With population aging, the incidence of osteoporosis continuously elevates worldwide, resulting in increased fracture risks and clinical demand for orthopedic fixation. However, under osteoporotic conditions, the stability and longevity of implants are severely compromised by the pathological microenvironment, thus developing effective therapeutic interventions to achieve successful osteoporotic osseointegration remains a critical challenge in the regenerative medicine field. Herein, the parathyroid hormone (PTH) is encapsulated in Sr2+/Zn2+ co-doped mesoporous silica nanoparticles (SrZn-MSNs) to synthesize P@SrZn-MSNs, which are then incorporated into gelatin methacrylate (GelMA) containing calcitonin gene related peptide (CGRP) for realizing bioactive ions/drugs co-delivery. The obtained Gel/P@SrZn-MSNs/G nanocomposite hydrogels are characterized by excellent injectability and photosensitivity, 3D interconnected porous architecture, durable degradation and concurrent releasing of Si/Sr/Zn ions, CGRP and PTH controlled within proper doses. These favorable properties endow Gel/P@SrZn-MSNs/G with superior biological multifunctionality that not only promotes functionality of DRG sensory neurons and BMSCs directly, but also manipulates mutually beneficial interactions of DRG/BMSCs to further stimulate neurogenesis/osteogenesis. Specifically, Gel/P@SrZn-MSNs/G mainly increases NGF and BDNF expressions in BMSCs to stimulate axonal outgrowth and activation of DRG neurons, and in turn, the up-regulation of Sema3A in DRG neurons could be responsible for the neuro-inductive osteogenesis. Consistently, the in vivo outcomes further validate the potent and timely peri-implant innervation and bone formation induced by Gel/P@SrZn-MSNs/G when applied to femoral condyle defects of OVX rats. These results highlight the efficient ions/drugs co-delivery system renders Gel/P@SrZn-MSNs/G exerting synergy bioeffects to orchestrate desired neuro-osteogenic niches for boosting osteoporotic osseointegration, thus may inspiring new therapeutic strategies for osteoporotic bone healing.
Jin et al. (Tue,) studied this question.