迷走神经刺激广泛应用于癫痫，抑郁和心衰等多种药物难治性疾病的治疗。电极与迷走神经界面的力电特性，是决定该疗法安全性和有效性的关键因素，也是实现精确的个性化治疗的基础，对临床应用具有重要意义。本文通过有限元建模和动物实验，研究了电极引起的神经受力、损伤以及电刺激响应的变化规律。首先，建立了电极与神经相互作用的力学模型，分析电极结构参数对神经受力的影响。利用超声剪切成像和单轴拉伸法表征了神经剪切模量和杨氏模量，在此基础上研究了神经受力随电极厚度、宽度、螺距以及内径等的变化规律，并给出了临床植入最佳的电极内径与神经直径的比值。分析了神经自身的工程弹性常数在其受力中的影响，有助于临床中电极植入位置的选择。其次，量化了电极对神经的力学作用与神经损伤的对应关系。为评价神经损伤，建立了刚体平板压缩模型，分析了神经尺寸和压缩率在神经受力中的影响，明确了以压缩率为控制参数。开展了急性和长期的中华小型猪活体实验，通过超氧化物歧化酶活性分析、脂质过氧化物丙二醛含量分析以及组织形态学分析，研究了神经不同受力状态下损伤的变化过程和表现形式，给出了神经承受压强的安全阈值。再次，以迷走神经复合动作电位为对象，研究了电极与神经界面的电学特性以及力电耦合特性。开展了中华小型猪的活体实验，分析了电流幅度、脉宽和频率等刺激参数与迷走神经复合动作电位响应的对应关系，进而提出个性化治疗参数的选择标准及选择范围。通过分析神经拉伸对复合动作电位的影响，明确了以其研究电刺激效应的关键因素为拉伸率。结合动物实验和仿真计算，分析了电极结构导致的神经受力，及其引起的复合动作电位变化规律。研究结论为电极结构的优化设计以及闭环迷走神经刺激疗法的发展奠定了基础。最后，在电极与神经界面力电特性研究的基础上，研制用于迷走神经刺激的螺旋电极。针对其中最为关键的电极粘接界面特性问题，建立了疲劳试验平台系统，并结合红外光谱法和溶液侵蚀法进行了分析和改进，实现了硅橡胶与铂铱合金两种材料的可靠粘接。进而系统解决了电极设计、工艺及测试等问题，在经过长期动物实验验证的基础上，实现了临床应用。
Vagus nerve stimulation (VNS) has been widely used to treat various refractory diseases, such as epilepsy, depression and heart failure. The mechanical and electrical characteristics of the interface between the electrode and the nerve are key factors to determine safety and effectiveness of the VNS therapy. They are also the basis to realize precise and personalized treatment, and are of great significance to clinical applications. In this dissertation the mechanical pressure on the nerve induced by the electrode, the resulting neural damages and neural responses to electrical stimulation were studied by finite element modeling, in vitro and in vivo experiments.Firstly, the mechanical model of the electrode-nerve interface was established. The influence of electrode structure parameters on the resulting stress imposed on the nerve was analyzed. Measurement methods adopting supersonic shear imaging and uniaxial tensile test were developed to characterize the shear modulus and Young's modulus of the vagus nerve. Based on the results, the relationship between the pressure exerted on the nerve and the electrode structure parameters was determined, including thickness, width, pitch and inner diameter of the helical structure. The optimal ratio of the inner diameter of the electrode and the diameter of the nerve for clinical application was concluded. The influence of the nerve engineering elastic constants on its stress was also clarified, which would be beneficial to better localize the electrode in clinic.Secondly, the relationship between the mechanical electrode-nerve interaction and neural damage of the vagus nerve was quantified. A rigid plate compression model was proposed to standardize the deformation of the nerve. The compression ratio was confirmed as the appropriate control parameter to evaluate the neural damage. Acute and long-term in vivo experiments were conducted using a pig model. By superoxide dismutase activity measurement, malondialdehyde content detection and histomorphology analysis, the developing process and manifestation of the neural damage were studied. The safety threshold of the nerve stress was determined.Thirdly, focusing on the compound action potential (CAP) response of the nerve, the electrical and electro-mechanical coupling characteristics of the electrode-nerve interface was investigated. Through in vivo experiments on pigs, the relationship between CAP and VNS parameters, including amplitude, pulse width and frequency of the currents, was analyzed. The selection criteria and range of the stimulation parameters for individual-based treatment were concluded. The key factor in the study of the stimulation effect using CAP was confirmed by analyzing the nerve CAP response after stretching. The nerve stress and the resulting CAP responses due to the variations in the electrode structure were analyzed by in vivo experiments and numerical simulation. It laid the foundation for the electrode optimization and the development of closed-loop VNS therapy.Finally, based on the previous study of the mechanical and electrical characteristics of the electrode-nerve interface, a helical electrode for VNS was developed. To analyze the adhesive characteristics between the silicone rubber and Pt-Ir alloy, which was a key issue in the electrode manufacturing, a self-made fatigue test system was established, and infrared spectroscopy and solution etching mothod were also adopted. Reliable bonding of the two materials was realized. Furthermore, the whole manufacturing process was completed by systematically tackling problems in design, process, reliability test, etc. The developed VNS electrode was validated by long-term animal implantation, and achieved clinical application.
