Ultrasonic Manipulation of Hydrodynamically Driven Microparticles in Vessel Bifurcation: Simulation, Optimization, Experimental Validation, and Potential for Targeted Drug Delivery.

Microrobots driven by multiple external power sources have emerged as promising tools for targeted drug and stem cell delivery in tissue regeneration. However, navigating and imaging these devices within a complex colloidal vascular system at a clinical scale is challenging. Ultrasonic actuators have gained interest in the field of non-contact manipulation of micromachines due to their label-free biocompatible nature and safe operation history. This research presents experimentally validated simulation results of ultrasonic actuation using a novel ultrasonic transducer array with a hemispherical arrangement that generates active traveling waves with phase modulation. Blood flow is used as a carrier force while the direction and path are controlled by blocking undesirable paths using a highly focused acoustic field. In the experiments, the microrobot cluster was able to follow a predefined trajectory and reach the target. The microrobot size, maximum radiation pressure, and focus position were optimized for certain blood flow conditions. The outcomes suggest that this acoustic manipulation module has potential applications in targeted tumor therapy.

Multifunctional microrobot with real-time visualization and magnetic resonance imaging for chemoembolization therapy of liver cancer.

Microrobots that can be precisely guided to target lesions have been studied for in vivo medical applications. However, existing microrobots have challenges in vivo such as biocompatibility, biodegradability, actuation module, and intra- and postoperative imaging. This study reports microrobots visualized with real-time x-ray and magnetic resonance imaging (MRI) that can be magnetically guided to tumor feeding vessels for transcatheter liver chemoembolization in vivo. The microrobots, composed of a hydrogel-enveloped porous structure and magnetic nanoparticles, enable targeted delivery of therapeutic and imaging agents via magnetic guidance from the actuation module under real-time x-ray imaging. In addition, the microrobots can be tracked using MRI as postoperative imaging and then slowly degrade over time. The in vivo validation of microrobot system-mediated chemoembolization was demonstrated in a rat liver with a tumor model. The proposed microrobot provides an advanced medical robotic platform that can overcome the limitations of existing microrobots and current liver chemoembolization.

Acoustically Driven Cell-Based Microrobots for Targeted Tumor Therapy.

Targeted drug delivery using microrobots manipulated by an external actuator has significant potential to be a practical approach for wireless delivery of therapeutic agents to the targeted tumor. This work aimed to develop a novel acoustic manipulation system and macrophage-based microrobots (Macbots) for a study in targeted tumor therapy. The Macbots containing superparamagnetic iron oxide nanoparticles (SPIONs) can serve as drug carriers. Under an acoustic field, a microrobot cluster of the Macbots is manipulated by following a predefined trajectory and can reach the target with a different contact angle. As a fundamental validation, we investigated an in vitro experiment for targeted tumor therapy. The microrobot cluster could be manipulated to any point in the 4 × 4 × 4 mm region of interest with a position error of less than 300 µm. Furthermore, the microrobot could rotate in the O-XY plane with an angle step of 45 degrees without limitation of total angle. Finally, we verified that the Macbots could penetrate a 3D tumor spheroid that mimics an in vivo solid tumor. The outcome of this study suggests that the Macbots manipulated by acoustic actuators have potential applications for targeted tumor therapy.

Sonazoid-Conjugated Natural Killer Cells for Tumor Therapy and Real-Time Visualization by Ultrasound Imaging.

Various cell therapy strategies, including chimeric antigen receptor-expressing T or natural killer (NK) cells and cell-mediated drug delivery, have been developed for tumor eradication. However, the efficiency of these strategies against solid tumors remains unclear. We hypothesized that real-time control and visualization of therapeutic cells, such as NK cells, would improve their therapeutic efficacy against solid tumors. In this study, we engineered Sonazoid microbubble-conjugated NK (NK_Sona) cells and demonstrated that they were detectable by ultrasound imaging in real-time and maintained their functions. The Sonazoid microbubbles on the cell membrane did not affect the cytotoxicity and viability of the NK cells in vitro. Additionally, the NK_Sona cells could be visualized by ultrasound imaging and inhibited tumor growth in vivo. Taken together, our findings demonstrate the feasibility of this new approach in the use of therapeutic cells, such as NK cells, against solid tumors.

Locomotion and disaggregation control of paramagnetic nanoclusters using wireless electromagnetic fields for enhanced targeted drug delivery.

Magnetic nanorobots (MNRs) based on paramagnetic nanoparticles/nanoclusters for the targeted therapeutics of anticancer drugs have been highlighted for their efficiency potential. Controlling the locomotion of the MNRs is a key challenge for effective delivery to the target legions. Here, we present a method for controlling paramagnetic nanoclusters through enhanced tumbling and disaggregation motions with a combination of rotating field and gradient field generated by external electromagnets. The mechanism is carried out via an electromagnetic actuation system capable of generating MNR motions with five degrees of freedom in a spherical workspace without singularity. The nanocluster swarm structures can successfully pass through channels to the target region where they can disaggregate. The results show significantly faster response and higher targeting rate by using rotating magnetic and gradient fields. The mean velocities of the enhanced tumbling motion are twice those of the conventional tumbling motion and approximately 130% higher than the gradient pulling motion. The effects of each fundamental factor on the locomotion are investigated for further MNR applications. The locomotion speed of the MNR could be predicted by the proposed mathematical model and agrees well with experimental results. The high access rate and disaggregation performance insights the potentials for targeted drug delivery application.

A Magnetically Guided Self-Rolled Microrobot for Targeted Drug Delivery, Real-Time X-Ray Imaging, and Microrobot Retrieval.

Targeted drug delivery using a microrobot is a promising technique capable of overcoming the limitations of conventional chemotherapy that relies on body circulation. However, most studies of microrobots used for drug delivery have only demonstrated simple mobility rather than precise targeting methods and prove the possibility of biodegradation of implanted microrobots after drug delivery. In this study, magnetically guided self-rolled microrobot that enables autonomous navigation-based targeted drug delivery, real-time X-ray imaging, and microrobot retrieval is proposed. The microrobot, composed of a self-rolled body that is printed using focused light and a surface with magnetic nanoparticles attached, demonstrates the loading of doxorubicin and an X-ray contrast agent for cancer therapy and X-ray imaging. The microrobot is precisely mobilized to the lesion site through automated targeting using magnetic field control of an electromagnetic actuation system under real-time X-ray imaging. The photothermal effect using near-infrared light reveals rapid drug release of the microrobot located at the lesion site. After drug delivery, the microrobot is recovered without potential toxicity by implantation or degradation using a magnetic-field-switchable coiled catheter. This microrobotic approach using automated control method of the therapeutic agents-loaded microrobot has potential use in precise localized drug delivery systems.

Multifunctional Biodegradable Microrobot with Programmable Morphology for Biomedical Applications.

We described a magnetic chitosan microscaffold tailored for applications requiring high biocompatibility, biodegradability, and monitoring by real-time imaging. Such magnetic microscaffolds exhibit adjustable pores and sizes depending on the target application and provide various functions such as magnetic actuation and enhanced cell adhesion using biomaterial-based magnetic particles. Subsequently, we fabricated the magnetic chitosan microscaffolds with optimized shape and pore properties to specific target diseases. As a versatile tool, the capability of the developed microscaffold was demonstrated through in vitro laboratory tasks and in vivo therapeutic applications for liver cancer therapy and knee cartilage regeneration. We anticipate that the optimal design and fabrication of the presented microscaffold will advance the technology of biopolymer-based microscaffolds and micro/nanorobots.

Human adipose-derived mesenchymal stem cell-based medical microrobot system for knee cartilage regeneration in vivo.

Targeted cell delivery by a magnetically actuated microrobot with a porous structure is a promising technique to enhance the low targeting efficiency of mesenchymal stem cell (MSC) in tissue regeneration. However, the relevant research performed to date is only in its proof-of-concept stage. To use the microrobot in a clinical stage, biocompatibility and biodegradation materials should be considered in the microrobot, and its efficacy needs to be verified using an in vivo model. In this study, we propose a human adipose-derived MSC-based medical microrobot system for knee cartilage regeneration and present an in vivo trial to verify the efficacy of the microrobot using the cartilage defect model. The microrobot system consists of a microrobot body capable of supporting MSCs, an electromagnetic actuation system for three-dimensional targeting of the microrobot, and a magnet for fixation of the microrobot to the damaged cartilage. Each component was designed and fabricated considering the accessibility of the patient and medical staff, as well as clinical safety. The efficacy of the microrobot system was then assessed in the cartilage defect model of rabbit knee with the aim to obtain clinical trial approval.

A Robotic Biopsy Endoscope with Magnetic 5-DOF Locomotion and a Retractable Biopsy Punch.

Capsule endoscopes (CEs) have emerged as an advanced diagnostic technology for gastrointestinal diseases in recent decades. However, with regard to robotic motions, they require active movability and multi-functionalities for extensive, untethered, and precise clinical utilization. Herein, we present a novel wireless biopsy CE employing active five degree-of-freedom locomotion and a biopsy needle punching mechanism for the histological analysis of the intestinal tract. A medical biopsy punch is attached to a screw mechanism, which can be magnetically actuated to extrude and retract the biopsy tool, for tissue extraction. The external magnetic field from an electromagnetic actuation (EMA) system is utilized to actuate the screw mechanism and harvest biopsy tissue; therefore, the proposed system consumes no onboard energy of the CE. This design enables observation of the biopsy process through the capsule's camera. A prototype with a diameter of 12 mm and length of 30 mm was fabricated with a medical biopsy punch having a diameter of 1.5 mm. Its performance was verified through numerical analysis, as well as in-vitro and ex-vivo experiments on porcine intestine. The CE could be moved to target lesions and obtain sufficient tissue samples for histological examination. The proposed biopsy CE mechanism utilizing punch biopsy and its wireless extraction-retraction technique can advance untethered intestinal endoscopic capsule technology at clinical sites.

Multifunctional Nanorobot System for Active Therapeutic Delivery and Synergistic Chemo-photothermal Therapy.

Nanorobots are safe and exhibit powerful functionalities, including delivery, therapy, and diagnosis. Therefore, they are in high demand for the development of new cancer therapies. Although many studies have contributed to the progressive development of the nanorobot system for anticancer drug delivery, these systems still face some critical limitations, such as potentially toxic materials in the nanorobots, unreasonable sizes for passive targeting, and the lack of several essential functions of the nanorobot for anticancer drug delivery including sensing, active targeting, controlling drug release, and sufficient drug loading capacity. Here, we developed a multifunctional nanorobot system capable of precise magnetic control, sufficient drug loading for chemotherapy, light-triggered controlled drug release, light absorption for photothermal therapy, enhanced magnetic resonance imaging, and tumor sensing. The developed nanorobot system exhibits an in vitro synergetic antitumor effect of photothermal therapy and chemotherapy and outstanding tumor-targeting efficiency in both in vitro and in vivo environments. The results of this study encourage further explorations of an efficient active drug delivery system for cancer treatment and the development of nanorobot systems for other biomedical applications.

A wireless tattooing capsule endoscope using external electromagnetic actuation and chemical reaction pressure.

In this paper, we present a tattooing capsule endoscope (TCE) that can localize an intestinal lesion or tumor for a preoperative laparoscopic surgery. The TCE is based on a wireless capsule endoscope (WCE) structure and can be actively controlled by an external electromagnetic actuation system to move, observe, and mark the target lesion in the gastrointestinal (GI) tract. The TCE is designed to perform capsule locomotion, needle extrusion and intrusion motions, and ink injection. First, the TCE is controlled to move to the target lesion during GI tract diagnosis via a capsule endoscopic camera. Further, a tattooing needle is extruded by an electromagnetically controlled mechanism to puncture the tissue. Finally, the tattooing ink is injected by the chemically reacted carbon dioxide gas pressure that is triggered by a shape memory alloy wire and a reed switch. The reed switch is also activated by the external magnetic field flux density. The suggested methods were verified by the ex-vivo experiments. The TCE prototype was able to move to the target lesion and inject the ink beneath the mucosa layer safely, thereby leaving a visible tattooed mark for surgical lesion identification. The proposed TCE method can accelerate the development of functionalities as well as tattooing procedures of the WCE in the GI tract.

A Miniaturized Capsule Endoscope Equipped a Marking Module for Intestinal Tumor Localization.

This study introduces a miniaturized capsule endoscope equipped with a marking module for intestinal tumor or lesion localization. The design concept is based on an active wireless capsule endoscope platform that is manipulated by an external electromagnetic actuation (EMA) system. The magnetic response of a permanent magnet inside the capsule is designed to have flexible movement in viscous environment of bowel. This magnet is also utilized to activate tattooing process by triggering a gas-generated chemical reaction. Once approaching to a target region, gradient magnetic field from EMA system is induced to push magnet down, releasing water to dry chemical powder mixture. Then the gas pressure increases and pushes the piston move to inject ink into target point. During traveling in digestive organs, injection needle is stowed inside the capsule to avoid damage to the organs. The whole procedure is manipulated by EMA system, the injection consumes no internal battery and is observable through capsule's camera which provides clinician vision. Basic tests were conducted to evaluate the performance of proposed robotic capsule. The success of creating a black visible bled from serosa of intestine proves the feasibility and potential of the design. This study could be an alternative for traditional tattooing endoscopy and motivate other research groups for further development of functional wireless capsule endoscope.

Real-time microrobot posture recognition via biplane X-ray imaging system for external electromagnetic actuation.

PURPOSE: As a promising intravascular therapeutic approach for autonomous catheterization, especially for thrombosis treatment, a microrobot or robotic catheter driven by an external electromagnetic actuation system has been recently investigated. However, the three-dimensional (3D) real-time position and orientation tracking of the microrobot remains a challenge for precise feedback control in clinical applications owing to the micro-size of the microrobot geometry in vessels, along with bifurcation and vulnerability. Therefore, in this paper, we propose a 3D posture recognition method for the unmanned microrobotic surgery driven by an external electromagnetic actuator system. METHODS: We propose a real-time position and spatial orientation tracking method for a millimeter-sized intravascular object or microrobot using a principal component analysis algorithm and an X-ray reconstruction. The suggested algorithm was implemented to an actual controllable wireless microrobot system composed of a bullet-shaped object, a biplane X-ray imaging device, and an electromagnetic actuation system. Numerical computations and experiments were conducted for the performance verification. RESULTS: The experimental results showed a good performance of the implemented system with tracking errors less than 0.4 mm in position and 2° in orientation. The proposed tracking technique accomplished a fast processing time, ~ 0.125 ms/frame, and high-precision recognition of the micro-sized object. CONCLUSIONS: Since the suggested method does not require pre-information of the object geometry in the human body for its 3D shape and position recognition, it could be applied to various elliptical shapes of the microrobot system with computation time efficacy and recognition accuracy. Hence, the method can be used for therapeutic millimeter- or micron-sized manipulator recognition in vascular, as well as implanted objects in the human body.

The First Interlaced Continuum Robot, Devised to Intrinsically Follow the Leader.

Flexible probes that are safely deployed to hard-to-reach targets while avoiding critical structures are strategic in several high-impact application fields, including the biomedical sector and the sector of inspections at large. A critical problem for these tools is the best approach for deploying an entire tool body, not only its tip, on a sought trajectory. A probe that achieves this deployment is considered to follow the leader (or to achieve follow-the-leader deployment) because its body sections follow the track traced by its tip. Follow-the-leader deployment through cavities is complicated due to a lack of external supports. Currently, no definitive implementation for a probe that is intrinsically able to follow the leader, i.e., without relying on external supports, has been achieved. In this paper, we present a completely new device, namely the first interlaced continuum robot, devised to intrinsically follow the leader. We developed the interlaced configuration by pursuing a conceptual approach irrespective of application-specific constraints and assuming two flexible tools with controllable stiffness. We questioned the possibility of solving the previously mentioned deployment problem by harnessing probe symmetry during the design process. This study examines the entire development of the novel interlaced probe: model-based conceptual design, detailed design and prototyping, and preliminary experimental assessment. Our probe can build a track with a radius of curvature that is as small as twice the probe diameter, which enables it to outperform state-of-the-art tools that are aimed at follow-the-leader deployment. Despite the limitations that are inherently associated with its original character, this study provides a prototypical approach to the design of interlaced continuum systems and demonstrates the first interlaced continuum probe, which is intrinsically able to follow the leader.

Development and preliminary assessment of a robotic platform for neuroendoscopy based on a lightweight robot.

BACKGROUND: Ventriculostomy is a widely performed neurosurgical procedure; some risk factors can be mitigated by computer/robot-assisted approaches. Platforms fostering synergistic robot-surgeon integration are pursued, for which lightweight robots with compliant controlled joints must be assessed (because compliance hampers accuracy). METHODS: We developed a platform encompassing, in particular, a lightweight robot and an optical tracker also used to enhance robot accuracy. Based on specifications by neurosurgeons, we designed a neuroendoscope-handling interface and assessed targeting accuracy in a model ventriculostomy where the robot was operated both autonomously and in hands-on (i.e. co-operative) mode. RESULTS: Targeting errors were systematically below the procedure accuracy threshold (1 mm); the rms targeting errors were 0.51 and 0.54 mm for autonomous and hands-on control, respectively. No significant difference was observed between the considered control modes. Very positive feedback was gathered from neurosurgeons. CONCLUSIONS: Accurate tool targeting under both autonomous and hands-on control was achieved.