Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing, 400014, China.
Department of Ultrasound, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
J Nanobiotechnology. 2022 Aug 13;20(1):378. doi: 10.1186/s12951-022-01587-3.
Low-intensity pulsed ultrasound (LIPUS) has been reported to accelerate fracture healing, but the mechanism is unclear and its efficacy needs to be further optimized. Ultrasound in combination with functionalized microbubbles has been shown to induce local shear forces and controllable mechanical stress in cells, amplifying the mechanical effects of LIPUS. Nanoscale lipid bubbles (nanobubbles) have high stability and good biosafety. However, the effect of LIPUS combined with functionalized nanobubbles on osteogenesis has rarely been studied.
In this study, we report cyclic arginine-glycine-aspartic acid-modified nanobubbles (cRGD-NBs), with a particle size of ~ 500 nm, able to actively target bone marrow mesenchymal stem cells (BMSCs) via integrin receptors. cRGD-NBs can act as nanomechanical force generators on the cell membrane, and further enhance the BMSCs osteogenesis and bone formation promoted by LIPUS. The polymerization of actin microfilaments and the mechanosensitive transient receptor potential melastatin 7 (TRPM7) ion channel play important roles in BMSCs osteogenesis promoted by LIPUS/cRGD-NBs. Moreover, the mutual regulation of TRPM7 and actin microfilaments promote the effect of LIPUS/cRGD-NBs. The extracellular Ca influx, controlled partly by TRPM7, could participated in the effect of LIPUS/cRGD-NBs on BMSCs.
The nanomechanical force generators cRGD-NBs could promote osteogenesis of BMSCs and bone formation induced by LIPUS, through regulation TRPM7, actin cytoskeleton, and intracellular calcium oscillations. This study provides new directions for optimizing the efficacy of LIPUS for fracture healing, and a theoretical basis for the further application and development of LIPUS in clinical practice.
低强度脉冲超声（LIPUS）已被报道可加速骨折愈合，但机制尚不清楚，其疗效需要进一步优化。超声联合功能化微泡已被证明可在细胞内诱导局部剪切力和可控机械应力，从而放大 LIPUS 的机械效应。纳米级脂质泡（纳米泡）具有高稳定性和良好的生物安全性。然而，LIPUS 联合功能化纳米泡对成骨作用的影响很少被研究。
在这项研究中，我们报告了循环精氨酸-甘氨酸-天冬氨酸修饰的纳米泡（cRGD-NBs），其粒径约为 500nm，能够通过整合素受体主动靶向骨髓间充质干细胞（BMSCs）。cRGD-NBs 可以作为细胞膜上的纳米机械力发生器，进一步增强 LIPUS 促进的 BMSCs 成骨和骨形成。肌动蛋白微丝的聚合和机械敏感瞬时受体电位 melastatin 7（TRPM7）离子通道在 LIPUS/cRGD-NBs 促进的 BMSCs 成骨中发挥重要作用。此外，TRPM7 和肌动蛋白微丝的相互调节促进了 LIPUS/cRGD-NBs 的作用。部分由 TRPM7 控制的细胞外 Ca2+内流参与了 LIPUS/cRGD-NBs 对 BMSCs 的作用。
纳米机械力发生器 cRGD-NBs 可通过调节 TRPM7、肌动蛋白细胞骨架和细胞内钙震荡，促进 LIPUS 诱导的 BMSCs 成骨和骨形成。本研究为优化 LIPUS 治疗骨折愈合的疗效提供了新的方向，为 LIPUS 在临床实践中的进一步应用和发展提供了理论依据。
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