Dual-Cross-Linked Magnetic Hydrogel with Programmed Release of Parathyroid Hormone Promotes Bone Healing.

Intermittent delivery of parathyroid hormone (PTH) could effectively promote bone regeneration, but the need for daily injection administration has limited its further clinical applications. Exposure to magnetic stimulation could regulate cell fate to promote osteogenesis. Herein, we developed a magnetized hydrogel with programmed PTH release and simultaneous magnetic actuation to promote osteogenic commitment. Ag dual-cross-linked hydrogel was formulated as GelMA - PVA (GP) biphasic reservoir with magnetic nanoparticles (GPM) and PTH (GPMP). Macroscopic and microscopic characterizations were performed to optimize the formulations. In vitro release assessment confirmed the programmable release of PTH with a pulsatile profile primed via magnetization in the first 4 days and a sustained release, controlled by an optimized GP matrix, for over a month. Stimulated by an alternating magnetic field, the hydrogels displayed a zigzag-shaped pulsatile release profile, and the cumulative release was enhanced by 8, 28, and 18% in In40, Ab40, and In20Ab20 (loading 40 μg PTH via incorporation, absorption, and their combination) formulations, respectively, compared with the same formulations without magnetic stimulation. An in vitro cytocompatibility test showed that all formulations were biocompatible and that PTH addition significantly promoted the proliferation of MC3T3-E1 pre-osteoblasts. In vivo studies presented enhanced new bone regeneration with significantly improved bone volume and bone mineral density in GPM and GPMP groups (increased by 120 and 251% compared with those of non-treated control), confirming their osteogenic effects and accelerated bone healing. This newly developed GPMP sample provides simultaneous osteogenesis effects via the programmed release of PTH and magnetically promoted bone regeneration and is promising in the facilitation of bone healing and treatment of various delayed/non-union conditions without the burden of daily injection.