Micromanipulation System Research Articles

Phase-shift feedback control for dielectrophoretic micromanipulation.

In this paper, we present a novel approach to noncontact micromanipulation by controlled dielectrophoresis (DEP). To steer micro-objects in the desired way, the solutions reported in the literature use either DEP cages or amplitude modulation of the voltages applied to the electrodes. In contrast, we modulate the phases, that is, we control the phase shifts of the voltages applied to the electrodes, which simplifies the hardware implementation and extends the set of feasible forces. Furthermore, we introduce an innovative micro-electrode array layout, composed of four sectors with parallel (colinear) electrodes, which is capable of inducing an arbitrary movement in the manipulation area and is easy to fabricate using just an affordable one-layer technology. We then propose a closed-loop cascade control strategy based on real-time numerical optimization and deploy it to our experimental set-up. Numerical simulations and laboratory experiments demonstrate the manipulation capabilities such as positioning and steering of one or several microscopic objects (microspheres with a diameter of 50 μm) and even bringing two objects together and then separating them again. The results from simulations and experiments are compared and the positioning accuracy is evaluated in the whole manipulation area. The error in position is 8 μm in the worst case, which corresponds to 16% of the microsphere size or 0.7% of the manipulation range.

Real-time 3D measurement system for micro-manipulation

Construction of an activated three-dimensional (3D) tissue outside the human body is highly desirable, and it is expected that micro-manipulation should be used to construct 3D organisations. In micro-manipulation, it is difficult to obtain depth information, as an object is usually observed using an optical microscope. Thus, empirical techniques that require extensive practice are employed. To overcome this problem, a system that can perform real-time 3D measurements is indispensable. In this study, an improvement in the speed of 3D measurements in a microhabitat is obtained, which would facilitate micro-manipulation and the construction of 3D cellular organisations.

Real-time 3D measurement system for micro-manipulation

Real-time 3D measurement system for micro-manipulation

Enhanced control of a flexure-jointed micromanipulation system using a vision-based servoing approach

This paper describes a high-precision motion control implementation for a flexure-jointed micromanipulator. A desktop experimental motion platform has been created based on a 3RUU parallel kinematic mechanism, driven by rotary voice coil actuators. The three arms supporting the platform have rigid links with compact flexure joints as integrated parts and are made by single-process 3D printing. The mechanism overall size is approximately 250x250x100 mm. The workspace is relatively large for a flexure-jointed mechanism, being approximately 20x20x6 mm. A servo-control implementation based on pseudo-rigid-body models (PRBM) of kinematic behavior combined with nonlinear-PID control has been developed. This is shown to achieve fast response with good noise-rejection and platform stability. However, large errors in absolute positioning occur due to deficiencies in the PRBM kinematics, which cannot accurately capture flexure compliance behavior. To overcome this problem, visual servoing is employed, where a digital microscopy system is used to directly measure the platform position by image processing. By adopting nonlinear PID feedback of measured angles for the actuated joints as inner control loops, combined with auxiliary feedback of vision-based measurements, the absolute positioning error can be eliminated. With controller gain tuning, fast dynamic response and low residual vibration of the end platform can be achieved with absolute positioning accuracy within ±1 micron.

Versatile on-stage microfluidic system for long term cell culture, micromanipulation and time lapse assays

We report here a versatile on-stage microfluidic cell culture and assay system which is compatible with different microscopes and sensors, can simultaneously perform steps of long term cell culture, high throughput time lapse cell assays/imaging, and cell micromanipulations. With the system, we cultured a variety of cells for different periods of time and monitored their cell morphology, migration and division. We also performed a series non-invasive real time in situ time lapse assays and micromanipulations on different cells. They include: the first time lapse imaging and measurements on the instantaneous variations of morphology, biomechanical properties and the intracellular protein of human red blood cells in responding to pH fluctuation, drug action and electromagnetic radiation; the first continuous time lapse Raman micro-spectroscopy on a CHO cell in different phases of its entire life cycles; the micro-transfection of GFP into B16 cells and the follow up observation of the cell's morphology and expressed GFP fluorescence varying with incubation time and cell generations. The performance of these experiments not only demonstrated the capability of the system, but also proposed a variety of novel methods for obtaining time- and spatially-resolved information about the cellular and molecular heterogeneity and transformation during development or stimulations.

A Model Compensation-Prediction Scheme for Control of Micromanipulation Systems With a Single Feedback Loop

Many micromanipulation systems employ sensorless actuators and possess unknown modeling errors, feedback measurement noises, and time delays. Conventional model-based control schemes ignore some of these uncertainties, and thus sacrifice the control system performance. This paper presents a new model compensation-prediction scheme for micromanipulation systems that can be described by two-dimensional state-space models, estimate the unknown modeling errors from noisy single feedback measurement, and predict and compensate the system time delay. This approach combines two modeling errors into a single equivalent modeling error through mathematical transformation, and estimates the combined term using a noise-insensitive extended high-gain observer. After removing the unknown term, the system is then transformed into a time-invariant form, and a Smith predictor is implemented to predict and compensate the time delay. The effectiveness of the proposed compensation-prediction scheme is demonstrated by both numerical simulations and experiments on two typical micromanipulation systems, namely a robotic biosample stimulator and a material characterization microgripper. The results show that this method can significantly improve the control performance of a conventional proportional-integral-derivative controller, by simultaneously reducing the settling time and overshoot of the micromanipulation systems.

Design and Precision Position/Force Control of a Piezo-Driven Microinjection System

This paper presents the design and development of a piezo-driven cell injection system with the fusion of force and position control. By integrating a polyvinylidene fluoride force sensor for detecting the penetration force of biological cells and a strain-gage sensor for measuring the micropipette relative position in real time, the entire cell micromanipulation system features low cost, convenient installation, and easy maintenance. The challenge of transition jerk between the force and position controller switching is reduced by introducing a weight coefficient method. An adaptive sliding mode control with parameter estimation scheme is implemented to compensate for the hysteresis nonlinearity and disturbance of the piezoelectric actuator. The injection force is controlled by realizing an incremental proportional-integral-derivative controller. The effectiveness of the developed cell injection system is experimentally verified by penetrating zebrafish embryos. The experimental results lay a foundation for the further biological manipulation research, such as the automatic batch injection of zebrafish embryos.

Design and analysis of a 3-DOF planar micromanipulation stage with large rotational displacement for micromanipulation system

Abstract. Flexure-based mechanisms have been widely used for scanning tunneling microscopy, nanoimprint lithography, fast servo tool system and micro/nano manipulation. In this paper, a novel planar micromanipulation stage with large rotational displacement is proposed. The designed monolithic manipulator has three degrees of freedom (DOF), i.e. two translations along the X and Y axes and one rotation around Z axis. In order to get a large workspace, the lever mechanism is adopted to magnify the stroke of the piezoelectric actuators and also the leaf beam flexure is utilized due to its large rotational scope. Different from conventional pre-tightening mechanism, a modified pre-tightening mechanism, which is less harmful to the stacked actuators, is proposed in this paper. Taking the circular flexure hinges and leaf beam flexures hinges as revolute joints, the forward kinematics and inverse kinematics models of this stage are derived. The workspace of the micromanipulator is finally obtained, which is based on the derived kinematic models.

Teleoperated Micromanipulation System Manufactured by Cut-and-Fold Techniques

We present a new teleoperated micromanipulation system in which all units of the system, wearable user interface devices and a slave micromanipulator, are manufactured by engraving, cutting, and folding two-dimensional materials. The designed manipulation system employs a simple hydraulic mechanism consisting of pairs of syringes that have different diameters, which allows for motion reduction and physical interaction between the master and the slave. As a result, users can precisely manipulate micro-objects without tremor, which was previously difficult with bare hands. This paper presents design considerations and features fabrication methods, performance metrics of this creative manipulation system, and a range of high-level micromanipulation abilities such as pick-and-place, microseparation, and three-dimensional microassembly. Highlighting rapid design and fabrication of a low-cost precision micromanipulation system, this paper proposes new applications of folded machines to wearable robots and microrobotics.

Generation of perfect vortex and vector beams based on Pancharatnam-Berry phase elements

Perfect vortex beams are the orbital angular momentum (OAM)-carrying beams with fixed annular intensities, which provide a better source of OAM than traditional Laguerre-Gaussian beams. However, ordinary schemes to obtain the perfect vortex beams are usually bulky and unstable. We demonstrate here a novel generation scheme by designing planar Pancharatnam-Berry (PB) phase elements to replace all the elements required. Different from the conventional approaches based on reflective or refractive elements, PB phase elements can dramatically reduce the occupying volume of system. Moreover, the PB phase element scheme is easily developed to produce the perfect vector beams. Therefore, our scheme may provide prominent vortex and vector sources for integrated optical communication and micromanipulation systems.

Bestimmung bakterieller Haftkräfte durch gezielte Scherkrafteinwirkung

Research in the field of bioadhesion is crucial to determine the antimicrobial efficacy. Experiments include cultivations with Escherichia coli K12 JM109 to reach bacteria adhesion in order to enable adhesion force measurements between bacterium and surface with a new micromanipulation system installed in atomic force microscope. To alter the surface, hydrophobic surfaces were generated with Argon/C4F8 plasma. The findings demonstrate the successful validation of the new micromanipulation system to measure the bacterial adhesion force and additionally show the antiadhesive effect of fluorine.

Freestanding electrostatic scratch drive microstructures using lamination of photosensitive films for microfluidics and microrobotics applications

With the deeply cognition of the micro domain, in biomedical, analytical chemistry, and integrated circuits manufacturing etc., there is an urgent need to develop some object which is micro-sized or able to be micro-operated. However, conventional micromanipulation systems are limited by space, accuracy and safety. In this work, a facile fabrication method is demonstrated to create three-dimensional (3D) electrostatic microstructures for microrobotics applications. The microstructures are developed using lamination of SU-8 photosensitive films and deposition of copper (Cu), which has potential for large-scale manufacturing. The simulation of the electrostatic microstructures movement was conducted; and the results showed the maximum deformation occurred in the waist; strain and stress concentrated at bottom edge of the microrobot. The microstructures were actuated moving on an electric substrate by varying the voltage. It was found that the microstructure step size is proportional to the square of voltage. When 1000 V, 50 Hz electric field was applied, the step size was 0.1 µm and average speed could achieve 300 µm/min, which shows great potential in microfluidics and microrobotics applications.

Analysis of multiple robotic assemblies by cooperation of multimobile micromanipulation systems (M4S)

This paper presents different analyses by cooperation of multimobile micromanipulation systems (M4S) for robotic microassembly where assembly is performed in a grid pattern by dividing it into different zones. To cater this need, a new design of M4S for robotic assembly is proposed where different peg-in-hole assemblies are carried out. For attempting the different combinations by cooperation of M4S, a novel algorithm is developed which provides a solution for robotic microassembly in a more efficient and precise manner within less time. Experientially, it is proved that this novel design of M4S is capable of performing the different manipulation tasks of miniature parts. Different analyses prove its potentiality of robotic assembly in industrial applications.

Progression in the Fountain Pen Approach: From 2D Writing to 3D Free-Form Micro/Nanofabrication.

The fountain pen approach, as a means for transferring materials to substrates, has shown numerous incarnations in recent years for creating 2D micro/nanopatterns and even generating 3D free-form nanostructures using a variety of material "inks". While the idea of filled reservoirs used to deliver material to a substrate via a capillary remains unchanged since antiquity, the advent of precise micromanipulation systems and functional material "inks" allows the extension of this mechanism to more high-tech applications. Herein, the recent growth in meniscus guided fountain pen approaches for benchtop micro/nanofabrication, which has occurred in the last decade, is discussed. Particular attention is given to the theory, equipment, and experimentation encompassing this unique direct writing approach. A detailed exploration of the diverse ink systems and functional device applications borne from this strategy is put forth to reveal its rapid expansion to a broad range of scientific and engineering disciplines. As such, this informative review is provided for researchers considering adoption of this recent advancement of a familiar technology.

Design and optimization of a novel magnetically-actuated micromanipulator

The ability of external magnetic fields to precisely control micromanipulators has received a great deal of attention from researchers in recent years due to its off-board power source. Researchers have proposed a number of designs for magnetically-actuated micromanipulators for various applications. However, in most of the proposed magnetically-actuated micromanipulators, the manipulator workspace area is small relative to the manipulator volume, and the ratio of the generated magnetic force to manipulator weight is low. In this paper, we introduce design and optimization procedures for a portable magnetically-actuated micromanipulator. The proposed micromanipulator has many potential applications, such as medical applications, pick and place operations, micro-assembly, and micro-machining processes. The proposed micromanipulator has two main subsystems: a magnetic actuator and an electromagnetic end-effector that is connected to the magnetic actuator by a needle. In this paper, we focus on the magnetic actuation concept of the proposed micromanipulator system. We present the optimal configuration that will maximize the micromanipulator actuation force, and a closed form solution for micromanipulator actuation force. We also present the force measurement experimental setup and results of finite element methods (FEM) analysis to validate the developed model. The results show an agreement between the model, the experiment, and the FEM results. The error difference between the FEM, experimental, and model data is approximately 0.05 N.

Switched Fuzzy-PD Control of Contact Forces in Robotic Microbiomanipulation.

Force sensing and control are of paramount importance in robotic micromanipulation. A contact force regulator capable of accurately applying mechanical stimuli to a live Drosophila larva could greatly facilitate mechanobiology research on Drosophila and may eventually lead to novel discoveries in mechanotransduction mechanisms of neuronal circuitries. In this paper, we present a novel contact force control scheme implemented in an automated Drosophila larvae micromanipulation system, featuring a switched fuzzy to proportional-differential (PD) controller and a noise-insensitive extended high gain observer (EHGO). The switched fuzzy-PD control law inherits the fast convergence of fuzzy control and overcomes its drawbacks such as large overshoot and steady-state oscillation. The noise-insensitive EHGO can reliably estimate system modeling errors and is robust to force measurement noises, which is advantageous over conventional high gain observers (sensitive to signal noises). Force control experiments show that, compared to a proportional-integral-differential (PID) controller, this new force control scheme significantly enhances the system dynamic performance in terms of rising time, overshoot, and oscillation. The developed robotic system and the force control scheme will be applied to mechanical stimulation and fluorescence imaging of Drosophila larvae for identifying new mechanotransduction mechanisms.

Microbubbles for High-Speed Assembly of Cell-Laden Vascular-Like Microtube

Vascular-like microtube takes an important role in delivering oxygen and nutrient to keep cell alive in the generated tissue. In this paper, we present an automated micromanipulation system to assemble 2-D gel micro-rings to vascular-like microtubes by means of generating and controlling microbubbles. The detailed automated assembly process is described. To enable the automated assembly, real-time image processing has been utilized to detect end-effectors and gel micro-rings in 2-D X-Y plane. Additionally, we can acquire an estimated depth information by implementing the optimized template match. The motion model of the microbubbles is analyzed and applied to control the microbubbles. As a preliminary test, a cell-laden microtube consisting of 33 layers gel micro-rings is fabricated. Experimental results show that the bubble-based assembly method and the automated micromanipulation system allow high efficiency and high success rate for the assembly of microtubes.

Modelling and adaptive dynamic sliding mode control of dielectrophoresis-based micromanipulation

Automated, precise single particle manipulation in the microscale is in great demand and is one of the great challenges in biomedical and biochemical engineering. Automatic micromanipulation has also become a microrobotics challenge. Following this challenge, control technology is integrated with dielectrophoresis (DEP)-based micromanipulation technology in this paper to construct automatic DEP-based micromanipulation systems. DEP micromanipulation systems with electrodes of quadrupole polynomial geometry are developed as controllable microactuators. A semianalytical modelling method is proposed to formulate the analytical models of the DEP manipulation systems, which manifests that the DEP manipulation systems are non-affine non-linear systems. Then, taking the parameter uncertainties, unmodelled dynamics and external disturbances into account, an adaptive law combined with a dynamic sliding mode controller is designed for two-dimensional trajectory tracking control of a DEP micromanipulation system. The closed-loop system is proved stable in the presence of bounded lumped uncertainty based on the Lyapunov theorem. Finally, simulation results show the validity of the proposed control design.

Isolation and characterization of circulating tumor cells using a novel workflow combining the CellSearch® system and the CellCelector™.

Circulating tumor cells (CTC) are rare cells which have left the primary tumor to enter the blood stream. Although only a small CTC subgroup is capable of extravasating, the presence of CTCs is associated with an increased risk of metastasis and a shorter overall survival. Understanding the heterogeneous CTC biology will optimize treatment decisions and will thereby improve patient outcome. For this, robust workflows for detection and isolation of CTCs are urgently required. Here, we present a workflow to characterize CTCs by combining the advantages of both the CellSearch® and the CellCelector™ micromanipulation system. CTCs were isolated from CellSearch® cartridges using the CellCelector™ system and were deposited into PCR tubes for subsequent molecular analysis (whole genome amplification (WGA) and massive parallel multigene sequencing). By a CellCelector™ screen we reidentified 97% of CellSearch® SKBR-3 cells. Furthermore, we isolated 97% of CellSearch® -proven patient CTCs using the CellCelector™ system. Therein, we found an almost perfect correlation of R2 =0.98 (Spearman's rho correlation, n=20, p<0.00001) between the CellSearch® CTC count (n=271) and the CellCelector™ detected CTCs (n=252). Isolated CTCs were analyzed by WGA and massive parallel multigene sequencing. In total, single nucleotide polymorphisms (SNPs) could be detected in 50 genes in seven CTCs, 12 MCF-7, and 3 T47D cells, respectively. Taken together, CTC quantification via the CellCelector™ system ensures a comprehensive detection of CTCs preidentified by the CellSearch® system. Moreover, the isolation of CTCs after CellSearch® using the CellCelector™ system guarantees for CTC enrichment without any contaminants enabling subsequent high throughput genomic analyses on single cell level. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:125-132, 2017.

An Automated Force-Controlled Robotic Micromanipulation System for Mechanotransduction Studies of Drosophila Larvae

The capability of accurately applying millinewton-level touch stimuli to Drosophila larvae and simultaneously observing their resultant fluorescence responses in mechanosensitive neuron transmission will enable novel studies of mechanotransduction neural circuitry. This paper presents an automated robotic micromanipulation system capable of force-controlled mechanical stimulation and quantitative fluorescence imaging of Drosophila larvae, which significantly improves the force regulation accuracy and operation consistency over conventional manual operations. An elastomeric microdevice is developed for efficient immobilization of an array of larvae for subsequent force-controlled touching. A microelectromechanical systems (MEMS) based force sensor is integrated into the robotic system for closed-loop force control of larva touching at a resolution of 50 $\mu{\rm N}$ . Two micromanipulators are coordinately servoed using orchestrated position and force control laws for automatic operations. The system performs simultaneous force-controlled larva touching and fluorescence imaging at a speed of four larvae per minute, with a success rate of 92.5%. This robotic system will greatly facilitate the dissection of mechanotransduction mechanisms of Drosophila larvae at both molecular and cellular levels.