Responsive Hydrogel-Based Modular Microrobots for Multi-Functional Micromanipulation.

Microrobots show great potential in biomedical applications such as drug delivery and cell manipulations. However, current microrobots are mostly fabricated as a single entity and type and the tasks they can perform are limited. In this paper, modular microrobots, with an overall size of 120 µm × 200 µm, are proposed with responsive mating components, made from stimuli-responsive hydrogels, and application specific end-effectors for microassembly tasks. The modular microrobots are fabricated based on photolithography and two-photon polymerization together or separately. Two types of modular microrobots are created based on the location of the responsive mating component. The first type of modular microrobot has a mating component that can shrink upon stimulation, while the second type has a double bilayer structure that can realize an open and close motion. The exchange of end-effectors with an identical actuation base is demonstrated for both types of microrobots. Finally, different manipulation tasks are performed with different types of end-effectors.

Magnetotactic Sperm Cells for Assisted Reproduction.

Biohybrid micromotors are active microscopic agents consisting of biological and synthetic components that are being developed as novel tools for biomedical applications. By capturing motile sperm cells within engineered microstructures, they can be controlled remotely while being propelled forward by the flagellar beat. This makes them an interesting tool for reproductive medicine that can enable minimally invasive sperm cell delivery to the oocyte in vivo, as a treatment for infertility. The generation of sperm-based micromotors in sufficiently large numbers, as they are required in biomedical applications has been challenging, either due to the employed fabrication techniques or the stability of the microstructure-sperm coupling. Here, biohybrid micromotors, which can be assembled in a fast and simple process using magnetic microparticles, are presented. These magnetotactic sperm cells show a high motility and swimming speed and can be transferred between different environments without large detrimental effects on sperm motility and membrane integrity. Furthermore, clusters of micromotors are assembled magnetically and visualized using dual ultrasound (US)/photoacoustic (PA) imaging. Finally, a protocol for the scaled-up assembly of micromotors and their purification for use in in vitro fertilization (IVF) is presented, bringing them closer to their biomedical implementation.

Magnetic Lateral Ladder for Unidirectional Transport of Microrobots: Design Principles and Potential Applications of Cells-on-Chip.

Functionalized microrobots, which are directionally manipulated in a controlled and precise manner for specific tasks, face challenges. However, magnetic field-based controls constrain all microrobots to move in a coordinated manner, limiting their functions and independent behaviors. This article presents a design principle for achieving unidirectional microrobot transport using an asymmetric magnetic texture in the shape of a lateral ladder, which the authors call the "railway track." An asymmetric magnetic energy distribution along the axis allows for the continuous movement of microrobots in a fixed direction regardless of the direction of the magnetic field rotation. The authors demonstrated precise control and simple utilization of this method. Specifically, by placing magnetic textures with different directionalities, an integrated cell/particle collector can collect microrobots distributed in a large area and move them along a complex trajectory to a predetermined location.  The authors can leverage the versatile capabilities offered by this texture concept, including hierarchical isolation, switchable collection, programmable pairing, selective drug-response test, and local fluid mixing for target objects. The results demonstrate the importance of microrobot directionality in achieving complex individual control. This novel concept represents significant advancement over conventional magnetic field-based control technology and paves the way for further research in biofunctionalized microrobotics.

Macrophages-Based Biohybrid Microrobots for Breast Cancer Photothermal Immunotherapy by Inducing Pyroptosis.

Pyroptosis-based immunotherapy can escape drug resistance as well as inhibit metastasis. It is urgently required to develop a delivery platform to induce targeted tumor-specific pyroptosis for cancer immunotherapy. Herein, macrophages-based biohybrid microrobots (IDN@MC) are constructed with IR-macrophage and decitabine-loaded Metal-organic frameworks (DZNPs). The integration of fluorescence photosensitizers and pH-sensitive DZNPs endow the microrobots properties such as photothermal conversion, fluorescent navigation, targeted drug delivery, and controlled drug release. In light of the inherent tumor targeting, tumor accumulation of IDN@MC is facilitated. Due to the sustained release of decitabine from packaged DZNPs, the host macrophages are differentiated into M1 phenotypes to exert the tumor phagocytosis at the tumor site, directly transporting the therapeutic agents into cancer cells. With laser control, the rapid and durable caspase 3-cleaved gasdermin E (GSDME)-related tumor pyroptosis is achieved with combined photothermal-chemotherapy, releasing inflammatory factors such as lactate dehydrogenase and interleukin-18. Subsequently, the robust and adaptive immune response is primed with dendritic cell maturation to initiate T-cell clone expansion and modulation of the immune suppressive microenvironment, thus enhancing the tumor immunotherapy to inhibit tumor proliferation and metastasis. This macrophages-based biohybrid microrobot is an efficient strategy for breast cancer treatment to trigger photo-induced pyroptosis and augment the immune response.

Engineered Microrobots for Targeted Delivery of Bacterial Outer Membrane Vesicles (OMV) in Thrombus Therapy.

In the realm of thrombosis treatment, bioengineered outer membrane vesicles (OMVs) offer a novel and promising approach, as they have rich content of bacterial-derived components. This study centers on OMVs derived from Escherichia coli BL21 cells, innovatively engineered to encapsulate the staphylokinase-hirudin fusion protein (SFH). SFH synergizes the properties of staphylokinase (SAK) and hirudin (HV) to enhance thrombolytic efficiency while reducing the risks associated with re-embolization and bleeding. Building on this foundation, this study introduces two cutting-edge microrobotic platforms: SFH-OMV@H for venous thromboembolism (VTE) treatment, and SFH-OMV@MΦ, designed specifically for cerebral venous sinus thrombosis (CVST) therapy. These platforms have demonstrated significant efficacy in dissolving thrombi, with SFH-OMV@H showcasing precise vascular navigation and SFH-OMV@MΦ effectively targeting cerebral thrombi. The study shows that the integration of these bioengineered OMVs and microrobotic systems marks a significant advancement in thrombosis treatment, underlining their potential to revolutionize personalized medical approaches to complex health conditions.

Magnetic Torque-Driven All-Terrain Microrobots.

All-terrain microrobots possess significant potential in modern medical applications due to their superior maneuverability in complex terrains and confined spaces. However, conventional microrobots often struggle with adaptability and operational difficulties in variable environments. This study introduces a magnetic torque-driven all-terrain multiped microrobot (MTMR) to address these challenges. By coupling the structure's multiple symmetries with different uniform magnetic fields, such as rotating and oscillating fields, the MTMR demonstrates various locomotion modes, including rolling, tumbling, walking, jumping, and their combinations. Experimental results indicate that the robot can navigate diverse terrains, including flat surfaces, steep slopes (up to 75°), and gaps over twice its body height. Additionally, the MTMR performs well in confined spaces, capable of passing through slits (0.1 body length) and low tunnels (0.25 body length). The robot shows potential for clinical applications like minimally invasive hemostasis in internal bleeding and thrombus removal from blood vessels through accurate cargo manipulation capability. Moreover, the MTMR can carry temperature sensors to monitor environmental temperature changes in real time while simultaneously manipulating objects, displaying its potential for in-situ sensing and parallel task implementation. This all-terrain microrobot technology demonstrates notable adaptability and versatility, providing a solid foundation for practical applications in interventional medicine.

Magnetically Powered Microrobotic Swarm for Integrated Mechanical/Photothermal/Photodynamic Thrombolysis.

Current thrombolytic drugs exhibit suboptimal therapeutic outcomes and potential bleeding risks due to their limited circulation time, inadequate thrombus penetration, and off-target biodistribution. Herein, a photosensitizer-loaded, red cell membrane-encapsuled multiple magnetic nanoparticles aggregate is successfully developed for integrated mechanical/photothermal/photodynamic thrombolysis. Red cell membrane coating endows magnetic particles with prolonged blood circulation and superior biocompatibility. Under a preset rotating magnetic field (RMF), the aggregate with asymmetric magnetic distribution initiates rolling motion toward the blood clot interface, and because of magnetic dipole-dipole interactions, the aggregate tends to self-assemble into longer, flexible chain-like microrobotic swarm with powerful mechanical stir forces, thereby facilitating thrombus penetration and mechanical thrombolysis. Moreover, precise magnetic control enables targeted photosensitizer accumulation, allowing effective conversion of near-infrared (NIR) light into heat and reactive oxygen species (ROS) for thrombus phototherapy. In thrombolysis assays, the weight of thrombi is massively reduced by ≈90%. The work presents a safer and more promising combination of magnetic microrobotic technology and phototherapy for multi-modality thrombolysis.

Field-Directed Motion, Cargo Capture, and Closed-Loop Controlled Navigation of Microellipsoids.

Microrobots have the potential for diverse applications, including targeted drug delivery and minimally invasive surgery. Despite advancements in microrobot design and actuation strategies, achieving precise control over their motion remains challenging due to the dominance of viscous drag, system disturbances, physicochemical heterogeneities, and stochastic Brownian forces. Here, a precise control over the interfacial motion of model microellipsoids is demonstrated using time-varying rotating magnetic fields. The impacts of microellipsoid aspect ratio, field characteristics, and magnetic properties of the medium and the particle on the motion are investigated. The role of mobile micro-vortices generated is highlighted by rotating microellipsoids in capturing, transporting, and releasing cargo objects. Furthermore, an approach is presented for controlled navigation through mazes based on real-time particle and obstacle sensing, path planning, and magnetic field actuation without human intervention. The study introduces a mechanism of directing motion of microparticles using rotating magnetic fields, and a control scheme for precise navigation and delivery of micron-sized cargo using simple microellipsoids as microbots.

Using Decellularized Magnetic Microrobots to Deliver Functional Cells for Cartilage Regeneration.

The use of natural cartilage extracellular matrix (ECM) has gained widespread attention in the field of cartilage tissue engineering. However, current approaches for delivering functional scaffolds for osteoarthritis (OA) therapy rely on knee surgery, which is limited by the narrow and complex structure of the articular cavity and carries the risk of injuring surrounding tissues. This work introduces a novel cell microcarrier, magnetized cartilage ECM-derived scaffolds (M-CEDSs), which are derived from decellularized natural porcine cartilage ECM. Human bone marrow mesenchymal stem cells are selected for their therapeutic potential in OA treatments. Owing to their natural composition, M-CEDSs have a biomechanical environment similar to that of human cartilage and can efficiently load functional cells while maintaining high mobility. The cells are released spontaneously at a target location for at least 20 days. Furthermore, cell-seeded M-CEDSs show better knee joint function recovery than control groups 3 weeks after surgery in preclinical experiments, and ex vivo experiments reveal that M-CEDSs can rapidly aggregate inside tissue samples. This work demonstrates the use of decellularized microrobots for cell delivery and their in vivo therapeutic effects in preclinical tests.

A Cost-Effective Integrated Methodology for Electromagnetic Actuation via Visual Feedback.

Electromagnetic actuation can support many fields of technology, such as robotics or biomedical applications. In this context, fully understanding the system behavior and proposing a low-cost package for feedback control is challenging. Modeling the electromagnetic force is particularly tricky because it is a nonlinear function of the actuated object's position and coil's current. Measuring in real time the position of the actuated object with the precision required for accurate motion control is also nontrivial. In this study, we propose a novel, cost-effective electromagnetic set-up to achieve position control via visual feedback. We actuated vertically and under different experimental conditions a 10 mm diameter steel ball hanging on a low-stiffness spring, demonstrating good tracking performance (the position error remained within ±0.5 mm, with a negligible phase delay in the best scenarios). The experimental results confirm the feasibility of the proposed set-up, which is characterized by minimum complexity and realized with off-the-shelf and cost-effective components. For these reasons, such a contribution helps to understand and apply electromagnetic actuation even further.

Multifunctional Hydrogel with 3D Printability, Fluorescence, Biodegradability, and Biocompatibility for Biomedical Microrobots.

As micron-sized objects, mobile microrobots have shown significant potential for future biomedical applications, such as targeted drug delivery and minimally invasive surgery. However, to make these microrobots viable for clinical applications, several crucial aspects should be implemented, including customizability, motion-controllability, imageability, biodegradability, and biocompatibility. Developing materials to meet these requirements is of utmost importance. Here, a gelatin methacryloyl (GelMA) and (2-(4-vinylphenyl)ethene-1,1,2-triyl)tribenzene (TPEMA)-based multifunctional hydrogel with 3D printability, fluorescence imageability, biodegradability, and biocompatibility is demonstrated. By using 3D direct laser writing method, the hydrogel exhibits its versatility in the customization and fabrication of 3D microstructures. Spherical hydrogel microrobots were fabricated and decorated with magnetic nanoparticles on their surface to render them magnetically responsive, and have demonstrated excellent movement performance and motion controllability. The hydrogel microstructures also represented excellent drug loading/release capacity and degradability by using collagenase, along with stable fluorescence properties. Moreover, cytotoxicity assays showed that the hydrogel was non-toxic, as well as able to support cell attachment and growth, indicating excellent biocompatibility of the hydrogel. The developed multifunctional hydrogel exhibits great potential for biomedical microrobots that are integrated with customizability, 3D printability, motion controllability, drug delivery capacity, fluorescence imageability, degradability, and biocompatibility, thus being able to realize the real in vivo biomedical applications of microrobots.

Template-Guided Silicon Micromotor Assembly for Enhanced Cell Manipulation.

Light-driven micro/nanorobots (LMNRs) are tiny, untethered machines with great potential in fields like precision medicine, nano manufacturing, and various other domains. However, their practicality hinges on developing light-manipulation strategies that combine versatile functionalities, flexible design options, and precise controllability. Our study introduces an innovative approach to construct micro/nanorobots (MNRs) by utilizing micro/nanomotors as fundamental building blocks. Inspired by silicon Metal-Insulator-Semiconductor (MIS) solar cell principles, we design a new type of optomagnetic hybrid micromotors (OHMs). These OHMs have been skillfully optimized with integrated magnetic constituent, resulting in efficient light propulsion, precise magnetic navigation, and the potential for controlled assembly. One of the key features of the OHMs is their ability to exhibit diverse motion modes influenced by fracture surfaces and interactions with the environment, streamlining cargo conveyance along "micro expressway"-the predesigned microchannels. Further enhancing their versatility, a template-guided assembly strategy facilitates the assembly of these micromotors into functional microrobots, encompassing various configurations such as "V-shaped", "N-shaped", and 3D structured microrobots. The heightened capabilities of these microrobots, underscore the innovative potential inherent in hybrid micromotor design and assembly, which provides a foundational platform for the realization of multi-component microrobots. Our work moves a step toward forthcoming microrobotic entities boasting advanced functionalities.

Microalgae-Based Biohybrid Microrobot for Accelerated Diabetic Wound Healing.

A variety of wound healing platforms have been proposed to alleviate the hypoxic condition and/or to modulate the immune responses for the treatment of chronic wounds in diabetes. However, these platforms with the passive diffusion of therapeutic agents through the blood clot result in the relatively low delivery efficiency into the deep wound site. Here, a microalgae-based biohybrid microrobot for accelerated diabetic wound healing is developed. The biohybrid microrobot autonomously moves at velocity of 33.3 µm s-1 and generates oxygen for the alleviation of hypoxic condition. In addition, the microrobot efficiently bound with inflammatory chemokines of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) for modulating the immune responses. The enhanced penetration of microrobot is corroborated by measuring fibrin clots in biomimetic wound using microfluidic devices and the enhanced retention of microrobot is confirmed in the real wounded mouse skin tissue. After deposition on the chronic wound in diabetic mice without wound dressing, the wounds treated with microrobots are completely healed after 9 days with the significant decrease of inflammatory cytokines below 31% of the control level and the upregulated angiogenesis above 20 times of CD31+ cells. These results confirm the feasibility of microrobots as a next-generation platform for diabetic wound healing.

Light-Powered Self-Adaptive Mesostructured Microrobots for Simultaneous Microplastics Trapping and Fragmentation via in situ Surface Morphing.

Microplastics, which comprise one of the omnipresent threats to human health, are diverse in shape and composition. Their negative impacts on human and ecosystem health provide ample incentive to design and execute strategies to trap and degrade diversely structured microplastics, especially from water. This work demonstrates the fabrication of single-component TiO2 superstructured microrobots to photo-trap and photo-fragment microplastics. In a single reaction, rod-like microrobots diverse in shape and with multiple trapping sites, are fabricated to exploit the asymmetry of the microrobotic system advantageous for propulsion. The microrobots work synergistically to photo-catalytically trap and fragment microplastics in water in a coordinated fashion. Hence, a microrobotic model of "unity in diversity" is demonstrated here for the phototrapping and photofragmentation of microplastics. During light irradiation and subsequent photocatalysis, the surface morphology of microrobots transformed into porous flower-like networks that trap microplastics for subsequent degradation. This reconfigurable microrobotic technology represents a significant step forward in the efforts to degrade microplastics.

A Multidrug Delivery Microrobot for the Synergistic Treatment of Cancer.

Multidrug combination therapy provides an effective strategy for malignant tumor treatment. This paper presents the development of a biodegradable microrobot for on-demand multidrug delivery. By combining magnetic targeting transportation with tumor therapy, it is hypothesized that loading multiple drugs on different regions of a single magnetic microrobot can enhance a synergistic effect for cancer treatment. The synergistic effect of using two drugs together is greater than that of using each drug separately. Here, a 3D-printed microrobot inspired by the fish structure with three hydrogel components: skeleton, head, and body structures is demonstrated. Made of iron oxide (Fe3 O4 ) nanoparticles embedded in poly(ethylene glycol) diacrylate (PEGDA), the skeleton can respond to magnetic fields for microrobot actuation and drug-targeted delivery. The drug storage structures, head, and body, made by biodegradable gelatin methacryloyl (GelMA) exhibit enzyme-responsive cargo release. The multidrug delivery microrobots carrying acetylsalicylic acid (ASA) and doxorubicin (DOX) in drug storage structures, respectively, exhibit the excellent synergistic effects of ASA and DOX by accelerating HeLa cell apoptosis and inhibiting HeLa cell metastasis. In vivo studies indicate that the microrobots improve the efficiency of tumor inhibition and induce a response to anti-angiogenesis. The versatile multidrug delivery microrobot conceptualized here provides a way for developing effective combination therapy for cancer.

Bubble-Based Microrobots with Rapid Circular Motions for Epithelial Pinning and Drug Delivery.

Remotely powered microrobots are proposed as next-generation vehicles for drug delivery. However, most microrobots swim with linear trajectories and lack the capacity to robustly adhere to soft tissues. This limits their ability to navigate complex biological environments and sustainably release drugs at target sites. In this work, bubble-based microrobots with complex geometries are shown to efficiently swim with non-linear trajectories in a mouse bladder, robustly pin to the epithelium, and slowly release therapeutic drugs. The asymmetric fins on the exterior bodies of the microrobots induce a rapid rotational component to their swimming motions of up to ≈150 body lengths per second. Due to their fast speeds and sharp fins, the microrobots can mechanically pin themselves to the bladder epithelium and endure shear stresses commensurate with urination. Dexamethasone, a small molecule drug used for inflammatory diseases, is encapsulated within the polymeric bodies of the microrobots. The sustained release of the drug is shown to temper inflammation in a manner that surpasses the performance of free drug controls. This system provides a potential strategy to use microrobots to efficiently navigate large volumes, pin at soft tissue boundaries, and release drugs over several days for a range of diseases.

Size-Dependent Locomotion Ability of Surface Microrollers on Physiologically Relevant Microtopographical Surfaces.

Controlled microrobotic navigation inside the body possesses significant potential for various biomedical engineering applications. Successful application requires considering imaging, control, and biocompatibility. Interaction with biological environments is also a crucial factor in ensuring safe application, but can also pose counterintuitive hydrodynamic barriers, limiting the use of microrobots. Surface rolling microrobots or surface microrollers is a robust microrobotic platform with significant potential for various applications; however, conventional spherical microrollers have limited locomotion ability over biological surfaces due to microtopography effects resulting from cell microtopography in the size range of 2-5 µm. Here, the impact of the microtopography effect on spherical microrollers of different sizes (5, 10, 25, and 50 µm) is investigated using computational fluid dynamics simulations and experiments. Simulations revealed that the microtopography effect becomes insignificant for increasing microroller sizes, such as 50 µm. Moreover, it is demonstrated that 50 µm microrollers exhibited smooth locomotion ability on in vitro cell layers and inside blood vessels of a chicken embryo model. These findings offer rational design principles for surface microrollers for their potential practical biomedical applications.

Microfluidic Approaches for Microactuators: From Fabrication, Actuation, to Functionalization.

Microactuators can autonomously convert external energy into specific mechanical motions. With the feature sizes varying from the micrometer to millimeter scale, microactuators offer many operation and control possibilities for miniaturized devices. In recent years, advanced microfluidic techniques have revolutionized the fabrication, actuation, and functionalization of microactuators. Microfluidics can not only facilitate fabrication with continuously changing materials but also deliver various signals to stimulate the microactuators as desired, and consequently improve microfluidic chips with multiple functions. Herein, this cross-field that systematically correlates microactuator properties and microfluidic functions is comprehensively reviewed. The fabrication strategies are classified into two types according to the flow state of the microfluids: stop-flow and continuous-flow prototyping. The working mechanism of microactuators in microfluidic chips is discussed in detail. Finally, the applications of microactuator-enriched functional chips, which include tunable imaging devices, micromanipulation tools, micromotors, and microsensors, are summarized. The existing challenges and future perspectives are also discussed. It is believed that with the rapid progress of this cutting-edge field, intelligent microsystems may realize high-throughput manipulation, characterization, and analysis of tiny objects and find broad applications in various fields, such as tissue engineering, micro/nanorobotics, and analytical devices.

Magnetically Powered Immunogenic Macrophage Microrobots for Targeted Multimodal Cancer Therapy.

Motile microrobots open a new realm for disease treatment. However, the concerns of possible immune elimination, targeted capability and limited therapeutic avenue of microrobots constrain its practical biomedical applications. Herein, a biogenic macrophage-based microrobot loaded with magnetic nanoparticles and bioengineered bacterial outer membrane vesicles (OMVs), capable of magnetic propulsion, tumor targeting, and multimodal cancer therapy is reported. Such cell robots preserve intrinsic properties of macrophages for tumor suppression and targeting, and bioengineered OMVs for antitumor immune regulation and fused anticancer peptides. Cell robots display efficient magnetic propulsion and directional migration in the confined space. In vivo tests show that cell robots can accumulate at the tumor site upon magnetic manipulation, coupling with tumor tropism of macrophages to greatly improve the efficacy of its multimodal therapy, including tumor inhibition of macrophages, immune stimulation, and antitumor peptides of OMVs. This technology offers an attractive avenue to design intelligent medical microrobots with remote manipulation and multifunctional therapy capabilities for practical precision treatment.

Amoeba-Inspired Magnetic Venom Microrobots.

Nature provides a successful evolutionary direction for single-celled organisms to solve complex problems and complete survival tasks - pseudopodium. Amoeba, a unicellular protozoan, can produce temporary pseudopods in any direction by controlling the directional flow of protoplasm to perform important life activities such as environmental sensing, motility, predation, and excretion. However, creating robotic systems with pseudopodia to emulate environmental adaptability and tasking capabilities of natural amoeba or amoeboid cells remains challenging. Here, this work presents a strategy that uses alternating magnetic fields to reconfigure magnetic droplet into Amoeba-like microrobot, and the mechanisms of pseudopodia generation and locomotion are analyzed. By simply adjusting the field direction, microrobots switch in monopodia, bipodia, and locomotion modes, performing all pseudopod operations such as active contraction, extension, bending, and amoeboid movement. The pseudopodia endow droplet robots with excellent maneuverability to adapt to environmental variations, including spanning 3D terrains and swimming in bulk liquids. Inspired by the "Venom," the phagocytosis and parasitic behaviors have also been investigated. Parasitic droplets inherit all the capabilities of amoeboid robot, expanding their applicable scenarios such as reagent analysis, microchemical reactions, calculi removal, and drug-mediated thrombolysis. This microrobot may provide fundamental understanding of single-celled livings, and potential applications in biotechnology and biomedicine.