Propulsive cell entry diverts pathogens from immune degradation by remodeling the phagocytic synapse.

Phagocytosis is a critical immune function for infection control and tissue homeostasis. During phagocytosis, pathogens are internalized and degraded in phagolysosomes. For pathogens that evade immune degradation, the prevailing view is that virulence factors are required to disrupt the biogenesis of phagolysosomes. In contrast, we present here that physical forces from motile pathogens during cell entry divert them away from the canonical degradative pathway. This altered fate begins with the force-induced remodeling of the phagocytic synapse formation. We used the parasite Toxoplasma gondii as a model because live Toxoplasma actively invades host cells using gliding motility. To differentiate the effects of physical forces from virulence factors in phagocytosis, we employed magnetic forces to induce propulsive entry of inactivated Toxoplasma into macrophages. Experiments and computer simulations show that large propulsive forces hinder productive activation of receptors by preventing their spatial segregation from phosphatases at the phagocytic synapse. Consequently, the inactivated parasites are engulfed into vacuoles that fail to mature into degradative units, similar to the live motile parasite's intracellular pathway. Using yeast cells and opsonized beads, we confirmed that this mechanism is general, not specific to the parasite used. These results reveal new aspects of immune evasion by demonstrating how physical forces during active cell entry, independent of virulence factors, enable pathogens to circumvent phagolysosomal degradation.

Real-time monitoring of intracellular biochemical response in locally stretched single cell by a nanosensor.

Mechanotransduction is the essential process that cells convert mechanical force into biochemical responses, and electrochemical sensor stands out from existing techniques by providing quantitative and real-time information about the biochemical signals during cellular mechanotransduction. However, the intracellular biochemical response evoked by mechanical force has been poorly monitored. In this paper, we report a method to apply local stretch on single cell and simultaneously monitor the ensuing intracellular biochemical signals. Specifically, a ferromagnetic micropipette was fabricated to locally stretch a single cell labeled with Fe3O4 nanoparticles under the external magnetic field, and the SiC@Pt nanowire electrode (SiC@Pt NWE) was inserted into the cell to monitor the intracellular hydrogen peroxide (H2O2) production induced by the local stretch. As a proof of concept, this work quantitatively investigated the elevated amount of H2O2 levels in single endothelial cell under different stretching amplitudes. This work puts forward a new research modality to manipulate and monitor the mechanotransduction at the single-cell level.

Synergistic Integration and Pharmacomechanical Function of Enzyme-Magnetite Nanoparticle Swarms for Low-Dose Fast Thrombolysis.

Magnetic micro-/nanoparticles are extensively explored over the past decade as active diagnostic/therapeutic agents for minimally invasive medicine. However, sufficient function integration on these miniaturized bodies toward practical applications remains challenging. This work proposes a synergistic strategy via integrating particle functionalization and bioinspired swarming, demonstrated by recombinant tissue plasminogen activator modified magnetite nanoparticles (rtPA-Fe3 O4 NPs) for fast thrombolysis in vivo with low drug dosage. The synthesized rtPA-Fe3 O4 NPs exhibit superior magnetic performance, high biocompatibility, and thrombolytic enzyme activity. Benefiting from a customized magnetic operation system designed for animal experiments and preclinical development, these agglomeration-free NPs can assemble into micro-/milli-scale swarms capable of robust maneuver and reconfigurable transformation for on-demand tasks in complex biofluids. Specifically, the spinning mode of the swarm exerts focused fluid shear stresses while rubbing on the thrombus surface, constituting a mechanical force for clot breakdown. The synergy of the NPs' inherent enzymatic effect and swarming-triggered fluid forces enables amplified efficacy of thrombolysis in an in vivo occlusion model of rabbit carotid artery, using lower drug concentration than clinical dosage. Furthermore, swarming-enhanced ultrasound signals aid in imaging-guided treatment. Therefore, the pharmacomechanical NP swarms herein represent an injectable thrombolytic tool joining advantages of intravenous drug therapy and robotic intervention.

Light-Driven Magnetic Encoding for Hybrid Magnetic Micromachines.

Remote manipulation of a micromachine under an external magnetic field is significant in a variety of applications. However, magnetic manipulation requires that either the target objects or the fluids should be ferromagnetic or superparamagnetic. To extend the applicability, we propose a versatile optical printing technique termed femtosecond laser-directed bubble microprinting (FsLDBM) for on-demand magnetic encoding. Harnessing Marangoni convection, evaporation flow, and capillary force for long-distance delivery, near-field attraction, and printing, respectively, FsLDBM is capable of printing nanomaterials on the solid-state substrate made of arbitrary materials. As a proof-of-concept, we actuate a 3D polymer microturbine under a rotating magnetic field by implementing γ-Fe2O3 nanomagnets on its blade. Moreover, we demonstrate the magnetic encoding on a living daphnia and versatile manipulation of the hybrid daphnia. With its general applicability, the FsLDBM approach provides opportunities for magnetic control of general microstructures in a variety of applications, such as smart microbots and biological microsurgery.

Soft Polymeric Matrix as a Macroscopic Cage for Magnetically Modulating Reversible Nanoscale Ligand Presentation.

A physical, noninvasive, and reversible means of controlling the nanoscale presentation of bioactive ligands is highly desirable for regulating and investigating the time-dependent responses of cells, including stem cells. Herein we report a magnetically actuated dynamic cell culture platform consisting of a soft hydrogel substrate conjugated with RGD-bearing magnetic nanoparticle (RGD-MNP). The downward/upward magnetic attraction conceals/promotes the presentation of the RGD-MNP in/on the soft hydrogel matrix, thereby inhibiting/enhancing the cell adhesion and mechanosensing-dependent differentiation. Meanwhile, the lateral magnetic attraction promotes the unidirectional migration of cells in the opposite direction on the hydrogel. Furthermore, cyclic switching between the "Exposed" and "Hidden" conditions induces the repeated cycles of differentiation/dedifferentiation of hMSCs which significantly enhances the differentiation potential of hMSCs. Our design approach capitalizes on the bulk biomaterial matrix as the macroscopic caging structure to enable dynamic regulation of cell-matrix interactions reversibly, which is hard to achieve by using conventional cell culture systems.

Jacobian-Based Iterative Method for Magnetic Localization in Robotic Capsule Endoscopy.

The purpose of this study is to validate a Jacobian-based iterative method for real-time localization of magnetically controlled endoscopic capsules. The proposed approach applies finite-element solutions to the magnetic field problem and least-squares interpolations to obtain closed-form and fast estimates of the magnetic field. By defining a closed-form expression for the Jacobian of the magnetic field relative to changes in the capsule pose, we are able to obtain an iterative localization at a faster computational time when compared with prior works, without suffering from the inaccuracies stemming from dipole assumptions. This new algorithm can be used in conjunction with an absolute localization technique that provides initialization values at a slower refresh rate. The proposed approach was assessed via simulation and experimental trials, adopting a wireless capsule equipped with a permanent magnet, six magnetic field sensors, and an inertial measurement unit. The overall refresh rate, including sensor data acquisition and wireless communication was 7 ms, thus enabling closed-loop control strategies for magnetic manipulation running faster than 100 Hz. The average localization error, expressed in cylindrical coordinates was below 7 mm in both the radial and axial components and 5° in the azimuthal component. The average error for the capsule orientation angles, obtained by fusing gyroscope and inclinometer measurements, was below 5°.

Combining magnetic nanoparticles with cell derived microvesicles for drug loading and targeting.

Inspired by microvesicle-mediated intercellular communication, we propose a hybrid vector for magnetic drug delivery. It consists of macrophage-derived microvesicles engineered to enclose different therapeutic agents together with iron oxide nanoparticles. Here, we investigated in vitro how magnetic nanoparticles may influence the vector effectiveness in terms of drug uptake and targeting. Human macrophages were loaded with iron oxide nanoparticles and different therapeutic agents: a chemotherapeutic agent (doxorubicin), tissue-plasminogen activator (t-PA) and two photosensitizers (disulfonated tetraphenyl chlorin-TPCS2a and 5,10,15,20-tetra(m-hydroxyphenyl)chlorin-mTHPC). The hybrid cell microvesicles were magnetically responsive, readily manipulated by magnetic forces and MRI-detectable. Using photosensitizer-loaded vesicles, we showed that the uptake of microvesicles by cancer cells could be kinetically modulated and spatially controlled under magnetic field and that cancer cell death was enhanced by the magnetic targeting. From the clinical editor: In this article, the authors devised a biogenic method using macrophages to produce microvesicles containing both iron oxide and chemotherapeutic agents. They showed that the microvesicles could be manipulated by magnetic force for targeting and subsequent delivery of the drug payload against cancer cells. This smart method could provide a novel way for future fight against cancer.

Emerging Issues and Future Developments in Capsule Endoscopy.

Capsule endoscopy (CE) has transformed from a research venture into a widely used clinical tool and the primary means for diagnosing small bowel pathology. These orally administered capsules traverse passively through the gastrointestinal tract via peristalsis and are used in the esophagus, stomach, small bowel, and colon. The primary focus of CE research in recent years has been enabling active CE manipulation and extension of the technology to therapeutic functionality; thus, widening the scope of the procedure. This review outlines clinical standards of the technology as well as recent advances in CE research. Clinical capsule applications are discussed with respect to each portion of the gastrointestinal tract. Promising research efforts are presented with an emphasis on enabling active capsule locomotion. The presented studies suggest, in particular, that the most viable solution for active capsule manipulation is actuation of a capsule via exterior permanent magnet held by a robot. Developing capsule procedures adhering to current healthcare standards, such as enabling a tool channel or irrigation in a therapeutic device, is a vital phase in the adaptation of CE in the clinical setting.

Magnetic Control of Macromolecular Conformations in Supramolecular Anionic Polysaccharide-Iron Complexes.

The anionic iota carrageenan polysaccharide is enriched with Fe(II) and Fe(III) by ion exchange against FeSO4 and FeCl3 . With divalent iron, portions of polymer chains undergo a secondary structure transition from random coils to single helices. The single-chain macromolecular conformations can be manipulated by an external magnetic field: upon exposure to 1.1 T, the helical portions exhibit 1.5-fold stiffening and 1.1-fold stretching, whereas the coil conformations respond much less as a result of lower contents of condensed iron ions. Along with the coil-helix transition, the trivalent iron triggers the formation of superstructures. The applicability of iron-enriched iota carrageenan as functional ingredient for food fortification is tested by free Fe(2+) and Fe(3+) contents, respectively, with the most promising iota-Fe(III) yielding 53% of bound iron, which is due to the superstructures, where the ferric ions are chelated by the supramolecularly self-assembled polymer host.

Hybrid helical magnetic microrobots obtained by 3D template-assisted electrodeposition.

Hybrid helical magnetic microrobots are achieved by sequential electrodeposition of a CoNi alloy and PPy inside a photoresist template patterned by 3D laser lithography. A controlled actuation of the microrobots by a rotating magnetic field is demonstrated in a fluidic environment.

Magnetically Manipulated Optoelectronic Hybrid Microrobots for Optically Targeted Non-Genetic Neuromodulation.

Optically controlled neuromodulation is a promising approach for basic research of neural circuits and the clinical treatment of neurological diseases. However, developing a non-invasive and well-controllable system to deliver accurate and effective neural stimulation is challenging. Micro/nanorobots have shown great potential in various biomedical applications because of their precise controllability. Here, a magnetically-manipulated optoelectronic hybrid microrobot (MOHR) is presented for optically targeted non-genetic neuromodulation. By integrating the magnetic component into the metal-insulator-semiconductor junction design, the MOHR has excellent magnetic controllability and optoelectronic properties. The MOHR displays a variety of magnetic manipulation modes that enables precise and efficient navigation in different biofluids. Furthermore, the MOHR could achieve precision neuromodulation at the single-cell level because of its accurate targeting ability. This neuromodulation is achieved by the MOHR's photoelectric response to visible light irradiation, which enhances the excitability of the targeted cells. Finally, it is shown that the well-controllable MOHRs effectively restore neuronal activity in neurons damaged by ß-amyloid, a pathogenic agent of Alzheimer's disease. By coupling precise controllability with efficient optoelectronic properties, the hybrid microrobot system is a promising strategy for targeted on-demand optical neuromodulation.

Magnetic Control of Nonmagnetic Living Organisms.

Living organisms inspire the design of microrobots, but their functionality is unmatched. Next-generation microrobots aim to leverage the sensing and communication abilities of organisms through magnetic hybridization, attaching magnetic particles to them for external control. However, the protocols used for magnetic hybridization are morphology specific and are not generalizable. We propose an alternative approach that leverages the principles of negative magnetostatics and magnetophoresis to control nonmagnetic organisms with external magnetic fields. To do this, we disperse model organisms in dispersions of Fe3O4 nanoparticles and expose them to either uniform or gradient magnetic fields. In uniform magnetic fields, living organisms align with the field due to external torque, while gradient magnetic fields generate a negative magnetophoretic force, pushing objects away from external magnets. The magnetic fields enable controlling the position and orientation of Caenorhabditis elegans larvae and flagellated bacteria through directional interactions and magnitude. This control is diminished in live spermatozoa and adult C. elegans due to stronger internal biological activity, i.e., force/torque. Our study presents a method for spatiotemporal organization of living organisms without requiring magnetic hybridization, opening the way for the development of controllable living microbiorobots.

Magnetic field control device for transplantation of corneal endothelial tissue with magnetic filaments.

The corneal endothelial transplantation involves the transfer and attachment of a single-layered corneal endothelial tissue to the narrow space between the cornea and iris. Given the high risk of damage to the endothelial tissue and surrounding corneal tissues when using sharp instruments inserted externally to apply force during the process, the development of a device capable of transferring corneal endothelial tissue using a magnetic field became necessary. This study aims to develop a magnetic control device for transferring corneal endothelial tissue with attached magnetic particles to the transplant site, validate its appropriate transfer capabilities, and assess its applicability to corneal endothelial transplantation. For this purpose, a magnetic field-generating manipulation device equipped with four electromagnets controlled by a joystick and microcomputer was developed. Through simulated experiments, the strength of the magnetic field and the attraction force on the tissue were predicted, and the actual magnetic field strength was measured for validation. To measure the magnetic transfer force, experiments were conducted by towing corneal endothelial tissue fixed with 6 mg, 12 mg, and 18 mg plastic weights. Subsequently, the tissue's transfer speed was measured after applying continuous and pulsed magnetic fields. The results confirmed the feasibility of tissue transfer using the magnetic control device, and it was observed that pulsed magnetic fields led to faster transfer speeds and easier control compared to continuous magnetic fields. Exploratory animal experiments using rabbits were conducted to simulate real surgical conditions, confirming the feasibility of corneal endothelial tissue transfer and attachment.

Sub-Nanogram Resolution Measurement of Inertial Mass and Density Using Magnetic-Field-Guided Bubble Microthruster.

Artificial micro/nanomotors using active particles hold vast potential in applications such as drug delivery and microfabrication. However, upgrading them to micro/nanorobots capable of performing precise tasks with sophisticated functions remains challenging. Bubble microthruster (BMT) is introduced, a variation of the bubble-driven microrobot, which focuses the energy from a collapsing microbubble to create an inertial impact on nearby target microparticles. Utilizing ultra-high-speed imaging, the microparticle mass and density is determined with sub-nanogram resolution based on the relaxation time characterizing the microparticle's transient response. Master curves of the BMT method are shown to be dependent on the viscosity of the solution. The BMT, controlled by a gamepad with magnetic-field guidance, precisely manipulates target microparticles, including bioparticles. Validation involves measuring the polystyrene microparticle mass and hollow glass microsphere density, and assessing the mouse embryo mass densities. The BMT technique presents a promising chip-free, real-time, highly maneuverable strategy that integrates bubble microrobot-based manipulation with precise bioparticle mass and density detection, which can facilitate microscale bioparticle characterizations such as embryo growth monitoring.

Nickel foil microcantilevers for magnetic manipulation and localized heating.

Cellular manipulation has been investigated by a number of techniques. In this manuscript nickel foil microcantilevers were used for magnetophoresis and manipulation of microparticles and magnetically labeled HeLa cells. The cantilevers were also used for localized heating in liquid, reaching biologically relevant temperatures. This work aims to develop cantilevers for sample enrichment, manipulation, and thermal applications, offering an inexpensive and versatile solution compatible with standard tools in research and clinical diagnostic testing, such as microwell plates.

Efficient Tumor Eradication at Ultralow Drug Concentration via Externally Controlled and Boosted Metallic Iron Magnetoplasmonic Nanocapsules.

With the aim to locally enhance the efficacy of cancer nanotherapies, here we present metal iron based magnetoplasmonic drug-loaded nanocapsules (MAPSULES), merging powerful external magnetic concentration in the tumor and efficient photothermal actuation to locally boost the drug therapeutic action at ultralow drug concentrations. The MAPSULES are composed of paclitaxel-loaded polylactic-co-glycolic acid (PLGA) nanoparticles partially coated by a nanodome shape iron/silica semishell. The iron semishell has been designed to present a ferromagnetic vortex for incorporating a large quantity of ferromagnetic material while maintaining high colloidal stability. The large iron semishell provides very strong magnetic manipulation via magnetophoretic forces, enabling over 10-fold higher trapping efficiency in microfluidic channels than typical superparamagnetic iron oxide nanoparticles. Moreover, the iron semishell exhibits highly damped plasmonic behavior, yielding intense broadband absorbance in the near-infrared biological windows and photothermal efficiency similar to the best plasmonic nanoheaters. The in vivo therapeutic assays in a mouse xenograft tumor model show a high amplification of the therapeutic effects by combining magnetic concentration and photothermal actuation in the tumor, leading to a complete eradication of the tumors at ultralow nanoparticle and drug concentration (equivalent to only 1 mg/kg PLGA nanoparticles containing 8 µg/kg of paclitaxel, i.e., 100-500-fold lower than the therapeutic window of the free and PLGA encapsulated drug and 13-3000-fold lower than current nanotherapies combining paclitaxel and light actuation). These results highlight the strength of this externally controlled and amplified therapeutic approach, which could be applied to locally boost a wide variety of drugs for different diseases.

Navigation and Control of Motion Modes with Soft Microrobots at Low Reynolds Numbers.

This study investigates the motion characteristics of soft alginate microrobots in complex fluidic environments utilizing wireless magnetic fields for actuation. The aim is to explore the diverse motion modes that arise due to shear forces in viscoelastic fluids by employing snowman-shaped microrobots. Polyacrylamide (PAA), a water-soluble polymer, is used to create a dynamic environment with non-Newtonian fluid properties. Microrobots are fabricated via an extrusion-based microcentrifugal droplet method, successfully demonstrating the feasibility of both wiggling and tumbling motions. Specifically, the wiggling motion primarily results from the interplay between the viscoelastic fluid environment and the microrobots' non-uniform magnetization. Furthermore, it is discovered that the viscoelasticity properties of the fluid influence the motion behavior of the microrobots, leading to non-uniform behavior in complex environments for microrobot swarms. Through velocity analysis, valuable insights into the relationship between applied magnetic fields and motion characteristics are obtained, facilitating a more realistic understanding of surface locomotion for targeted drug delivery purposes while accounting for swarm dynamics and non-uniform behavior.

Magnetic Beads inside Droplets for Agitation and Splitting Manipulation by Utilizing a Magnetically Actuated Platform.

We successfully developed a platform for the magnetic manipulation of droplets containing magnetic beads and examined the washing behaviors of the droplets, including droplet transportation, magnetic bead agitation inside droplets, and separation from parent droplets. Magnetic field gradients were produced with two layers of 6 × 1 planar coils fabricated by using printed circuit board technology. We performed theoretical analyses to understand the characteristics of the coils and successfully predicted the magnetic field and thermal temperature of a single coil. We then investigated experimentally the agitation and splitting kinetics of the magnetic beads inside droplets and experimentally observed the washing performance in different neck-shaped gaps. The performance of the washing process was evaluated by measuring both the particle loss ratio and the optical density. The findings of this work will be used to design a magnetic-actuated droplet platform, which will separate magnetic beads from their parent droplets and enhance washing performance. We hope that this study will provide digital microfluidics for application in point-of-care testing. The developed microchip will be of great benefit for genetic analysis and infectious disease detection in the future.

Magnetic Manipulation of Locomotive Liquid Electrodes for Wireless Active Cardiac Monitoring.

For electrocardiogram (ECG) detection, the position of conventional patch-type electrodes based on solid-state metals are difficult to manipulate after attachment and also can lead to poor interface with stretchable, rough skin surfaces. Herein, we present a liquid form of ECG electrodes that can be magnetically reconfigured on human skin by providing its conformal interfacing. These electrodes consist of biocompatible liquid-metal droplets where magnetic particles are homogeneously dispersed, and their conformal contact with skin can yield significantly low impedance as well as high signal-to-noise ratio of ECG peaks. These electrodes are also capable of complex motions such as linear movements, splitting, and merging under external magnetic fields. Furthermore, magnetic manipulation of each electrode position on human skin enables precise monitoring of ECG signals with the change in ECG vectors. The integration of liquid-state electrodes with electronic circuitry demonstrates wireless and continuous ECG monitoring while magnetically moving this entire system on human skin.

A streptavidin-biotin system combined with magnetic actuators for remote neuronal guidance.

The ability to control neuronal mobility and organization is of great importance in developing neuronal interfaces and novel therapeutic approaches. An emerging promising method is the manipulation of neuronal cells from afar via magnetic forces. Nevertheless, using magnetic iron oxide nanoparticles as internal actuators may lead to biotoxicity, adverse influence on intracellular processes, and thus requires prerequisite considerations for therapeutic approaches. Magnetizing the cells via the incorporation of magnetic particles that can be applied extracellularly is advantageous. Herein, we have developed a magnetic system based on streptavidin-biotin interaction to decorate cellular membrane with magnetic elements. In this model, superparamagnetic microparticles, coated with streptavidin, were specifically bound to biotinylated PC12 cells. We demonstrated that cell movement can be directed remotely by the forces produced by pre-designed magnetic fields. First, using time lapse imaging, we analyzed the kinetics of cell migration towards the higher flux zone. Next, to form organized networks of cells we designed and fabricated micro-patterned magnetic devices. The fabricated devices were composed of a variety of ferromagnetic shapes, sputter-deposited onto glass substrates. Cells that were conjugated to the magnetic particles were plated atop the micro-patterned substrates, attracted to the magnetic actuators and became fixed onto the magnetic patterns. In all, our study presents a novel system based on a well-known molecular technology combined with nanotechnology that may well lead to the expansion of implantable magnetic actuators to organize and direct cellular growth.