3D-printed polycaprolactone scaffolds functionalized with poly(lactic-co-glycolic) acid microparticles enhance bone regeneration through tunable drug release

Numerous tissue engineering strategies aim to enable the in situ and controlled release of both cells and biologically relevant factors, mimicking physiological regenerative processes. A notable example is the release of rhBMP-2 for treating bone nonunion. By adopting a quasi-physiological approach, we can mitigate the side effects that have hindered its clinical application. Here, we present a customizable 3D-printed polycaprolactone (PCL) scaffold functionalized with poly(lactic-co-glycolic) acid (PLGA) microparticles through covalent binding, designed to mimic the periosteum structure. This scaffold was then functionalized with PLGA microparticles through covalent binding, enabling in situ delivery of rhBMP-2. This construct exhibits significant osteogenic and osteoinductive potential in vitro, promoting the differentiation of periosteum-derived mesenchymal progenitor cells into osteoblasts. Moreover, in vivo testing using a nonunion model (critical size defect) demonstrated therapeutic efficacy with a reduced net morphogen dose. Therefore, this customizable 3D scaffold represents a valuable approach for enhancing bone regeneration and holds significant potential for promoting healing in cases of nonunion fractures. This approach combines a customizable 3D scaffold with controlled rhBMP-2 release, offering a potentially more effective and safer solution for bone regeneration compared to current methods. STATEMENT OF SIGNIFICANCE: As the incidence of bone fractures continues to rise, nonunion remains a significant challenge in orthopedics, becoming a major clinical and economic burden. We present a tissue engineering strategy employing a customizable 3D-printed polycaprolactone scaffold functionalized with covalently bound poly(lactic-co-glycolic acid) microparticles for the localized release of rhBMP-2. By mimicking key features of the periosteum, this scaffold promotes bone regeneration while minimizing the risk of ectopic bone formation. In vivo tests conducted in a critical-size defect model demonstrated effective bone bridging, highlighting the therapeutic potential of the scaffold. The simple manufacturing process, potential for scale-up production, long-term storage capability, and options for customization, including combinations of different molecules or adjuvants, demonstrate that this approach possesses significant translational potential.