Graphene-Based 3D Scaffolds in Bone Regeneration: Emerging Opportunities for MRONJ Treatment

: Background: Medication-related osteonecrosis of the jaw (MRONJ) remains a challenging complication associated with antiresorptive and antiangiogenic therapies, characterized by impaired bone healing, infection, and compromised vascularization. Advanced biomaterials capable of promoting bone regeneration and modulating the local microenvironment are being investigated as potential therapeutic strategies. Graphene-based biomaterials have recently emerged as promising candidates due to their unique physicochemical properties and multifunctional biological effects. Objective: This systematic review aimed to analyze and synthesize current evidence on graphene-based 3D scaffolds and related graphene-based biomaterials for bone regeneration, with particular attention to their potential relevance in MRONJ treatment and prevention. Data Sources: A systematic literature search was conducted in PubMed and Scopus databases, complemented by manual screening of reference lists from relevant publications. Eligibility Criteria: Studies investigating graphene-based scaffolds, composites, or graphene-derived biomaterials for bone regeneration were considered. Experimental in vitro and in vivo studies, as well as translational studies addressing osteogenesis, angiogenesis, antimicrobial activity, immunomodulation, or drug-delivery properties relevant to bone healing and MRONJ, were included. Editorials, conference abstracts, and non-English publications were excluded. Methods: Titles and abstracts were independently screened by the authors, followed by full-text assessment for eligibility. Data regarding scaffold composition, graphene derivatives, biological mechanisms, and regenerative outcomes were qualitatively synthesized due to heterogeneity in study designs and outcome measures. Results: The identified literature highlights the multifaceted role of graphene-based biomaterials in bone regeneration. Graphene and its derivatives enhance osteogenic differentiation, promote angiogenesis, modulate immune responses, and exhibit intrinsic antimicrobial properties. In addition, graphene-based scaffolds provide versatile platforms for drug delivery and photothermal or photodynamic therapeutic strategies. These multifunctional properties may address key pathophysiological mechanisms involved in MRONJ, including impaired bone remodeling, infection control, and tissue regeneration. Limitations: The available evidence is predominantly derived from preclinical studies, with limited direct investigation in MRONJ-specific models and considerable heterogeneity in scaffold design and experimental methodologies. Conclusions: Graphene-based 3D scaffolds represent a promising and versatile platform for bone regenerative strategies potentially applicable to MRONJ management. Further translational research and well-designed preclinical and clinical studies are required to clarify their safety, efficacy, and therapeutic applicability. Registration: This review was conducted according to PRISMA 2020 guidelines. The review protocol was not registered.