应用机器人光镊细胞手术系统研究生物细胞微米级操控

发布时间：2018-03-27 23:19

本文选题：细胞操作　切入点：细胞移动　出处：《中国科学技术大学》2016年博士论文

【摘要】：单细胞手术由于其在生理,病理,和药理学研究领域有着重要的作用,已经受到越来越多的关注和研究。然而目前大多数单细胞手术研究仅限于概念演示验证阶段。由于没有有效细胞手术系统能够精确地操作和控制单个细胞的位置和姿态角,同时可以处理大批量细胞以增加操作精度,实验数据的吞吐量和实验结果的可靠性,这些都进一步阻碍了单细胞手术研究进步。本文中,建立了一个集成机器人光镊的细胞手术系统能够实现批量细胞同时操控,以及单细胞位置和方位角的精确控制,其中光镊可以看做是机器人受控的末端执行器进行捕获和操作生物细胞。本文从以下三个方面进行展开。首先,建立了一个自治控制系统实现细胞位置的精确控制。该控制策略保证了被捕获的细胞能够始终保持在光镊中心附近的小邻域内,从而确保在整个操作过程中细胞能够稳定的光捕获。基于被光镊束缚的细胞动力学方程,提出了一个简单的饱和PID控制器实现细胞位置的渐近调控。该控制策略不精确依赖于细胞动力学模型参数和细胞速度的测量。最后实验验证所提控制策略的有效性。其次,利用机器人光镊细胞操纵系统,结合全息光镊(HOTs)技术,建立了多组细胞移动配对框架。所提的细胞配对方法是基于人工势场函数和同心圆思想。设计了特定的人工势能场函数用于驱动多组细胞到达期望的拓扑,同时避障。根据光镊俘获细胞的动力学方程,设计了基于人工势能场函数的控制器来驱动多组细胞分别到达各自的圆。利用同心圆的对称性,自动实现多组细胞配对控制,同时配对的细胞间距是可控的，配对细胞的间距依赖于同心圆的拓扑结构。用酵母菌细胞实验来阐释本文所提的细胞配对方法的有效性。最后,本文利用受控的机器人光镊平台,研究了动态建模和控制多自由度细胞旋转。采用机器人控制的全息光镊产生的两个光阱来实现细胞旋转。首先建立了广义的细胞运动动力学模型,该模型涵盖了细胞旋转运动动力学方程。利用T-matrix方法来计算建模光镊,标定了光镊施加给细胞的力矩与其在在细胞内坐标的关系。建立的视觉追踪框架可以提取细胞旋转过程中的方位角和角速度。根据简化的多自由度细胞旋转的动力学模型,设计了视觉反馈控制器实现细胞像平面内和像平面外旋转操作。选取具有特征点的酵母细胞进行旋转操控实验来验证本文所提方法的有效性。概括来说，，基于机器人光镊细胞手术控制系统能够提供强有力的平台实现细胞位置和方位角精确控制,以及多细胞同时操控任务。自治的细胞位置控制系统不仅能够实现细胞操作过程在稳定的光镊捕获,而且是依赖于细胞位置的细胞手术应用或是相关的生物医学工程领域最基本最重要的操作技术。多组细胞配对操作很大程度上提高操作效率和测量结果的吞吐量。该研究能够有助于揭示细胞内和细胞间生理活动的功能机理。自动的多自由度细胞旋转控制能够实现细胞全方位细胞姿态控制,它也是许多单细胞手术操作过程中最基本却是非常重要的操作技术。本文将为探究单细胞层面的生理和病理机理研究奠定了坚实的基础：在精确医药领域,将有助于进一步提高细胞或是亚细胞层面靶向治疗。
[Abstract]:Single cell operation due to the physiology, pathology, pharmacology and plays an important role in research field, is attracting more and more attention and research. However, most studies on single cell operation is limited to the concept demonstration phase. The position and attitude of no effective cell operation system can accurately control the angle of operation and single cells, at the same time can handle a large number of cells to increase the operation precision, reliability and throughput of the experimental results of the experimental data, which further hinders the progress of single cell operation. This paper established an integrated robot cell operation system of optical tweezers can realize mass cell control, and accurate control of position and orientation angle of single cell. The optical tweezers can be seen as the end of the robot controlled actuator is captured and operation of biological cells. This paper from the following three aspects . first of all, set up an autonomous control system to realize the precise control of cell position. The control strategy can guarantee the captured cells can keep a small neighborhood near the center of the optical tweezers, so as to ensure that in the whole process of the cell can stabilize the light trapping. Cell kinetics equation is bound based on optical tweezers. We propose a simple saturated PID controller to realize the position control cell of the control strategy. The asymptotic measurement imprecision dependent on cell kinetics model parameters and cell speed. The experiments verify the effectiveness of the proposed control strategy. Second, using a robot cell control system with optical tweezers, holographic optical tweezers (HOTs) technology. The establishment of multiple groups of cells. The proposed framework of paired mobile cell pairing method is artificial potential field function and concentric circles. Based on the idea of design of the artificial potential field function specific for driving multi group The cells reach the desired topology, and obstacle avoidance. According to the dynamic equation of optical tweezers capture cell, the controller function based on artificial potential field to drive a plurality of cells respectively reach the circular design. By the symmetry of the concentric circle, automatically paired with control group cells, when paired cell spacing is controllable. Distance between paired cells depends on the topological structure of concentric circles. The effectiveness of method of paired with yeast cell experiments to explain the cells. Finally, this paper use optical tweezers controlled robot platform, research the dynamic modeling and control of multi degree of freedom cell rotation. By two optical holographic optical tweezers control robot the implementation of cell rotation. First cell motion dynamics model of generalized is established. The model covers the dynamic cell rotation. The equations of motion to calculate the modeling of optical tweezers using T-matrix method, The calibration of optical tweezers is applied to the relationship between the cell and the coordinate torque within the cell. The establishment of visual tracking framework can azimuth angle and angular velocity rotation in the process of cell extraction. According to the dynamic model of multi DOF rotary cell simplified, visual feedback controller to realize cell image plane and image plane rotation operation the design of rotation control. Experiments to verify the validity of the proposed method are the selection of yeast cells with the feature point. In general, the robot control system of optical tweezers cell surgery can provide powerful platform to realize the precise control of cell position and azimuth based on control and multicellular task. Cell autonomous position control system can not only realize the operation process of cell capture in optical tweezers is stable, and the cell surgery depends on cell location or biomedical engineering. The most basic and the most important technique. Many groups of cells matching operation can greatly improve the operating efficiency and the measurement results of the throughput. Function mechanism of this study will help to reveal the cellular and intercellular physiological activities. Multi degree of freedom rotation control can realize the automatic cell cell cell omnidirectional attitude control, operation technology the most basic is very important and it is many single cell operation process. This paper will lay a solid foundation for the physiological and pathological mechanism research on single cell level: in the precise field of medicine, will help to further improve the cellular or subcellular level in targeted therapy.

【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：TP242

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