Validation of high gradient magnetic field based drug delivery to magnetizable implants under flow

IEEE Transactions on Biomedical Engineering, 55(2): pp. 643-649.The drug-eluting stent’s increasingly frequent occurrence late stage thrombosis have created a need for new strategies for intervention in coronary artery disease. This paper demonstrates further development of our minimally invasive, targeted drug delivery system that uses induced magnetism to administer repeatable and patient specific dosages of therapeutic agents to specific sites in the human body. Our first aim is the use of magnetizable stents for the prevention and treatment of coronary restenosis; however, future applications include the targeting of tumors, vascular defects, and other localized pathologies. Future doses can be administered to the same site by intravenous injection. This implant-based drug delivery system functions by placement of a weakly magnetizable stent or implant at precise locations in the cardiovascular system, followed by the delivery of magnetically susceptible drug carriers. The stents are capable of applying high local magnetic field gradients within the body, while only exposing the body to a modest external field. The local gradients created within the blood vessel create the forces needed to attract and hold drug-containing magnetic nanoparticles at the implant site. Once these particles are captured, they are capable of delivering therapeutic agents such as antineoplastics, radioactivity, or biological cells

Biodistribution, biocompatibility and targeted accumulation of magnetic nanoporous silica nanoparticles as drug carrier in orthopedics

Background: In orthopedics, the treatment of implant-associated infections represents a high challenge. Especially, potent antibacterial effects at implant surfaces can only be achieved by the use of high doses of antibiotics, and still often fail. Drug-loaded magnetic nanoparticles are very promising for local selective therapy, enabling lower systemic antibiotic doses and reducing adverse side effects. The idea of the following study was the local accumulation of such nanoparticles by an externally applied magnetic field combined with a magnetizable implant. The examination of the biodistribution of the nanoparticles, their effective accumulation at the implant and possible adverse side effects were the focus. In a BALB/c mouse model (n = 50) ferritic steel 1.4521 and Ti90Al6V4 (control) implants were inserted subcutaneously at the hindlimbs. Afterwards, magnetic nanoporous silica nanoparticles (MNPSNPs), modified with rhodamine B isothiocyanate and polyethylene glycol-silane (PEG), were administered intravenously. Directly/1/7/21/42 day(s) after subsequent application of a magnetic field gradient produced by an electromagnet, the nanoparticle biodistribution was evaluated by smear samples, histology and multiphoton microscopy of organs. Additionally, a pathohistological examination was performed. Accumulation on and around implants was evaluated by droplet samples and histology. Results: Clinical and histological examinations showed no MNPSNP-associated changes in mice at all investigated time points. Although PEGylated, MNPSNPs were mainly trapped in lung, liver, and spleen. Over time, they showed two distributional patterns: early significant drops in blood, lung, and kidney and slow decreases in liver and spleen. The accumulation of MNPSNPs on the magnetizable implant and in its area was very low with no significant differences towards the control. Conclusion: Despite massive nanoparticle capture by the mononuclear phagocyte system, no significant pathomorphological alterations were found in affected organs. This shows good biocompatibility of MNPSNPs after intravenous administration. The organ uptake led to insufficient availability of MNPSNPs in the implant region. For that reason, among others, the nanoparticles did not achieve targeted accumulation in the desired way, manifesting future research need. However, with different conditions and dimensions in humans and further modifications of the nanoparticles, this principle should enable reaching magnetizable implant surfaces at any time in any body region for a therapeutic reason. © 2020 The Author(s)

Increased accumulation of magnetic nanoparticles by magnetizable implant materials for the treatment of implant-associated complications

Background: In orthopaedic surgery, accumulation of agents such as anti-infectives in the bone as target tissue is difficult. The use of magnetic nanoparticles (MNPs) as carriers principally enables their accumulation via an externally applied magnetic field. Magnetizable implants are principally able to increase the strength of an externally applied magnetic field to reach also deep-seated parts in the body. Therefore, the integration of bone-addressed therapeutics in MNPs and their accumulation at a magnetic orthopaedic implant could improve the treatment of implant related infections. In this study a martensitic steel platelet as implant placeholder was used to examine its accumulation and retention capacity of MNPs in an in vitro experimental set up considering different experimental frame conditions as magnet quantity and distance to each other, implant thickness and flow velocity.Results: The magnetic field strength increased to approximately 112% when a martensitic stainless steel platelet was located between the magnet poles. Therewith a significantly higher amount of magnetic nanoparticles could be accumulated in the area of the platelet compared to the sole magnetic field. During flushing of the tube system mimicking the in vivo blood flow, the magnetized platelet was able to retain a higher amount of MNPs without an external magnetic field compared to the set up with no mounted platelet during flushing of the system. Generally, a higher flow velocity led to lower amounts of accumulated MNPs. A higher quantity of magnets and a lower distance between magnets led to a higher magnetic field strength. Albeit not significantly the magnetic field strength tended to increase with thicker platelets.Conclusion: A martensitic steel platelet significantly improved the attachment of magnetic nanoparticles in an in vitro flow system and therewith indicates the potential of magnetic implant materials in orthopaedic surgery. The use of a remanent magnetic implant material could improve the efficiency of capturing MNPs especially when the external magnetic field is turned off thus facilitating and prolonging the effect. In this way higher drug levels in the target area might be attained resulting in lower inconveniences for the patient

Magnetic Drug Targeting: Developing the Basics

Focusing medicine to disease locations is a needed ability to treat a variety of pathologies. During chemotherapy, for example, typically less than 0.1% of the drugs are taken up by tumor cells, with the remaining 99.9% going into healthy tissue. Physicians often select the dosage by how much a patient can physically withstand rather than by how much is needed to kill all the tumor cells. The ability to actively position medicine, to physically direct and focus it to specific locations in the body, would allow better treatment of not only cancer but many other diseases. Magnetic drug targeting (MDT) harnesses therapeutics attached to magnetizable particles, directing them to disease locations using magnetic fields. Particles injected into the vasculature will circulate throughout the body as the applied magnetic field is used to attempt confinement at target locations. The goal is to use the reservoir of particles in the general circulation and target a specific location by pulling the nanoparticles using magnetic forces. This dissertation adds three main advancements to development of magnetic drug targeting. Chapter 2 develops a comprehensive ferrofluid transport model within any blood vessel and surrounding tissue under an applied magnetic field. Chapter 3 creates a ferrofluid mobility model to predict ferrofluid and drug concentrations within physiologically relevant tissue architectures established from human autopsy samples. Chapter 4 optimizes the applied magnetic fields within the particle mobility models to predict the best treatment scenarios for two classes of chemotherapies for treating future patients with hepatic metastatic breast cancer microtumors

Computational Simulations of Magnetic Particle Capture in Arterial Flows

The aim of Magnetic Drug Targeting (MDT) is to concentrate drugs, attached to magnetic particles, in a specific part of the human body by applying a magnetic field. Computational simulations are performed of blood flow and magnetic particle motion in a left coronary artery and a carotid artery, using the properties of presently available magnetic carriers and strong superconducting magnets (up to B $\approx$ 2 T). For simple tube geometries it is deduced theoretically that the particle capture efficiency scales as $\eta \sim \sqrt{\textrm{Mn}_p}$ , with $\textrm{Mn}_p$ the characteristic ratio of the particle magnetization force and the drag force. This relation is found to hold quite well for the carotid artery. For the coronary artery, the presence of side branches and domain curvature causes deviations from this scaling rule, viz. $\eta \sim \textrm{Mn}_p ^ {\beta}$, with $\beta>1/2$. The simulations demonstrate that approximately a quarter of the inserted 4 $\mu$m particles can be captured from the bloodstream of the left coronary artery, when the magnet is placed at a distance of 4.25 cm. When the same magnet is placed at a distance of 1 cm from a carotid artery, almost all of the inserted 4 $\mu$m particles are captured. The performed simulations, therefore, reveal significant potential for the application of MDT to the treatment of atherosclerosis

Using Heparin-Coated Nanoparticles in the Treatment of Neointimal Hyperplasia

The use of stents in the treatment of atherosclerosis leads to a potential risk of restenosis, caused by neointimal hyperplasia. Neointimal hyperplasia is mainly caused by an injury to the endothelial layer of the blood vessel followed by the proliferation of smooth muscle cells into the lumen of the blood vessel. To address this, we designed a magnetically-guided drug delivery system to locally deliver heparin to a stented artery. The nanoparticles were synthesized, characterized, and tested on relevant human cell lines. The particles were non-toxic to human smooth muscle cells, endothelial cells, and fibroblasts. They reduced the proliferation of the smooth muscle cells and increased the proliferation of endothelial cells at concentrations as low as 10 μg/mL. The particles also shifted the smooth muscle cells from their synthetic phenotype to their contractile phenotype. The capture of the nanoparticles by the stent struts, under relevant magnetic field and blood velocity was modeled using COMSOL Multiphysics. The coronary artery was modeled using a 2D axisymmetric model with stainless steel stent struts. A Magnetic field of 1 T was applied to magnetize the stent struts. Three different strut geometries were compared for their effect of the capture efficiency. The model had a capture efficiency 0f 34-42%, which is comparable to models using the same particle sizes. Ex vivo organ culture studies using porcine right coronary arteries were performed. The arteries were conditioned either statically in cell culture flasks or dynamically in an organ culture bioreactor. Nanoparticles reduced intimal thickening in and expressed contractile properties in the treated arteries compared to the controls. We were successfully able to synthesize heparin-coated magnetic nanoparticles and achieve high heparin loading. Particle capture efficiency around the stent in the ex vivo porcine artery model was found to be similar to that predicted by the computational model. Consistent with the prior results of systemic heparin delivery, the nanoparticles reduce the proliferation and dedifferentiation of vascular smooth muscle cells while promoting endothelialization, both in vitro and ex vivo. Thus, these particles may be a promising treatment option for neointimal hyperplasia.

Magnetic manipulation of colloids at the micro and nanoscale

Manipulation and assembly of colloidal sub-micron and nanometer sized particles is important in many applications ranging from drug delivery and separation of biologically different species of micro-organisms and molecules to fabrication of meta-material micro- and nanostructures consisting of regular arrays of particles. Most of the methods that have been proposed are based on short-range interactions including chemical affinity and surface forces. Such forces are difficult and, most often, impossible to manipulate using externally tunable apparatus. Electric fields have been employed to create longer range forces. However, electric fields often affect biological molecules and can be substantially screened in ionic solutions. Magnetic field manipulation is a relatively unexplored method of manipulation of colloidal particles. Some work has been performed in the recent decade to develop methods of manipulation and assembly of non-magnetic colloidal particles near surfaces. However, the developed methods have been limited mainly to particles greater than 1 micrometer in diameter which experience relatively small Brownian motion. The question can arises: To what extent similar methods are applicable to manipulation of much smaller particles and molecules? Can Brownian motion be helpful for some applications? Another important question is: Can non-magnetic colloidal objects be manipulated away from surfaces?These are the main questions addressed in this work. The main contribution of this thesis is the development of a series of magnetic manipulation methods by which non-magnetic colloidal sub-micron particles and molecules can be manipulated near surfaces and in the bulk of a fluid suspension. One specific important contribution of this thesis is demonstration of magnetic trapping and transport of non-magnetic sub-micron particles and molecules near surfaces patterned with ferromagnetic material. This work is the first to demonstrate that biological molecules can be attached to designated areas on a substrate using magnetic trapping, for example. Development of a method for magnetic fractionation of non-magnetic colloids by size in bulk fluid suspension is also an important specific contribution of this thesis. Such fractionation dramatically improves on the speed of previously proposed depletion fractionation technique. Each specific method mentioned above will be described in separate chapters of this thesis.Ph.D., Electrical Engineering -- Drexel University, 200

OPTIMAL CONTROL OF OBJECTS ON THE MICRO- AND NANO-SCALE BY ELECTROKINETIC AND ELECTROMAGNETIC MANIPULATION: FOR BIO-SAMPLE PREPARATION, QUANTUM INFORMATION DEVICES AND MAGNETIC DRUG DELIVERY

In this thesis I show achievements for precision feedback control of objects inside micro-fluidic systems and for magnetically guided ferrofluids. Essentially, this is about doing flow control, but flow control on the microscale, and further even to nanoscale accuracy, to precisely and robustly manipulate micro and nano-objects (i.e. cells and quantum dots). Target applications include methods to miniaturize the operations of a biological laboratory (lab-on-a-chip), i.e. presenting pathogens to on-chip sensing cells or extracting cells from messy bio-samples such as saliva, urine, or blood; as well as non-biological applications such as deterministically placing quantum dots on photonic crystals to make multi-dot quantum information systems. The particles are steered by creating an electrokinetic fluid flow that carries all the particles from where they are to where they should be at each time step. The control loop comprises sensing, computation, and actuation to steer particles along trajectories. Particle locations are identified in real-time by an optical system and transferred to a control algorithm that then determines the electrode voltages necessary to create a flow field to carry all the particles to their next desired locations. The process repeats at the next time instant. I address following aspects of this technology. First I explain control and vision algorithms for steering single and multiple particles, and show extensions of these algorithms for steering in three dimensional (3D) spaces. Then I show algorithms for calculating power minimum paths for steering multiple particles in actuation constrained environments. With this microfluidic system I steer biological cells and nano particles (quantum dots) to nano meter precision. In the last part of the thesis I develop and experimentally demonstrate two dimensional (2D) manipulation of a single droplet of ferrofluid by feedback control of 4 external electromagnets, with a view towards enabling feedback control of magnetic drug delivery to reach deeper tumors in the long term. To this end, I developed and experimentally demonstrated an optimal control algorithm to effectively manipulate a single ferrofluid droplet by magnetic feedback control. This algorithm was explicitly designed to address the nonlinear and cross-coupled nature of dynamic magnetic actuation and to best exploit available electromagnetic forces for the applications of magnetic drug delivery

Modeling and design of an electromagnetic actuation system for the manipulation of microrobots in blood vessels

Tese de mestrado integrado em Física, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2015A navegação de nano/microdispositivos apresenta um grande potencial para aplicações biomédicas, oferecendo meios de diagnóstico e procedimentos terapêuticos no interior do corpo humano. Dada a sua capacidade de penetrar quase todos os materiais, os campos magnéticos são naturalmente adequados para controlar nano/microdispositivos magnéticos em espaços inacessíveis. Uma abordagem recente é o uso de um aparelho personalizado, capaz de controlar campos magnéticos. Esta é uma área de pesquisa prometedora, mas mais simulações e experiências são necessárias para avaliar a viabilidade destes sistemas em aplicações clínicas. O objectivo deste projecto foi a simulação e desenho de um sistema de atuação eletromagnética para estudar a locomoção bidimensional de microdispositivos. O primeiro passo foi identificar, através da análise de elementos finitos, usando o software COMSOL, diferentes configurações de bobines que permitiriam o controlo de dispositivos magnéticos em diferentes escalas. Baseado nos resultados das simulações, um protótipo de um sistema de atuação magnética para controlar dispositivos com mais de 100 m foi desenhado e construído de raiz, tendo em conta restrições de custos. O sistema consistiu num par de bobines de Helmholtz e rotacionais e um par de bobines de Maxwell dispostas no mesmo eixo. Além disso, componentes adicionais tiveram de ser desenhados ou selecionados para preencher os requisitos do sistema. Para a avaliação do sistema fabricado, testes preliminares foram realizados. A locomoção do microrobot foi testada em diferentes direções no plano x-y. As simulações e experiências confirmaram que é possível controlar a força magnética e o momento da força que atuam num microdispositivo através do campos produzidos pelas bobines de Maxwell e Helmholtz, respectivamente. Assim, este tipo de atuação magnética parece ser uma forma adequada de transferência de energia para futuros microdispositivos biomédicos.Navigation of nano/microdevices has great potential for biomedical applications, offering a means for diagnosis and therapeutic procedures inside the human body. Due to their ability to penetrate most materials, magnetic fields are naturally suited to control magnetic nano/microdevices in inaccessible spaces. One recent approach is the use of custom-built apparatus capable of controlling magnetic devices. This is a promising area of research, but further simulation studies and experiments are needed to estimate the feasibility of these systems in clinical applications. The goal of this project was the simulation and design of an electromagnetic actuation system to study the two dimensional locomotion of microdevices. The first step was to identify, through finite element analysis using software COMSOL, different coil configurations that would allow the control of magnetic devices at different scales. Based on the simulation results, a prototype of a magnetic actuation system to control devices with more than 100 m was designed and built from the ground up, taking into account cost constraints. The system comprised one pair of rotational Helmholtz coils and one pair of rotational Maxwell coils placed along the same axis. Furthermore, additional components had to be designed or selected to fulfil the requirements of the system. For the evaluation of the fabricated system, preliminary tests were carried out. The locomotion of a microdevice was tested along different directions in the x-y plane. The simulations and experiments confirmed that it is possible to control the magnetic force and torque acting on a microdevice through the fields produced by Maxwell and Helmholtz coils, respectively. Thus, this type of magnetic actuation seems to provide a suitable means of energy transfer for future biomedical microdevices

Feasibility of capturing circulating tumor cells with a magnetized device

A standard inferior vena cava (IVC) filter is plated with Nickel in order to be rendered magnetizable. In the presence of an applied magnetic field, the IVC filter has a strong magnetic gradient near the surface that captures circulating tumor cells (CTCs) tagged with paramagnetic nanoparticles. Particle motion and capture includes a balance of the magnetization force and hydrodynamic drag force. ANSYS Fluent CFD software and ANSYS Workbench Magnetostatics were used independently to obtain fluid velocity and magnetic field intensity solutions. The separate solutions were combined in Matlab for numerical particle tracking. Empirical capture efficiency was determined using in-flow spectrometer absorbance measurements as well as measuring image intensity from time-lapse fluorescent images. Three control experiments were used to ensure particles caught in the continuous flow loop are not falsely attributed to the magnetizable IVC filter. Fluorescent magnetite coated spheres, 8.34 micron in diameter, were used for developing methods while magnetically tagged cancer cells were used to determine practical feasibility. Results from the numerical model predict eight percent capture efficiency for a single pass through the IVC filter. Experimental results showed capture efficiency of paramagnetic particles in a continuous loop at 0.3 L/min was ninety-five percent after six hours. For the same experiment, tagged cancer cells resulted in capture efficiency up to ten percent after two hours. A second trial was unable to confirm the magnetized IVC filter had a distinguishable effect on the tagged cancer cells. This work has provided reasonable empirical evidence and numerical results to confirm the feasibility of using a nickel-plated IVC filter for capturing tagged cancer cells