Immune Cell-Based Microrobots for Remote Magnetic Actuation, Antitumor Activity, and Medical Imaging.

Translating medical microrobots into clinics requires tracking, localization, and performing assigned medical tasks at target locations, which can only happen when appropriate design, actuation mechanisms, and medical imaging systems are integrated into a single microrobot. Despite this, these parameters are not fully considered when designing macrophage-based microrobots. This study presents living macrophage-based microrobots that combine macrophages with magnetic Janus particles coated with FePt nanofilm for magnetic steering and medical imaging and bacterial lipopolysaccharides for stimulating macrophages in a tumor-killing state. The macrophage-based microrobots combine wireless magnetic actuation, tracking with medical imaging techniques, and antitumor abilities. These microrobots are imaged under magnetic resonance imaging and optoacoustic imaging in soft-tissue-mimicking phantoms and ex vivo conditions. Magnetic actuation and real-time imaging of microrobots are demonstrated under static and physiologically relevant flow conditions using optoacoustic imaging. Further, macrophage-based microrobots are magnetically steered toward urinary bladder tumor spheroids and imaged with a handheld optoacoustic device, where the microrobots significantly reduce the viability of tumor spheroids. The proposed approach demonstrates the proof-of-concept feasibility of integrating macrophage-based microrobots into clinic imaging modalities for cancer targeting and intervention, and can also be implemented for various other medical applications.

Machine Learning-Based Shear Optimal Adhesive Microstructures with Experimental Validation.

Bioinspired fibrillar structures are promising for a wide range of disruptive adhesive applications. Especially micro/nanofibrillar structures on gecko toes can have strong and controllable adhesion and shear on a wide range of surfaces with residual-free, repeatable, self-cleaning, and other unique features. Synthetic dry fibrillar adhesives inspired by such biological fibrils are optimized in different aspects to increase their performance. Previous fibril designs for shear optimization are limited by predefined standard shapes in a narrow range primarily based on human intuition, which restricts their maximum performance. This study combines the machine learning-based optimization and finite-element-method-based shear mechanics simulations to find shear-optimized fibril designs automatically. In addition, fabrication limitations are integrated into the simulations to have more experimentally relevant results. The computationally discovered shear-optimized structures are fabricated, experimentally validated, and compared with the simulations. The results show that the computed shear-optimized fibrils perform better than the predefined standard fibril designs. This design optimization method can be used in future real-world shear-based gripping or nonslip surface applications, such as robotic pick-and-place grippers, climbing robots, gloves, electronic devices, and medical and wearable devices.

Acoustic Trapping and Manipulation of Hollow Microparticles under Fluid Flow Using a Single-Lens Focused Ultrasound Transducer.

Microparticle manipulation and trapping play pivotal roles in biotechnology. To achieve effective manipulation within fluidic flow conditions and confined spaces, it is necessary to consider the physical properties of microparticles and the types of trapping forces applied. While acoustic waves have shown potential for manipulating microparticles, the existing setups involve complex actuation mechanisms and unstable microbubbles. Consequently, the need persists for an easily deployable acoustic actuation setup with stable microparticles. Here, we propose the use of hollow borosilicate microparticles possessing a rigid thin shell, which can be efficiently trapped and manipulated using a single-lens focused ultrasound (FUS) transducer under physiologically relevant flow conditions. These hollow microparticles offer stability and advantageous acoustic properties. They can be scaled up and mass-produced, making them suitable for systemic delivery. Our research demonstrates the successful trapping dynamics of FUS within circular tubings of varying diameters, validating the effectiveness of the method under realistic flow rates and ultrasound amplitudes. We also showcase the ability to remove hollow microparticles by steering the FUS transducer against the flow. Furthermore, we present potential biomedical applications, such as active cell tagging and navigation in bifurcated channels as well as ultrasound imaging in mouse cadaver liver tissue.

Acoustic Streaming-Induced Multimodal Locomotion of Bubble-Based Microrobots.

Acoustically-driven bubbles at the micron scale can generate strong microstreaming flows in its surrounding fluidic medium. The tunable acoustic streaming strength of oscillating microbubbles and the diversity of the generated flow patterns enable the design of fast-moving microrobots with multimodal locomotion suitable for biomedical applications. The acoustic microrobots holding two coupled microbubbles inside a rigid body are presented; trapped bubbles inside the L-shaped structure with different orifices generate various streaming flows, thus allowing multiple degrees of freedom in locomotion. The streaming pattern and mean streaming speed depend on the intensity and frequency of the acoustic wave, which can trigger four dominant locomotion modes in the microrobot, denoted as translational and rotational, spinning, rotational, and translational modes. Next, the effect of various geometrical and actuation parameters on the control and navigation of the microrobot is investigated. Furthermore, the surface-slipping multimodal locomotion, flow mixing, particle manipulation capabilities, the effective interaction of high flow rates with cells, and subsequent cancerous cell lysing abilities of the proposed microrobot are demonstrated. Overall, these results introduce a design toolbox for the next generation of acoustic microrobots with higher degrees of freedom with multimodal locomotion in biomedical applications.

Programmable nanocomposites of cellulose nanocrystals and zwitterionic hydrogels for soft robotics.

Stimuli-responsive hydrogels have garnered significant attention as a versatile class of soft actuators. Introducing anisotropic properties, and shape-change programmability to responsive hydrogels promises a host of opportunities in the development of soft robots. Herein we report the synthesis of pH-responsive hydrogel nanocomposites with predetermined microstructural anisotropy, shape-transformation, and self-healing. Our hydrogel nanocomposites are largely composed of zwitterionic monomers and asymmetric cellulose nanocrystals. While the zwitterionic nature of the network imparts both self-healing and cytocompatibility to our hydrogel nanocomposites, the shear-induced alignment of cellulose nanocrystals renders their anisotropic swelling and mechanical properties. Thanks to the self-healing properties, we utilized a cut-and-paste approach to program reversible, and complex deformation into our hydrogels. As a proof-of-concept, we demonstrated the transport of light cargo using tethered and untethered soft robots made from our hydrogels. We believe the proposed material system introduce a powerful toolbox for the development of future generations of biomedical soft robots.

Designing Covalent Organic Framework-Based Light-Driven Microswimmers toward Therapeutic Applications.

While micromachines with tailored functionalities enable therapeutic applications in biological environments, their controlled motion and targeted drug delivery in biological media require sophisticated designs for practical applications. Covalent organic frameworks (COFs), a new generation of crystalline and nanoporous polymers, offer new perspectives for light-driven microswimmers in heterogeneous biological environments including intraocular fluids, thus setting the stage for biomedical applications such as retinal drug delivery. Two different types of COFs, uniformly spherical TABP-PDA-COF sub-micrometer particles and texturally nanoporous, micrometer-sized TpAzo-COF particles are described and compared as light-driven microrobots. They can be used as highly efficient visible-light-driven drug carriers in aqueous ionic and cellular media. Their absorption ranging down to red light enables phototaxis even in deeper and viscous biological media, while the organic nature of COFs ensures their biocompatibility. Their inherently porous structures with ≈2.6  and ≈3.4 nm pores, and large surface areas allow for targeted and efficient drug loading even for insoluble drugs, which can be released on demand. Additionally, indocyanine green (ICG) dye loading in the pores enables photoacoustic imaging, optical coherence tomography, and hyperthermia in operando conditions. This real-time visualization of the drug-loaded COF microswimmers enables unique insights into the action of photoactive porous drug carriers for therapeutic applications.

Reduced rotational flows enable the translation of surface-rolling microrobots in confined spaces.

Biological microorganisms overcome the Brownian motion at low Reynolds numbers by utilizing symmetry-breaking mechanisms. Inspired by them, various microrobot locomotion methods have been developed at the microscale by breaking the hydrodynamic symmetry. Although the boundary effects have been extensively studied for microswimmers and employed for surface-rolling microrobots, the behavior of microrobots in the proximity of multiple wall-based "confinement" is yet to be elucidated. Here, we study the confinement effect on the motion of surface-rolling microrobots. Our experiments demonstrate that the locomotion efficiency of spherical microrollers drastically decreases in confined spaces due to out-of-plane rotational flows generated during locomotion. Hence, a slender microroller design, generating smaller rotational flows, is shown to outperform spherical microrollers in confined spaces. Our results elucidate the underlying physics of surface rolling-based locomotion in confined spaces and present a design strategy with optimal flow generation for efficient propulsion in such areas, including blood vessels and microchannels.

Real-time 3D optoacoustic tracking of cell-sized magnetic microrobots circulating in the mouse brain vasculature.

Mobile microrobots hold remarkable potential to revolutionize health care by enabling unprecedented active medical interventions and theranostics, such as active cargo delivery and microsurgical manipulations in hard-to-reach body sites. High-resolution imaging and control of cell-sized microrobots in the in vivo vascular system remains an unsolved challenge toward their clinical use. To overcome this limitation, we propose noninvasive real-time detection and tracking of circulating microrobots using optoacoustic imaging. We devised cell-sized nickel-based spherical Janus magnetic microrobots whose near-infrared optoacoustic signature is enhanced via gold conjugation. The 5-, 10-, and 20-µm-diameter microrobots are detected volumetrically both in bloodless ex vivo tissues and under real-life conditions with a strongly light-absorbing blood background. We further demonstrate real-time three-dimensional tracking and magnetic manipulation of the microrobots circulating in murine cerebral vasculature, thus paving the way toward effective and safe operation of cell-sized microrobots in challenging and clinically relevant intravascular environments.

Soft actuators for real-world applications.

Inspired by physically adaptive, agile, reconfigurable and multifunctional soft-bodied animals and human muscles, soft actuators have been developed for a variety of applications, including soft grippers, artificial muscles, wearables, haptic devices and medical devices. However, the complex performance of biological systems cannot yet be fully replicated in synthetic designs. In this Review, we discuss new materials and structural designs for the engineering of soft actuators with physical intelligence and advanced properties, such as adaptability, multimodal locomotion, self-healing and multi-responsiveness. We examine how performance can be improved and multifunctionality implemented by using programmable soft materials, and highlight important real-world applications of soft actuators. Finally, we discuss the challenges and opportunities for next-generation soft actuators, including physical intelligence, adaptability, manufacturing scalability and reproducibility, extended lifetime and end-of-life strategies.

High shear rate propulsion of acoustic microrobots in complex biological fluids.

Untethered microrobots offer a great promise for localized targeted therapy in hard-to-access spaces in our body. Despite recent advancements, most microrobot propulsion capabilities have been limited to homogenous Newtonian fluids. However, the biological fluids present in our body are heterogeneous and have shear rate-dependent rheological properties, which limit the propulsion of microrobots using conventional designs and actuation methods. We propose an acoustically powered microrobotic system, consisting of a three-dimensionally printed 30-micrometer-diameter hollow body with an oscillatory microbubble, to generate high shear rate fluidic flow for propulsion in complex biofluids. The acoustically induced microstreaming flow leads to distinct surface-slipping and puller-type propulsion modes in Newtonian and non-Newtonian fluids, respectively. We demonstrate efficient propulsion of the microrobots in diverse biological fluids, including in vitro navigation through mucus layers on biologically relevant three-dimensional surfaces. The microrobot design and high shear rate propulsion mechanism discussed herein could open new possibilities to deploy microrobots in complex biofluids toward minimally invasive targeted therapy.

Liquid Crystal Structure of Supercooled Liquid Gallium and Eutectic Gallium-Indium.

Understanding the origin of structural ordering in supercooled liquid gallium (Ga) has been a great scientific quest in the past decades. Here, reflective polarized optical microscopy on Ga sandwiched between glasses treated with rubbed polymers reveals the onset of an anisotropic reflection at 120 °C that increases on cooling and persists down to room temperature or below. The polymer rubbing usually aligns the director of thermotropic liquid crystals (LCs) parallel to the rubbing direction. On the other hand, when Ga is sandwiched between substrates that align conventional LC molecules normal to the surface, the reflection is isotropic, but mechanical shear force induces anisotropic reflection that relaxes in seconds. Such alignment effects and shear-induced realignment are typical to conventional thermotropic LCs and indicate a LC structure of liquid Ga. Specifically, Ga textures obtained by atomic force and scanning electron microscopy reveal the existence of a lamellar structure corresponding to a smectic LC phase, while the nanometer-thin lamellar structure is transparent under transmission polarized optical microscopy. Such spatial molecular arrangements may be attributed to dimer molecular entities in the supercooled liquid Ga. The LC structure observation of electrically conductive liquid Ga can provide new opportunities in materials science and LC applications.

Shape anisotropy-governed locomotion of surface microrollers on vessel-like microtopographies against physiological flows.

Surface microrollers are promising microrobotic systems for controlled navigation in the circulatory system thanks to their fast speeds and decreased flow velocities at the vessel walls. While surface propulsion on the vessel walls helps minimize the effect of strong fluidic forces, three-dimensional (3D) surface microtopography, comparable to the size scale of a microrobot, due to cellular morphology and organization emerges as a major challenge. Here, we show that microroller shape anisotropy determines the surface locomotion capability of microrollers on vessel-like 3D surface microtopographies against physiological flow conditions. The isotropic (single, 8.5 µm diameter spherical particle) and anisotropic (doublet, two 4 µm diameter spherical particle chain) magnetic microrollers generated similar translational velocities on flat surfaces, whereas the isotropic microrollers failed to translate on most of the 3D-printed vessel-like microtopographies. The computational fluid dynamics analyses revealed larger flow fields generated around isotropic microrollers causing larger resistive forces near the microtopographies, in comparison to anisotropic microrollers, and impairing their translation. The superior surface-rolling capability of the anisotropic doublet microrollers on microtopographical surfaces against the fluid flow was further validated in a vessel-on-a-chip system mimicking microvasculature. The findings reported here establish the design principles of surface microrollers for robust locomotion on vessel walls against physiological flows.

Flexural wave-based soft attractor walls for trapping microparticles and cells.

Acoustic manipulation of microparticles and cells, called acoustophoresis, inside microfluidic systems has significant potential in biomedical applications. In particular, using acoustic radiation force to push microscopic objects toward the wall surfaces has an important role in enhancing immunoassays, particle sensors, and recently microrobotics. In this paper, we report a flexural-wave based acoustofluidic system for trapping micron-sized particles and cells at the soft wall boundaries. By exciting a standard microscope glass slide (1 mm thick) at its resonance frequencies <200 kHz, we show the wall-trapping action in sub-millimeter-size rectangular and circular cross-sectional channels. For such low-frequency excitation, the acoustic wavelength can range from 10-150 times the microchannel width, enabling a wide design space for choosing the channel width and position on the substrate. Using the system-level acousto-structural simulations, we confirm the acoustophoretic motion of particles near the walls, which is governed by the competing acoustic radiation and streaming forces. Finally, we investigate the performance of the wall-trapping acoustofluidic setup in attracting the motile cells, such as Chlamydomonas reinhardtii microalgae, toward the soft boundaries. Furthermore, the rotation of microalgae at the sidewalls and trap-escape events under pulsed ultrasound are demonstrated. The flexural-wave driven acoustofluidic system described here provides a biocompatible, versatile, and label-free approach to attract particles and cells toward the soft walls.

Bioinspired underwater locomotion of light-driven liquid crystal gels.

Soft-bodied aquatic invertebrates, such as sea slugs and snails, are capable of diverse locomotion modes under water. Recapitulation of such multimodal aquatic locomotion in small-scale soft robots is challenging, due to difficulties in precise spatiotemporal control of deformations and inefficient underwater actuation of existing stimuli-responsive materials. Solving this challenge and devising efficient untethered manipulation of soft stimuli-responsive materials in the aquatic environment would significantly broaden their application potential in biomedical devices. We mimic locomotion modes common to sea invertebrates using monolithic liquid crystal gels (LCGs) with inherent light responsiveness and molecular anisotropy. We elicit diverse underwater locomotion modes, such as crawling, walking, jumping, and swimming, by local deformations induced by selective spatiotemporal light illumination. Our results underpin the pivotal role of the physicomechanical properties of LCGs in the realization of diverse modes of light-driven robotic underwater locomotion. We envisage that our results will introduce a toolbox for designing efficient untethered soft robots for fluidic environments.

Acoustically powered surface-slipping mobile microrobots.

Untethered synthetic microrobots have significant potential to revolutionize minimally invasive medical interventions in the future. However, their relatively slow speed and low controllability near surfaces typically are some of the barriers standing in the way of their medical applications. Here, we introduce acoustically powered microrobots with a fast, unidirectional surface-slipping locomotion on both flat and curved surfaces. The proposed three-dimensionally printed, bullet-shaped microrobot contains a spherical air bubble trapped inside its internal body cavity, where the bubble is resonated using acoustic waves. The net fluidic flow due to the bubble oscillation orients the microrobot's axisymmetric axis perpendicular to the wall and then propels it laterally at very high speeds (up to 90 body lengths per second with a body length of 25 µm) while inducing an attractive force toward the wall. To achieve unidirectional locomotion, a small fin is added to the microrobot's cylindrical body surface, which biases the propulsion direction. For motion direction control, the microrobots are coated anisotropically with a soft magnetic nanofilm layer, allowing steering under a uniform magnetic field. Finally, surface locomotion capability of the microrobots is demonstrated inside a three-dimensional circular cross-sectional microchannel under acoustic actuation. Overall, the combination of acoustic powering and magnetic steering can be effectively utilized to actuate and navigate these microrobots in confined and hard-to-reach body location areas in a minimally invasive fashion.

Monolithic shape-programmable dielectric liquid crystal elastomer actuators.

Soft robotics may enable many new technologies in which humans and robots physically interact, yet the necessary high-performance soft actuators still do not exist. The optimal soft actuators need to be fast and forceful and have programmable shape changes. Furthermore, they should be energy efficient for untethered applications and easy to fabricate. Here, we combine desirable characteristics from two distinct active material systems: fast and highly efficient actuation from dielectric elastomers and directed shape programmability from liquid crystal elastomers. Via a top-down photoalignment method, we program molecular alignment and localized giant elastic anisotropy into the liquid crystal elastomers. The linearly actuated liquid crystal elastomer monoliths achieve strain rates over 120% per second with an energy conversion efficiency of 20% while moving loads over 700 times the elastomer weight. The electric actuation mechanism offers unprecedented opportunities toward miniaturization with shape programmability, efficiency, and more degrees of freedom for applications in soft robotics and beyond.

HapTable: An Interactive Tabletop Providing Online Haptic Feedback for Touch Gestures.

We present HapTable; a multi-modal interactive tabletop that allows users to interact with digital images and objects through natural touch gestures, and receive visual and haptic feedback accordingly. In our system, hand pose is registered by an infrared camera and hand gestures are classified using a Support Vector Machine (SVM) classifier. To display a rich set of haptic effects for both static and dynamic gestures, we integrated electromechanical and electrostatic actuation techniques effectively on tabletop surface of HapTable, which is a surface capacitive touch screen. We attached four piezo patches to the edges of tabletop to display vibrotactile feedback for static gestures. For this purpose, the vibration response of the tabletop, in the form of frequency response functions (FRFs), was obtained by a laser Doppler vibrometer for 84 grid points on its surface. Using these FRFs, it is possible to display localized vibrotactile feedback on the surface for static gestures. For dynamic gestures, we utilize the electrostatic actuation technique to modulate the frictional forces between finger skin and tabletop surface by applying voltage to its conductive layer. To our knowledge, this hybrid haptic technology is one of a kind and has not been implemented or tested on a tabletop. It opens up new avenues for gesture-based haptic interaction not only on tabletop surfaces but also on touch surfaces used in mobile devices with potential applications in data visualization, user interfaces, games, entertainment, and education. Here, we present two examples of such applications, one for static and one for dynamic gestures, along with detailed user studies. In the first one, user detects the direction of a virtual flow, such as that of wind or water, by putting their hand on the tabletop surface and feeling a vibrotactile stimulus traveling underneath it. In the second example, user rotates a virtual knob on the tabletop surface to select an item from a menu while feeling the knob's detents and resistance to rotation in the form of frictional haptic feedback.

Seed-mediated synthesis of plasmonic gold nanoribbons using cancer cells for hyperthermia applications.

A surfactant-less, seed mediated, biological synthesis of two dimensional (2-D) nanoribbons in the presence of breast cancer cells (MCF7) is demonstrated. The diameter and yield of nanoribbons are tunable via seeds and gold precursor concentration. Such crystalline nanoribbons serve to enhance the Raman signals over MCF7 cells. The side and slopes of the triangular nanoplatelets fused as nanoribbons exhibit plasmon excitement in quadrupole resonance modes in the infrared region. Consequently, when irradiated with an infrared laser they show an excellent photothermal effect and rapid rise in temperature. The experimental results verified by finite-difference time-domain (FTDT) calculations reveal the presence of wedge-plasmon polaritons propagating along the edges of the nanoribbons. These simulations confirm that long aspect ratio nanoribbon's edges and vertices act as an active optical waveguide, allowing for heat propagation along the long axis, killing cancer cells in the process at lower power doses.