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

Intermittent delivery of parathyroid hormone (PTH) couldeffectivelypromote bone regeneration, but the need for daily injection administrationhas limited its further clinical applications. Exposure to magneticstimulation could regulate cell fate to promote osteogenesis. Herein,we developed a magnetized hydrogel with programmed PTH release andsimultaneous magnetic actuation to promote osteogenic commitment.Ag dual-cross-linked hydrogel was formulated as GelMA-PVA (GP) biphasic reservoir with magnetic nanoparticles (GPM) andPTH (GPMP). Macroscopic and microscopic characterizations were performedto optimize the formulations. In vitro release assessmentconfirmed the programmable release of PTH with a pulsatile profileprimed via magnetization in the first 4 days anda sustained release, controlled by an optimized GP matrix, for overa month. Stimulated by an alternating magnetic field, the hydrogelsdisplayed a zigzag-shaped pulsatile release profile, and the cumulativerelease was enhanced by 8, 28, and 18% in In40, Ab40, and In20Ab20(loading 40 & mu;g PTH via incorporation, absorption,and their combination) formulations, respectively, compared with thesame formulations without magnetic stimulation. An in vitro cytocompatibility test showed that all formulations were biocompatibleand that PTH addition significantly promoted the proliferation ofMC3T3-E1 pre-osteoblasts. In vivo studies presentedenhanced new bone regeneration with significantly improved bone volumeand bone mineral density in GPM and GPMP groups (increased by 120and 251% compared with those of non-treated control), confirming theirosteogenic effects and accelerated bone healing. This newly developedGPMP sample provides simultaneous osteogenesis effects via the programmed release of PTH and magnetically promoted bone regenerationand is promising in the facilitation of bone healing and treatmentof various delayed/non-union conditions without the burden of dailyinjection.