Design and Implementation of Electromagnetic Actuation System to Actuate Micro/NanoRobots in Viscous Environment

The navigation of Micro/Nanorobots (MNRs) with the ability to track a selected trajectory accurately holds significant promise for different applications in biomedicine, providing methods for diagnoses and treatments inside the human body. The critical challenge is ensuring that the required power can be generated within the MNR. Furthermore, ensuring that it is feasible for the robot to travel inside the human body with the necessary power availability. Currently, MNRs are widely driven either by exogenous power sources (light energy, magnetic fields, electric fields, acoustics fields, etc.) or by endogenous energy sources, such as chemical interaction energy. Various driving techniques have been established, including piezoelectric as a driving source, thermal driving, electro-osmotic force driven by biological bacteria, and micro-motors powered by chemical fuel. These driving techniques have some restrictions, mainly when used in biomedicine. External magnetic fields are another potential power source of MNRs. Magnetic fields can permeate deep tissues and be safe for human organisms. As a result, magnetic fields’ magnetic forces and moments can be applied to MNRs without affecting biological fluids and tissues. Due to their features and characteristics of magnetic fields in generating high power, they are naturally suited to control the electromagnetically actuated MNRs in inaccessible locations due to their ability to go through tiny spaces. From the literature, it can be inferred from the available range of actuation technologies that magnetic actuation performs better than other technologies in terms of controllability, speed, flexibility of the working environment, and far less harm may cause to people. Also, electromagnetic actuation systems may come in various configurations that offer many degrees of freedom, different working mediums, and controllability schemes. Although this is a promising field of research, further simulation studies, and analysis, new smart materials, and the development and building of new real systems physically, and testing the concepts under development from different aspects and application requirements are required to determine whether these systems could be implemented in natural clinical settings on the human body. Also, to understand the latest development in MNRs and the actuation techniques with the associated technologies. Also, there is a need to conduct studies and comparisons to conclude the main research achievements in the field, highlight the critical challenges waiting for answers, and develop new research directions to solve and improve the performance. Therefore, this thesis aims to model and analyze, simulate, design, develop, and implement (with complete hardware and software integration) an electromagnetic actuation (EMA) system to actuate MNRs in the sixdimensional (6D) motion space inside a relatively large region of interest (ROI). The second stage is a simulation; simulation and finite element analysis were conducted. COMSOL multi-physics software is used to analyze the performance of different coils and coil pairs for Helmholtz and Maxwell coil configurations and electromagnetic actuation systems. This leads to the following.: • Finite element analysis (FEA) demonstrates that the Helmholtz coils generate a uniform and consistent magnetic field within a targeted ROI, and the Maxwell coils generate a uniform magnetic gradient. • The possibility to combine Helmholtz and Maxwell coils in different space dimensions. With the ability to actuate an MNR in a 6D space: 3D as a position and 3D as orientation. • Different electromagnetic system configurations are proposed, and their effectiveness in guiding an MNR inside a mimicked blood vessel environment was assessed. • Three pairs of Helmholtz coils and three pairs of coils of Maxwell coils are combined to actuate different size MNRs inside a mimicked blood vessel environment and in 6D. Based on the modeling results, a magnetic actuation system prototype that can control different sizes MNRs was conceived. A closed-loop control algorithm was proposed, and motion analysis of the MNR was conducted and discussed for both position and orientation. Improved EMA location tracking along a chosen trajectory was achieved using a PID-based closed-loop control approach with the best possible parameters. Through the model and analysis stage, the developed system was simulated and tested using open- and closed-loop circumstances. Finally, the closedloop controlled system was concluded and simulated to verify the ability of the proposed EMA to actuate an MN under different trajectory tracking examples with different dimensionality and for different sizes of MNRs. The last stage is developing the experimental setup by manufacturing the coils and their base in-house. Drivers and power supplies are selected according to the specifications that actuate the coils to generate the required magnetic field. Three digital microscopes were integrated with the electromagnetic actuation system to deliver visual feedback aiming to track in real-time the location of the MNR in the 6D high viscous fluidic environment, which leads to enabling closed-loop control. The closed-loop control algorithm is developed to facilitate MNR trajectory tracking and minimize the error accordingly. Accordingly, different tests were carried out to check the uniformity of the magnetic field generated from the coils. Also, a test was done for the digital microscope to check that it was calibrated and it works correctly. Experimental tests were conducted in 1D, 2D plane, and 3D trajectories with two different MNR sizes. The results show the ability of the proposed EMA system to actuate the two different sizes with a tracking error of 20-45 µm depending on the axis and the size of the MNR. The experiments show the ability of the developed EMA system to hold the MNR at any point within the 3D fluidic environment while overcoming the gravity effects. A comparison was made between the results achieved (in simulation and physical experiments) and the results deduced from the literature. The comparison shows that the thesis’s outcomes regarding the error and MNR size used are significant, with better performance relative to the MNR size and value of the error

Microfluidics and Bio-MEMS for Next Generation Healthcare.

Ph.D. Thesis. University of Hawaiʻi at Mānoa 2018

Advances in colloidal manipulation and transport via hydrodynamic interactions

In this review article, we highlight many recent advances in the field of micromanipulation of colloidal particles using hydrodynamic interactions (HIs), namely solvent mediated long-range interactions. At the micrsocale, the hydrodynamic laws are time reversible and the flow becomes laminar, features that allow precise manipulation and control of colloidal matter. We focus on different strategies where externally operated microstructures generate local flow fields that induce the advection and motion of the surrounding components. In addition, we review cases where the induced flow gives rise to hydrodynamic bound states that may synchronize during the process, a phenomenon essential in different systems such as those that exhibit self-assembly and swarming

Light modulation of electric field driven semiconductor micromotors

The future micro/nanorobots require high degrees of freedom in motion control to perform complex tasks by individuals or by a swarm. It remains a great challenge to control the motions of an individual nanomachine amidst many, to switch the operation modes facilely, and it is even more difficult to actuate several components of a nanomachine coordinately for purposed actions. This high degree of versatility is essential for the future micro/nanorobots and requires investigation of innovative actuation mechanisms. In this dissertation, we report our recent finding about a new approach combining two types of stimulation to achieve such goal. The micromotors being studied are made of semiconductor silicon nanowires. Mechanical motion of the motors is driven by several types of AC electric field. Meanwhile, the electrical property of the nanowires can be locally and instantaneously modulated by visible light illumination in a reversible manner. We demonstrate that visible light is able to change the electric polarization of semiconductor nanowires under AC electric field, and reflected by the dramatic change of mechanical motions with very rich configurations. Under a rotating electric field, the rotation speed of semiconductor Si nanowires in electric fields can instantly increase, decrease, and even reverse the orientation by light illumination in the visible to infrared regime at various AC E-field frequencies. Under a linear AC electric field, instantaneous change of alignment direction and speed of semiconductor nanowires is observed under visible-light exposure. With theoretical analysis and simulation, the working principle can be attributed to the optically tuned imaginary-part (out-phase) and real-part (in-phase) electrical polarization of a semiconductor nanowire in aqueous suspension. Based on the understanding of this system, we further propose a new approach to control the semiconductor micromotor via light tunable dielectrophoresis. Localized control of collective behavior in a highly density silicon nanowire suspension is also investigated. Finally, we demonstrated how to utilize the mechanical motion at microscale for practical application of biosensing.Materials Science and Engineerin

Enzyme Powered Nanomotors Towards Biomedical Applications

[eng] The advancements in nanotechnology enabled the development of new diagnostic tools and drug delivery systems based on nanosystems, which offer unique features such as large surface area to volume ratio, cargo loading capabilities, increased circulation times, as well as versatility and multifunctionality. Despite this, the majority of nanomedicines do not translate into clinics, in part due to the biological barriers present in the body. Synthetic nano- and micromotors could be an alternative tool in nanomedicine, as the continuous propulsion force and potential to modulate the medium may aid tissue penetration and drug diffusion across biological barriers. Enzyme-powered motors are especially interesting for biomedical applications, owing to their biocompatibility and use of bioavailable substrates as fuel for propulsion. This thesis aims at exploring the potential applications of urease-powered nanomotors in nanomedicine. In the first work, we evaluated these motors as drug delivery systems. We found that active urease- powered nanomotors showed active motion in phosphate buffer solutions, and enhanced in vitro drug release profiles in comparison to passive nanoparticles. In addition, we observed that the motors were more efficient in delivering drug to cancer cells and caused higher toxicity levels, due to the combination of boosted drug release and local increase of pH produced by urea breakdown into ammonia and carbon dioxide. One of the major goals in nanomedicine is to achieve localized drug action, thus reducing side-effects. A commonly strategy to attain this is the use moieties to target specific diseases. In our second work, we assessed the ability of urease-powered nanomotors to improve the targeting and penetration of spheroids, using an antibody with therapeutic potential. We showed that the combination of active propulsion with targeting led to a significant increase in spheroid penetration, and that this effect caused a decrease in cell proliferation due to the antibody’s therapeutic action. Considering that high concentrations of nanomedicines are required to achieve therapeutic efficiency; in the third work we investigated the collective behavior of urease-powered nanomotors. Apart from optical microscopy, we evaluated the tracked the swarming behavior of the nanomotors using positron emission tomography, which is a technique widely used in clinics, due to its noninvasiveness and ability to provide quantitative information. We showed that the nanomotors were able to overcome hurdles while swimming in confined geometries. We observed that the nanomotors swarming behavior led to enhanced fluid convection and mixing both in vitro, and in vivo within mice’s bladders. Aiming at conferring protecting abilities to the enzyme-powered nanomotors, in the fourth work, we investigated the use of liposomes as chassis for nanomotors, encapsulating urease within their inner compartment. We demonstrated that the lipidic bilayer provides the enzymatic engines with protection from harsh acidic environments, and that the motility of liposome-based motors can be activated with bile salts. Altogether, these results demonstrate the potential of enzyme-powered nanomotors as nanomedicine tools, with versatile chassis, as well as capability to enhance drug delivery and tumor penetration. Moreover, their collective dynamics in vivo, tracked using medical imaging techniques, represent a step-forward in the journey towards clinical translation.[spa] Recientes avances en nanotecnología han permitido el desarrollo de nuevas herramientas para el diagnóstico de enfermedades y el transporte dirigido de fármacos, ofreciendo propiedades únicas como encapsulación de fármacos, el control sobre la biodistribución de estos, versatilidad y multifuncionalidad. A pesar de estos avances, la mayoría de nanomedicinas no consiguen llegar a aplicaciones médicas reales, lo cual es en parte debido a la presencia de barreras biológicas en el organismo que limitan su transporte hacia los tejidos de interés. En este sentido, el desarrollo de nuevos micro- y nanomotores sintéticos, capaces de autopropulsarse y causar cambios locales en el ambiente, podrían ofrecer una alternativa para la nanomedicina, promoviendo una mayor penetración en tejidos de interés y un mejor transporte de fármacos a través de las barreras biológicas. En concreto, los nanomotores enzimáticos poseen un alto potencial para aplicaciones biomédicas gracias a su biocompatibilidad y a la posibilidad de usar sustancias presentes en el organismo como combustible. Los trabajos presentados en esta tesis exploran el potenical de nanomotores, autopropulsados mediante la enzima ureasa, para aplicaciones biomédicas, y investigan su uso como vehículos para transporte de fármacos, su capacidad para mejorar penetración de tejidos diana, su versatilidad y movimiento colectivo. En conjunto, los resultados presentados en esta tesis doctoral demuestran el potencial del uso de nanomotores autopropulsados mediante enzimas como herramientas biomédicas, ofreciendo versatilidad en su diseño y una alta capacidad para promover el transporte de fármacos y la penetración en tumores. Por último, su movimiento colectivo observado in vivo mediante técnicas de imagen médicas representan un significativo avance en el viaje hacia su aplicación en medicina

Modeling, simulation and control of microrobots for the microfactory.

Future assembly technologies will involve higher levels of automation in order to satisfy increased microscale or nanoscale precision requirements. Traditionally, assembly using a top-down robotic approach has been well-studied and applied to the microelectronics and MEMS industries, but less so in nanotechnology. With the boom of nanotechnology since the 1990s, newly designed products with new materials, coatings, and nanoparticles are gradually entering everyone’s lives, while the industry has grown into a billion-dollar volume worldwide. Traditionally, nanotechnology products are assembled using bottom-up methods, such as self-assembly, rather than top-down robotic assembly. This is due to considerations of volume handling of large quantities of components, and the high cost associated with top-down manipulation requiring precision. However, bottom-up manufacturing methods have certain limitations, such as components needing to have predefined shapes and surface coatings, and the number of assembly components being limited to very few. For example, in the case of self-assembly of nano-cubes with an origami design, post-assembly manipulation of cubes in large quantities and cost-efficiency is still challenging. In this thesis, we envision a new paradigm for nanoscale assembly, realized with the help of a wafer-scale microfactory containing large numbers of MEMS microrobots. These robots will work together to enhance the throughput of the factory, while their cost will be reduced when compared to conventional nanopositioners. To fulfill the microfactory vision, numerous challenges related to design, power, control, and nanoscale task completion by these microrobots must be overcome. In this work, we study two classes of microrobots for the microfactory: stationary microrobots and mobile microrobots. For the stationary microrobots in our microfactory application, we have designed and modeled two different types of microrobots, the AFAM (Articulated Four Axes Microrobot) and the SolarPede. The AFAM is a millimeter-size robotic arm working as a nanomanipulator for nanoparticles with four degrees of freedom, while the SolarPede is a light-powered centimeter-size robotic conveyor in the microfactory. For mobile microrobots, we have introduced the world’s first laser-driven micrometer-size locomotor in dry environments, called ChevBot to prove the concept of the motion mechanism. The ChevBot is fabricated using MEMS technology in the cleanroom, following a microassembly step. We showed that it can perform locomotion with pulsed laser energy on a dry surface. Based on the knowledge gained with the ChevBot, we refined tits fabrication process to remove the assembly step and increase its reliability. We designed and fabricated a steerable microrobot, the SerpenBot, in order to achieve controllable behavior with the guidance of a laser beam. Through modeling and experimental study of the characteristics of this type of microrobot, we proposed and validated a new type of deep learning controller, the PID-Bayes neural network controller. The experiments showed that the SerpenBot can achieve closed-loop autonomous operation on a dry substrate

Emergent Properties of Biomolecular Organization

The organization of molecules within a cell is central to cellular processes ranging from metabolism and damage repair to migration and replication. Uncovering the emergent properties of this biomolecular organization can improve our understanding of how organisms function and reveal ways to repurpose their components outside of the cell. This dissertation focuses on the role of organization in two widely studied systems: enzyme cascades and active cytoskeletal filaments.Part I of this dissertation studies the emergent properties of the spatial organization of enzyme cascades. Enzyme cascades consist of a series of enzymes that catalyze sequential reactions: the product of one enzyme is the substrate of a subsequent enzyme. Enzyme cascades are a fundamental component of cellular reaction pathways, and spatial organization of the cascading enzymes is often essential to their function. For example, cascading enzymes assembled into multi-enzyme complexes can protect unstable cascade intermediates from the environment by forming tunnels between active sites. We use mathematical modeling to investigate the role of spatial organization in three specific systems. First, we examine enzyme cascade reactions occurring in multi-enzyme complexes where active sites are connected by tunnels. Using stochastic simulations and theoretical results from queueing theory, we demonstrate that the fluctuations arising from the small number of molecules involved can cause non-negligible disruptions to cascade throughput. Second, we develop a set of design principles for a compartmentalized cascade reaction with an unstable intermediate and show that there exists a critical kinetics-dependent threshold at which compartments become useful. Third, we investigate enzyme cascades immobilized on a synthetic DNA origami scaffold and show that the scaffold can create a favorable microenvironment for catalysis. Part II of this dissertation focuses on the organization of active cytoskeletal filaments. Many mechanical processes of a cell, such as cell division, cell migration, and intracellular transport, are driven by the ATP-fueled motion of motor proteins (kinesin, dynein, or myosin) along cytoskeletal filaments (microtubules or actin filaments). Over the past two decades, researchers have been repurposing motor protein-driven propulsion outside of the cell to create systems where cytoskeletal filaments glide on surfaces coated with motor proteins. The study of these systems not only elucidates the mechanisms of force production within the cell, but also opens new avenues for applications ranging from molecular detection to computation. We examine how microtubules gliding on surfaces coated with kinesin motor proteins can generate collective behavior in response to mutualistic interactions between the filaments and motors, thereby maximizing the utilization of system components and production. To this end, we used a microtubule-kinesin system where motors reversibly bind to the surface. In experiments, microtubules gliding on these reversibly bound motors were unable to cross each other and at high enough densities began to align and form long, dense bundles. The kinesin motors accumulated in trails surrounding the microtubule bundles and participated in microtubule transport. In conclusion, our study of the emergent properties of the spatial organization of enzyme cascades and the mutualistic interactions within active systems of motor proteins and cytoskeletal filaments provides insight into both how these systems function within cells and how they can be repurposed outside of them