Human gait-labeling uncertainty and a hybrid model for gait segmentation.

Motion capture systems are widely accepted as ground-truth for gait analysis and are used for the validation of other gait analysis systems. To date, their reliability and limitations in manual labeling of gait events have not been studied. Objectives: Evaluate manual labeling uncertainty and introduce a hybrid stride detection and gait-event estimation model for autonomous, long-term, and remote monitoring. Methods: Estimate inter-labeler inconsistencies by computing the limits-of-agreement. Develop a hybrid model based on dynamic time warping and convolutional neural network to identify valid strides and eliminate non-stride data in inertial (walking) data collected by a wearable device. Finally, detect gait events within a valid stride region. Results: The limits of inter-labeler agreement for key gait events heel off, toe off, heel strike, and flat foot are 72, 16, 24, and 80 ms, respectively; The hybrid model's classification accuracy for stride and non-stride are 95.16 and 84.48%, respectively; The mean absolute error for detected heel off, toe off, heel strike, and flat foot are 24, 5, 9, and 13 ms, respectively, when compared to the average human labels. Conclusions: The results show the inherent labeling uncertainty and the limits of human gait labeling of motion capture data; The proposed hybrid-model's performance is comparable to that of human labelers, and it is a valid model to reliably detect strides and estimate the gait events in human gait data. Significance: This work establishes the foundation for fully automated human gait analysis systems with performances comparable to human-labelers.

Real-Time Gait Phase Detection on Wearable Devices for Real-World Free-Living Gait.

Detecting gait phases with wearables unobtrusively and reliably in real-time is important for clinical gait rehabilitation and early diagnosis of neurological diseases. Due to hardware limitations of microcontrollers in wearable devices (e.g., memory and computation power), reliable real-time gait phase detection on the microcontrollers remains a challenge, especially for long-term real-world free-living gait. In this work, a novel algorithm based on a reduced support vector machine (RSVM) and a finite state machine (FSM) is developed to address this. The RSVM is developed by exploiting the cascaded K-means clustering to reduce the model size and computation time of a standard SVM by 88% and a factor of 36, with only minor degradation in gait phase prediction accuracy of around 4%. For each gait phase prediction from the RSVM, the FSM is designed to validate the prediction and correct misclassifications. The developed algorithm is implemented on a microcontroller of a wearable device and its real-time (on the fly) classification performance is evaluated by twenty healthy subjects walking along a predefined real-world route with uncontrolled free-living gait. It shows a promising real-time performance with an accuracy of 91.51%, a sensitivity of 91.70%, and a specificity of 95.77%. The algorithm also demonstrates its robustness with varying walking conditions.

Integrated Pedal System for Data Driven Rehabilitation.

We present a system capable of providing visual feedback for ergometer training, allowing detailed analysis and gamification. The presented solution can easily upgrade any existing ergometer device. The system consists of a set of pedals with embedded sensors, readout electronics and wireless communication modules and a tablet device for interaction with the users, which can be mounted on any ergometer, transforming it into a full analytical assessment tool with interactive training capabilities. The methods to capture the forces and moments applied to the pedal, as well as the pedal's angular position, were validated using reference sensors and high-speed video capture systems. The mean-absolute error (MAE) for load is found to be 18.82 N, 25.35 N, 0.153 Nm for Fx, Fz and Mx respectively and the MAE for the pedal angle is 13.2°. A fully gamified experience of ergometer training has been demonstrated with the presented system to enhance the rehabilitation experience with audio visual feedback, based on measured cycling parameters.

Helical Klinotactic Locomotion of Two-Link Nanoswimmers with Dual-Function Drug-Loaded Soft Polysaccharide Hinges.

Inspired by the movement of bacteria and other microorganisms, researchers have developed artificial helical micro- and nanorobots that can perform corkscrew locomotion or helical path swimming under external energy actuation. In this paper, for the first time the locomotion of nonhelical multifunctional nanorobots that can swim in helical klinotactic trajectories, similarly to rod-shaped bacteria, under rotating magnetic fields is investigated. These nanorobots consist of a rigid ferromagnetic nickel head connected to a rhodium tail by a flexible hydrogel-based hollow hinge composed of chemically responsive chitosan and alginate multilayers. This design allows nanoswimmers switching between different dynamic behaviors-from in-plane tumbling to helical klinotactic swimming-by varying the rotating magnetic field frequency and strength. It also adds a rich spectrum of swimming capabilities that can be adjusted by varying the type of applied magnetic fields and/or frequencies. A theoretical model is developed to analyze the propulsion mechanisms and predict the swimming behavior at distinct rotating magnetic frequencies. The model shows good agreement with the experimental results. Additionally, the biomedical capabilities of the nanoswimmers as drug delivery platforms are demonstrated. Unlike previous designs constitute metallic segments, the proposed nanoswimmers can encapsulate drugs into their hollow hinge and successfully release them to cells.

An Intelligent In-Shoe System for Gait Monitoring and Analysis with Optimized Sampling and Real-Time Visualization Capabilities.

The deterioration of gait can be used as a biomarker for ageing and neurological diseases. Continuous gait monitoring and analysis are essential for early deficit detection and personalized rehabilitation. The use of mobile and wearable inertial sensor systems for gait monitoring and analysis have been well explored with promising results in the literature. However, most of these studies focus on technologies for the assessment of gait characteristics, few of them have considered the data acquisition bandwidth of the sensing system. Inadequate sampling frequency will sacrifice signal fidelity, thus leading to an inaccurate estimation especially for spatial gait parameters. In this work, we developed an inertial sensor based in-shoe gait analysis system for real-time gait monitoring and investigated the optimal sampling frequency to capture all the information on walking patterns. An exploratory validation study was performed using an optical motion capture system on four healthy adult subjects, where each person underwent five walking sessions, giving a total of 20 sessions. Percentage mean absolute errors (MAE%) obtained in stride time, stride length, stride velocity, and cadence while walking were 1.19%, 1.68%, 2.08%, and 1.23%, respectively. In addition, an eigenanalysis based graphical descriptor from raw gait cycle signals was proposed as a new gait metric that can be quantified by principal component analysis to differentiate gait patterns, which has great potential to be used as a powerful analytical tool for gait disorder diagnostics.

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.

Nanomechanics on FGF-2 and Heparin Reveal Slip Bond Characteristics with pH Dependency.

Fibroblast growth factor 2 (FGF-2), an important paracrine growth factor, binds electrostatically with low micromolar affinity to heparan sulfates present on extracellular matrix proteins. A single molecular analysis served as a basis to decipher the nanomechanical mechanism of the interaction between FGF-2 and the heparan sulfate surrogate, heparin, with a modular atomic force microscope (AFM) design combining magnetic actuators with force measurements at the low force regime (1 × 101 to 1 × 104 pN/s). Unbinding events between FGF-2-heparin complexes were specific and short-lived. Binding between FGF-2 and heparin had strong slip bond characteristics as demonstrated by a decrease of lifetime with tensile force on the complex. Unbinding forces between FGF-2 and heparin were further detailed at different pH as relevant for (patho-) physiological conditions. An acidic pH environment (5.5) modulated FGF-2-heparin binding as demonstrated by enhanced rupture forces needed to release FGF-2 from the heparin-FGF-2 complex as compared to physiological conditions. This study provides a mechanistic and hypothesis driven model on how molecular forces may impact FGF-2 release and storage during tissue remodeling and repair.

An Atomic Force Microscope with Dual Actuation Capability for Biomolecular Experiments.

We report a modular atomic force microscope (AFM) design for biomolecular experiments. The AFM head uses readily available components and incorporates deflection-based optics and a piezotube-based cantilever actuator. Jetted-polymers have been used in the mechanical assembly, which allows rapid manufacturing. In addition, a FeCo-tipped electromagnet provides high-force cantilever actuation with vertical magnetic fields up to 0.55 T. Magnetic field calibration has been performed with a micro-hall sensor, which corresponds well with results from finite element magnetostatics simulations. An integrated force resolution of 1.82 and 2.98 pN, in air and in DI water, respectively was achieved in 1 kHz bandwidth with commercially available cantilevers made of Silicon Nitride. The controller and user interface are implemented on modular hardware to ensure scalability. The AFM can be operated in different modes, such as molecular pulling or force-clamp, by actuating the cantilever with the available actuators. The electromagnetic and piezoelectric actuation capabilities have been demonstrated in unbinding experiments of the biotin-streptavidin complex.

Dually actuated atomic force microscope with miniaturized magnetic bead-actuators for single-molecule force measurements.

We report a novel atomic force microscopy (AFM) technique with dual actuation capabilities using both piezo and magnetic bead actuation for advanced single-molecule force spectroscopy experiments. The experiments are performed by manipulating magnetic microbeads using an electromagnet against a stationary cantilever. Magnetic actuation has been demonstrated before to actuate cantilevers, but here we keep the cantilever stationary and accomplish actuation via free-manipulated microstructures. The developed method benefits from significant reduction of drift, since the experiments are performed without a substrate contact and the measured force is inherently differential. In addition, shrinking the size of the actuator can minimize hydrodynamic forces affecting the cantilever. The new method reported herein allows for the application of constant force to perform force-clamp experiments without any active feedback, profiled for a deeper understanding of biomolecular interactions.

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.

Measuring localized viscoelasticity of the vitreous body using intraocular microprobes.

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.

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.

Visible light curing of Epon SU-8 based superparamagnetic polymer composites with random and ordered particle configurations.

The performance of superparamagnetic polymer composite microdevices is highly dependent on the magnetic particle content. While high loading levels are desired for many applications, the UV absorption of these nanoparticles limits the overall thickness of the fabricated microstructures and subsequently their capability of magnetic interaction. The combination of a visible-light-sensitive photoinitiator and particle self-organization is proposed to extend the exposure depth limitation in Epon SU-8 based superparamagnetic polymer composites. While superparamagnetic iron oxide particles strongly absorb i-line radiation required to cross-link the Epon SU-8 polymer matrix, we propose the utilization of H-Nu 470 photoinitiator to expand the photosensitivity of the composite toward the visible spectrum, where the dispersed nanoparticles are more transparent. The novel photoinitiator preserves the composite's superparamagnetic properties as well as a homogeneous particle distribution. As a result, particle load or resist thickness can be more than doubled while maintaining exposure time. The self-organization of ordered magnetic structures allows for an additional increase in exposure depth of up to 40%, resulting in a 2.5-fold saturation magnetization.

Microrobots: a new era in ocular drug delivery.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Inkjet printed superparamagnetic polymer composite hemispheres with programmed magnetic anisotropy.

We present the fabrication and characterization of large arrays of inkjet-printed superparamagnetic polymer composite (SPMPC) hemispherical microstructures. SPMPCs are appealing for applications in microsystems and nanorobotics due to the added functionality of polymers and the significant magnetic attributes of embedded nanostructures. SPMPC-based microarchitectures can be used to perform different functions wirelessly in various media (e.g. water, solvents) using external magnetic fields: handling and assembling small objects, delivering drugs or biomass, or sensing specific physical or chemical changes. In this work superparamagnetic magnetite nanoparticles are dispersed in SU-8 to form magnetic hemispheres. Magnetically anisotropic hemispheres as well as standard SPMPC hemispheres are fabricated. Magnetic anisotropy is programmed by applying a magnetic field during curing. The distribution of nanoparticles inside the polymer matrix and magnetic characteristics of the SPMPC are investigated. Magnetic manipulation of hemispheres is demonstrated at liquid-liquid interfaces. Different assembly strategies to form lines or geometric shapes from hemispheres as well as their independent dynamic control are demonstrated. Finally, a two-interface assembly strategy is demonstrated to assemble hemispheres into complete spheres for advanced self-assembly tasks.

Electrophoretic deposition as a new approach to produce optical sensing films adaptable to microdevices.

We report the fabrication of optical oxygen sensor films using electrophoretic deposition (EPD) of poly(styrene-co-maleic anhydride) nanoparticles containing the oxygen-sensitive dye platinum(ii) meso-tetra(pentafluorophenyl)porphine. Compared to other deposition methods, the EPD is simple and allows easy control over deposition, which is crucial for the implementation of optical sensing films in microdevices. By optimizing the synthesis of the functional nanoparticles, anodic EPD can be performed. The amount of deposited particles can be tuned by varying either the electrical potential or the deposition time. The sensing phases were characterized using a phase-modulation technique showing a Stern-Volmer constant (kSV1) between 45 and 52 bar(-1) for gas and of 20.72 bar(-1) in the aqueous phase without leaching of the particles from the surface. The small thickness of the layers lead to short response times (<0.4 s). This is the first time that polymeric optical sensing films have been obtained by EPD from dispersions of oxygen sensing nanoparticles.

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.

Superparamagnetic microrobots: fabrication by two-photon polymerization and biocompatibility.

This work presents the fabrication and controlled actuation of swimming microrobots made of a magnetic polymer composite (MPC) consisting of 11-nm-diameter magnetite (Fe3O4) nanoparticles and photocurable resin (SU-8). Two-photon polymerization (TPP) is used to fabricate the magnetic microstructures. The material properties and the cytotoxicity of the MPC with different nanoparticle concentrations are characterized. The live/dead staining tests indicate that MPC samples with varied concentrations, up to 10 vol.%, have negligible cytotoxicity after 24 h incubation. Fabrication parameters of MPC with up to 4 vol.% were investigated. We demonstrate that the helical microdevices made of 2 vol.% MPC were capable of performing corkscrew motion in water applying weak uniform rotating magnetic fields.

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.