Abstract：
Electrical stimulation (ES) of cellular systems can be utilized for biotechnological applications and electroceuticals (bioelectric medicine). Neural cell stimulation especially has a long history in neuroscience research and is increasingly applied for clinical therapies. Application of ES via conventional electrodes requires external connectors and power sources, hindering scientific and therapeutic applications. Here engineering novel 3D scaffold-free human neural stem cell constructs with integrated piezoelectric nanoparticles for enhanced neural tissue induction and function is described. Tetragonal barium titanate (BaTi03) nanoparticles are employed as piezoelectric stimulators prepared as cytocompatible dispersions, incorporated into 3D self-organizing neural spheroids, and activated wirelessly by ultrasound. Ultrasound delivery (low frequency; 40 kHz) is optimized for cell survival, and nanoparticle activation enabled ES throughout the spheroids during differentiation, tissue formation, and maturation. The resultant human neural tissues represent the first example of direct tissue loading with piezoelectric particles for ensuing 3D ultrasound-mediated piezoelectric enhancement of human neuronal induction from stem cells, including augmented neuritogenesis and synaptogenesis. It is anticipated that the platform described will facilitate advanced tissue engineering and in vitro modeling of human neural (and potentially non-neural) tissues, with modeling including tissue development and pathology, and applicable to preclinical testing and prototyping of both electroceuticals and pharmaceuticals.
摘要：
细胞系统的电刺激（ES）可用于生物技术应用和电治疗（生物电医学）。特别是神经细胞刺激在神经科学研究中具有悠久的历史，并且越来越多地用于临床治疗。通过常规电极应用ES需要外部连接器和电源，阻碍科学和治疗应用。这里描述了具有集成压电纳米颗粒的新型3D无支架人类神经干细胞构建体，用于增强神经组织诱导和功能。四方钛酸钡（BaTi03）纳米颗粒用作压电刺激剂，制备为细胞相容性分散体，整合到3D自组织神经球体中，并通过超声波无线激活。超声传输（低频；40kHz）针对细胞存活进行了优化，在分化过程中，纳米颗粒活化使ES能够贯穿整个球体，组织形成,和成熟。所得的人类神经组织代表了用压电颗粒直接组织加载的第一个示例，用于随后3D超声介导的压电增强干细胞对人类神经元的诱导。包括增强的神经生成和突触发生。预计所描述的平台将促进人类神经（和潜在的非神经）组织的先进组织工程和体外建模，包括组织发育和病理学在内的建模，适用于药品和药品的临床前测试和原型设计。
