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Background: Osteoporosis is characterized by an imbalance in bone homeostasis, resulting in the excessive dissolution of bone minerals due to the acidified microenvironment mediated by overactive osteoclasts. Oroxylin A (ORO), a natural flavonoid, has shown potential in reversing osteoporosis by inhibiting osteoclast-mediated bone resorption. The limited water solubility and lack of targeting specificity hinder the effective accumulation of Oroxylin A within the pathological environment of osteoporosis. Results: Osteoclasts' microenvironment-responsive nanoparticles are prepared by incorporating Oroxylin A with amorphous calcium carbonate (ACC) and coated with glutamic acid hexapeptide-modified phospholipids, aiming at reinforcing the drug delivery efficiency as well as therapeutic effect. The obtained smart nanoparticles, coined as OAPLG, could instantly neutralize acid and release Oroxylin A in the extracellular microenvironment of osteoclasts. The combination of Oroxylin A and ACC synergistically inhibits osteoclast formation and activity, leading to a significant reversal of systemic bone loss in the ovariectomized mice model. Conclusion: The work highlights an intelligent nanoplatform based on ACC for spatiotemporally controlled release of lipophilic drugs, and illustrates prominent therapeutic promise against osteoporosis. [ABSTRACT FROM AUTHOR]

In the past few decades, although tissue engineering has made significant progress and achieved many accomplishments, there are still some key problems that remain unsolved. One of the urgent research challenges in this field is how to prepare large-scale tissue engineering scaffolds with spatially complex structures. In this work, a sacrificial template process using sucrose as the sacrificial material and a gelatin/microbial transglutaminase mixed solution as the bio-scaffold material is proposed to fabricate a bio-scaffold with multi-level branching and spatially complex vascular network channels that mimic the structure and function of the human vascular network. To validate the feasibility of the fabrication process and the rationality of the process parameters, the morphological characteristics, connectivity of vascular network channels, shaping accuracy, and mechanical properties of the bio-scaffold were tested and analyzed. The results showed that the bio-scaffold fabricated using this process had a complete morphology and excellent connectivity. The diameter of the sucrose sacrificial template showed a linear relationship with the feeding speed, and the average diameter error rate between the sucrose sacrificial template and the vascular network channels inside the bio-scaffold was less than 8%. The mechanical properties of the bio-scaffold met the requirements for large-scale tissue defect repair. To evaluate the effect of the bio-scaffold on cell activity, human umbilical vein endothelial cells (HUVECs) were seeded into the vascular network channels of the bio-scaffold, and their attachment, growth, and proliferation on the surface of the vascular network channels were observed. To further assess the biocompatibility of the bio-scaffold, the bio-scaffold was implanted subcutaneously in the dorsal tissue of rats, and the tissue regeneration status was compared and analyzed through immunohistochemical analysis. The results showed that the vascular network channels within the bio-scaffold allowed uniform cell attachment, growth, with fewer dead cells and high cell viability. Moreover, clear cell attachment and growth were observed within the vascular network channels of the bio-scaffold after implantation in rats. These results indicate that the fabricated bio-scaffold meets the basic performance requirements for the repair and regeneration of large-scale tissue defects, providing a new approach for oxygen and nutrient transport in large-scale tissues and opening up new avenues for clinical applications., (© 2023 IOP Publishing Ltd.)