Development and use of a porcine model with clinically relevant chronic infected wounds.

Chronic ischemic wounds affect millions of people causing significant pain and disability. They can be considered to be stalled in the inflammatory stage and cannot heal without additional measures. A valid animal model is necessary to evaluate the efficacy of topical wound healing therapies and wearable technologies. A porcine model, although higher in cost, maintenance, and space requirements, is superior to the commonly used rodent or rabbit model for wound healing. Previous studies have shown that pig wounds have greater similarity to human wounds in responses to a variety of treatments, including wound dressings and antibiotics. The current study created a porcine model of large chronic wounds to assess a wearable electroceutical technology, with monitoring of healing variables and infection. Electroceutical therapy is the only adjunctive treatment recommended for chronic wound therapy. A porcine model of large chronic wounds of clinically realistic size was created and utilized to evaluate a wearable electroceutical biotechnology. Multivariate non-invasive assessment was used to monitor wound progression over multiple timepoints. Outcomes suggest that a wearable electrostimulation bandage, has the potential to offer therapeutic benefit in human wounds. The tested wearable device provides the same proven effectiveness of traditional electroceutical therapy while mitigating commonly cited barriers, including substantial time requirements, and availability and complexity of currently available equipment, preventing its implementation in routine wound care. The model is also appropriate for evaluation of other wearables or topical therapeutics.

Pharmacological and Electroceutical Targeting of the Cholinergic Anti-Inflammatory Pathway in Autoimmune Diseases.

Continuous dialogue between the immune system and the brain plays a key homeostatic role in various immune responses to environmental cues. Several functions are under the control of the vagus nerve-based inflammatory reflex, a physiological mechanism through which nerve signals regulate immune functions. In the cholinergic anti-inflammatory pathway, the vagus nerve, its pivotal neurotransmitter acetylcholine, together with the corresponding receptors play a key role in modulating the immune response of mammals. Through communications of peripheral nerves with immune cells, it modulates proliferation and differentiation activities of various immune cell subsets. As a result, this pathway represents a potential target for treating autoimmune diseases characterized by overt inflammation and a decrease in vagal tone. Consistently, converging observations made in both animal models and clinical trials revealed that targeting the cholinergic anti-inflammatory pathway using pharmacologic approaches can provide beneficial effects. In parallel, bioelectronic medicine has recently emerged as an alternative approach to managing systemic inflammation. In several studies, nerve electrostimulation was reported to be clinically relevant in reducing chronic inflammation in autoimmune diseases, including rheumatoid arthritis and diabetes. In the future, these new approaches could represent a major therapeutic strategy for autoimmune and inflammatory diseases.

Abdominal vagus nerve stimulation alleviates collagen-induced arthritis in rats.

Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory disease. Despite therapeutic advances, a significant proportion of RA patients are resistant to pharmacological treatment. Stimulation of the cervical vagus nerve is a promising alternative bioelectric neuromodulation therapeutic approach. However, recent clinical trials show cervical vagus nerve stimulation (VNS) was not effective in a significant proportion of drug resistant RA patients. Here we aim to assess if abdominal vagus nerve stimulation reduces disease severity in a collagen-induced arthritis (CIA) rat model. The abdominal vagus nerve of female Dark Agouti rats was implanted and CIA induced using collagen type II injection. VNS (1.6 mA, 200 µs pulse width, 50 µs interphase gap, 27 Hz frequency) was applied to awake freely moving rats for 3 h/day (days 11-17). At 17 days following the collagen injection, unstimulated CIA rats (n = 8) had significantly worse disease activity index, tumor necrosis factor-alpha (TNF-α) and receptor activator of NFκB ligand (RANKL) levels, synovitis and cartilage damage than normal rats (n = 8, Kruskal-Wallis: P < 0.05). However, stimulated CIA rats (n = 5-6) had significantly decreased inflammatory scores and ankle swelling (Kruskal-Wallis: P < 0.05) compared to unstimulated CIA rats (n = 8). Levels of tumor necrosis factor-alpha (TNF-α) remained at undetectable levels in stimulated CIA rats while levels of receptor activator of NFκB ligand (RANKL) were significantly less in stimulated CIA rats compared to unstimulated CIA rats (P < 0.05). Histopathological score of inflammation and cartilage loss in stimulated CIA rats were no different from that of normal (P > 0.05). In conclusion, abdominal VNS alleviates CIA and could be a promising therapy for patients with RA.

Vagus nerve stimulation for the treatment of epilepsy: things to note on the protocols, the effects and the mechanisms of action.

Epilepsy is a chronic brain disorder that is characterized by repetitive un-triggered seizures that occur severally within 24 h or more. Non-pharmacological methods for the management of epilepsy were discussed. The non-pharmacological methods include the vagus nerve stimulation (VNS) which is subdivided into invasive and non-invasive techniques. For the non-invasive techniques, the auricular VNS, stimulation of the cervical branch of vagus nerve in the neck, manual massage of the neck, and respiratory vagal nerve stimulation were discussed. Similarly, the stimulation parameters used and the mechanisms of actions through which VNS improves seizures were also discussed. Use of VNS to reduce seizure frequency has come a long way. However, considering the cost and side effects of the invasive method, non-invasive techniques should be given a renewed attention. In particular, respiratory vagal nerve stimulation should be considered. In doing this, the patients should for instance carry out slow-deep breathing exercise 6 to 8 times every 3 h during the waking hours. Slow-deep breathing can be carried out by the patients on their own; therefore this can serve as a form of self-management.HIGHLIGHTSEpilepsy can interfere with the patients' ability to carry out their daily activities and ultimately affect their quality of life.Medications are used to manage epilepsy; but they often have their serious side effects.Vagus nerve stimulation (VNS) is gaining ground especially in the management of refractory epilepsy.The VNS is administered through either the invasive or the non-invasive methodsThe invasive method of VNS like the medication has potential side effects, and can be costly.The non-invasive method includes auricular VNS, stimulation of the neck muscles and skin and respiratory vagal nerve stimulation via slow-deep breathing exercises.The respiratory vagal nerve stimulation via slow-deep breathing exercises seems easy to administer even by the patients themselves.Consequently, it is our opinion that patients with epilepsy be made to carry out slow-deep breathing exercise 6-8 times every 3 h during the waking hours.

An fMRI-compatible system for targeted electrical stimulation.

BACKGROUND: Neuromodulation is a rapidly expanding therapeutic option considered within neuropsychiatry, pain and rehabilitation therapy. Combining electrostimulation with feedback from fMRI can provide information about the mechanisms underlying the therapeutic effects, but so far, such studies have been hampered by the lack of technology to conduct safe and accurate experiments. Here we present a system for fMRI compatible electrical stimulation, and the first proof-of-concept neuroimaging data with deep brain stimulation (DBS) in pigs obtained with the device. NEW METHOD: The system consists of two modules, placed in the control and scanner room, connected by optical fiber. The system also connects to the MRI scanner to timely initiate the stimulation sequence at start of scan. We evaluated the system in four pigs with DBS in the subthalamic nucleus (STN) while we acquired BOLD responses in the STN and neocortex. RESULTS: We found that the system delivered robust electrical stimuli to the implanted electrode in sync with the preprogrammed fMRI sequence. All pigs displayed a DBS-STN induced neocortical BOLD response, but none in the STN. COMPARISONS WITH EXISTING METHOD: The system solves three major problems related to electric stimuli and fMRI examinations, namely preventing distortion of the fMRI signal, enabling communication that synchronize the experimental conditions, and surmounting the safety hazards caused by interference with the MRI scanner. CONCLUSIONS: The fMRI compatible electrical stimulator circumvents previous problems related to electroceuticals and fMRI. The system allows flexible modifications for fMRI designs and stimulation parameters, and can be customized to electroceutical applications beyond DBS.

Disease-Modifying Effects of Non-Invasive Electroceuticals on ß-Amyloid Plaques and Tau Tangles for Alzheimer's Disease.

Electroceuticals refer to various forms of electronic neurostimulators used for therapy. Interdisciplinary advances in medical engineering and science have led to the development of the electroceutical approach, which involves therapeutic agents that specifically target neural circuits, to realize precision therapy for Alzheimer's disease (AD). To date, extensive studies have attempted to elucidate the disease-modifying effects of electroceuticals on areas in the brain of a patient with AD by the use of various physical stimuli, including electric, magnetic, and electromagnetic waves as well as ultrasound. Herein, we review non-invasive stimulatory systems and their effects on ß-amyloid plaques and tau tangles, which are pathological molecular markers of AD. Therefore, this review will aid in better understanding the recent technological developments, applicable methods, and therapeutic effects of electronic stimulatory systems, including transcranial direct current stimulation, 40-Hz gamma oscillations, transcranial magnetic stimulation, electromagnetic field stimulation, infrared light stimulation and ionizing radiation therapy, and focused ultrasound for AD.

Clinical outcomes and cost-effectiveness of an externally applied electroceutical device in managing venous leg ulcers in clinical practice in the UK.

OBJECTIVE: To estimate the cost-effectiveness of treating patients with a venous leg ulcer (VLU) with an externally applied electroceutical (EAE) device, plus dressings and compression bandaging or continuing with their previous care plan, from the perspective of the National Health Service (NHS) in the UK. METHOD: This was a prospective, single-arm, non-blinded, clinical and economic evaluation of EAE therapy performed in 2013/14. Patients' VLUs were treated with six active units of EAE therapy (each unit for two days) plus dressings and compression bandaging over a period of 12 days. Afterwards, patients were managed with a combination of dressings and bandages. Each patient acted as their own control so that clinical outcomes, resource use and costs associated with the wound over 12 months before the start of EAE therapy were retrospectively compared with the first 12 months after the start of treatment. The relative cost-effectiveness of EAE therapy was estimated at 2013/14 prices. RESULTS: Within 12 months of starting EAE therapy 77% of all wounds healed and the other 23% improved. This difference in effectiveness between the 12-months period before and after EAE therapy was estimated to yield a 12% improvement in health gain of 0.09 QALYs (p<0.01), a 34% reduction in the requirement for nurse visits (from a mean 50.7 to 33.3 visits per patient) and a 26% reduction in the number of dressings. This resulted in an 11% reduction in the NHS cost of VLU management over 12 months after the start of treatment when compared with the previous 12 months (from £1,981 to £1,754 per patient). Hence, use of EAE therapy was found to be a dominant treatment (i.e. improved outcome for less cost). CONCLUSION: Within the study's limitations, use of the EAE device potentially affords the NHS a cost-effective treatment for managing VLUs when compared with patients remaining on their previous care plan.