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.

Localization and Control of Magnetic Suture Needles in Cluttered Surgical Site with Blood and Tissue.

Real-time visual localization of needles is necessary for various surgical applications, including surgical automation and visual feedback. In this study we investigate localization and autonomous robotic control of needles in the context of our magneto-suturing system. Our system holds the potential for surgical manipulation with the benefit of minimal invasiveness and reduced patient side effects. However, the nonlinear magnetic fields produce unintuitive forces and demand delicate position-based control that exceeds the capabilities of direct human manipulation. This makes automatic needle localization a necessity. Our localization method combines neural network-based segmentation and classical techniques, and we are able to consistently locate our needle with 0.73 mm RMS error in clean environments and 2.72 mm RMS error in challenging environments with blood and occlusion. The average localization RMS error is 2.16 mm for all environments we used in the experiments. We combine this localization method with our closed-loop feedback control system to demonstrate the further applicability of localization to autonomous control. Our needle is able to follow a running suture path in (1) no blood, no tissue; (2) heavy blood, no tissue; (3) no blood, with tissue; and (4) heavy blood, with tissue environments. The tip position tracking error ranges from 2.6 mm to 3.7 mm RMS, opening the door towards autonomous suturing tasks.

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.

Kilohertz rotation of nanorods propelled by ultrasound, traced by microvortex advection of nanoparticles.

We measure the microvortical flows around gold nanorods propelled by ultrasound in water using polystyrene nanoparticles as optical tracers. We infer the rotational frequencies of such nanomotors assuming a hydrodynamic model of this interaction. In this way, we find that nanomotors rotate around their longitudinal axes at frequencies of up to ≈ 2.5 kHz, or ≈ 150 000 rpm, in the planar pressure node of a half-wavelength layered acoustic resonator driven at ≈ 3 MHz with an acoustic energy density of <10 J·m(-3). The corresponding tangential speeds of up to ≈ 2.5 mm·s(-1) at a nanomotor radius of ≈ 160 nm are 2 orders of magnitude faster than the translational speeds of up to ≈ 20 µm·s(-1). We also find that rotation and translation are independent modes of motion within experimental uncertainty. Our study is an important step toward understanding the behavior and fulfilling the potential of this dynamic nanotechnology for hydrodynamically interacting with biological media, as well as other applications involving nanoscale transport, mixing, drilling, assembly, and rheology. Our results also establish the fastest reported rotation of a nanomotor in aqueous solution.

Acoustic propulsion of nanorod motors inside living cells.

The ultrasonic propulsion of rod-shaped nanomotors inside living HeLa cells is demonstrated. These nanomotors (gold rods about 300 nm in diameter and about 3 mm long) attach strongly to the external surface of the cells, and are readily internalized by incubation with the cells for periods longer than 24 h. Once inside the cells, the nanorod motors can be activated by resonant ultrasound operating at 4 MHz, and show axial propulsion as well as spinning. The intracellular propulsion does not involve chemical fuels or high-power ultrasound and the HeLa cells remain viable. Ultrasonic propulsion of nanomotors may thus provide a new tool for probing the response of living cells to internal mechanical excitation, for controllably manipulating intracellular organelles, and for biomedical applications.

Steering acoustically propelled nanowire motors toward cells in a biologically compatible environment using magnetic fields.

The recent discovery of fuel-free propulsion of nanomotors using acoustic energy has provided a new avenue for using nanomotors in biocompatible media. Crucial to the application of nanomotors in biosensing and biomedical applications is the ability to remotely control and steer them toward targets of interest, such as specific cells and tissues. We demonstrate in vitro magnetic steering of acoustically powered nanorod motors in a biologically compatible environment. Steering was accomplished by incorporating (40 ± 5) nm thick nickel stripes into the electrochemically grown nanowires. An external magnetic field of 40-45 mT was used to orient the motors, which were acoustically propelled along their long axes. In the absence of a magnetic field, (300 ± 30) nm diameter, (4.3 ± 0.2) µm long nanowires with (40 ± 5) nm thick magnetic stripes exhibit the same self-acoustophoretic behavior, including pattern formation into concentric nanowire circles, aligned spinning chains, and autonomous axial motion, as their non-magnetic counterparts. In a magnetic field, these wires and their paths are oriented as evidenced by their relatively linear trajectories. Coordinated motion of multiple motors and targeting of individual motors toward HeLa cells with micrometer-level precision was demonstrated.

Multifunctional shape and size specific magneto-polymer composite particles.

Interest in uniform multifunctional magnetic particles is driven by potential applications in biomedical and materials science. Here we demonstrate the fabrication of highly tailored nanoscale and microscale magneto-polymer composite particles using a template based approach. Regiospecific surface functionalization of the particles was performed by chemical grafting and evaporative Pt deposition. Manipulation of the particles by an applied magnetic field was demonstrated in water and hydrogen peroxide.

Size-uniform 200 nm particles: fabrication and application to magnetofection.

We report on the fabrication of arrays of mono- and multimetallic particles via metal evaporation onto lithographically patterned posts, as well as the magnetic force calibration and successful magnetofection of iron particles grown via this method. This work represents the first instance in which metal evaporation onto post structures was used for the formation of released, shape-defined metal particles. Also, our work represents the first use of lithographically defined particles as agents of magnetofection. Using these techniques it is possible to create particles with complex shapes and lateral dimensions as small as 40 nm. Our demonstrated compositionally flexible particles are highly size-uniform due to their photolithographically defined growth substrates, with particle dimensions along two axes fixed at 200 nm; the third axis dimension can be varied from 20 nm to 300 nm during the deposition procedure. Atomic percent of metals incorporated into the particle volume is highly tunable and particles have been synthesized with as many as four different metals. We performed magnetic force calibrations on a single particle size for iron particles using an axially magnetized NeFeB permanent magnet and comparisons are made with commercially available magnetic beads. In order to evalutate their usefulness as magnetofection agents, an antisense oligonucleotide (ODN) designed to correct the aberrant splicing of enhanced green fluorescent protein mRNA, was successfully transfected into a modified HeLa cell line. Magnetically enhanced gene delivery was accomplished in vitro using antisense ODN-laden iron particles followed by application of a field gradient. Magnetically enhanced transfection resulted in a 76% and 139% increase in fluorescence intensity when compared to Lipofectamine and antisense ODN-loaded particles delivered without magnetic treatment, respectively. To our knowledge, these experiments constitute the first use of lithographically defined particles as successful agents for magnetically enhanced transfection of an antisense oligonucleotide.