Sustained Release of Carvacrol Aldehyde from Hydroxyapatite for Osteosarcoma Inhibition

The clinical management of bone cancer and infections remains a critical challenge due to limitations in localized drug delivery and rising antibiotic resistance. In our previous studies, we demonstrated carvacrol's (CA) osteogenic and antibacterial potential when loaded onto 3D-printed TCP scaffolds. However, the rapid release and limited retention of CA restricted long-term efficacy. Herein, we develop a hydroxyapatite (HA) substrate to locally deliver CA and its aldehyde derivative (carvacrol aldehyde) (CA-CHO) to enhance its biological properties. CA-CHO is synthesized via SnCl₂-mediated ortho-formylation, introducing an aldehyde (-CHO) group that modulates drug-substrate interactions. Drug release kinetics exhibit a biphasic pattern, with CA showing 90% release, while CA-CHO demonstrates a controlled 50% release, within 10 days. Cell viability confirms that CA-CHO is not cytotoxic to osteoblast cells. JC-1 staining shows mitochondrial depolarization in osteosarcoma cells, leading to an ∼8-fold reduction in cell viability by day 11 compared to the HA. CA-CHO showed >90% inhibition of Staphylococcus aureus (S. aureus) at 72 h, compared to CA. This approach offers a biodegradable, antibiotic-free coating for orthopedic implants that simultaneously prevents infection and suppresses osteosarcoma recurrence.