Inhibition of Sympathetic Activation by Delivering Calcium Channel Blockers from a 3D Printed Scaffold to Promote Bone Defect Repair

Enhancing osteogenesis by promoting neural network reconstruction and neuropeptide release is considered to be an attractive strategy for repairing of critical size bone defects. However, traumatic bone defects often activate the damaged sympathetic nervous system (SNS) in the defect area and release excessive catecholamine to hinder bone defect repair. Herein, a 3D printed scaffold loaded with the calcium channel blocker-nifedipine is proposed to reduce the concentration of catecholamine present in the bone defect region and to accelerate bone healing. To this end, nifedipine-loaded ethosome and laponite are added into a mixed solution containing sodium alginate, methacrylated gelatin, and bone mesenchymal stem cells (BMSCs) to prepare a cell-laden scaffold using 3D bioprinting. The released nifedipine is able to close the calcium channels of nerve cells, thereby blocking sympathetic activation and ultimately inhibiting the release of catecholamine by sympathetic nerve cells, which further promotes the osteogenic differentiation and migration of BMSCs, inhibits osteoclastogenesis in vitro, and effectively improves bone regeneration in a rat critical-size calvarial defect model. Therefore, the results suggest that sustained release of nifedipine from the scaffold can effectively block SNS activation, providing promising strategies for future treatment of bone defects.