A Novel Ingestible Biosensor for Intestinal Metabolite Monitoring

Blog post by Nina Culum, MSc

Functional gastrointestinal disorders such as irritable bowel syndrome (IBS) are highly complex, involving a bidirectional dysregulation of the gut-brain interaction, and cause a wide range of unpleasant symptoms, from abdominal pain and bloating to nausea and vomiting [1]. In a recently published large-scale study, more than 40% of the global population was found to suffer from these disorders, which not only negatively affects quality of life, but also places a significant economic burden on healthcare systems [2]. The human gut microbiome and the metabolites therein have gained considerable attention as a result, as they are thought to play a role in the etiology of a diverse range of diseases such as IBS, type 2 diabetes, and even colorectal cancer [3]. Although our knowledge of these disorders has advanced, their diagnosis still often requires invasive procedures or non-real-time analysis [4].

Recent advances in electronics, optics, materials science, and chemistry have allowed for the development of noninvasive ingestible biosensors or “smart pills” [5]. These devices pass through the gastrointestinal tract, and therefore have direct access to the gut microenvironment, enabling measurement of a wide range of biomarkers and therapeutic targets [4, 5]. Unfortunately, biosensing via ingestible devices is still in its infancy, with commercial availability limited by understanding of gastrointestinal function and regulatory hurdles. Since no ingestible, real-time intestinal metabolite monitors currently exist, De la Paz et al. have developed a self-powered, wireless, and energy-efficient biosensing capsule and demonstrated its capabilities in a porcine model [4]. The results of this pilot study were published this month in Nature Communications, which we review in this blog post.

To develop an entirely energy-autonomous ingestible device, the authors incorporated a glucose biofuel cell (BFC) that generates power while measuring changes in glucose concentration. A magnetic human body communication (mHBC) scheme is also employed, which efficiently reduces electromagnetic energy loss during operation. These components are housed in a capsule with a pH-responsive coating, allowing the device to safely pass through the acidic stomach environment and into the neutral intestinal medium, as well as a silicone/polyurethane coating for electronic insulation (Figure 1). The self-powering mechanism negates the need for a battery and allows for device miniaturization, with diameter and length measuring 0.9 cm and 2.6 cm, respectively.

Figure 1: Schematic illustration of the ingestible biosensing capsule’s design and operation in a porcine model. © 2022 De la Paz et al., licensed under CC BY 4.0.

The anode and cathode are constructed on carbon nanotube-coated nickel foam, at which glucose oxidation and oxygen reduction reactions occur, respectively. The cell voltage is correlated with glucose concentration upon calibration, which is converted to a frequency signal and transmitted through an integrated circuit. The frequency signal is positively shifted as glucose levels are increased (i.e., when the subject is given a glucose-containing solution). The authors also extensively detail the device’s circuit and electrochemical design and fabrication, though we will focus on its in situ performance for this review.

Due to the anatomical and physiological similarities between pig and human gastrointestinal tracts, the authors selected a porcine model to demonstrate the device’s in situ performance. Anesthetized animals were fed glucose-containing saline solutions through esophageal tubes to simulate food consumption, which were also used for capsule delivery to prevent its physical damage by chewing. X-ray imaging confirmed that the capsule reached the stomach and entered the small intestine at 14 hours post-administration (Figure 2). Using a glucose calibration curve, the mHBC signals captured upon dissolution of the enteric coating were converted to intestinal glucose levels (IGLs) in real time, which were validated through blood glucose level (BGL) measurements using a commercial kit.

Figure 2: X-ray images of a biosensing capsule in a pig (top) and a schematic of the experimental timeline (bottom). Scale bars = 5 cm. © 2022 De la Paz et al., licensed under CC BY 4.0.

First, fasted animals were fed a saline solution that contained 60 mM of glucose, which caused IGL to rapidly increase and plateau at 20-22 mM after one hour, while BGL increased from approximately 65 mM to 110 mM. The authors note that the discrepancy between the administered glucose concentration and observed IGL could be a result of glucose retention in the stomach or dilution by intestinal fluid. Additionally, the device was shown to be capable of operating without the delivery of any solution, as the authors were able to record IGL for 30 minutes prior to feeding.

The authors also demonstrated that the device can distinguish between two different and sequentially delivered glucose concentrations, indicated by distinct plateaus at different IGLs. In a subsequent experiment, the authors also observed that the delivery of a glucose-containing solution followed by saline-only led to a sharp decrease in IGL, which eventually dropped to near-zero after three hours (Figure 3). Although a decline in IGL was observed during this experiment, BGL continuously increased, which the authors note is due to continuous glucose absorption from the gastrointestinal tract into blood.

Figure 3: In situ IGL and BGL monitoring. © 2022 De la Paz et al., licensed under CC BY 4.0.

Although only presented as a proof-of-concept, this novel ingestible biosensor was shown to be capable of monitoring intestinal glucose in real time, which the authors claim could provide a more comprehensive understanding of metabolic interactions under normal conditions, or in people who are pregnant and/or have diabetes. As previously mentioned, this device could also be used for the noninvasive diagnosis of various gastrointestinal disorders and malabsorptive conditions such as chronic pancreatitis.

However, this device is not without its limitations. For example, the prototype was only tested in anesthetized animals who were fed a liquid diet; the authors note that future studies using awake animals and procedures involving solid food ingestion will expand its functionality. Additionally, while certainly small in size, the device requires further miniaturization to be comfortably ingested. Lastly, although this biosensor was limited to glucose monitoring in solution, the authors note that advances in integrated circuit research could expand its capabilities to track parameters such as pH, oxygen, electrolytes, fatty acids, vitamins, and foreign drugs for a more comprehensive look into the gut microenvironment.

1. Black CJ, Drossman DA, Talley NJ, Ruddy J, Ford AC. Functional gastrointestinal disorders: advances in understanding and management. Lancet. 2020;396(10263):1664-74. DOI: 10.1016/S0140-6736(20)32115-2.
2. Sperber AD, Bangdiwala SI, Drossman DA, Ghosal UC, Simren M, Tack J, et al. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation global study. Gastroenterology. 2021;160(1):99-114.e3. DOI: 10.1053/j.gastro.2020.04.014.
3. Manor O, Dai CL, Kornilov SA, Smith B, Price ND, Lovejoy JC, et al. Health and disease markers correlate with gut microbiome composition across thousands of people. Nat Commun. 2020;11:5206. DOI: 10.1038/s41467-020-18871-1.
4. De la Paz E, Maganti NH, Trifonov A, Jeerapan I, Mahato K, Yin L, et al. A self-powered ingestible wireless biosensing system for real-time in situ monitoring of gastrointestinal tract metabolites. Nat Commun. 2022;13:7405. DOI: 10.1038/s41467-022-35074-y.
5. Kalantar-zadeh K, Ha N, Ou JZ, Berean KJ. Ingestible sensors. ACS Sens. 2017;2(4):468-83. DOI: 10.1021/acssensors.7b00045.