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openaire: EC/H2020/101030869/EU//ROBOT Sensing Orientational control of anisotropic plasmonic nanoparticles is an attractive proposition to generate dynamic plasmonic responses. Particularly, the use of light as a stimulus to modulate the orientation is extremely useful owing to its spatiotemporal operative ability. This work showcases a light-mediated approach to tune the orientational features of gold nanorods in DNA-engineered hydrogel materials. The strategy relies on the use of visible-light-induced photothermal effects to cause deformation of the hydrogel matrix, resulting in temperature-controlled polarization-dependent optical responses whose anisotropy features are highly adaptive to the nature of DNA crosslinks. The visible-light-mediated approach showcased here can open novel avenues to create dynamic light-responsive materials with reconfigurable plasmonic responses.

Changes in extracellular matrix stiffness impact a variety of biological processes including cancer progression. However, cells also actively remodel the matrices they interact with, dynamically altering the matrix mechanics they respond to. Further, cells not only react to matrix stiffness, but also have a distinct reaction to matrix viscoelasticity. The impact of cell-driven matrix remodeling on matrix stiffness and viscoelasticity at the microscale remains unclear, as existing methods to measure mechanics are largely at the bulk scale or probe only the surface of matrices, and focus on stiffness. Yet, establishing the impact of the matrix remodeling at the microscale is crucial to obtaining an understanding of mechanotransduction in biological matrices, and biological matrices are not just elastic, but are viscoelastic. Here, we advanced magnetic probe-based microrheology to overcome its previous limitations in measuring viscoelasticity at the cell-size-scale spatial resolution within 3D cell cultures that have tissue-relevant stiffness levels up to a Young’s modulus of 0.5 kPa. Our magnetic microrheometers exert controlled magnetic forces on magnetic microprobes within reconstituted extracellular matrices and detect microprobe displacement responses to measure matrix viscoelasticity and determine the frequency-dependent shear modulus (stiffness), the loss tangent, and spatial heterogeneity. We applied these tools to investigate how microscale viscoelasticity of collagen matrices is altered by fibroblast cells as they contract collagen gels, a process studied extensively at the macroscale. Interestingly, we found that fibroblasts first soften the matrix locally over the first 32 hours of culture, and then progressively stiffen the matrix thereafter. Fibroblast activity also progressively increased the matrix loss tangent. We confirmed that the softening is caused by matrix-metalloproteinase-mediated collagen degradation, whereas stiffening is associated with local alignment and densification of collagen fibers around the fibroblasts. This work paves the way for the use of measurement systems that quantify microscale viscoelasticity within 3D cell cultures for studies of cell–matrix interactions in cancer progression and other areas. Supplementary Information The online version contains supplementary material available at 10.1007/s10544-021-00547-2.

In this work, sustainable hydrophobic and oleophilic macroporous Fe–Cu films are fabricated using a straightforward, inexpensive and environmentally friendly two-step procedure which combines electrodeposition with the colloidal lithography technique. Elemental, morphological and structural characterization of the resulting pseudo-ordered meshes is carried out and wettability is assessed using contact angle measurements with respect to two distinct film compositions (3 at.% Fe vs 75–85 at.% Fe) and three different pore diameters (namely, 200 nm, 350 nm and 500 nm). Water contact angles are measured to be in the range of approximately 109.0–155.1° (without any post-surface functionalization) and a low contact angle hysteresis is observed in the superhydrophobic samples. The increase in the hydrophobic character of the films correlates well with an increase in surface roughness, whereas differences in composition play a minor role. For the superhydrophobic Fe-rich macroporous film, water–oil separation capability and recyclability are also demonstrated while the pore size is favorable for effective water–oil mixture and emulsion separation. The results shown here demonstrate that sustainable and affordable materials processed in a simple and cheap manner can be an asset for the removal of water-immiscible organic compounds from aqueous environments.

We describe a double template-assisted electrodeposition of porous metal microstructures. The method combines two-dimensional photolithography and electrophoretic assembly of polystyrene beads, in order to confine the electrochemical growth of a porous magnetic cobalt–nickel alloy within well-defined microscale boundaries. Polystyrene beads are electrophoretically deposited onto a sulfonate derivatized gold substrate where a patterned photoresist layer (first template) is applied. The polystyrene beads trapped in the first template act as the second template, and cobalt–nickel alloy is electrochemically grown through the voids between the beads. After removal of both templates, magnetic microstructures with well-defined shapes and porosity are successfully obtained. Additionally, we demonstrate the capabilities of these magnetic microstructures as wireless cargo microtransporters by loading their pores with a stimulus-responsive hydrogel. Magnetic manipulation experiments are also demonstrated. Keywords: Cobalt–nickel, Porous structure, Electrochemical synthesis, Hydrogel, Magnetic manipulation

Purpose To quantify the effect of silicone hydrogel crosslink density on the adhesion at corneal epithelial cells/silicone hydrogel contact lens interface. Methods A custom-built rheometer, referred to as the live cell monolayer rheometer, was used to measure the adhesive strengths between corneal epithelial cell monolayers and silicone hydrogel lens surfaces. The resulting stress relaxations of senofilcon A-derived silicone hydrogel materials with varying crosslinking densities and delefilcon A were tested. Senofilcon A-like materials labeled L1, L2, L3, L4, and L5 contained crosslinker concentrations of 1.2, 1.35, 1.5, 1.65, and 1.8 wt%, respectively. The residual modulus measured from the live cell monolayer rheometer provided a direct indication of adhesive attachment. Results Within the senofilcon-derived series, the adhesive strength shows a surprising minimum with respect to crosslink density. Specifically, L1 (1.20%) has the highest adhesive strength of 39.5 ± 11.2 Pa. The adhesive strength diminishes to a minimum of 11.2 ± 2.1 Pa for L3, whereafter it increases to 14.5 ± 2.5 Pa and 18.1 ± 5.1 Pa for L4 and L5, respectively. The delefilcon A lens exhibits a comparable adhesive strength of 27.8 ± 6.3 Pa to L1. Conclusions These results demonstrated that increasing the crosslink density has a nonmonotonic influence on the adherence of lenses to mucin-expressing corneal epithelial cells, which suggests a competition mechanism at the cell/lens interface. Translational relevance Because the adhesiveness of contact lenses to ocular tissues may impact the comfort level for lens wearers and affect ease of removal, this study suggests that lens adhesion can be optimized through the control of crosslink density.

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.

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.

Nanoletters, 15 (7), ISSN:2079-4991

Ocular microrobots have the potential to change the way in which we treat a variety of diseases at the anterior and the posterior segments of the eye. Wireless manipulation and positioning of drug delivery magnetic millimeter and submillimeter platforms into the eye constitute a potential route for minimally invasive targeted therapy. However, the field is still in its infancy and faces challenges related to the fabrication, control an interaction with complex biological environments.This review briefly introduces the complex anatomy and physiology of the eye, which renders limitations to the current treatments of ocular diseases. The topical administration of eye drops, intravitreal injections and drug delivery implants is briefly mentioned together with their drawbacks. The authors also analyze the minimally invasive microrobotic approach as an alternative method and report the recent advancements in the fabrication, control, manipulation and drug delivery.Although microrobotics is a young field, a significant amount of work has been developed to face different challenges related to the minimally invasive manipulation of microdevices in the eye. Current research is already at the state of in vivo testing for systems and their biocompatibility. It is expected that the general concepts acquired will soon be applied for specific interventions, especially for posterior eye pathologies.

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.

In this paper we probe the structural response to oscillatory shear deformations of polycrystalline monolayers of soft repulsive colloids with varying area fraction over a broad range of frequencies and amplitudes. The particles are confined at a fluid interface, sheared using a magnetic microdisk, and imaged through optical microscopy. The structural and mechanical response of soft materials is highly dependent on their microstructure. If crystals are well understood and deform through the creation and mobilization of specific defects, the situation is much more complex for disordered jammed materials, where identifying structural motifs defining plastically rearranging regions remains an elusive task. Our materials fall between these two classes and allow the identification of clear pathways for structural evolution. In particular, we demonstrate that large enough strains are able to fluidize the system, identifying critical strains that fulfill a local Lindemann criterion. Conversely, smaller strains lead to localized and erratic irreversible particle rearrangements due to the motion of structural defects. In this regime, oscillatory shear promotes defect annealing and leads to the growth of large crystalline domains. Numerical simulations help identify the population of rearranging particles with those exhibiting the largest deviatoric stresses and indicate that structural evolution proceeds towards the minimization of the stress stored in the system. The particles showing high deviatoric stresses are localized around grain boundaries and defects, providing a simple criterion to spot regions likely to rearrange plastically under oscillatory shear.

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.

Vitrectomy is a standard ophthalmic procedure to remove the vitreous body from the eye. The biomechanics of the vitreous affects its duration (by changing the removal rate) and the mechanical forces transmitted via the vitreous on the surrounding tissues during the procedure. Biomechanical characterization of the vitreous is essential for optimizing the design and control of instruments that operate within the vitreous for improved precision, safety, and efficacy. The measurements are carried out using a magnetic microprobe inserted into the vitreous, a method known as magnetic microrheology. The location of the probe is tracked by a microscope/camera while magnetic forces are exerted wirelessly by applied magnetic fields. In this work, in vitro artificial vitreous, ex vivo human vitreous and ex vivo porcine vitreous were characterized. In addition, in vivo rabbit measurements were performed using a suturelessly injected probe. Measurements indicate that viscoelasticity parameters of the ex vivo human vitreous are an order of magnitude different from those of the ex vivo porcine vitreous. The in vivo intra-operative measurements show typical viscoelastic behavior of the vitreous with a lower compliance than the ex vivo measurements. The results of the magnetic microrheology measurements were validated with those obtained by a standard atomic force microscopy (AFM) method and in vitro artificial vitreous. This method allows minimally-invasive characterization of localized mechanical properties of the vitreous in vitro, ex vivo, and in vivo. A better understanding of the characteristics of the vitreous can lead to improvements in treatments concerning vitreal manipulation such as vitrectomy., Biomedical Microdevices, 17 (5), ISSN:1387-2176, ISSN:1572-8781

Manipulation and transport of microscale objects in 3D with high spatiotemporal resolution require precise control over the applied forces. We report a strategy that uses specially engineered microbars having engagement points and multiple helical microcarriers that can apply reversible loads onto these holders. The helical microcarriers are actuated by externally generated, low strength magnetic fields. By optimizing the design of helical structures for precise manipulation, we fabricated microcarriers that swim with little wobbling even at low rotating frequencies. The cooperation of microcarriers generates higher propulsive forces while application of forces at multiple locations results in motion control with multiple degrees of freedom (DOF). The microbar loaded with multiple microcarriers can be employed as a single mobile device for the realization of higher order manipulation tasks., RSC Advances, 4 (51), ISSN:2046-2069

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.

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.

Micro/nano robots have the potential to revolutionize many aspects of medicine. These untethered, wirelessly controlled and powered devices will make existing therapeutic and diagnostic procedures less invasive and will enable new procedures never before possible. Here we present five degree of freedom (5-DOF) wireless control of fully untethered magnetic micro/nano agents (3-DOF position, 2-DOF orientation). We accomplish this level of wireless control with electromagnetic manipulation systems that we call OctoMag and MiniMag. We demonstrate different magnetic control strategies and combination thereof for potential in vivo and in vitro applications. We show that these systems have the potential to be employed for targeted drug delivery and for procedures such as retinal-vein cannulation that require a high degree of dexterity.

For this study, we have collected puncture force data from the vasculature of the chorioallantoic membranes (CAM) of developing chicken embryos to examine forces required for retinal vein cannulation. The CAM vessels of a developing chicken embryo have been shown to be an appropriate model for human retinal veins. The effect of microneedle geometry and vessel size on puncture forces was investigated. The results of this work are important for researchers working on robotic vitreoretinal surgical systems. [DOI: 10.1115/1.4005318]

We present a luminescence oxygen sensor incorporated in a wireless intraocular microrobot for minimally-invasive diagnosis. This microrobot can be accurately controlled in the intraocular cavity by applying magnetic fields. The microrobot consists of a magnetic body susceptible to magnetic fields and a sensor coating. This coating embodies Pt(II) octaethylporphine (PtOEP) dyes as the luminescence material and polystyrene as a supporting matrix, and it can be wirelessly excited and read out by optical means. The sensor works based on quenching of luminescence in the presence of oxygen. The excitation and emission spectrum, response time, and oxygen sensitivity of the sensor were characterized using a spectrometer. A custom device was designed and built to use this sensor for intraocular measurements with the microrobot. Due to the intrinsic nature of luminescence lifetimes, a frequency-domain lifetime measurement approach was employed. An alternative sensor implementation using poly(styrene-co-maleic anhydride) (PS-MA) and PtOEP was successfully demonstrated with nanospheres to increase sensor performance.

Porous nanostructures of polypyrrole (Ppy) were fabricated using colloidal lithography and electrochemical techniques for potential applications in drug delivery. A sequential fabrication method was developed and optimized to maximize the coverage of the Ppy nanostructures and to obtain a homogeneous layer over the substrate. This was realized by masking with electrophoretically-assembled polystyrene (PS) nanospheres and then electroplating. Drug/biomolecule adsorption and the release characteristics for the porous nanostructures of Ppy were investigated using rhodamine B (Rh-B). Rh-B is an easily detectable small hydrophobic molecule that is used as a model for many drugs or biological substances. The porous Ppy nanostructures with an enhanced surface area exhibited higher Rh-B loading capacity than bulk planar films of Ppy. Moreover, tunability of surface morphology for further applications (e.g., sensing, cell adhesion) was demonstrated.

A magnetic hyperthermia cancer treatment strategy that does not operate by means of conventional heating mechanisms is presented. The proposed approach consists of injecting a gel with homogeneously distributed magnetic nanowires into a tumor. Upon the application of a low-frequency rotating or circularly polarized magnetic field, nanowires spin around their center of viscous drag due to torque generated by shape anisotropy. As a result of external rotational forcing and fluid friction in the nanoparticle's boundary layer, heating occurs. The nanowire dynamics is theoretically and experimentally investigated, and different feasibility proofs of the principle by physical modeling, which adhere to medical guidelines, are presented. The magnetic nanorotors exhibit rotations and oscillations with quite a steady center of gravity, which proves an immobile behavior and guarantees a time-independent homogeneity of the spatial particle distribution in the tumor. Furthermore, a fluid dynamic and thermodynamic heating model is briefly introduced. This model is a generalization of Penne's model that for this method reveals theoretic heating rates that are sufficiently high, and fits well into medical limits defined by present standards.