Micro/nanoscale magnetic robots for biomedical applications

Magnetic small-scale robots are devices of great potential for the biomedical field because of the several benefits of this method of actuation. Recent work on the development of these devices has seen tremendous innovation and refinement toward ​improved performance for potential clinical applications. This review briefly details recent advancements in small-scale robots used for biomedical applications, covering their design, fabrication, applications, and demonstration of ability, and identifies the gap in studies and the difficulties that have persisted in the optimization of the use of these devices. In addition, alternative biomedical applications are also suggested for some of the technologies that show potential for other functions. This study concludes that although the field of small-scale robot research is highly innovative ​there is need for more concerted efforts to improve functionality and reliability of these devices particularly in clinical applications. Finally, further suggestions are made toward ​the achievement of commercialization for these devices

Light-activated shape morphing and light-tracking materials using biopolymer-based programmable photonic nanostructures

Natural systems display sophisticated control of light-matter interactions at multiple length scales for light harvesting, manipulation, and management, through elaborate photonic architectures and responsive material formats. Here, we combine programmable photonic function with elastomeric material composites to generate optomechanical actuators that display controllable and tunable actuation as well as complex deformation in response to simple light illumination. The ability to topographically control photonic bandgaps allows programmable actuation of the elastomeric substrate in response to illumination. Complex three-dimensional configurations, programmable motion patterns, and phototropic movement where the material moves in response to the motion of a light source are presented. A “photonic sunflower” demonstrator device consisting of a light-tracking solar cell is also illustrated to demonstrate the utility of the material composite. The strategy presented here provides new opportunities for the future development of intelligent optomechanical systems that move with light on demand

Lab-on-a-Chip Fabrication and Application

The necessity of on-site, fast, sensitive, and cheap complex laboratory analysis, associated with the advances in the microfabrication technologies and the microfluidics, made it possible for the creation of the innovative device lab-on-a-chip (LOC), by which we would be able to scale a single or multiple laboratory processes down to a chip format. The present book is dedicated to the LOC devices from two points of view: LOC fabrication and LOC application

Locomotion Optimization of Photoresponsive Small-scale Robot: A Deep Reinforcement Learning Approach

Soft robots comprise of elastic and flexible structures, and actuatable soft materials are often used to provide stimuli-responses, remotely controlled with different kinds of external stimuli, which is beneficial for designing small-scale devices. Among different stimuli-responsive materials, liquid crystal networks (LCNs) have gained a significant amount of attention for soft small-scale robots in the past decade being stimulated and actuated by light, which is clean energy, able to transduce energy remotely, easily available and accessible to sophisticated control. One of the persistent challenges in photoresponsive robotics is to produce controllable autonomous locomotion behavior. In this Thesis, different types of photoresponsive soft robots were used to realize light-powered locomotion, and an artificial intelligence-based approach was developed for controlling the movement. A robot tracking system, including an automatic laser steering function, was built for efficient robotic feature detection and steering the laser beam automatically to desired locations. Another robot prototype, a swimmer robot, driven by the automatically steered laser beam, showed directional movements including some degree of uncertainty and randomness in their locomotion behavior. A novel approach is developed to deal with the challenges related to the locomotion of photoresponsive swimmer robots. Machine learning, particularly deep reinforcement learning method, was applied to develop a control policy for autonomous locomotion behavior. This method can learn from its experiences by interacting with the robot and its environment without explicit knowledge of the robot structure, constituent material, and robotic mechanics. Due to the requirement of a large number of experiences to correlate the goodness of behavior control, a simulator was developed, which mimicked the uncertain and random movement behavior of the swimmer robots. This approach effectively adapted the random movement behaviors and developed an optimal control policy to reach different destination points autonomously within a simulated environment. This work has successfully taken a step towards the autonomous locomotion control of soft photoresponsive robots

Hybrid bio-robotics: from the nanoscale to the macroscale

[eng] Hybrid bio-robotics is a discipline that aims at integrating biological entities with synthetic materials to incorporate features from biological systems that have been optimized through millions of years of evolution and are difficult to replicate in current robotic systems. We can find examples of this integration at the nanoscale, in the field of catalytic nano- and micromotors, which are particles able to self-propel due to catalytic reactions happening in their surface. By using enzymes, these nanomotors can achieve motion in a biocompatible manner, finding their main applications in active drug delivery. At the microscale, we can find single-cell bio-swimmers that use the motion capabilities of organisms like bacteria or spermatozoa to transport microparticles or microtubes for targeted therapeutics or bio-film removal. At the macroscale, cardiac or skeletal muscle tissue are used to power small robotic devices that can perform simple actions like crawling, swimming, or gripping, due to the contractions of the muscle cells. This dissertation covers several aspects of these kinds of devices from the nanoscale to the macro-scale, focusing on enzymatically propelled nano- and micromotors and skeletal muscle tissue bio-actuators and bio-robots. On the field of enzymatic nanomotors, there is a need for a better description of their dynamics that, consequently, might help understand their motion mechanisms. Here, we focus on several examples of nano- and micromotors that show complex dynamics and we propose different strategies to analyze their motion. We develop a theoretical framework for the particular case of enzymatic motors with exponentially decreasing speed, which break the assumptions of constant speed of current methods of analysis and need different strategies to characterize their motion. Finally, we consider the case of enzymatic nanomotors moving in complex biological matrices, such as hyaluronic acid, and we study their interactions and the effects of the catalytic reaction using dynamic light scattering, showing that nanomotors with negative surface charge and urease-powered motion present enhanced parameters of diffusion in hyaluronic acid. Moving towards muscle-based robotics, we investigate the application of 3D bioprinting for the bioengineering of skeletal muscle tissue. We demonstrate that this technique can yield well-aligned and functional muscle fibers that can be stimulated with electric pulses. Moreover, we develop and apply a novel co-axial approach to obtain thin and individual muscle fibers that resemble the bundle-like organization of native skeletal muscle tissue. We further exploit the versatility of this technique to print several types of materials in the same process and we fabricate bio-actuators based on skeletal muscle tissue with two soft posts. Due to the deflection of these cantilevers when the tissue contracts upon stimulation, we can measure the generated forces, therefore obtaining a force measurement platform that could be useful for muscle development studies or drug testing. With these applications in mind, we study the adaptability of muscle tissue after applying various exercise protocols based on different stimulation frequencies and different post stiffness, finding an increase of the force generation, especially at medium frequencies, that resembles the response of native tissue. Moreover, we adapt the force measurement platform to be used with human-derived myoblasts and we bioengineer two models of young and aged muscle tissue that could be used for drug testing purposes. As a proof of concept, we analyze the effects of a cosmetic peptide ingredient under development, focusing on the kinematics of high stimulation contractions. Finally, we present the fabrication of a muscle-based bio-robot able to swim by inertial strokes in a liquid interface and a nanocomposite-laden bio-robot that can crawl on a surface. The first bio-robot is thoroughly characterized through mechanical simulations, allowing us to optimize the skeleton, based on a serpentine or spring-like structure. Moreover, we compare the motion of symmetric and asymmetric designs, demonstrating that, although symmetric bio-robots can achieve some motion due to spontaneous symmetry breaking during its self-assembly, asymmetric bio-robots are faster and more consistent in their directionality. The nanocomposite-laden crawling bio-robot consisted of embedded piezoelectric boron nitride nanotubes that improved the differentiation of the muscle tissue due to a feedback loop of piezoelectric effect activated by the same spontaneous contractions of the tissue. We find that bio-robots with those nanocomposites achieve faster motion and stronger force outputs, demonstrating the beneficial effects in their differentiation. This research presented in this thesis contributes to the development of the field of bio-hybrid robotic devices. On enzymatically propelled nano- and micromotors, the novel theoretical framework and the results regarding the interaction of nanomotors with complex media might offer useful fundamental knowledge for future biomedical applications of these systems. The bioengineering approaches developed to fabricate murine- or human-based bio-actuators might find applications in drug screening or to model heterogeneous muscle diseases in biomedicine using the patient’s own cells. Finally, the fabrication of bio-hybrid swimmers and nanocomposite crawlers will help understand and improve the swimming motion of these devices, as well as pave the way towards the use of nanocomposite to enhance the performance of future actuators.[spa] La bio-robótica híbrida es una disciplina cuyo objetivo es la integración de entidades biológicas con materiales sintéticos para superar los desafíos existentes en el campo de la robótica blanda, incorporando características de los sistemas biológicos que han sido optimizadas durante millones de años de evolución natural y no son fáciles de reproducir artificialmente. Esta tesis cubre varios aspectos de este tipo de dispositivos desde la nanoescala a la macroescala, enfocándose en nano- y micromotores propulsados enzimáticamente y bio-actuadores y bio-robots basados en tejido muscular esquelético. En el campo de nanomotores enzimáticos, existe la necesidad de encontrar mejores modelos que puedan describir la dinámica de su movimiento para llegar a entender sus mecanismos de propulsión subyacentes. Aquí, nos enfocamos en diversos ejemplos de nano- y micromotores que muestran dinámicas de movimiento complejas y proponemos diferentes estrategias que se pueden utilizar para analizar y caracterizar este movimiento. Moviéndonos hacia robots basados en células musculares, investigamos la aplicación de la técnica de bioimpresión en 3D para la biofabricación de músculo esquelético. Demostramos que esta técnica puede producir fibras musculares funcionales y bien alineadas que puede ser estimuladas y contraerse con pulsos eléctricos. Investigamos la versatilidad de esta técnica para imprimir varios tipos de materiales en el mismo proceso y fabricamos bio-actuadores basados en músculo esquelético. Debido a los movimientos de unos postes gracias a las contracciones musculares, podemos obtener medidas de la fuerza ejercida, obteniendo una plataforma de medición de fuerzas que podría ser de utilidad para estudios sobre el desarrollo del músculo o para testeo de fármacos. Finalmente, presentamos la fabricación de un bio-robot basado en músculo esquelético capaz de nadar en la superficie de un líquido y un bio-robot con nanocompuestos incrustados que puede arrastrarse por una superficie sólida. El primer de ellos es minuciosamente caracterizado a través de simulaciones mecánicas, permitiéndonos optimizar su esqueleto, basado en una estructura tipo serpentina o muelle. El segundo bio-robot contiene nanotubos piezoeléctricos incrustados en su tejido, los cuales ayudan en la diferenciación del músculo debido a una retroalimentación basada en su efecto piezoeléctrico y activada por las contracciones espontáneas del tejido. Mostramos que estos bio-robots pueden generar un movimiento más rápido y una mayor generación de fuerza, demostrando los efectos beneficiales en la diferenciación del tejido

Manipulation of Cell and Particle Trajectory in Microfluidic Devices

Microfluidics, the manipulation of fluid samples on the order of nanoliters and picoliters, is rapidly emerging as an important field of research. The ability to miniaturize existing scientific and medical tools, while also enabling entirely new ones, positions microfluidic technology at the forefront of a revolution in chemical and biological analysis. There remain, however, many hurdles to overcome before mainstream adoption of these devices is realized. One area of intense study is the control of cell motion within microfluidic channels. To perform sorting, purification, and analysis of single cells or rare populations, precise and consistent ways of directing cells through the microfluidic maze must be perfected. The aims of this study focused on developing novel and improved methods of controlling the motion of cells within microfluidic devices, while simultaneously probing their physical and chemical properties. To this end we developed protein-patterned smart surfaces capable of inducing changes in cell motion through interaction with membrane-bound ligands. By linking chemical properties to physical behavior, protein expression could then be visually identified without the need for traditional fluorescent staining. Tracking and understanding motion on cytotactic surfaces guided our development of new software tools for analyzing this motion. To enhance these cell-surface interactions, we then explored methods to adjust and measure the proximity of cells to the channel walls using electrokinetic forces and 3D printed microstructures. Combining our work with patterned substrates and 3-dimensional microfabrication, we created micro-robots capable of rapid and precise movements via magnetic actuation. The micro-robots were shown to be effective tools for mixing laminar flows, capturing or transporting individual cells, and selectively isolating cells on the basis of size. In the course of development of these microfluidic tools we gained valuable new insights into the differences and limitations of planar vs. 3D lithography, especially for fabrication of magnetic micro-machines. This work as a whole enables new mechanisms of control within microfluidics, improving our ability to detect, sort, and analyze cells in both a high throughput and high resolution manner

Magnetic Drug Targeting: Developing the Basics

Focusing medicine to disease locations is a needed ability to treat a variety of pathologies. During chemotherapy, for example, typically less than 0.1% of the drugs are taken up by tumor cells, with the remaining 99.9% going into healthy tissue. Physicians often select the dosage by how much a patient can physically withstand rather than by how much is needed to kill all the tumor cells. The ability to actively position medicine, to physically direct and focus it to specific locations in the body, would allow better treatment of not only cancer but many other diseases. Magnetic drug targeting (MDT) harnesses therapeutics attached to magnetizable particles, directing them to disease locations using magnetic fields. Particles injected into the vasculature will circulate throughout the body as the applied magnetic field is used to attempt confinement at target locations. The goal is to use the reservoir of particles in the general circulation and target a specific location by pulling the nanoparticles using magnetic forces. This dissertation adds three main advancements to development of magnetic drug targeting. Chapter 2 develops a comprehensive ferrofluid transport model within any blood vessel and surrounding tissue under an applied magnetic field. Chapter 3 creates a ferrofluid mobility model to predict ferrofluid and drug concentrations within physiologically relevant tissue architectures established from human autopsy samples. Chapter 4 optimizes the applied magnetic fields within the particle mobility models to predict the best treatment scenarios for two classes of chemotherapies for treating future patients with hepatic metastatic breast cancer microtumors

Biofunctional hydrogels for skeletal muscle constructs

Skeletal muscle tissue damage costs the US government hundreds of billions of dollars annually. Meanwhile, there is great potential to use skeletal muscle as a scalable actuator system, covering wide length scales, frequencies, and force regimes. Hence, the interest in soft robotics and regenerative medicine methods to engineer skeletal muscle has increased in recent years. The challenges to generate a functional muscle strip are typical to those of tissue engineering, where common issues such as cell source, material scaffold, bioreactor method or configuration play key roles. Specifically, it is important to translate the existing body of myogenesis knowledge into engineering muscle constructs by examining the impact of the cell microenvironment on growth, alignment, fusion, and differentiation of skeletal muscle cells. The main motivation behind this thesis was to generate a contractile 3D skeletal muscle construct utilizing organized biochemical and physical cues to guide muscle cell differentiation and maturation. Such a construct is expected to play an important role in medical applications and the development of soft robotics. To do this, 3D, swollen hydrogels were chosen to provide tailorable platforms that support cellular activities to similar extents as native matrices. For this work, we utilized an engineered bio-functionalized poly(ethylene glycol)-(PEG)-hydrogel with maleimide (MAL) cross-linking reaction chemistry that gels rapidly with high reaction efficiency under cytocompatible reaction conditions. PEG alone has been shown to have low protein adsorption, a minimal inflammatory profile, well established chemistry, and a long history of safety in vivo. The PEG-MAL system in particular allows “plug-and-play” design variation, control over polymerization time, and small degradation products. To develop an effective soft biomaterial for the development of an aligned, functional muscle construct, we (i) screened hydrogel properties for differentiation, (ii) recreated alignment of skeletal muscle cells, (iii) determined effective generated force upon action of an external agonist. The impact of this study in generating a controllable force actuator will be significant in the construction of biological machines. Concomitantly, this study will provide a unique regenerative solution for skeletal muscle tissue repair and regeneration.Ph.D