A Naturally Inspired Extrusion-Based Microfluidic Approach for Manufacturing Tailorable Magnetic Soft Continuum Microrobotic Devices.

Soft materials play a crucial role in small-scale robotic applications by closely mimicking the complex motion and morphing behavior of organisms. However, conventional fabrication methods face challenges in creating highly integrated small-scale soft devices. In this study, microfluidics is leveraged to precisely control reaction-diffusion (RD) processes to generate multifunctional and compartmentalized calcium-cross-linkable alginate-based microfibers. Under RD conditions, sophisticated alginate-based fibers are produced for magnetic soft continuum robotics applications with customizable features, such as geometry (compact or hollow), degree of cross-linking, and the precise localization of magnetic nanoparticles (inside the core, surrounding the fiber, or on one side). This fine control allows for tuning the stiffness and magnetic responsiveness of the microfibers. Additionally, chemically cleavable regions within the fibers enable disassembly into smaller robotic units or roll-up structures under a rotating magnetic field. These findings demonstrate the versatility of microfluidics in processing highly integrated small-scale devices.

A Human-Scale Clinically Ready Electromagnetic Navigation System for Magnetically Responsive Biomaterials and Medical Devices.

Magnetic navigation systems are used to precisely manipulate magnetically responsive materials enabling the realization of new minimally invasive procedures using magnetic medical devices. Their widespread applicability has been constrained by high infrastructure demands and costs. The study reports on a portable electromagnetic navigation system, the Navion, which is capable of generating a large magnetic field over a large workspace. The system is easy to install in hospital operating rooms and transportable through health care facilities, aiding in the widespread adoption of magnetically responsive medical devices. First, the design and implementation approach for the system are introduced and its performance is characterized. Next, in vitro navigation of different microrobot structures is demonstrated using magnetic field gradients and rotating magnetic fields. Spherical permanent magnets, electroplated cylindrical microrobots, microparticle swarms, and magnetic composite bacteria-inspired helical structures are investigated. The navigation of magnetic catheters is also demonstrated in two challenging endovascular tasks: 1) an angiography procedure and 2) deep navigation within the circle of Willis. Catheter navigation is demonstrated in a porcine model in vivo to perform an angiography under magnetic guidance.

Design and Development of Transient Sensing Devices for Healthcare Applications.

With the ever-growing requirements in the healthcare sector aimed at personalized diagnostics and treatment, continuous and real-time monitoring of relevant parameters is gaining significant traction. In many applications, health status monitoring may be carried out by dedicated wearable or implantable sensing devices only within a defined period and followed by sensor removal without additional risks for the patient. At the same time, disposal of the increasing number of conventional portable electronic devices with short life cycles raises serious environmental concerns due to the dangerous accumulation of electronic and chemical waste. An attractive solution to address these complex and contradictory demands is offered by biodegradable sensing devices. Such devices may be able to perform required tests within a programmed period and then disappear by safe resorption in the body or harmless degradation in the environment. This work critically assesses the design and development concepts related to biodegradable and bioresorbable sensors for healthcare applications. Different aspects are comprehensively addressed, from fundamental material properties and sensing principles to application-tailored designs, fabrication techniques, and device implementations. The emerging approaches spanning the last 5 years are emphasized and a broad insight into the most important challenges and future perspectives of biodegradable sensors in healthcare are provided.

Electrostatic catalysis of a click reaction in a microfluidic cell.

Electric fields have been highlighted as a smart reagent in nature's enzymatic machinery, as they can directly trigger or accelerate chemical processes with stereo- and regio-specificity. In enzymatic catalysis, controlled mass transport of chemical species is also key in facilitating the availability of reactants in the active reaction site. However, recent progress in developing a clean catalysis that profits from oriented electric fields is limited to theoretical and experimental studies at the single molecule level, where both the control over mass transport and scalability cannot be tested. Here, we quantify the electrostatic catalysis of a prototypical Huisgen cycloaddition in a large-area electrode surface and directly compare its performance to the conventional Cu(I) catalysis. Our custom-built microfluidic cell enhances reagent transport towards the electrified reactive interface. This continuous-flow microfluidic electrostatic reactor is an example of an electric-field driven platform where clean large-scale electrostatic catalytic processes can be efficiently implemented and regulated.

3D Motion Manipulation for Micro- and Nanomachines: Progress and Future Directions.

In the past decade, micro- and nanomachines (MNMs) have made outstanding achievements in the fields of targeted drug delivery, tumor therapy, microsurgery, biological detection, and environmental monitoring and remediation. Researchers have made significant efforts to accelerate the rapid development of MNMs capable of moving through fluids by means of different energy sources (chemical reactions, ultrasound, light, electricity, magnetism, heat, or their combinations). However, the motion of MNMs is primarily investigated in confined two-dimensional (2D) horizontal setups. Furthermore, three-dimensional (3D) motion control remains challenging, especially for vertical movement and control, significantly limiting its potential applications in cargo transportation, environmental remediation, and biotherapy. Hence, an urgent need is to develop MNMs that can overcome self-gravity and controllably move in 3D spaces. This review delves into the latest progress made in MNMs with 3D motion capabilities under different manipulation approaches, discusses the underlying motion mechanisms, explores potential design concepts inspired by nature for controllable 3D motion in MNMs, and presents the available 3D observation and tracking systems.

Tailored Design of a Water-Based Nanoreactor Technology for Producing Processable Sub-40 Nm 3D COF Nanoparticles at Atmospheric Conditions.

Covalent organic frameworks (COFs) are crystalline materials with intrinsic porosity that offer a wide range of potential applications spanning diverse fields. Yet, the main goal in the COF research area is to achieve the most stable thermodynamic product while simultaneously targeting the desired size and structure crucial for enabling specific functions. While significant progress is made in the synthesis and processing of 2D COFs, the development of processable 3D COF nanocrystals remains challenging. Here, a water-based nanoreactor technology for producing processable sub-40 nm 3D COF nanoparticles at ambient conditions is presented. Significantly, this technology not only improves the processability of the synthesized 3D COF, but also unveils exciting possibilities for their utilization in previously unexplored domains, such as nano/microrobotics and biomedicine, which are limited by larger crystallites.

"On-The-Fly" Synthesis of Self-Supported LDH Hollow Structures Through Controlled Microfluidic Reaction-Diffusion Conditions.

Layered double hydroxides (LDHs) are a class of functional materials that exhibit exceptional properties for diverse applications in areas such as heterogeneous catalysis, energy storage and conversion, and bio-medical applications, among others. Efforts have been devoted to produce millimeter-scale LDH structures for direct integration into functional devices. However, the controlled synthesis of self-supported continuous LDH materials with hierarchical structuring up to the millimeter scale through a straightforward one-pot reaction method remains unaddressed. Herein, it is shown that millimeter-scale self-supported LDH structures can be produced by means of a continuous flow microfluidic device in a rapid and reproducible one-pot process. Additionally, the microfluidic approach not only allows for an "on-the-fly" formation of unprecedented LDH composite structures, but also for the seamless integration of millimeter-scale LDH structures into functional devices. This method holds the potential to unlock the integrability of these materials, maintaining their performance and functionality, while diverging from conventional techniques like pelletization and densification that often compromise these aspects. This strategy will enable exciting advancements in LDH performance and functionality.

On-Command Disassembly of Microrobotic Superstructures for Transport and Delivery of Magnetic Micromachines.

Magnetic microrobots have been developed for navigating microscale environments by means of remote magnetic fields. However, limited propulsion speeds at small scales remain an issue in the maneuverability of these devices as magnetic force and torque are proportional to their magnetic volume. Here, a microrobotic superstructure is proposed, which, as analogous to a supramolecular system, consists of two or more microrobotic units that are interconnected and organized through a physical (transient) component (a polymeric frame or a thread). The superstructures consist of microfabricated magnetic helical micromachines interlocked by a magnetic gelatin nanocomposite containing iron oxide nanoparticles (IONPs). While the microhelices enable the motion of the superstructure, the IONPs serve as heating transducers for dissolving the gelatin chassis via magnetic hyperthermia. In a practical demonstration, the superstructure's motion with a gradient magnetic field in a large channel, the disassembly of the superstructure and release of the helical micromachines by a high-frequency alternating magnetic field, and the corkscrew locomotion of the released helices through a small channel via a rotating magnetic field, is showcased. This adaptable microrobotic superstructure reacts to different magnetic inputs, which can be used to perform complex delivery procedures within intricate regions of the human body.

Delivering drugs with microrobots.

Biomedical microrobots could overcome current challenges in targeted therapies.

Recent Developments in Metallic Degradable Micromotors for Biomedical and Environmental Remediation Applications.

Synthetic micromotor has gained substantial attention in biomedicine and environmental remediation. Metal-based degradable micromotor composed of magnesium (Mg), zinc (Zn), and iron (Fe) have promise due to their nontoxic fuel-free propulsion, favorable biocompatibility, and safe excretion of degradation products Recent advances in degradable metallic micromotor have shown their fast movement in complex biological media, efficient cargo delivery and favorable biocompatibility. A noteworthy number of degradable metal-based micromotors employ bubble propulsion, utilizing water as fuel to generate hydrogen bubbles. This novel feature has projected degradable metallic micromotors for active in vivo drug delivery applications. In addition, understanding the degradation mechanism of these micromotors is also a key parameter for their design and performance. Its propulsion efficiency and life span govern the overall performance of a degradable metallic micromotor. Here we review the design and recent advancements of metallic degradable micromotors. Furthermore, we describe the controlled degradation, efficient in vivo drug delivery, and built-in acid neutralization capabilities of degradable micromotors with versatile biomedical applications. Moreover, we discuss micromotors' efficacy in detecting and destroying environmental pollutants. Finally, we address the limitations and future research directions of degradable metallic micromotors.

Site-specific PEGylation of recombinant tissue-type plasminogen activator.

Tissue-type plasminogen activator (tPA) is the gold standard for emergency treatment of ischemic stroke, which is the third leading cause of death worldwide. Major challenges of tPA therapy are its rapid elimination by plasminogen activator inhibitor-1 (PAI-1) and hepatic clearance, leading to the use of high doses and consequent serious side effects, including internal bleeding, swelling and low blood pressure. In this regard, we developed three polyethylene glycol (PEG)ylated tPA bioconjugates based on the recombinant human tPA drug Alteplase using site-specific conjugation strategies. The first bioconjugate with PEGylation at the N-terminus of tPA performed by reductive alkylation showed a reduced proteolytic activity of 68 % compared to wild type tPA. PEGylation at the single-free cysteine of tPA with linear and branched PEG revealed similar proteolytic activities as the wild-type protein. Moreover, both bioconjugates with PEG-cysteine-modification showed 2-fold slower inhibition kinetics by PAI-1. All bioconjugates increased in hydrodynamic size as a critical requirement for half-life extension.

Magnetic PiezoBOTs: a microrobotic approach for targeted amyloid protein dissociation.

Piezoelectric nanomaterials have become increasingly popular in the field of biomedical applications due to their high biocompatibility and ultrasound-mediated piezocatalytic properties. In addition, the ability of these nanomaterials to disaggregate amyloid proteins, which are responsible for a range of diseases resulting from the accumulation of these proteins in body tissues and organs, has recently gained considerable attention. However, the use of nanoparticles in biomedicine poses significant challenges, including targeting and uncontrolled aggregation. To address these limitations, our study proposes to load these functional nanomaterials on a multifunctional mobile microrobot (PiezoBOT). This microrobot is designed by coating magnetic and piezoelectric barium titanate nanoparticles on helical biotemplates, allowing for the combination of magnetic navigation and ultrasound-mediated piezoelectric effects to target amyloid disaggregation. Our findings demonstrate that acoustically actuated PiezoBOTs can effectively reduce the size of aggregated amyloid proteins by over 80% in less than 10 minutes by shortening and dissociating constituent amyloid fibrils. Moreover, the PiezoBOTs can be easily magnetically manipulated to actuate the piezocatalytic nanoparticles to specific amyloidosis-affected tissues or organs, minimizing side effects. These biocompatible PiezoBOTs offer a promising non-invasive therapeutic approach for amyloidosis diseases by targeting and breaking down protein aggregates at specific organ or tissue sites.

Magnetically Enhanced Intracellular Uptake of Superparamagnetic Iron Oxide Nanoparticles for Antitumor Therapy.

Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely employed in biomedical fields, including targeted delivery of antitumor therapy. Conventional magnetic tumor targeting has used simple static magnetic fields (SMFs), which cause SPIONs to linearly aggregate into a long chain-like shape. Such agglomeration greatly hinders the intracellular targeting of SPIONs into tumors, thus reducing the therapeutic efficacy. In this study, we investigated the enhancement of the intracellular uptake of SPIONs through the application of rotating magnetic fields (RMFs). Based on the physical principles of SPION chain disassembly, we investigated physical parameters to predict the chain length favorable for intracellular uptake. Our prediction was validated by clear visualization of the intracellular distributions of SPIONs in tumor cells at both cellular and three-dimensional microtissue levels. To identify the potential therapeutic effects of enhanced intracellular uptake, magnetic hyperthermia as antitumor therapy was investigated under varying conditions of magnetic hyperthermia and RMFs. The results showed that enhanced intracellular uptake reduced magnetic hyperthermia time and strength as well as particle concentration. The proposed method will be useful in the development of techniques to determine the optimized physical conditions for the enhanced intracellular uptake of SPIONs in antitumor therapy.

Can We Rationally Design and Operate Spatial Atomic Layer Deposition Systems for Steering the Growth Regime of Thin Films?

Fine control over the growth of materials is required to precisely tailor their properties. Spatial atomic layer deposition (SALD) is a thin-film deposition technique that has recently attracted attention because it allows producing thin films with a precise number of deposited layers, while being vacuum-free and much faster than conventional atomic layer deposition. SALD can be used to grow films in the atomic layer deposition or chemical vapor deposition regimes, depending on the extent of precursor intermixing. Precursor intermixing is strongly influenced by the SALD head design and operating conditions, both of which affect film growth in complex ways, making it difficult to predict the growth regime prior to depositions. Here, we used numerical simulation to systematically study how to rationally design and operate SALD systems for growing thin films in different growth regimes. We developed design maps and a predictive equation allowing us to predict the growth regime as a function of the design parameters and operation conditions. The predicted growth regimes match those observed in depositions performed for various conditions. The developed design maps and predictive equation empower researchers in designing, operating, and optimizing SALD systems, while offering a convenient way to screen deposition parameters, prior to experimentation.

The magnetopyroelectric effect: heat-mediated magnetoelectricity in magnetic nanoparticle-ferroelectric polymer composites.

Magnetoelectricity enables a solid-state material to generate electricity under magnetic fields. Most magnetoelectric composites are developed through a strain-mediated route by coupling piezoelectric and magnetostrictive phases. However, the limited availability of high-performance magnetostrictive components has become a constraint for the development of novel magnetoelectric materials. Here, we demonstrate that nanostructured composites of magnetic and pyroelectric materials can generate electrical output, a phenomenon we refer to as the magnetopyroelectric (MPE) effect, which is analogous to the magnetoelectric effect in strain-mediated composite multiferroics. Our composite consists of magnetic iron oxide nanoparticles (IONPs) dispersed in a ferroelectric (and also pyroelectric) poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) matrix. Under a high-frequency low-magnitude alternating magnetic field, the IONPs generate heat through hysteresis loss, which stimulates the depolarization process of the pyroelectric polymer. This magnetopyroelectric approach creates a new opportunity to develop magnetoelectric materials for a wide range of applications.

Filler-Enhanced Piezoelectricity of Poly-L-Lactide and Its Use as a Functional Ultrasound-Activated Biomaterial.

Poly-L-lactide (PLLA) offers a unique possibility for processing into biocompatible, biodegradable, and implantable piezoelectric structures. With such properties, PLLA has potential to be used as an advanced tool for mimicking biophysical processes that naturally occur during the self-repair of wounds and damaged tissues, including electrostimulated regeneration. The piezoelectricity of PLLA strongly depends on the possibility of controlling its crystallinity and molecular orientation. Here, it is shown that modifying PLLA with a small amount (1 wt%) of crystalline filler particles with a high aspect ratio, which act as nucleating agents during drawing-induced crystallization, promotes the formation of highly crystalline and oriented PLLA structures. This increases their piezoelectricity, and the filler-modified PLLA films provide a 20-fold larger voltage output than nonmodified PLLA during ultrasound (US)-assisted activation. With 99% PLLA content, the ability of the films to produce reactive oxygen species (ROS) and increase the local temperature during interactions with US is shown to be very low. US-assisted piezostimulation of adherent cells directly attach to their surface (such as skin keratinocytes), stimulate cytoskeleton formation, and as a result cells elongate and orient themselves in a specific direction that align with the direction of PLLA film drawing and PLLA dipole orientation.

In Situ Sprayed Nanovaccine Suppressing Exosomal PD-L1 by Golgi Apparatus Disorganization for Postsurgical Melanoma Immunotherapy.

The anti-PD-L1 immunotherapy has shown promise in treating cancer. However, certain patients with metastatic cancer have low response and high relapse rates. A main reason is systemic immunosuppression caused by exosomal PD-L1, which can circulate in the body and inhibit T cell functions. Here, we show that Golgi apparatus-Pd-l1-/- exosome hybrid membrane coated nanoparticles (GENPs) can significantly reduce the secretion of PD-L1. The GENPs can accumulate in tumors through homotypic targeting and effectively deliver retinoic acid, inducing disorganization of the Golgi apparatus and a sequence of intracellular events including alteration of endoplasmic reticulum (ER)-to-Golgi trafficking and subsequent ER stress, which finally disrupts the PD-L1 production and the release of exosomes. Furthermore, GENPs could mimic exosomes to access draining lymph nodes. The membrane antigen of PD-l1-/- exosome on GENPs can activate T cells through a vaccine-like effect, strongly promoting systemic immune responses. By combining GENPs with anti-PD-L1 treatment in the sprayable in situ hydrogel, we have successfully realized a low recurrence rate and substantially extended survival periods in mice models with incomplete metastatic melanoma resection.

Shape Memory Alloy (SMA) Actuators: The Role of Material, Form, and Scaling Effects.

Shape memory alloys (SMAs) are smart materials that are widely used to create intelligent devices because of their high energy density, actuation strain, and biocompatibility characteristics. Given their unique properties, SMAs are found to have significant potential for implementation in many emerging applications in mobile robots, robotic hands, wearable devices, aerospace/automotive components, and biomedical devices. Here, the state-of-the-art of thermal and magnetic SMA actuators in terms of their constituent materials, form, and scaling effects are summarized, including their surface treatments and functionalities. The motion performance of various SMA architectures (wires, springs, smart soft composites, and knitted/woven actuators) is also analyzed. Based on the assessment, current challenges of SMAs that need to be addressed for their practical application are emphasized. Finally, how to advance SMAs by synergistically considering the effects of material, form, and scale is suggested.

Shape-memory effect in twisted ferroic nanocomposites.

The shape recovery ability of shape-memory alloys vanishes below a critical size (~50 nm), which prevents their practical applications at the nanoscale. In contrast, ferroic materials, even when scaled down to dimensions of a few nanometers, exhibit actuation strain through domain switching, though the generated strain is modest (~1%). Here, we develop freestanding twisted architectures of nanoscale ferroic oxides showing shape-memory effect with a giant recoverable strain (>8%). The twisted geometrical design amplifies the strain generated during ferroelectric domain switching, which cannot be achieved in bulk ceramics or substrate-bonded thin films. The twisted ferroic nanocomposites allow us to overcome the size limitations in traditional shape-memory alloys and open new avenues in engineering large-stroke shape-memory materials for small-scale actuating devices such as nanorobots and artificial muscle fibrils.

Inkjet-Assisted Electroformation of Magnetically Guidable Water Striders for Interfacial Microfluidic Manipulation.

Gerridae, colloquially called water striders, are a peculiar class of insects characterized by the extraordinary ability to walk on the surface of water bodies. Owing to this capacity, they constitute an ideal source of inspiration for designing untethered microdevices capable of navigating the interface between two fluids. Such steerable micrometric objects can be of great interest for various applications, ranging from the handling of floating objects to the remote control of microreactions and the manipulation of self-assembled monolayers. This paper describes the realization of artificial water striders via an inkjet-assisted electroforming approach. Inkjet deposition patterns the negative mask, which is subsequently filled with different layers of metals through electroforming. One of such layers is the magnetic alloy NiFe, which allows wireless propulsion of the striders by means of externally applied magnetic fields. The magnetic actuation tests prove good maneuverability at the water-air and silicone oil-air interfaces, with superior control over the speed and position of the devices. The surface of the devices is modified to tune its superficial energy in order to maximize buoyancy on these different combinations of fluids. A magnetic field-controlled strider manipulates a droplet and demonstrates collecting oil microdroplets and synthesizing platinum nanoparticles by chemical microreactions. Finally, the remotely operated microrobot could be employed in laboratories as a real avatar of chemists.