Exciting innovations for the spinally injured

Spinal injury can be devastating, resulting, as it often does, in some paralysis and loss of sensation. Engineering plays an important role in spinal cord injury rehabilitation. Here, the authors survey current research into the uses of functional electrical stimulation to improve the quality of life of spinally injured people. Touching on the area of spinal cord repair and nerve regeneration, they also consider the question of whether technology can help paraplegics to take steps again

Upper-limb exercise in tetraplegia using functional electrical stimulation

Cervical spinal cord injury can result in dysfunction in both the lower and upper limbs (tetraplegia), andmay be accompanied by a range of secondary complications. The degree of upper-limb dysfunctiondepends upon the level and completeness of the lesion; in this paper we consider tetraplegics with a neurological level in the range C4-C6. A person with a C5- or C6-level injury will generally retain control of the shoulder and elbow flexor muscles biceps), but will have no control of the hand, wrist or elbow extensors (triceps).With a complete C4 injury voluntary control of the entire arm is lost. Thus, we propose that functional electrical stimulation (FES) of the biceps and triceps muscles may enhance the efficacy of cyclical upper-limb exercise. Alternatives for partial restoration of function include tendon transfer surgery or mechanical orthoses1. Previous FES research for C4-C6 tetraplegics has focused on systems for hand function2,3 and improved working area (i.e. overhead reach)4,5,6,7, but the provision of upper-limb exercise modalities using FES assistance has been neglected. This is important because the lack of effective exercise can lead rapidly to severe cardiopulmonary deconditioning in this population

Automatic electrical stimulation of abdominal wall muscles increases tidal volume and cough peak flow in tetraplegia

<p>Paralysis of the respiratory muscles in people with tetraplegia affects their ability to breathe and contributes to respiratory complications. Surface functional electrical stimulation (FES) of abdominal wall muscles can be used to increase tidal volume (V_{T}) and improve cough peak flow (CPF) in tetraplegic subjects who are able to breathe spontaneously.</p> <p>This study aims to evaluate the feasibility and effectiveness of a novel abdominal FES system which generates stimulation automatically, synchronised with the subjects' voluntary breathing activity. Four subjects with complete tetraplegia (C4-C6), breathing spontaneously, were recruited.</p> <p>The automatic stimulation system ensured that consistent stimulation was achieved. We compared spirometry during unassisted and FES-assisted quiet breathing and coughing, and measured the effect of stimulation on end-tidal CO_2 (EtCO_2) during quiet breathing.</p> <p>The system dependably recognised spontaneous respiratory effort, stimulating appropriately, and was well tolerated by patients. Significant increases in V_T during quiet breathing (range 0.05–0.23 L) and in CPF (range 0.04–0.49 L/s) were observed. Respiratory rate during quiet breathing decreased in all subjects when stimulated, whereas minute ventilation increased by 1.05–2.07 L/min. The changes in EtCO_2 were inconclusive.</p> <p>The automatic stimulation system augmented spontaneous breathing and coughing in tetraplegic patients and may provide a potential means of respiratory support for tetraplegic patients with reduced respiratory capacity.</p&gt

Arm-cranking exercise assisted by Functional Electrical Stimulation in C6 tetraplegia: a pilot study

Tetraplegic volunteers undertook progressive exercise training, using novel systems for arm-cranking exercise assisted by Functional Electrical Stimulation (FES). The main aim was to determine potential training effects of FES-assisted arm-crank ergometry (FES-ACE) on upper limb strength and cardiopulmonary {fitness} in tetraplegia. Surface FES was applied to the biceps and triceps during exercise on an instrumented ergometer. Two tetraplegic volunteers with C6 Spinal Cord Injury (SCI) went through muscle strengthening, baseline exercise testing and three months of progressive FES-ACE training. Repeat exercise tests were carried out every four weeks during training, and post-training, to monitor upper-limb strength and cardiopulmonary fitness. At each test point, an incremental test was carried out to determine peak work rate, peak oxygen uptake, gas exchange threshold and oxygen uptake-work rate relationship during FES-ACE. Peak oxygen uptake for Subject A increased from 0.7 l/min to 1.1 l/min, and peak power output increased from 7 W to 38 W after FES-ACE training. For Subject B, peak oxygen uptake was unchanged, but peak power output increased from 3 W to 8 W. These case studies illustrate potential benefits of FES-ACE in tetraplegia, but also the differences in exercise responses between individuals. Keywords: electrical stimulation; spinal cord injury; cardiopulmonary fitness; rehabilitation; tetraplegi

Alarmins in frozen shoulder: a molecular association between inflammation and pain

Background: The pathophysiological mechanisms behind proliferation of fibroblasts and deposition of dense collagen matrix in idiopathic frozen shoulder remain unclear. Alarmins (also known as danger signals) are endogenous molecules that are released into the extracellular milieu after infection or tissue injury and that signal cell and tissue damage. Purpose: To investigate whether the presence of alarmins is higher in patients with idiopathic frozen shoulder than in control subjects. Study Design: Controlled laboratory study. Methods: Shoulder capsule samples were collected from 10 patients with idiopathic frozen shoulder and 10 patients with unstable shoulders (control). The samples were stained with hematoxylin and eosin (H&E) and analyzed by immunohistochemistry using antibodies against alarmin molecules including high-mobility group protein B1 (HMGB1), interleukin 33, S100A8, S100A9, and the peripheral nerve marker PGP9.5. Immunoreactivities were rated in a blinded fashion from “none” to “strong.” Immunohistochemical distribution within the capsule was noted. Before surgery, patient-ranked pain frequency, severity, stiffness, and the range of passive shoulder motion were recorded and statistically analyzed. Results: Compared with control patients, patients with frozen shoulder had greater frequency and severity of self-reported pain (P = .02) and more restricted range of motion in all planes (P < .05). H&E-stained capsular tissue from frozen shoulder showed fibroblastic hypercellularity and increased subsynovial vascularity. Immunoreactivity of alarmins was significantly stronger in frozen shoulder capsules compared with control capsules (P < .05). Furthermore, the expression of the alarmin molecule HMGB1 significantly correlated (r > 0.9, P < .05) with the severity of patient-reported pain. Conclusion: This study demonstrates a potential role for key molecular danger signals in frozen shoulder and suggests an association between the expression of danger molecules and the pain experienced by patients

Methods and protocols for incremental exercise testing in tetraplegia, using arm-crank ergometry assisted by Functional Electrical Stimulation

Cervical spinal cord injury (SCI) leads to tetraplegia, with paralysis and loss of sensation in the upper and lower limbs. The associated sedentary lifestyle results in an increased risk of cardiovascular disease. To address this, we require the design of exercise modalities aimed specifically at tetraplegia and methods to assess their efficacy. This paper describes methods for arm-crank ergometry (ACE) assisted by Functional Electrical Stimulation (FES) applied to the biceps and triceps. The instrumented ergometer enables work-rate control during exercise, implemented here for incremental exercise testing during FES-ACE. Detailed protocols for the tests are given. Experimental data collected during exercise tests with tetraplegic volunteers are provided to illustrate the feasibility of the proposed approach to testing and data analysis. Incremental tests enabled calculation of peak power output and peak oxygen uptake. We propose that the high-precision exercise testing protocols described here are appropriate to assess the efficacy of the novel exercise modality, FES-ACE, in tetraplegia

Comparison of stimulation patterns for FES-cycling using measures of oxygen cost and stimulation cost

<b>Aim</b><p></p> The energy efficiency of FES-cycling in spinal cord injured subjects is very much lower than that of normal cycling, and efficiency is dependent upon the parameters of muscle stimulation. We investigated measures which can be used to evaluate the effect on cycling performance of changes in stimulation parameters, and which might therefore be used to optimise them. We aimed to determine whether oxygen cost and stimulation cost measurements are sensitive enough to allow discrimination between the efficacy of different activation ranges for stimulation of each muscle group during constant-power cycling. <p></p> <b>Methods</b><p></p> We employed a custom FES-cycling ergometer system, with accurate control of cadence and stimulated exercise workrate. Two sets of muscle activation angles (“stimulation patterns”), denoted “P1” and “P2”, were applied repeatedly (eight times each) during constant-power cycling, in a repeated measures design with a single paraplegic subject. Pulmonary oxygen uptake was measured in real time and used to determine the oxygen cost of the exercise. A new measure of stimulation cost of the exercise is proposed, which represents the total rate of stimulation charge applied to the stimulated muscle groups during cycling. A number of energy-efficiency measures were also estimated. <p></p> <b>Results</b><p></p> Average oxygen cost and stimulation cost of P1 were found to be significantly lower than those for P2 (paired <i>t</i>-test, <i>p</i> < 0.05): oxygen costs were 0.56 ± 0.03 l min<sup>−1</sup> and 0.61 ± 0.04 l min<sup>−1</sup>(mean ± S.D.), respectively; stimulation costs were 74.91 ± 12.15 mC min<sup>−1</sup> and 100.30 ± 14.78 mC min<sup>−1</sup> (mean ± S.D.), respectively. Correspondingly, all efficiency estimates for P1 were greater than those for P2. <p></p> <b>Conclusion</b><p></p> Oxygen cost and stimulation cost measures both allow discrimination between the efficacy of different muscle activation patterns during constant-power FES-cycling. However, stimulation cost is more easily determined in real time, and responds more rapidly and with greatly improved signal-to-noise properties than the ventilatory oxygen uptake measurements required for estimation of oxygen cost. These measures may find utility in the adjustment of stimulation patterns for achievement of optimal cycling performance. <p></p&gt

Fibroblast activation and inflammation in frozen shoulder

Introduction: Frozen shoulder is a common, fibro-proliferative disease characterised by the insidious onset of pain and progressively restricted range of shoulder movement. Despite the prevalence of this disease, there is limited understanding of the molecular mechanisms underpinning the pathogenesis of this debilitating disease. Previous studies have identified increased myofibroblast differentiation and proliferation, immune cell influx and dysregulated cytokine production. We hypothesised that subpopulations within the fibroblast compartment may take on an activated phenotype, thus initiating the inflammatory processes observed in frozen shoulder. Therefore, we sought to evaluate the presence and possible pathogenic role of known stromal activation proteins in Frozen shoulder, Methods: Shoulder capsule samples were collected from 10 patients with idiopathic frozen shoulder and 10 patients undergoing shoulder stabilisation surgery. Fibroblast activation marker expression (CD248, CD146, VCAM and PDPN, FAP) was quantified using immunohistochemistry. Control and diseased fibroblasts were cultured for in vitro studies from capsule biopsies from instability and frozen shoulder surgeries, respectively. The inflammatory profile and effects of IL-1β upon diseased and control fibroblasts was assessed using ELISA, immunohistochemistry and qPCR. Results: Immunohistochemistry demonstrated increased expression of fibroblast activation markers CD248, CD146, VCAM and PDPN in the frozen shoulder group compared with control (p < 0.05). Fibroblasts cultured from diseased capsule produced elevated levels of inflammatory protein (IL-6, IL-8 & CCL-20) in comparison to control fibroblasts. Exposing control fibroblasts to an inflammatory stimuli, (IL-1ß) significantly increased stromal activation marker transcript and protein expression (CD248, PDPN and VCAM). Conclusions: These results show that fibroblasts have an activated phenotype in frozen shoulder and this is associated with inflammatory cytokine dysregulation. Furthermore, it supports the hypothesis that activated fibroblasts may be involved in regulating the inflammatory and fibrotic processes involved in this disease

S100A8 & S100A9: alarmin mediated inflammation in tendinopathy

Alarmins S100A8 and S100A9 are endogenous molecules released in response to environmental triggers and cellular damage. They are constitutively expressed in immune cells such as monocytes and neutrophils and their expression is upregulated under inflammatory conditions. The molecular mechanisms that regulate inflammatory pathways in tendinopathy are largely unknown therefore identifying early immune effectors is essential to understanding the pathology. Based on our previous investigations highlighting tendinopathy as an alarmin mediated pathology we sought evidence of S100A8 & A9 expression in a human model of tendinopathy and thereafter, to explore mechanisms whereby S100 proteins may regulate release of inflammatory mediators and matrix synthesis in human tenocytes. Immunohistochemistry and quantitative RT-PCR showed S100A8 & A9 expression was significantly upregulated in tendinopathic tissue compared with control. Furthermore, treating primary human tenocytes with exogenous S100A8 & A9 significantly increased protein release of IL-6, IL-8, CCL2, CCL20 and CXCL10; however, no alterations in genes associated with matrix remodelling were observed at a transcript level. We propose S100A8 & A9 participate in early pathology by modulating the stromal microenvironment and influencing the inflammatory profile observed in tendinopathy. S100A8 and S100A9 may participate in a positive feedback mechanism involving enhanced leukocyte recruitment and release of pro-inflammatory cytokines from tenocytes that perpetuates the inflammatory response within the tendon in the early stages of disease

Novel self-amplificatory loop between T cells and tenocytes as a driver of chronicity in tendon disease

Objectives: Increasing evidence suggests that inflammatory mechanisms play a key role in chronic tendon disease. After observing T cell signatures in human tendinopathy, we explored the interaction between T cells and tendon stromal cells or tenocytes to define their functional contribution to tissue remodelling and inflammation amplification and hence disease perpetuation. Methods: T cells were quantified and characterised in healthy and tendinopathic tissues by flow cytometry (FACS), imaging mass cytometry (IMC) and single cell RNA-seq. Tenocyte activation induced by conditioned media from primary damaged tendon or interleukin-1β was evaluated by qPCR. The role of tenocytes in regulating T cell migration was interrogated in a standard transwell membrane system. T cell activation (cell surface markers by FACS and cytokine release by ELISA) and changes in gene expression in tenocytes (qPCR) were assessed in cocultures of T cells and explanted tenocytes. Results: Significant quantitative differences were observed in healthy compared with tendinopathic tissues. IMC showed T cells in close proximity to tenocytes, suggesting tenocyte–T cell interactions. On activation, tenocytes upregulated inflammatory cytokines, chemokines and adhesion molecules implicated in T cell recruitment and activation. Conditioned media from activated tenocytes induced T cell migration and coculture of tenocytes with T cells resulted in reciprocal activation of T cells. In turn, these activated T cells upregulated production of inflammatory mediators in tenocytes, while increasing the pathogenic collagen 3/collagen 1 ratio. Conclusions: Interaction between T cells and tenocytes induces the expression of inflammatory cytokines/chemokines in tenocytes, alters collagen composition favouring collagen 3 and self-amplifies T cell activation via an auto-regulatory feedback loop. Selectively targeting this adaptive/stromal interface may provide novel translational strategies in the management of human tendon disorders