Micromanipulation Tools Research Articles

Light-Driven Microrobots for Targeted Drug Delivery.

As a new micromanipulation tool with the advantages of small size, flexible movement and easy manipulation, light-driven microrobots have a wide range of prospects in biomedical fields such as drug targeting and cell manipulation. Recently, microrobots have been controlled in various ways, and light field has become a research hotspot by its advantages of noncontact manipulation, precise localization, fast response, and biocompatibility. It utilizes the force or deformation generated by the light field to precisely control the microrobot, and combines with the drug release technology to realize the targeted drug application. Therefore, this paper provides an overview of light-driven microrobots with drug targeting to provide new ideas for the manipulation of microrobots. Here, this paper briefly categorizes the driving mechanisms and materials of light-driven microrobots, which mainly include photothermal, photochemical, and biological. Then, typical designs of light-driven microrobots with different driving mechanisms and control strategies for multiple physical fields are summarized. Finally, the applications of microrobots in the fields of drug targeting and bioimaging are presented as well as the future prospects of light-driven microrobots in the biomedical field are demonstrated.

Ergonomic Practice in Medical Laboratory Workers in a Tertiary Care Hospital in Lahore

Objective: To evaluate the ergonomics practice pattern among medical laboratory professionals to determine the ergonomic deficiencies to improve the workplace quality and safety at a tertiary care hospital in Lahore Methodology: This was a cross-sectional study conducted in department of pathology, King Edward Medical University/Mayo Hospital, Lahore from November 2019 to January 2020. All the workers engaged in all the sections of the clinical laboratory were included in the study. The results were collected using a self-administered questionnaire, which included demographic information, ergonomic practices, workplace layouts and equipment utilization pattern. Individuals were instructed to complete the questionnaires in accordance to their own specific time range and return it after filling. All the data was gathered from the surveys and then coded and securely stored in a database for further analysis and interpretation. Results: Average age of the participants was 26.80±5.70 years. Several participants reported appropriate bench heights (70.7%) and tools within arm’s reach (62.2%), deficiencies were noted in foot and knee clearance, with only 50.0% and 53.7% respectively. Limited provision of foot rails (11.0%) and floor mats (31.7%) for prolonged standing tasks was seen. Seated benches showed similar disparities, with notable deficiencies in adjustable armrests (32.9%) and footrests (29.3%). Microscope usage demonstrated challenges in maintaining neutral posture (65.1%), while pipette use and micro-manipulation tools highlighted the need for improved accessibility and ergonomic support. Conclusion: Study revealed the varying levels of ergonomic appropriateness across the workplace and equipment among medical laboratory workers, with significant inadequacies in foot and knee clearance, the presence of foot rails, floor mats, adjustable armrests, and foot rests. Difficulties in using a microscope, as well as concerns about pipettes and micro-manipulation equipment, underscored the need for improved accessibility and ergonomics.

Mixed-Transducer Micro-Origami for Efficient Motion and Decoupled Sensing.

This work introduces a mixed-transducer micro-origami to achieve efficient vibration, controllable motion, and decoupled sensing. Existing micro-origami systems tend to have only one type of transducer (actuator/sensor), which limits their versatility and functionality because any given transducer system has a narrow range of advantageous working conditions. However, it is possible to harness the benefit of different micro-transducer systems to enhance the performance of functional micro-origami. More specifically, this work introduces a micro-origami system that can integrate the advantages of three transducer systems: strained morph (SM) systems, polymer based electro-thermal (ET) systems, and thin-film lead zirconate titanate (PZT) systems. A versatile photolithography fabrication process is introduced to build this mixed-transducer micro-origami system, and their performance is investigated through experiments and simulation models. This work shows that mixed-transducer micro-origami can achieve power efficient vibration with high frequency, large vibration ranges, and little degradation; can produce decoupled folding motion with good controllability; and can accomplish simultaneous sensing and actuation to detect and interact with external environments and small-scale samples. The superior performance of mixed-transducer micro-origami systems makes them promising tools for micro-manipulation, micro-assembly, biomedical probes, self-sensing metamaterials, and more.

Optimal calibration of optical tweezers with arbitrary integration time and sampling frequencies: a general framework [Invited

Optical tweezers (OT) have become an essential technique in several fields of physics, chemistry, and biology as precise micromanipulation tools and microscopic force transducers. Quantitative measurements require the accurate calibration of the trap stiffness of the optical trap and the diffusion constant of the optically trapped particle. This is typically done by statistical estimators constructed from the position signal of the particle, which is recorded by a digital camera or a quadrant photodiode. The finite integration time and sampling frequency of the detector need to be properly taken into account. Here, we present a general approach based on the joint probability density function of the sampled trajectory that corrects exactly the biases due to the detector's finite integration time and limited sampling frequency, providing theoretical formulas for the most widely employed calibration methods: equipartition, mean squared displacement, autocorrelation, power spectral density, and force reconstruction via maximum-likelihood-estimator analysis (FORMA). Our results, tested with experiments and Monte Carlo simulations, will permit users of OT to confidently estimate the trap stiffness and diffusion constant, extending their use to a broader set of experimental conditions.

Solving the Non-Linear Motion in a Micromanipulation System Powered by Thermocapillary Flows

Non-contact micromanipulation tools have emerged as a promising solution for manipulating small components. However, they are mainly based on non-linear actuation principles requiring ad-hoc control strategies. This paper proposes non-linear control laws to actuate a non-contact manipulation system based on thermocapillary flows for the manipulation of micro-objects on an air-water interface. The actuation system consists of steering a laser beam to locally heat the liquid surface, thus inducing a thermocapillary flow. The resulting flow propels floating objects away from the laser spot with a significant velocity (up to ten body-length per second) but the behavior is highly non-linear. Notably, small errors in the laser positioning are amplified and give place to non-linear motion. Therefore, we developed a control method consisting of a non-linear position controller including a laser position observer. We achieve stable 2D position control in this non-linear system, with a precision of 0.3 mm on a 0.5 mm object.

Precise electrokinetic position and three-dimensional orientation control of a nanowire bioprobe in solution.

Owing to Brownian-motion effects, the precise manipulation of individual micro- and nanoparticles in solution is challenging. Therefore, scanning-probe-based techniques, such as atomic force microscopy, attach particles to cantilevers to enable their use as nanoprobes. Here we demonstrate a versatile electrokinetic trap that simultaneously controls the two-dimensional position with a precision of 20 nm and 0.5° in the three-dimensional orientation of an untethered nanowire, as small as 300 nm in length, under an optical microscope. The method permits the active transport of nanowires with a speed-dependent accuracy reaching 90 nm at 2.7 μm s-1. It also allows for their synchronous three-dimensional alignment and rotation during translocation along complex trajectories. We use the electrokinetic trap to accurately move a nanoprobe and stably position it on the surface of a single bacterial cell for sensing secreted metabolites for extended periods. The precision-controlled manipulation underpins developing nanorobotic tools for assembly, micromanipulation and biological measurements with subcellular resolution.

Optically induced electrothermal microfluidic tweezers in bio-relevant media

Non-contact micro-manipulation tools have enabled invasion-free studies of fragile synthetic particles and biological cells. Rapid electrokinetic patterning (REP) traps target particles/cells, suspended in an electrolyte, on an electrode surface. This entrapment is electrokinetic in nature and thus depends strongly on the suspension medium’s properties. REP has been well characterized for manipulating synthetic particles suspended in low concentration salt solutions (~ 2 mS/m). However, it is not studied as extensively for manipulating biological cells, which introduces an additional level of complexity due to their limited viability in hypotonic media. In this work, we discuss challenges posed by isotonic electrolytes and suggest solutions to enable REP manipulation in bio-relevant media. Various formulations of isotonic media (salt and sugar-based) are tested for their compatibility with REP. REP manipulation is observed in low concentration salt-based media such as 0.1× phosphate buffered saline (PBS) when the device electrodes are passivated with a dielectric layer. We also show manipulation of murine pancreatic cancer cells suspended in a sugar-based (8.5% w/v sucrose and 0.3% w/v dextrose) isotonic medium. The ability to trap mammalian cells and deposit them in custom patterns enables high-impact applications such as determining their biomechanical properties and 3D bioprinting for tissue scaffolding.

Microfluidic Approaches for Microactuators: From Fabrication, Actuation, to Functionalization.

Microactuators can autonomously convert external energy into specific mechanical motions. With the feature sizes varying from the micrometer to millimeter scale, microactuators offer many operation and control possibilities for miniaturized devices. In recent years, advanced microfluidic techniques have revolutionized the fabrication, actuation, and functionalization of microactuators. Microfluidics can not only facilitate fabrication with continuously changing materials but also deliver various signals to stimulate the microactuators as desired, and consequently improve microfluidic chips with multiple functions. Herein, this cross-field that systematically correlates microactuator properties and microfluidic functions is comprehensively reviewed. The fabrication strategies are classified into two types according to the flow state of the microfluids: stop-flow and continuous-flow prototyping. The working mechanism of microactuators in microfluidic chips is discussed in detail. Finally, the applications of microactuator-enriched functional chips, which include tunable imaging devices, micromanipulation tools, micromotors, and microsensors, are summarized. The existing challenges and future perspectives are also discussed. It is believed that with the rapid progress of this cutting-edge field, intelligent microsystems may realize high-throughput manipulation, characterization, and analysis of tiny objects and find broad applications in various fields, such as tissue engineering, micro/nanorobotics, and analytical devices.

The Full Model of Micropipette Aspiration of Cells: A Mesoscopic Simulation.

Studies on the interaction between cells and micromanipulation tools are necessary to optimize the procedures and improve the developmental potential of cells. The molecular dynamics simulation is not possible for such a large-scale simulation, and the spring-damped viscoelastic models and the constitutive equationsof the continuum are usually adopted to model the cells as a whole without consideration of the different properties presented by the heterogeneous subcellular components. In this study, we utilized coarse-grained modeling to develop a subcellular model of suspension cell dynamics and a model of a holding micropipette for the fixation of a suspension cell, and designed a large-scale, accurate mesoscopic simulation environment for specific cell micromanipulation. We established a triangular mesh cell membrane and a uniformly distributed, non-intersecting cytoskeleton network and added polymerization/depolymerization processes to connect the cytoskeleton chains with the membrane and cross-linking proteins. In the cell aspiration model, we adopted the profile of the reversed Poiseuille flow to calibrate the viscosity of the fluid and set the bounce-back condition and the appropriate solid-fluid force coefficient to realize non-slip flow at the boundary. The rheological properties of the cells during micropipette aspiration were further analyzed in the simulation by varying parameters such as the inner diameter of the micropipette, negative pressure, and maximum bond length. The model well reproduced the experimentally observed cell deformation phenomenon at low and high pressures. The dynamic response of the cell elongation observed from the simulation was consistent with that obtained from the analysis of the experimental data collected from a custom-designed micromanipulation system. STATEMENT OF SIGNIFICANCE: In this study, we extended the coarse-grained modeling of cells by developing a relatively large-scale micromanipulation environment consisting of a subcellular cell dynamics model and a fluid flow model for cell aspiration. We simulated cytoskeleton filaments that were uniformly distributed in space via applying Harmonic energy to model cytoskeleton with a high level of fidelity. The shortcoming of the soft repulsion in the solid-fluid interaction in the current simulation technique was solved by implementing the bounce-back boundary and the condition that the total force imposed by the wall particles on the fluid particles was equal to the pressure of the fluid. This work paved the way for understanding the mechanical properties of cells and improving the biological efficacy of micromanipulation.

Past, present and future prospect on microinjection gene transfer in aquaculture

Microinjection is arguably the most direct and reliable gene transfer method to date. Since the development of the first transgenic fish in 1984, microinjection continues to be the most commonly used gene transfer method in aquaculture. Microinjection is used to inject cells, nucleic acid, gene constructs, recombinant DNA, and morpholino oligonucleotides into fish cells, embryos, and larvae. Despite the development of various gene transfer methods, microinjection is preferable. Continuous improvement in micromanipulation tools and micro capillary further develop microinjection method. This review describes the past and present use of microinjection gene transfer methods for genetic manipulation and genetic improvement in fisheries and aquaculture, especially in fish transgenesis. Furthermore, we discuss the future prospects of microinjection method in tandem with recombinant DNA technology and CRISPR-Cas9 and its application in the aquaculture industry.

Optimal in-depth trapping by tuning the correction collar of a dry objective lens

Optical tweezers are proven and indispensable micro-manipulation tools. It is very common to use an immersion-assisted high NA objective for optical trapping of micrometer-sized beads. However, such objectives suffer from low working depth range. Here we show, both by theory and experiment, that a dry objective can be utilized for optimal trapping of even sub-micrometer objects. For the first time, to the best of our knowledge, we were able to stably trap polystyrene beads with radii of 270 and 175 nm in 3D using an objective with numerical aperture of 0.9.

Performance Analysis of a CSFH-Based Microgripper: Analytical Modeling and Simulation.

Microgrippers are promising tools for micro-manipulation and characterization of cells. In this paper, a biocompatible electro-thermally actuated microgripper with rotary capacitive position sensor is presented. To overcome the limited displacement possibilities usually provided by electrothermal actuators and to achieve the desired tweezers output displacement, conjugate surface flexure hinges (CSFH) are adopted. The microgripper herein reported can in principle manipulate biological samples in the size range between 15 and 120 µm. A kinematics modeling approach based on the pseudo-rigid-body-method (PRBM) is applied to describe the microgripper’s working mechanism, and analytical modeling, based on finite elements method (FEM), is used to optimize the electrothermal actuator design and the heat dissipation mechanism. Finally, FEM-based simulations are carried out to verify the microgripper, the electrothermal actuator and heat dissipation mechanism performance, and to assess the validity of the analytical modeling.

Design and fabrication of micromanipulation tools for electrochemical-based manipulation of metal microcomponents

Design and fabrication of micromanipulation tools for electrochemical-based manipulation of metal microcomponents

Towards a Comprehensive and Robust Micromanipulation System with Force-Sensing and VR Capabilities.

In this modern world, with the increase of complexity of many technologies, especially in the micro and nanoscale, the field of robotic manipulation has tremendously grown. Microrobots and other complex microscale systems are often to laborious to fabricate using standard microfabrication techniques, therefore there is a trend towards fabricating them in parts then assembling them together, mainly using micromanipulation tools. Here, a comprehensive and robust micromanipulation platform is presented, in which four micromanipulators can be used simultaneously to perform complex tasks, providing the user with an intuitive environment. The system utilizes a vision-based force sensor to aid with manipulation tasks and it provides a safe environment for biomanipulation. Lastly, virtual reality (VR) was incorporated into the system, allowing the user to control the probes from a more intuitive standpoint and providing an immersive platform for the future of micromanipulation.

Mechanophotonics-Mechanical Micromanipulation of Single-Crystals toward Organic Photonic Integrated Circuits.

The advent of molecular crystals as "smart" nanophotonic components namely, organic waveguides, resonators, lasers, and modulators are drawing wider attention of solid-state materials scientists and microspectroscopists. Crystals are usually rigid, and undeniably developing next-level crystalline organic photonic circuits of complex geometries demands using mechanically flexible crystals. The mechanical shaping of flexible crystals necessitates applying challenging micromanipulation methods. The rise of atomic force microscopy as a mechanical micromanipulation tool has increased the scope of mechanophotonics and subsequently, crystal-based microscale organic photonic integrated circuits (OPICs). The unusual higher adhesive energy of the flexible crystals to the surface than that of crystal shape regaining energy enables carving intricate crystal geometries using micromanipulation. This perspective reviews the progress made in a key research area developed by my research group, namely mechanophotonics-a discipline that uses mechanical micromanipulation of single-crystal optical components, to advance nanophotonics. The precise fabrication of photonic components and OPICs from both rigid and flexible microcrystal via AFM mechanical operations namely, moving, lifting, cutting, slicing, bending, and transferring of crystals are presented. The ability of OPICs to guide, split, couple, and modulate visible electromagnetic radiation using passive, active, and energy transfer mechanism are discussed as well with recent literature examples.

A microrobotic platform actuated by thermocapillary flows for manipulation at the air-water interface.

Future developments in micromanufacturing will require advances in micromanipulation tools. Several robotic micromanipulation methods have been developed to position micro-objects mostly in air and in liquids. The air-water interface is a third medium where objects can be manipulated, offering a good compromise between the two previously mentioned ones. Objects at the interface are not subjected to stick-slip due to dry friction in air and profit from a reduced drag compared with those in water. Here, we present the ThermoBot, a microrobotic platform dedicated to the manipulation of objects placed at the air-water interface. For actuation, ThermoBot uses a laser-induced thermocapillary flow, which arises from the surface stress caused by the temperature gradient at the fluid interface. The actuated objects can reach velocities up to 10 times their body length per second without any on-board actuator. Moreover, the localized nature of the thermocapillary flow enables the simultaneous and independent control of multiple objects, thus paving the way for microassembly operations at the air-water interface. We demonstrate that our setup can be used to direct capillary-based self-assemblies at this interface. We illustrate the ThermoBot's capabilities through three examples: simultaneous control of up to four spheres, control of complex objects in both position and orientation, and directed self-assembly of multiple pieces.

Nature of trapping forces in optically induced electrothermal vortex based tweezers

Precise manipulation of micro and nanosized particles has enabled investigations into various applications ranging from mechanobiology of biomolecules and cells to self-assembly of two-dimensional colloids. This work is focussed on studying the nature of a noninvasive electrothermal vortex based micro-manipulation tool called rapid electrokinetic patterning (REP). Using the equipartition method, we show that a REP trap is Hookean in nature and has an ultralow trap stiffness on the order of femtonewtons/\ensuremath{\mu}m. The dynamic tunability of an optically induced REP trap makes it a versatile tool for various biophysical applications.

Applications of Optically Controlled Gold Nanostructures in Biomedical Engineering.

Since their inception, optical tweezers have proven to be a useful tool for improving human understanding of the microscopic world with wide-ranging applications across science. In recent years, they have found many particularly appealing applications in the field of biomedical engineering which harnesses the knowledge and skills in engineering to tackle problems in biology and medicine. Notably, metallic nanostructures like gold nanoparticles have proven to be an excellent tool for OT-based micromanipulation due to their large polarizability and relatively low cytotoxicity. In this article, we review the progress made in the application of optically trapped gold nanomaterials to problems in bioengineering. After an introduction to the basic methods of optical trapping, we give an overview of potential applications to bioengineering specifically: nano/biomaterials, microfluidics, drug delivery, biosensing, biophotonics and imaging, and mechanobiology/single-molecule biophysics. We highlight the recent research progress, discuss challenges, and provide possible future directions in this field.

Bubbles in microfluidics: an all-purpose tool for micromanipulation.

In recent decades, the integration of microfluidic devices and multiple actuation technologies at the microscale has greatly contributed to the progress of related fields. In particular, microbubbles are playing an increasingly important role in microfluidics because of their unique characteristics that lead to specific responses to different energy sources and gas-liquid interactions. Many effective and functional bubble-based micromanipulation strategies have been developed and improved, enabling various non-invasive, selective, and precise operations at the microscale. This review begins with a brief introduction of the morphological characteristics and formation of microbubbles. The theoretical foundations and working mechanisms of typical micromanipulations based on acoustic, thermodynamic, and chemical microbubbles in fluids are described. We critically review the extensive applications and the frontline advances of bubbles in microfluidics, including microflow patterns, position and orientation control, biomedical applications, and development of bubble-based microrobots. We lastly present an outlook to provide directions for the design and application of microbubble-based micromanipulation tools and attract the attention of relevant researchers to the enormous potential of microbubbles in microfluidics.

Optical trapping in the presence of laser-induced thermal effects.

The inclusion of thermal effects in optical manipulation has been explored in diverse experiments, increasing the possibilities for applications in diverse areas. In this Letter, the results of combined optical and thermal manipulation in the vicinity of a highly absorbent hydrogenated amorphous silicon layer, which induces both the generation of convective currents and thermophoresis, are presented. In combination with the optical forces, thermal forces help reduce the optical power required to trap and manipulate micrometric polystyrene beads. Moreover, the inclusion of these effects allows the stacking and manipulation of multiple particles with a single optical trap along with the beam propagation, providing an extra tool for micromanipulation of a variety of samples.