Electrospun Bioresorbable Membrane Eluting Chlorhexidine for Dental Implants.

To prevent the uncontrolled development of a pathogenic biofilm around a dental implant, an antimicrobial drug-release electrospun membrane, set up between the implant and the gingival tissue, was developed by taking several technical, industrial and regulatory specifications into account. The membrane formulation is made of a blend of poly(l-lactic-co-gycolic acid) (PLGA, 85:15) and poly(l-lactic acide-co-ɛ-caprolactone) (PLC, 70:30) copolymers with chlorhexidine diacetate (CHX) complexed with ß-cyclodextrin (CD). The amount of residual solvent, the mechanical properties and the drug release kinetics were tuned by the copolymers' ratio, between 30% and 100% of PLC, and a CHX loading up to 20% w/w. The membranes were sterilized by γ-irradiation without significant property changes. The fiber's diameter was between 600 nm and 3 µm, depending on the membrane composition and the electrospinning parameters. CHX was released in vitro over 10 days and the bacterial inhibitory concentration, 80 µg·mL-1, was reached within eight days. The optimal membrane, PGLA/PLC/CHX-CD (60%/40%/4%), exhibited a breaking strain of 50%, allowing its safe handling. This membrane and a membrane without CHX-CD were implanted subcutaneous in a rat model. The cell penetration remained low. The next step will be to increase the porosity of the membrane to improve the dynamic cell penetration and tissue remodeling.

Therapeutic magnetic microcarriers guided by magnetic resonance navigation for enhanced liver chemoembilization: a design review.

This review paper describes the past, present and future design of therapeutic magnetic carriers (TMMC) being guided in the vascular network using a novel technique known as magnetic resonance navigation (MRN). This targeting method is an extension of magnetic resonance imaging (MRI) technologies. MRN, based on magnetic gradient variation, aims to navigate carriers in real-time along a pre-planned trajectory from their injection site to a targeted area. As such, this approach should minimize systemic distribution of toxic agents loaded into the carriers and improve therapeutic efficacy by delivering a larger proportion of the drug injected. MRN-compatible carriers (shape, material, size, magnetic properties, biocompatibility) have to be designed by taking into consideration the constraints of the medical task and MRN. In the past, as a proof of concept of MRN feasibility, a 1.5-mm ferromagnetic bead was guided in the artery of a living swine with a clinical MRI system. Present day, to aim at medical applications, TMMC have been designed for targeted liver chemoembolization by MRN. TMMC are 50-µm biodegradable microparticles loaded with iron-cobalt nanoparticles and doxorubicin as an antitumor drug. TMMC were selectively guided to the right or left liver lobes in a rabbit model with a clinical MRI scanner upgraded with steering coils. To treat human liver tumor, according to the theoretical MRN model, future TMMC design should take into consideration magnetic nanoparticle properties (nature and loading), MRN platform performances (gradient amplitude and rise time) and vascular hepatic network properties (blood flow velocity and geometry) to optimize the carrier diameter for efficient chemoembolization.

MR imaging of therapeutic magnetic microcarriers guided by magnetic resonance navigation for targeted liver chemoembolization.

PURPOSE: Magnetic resonance navigation (MRN), achieved with an upgraded MRI scanner, aims to guide new therapeutic magnetic microcarriers (TMMC) from their release in the hepatic vascular network to liver tumor. In this technical note, in vitro and in vivo MRI properties of TMMC, loaded with iron-cobalt nanoparticles and doxorubicin, are reported by following three objectives: (1) to evaluate the lengthening of echo-time (TE) on nano/microparticle imaging; (2) to characterize by MRI TMMC distribution in the liver; and (3) to confirm the feasibility of monitoring particle distribution in real time. METHODS: Phantom studies were conducted to analyze nano/microparticle signals on T 2*-weighted gradient-echo (GRE) MR images according to sample weight and TE. Twelve animal experiments were used to determine in vivo MRI parameters. TMMC tracking was evaluated by magnetic resonance imaging (MRI) in four rabbits, which underwent MRN in the hepatic artery, three without steering, two in real-time, and three as blank controls. TMMC distribution in the right and left liver lobes, determined by ex vivo MR image analysis, was compared to the one obtained by cobalt level analysis. RESULTS: TMMC induced a hypointense signal that overran the physical size of the sample on MR images. This signal, due to the nanoparticles embedded into the microparticles, increased significantly with echo-time and sample amount (p < 0.05). In vivo, without steering, contrast-to-noise ratio (CNR) values for the right and left lobes were similar. With MRN, the CNR in the targeted lobe was different from that in the untargeted lobe (p = 0.003). Ex vivo, TMMC distribution, based on MRI signal loss volume measurement, was correlated with that quantified by Co level analysis (r = 0.92). TMMC accumulation was tracked in real time with an 8-s GRE sequence. CONCLUSIONS: MRI signal loss induced by TMMC can serve to track particle accumulation and to assess MRN efficiency.

Co-encapsulation of magnetic nanoparticles and doxorubicin into biodegradable microcarriers for deep tissue targeting by vascular MRI navigation.

Magnetic tumor targeting with external magnets is a promising method to increase the delivery of cytotoxic agents to tumor cells while reducing side effects. However, this approach suffers from intrinsic limitations, such as the inability to target areas within deep tissues, due mainly to a strong decrease of the magnetic field magnitude away from the magnets. Magnetic resonance navigation (MRN) involving the endovascular steering of therapeutic magnetic microcarriers (TMMC) represents a clinically viable alternative to reach deep tissues. MRN is achieved with an upgraded magnetic resonance imaging (MRI) scanner. In this proof-of-concept preclinical study, the preparation and steering of TMMC which were designed by taking into consideration the constraints of MRN and liver chemoembolization are reported. TMMC were biodegradable microparticles loaded with iron-cobalt nanoparticles and doxorubicin (DOX). These particles displayed high saturation magnetization (Ms = 72 emu g(-1)), MRI tracking compatibility (strong contrast on T2∗-weighted images), appropriate size for the blood vessel embolization (∼50 µm), and sustained release of DOX (over several days). The TMMC were successfully steered in vitro and in vivo in the rabbit model. In vivo targeting of the right or left liver lobes was achieved by MRN through the hepatic artery located 4 cm beneath the skin. Parameters such as flow velocity, TMMC release site in the artery, magnetic gradient and TMMC properties, affected the steering efficiency. These data illustrate the potential of MRN to improve drug targeting in deep tissues.

Corrosion study of single crystal Ni-Mn-Ga alloy and Tb0.27Dy0.73Fe1.95 alloy for the design of new medical microdevices.

Once placed in a magnetic field, smart magnetic materials (SMM) change their shape, which could be use for the development of smaller minimally invasive surgery devices activated by magnetic field. However, the potential degradation and release of cytotoxic ions by SMM corrosion has to be determined. This paper evaluates the corrosion resistance of two SMM: a single crystal Ni-Mn-Ga alloy and Tb(0.27)Dy(0.73)Fe(1.95) alloy. Ni-Mn-Ga alloy displayed a corrosion potential (E (corr)) of -0.58 V/SCE and a corrosion current density (i (corr)) of 0.43 µA/cm(2). During the corrosion assay, Ni-Mn-Ga sample surface was partially protected; local pits were formed on 20% of the surface and nickel ions were mainly found in the electrolyte. Tb(0.27)Dy(0.73)Fe(1.95) alloy exhibited poor corrosion properties such as E (corr) of -0.87 V/SCE and i (corr) of 5.90 µA/cm(2). During the corrosion test, this alloy was continuously degraded, its surface was impaired by pits and cracks extensively and a high amount of iron ions was measured in the electrolyte. These alloys exhibited low corrosion parameters and a selective degradation in the electrolyte. They could only be used for medical applications if they are coated with high strain biocompatible materials or embedded in composites to prevent direct contact with physiological fluids.

Corrosion study of iron-cobalt alloys for MRI-based propulsion embedded in untethered microdevices operating in the vascular network.

Our group have shown in an experiment performed in the carotid artery of a living swine that magnetic gradients generated by a clinical magnetic resonance imaging (MRI) system could propel and navigate untethered medical microdevices and micro-nanorobots in the human vasculature. The main problem with these devices is that the metal necessary for magnetic propulsion may corrode and induce cytotoxic effects. The challenge, then, is to find an alloy with low corrosion yet providing an adequate magnetization level for propulsion in often stringent physiological conditions. Because of their high magnetization, we studied the corrosion behavior of two iron-cobalt alloys, Permendur (49% Fe, 49% Co, 2% V) and Vacoflux 17 (81% Fe, 17% Co, 2% Cr), in physiological solution by potentiodynamic polarization assay, surface analysis, and corrosion electrolyte analysis. Both alloys exhibited low corrosion parameters such as a corrosion potential (E(corr)) of -0.57 V/SCE and E(corr) of -0.42 V/SCE for Vacoflux 17. The surface of Permendur samples was homogenously degraded. Vacoflux 17 surface was impaired by cracks and crevices. Both alloys had a stoichiometric dissolution in the electrolyte, and they released enough cobalt to induce cytotoxic effects. This study concluded that Fe-Co alloys could be used preferably in medical microdevices if they were coated so as not to come in contact with physiological solutions.

Flagellated Magnetotactic Bacteria as Controlled MRI-trackable Propulsion and Steering Systems for Medical Nanorobots Operating in the Human Microvasculature.

Although nanorobots may play critical roles for many applications in the human body such as targeting tumoral lesions for therapeutic purposes, miniaturization of the power source with an effective onboard controllable propulsion and steering system have prevented the implementation of such mobile robots. Here, we show that the flagellated nanomotors combined with the nanometer-sized magnetosomes of a single Magnetotactic Bacterium (MTB) can be used as an effective integrated propulsion and steering system for devices such as nanorobots designed for targeting locations only accessible through the smallest capillaries in humans while being visible for tracking and monitoring purposes using modern medical imaging modalities such as Magnetic Resonance Imaging (MRI). Through directional and magnetic field intensities, the displacement speeds, directions, and behaviors of swarms of these bacterial actuators can be controlled from an external computer.

Magnetic nanoparticles encapsulated into biodegradable microparticles steered with an upgraded magnetic resonance imaging system for tumor chemoembolization.

In this work, therapeutic magnetic micro carriers (TMMC) guided in real time by a magnetic resonance imaging (MRI) system are proposed as a mean to improve drug delivery to tumor sites. MRI steering constraints and physiological parameters for the chemoembolization of liver tumors were taken into account to design magnetic iron-cobalt nanoparticles encapsulated into biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) microparticles with the appropriate saturation magnetization (M(s)). FeCo nanoparticles displayed a diameter of 182nm and an M(s) of 209 emicrog(-1). They were coated with a multilayered graphite shell to minimize the reduction of M(s) during the encapsulation steps. FeCo-PLGA microparticles, with a mean diameter of 58 microm and an M(s) of 61emicrog(-1), were steered in a phantom mimicking the hepatic artery and its bifurcation, with a flow in the same order of magnitude as that of the hepatic artery flow. The steering efficiency, defined as the amount of FeCo-PLGA microparticles in the targeted bifurcation channel divided by the total amount of FeCo-PLGA microparticles injected, reached 86%. The data presented in this paper confirms the feasibility of the steering of these TMMC.

A computer-assisted protocol for endovascular target interventions using a clinical MRI system for controlling untethered microdevices and future nanorobots.

The possibility of automatically navigating untethered microdevices or future nanorobots to conduct target endovascular interventions has been demonstrated by our group with the computer-controlled displacement of a magnetic sphere along a pre-planned path inside the carotid artery of a living swine. However, although the feasibility of propelling, tracking and performing real-time closed-loop control of an untethered ferromagnetic object inside a living animal model with a relatively close similarity to human anatomical conditions has been validated using a standard clinical Magnetic Resonance Imaging (MRI) system, little information has been published so far concerning the medical and technical protocol used. In fact, such a protocol developed within technological and physiological constraints was a key element in the success of the experiment. More precisely, special software modules were developed within the MRI software environment to offer an effective tool for experimenters interested in conducting such novel interventions. These additional software modules were also designed to assist an interventional radiologist in all critical real-time aspects that are executed at a speed beyond human capability, and include tracking, propulsion, event timing and closed-loop position control. These real-time tasks were necessary to avoid a loss of navigation control that could result in serious injury to the patient. Here, additional simulation and experimental results for microdevices designed to be targeted more towards the microvasculature have also been considered in the identification, validation and description of a specific sequence of events defining a new computer-assisted interventional protocol that provides the framework for future target interventions conducted in humans.

Medical and technical protocol for automatic navigation of a wireless device in the carotid artery of a living swine using a standard clinical MRI system.

A 1.5 mm magnetic sphere was navigated automatically inside the carotid artery of a living swine. The propulsion force, tracking and real-time capabilities of a Magnetic Resonance Imaging (MRI) system were integrated into a closed loop control platform. The sphere was released using an endovascular catheter approach. Specially developed software is responsible for the tracking, propulsion, event timing and closed loop position control in order to follow a 10 roundtrips preplanned trajectory on a distance of 5 cm inside the right carotid artery of the animal. Experimental protocol linking the technical aspects of this in vivo assay is presented. In the context of this demonstration, many challenges which provide insights about concrete issues of future nanomedical interventions and interventional platforms have been identified and addressed.

Biocompatibility of candidate materials for the realization of medical microdevices.

The propulsion of ferromagnetic micro-carriers in the blood vessels by magnetic gradients generated from a Magnetic Resonance Imaging (MRI) system is of special interest for targeted interventions such as chemotherapy or chemo-embolization. As such, Fe-Co alloys for its highest magnetization saturation, and single crystal Ni-Mn-Ga powder and Terfenol-D for their deformation in magnetic field are evaluated for their biocompatibility. The toxicity of these materials is evaluated with MTT cell viability tests. The tests show that Fe-Co (Permendur and Vacoflux 17) alloys are toxic within 24 hours while the single crystal Ni-Mn-Ga powder becomes toxic after 48 hours. The Terfenol-D, despite its high degradation, has 90% cell viability after 72 hours. These results indicate that such candidate materials to be considered in untethered micro-carriers or devices in the blood vessels would require, depending upon the time spent in the blood vessels, further processes to be viable for such applications.