Robotic Localization Based on Planar Cable Robot and Hall Sensor Array Applied to Magnetic Capsule Endoscope.

Recently an active locomotive capsule endoscope (CE) for diagnosis and treatment in the digestive system has been widely studied. However, real-time localization to achieve precise feedback control and record suspicious positioning in the intestine is still challenging owing to the limitation of capsule size, relatively large diagnostic volume, and compatibility of other devices in clinical site. To address this issue, we present a novel robotic localization sensing methodology based on the kinematics of a planar cable driven parallel robot (CDPR) and measurements of the quasistatic magnetic field of a Hall effect sensor (HES) array. The arrangement of HES and the Levenberg-Marquardt (LM) algorithm are applied to estimate the position of the permanent magnet (PM) in the CE, and the planar CDPR is incorporated to follow the PM in the CE. By tracking control of the planar CDPR, the position of PM in any arbitrary position can be obtained through robot forward kinematics with respect to the global coordinates at the bedside. The experimental results show that the root mean square error (RMSE) for the estimated position value of PM was less than 1.13 mm in the X, Y, and Z directions and less than 1.14° in the θ and φ orientation, where the sensing space could be extended to ±70 mm for the given 34 × 34 mm2 HES array and the average moving distance in the Z-direction is 40 ± 2.42 mm. The proposed method of the robotic sensing with HES and CDPR may advance the sensing space expansion technology by utilizing the provided single sensor module of limited sensible volume.

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.

Observer-Based Deconvolution of Deterministic Input in Coprime Multichannel Systems With Its Application to Noninvasive Central Blood Pressure Monitoring.

Estimating central aortic blood pressure (BP) is important for cardiovascular (CV) health and risk prediction purposes. CV system is a multichannel dynamical system that yields multiple BPs at various body sites in response to central aortic BP. This paper concerns the development and analysis of an observer-based approach to deconvolution of unknown input in a class of coprime multichannel systems applicable to noninvasive estimation of central aortic BP. A multichannel system yields multiple outputs in response to a common input. Hence, the relationship between any pair of two outputs constitutes a hypothetical input-output system with unknown input embedded as a state. The central idea underlying our approach is to derive the unknown input by designing an observer for the hypothetical input-output system. In this paper, we developed an unknown input observer (UIO) for input deconvolution in coprime multichannel systems. We provided a universal design algorithm as well as meaningful physical insights and inherent performance limitations associated with the algorithm. The validity and potential of our approach were illustrated using a case study of estimating central aortic BP waveform from two noninvasively acquired peripheral arterial pulse waveforms. The UIO could reduce the root-mean-squared error (RMSE) associated with the central aortic BP by up to 27.5% and 28.8% against conventional inverse filtering (IF) and peripheral arterial pulse scaling techniques.

Unobtrusive Estimation of Cardiovascular Parameters with Limb Ballistocardiography.

This study investigates the potential of the limb ballistocardiogram (BCG) for unobtrusive estimation of cardiovascular (CV) parameters. In conjunction with the reference CV parameters (including diastolic, pulse, and systolic pressures, stroke volume, cardiac output, and total peripheral resistance), an upper-limb BCG based on an accelerometer embedded in a wearable armband and a lower-limb BCG based on a strain gauge embedded in a weighing scale were instrumented simultaneously with a finger photoplethysmogram (PPG). To standardize the analysis, the more convenient yet unconventional armband BCG was transformed into the more conventional weighing scale BCG (called the synthetic weighing scale BCG) using a signal processing procedure. The characteristic features were extracted from these BCG and PPG waveforms in the form of wave-to-wave time intervals, wave amplitudes, and wave-to-wave amplitudes. Then, the relationship between the characteristic features associated with (i) the weighing scale BCG-PPG pair and (ii) the synthetic weighing scale BCG-PPG pair versus the CV parameters, was analyzed using the multivariate linear regression analysis. The results indicated that each of the CV parameters of interest may be accurately estimated by a combination of as few as two characteristic features in the upper-limb or lower-limb BCG, and also that the characteristic features recruited for the CV parameters were to a large extent relevant according to the physiological mechanism underlying the BCG.

Indirect Force Control of a Cable-Driven Parallel Robot: Tension Estimation using Artificial Neural Network trained by Force Sensor Measurements.

In a cable-driven parallel robot (CDPR), force sensors are utilized at each winch motor to measure the cable tension in order to obtain the force distribution at the robot end-effector. However, because of the effects of friction in the pulleys and the unmodeled cable properties of the robot, the measured cable tensions are often inaccurate, which causes force-control difficulties. To overcome this issue, this paper presents an artificial neural network (ANN)-based indirect end-effector force-estimation method, and its application to CDPR force control. The pulley friction and other unmodeled effects are considered as black-box uncertainties, and the tension at the end-effector is estimated by compensating for these uncertainties using an ANN that is developed using the training datasets from CDPR experiments. The estimated cable tensions at the end-effector are used to design a P-controller to track the desired force. The performance of the proposed ANN model is verified through comparisons with the forces measured directly at the end-effector. Furthermore, cable force control is implemented based on the compensated tensions to evaluate the performance of the CDPR in wrench space. The experimental results show that the proposed friction-compensation method is suitable for application in CDPRs to control the cable force.

Geometric Parameter Calibration for a Cable-Driven Parallel Robot Based on a Single One-Dimensional Laser Distance Sensor Measurement and Experimental Modeling.

A cable-driven parallel robot has benefits of wide workspace, high payload, and high dynamic response owing to its light cable actuator utilization. For wide workspace applications, in particular, the body frame becomes large to cover the wide workspace that causes robot kinematic errors resulting from geometric uncertainty. However, appropriate sensors as well as inexpensive and easy calibration methods to measure the actual robot kinematic parameters are not currently available. Hence, we present a calibration sensor device and an auto-calibration methodology for the over-constrained cable-driven parallel robots using one-dimension laser distance sensors attached to the robot end-effector, to overcome the robot geometric uncertainty and to implement precise robot control. A novel calibration workflow with five phases-preparation, modeling, measuring, identification, and adjustment-is proposed. The proposed calibration algorithms cover the cable-driven parallel robot kinematics, as well as uncertainty modeling such as cable elongation and pulley kinematics. We performed extensive simulations and experiments to verify the performance of the suggested method using the MINI cable robot. The experimental results show that the kinematic parameters can be identified correctly with 0.92 mm accuracy, and the robot position control accuracy is increased by 58%. Finally, we verified that the developed calibration sensor devices and the calibration methodology are applicable to the massive-size cable-driven parallel robot system.

Data-driven lossy tube-load modeling of arterial tree: in-human study.

In this paper, we present and validate a data-driven method to lossy tube-load modeling of arterial tree in humans. In the proposed method, the lossy tube-load model is fitted to central aortic and peripheral blood pressure (BP) waves in the time domain. For this purpose, we employ a time-domain lossy tube-load model in which the wave propagation constant is formulated to two terms: one responsible for the alteration of wave amplitude and the other for the transport delay. Using the experimental BP data collected from 17 cardiac surgery patients, we showed that the time-domain lossy tube-load model is able to accurately represent the relation between central aortic versus upper-limb and lower-limb BP waves. In addition, the comparison of lossy versus lossless tube-load models revealed that (1) the former outperformed the latter in general with the root-mean-squared errors (RMSE) of 3.1 mm Hg versus 3.5 mm Hg, respectively (p-value < 0.05), and (2) the efficacy of the former over the latter was more clearly observed in case the normalized difference in the mean central aortic versus peripheral BP was large; when the difference was >5% of the underlying mean BP, lossy and lossless models showed the RMSE of 2.7 mm Hg and 3.7 mm Hg, respectively (p-value < 0.05).

Tripolar Electrode Electrochemical Impedance Spectroscopy for Endoscopic Devices toward Early Colorectal Tumor Detection.

Embedded sensors for endoscopy devices have been studied toward a convenient and decision-supportive methodology in colorectal cancer (CRC) diagnosis, but no device could provide direct CRC screening with in situ measurements. In this study, we proposed a millimeter-scale electrical impedance spectroscopy (EIS) device that can be integrated into a biopsy tool in endoscopy for colorectal tumor detection. A minimally invasive tripolar electrode was designed to sense the tissue impedance, and a multilayer neural network was implemented for the classification algorithm. The sensor performance was investigated in terms of sensitivity, reliability, and repeatability using dummy tissues made of agarose hydrogels at various saline concentrations. In addition, an in vivo study was conducted in mice with an implanted CT-26 colon tumor line. The results demonstrated that the prototyped EIS device and algorithm can detect the tumor tissue in suspicious lesions with high sensitivity and specificity of 87.2 and 92.5%, respectively, and a low error of 7.1%. The findings of this study are promising for in situ CRC screening and may advance the diagnostic efficacy of CRC detection during endoscopic procedures.

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.

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.

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.

Magnetically controlled reversible shape-morphing microrobots with real-time X-ray imaging for stomach cancer applications.

Stomach cancer is a global health concern as millions of cases are reported each year. In the present study, we developed a pH-responsive microrobot with good biocompatibility, magnetic-field controlled movements, and the ability to be visualized via X-ray imaging. The microrobot consisted of composite resin and a pH-responsive layer. This microrobot was found to fold itself in high pH environments and unfold itself in low pH environments. In addition, the neodymium (NdFeB) magnetic nanoparticles present inside the composite resin provided the microrobot with an ability to be controlled by a magnetic field through an electromagnetic actuation system, and the monomeric triiodobenzoate-based particles were found to act as contrast agents for real-time X-ray imaging. The doxorubicin coating on the microrobot's surface resulted in a high cancer-cell killing effect. Finally, we demonstrated the proposed microrobot under an ex vivo environment using a pig's stomach. Thus, this approach can be a potential alternative to targeted drug carriers, especially for stomach cancer 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.

Automated Bowel Polyp Detection Based on Actively Controlled Capsule Endoscopy: Feasibility Study.

This paper presents an active locomotion capsule endoscope system with 5D position sensing and real-time automated polyp detection for small-bowel and colon applications. An electromagnetic actuation system (EMA) consisting of stationary electromagnets is utilized to remotely control a magnetic capsule endoscope with multi-degree-of-freedom locomotion. For position sensing, an electronic system using a magnetic sensor array is built to track the position and orientation of the magnetic capsule during movement. The system is integrated with a deep learning model, named YOLOv3, which can automatically identify colorectal polyps in real-time with an average precision of 85%. The feasibility of the proposed method concerning active locomotion and localization is validated and demonstrated through in vitro experiments in a phantom duodenum. This study provides a high-potential solution for automatic diagnostics of the bowel and colon using an active locomotion capsule endoscope, which can be applied for a clinical site in the future.

Automated three-dimensional vessel reconstruction based on deep segmentation and bi-plane angiographic projections.

Automated three-dimensional (3D) blood vessel reconstruction to improve vascular diagnosis and therapeutics is a challenging task in which the real-time implementation of automatic segmentation and specific vessel tracking for matching artery sequences is essential. Recently, a deep learning-based segmentation technique has been proposed; however, existing state-of-the-art deep architectures exhibit reduced performance when they are employed using real in-vivo imaging because of serious issues such as low contrast and noise contamination of the X-ray images. To overcome these limitations, we propose a novel methodology composed of the de-haze image enhancement technique as pre-processing and multi-level thresholding as post-processing to be applied to the lightweight multi-resolution U-shaped architecture. Specifically, (1) bi-plane two-dimensional (2D) vessel images were extracted simultaneously using the deep architecture, (2) skeletons of the vessels were computed via a morphology operation, (3) the corresponding skeleton structure between image sequences was matched using the shape-context technique, and (4) the 3D centerline was reconstructed using stereo geometry. The method was validated using both in-vivo and in-vitro models. The results show that the proposed technique could improve the segmentation quality, reduce computation time, and reconstruct the 3D skeleton automatically. The algorithm accurately reconstructed the phantom model and the real mouse vessel in 3D in 2 s. Our proposed technique has the potential to allow therapeutic micro-agent navigation in clinical practice, thereby providing the 3D position and orientation of the vessel.

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.

Magnetization-Switchable Implant System to Target Delivery of Stem Cell-Loaded Bioactive Polymeric Microcarriers.

Various magnetic microcarrier systems capable of transporting cells to target lesions are developed for therapeutic agent-based tissue regeneration. However, the need for bioactive molecules and cells, the potential toxicity of the microcarrier, and the large volume and limited workspace of the magnetic targeting device remain challenging issues associated with microcarrier systems. Here, a multifunctional magnetic implant system is presented for targeted delivery, secure fixation, and induced differentiation of stem cells. This magnetic implant system consists of a biomaterial-based microcarrier containing bioactive molecules, a portable magnet array device, and a biocompatible paramagnetic implant. Among biomedical applications, the magnetic implant system is developed for knee cartilage repair. The various functions of these components are verified through in vitro, phantom, and ex vivo tests. As a result, a single microcarrier can load ≈1.52 ng of transforming growth factor ß (TGF-ß1) and 3.3 × 103 of stem cells and stimulate chondrogenic differentiation without extra bioactive molecule administration. Additionally, the implant system demonstrates high targeting efficiency (over 90%) of the microcarriers in a knee phantom and ex vivo pig knee joint. The results show that this implant system, which overcomes the limitations of the existing magnetic targeting system, represents an important advancement in the field.

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.

Primary Macrophage-Based Microrobots: An Effective Tumor Therapy In Vivo by Dual-Targeting Function and Near-Infrared-Triggered Drug Release.

Macrophages (MΦs) have the capability to sense chemotactic cues and to home tumors, therefore presenting a great approach to engineer these cells to deliver therapeutic agents to treat diseases. However, current cell-based drug delivery systems usually use commercial cell lines that may elicit an immune response when injected into a host animal. Furthermore, premature off-target drug release also remains an enormous challenge. Here, we isolated and differentiated MΦs from the spleens of BALB/c mice and developed dual-targeting MΦ-based microrobots, regulated by chemotaxis and an external magnetic field, and had a precise spatiotemporal controlled drug release at the tumor sites in response to the NIR laser irradiation. These microrobots were prepared by coloading citric acid (CA)-coated superparamagnetic nanoparticles (MNPs) and doxorubicin (DOX)-containing thermosensitive nanoliposomes (TSLPs) into the MΦs. CA-MNPs promoted a magnetic targeting function to the microrobots and also permitted photothermal heating in response to the NIR irradiation, triggering drug release from TSLPs. In vitro experiments showed that the microrobots effectively infiltrated tumors in 3D breast cancer tumor spheroids, particularly in the presence of the magnetic field, and effectively induced tumor cell death, further enhanced by the NIR laser irradiation. In vivo experiments confirmed that the application of the magnetic field and NIR laser could markedly inhibit the growth of tumors with a subtherapeutic dose of DOX and a single injection of the microrobots. In summary, the study proposes a strategy for the effective anticancer treatment using the developed microrobots.

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.