Bioelectronic Therapy for the Treatment of Rheumatoid Arthritis and Inflammatory Bowel Disease

Levine, Yaakov A.; Simon, Jesse; Faltys, Michael; Zitnik, Ralph

doi:10.1016/b978-0-12-805353-9.00127-3

Cited by 4 publications

(4 citation statements)

References 31 publications

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“…Furthering our understanding of the VNS parameter requirements for clinical benefit can therefore allow for optimization of device design and stimulation protocols. Longer periods between stimulations may also reduce patient discomfort both by limiting the stimulation-associated laryngeal muscle contraction and temporary voice changes as well as enabling smaller devices that are easier to implant and maintain ( Levine et al, 2018b , c ). Therefore, the observation that a short VNS period of 60 s was followed by a prolonged anti-inflammatory effect provides important information for the development of future clinical therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation

et al. 2022

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Crohn’s disease is a chronic, idiopathic condition characterized by intestinal inflammation and debilitating gastrointestinal symptomatology. Previous studies of inflammatory bowel disease (IBD), primarily in colitis, have shown reduced inflammation after electrical or pharmacological activation of the vagus nerve, but the scope and kinetics of this effect are incompletely understood. To investigate this, we studied the effect of electrical vagus nerve stimulation (VNS) in a rat model of indomethacin-induced small intestinal inflammation. 1 min of VNS significantly reduced small bowel total inflammatory lesion area [(mean ± SEM) sham: 124 ± 14 mm2, VNS: 62 ± 14 mm2, p = 0.002], intestinal peroxidation and chlorination rates, and intestinal and systemic pro-inflammatory cytokine levels as compared with sham-treated animals after 24 h following indomethacin administration. It was not known whether this observed reduction of inflammation after VNS in intestinal inflammation was mediated by direct innervation of the gut or if the signals are relayed through the spleen. To investigate this, we studied the VNS effect on the small bowel lesions of splenectomized rats and splenic nerve stimulation (SNS) in intact rats. We observed that VNS reduced small bowel inflammation also in splenectomized rats but SNS alone failed to significantly reduce small bowel lesion area. Interestingly, VNS significantly reduced small bowel lesion area for 48 h when indomethacin administration was delayed. Thus, 1 min of electrical activation of the vagus nerve reduced indomethacin-induced intestinal lesion area by a spleen-independent mechanism. The surprisingly long-lasting and spleen-independent effect of VNS on the intestinal response to indomethacin challenge has important implications on our understanding of neural control of intestinal inflammation and its potential translation to improved therapies for IBD.

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Section: Discussionmentioning

confidence: 99%

Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation

et al. 2022

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“…The device settings chosen for this study were based on extensive preclinical studies, the proof-of-concept clinical study that was performed with the same device in two rheumatoid arthritis cohorts, as well as clinical vagus nerve stimulation experience with these devices used in epilepsy and depression. 39 , 41 , 42 The study used a pulse frequency and pulse duration of 10 Hz and 250 µs, respectively, well below the specified upper limits allowed in the currently approved vagus nerve stimulation device product labelling in approved indications of drug-refractory epilepsy and depression. 43 …”

Section: Methodsmentioning

confidence: 99%

Neuroimmune Modulation Through Vagus Nerve Stimulation Reduces Inflammatory Activity in Crohn’s Disease Patients: A Prospective Open-label Study

D’Haens,

Eberhardson,

Cabrijan

et al. 2023

Journal of Crohn's and Colitis

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Background and Aims Crohn’s disease (CD) is a debilitating inflammatory condition affecting the gastrointestinal tract. There is no cure and sustained clinical and endoscopic remission is achieved by fewer than half of patients with current therapies. The immunoregulatory function of the vagus nerve, the “inflammatory reflex”, has been established in patients with rheumatoid arthritis and biologic-naive CD. The aim of this study was to explore the safety and efficacy of vagus nerve stimulation in patients with treatment-refractory CD in a 16-week open-label multicentre clinical trial. Methods A vagus nerve stimulator was implanted in 17 biological drug-refractory patients with moderately-to-severely active CD. One patient exited the study pre-treatment, and 16 patients were treated with vagus nerve stimulation (4/16 receiving concomitant biologics) during 16 weeks of induction and 24 months of maintenance treatment. Endpoints included clinical improvement, patient reported outcomes, objective measures of inflammation (endoscopic/molecular), and safety. Results There was a statistically significant and clinically meaningful decrease in CD Activity Index at Week-16 (mean±SD:-86.2±92.8, p=0.003), a significant decrease in faecal calprotectin (-2923±4104, p=0.015), a decrease in mucosal inflammation in 11/15 patients with paired endoscopies (-2.1±1.7, p=0.23), and a decrease in serum TNF and IFN-γ (46-52%). Two quality-of-life indices improved in 7/11 patients treated without biologics. There was one study-related SAE: a post-operative infection requiring device explantation. Conclusions Neuroimmune modulation via vagus nerve stimulation was generally safe and well-tolerated with a clinically meaningful reduction in clinical disease activity associated with endoscopic improvement, reduced levels of faecal calprotectin and serum cytokines, and improved quality-of-life.

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“…This is important for accommodating both natural, subject‐to‐subject variation in anatomy and changes in nerve size due to post‐implant inflammation/swelling, disease processes, and subject/nerve growth. Importantly, the μcPNI is significantly smaller in size to minimize progressive neuropathy caused by stretching or rubbing of the nerve or surrounding tissue, [ 82 ] while having more electrodes than commercial cuff‐type electrodes. Here, we report full electromechanical evaluation of the μcPNI and functionally validate acute and chronic recording and stimulating capabilities in vivo on the tracheosyringeal nerve (TSN) of the zebra finch, a songbird.…”

Section: Introductionmentioning

confidence: 99%

A Microclip Peripheral Nerve Interface (μcPNI) for Bioelectronic Interfacing with Small Nerves

2021

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Peripheral nerves carry sensory (afferent) and motor (efferent) signals between the central nervous system and other parts of the body. The peripheral nervous system (PNS) is therefore rich in targets for therapeutic neuromodulation, bioelectronic medicine, and neuroprosthetics. Peripheral nerve interfaces (PNIs) generally suffer from a tradeoff between selectivity and invasiveness. This work describes the fabrication, evaluation, and chronic implantation in zebra finches of a novel PNI that breaks this tradeoff by interfacing with small nerves. This PNI integrates a soft, stretchable microelectrode array with a 2‐photon 3D printed microclip (μcPNI). The advantages of this μcPNI compared to other designs are: a) increased spatial resolution due to bi‐layer wiring of the electrode leads, b) reduced mismatch in biomechanical properties with the nerve, c) reduced disturbance to the host tissue due to the small size, d) elimination of sutures or adhesives, e) high circumferential contact with small nerves, f) functionality under considerable strain, and g) graded neuromodulation in a low‐threshold stimulation regime. Results demonstrate that the μcPNIs are electromechanically robust, and are capable of reliably recording and stimulating neural activity in vivo in small nerves. The μcPNI may also inform the development of new optical, thermal, ultrasonic, or chemical PNIs as well.

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Bioelectronic Therapy for the Treatment of Rheumatoid Arthritis and Inflammatory Bowel Disease

Cited by 4 publications

References 31 publications

Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation

Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation

Neuroimmune Modulation Through Vagus Nerve Stimulation Reduces Inflammatory Activity in Crohn’s Disease Patients: A Prospective Open-label Study

A Microclip Peripheral Nerve Interface (μcPNI) for Bioelectronic Interfacing with Small Nerves

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