Protective coatings for intraocular wirelessly controlled microrobots for implantation: Corrosion, cell culture, and in vivo animal tests.

Diseases in the ocular posterior segment are a leading cause of blindness. The surgical skills required to treat them are at the limits of human manipulation ability, and involve the risk of permanent retinal damage. Instrument tethering and design limit accessibility within the eye. Wireless microrobots suturelessly injected into the posterior segment, steered using magnetic manipulation are proposed for procedures involving implantation. Biocompatibility is a prerequisite for these procedures. This article investigates the use of polypyrrole- and gold-coated cobalt-nickel microrobots. While gold has been used in ocular implants, no ocular implantation involving polypyrrole is reported, despite its well-established biocompatibility properties. Coated and uncoated microrobots were investigated for their corrosion properties, and solutions that had contained coated and uncoated microrobots for one week were tested for cytotoxicity by monitoring NIH3T3 cell viability. None of the microrobots showed significant corrosion currents and corrosion potentials were as expected in relation to the intrinsic nobility of the materials. NIH3T3 cell viability was not affected by the release medium, in which coated/uncoated microrobots were stored. In vivo tests inside rabbit eyes were performed using coated microrobots. There were no significant inflammatory responses during the first week after injection. An inflammatory response detected after 2 weeks was likely due to a lack of longer-duration biocompatibility. The results provide valuable information for those who work on implant technology and biocompatibility. Coated microrobots have the potential to facilitate a new generation of surgical treatments, diagnostics and drug-delivery techniques, when implantation in the ocular posterior segment will be possible. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 836-845, 2017.

Mobility-Enhancing Coatings for Vitreoretinal Surgical Devices: Hydrophilic and Enzymatic Coatings Investigated by Microrheology.

Ophthalmic wireless microrobots are proposed for minimally invasive vitreoretinal surgery. Devices in the vitreous experience nonlinear mobility as a result of the complex mechanical properties of the vitreous and its interaction with the devices. A microdevice that will minimize its interaction with the macromolecules of the vitreous (i.e., mainly hyaluronan (HA) and collagen) can be utilized for ophthalmic surgeries. Although a few studies on the interactions between the vitreous and microdevices exist, there is no literature on the influence of coatings on these interactions. This paper presents how coatings on devices affect mobility in the vitreous. Surgical catheters in the vasculature use hydrophilic polymer coatings that reduce biomolecular absorption and enhance mobility. In this work such polymers, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and HA coatings were utilized, and their effects on mobility in the vitreous were characterized. Hydrophilic titanium dioxide (TiO2) coating was also developed and characterized. Collagenase and hyaluronidase enzymes were coated on probes' surfaces with a view to enhancing their mobility by enzymatic digestion of the collagen and HA of the vitreous, respectively. To model the human vitreous, ex vivo porcine vitreous and collagen were used. For studying the effects of hyaluronidase, the vitreous and HA were used. The hydrophilic and enzymatic coatings were characterized by oscillatory magnetic microrheology. The statistical significance of the mean relative displacements (i.e., mobility) of the coated probes with respect to control probes was assessed. All studied hydrophilic coatings improve mobility, except for HA which decreases mobility potentially due to bonding with vitreal macromolecules. TiO2 coating improves mobility in collagen by 28.3% and in the vitreous by 15.4%. PEG and PVP coatings improve mobility in collagen by 19.4 and by 39.6%, respectively, but their improvement in the vitreous is insignificant at a 95% confidence level (CL). HA coating affects mobility by reducing it in collagen by 35.6% (statistically significant) and in the vitreous by 16.8% (insignificant change at 95% CL). The coatings cause similar effects in collagen and in the vitreous. However, the effects are lower in the vitreous, which can be due to a lower concentration of collagen in the vitreous than in the prepared collagen samples. The coatings based on enzymatic activity increase mobility (i.e., >40% after 15 min experiments in the vitreous models) more than the hydrophilic coatings based on physicochemical interactions. However, the enzymes have time-dependent effects, and they dissolve from the probe surface with time. The presented results are useful for researchers and companies developing ophthalmic devices. They also pave the way to understanding how to adjust mobility of a microdevice in a complex fluid by choice of an appropriate coating.

Undulatory Locomotion of Magnetic Multilink Nanoswimmers.

Micro- and nanorobots operating in low Reynolds number fluid environments require specialized swimming strategies for efficient locomotion. Prior research has focused on designs mimicking the rotary corkscrew motion of bacterial flagella or the planar beating motion of eukaryotic flagella. These biologically inspired designs are typically of uniform construction along their flagellar axis. This work demonstrates for the first time planar undulations of composite multilink nanowire-based chains (diameter 200 nm) induced by a planar-oscillating magnetic field. Those chains comprise an elastic eukaryote-like polypyrrole tail and rigid magnetic nickel links connected by flexible polymer bilayer hinges. The multilink design exhibits a high swimming efficiency. Furthermore, the manufacturing process enables tuning the geometrical and material properties to specific applications.

Electroforming of implantable tubular magnetic microrobots for wireless ophthalmologic applications.

Magnetic tubular implantable micro-robots are batch fabricated by electroforming. These microdevices can be used in targeted drug delivery and minimally invasive surgery for ophthalmologic applications. These tubular shapes are fitted into a 23-gauge needle enabling sutureless injections. Using a 5-degree-of-freedom magnetic manipulation system, the microimplants are conveniently maneuvered in biological environments. To increase their functionality, the tubes are coated with biocompatible films and can be successfully filled with drugs.

Viscoelastic interaction between intraocular microrobots and vitreous humor: a finite element approach.

Vitreous humor exhibits complex biomechanical properties and determination of these properties is essential for designing ophthalmic biomedical microdevices. In this paper, the viscoelastic properties of porcine vitreous humor were studied based on ex vivo creep experiments, in which a microrobot was magnetically actuated inside the vitreous. A three-dimensional (3D) finite element (FE) model was proposed to simulate the viscoelastic interaction between the microrobot and porcine vitreous humor. An optimization-based method was employed to estimate the viscoelastic parameters of the vitreous humor. The proposed model successfully validated the experimental measurements. The estimated parameters were compared with published data in literature. The model was then used to study the shape-dependent interaction of the microrobot with the vitreous humor. The methods presented in this paper can be used for the optimization of ophthalmic microrobots and microsurgical tools.

Mobility experiments with microrobots for minimally invasive intraocular surgery.

PURPOSE: To investigate microrobots as an assistive tool for minimally invasive intraocular surgery and to demonstrate mobility and controllability inside the living rabbit eye. METHODS: A system for wireless magnetic control of untethered microrobots was developed. Mobility and controllability of a microrobot are examined in different media, specifically vitreous, balanced salt solution (BSS), and silicone oil. This is demonstrated through ex vivo and in vivo animal experiments. RESULTS: The developed electromagnetic system enables precise control of magnetic microrobots over a workspace that covers the posterior eye segment. The system allows for rotation and translation of the microrobot in different media (vitreous, BSS, silicone oil) inside the eye. CONCLUSIONS: Intravitreal introduction of untethered mobile microrobots can enable sutureless and precise ophthalmic procedures. Ex vivo and in vivo experiments demonstrate that microrobots can be manipulated inside the eye. Potential applications are targeted drug delivery for maculopathies such as AMD, intravenous deployment of anticoagulation agents for retinal vein occlusion (RVO), and mechanical applications, such as manipulation of epiretinal membrane peeling (ERM). The technology has the potential to reduce the invasiveness of ophthalmic surgery and assist in the treatment of a variety of ophthalmic diseases.

Chitosan electrodeposition for microrobotic drug delivery.

A method to functionalize steerable magnetic microdevices through the co-electrodeposition of drug loaded chitosan hydrogels is presented. The characteristics of the polymer matrix have been investigated in terms of fabrication, morphology, drug release and response to different environmental conditions. Modifications of the matrix behavior could be achieved by simple chemical post processing. The system is able to load and deliver 40-80 µg cm(-2) of a model drug (Brilliant Green) in a sustained manner with different profiles. Chitosan allows a pH responsive behavior with faster and more efficient release under slightly acidic conditions as can be present in tumor or inflamed tissue. A prototype of a microrobot functionalized with the hydrogel is presented and proposed for the treatment of posterior eye diseases.

Redox cycling for passive modification of polypyrrole surface properties: effects on cell adhesion and proliferation.

The surface properties of electrodeposited poly(pyrrole) (Ppy) doped with sodium dodecylbenzenesulphonate (NaDBS) are modified by two methods: addition of poly(ethylene glycol) (PEG) during the electrodeposition and through redox cycling post electrodeposition. X-ray photoelectron spectroscopy (XPS) was used to ascertain PEG incorporation and to analyze the change in the oxidation state of the polymer. Anodic cycling resulted in the formation of micrometer-sized surface cracks which increased the amount of Rhodamine-B dye adsorbed onto the surface, and played a role in decreasing the wettability of the surface. The change in surface wettability caused by these cracks was mitigated by the presence of PEG in the Ppy matrix. Compared to the incorporation of PEG, redox cycling was more effective in passively modulating the adhesion of NIH 3T3 fibroblast cells on the Ppy surface. Based on the attenuation of surface polarity of the Ppy surfaces by the incorporated PEG, a mechanism is proposed to explain the observed cell adhesion behavior.

Tailoring the drug loading capacity of polypyrrole films for use in intraocular biomicrorobots.

Preliminary results concerning impregnation of polypyrrole (Ppy) films with rhodamine B (Rh-B) are presented. The films are envisioned to be functional surface coatings on biomicrorobots for controlled drug delivery. The polypyrrole films were obtained on gold substrates by anodic oxidation of pyrrole in aqueous solutions containing sodium dodecylbenzenesulfonate (SDBS) as doping agent. The influence of the sodium doping level on the wettability of the Ppy surfaces, and the loading capacity of Rh-B is systematically analyzed. The undoping of the films results in the formation of surface microcracks and tends to make the surface hydrophobic in nature, which subsequently leads to an increase of the adsorption capacity of Rh-B on the Ppy deposit. This controllable increase in adsorption capacity provides an opportunity to tailor the drug loading capacity of Ppy films.