Dual and sequential drug delivery systems with antimicrobial and bone regenerative therapeutic effects

Abstract

Bone defect healing is often compromised by infections acquired during surgery, hindering regeneration. An effective solution should first prevent infection and then promote bone repair. Localised drug-delivery systems capable of dual and sequential release of antimicrobial and bone-regenerative agents represent a promising solution; however, precisely controlling this sequential release remains an unmet challenge. To address this issue, this study explores a novel approach by developing delivery systems based on either hollow or non-hollow porous bioceramics with an alginate hydrogel matrix, resulting in cutting-edge systems with a controlled, stage-specific release of antimicrobial and bone regenerative agents that meet the clinical needs. Gentamicin served as the antimicrobial agent, while raloxifene and/or alendronate represented hydrophobic and hydrophilic bone-regenerative agents. The systems were evaluated for release profiles, kinetic modelling, and the effects of lyophilisation and sterilisation (using ethylene oxide or supercritical CO₂) on drug stability and release kinetics. The release followed a precise dual-sequential pattern: gentamicin was released over 2–3 weeks, followed by another 2–3 weeks of bone-regenerative agents. Kinetic model fitting showed that gentamicin release was driven mainly by diffusion (with or without hydrogel swelling), and raloxifene/alendronate release was dominated by a mixture of diffusion and polymeric matrix swelling/erosion. Lyophilisation and sterilisation preserved release profiles, though timeframes shifted slightly, with supercritical CO₂ causing minimal delay. Gentamicin retained strong antimicrobial activity post-processing, confirming the system's potential for infection control and bone repair.