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Circadian rhythm (CR) disruption contributes to tumor initiation and progression, however the pharmacological targeting of circadian regulators reversely inhibits tumor growth. Precisely controlling CR in tumor cells is urgently required to investigate the exact role of CR interruption in tumor therapy. Herein, based on KL001, a small molecule that specifically interacts with the clock gene cryptochrome (CRY) functioning at disruption of CR, we fabricated a hollow MnO 2 nanocapsule carrying KL001 and photosensitizer BODIPY with the modification of alendronate (ALD) on the surface (H-MnSiO/K&B-ALD) for osteosarcoma (OS) targeting. The H-MnSiO/K&B-ALD nanoparticles reduced the CR amplitude in OS cells without affecting cell proliferation. Furthermore, nanoparticles-controlled oxygen consumption by inhibiting mitochondrial respiration via CR disruption, thus partially overcoming the hypoxia limitation for photodynamic therapy (PDT) and significantly promoting PDT efficacy. An orthotopic OS model demonstrated that KL001 significantly enhanced the inhibitory effect of H-MnSiO/K&B-ALD nanoparticles on tumor growth after laser irradiation. CR disruption and oxygen level enhancement induced by H-MnSiO/K&B-ALD nanoparticles under laser irradiation were also confirmed in vivo. This discovery first demonstrated the potential of CR controlling for tumor PDT ablation and provided a promising strategy for overcoming tumor hypoxia., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Study Design: This is an experimental animal study., Objective: The objective of this study was to compare an anterior cervical discectomy and interbody fusion of a novel polylactide/nano-sized β-tricalcium phosphate (PLA/nβ-TCP) bioabsorbable self-retaining cervical fusion cage (BCFC) with an autologous bone graft and polyetheretherketone (PEEK) cages., Background: Although PLA cervical cages have potential advantages compared with traditional materials, they are not currently routinely used in spine surgery because of undesirable effects such as the lack of osteoconductivity and osteolysis around the implant. This study involved the manufacturing of a bioabsorbable cage from PLA/nβ-TCP that was then used as a device for anterior cervical discectomy and fusion (ACDF) on a goat cervical spine fusion model., Materials and Methods: Eighteen goats underwent C3/C4 discectomy and were randomly divided into three groups based on the following methods: Group A (n=6), an autologous bone graft; Group B (n=6), PEEK cage filled with an autologous graft; and Group C (n=6), BCFC filled with an autologous iliac bone. Radiography was performed preoperatively and postoperatively and at 1, 4, 8, and 12 weeks after the operation. Disc space height (DSH) was measured at the same time. After 12 weeks, the fused segments were harvested and evaluated with functional radiographic views, biomechanical testing, and histological analyses., Results: Over a 12-week period, the BCFC and PEEK cage groups exhibited significantly higher DSH values than the bone graft group. Additionally, the BCFC group yielded a significantly lower range of motion in axial rotation than both the autologous bone graft and PEEK cage groups. A histologic evaluation revealed an increased intervertebral bone volume/total volume ratio and better interbody fusion in the BCFC group than in the other groups., Conclusion: The BCFC device exhibited better results than the autologous bone graft and PEEK cages in single-level ACDF models in vivo. This device may be a potential alternative to the current PEEK cages., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Zn(2+) is an essential component of metalloproteinases, and is required for their activity in cartilage; however, the effect of Zn(2+) on nucleus pulposus (NP) cells has not been widely investigated. The aim of this paper was to investigate the effect of intracellular Zn(2+) concentration ([Zn(2+)]i) in hypoxia-induced regulation of metalloproteinases (MMPs) and extracellular matrix (ECM) production in NP cells. NP cells from Sprague-Dawley (SD) rats were cultured as monolayers or in alginate beads. [Zn(2+)]i was assayed by FluoZin-3 AM staining. Alcian Blue staining, immunochemistry, 1,9-dimethylmethylene blue (DMMB) assay, and real-time PCR were used to assay collagen II, proteoglycan, and COL2A1, MMP-13, and ADAMTS-5 mRNA expression. ZIP8, a main Zn(2+) transporter in chondrocytes, was assayed by immunochemistry and in Western blotting. Interleukin (IL)-1β- and ZnCl2-induced increases of [Zn(2+)]i were significantly inhibited by hypoxia. Hypoxia did not reverse a decline of ECM expression caused by IL-1β and ZnCl2 in monolayer cultures, but did significantly attenuate the decreases of proteoglycan, glycosaminoglycan (GAG), and COL2A1 mRNA expression following IL-1β and ZnCl2 treatment in alginate bead cultures. However, ZnCl2 inhibited the protective effect of hypoxia. Both an intracellular Zn(2+) chelator and hypoxia prevented the increase in MMP-13 mRNA expression. IL-1β and ZnCl2 treatment increased ZIP8 expression in NP cells, and hypoxia inhibited ZIP8 expression. In conclusion, decrease of Zn(2+) influx mediates the protective role of hypoxia on ECM and MMP-13 expression. Consequently, changes in intracellular Zn(2+) concentration maybe involved in intervertebral disc degeneration.