An Ingestible Self-Polymerizing System for Targeted Sampling of Gut Microbiota and Biomarkers

Abstract

A proof-of-concept for the fabrication of a self-polymerizing system for sampling of gut microbiome in the upper gastrointestinal (GI) tract is presented. An orally ingestible microdevice is loaded with the self-polymerizing reaction mixture to entrap gut microbiota and biomarkers. This polymerization reaction is activated in the aqueous environment, like fluids in the intestinal lumen, and causes site-specific microsampling in the gastrointestinal tract. The sampled microbiota and protein biomarkers can be isolated and analyzed via high-throughput multiomic analyses. The study utilizes a hollow microdevice (Su-8, ca. 250 μm), loaded with an on-board reaction mixture (iron chloride, ascorbic acid, and poly­(ethylene glycol) diacrylate monomers) for diacrylate polymerization in the gut of an animal model. An enteric-coated rat capsule was used to orally gavage these microdevices in a rat model, thereby, protecting the microdevices in the stomach (pH 2), but releasing them in the intestine (pH 6.6). Upon capsule disintegration, the microdevices were released in the presence of luminal fluids (in the small intestine region), where iron chloride reacts with ascorbic acid, to initiate poly­(ethylene glycol) diacrylate polymerization via a free radical mechanism. Upon retrieval of the microdevices, gut microbiota was found to be entrapped in the polymerized hydrogel matrix, and genomic content was analyzed via 16s rRNA amplicon sequencing. Herein, the results show that the bacterial composition recovered from the microdevices closely resemble the bacterial composition of the gut microenvironment to which the microdevice is exposed. Further, histological assessment showed no signs of local tissue inflammation or toxicity. This study lays a strong foundation for the development of untethered, non-invasive microsampling technologies in the gut and advances our understanding of host–gut microbiome interactions, leading to a better understanding of their commensal behavior and associated GI disease progression in the near future.

In vitro models to evaluate ingestible devices: Present status and current trends

“…Several ingestible microdevices serve as sampling and biomolecular detection tools. Chen et al (2020) [60] developed an orally ingestible microdevice for site-specific microsampling of microbiota and protein biomarkers in the GI tract. Mimee et al (2018) [61] devised the ingestible microbio-electronic device (IMBED) to detect GI bleeding.…”

Robotic Pill for Biomarker and Fluid Sampling in the Gastrointestinal Tract

“…[ 25–33 ] More recently, smart pills have been applied to capture and sense biomarkers through lab‐on‐a‐chip systems, [ 26–28 ] osmotic gradients, [ 29 ] and passive absorption in refs. [30‐32] methods. The ability to isolate biomarkers within localized environments could help discover novel early disease signals and monitor health status by generating comprehensive datasets encompassing the shift from healthy to disease states and vice versa.…”

“…[19][20][21][22][23][24] For instance, the PillCam, an ingestible capsule with an embed camera, is commonly used to search for polyps in the GI. [25][26][27][28][29][30][31][32][33] More recently, smart pills have been applied to capture and sense biomarkers through lab-on-a-chip systems, [26][27][28] osmotic gradients, [29] and passive absorption in refs. [30][31][32] methods.…”

“…[25][26][27][28][29][30][31][32][33] More recently, smart pills have been applied to capture and sense biomarkers through lab-on-a-chip systems, [26][27][28] osmotic gradients, [29] and passive absorption in refs. [30][31][32] methods. The ability to isolate biomarkers within localized environments…”

Robotic Pill for Biomarker and Fluid Sampling in the Gastrointestinal Tract

“…Smart pills have been deployed as a method to sample cavities inside the body. (Yim et al, 2014;Cummins, 2021;Mandsberg et al, 2020;Iddan et al, 2000;Min et al, 2019;Steiger et al, 2018) For instance, microfluidic chips, (Mimee et al, 2018;Qiao et al, 2016;Nemiroski et al, 2015) osmotic gradients, (Rezaei Nejad et al, 2019) and passive absorption (Waimin et al, 2020;Rios-Morales et al, 2021;Chen et al, 2020) have been deployed to collect biomarkers in the GI tract. Previous pill-based approaches are designed to focus on imaging of the GI tract (Iddan et al, 2000) or have active electrical components, (Schostek et al, 2016) and here we focus on capturing low abundance biomarkers via a simple.…”