Color-Transfer-Enhanced Data Construction and Validation for Deep Learning-Based Upper Gastrointestinal Landmark Classification in Wireless Capsule Endoscopy.

While the adoption of wireless capsule endoscopy (WCE) has been steadily increasing, its primary application remains limited to observing the small intestine, with relatively less application in the upper gastrointestinal tract. However, there is a growing anticipation that advancements in capsule endoscopy technology will lead to a significant increase in its application in upper gastrointestinal examinations. This study addresses the underexplored domain of landmark identification within the upper gastrointestinal tract using WCE, acknowledging the limited research and public datasets available in this emerging field. To contribute to the future development of WCE for gastroscopy, a novel approach is proposed. Utilizing color transfer techniques, a simulated WCE dataset tailored for the upper gastrointestinal tract is created. Using Euclidean distance measurements, the similarity between this color-transferred dataset and authentic WCE images is verified. Pioneering the exploration of anatomical landmark classification with WCE data, this study integrates similarity evaluation with image preprocessing and deep learning techniques, specifically employing the DenseNet169 model. As a result, utilizing the color-transferred dataset achieves an anatomical landmark classification accuracy exceeding 90% in the upper gastrointestinal tract. Furthermore, the application of sharpen and detail filters demonstrates an increase in classification accuracy from 91.32% to 94.06%.

Acoustic Actuators for the Manipulation of Micro/Nanorobots: State-of-the-Art and Future Outlooks.

Compared to other actuating methods, acoustic actuators offer the distinctive capability of the contactless manipulation of small objects, such as microscale and nanoscale robots. Furthermore, they have the ability to penetrate the skin, allowing for the trapping and manipulation of micro/nanorobots that carry therapeutic agents in diverse media. In this review, we summarize the current progress in using acoustic actuators for the manipulation of micro/nanorobots used in various biomedical applications. First, we introduce the actuating method of using acoustic waves to manipulate objects, including the principle of operation and different types of acoustic actuators that are usually employed. Then, applications involving manipulating different types of devices are reviewed, including bubble-based microrobots, bubble-free robots, biohybrid microrobots, and nanorobots. Finally, we discuss the challenges and future perspectives for the development of the field.

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.

Fabrication, Acoustic Characterization and Phase Reference-Based Calibration Method for a Single-Sided Multi-Channel Ultrasonic Actuator.

The ultrasonic actuator can be used in medical applications because it is label-free, biocompatible, and has a demonstrated history of safe operation. Therefore, there is an increasing interest in using an ultrasonic actuator in the non-contact manipulation of micromachines in various materials and sizes for therapeutic applications. This research aims to design, fabricate, and characterize a single-sided transducer array with 56 channels operating at 500 kHz, which provide benefits in the penetration of tissue. The fabricated transducer is calibrated using a phase reference calibration method to reduce position misalignment and phase discrepancies caused by acoustic interaction. The acoustic fields generated by the transducer array are measured in a 300 mm × 300 mm × 300 mm container filled with de-ionized water. A hydrophone is used to measure the far field in each transducer array element, and the 3D holographic pattern is analyzed based on the scanned acoustic pressure fields. Next, the phase reference calibration is applied to each transducer in the ultrasonic actuator. As a result, the homogeneity of the acoustic pressure fields surrounding the foci area is improved, and the maximum pressure is also increased in the twin trap. Finally, we demonstrate the capability to trap and manipulate micromachines with acoustic power by generating a twin trap using both optical camera and ultrasound imaging systems in a water medium. This work not only provides a comprehensive study on acoustic actuators but also inspires the next generation to use acoustics in medical applications.

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.

Holographic Acoustic Tweezers for 5-DoF Manipulation of Nanocarrier Clusters toward Targeted Drug Delivery.

Acoustic tweezers provide unique capabilities in medical applications, such as contactless manipulation of small objects (e.g., cells, compounds or living things), from nanometer-sized extracellular vesicles to centimeter-scale structures. Additionally, they are capable of being transmitted through the skin to trap and manipulate drug carriers in various media. However, these capabilities are hindered by the limitation of controllable degrees of freedom (DoFs) or are limited maneuverability. In this study, we explore the potential application of acoustical tweezers by presenting a five-DoF contactless manipulation acoustic system (AcoMan). The system has 30 ultrasound transducers (UTs) with single-side arrangement that generates active traveling waves to control the position and orientation of a fully untethered nanocarrier clusters (NCs) in a spherical workspace in water capable of three DoFs translation and two DoFs rotation. In this method, we use a phase modulation algorithm to independently control the phase signal for 30 UTs and manipulate the NCs' positions. Phase modulation and switching power supply for each UT are employed to rotate the NCs in the horizontal plane and control the amplitude of power supply to each UT to rotate the NCs in the vertical plane. The feasibility of the method is demonstrated by in vitro and ex vivo experiments using porcine ribs. A significant portion of this study could advance the therapeutic application such a system as targeted drug delivery.

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.

Micromotor Manipulation Using Ultrasonic Active Traveling Waves.

The ability to manipulate therapeutic agents in fluids is of interest to improve the efficiency of targeted drug delivery. Ultrasonic manipulation has great potential in the field of therapeutic applications as it can trap and manipulate micro-scale objects. Recently, several methods of ultrasonic manipulation have been studied through standing wave, traveling wave, and acoustic streaming. Among them, the traveling wave based ultrasonic manipulation is showing more advantage for in vivo environments. In this paper, we present a novel ultrasonic transducer (UT) array with a hemispherical arrangement that generates active traveling waves with phase modulation to manipulate a micromotor in water. The feasibility of the method could be demonstrated by in vitro and ex vivo experiments conducted using a UT array with 16 transducers operating at 1 MHz. The phase of each transducer was controlled independently for generating a twin trap and manipulation of a micromotor in 3D space. This study shows that the ultrasonic manipulation device using active traveling waves is a versatile tool that can be used for precise manipulation of a micromotor inserted in a human body and targeted for drug delivery.

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.

Guide-Wired Helical Microrobot for Percutaneous Revascularization in Chronic Total Occlusion in-Vivo Validation.

OBJECTIVE: For the revascularization in small vessels such as coronary arteries, we present a guide-wired helical microrobot mimicking the corkscrew motion for mechanical atherectomy that enables autonomous therapeutics and minimizing the radiation exposure to clinicians. METHODS: The microrobot is fabricated with a spherical joint and a guidewire. A previously developed external electromagnetic manipulation system capable of high power and frequency is incorporated and an autonomous guidance motion control including driving and steering is implemented in the prototype. We tested the validity of our approach in animal experiments under clinical settings. For the in vivo test, artificial thrombus was fabricated and placed in a small vessel and atherectomy procedures were conducted. RESULTS: The devised approach enables us to navigate the helical robot to the target area and successfully unclog the thrombosis in rat models in vivo. CONCLUSION: This technology overcomes several limitations associated with a small vessel environment and promises to advance medical microrobotics for real clinical applications while achieving intact operation and minimizing radiation exposures to clinicians. SIGNIFICANCE: Advanced microrobot based on multi-discipline technology could be validated in vivo for the first time and that may foster the microrobot application at clinical sites.

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.

Wearable Fixation Device for a Magnetically Controllable Therapeutic Agent Carrier: Application to Cartilage Repair.

Recently, significant research efforts have been devoted toward the development of magnetically controllable drug delivery systems, however, drug fixation after targeting remains a challenge hindering long-term therapeutic efficacy. To overcome this issue, we present a wearable therapeutic fixation device for fixing magnetically controllable therapeutic agent carriers (MCTACs) at defect sites and its application to cartilage repair using stem cell therapeutics. The developed device comprises an array of permanent magnets based on the Halbach array principle and a wearable band capable of wrapping the target body. The design of the permanent magnet array, in terms of the number of magnets and array configuration, was determined through univariate search optimization and 3D simulation. The device was fabricated for a given rat model and yielded a strong magnetic flux density (exceeding 40 mT) in the region of interest that was capable of fixing the MCTAC at the desired defect site. Through in-vitro and in-vivo experiments, we successfully demonstrated that MCTACs, both a stem cell spheroid and a micro-scaffold for cartilage repair, could be immobilized at defect sites. This research is expected to advance precise drug delivery technology based on MCTACs, enabling subject-specific routine life therapeutics. Further studies involving the proposed wearable fixation device will be conducted considering prognostics under actual clinical settings.

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.

A Guide-Wired Helical Microrobot for Mechanical Thrombectomy: A Feasibility Study.

In this paper, we present a novel guide-wired helical microrobot for mechanical thrombectomy in cardiovascular system, especially for calcified thrombus therapeutics. We designed and fabricated a prototype of the helical shape microrobot equipped with a freely rotatable spherical joint connected to a catheter guidewire, that enables drilling capability to remove calcified objects in vascular. The guidewire helps supporting and maneuvering the microrobot against blood flow during thrombus removal procedure. In addition to the microrobot, an enhanced electromagnetic navigation system (ENS) is implemented to utilize high frequency operation based on resonant effect, which enables powerful drilling force of the microrobot. The in-vitro experimental results illustrate that the suggested method could successfully enhance the locomotion and the drilling force of the helical microrobot that would be sufficient for future mechanical thrombectomy application in cardiovascular therapeutics.