Human-scale navigation of magnetic microrobots in hepatic arteries.

Using external actuation sources to navigate untethered drug-eluting microrobots in the bloodstream offers great promise in improving the selectivity of drug delivery, especially in oncology, but the current field forces are difficult to maintain with enough strength inside the human body (>70-centimeter-diameter range) to achieve this operation. Here, we present an algorithm to predict the optimal patient position with respect to gravity during endovascular microrobot navigation. Magnetic resonance navigation, using magnetic field gradients in clinical magnetic resonance imaging (MRI), is combined with the algorithm to improve the targeting efficiency of magnetic microrobots (MMRs). Using a dedicated microparticle injector, a high-precision MRI-compatible balloon inflation system, and a clinical MRI, MMRs were successfully steered into targeted lobes via the hepatic arteries of living pigs. The distribution ratio of the microrobots (roughly 2000 MMRs per pig) in the right liver lobe increased from 47.7 to 86.4% and increased in the left lobe from 52.2 to 84.1%. After passing through multiple vascular bifurcations, the number of MMRs reaching four different target liver lobes had a 1.7- to 2.6-fold increase in the navigation groups compared with the control group. Performing simulations on 19 patients with hepatocellular carcinoma (HCC) demonstrated that the proposed technique can meet the need for hepatic embolization in patients with HCC. Our technology offers selectable direction for actuator-based navigation of microrobots at the human scale.

Improving flat fluorescence microscopy in scattering tissue through deep learning strategies.

Intravital microscopy in small animals growingly contributes to the visualization of short- and long-term mammalian biological processes. Miniaturized fluorescence microscopy has revolutionized the observation of live animals' neural circuits. The technology's ability to further miniaturize to improve freely moving experimental settings is limited by its standard lens-based layout. Typical miniature microscope designs contain a stack of heavy and bulky optical components adjusted at relatively long distances. Computational lensless microscopy can overcome this limitation by replacing the lenses with a simple thin mask. Among other critical applications, Flat Fluorescence Microscope (FFM) holds promise to allow for real-time brain circuits imaging in freely moving animals, but recent research reports show that the quality needs to be improved, compared with imaging in clear tissue, for instance. Although promising results were reported with mask-based fluorescence microscopes in clear tissues, the impact of light scattering in biological tissue remains a major challenge. The outstanding performance of deep learning (DL) networks in computational flat cameras and imaging through scattering media studies motivates the development of deep learning models for FFMs. Our holistic ray-tracing and Monte Carlo FFM computational model assisted us in evaluating deep scattering medium imaging with DL techniques. We demonstrate that physics-based DL models combined with the classical reconstruction technique of the alternating direction method of multipliers (ADMM) perform a fast and robust image reconstruction, particularly in the scattering medium. The structural similarity indexes of the reconstructed images in scattering media recordings were increased by up to 20% compared with the prevalent iterative models. We also introduce and discuss the challenges of DL approaches for FFMs under physics-informed supervised and unsupervised learning.

Design of a Low-Cost, Self-Adaptive and MRI-Compatible Cardiac Gating System.

OBJECTIVE: Cardiac gating, synchronizing medical scans with cardiac activity, is widely used to make quantitative measurements of physiological events and to obtain high-quality scans free of pulsatile artefacts. This can provide important information for disease diagnosis, targeted control of medical microrobots, etc. The current work proposes a low-cost, self-adaptive, MRI-compatible cardiac gating system. METHOD: The system and its processing algorithm, based on the monitoring and analysis of blood pressure waveforms, are proposed. The system is tested in an in vitro experiment and two living pigs using four-dimensional (4D) flow magnetic resonance imaging (MRI) and two-dimensional phase-contrast (2D-PC) sequences. RESULTS: in vitro and in vivo experiments reveal that the proposed system can provide stable cardiac synchronicity, has good MRI compatibility, and can cope with the fringe magnetic field of the MRI scanner, radiofrequency signals during image acquisition, and heart rate changes. High-resolution 4D flow imaging is successfully acquired both in vivo and in vitro. The difference between the 2D and 4D measurements is ≤ 21%. The incidence of false triggers is 0% in all tests, which is unattainable for other known cardiac gating methods. CONCLUSION: The system has good MRI compatibility and can provide a stable and accurate trigger signal based on pressure waveform. It opens the door to applications where the previous gating methods were difficult to implement or not applicable.

Design of a Patient-Specific Respiratory-Motion-Simulating Platform for In Vitro 4D Flow MRI.

Four-dimensional (4D) flow magnetic resonance imaging (MRI) is a leading-edge imaging technique and has numerous medicinal applications. In vitro 4D flow MRI can offer some advantages over in vivo ones, especially in accurately controlling flow rate (gold standard), removing patient and user-specific variations, and minimizing animal testing. Here, a complete testing method and a respiratory-motion-simulating platform are proposed for in vitro validation of 4D flow MRI. A silicon phantom based on the hepatic arteries of a living pig is made. Under the free-breathing, a human volunteer's liver motion (inferior-superior direction) is tracked using a pencil-beam MRI navigator and is extracted and converted into velocity-distance pairs to program the respiratory-motion-simulating platform. With the magnitude displacement of about 1.3 cm, the difference between the motions obtained from the volunteer and our platform is ≤ 1 mm which is within the positioning error of the MRI navigator. The influence of the platform on the MRI signal-to-noise ratio can be eliminated even if the actuator is placed in the MRI room. The 4D flow measurement errors are respectively 0.4% (stationary phantom), 9.4% (gating window = 3 mm), 27.3% (gating window = 4 mm) and 33.1% (gating window = 7 mm). The vessel resolutions decreased with the increase of the gating window. The low-cost simulation system, assembled from commercially available components, is easy to be duplicated.

Quantification and 3D Localization of Magnetically Navigated Superparamagnetic Particles Using MRI in Phantom and Swine Chemoembolization Models.

OBJECTIVE: Superparamagnetic nanoparticles (SPIONs) can be combined with tumor chemoembolization agents to form magnetic drug-eluting beads (MDEBs), which are navigated magnetically in the MRI scanner through the vascular system. We aim to develop a method to accurately quantify and localize these particles and to validate the method in phantoms and swine models. METHODS: MDEBs were made of Fe3O4 SPIONs. After injected known numbers of MDEBs, susceptibility artifacts in three-dimensional (3D) volumetric interpolated breath-hold examination (VIBE) sequences were acquired in glass and Polyvinyl alcohol (PVA) phantoms, and two living swine. Image processing of VIBE images provided the volume relationship between MDEBs and their artifact at different VIBE acquisitions and post-processing parameters. Simulated hepatic-artery embolization was performed in vivo with an MRI-conditional magnetic-injection system, using the volume relationship to locate and quantify MDEB distribution. RESULTS: Individual MDEBs were spatially identified, and their artifacts quantified, showing no correlation with magnetic-field orientation or sequence bandwidth, but exhibiting a relationship with echo time and providing a linear volume relationship. Two MDEB aggregates were magnetically steered into desired liver regions while the other 19 had no steering, and 25 aggregates were injected into another swine without steering. The MDEBs were spatially identified and the volume relationship showed accuracy in assessing the number of the MDEBs, with small errors (≤ 8.8%). CONCLUSION AND SIGNIFICANCE: MDEBs were able to be steered into desired body regions and then localized using 3D VIBE sequences. The resulting volume relationship was linear, robust, and allowed for quantitative analysis of the MDEB distribution.

Navigation of Microrobots by MRI: Impact of Gravitational, Friction and Thrust Forces on Steering Success.

INTRODUCTION: Magnetic resonance navigation (MRN) uses MRI gradients to steer magnetic drug-eluting beads (MDEBs) across vascular bifurcations. We aim to experimentally verify our theoretical forces balance model (gravitational, thrust, friction, buoyant and gradient steering forces) to improve the MRN targeted success rate. METHOD: A single-bifurcation phantom (3 mm inner diameter) made of poly-vinyl alcohol was connected to a cardiac pump at 0.8 mL/s, 60 beats/minutes with a glycerol solution to reproduce the viscosity of blood. MDEB aggregates (25 ± 6 particles, 200 [Formula: see text]) were released into the main branch through a 5F catheter. The phantom was tilted horizontally from - 10° to +25° to evaluate the MRN performance. RESULTS: The gravitational force was equivalent to 71.85 mT/m in a 3T MRI. The gradient duration and amplitude had a power relationship (amplitude=78.717 [Formula: see text]). It was possible, in 15° elevated vascular branches, to steer 87% of injected aggregates if two MRI gradients are simultaneously activated ([Formula: see text] = +26.5 mT/m, [Formula: see text]= +18 mT/m for 57% duty cycle), the flow velocity was minimized to 8 cm/s and a residual pulsatile flow to minimize the force of friction. CONCLUSION: Our experimental model can determine the maximum elevation angle MRN can perform in a single-bifurcation phantom simulating in vivo conditions.

Patterns of bacterial motility in microfluidics-confining environments.

Understanding the motility behavior of bacteria in confining microenvironments, in which they search for available physical space and move in response to stimuli, is important for environmental, food industry, and biomedical applications. We studied the motility of five bacterial species with various sizes and flagellar architectures (Vibrio natriegens, Magnetococcus marinus, Pseudomonas putida, Vibrio fischeri, and Escherichia coli) in microfluidic environments presenting various levels of confinement and geometrical complexity, in the absence of external flow and concentration gradients. When the confinement is moderate, such as in quasi-open spaces with only one limiting wall, and in wide channels, the motility behavior of bacteria with complex flagellar architectures approximately follows the hydrodynamics-based predictions developed for simple monotrichous bacteria. Specifically, V. natriegens and V. fischeri moved parallel to the wall and P. putida and E. coli presented a stable movement parallel to the wall but with incidental wall escape events, while M. marinus exhibited frequent flipping between wall accumulator and wall escaper regimes. Conversely, in tighter confining environments, the motility is governed by the steric interactions between bacteria and the surrounding walls. In mesoscale regions, where the impacts of hydrodynamics and steric interactions overlap, these mechanisms can either push bacteria in the same directions in linear channels, leading to smooth bacterial movement, or they could be oppositional (e.g., in mesoscale-sized meandered channels), leading to chaotic movement and subsequent bacterial trapping. The study provides a methodological template for the design of microfluidic devices for single-cell genomic screening, bacterial entrapment for diagnostics, or biocomputation.

Magnetic Resonance Navigation for Targeted Embolization in a Two-Level Bifurcation Phantom.

This work combines a particle injection system with our proposed magnetic resonance navigation (MRN) sequence with the intention of validating MRN in a two-bifurcation phantom for endovascular treatment of hepatocellular carcinoma (HCC). A theoretical physical model used to calculate the most appropriate size of the magnetic drug-eluting bead (MDEB, 200 µm) aggregates was proposed. The aggregates were injected into the phantom by a dedicated particle injector while a trigger signal was automatically sent to the MRI to start MRN which consists of interleaved tracking and steering sequences. When the main branch of the phantom was parallel to B0, the aggregate distribution ratio in the (left-left, left-right, right-left and right-right divisions was obtained with results of 8, 68, 24 and 0% respectively at baseline (no MRN) and increased to 84%, 100, 84 and 92% (p < 0.001, p = 0.004, p < 0.001, p < 0.001) after implementing our MRN protocol. When the main branch was perpendicular to B0, the right-left branch, having the smallest baseline distribution rate of 0%, reached 80% (p < 0.001) after applying MRN. Moreover, the success rate of MRN was always more than 92% at the 1st bifurcation in the experiments above.

Multifunctional Self-Assembled Supernanoparticles for Deep-Tissue Bimodal Imaging and Amplified Dual-Mode Heating Treatment.

Developing multifunctional therapeutic and diagnostic (theranostic) nanoplatforms is critical for addressing challenging issues associated with cancers. Here, self-assembled supernanoparticles consisting of superparamagnetic Fe3O4 nanoparticles and photoluminescent PbS/CdS quantum dots whose emission lies within the second biological window (II-BW) are developed. The proposed self-assembled Fe3O4 and PbS/CdS (II-BW) supernanoparticles [SASNs (II-BW)] exhibit outstanding photoluminescence detectable through a tissue as thick as 14 mm, by overcoming severe light extinction and concomitant autofluorescence in II-BW, and significantly enhanced T2 relaxivity (282 mM-1 s-1, ca. 4 times higher than free Fe3O4 nanoparticles) due to largely enhanced magnetic field inhomogeneity. On the other hand, SASNs (II-BW) possess the dual capacity to act as both magnetothermal and photothermal agents, overcoming the main drawbacks of each type of heating separately. When SASNs (II-BW) are exposed to the dual-mode (magnetothermal and photothermal) heating, the thermal energy transfer efficiency is amplified 7-fold compared with magnetic heating alone. These results, in hand with the excellent photo- and colloidal stability, and negligible cytotoxicity, demonstrate the potential use of SASNs (II-BW) for deep-tissue bimodal (magnetic resonance and photoluminescence) in vivo imaging, while simultaneously providing the possibility of SASNs (II-BW)-mediated amplified dual-mode heating treatment for cancer therapy.

Using the fringe field of a clinical MRI scanner enables robotic navigation of tethered instruments in deeper vascular regions.

Navigating tethered instruments through the vasculatures to reach deeper physiological locations presently inaccessible would extend the applicability of many medical interventions, including but not limited to local diagnostics, imaging, and therapies. Navigation through narrower vessels requires minimizing the diameter of the instrument, resulting in a decrease of its stiffness until steerability becomes unpractical, while pushing the instrument at the insertion site to counteract the friction forces from the vessel walls caused by the bending of the instrument. To reach beyond the limit of using a pushing force alone, we report a method relying on a complementary directional pulling force at the tip created by gradients resulting from the magnetic fringe field emanating outside a clinical magnetic resonance imaging (MRI) scanner. The pulling force resulting from gradients exceeding 2 tesla per meter in a space that supports human-scale interventions allows the use of smaller magnets, such as the deformable spring as described here, at the tip of the instrument. Directional forces are achieved by robotically positioning the patient at predetermined successive locations inside the fringe field, a method that we refer to as fringe field navigation (FFN). We show through in vitro and in vivo experiments that x-ray-guided FFN could navigate microguidewires through complex vasculatures well beyond the limit of manual procedures and existing magnetic platforms. Our approach facilitated miniaturization of the instrument by replacing the torque from a relatively weak magnetic field with a configuration designed to exploit the superconducting magnet-based directional forces available in clinical MRI rooms.

Selective embolization with magnetized microbeads using magnetic resonance navigation in a controlled-flow liver model.

PURPOSE: The purpose of this study was to demonstrate the feasibility of using a custom gradient sequence on an unmodified 3T magnetic resonance imaging (MRI) scanner to perform magnetic resonance navigation (MRN) by investigating the blood flow control method in vivo, reproducing the obtained rheology in a phantom mimicking porcine hepatic arterial anatomy, injecting magnetized microbead aggregates through an implantable catheter, and steering the aggregates across arterial bifurcations for selective tumor embolization. MATERIALS AND METHODS: In the first phase, arterial hepatic velocity was measured using cine phase-contrast imaging in seven pigs under free-flow conditions and controlled-flow conditions, whereby a balloon catheter is used to occlude arterial flow and saline is injected at different rates. Three of the seven pigs previously underwent selective lobe embolization to simulate a chemoembolization procedure. In the second phase, the measured in vivo controlled-flow velocities were approximately reproduced in a Y-shaped vascular bifurcation phantom by injecting saline at an average rate of 0.6 mL/s with a pulsatile component. Aggregates of 200-µm magnetized particles were steered toward the right or left hepatic branch using a 20-mT/m MRN gradient. The phantom was oriented at 0°, 45°, and 90° with respect to the B0 magnetic field. The steering differences between left-right gradient and baseline were calculated using Fisher's exact test. A theoretical model of the trajectory of the aggregate within the main phantom branch taking into account gravity, magnetic force, and hydrodynamic drag was also designed, solved, and validated against the experimental results to characterize the physical limitations of the method. RESULTS: At an injection rate of 0.5 mL/s, the average flow velocity decreased from 20 ± 15 to 8.4 ± 5.0 cm/s after occlusion in nonembolized pigs and from 13.6 ± 2.0 to 5.4 ± 3.0 cm/s in previously embolized pigs. The pulsatility index measured to be 1.7 ± 1.8 and 1.1 ± 0.1 for nonembolized and embolized pigs, respectively, decreased to 0.6 ± 0.4 and 0.7 ± 0.3 after occlusion. For MRN performed at each orientation, the left-right distribution of aggregates was 55%, 25%, and 75% on baseline and 100%, 100%, and 100% (P < 0.001, P = 0.003, P = 0.003) after the application of MRN, respectively. According to the theoretical model, the aggregate reaches a stable transverse position located toward the direction of the gradient at a distance equal to 5.8% of the radius away from the centerline within 0.11 s, at which point the aggregate will have transited through a longitudinal distance of 1.0 mm from its release position. CONCLUSION: In this study, we showed that the use of a balloon catheter reduces arterial hepatic flow magnitude and variation with the aim to reduce steering failures caused by fast blood flow rates and low magnetic steering forces. A mathematical model confirmed that the reduced flow rate is low enough to maximize steering ratio. After reproducing the flow rate in a vascular bifurcation phantom, we demonstrated the feasibility of MRN after injection of microparticle aggregates through a dedicated injector. This work is an important step leading to MRN-based selective embolization techniques in humans.

MRI-Compatible Injection System for Magnetic Microparticle Embolization.

OBJECTIVE: Dipole field navigation and magnetic resonance navigation exploit B0 magnetic fields and imaging gradients for targeted intra-arterial therapies by using magnetic drug-eluting beads (MDEBs). The strong magnetic strength (1.5 or 3 T) of clinical magnetic resonance imaging (MRI) scanners is the main challenge preventing the formation and controlled injection of specific-sized particle aggregates. Here, an MRI-compatible injector is proposed to solve the above problem. METHODS: The injector consists of two peristaltic pumps, an optical counter, and a magnetic trap. The magnetic property of microparticles, the magnetic compatibility of different parts within the injector, and the field distribution of the MRI system were studied to determine the optimal design and setup of the injector. The performance was investigated through 30.4-emu/g biocompatible magnetic microparticles (230 ± 35 µm in diameter) corresponding to the specifications needed for trans-arterial chemoembolization in human adults. RESULTS: The system can form aggregates containing 20 to 60 microparticles with a precision of six particles. The corresponding aggregate lengths range from 1.6 to 3.2 mm. Based on the injections of 50 MRI-visible boluses into a phantom which mimics realistic physiological conditions, 82% of the aggregates successfully reached subbranches. CONCLUSION AND SIGNIFICANCE: This system has the capability to operate within the strong magnetic field of a clinical 3-T MRI, to form proper particle aggregates and to automatically inject these aggregates into the MRI bore. Moreover, the versatility of the proposed injector renders it suitable for selective injections of MDEBs during MR-guided embolization procedures.

A Wireless Fiber Photometry System Based on a High-Precision CMOS Biosensor With Embedded Continuous-Time Modulation.

Fluorescence biophotometry measurements require wide dynamic range (DR) and high-sensitivity laboratory apparatus. Indeed, it is often very challenging to accurately resolve the small fluorescence variations in presence of noise and high-background tissue autofluorescence. There is a great need for smaller detectors combining high linearity, high sensitivity, and high-energy efficiency. This paper presents a new biophotometry sensor merging two individual building blocks, namely a low-noise sensing front-end and a order continuous-time modulator (CTSDM), into a single module for enabling high-sensitivity and high energy-efficiency photo-sensing. In particular, a differential CMOS photodetector associated with a differential capacitive transimpedance amplifier-based sensing front-end is merged with an incremental order 1-bit CTSDM to achieve a large DR, low hardware complexity, and high-energy efficiency. The sensor leverages a hardware sharing strategy to simplify the implementation and reduce power consumption. The proposed CMOS biosensor is integrated within a miniature wireless head mountable prototype for enabling biophotometry with a single implantable fiber in the brain of live mice. The proposed biophotometry sensor is implemented in a 0.18- CMOS technology, consuming from a 1.8- supply voltage, while achieving a peak dynamic range of over a 50- input bandwidth, a sensitivity of 24 mV/nW, and a minimum detectable current of 2.46- at a 20- sampling rate.

Development of a Coflowing Device for the Size-Controlled Preparation of Magnetic-Polymeric Microspheres as Embolization Agents in Magnetic Resonance Navigation Technology.

Droplet microfluidics technology has recently been introduced to generate particles for many biomedical applications that include therapeutic embolizing agents in hepatic, uterine or bronchial arteries. Embolic agents are available in a variety of shapes and sizes that are adjusted according to the target vessel characteristics. Magnetic embolic agents can additionally be navigated to the target location (e.g., a tumor) through the blood system by applying an external magnetic field. This technology is termed Magnetic Resonance Navigation (MRN). Here we introduce a high throughput method to produce homogeneously sized magnetic microspheres (MMS) as blood vessel embolic agents for use in combination with MRN. The system for MMS production consists of a simple 3D printed micro coflowing device that is able to produce biocompatible, degradation rate controllable poly(lactic-co-glycolic acid) (PLGA) microspheres encasing magnetic nanoparticles. Axisymmetric flow is obtained with a central needle injecting the dispersed phase surrounded by a continuous phase and leads to the formation of size-controlled droplets that turn into homogeneously sized MMS linearly dependent on the inner needle diameter. MMS morphology, mean particle size and size distribution were quantified from SEM images. Magnetic performance of MMS was investigated using a vibrating sample magnetometer. MMS were nontoxic toward HUVEC (human umbilical vein endothelial cells) and HEK293 (human embryonic kidney) cells. The presented micro coflowing method allows for the reliable production of large MMS sized 130-700 µm with narrow size distribution (CV < 7%) and magnetic properties useful for MRN.

Targeting active cancer cells with smart bullets.

Paul Ehrlich's 'magic bullet' concept has stimulated research for therapeutic agents with the capability to go straight to their intended targets. The 'magic bullet' concept is still considered the ultimate approach to maximize the therapeutic effects of a given therapeutic agent without affecting nontargeted tissues. But so far, there has never been a therapeutic agent or a delivery system that goes straight to the target in the body, and no approach has provided anything better than just a few percents of the total administered dose reaching the intended target sites. But engineering principles can transform systematically circulating vectors that so far were based primarily on physical characteristics and biochemical principles alone, as smart therapeutic agents with the required propulsion-navigation-homing capabilities to enable them to go straight to their intended targets.

A prototype of injector to control and to detect the release of magnetic beads within the constraints of multibifurcation magnetic resonance navigation procedures.

PURPOSE: An injector equipped with a bead capture and a bead detection system is presented. In the context of magnetic resonance navigation (MRN), in which MRI gradients are used to steer intravascular therapeutic carriers, fast and reliable injection is essential. In this paper, we present a prototype of injector to control and to detect the release of magnetic beads. METHODS: The injector relies on two distinct subsystems: (1) the capture subsystem, which creates local magnetic force to stop the flow of magnetic beads; and (2) the detection subsystem, which detects flowing beads and generates a trigger signal to start MRI gradient pulses. Both systems rely on small microcoils wound on the tubing. RESULTS: Five-turn microcoils show the best compromise between size and performance. Less than 5 mW of power is required to capture 0.8-mm beads moving in a flow above 5 mL min-1 or when a gradient above 200 mT m-1 is applied. The detection system is not sensitive to noise and detects every 0.8-mm bead in flow rates up to 14 mL m-1 . CONCLUSION: The prototype of injector shows performance above the requirements inherent to magnetic resonance navigation. This system is a step toward in vivo multibifurcation MRN. Magn Reson Med 77:444-452, 2017. © 2016 Wiley Periodicals, Inc.

Beyond imaging: Macro- and microscale medical robots actuated by clinical MRI scanners.

Magnetic resonance actuation has potential for use in medical therapies.

Medical robotics-Regulatory, ethical, and legal considerations for increasing levels of autonomy.

The regulatory, ethical, and legal barriers imposed on medical robots necessitate careful consideration of different levels of autonomy, as well as the context for use.