Computational methodology for drug delivery to the inner ear using magnetic nanoparticle aggregates.

BACKGROUND AND OBJECTIVE: The main goal of the proposed study is to improve the efficiency of the ear treatment via targeted drug delivery to the inner ear, i.e. the cochlea. Although pharmacotherapy has been proposed as a solution to prevent damage or restore functionality to hair cells, the main challenge in such treatments is ensuring adequate drug delivery to the cells. To this end, we present a methodology for the evaluation of the magnetic forces needed to move magnetic particle nanorobots (abbreviated as MNP) and their aggregates through the cochlea round window membrane (RWM). METHODS: The FEM - Lagrangian-Eulerian approach (Abaqus software) was used to determine the specific parameters of movement of the nanoparticles crossing the RWM. This method results in a high consistency of FEM simulations and in-vivo experimental results in regards to the required magnetic force during the movement of spherical nanoparticles with a given viscosity ηave. Based on the analysis of the experimental studies found in subject literature, the sizes of the MNPs and their aggregates able to cross RWM with and without the application of magnetic force FM have been determined. RESULTS: The present work accounts for both the experimental and theoretical aspects of these investigations. Presented research confirms the definite usability of the Lagrange-Euler method for the precise determination of the required magnetic force value FM to control the accelerated motion of MNP aggregates of complex shapes through RWM. It is possible to determine the predominant parameters with a precision of less than 5% for single-layer aggregates and spatial aggregates crossing the RWM. It can be concluded that the MNPs and their aggregates should not be larger than 500-750 nm to cross the RWM with high velocities of penetration close to 800 nm/s for magnetic forces of hundreds 10-14 Newtons. CONCLUSIONS: The proposed Lagrangian-Eulerian approach is capable of accurately predicting the movement parameters of MNP aggregates of irregular shape that are close to the experimental test cases. The presented method can serve as a supplementary tool for the design of drug delivery systems to the inner ear using MNPs.

Optimal Design of a Multipole-Electromagnet Robotic Platform for Ophthalmic Surgery.

The aim of this study was to design a multipole-electromagnet robotic platform named OctoRob. This platform provides a minimally invasive means for targeted therapeutic interventions in specific intraocular areas. OctoRob is capable of generating both appropriate magnetic fields and gradients. The main scientific objectives were: (i) To propose an optimal reconfigurable arrangement of electromagnets suitable for ophthalmic interventions. (ii) To model, design and implement a one-degree-of-freedom robotic arm connected with an electromagnet in order to optimize the generation of magnetic fields and gradients. (iii) To evaluate the magnetic performances of the OctoRob platform, including different tilted angles. The results show that OctoRob platform has great potential to be applied for ophthalmic surgery.

Study the effect of static magnetic field intensity on drug delivery by magnetic nanoparticles.

Employing the magnets in therapy has a long history of treating diseases, and currently new applications such as drug delivery by magnetic nanoparticles are gaining more attention. This research tried to study the effect of static magnetic field intensity on drug delivery by magnetic nanoparticles carrying thrombolytic agents. In this research, Fe3O4@SiO2 nanoparticles carrying streptokinase were applied. The efficiency of thrombolysis and micro-CT-scan images are utilized to study the effect of different magnetic fields (0.1, 0.2, 0.3 and 0.5 T) on thrombolysis. The results confirm that increasing the static magnetic field intensity accelerated the thrombolysis. Increasing the intensity of the magnetic field from 0.1 to 0.3 T leads to an increase in clot dissolution rate from 55 to 89%, respectively. Moreover, micro-CT-scan images revealed that magnetic nanoparticles carrying a thrombolytic agent penetrated deeper into the mesh-like structure of clot as the magnetic field intensities increased, which could lead to further dissolution of the clot.

Noninvasive thrombectomy of graft by nano-magnetic ablating particles.

Artificial vascular treatment is an emerging interdisciplinary subject of medicine. Although the use of artificial vessels has led to many successful advancements, blood clotting remains a major challenge, especially in terms of mural clots created along the vessel wall that do not completely block the vessel. The main objective of this study is to present a method for declotting artificial vessels. This research introduces a novel thrombectomy technique in artificial vessels by employing nano-magnetic particles under a rotating magnetic field to remove mural clots in artificial vessels. A mathematical model describes the relationship between process parameters. In vitro tests confirm the feasibility of nano-magnetic thrombectomy in cleaning and declotting artificial vessels. The results show that the clot fragments are nano-sized, which eliminates the risk of distal emboli as a concern of using current atherectomy techniques. Meanwhile, no damage to the artificial vessels is observed. The results show that the frequency of rotating the magnetic field has the greatest effect on clot removal. The conceptual principles stated in this study also have the potential to be used in other vascular depositions, such as the accumulation of lipids, and calcification atherosclerosis.

Catalytic Locomotion of Core-Shell Nanowire Motors.

We report Au/Ru core-shell nanowire motors. These nanowires are fabricated using our previously developed electrodeposition-based technique, and their catalytic locomotion in the presence of H2O2 is investigated. Unlike conventional bimetallic nanowires that are self-electroosmotically propelled, our open-ended Au/Ru core-shell nanowires show both a noticeable decrease in rotational diffusivity and increase in motor speed with increasing nanowire length. Numerical modeling based on self-electroosmosis attributes decreases in rotational diffusivity to the formation of toroidal vortices at the nanowire tail, but fails to explain the speed increase with length. To reconcile this inconsistency, we propose a combined mechanism of self-diffusiophoresis and electroosmosis based on the oxygen gradient produced by catalytic shells. This mechanism successfully explains not only the speed increase of Au/Ru core-shell nanomotors with increasing length, but also the large variation in speed among Au/Ru, Au/Rh, and Rh/Au core-shell nanomotors. The possible contribution of diffusiophoresis to an otherwise well-established electroosmotic mechanism sheds light on future designs of nanomotors, at the same time highlighting the complex nature of nanoscale propulsion.

Modeling of Optimal Targeted Therapies Using Drug-Loaded Magnetic Nanoparticles for Liver Cancer.

To enhance locoregional therapies for liver cancer treatment, we propose in this study a mathematical model to optimize the transcatheter arterial delivery of therapeutical agents. To maximize the effect of the treatment and minimize adverse effects on the patient, different mathematical models of the tumor growth are considered in this study to find the optimal number of the therapeutic drug-loaded magnetic nanoparticles to be administered. Three types of therapy models are considered, e.g., angiogenesis inhibition therapy, chemotherapy and radiotherapy. We use state-dependent Riccati equations (SDRE) as an optimal control methodology framework to the Hahnfeldt's tumor growth formulation. Based on this, design optimal rules are derived for each therapy to reduce the growth of a tumor through the administration of appropriate dose of antiangiogenic, radio- and chemo-therapeutic agents. Simulation results demonstrate the validity of the proposed optimal delivery approach, leading to reduced intervention time, low drug administration rates and optimal targeted delivery.

Micro-to-nano biomechanical modeling for assisted biological cell injection.

To facilitate training of biological cell injection operations, we are developing an interactive virtual environment to simulate needle insertion into biological cells. This paper presents methodologies for dynamic modeling, visual/haptic display, and model validation of cell injection. We first investigate the challenging issues in the modeling of the biomechanical properties of living cells. We propose two dynamic models to simulate cell deformation and puncture. The first approach is based on the assumptions that the mechanical response of living cells is mainly determined by the cytoskeleton and that the cytoskeleton is organized as a tensegrity structure including microfilaments, microtubules, and intermediate filaments. Equivalent microtubules struts are represented with a linear mass-tensor finite-element model and equivalent microfilaments and intermediate filaments with viscoelastic Kelvin-Voigt elements. The second modeling method assumes the overall cell as an homogeneous hyperelastic model (St, Venant-Kirchhoff). Both graphic and haptic rendering are provided in real time to the operator through a 3-D virtual environment. Simulated responses are compared to experimental data to show the effectiveness of the proposed physically based model.

Simulation and planning of a magnetically actuated microrobot navigating in the arteries.

This paper presents a preoperative microrobotic surgical simulation and planning application. The main contribution is to support computer-aided minimally invasive surgery (MIS) procedure using untethered microrobots that have to navigate within the arterial networks. We first propose a fast interactive application (with endovascular tissues) able to simulate the blood flow and microrobot interaction. Second, we also propose a microrobotic surgical planning framework, based on the anisotropic fast marching method (FMM), that provides a feasible pathway robust to biomedical navigation constraints. We demonstrate the framework performance in a case study of the treatment of peripheral arterial diseases.

Endovascular magnetically guided robots: navigation modeling and optimization.

This paper deals with the benefits of using a nonlinear model-based approach for controlling magnetically guided therapeutic microrobots in the cardiovascular system. Such robots used for minimally invasive interventions consist of a polymer binded aggregate of nanosized ferromagnetic particles functionalized by drug-conjugated micelles. The proposed modeling addresses wall effects (blood velocity in minor and major vessels' bifurcations, pulsatile blood flow and vessel walls, and effect of robot-to-vessel diameter ratio), wall interactions (contact, van der Waals, electrostatic, and steric forces), non-Newtonian behavior of blood, and different driving designs as well. Despite nonlinear and thorough, the resulting model can both be exploited to improve the targeting ability and be controlled in closed-loop using nonlinear control theory tools. In particular, we infer from the model an optimization of both the designs and the reference trajectory to minimize the control efforts. Efficiency and robustness to noise and model parameter's uncertainties are then illustrated through simulations results for a bead pulled robot of radius 250 µm in a small artery.

Mechanical phenotyping of mouse embryonic stem cells: increase in stiffness with differentiation.

Atomic force microscopy (AFM) has emerged as a promising tool to characterize the mechanical properties of biological materials and cells. In our studies, undifferentiated and early differentiating mouse embryonic stem cells (mESCs) were assessed individually using an AFM system to determine if we could detect changes in their mechanical properties by surface probing. Probes with pyramidal and spherical tips were assessed, as were different analytical models for evaluating the data. The combination of AFM probing with a spherical tip and analysis using the Hertz model provided the best fit to the experimental data obtained and thus provided the best approximation of the elastic modulus. Our results showed that after only 6 days of differentiation, individual cell stiffness increased significantly with early differentiating mESCs having an elastic modulus two- to threefold higher than undifferentiated mESCs, regardless of cell line (R1 or D3 mESCs) or treatment. Single-touch (indentation) probing of individual cells is minimally invasive compared to other techniques. Therefore, this method of mechanical phenotyping should prove to be a valuable tool in the development of improved methods of identification and targeted cellular differentiation of embryonic, adult, and induced-pluripotent stem cells for therapeutic and diagnostic purposes.

MRI-guided nanorobotic systems for therapeutic and diagnostic applications.

This review presents the state of the art of magnetic resonance imaging (MRI)-guided nanorobotic systems that can perform diagnostic, curative, and reconstructive treatments in the human body at the cellular and subcellular levels in a controllable manner. The concept of an MRI-guided nanorobotic system is based on the use of an MRI scanner to induce the required external driving forces to propel magnetic nanocapsules to a specific target. It is an active targeting mechanism that provides simultaneous propulsion and imaging capabilities, which allow the implementation of real-time feedback control of the targeting process. The architecture of the system comprises four main modules: (a) the nanocapsules, (b) the MRI propulsion module, (c) the MRI tracking module (for image processing), and (d) the controller module. A key concept is the nanocapsule technology, which is based on carriers such as liposomes, polymer micelles, gold nanoparticles, quantum dots, metallic nanoshells, and carbon nanotubes. Descriptions of the significant challenges faced by the MRI-guided nanorobotic system are presented, and promising solutions proposed by the involved research community are discussed. Emphasis is placed on reviewing the limitations imposed by the scaling effects that dominate within the blood vessels and also on reviewing the control algorithms and computational tools that have been developed for real-time propulsion and tracking of the nanocapsules.

Optimal trajectory for a microrobot navigating in blood vessels.

The chemotherapy magnetically controlled under Magnetic Resonance Imaging (MRI) is currently one of the active areas of cancer research. This paper proposes a precise model of a therapeutic microrobot magnetically steered in blood vessels. This modeling approach takes into account the non-Newtonian behavior of blood, as well as wall effect on the blood's profile and robot-to-wall interaction forces. A backstepping approach law is used to ensure a null error between the real trajectory and an optimal reference trajectory deduced from the highly nonlinear model. The strengths and limitations of the overall study are evaluated by simulations.

MRI-based microrobotic system for the propulsion and navigation of ferromagnetic microcapsules.

This paper presents real-time MRI-based control of a ferromagnetic microcapsule for endovascular navigation. The concept was studied for future development of microdevices designed to perform minimally invasive interventions in remote sites accessible through the human cardiovascular system. A system software architecture is presented illustrating the different software modules to allow 3-D navigation of a microdevice in blood vessels, namely: (i) vessel path planner, (ii) magnetic gradient steering, (iii) tracking and (iv) closed-loop navigation control. First, the position recognition of the microrobot into the blood vessel is extracted using Frangi vesselness filtering from the pre-operation images (3-D MRI imaging). Then, a set of minimal trajectories is predefined, using path-planning algorithms, to guide the microrobot from the injection point to the tumor area through the anarchic vessel network. Based on the pre-computed path, a Generalized Predictive Controller (GPC) is proposed for robust time-multiplexed navigation along a two-dimensional (2D) path in presence of pulsative flow.

Mechanical characterization of mouse embryonic stem cells.

Current cell detection techniques are antibody staining of specific protein markers, morphometric parameters and transgenic markers. These assays are often qualitative and do not quantitatively define the outcome of a cell progression during differentiation. Consequently, we propose to characterize the mechanical behavior of embryonic stem cell, which will predict its stage of differentiation during lineage differentiation. Using the atomic force microscope, we have performed several experiments on mouse embryonic stem cells (mESC) roughly 7-17 microm in diameter and height at the interphase stage of the cell cycle process. Specifically, we conducted single indentation studies on undifferentiated and early differentiating (6 days under differentiation conditions) mESC with a cell indentation range of 2-2.5 microm. The data was used to analyze various contact models that can accurately model the geometry of the AFM tip and mESC interaction. With the choice of appropriate contact model, we can determine the accurate modulus of the cell membrane. The experimental results confirmed our research hypothesis that the mechanical property of undifferentiated mESC is different from differentiating (6th day) mESC.

Nanotube fluidic junctions: internanotube attogram mass transport through walls.

We report an experimental and theoretical investigation into mass transport between individual carbon nanotubes (CNTs) via their central cores. These CNT fluidic junctions can serve as basic elements for more complex nanofluidic systems and can also provide a structure for testing theories of fluid flow at the nanoscale. Controlled melting, evaporation, and flowing of copper and tin within and between nanotube shells are investigated experimentally. Cap-to-wall and wall-to-cap mass flow are realized by electric current driven heating, diffusion, and electromigration under low bias voltages between 1.5 and 1.8 V. A comparison shows that the mass loss for the cap-to-wall architecture is much smaller than that for the wall-to-cap junction. A molecular dynamics simulation is presented that provides further insight into the transport mechanism.