Generation of magnetic biohybrid microrobots based on MSC.sTRAIL for targeted stem cell delivery and treatment of cancer.

Background: Combining the power of magnetic guidance and the biological activities of stem cells transformed into biohybrid microrobots holds great promise for the treatment of several diseases including cancer. Results: We found that human MSCs can be readily loaded with magnetic particles and that the resulting biohybrid microrobots could be guided by a rotating magnetic field. Rotating magnetic fields have the potential to be applied in the human setting and steer therapeutic stem cells to the desired sites of action in the body. We could demonstrate that the required loading of magnetic particles into stem cells is compatible with their biological activities. We examined this issue with a particular focus on the expression and functionality of therapeutic genes inside of human MSC-based biohybrid microrobots. The loading with magnetic particles did not cause a loss of viability or apoptosis in the human MSCs nor did it impact on the therapeutic gene expression from the cells. Furthermore, the therapeutic effect of the gene products was not affected, and the cells also did not lose their migration potential. Conclusion: These results demonstrate that the fabrication of guidable MSC-based biohybrid microrobots is compatible with their biological and therapeutic functions. Thus, MSC-based biohybrid microrobots represent a novel way of delivering gene therapies to tumours as well as in the context of other diseases.

A Novel Non-Invasive Intervention for Removing Occlusions From Shunts Using an Abrading Magnetic Microswarm.

OBJECTIVE: Shunts are often employed as internal medical devices for draining aberrant fluids from organs. However, depositions of calcification in the shunt walls lead to its failure, requiring frequent replacements. The current surgical procedures for implanting shunts are invasive. METHODS: This paper introduces a novel, non-invasive approach for eliminating shunt deposits. In this non-invasive intervention, a swarm of magnetic nanoparticles (MNPs) guided by an external magnetic field removes the shunt deposition. A prototype device was fabricated to provide a proof of concept. MNPs were steered within the shunt channel containing calcification layers and successfully abraded the deposition layer. The proof-of-concept experiments used a moving magnetic field ranging from 0.1 to 0.3 T and a velocity between 1 to 12 cm/s. The average nanoparticles size was 45 nm. Five diverse contact theories predicted the amount of wear and indentation depth created by the abrading microswarm. RESULTS: Experimental results confirm that MNPs under a moving magnetic field can abrade shunt deposits. Also, there is a direct relation between the intensity of the magnetic field, the speed of magnet movement, and the rate of abrading the calcification deposits. The simulation results showed that the Hoeprich model deviated 12.1% from the experimental results and was the most suitable model. Conclusion & significance: This research has introduced a novel minimally invasive approach to remove shunt depositions that can reduce the number of revision surgeries and prevent surgical complications.

A Needle-Type Microrobot for Targeted Drug Delivery by Affixing to a Microtissue.

A needle-type microrobot (MR) for targeted drug delivery is developed to stably deliver drugs to a target microtissue (MT) for a given period time without the need for an external force after affixing. The MRs are fabricatedby 3D laser lithography and nickel (Ni)/titanium oxide (TiO2 ) layers are coated by physical vapor deposition. The translational velocity of the MR is 714 µm s-1 at 20 mT and affixed to the target MT under the control of a rotating magnetic field. The manipulability of the MR is shown by using both manual and automatic controls. Finally, drug release from the paclitaxel-loaded MR is characterized to determine the efficiency of targeted drug delivery. This study demonstrates the utility of the proposed needle-type MR for targeted drug delivery to MT with various flow rates in vitro physiological fluidic environments.

A Magnetically Controlled Soft Microrobot Steering a Guidewire in a Three-Dimensional Phantom Vascular Network.

Magnetically actuated soft robots may improve the treatment of disseminated intravascular coagulation. Significant progress has been made in the development of soft robotic systems that steer catheters. A more challenging task, however, is the development of systems that steer sub-millimeter-diameter guidewires during intravascular treatments; a novel microrobotic approach is required for steering. In this article, we develop a novel, magnetically actuated, soft microrobotic system, increasing the steerability of a conventional guidewire. The soft microrobot is attached to the tip of the guidewire, and it is magnetically steered by changing the direction and intensity of an external magnetic field. The microrobot is fabricated via replica molding and features a soft body made of polydimethylsiloxane, two permanent magnets, and a microspring. We developed a mathematical model mapping deformation of the soft microrobot using a feed-forward approach toward steering. Then, we used the model to steer a guidewire. The angulation of the microrobot can be controlled from 21.1° to 132.7° by using a magnetic field of an intensity of 15 mT. Steerability was confirmed by two-dimensional in vitro tracking. Finally, a guidewire with the soft microrobot was tested by using a three-dimensional (3D) phantom of the coronary artery to verify steerability in 3D space.

A Novel Magnetic Actuation Scheme to Disaggregate Nanoparticles and Enhance Passage across the Blood-Brain Barrier.

The blood-brain barrier (BBB) hinders drug delivery to the brain. Despite various efforts to develop preprogramed actuation schemes for magnetic drug delivery, the unmodeled aggregation phenomenon limits drug delivery performance. This paper proposes a novel scheme with an aggregation model for a feed-forward magnetic actuation design. A simulation platform for aggregated particle delivery is developed and an actuation scheme is proposed to deliver aggregated magnetic nanoparticles (MNPs) using a discontinuous asymmetrical magnetic actuation. The experimental results with a Y-shaped channel indicated the success of the proposed scheme in steering and disaggregation. The delivery performance of the developed scheme was examined using a realistic, three-dimensional (3D) vessel simulation. Furthermore, the proposed scheme enhanced the transport and uptake of MNPs across the BBB in mice. The scheme presented here facilitates the passage of particles across the BBB to the brain using an electromagnetic actuation scheme.

Functionalized electromagnetic actuation method for aggregated nanoparticles steering.

Despite the promising results in magnetic nanoparticles (MNPs) based targeted drug delivery (TDD), the aggregation of the magnetic nanoparticles deteriorates targeting performance. This paper aims to introduce a magnetic actuation function for aggregated nanoparticles steering in vascular network. To improve the drug delivery performance, first the governing dynamics has been introduced, next the modified field function (MFF) concept has been proposed and finally a computational platform for a Y-shape channel has been used to simulate the particles steering performance. The results showed an acceptable agreement with the experimental results. The proposed actuation method enables us to more accurately steer aggregated nanoparticles and improves targeting performance.

Real-Time Two-Dimensional Magnetic Particle Imaging for Electromagnetic Navigation in Targeted Drug Delivery.

Magnetic nanoparticles (MNPs) are effective drug carriers. By using electromagnetic actuated systems, MNPs can be controlled noninvasively in a vascular network for targeted drug delivery (TDD). Although drugs can reach their target location through capturing schemes of MNPs by permanent magnets, drugs delivered to non-target regions can affect healthy tissues and cause undesirable side effects. Real-time monitoring of MNPs can improve the targeting efficiency of TDD systems. In this paper, a two-dimensional (2D) real-time monitoring scheme has been developed for an MNP guidance system. Resovist particles 45 to 65 nm in diameter (5 nm core) can be monitored in real-time (update rate = 2 Hz) in 2D. The proposed 2D monitoring system allows dynamic tracking of MNPs during TDD and renders magnetic particle imaging-based navigation more feasible.

Comprehensive modelling and simulation of cylindrical nanoparticles manipulation by using a virtual reality environment.

With the expansion of nanotechnology, robots based on atomic force microscope (AFM) have been widely used as effective tools for displacing nanoparticles and constructing nanostructures. One of the most limiting factors in AFM-based manipulation procedures is the inability of simultaneously observing the controlled pushing and displacing of nanoparticles while performing the operation. To deal with this limitation, a virtual reality environment has been used in this paper for observing the manipulation operation. In the simulations performed in this paper, first, the images acquired by the atomic force microscope have been processed and the positions and dimensions of nanoparticles have been determined. Then, by dynamically modelling the transfer of nanoparticles and simulating the critical force-time diagrams, a controlled displacement of nanoparticles has been accomplished. The simulations have been further developed for the use of rectangular, V-shape and dagger-shape cantilevers. The established virtual reality environment has made it possible to simulate the manipulation of biological particles in a liquid medium.

Osmotin-loaded magnetic nanoparticles with electromagnetic guidance for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, pathologically characterized by the accumulation of aggregated amyloid beta (Aß) in the brain. Here, we describe for the first time the development of a new, pioneering nanotechnology-based drug delivery approach for potential therapies for neurodegenerative diseases, particularly AD. We demonstrated the delivery of fluorescent carboxyl magnetic Nile Red particles (FMNPs) to the brains of normal mice using a functionalized magnetic field (FMF) composed of positive- and negative-pulsed magnetic fields generated by electromagnetic coils. The FMNPs successfully reached the brain in a few minutes and showed evidence of blood-brain barrier (BBB) crossing. Moreover, the best FMF conditions were found for inducing the FMNPs to reach the cortex and hippocampus regions. Under the same FMF conditions, dextran-coated Fe3O4 magnetic nanoparticles (MNPs) loaded with osmotin (OMNP) were transported to the brains of Aß1-42-treated mice. Compared with native osmotin, the OMNP potently attenuates Aß1-42-induced synaptic deficits, Aß accumulation, BACE-1 expression and tau hyperphosphorylation. This magnetic drug delivery approach can be extended to preclinical and clinical use and may advance the chances of success in the treatment of neurological disorders like AD in the future.