In-channel experiments on vertical swimming with bacteria-like robots

Bio-inspired micro-robots are of great importance as to implement versatile microsystems for a variety of in vivo and in vitro applications in medicine and biology. Accurate models are necessary to understand the swimming and rigidbody dynamics of such systems. In this study, a series of experiments are conducted with a two-link cm-scale bioinspired robot moving vertically without a tether, in siliconefilled narrow cylindrical glass channels. Swimming velocities are obtained for a set of varying tail and wave geometries, and employed to validate a resistive force theory (RFT) model using modified resistance coefficients based on measured forward velocity and body rotation rates

Pushing bacterial biohybrids to in vivo applications

Bacterial biohybrids use the energy of bacteria to manipulate synthetic materials with the goal of solving biomedical problems at the micro- and nanoscale. We explore current in vitro studies of bacterial biohybrids, the first attempts at in vivo biohybrid research, and problems to be addressed for the future

Improved kinematic models for two-link helical micro/nano-swimmers

Accurate prediction of the three-dimensional trajectories of micro/nano-swimmers is a key element as to achieve high precision motion control in therapeutic applications. Rigid-body kinematics of such robotic systems is dominated by viscous forces. The induced flow field around a two-link swimmer is investigated with a validated computational fluid dynamics (CFD) model. Force-free-swimming constraints are employed in order to simulate motion of bacteria-like swimmers in viscous medium. The fluid resistance exerted on the body of the swimmer is quantified by an improved resistance matrix, which is embedded in a validated resistive force theory (RFT) model, based on complex-impedance approach. Parametric studies confirmed that the hydrodynamic interaction between body and tail are of great importance in predicting the trajectories for such systems

Computationally-validated surrogate models for optimal geometric design of bio-inspired swimming robots: helical swimmers

Research on micro-swimming robots without tether is growing fast owing to their potential impact on minimally invasive medical procedures. Candidate propulsion mechanisms of robots are vastly based on micro-organisms with rotating helical tails. For design of swimming robots, accurate models are necessary to compute velocities with corresponding hydrodynamic forces. Resistive force theory (RFT) provides an excellent framework for six degrees-of-freedom (dof) surrogate models in order to carry out effective design studies. However, resistance coefficients reported in literature are based on approximate analytical solutions for asymptotical cases, and do not address the effect of hydrodynamic interactions between the body and the tail, even in unbounded fluid media. Here, we use hydrodynamic interaction coefficients that multiply the body resistance coefficients along with no further modification to local resistance coefficients of the tail. Interaction coefficients are obtained from the solution of the inverse problem once for a fixed representative design with a computational fluid dynamics (CFD) simulation or an experiment. Results of the RFT-based hydrodynamic model are compared against further CFD simulations, and indicate that the model with hydrodynamic interaction coefficients obtained from a representative design provides a viable surrogate for computationally intensive three-dimensional time-dependent CFD models for a range of design variables. Finally, the validated hydrodynamic model is employed to investigate efficient geometric designs with helical wave propagation method within a wider range of design parameters

MRI-Based Tumour Targeting Enhancement with Magnetotactic Bacterial Carriers

RÉSUMÉ Le cancer constitue la première cause de mortalité au Québec, avec 20,000 décès estimés par année. Parmi tous les patients atteints du cancer, une grande proportion pourrait profiter de l’avancement technologique en ce qui concerne le transport de médicaments. En effet, l’un des meilleurs moyens d’augmenter l’efficacité d’un médicament contre le cancer, tout en réduisant sa toxicité sur les cellules saines, est de le diriger vers la tumeur et de le maintenir à cet endroit jusqu’à ce qu’un effet thérapeutique se produise. Le transport ciblé de médicaments vers la tumeur peut considérablement améliorer l’efficacité thérapeutique, surtout si le transporteur est capable d’atteindre les zones nécrotiques et se répartir uniformément dans la zone à traiter. Les bactéries, de par leur motilité, sont d’excellents candidats pour une telle application, surtout qu’elles peuvent aussi être facilement fonctionnalisées. Ainsi, la recherche sur le traitement du cancer utilisant des bactéries s’est imposée comme une approche prometteuse surtout qu’elle pallie à une limitation majeure de la chimiothérapie et de la radiothérapie en permettant le traitement des zones anaérobies. Alors que des laboratoires à travers le monde tentent de fabriquer des systèmes miniatures en se basant sur le modèle bactérien, nous avons opté pour l’utilisation des bactéries qui existent dans la nature. Notre stratégie a été de trouver un système biologique ayant les caractéristiques essentielles (e.x. diamètre total de moins de deux micromètres, force de poussée de plus de 4 pN, etc.) et de concentrer nos efforts à identifier une interface et une méthode permettant son contrôle pour des fins de ciblages thérapeutiques dans les lésions tumorales. Nous avons identifié les bactéries magnétotactiques de type MC-1 comme le meilleur transporteur potentiel de médicaments pour le ciblage du cancer. Les MC-1 sont à la fois dirigeables par champs magnétiques et anaérobies, ce qui leur donne un grand avantage par rapport aux bactéries traditionnellement utilisées pour le ciblage du cancer. Le ciblage du cancer avec des bactéries exploite le plus souvent l’affinité des bactéries anaérobies à la région nécrotique faible en oxygène de la tumeur. Certes, ce ciblage manque de spécificité et un des problèmes le plus reconnu est la nécessité d’injecter une forte dose de bactéries pour assurer une croissance de celles-ci à l’intérieur de la tumeur. Ceci n’est pas le cas avec les MC-1 car elles sont à la fois anaérobies et magnétotactiques grâce à une chaîne de nanoparticules d’environ 70 nanomètres de diamètre, formant une sorte de « nano-boussole » magnétique à----------ABSTRACT Magnetotactic Bacteria (MTB) are being explored as potential drug transporters to solid tumours. The MTB’s active motility combined with magnetotaxism (their ability to swim following the direction of a magnetic field) offer new and potentially more accurate solutions in delivering drugs to tumours. In fact, the flagella bundles of the MC-1 bacteria (with an overall ideal cell diameter of approximately 50% the diameter of the tiniest human blood vessels) provide 4.0 to 4.7pN of thrust force for propulsion (roughly 10 times the value of many other well-known flagellated bacteria). Since there are no existing methods or technologies capable of inducing an equivalent force on a carrier of appropriate size for traveling inside a tumour’s microvasculature, live microorganisms are considered as a viable option. Many of the parameters in a tumour microenvironment, such as malformed angiogenesis capillaries, heterogeneous blood flow, and high interstitial pressure, hinder the delivery of blood-borne drugs to the affected area. Active motility might prove to be helpful in bypassing these limitations and may facilitate the uniform distribution of the drug in the targeted area. An MTB navigation technique that allows targeting without prior knowledge of the exact architecture of the vessels network has been developed. This navigation technique exploits both the ability of the MTB to swim following an imposed magnetic field and their random, continuous motion at low magnetic fields. Firstly, a focused magnetic field on the target sets the overall direction of the bacteria. Then, as the bacteria approach the targeted zone, the intensity of the magnetic field is decreased, which allows better bacteria repartition by exploiting their free motion. An additional approach that enhances MTB targeting relies on modulating the magnetic field direction in time, while keeping the magnetic field lines pointed toward the target. Navigation experiments in complex micro-channel networks highlight this process, where the successful targeting of bacteria is demonstrated when an appropriate magnetic field algorithm is applied, especially when it takes into account the nature of the channel network. Tridimensional control and navigation of MTB is also possible with the same technique through proper powering of the magnetic coils. In fact, by controlling their magnetic environment, it is possible to form a swarm of MTB, control its size and position within a given volume using a computer program

Attachment of Therapeutic and Imaging Agents to Magnetotactic Bacteria Acting as Self-Propelled Bio-Carriers for Cancer Treatment

RÉSUMÉ Malgré les progrès de la médecine moderne, les traitements anticancéreux actuels n’arrivent toujours pas à vaincre le cancer. Seulement une fraction des doses de médicaments administrées parvient à la tumeur en raison d’un ciblage non spécifique, de barrières physiologiques au niveau du système vasculaire ainsi que de l’élimination immédiate de médicaments par le système immunitaire. Des dosages fréquents de médicaments deviennent nécessaires afin de surmonter ces obstacles, entraînant une toxicité systémique, des effets secondaires et un échec thérapeutique. De plus, les systèmes actuels d’imagerie médicale sont incapables de produire des images de haute qualité des structures tumorales pour les diagnostiques et les traitements. Ceci est dû aux restrictions de la résolution spatiale et de l’incapacité des agents de contraste à pénétrer dans les zones tumorales afin de générer un signal suffisamment intense. Le développement de nouveaux agents thérapeutiques ainsi que de nouvelles techniques de ciblage thérapeutique sont donc requis afin d’améliorer l’efficacité des traitements actuels. Pour ce projet de recherche doctorale, l'attachement de charges utiles à la surface de bactéries magnétotactiques flagellées Magnetococcus Marinus MC-1 (BMT) a été mise en place pour transporter de façon ciblée une quantité optimale de médicaments profondément dans les zones tumorales. Ces bio-robots autopropulsés de dimensions adéquates sont équipés d’un système de propulsion dirigeable, d’un système de navigation, et de capacités sensorielles. Divers types de complexes BMT ont été fabriquées en attachant aux BMT (i) des liposomes vides (BMT-LP), (ii) des liposomes contenant un agent anticancéreux SN38 (BMT-LSC), et (iii) des nanoparticules superparamagnétiques de magnétite (BMT-S200). L’efficacité de l'attachement des charges et du comportement des bactéries soumises à un champ magnétique directionnel ont été étudiés. Par la suite, la capacité des complexes BMT à naviguer le long d’une trajectoire prédéterminée, à infiltrer profondément l'espace interstitiel, et à cibler des zones tumorales inaccessibles, ont été étudiés dans un modèle animal soumis à un champ magnétique externe. Pour parvenir à des complexes BMT aptes à transporter suffisamment de produits pharmaceutiques et de s’accumuler préférentiellement dans les régions affectées, il faut assurer un attachement solide et stable qui ne compromet pas la motilité des BMT.----------ABSTRACT Despite the substantial achievements of modern medicine, current medical therapies cannot eradicate cancer. Due to nonspecific targeting, the multiple physiological barriers that blood-borne agents must encounter, and the rapid sequestration of drugs by the immune system, a suboptimal fraction of the total injected dose reaches the intended target. These obstacles necessitate frequent dosing to compensate therapeutic effects, resulting in systemic toxicity, undesirable side effects, and treatment failure. In addition, existing medical imaging modalities struggle to provide high quality clinical images of tumor structures for treatment purposes due to limitations in spatial resolution and lack of penetration of contrast agents into tumoral regions to induce sufficient signal intensity. To address these issues, the development of new therapeutic agents alongside improved strategies for targeting therapy with the ability to control their fate is required. The attachment of payloads to the flagellated Magnetococcus Marinus MC-1 magnetotactic bacteria (MTB) to directly transport optimal quantities of pharmaceutical agents to regions located deep in tumors is what has been proposed during the accomplishment of this PhD project. These engineered self-propelled bio-robots with an appropriate dimension are equipped with steerable propulsion, navigation system, and onboard sensory capabilities. MTB complexes were fabricated by attaching the MTB to (i) empty liposomes (MTB-LP), (ii) SN38 anticancer drug encapsulated in liposomes (MTB-LSC), and (iii) 200 nm superparamagnetic magnetite nanoparticles (MTB-S200). The attachment efficacy and magnetic response behavior from the influence of a directional magnetic field of loaded bacteria with therapeutic or imaging agents were studied. Subsequently, results showed that the attachment method was suitable to allow MC-1 MTB to transport therapeutic and imaging agents along a planned trajectory prior to penetrate deep through the interstitial space in order to reach the hypoxic regions of a tumor in an animal model. To achieve MTB complexes capable of carrying sufficient pharmaceutical agents and accumulating preferentially at disease sites, the attachment must be strong and stable without compromising the natural motility of MTB. The MTB-LP were prepared by direct covalent attachment of functionalized liposomes to the amine groups naturally presented on the surface of MTB using carbodiimide (EDC/NHS) chemistry

MS FT-2-2 7 Orthogonal polynomials and quadrature: Theory, computation, and applications

Quadrature rules find many applications in science and engineering. Their analysis is a classical area of applied mathematics and continues to attract considerable attention. This seminar brings together speakers with expertise in a large variety of quadrature rules. It is the aim of the seminar to provide an overview of recent developments in the analysis of quadrature rules. The computation of error estimates and novel applications also are described