Macro–micromanipulation platform for inner ear drug delivery
Introduction
Robotic agents controlled within the human body allow minimal invasive interventions for the improved treatment and diagnosis of disease, while reducing the risk of complications and allowing for faster recovery. To this end, the magnetic actuation solution has proven to be effective for remote navigation devices or small particles to reach deeper areas in the human body [[1], [2]]. By using magnetic fields and gradients, pushing and pulling forces can be applied on magnetic microparticles functionalized with drug molecules. As example, recent medical applications demonstrate the difficulty for drug delivery to reach the human ear due to its complex structure [3].
As shown in Fig. 1, the ear is a complex and important organ of the living being. It is responsible of two senses which are balance and hearing sense. The first one is given by the three semicircular channels which define the orientation of the head according to the dimensions of the space with respect to the gravitational axis [[4], [5]]. The second one is related to the anatomy of the cochlea. It allows to treat the sound waves going from to 20.000 Hz and contains a liquid called perilymph [6], through which the sound waves are transmitted to the different regions of the cochlea. Access to the inner ear is limited by the presence of a blood–cochlear barrier, which is anatomically and functionally similar to the blood–brain barrier [[7], [8]]. As depicted in Fig. 1, the inner ear provides a unique opportunity for local drug delivery through the round window membrane (RWM) [9]. Due to tight junctions between cells, substances in systemic circulation encounter substantial physical barriers to entry, preventing many substances with potentially therapeutic effect from gaining access to their inner ear targets. Additionally, the cochlea is a closed space, and cochlear function is sensitive to small changes in fluid volume. Therefore, delicate approaches are required to avoid possible damage from the delivery method itself.
Usually, three conventional medical techniques are used to drug delivery into the human cochlea. The first one is the intratympanic injection [[10], [11]] where drugs are placed in the tympanic cavity, close to the RWM. The problem is that a large quantity of drug is lost through the eustachian tube, which limits the diffusion into deeper regions of the cochlea. The second one consists of injecting directly drugs into the cochlea which is under the liquid pressure [[12], [13], [14]]. However, this solution will create an overpressure which causes severe damages. The third one is by applying a gel bolus on the RWM embedding nanoparticles functionalized with therapeutic drugs [15]. This solution demonstrated already that a small quantity of drug molecules is able to cross the RWM. However, it takes a long time to extract the drug molecules from the gel and their diffusion in deeper regions of the cochlea is limited. The best way is to use functionalized magnetic particles actuated by external magnetic devices. Gao et al. [16] demonstrated the transfer of iron oxide nanoparticles (encapsulated by PLGAs of 10–20 ) through the RWM increases by using directed magnetic fields.
In recent years, the use of permanent magnets has increased considerably in medical applications, especially in view of replacing technologies using large magnetic systems, such as magnetic coils or electromagnets. Permanent magnets are based on hard magnetic materials, which are previously magnetized along a given direction. This approach allows to generate magnetic fields without any power supply, with higher magnetic and gradient fields. It constitutes an excellent magnetic actuator by depriving constraints such as the heating of the coils, supply power and cooling device. This makes possible to design a portable and light magnetic actuator, which can be used as the end-effector of a serial robotic manipulator. For example, Abbott [17] developed a control of a magnetic capsule endoscope navigating in fluid by using a single permanent magnet coupled to a robotic manipulator. In similar works [18], they developed an ability to control an untethered magnetic microrobot in a human body using a single rotating permanent magnet. Otherwise, a 6 DOF robotic platform has been developed for magnetic steering of a capsular endoscope in a pig colon [19]. However, these systems are not suitable for the actuation of spherical magnetic micro/nano-particles in medical applications (embolization or drug delivery). First, the strong magnetic attraction between both magnet and particles prevents any control of particle’s motion. Second, depending on the location of the target tissue and any anatomical obstacles; pulling the particles by an external magnet is either not optimal or not possible. Unlike the systems that use single permanent magnet, a device combining two permanent magnets has demonstrated its ability to create both push and pull forces [[20], [21]]. The proposed system is not motorized, which limits its use to inject and to control the nanoparticles inside the cochlea. To face with these technological limitations, we proposed a motorized magnetic actuator prototype based on two permanent magnets [22]. In the same work, we also demonstrated the presence of the Lagrange point towards which the magnetic forces converge . To control the position of this Lagrange point we developed an analytical model of the magnetic field generated by this actuator [23]. In [24], we proposed an hybrid vision platform. It allows real time tracking of magnetic particles inside the artificial cochlea and validate the correct operation of our actuator.
In this study we propose a novel steering strategy for inner ear drug delivery. This strategy is based on planning sequences for targeted drug delivery and using a magnetic actuator design proposed in [22]. This paper is organized as follows. Section 2 describes a robotic macro–micromanipulation platform for inner ear drug delivery. We introduce the design of the proposed robotic end-effector constituted by a magnetic actuator device based on permanent magnets. Then, the forward kinematics of the serial manipulator robot is proposed. Section 3 describes the planning sequences for targeted drug delivery. Using the Roboguide software™, simulations are performed in order to evaluate the macro–micromanipulation robotic workspace. Finally, Section 4 presents several simulation and experimental results to validate the inner ear drug delivery strategy. This paper is concluded in Section 5.
Section snippets
Robotic platform for inner drug delivery
The overall experimental robotic platform for inner ear drug delivery is presented in Fig. 2. It includes the magnetic actuator-based permanent magnets end-effector, the FANUC LR-MATE 200iD manipulator and a microscope used to track the motion of the magnetic microparticles. A silicon head of a dummy is used to model the patient’ head. On this last were fixed four fiducial markers on back, right, left and high position for use as a point of reference in the local coordinates frame. An
Cochlea parameters
The cochlea is a part of the inner ear and its mechanical response provides us with many aspects of our sensitive and selective hearing. The human cochlea is a cylindrical tube, with two main fluid chambers running along its length [28], and looking much like the snail shell. The cochlea consists of a coiled labyrinth, which is about 2.5 turns in humans [29], with diameter at the entrance of the cochlea to in the apex [[6], [30]]. The cochlea is
Calibration process
The 3-D scanning data of the dummy head used in our experiments has been performed at the Hospital University of Dijon, France. The D reconstructed image provides the coordinates of points according to the four markers. The distances are calculated from the following:
From Eq. (14), we extract a set of coordinates defining the cochlea trajectory in
Conclusion
In this paper, a new strategy of drug delivery on an artificial cochlea is presented. A new actuator based on two permanent magnets is proposed as micro end-effector in order to provide pushing and pulling forces capable to steer a magnetic microparticle in a fluidic environment. This actuator is fixed at the end effector of a serial robotic manipulator 200iD. To control the trajectory of this mechanism, the forward kinematics was studied with respect to two approaches: Denavit and Hartenberg
Walid Amokrane was born in Algiers, Algeria, in 1990. He received the master degree in Industrial Automation from Unversity of Sciences and technology, Algiers, in 2012 and a master degree in Automation and systems from Supelec, Paris, in 2014. He is currently pursuing the Ph.D. degree in microrobotic at INSA Centre Val de Loire in France. His main interest is modeling and design of magnetic actuator for ear application.
References (30)
- et al.
Hydrodynamic modeling of cochlea and numerical simulation for cochlear traveling wave with consideration of fluid–structure interaction
J. Hydrodyn. Ser. B
(2013) - et al.
Clinical efficacy of initial intratympanic steroid treatment on sudden sensorineural hearing loss with diabetes
Otolaryngol.–Head Neck Surg.
(2009) - et al.
Round window membrane intracochlear drug delivery enhanced by induced advection
J. Control. Release
(2014) - et al.
Quantification of solute entry into cochlear perilymph through the round window membrane
Hear. Res.
(2001) - et al.
Inner ear drug delivery for auditory applications
Adv. Drug Delivery Rev.
(2008) - et al.
Effects of a perilymphatic fistula on the passive vibration response of the basilar membrane
Hear. Res.
(2012) - et al.
Two-dimensional actuation of a microrobot with a stationary two-pair coil system
Smart Mater. Struct.
(2009) - et al.
Adapting mri systems to propel and guide microdevices in the human blood circulatory system
Atlas of Human Anatomy
(2013)The sense of rotation and the anatomy and physiology of the semicircular canals of the internal ear
J. Anat. Physiol.
(1874)
Vertigo: Its Multisensory Syndromes
Barrier systems in the inner ear
Acta Oto-Laryngol.
Extraneous round window membranes and plugs: possible effect on intratympanic therapy
Ann. Otol. Rhinol. Laryngol.
Round window membrane permeability: An in vitro model
Acta Oto-Laryngol.
Intratympanic steroid perfusion for the treatment of meniere’s disease: a retrospective study
Ear Nose Throat J.
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Walid Amokrane was born in Algiers, Algeria, in 1990. He received the master degree in Industrial Automation from Unversity of Sciences and technology, Algiers, in 2012 and a master degree in Automation and systems from Supelec, Paris, in 2014. He is currently pursuing the Ph.D. degree in microrobotic at INSA Centre Val de Loire in France. His main interest is modeling and design of magnetic actuator for ear application.
Karim Belharet received the Engineer degree in Electronics from Mouloud Mammeri University, Algeria, in 2007. He prepared his Master’s degree in Virtual Reality and Intelligent Systems at Evry Val d’Essone University, France, in 2008. Between 2008 and 2009, he worked for in the INRETS Institute, Paris. He received his Ph.D. degrees in robotics from the Loire Valley University, France, in 2013. In his thesis work, he became interested in modeling, propulsion, control and navigation of microrobots in the cardiovascular system using the magnetic resonance imaging system. Since 2013, he has been an Associate Professor at HEI campus Centre de Châteauroux, France. He is now working on the design, modeling, control of micro and macrorobotic systems for medical applications.
Mouna Souissi was born in Bizert in Tunisia,1984. She received her Ph.D. degree in Robotic from the University of Versailles Saint Quentin en Yvelines in Juin 2012 in france. She received her Master degree and engineer degree from the School of Engineering Eniso of Sousse in Tunisia in 2009 and 2008, respectively. She teached the mechatronics from 2010 until 2012 in the School of Engineering of Leonard de Vinci in Paris. Now she is teacher researcher in School of Engineering HEI in Chateauroux in France and works in the laboratory PRSIME in Bourges. She is author of many scientific papers in the field of conception of modeling, conception and control of mechatronic systems.
Alexis Bozorg Graeyli is a Professor of Otolaryngology-Head and Neck Surgery and a senior researcher in CNRS Imaging, computer and electronic research laborotaory (UMR-6306) at Burgundy University. He has the Chair of Otolaryngology at Dijon Medical School and is the head of Otolaryngology-Head and Neck Surgery Department at Dijon University Hospital, France.
He obtained his MD degree and French Board of Otolaryngology-Head and Neck Surgery, University of Paris 7, France, on 1997, and his Ph.D. degree in the field of Physiology and Pathophysiology of Epithelia at the University of Paris 7, France on 2000. He has also a university Diploma of Head and Neck Imaging Techniques from the University of Paris 10, France. His clinical activity is focused on otology, neurotology and cranial base surgery. He has conducted several research projects in the field of minimally invasive and robot-based ear surgery since 2006.
Antoine Ferreira (M’04) received the M.S. and Ph.D. degrees in electrical and electronics engineering from University of Franche-Comté, Besancon, France, in 1993 and 1996, respectively. In 1997, he was a Visiting Researcher in the ElectroTechnical Laboratory, Tsukuba, Japan. He is currently a Professor of robotics engineering with Laboratoire PRISME, Institut National des Sciences Appliquees Centre Val de Loire, campus Bourges, France. He has authored three books on micro- and nanorobotics and more than 200 journal and conference papers, as well as book contributions. His research interests include the design, modeling, and control of micro- and nanorobotic systems using active materials, micro- and nanomanipulation systems, biological nanosystems, and bionanorobotics. Dr. Ferreira was the Guest Editor for special issues of IEEE Transactions on Robotics in 2014, IEEE/ASME Transactions on Mechatronics in 2009, International Journal of Robotics Research in 2009, and IEEE Nanotechnology Magazine in 2008.