Design and Implementation of a Micromanipulation System Using a Magnetically Levitated MEMS Robot

Magnetic levitation of microrobots is presented as a new technology for micromanipulation tasks. The microrobots were fabricated based on microelectromechanical systems technology and weigh less than 1 g. The robots can be positioned in 3-D using magnetic field. It is shown that microrobots can be produced using commercially available magnets or electrodeposited magnetic films. A photothermal microgripper is integrated to the microrobots to perform micromanipulation operations. The microgrippers can be actuated remotely by laser focusing that makes the microrobot free of any wiring. This leads to increased motion range with more functionality in addition to dust-free motion and ability to work in closed environments. The 3-D motion capability of the microrobots is verified experimentally and it was demonstrated that the microgrippers can be operated in a vertical range of 4 mm and a horizonal range of 4 mm $,times,$5 mm. Micromanipulation experiments such as pick-and-place, pushing, and pulling were demonstrated using objects with 100 $mu$ m and 1 mm diameter.      

A Soft Biodegradable Chitosan-Based Medical Microrobot with Optimized Structural Design and X-Ray Visibility for Targeted Vessel Chemoembolization

Although many medical microrobots have been developed for treating diseases, their designs have not been optimized for disease environments and their functionality and capabilities have been primarily demonstrated in vitro. In addition, the imaging of microrobots within blood vessels in deep tissues remains a challenge. Herein, a chitosan-based biodegradable microrobot with optimized structural design and X-ray imaging for targeted vessel chemoembolization is reported. The design of the microrobot takes into account its magnetizability and stackability in blood vessels. The microrobot is prepared through laser micromachining of a porous chitosan sheet, attachment of nanoparticles, and filling the pores with gelatin. The optimized microrobot is biocompatible, biodegradable, thrombogenic, magnetically targetable, and drug-loadable, as demonstrated both in vitro and in a blood vessel phantom. X-ray imaging of the gold nanoparticle-attached microrobots compares well with using commercial iodinated contrast materials, thereby demonstrating their real-time long-term X-ray imaging capability. The in vivo real-time imaging and targeted vessel embolization of the microrobot are demonstrated in rat liver. The proposed microrobot overcomes the limitations of embolic microbeads currently used in targeted vessel chemoembolization (i.e., targeted vessel blocking and X-ray visibility) and expands the capability of microrobots in advanced platforms for treating human diseases.     

Magnetic Targeting Enhanced Theranostic Strategy Based on Multimodal Imaging for Selective Ablation of Cancer

The booming development of nanomedicine offers great opportunities for cancer diagnostics and therapeutics. Herein, a magnetic targeting‐enhanced cancer theranostic strategy using a multifunctional magnetic‐plasmonic nano‐agent is developed, and a highly effective in vivo tumor photothermal therapy, which is carefully planed based on magnetic resonance (MR)/photoacoustic (PA) multimodal imaging, is realized. By applying an external magnetic field (MF) focused on the targeted tumor, a magnetic targeting mediated enhanced permeability and retention (MT‐EPR) effect is observed. While MR scanning provides tumor localization and reveals time‐dependent tumor homing of nanoparticles for therapeutic planning, photoacoustic imaging with higher spatial resolution allows noninvasive fine tumor margin delineation and vivid visualization of three dimensional distributions of theranostic nanoparticles inside the tumor. Utilizing the near‐infrared (NIR) plasmonic absorbance of those nanoparticles, selective photothermal tumor ablation, whose efficacy is predicted by real‐time infrared thermal imaging intra‐therapeutically, is carried out and then monitored by MR imaging for post‐treatment prognosis. Overall, this study illustrates the concept of imaging‐guided MF‐targeted photothermal therapy based on a multifunctional nano‐agent, aiming at optimizing therapeutic planning to achieve the most efficient cancer therapy.     

“All‐in‐One” Nanoparticles for Trimodality Imaging‐Guided Intracellular Photo‐magnetic Hyperthermia Therapy under Intravenous Administration

Great efforts have been devoted so far to combine nano‐magnetic hyperthermia and nano‐photothermal therapy to achieve encouraging additive therapeutic performance in vitro and in vivo with limitation to direct intratumoral injection and no guidance of multimodality molecular imaging. In this study, a novel multifunctional theranostic nanoplatform (MNP@PES‐Cy7/2‐DG) consisting of magnetic nanoparticles (MNPs), poly(3,4‐ethylenedioxythiophene):poly(4‐styrenesulfonate) (PES), Cyanine7 (Cy7), and 2‐deoxyglucose (2‐DG)‐polyethylene glycol is developed. They are then applied to combined photo‐magnetic hyperthermia therapy under intravenous administration that is simultaneously guided by trimodality molecular imaging. Remarkably, nanoparticles are found aggregated mainly in the cytoplasm of tumor cells in vitro and in vivo, and exhibit stealth‐like behavior with a long second‐phase blood circulation half‐life of 20.38 ± 4.18 h. Under the guidance of photoacoustic/near‐infrared fluorescence/magnetic resonance trimodality imaging, tumors can be completely eliminated under intracellular photo‐magnetic hyperthermia therapy with additive therapeutic effect due to precise hyperthermia. This study may promote a further exploration of such a platform for clinical applications.     

Gold‐Coated Fe3O4 Nanoroses with Five Unique Functions for Cancer Cell Targeting,Imaging, and Therapy

The development of nanomaterials that combine diagnostic and therapeutic functions within a single nanoplatform is extremely important for molecular medicine. Molecular imaging with simultaneous diagnosis and therapy will provide the multimodality needed for accurate diagnosis and targeted therapy. Here, gold‐coated iron oxide (Fe₃O₄@Au) nanoroses with five distinct functions are demonstrated, integrating aptamer‐based targeting, magnetic resonance imaging (MRI), optical imaging, photothermal therapy. and chemotherapy into one single probe. The inner Fe₃O₄ core functions as an MRI agent, while the photothermal effect is achieved through near‐infrared absorption by the gold shell, causing a rapid rise in temperature and also resulting in a facilitated release of the anticancer drug doxorubicin carried by the nanoroses. Where the doxorubicin is released, it is monitored by its fluorescence. Aptamers immobilized on the surfaces of the nanoroses enable efficient and selective drug delivery, imaging, and photothermal effect with high specificity. The five‐function‐embedded nanoroses show great advantages in multimodality.     

Biocompatible Cup‐Shaped Nanocrystal with Ultrahigh Photothermal Efficiency as Tumor Therapeutic Agent

As an emerging treatment for cancer, phototherapy has received much clinical attention. Here, a multifunctional Au nanocup (Au NC) for the targeted computed tomographic and photoacoustic imaging of cancerous tumors and phototherapy is reported. The Au NC has an intrinsic photothermal conversion efficiency of 38.5% and offers a tumor‐specific targeted computed tomographic and photoacoustic imaging system. Furthermore, when treated with nontoxic Au NC‐Ce6, cancer cells and tumors are obliterated with low doses of irradiation and safe power levels, with both photothermal and photodynamic therapeutic effects, in vitro and vivo. These data provide a solid foundation for the clinical application of Au NC.     

Nanostructural Control Enables Optimized Photoacoustic–Fluorescence–Magnetic Resonance Multimodal Imaging and Photothermal Therapy of Brain Tumor

The performance of current multimodal imaging contrast agents is often constrained by the tunability of nanomaterial structural design. Herein, the influence of nanostructure on the overall imaging performance of a composite nanomaterial for multimodal imaging of brain tumors is studied. Newly designed near‐infrared molecules (TC1) are encapsulated into nanocomposites with ultrasmall iron oxide nanoparticles (UIONPs), forming stable nanoagents for multimodal imaging and photothermal therapy (PTT). Through a modified nanoprecipitation method, the synthesis of nanocomposites denoted as HALF is realized, in which UIONPs are restricted to half of the nanosphere. Such a unique nanostructure that physically separates TC1 and UIONPs is found with capabilities of mitigating fluorescence quenching, preserving the good performance of photoacoustic imaging, and enhancing the magnetic resonance imaging signals. Decorated with a peptide ligand cRGD for better brain tumor targeting, HALF‐cRGD is evaluated both in vitro and in vivo as imaging contrast agents and photothermal therapeutic agents. The good imaging performance and PTT effect of HALF‐cRGD in mice models indicate that the rational design and control of nanostructures could optimize multimodal imaging performance using the same components.     

Spiky Fe3O4@Au Supraparticles for Multimodal In Vivo Imaging

Nanomaterials with high biocompatibility and efficient photothermal conversion have drawn tremendous attention for tumor diagnosis and treatment. In this study, spiky Fe₃O₄@Au supraparticles (SPs) are used as phototherapy and multimodal imaging agents. The SPs show excellent photothermal and photodynamic therapeutic effects, with a photothermal conversion efficiency of 31%, and allow tumor‐targeted imaging, including computed tomographic, photoacoustic, and magnetic resonance imaging. The SPs show excellent biocompatibility both in vitro and in vivo. Furthermore, because of their remarkable absorption at near‐infrared region, the SPs obliterate a tumor under 808 nm irradiation. With their capacity for highly integrated multimodal imaging and multiple therapeutic functions, SPs are a promising agent for application to clinical practice.     

Swimming microrobot actuated by two pairs of Helmholtz coils system

Various electromagnetic based actuation (EMA) methods have been proposed for the actuation of microrobots. The advantage of EMA is that it can generate a wireless driving force for the microrobot, and this is the reason why many researchers have focused on the EMA driven microrobot. This paper proposes a swimming microrobot driven by an external alternating magnet field using two pairs of Helmholtz coils. The microrobot with a fish like shape consists of a buoyant robot body, a permanent magnet, and a fin. Especially, the fin is directly linked to the permanent magnet and is swung by the alternating magnet field. The external alternating magnetic field generates the propulsion and steering force of the microrobot. In this paper, firstly, we design and fabricate the EMA coil system and the tadpole type microrobot. Secondly, we propose the locomotive mechanism of the microrobot using EMA. Thirdly, we set up the control system for the EMA driven microrobot. Finally, through various experiments, we demonstrate and evaluate the performance of the swimming microrobot.     

Breaking Polymer Chains with Self-Propelled Light-Controlled Navigable Hematite Microrobots

The increasing use of polymers has led to an uncontrollable accumulation of polymer waste in the environment, evidencing the urgent need for effective and definitive strategies to degrade them. Here, self-propelled light-powered magnetic field-navigable hematite/metal Janus microrobots that can actively move, capture, and degrade polymers are presented. Janus microrobots are fabricated by asymmetrically depositing different metals on hematite microspheres prepared by low-cost and large-scale chemical synthesis. All microrobots exhibit fuel-free motion capability, with light-controlled on/off switching of motion and magnetic field-controlled directionality. Higher speeds are observed for bimetallic coatings with respect to single metals. This is due to their larger mixed potential difference with hematite as indicated by Tafel measurements. As a model for polymers, the total degradation of high molecular weight polyethylene glycol is demonstrated by matrix-assisted laser desorption/ionization mass spectrometry. This result is attributed to the active motion of microrobots, enhanced electrostatic capture of polymer chains, improved charge separation at the hematite/metal interface, and catalyzed photo-Fenton reaction. This work opens the route toward the degradation of polymers and plastics in water using light.     

Photosynthetic Biohybrid Nanoswimmers System to Alleviate Tumor Hypoxia for FL/PA/MR Imaging‐Guided Enhanced Radio‐Photodynamic Synergetic Therapy

Biohybrid microswimmers have recently shown to be able to actively perform in targeted delivery and in vitro biomedical applications. However, more envisioned functionalities of the microswimmers aimed at in vivo treatments are still challenging. A photosynthetic biohybrid nanoswimmers system (PBNs), magnetic engineered bacteria‐Spirulina platensis, is utilized for tumor‐targeted imaging and therapy. The engineered PBNs is fabricated by superparamagnetic magnetite (Fe₃O₄ NPs) via a dip‐coating process, enabling its tumor targeting ability and magnetic resonance imaging property after intravenous injection. It is found that the PBNs can be used as oxygenerator for in situ O₂ generations in hypoxic solid tumors through photosynthesis, modulating the tumor microenvironment (TME), thus improving the effectiveness of radiotherapy (RT). Furthermore, the innate chlorophyll released from the RT‐treated PBNs, as a photosensitizer, can produce cytotoxic reactive oxygen species under laser irradiation to achieve photodynamic therapy. Excellent tumor inhibition can be realized by the combined multimodal therapies. The PBNs also possesses capacities of chlorophyll‐based fluorescence and photoacoustic imaging, which can monitor the tumor therapy and tumor TME environment. These intriguing properties of the PBNs provide a promising microrobotic platform for TME hypoxic modulation and cancer theranostic applications.     

One‐Pot Synthesis of Dual Stimulus‐Responsive Degradable Hollow Hybrid Nanoparticles for Image‐Guided Trimodal Therapy

Exploiting exogenous and endogenous stimulus‐responsive degradable nanoparticles as drug carriers can improve drug delivery systems (DDSs). The use of hollow nanoparticles may facilitate degradation, and combination of DDS with photodynamic therapy (PDT) and photothermal therapy (PTT) may enhance the anticancer effects of treatments. Here, a one‐pot synthetic method is presented for an anticancer drug (doxorubicin [DOX]) and photosensitizer‐containing hollow hybrid nanoparticles (HNPs) with a disulfide and siloxane framework formed in response to exogenous (light) and endogenous (intracellular glutathione [GSH]) stimuli. The hollow HNPs emit fluorescence within the near‐infrared window and allow for the detection of tumors in vivo by fluorescence imaging. Furthermore, the disulfides within the HNP framework are cleaved by intracellular GSH, deforming the HNPs. Light irradiation facilitates penetration of GSH into the HNP framework and leads to the collapse of the HNPs. As a result, DOX is released from the hollow HNPs. Additionally, the hollow HNPs generate singlet oxygen (¹O₂) and heat in response to light; thus, fluorescence imaging of tumors combined with trimodal therapy consisting of DDS, PDT, and PTT is feasible, resulting in superior therapeutic efficacy. Thus, this method may have several applications in imaging and therapeutics in the future.     

Non‐Fenton‐Type Hydroxyl Radical Generation and Photothermal Effect by Mitochondria‐Targeted WSSe/MnO2 Nanocomposite Loaded with Isoniazid for Synergistic Anticancer Treatment

Here, in terms of the highly reactive oxidative hydroxyl radical (?OH) generation ability of isoniazid (INH) catalyzed by Mn²⁺ ion and the photothermal effect of WSSe nanoflakes, a WSSe/MnO₂‐INH nanocomposite for synergistic anticancer treatment is developed. Advanced INH‐induced ?OH formation ability is systemically demonstrated in the presence of manganese and relevant non‐Fenton‐type mechanism, and good photothermal conversion efficiency of the WSSe/MnO₂ nanocomposite. After modifying with mitochondria‐targeted triphenylphosphonium bromide (TPP) moieties and camouflaging with cancer cells membrane (WSSe/MnO₂‐INH‐TPP@CM), it confers a sequential cell‐to‐mitochondria targeting ability. In vivo X‐ray computed tomography and magnetic resonance tumor imaging capability of the nanocomposite are also revealed. The mitochondria‐targeted oxidative damage and photothermal therapy by WSSe/MnO₂‐INH‐TPP@CM results in excellent anticancer treatment efficacy both in vitro and in vivo. This is the first exploration of the possibility of non‐Fenton‐type ?OH formation for anticancer treatment, which opens new opportunities for ROS‐based and combined cancer treatment strategies.     

Design and control of a microrobotic system using magneticlevitation

Presents a prototype microrobot based on magnetic principles. Miniature items are to be transported and assembled in hazardous environments. A microrobot can be remotely operated with 3 DOF in an enclosed environment by transferring magnetic energy and optical signals from outside. The magnetic drive unit consists of 8 electromagnets (4 pairs), 2 permanent magnets, a return yoke and a pole piece. The microrobot is manipulated under the pole piece by regulating magnetic field. It consists of a magnetic head, a body (electronic circuit and batteries), and copper alloy ribbon ringers. A shape memory alloy actuator activates the fingers by illuminating/extinguishing several LED. PID controls were applied. To cope with uncertainties and variations in payload masses, an adaptive control law was also employed for positioning along the z axis to enable the controller parameters to be adjusted in real-time. Effectiveness of the control was verified by the results of several experiments. The microrobot has a net mass of 8.1 g and it can elevate and manipulate objects with masses up to 1.5 g within a volume of 29×29×26 mm³ with a precision of 0.05 mm     

Gold Nanoshell Nanomicelles for Potential Magnetic Resonance Imaging,Light‐Triggered Drug Release,and Photothermal Therapy

A novel multifunctional drug‐delivery platform is developed based on cholesteryl succinyl silane (CSS) nanomicelles loaded with doxorubicin, Fe₃O₄ magnetic nanoparticles, and gold nanoshells (CDF‐Au‐shell nanomicelles) to combine magnetic resonance (MR) imaging, magnetic‐targeted drug delivery, light‐triggered drug release, and photothermal therapy. The nanomicelles show improved drug‐encapsulation efficiency and loading level, and a good response to magnetic fields, even after the formation of the gold nanoshell. An enhancement for T₂‐weighted MR imaging is observed for the CDF‐Au‐shell nanomicelles. These nanomicelles display surface plasmon absorbance in the near‐infrared (NIR) region, thus exhibiting an NIR (808 nm)‐induced temperature elevation and an NIR light‐triggered and stepwise release behavior of doxorubicin due to the unique characteristics of the CSS nanomicelles. Photothermal cytotoxicity in vitro confirms that the CDF‐Au‐shell nanomicelles cause cell death through photothermal effects only under NIR laser irradiation. Cancer cells incubated with CDF‐Au‐shell nanomicelles show a significant decrease in cell viability only in the presence of both NIR irradiation and a magnetic field, which is attributed to the synergetic effects of the magnetic‐field‐guided drug delivery and the photothermal therapy. Therefore, such multicomponent nanomicelles can be developed as a smart and promising nanosystem that integrates multiple capabilities for effective cancer diagnosis and therapy.     

Fabricating Aptamer‐Conjugated PEGylated‐MoS2/Cu1.8S Theranostic Nanoplatform for Multiplexed Imaging Diagnosis and Chemo‐Photothermal Therapy of Cancer

Fabricating theranostic nanoparticles combining multimode disease diagnosis and therapeutic has become an emerging approach for personal nanomedicine. However, the diagnostic capability, biocompatibility, and therapeutic efficiency of theranostic nanoplatforms limit their clinic widespread applications. Targeting to the theme of accurate diagnosis and effective therapy of cancer cells, a multifunctional nanoplatform of aptamer and polyethylene glycol (PEG) conjugated MoS₂ nanosheets decorated with Cu_1.8S nanoparticles (ATPMC) is developed. The ATPMC nanoplatform accomplishes photoluminescence imaging, photoacoustic imaging, and photothermal imaging for in vitro and in vivo tumor cells imaging diagnosis. Meanwhile, the ATPMC nanoplatform facilitates selective delivery of gene probe to detect intracellular microRNA aberrantly expressed in cancer cells and anticancer drug doxorubicin (DOX) for chemotherapy. Moreover, the synergistic interaction of MoS₂ and Cu_1.8S renders the ATPMC nanoplatform with superb photothermal conversion efficiency. The ATPMC nanoplatform loaded with DOX displays near‐infrared laser‐induced programmed chemotherapy and advanced photothermal therapy, and the targeted chemo‐photothermal therapy presents excellent antitumor efficiency.     

Magnetic Hydrogel Microrobots Delivery System for Deafness Prevention

Hydrogel microrobots have blazed new avenues for local drug administration, while their values in inner ear drug delivery remain to be explored. Here, novel magnetic alpha-lipoic acid (ALA)-conjugated gelatin methacryloyl hydrogel microrobots are presented for inner ear drug delivery and deafness prevention. The magnetic hydrogel microrobots with features of slow drug release, targeted movement, and biosafety are generated from microfluidic devices. After intratympanic injection, the microrobots can be oriented in the middle ear cavity under a specific magnetic field. In addition, the ALA drug released from the magnetic hydrogel microrobots can remain in the inner ear for a long time. Based on these advantages, the practical value of the magnetic hydrogel microrobots in deafness prevention is demonstrated by pre-injecting them in the middle ear of cisplatin-deafened mice. These results indicate that the proposed smart magnetic hydrogel microrobots can effectively deliver drugs to the inner ear through the middle ear drug delivery route, thus opening a new chapter for middle ear deafness treatment.     

Engineering of Multifunctional Nano‐Micelles for Combined Photothermal and Photodynamic Therapy Under the Guidance of Multimodal Imaging

The integration of diagnostic and therapeutic functionalities on a single theranostic nano‐system holds great promise to enhance the accuracy of diagnosis and improve the efficacy of therapy. Herein, a multifunctional polymeric nano‐micelle system that contains a photosensitizer chlorin e6 (Ce6) is successfully fabricated, at the same time serving as a chelating agent for Gd³⁺, together with a near‐infrared (NIR) dye, IR825. With a r₁ relativity 7 times higher than that of the commercial agent Magnevist, strong fluorescence offered by Ce6, and high NIR absorbance attributed to IR825, these theranostic micelles can be utilized as a contrast agent for triple modal magnetic resonance (MR), fluorescence, and photoacoustic imaging of tumors in a mouse model. The combined photothermal and photodynamic therapy is then carried out, achieving a synergistic anti‐tumor effect both in vitro and in vivo. Different from single photo treatment modalities which only affect the superficial region of the tumor under mild doses, the combination therapy at the same dose using this agent is able to induce significant damage to both superficial and deep parts of the tumor. Therefore, this work presents a polymer based theranostic platform with great potential in multimodal imaging and combination therapy of cancer.     

Mesoporous Polydopamine Carrying Manganese Carbonyl Responds to Tumor Microenvironment for Multimodal Imaging‐Guided Cancer Therapy

Multifunctional nanodrugs integrating multiple therapeutic and imaging functions may find tremendous biomedical applications. However, the development of a simple yet potent theranostic nanosystem with a high payload and microenvironment responsiveness enhancing imaging‐guided cancer therapy is still a great challenge. Herein, a kind of MnCO‐entrapped mesoporous polydopamine nanoparticles are developed, which reach a 1.5 mg payload per gram carrier and exhibit marked theranostic capability through effective CO/Mn²⁺ generation and photothermal conversion inside the H⁺ and H₂O₂‐enriched tumor microenvironment, for a magnetic resonance/photoacoustic bimodal imaging‐guided tumor therapy. The multifunctional nanosystem exhibits a biocompatibility highly desirable for in vivo application and superior performance in inhibiting tumor growth and recurrence via combination CO and photothermal therapy.     

Camouflaging Nanoparticles with Brain Metastatic Tumor Cell Membranes: A New Strategy to Traverse Blood–Brain Barrier for Imaging and Therapy of Brain Tumors

Glioblastoma multiforme is one of the most fatal intracranial tumors with no effective treatment. The drug concentration in tumor sites is usually insufficient to reach therapeutic levels, due to poor blood–brain‐barrier (BBB) permeability and short biological half‐life. Inspired by the proneness of those malignant tumors to brain metastasis, a brain metastatic tumor cell membrane‐coated nanocarrier with core–shell structure is constructed to cross BBB for imaging and photothermal therapy of early brain tumors. The cell membranes as the shell are extracted from different metastatic tumor cells, which endow the nanoparticles with BBB‐crossing ability and long circulation. Indocyanine green (ICG)‐loaded polymeric nanoparticle as the core allows fluorescence imaging and phototherapy of brain tumors. The as‐prepared biomimetic nanoparticles display superb BBB penetration and effective suppression of tumor growth. These findings suggest the biomimetic nanotechnology provides a new insight for the design of BBB‐crossing nanomaterials and is promising to treat brain diseases.