Exosuit-induced improvements in walking after stroke: comprehensive analysis on gait energetics and biomechanics

Outstanding Poster Presentation Finalis

Biomechanical mechanisms underlying exosuit-induced improvements in walking economy after stroke

Stroke-induced hemiparetic gait is characteristically asymmetric and metabolically expensive. Weakness and impaired control of the paretic ankle contribute to reduced forward propulsion and ground clearance—walking subtasks critical for safe and efficient locomotion. Targeted gait interventions that improve paretic ankle function after stroke are therefore warranted. We have developed textile-based, soft wearable robots that transmit mechanical power generated by off-board or body-worn actuators to the paretic ankle using Bowden cables (soft exosuits) and have demonstrated the exosuits can overcome deficits in paretic limb forward propulsion and ground clearance, ultimately reducing the metabolic cost of hemiparetic walking. This study elucidates the biomechanical mechanisms underlying exosuit-induced reductions in metabolic power. We evaluated the relationships between exosuit-induced changes in the body center of mass (COM) power generated by each limb, individual joint powers, and metabolic power. Compared to walking with an exosuit unpowered, exosuit assistance produced more symmetrical COM power generation during the critical period of the step-to-step transition (22.4±6.4% more symmetric). Changes in individual limb COM power were related to changes in paretic (R2= 0.83, P= 0.004) and nonparetic (R2= 0.73, P= 0.014) ankle power. Interestingly, despite the exosuit providing direct assistance to only the paretic limb, changes in metabolic power were related to changes in nonparetic limb COM power (R2= 0.80, P= 0.007), not paretic limb COM power (P> 0.05). These findings provide a fundamental understanding of how individuals poststroke interact with an exosuit to reduce the metabolic cost of hemiparetic walking.Accepted manuscript2019-03-0

The effect of reinfection and mixed Trypanosoma cruzi infections on disease progression in mice

The progression of Chagas disease (CD) varies significantly from host to host and is affected by multiple factors. In particular, mixed strain infections and reinfections have the potential to exacerbate disease progression subsequently affecting clinical management of patients with CD. Consequently, an associated reduction in therapeutic intervention and poor prognosis may occur due to this exacerbated disease state. This study investigated the effects of mixed strain infections and reinfection with Trypanosoma cruzi in mice, using two isolates from different discrete typing units, TcI (C8 clone 1) and TcIV (10R26). There were no significant differences in mortality rate, body weight or body condition among mice infected with either C8 clone 1, 10R26, or a mixture of both isolates. However, the parasite was found in a significantly greater number of host organs in mice infected with a mixture of isolates, and the histopathological response to infection was significantly greater in mice infected with C8 clone 1 alone, and C8 clone 1 + 10R26 mixed infections than in mice infected with 10R26 alone. To investigate the effects of reinfection, mice received either a double exposure to C8 clone 1; a double exposure to 10R26; exposure to C8 clone 1 followed by 10R26; or exposure to 10R26 followed by C8 done 1. Compared to single infection groups, mortality was significantly increased, while survival time, body weight and body condition were all significantly decreased across all reinfection groups, with no significant differences among these groups. The mortality rate over all reinfection groups was 63.6%, compared to 0% in single infection groups, however there was no evidence of a greater histopathological response to infection. These results suggest firstly, that the C8 clone 1 isolate is more virulent than the 10R26 isolate, and secondly, that a more disseminated infection may occur with a mixture of isolates than with single isolates, although there is no evidence that mixed infections have a greater pathological effect. By contrast, reinfections do have major effects on host survivability and thus disease outcome. This confirms previous research demonstrating spontaneous deaths following reinfection, a phenomenon that to our knowledge has only been reported once before

Peptide sequence effects control the single pot reduction, nucleation, and growth of Au nanoparticles

YesPeptides have demonstrated unique capabilities to fabricate inorganic nanomaterials of numerous compositions through noncovalent binding of the growing surface in solution. In this contribution, we demonstrate that these biomolecules can control all facets of Au nanoparticle fabrication, including Au3+ reduction, without the use of secondary reagents. In this regard using the AuBP1 peptide, the N-terminal tryptophan residue is responsible for driving Au3+ reduction to generate Au nanoparticles passivated by the oxidized peptide in solution, where localized residue context effects control the reducing strength of the biomolecule. The process was fully monitored by both time-resolved monitoring of the growth of the localized surface plasmon resonance and transmission electron microscopy. Nanoparticle growth occurs by a unique disaggregation of nanoparticle aggregates in solution. Computational modeling demonstrated that the oxidized residue of the peptide sequence does not impact the biomolecule’s ability to bind the inorganic surface, as compared to the parent peptide, confirming that the biomolecule can be exploited for all steps in the nanoparticle fabrication process. Overall, these results expand the utility of peptides for the fabrication of inorganic nanomaterials, more strongly mimicking their use in nature via biomineralization processes. Furthermore, these capabilities enhance the simplicity of nanoparticle production and could find rapid use in the generation of complex multicomponent materials or nanoparticle assembly.Air Force Office of Scientific Research, grant FA9550-12-1-0226

Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase

The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 μM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes

Indirect measurement of anterior-posterior ground reaction forces using a minimal set of wearable inertial sensors: from healthy to hemiparetic walking

BACKGROUND: The anterior-posterior ground reaction force (AP-GRF) and propulsion and braking point metrics derived from the AP-GRF time series are indicators of locomotor function across healthy and neurological diagnostic groups. In this paper, we describe the use of a minimal set of wearable inertial measurement units (IMUs) to indirectly measure the AP-GRFs generated during healthy and hemiparetic walking. METHODS: Ten healthy individuals and five individuals with chronic post-stroke hemiparesis completed a 6-minute walk test over a walking track instrumented with six forceplates while wearing three IMUs securely attached to the pelvis, thigh, and shank. Subject-specific models driven by IMU-measured thigh and shank angles and an estimate of body acceleration provided by the pelvis IMU were used to generate indirect estimates of the AP-GRF time series. Propulsion and braking point metrics (i.e., peaks, peak timings, and impulses) were extracted from the IMU-generated time series. Peaks and impulses were expressed as % bodyweight (%bw) and peak timing was expressed as % stance phase (%sp). A 75%-25% split of 6-minute walk test data was used to train and validate the models. Indirect estimates of the AP-GRF time series and point metrics were compared to direct measurements made by the forceplates. RESULTS: Indirect measurements of the AP-GRF time series approximated the direct measurements made by forceplates, with low error and high consistency in both the healthy (RMSE= 4.5%bw; R2= 0.93) and post-stroke (RMSE= 2.64%bw; R2= 0.90) cohorts. In the healthy cohort, the average errors between indirect and direct measurements of the peak propulsion magnitude, peak propulsion timing, and propulsion impulse point estimates were 2.37%bw, 0.67%sp, and 0.43%bw. In the post-stroke cohort, the average errors for these point estimates were 1.07%bw, 1.27%sp, and 0.31%bw. Average errors for the braking estimates were higher, but comparable. CONCLUSIONS: Accurate estimates of AP-GRF metrics can be generated using three strategically mounted IMUs and subject-specific calibrations. This study advances the development of point-of-care diagnostic systems that can catalyze the routine assessment and management of propulsion and braking locomotor deficits during rehabilitation.KL2 TR001411 - NCATS NIH HHSPublished versio