Anionic Citrate‐Based 3D‐Printed Scaffolds for Tunable and Sustained Orthobiologic Delivery to Enhance Tissue Regeneration

Abstract Sustained and controlled release systems for orthobiologics enhance therapeutic efficacy by enabling precise biomolecule delivery. While bone morphogenetic protein‐2 (BMP‐2) in combination with bone grafts has shown promise in orthopedic applications, adverse effects related to the burst release of supraphysiological doses limit its clinical utility. To address this challenge, a novel anionic citrate‐based 3D‐printed scaffold was developed designed to sequester and localize orthobiologic activity at the target site, allowing effective delivery at significantly lower concentrations. Composed of an anionic citrate‐based polymer and β‐tricalcium phosphate (β‐TCP), the 3D‐printed scaffold features a hierarchical porous structure that enhances protein binding, cell infiltration, and nutrient exchange. Using BMP‐2 as a model orthobiologic, in vitro studies confirmed its strong protein binding, sustained release, cytocompatibility, and osteogenic gene activation. Furthermore, in a comprehensive rabbit posterolateral fusion study, the scaffold's localized BMP‐2 promoted osteogenic differentiation and bone fusion was demonstrated at doses ≈45‐fold lower than current clinical applications. This study advances orthopedic regenerative engineering by providing a safe and effective platform for controlled orthobiologic delivery in complex tissue reconstruction, such as spinal fusion.