Electrical stimulation, as a physical stimulation method, can effectively regulate tissue damage repair. In the process of nerve injury repair, electrical stimulation can effectively regulate the differentiation of nerve cells, achieving a certain degree of neural network reconstruction. Ultrasound (US) triggered piezoelectric nanomaterials generate electrical signals as a new type of wireless electrical stimulation method, effectively addressing various drawbacks of traditional electrical stimulation. However, the built-in electric field generated by piezoelectric nanoparticles is short-range, requiring the interaction between cells and nanoparticles to remain relatively close to achieve effective electrical signal transmission. Additionally, due to the occurrence of fluid washout in vitro and in vivo, piezoelectric nanomaterials inevitably experience material loss when resisting fluid washout, significantly reducing the efficiency of piezoelectric wireless electrical stimulation. Therefore, the close anchoring of piezoelectric nanoparticles to cell membranes is a necessary condition for achieving efficient electrical transmission.
Recently, Professor Fan Hongsong from Sichuan University collaborated with Professor Wu Jiagang to publish their work titled “Cell-Anchored Lead-Free Piezoelectric KNN NPs Resisting Washout for Low-Intensity Ultrasound Driven Neuromodulation” in the journal Advanced Functional Materials.
Figure 1: Schematic diagram of cholesterol-modified cell-anchored KNN NPs for efficient cell behavior regulation.
This study modified cholesterol, a highly affinity molecule for cell membranes, onto the surface of high-performance lead-free potassium sodium niobate-based (KNN) piezoelectric nanoparticles, resulting in cholesterol-modified KNN nanoparticles (KNNC) with cell anchoring functionality. Compared to unmodified nanoparticles, the cell-anchored KNNC nanoparticles can effectively resist fluid washing due to the high affinity of cholesterol for cell membranes, achieving efficient wireless electrical stimulation under low-intensity ultrasound.
Figure 2: Characterization of the fluid washout resistance of KNN and KNNC NPs co-cultured with SH-SY5Y cells.
Through dynamic calcium ion staining imaging, it was confirmed that KNNC can effectively activate voltage-gated calcium ion channels in neuroblastoma SH-SY5Y cells under ultrasound, triggering calcium ion influx. After washing the samples, KNNC nanoparticles remained on the cell membrane surface and could produce similar electrical stimulation effects to the unwashed state. In contrast, unmodified KNN NPs showed a significant reduction in the number of nanoparticles on the cell membrane surface after washing due to weak interactions with the cell membrane, leading to a noticeable decrease in cellular response under the same stimulation conditions. Therefore, cell-anchored KNNC NPs can achieve efficient wireless electrical stimulation while resisting fluid washout.
Figure 3: Mechanistic study of cell-anchored KNNC nanoparticles regulating calcium ion influx in cells.
Furthermore, this study co-cultured KNNC nanoparticles with neural stem cells (NSCs) to explore the promoting effect of ultrasound-mediated wireless electrical stimulation by KNNC NPs on NSCs’ neural differentiation and synapse formation. The results indicated that KNNC under ultrasound can produce wireless electrical stimulation, promoting the influx of Ca2+ ions into cells. The binding of Ca2+ ions to calmodulin (CaM) regulates the activity level of calmodulin-dependent protein kinase II (CaMKII), subsequently activating the downstream expression of genes related to promoting neural differentiation, thereby enhancing synaptic plasticity.
Figure 4: Promoting effect and mechanism of ultrasound-mediated KNNC NPs wireless electrical stimulation on NSCs’ neural differentiation and synapse formation.
In summary, this study developed a cell-anchored KNNC NPs platform for efficient wireless electrical stimulation triggered by low ultrasound intensity. These nanoparticles can effectively resist fluid washout and achieve wireless electrical stimulation under <10mW cm−2 ultrasound intensity, activating voltage-gated calcium ion channels in nerve cells. The regulation of intracellular calcium ion concentration triggered by this electrical stimulation can effectively modulate downstream signaling pathways, promoting neural differentiation and synaptic structure formation. The development of this platform provides a new strategy for efficient cell behavior regulation and offers new insights into the biological applications of piezoelectric nanoparticles.
Professor Fan Hongsong from the School of Biomedical Engineering and Associate Researcher Zheng Ting from the School of Materials Science and Engineering at Sichuan University are the corresponding authors of this paper. The first author is Dr. Zhang Yusheng from the School of Biomedical Engineering. This research was funded by the National Natural Science Foundation (Fund Number: 52303195, 32361133548).
Y. Zhang, J. Jiang, X. Xie, L. Jiang, C. Wu, J. Sun, T. Zheng, H. Fan, J. Wu, Cell-Anchored Lead-Free Piezoelectric KNN NPs Resisting Washout for Low-Intensity Ultrasound Driven Neuromodulation. Adv. Funct. Mater. 2024, 2406919. https://doi.org/10.1002/adfm.202406919
Source: BioMed Technology
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