Miniaturization of on-board actuation and powering engenders the proliferation of biohybrid microrobots, which integrate motile bacteria or cells with synthetic functional components to achieve micron-scale actuations. Flagellated bacteria like S. marcescens are among the leading candidates for the actuators of swimming microrobots. However, the high intrinsic stochasticity in bacteria-driven microrobots severely limits their potential applications, such as targeted drug delivery. Taxis behaviors (e.g., chemotaxis), which help free-swimming bacteria to navigate towards favorable environments and away from hazardous ones, may offer an elegant means to control the motion of bacteria-driven microrobots. Therefore, this thesis focuses on: (a) addressing the motion guiding of bacteria-driven microrobots using common bacterial taxis behaviors, specifically chemotaxis and pH-taxis, (b) explaining the physical mechanisms associated with the tactic motions in bacteria-driven microrobots, and (c) developing a biophysical model to describe the bacterial propulsion and the chemotaxis in bacteria-driven microrobots. In order to produce considerable chemotactic motion in bacteria-driven microrobots, an appropriate chemical concentration profile needs to be determined, which requires the knowledge of the chemotaxis response of the integrated bacterial species. Thus, we first propose an experimental and modeling framework to characterize bacterial chemotaxis. The chemotaxis response of a species against a chemoattractant is experimentally quantified under a linear concentration gradient of the attractant. A signaling pathway model is fitted to the experimental measurements over a series of gradients to determine the species-specific parameters in the model, thereby fulfilling an analytical characterization of the chemotaxis. Subsequently, in a multi-bacteria-driven microrobotic system, we quantify the chemotactic drift of the microrobotic swarms towards a potent chemoattractant L-serine and elucidate the physical mechanisms associated with the drift motion by statistical trajectory analysis. It shows that the microrobots have an apparent heading preference for moving up the gradient, which constitutes the major factor that produces the chemotactic drift. The apparent heading bias is caused by a higher persistence in the heading direction when a microrobot moves up the the L-serine gradient compared to traveling down the gradient. Besides chemotaxis, we explore the potential of utilizing ambient pH to guide the motion of the bacteria-driven microrobots. Under three different pH gradients, we demonstrate that the microrobots exhibit both unidirectional and bidirectional pH-tactic behaviors. Two factors, a swimming heading bias and a speed bias, are found to be responsible for the pH-tactic motion while the heading bias contributes more. Like in chemotaxis, the heading directions of the microrobots are also significantly more persistent when they move towards favored pH regions. Finally, a biophysical model is developed to describe the bacterial propulsion and the chemotaxis in an extensively adopted design of bacteria-driven microrobots. The model traces helical trajectories and chemotactic motion that resemble those observed from experiments, which validates the basic correctness of the model. The model simulation also suggests that the seemingly collective chemotaxis among the multiple bacteria attached to a microrobot could be explained by a synchronized signaling pathway response among these bacteria. Furthermore, we investigate the dependencies of the microrobots’ per

Un grand nombre de traitements sont aujourd'hui disponibles pour la cancérologie, dont l'objectif est d'éliminer tous les tissus cancéreux en minimisant les dommages occasionnés sur les tissus sains. La chimio-embolisation est considérée comme un régime de traitement localisé, préconisé pour certains cancers. Cependant, le ciblage des tumeurs profondément enfouies par chimio-embolisation est actuellement limité en raison de la taille des cathéters. Compte tenu des échelles envisagées, l'utilisation des microrobots magnétiquement guidés est l'une des approches les plus prometteuses. L'objectif de cette thèse consiste à développer les outils permettant à des microrobots endovasculaires (ou transporteurs magnétiques), de naviguer dans le corps humain, en utilisant les gradients magnétiques d'un appareil IRM clinique amélioré. Pour cela, une compréhension approfondie de l'environnement d'évolution du microrobot est une étape au préalable, en vue d'établir des stratégies de navigation adéquates. La variation des paramètres physiologiques de l'humain et l'utilisation d'un scanner IRM nécessitent d'une part, une robustesse du contrôleur vis-à-vis des erreurs de modélisation, et d'autre part, l'anticipation du comportement du système. A cet effet, la commande prédictive, trouve ici toute son efficacité pour résoudre les problèmes de poursuite. En outre, une plateforme d'instrumentation a été conçue au sein du laboratoire en vue de démontrer les concepts proposés, et de valider les stratégies de navigation prédictives développées dans nos travaux. Puis, dans un deuxième temps, nous avons intégré ces approches dans une plateforme d'IRM clinique. / Today, many cancer treatments are available, whose goal is to kill the cancerous tissue and to minimize damage to healthy tissue. Chemoemobilization is considered as a targeting treatment recommended for some cancers. However, targeting tumor deeply buried using chemoemobilization is currently limited due to the size of the microcatheters. Taking into account the scales considered, the use of magnetically guided microrobots is one of the most promoting approaches. The objective of this thesis is to develop tools for endovascular microrobots (or carriers), navigate in the human body using magnetic gradients of an improved clinical MRI. For this, understanding microrobot evolution environment is a first step, in order to develop appropriate navigation strategies. The variation of the human physiological parameters and the use of MRI scanner require a robustness of the controller to the modeling errors, and the anticipation of the system behavior. For this, predictive control is fully effective to solve the tracking problem. In addition, an instrumentation platform was designed to demonstrate the proposed concepts and to validate the predictive navigation strategies developed in our work. Then, in a second step, we investigated these approaches in clinical MRI platform.

Biological research over the past several decades has elucidated some of the mechanisms behind highly mobile, efficient, and robust locomotion in insects such as the cockroach. Roboticists have used this information to create biologically-inspired machines capable of running, jumping, and climbing robustly over a variety of terrains. To date, little work has been done to develop an at-scale insect-inspired robot capable of similar feats, due to limitations in fabrication, actuation, and electronics integration at small scales. This thesis addresses these challenges, focusing on the mechanical design and fabrication of a sub-2g walking robot, the Harvard Ambulatory MicroRobot (HAMR). The development of HAMR includes modeling and parameter selection for a two degree of freedom leg powertrain that enables locomotion. In addition, a design inspired by pop-up books that enables fast and repeatable assembly of the miniature walking robot is presented. Finally, a method to drive HAMR resulting in speeds up to 37cm/s is presented, along with simple control schemes. / Engineering and Applied Sciences

<p>The diminutive size of microrobots makes them advantageous for minimally invasive operations and precise, localized treatment. One such application is aiding in localized drug delivery for colorectal cancer as microrobots could offer reduced patient trauma, lower risk of side effects, and higher drug retention rates. In this study, we evaluate the abilities of a magnetic microrobot in a variety of conditions using a high frequency ultrasound system. Under the influence of an external rotating magnetic field, the microrobot tumbles end-over-end to propel itself forward. Cytotoxicity tests demonstrated the constituent materials of polydimethylsiloxane (PDMS) and SU-8 were nontoxic to murine fibroblasts. Then, we quantified robot locomotion in an <i>ex vivo</i> porcine colon, testing the materials, the tumbling orientation, and three magnet rotation frequencies. Significant differences were found between materials and tumbling orientation, revealing that SU-8 lengthwise microrobots were the fastest with an average velocity of 2.12±0.25mm/s at a frequency of 1Hz. With this finding, the next tests were completed at 1Hz frequency with SU-8 lengthwise microrobots. We used <i>in vitro</i> agarose gels to maneuver the robot through a variety of trajectories, tested the microrobots <i>in situ</i> and <i>in vivo</i> murine colons as well. Average velocities were calculated for all tests with the <i>in vivo</i> murine colon tests finding an average velocity of 2.07±0.05mm/s. Finally, the microrobots were coated with a fluorescein payload and were shown to release a payload over a one-hour time period. These findings suggest microrobots are promising for targeted drug delivery and other <i>in vivo</i> biomedical applications.</p>

<p dir="ltr">In the past decade, magnetic microrobots have gain lots of attention because of their potentials in biomedical applications, such as cell/tissue manipulation, biopsy, and drug delivery. Recent development on materials and microfabrication techniques also provide more opportunities for microrobots. Especially, the emergence of smart polymers that are responsive to environments like hydrogels has given microrobots an additional degree-of-freedom. In the meantime, the two-photon polymerization (TPP) microscale 3D printing technique has enable fabrication process that cannot be achieved easily by traditional microfabrication techniques. In general, the goal of the research presented in this dissertation is to use both hydrogels and TPP to realize novel microrobots with multiple advanced functionalities, including adaptive locomotion and micromanipulation, and modular microrobots capable of changing end-effectors for different modes of micromanipulation to facilitate the development of the field. </p><p dir="ltr">This dissertation can be divided into four main parts: (i) a proof-of-concept study on adaptive helical microrobots with finite element analysis (FEA) and dynamic calculation, (ii) material calibrations and property testing, (iii) a helical adaptive multi-material microrobot (HAMMR), and (iv) a modular microrobot achieved by a responsive mating component. A environment-responsive hydrogel is adopted here to realize the adaptive locomotion for helical microrobot and the responsive mating component for the modular microrobot. All microrobots fabricated in this dissertation are achieved by the combination of TPP and traditional photolithography techniques. </p><p dir="ltr">In part (i), FEA is applied with classic parameters for a proof-of-concept study of helical microrobot made of the classic hydrogel upon the stimulation of temperature. At different temperature, the hydrogel is going to deform and therefore the microrobot. Based on the geometrical parameters predicted by FEA before and after stimulations, dynamic calculations are then applied to predict the change of swimming performance accordingly. In part (ii), material calibrations have been done in order to realize a homogeneous material for testing (for oil-immersion mode). However, due to the limitation of the custom-built testing system, a different approach (dip-in mode) is adopted and the material properties are successfully obtained. In part (iii), two generations of HAMMRs are investigated. The first generation of HAMMR is prepared by the oil-immersion mode which shows a record-breaking swimmering velocity with the capability of adaptive locomotion. The second generation is obtained by the dip-in mode which provides the opportunities for combining FEA, dynamic calculation, and experiment to realize a comprehensive studied for such microrobot. Moveover, advances have been made to the microrobot with a functional end-effector for micromanipulation tasks. In part (iv), a modular microrobot is proposed and realized by the introduction of a responsive mating component. The responsive mating component provides a locking mechanism between different modules of the microrobot. The microrobot is able to change its end-effector to perform different types of tasks. </p><p dir="ltr">By using TPP to pattern microscale hydrogel structures, microrobots are able to be implemented with advanced functional structures. The helical microrobots capable of adaptive locomotion and micromanipulation, and the modular microrobot that can switch end-effectors for different applications are advances toward the next generation of microrobots. Moreover, a standardized method is proposed for adaptive helical microrobots towards future biomedical applications. Both the proposed helical microrobot and the modular microrobot show great potential for future application and we believe the development of these microrobots will facilitate the development of the field of microrobot.</p>

<p dir="ltr">Approximately 2.39 million Americans suffer from inflammatory bowel disease (IBD), an autoimmune disorder that is characterized by chronic inflammation of the gastrointestinal (GI) tract. Current treatment options for IBD, which are limited, include oral medications, surgery, and supportive care. These therapeutics often times are not effective and are associated with high toxicity. Thus, there is a pressing clinical need for a therapy that can be delivered both locally and precisely, while also having an improvement in efficacy and lower toxicity.</p><p dir="ltr">This study introduces three novel microrobot designs fabricated using stereolithography (SLA) 3D printing, which aims to address the challenges seen in IBD treatment. The microrobots utilize a reservoir design to encapsulate the drug for an on-demand release, allowing for improved control and precision. The SLA microrobots were evaluated for cytotoxicity as well as drug release capabilities. We were able to demonstrate a local release of a protein on-demand at a biologically relevant temperature. The integration of microrobots in IBD therapy has the capability to significantly improve patient outcomes and quality of life, offering a more efficient and less toxic treatment approach.</p>

La chirurgie minimalement invasive est aujourd’hui une thématique de recherche particulièrement active. Un traitement thérapeutique ciblé et la possibilité d’établir un diagnostic précis grâce à l’utilisation de systèmes miniaturisés peuvent considérablement améliorer de nombreuses pratiques médicales. Le recours à des microrobots actionnés à distance et naviguant dans le système cardiovasculaire ouvre de nouvelles perspectives. L’objectif de cette thèse est de proposer un socle théorique solide concernant i) la modélisation d’un microrobot naviguant dans le système cardiovasculaire, ii) l’élaboration de lois de commande et d’observateurs assurant un bon suivi de trajectoire depuis la zone d’injection jusqu’à une zone cible. La modélisation du système fait intervenir de nombreuses forces : forces hydrodynamiques, forces surfaciques (électrostatique, van der Waals, stériques), forces de contact et poids apparent du microrobot. Ce microrobot est contrôlé dans le système cardiovasculaire par l’application de champs ou de gradients de champ magnétique selon le design du microrobot. La prise en compte de l’ensemble des forces aboutit à une représentation d’état sous la forme d’un système non-linéaire affine en la commande avec dérive comportant de nombreux paramètres physiologiques incertains. Une trajectoire de référence optimisée est déduite du modèle. L’approche de commande adoptée est établie à partir de critères de stabilité du système. Le système étant non-linéaire, une commande de type Lyapunov stabilisante est développée suivant une approche de type backstepping. L’estimation de certains paramètres physiologiques est rendue possible par une commande de type backstepping adaptatif. Un observateur grand gain reconstruit l’état complet du système nécessaire au calcul de la commande. La stabilité et la robustesse de l’ensemble sont établies au travers de nombreuses simulations en présence de bruits de mesure et d’erreurs paramétriques. / Minimally invasive medical procedures are currently an active research aera. A drug targeted therapy and the possibility of establishing an accurate diagnosis through the use of miniaturized systems can greatly improve many medical practices. The use of untethered microrobots navigating in the cardiovascular system opens new perspectives. The objective of this PhD work is to provide a theoretical approach on i) the modeling of a microrobot navigating in the cardiovascular system, ii) the development of control laws and observers to ensure a fine tracking from the injection to a target area. Modeling such as system involves many forces : hydrodynamic forces, surface forces (electrostatic, van derWaals, steric), contact forces and apparent weight of the microrobot. This microrobot is controlled in the cardiovascular system by the application of magnetic fields or magnetic field gradients according to the design of the microrobot. The consideration of all the forces leads to a state representation in the form of a nonlinear system with many physiological uncertain parameters, but gives us sufficient informations to plan an optimal trajectory. The control approach is established based on stability consideration. A Lyapunov-stabilizing control is then developed using a backstepping approach. An adaptive backstepping control law estimates some physiological parameters. A high gain observer reconstructs the full state of the system required for implementing the control approach. Robustness and stability of the controller with respect to noise measurement, parameters variations and uncertainties are illustrated by simulations.

Le cancer est une maladie caractérisée par la croissance incontrôlée des cellules. Le nombre de personnes atteintes par le carcinome hépatocellulaire (CHC) est en progression croissante. Les traitements utilisés jusqu'à présent par les médecins tels que la chimioembolisation transartérielle (TACE) et la radioembolisation transartérielle (TARE) présentent des limitations à cause des effets secondaires causés sur les tissus sains. En vue d'atteindre un meilleur contrôle tumoral avec le minimum de complications des tissus sains, les approches microrobotiques peuvent apporter des solutions au problème du ciblage thérapeutique. Une solution consiste à contrôler la direction de transporteurs thérapeutiques (bolus magnétiques), composés de microparticules magnétiques et d’agents anti-cancéreux, à l’intérieur des vaisseaux sanguins vers la zone tumorale. Des champs magnétiques extérieurs sont alors utilisés pour propulser, guider et naviguer une flottille de bolus magnétiques au travers du réseau artériel. Cette thèse propose donc une méthodologie globale à mettre en place afin de rendre les procédures locorégionales transartérielles robotisées plus ciblées et plus localisées. Dans un premier temps, nous avons optimisé la quantité de médicament à injecter sous forme de bolus magnétiques. Ensuite, nous nous sommes intéressés à l'optimisation de la structure du bolus en vue d’assurer d’une part, la navigation optimale à l’intérieur des vaisseaux et d’autre part, d’offrir la possibilité d’embarquer une quantité d’agents thérapeutiques plus importante. La navigation des bolus délivrés par un cathéter vers la zone ciblée (tumeur) est assurée grâce au développement et à l'implémentation d’une loi de commande optimale. La validation de l'injection et de la navigation des bolus magnétiques a été réalisée sur une plateforme magnétique robotisée développée dans le cadre de cette thèse. / Cancer is a disease characterized by an uncontrolled cell growth. The number of people with hepatocellular carcinoma (HCC) is growing constantly. The treatments used by doctors until nowadays such as transarterial chemoembolization (TACE) and transarterial Radioembolization (TARE) have limitations because of the side effects caused to healthy tissues. In order to achieve best tumor control with minimal complications on healthy tissues, microrobotics technology can provide solutions to the problem of therapeutic targeting. One solution is to control the direction of the therapeutic carriers (magnetic bolus), composed of magnetic microparticles and anti-cancer agents, inside the blood vessels to the tumor area (target). External magnetic fields are then used to propel, steer and navigate a magnetic bolus fleet through the arterial system. This thesis offers a global methodology to implement in order to make the robotic transarterial locoregional procedures more targeted and localized. First, we have optimized the amount of drug to be injected as magnetic boluses. Then, we have carried out the optimization of the magnetic bolus structure in order to ensure firstly, the optimal navigation inside the vessels and secondly, to offer the possibility of carrying a larger amount of therapeutic agents. The navigation of boluses delivered by the catheter to the target area (tumor) is ensured through the development and implementation of the optimal control law. The validation of the injection and navigation magnetic bolus are performed on a magnetic microrobotic platform.

Le développement récent en micro- et nanotechnologies (dans des domaines tels que l’horlogerie,l’électronique, l’optique, le biomédical, . . .) a créé un fort besoin concernant des systèmes capables de manipuler et d’assembler des objets de plus en plus petits. La conception de stations robotisées, capables de manipuler des micro-objets, s’est multipliée à travers le monde, faisant intervenir des actionneurs de haute résolution adaptés au micro monde, ainsi que de nombreux capteurs.Ce mémoire ouvre une nouvelle voie pour le développement de robots de micromanipulation. Il présente la conception, la modélisation, la fabrication et la commande d’un nouveau concept de micro robot, le DiMiBot (Digital MicroroBot). Il s’agit du premier micro robot numérique – inspiré ´e de l’ ´électronique numérique – qui fait intervenir des actionneurs binaires pour générer un déplacement discret d’une grande précision sans nécessiter de capteur (en boucle ouverte). Ces actionneurs binaires extrêmement répétables et robustes (les modules bistables), assurent chacun un déplacement précis de 25 μm. Ils sont associés de manière monolithique à une architecture robotique parallèle flexible, assurant la génération d’un espace de travail discret, dont les 2N (N est le nombre de modules bistables utilisés au sein du DiMiBot) positions distincts atteignables sont parfaitement stables, répétables et robustes mécaniquement. Elles sont réparties de manière homogène dans un carré de 10,5 μm de côté La micro fabrication du premier prototype de micro robot numérique en silicium – faisant suite `a un dimensionnement minutieux en élément finis – a été réalisé au sein de la salle blanche MIMENTO de l’institut FEMTO-ST. Ce DiMiBot possédant 4 modules bistables assure une résolution de 3,5 μm pour une répétable de chacune des 16 positions atteignables de 90 nm. / With the current expansion of micro- and nano-technologies (in such domains as watchmaking, electronics,optics, biomedical, . . .), came the necessity to build systems able to manipulate and make the assembly ofsmaller and smaller objects. Design of robotic stations, able to manipulate micro-objects, expanded all over theworld, making use of high resolution actuators and numerous sensors adapted to the microworld.This thesis opens a new paradigm in the design of micromanipulation robotics. We present the design, modeling,fabrication and control of a new microrobot, the DiMiBot (Digital MicroroBot). It is the first digital microrobot— inspired from digital electronics — which makes use of binary actuators for the generation of discretedisplacements with high accuracy without any sensors (open-loop control). These highly repeatable and robustbinary actuators (bistable modules) generate an accurate displacement of 25 μm. They are monolithicallyconbined with a parallel flexible architecture, allowing the generation of a discrete workspace, in which all the2N (N is the number of bistable modules used) distinct reachable positions are perfectly stable, repeatable andmechanically robust. They are evenly spread inside a 10.5 μm length square.After dimensioning, the first digital microrobot prototype in silicon was microfabricated in MIMENTO clean-roomof FEMTO-ST institute. This DiMiBot has 4 bistable modules and generates a workspace of 3.5 μm resolutionwith 90 nm repeatability

La chirurgie minimalement invasive est un domaine de recherche très actif puisqu’elle permet d’envisagerdes thérapies ciblées et des diagnostics in situ tout en minimisant traumatismes, effets secondaires et tempsde convalescence. En particulier, l’utilisation de systèmes miniaturisés actionnés à distance ouvre la voie àune navigation dans le système cardiovasculaire, permettant ainsi le ciblage et l’intervention sur zones dif-ficilement accessibles du corps humain. L’objectif de cette thèse est de proposer i) un état de l’art sur lamodélisation des forces s’exerçant sur un ou plusieurs microrobots naviguant dans des vaisseaux sanguins,ii) des représentations d’état exploitables à des fins de commande et d’observation, iii) différentes synthèsesde lois de commande pour stabiliser un ou plusieurs microrobots le long d’une trajectoire de référence, iv)des observateurs d’état pour reconstruire les états non mesurables du système. Un microrobot magnétiquenaviguant dans un vaisseau sanguin subit la force de traînée, les forces surfaciques, de contact, d’interactionmagnétique, et son poids apparent. Son actionnement est assuré par l’application de champs ou de gradientsde champ magnétiques, et sa localisation est assurée par un imageur médical. La dynamique du ou desmicrorobots (système réduit) est sous forme d’état non linéaire affine en la commande avec dérive, et dé-pend de plusieurs paramètres physiologiques incertains, en particulier de la vitesse du sang, qui est difficileà mesurer. La dynamique du flux sanguin (système fluidique) est alors modélisée sous forme d’une repré-sentation d’état autonome, combinée avec le système réduit pour aboutir au système étendu. L’objectif decommande est de stabiliser les états du système réduit le long d’une trajectoire de référence. Une commandestabilisante est synthétisée par backstepping, mais elle n’est pas utilisable en l’état. Des observateurs baséssur le théorème de la valeur moyenne et sur une immersion sont synthétisés respectivement dans le cas oùla pulsation cardiaque est connue ou non. La stabilité du retour de sortie est alors démontrée. La stabilitéet la robustesse aux bruits de mesure, aux incertitudes paramétriques, et aux erreurs de modélisation desapproches proposées sont alors illustrées par des simulations. / Minimally invasive surgery is an active research area since such systems have the potential to perform complex surgical procedures such as targeted therapies or in situ diagnosis, while minimizing trauma, side effects and recovery time. Miniaturized systems magnetically propelled by remote actuation can achieve swimming through the blood vessels network in order to provide targeted therapy, even for hard-to-reach human organs. This PhD thesis aims at addressing i) a review on the modeling of microrobots immersed in blood vessels, ii) a classification of the state space forms of such systems, iii) the synthesis of state feedbacks ensuring the stabilization of the microrobots along a reference trajectory, iv) the synthesis of observers to rebuild the unmeasured state variables. Magnetic microrobots swimming in a blood vessel face the hydrodynamic drag, surfacic and contact forces, magnetic interactions, and their apparent weight. These untethered robots are actuated by magnetic fields or magnetic gradients generation, and their localization is ensured by a medical imager. The microrobots dynamics (the so-called reduced system) lead to a nonlinear affine control subsystem with drift, and exhibits many uncertain physiological parameters, such as the blood velocity which can hardly be measured. The blood flow dynamics (the so-called fluidic system) are then modeled as an autonomous subsystem. These two subsystems result in an extended system describing the whole (robot and fluid) dynamics. The control objective is to stabilize the state of the reduced system along a reference trajectory, which is performed by an adaptive backstepping synthesis. Yet the full state is not accessible. We then synthesize either MVT or immersion based observers for the extended system, when the blood pulsation is either known or not. The output feedback stability is then proved. The stability and robustness to output noise, parametric uncertainty, and modeling errors are then illustrated by simulations.