Biosynthetic self-healing materials for soft machines.

Self-healing materials are indispensable for soft actuators and robots that operate in dynamic and real-world environments, as these machines are vulnerable to mechanical damage. However, current self-healing materials have shortcomings that limit their practical application, such as low healing strength (below a megapascal) and long healing times (hours). Here, we introduce high-strength synthetic proteins that self-heal micro- and macro-scale mechanical damage within a second by local heating. These materials are optimized systematically to improve their hydrogen-bonded nanostructure and network morphology, with programmable healing properties (2-23 MPa strength after 1 s of healing) that surpass by several orders of magnitude those of other natural and synthetic soft materials. Such healing performance creates new opportunities for bioinspired materials design, and addresses current limitations in self-healing materials for soft robotics and personal protective equipment.

Multifarious Transit Gates for Programmable Delivery of Bio-functionalized Matters.

Programmable delivery of biological matter is indispensable for the massive arrays of individual objects in biochemical and biomedical applications. Although a digital manipulation of single cells has been implemented by the integrated circuits of micromagnetophoretic patterns with current wires, the complex fabrication process and multiple current operation steps restrict its practical application for biomolecule arrays. Here, a convenient approach using multifarious transit gates is proposed, for digital manipulation of biofunctionalized microrobotic particles that can pass through the local energy barriers by a time-dependent pulsed magnetic field instead of multiple current wires. The multifarious transit gates including return, delay, and resistance linear gates, as well as dividing, reversed, and rectifying T-junction gates, are investigated theoretically and experimentally for the programmable manipulation of microrobotic particles. The results demonstrate that, a suitable angle of the gating field at a suitable time zone is crucial to implement digital operations at integrated multifarious transit gates along bifurcation paths to trap microrobotic particles in specific apartments, paving the way for flexible on-chip arrays of biomolecules and cells.

Biohybrid Microtube Swimmers Driven by Single Captured Bacteria.

Bacteria biohybrids employ the motility and power of swimming bacteria to carry and maneuver microscale particles. They have the potential to perform microdrug and cargo delivery in vivo, but have been limited by poor design, reduced swimming capabilities, and impeded functionality. To address these challenge, motile Escherichia coli are captured inside electropolymerized microtubes, exhibiting the first report of a bacteria microswimmer that does not utilize a spherical particle chassis. Single bacterium becomes partially trapped within the tube and becomes a bioengine to push the microtube though biological media. Microtubes are modified with "smart" material properties for motion control, including a bacteria-attractant polydopamine inner layer, addition of magnetic components for external guidance, and a biochemical kill trigger to cease bacterium swimming on demand. Swimming dynamics of the bacteria biohybrid are quantified by comparing "length of protrusion" of bacteria from the microtubes with respect to changes in angular autocorrelation and swimmer mean squared displacement. The multifunctional microtubular swimmers present a new generation of biocompatible micromotors toward future microbiorobots and minimally invasive medical applications.

Microstructured elastomeric surfaces with reversible adhesion and examples of their use in deterministic assembly by transfer printing.

Reversible control of adhesion is an important feature of many desired, existing, and potential systems, including climbing robots, medical tapes, and stamps for transfer printing. We present experimental and theoretical studies of pressure modulated adhesion between flat, stiff objects and elastomeric surfaces with sharp features of surface relief in optimized geometries. Here, the strength of nonspecific adhesion can be switched by more than three orders of magnitude, from strong to weak, in a reversible fashion. Implementing these concepts in advanced stamps for transfer printing enables versatile modes for deterministic assembly of solid materials in micro/nanostructured forms. Demonstrations in printed two- and three-dimensional collections of silicon platelets and membranes illustrate some capabilities. An unusual type of transistor that incorporates a printed gate electrode, an air gap dielectric, and an aligned array of single walled carbon nanotubes provides a device example.

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.

Chemotactic steering of bacteria propelled microbeads.

Flagellated bacteria have been embraced by the micro-robotics community as a highly efficient microscale actuation method, capable of converting chemical energy into mechanical actuation for microsystems that require a small payload and high rate of actuation. Along with being highly motile, Serratia marcescens (S. marcescens), our bacterium species of interest, is a highly agile biomotor capable of being steered via chemotaxis. In this paper, we attached S. marcescens bacteria to polystyrene microbeads towards creating biohybrid that can propel themselves towards an attractive chemical source. Using a three-channel microfluidic device, linear chemical gradients are generated to compare the behavior of bacteria-propelled beads in the presence and absence of a chemoattractant, L-aspartate. We tested and compared the behavior of three different bacteria-attached bead sizes (5, 10 and 20 µm diameter) using a visual particle-tracking algorithm, and noted their behavioral differences. The results indicate that in the presence of a chemoattractant, the S. marcescens-attached polystyrene beads exhibit a clear indication of directionality and steering control through the coordination of the bacteria present on each bead. This directionality is observed in all bead size cases, suggesting potential for targeted payload delivery using such a biohybrid micro-robotic approach.

Liquid Metal-Elastomer Composites with Dual-Energy Transmission Mode for Multifunctional Miniature Untethered Magnetic Robots.

Miniature untethered robots attract growing interest as they have become more functional and applicable to disruptive biomedical applications recently. Particularly, the soft ones among them exhibit unique merits of compliance, versatility, and agility. With scarce onboard space, these devices mostly harvest energy from environment or physical fields, such as magnetic and acoustic fields and patterned lights. In most cases, one device only utilizes one energy transmission mode (ETM) in powering its activities to achieve programmed tasks, such as locomotion and object manipulation. But real-world tasks demand multifunctional devices that require more energy in various forms. This work reports a liquid metal-elastomer composite with dual-ETM using one magnetic field for miniature untethered multifunctional robots. The first ETM uses the low-frequency (<100 Hz) field component to induce shape-morphing, while the second ETM employs energy transmitted via radio-frequency (20 kHz-300 GHz) induction to power onboard electronics and generate excess heat, enabling new capabilities. These new functions do not disturb the shape-morphing actuated using the first ETM. The reported material enables the integration of electric and thermal functionalities into soft miniature robots, offering a wealth of inspirations for multifunctional miniature robots that leverage developments in electronics to exhibit usefulness beyond self-locomotion.

3D-printed microrobots from design to translation.

Microrobots have attracted the attention of scientists owing to their unique features to accomplish tasks in hard-to-reach sites in the human body. Microrobots can be precisely actuated and maneuvered individually or in a swarm for cargo delivery, sampling, surgery, and imaging applications. In addition, microrobots have found applications in the environmental sector (e.g., water treatment). Besides, recent advancements of three-dimensional (3D) printers have enabled the high-resolution fabrication of microrobots with a faster design-production turnaround time for users with limited micromanufacturing skills. Here, the latest end applications of 3D printed microrobots are reviewed (ranging from environmental to biomedical applications) along with a brief discussion over the feasible actuation methods (e.g., on- and off-board), and practical 3D printing technologies for microrobot fabrication. In addition, as a future perspective, we discussed the potential advantages of integration of microrobots with smart materials, and conceivable benefits of implementation of artificial intelligence (AI), as well as physical intelligence (PI). Moreover, in order to facilitate bench-to-bedside translation of microrobots, current challenges impeding clinical translation of microrobots are elaborated, including entry obstacles (e.g., immune system attacks) and cumbersome standard test procedures to ensure biocompatibility.

Wireless Miniature Magnetic Phase-Change Soft Actuators.

Wireless miniature soft actuators are promising for various potential high-impact applications in medical, robotic grippers, and artificial muscles. However, these miniature soft actuators are currently constrained by a small output force and low work capacity. To address such challenges, a miniature magnetic phase-change soft composite actuator is reported. This soft actuator exhibits an expanding deformation and enables up to a 70 N output force and 175.2 J g-1 work capacity under remote magnetic radio frequency heating, which are 106 -107 times that of traditional magnetic soft actuators. To demonstrate its capabilities, a wireless soft robotic device is first designed that can withstand 0.24 m s-1 fluid flows in an artery phantom. By integrating it with a thermally-responsive shape-memory polymer and bistable metamaterial sleeve, a wireless reversible bistable stent is designed toward future potential angioplasty applications. Moreover, it can additionally locomote inside and jump out of granular media. At last, the phase-change actuator can realize programmable bending deformations when a specifically designed magnetization profile is encoded, enhancing its shape-programming capability. Such a miniature soft actuator provides an approach to enhance the mechanical output and versatility of magnetic soft robots and devices, extending their medical and other potential applications.

A Tissue Adhesion-Controllable and Biocompatible Small-Scale Hydrogel Adhesive Robot.

Recently, the realization of minimally invasive medical interventions on targeted tissues using wireless small-scale medical robots has received an increasing attention. For effective implementation, such robots should have a strong adhesion capability to biological tissues and at the same time easy controlled detachment should be possible, which has been challenging. To address such issue, a small-scale soft robot with octopus-inspired hydrogel adhesive (OHA) is proposed. Hydrogels of different Young's moduli are adapted to achieve a biocompatible adhesive with strong wet adhesion by preventing the collapse of the octopus-inspired patterns during preloading. Introduction of poly(N-isopropylacrylamide) hydrogel for dome-like protuberance structure inside the sucker wall of polyethylene glycol diacrylate hydrogel provides a strong tissue attachment in underwater and at the same time enables easy detachment by temperature changes due to its temperature-dependent volume change property. It is finally demonstrated that the small-scale soft OHA robot can efficiently implement biomedical functions owing to strong adhesion and controllable detachment on biological tissues while operating inside the body. Such robots with repeatable tissue attachment and detachment possibility pave the way for future wireless soft miniature robots with minimally invasive medical interventions.

Enhanced adhesion of dopamine methacrylamide elastomers via viscoelasticity tuning.

We present a study on the effects of cross-linking on the adhesive properties of bio-inspired 3,4-dihydroxyphenylalanine (DOPA). DOPA has a unique catechol moiety found in adhesive proteins in marine organisms, such as mussels and polychaete, which results in strong adhesion in aquatic conditions. Incorporation of this functional group in synthetic polymers provides the basis for pressure-sensitive adhesives for use in a broad range of environments. A series of cross-linked DOPA-containing polymers were prepared by adding divinyl cross-linking agent ethylene glycol dimethacrylate (EGDMA) to monomer mixtures of dopamine methacrylamide (DMA) and 2-methoxyethyl acrylate (MEA). Samples were prepared using a solvent-free microwave-assisted polymerization reaction and compared to a similar series of cross-linked MEA materials. Cross-linking with EGDMA tunes the viscoelastic properties of the adhesive material and has the advantage of not reacting with the catechol group that is responsible for the excellent adhesive performance of this material. Adhesion strength was measured by uniaxial indentation tests, which indicated that 0.001 mol % of EGDMA-cross-linked copolymer showed the highest work of adhesion in dry conditions, but non-cross-linked DMA was the highest in wet conditions. The results suggest that there is an optimal cross-linking degree that displays the highest adhesion by balancing viscous and elastic behaviors of the polymer but this appears to depend on the conditions. This concentration of cross-linker is well below the theoretical percolation threshold, and we propose that subtle changes in polymer viscoelastic properties can result in significant improvements in adhesion of DOPA-based materials. The properties of lightly cross-linked poly(DMA-co-MEA) were investigated by measurement of the frequency dependence of the storage modulus (G') and loss modulus (G''). The frequency-dependence of G' and magnitude of G'' showed gradual decreases with the fraction of EGDMA. Loosely cross-linked DMA copolymers, containing 0% and 0.001 mol % of EGDMA-cross-linked copolymers, displayed rheological behavior appropriate for pressure-sensitive adhesives characterized by a higher G' at high frequencies and lower G' at low frequencies. Our results indicate that dimethacrylate cross-linking of DMA copolymers can be used to enhance the adhesive properties of this unique material.

3D Printing of Elastomeric Bioinspired Complex Adhesive Microstructures.

Bioinspired elastomeric structural adhesives can provide reversible and controllable adhesion on dry/wet and synthetic/biological surfaces for a broad range of commercial applications. Shape complexity and performance of the existing structural adhesives are limited by the used specific fabrication technique, such as molding. To overcome these limitations by proposing complex 3D microstructured adhesive designs, a 3D elastomeric microstructure fabrication approach is implemented using two-photon-polymerization-based 3D printing. A custom aliphatic urethane-acrylate-based elastomer is used as the 3D printing material. Two designs are demonstrated with two combined biological inspirations to show the advanced capabilities enabled by the proposed fabrication approach and custom elastomer. The first design focuses on springtail- and gecko-inspired hybrid microfiber adhesive, which has the multifunctionalities of side-surface liquid super-repellency, top-surface liquid super-repellency, and strong reversible adhesion features in a single fiber array. The second design primarily centers on octopus- and gecko-inspired hybrid adhesive, which exhibits the benefits of both octopus- and gecko-inspired microstructured adhesives for strong reversible adhesion on both wet and dry surfaces, such as skin. This fabrication approach could be used to produce many other 3D complex elastomeric structural adhesives for future real-world applications.

Voxelated three-dimensional miniature magnetic soft machines via multimaterial heterogeneous assembly.

Small-scale soft-bodied machines that respond to externally applied magnetic field have attracted wide research interest because of their unique capabilities and promising potential in a variety of fields, especially for biomedical applications. When the size of such machines approach the sub-millimeter scale, their designs and functionalities are severely constrained by the available fabrication methods, which only work with limited materials, geometries, and magnetization profiles. To free such constraints, here, we propose a bottom-up assembly-based 3D microfabrication approach to create complex 3D miniature wireless magnetic soft machines at the milli- and sub-millimeter scale with arbitrary multimaterial compositions, arbitrary 3D geometries, and arbitrary programmable 3D magnetization profiles at high spatial resolution. This approach helps us concurrently realize diverse characteristics on the machines, including programmable shape morphing, negative Poisson's ratio, complex stiffness distribution, directional joint bending, and remagnetization for shape reconfiguration. It enlarges the design space and enables biomedical device-related functionalities that are previously difficult to achieve, including peristaltic pumping of biological fluids and transport of solid objects, active targeted cargo transport and delivery, liquid biopsy, and reversible surface anchoring in tortuous tubular environments withstanding fluid flows, all at the sub-millimeter scale. This work improves the achievable complexity of 3D magnetic soft machines and boosts their future capabilities for applications in robotics and biomedical engineering.

Enhanced wet adhesion and shear of elastomeric micro-fiber arrays with mushroom tip geometry and a photopolymerized p(DMA-co-MEA) tip coating.

Using principles inspired by the study of naturally occurring sticky systems such as the micro- and nanoscale fibers on the toes of geckos and the adhesive proteins secreted by marine animals such as mussels, this study describes the development and evaluation of a novel patterned and coated elastomeric microfibrillar material for enhanced repeatable adhesion and shear in wet environments. A multistep fabrication process consisting of optical lithography, micromolding, polymer synthesis, dipping, stamping, and photopolymerization is described to produce uniform arrays of polyurethane elastomeric microfibers with mushroom-shaped tips coated with a thin layer of lightly cross-linked p(DMA-co-MEA), an intrinsically adhesive synthetic polymer. Adhesion and shear force characterization of these arrays in contact with a glass hemisphere is demonstrated, and significant pull-off force, overall work of adhesion, and shear force enhancements in submerged aqueous environments are shown when compared to both unpatterned and uncoated samples, as well as previously evaluated patterned and coated arrays with differing geometry. Such materials may have potential value as repeatable adhesives for wet environments, such as for medical devices.

Multi-functional soft-bodied jellyfish-like swimming.

The functionalities of the untethered miniature swimming robots significantly decrease as the robot size becomes smaller, due to limitations of feasible miniaturized on-board components. Here we propose an untethered jellyfish-inspired soft millirobot that could realize multiple functionalities in moderate Reynolds number by producing diverse controlled fluidic flows around its body using its magnetic composite elastomer lappets, which are actuated by an external oscillating magnetic field. We particularly investigate the interaction between the robot's soft body and incurred fluidic flows due to the robot's body motion, and utilize such physical interaction to achieve different predation-inspired object manipulation tasks. The proposed lappet kinematics can inspire other existing jellyfish-like robots to achieve similar functionalities at the same length and time scale. Moreover, the robotic platform could be used to study the impacts of the morphology and kinematics changing in ephyra jellyfish.

Multifunctional magnetic hairbot for untethered osteogenesis, ultrasound contrast imaging and drug delivery.

To explore novel materials graded for biological functions is one of the grand challenges and ambitions of robotics. In this study, the design, development, and external guidance of micron-sized hair-derived robots (hairbots) are shown as autologous cargo carriers for guided drug delivery, untethered osteogenesis, and sonographic contrast agents. Having biogenic origin, the hairbots show excellent biocompatibility, as demonstrated with cell adhesion, spreading and proliferation. External magnetic fields are used to enhance differentiation of mesenchymal stem cells (MSCs) into bone like cells, which can be used as magnetic therapy for bone healing. Effect of external magnetic forces was simulated by COMSOL Multiphysics® modelling software. The action of hairbots as osteoconductive material triggering osteogenic differentiations of MSCs is studied via calcium signaling by fluorescence microscopy. Further, by exploiting the hollow medullary region, the proposed hairbots are designed to perform theranostic dual functions (therapy + diagnostic) - as Doxorubicin drug delivery vehicle, and for Ultrasound contrast imaging. Harnessing sensing and actuation due to magnetic capabilities of hairbots, for enhanced biological functionality shown herein, provides a novel material in the search of new multifunctional microrobots.

Light-Triggered Drug Release from 3D-Printed Magnetic Chitosan Microswimmers.

Advances in design and fabrication of functional micro/nanomaterials have sparked growing interest in creating new mobile microswimmers for various healthcare applications, including local drug and other cargo ( e. g., gene, stem cell, and imaging agent) delivery. Such microswimmer-based cargo delivery is typically passive by diffusion of the cargo material from the swimmer body; however, controlled active release of the cargo material is essential for on-demand, precise, and effective delivery. Here, we propose a magnetically powered, double-helical microswimmer of 6 µm diameter and 20 µm length that can on-demand actively release a chemotherapeutic drug, doxorubicin, using an external light stimulus. We fabricate the microswimmers by two-photon-based 3D printing of a natural polymer derivative of chitosan in the form of a magnetic polymer nanocomposite. Amino groups presented on the microswimmers are modified with doxorubicin by means of a photocleavable linker. Chitosan imparts the microswimmers with biocompatibility and biodegradability for use in a biological setting. Controlled steerability of the microswimmers is shown under a 10 mT rotating magnetic field. With light induction at 365 nm wavelength and 3.4 × 10-1 W/cm2 intensity, 60% of doxorubicin is released from the microswimmers within 5 min. Drug release is ceased by controlled patterns of light induction, so as to adjust the desired release doses in the temporal domain. Under physiologically relevant conditions, substantial degradation of the microswimmers is shown in 204 h to nontoxic degradation products. This study presents the combination of light-triggered drug delivery with magnetically powered microswimmer mobility. This approach could be extended to similar systems where multiple control schemes are needed for on-demand medical tasks with high precision and efficiency.

Self-Folded Hydrogel Tubes for Implantable Muscular Tissue Scaffolds.

Programming materials with tunable physical and chemical interactions among its components pave the way of generating 3D functional active microsystems with various potential applications in tissue engineering, drug delivery, and soft robotics. Here, the development of a recapitulated fascicle-like implantable muscle construct by programmed self-folding of poly(ethylene glycol) diacrylate hydrogels is reported. The system comprises two stacked layers, each with differential swelling degrees, stiffnesses, and thicknesses in 2D, which folds into a 3D tube together. Inside the tubes, muscle cell adhesion and their spatial alignment are controlled. Both skeletal and cardiac muscle cells also exhibit high viability, and cardiac myocytes preserve their contractile function over the course of 7 d. Integration of biological cells with smart, shape-changing materials could give rise to the development of new cellular constructs for hierarchical tissue assembly, drug testing platforms, and biohybrid actuators that can perform sophisticated tasks.

Three-dimensional patterning in biomedicine: Importance and applications in neuropharmacology.

Nature manufactures biological systems in three dimensions with precisely controlled spatiotemporal profiles on hierarchical length and time scales. In this article, we review 3D patterning of biological systems on synthetic platforms for neuropharmacological applications. We briefly describe 3D versus 2D chemical and topographical patterning methods and their limitations. Subsequently, an overview of introducing a third dimension in neuropharmacological research with delineation of chemical and topographical roles is presented. Finally, toward the end of this article, an explanation of how 3D patterning has played a pivotal role in relevant fields of neuropharmacology to understand neurophysiology during development, normal health, and disease conditions is described. The future prospects of organs-on-a--like devices to mimic patterned blood-brain barrier in the context of neurotherapeutic discovery and development for the prioritization of lead candidates, membrane potential, and toxicity testing are also described. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1369-1382, 2018.

Bioinspired Composite Microfibers for Skin Adhesion and Signal Amplification of Wearable Sensors.

A facile approach is proposed for superior conformation and adhesion of wearable sensors to dry and wet skin. Bioinspired skin-adhesive films are composed of elastomeric microfibers decorated with conformal and mushroom-shaped vinylsiloxane tips. Strong skin adhesion is achieved by crosslinking the viscous vinylsiloxane tips directly on the skin surface. Furthermore, composite microfibrillar adhesive films possess a high adhesion strength of 18 kPa due to the excellent shape adaptation of the vinylsiloxane tips to the multiscale roughness of the skin. As a utility of the skin-adhesive films in wearable-device applications, they are integrated with wearable strain sensors for respiratory and heart-rate monitoring. The signal-to-noise ratio of the strain sensor is significantly improved to 59.7 because of the considerable signal amplification of microfibrillar skin-adhesive films.