Zhang Xiaoguang, Liang Huaizhen, Liao Zhiwei, Tong Bide, Wu Di, Ma Liang, Lei Jie, Zhou Xingyu, Zhu Dingchao, Ou Zixuan, Wei Junyu, Tan Lei, Yang Cao
Department of Orthopedics, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, China.
Sci Adv. 2025 Aug 8;11(32):eadu6860. doi: 10.1126/sciadv.adu6860.
Cell cycle regulation is pivotal for tissue regeneration yet remains challenging in degenerative microenvironments. We engineered a sonosensitive conductive hydrogel incorporating polypyrrole-encapsulated porphyrin derivatives {[Tetrakis (4-carboxyphenyl) porphyrin (TCPP)]@PPy} to regulate cell cycle dynamics. Upon ultrasound irradiation, TCPP@PPy generates free electrons, establishing a controlled microcurrent within degenerative tissues. This sonoelectric niche induces nucleus pulposus cell (NPC) membrane depolarization, activating calcium voltage-gated channels (Ca) to drive Ca influx. Subsequent calcium- and calmodulin-dependent protein kinase I activation up-regulates cyclin-dependent kinases CDK1/CDK2, forming a sonoelectricity-ion-kinase axis that stimulates NPC proliferation and anabolism. Concurrently, ultrasound-responsive borate ester bonds in the hydrogel amplify reactive oxygen species scavenging, counteracting oxidative stress-induced NPC ferroptosis. In a goat model of intervertebral disc degeneration, ultrasound-guided hydrogel implantation alleviated degenerative progression by synergistically reactivating cell cycle progression and suppressing oxidative damage. This strategy demonstrates a noninvasive, dual-targeted approach to regulate degenerative microenvironments through spatiotemporal control of sonoelectric and biochemical cues, offering a translatable strategy for tissue regeneration therapies.
细胞周期调控对于组织再生至关重要，但在退行性微环境中仍然具有挑战性。我们设计了一种包含聚吡咯包裹的卟啉衍生物{四（4-羧基苯基）卟啉（TCPP）]@PPy}的超声敏感导电水凝胶，以调节细胞周期动态。在超声照射下，TCPP@PPy产生自由电子，在退行性组织内建立可控的微电流。这种超声电小生境诱导髓核细胞（NPC）膜去极化，激活钙电压门控通道（Ca）以驱动Ca内流。随后钙和钙调蛋白依赖性蛋白激酶I的激活上调细胞周期蛋白依赖性激酶CDK1/CDK2，形成超声电-离子-激酶轴，刺激NPC增殖和合成代谢。同时，水凝胶中超声响应性硼酸酯键增强活性氧清除，抵消氧化应激诱导的NPC铁死亡。在山羊椎间盘退变模型中，超声引导的水凝胶植入通过协同重新激活细胞周期进程和抑制氧化损伤来减轻退变进展。该策略展示了一种通过对超声电和生化信号进行时空控制来调节退行性微环境的非侵入性、双靶点方法，为组织再生治疗提供了一种可转化的策略。
