Localized Sustained Release of Copper Enhances Antitumor Effects of Disulfiram in Head and Neck Cancer.

Drug repurposing uses approved drugs as candidate anticancer therapeutics, harnesses previous research and development efforts, and benefits from available clinically suitable formulations and evidence of patient tolerability. In this work, the drug used clinically to treat chronic alcoholism, disulfiram (DSF), was studied for its antitumor efficacy in a copper-dependent manner. The combination of DSF and copper could achieve a tumor cell growth inhibition effect comparable to those of 5-fluorouracil and taxol on head and neck cancer cells. Both bulk dendrimer hydrogel and microsized dendrimer hydrogel particles were utilized for the localized sustained release of copper in the tumor site. The localized sustained release of copper facilitated the tumor inhibition effect following intratumoral injection in a mouse's head and neck cancer model.

Teaching Motor Skills Without a Motor: A Semi-Passive Robot to Facilitate Learning.

Semi-passive rehabilitation robots resist and steer a patient's motion using only controllable passive force elements (e.g., controllable brakes). Contrarily, passive robots use uncontrollable passive force elements (e.g., springs), while active robots use controllable active force elements (e.g., motors). Semi-passive robots can address cost and safety limitations of active robots, but it is unclear if they have utility in rehabilitation. Here, we assessed if a semi-passive robot could provide haptic guidance to facilitate motor learning. We first performed a theoretical analysis of the robot's ability to provide haptic guidance, and then used a prototype to perform a motor learning experiment that tested if the guidance helped participants learn to trace a shape. Unlike prior studies, we minimized the confounding effects of visual feedback during motor learning. Our theoretical analysis showed that our robot produced guidance forces that were, on average, 54° from the current velocity (active devices achieve 90). Our motor learning experiment showed, for the first time, that participants who received haptic guidance during training learned to trace the shape more accurately (97.57% error to 52.69%) than those who did not receive guidance (81.83% to 78.18%). These results support the utility of semi-passive robots in rehabilitation.

Bioinspired preactivation reflex increases robustness of walking on rough terrain.

Walking on unknown and rough terrain is challenging for (bipedal) robots, while humans naturally cope with perturbations. Therefore, human strategies serve as an excellent inspiration to improve the robustness of robotic systems. Neuromusculoskeletal (NMS) models provide the necessary interface for the validation and transfer of human control strategies. Reflexes play a crucial part during normal locomotion and especially in the face of perturbations, and provide a simple, transferable, and bio-inspired control scheme. Current reflex-based NMS models are not robust to unexpected perturbations. Therefore, in this work, we propose a bio-inspired improvement of a widely used NMS walking model. In humans, different muscles show an increase in activation in anticipation of the landing at the end of the swing phase. This preactivation is not integrated in the used reflex-based walking model. We integrate this activation by adding an additional feedback loop and show that the landing is adapted and the robustness to unexpected step-down perturbations is markedly improved (from 3 to 10 cm). Scrutinizing the effect, we find that the stabilizing effect is caused by changed knee kinematics. Preactivation, therefore, acts as an accommodation strategy to cope with unexpected step-down perturbations, not requiring any detection of the perturbation. Our results indicate that such preactivation can potentially enable a bipedal system to react adequately to upcoming unexpected perturbations and is hence an effective adaptation of reflexes to cope with rough terrain. Preactivation can be ported to robots by leveraging the reflex-control scheme and improves the robustness to step-down perturbation without the need to detect the perturbation. Alternatively, the stabilizing mechanism can also be added in an anticipatory fashion by applying an additional knee torque to the contralateral knee.

Using a low-dose ultraviolet-B lighting solution during working hours: An explorative investigation towards the effectivity in maintaining healthy vitamin D levels.

OBJECTIVE: This study examined whether daily safe, low-dose ultraviolet-B (UVB) exposure using a home-based lighting solution could maintain healthy serum 25(OH)D during winter. METHODS: Twenty-eight (12 male, 16 female) daytime (~9:00 to 17:00) indoor workers (mean age = 42.46; SD = 14.23) participated in this study and were allocated to one of the two study conditions. During an 8-week period, fourteen participants received extra UVB exposure (max 0.3 standard erythema dose (SED) daily), while fourteen participants in the control group did not receive extra UVB exposure. Daily questionnaires were used to measure UVB exposure time, exposed body surface area (BSA), and time spent outside in daylight. Serum 25(OH)D, vitamin D related food intake, and secondary parameters (i.e., subjective fatigue, sleep timing and quality) were investigated at baseline, Week 4, and Week 8. RESULTS: Serum 25(OH)D significantly declined over the 8-week study period in both groups. The combination of using a low-dose UVB exposure, a small BSA, and a lower-than-expected amount of exposure hours likely resulted in an insufficient UVB dose to significantly improve serum 25(OH)D. Changes in serum 25(OH)D over time did not significantly correlate with changes in secondary parameters of sleep and fatigue. CONCLUSION: The received low-dose UVB exposure in this study did not significantly change serum 25(OH)D during the winter period. Future research could explore whether a longer lasting exposure period and/or using different exposure positions of the device (maximizing exposed skin surface) yields more promising results for improving serum 25(OH)D. TRIAL REGISTRATION: Trial registration: https://www.isrctn.com/ISRCTN47902923.

The role of user preference in the customized control of robotic exoskeletons.

User preference is a promising objective for the control of robotic exoskeletons because it may capture the multifactorial nature of exoskeleton use. However, to use it, we must first understand its characteristics in the context of exoskeleton control. Here, we systematically measured the control preferences of individuals wearing bilateral ankle exoskeletons during walking. We investigated users' repeatability identifying their preferences and how preference changes with walking speed, device exposure, and between individuals with different technical backgrounds. Twelve naive and 12 knowledgeable nondisabled participants identified their preferred assistance in repeated trials by simultaneously self-tuning the magnitude and timing of peak torque. They were blinded to the control parameters and relied solely on their perception of the assistance to guide their tuning. We found that participants' preferences ranged from 7.9 to 19.4 newton-meters and 54.1 to 59.2 percent of the gait cycle. Across trials, participants repeatably identified their preferences with a mean standard deviation of 1.7 newton-meters and 1.5 percent of the gait cycle. Within a trial, participants converged on their preference in 105 seconds. As the experiment progressed, naive users preferred higher torque magnitude. At faster walking speeds, these individuals were more precise at identifying the magnitude of their preferred assistance. Knowledgeable users preferred higher torque than naive users. These results highlight that although preference is a dynamic quantity, individuals can reliably identify their preferences. This work motivates strategies for the control of lower limb exoskeletons in which individuals customize assistance according to their unique preferences and provides meaningful insight into how users interact with exoskeletons.

Nano-in-Nano Dendrimer Gel Particles for Efficient Topical Delivery of Antiglaucoma Drugs into the Eye.

Low bioavailability of topically applied drugs remains a significant challenge for long-term glaucoma therapy. To enhance drug delivery efficiency, we developed dendrimer gel particles that collectively exhibit structural benefits of dendrimer, hydrogel, and particles, using the inverse emulsion method coupled with the highly efficient aza-Michael addition reaction (IEaMA). This hierarchical approach would maximize the utility of the structural features of existing ocular drug delivery systems. We have tested the delivery efficiency and efficacy of two first-line antiglaucoma drugs, brimonidine tartrate (BT) and timolol maleate (TM), which were loaded into dendrimer gel particles of various sizes, i.e., nDHP (nano-in-nano dendrimer hydrogel particles, ~200 nm), µDHP3 (3 µm), and µDHP10 (9 µm). We found that nDHP was superior to µDHP3 and µDHP10 in terms of cytocompatibility, degradability, drug release kinetics, and corneal permeability. The nDHPs increased drug corneal permeability by 17-fold compared to plain drug solution and enabled zero-order prolonged drug release kinetics. The nDHP-based formulation demonstrated pronounced IOP-lowering effects in both single-dose test and 7-day chronic daily dosing test in both Brown Norway rats and glaucoma mice. Taken together, we have developed nano-in-nano dendrimer gel particles for precise dosing and enabling sustained and synergistic efficacy of antiglaucoma drugs, which could be clinically impactful for improving glaucoma treatment.

Over-Expression of Intestinal Alkaline Phosphatase Attenuates Atherosclerosis.

[Figure: see text].

Duplex of Polyamidoamine Dendrimer/Custom-Designed Nuclear-Localization Sequence Peptide for Enhanced Gene Delivery.

Background: Dendrimers are an attractive alternative to viral vectors due to the low cost of production, larger genetic insert-carrying capacity, and added control over immune- and genotoxic complications through versatile functionalization. However, their transfection rates pale in comparison to their viral counterparts, resulting in widespread research efforts in the attempt to improve transfection efficiency. Materials and Methods: In this work, we designed a synthetic diblock nuclear-localization sequence peptide (NLS) (DDDDDDVKRKKKP) and complexed it with polyamidoamine (PAMAM) dendrimer G4 to form a duplex for gene delivery. We conducted transmission electron microscopy, gel mobility shift assay, and intracellular trafficking studies. We also assessed its transfection efficiency for the delivery of a green fluorescent protein-encoding plasmid (pGFP) to NIH3T3 cells. Results: PAMAM dendrimer G4, NLS, and plasmid DNA can form a stable three-part polyplex and gain enhanced entry into the nucleus. We found transfection efficiency, in large part, depends on the ratio of G4:NLS:plasmid. The triplex prepared at the ratio of 1:60:1 for G4:NLS:pGFP has been shown to be more significantly efficient in transfecting cells than the control group (G4/pGFP, 0.5:1). Conclusions: This new diblock NLS peptide can facilely complex with dendrimers to improve dendrimer-based gene transfection. It can also complex with other polycationic polymers to produce more potent nonviral duplex gene delivery vehicles.

Motor Modules are Impacted by the Number of Reaching Directions Included in the Analysis.

Muscle synergy analysis is commonly used to study how the nervous system coordinates the activation of a large number of muscles during human reaching. In synergy analysis, muscle activation data collected from various reaching directions are subjected to dimensionality reduction techniques to extract muscle synergies. Typically, muscle activation data are obtained only from a limited set of reaches with an inherent assumption that the performed reaches adequately represent all possible reaches. In this study, we investigated how the number of reaching directions included in the synergy analysis influences the validity of the extracted synergies. We used a musculoskeletal model to compute muscle activations required to perform 36 evenly spaced planar reaches. Nonnegative matrix factorization (NMF) and principal component analysis (PCA) were then used to extract reference synergies. We then selected several subsets of reaches and compared the ability of the extracted synergies from each subset to represent the muscle activation from all 36 reaches. We found that 6 reaches were required to extract valid synergies, and a further reduction in the number of reaches changed the composition of the resulting synergies. Further, we found that the choice of reaching directions included in the analysis for a given number of reaches also affected the validity of the extracted synergies. These findings indicate that both the number and the choice of reaching directions included in the analysis impacted the validity of the extracted synergies.

Polyamidoamine Dendrimer Grafted with an Acid-Responsive Charge-Reversal Layer for Improved Gene Delivery.

We report on a heterogeneous dendrimer (G3-acetal-NH2) derivative possessing an acid-responsive charge-reversal layer. The synthesis of G3-acetal-NH2 starts with a polyamidoamine (PAMAM) dendrimer G3 core and follows the aza-Michael addition with N-(2-(1-(allyloxy)ethoxy)ethyl)acrylamide synthesized by us and the thiol-ene click chemistry with cysteamine hydrochloride in sequence. In a weakly acidic environment, the surface of this newly formed dendrimer can turn from amine-terminated to hydroxyl-terminated due to the cleavage of the acetal groups. This charge conversion from 34.3 ± 2.7 to 18.0 ± 0.3 mV in 24 h at pH 5.3 enables its capacity as a gene delivery vehicle. G3-acetal-NH2 with a positively charged surface can condense pMAX GFP plasmid at similar weight ratios as native G4-NH2 (above 2:1), allowing for its protected uptake into cells and endosomal escape. Meanwhile, in the endosome, the drop in vesicle pH cleaves the acetal bond, releasing the genetic payload and limiting its recondensation by the reduction in the dendrimer surface charge. When the vector/plasmid weight ratio was 2:1, G3-acetal-NH2 improved transfection of pMAX GFP plasmid by 5-fold over native G4-NH2 in NIH3T3 cells in terms of GFP protein expression. Taken together, we show that this surface charge conversion performance makes the synthesized heterogeneous dendrimer an improved vehicle for gene transfection.

Injectable Multicomponent Biomimetic Gel Composed of Inter-Crosslinked Dendrimeric and Mesoporous Silica Nanoparticles Exhibits Highly Tunable Elasticity and Dual Drug Release Capacity.

There is a growing need for cartilage defect grafts that are structurally adaptable to possess multifaceted functions to promote bone regeneration, sustain medication efficacy, and preferably remain injectable but solidify quickly upon injection. In this work, we developed an injectable multicomponent biomimetic gel (MBG) by integrating polyamidoamine dendrimer G3 (G3), mesoporous silica nanoparticles (MSNs), and dendrimer-templated silver nanoparticles (G3-Ag) into a well-defined cross-linked network. MBGs composed of one particulate component (G3 alone), i.e., MBG-1, two particulate components (G3 and MSN-NH2), i.e., MBG-2, and three particulate components (G3, MSN-NH2, and G3-Ag), i.e., MBG-3, were prepared by inter-cross-linking dendrimeric and mesoporous silica nanoparticles with poly(ethylene glycol) diglycidyl ether (PEG-DGE, Mn = 2000 g/mol) via the facile amine-epoxy click reaction. The water-soluble antibiotic isoniazid was loaded to the cross-linked PEG network, whereas the hydrophobic antibiotic rifampicin was encapsulated into mesoporous MSNs. Our studies revealed that elasticity and mechanical strengths could be modulated and enhanced significantly with the inclusion of MSNs and silver nanoparticles. Isoniazid was released rapidly while rifampicin was released over an extended period of time. In addition, MBGs showed injectability, high swelling capacity, structural stability, and cytocompatibility. Taken together, MBGs have shown structural features that allow for the development of injectable gel grafts with the ability to promote cartilage defect repair and offer antibiotic medication benefits.

Hydrogel-based ocular drug delivery systems: Emerging fabrication strategies, applications, and bench-to-bedside manufacturing considerations.

The physiological barriers of the eye pose challenges to the delivery of the array of therapeutics for ocular diseases. Hydrogels have been widely explored for medical applications and introduce possible solutions to overcoming the medication challenges of the ocular environment. While the innovations in drug encapsulation and release mechanisms, biocompatibility, and treatment duration have become highly sophisticated, the challenge of widespread application of hydrogel formulations in the clinic is still apparent. This article reviews the latest hydrogel formulations and their associated chemistries for use in ocular therapies, spanning from external anterior to internal posterior regions of the eye in order to evaluate the state of recent research. This article discusses the utility of hydrogels in soft contact lens, wound dressings, intraocular lens, vitreous substitutes, vitreous drug release hydrogels, and cell-based therapies for regeneration. Additional focus is placed on the pre-formulation, formulation, and manufacturing considerations of the hydrogels based on individual components (polymer chains, linkers, and therapeutics), final hydrogel product, and required preparations for clinical/commercial applications, respectively.

Drug-Conjugated Dendrimer Hydrogel Enables Sustained Drug Release via a Self-Cleaving Mechanism.

In this study, the anticancer drug, camptothecin (CPT), was covalently grafted onto polyamidoamine (PAMAM) dendrimer surface and then reacted with polyethylene glycol diacrylate (PEG-DA) to form dendrimer hydrogel (DH-G3-CPT) with low cross-linking density. In this novel drug delivery system, CPT was cleaved from dendrimer via the ammonolysis of ester bonds and then diffused out of the hydrogel network, thus leading to significantly prolonged drug release. The self-cleaving release kinetics of camptothecin can be further tuned by pH. This DH-G3-CPT drug delivery system has both injectability and sustained drug release. It showed an excellent tumor inhibition effect following intratumoral injection in a head and neck cancer model of mouse.

An Inductance-Based Sensing System for Bellows-Driven Continuum Joints in Soft Robots.

In this work we present a novel, inductance-based system to measure and control the motion of bellows-driven continuum joints in soft robots. The sensing system relies on coils of wire wrapped around the minor diameters of each bellows on the joint. As the bellows extend, these coils of wire become more distant, decreasing their mutual inductance. Measuring this change in mutual inductance allows us to measure the motion of the joint. By dividing the sensing of the joint into two sections and measuring the motion of each section independently, we are able to measure the overall deformation of the joint with a piece-wise constant-curvature approximation. This technique allows us to measure lateral displacements that would be otherwise unobservable. When measuring bending, the inductance sensors measured the joint orientation with an RMS error of 1.1 °. The inductance sensors were also successfully used as feedback to control the orientation of the joint. The sensors proposed and tested in this work provided accurate motion feedback that would be difficult to achieve robustly with other sensors. This sensing system enables the creation of robust, self-sensing soft robots based on bellows-driven continuum joints.

Evaluating physiological signal salience for estimating metabolic energy cost from wearable sensors.

Body-in-the-loop optimization algorithms have the capability to automatically tune the parameters of robotic prostheses and exoskeletons to minimize the metabolic energy expenditure of the user. However, current body-in-the-loop algorithms rely on indirect calorimetry to obtain measurements of energy cost, which are noisy, sparsely sampled, time-delayed, and require wearing a respiratory mask. To improve these algorithms, the goal of this work is to predict a user's steady-state energy cost quickly and accurately using physiological signals obtained from portable, wearable sensors. In this paper, we quantified physiological signal salience to discover which signals, or groups of signals, have the best predictive capability when estimating metabolic energy cost. We collected data from 10 healthy individuals performing 6 activities (walking, incline walking, backward walking, running, cycling, and stair climbing) at various speeds or intensities. Subjects wore a suite of physiological sensors that measured breath frequency and volume, limb accelerations, lower limb EMG, heart rate, electrodermal activity, skin temperature, and oxygen saturation; indirect calorimetry was used to establish the 'ground truth' energy cost for each activity. Evaluating Pearson's correlation coefficients and single and multiple linear regression models with cross validation (leave-one- subject-out and leave-one- task-out), we found that 1) filtering the accelerations and EMG signals improved their predictive power, 2) global signals (e.g., heart rate, electrodermal activity) were more sensitive to unknown subjects than tasks, while local signals (e.g., accelerations) were more sensitive to unknown tasks than subjects, and 3) good predictive performance was obtained combining a small number of signals (4-5) from multiple sensor modalities. NEW & NOTEWORTHY In this paper, we systematically compare a large set of physiological signals collected from portable sensors and determine which sensor signals contain the most salient information for predicting steady-state metabolic energy cost, robust to unknown subjects or tasks. This information, together with the comprehensive data set that is published in conjunction with this paper, will enable researchers and clinicians across many fields to develop novel algorithms to predict energy cost from wearable sensors.

Self-powered robots to reduce motor slacking during upper-extremity rehabilitation: a proof of concept study.

BACKGROUND: Robotic rehabilitation is a highly promising approach to recover lost functions after stroke or other neurological disorders. Unfortunately, robotic rehabilitation currently suffers from "motor slacking", a phenomenon in which the human motor system reduces muscle activation levels and movement excursions, ostensibly to minimize metabolic- and movement-related costs. Consequently, the patient remains passive and is not fully engaged during therapy. To overcome this limitation, we envision a new class of body-powered robots and hypothesize that motor slacking could be reduced if individuals must provide the power to move their impaired limbs via their own body (i.e., through the motion of a healthy limb). OBJECTIVE: To test whether a body-powered exoskeleton (i.e. robot) could reduce motor slacking during robotic training. METHODS: We developed a body-powered robot that mechanically coupled the motions of the user's elbow joints. We tested this passive robot in two groups of subjects (stroke and able-bodied) during four exercise conditions in which we controlled whether the robotic device was powered by the subject or by the experimenter, and whether the subject's driven arm was engaged or at rest. Motor slacking was quantified by computing the muscle activation changes of the elbow flexor and extensor muscles using surface electromyography. RESULTS: Subjects had higher levels of muscle activation in their driven arm during self-powered conditions compared to externally-powered conditions. Most notably, subjects unintentionally activated their driven arm even when explicitly told to relax when the device was self-powered. This behavior was persistent throughout the trial and did not wane after the initiation of the trial. CONCLUSIONS: Our findings provide novel evidence indicating that motor slacking can be reduced by self-powered robots; thus demonstrating promise for rehabilitation of impaired subjects using this new class of wearable system. The results also serve as a foundation to develop more sophisticated body-powered robots (e.g., with controllable transmissions) for rehabilitation purposes.

Choosing appropriate prosthetic ankle work to reduce the metabolic cost of individuals with transtibial amputation.

Powered ankle prostheses have been designed to reduce the energetic burden that individuals with transtibial amputation experience during ambulation. There is an open question regarding how much power the prosthesis should provide, and whether approximating biological ankle kinetics is optimal to reduce the metabolic cost of users. We tested 10 individuals with transtibial amputation walking on a treadmill wearing the BiOM powered ankle prosthesis programmed with 6 different power settings (0-100%), including a prosthetist-chosen setting, chosen to approximate biological ankle kinetics. We measured subjects' metabolic cost of transport (COT) and the BiOM's net ankle work during each condition. Across participants, power settings greater than 50% resulted in lower COT than 0% or 25%. The relationship between power setting, COT, and net ankle work varied considerably between subjects, possibly due to individual adaptation and exploitation of the BiOM's reflexive controller. For all subjects, the best tested power setting was higher than the prosthetist-chosen setting, resulting in a statistically significant and meaningful difference in COT between the best tested and prosthetist-chosen power settings. The results of this study demonstrate that individuals with transtibial amputation may benefit from prescribed prosthetic ankle push-off work that exceeds biological norms.

All common bipedal gaits emerge from a single passive model.

In this paper, we systematically investigate passive gaits that emerge from the natural mechanical dynamics of a bipedal system. We use an energetically conservative model of a simple spring-leg biped that exhibits well-defined swing leg dynamics. Through a targeted continuation of periodic motions of this model, we systematically identify different gaits that emerge from simple bouncing in place. We show that these gaits arise along one-dimensional manifolds that bifurcate into different branches with distinctly different motions. The branching is associated with repeated breaks in symmetry of the motion. Among others, the resulting passive dynamic gaits include walking, running, hopping, skipping and galloping. Our work establishes that the most common bipedal gaits can be obtained as different oscillatory motions (or nonlinear modes) of a single mechanical system with a single set of parameter values. For each of these gaits, the timing of swing leg motion and vertical motion is matched. This work thus supports the notion that different gaits are primarily a manifestation of the underlying natural mechanical dynamics of a legged system. Our results might explain the prevalence of certain gaits in nature, and may provide a blueprint for the design and control of energetically economical legged robots.

Correction to: A Semi-passive Planar Manipulandum for Upper-Extremity Rehabilitation.

Authors would like to correct their acknowledgments. Correct acknowledgments appear here.