Microfluidic-based intra-articular sustained release of triamcinolone acetonide microsphere-gel composite system

Objective This study presents a novel injectable microsphere-gel system for sustained intra-articular delivery of triamcinolone acetonide (TA) to treat osteoarthritis.Significance This system aims to overcome the shortcomings of conventional TA suspensions, such as short joint residence time and significant systemic exposure, thereby improving therapeutic efficacy and safety for osteoarthritis treatment.Methods TA-loaded polycaprolactone (PCL) microspheres (TA@PCL) were prepared using microfluidic technology under optimized conditions. The TA@PCL microspheres were incorporated into the cross-linked hyaluronic acid (CLHA) gel matrix to form an injectable composite (TA@PCL@CLHA), which was evaluated by in vitro studies (rheological property, stability, and drug release) and in vivo studies (plasma pharmacokinetics and drug retention in knee joints).Results TA@PCL microspheres with uniform size (D50 value of 61.4 ± 1.9 µm, span value of 0.075) and high encapsulation efficiency (87.2 ± 4.1%) were successfully prepared. The TA@PCL@CLHA composite exhibited excellent injectability (extrusion force of 12.1 ± 0.4 N) and physical stability over 90 days. In vitro, the CLHA gel effectively mitigated the initial burst release and provided a more sustained TA release profile over one month. In vivo evaluation in rabbits demonstrated that TA@PCL@CLHA significantly reduced the peak plasma concentration (Cmax reduced by approximately 65%) and decreased systemic exposure (AUC0-∞ reduced by about 49%), while maintaining detectable drug levels in the synovial fluid for at least 30 days.Conclusion The TA@PCL@CLHA microsphere-gel composite provides an effective local drug delivery system with minimized systemic exposure, offering a promising strategy for OA treatment.