Bioactive hydrogels with macrophage-derived extracellular vesicles: an immunomodulatory and osteoinductive approach for critical bone defect repair.

• Grant number: 25/03116-7
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2026
• End date: January 31, 2029
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Elizabeth Ferreira Martinez
• Grantee: Elizabeth Ferreira Martinez
• Host Institution: Centro de Pesquisas Odontológicas São Leopoldo Mandic. Faculdade São Leopoldo Mandic (SLMANDIC). Campinas , SP, Brazil
• City of the host institution: Campinas
• Associated researchers: Lucas Novaes Teixeira ; Lucia Helena Innocentini Mei ; Marco Cicero Bottino ; Tahmasb Hatami

Abstract

Bone regeneration in critical defects is a significant challenge in regenerative medicine due to the complexity of the repair process and the limitations of conventional therapies. This study proposes an innovative therapeutic approach using bioactive hydrogels combined with extracellular vesicles (EV) derived from M0, M1, and M2 macrophages as a novel therapeutic strategy to modulate the inflammatory microenvironment and promote bone regeneration. EV play an important role in intercellular communication, transporting bioactive molecules that can modulate the inflammatory microenvironment and favor the healing process. To explore this potential, in this study, EVs from different macrophage variants (M0, M1, and M2) will be associated with hydrogels, and their effectiveness in repairing critical bone defects will be assessed in an experimental rat calvarial model. Hydrogels were selected as the matrix to carry the EV due to their biocompatibility, injectability, and capacity for controlled release of bioactive agents, which are ideal for improving osteoinduction. A thermosensitive hydrogel based on chitosan and poloxamer 407, associated with the disodium salt of beta-glycerol phosphate, will be manufactured to improve its injectability and suitability for bone repair. Nanomaterials, such as zinc oxide nanoparticles, cellulose nanofibers, and graphene nanosheets, will be incorporated to improve their mechanical properties, as well as optimize their efficiency in releasing EV and bioactive factors. The characterization of the hydrogels will include the analysis of physicochemical and biological properties, such as degree of cross-linking, mechanical properties (rheology), gelation time, swelling capacity, thermal stability (TGA), and morphology (SEM and AFM). The potential of the hydrogel to optimize bone neoformation in vitro and in vivo will be evaluated. The results may represent a promising solution for tissue engineering, combining immunomodulation and osteoinduction strategies with potential clinical applications in repairing critical bone defects. (AU)