Enhanced Accuracy in Magnetic Actuation: Closed-loop Control of a Magnetic Agent with Low-Error Numerical Magnetic Model Estimation.

Magnetic actuation holds promise for wirelessly controlling small, magnetic surgical tools and may enable the next generation of ultra minimally invasive surgical robotic systems. Precise torque and force exertion are required for safe surgical operations and accurate state control. Dipole field estimation models perform well far from electromagnets but yield large errors near coils. Thus, manipulations near coils suffer from severe (10×) field modeling errors. We experimentally quantify closed-loop magnetic agent control performance by using both a highly erroneous dipole model and a more accurate numerical magnetic model to estimate magnetic forces and torques for any given robot pose in 2D. We compare experimental measurements with estimation errors for the dipole model and our finite element analysis (FEA) based model of fields near coils. With five different paths designed for this study, we demonstrate that FEA-based magnetic field modeling reduces positioning root-mean-square (RMS) errors by 48% to 79% as compared with dipole models. Models demonstrate close agreement for magnetic field direction estimation, showing similar accuracy for orientation control. Such improved magnetic modelling is crucial for systems requiring robust estimates of magnetic forces for positioning agents, particularly in force-sensitive environments like surgical manipulation.

Overcoming the Force Limitations of Magnetic Robotic Surgery: Magnetic Pulse Actuated Collisions for Tissue-Penetrating-Needle for Tetherless Interventions.

The field of magnetic robotics aims to obviate physical connections between the actuators and end-effectors. Such tetherless control may enable new ultra-minimally invasive surgical manipulations in clinical settings. While wireless actuation offers advantages in medical applications, the challenge of providing sufficient force to magnetic needles for tissue penetration remains a barrier to practical application. Applying sufficient force for tissue penetration is required for tasks such as biopsy, suturing, cutting, drug delivery, and accessing deep seated regions of complex structures in organs such as the eye. To expand the force landscape for such magnetic surgical tools, an impact-force based suture needle capable of penetrating in vitro and ex vivo samples with 3-DOF planar motion is proposed. Using custom-built 14G and 25G needles, we demonstrate generation of 410 mN penetration force, a 22.7-fold force increase with more than 20 times smaller volume compared to similar magnetically guided needles. With the MPACT-Needle, in vitro suturing of a gauze mesh onto an agar gel is demonstrated. In addition, we have reduced the tip size to 25G, which is a typical needle size for interventions in the eye, to demonstrate ex vivo penetration in a rabbit eye, mimicking procedures such as corneal injections and transscleral drug delivery.

Opening the Blood Brain Barrier with an Electropermanent Magnet System.

Opening the blood brain barrier (BBB) under imaging guidance may be useful for the treatment of many brain disorders. Rapidly applied magnetic fields have the potential to generate electric fields in brain tissue that, if properly timed, may enable safe and effective BBB opening. By tuning magnetic pulses generated by a novel electropermanent magnet (EPM) array, we demonstrate the opening of tight junctions in a BBB model culture in vitro, and show that induced monophasic electrical pulses are more effective than biphasic ones. We confirmed, with in vivo contrast-enhanced MRI, that the BBB can be opened with monophasic pulses. As electropermanent magnets have demonstrated efficacy at tuning B0 fields for magnetic resonance imaging studies, our results suggest the possibility of implementing an EPM-based hybrid theragnostic device that could both image the brain and enhance drug transport across the BBB in a single sitting.

Parallel Multichannel Assessment of Rotationally Manipulated Magnetic Nanoparticles.

Background: Rotational manipulation of chains or clusters of magnetic nanoparticles (MNPs) offers a means for directed translation and payload delivery that should be explored for clinical use. Multiple MNP types are available, yet few studies have performed side-by-side comparisons to evaluate characteristics such as velocity, movement at a distance, and capacity for drug conveyance or dispersion. Purpose: Our goal was to design, build, and study an electric device allowing simultaneous, multichannel testing (e.g., racing) of MNPs in response to a rotating magnetic field. We would then select the "best" MNP and use it with optimized device settings, to transport an unbound therapeutic agent. Methods: A magnetomotive system was constructed, with a Helmholtz pair of coils on either side of a single perpendicular coil, on top of which was placed an acrylic tray having multiple parallel lanes. Five different MNPs were tested: graphene-coated cobalt MNPs (TurboBeads™), nickel nanorods, gold-iron alloy MNPs, gold-coated Fe3O4 MNPs, and uncoated Fe3O4 MNPs. Velocities were determined in response to varying magnetic field frequencies (5-200 Hz) and heights (0-18 cm). Velocities were normalized to account for minor lane differences. Doxorubicin was chosen as the therapeutic agent, assayed using a CLARIOstar Plus microplate reader. Results: The MMS generated a maximal MNP velocity of 0.9 cm/s. All MNPs encountered a "critical" frequency at 20-30 Hz. Nickel nanorods had the optimal response based on tray height and were then shown to enable unbound doxorubicin dispersion along 10.5 cm in <30 sec. Conclusion: A rotating magnetic field can be conveniently generated using a three-coil electromagnetic device, and used to induce rotational and translational movement of MNP aggregates over mesoscale distances. The responses of various MNPs can be compared side-by-side using multichannel acrylic trays to assess suitability for drug delivery, highlighting their potential for further in vivo applications.

Control of Magnetic Surgical Robots With Model-Based Simulators and Reinforcement Learning.

Magnetically manipulated medical robots are a promising alternative to current robotic platforms, allowing for miniaturization and tetherless actuation. Controlling such systems autonomously may enable safe, accurate operation. However, classical control methods require rigorous models of magnetic fields, robot dynamics, and robot environments, which can be difficult to generate. Model-free reinforcement learning (RL) offers an alternative that can bypass these requirements. We apply RL to a robotic magnetic needle manipulation system. Reinforcement learning algorithms often require long runtimes, making them impractical for many surgical robotics applications, most of which require careful, constant monitoring. Our approach first constructs a model-based simulation (MBS) on guided real-world exploration, learning the dynamics of the environment. After intensive MBS environment training, we transfer the learned behavior from the MBS environment to the real-world. Our MBS method applies RL roughly 200 times faster than doing so in the real world, and achieves a 6 mm root-mean-square (RMS) error for a square reference trajectory. In comparison, pure simulation-based approaches fail to transfer, producing a 31 mm RMS error. These results demonstrate that MBS environments are a good solution for domains where running model-free RL is impractical, especially if an accurate simulation is not available.

Soft Capsule Magnetic Millirobots for Region-Specific Drug Delivery in the Central Nervous System.

Small soft robotic systems are being explored for myriad applications in medicine. Specifically, magnetically actuated microrobots capable of remote manipulation hold significant potential for the targeted delivery of therapeutics and biologicals. Much of previous efforts on microrobotics have been dedicated to locomotion in aqueous environments and hard surfaces. However, our human bodies are made of dense biological tissues, requiring researchers to develop new microrobotics that can locomote atop tissue surfaces. Tumbling microrobots are a sub-category of these devices capable of walking on surfaces guided by rotating magnetic fields. Using microrobots to deliver payloads to specific regions of sensitive tissues is a primary goal of medical microrobots. Central nervous system (CNS) tissues are a prime candidate given their delicate structure and highly region-specific function. Here we demonstrate surface walking of soft alginate capsules capable of moving on top of a rat cortex and mouse spinal cord ex vivo, demonstrating multi-location small molecule delivery to up to six different locations on each type of tissue with high spatial specificity. The softness of alginate gel prevents injuries that may arise from friction with CNS tissues during millirobot locomotion. Development of this technology may be useful in clinical and preclinical applications such as drug delivery, neural stimulation, and diagnostic imaging.

Towards Autonomous Control of Magnetic Suture Needles.

This paper proposes a magnetic needle steering controller to manipulate mesoscale magnetic suture needles for executing planned suturing motion. This is an initial step towards our research objective: enabling autonomous control of magnetic suture needles for suturing tasks in minimally invasive surgery. To demonstrate the feasibility of accurate motion control, we employ a cardinally-arranged four-coil electromagnetic system setup and control magnetic suture needles in a 2-dimensional environment, i.e., a Petri dish filled with viscous liquid. Different from only using magnetic field gradients to control small magnetic agents under high damping conditions, the dynamics of a magnetic suture needle are investigated and encoded in the controller. Based on mathematical formulations of magnetic force and torque applied on the needle, we develop a kinematically constrained dynamic model that controls the needle to rotate and only translate along its central axis for mimicking the behavior of surgical sutures. A current controller of the electromagnetic system combining with closed-loop control schemes is designed for commanding the magnetic suture needles to achieve desired linear and angular velocities. To evaluate control performance of magnetic suture needles, we conduct experiments including needle rotation control, needle position control by using discretized trajectories, and velocity control by using a time-varying circular trajectory. The experiment results demonstrate our proposed needle steering controller can perform accurate motion control of mesoscale magnetic suture needles.

MagnetoSuture: Tetherless Manipulation of Suture Needles.

This paper demonstrates the feasibility of ligation and tissue penetration for surgical suturing tasks using magnetically actuated suture needles. Manipulation of suture needles in minimally invasive surgery involves using articulated manual/robotic tools for needle steering and controlling needle-tissue or thread-tissue interactions. The large footprints of conventional articulated surgical tools significantly increase surgical invasiveness, potentially leading to longer recovery times, tissue damage, scarring, or associated infections. Aiming to address these issues, we investigate the feasibility of using magnetic fields to tetherlessly steer suture needles. The primary challenge of such a concept is to provide sufficient force for tissue penetration and ligation. In this work, we demonstrate proof-of-concept capabilities using the MagnetoSuture™ system, performing tissue penetration and ligation tasks using ex vivo tissues, customized NdFeB suture needles with attached threads, and remote-controlled magnetic fields. To evaluate the system performance, we conducted experiments demonstrating tetherless recreation of a purse string suture pattern, ligation of an excised segment of a rat intestine, and penetration of rat intestines.

Magnetic Microdevices for MRI-Based Detection of SARS-CoV-2 Viruses.

GOAL: To develop a micron-scale device that can operate as an MRI-based reporter for the presence of SARS-CoV-2 virus. METHODS: Iron rod microdevices were constructed via template-guided synthesis and suspended in phosphate buffered saline (PBS). Heat-inactivated SARS-CoV-2 viruses were added to the samples and imaged with low-field MRI. RESULTS: MRI of microdevices and viruses showed decreased signal intensity at low concentrations of viruses that recovered at higher concentrations. Electron micrographs suggest that reduced MRI intensity may be due to concentration-dependent shielding of water protons from local magnetic inhomogeneities caused by the iron microdevices. CONCLUSIONS: The preliminary results presented in this letter provide justification for further studies exploring the potential diagnostic role of magnetic microdevices in assessing the presence and concentration of SARS-CoV-2 viruses.

Magnetically Aligned Nanorods in Alginate Capsules (MANiACs): Soft Matter Tumbling Robots for Manipulation and Drug Delivery.

Soft, untethered microrobots composed of biocompatible materials for completing micromanipulation and drug delivery tasks in lab-on-a-chip and medical scenarios are currently being developed. Alginate holds significant potential in medical microrobotics due to its biocompatibility, biodegradability, and drug encapsulation capabilities. Here, we describe the synthesis of MANiACs-Magnetically Aligned Nanorods in Alginate Capsules-for use as untethered microrobotic surface tumblers, demonstrating magnetically guided lateral tumbling via rotating magnetic fields. MANiAC translation is demonstrated on tissue surfaces as well as inclined slopes. These alginate microrobots are capable of manipulating objects over millimeter-scale distances. Finally, we demonstrate payload release capabilities of MANiACs during translational tumbling motion.

Electropermanent magnets for variable-field NMR.

In this work, a dynamically tunable B0 field is used to perform variable-field NMR. The system consists of an array of electropermanent AlNiCo-5 magnets whose magnetizations are individually programmed using pulse-power control. This design allows the field strength to be varied for field-dispersion measurements. An ultra-broadband front-end is utilized that maintains efficient power transmission over a broad range of frequencies for robust operation without probe tuning. We perform T1-T2 correlation measurements at various B0 field strengths (0.5-2 MHz) and demonstrate discrimination of different dairy products. We observe variation in the frequency dependence of the proton spin-lattice relaxation for the different products as a function of the degree of protein hydration. This variable-field technique provides a low-cost alternative to fast field-cycling NMR and could open possibilities for novel contrast measurements and spatial encoding in magnetic resonance imaging.

Analysis of Driven Nanorod Transport Through a Biopolymer Matrix.

Applying magnetic fields to guide and retain drug-loaded magnetic particles in vivo has been proposed as a way of treating illnesses. Largely, these efforts have been targeted at tumors. One significant barrier to long range transport within tumors is the extracellular matrix (ECM). We perform single particle measurements of 18 nm diameter nanorods undergoing magnetophoresis through ECM, and analyze the motion of these nanorods in two dimensions. We observe intra-particle magnetophoresis in this viscoelastic environment and measure the fraction of time these nanorods spend effectively hindered, versus effectively translating.

Open challenges in magnetic drug targeting.

The principle of magnetic drug targeting, wherein therapy is attached to magnetically responsive carriers and magnetic fields are used to direct that therapy to disease locations, has been around for nearly two decades. Yet our ability to safely and effectively direct therapy to where it needs to go, for instance to deep tissue targets, remains limited. To date, magnetic targeting methods have not yet passed regulatory approval or reached clinical use. Below we outline key challenges to magnetic targeting, which include designing and selecting magnetic carriers for specific clinical indications, safely and effectively reaching targets behind tissue and anatomical barriers, real-time carrier imaging, and magnet design and control for deep and precise targeting. Addressing these challenges will require interactions across disciplines. Nanofabricators and chemists should work with biologists, mathematicians, and engineers to better understand how carriers move through live tissues and how to optimize carrier and magnet designs to better direct therapy to disease targets. Clinicians should be involved early on and throughout the whole process to ensure the methods that are being developed meet a compelling clinical need and will be practical in a clinical setting. Our hope is that highlighting these challenges will help researchers translate magnetic drug targeting from a novel concept to a clinically available treatment that can put therapy where it needs to go in human patients.

Increasing the oscillation frequency of strong magnetic fields above 101 kHz significantly raises peripheral nerve excitation thresholds.

PURPOSE: A time-varying magnetic field can cause unpleasant peripheral nerve stimulation (PNS) when the maximum excursion of the magnetic field (ΔB) is above a frequency-dependent threshold level [P. Mansfield and P. R. Harvey, Magn. Reson. Med. 29, 746-758 (1993)]. Clinical and research magnetic resonance imaging (MRI) gradient systems have been designed to avoid such bioeffects by adhering to regulations and guidelines established on the basis of clinical trials. Those trials, generally employing sinusoidal waveforms, tested human responses to magnetic fields at frequencies between 0.5 and 10 kHz [W. Irnich and F. Schmitt, Magn. Reson. Med. 33, 619-623 (1995), T. F. Budinger et al., J. Comput. Assist. Tomogr. 15, 909-914 (1991), and D. J. Schaefer et al., J. Magn. Reson. Imaging 12, 20-29 (2000)]. PNS thresholds for frequencies higher than 10 kHz had been extrapolated, using physiological models [J. P. Reilly et al., IEEE Trans. Biomed. Eng. BME-32(12), 1001-1011 (1985)]. The present study provides experimental data on human PNS thresholds to oscillating magnetic field stimulation from 2 to 183 kHz. Sinusoidal waveforms were employed for several reasons: (1) to facilitate comparison with earlier reports that used sine waves, (2) because prior designers of fast gradient hardware for generalized waveforms (e.g., including trapezoidal pulses) have employed quarter-sine-wave resonant circuits to reduce the rise- and fall-times of pulse waveforms, and (3) because sinusoids are often used in fast pulse sequences (e.g., spiral scans) [S. Nowak, U.S. patent 5,245,287 (14 September 1993) and K. F. King and D. J. Schaefer, J. Magn. Reson. Imaging 12, 164-170 (2000)]. METHODS: An IRB-approved prospective clinical trial was performed, involving 26 adults, in which one wrist was exposed to decaying sinusoidal magnetic field pulses at frequencies from 2 to 183 kHz and amplitudes up to 0.4 T. Sham exposures (i.e., with no magnetic fields) were applied to all subjects. RESULTS: For 0.4 T pulses at 2, 25, 59, 101, and 183 kHz, stimulation was reported by 22 (84.6%), 24 (92.3%), 15 (57.7%), 2 (7.7%), and 1 (3.8%) subjects, respectively. CONCLUSIONS: The probability of PNS due to brief biphasic time-varying sinusoidal magnetic fields with magnetic excursions up to 0.4 T is shown to decrease significantly at and above 101 kHz. This phenomenon may have particular uses in dynamic scenarios (e.g., cardiac imaging) and in studying processes with short decay times (e.g., electron paramagnetic resonance imaging, bone and solids imaging). The study suggests the possibility of new designs for human and preclinical MRI systems that may be useful in clinical practice and scientific research.

High-resolution fluorodeoxyglucose positron emission tomography with compression ("positron emission mammography") is highly accurate in depicting primary breast cancer.

We sought to prospectively assess the diagnostic performance of a high-resolution positron emission tomography (PET) scanner using mild breast compression (positron emission mammography [PEM]). Data were collected on concomitant medical conditions to assess potential confounding factors. At four centers, 94 consecutive women with known breast cancer or suspicious breast lesions received 18F-fluorodeoxyglucose (FDG) intravenously, followed by PEM scans. Readers were provided clinical histories and x-ray mammograms (when available). After excluding inevaluable cases and two cases of lymphoma, PEM readings were correlated with histopathology for 92 lesions in 77 women: 77 index lesions (42 malignant), 3 ipsilateral lesions (3 malignant), and 12 contralateral lesions (3 malignant). Of 48 cancers, 16 (33%) were clinically evident; 11 (23%) were ductal carcinoma in situ (DCIS), and 37 (77%) were invasive (30 ductal, 4 lobular, and 3 mixed; median size 21 mm). PEM depicted 10 of 11 (91%) DCIS and 33 of 37 (89%) invasive cancers. PEM was positive in 1 of 2 T1a tumors, 4 of 6 T1b tumors, 7 of 7 T1c tumors, and 4 of 4 cases where tumor size was not available (e.g., no surgical follow-up). PEM sensitivity for detecting cancer was 90%, specificity 86%, positive predictive value (PPV) 88%, negative predictive value (NPV) 88%, accuracy 88%, and area under the receiver-operating characteristic curve (Az) 0.918. In three patients, cancer foci were identified only on PEM, significantly changing patient management. Excluding eight diabetic subjects and eight subjects whose lesions were characterized as clearly benign with conventional imaging, PEM sensitivity was 91%, specificity 93%, PPV 95%, NPV 88%, accuracy 92%, and Az 0.949 when interpreted with mammographic and clinical findings. FDG PEM has high diagnostic accuracy for breast lesions, including DCIS.

Applications for positron emission mammography.

High resolution positron emission mammography (PEM) can address the current clinical needs of breast cancer patients and the requirements for future translational work. Combining the quantitative capabilities of positron emission tomography (PET) with millimeter resolution, PEM can image the earliest in situ forms of breast cancer as well as putative cancer precursor lesions (e.g., atypical ductal hyperplasia) whose behavior is important for prevention studies. The importance of the ability to detect intraductal cancer cannot be overemphasized, for several reasons: at least one-third of new cancers are detected at this intraductal stage, intervention at this stage represents the best opportunity for complete cure, and a significant number of invasive cancers contain an intraductal component. Without knowledge of the extent of the intraductal component, surgeons are unable to completely excise cancers about a third of the time, leading to unnecessary re-excisions or radiation therapy. Current investigations aimed at specifying best practices in radiotherapy of DCIS patients are stymied by the lack of objective quantitative methods of rapidly assessing response. Other future applications of PEM are suggested, including an information technology project built on PEM that promises to individualize therapy and facilitate surveillance of high risk populations. The high overall accuracy of PEM (i.e., both specificity and sensitivity) is an unusual and welcome development in the history of breast imaging. With this high accuracy, and continued technical innovation to reduce radiation dose, PEM may someday replace X-ray mammography as a first line approach to breast cancer detection.

Pilot clinical trial of 18F-fluorodeoxyglucose positron-emission mammography in the surgical management of breast cancer.

BACKGROUND: High-resolution positron-emission mammography (PEM) is a new device, which allows the imaging of breast tissue. A prospective study was performed to assess the accuracy of PEM in newly diagnosed breast cancer patients. METHODS: In a prospective multicenter study, 44 women with confirmed breast cancers were imaged with a high-resolution PEM scanner (Naviscan PET Systems, Rockville, MD) with 18F-fluorodeoxyglucose. The images were blindly evaluated and were compared with final pathology. RESULTS: The majority of the index lesions were seen on PEM (89%, 39/44). PEM detected 4 of 5 incidental breast cancers, 3 of which were not seen by any other imaging modalities. Of 19 patients undergoing breast-conserving surgery, PEM correctly predicted 6 of 8 (75%) patients with positive margins and 100% (11/11) with negative margins. CONCLUSION: The current PEM device shows promise in detecting breast malignancies and may assist in the planning of adequate partial mastectomy procedures to better ensure negative margins.

Positron emission mammography: high-resolution biochemical breast imaging.

Positron emission mammography (PEM) provides images of biochemical activity in the breast with spatial resolution matching individual ducts (1.5 mm full-width at half-maximum). This spatial resolution, supported by count efficiency that results in high signal-to-noise ratio, allows confident visualization of intraductal as well as invasive breast cancers. Clinical trials with a full-breast PEM device have shown high clinical accuracy in characterizing lesions identified as suspicious on the basis of conventional imaging or physical examination (sensitivity 93%, specificity 83%, area under the ROC curve of 0.93), with high sensitivity preserved (91%) for intraductal cancers. Increased sensitivity did not come at a cost of reduced specificity. Considering that intraductal cancer represents more than 30% of reported cancers, and is the form of cancer with the highest probability of achieving surgical cure, it is likely that the use of PEM will complement anatomic imaging modalities in the areas of surgical planning, high-risk monitoring, and minimally invasive therapy. The quantitative nature of PET promises to assist researchers interested studying the response of putative cancer precursors (e.g., atypical ductal hyperplasia) to candidate prevention agents.

Method for combined FDG-PET and radiographic imaging of primary breast cancers.

The purpose of the study was to demonstrate the feasibility of a hybrid functional/anatomic breast imaging platform with biopsy capability for facilitating lesion detection and diagnosis. This platform consists of an investigative dedicated positron emission mammography (PEM) device mounted on a stereotactic X-ray mammography system, permitting sequential acquisition of mammographic and emission images during a single breast compression. There is automatic coregistration of images from both modalities, and these results can be successfully correlated with histopathologic findings. The potential utility of functional images correlated to anatomic images would include noninvasively detecting clinically and radiographically occult cancers, assessing response to therapy, discriminating between benign and malignant breast masses, and ultimately reducing the number of invasive and costly surgical interventions. A spot-digital mammogram and subsequent PEM image, collected over a 4-minute period, were obtained in a single patient with the breast in compression after intravenous injection of (F-18)-2-deoxy-2-fluoro-D-glucose (FDG) at the time of stereotactic biopsy. The authors conclude that FDG-based lesion localization information may be combined with the lesion X-ray attenuation characteristics using this common imaging platform.

Positron emission mammography: initial clinical results.

BACKGROUND: Evaluation of high-risk mammograms represents an enormous clinical challenge. Functional breast imaging coupled with mammography (positron emission mammography [PEM]) could improve imaging of such lesions. A prospective study was performed using PEM in women scheduled for stereotactic breast biopsy. METHODS: Patients were recruited from the surgical clinic. Patients were injected with 10 mCi of 2-[18F] fluorodeoxyglucose. One hour later, patients were positioned on the stereotactic biopsy table, imaged with a PEM scanner, and a stereotactic biopsy was performed. Imaging was reviewed and compared with pathologic results. RESULTS: There were 18 lesions in 16 patients. PEM images were analyzed by drawing a region of interest at the biopsy site and comparing the count density in the region of interest with the background. A lesion-to-background ratio >2.5 appeared to be a robust indicator of malignancy and yielded a sensitivity of 86%, specificity of 91%, and overall diagnostic accuracy of 89%. No adverse events were associated with the PEM imaging. CONCLUSIONS: The data show that PEM is safe, feasible, and has an encouraging accuracy rate in this initial experience. Lesion-to-background ratios >2.5 were found to be a useful threshold value for identifying positive (malignant) results. This study supports the further development of PEM.