Magnetic Microsphere Scaffold-Based Soft Microbots for Targeted Mesenchymal Stem Cell Delivery.

A soft microbot assembled from individual magnetic microsphere scaffold (MMS) beads carrying mesenchymal stem cells (MSC) is navigated under magnetic actuation, where an oscillating field induces mechanical flexion to propel the microbot toward the target site. A seven-bead microbot attained a top translational speed of 205.6 µm s-1 (0.068 body length s-1 ) under 10 mT and 2 Hz field oscillation. The shallow flexion angle (10-24.5°) allows precision movements required to navigate narrow spaces. Upon arrival at the target site, the MMS beads unload their MSC cargo following exposure to a phosphate-buffered saline (PBS) solution, mimicking the extracellular fluid's sodium concentration. The released stem cells have excellent viability and vitality, promoting rapid healing (i.e., 83.2% vs 49%) in a scratch-wound assay. When paired with minimally invasive surgical methods, such as laparoscopy and endoscopic surgery, the microbot can provide precise stem cell delivery to hard-to-reach injury sites in the body to promote healing. Moreover, the microbot is designed to be highly versatile, with individual MMS beads customizable for cargoes of live cells, biomolecules, bionanomaterials, and pharmaceutical compounds for various therapeutic requirements.

Establishment of ultrasound-responsive SonoBacteriaBot for targeted drug delivery and controlled release.

Bacteria-driven biohybrid microbots have shown great potential in cancer treatment. However, how precisely controlling drug release at the tumor site is still an issue. To overcome the limitation of this system, we proposed the ultrasound-responsive SonoBacteriaBot (DOX-PFP-PLGA@EcM). Doxorubicin (DOX) and perfluoro-n-pentane (PFP) were encapsulated in polylactic acid-glycolic acid (PLGA) to form ultrasound-responsive DOX-PFP-PLGA nanodroplets. Then, DOX-PFP-PLGA@EcM is created by DOX-PFP-PLGA amide-bonded to the surface of E. coli MG1655 (EcM). The DOX-PFP-PLGA@EcM was proved to have the characteristics of high tumor-targeting efficiency, controlled drug release capability, and ultrasound imaging. Based on the acoustic phase change function of nanodroplets, DOX-PFP-PLGA@EcM enhance the signal of US imaging after ultrasound irradiation. Meanwhile, the DOX loaded into DOX-PFP-PLGA@EcM can be released. After being intravenously injected, DOX-PFP-PLGA@EcM can efficiently accumulate in tumors without causing harm to critical organs. In conclusion, the SonoBacteriaBot has significant benefits in real-time monitoring and controlled drug release, which has significant potential applications for therapeutic drug delivery in clinical settings.

Biohybrid Microswimmers for Antibiotic Drug Delivery Based on a Thiol-Sensitive Release Platform.

This study reports on the design and engineering of biohybrid microswimmers exploiting a thiol-mediated self-immolative antibiotic release strategy. The design features a covalent attachment of a vancomycin conjugate via a disulfide-based linker to the surface of the microalgae Chlamydomonas reinhardtii. The antibiotic release from the surface of these biohybrids was triggered by the addition of a thiol-based reducing agent, and, subsequently, the inhibition of bacterial growth was observed for Bacillus subtilis and Staphylococcus aureus. These engineered microbots represent the first example of a microalgae-based drug delivery system with a thiol-mediated, reductive release of an antibiotic drug.

Delivery and actuation of aerosolized microbots.

For disease of the lung, the physical key to effective inhalation-based therapy is size; too large (10's of µm) and the particles or droplets do not remain suspended in air to reach deep within the lungs, too small (subµm) and they are simply exhaled without deposition. µBots within this ideal low-µm size range however are challenging to fabricate and would lead to devices that lack the speed and power necessary for performing work throughout the pulmonary network. To uncouple size from structure and function, here we demonstrate an approach where individual building blocks are aerosolized and subsequently assembled in situ into µbots capable of translation, drug delivery, and mechanical work deep within lung mimics. With this strategy, a variety of pulmonary diseases previously difficult to treat may now be receptive to µbot-based therapies.

Hemodynamics Challenges for the Navigation of Medical Microbots for the Treatment of CVDs.

Microbots have been considered powerful tools in minimally invasive medicine. In the last few years, the topic has been highly studied by researchers across the globe to further develop the capabilities of microbots in medicine. One of many applications of these devices is performing surgical procedures inside the human circulatory system. It is expected that these microdevices traveling along the microvascular system can remove clots, deliver drugs, or even look for specific cells or regions to diagnose and treat. Although many studies have been published about this subject, the experimental influence of microbot morphology in hemodynamics of specific sites of the human circulatory system is yet to be explored. There are numerical studies already considering some of human physiological conditions, however, experimental validation is vital and demands further investigations. The roles of specific hemodynamic variables, the non-Newtonian behavior of blood and its particulate nature at small scales, the flow disturbances caused by the heart cycle, and the anatomy of certain arteries (i.e., bifurcations and tortuosity of vessels of some regions) in the determination of the dynamic performance of microbots are of paramount importance. This paper presents a critical analysis of the state-of-the-art literature related to pulsatile blood flow around microbots.

Magneto-conducting multifunctional Janus microbots for intracellular delivery of biomolecules.

Although several advances have been made in the field of medicine during the last few decades, yet targeted delivery of biomolecules is still a significant challenge. Thus, the present study illustrates the fabrication of dual nature magneto-conducting Fe3 O4 -SU8 derived carbon-based Janus microbots that could deliver biomolecules efficiently inside cells. These microsystems possess dual properties, that is, the half part is magneto-conducting, and another half is only conducting for sufficing the therapeutic payloads efficiently under electromagnetic stimulations. These microbots are intrinsically fluorescent, which can help to trace them intracellularly without using any dye. UV photolithography was employed to design these low aspect ratio microbots (feature size âˆ¼2.5 µm diameter and 3.7 µm length) for attaining better control over locomotion with minimum magnetic field intensity. Interestingly, Janus microbots achieved a higher speed in the electric field (44 µm/s) as compared to the magnetic field (18 µm/s). Moreover, in vitro studies show a higher microbots uptake by HeLa cells in the presence of an external electric field as compared to without electrical field stimulation.

A Bacteria-Inspired Morphology Genetic Biomedical Material: Self-Propelled Artificial Microbots for Metastatic Triple Negative Breast Cancer Treatment.

Morphology genetic biomedical materials (MGBMs), referring to fabricating materials by learning from the genetic morphologies and strategies of natural species, hold great potential for biomedical applications. Inspired by the cargo-carrying-bacterial therapy (microbots) for cancer treatment, a MGBM (artificial microbots, AMBs) was constructed. Rather than the inherent bacterial properties (cancerous chemotaxis, tumor invasion, cytotoxicity), AMBs also possessed ingenious nitric oxide (NO) generation strategy. Mimicking the bacterial construction, the hyaluronic acid (HA) polysaccharide was induced as a coating capsule of AMBs to achieve long circulation in blood and specific tissue preference (tumor tropism). Covered under the capsule-like polysaccharide was the combinatorial agent, the self-assembly constructed by the amphiphilic dendrons with abundant l-arginine residues peripherally (as endogenous NO donor) and hydrophobic chemotherapeutic drugs at the core stacking on the surface of SWNTs (the photothermal agent) for a robust chemo-photothermal therapy (chemo-PTT) and the elicited immune therapy. Subsequently, the classic inducible nitric oxide synthase (iNOS) pathway aroused by immune response was revolutionarily utilized to oxidize the l-arginine substrates for NO production, the process for which could also be promoted by the high reactive oxygen species level generated by chemo-PTT. The NO generated by AMBs was intended to regulate vasodilation and cause a dramatic invasion (as the microbots) to disperse the therapeutic agents throughout the solid tumor for a much more enhanced curative effect, which we defined as "self-propulsion". The self-propelled AMBs exhibiting impressive primary tumor ablation, as well as the distant metastasis regression to conquer the metastatic triple negative breast cancer, provided pioneering potential therapeutic opportunities, and enlightened broad prospects in biomedical application.

Magnetotactic T-Budbots to Kill-n-Clean Biofilms.

Treatment of persistent biofilm infections has turned out to be a formidable challenge even with broad-spectrum antibiotic therapies. In this direction, intelligent micromachines may serve as active mechanical means to dislodge such deleterious bacterial communities. Herein, we have designed biocompatible micromotors from tea buds, namely, T-Budbots, which shows the capacity to be magnetically driven on a biofilm matrix and remove or fragment biofilms with precision, as a part of the proposed non-invasive "Kill-n-Clean" strategy. In a way, we present a bactericidal robotic platform decorated with magnetite nanoparticles aimed at clearing in vitro biofilms present on the surfaces. We have also shown that the smart porous T-Budbots can integrate antibiotic ciprofloxacin due to electrostatic interaction on their surface to increase their antibacterial efficacy against dreadful pathogenic bacterial communities of Pseudomonas aeruginosa and Staphylococcus aureus. It is noteworthy that the release of this drug can be controlled by tuning the surrounding pH of the T-Budbots. For example, while the acidic environment of the biofilm facilitates the release of antibiotics from the porous T-Budbots, the drug release was rather minimal at higher pH. The work represents a first step in the involvement of a plant-based microbot exhibiting magneto-robotic therapeutic properties, providing a non-invasive and safe approach to dismantle harmful biofilm infections.

Real-Time Optoacoustic Tracking of Single Moving Micro-objects in Deep Phantom and Ex Vivo Tissues.

Medical imaging plays an important role in diagnosis and treatment of multiple diseases. It is a field which seeks for improved sensitivity and spatiotemporal resolution to allow the dynamic monitoring of diverse biological processes that occur at the micro- and nanoscale. Emerging technologies for targeted diagnosis and therapy such as nanotherapeutics, microimplants, catheters, and small medical tools also need to be precisely located and monitored while performing their function inside the human body. In this work, we show for the first time the real-time tracking of moving single micro-objects below centimeter thick phantom tissue and ex vivo chicken breast, using multispectral optoacoustic tomography (MSOT). This technique combines the advantages of ultrasound imaging regarding depth and resolution with the molecular specificity of optical methods, thereby facilitating the discrimination between the spectral signatures of the micro-objects from those of intrinsic tissue molecules. The resulting MSOT signal is further improved in terms of contrast and specificity by coating the micro-objects' surface with gold nanorods, possessing a unique absorption spectrum, which facilitate their discrimination from surrounding biological tissues when translated to future in vivo settings.

Bioinspired 3D Printed Locomotion Devices Based on Anisotropic Friction.

Anisotropic friction plays a key role in natural systems, particularly for realizing the purpose of locomotion and strong attachment for the survival of organisms. Of particular interest, here, is the observation that friction anisotropy is promoted numerous times by nature, for example, by wild wheat awn for its targeted and successful seed anchorage and dispersal. Such feature is, however, not fully exploited in man-made systems, such as microbots, due to technical limitations and lack of full understanding of the mechanisms. To unravel the complex dynamics occurring in the sliding interaction between anisotropic microstructured surfaces, the friction induced by asymmetric plant microstructures is first systematically investigated. Inspired by this, anisotropic polymer microactuators with three-dimensional (3D) printed microrelieves are then prepared. By varying geometric parameters, the capability of microactuators to generate strong friction anisotropy and controllable motion in remotely stretched cylindrical tubes is investigated. Advanced theoretical models are proposed to understand and predict the dynamic behavior of these synthetic systems and to shed light on the parameters and mechanisms governing their behavior. Finally, a microbot prototype is developed and cargo transportation functions are successfully realized. This research provides both in-depth understanding of anisotropic friction in nature and new avenues for developing intelligent actuators and microbots.

Biohybrid and Bioinspired Magnetic Microswimmers.

Many motile microorganisms swim and navigate in chemically and mechanically complex environments. These organisms can be functionalized and directly used for applications (biohybrid approach), but also inspire designs for fully synthetic microbots. The most promising designs of biohybrids and bioinspired microswimmers include one or several magnetic components, which lead to sustainable propulsion mechanisms and external controllability. This Review addresses such magnetic microswimmers, which are often studied in view of certain applications, mostly in the biomedical area, but also in the environmental field. First, propulsion systems at the microscale are reviewed and the magnetism of microswimmers is introduced. The review of the magnetic biohybrids and bioinspired microswimmers is structured gradually from mostly biological systems toward purely synthetic approaches. Finally, currently less explored parts of this field ranging from in situ imaging to swarm control are discussed.

Medical Imaging for the Tracking of Micromotors.

Micro/nanomotors are useful tools for several biomedical applications, including targeted drug delivery and minimally invasive microsurgeries. However, major challenges such as in vivo imaging need to be addressed before they can be safely applied on a living body. Here, we show that positron emission tomography (PET), a molecular imaging technique widely used in medical imaging, can also be used to track a large population of tubular Au/PEDOT/Pt micromotors. Chemisorption of an iodine isotope onto the micromotor's Au surface rendered them detectable by PET, and we could track their movements in a tubular phantom over time frames of up to 15 min. In a second set of experiments, micromotors and the bubbles released during self-propulsion were optically tracked by video imaging and bright-field microscopy. The results from direct optical tracking agreed with those from PET tracking, demonstrating that PET is a suitable technique for the imaging of large populations of active micromotors in opaque environments, thus opening opportunities for the use of this mature imaging technology for the in vivo localization of artificial swimmers.

MRI-powered biomedical devices.

Magnetic resonance imaging (MRI) is beneficial for imaging-guided procedures because it provides higher resolution images and better soft tissue contrast than computed tomography (CT), ultrasound, and X-ray. MRI can be used to streamline diagnostics and treatment because it does not require patients to be repositioned between scans of different areas of the body. It is even possible to use MRI to visualize, power, and control medical devices inside the human body to access remote locations and perform minimally invasive procedures. Therefore, MR conditional medical devices have the potential to improve a wide variety of medical procedures; this potential is explored in terms of practical considerations pertaining to clinical applications and the MRI environment. Recent advancements in this field are introduced with a review of clinically relevant research in the areas of interventional tools, endovascular microbots, and closed-loop controlled MRI robots. Challenges related to technology and clinical feasibility are discussed, including MRI based propulsion and control, navigation of medical devices through the human body, clinical adoptability, and regulatory issues. The development of MRI-powered medical devices is an emerging field, but the potential clinical impact of these devices is promising.

Development and application of anticancer fluorescent CdS nanoparticles enriched Lactobacillus bacteria as therapeutic microbots for human breast carcinoma.

Applications of probiotic bacteria and nanoparticles (NPs) as therapeutic agents have great importance. This study demonstrates a combinatorial approach of both the probiotic Lactobacillus spp. (Lactobacillus fermentum and Lactobacillus plantarum) with fluorescent cadmium sulfide (CdS) NPs as therapeutic agents to target MCF-7 cancer cells (human breast cancer cells). In this study, facultative anaerobic Lactobacillus was successfully used as a vehicle to transport NPs into MCF-7 cancer cells. The cell viability assay and invasion study along with confocal and field emission scanning electron microscopy (FESEM) confirmed the release of payload (CdS NPs) into cytoplasm without any external stimuli. The biosynthesized CdS NPs of ∼22 nm were characterized by FESEM, transmission electron microscopy (TEM), atomic force microscopy (AFM), and fluorescence spectroscopy. The bacteria-NPs (microbots) interaction was investigated by growth curve studies, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), FESEM, energy dispersive X-ray spectroscopy (EDX), and fluorescence and confocal microscopy. This alternative approach showed an approved and inexpensive delivering mode of specific functional cargos or therapeutic agents into the cancer cells.

Graphene-Based Microbots for Toxic Heavy Metal Removal and Recovery from Water.

Heavy metal contamination in water is a serious risk to the public health and other life forms on earth. Current research in nanotechnology is developing new nanosystems and nanomaterials for the fast and efficient removal of pollutants and heavy metals from water. Here, we report graphene oxide-based microbots (GOx-microbots) as active self-propelled systems for the capture, transfer, and removal of a heavy metal (i.e., lead) and its subsequent recovery for recycling purposes. Microbots' structure consists of nanosized multilayers of graphene oxide, nickel, and platinum, providing different functionalities. The outer layer of graphene oxide captures lead on the surface, and the inner layer of platinum functions as the engine decomposing hydrogen peroxide fuel for self-propulsion, while the middle layer of nickel enables external magnetic control of the microbots. Mobile GOx-microbots remove lead 10 times more efficiently than nonmotile GOx-microbots, cleaning water from 1000 ppb down to below 50 ppb in 60 min. Furthermore, after chemical detachment of lead from the surface of GOx-microbots, the microbots can be reused. Finally, we demonstrate the magnetic control of the GOx-microbots inside a microfluidic system as a proof-of-concept for automatic microbots-based system to remove and recover heavy metals.