Effects of membrane viscoelasticity on the red blood cell dynamics in a microcapillary.

The mechanical properties of red blood cells (RBCs) play key roles in their biological functions in microcirculation. In particular, RBCs must deform significantly to travel through microcapillaries with sizes comparable with or even smaller than their own. Although the dynamics of RBCs in microcapillaries have received considerable attention, the effect of membrane viscoelasticity has been largely overlooked. In this work, we present a computational study based on the boundary integral method and thin-shell mechanics to examine how membrane viscoelasticity influences the dynamics of RBCs flowing through straight and constricted microcapillaries. Our results reveal that the cell with a viscoelastic membrane undergoes substantially different motion and deformation compared with results based on a purely elastic membrane model. Comparisons with experimental data also suggest the importance of accounting for membrane viscoelasticity to properly capture the transient dynamics of an RBC flowing through a microcapillary. Taken together, these findings demonstrate the significant effects of membrane viscoelasticity on RBC dynamics in different microcapillary environments. The computational framework also lays the groundwork for more accurate quantitative modeling of the mechanical response of RBCs in their mechanotransduction process in subsequent investigations.

Elastohydrodynamic propulsion of a filament magnetically driven at both ends.

The elastohydrodynamic interaction between an elastic filament and its surrounding fluid was exploited to develop the first microswimmers. These flexible microswimmers are typically actuated magnetically at one end and their propulsion behavior is relatively well understood. In this work, we move beyond the traditional single-end actuation setup and explore the propulsion characteristics of an elastic filament driven by magnetic torques at both ends. We report the emergence of new modes of propulsion behaviors in different physical regimes, depending on the balance of elastic and viscous forces as well as the arrangement of the magnetic moments at the filament ends. In particular, under the same magnetic actuation, a filament driven at both ends can propel either forward or backward depending on its relative stiffness. Moreover, this new backward propulsion mode can generate a magnitude of propulsion that is unattainable by the traditional single-end actuation setup. We characterize these new propulsion behaviors and provide some physical insights into how they emerge from the complex interplay between viscous and elastic forces and magnetic actuation in various configurations. Taken together, these findings could guide the development of soft microrobots with enhanced propulsion performance and maneuverability for future biomedical applications.

Propulsion of an elastic filament in a shear-thinning fluid.

Some micro-organisms and artificial micro-swimmers propel at low Reynolds numbers (Re) via the interaction of their flexible appendages with the surrounding fluid. While their locomotion has been extensively studied with a Newtonian fluid assumption, in realistic biological environments these micro-swimmers invariably encounter rheologically complex fluids. In particular, many biological fluids such as blood and different types of mucus have shear-thinning viscosities. The influence of this ubiquitous non-Newtonian rheology on the performance of flexible swimmers remains largely unknown. Here, we present a first study to examine how shear-thinning rheology alters the fluid-structure interaction and hence the propulsion performance of elastic swimmers at low Re. Via a simple elastic swimmer actuated magnetically, we demonstrate that shear-thinning rheology can either enhance or hinder elastohydrodynamic propulsion, depending on the intricate interplay between elastic and viscous forces as well as the magnetic actuation. We also use a reduced-order model to elucidate the mechanisms underlying the enhanced and hindered propulsion observed in different physical regimes. These results and improved understanding could guide the design of flexible micro-swimmers in non-Newtonian fluids.

Medical micro/nanorobots in complex media.

Medical micro/nanorobots have received tremendous attention over the past decades owing to their potential to be navigated into hard-to-reach tissues for a number of biomedical applications ranging from targeted drug/gene delivery, bio-isolation, detoxification, to nanosurgery. Despite the great promise, the majority of the past demonstrations are primarily under benchtop or in vitro conditions. Many developed micro/nanoscale propulsion mechanisms are based on the assumption of a homogeneous, Newtonian environment, while realistic biological environments are substantially more complex. Moving toward practical medical use, the field of micro/nanorobotics must overcome several major challenges including propulsion through complex media (such as blood, mucus, and vitreous) as well as deep tissue imaging and control in vivo. In this review article, we summarize the recent research efforts on investigating how various complexities in biological environments impact the propulsion of micro/nanoswimmers. We also highlight the emerging technological approaches to enhance the locomotion of micro/nanorobots in complex environments. The recent demonstrations of in vivo imaging, control and therapeutic medical applications of such micro/nanorobots are introduced. We envision that continuing materials and technological innovations through interdisciplinary collaborative efforts can bring us steps closer to the fantasy of "swallowing a surgeon".

Gating of a mechanosensitive channel due to cellular flows.

A multiscale continuum model is constructed for a mechanosensitive (MS) channel gated by tension in a lipid bilayer membrane under stresses due to fluid flows. We illustrate that for typical physiological conditions vesicle hydrodynamics driven by a fluid flow may render the membrane tension sufficiently large to gate a MS channel open. In particular, we focus on the dynamic opening/closing of a MS channel in a vesicle membrane under a planar shear flow and a pressure-driven flow across a constriction channel. Our modeling and numerical simulation results quantify the critical flow strength or flow channel geometry for intracellular transport through a MS channel. In particular, we determine the percentage of MS channels that are open or closed as a function of the relevant measure of flow strength. The modeling and simulation results imply that for fluid flows that are physiologically relevant and realizable in microfluidic configurations stress-induced intracellular transport across the lipid membrane can be achieved by the gating of reconstituted MS channels, which can be useful for designing drug delivery in medical therapy and understanding complicated mechanotransduction.

Maximizing propulsive thrust of a driven filament at low Reynolds number via variable flexibility.

At low Reynolds numbers the locomotive capability of a body can be dramatically hindered by the absence of inertia. In this work, we show how propulsive performance in this regime can be significantly enhanced by employing spatially varying flexibility. As a prototypical example, we consider the propulsive thrust generated by a filament periodically driven at one end. The rigid case leads to zero propulsion, as so constrained by Purcell's scallop theorem, while for uniform filaments there exists a bending stiffness maximizing the propulsive force at a given frequency; here we demonstrate explicitly how considerable further improvement can be achieved by simply varying the stiffness along the filament. The optimal flexibility distribution is strongly configuration-dependent: while increasing the flexibility towards the tail-end enhances the propulsion of a clamped filament, for a hinged filament decreasing the flexibility towards the tail-end is instead favorable. The results reveal new design principles for maximizing propulsion at low Reynolds numbers, potentially useful for developing synthetic micro-swimmers requiring large propulsive force for various biomedical applications.

Rotational propulsion enabled by inertia.

The fluid mechanics of small-scale locomotion has recently attracted considerable attention, due to its importance in cell motility and the design of artificial micro-swimmers for biomedical applications. Most studies on the topic consider the ideal limit of zero Reynolds number. In this paper, we investigate a simple propulsion mechanism --an up-down asymmetric dumbbell rotating about its axis of symmetry-- unable to propel in the absence of inertia in a Newtonian fluid. Inertial forces lead to continuous propulsion for all finite values of the Reynolds number. We study computationally its propulsive characteristics as well as analytically in the small-Reynolds-number limit. We also derive the optimal dumbbell geometry. The direction of propulsion enabled by inertia is opposite to that induced by viscoelasticity.

Filaments in curved streamlines: Rapid formation of Staphylococcus aureus biofilm streamers.

Biofilms are surface-associated conglomerates of bacteria that are highly resistant to antibiotics. These bacterial communities can cause chronic infections in humans by colonizing, for example, medical implants, heart valves, or lungs. Staphylococcus aureus, a notorious human pathogen, causes some of the most common biofilm-related infections. Despite the clinical importance of S. aureus biofilms, it remains mostly unknown how physical effects, in particular flow, and surface structure influence biofilm dynamics. Here we use model microfluidic systems to investigate how environmental factors, such as surface geometry, surface chemistry, and fluid flow affect biofilm development in S. aureus. We discovered that S. aureus rapidly forms flow-induced, filamentous biofilm streamers, and furthermore if surfaces are coated with human blood plasma, streamers appear within minutes and clog the channels more rapidly than if the channels are uncoated. To understand how biofilm streamer filaments reorient in flows with curved streamlines to bridge the distances between corners, we developed a mathematical model based on resistive force theory of slender filaments. Understanding physical aspects of biofilm formation in S. aureus may lead to new approaches for interrupting biofilm formation of this pathogen.

Data-Driven Intelligent Manipulation of Particles in Microfluidics.

Automated manipulation of small particles using external (e.g., magnetic, electric and acoustic) fields has been an emerging technique widely used in different areas. The manipulation typically necessitates a reduced-order physical model characterizing the field-driven motion of particles in a complex environment. Such models are available only for highly idealized settings but are absent for a general scenario of particle manipulation typically involving complex nonlinear processes, which has limited its application. In this work, the authors present a data-driven architecture for controlling particles in microfluidics based on hydrodynamic manipulation. The architecture replaces the difficult-to-derive model by a generally trainable artificial neural network to describe the kinematics of particles, and subsequently identifies the optimal operations to manipulate particles. The authors successfully demonstrate a diverse set of particle manipulations in a numerically emulated microfluidic chamber, including targeted assembly of particles and subsequent navigation of the assembled cluster, simultaneous path planning for multiple particles, and steering one particle through obstacles. The approach achieves both spatial and temporal controllability of high precision for these settings. This achievement revolutionizes automated particle manipulation, showing the potential of data-driven approaches and machine learning in improving microfluidic technologies for enhanced flexibility and intelligence.

Learning to cooperate for low-Reynolds-number swimming: a model problem for gait coordination.

Biological microswimmers can coordinate their motions to exploit their fluid environment-and each other-to achieve global advantages in their locomotory performance. These cooperative locomotion require delicate adjustments of both individual swimming gaits and spatial arrangements of the swimmers. Here we probe the emergence of such cooperative behaviors among artificial microswimmers endowed with artificial intelligence. We present the first use of a deep reinforcement learning approach to empower the cooperative locomotion of a pair of reconfigurable microswimmers. The AI-advised cooperative policy comprises two stages: an approach stage where the swimmers get in close proximity to fully exploit hydrodynamic interactions, followed a synchronization stage where the swimmers synchronize their locomotory gaits to maximize their overall net propulsion. The synchronized motions allow the swimmer pair to move together coherently with an enhanced locomotion performance unattainable by a single swimmer alone. Our work constitutes a first step toward uncovering intriguing cooperative behaviors of smart artificial microswimmers, demonstrating the vast potential of reinforcement learning towards intelligent autonomous manipulations of multiple microswimmers for their future biomedical and environmental applications.

Cargo-towing fuel-free magnetic nanoswimmers for targeted drug delivery.

Fuel-free nanomotors are essential for future in-vivo biomedical transport and drug-delivery applications. Herein, the first example of directed delivery of drug-loaded magnetic polymeric particles using magnetically driven flexible nanoswimmers is described. It is demonstrated that flexible magnetic nickel-silver nanoswimmers (5-6 µm in length and 200 nm in diameter) are able to transport micrometer particles at high speeds of more than 10 µm s(-1) (more than 0.2 body lengths per revolution in dimensionless speed). The fundamental mechanism of the cargo-towing ability of these magnetic (fuel-free) nanowire motors is modelled, and the hydrodynamic features of these cargo-loaded motors discussed. The effect of the cargo size on swimming performance is evaluated experimentally and compared to a theoretical model, emphasizing the interplay between hydrodynamic drag forces and boundary actuation. The latter leads to an unusual increase of the propulsion speed at an intermediate particle size. Potential applications of these cargo-towing nanoswimmers are demonstrated by using the directed delivery of drug-loaded microparticles to HeLa cancer cells in biological media. Transport of the drug carriers through a microchannel from the pick-up zone to the release microwell is further illustrated. It is expected that magnetically driven nanoswimmers will provide a new approach for the rapid delivery of target-specific drug carriers to predetermined destinations.

Ingestible Functional Magnetic Robot with Localized Flexibility (MR-LF).

The integration of an ingestible dosage form with sensing, actuation, and drug delivery capabilities can enable a broad range of surgical-free diagnostic and treatment strategies. However, the gastrointestinal (GI) tract is a highly constrained and complex luminal construct that fundamentally limits the size of an ingestible system. Recent advancements in mesoscale magnetic crawlers have demonstrated the ability to effectively traverse complex and confined systems by leveraging magnetic fields to induce contraction and bending-based locomotion. However, the integration of functional components (e.g., electronics) in the proposed ingestible system remains fundamentally challenging. Herein, the creation of a centralized compartment in a magnetic robot by imparting localized flexibility (MR-LF) is demonstrated. The centralized compartment enables MR-LF to be readily integrated with modular functional components and payloads, such as commercial off-the-shelf electronics and medication, while preserving its bidirectionality in an ingestible form factor. The ability of MR-LF to incorporate electronics, perform drug delivery, guide continuum devices such as catheters, and navigate air-water environments in confined lumens is demonstrated. The MR-LF enables functional integration to create a highly-integrated ingestible system that can ultimately address a broad range of unmet clinical needs.

A 3D-Printed Self-Learning Three-Linked-Sphere Robot for Autonomous Confined-Space Navigation.

Reinforcement learning control methods can impart robots with the ability to discover effective behavior, reducing their modeling and sensing requirements, and enabling their ability to adapt to environmental changes. However, it remains challenging for a robot to achieve navigation in confined and dynamic environments, which are characteristic of a broad range of biomedical applications, such as endoscopy with ingestible electronics. Herein, a compact, 3D-printed three-linked-sphere robot synergistically integrated with a reinforcement learning algorithm that can perform adaptable, autonomous crawling in a confined channel is demonstrated. The scalable robot consists of three equally sized spheres that are linearly coupled, in which the extension and contraction in specific sequences dictate its navigation. The ability to achieve bidirectional locomotion across frictional surfaces in open and confined spaces without prior knowledge of the environment is also demonstrated. The synergistic integration of a highly scalable robotic apparatus and the model-free reinforcement learning control strategy can enable autonomous navigation in a broad range of dynamic and confined environments. This capability can enable sensing, imaging, and surgical processes in previously inaccessible confined environments in the human body.

Squirming in a viscous fluid enclosed by a Brinkman medium.

Cell motility plays important roles in a range of biological processes, such as reproduction and infections. Studies have hypothesized that the ulcer-causing bacterium Helicobacter pylori invades the gastric mucus layer lining the stomach by locally turning nearby gel into sol, thereby enhancing its locomotion through the biological barrier. In this work, we present a minimal theoretical model to investigate how heterogeneity created by a swimmer affects its own locomotion. As a generic locomotion model, we consider the swimming of a spherical squirmer in a purely viscous fluid pocket (representing the liquified or degelled region) surrounded by a Brinkman porous medium (representing the mucus gel). The use of the squirmer model enables an exact, analytical solution to this hydrodynamic problem. We obtain analytical expressions for the swimming speed, flow field, and power dissipation of the swimmer. Depending on the details of surface velocities and fluid properties, our results reveal the existence of a minimum threshold size of mucus gel that a swimmer needs to liquify in order to gain any enhancement in swimming speed. The threshold size can be as much as approximately 30% of the swimmer size. We contrast these predictions with results from previous models and highlight the significant role played by the details of surface actuations. In addition to their biological implications, these results could also inform the design of artificial microswimmers that can penetrate into biological gels for more effective drug delivery.

Helical locomotion in a porous medium.

Microorganisms and artificial microswimmers often need to swim through environments that are more complex than purely viscous liquids in their natural habitats or operational environments, such as gel-like mucus, wet soil, and aquifers. The question of how the properties of these complex environments affect locomotion has attracted considerable recent attention. In this paper, we present a theoretical model to examine how the additional resistance due to the network of stationary obstacles in a porous medium affects helical locomotion. Here, we focus on helical locomotion for its ubiquity as a propulsion mechanism adopted by many swimming bacteria and artificial microswimmers. We show that the additional resistance can have qualitatively different effects on various scenarios of helical locomotion: (1) a helical propeller driven by an external torque, (2) a free swimming bacterium consisting of a helical flagellum and a head, and (3) a cargo-carrying helical propeller driven by an external torque. Our results elucidate the subtle and significant differences between torqued helical propulsion versus force-free and torque-free swimming in a porous medium. We also remark on the limitations as well as potential connections of our results with experimental measurements of bacterial swimming speeds in polymeric solutions.

A laser-engraved wearable sensor for sensitive detection of uric acid and tyrosine in sweat.

Wearable sweat sensors have the potential to provide continuous measurements of useful biomarkers. However, current sensors cannot accurately detect low analyte concentrations, lack multimodal sensing or are difficult to fabricate at large scale. We report an entirely laser-engraved sensor for simultaneous sweat sampling, chemical sensing and vital-sign monitoring. We demonstrate continuous detection of temperature, respiration rate and low concentrations of uric acid and tyrosine, analytes associated with diseases such as gout and metabolic disorders. We test the performance of the device in both physically trained and untrained subjects under exercise and after a protein-rich diet. We also evaluate its utility for gout monitoring in patients and healthy controls through a purine-rich meal challenge. Levels of uric acid in sweat were higher in patients with gout than in healthy individuals, and a similar trend was observed in serum.

Effects of surfactant transport on electrodeformation of a viscous drop.

In this work we quantify the effects of surfactant transport on the deformation of a viscous drop under a DC electric field. We study how convective and diffusive transport of surfactants at drop surfaces influence the equilibrium and dynamic deformation of a leaky dielectric drop and a conducting drop. Focusing on the prolate drop shape (elongates along the electric field), we show the differences in equilibrium deformation and flow circulation between a leaky dielectric drop and a conducting drop. We quantify the drop electrodeformation via its dependence on the interior flow circulation and the dominant surfactant transport regime (characterized by the surface Péclet number Pe_{s}). For a leaky dielectric drop with dominant surfactant diffusion (Pe_{s}≪1), equator-to-pole (pole-to-equator) circulation yields smaller (larger) equilibrium deformation with increasing surfactant coverage, compared to a clean drop. However, when convection dominates (Pe_{s}≫1), the equilibrium drop deformation increases (decreases) with larger surfactant coverage for equator-to-pole (pole-to-equator) circulation. Larger equilibrium drop deformation is found for a leaky dielectric drop than a conducting drop when the interior flow is from equator to pole. For an interior flow from pole to equator, we identify cases where larger deformation is found for a conducting interior fluid. Finally, we study the effect of the surfactant transport on the dynamic evolution of drop shape. We found the drop undergoes an overshoot in the early deformation phase, before settling to its equilibrium shape-similar to the overshoot observed for unsteady Stokes flow.

Sorting by interfacial tension (SIFT): Label-free enzyme sorting using droplet microfluidics.

Droplet microfluidics has the ability to greatly increase the throughput of screening and sorting of enzymes by carrying reagents in picoliter droplets flowing in inert oils. It was found with the use of a specific surfactant, the interfacial tension of droplets can be very sensitive to droplet pH. This enables the sorting of droplets of different pH when confined droplets encounter a microfabricated trench. The device can be extended to sort enzymes, as a large number of enzymatic reactions lead to the production of an acidic or basic product and a concurrent change in solution pH. The progress of an enzymatic reaction is tracked from the position of a flowing train of droplets. We demonstrate the sorting of esterase isoenzymes based on their enzymatic activity. This label-free technology, that we dub droplet sorting by interfacial tension (SIFT), requires no active components and would have applications for enzyme sorting in high-throughput applications that include enzyme screening and directed evolution of enzymes.