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

Abstract

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.

Unveiling the versatility of gelatin methacryloyl hydrogels: a comprehensive journey into biomedical applications

“…In vitro assessments verified the controlled release of programmed PTH with a pulsatile profile within the initial four days, pursued by sustained release for more than 30 d. Magnetic stimulation under an alternating magnetic field induced a pulsatile release profile with a zigzag shape, promoting cumulative release in contrast to non-stimulated formulations. In vivo assays demonstrated improved regeneration of new bone with substantially enhanced volume of bone and mineral density of bone in GPM and GPMP groups, underscoring the potential for osteogenic effects and accelerated healing of bone without the requirement for daily injections [115].…”

Enzyme-Mineralized PVASA Hydrogels with Combined Toughness and Strength for Bone Tissue Engineering

“…To address these issues, we selected the PVA system, a hydrophilic and biocompatible system ideal for tissue engineering applications, ,, and integrated SA into the system to form a double-network structure. The structural advantages of the PVASA system over the PVA one are observed in terms of the continued existence of pores, the smaller size of mineralized particles (230 vs 529 nm), and uniformly distributed mineralized particles (throughout the sample vs mostly at the edge region) during enzymatic mineralization.…”

“…Different approaches have been adopted to enhance the mechanical properties of the PVA hydrogels, including multinetwork hydrogels, nanoparticle composite, in situ mineralization, salting out, etc. (Table S1).…”

“…Due to its hydrophilic properties and biocompatibility, − poly­(vinyl alcohol) (PVA) has been widely used for medical applications such as wound dressing, artificial vessels, and bone repair. , However, like other hydrogels, the PVA hydrogels have poor mechanical strength, which limits their usage in tissue engineering applications. There have been many strengthening strategies adopted for PVA, such as freeze–thawing, mineralization, , nanocomposite, interpenetrating double-network hydrogels, , etc.…”

Fostering tissue engineering and regenerative medicine to treat musculoskeletal disorders in bone and muscle

“…Magnetic nanoparticles, when used alone or combined with a magnetic field, are promising for bone tissue engineering applications. Magnetic nanoparticles can substantially modify and improve the three critical factors in bone regeneration - stem cells, scaffolds, and growth factors [ 162 ]. Magnetic scaffolds can be prepared using magnetic nanoparticles and magnetic fields; a magnetic field can enhance the cells via up- and down-regulation of the PPAR signal transduction and JAK-STAT pathway, respectively ( Fig.…”