Development and In Vivo Evaluation of a Bioinspired, Ingestible Electroceutical Capsule for Hunger-regulating Hormone Modulation

Introduction:: Gastric electrical stimulation via surgically implanted serosal electrodes is an approved treatment for gastroparesis, a condition defined by delayed gastric emptying that oftentimes results in chronic nausea and vomiting. Gastric electrical stimulation has been observed to reduce the symptoms associated with gastroparesis, although it does not appear to improve gastric emptying time. This led us to hypothesize that electrical stimulation may be inducing the release of hormones known to treat nausea. Here we report the characterization of the effects of endoscopic-mediated endoluminal stimulation of the gastric cavity in large animal models which lead to increases in plasma ghrelin levels, a hormone known to stimulate appetite. Moreover, we demonstrate that these increases are vagally mediated. To support the potential for an ingestible electroceutical we developed a bio-inspired (fl)uid-wicking capsule for (a)ctive (s)timulation and (h)ormone modulation (FLASH). The capsule has surface-embedded electrodes and fluid wicking grooves with the capacity to displace fluid in the gastric cavity away from the capsule electrodes to promote optimal contact at the electrode-mucosa interface. We demonstrate the ability for the capsule to stimulate release of ghrelin. Overall, this presents a new platform for ingestible electroceuticals which can be applied to eating disorders, chemotherapy-induced cachexia, and potentially beyond to metabolic conditions.


Materials and Methods:: All animal experiments were performed in accordance with protocols approved by the Committee on Animal Care at MIT. Gastric mucosal stimulation was assessed in a large animal model (30-75kg Yorkshire Swine, Cummings School of Veterinary Medicine at Tufts University, Grafton, MA). A bipolar gold probe (Boston Scientific) was introduced through an endoscopic channel and the probe tip was placed on the gastric mucosa. Stimulation was then turned on for 20 minutes and blood samples were collected and processed into plasma and stored for hormone analysis. In vagotomy experiments, a bilateral vagotomy was performed via surgical cutdown on the neck in a terminal setting. In vivo studies with FLASH replicated the gold probe procedure, except the devices were deployed freely. FLASH capsules were tracked via x-ray to observe passage through the GI tract. Hormone analysis was performed via ELISA (Ghrelin Acylated Porcine; BioVendor R&D, Asheville, NC) on the collected plasma samples.

Capsule bodies were designed in CAD (Fusion 360) and printed in RGD450 resin (Stratasys) at maximum resolution. Two 1.5 V silver oxide batteries were connected in series with silver epoxy. Electrodes made out of 14K gold wire were attached to the printed circuit board (PCB) and then the battery stack was connected to the PCB. The 3D printed capsule was treated with O₂ plasma for 5 minutes at 100 W power (AutoGlow from Glow Research). Immediately following, the electronics were then inserted into the capsule, electrodes wound around the capsule, and everything was sealed using a UV epoxy (Loctite 4305).


Results, Conclusions, and Discussions:: The gastric mucosa regularly secretes gastric fluid that can prevent stable electrode-mucosa contact in an ingestible device. To overcome this challenge, we developed a bio-inspired capsule surface that utilizes an electrode-embedded surface with fluid-wicking grooves that channel the gastric fluid away from the electrodes to ensure reliable contact. Fluid wicking in the rectangular-cross-sectioned grooves was modeled via capillary action in a vertical rectangular three-walled channel in the below equation:

H_rec = [σ*(2*D + W)*cosθ – W]/[ρ*g*D*W]

Where σ is the surface tension, D is the channel depth, W is the channel width, θ is the contact angle, ρ is the density, and g is the gravitational constant. In order to improve fluid-wicking ability, a surface plasma treatment was performed on these capsules to reduce the contact angle, and effectively increase the cosine term in the above equation to increase wicking height.

Endoscopic gold probe stimulation showed +70.23 pg/ml plasma ghrelin levels 60 minutes after beginning stimulation compared to -80.11 pg/ml in sham studies. In a vagotomized animal, this modulation effect was completely abrogated, suggesting the mechanism of controlling plasma ghrelin concentration levels relies on both afferent and efferent stomach-brain circuitry in the vagus nerve. FLASH administration also demonstrated reliable increases in plasma ghrelin, showing +74.7 pg/ml compared to -29.8 pg/ml sham.

FLASH capsules were well tolerated and all passed within 2 weeks of ingestion. All capsules retrieved after passage were fully intact.

FLASH is the first demonstration of an ingestible electroceutical capsule capable of endogenous hormone modulation, demonstrating the ability to increase ghrelin levels in a large animal model. There are direct applications for patients suffering from eating disorders or chemotherapy-induced cachexia. Beyond this, FLASH is a platform for ingestible stimulation of various parameters and locations, with the potential to provide a new treatment paradigm that utilizes non-invasive electrical stimulation.


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