Protease-Activatable Adeno-Associated Virus Vector for Gene Delivery to Damaged Heart Tissue.

Adeno-associated virus (AAV) has emerged as a promising gene delivery vector because of its non-pathogenicity, simple structure and genome, and low immunogenicity compared to other viruses. However, its adoption as a safe and effective delivery vector for certain diseases relies on altering its tropism to deliver transgenes to desired cell populations. To this end, we have developed a protease-activatable AAV vector, named provector, that responds to elevated extracellular protease activity commonly found in diseased tissue microenvironments. The AAV9-based provector is initially inactive, but then it can be switched on by matrix metalloproteinases (MMP)-2 and -9. Cryo-electron microscopy and image reconstruction reveal that the provector capsid is structurally similar to that of AAV9, with a flexible peptide insertion at the top of the 3-fold protrusions. In an in vivo model of myocardial infarction (MI), the provector is able to deliver transgenes site specifically to high-MMP-activity regions of the damaged heart, with concomitant decreased delivery to many off-target organs, including the liver. The AAV provector may be useful in the future for enhanced delivery of transgenes to sites of cardiac damage.

Assessment of Dry Epidermal Electrodes for Long-Term Electromyography Measurements.

Commercially available electrodes can only provide quality surface electromyography (sEMG) measurements for a limited duration due to user discomfort and signal degradation, but in many applications, collecting sEMG data for a full day or longer is desirable to enhance clinical care. Few studies for long-term sEMG have assessed signal quality of electrodes using clinically relevant tests. The goal of this research was to evaluate flexible, gold-based epidermal sensor system (ESS) electrodes for long-term sEMG recordings. We collected sEMG and impedance data from eight subjects from ESS and standard clinical electrodes on upper extremity muscles during maximum voluntary isometric contraction tests, dynamic range of motion tests, the Jebsen Taylor Hand Function Test, and the Box & Block Test. Four additional subjects were recruited to test the stability of ESS signals over four days. Signals from the ESS and traditional electrodes were strongly correlated across tasks. Measures of signal quality, such as signal-to-noise ratio and signal-to-motion ratio, were also similar for both electrodes. Over the four-day trial, no significant decrease in signal quality was observed in the ESS electrodes, suggesting that thin, flexible electrodes may provide a robust tool that does not inhibit movement or irritate the skin for long-term measurements of muscle activity in rehabilitation and other applications.

Accuracy of Video-Based Hand Tracking for People With Upper-Body Disabilities.

Utilization of hand-tracking cameras, such as Leap, for hand rehabilitation and functional assessments is an innovative approach to providing affordable alternatives for people with disabilities. However, prior to deploying these commercially-available tools, a thorough evaluation of their performance for disabled populations is necessary. In this study, we provide an in-depth analysis of the accuracy of Leap's hand-tracking feature for both individuals with and without upper-body disabilities for common dynamic tasks used in rehabilitation. Leap is compared against motion capture with conventional techniques such as signal correlations, mean absolute errors, and digit segment length estimation. We also propose the use of dimensionality reduction techniques, such as Principal Component Analysis (PCA), to capture the complex, high-dimensional signal spaces of the hand. We found that Leap's hand-tracking performance did not differ between individuals with and without disabilities, yielding average signal correlations between 0.7-0.9. Both low and high mean absolute errors (between 10-80mm) were observed across participants. Overall, Leap did well with general hand posture tracking, with the largest errors associated with the tracking of the index finger. Leap's hand model was found to be most inaccurate in the proximal digit segment, underestimating digit lengths with errors as high as 18mm. Using PCA to quantify differences between the high-dimensional spaces of Leap and motion capture showed that high correlations between latent space projections were associated with high accuracy in the original signal space. These results point to the potential of low-dimensional representations of complex hand movements to support hand rehabilitation and assessment.

Effect of Handedness on Learned Controllers and Sensorimotor Noise During Trajectory-Tracking.

In human-in-the-loop control systems, operators can learn to manually control dynamic machines with either hand using a combination of reactive (feedback) and predictive (feedforward) control. This article studies the effect of handedness on learned controllers and performance during a trajectory-tracking task. In an experiment with 18 participants, subjects perform an assay of unimanual trajectory-tracking and disturbance-rejection tasks through second-order machine dynamics, first with one hand then the other. To assess how hand preference (or dominance) affects learned controllers, we extend, validate, and apply a nonparametric modeling method to estimate the concurrent feedback and feedforward controllers. We find that performance improves because feedback adapts, regardless of the hand used. We do not detect statistically significant differences in performance or learned controllers between hands. Adaptation to reject disturbances arising exogenously (i.e., applied by the experimenter) and endogenously (i.e., generated by sensorimotor noise) explains observed performance improvements.

How Do People with Limited Movement Personalize Upper-Body Gestures? Considerations for the Design of Personalized and Accessible Gesture Interfaces.

Always-on, upper-body input from sensors like accelerometers, infrared cameras, and electromyography hold promise to enable accessible gesture input for people with upper-body motor impairments. When these sensors are distributed across the person's body, they can enable the use of varied body parts and gestures for device interaction. Personalized upper-body gestures that enable input from diverse body parts including the head, neck, shoulders, arms, hands and fingers and match the abilities of each user, could be useful for ensuring that gesture systems are accessible. In this work, we characterize the personalized gesture sets designed by 25 participants with upper-body motor impairments and develop design recommendations for upper-body personalized gesture interfaces. We found that the personalized gesture sets that participants designed were highly ability-specific. Even within a specific type of disability, there were significant differences in what muscles participants used to perform upper-body gestures, with some pre-dominantly using shoulder and upper-arm muscles, and others solely using their finger muscles. Eight percent of gestures that participants designed were with their head, neck, and shoulders, rather than their hands and fingers, demonstrating the importance of tracking the whole upper-body. To combat fatigue, participants performed 51% of gestures with their hands resting on or barely coming off of their armrest, highlighting the importance of using sensing mechanisms that are agnostic to the location and orientation of the body. Lastly, participants activated their muscles but did not visibly move during 10% of the gestures, demonstrating the need for using sensors that can sense muscle activations without movement. Both inertial measurement unit (IMU) and electromyography (EMG) wearable sensors proved to be promising sensors to differentiate between personalized gestures. Personalized upper-body gesture interfaces that take advantage of each person's abilities are critical for enabling accessible upper-body gestures for people with upper-body motor impairments.

Effects of virtual reality environments on overground walking in people with Parkinson disease and freezing of gait.

BACKGROUND: Freezing of gait (FoG) is a common target of rehabilitative interventions for people with Parkinson disease (PD). Virtual reality (VR) holds potential for advancing research and clinical management of FoG through flexible creation of FoG-provoking environments that are not easily or safely replicated in the clinic. OBJECTIVE: The aim of this study was to investigate whether VR environments that replicate FoG-provoking situations would exacerbate gait impairments associated with FoG compared to unobstructed VR and physical laboratory environments. METHODS: Gait characteristics (pace, rhythm, variability, asymmetry, and postural control domains) and festination were measured using motion capture while people with PD walked in VR environments based on FoG-provoking situations (doorway, hallway, and crowd environments) compared to unobstructed VR and physical laboratory environments. The effect of VR environments was assessed using one-way repeated measures ANOVAs with planned contrasts. RESULTS: Ten participants (mean age 74.1 years, 3 females, Hoehn and Yahr stage 2-3) with PD who self-reported FoG participated. Gait speed and step length were reduced in all VR environments compared to the physical laboratory. Step width was wider, step length was more variable, and festination was more common for some of the VR environments compared to the physical laboratory environment. Compared to the unobstructed virtual laboratory environment, step length was more variable in VR crowd and doorway environments. CONCLUSIONS: The exacerbation of gait impairments that are characteristic precursors of FoG in FoG-provoking VR environments supports the potential utility of VR technology in the assessment and treatment of gait impairments in PD.Implications for rehabilitationFreezing increases fall risk and reduces quality of life in Parkinson disease (PD).Virtual reality (VR) can simulate visuospatial environments that provoke freezing.Immersive VR doorway, hallway, and crowd environments were developed.Gait speed slowed when people with PD walked overground in all VR environments.Step variability and festination increased in freeze-provoking environments.

"That's frustrating": Perceptions of ankle foot orthosis provision, use, and needs among people with cerebral palsy and caregivers.

BACKGROUND: Cerebral palsy (CP) affects roughly 3 per 1000 births in the United States and is the most common pediatric developmental motor disability. Ankle foot orthoses (AFOs) are commonly prescribed to provide support and improve function for individuals with CP. OBJECTIVES: The study objective was to evaluate the lived experiences of individuals with CP and their caregivers regarding AFO access, use, and priorities. We examined experiences around the perceived purpose of AFOs, provision process, current barriers to use, and ideas for future AFO design. STUDY DESIGN: Secondary qualitative data analysis. METHODS: Secondary data analysis was performed on semistructured focus groups that included 68 individuals with CP and 74 caregivers. Of the focus group participants, 66 mentioned AFOs (16 individuals with CP and 50 caregivers). Deidentified transcripts were analyzed using inductive coding, and the codes were consolidated into themes. RESULTS: Four themes emerged: 1) AFO provision is a confusing and lengthy process, 2) participants want more information during AFO provision, 3) AFOs are uncomfortable and difficult to use, and 4) AFOs can benefit mobility and independence. Caregivers and individuals with CP recommended ideas such as 3D printing orthoses and education for caregivers on design choices to improve AFO design and provision. CONCLUSIONS: Individuals with CP and their caregivers found the AFO provision process frustrating but highlight that AFOs support mobility and participation. Further opportunities exist to support function and participation of people with CP by streamlining AFO provision processes, creating educational materials, and improving AFO design for comfort and ease of use.

Virtual reality doorway and hallway environments alter gait kinematics in people with Parkinson disease and freezing.

BACKGROUND: Many people with Parkinson disease (PD) experience freezing of gait (FoG), a transient gait disturbance associated with increased fall risk and reduced quality of life. Head-mounted virtual reality (VR) systems allow overground walking and can create immersive simulations of physical environments that induce FoG. RESEARCH QUESTION: For people with PD who experience FoG (PD+FoG), are kinematic gait changes observed in VR simulations of FoG-provoking environments? METHODS: In a cross-sectional experiment, people with PD+FoG walked at their self-selected speed in a physical laboratory and virtual laboratory, doorway, and hallway environments. Motion analysis assessed whole-body kinematics, including lower extremity joint excursions, swing phase toe clearance, trunk flexion, arm swing, sagittal plane inclination angle, and spatiotemporal characteristics. One-way repeated measures analysis of variance was conducted to examine the effects of environment on gait variables, with planned contrasts between laboratory environments and the virtual doorway and hallway. RESULTS: Twelve participants with PD+FoG (mean age [standard deviation]=72.8 [6.5] years, disease duration=8.8 [8.9] years, 3 females) completed the protocol. The environment had significant and widespread effects on kinematic and spatiotemporal variables. Compared to the physical laboratory, reduced joint excursions were observed in the ankle, knee, and hip when walking in the virtual doorway and in the knee and hip when walking in the virtual hallway. In both the virtual doorway and hallway compared to the physical laboratory, peak swing phase toe clearance, arm swing, and inclination angle were reduced, and walking was slower, with shorter, wider steps. SIGNIFICANCE: Virtual doorway and hallway environments induced kinematic changes commonly associated with FoG episodes, and these kinematic changes are consistent with forward falls that are common during FoG episodes. Combined with the flexibility of emerging VR technology, this research supports the potential of VR applications designed to improve the understanding, assessment, and treatment of FoG.

Decoding Intent With Control Theory: Comparing Muscle Versus Manual Interface Performance.

Manual device interaction requires precise coordination which may be difficult for users with motor impairments. Muscle interfaces provide alternative interaction methods that may enhance performance, but have not yet been evaluated for simple (eg. mouse tracking) and complex (eg. driving) continuous tasks. Control theory enables us to probe continuous task performance by separating user input into intent and error correction to quantify how motor impairments impact device interaction. We compared the effectiveness of a manual versus a muscle interface for eleven users without and three users with motor impairments performing continuous tasks. Both user groups preferred and performed better with the muscle versus the manual interface for the complex continuous task. These results suggest muscle interfaces and algorithms that can detect and augment user intent may be especially useful for future design of interfaces for continuous tasks.

Effective Gene Delivery to Valvular Interstitial Cells Using Adeno-Associated Virus Serotypes 2 and 3.

Currently, curative therapies for heart valve diseases do not exist, thus motivating the need for new therapeutics, regenerative and tissue-engineered valves, and further basic research into pathological mechanisms. For studying valve diseases and developing valve therapies, effective methods to manipulate gene expression in primary valvular interstitial cells (VICs), which promote calcification in disease, would be valuable. Unfortunately, there is little information reported about effective gene delivery methods for VICs. Adeno-associated virus (AAV) is a clinically proven gene delivery vector capable of transducing many cell types and tissues, but has not yet been reported to infect valvular cells. In this study, AAV serotypes 1-9 were tested for their ability to deliver a green fluorescent protein (GFP) reporter into VICs in vitro. Flow cytometry results indicate AAV2 and AAV3 are capable of transducing VICs more efficiently than other serotypes. Furthermore, transduction efficiencies can be optimized by increasing the multiplicity of infection (MOI) and using self-complementary, double-stranded genomes, yielding up to 98% successfully transduced cells. Transduction of VICs by AAV2 or AAV3 in the presence of competing soluble heparin significantly reduces delivery efficiencies, suggesting heparan sulfate proteoglycans act as the primary VIC receptors of these two serotypes. Overall, this study establishes AAV2 and AAV3 as efficient gene delivery vehicles for primary VICs. Such effective delivery vectors for valve cells may be broadly useful for numerous applications, including the study of valvular cell biology, development of valve disease therapies, and regulation of genes for tissue engineering heart valves.