of GO and Standard Characterization Criteria

A wide range of methods is available for the preparation of graphene oxide (GO),

including the chemical, electrochemical, and microbial oxidation of various carbon-based

materials (Liu et al., 2015; Nishina & Eigler, 2020; Yang et al., 2019). Most studies reported in

the literature have focused on GO produced through the chemical oxidation of graphite or, more

recently, through the rapid direct oxidation of graphene (Costa et al., 2021). Because most GO

preparation methods employ strong oxidizing agents, such as potassium permanganate, GO

typically contains a substantial number of defects within its crystalline lattice (Jahan et al.,

2022). This variability in synthesis necessitates rigorous characterization of its physicochemical

properties before biological use.

Critical Characterization Parameters and Spectroscopic Analysis

Number of Layers and Lateral Thickness

Determination: Atomic Force Microscopy (AFM) and High-Resolution Transmission

Electron Microscopy (HR-TEM) [ISO/TS 21356-1] (Xi et al., 2026).

Biological relevance: Monolayer GO sheets (thickness ≈ 1 nm) exhibit substantially

greater mechanical flexibility and specific surface area (>2,000 m²/g) than multilayer sheets (>5

layers; thickness >5 nm) (Xi et al., 2026). Lateral sheet size determines cellular translocation

capacity and the mechanism of macrophage internalization. Large sheets (>5 µm) can induce

frustrated phagocytosis and granulomatous inflammatory responses (Liu et al., 2022), whereas

submicron sheets (<500 nm) are efficiently internalized through clathrin- or caveolin-dependent

endocytic pathways (Xi et al., 2026).

Carbon-to-Oxygen Ratio (C/O Ratio)

Determination: X-ray Photoelectron Spectroscopy (XPS) (Costa et al., 2021; Yang et al.,

2019).

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Biological relevance: The C/O ratio quantifies the degree of oxidation of the carbon

network, typically ranging from 1.5 to 2.5 for GO synthesized using the Hummers method

(Suhaimin et al., 2022). A high oxygen content (C/O <2.0) increases the negative surface

charge and hydrophilicity, thereby promoting dispersion in aqueous media (Jahan et al., 2022;

Xi et al., 2026), but may also generate higher levels of reactive oxygen species (ROS) through

edge reactivity and interfacial electronic interactions (Pradyumn et al., 2026). Deconvolution of

the XPS C1s spectrum is essential to distinguish different hybridization states and chemical

bonds: C–C/C=C (284.8 eV), C–O (286.5 eV), C=O (287.8 eV), and O–C=O (289.0 eV) (Liu et

al., 2022).

Degree of Crystalline Lattice Defects (ID/IG)

Determination: Raman spectroscopy using a 532- or 633-nm laser (Nishina & Eigler,

2020; Xi et al., 2026). Biological relevance: The G band (≈1,580 cm⁻¹) corresponds to the E2g

vibrational mode of the sp² carbon plane, whereas the D band (≈1,350 cm⁻¹) reflects symmetry

breaking associated with sp³ defects and sheet edges (Kabore et al., 2026). The intensity ratio

ID/IG (frequently >0.95 in GO) provides an estimate of defect density within the basal plane

(Nishina & Eigler, 2020; Xi et al., 2026). A high ID/IG ratio indicates substantial disruption of π

conjugation, which may reduce the capacity for drug or protein adsorption through π–π stacking

(Costa et al., 2021; Jahan et al., 2022), while substantially increasing the number of active sites

susceptible to neutrophil myeloperoxidase (MPO)-mediated enzymatic degradation (Costa et

al., 2021; Liu et al., 2015).

Zeta Potential (ζ) and Aggregation Kinetics

Determination: Dynamic Light Scattering (DLS) and laser Doppler electrophoresis

(Jahan et al., 2022; Nishina & Eigler, 2020).

Biological relevance: GO exhibits a strongly negative zeta potential (typically −30 to −50

mV in deionized water at pH 7.0), primarily due to the deprotonation of carboxyl groups (Jahan

et al., 2022; Xi et al., 2026). However, in physiological media, including saliva, gingival

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crevicular fluid, and plasma, the presence of divalent cations (Ca²⁺, Mg²⁺) neutralizes the

surface charge through electrostatic screening, inducing extensive aggregation into secondary

microstructures (Costa et al., 2021; Jahan et al., 2022). This aggregation alters the effective

dose exposed to tissues, modifies interactions with the plasma membrane, and may enhance

mechanical cytotoxicity (Costa et al., 2021; Liu et al., 2015).

These characteristics make GO particularly effective in promoting cellular growth,

differentiation, and bone tissue regeneration (Gao et al., 2024). In particular, GO coatings may

improve clinical outcomes in dental surgery. Enhanced osseointegration and cytocompatibility

may be beneficial for the placement of GO-coated implants (Inchingolo et al., 2023). However,

despite these advantages, studies conducted by the U.S. Food and Drug Administration (FDA)

and independent experimental investigations have indicated that GO may exhibit toxic effects

both in vitro and in vivo (Qiu et al., 2024).

Furthermore, interactions between GO and proteins are fundamental to the performance

of GO- based biomaterials (Shahriari et al., 2026). Owing to their large surface area and

capacity to interact with proteins and peptides, GO materials exhibit valuable physicochemical

and biological properties for biomedical applications and have been successfully employed to

optimize scaffold architecture across a broad range of tissues and organs, from skin to cardiac

tissue (Biru et al., 2022).

Biological Properties of GO

Biocompatibility and Tissue Tolerance: Interfacial Interactions and Cellular Modulation

The biocompatibility of graphene oxide (GO) should not be regarded as an intrinsic or

absolute property of the nanomaterial, but rather as a conditional and multifactorial biological

response. This response is governed by inherent physicochemical parameters, including

nanosheet lateral dimensions, degree of oxidation (C/O ratio), concentration, cumulative dose,

synthesis method, and surface functionalization state (Kwak et al., 2022). At sublethal

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concentrations, GO acts as a bioactive matrix capable of promoting cell adhesion and

proliferation through modulation of interactions with the extracellular matrix (ECM) and

cytoskeleton, without compromising the viability of adjacent tissues (Yang et al., 2023).

However, cellular tolerance is intrinsically constrained by the colloidal stability of the

nanomaterial within the tissue microenvironment. Optimization of biocompatibility is achieved

primarily through surface modification and functionalization to regulate the protein adsorption

profile and mitigate physical damage to plasma membranes.

Modification of high-performance polymers (PEEK): Deposition of self-assembled GO

coatings onto polyether ether ketone (PEEK) markedly alters the surface energy and nanoscale

roughness of the substrate. This modification enhances initial cell adhesion, osteoblast

proliferation, and matrix-specific differentiation, while also providing a preventive bactericidal

response against opportunistic pathogens (Huang et al., 2024).

Bioactivation of titanium implants and trans-tissue response: Functionalization of titanium

with GO nanostructures simultaneously enhances the viability and osteogenic differentiation of

bone marrow stromal cells (BMSCs) and the response of human gingival fibroblasts (Kwak et

al., 2022). In in vivo preclinical models involving rabbit tibial defects, GO-modified surfaces

demonstrated a significant quantitative increase in bone-to-implant contact (BIC) and

accelerated osseointegration indices (Kwak et al., 2022), supporting the capacity of GO to

function as a bifunctional interface suitable for both peri-implant hard and soft tissues.

Despite these favorable findings for immobilized GO surfaces and coatings, the

biocompatibility of free GO suspensions is substantially constrained by the risks of dose-

dependent cytotoxicity, oxidative stress induced by intracellular ROS generation, and DNA

fragmentation. These effects must be rigorously evaluated before clinical application.

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Controlled-Release Properties

One of the most relevant functional characteristics of graphene oxide (GO) is its ability to

serve as a platform for the sustained and site-specific delivery of biomolecules and therapeutic

agents. Unlike conventional polymeric matrices, which are subject to rapid and uncontrolled

diffusion, the two-dimensional architecture of GO provides a high specific surface area and a

high density of functional groups, enabling exceptional loading efficiencies through non-covalent

interactions, including π–π stacking, electrostatic attraction, and hydrogen bonding (Jeong et

al., 2022).

Release kinetics from the GO matrix are regulated by the physicochemical conditions of

the local microenvironment and can respond dynamically to variations in pH, ionic strength, and

enzymatic degradation of the polymeric scaffold. This controlled behavior reduces the need for

repeated dosing and maintains therapeutic concentrations within the desired therapeutic

window over extended periods (Jeong et al., 2022).

Immobilization and sustained release of growth factors (BMP-2): Incorporation of GO

into three- dimensional scaffolds enhances the adsorption of bone morphogenetic protein 2

(BMP-2), effectively preventing the initial burst release commonly associated with secondary or

ectopic inflammatory responses. Progressive and controlled desorption of BMP-2 over several

weeks promotes sustained osteogenic signaling in mesenchymal stem cells (MSCs), as

evidenced by sustained increases in alkaline phosphatase (ALP) activity, enhanced matrix

mineralization (calcium deposition), and upregulation of key osteogenic markers compared with

conventional GO-free matrices (Jeong et al., 2022).

Multifunctional platforms for periodontal regeneration: Beyond osteoinductive factors,

GO enables the co-transport and combined release of synthetic or naturally derived

antimicrobial agents and immunomodulatory molecules. This multifunctional capacity is

particularly relevant to regeneration of the periodontal complex, in which suppression of

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bacterial colonization and resolution of the local inflammatory response must occur concurrently

with the formation of new bone and cementum (Li et al., 2022).

Antibacterial Activity and Membrane Disruption Mechanisms

The antimicrobial activity of graphene oxide (GO) is a critical property for mitigating

biomaterial- associated infections, including peri-implantitis and periodontal disease. The

antibacterial action of GO is not attributable to a single chemical effect but rather to a dynamic,

multifactorial, and synergistic mechanism determined by its sp²-hybridized aromatic domains,

the density of oxygen- containing groups across the basal plane and sheet edges, and its high

specific surface area (Kwak et al., 2022; Lin et al., 2023).

The mechanisms underlying bacterial inhibition can be broadly classified into two

principal pathways involving physical and metabolic damage.

Direct mechanical damage and lipid extraction: Two-dimensional GO sheets interact with

bacterial envelopes through a combination of electrostatic, van der Waals, and hydrophobic

interactions. The sharp edges of GO nanosheets can act as nanoscale cutting edges or “nano-

blades,” inducing direct disruption of the cell wall and cytoplasmic membrane. This process is

further enhanced by extensive phospholipid extraction, whereby hydrophobic domains of GO

attract membrane lipid tails toward the basal plane, compromising structural integrity, increasing

membrane permeability, and ultimately causing cell lysis through irreversible leakage of

cytoplasmic contents (Bousiakou et al., 2022).

Oxidative stress and metabolic inhibition: Independently of direct physical damage, GO

can act as a redox mediator capable of accepting electrons from bacterial membranes and

perturbing intracellular electron-transport processes. This may promote the generation of

reactive oxygen species (ROS), including hydroxyl radicals (•OH) and superoxide anions (O₂•⁻),

which can trigger lipid peroxidation, oxidation of structural proteins, and lethal damage to

bacterial DNA (Kwak et al., 2022; Lin et al., 2023).

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Nanocomposite synergy and applications in three-dimensional scaffolds: To overcome

bacterial resistance and reduce the GO concentrations required, the nanomaterial can serve as

a synergistic platform for the immobilization of metallic nanoparticles or bioactive oligoelements.

For example, GO integrated with nickel nanoparticles exhibits substantially greater bactericidal

activity against Gram-positive microorganisms (Staphylococcus aureus) and Gram-negative

microorganisms (Escherichia coli) than either component alone (Wu et al., 2022).

From a tissue bioengineering perspective, incorporating GO into biocompatible three-

dimensional scaffolds, such as polycaprolactone (PCL) matrices fabricated by 3D printing, not

only enhances the mechanical properties and surface topography of the scaffold but also

confers prophylactic bactericidal activity. This may help prevent pathogenic biofilm formation

during the early stages of osteoblast proliferation and in vivo new bone formation (Du et al.,

2022).

Osteogenic Differentiation Properties

The ability of GO to induce and promote osteogenic differentiation is one of its most

relevant properties for applications in bone tissue engineering and periodontal regeneration.

This biological activity is associated with the combination of GO physicochemical

characteristics, including its high specific surface area, abundance of oxygen-containing

functional groups, capacity to adsorb osteoinductive proteins, and availability of aromatic

domains capable of interacting with extracellular matrix components (Jeong et al., 2022).

At the cellular level, GO can modulate signaling pathways associated with osteogenesis,

particularly the Wnt/β-catenin, BMP/Smad, and MAPK pathways, thereby promoting the

expression of genes involved in osteoblastic differentiation, including RUNX2, ALP, COL1A1,

OCN, and OPN. In addition, its two-dimensional structure facilitates the local concentration of

calcium and phosphate, thereby promoting extracellular matrix mineralization (Jeong et al.,

2022).

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The influence of GO on osteogenic differentiation is also associated with its ability to

enhance cell–biomaterial surface interactions. The presence of carboxyl and hydroxyl groups

facilitates the adsorption of cell-adhesion proteins, such as fibronectin and vitronectin, thereby

promoting integrin-mediated adhesion and activation of intracellular signaling pathways

associated with bone formation (Kwak et al., 2022).

In addition to directly stimulating osteoblastic activity, GO may promote bone regeneration

through immunomodulatory mechanisms. The initial inflammatory response following tissue

injury is a major determinant of regenerative success, and biomaterials capable of regulating

macrophage polarization toward a reparative phenotype may substantially enhance new bone

formation (Jeong et al., 2022).

Induction of Osteogenic Differentiation and Signal Transduction Mechanisms

The ability of graphene oxide (GO) to promote lineage commitment and accelerate the

osteogenic differentiation of progenitor cells, such as mesenchymal stem cells (MSCs) and

bone marrow stromal cells (BMSCs), represents one of the strongest rationales for its

integration into bone and periodontal regeneration matrices. This osteoinductive effect is not

merely contact-induced but rather results from a complex physicochemical and biomechanical

interplay driven by its high specific surface area, nanoscale topography, and functional domains

(Lin et al., 2023).

The biological and molecular mechanisms through which GO modulates the cellular

microenvironment to promote osteogenesis can be organized into the following principal

pathways.

Activation of signal-transduction pathways and gene expression: Interfacial interactions

with GO induce the phosphorylation and activation of key signaling cascades involved in

osteoblastic maturation, predominantly the Wnt/β-catenin, BMP/Smad, and MAPK/ERK

pathways. This mechanotransduction culminates in the coordinated upregulation of master

transcription factors, including RUNX2 (Runt-related transcription factor 2) and OSTERIX, as

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well as matrix-associated genes encoding alkaline phosphatase (ALP), type I collagen

(COL1A1), osteocalcin (OCN), and osteopontin (OPN) (Lin et al., 2023). In addition, the

electronegative basal plane of GO attracts and nucleates divalent ions, acting as a physical

template that accelerates hydroxyapatite precipitation and extracellular matrix (ECM)

mineralization (Lin et al., 2023).

Selective adsorption of adhesion proteins: The carboxyl and hydroxyl groups of GO,

together with its sp²-hybridized aromatic domains, facilitate the selective adsorption of

extracellular matrix proteins, such as fibronectin and vitronectin, while preserving conformations

conducive to biological activity (Ahn et al., 2020). This protein corona exposes specific Arg-Gly-

Asp (RGD) tripeptide sequences, promoting their interaction with cell-surface integrins. The

resulting actin cytoskeletal rearrangement generates cellular tension forces that activate

osteogenic signaling through direct mechanotransduction (Ahn et al., 2020).

Osteogenic immunomodulation and macrophage polarization: Beyond its direct effects

on the osteoblastic lineage, GO plays an active role in the peri-implant immune

microenvironment. Following implantation, GO can modulate the acute inflammatory response

by promoting the phenotypic transition of macrophages from a pro-inflammatory M1 state

toward a pro-regenerative M2 phenotype (Lin et al., 2023). This immunomodulatory polarization

promotes the secretion of pro- osteogenic cytokines and pro-angiogenic factors, such as VEGF

and TGF-β1, thereby establishing an immune microenvironment conducive to sustained tissue

repair and the formation of highly mineralized new bone (Lin et al., 2023).

Applications of Graphene Oxide in Veterinary Dentistry

Advanced Periodontal Regeneration: Immunomodulation and Reconstruction of the

Root- Associated Complex Periodontal regeneration represents one of the major challenges in

dental and veterinary tissue engineering because of the complex tripartite architecture of the

periodontal attachment apparatus. Successful regeneration requires the coordinated restoration

of root cementum, the periodontal ligament (PDL), and alveolar bone, together with the

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functional reinsertion of Sharpey’s fibers (Mashhadi et al., 2024; Sánchez-Cepeda et al., 2024;

Xie et al., 2024).

Within this context, periodontal ligament stem cells (PDLSCs) represent a major

progenitor cell population involved in periodontal tissue repair. Graphene oxide (GO) derivatives

can act as instructive modulators of the PDLSC cellular microenvironment through advanced

biological.

Modulation of mitochondrial dynamics and GO quantum dots (GQDs): Incorporation of

graphene oxide quantum dots (GQDs) into gelatin methacrylate (GelMA) hydrogel matrices

promotes the osteogenic differentiation of PDLSCs by regulating cellular metabolic

homeostasis. Specifically, GQDs promote mitochondrial fusion and attenuate excessive fission,

thereby preserving mitochondrial membrane potential and accelerating the repair of periodontal

bone defects in vivo (An et al., 2024).

Three-dimensional PCL/GO scaffolds: Surface functionalization of three-dimensional

polycaprolactone (PCL) matrices with GO coatings optimizes nanoscale topography and surface

free energy. This results in enhanced initial adhesion and proliferation of PDLSCs and promotes

rapid extracellular matrix (ECM) mineralization (Park et al., 2021).

Preclinical evidence in canine models: Application of GO-modified three-dimensional

collagen scaffolds to Class II furcation periodontal defects in canines demonstrated superior

regenerative capacity after four weeks of implantation. Histological analyses revealed not only

new alveolar bone formation and tissues exhibiting cementum- and periodontal ligament-like

morphology, but also active perpendicular insertion of Sharpey’s fibers into the newly formed

root surface, supporting restoration of the biomechanical integrity of the periodontal attachment

apparatus (Kawamoto et al., 2018).

Immunomodulation in compromised microenvironments: Under complex

pathophysiological conditions, such as diabetic microenvironments or chronic periodontitis, the

regenerative potential of GO extends beyond direct osteoinduction. Alginate/gelatin hybrid

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matrices functionalized with polydopamine (PDA)-modified GO and hydroxyapatite

nanoparticles (nHA) exhibit substantial reactive oxygen species (ROS)-scavenging capacity and

the ability to activate Ca²⁺ signaling pathways, thereby modulating the inflammatory

macrophage phenotype and promoting osteogenesis in tissues characterized by elevated

oxidative stress (Li et al., 2022).

Critical Perspective and Veterinary Clinical Translation

Despite the advances reported to date—including in vivo proof-of-concept studies in

canine models (Kawamoto et al., 2018)—the application of graphene oxide (GO) in clinical

veterinary dentistry, particularly for the treatment of canine and feline periodontal disease,

remains at an early experimental stage.

Most findings reported to date have originated from in vitro studies using human cells or

in vivo experiments conducted in rodent models. Before systematic clinical translation into

veterinary medicine can be considered, several critical knowledge gaps must be addressed.

Physicochemical standardization: The effective dose, optimal lateral size range of GO

nanosheets, and density of oxygen-containing functional groups must be established to

minimize the risk of systemic cytotoxicity.

Biodegradation kinetics and long-term safety: Biological clearance, myeloperoxidase-

mediated degradation, and the potential for undesirable tissue deposition following defect

resolution must be systematically evaluated.

Controlled clinical trials in canine patients: Prospective randomized studies should be

conducted in real-world veterinary patients with naturally occurring periodontitis, with long-term

assessment of clinical periodontal parameters, including probing depth, clinical attachment

level, and tomographic bone density.

Regeneration of the Dentin–Pulp Complex: Odontogenic Induction and Tissue

Reconstruction Preservation and regeneration of the dentin–pulp complex represent primary

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objectives in modern regenerative dentistry, as loss of pulp vitality interrupts tertiary

dentinogenesis, compromises proprioception, and leaves the tooth highly susceptible to fracture

and root resorption. Unlike conventional endodontic treatment, which focuses on inert obturation

of the root canal, tissue engineering aims to restore a highly vascularized and innervated tissue

characterized by a palisaded layer of functional odontoblasts capable of synthesizing reparative

tubular dentin (Huang et al., 2024; Qin et al., 2022).

In this process, dental pulp stem cells (DPSCs) represent the most relevant progenitor

cell population. Graphene oxide (GO) nanostructures act on DPSCs as potent biological and

physicochemical inducers, modulating odontogenesis through the following principal

mechanisms.

Table 1.

Graphene oxide combinations with natural and synthetic biomaterials investigated experimentally

Material combination

Experimental model

Study objective

Main findings

Potential dental

application

GO+PCL

Rabbit bone defect

To evaluate 3D-printed

PCL scaffolds enriched with

GO for bone regeneration

GO-containing scaffolds showed

greater new bone formation; GO

concentrations of 1% and 3% were

Regeneration of alveolar

and maxillofacial bone

defects

GO+PLA+ hardystonite

Characterization and

experimental

evaluation of 3D

scaffolds

To develop a

nanocomposite scaffold

using 3D printing

GO acted as a component/coupling

agent within the PLA–hardystonite

system, improving scaffold-related

properties for bone regeneration

Alveolar and

maxillofacial bone

regeneration through

additive manufacturing

GO+collagen

+curcumin

Biological and

structural evaluation

of a scaffold

To develop a collagen

scaffold incorporating GO

and loaded with curcumin

The system exhibited favorable

structural and biological

characteristics for bone

regeneration and antibacterial

Periodontal and bone

regeneration; potential

multifunctional system

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GO+PLA

Cell culture and 3D

scaffold

To evaluate the effect of a

GO coating on 3D-printed

PLA scaffolds

GO surface treatment increased

wettability and resulted in an

increase of up to 220% in cell

viability under dynamic culture

Scaffolds for bone

regeneration and

maxillofacial defects

GO+PLA+

β-TCP

3D-printed scaffolds;

physicochemical,

mechanical, and

biological evaluation

To develop a PLA scaffold

reinforced with GO and β-

tricalcium phosphate

Structure, mechanical properties,

and bioactivity of the system were

characterized

Alveolar and

maxillofacial bone

regeneration

GO+PLGA

Rats with mandibular

fractures

To compare absorbable

GO–PLGA nanofibrous

plates with titanium plates

Bone stability, viability, and healing

of mandibular fractures were

evaluated

Fixation and

regeneration of

mandibular/maxillofacial

GO+PEEK

Experimental surface

evaluation

To develop a self-

assembled GO coating on

PEEK

The coating improved the

bactericidal and osteogenic

properties of PEEK

Dental implants and

implant surfaces

GO+collagen+

Attapulgite

3D scaffold;

experimental bone

regeneration

To fabricate a

biocompatible scaffold

using 3D printing

The combination was designed to

provide structural support and

promote bone regeneration, with

potential for patient-specific

fabrication

Alveolar and

maxillofacial bone

regeneration

GO+bioglass

Scaffold evaluation

for bone regeneration

To develop a composite

scaffold comprising GO and

nanobioglass

A composite material with favorable

characteristics for bone tissue

engineering was obtained

Regeneration of alveolar

bone defects

GO+chitosan

+alginate + Se

Rabbit with bone

defect

To evaluate a biopolymeric

scaffold containing GO and

selenium

GO and Se enhanced the physical

properties of the scaffold and

resulted in significantly greater

bone regeneration than the control

Regeneration of

periodontal and bone

defects

GO + PLLA/PGA+

polydopamine+Sr

Scaffold for bone

tissue engineering;

mechanical and

osteogenic

evaluation

To incorporate strontium-

functionalized GO into a

PLLA/PGA scaffold

The system demonstrated

improved mechanical properties

and osteogenic induction

Alveolar/maxillofacial

bone regeneration

GO + titanium +

antimicrobial peptide

Nal-P-113

Titanium surface;

antimicrobial and

cytocompatibility

To develop a GO coating

loaded with an antimicrobial

peptide

The coating was evaluated for

antibacterial activity and

cytocompatibility

Dental implants and

prevention of peri-

implantitis

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GO+titanium

Dental implant

surface; antimicrobial

evaluation

To evaluate GO

nanoparticles as a surface

treatment for titanium

implants

The synthesis, characterization,

and potential antimicrobial activity

of the coating were

Dental implants and

control of peri-implant

infection

GO+titanium +

minocycline

Titanium implants;

experimental

evaluation

To develop a GO/multilayer

coating incorporating

minocycline

Coating characteristics, cellular

response, and properties related to

bacterial control were evaluated

Prevention/treatment of

peri-implantitis

GO+bioglass

+ PEEK

Experimental dental

implant

To develop a bioglass/GO

composite coating for

PEEK

System was designed to overcome

the low bioactivity and limited

antimicrobial activity of PEEK

Dental implants and

osseointegration

Modulation of cellular metabolism and AMPK/mTOR signaling by GQDs: Exposure of

DPSCs to optimized concentrations of graphene oxide quantum dots (GQDs) significantly

stimulates cell proliferation, alkaline phosphatase (ALP) activity, and mineralized nodule

deposition. At the molecular level, this odontogenic stimulus is mediated by regulation of the

AMPK/mTOR metabolic pathway, which promotes the upregulation of key dentin-matrix

proteins, including dentin sialophosphoprotein (DSPP), dentin matrix protein 1 (DMP-1), and the

transcription factor RUNX2 (Lin et al., 2023).

Synergy in three-dimensional mesoporous bioactive glass/GO (MBG/GO)

nanocomposites: Incorporation of GO into mesoporous bioactive glass (MBG) matrices

generates an ionic-exchange and topographical microenvironment conducive to human DPSC

activity. This hybrid platform not only induces coordinated upregulation of advanced

odontogenic markers, including DSPP, DMP- 1, BMP-2, MEPE, RUNX2, and ALP, but also

accelerates biomineralization kinetics through the epitaxial nucleation of apatite crystals on the

surface network (Ahn et al., 2020).

Multifunctional growth-factor retention platforms: The abundance of carboxyl and

hydroxyl groups at the edges and basal plane of GO enables the non-covalent adsorption of

bioactive biomolecules, particularly members of the transforming growth factor-β (TGF-β)

superfamily, such as BMP-2 and BMP-7. Incorporation of GO into injectable hydrogels or

porous scaffolds enables the development of sustained-release systems that mimic the native

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odontogenic niche, protecting growth factors from proteolytic degradation and maintaining their

local bioavailability to guide DPSC differentiation (Ahn et al., 2020).

Critical Perspective and Clinical Challenges in Canine Veterinary Dentistry

Despite promising in vitro and in vivo findings from basic preclinical models, the current

scientific literature presents conceptual and methodological limitations that must be addressed

before clinical translation into veterinary dentistry can be contemplated:

Partial evidence versus comprehensive regeneration: Most available evidence evaluates

indirect markers or partial endpoints, such as in vitro differentiation, formation of mineralized

nodules, or gene expression (Huang et al., 2024; Qin et al., 2022). However, there is still no

conclusive evidence that GO alone can orchestrate the complete regeneration of a vascularized

and innervated dental pulp within complex pulp chambers.

Translational gap to the canine species: Direct extrapolation of findings obtained from

human DPSCs to canine veterinary clinical practice is neither biomechanically nor

immunologically valid. The canine oral cavity presents specific challenges, including:

Severe masticatory forces and microleakage: Substantial occlusal loads in dogs impose

more stringent mechanical-resistance requirements on the regenerated dentin–pulp complex

Species-specific microbial burden: The canine endodontic microbiota differs in composition and

pathogenic potential from that of humans, necessitating biomaterials with enhanced bactericidal

capacity against dog-specific pathogens.

Need for species-specific in vivo trials: GO should currently be regarded as a promising

experimental biomaterial platform. Progress toward clinical applications in direct pulp capping or

regenerative pulpotomy in dogs requires the design of orthotopic in vivo studies in canine

models, with quantitative assessment of tertiary dentin formation, pulp revascularization, and

long-term pulp biocompatibility.

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Alveolar Bone Regeneration and Maxillofacial Reconstruction: Hybrid Nanocomposites

and Osteoangiogenic Systems.

The reconstruction of alveolar and maxillofacial bone defects represents a major

biomechanical and physiological challenge because it requires simultaneous restoration of

structural rigidity, alveolar ridge stability, and bone volume lost following severe periodontitis,

dental avulsion, high- energy trauma, or oncological surgical resection. Many of these defects

exceed the physiological capacity for spontaneous regeneration and therefore constitute critical-

sized defects, requiring three-dimensional matrices that integrate osteoconductive,

osteoinductive, and angiogenic properties (Kumari et al., 2022; Yang et al., 2024).

The physicochemical properties of graphene oxide (GO) enable its use as both a

mechanical reinforcing agent and a bioactive component in bone tissue engineering, giving rise

to several families of hybrid nanocomposites.

Hydroxyapatite/GO hybrid systems and bone immunomodulation: Combining GO with

hydroxyapatite (HA) mimics the native inorganic phase of bone while enhancing the fracture

toughness of the inorganic matrix. Multifunctional matrices composed of polydopamine (PDA)-

modified GO and integrated hydroxyapatite nanoparticles (nHA) within alginate/gelatin

hydrogels have been shown to orchestrate regeneration in inflammatory microenvironments.

This nanocomposite scavenges reactive oxygen species (ROS) and promotes macrophage

polarization from the pro-inflammatory M1 phenotype toward the reparative M2 phenotype,

thereby increasing the density of mineralized matrix formation in vivo (Li et al., 2022).

Mesoporous bioactive glass/GO composites (MBG/GO): Incorporation of GO into

bioactive glasses modifies surface microtopography and ion-exchange kinetics. These

composites enhance protein adsorption and stimulate epitaxial biomineralization, promoting

progenitor-cell differentiation through accelerated formation of a biologically active carbonate-

substituted apatite layer (Li et al., 2022).

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Dual loading and sustained release of osteoangiogenic factors (BMP-2 and VEGF):

Reconstruction of critical-sized defects requires rapid vascularization coordinated with

osteogenesis. GO acts as a highly efficient molecular reservoir through non-covalent

interactions, including π–π stacking, hydrogen bonding, and electrostatic attraction.

Incorporation of GO into PCL/PVP nanofibrous scaffolds suppresses the initial burst release of

bone morphogenetic protein 2 (BMP-2), maintaining sustained desorption over prolonged

periods. This modulated release kinetics results in enhanced osteoblastic maturation and

calcium phosphate deposition (Jeong et al., 2022). Similarly, incorporation of vascular

endothelial growth factor (VEGF) into GO-based matrices enables coupling of

neovascularization with bone mineralization.

Tissue integration and in vivo immuno-osseointegration: Preclinical studies demonstrate

that titanium surfaces modified with GO nanolayers quantitatively increase bone-to-implant

contact (BIC) and accelerate osseointegration in rabbit tibial models (Yang et al., 2024),

supporting the interfacial biocompatibility of the nanomaterial with both cortical and trabecular

bone in vivo (Kwak et al., 2022).

Critical Perspective and Translation to Canine Veterinary Dentistry

The development of GO-based biomaterials for alveolar and maxillofacial reconstruction

in dogs has considerable potential given the high prevalence of advanced periodontal disease

and extensive bone loss encountered in small-animal clinical practice. However, the clinical

translation gap requires several technical and biological limitations to be addressed.

Species-specific biomechanical requirements: The canine maxillofacial complex is

subjected to substantially greater masticatory occlusal forces than those experienced in rodents

and rabbits.

It is therefore essential to characterize the compressive, shear, and fatigue properties of

GO-based hybrid scaffolds under physiologically relevant cyclic loading conditions.

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Dependence on vascularization in extensive defects: Although VEGF adsorption onto

GO- based matrices has demonstrated biological plausibility, the in vivo degradation kinetics of

the scaffold must be precisely synchronized with the rate of angiogenesis and capillary ingrowth

from adjacent cortical bone to prevent central necrosis in large-volume defects.

Optimization of Synthesis Parameters and Longitudinal Safety

Standardization of the threshold dose, degree of oxidation (C/O ratio), and lateral

dimensions of GO sheets is required in orthotopic canine maxillofacial models. In addition, long-

term histomorphometric and tomographic assessments are imperative to rule out chronic

foreign-body inflammation or undesirable tissue migration of free GO nanosheets.

Bioactive Coatings on Titanium Dental Implants: Surface Modification and Interfacial

Performance.

Commercially pure titanium (cp-Ti) and its alloys (e.g., Ti-6Al-4V) constitute the gold

standard in dental and maxillofacial implantology because of their high yield strength, corrosion

resistance, and passive biocompatibility conferred by the titanium dioxide (TiO₂) surface oxide

layer. However, the relative biological inertness of titanium may result in prolonged

osseointegration times or premature failure associated with bacterial peri-implantitis or

inadequate primary and secondary stability (Kwak et al., 2022).

Topographical and functional modification of titanium surfaces using graphene oxide

(GO) nanocoatings transforms a passive interface into a bioactive instructive microenvironment,

modulating osteogenesis and providing antimicrobial protection without altering the structural

mechanical properties of the metallic core.

Surface anchoring and integration techniques (micro-arc oxidation—MAO): Deposition of

GO onto titanium by micro-arc oxidation (MAO) generates a porous TiO₂ layer that functions as

a rough mechanical anchor at the micro- and submicrometre scales. Subsequent immobilization

of GO nanosheets within the pores of the MAO layer optimizes surface free energy and

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wettability, generating a nanotopography with high affinity for cellular attachment (Kwak et al.,

2022).

Mechanotransduction and in vitro and in vivo osteogenic response: Ti/MAO-GO surfaces

induce a significant increase in the expression of alkaline phosphatase (ALP), the transcription

factor RUNX2, osteopontin (OPN), and osteocalcin (OCN) in bone progenitor cells (Kwak et al.,

2022). In in vivo animal models (rabbit tibia), implants modified with GO coatings demonstrated

a marked quantitative increase in bone-to-implant contact (BIC) and peri-implant trabecular

bone volume compared with conventional surfaces (Kwak et al., 2022), thereby accelerating

bone consolidation at the implant– bone interface.

Multifunctional multilayer coatings: The ability of GO to function as an immobilization

matrix enables the development of multifunctional coatings on titanium.

Biomimetics and mineralization: Co-deposition of GO with hydroxyapatite (HA) accelerates the

formation of a biologically active apatite layer.

Dual antimicrobial effect: The presence of GO prevents the initial colonization of oral

pathogens in the peri-implant sulcus through mechanical membrane damage and ROS

generation.

Sustained growth-factor release: GO enables the physical adsorption and kinetically

regulated release of BMP-2 or immunomodulatory agents into the peri-implant surgical site

(Kwak et al., 2022).

Critical Perspective and Challenges for Translation to Canine Veterinary Implantology

The use of GO-functionalized titanium implants in canine patients represents a highly attractive

alternative for oral rehabilitation, fixation of maxillofacial prostheses, and stabilization of complex

bone defects in veterinary medicine. However, safe clinical translation requires the resolution of

specific methodological and biomechanical challenges.

Coating adhesion and shear resistance: During dental implant insertion into the bone

bed under mechanical torque, the GO coating is exposed to substantial frictional and shear

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forces. It is therefore essential to quantify delamination resistance and mechanical stability of

the coating to prevent unintended release of free nanosheets into the bone bed, which could

trigger foreign-body responses or frustrated phagocytosis by macrophages.

Canine oral environment and peri-implant biofilm: Canine saliva differs from standard

laboratory models in pH, viscosity, and bacterial burden, including the presence of species such

as Porphyromonas gulae. It is therefore necessary to determine whether the bioactivity and

antibacterial effects of GO coatings remain stable in the presence of enzymatic degradation and

canine dental plaque formation in vivo.

Standardization and veterinary clinical trials: Prospective canine studies evaluating

primary stability, implant stability quotient (ISQ) values using resonance frequency analysis, and

long-term implant success rates under physiological occlusal loading are currently lacking.

Consequently, Ti–GO remains an experimental biomaterial system with substantial translational

potential.

Three-Dimensional Scaffolds: Hybrid Nanocomposite Architectures and Biofabrication

Three-dimensional scaffolds constitute a fundamental component of dental and maxillofacial

tissue engineering by functioning as synthetic extracellular matrix mimetics that provide

temporary mechanical support, guide cellular behavior, and immobilize osteoinductive cues.

Incorporation of graphene oxide (GO) into polymeric, protein-based, or hydrogel matrices can

overcome the inherent limitations of pristine materials, such as low toughness, rapid

degradation, or limited bioactivity, through the formation of multifunctional hybrid networks.

The interfacial integration of GO into the different families of three-dimensional matrices

can be organized according to the following biomaterial strategies:

Bioprintable Hydrogels (GelMA and Bioactive Peptides)

Gelatin methacryloyl (GelMA) hydrogels mimic the viscoelasticity of soft tissues and

facilitate cellular encapsulation. Incorporation of GO optimizes the hydrogel storage modulus,

increases shape fidelity during the 3D bioprinting process, and promotes mesenchymal stem

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cell adhesion and osteogenic differentiation, as evidenced by the upregulation of RUNX2,

osteopontin, and osteocalcin. In addition, GelMA/GO hydrogels functionalized with bone-forming

peptide-1 (BFP- 1) act as delivery platforms for osteogenic cues, accelerating alkaline

phosphatase (ALP) activity and mineralized matrix deposition.

Biodegradable Synthetic Polymers and the Formulation Window Effect (PCL/GO)

Poly(ε-caprolactone) (PCL) offers high processability for scaffold fabrication by fused

deposition modeling (FDM). Incorporation of GO reduces the hydrophobicity of PCL and

increases nanoscale surface roughness. In vivo experiments in rabbit bone defects

demonstrated a narrow formulation window: the addition of 1 wt% GO significantly increased

new bone formation. However, higher concentrations induced nanosheet aggregation,

undesirable acceleration of biodegradation due to structural mismatch, and local cytotoxicity,

demonstrating that the biological response does not exhibit a direct linear relationship with

nanophase loading.

Natural Protein Matrices and Antimicrobial Biopolymers (Collagen and Chitosan)

Collagen/GO systems: The combination of GO with collagen restores the protein

component of the extracellular matrix (ECM), while the nanosheets enhance thermal stability

and resistance to enzymatic degradation by collagenases. The incorporation of minerals

(attapulgite) or phytochemicals (curcumin) into three-dimensional collagen/GO matrices

generates multifunctional scaffolds that combine structural support with antibacterial and

antioxidant activity.

Chitosan/GO composites: Electrostatic interactions between the positively charged

amino groups of chitosan and the electronegative carboxyl groups of GO reinforce the three-

dimensional network. In critical-sized defects, chitosan/GO scaffolds increase new bone

formation and the expression of osteogenic markers (BMP, RUNX2, OPN, and OCN) compared

with the biopolymer alone, while also serving as controlled-release matrices for bactericidal

agents.

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Figure 1

Critical Parameters of GO/Scaffold Systems

The systematic balance among these variables determines whether the scaffold will

induce a regenerative tissue response or a foreign-body reaction, thereby establishing the

framework for the development of three-dimensional matrices for clinical veterinary and

biomedical applications.

Incorporation of Bioceramics and Multicomponent Hybrid Systems

Coupling GO with osteoconductive bioceramics, including hydroxyapatite, β-tricalcium

phosphate (β-TCP), and bioactive glasses, generates ternary or quaternary nanocomposites

(e.g., chitosan/gelatin/bioactive nanoglass/GO or β-TCP/polymer/GO). In these systems, the

bioceramic component provides inorganic nucleation sites, whereas GO acts as a network-

forming cross- linker and mechanical reinforcement against bending and compressive stresses.

Critical Perspective on Scaffold Synthesis and Design

The accumulated evidence indicates that GO should be conceptualized as an interfacial

dopant and instructive agent rather than merely as a passive reinforcing nanofiller. To maximize

the regenerative performance of three-dimensional scaffolds and ensure an appropriate cellular

response, biomaterial design should consider a multidimensional matrix of variables:

Nanofunctional Platforms for Controlled Release and Local Delivery of Bioactive Agents

The ability of graphene oxide (GO) to function as a sustained and site-specific delivery

platform (targeted delivery system) stems from its interfacial physicochemical properties. Its

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high specific surface area, combined with the basal plane of sp²-hybridized carbon atoms and

peripheral functional groups (carboxyl, hydroxyl, and epoxy groups), enables stable yet

reversible non- covalent interactions, including π–π stacking, hydrogen bonding, hydrophobic

interactions, and electrostatic forces.

In dental and maxillofacial tissue engineering, localized release kinetics can minimize

rapid dissipation or washout through blood or salivary flow, suppressing the initial burst release

and maintaining the bioactive dose within the effective therapeutic window for prolonged periods

compatible with bone and periodontal histogenesis.

The major advances in the delivery of bioactive and therapeutic agents using GO-based

systems can be organized into the following main areas

Delivery of Osteoinductive Factors (BMP-2) Using Macro- and Nanoscale Matrices

Macro-/microstructured scaffold systems (PCL/GO–PVP): The incorporation of

GO/polyvinylpyrrolidone (PVP) hydrogels into electrospun nanofibrous poly(ε-caprolactone)

(PCL) scaffolds modulates the desorption of bone morphogenetic protein-2 (BMP-2). Non-

covalent interactions between GO and BMP-2 prolong the bioavailability of the osteoinductive

protein, continuously promoting mineral deposition and the upregulation of osteogenic markers

in critical-sized defects.

Nanoscale delivery platforms (GO–PLL/albumin): Beyond rigid three-dimensional

scaffolds, functionalization of bovine serum albumin nanoparticles with poly-L-lysine and GO

(GO–PLL) enables the formation of colloidal nanocarriers for BMP-2. This GO–PLL/BMP-2

nanoscale complex attenuates the initial diffusion rate, enhances cellular uptake, and stimulates

the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs), providing a

potential route for injectable therapies targeting alveolar defects with irregular geometries.

Stimuli-Responsive Systems for Antimicrobial Agents

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pH-dependent antibiotic release (vancomycin): Incorporation of GO into polymeric

hydrogel matrices composed of poly (vinylsulfonic acid)–Sterculia gum enables modulation of

vancomycin diffusion kinetics through pH responsiveness. Changes in the protonation state of

GO carboxyl groups under acidic or neutral conditions alter electrostatic interactions with the

charged drug, thereby regulating its release. Although this model was initially developed for

gastrointestinal drug delivery, it establishes the biophysical principle underlying GO-based

hydrogels responsive to microenvironmental changes, such as the acidification observed in

periodontal disease or active peri-implant infection.

Carriers for Low-Molecular-Weight Phytotherapeutic Bioactive Molecules

PLLA/GO biomimetic scaffolds (salvianolic acid B): The incorporation of GO into

porous poly (L-lactic acid) (PLLA) matrices alters polymer-fiber topography and enables

sustained release of small molecules such as salvianolic acid B. π–π stacking interactions

between the aromatic ring of the drug and the sp² domains of GO regulate the desorption

profile, coupling the antioxidant and vasodilatory effects of the bioactive molecule with structural

regeneration of the matrix.

Critical Perspective and Veterinary Clinical Translation: The integration of four

independent functions—structural support, osteoinduction/odontogenesis, bacterial control, and

kinetically regulated bioactive delivery—within a single biomaterial platform positions GO as a

highly versatile material.

However, before translation into canine dental practice, particularly for the regeneration

of periodontal and osseous defects associated with previous infection, the following scientific

gaps must be addressed

Species-specific in vivo evidence in dogs: Although the release kinetics of factors

such as BMP- 2 and antibiotics such as vancomycin have been demonstrated in vitro or in non-

dental preclinical models, empirical evidence validating the efficacy of GO–vancomycin or GO–

BMP-2 systems within the canine periodontal microenvironment is still lacking.

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Kinetic–metabolic synchronization: Growth-factor release kinetics must be synchronized

with scaffold degradation and the rate of bone remodeling in dogs. Decoupled release may

result in ectopic bone formation if release is excessively rapid, or fibrous encapsulation if the

bioactive agent becomes irreversibly entrapped within the GO network.

Validation of stability and immunological safety: Local pharmacokinetics, long-term

cytotoxicity profiles, stability of the nanocarrier–drug complex in the presence of canine salivary

enzymes, and the immune response to repeated or prolonged administration of GO-based

delivery vectors must be determined.

Surface Antimicrobial Strategies and Control of Multispecies Oral Biofilms

Pathogenic colonization and invasion mediated by oral biofilms on biomaterials

constitute a primary etiological factor in the pathogenesis of dental caries, periodontal disease,

and peri- implantitis. The limited efficacy of conventional therapies in eliminating the

extracellular polymeric substance (EPS) matrix of established biofilms has driven the

development of bioactive and instructive GO-based surfaces that act through direct contact

(physical action/"nano-knives"), oxidative stress generation, or function as nanovectors for

pharmacological synergy.

The antibacterial applications of GO in dental and regenerative biomaterials can be

organized into three principal platforms:

Functionalization of Implant and Titanium/Zirconia Device Surfaces

Layer-by-layer (LbL) nanocoatings and antimicrobial peptides: Immobilization of the

antimicrobial peptide Nal-P-113 onto titanium using GO as a supporting matrix enables

continuous and controlled release of the peptide agent. This hybrid coating significantly

suppresses the growth of Streptococcus mutans and Porphyromonas gingivalis without inducing

cytotoxicity in human gingival fibroblasts (hGFs).

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GO/ε-poly-L-lysine multilayers: The nanostructured assembly of 20 alternating layers

of GO and ε-poly-L-lysine on titanium generates a highly effective biocidal coating against the

primary periodontal pathogen P. gingivalis, while maintaining adequate cellular biocompatibility.

Plasma-mediated surface modification of zirconia: Plasma treatment for deposition

of graphene/GO nanocoatings onto zirconium oxide substrates (zirconia, ZrO₂) markedly

reduces initial bacterial adhesion and the hydration energy required for attachment of S. mutans

and P. gingivalis, demonstrating that graphene-based surface modification can be extended to

ceramic substrates used in restorative and prosthodontic applications.

Direct and Indirect Restorative Materials (Resin Composites and Doped Hydroxyapatite)

Hybrid resin cements (GO/HA-Ag): The formulation of experimental dental resins and

cements enriched with GO and silver-doped hydroxyapatite (HA-Ag) inhibits the proliferation of

cariogenic pathogens (S. mutans) and periodontopathogens (P. gingivalis). Incorporation of

trace concentrations of GO nanophases enhances the fracture toughness of the polymer

composite and acts as a bactericidal synergist, potentially preventing secondary caries at

restoration margins.

Inhibition of primary colonizers and bridging species (historical model): Two-

dimensional GO nanosheets exert a direct bactericidal effect against the reference pathogenic

bacterial triad: S. mutans (matrix initiator), Fusobacterium nucleatum (bridging/adhesive

microorganism), and P. gingivalis (strict periodontal pathogen).

Targeted Antimicrobial Photodynamic Therapies (aPDT)

Aptamer–NGO systems: Conjugation of DNA aptamers specifically targeting

membrane receptors of P. gingivalis onto nano-sized graphene oxide (NGO) enables targeted

delivery of photosensitizing agents. Upon irradiation, antimicrobial photodynamic therapy

(aPDT) generates a localized burst of reactive oxygen species (ROS), selectively eliminating P.

gingivalis biofilms while preserving the commensal microbial balance of the oral tissue

microenvironment.

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Critical Perspective and Translational Gap in Canine Veterinary Medicine

Although in vitro and in vivo evidence demonstrates high bactericidal efficacy against

human- derived strains (S. mutans, P. gingivalis, and F. nucleatum), translation of GO-based

antibacterial biomaterials to canine dentistry faces critical biological limitations that must be

addressed.

Divergence of the periodontal microbiome: The canine periodontal disease-

associated microbial complex is predominantly characterized by Porphyromonas gulae,

Porphyromonas salivosa, and Peptostreptococcus canis, rather than human P. gingivalis.

Therefore, findings demonstrated against human periodontal pathogens should be regarded as

evidence of translational potential rather than as proof of in vivo efficacy in dogs.

Canine biofilm resilience in alkaline microenvironments: Canine saliva exhibits a

substantially more alkaline pH (pH 8.0–8.5) and a higher rate of mineral precipitation

(accelerated tartar/calculus formation) than human saliva. This necessitates evaluation of

whether GO surface bioactivity and the release of antimicrobial peptides or ions remain stable in

the face of rapid mineralization and alkalinization of the canine oral environment.

Research perspective: Experimental evaluation of GO coatings against wild-type

strains isolated from canine P. gulae is required, together with the development of orthotopic

studies to validate biocompatibility and control of periodontal dysbiosis in dogs with naturally

occurring periodontitis.

Current State of Research and Translational Gaps in Canine Veterinary Medicine

The development of graphene oxide (GO)-based biomaterials for dental applications and

tissue regeneration has grown exponentially over the past decade. Nevertheless, a recent

systematic review (2013–2023) of GO applications in oral surgery identified 293 initial records,

of which only 19 publications met the inclusion criteria for specific applications involving implant

surfaces, prosthetic abutments, guided bone regeneration (GBR) membranes, and bone-

regeneration scaffolds (Inchingolo et al., 2023). This quantitative analysis confirms that,

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although interest in GO for oral tissue engineering is rapidly expanding, the available evidence

remains predominantly preclinical (Inchingolo et al., 2023).

When the literature is examined specifically for canine subjects, the available evidence is

reduced to a limited number of isolated preclinical studies published between 2016 and 2020:

Post-extraction alveolar ridge preservation: Implantation of GO-coated collagen scaffolds into

dental extraction sockets in dogs resulted in an approximately fivefold increase in new bone

formation compared with non-functionalized controls, accompanied by substantial cellular

infiltration and stromal vascularization (Miyaji et al., 2016).

Periodontal regeneration in furcation defects: The use of three-dimensional collagen/GO

matrices in Class II furcation defects in dogs promoted histological reconstruction of the

periodontal attachment apparatus, with newly formed alveolar bone, cementum-like tissue, and

functional periodontal ligament being observed (Kawamoto et al., 2018).

Management of experimental peri-implantitis: In beagle dog models with experimentally

induced peri-implantitis, the use of minocycline-functionalized GO films on implant abutments

attenuated marginal bone resorption and inhibited the progression of inflammatory infiltration

(Qian et al., 2020).

Despite these pioneering findings spanning the three major areas of regenerative

dentistry— alveolar preservation, periodontal reconstruction, and peri-implant therapy—

evidence in dogs has not yet developed into a continuous or consolidated research programme.

Notably, there has been no proportional increase in in vivo canine studies after 2022; instead,

recent research has shifted towards in vitro cultures of stem cells (MSCs, PDLSCs, and DPSCs)

and rodent/rabbit models.

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Figure 2

Evidence flow of research on GO in dentistry and canine veterinary medicine.

Methodological Limitations and Barriers to Clinical Translation

The safe translation of GO-based biomaterials from laboratory research to clinical

veterinary practice requires overcoming three fundamental methodological biases and barriers:

Methodological bias arising from the predominance of in vitro studies and model incompatibility:

The abundance of monolayer cell assays, in which upregulation of ALP, RUNX2, DSPP, or

DMP-1 is interpreted as evidence of biological potential, does not capture the haemodynamic

complexity, occlusal biomechanics, or immunological and microbiological microenvironment of a

living dog.

Likewise, rodent and rabbit models differ substantially from domestic carnivores in terms

of bone-remodelling rates and maxillofacial mechanical loading. Physicochemical heterogeneity

of GO: The designation "graphene oxide" encompasses materials exhibiting substantial

variation in nanosheet lateral dimensions, degree of oxidation (C/O ratio), number of layers,

purity, and synthesis method. These variables can markedly alter cytotoxicity thresholds,

enzymatic degradation rates, and tissue reactivity, making direct comparisons between studies

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impossible unless the physicochemical profile of the starting material is standardized. Figure 2.

Translational gap of graphene oxide in canine veterinary dentistry.

Note. The figure synthesizes the distribution of the available evidence, ranging from in

vitro studies and experimental animal models to studies conducted specifically in dogs and their

potential eventual application in veterinary clinical practice. The identified canine evidence is

concentrated on alveolar regeneration, periodontal regeneration, and peri-implantitis, whereas a

marked lack of veterinary clinical studies persists.

Scarcity of long-term immunosafety and clearance assessments: The lack of longitudinal

studies prevents adequate characterization of myeloperoxidase-mediated biodegradation

kinetics, interactions with macrophages, and potential accumulation or tissue migration of

nanosheets following degradation of the host matrix (PCL, GelMA, or collagen). In veterinary

patients, short- term acute biocompatibility cannot substitute for evidence of long-term safety

against foreign- body reactions or delayed chronic peri-implant inflammation.

Future Research Opportunities in Veterinary Dentistry

Because the dog is a biologically relevant translational model for periodontology and

implantology owing to its anatomical and pathophysiological similarities to higher mammals,

there is a key opportunity to reinvigorate targeted preclinical research. Rigorous in vivo studies

are needed to evaluate contemporary multifunctional formulations—including GO composites

with GelMA, hydroxyapatite, bioactive glass, bioceramics, and osteoangiogenic factors—under

orthotopic conditions that reproduce the actual pathogenesis of canine periodontal disease.

Such studies should incorporate histomorphometric analyses, micro-computed tomography

(micro-CT), pathogen-specific microbiological assessment against Porphyromonas gulae, and

longitudinal monitoring of biocompatibility.

Accordingly, the available evidence currently supports classifying the application of GO

in canine veterinary dentistry as a promising preclinical technology that remains insufficiently

validated. The available literature provides proof-of-concept evidence in dogs and a substantial

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experimental basis derived from human and laboratory animal models; however, there is still

insufficient evidence to establish veterinary clinical protocols, optimal therapeutic

concentrations, or standardized formulations. This gap between biomaterial development and

clinical validation represents one of the major challenges for the future application of GO in

canine dentistry and, at the same time, constitutes one of the areas with the greatest potential

for translational research.

Future Perspectives and Translational Research The gap between nanostructured

material design and application in canine patients defines the priorities for future research in

biomaterials and veterinary dentistry: Standardization and Physicochemical Characterization:

Establish strict formulation ranges (the “therapeutic window”) that optimize bioactivity without

triggering cytotoxicity or foreign- body responses. Species-Specific Orthotopic Models: Develop

longitudinal preclinical studies in dogs to evaluate contemporary multifunctional scaffolds (GO-

doped GelMA, PCL, collagen, chitosan, or bioceramics) under conditions that reproduce

naturally occurring periodontal disease and peri- implantitis, integrating histomorphometric

analyses, micro-CT, and pathogen-specific microbiological assessment. Long-Term Tissue

Safety: Evaluate the shear strength of coatings on titanium implants, the kinetics of

biodegradation mediated by local enzymes, and extended-term systemic biocompatibility.

DISCUSSION

The evidence analyzed indicates that graphene oxide (GO) is a nanobiomaterial with

physicochemical and biological characteristics of considerable interest for regenerative

dentistry. The presence of oxygen-containing functional groups, its high specific surface area,

and its ability to interact with proteins, polymers, and bioactive molecules allow its incorporation

into scaffolds, coatings, and controlled-release systems. However, the properties of GO depend

on variables such as the degree of oxidation, lateral sheet size, concentration, and surface

functionalization; therefore, it cannot be regarded as a material with uniform biological behavior.

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Jiříčková et al. (2022) and Kabore et al. (2026) specifically highlighted the influence of the

structural and physicochemical characteristics of GO on its biological behavior, an aspect that is

essential for the appropriate interpretation of experimental findings.

Osteogenic differentiation represents one of the applications with the strongest

experimental support. Park et al. (2021) demonstrated that a poly(ε-caprolactone) scaffold

coated with GO enhanced the adhesion, proliferation, and mineralization of periodontal ligament

stem cells, whereas An et al. (2024) observed that GO quantum dots promoted the osteogenic

differentiation of periodontal ligament stem cells through mechanisms associated with

mitochondrial dynamics. These findings support the potential use of GO as a bioactive

component of matrices designed for periodontal and bone regeneration. Complementarily, Qin

et al. (2022) and Alazab et al. (2023) demonstrated the potential of GO-based collagen and PCL

composite scaffolds, respectively, for bone-regeneration applications.

In dentin–pulp regeneration, Qiu et al. (2024) demonstrated that a GO/poly-L-lactic acid

scaffold could favorably modulate the biological properties of human dental pulp stem cells.

These findings suggest that GO may contribute to the development of microenvironments

conducive to processes associated with odontogenesis and mineralization. Nevertheless, the

expression of odontogenic markers or the formation of mineralized deposits must be

distinguished from complete functional regeneration of the dentin–pulp complex. Therefore,

further in vivo studies are required to evaluate tissue organization, vascularization, and

maintenance of pulp vitality.

Another relevant application involves controlled-release systems. Jeong et al. (2022)

developed a GO/polyvinylpyrrolidone-based system incorporated into a PCL scaffold, which

enabled BMP-2 release and stimulated mineralization processes. This strategy is particularly

attractive for bone regeneration because it combines structural support with localized delivery of

bioactive factors. However, demonstration of controlled release in vitro does not, by itself,

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guarantee therapeutic efficacy in vivo. Parameters such as release kinetics, stability,

biodistribution, and formulation safety must therefore be determined.

The ability of GO to combine regenerative and antibacterial properties represents a

potential advantage for dentistry. Radunovic et al. (2022) demonstrated antibiofilm activity on

GO-functionalized titanium discs and collagen membranes, whereas Huang et al. (2024)

developed GO coatings on PEEK with enhanced bactericidal and osteogenic properties.

Similarly, Al-Noaman and Rawlinson (2023) evaluated a bioactive glass/GO coating for dental

implants. These findings suggest that GO may serve as a multifunctional platform capable of

controlling bacterial colonization while simultaneously promoting biomaterial–tissue interactions.

The evidence becomes particularly relevant when specifically considering canine veterinary

medicine. Miyaji et al. (2016) demonstrated that a GO-modified collagen scaffold promoted

bone formation in post-extraction dental sockets in dogs. Subsequently, Kawamoto et al. (2018)

evaluated a GO-based scaffold in periodontal furcation defects in dogs and observed the

formation of alveolar bone and tissues compatible with cementum and periodontal ligament. In

turn, Qian et al. (2020) demonstrated that minocycline-loaded GO films could reduce marginal

bone loss and the inflammatory response in a canine model of peri-implantitis. These three

studies constitute particularly relevant evidence because they demonstrate that effects

observed in cellular models can, at least partially, translate to the oral tissues of dogs.

However, these findings also highlight the principal translational gap identified in this

review. Research on GO in dentistry is dominated by in vitro studies and laboratory animal

models, whereas canine-specific evidence remains limited. The studies by Miyaji et al. (2016),

Kawamoto et al. (2018), and Qian et al. (2020) represent important advances but are insufficient

to establish veterinary clinical protocols. Furthermore, the heterogeneity of GO formulations

makes comparisons across studies difficult and hinders the identification of optimal

concentrations and physicochemical characteristics.

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Consequently, GO can currently be considered a promising but still experimental

biomaterial for canine veterinary dentistry. Its greatest potential appears to lie in multifunctional

systems integrating structural support, antibacterial activity, osteogenic or odontogenic

stimulation, and localized delivery of therapeutic agents. Future research should prioritize

canine preclinical models, physicochemically standardized formulations, long-term follow-up,

and the simultaneous assessment of safety, inflammatory responses, tissue regeneration, and

microbial control. Such an approach will be essential to determine whether the substantial body

of experimental evidence accumulated on GO can ultimately be translated into safe and

effective clinical applications in canine veterinary medicine.

CONCLUSIONS

The accumulated scientific evidence supports classifying the use of graphene oxide

(GO) and its hybrid nanocomposites in canine veterinary dentistry as a disruptive preclinical

technology at the proof-of-concept stage, characterized by high bioactive potential but still

insufficient clinical validation.

Multifunctional Bioactive Platform: Findings from in vitro studies and laboratory animal

models confirm that GO extends beyond the role of a passive mechanical reinforcement. It acts

as an instructive microenvironment capable of modulating osteogenesis, promoting regenerative

immunomodulation through M1-to-M2 macrophage polarization, preventing multispecies biofilm

formation, and controlling the release kinetics of growth factors (e.g., BMP-2 and VEGF) and

antimicrobial agents.

Limited Canine Preclinical Evidence: Although early in vivo milestones have

demonstrated the efficacy of GO-based matrices for preservation of post-extraction alveolar

bone, regeneration of the periodontal ligament and cementum in furcation defects, and

attenuation of marginal bone loss in experimental peri-implantitis, the dog-specific literature is

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characterized by marked temporal discontinuity and lacks contemporary studies published after

2022.

Biological and Methodological Gap: A critical disconnect persists between the expansion

of GO biomaterial synthesis and its in vivo validation. The physicochemical heterogeneity of the

nanomaterial (C/O ratio, lateral sheet size, and purity), the lack of standardized therapeutic

doses, the absence of long-term immunosafety and clearance data, and the divergence

between human bacterial models and interactions with the canine periodontal microbiome,

particularly Porphyromonas gulae, represent the principal barriers to establishing clinically

applicable protocols.

Declaration of conflict of interest

The author declares no conflict of interest related to this research.

Declaration of authorship contribution

Segundo Fabricio Mera Juaregui: Conceptualization, data curation, formal analysis,

investigation, methodology, project administration, validation, visualization, writing – original

draft, and writing – review and editing.

Artificial Intelligence Usage Statement

The author declare that they used Artificial Intelligence as support for this article, and

also that this tool does not replace the intellectual task or process in any way. After rigorous

reviews with different tools in which it was verified that there is no plagiarism as evidenced in

the evidence, the authors state and acknowledge that this work was the product of their own

intellectual work, that it has not been written or published on any electronic or AI platform.

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