Pentoxifylline and tocopherol in bioactive scaffolds modulate osteogenesis-related markers in osteoblast cultures

Pentoxifylline and tocopherol are widely used as adjunctive therapies for osteoradionecrosis and medication-related osteonecrosis of the jaw; however, their direct effects on osteoblasts remain unclear, particularly when incorporated into biomaterial-based scaffolds. This study investigated the effects of these drugs incorporated into bioactive scaffolds on osteoblastic behavior. Molecular docking simulations were initially performed to evaluate potential interactions with bone-related proteins, followed by analysis of osteogenesis-related mRNA expression. Subsequently, scaffolds composed of polyethylene glycol (PEG) and polycaprolactone (PCL) loaded with pentoxifylline and tocopherol were evaluated for irritation potential using the HET-CAM assay and tested in murine osteoblast cultures. Cellular metabolic activity, alkaline phosphatase (ALP) activity, and mineralization were assessed. Exploratory molecular docking predicted favorable binding affinities of both compounds to BMP2, RANKL, and GSK3β. The combined treatment preserved cell viability, modulated ALP activity, and increased mineralized matrix formation. Gene expression analysis showed increased BMP2 and Frizzled mRNA expression and reduced RANKL, OPG, and GSK3β mRNA expression. In addition, the scaffolds were classified as non-irritating in the HET-CAM assay under the experimental conditions evaluated. The findings suggest that PEG/PCL scaffolds loaded with pentoxifylline and α-tocopherol support further investigation as a biomaterial-based approach for bone regeneration.