Document Type : Review article
Authors
1
Cancer Epidemiology Research Center, AJA University of Medical Sciences, Tehran, Iran.
2
Medical Biotechnology Research Center, AJA University of Medical Sciences, Tehran, Iran.
3
School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran. & Department of Oral and Maxillofacial Surgery, TD.C., Islamic Azad University, Tehran, Iran.
4
Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran.
5
Department of Orthopedic Surgery, TMS.C., Islamic Azad University, Tehran, Iran.
6
Department of Orthopedics, School of Medicine, AJA University of Medical Sciences Tehran, Iran.
7
Trauma and Surgery Research Center, AJA University of Medical Science, Tehran, Iran. & Biomaterial and Medicinal Chemistry Research Center, Aja University of Medical Science, Tehran, Iran.
Abstract
Background: Bone regeneration remains a major challenge in regenerative medicine because successful repair requires the coordinated regulation of osteogenesis, angiogenesis, and immune responses within complex defect microenvironments. Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as promising acellular therapeutic agents capable of reproducing many of the regenerative effects of stem and progenitor cells while reducing the risks associated with cell-based therapies.
Methods: This narrative review synthesizes current evidence on the biological functions, cellular sources, engineering strategies, and therapeutic applications of EVs in bone regeneration. Relevant studies published between 2015 and 2025 were reviewed, focusing on molecular mechanisms, bioengineering approaches, disease-specific applications, and translational challenges associated with EV-based therapies.
Results: EVs derived from diverse sources, including bone marrow, adipose tissue, dental pulp, muscle cells, and gut microbiota, were shown to promote bone regeneration through the delivery of bioactive proteins, lipids, nucleic acids, and metabolites. These vesicles regulate key regenerative pathways, including PI3K/AKT, BMP/Smad/RUNX2, Wnt/β-catenin, TGF-β1/Smad/MAPK, and microRNA-mediated signaling. EVs enhance osteogenesis, stimulate angiogenic–osteogenic coupling, modulate macrophage polarization toward a reparative M2 phenotype, and improve bone healing under aging, diabetic, and osteoporotic conditions. Advanced bioengineering strategies, such as scaffold functionalization, hydrogels, nanoparticle conjugation, and genetic engineering, further improve EV targeting, retention, and controlled release. Preclinical studies demonstrate substantial regenerative benefits across a range of musculoskeletal disorders.
Conclusion: EV-based therapies represent a promising and versatile platform for bone regeneration by integrating osteogenic, angiogenic, and immunomodulatory functions within a cell-free therapeutic framework. Although significant challenges remain, including standardization of EV isolation, scalable manufacturing, potency assessment, and clinical reproducibility, ongoing advances in bioengineering and precision medicine may accelerate the translation of EV-based therapeutics into clinical practice for musculoskeletal repair.
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