Osteoporosis bone defect is a refractory orthopaedic disease which characterized by impaired bone quality and bone regeneration capacity. Current therapies, including antiosteoporosis drugs and artificial bone grafts, are not always satisfactory. Herein, a strontium-substituted calcium phosphate silicate bioactive ceramic (Sr-CPS) was fabricated. In the present study, the extracts of Sr-CPS were prepared for in vitro study and Sr-CPS scaffolds were used for in vivo study. The cytocompatibility, osteogenic and osteoclastogenic properties of Sr-CPS extracts were characterized in comparison to CPS. Molecular mechanisms were also evaluated by Western blot. Sr-CPS extracts were found to promote osteogenesis by upregulating Wnt/β-catenin signal pathways and inhibit osteoclastogenesis through downregulating NF-κB signal pathway. In vivo, micro-CT, histological and histomorphometric observation were conducted after 8 weeks of implantation to evaluate the bone formation using calvarial defects model in ovariectomized rats. Compared with CPS, Sr-CPS significantly promoted critical sized ovariectomy (OVX) calvarial defects healing. Among all the samples, Sr-10 showed the best performance due to a perfect match of bone formation and scaffold degradation rates. Overall, the present study demonstrated that Sr-CPS ceramic can dually modulate both bone formation and resorption, which might be a promising candidate for the reconstruction of osteoporotic bone defect.

As an innovative regenerative medicine technology, bone organoids represent a promising therapy for refractory bone injury repair, whereas the key to fabricating bone organoids is grounded in the utilization of biomaterials with osteogenesis cues. Considering the intricate crosstalk between neurons and osteocytes would support bone organoid development and bone wound healing, it is extremely essential to predicate biomaterial design and osteo-organoid construction on understanding the roles of neural growth in ossification center formation and bone-like tissue development. Therefore, this review presents the recent advances of bone organoids with innervated ossification centers after the detailed introduction in the nerve–bone crosstalk. Beginning with the exploration of underlying interaction mechanisms within the osteogenic microenvironment, the importance of the nerve–bone crosstalk on skeleton development and bone regeneration is emphasized at first. The following discussions mainly include diverse biomaterial strategies designed to enhance osteogenesis through early innervation, such as the incorporation of bioactive minerals, controlled release of neurotrophic factors, and exosome-mediated nerve regeneration. Last but not least, the review highlights the advanced technologies in fabricating tissue-engineered bone organoids, with a focus on the applications of cell-laden and multicellular 3D-bioprinted bone microtissues for constructing bone organoids with neurovascularization. These insights are critical to the development of novel biomaterials to construct innervated osteo-organoids, with significant implications for future clinical applications, while also exploring the potential to advance bone regenerative therapies through enhanced nerve–bone crosstalk and laying the foundation for innovative translational research in this field.

The intervertebral administration of anti-inflammatory drugs is a promising local delivery approach to the intervertebral disc integrity restoration for treatment of intervertebral disc degeneration (IVDD), whereas the fast drug clearance in an intervertebral space is always a troublesome issue for the local drug delivery. In this study, we have developed a zeolitic imidazolate framework 8 (ZIF-8) nanoplatform with pH-sensitive property to load melatonin molecules (MT), a hormone with anti-inflammatory and anti-oxidative effects. Thus-synthesized MT@ZIF-8 nanoparticles not only showed good cytocompatibility and pH-dependent drug releasing behavior, but also effectively decreased the intracellular reactive oxygen species level and inhibited the pro-inflammatory cytokine expression for in vitro nucleus pulposus cell (NPC) culture under lipopolysaccharide (LPS) stimulus. Additionally, it was found that NF-κB and MAPK signal pathways are significantly suppressed by the MT@ZIF-8 nanoparticles for the LPS-treated NPCs, revealing the underlying mechanism of restoring extracellular matrix synthesis of the LPS-treated NPCs by the MT@ZIF-8 nanoparticles. Last but not least, the recovery of intervertebral disc components and integrity were observed on a rat caudal IVDD model after injection of the MT@ZIF-8 nanoparticles into the intervertebral space. In brief, this work offered a promising local delivery strategy and a controlled releasing nanoplatform for the applications of melatonin in the IVDD therapy, which we think may have beneficial effects for future clinical treatment of low back pain caused by the IVDD.