Dual-Drug Delivery via Zein In Situ Forming Implants Augmented with Titanium-Doped Bioactive Glass for Bone Regeneration: Preparation, In Vitro Characterization, and In Vivo Evaluation.

In situ forming implants (IFIs) are non-surgical approach using biodegradable polymers to treat bone fractures. The study aimed at preparing dual-drug-loaded IFIs to deliver pitavastatin (osteogenic drug) and tedizolid (antibiotic) using zein as the implant matrix via solvent-induced phase inversion method. At first, several investigations were done on pitavastatin-loaded zein IFIs, where three concentrations of zein were used (10, 20, and 30% w/v ). IFIs were evaluated for their solidification time, rheological properties, injectability, and in vitro release. IFIs containing bioactive glass nanoparticles were prepared by the addition of non-doped bioactive glass nanoparticles (BGT 0 ; 1, 3, 5, and 10% w/v ) or titanium-doped bioactive glass nanoparticles (BGT 5 ; 1% w/v ) to the selected concentration of zein (30% w/v ) and then evaluated. The optimized dual-medicated implant (D-ZIFI 1) containing pitavastatin, tedizolid, sodium hyaluronate (3% w/v ), and BGT 5 (1% w/v ) was prepared and compared to IFI lacking both sodium hyaluronate and BGT 5 (D-ZIFI 2). D-ZIFI 1 and 2 sustained the release profiles of both drugs for 28 days. SEM images proved the interconnected porous structure of D-ZIFI 1 due to sodium hyaluronate. In vivo studies on surgically induced bone defects in Sprague-Dawley rats signified the proper accelerated bone healing ability of D-ZIFI 1 over D-ZIFI 2. Results presented D-ZIFI 1 as a promising, effective, non-surgical approach for bone healing.