A Smart Ingestible Capsule for Real-Time Monitoring of Stimuli-Responsive Polymer Dissolution Kinetics and Oral Drug Release in the Gastrointestinal Tract

Abstract

Oral drug delivery relies on precise, site-specific release within the gastrointestinal (GI) tract, commonly achieved using stimuli-responsive polymer (SRP) coatings that regulate dissolution under varying physiological conditions to maximize therapeutic efficacy. Continuous advancements in polymer chemistry and composite formulations have enabled increasingly sophisticated control over drug release profiles. However, a critical challenge remains in accurately assessing how these materials degrade, dissolve, and perform under true in vivo GI conditions.

While numerous in vitro models have been developed to approximate physiological environments, they often fail to capture the complexity of GI dynamics, including variations in pH, fluid composition, motility, and transit behavior. As a result, there is a significant need for technologies capable of directly monitoring the real-time behavior of these materials during in vivo transit to better understand their performance and guide formulation design. To address this unmet need, we present a miniaturized ingestible sensing capsule designed for in situ, formulation-centric evaluation of polymer dissolution dynamics within the GI tract. The platform integrates impedance-based sensing to monitor changes in the physical and structural integrity of SRP coatings and polymeric pharmaceutical formulations during dissolution, alongside potentiometric pH sensing for anatomical localization within the GI environment. This dual-sensing approach enables simultaneous tracking of material degradation and spatial positioning, providing direct insight into where and how dissolution occurs in vivo.

Systematic in vitro characterization using simulated and extracted GI fluids across physiologically relevant conditions demonstrated an approximately 100-fold reduction in impedance upon dissolution of the polymeric coating, reflecting sensitivity to structural breakdown and fluid ingress. The integrated pH sensor exhibited a linear response across the physiologically relevant range of pH 2 to 8, enabling reliable identification of GI segments. A power-optimized hardware–software co-design enabled periodic sensing and wireless data transmission at intervals between 250 ms and 1 s, achieving an average power consumption as low as 90.7 μW.

This low-power operation supports extended device functionality over time scales exceeding typical GI transit durations, while maintaining stable performance and minimizing battery-related risks. As a proof of concept, the system was evaluated using widely used pH-responsive SRP coatings, including Eudragit® EPO (gastric-targeted dissolution) and Eudragit® L100 (intestinal-targeted dissolution). Device performance was validated through both in vitro studies and in vivo evaluation in a porcine model under endoscopy-guided placement, demonstrating accurate tracking of coating dissolution kinetics with spatial correlation to GI segments. Drug release profiles were independently confirmed using spectrometric quantification of identically coated commercial pharmaceutical tablets, establishing consistency between electrical sensing outputs and pharmacological release behavior. Overall, this ingestible platform enables quantitative, spatially resolved, in vivo assessment of polymer-based drug delivery systems, providing a powerful tool for researchers and pharmaceutical developers to directly evaluate formulation performance under realistic physiological conditions. The technology is envisioned to support the design, optimization, and clinical translation of advanced oral drug delivery systems by enabling improved understanding of material behavior, release kinetics, and patient-specific variability in the GI tract.

Introduction

Advances in pharmaceutical formulation and drug delivery technologies have significantly transformed modern healthcare by enabling precise, safe, and patient-centric treatment of both acute and chronic diseases (Vargason et al., 2021). Among these approaches, oral drug delivery remains the most widely utilized route due to its patient compliance, convenience, scalability, and compatibility with a broad range of active pharmaceutical ingredients (Hua, 2020; Robert Langer, 1998). Consequently, oral dosage forms account for more than 50% of all pharmaceutical formulations and continue to dominate across therapeutic applications (Robert Langer, 1998).

Despite these advantages, oral drug delivery faces critical limitations, as therapeutic efficacy is highly dependent on achieving precise spatiotemporal control over drug release within the GI tract. This control is typically mediated by SRP coatings, which are engineered to dissolve under specific physiological conditions, such as pH, thereby enabling targeted drug release at defined anatomical locations (Mitchell et al., 2021). Such precision is essential for optimizing localized drug exposure while minimizing systemic side effects. This requirement is particularly critical for drugs with narrow absorption windows, where premature or delayed release can significantly reduce bioavailability and therapeutic effectiveness (Omidian, 2025). Similarly, formulations designed for delayed, sustained, or colonic delivery rely on tightly controlled dissolution profiles to achieve their intended function (McCoubrey et al., 2023).

However, achieving this level of control is fundamentally challenged by the complex and highly variable nature of the GI environment. Physiological factors including pH gradients, gastric emptying rates, intestinal transit times, luminal fluid composition, dietary intake, disease state, medication use, and microbiome variability can significantly alter the dissolution behavior of SRP coatings in vivo (Procházková et al., 2024; Zhao et al., 2023). As a result, formulations optimized under standardized in vitro conditions or preclinical animal models often fail to reproduce their intended release profiles in human subjects (Amaral Silva et al., 2020; Ingber, 2022; Loewa et al., 2023). This discrepancy highlights a fundamental limitation in current evaluation paradigms and underscores the need for direct, in vivo characterization of formulation behavior.

A critical unmet need, therefore, is the ability to directly verify where and when coating dissolution occurs within the GI tract under realistic physiological conditions. Although extensive efforts have been devoted to developing advanced polymer chemistries and composite formulations that demonstrate desirable dissolution kinetics in vitro, these models frequently fail to capture key in vivo factors such as mechanical shear, peristaltic motion, luminal mixing, pressure variations, particulate interactions, and complex fluid rheology. Furthermore, discrepancies between animal models and human physiology, as well as inter- and intra-subject variability among human populations, often result in inconsistent or unpredictable therapeutic outcomes. These challenges collectively emphasize the importance of technologies capable of real-time, in vivo monitoring of material degradation and drug release behavior, thereby enabling more accurate assessment of formulation performance under true physiological conditions.

Direct measurement of coating dissolution would provide actionable insights to guide the rational design and optimization of polymer systems, including parameters such as composition, thickness, crosslinking density, and dissolution thresholds (Shravani et al., 2011). Such capability would enable researchers and pharmaceutical developers to better understand how formulations behave during GI transit and to iteratively refine material properties to achieve targeted release profiles. However, existing methodologies for assessing dissolution kinetics in vivo remain limited and can broadly be categorized into direct imaging-based approaches and indirect systemic or metabolic monitoring techniques, each with inherent limitations.

Imaging-based approaches, including X-ray, computed tomography (CT), and magnetic resonance imaging (MRI), have been employed to visualize the position, transit, and disintegration of oral dosage forms within the GI tract (Chen et al., 2013; Curley et al., 2017; Gengji et al., 2023; Kjeldsen et al., 2021; Quodbach et al., 2014). While these methods provide valuable anatomical information, they are limited by significant practical constraints. X-ray and CT rely on ionizing radiation, restricting repeated or longitudinal studies, while MRI, although radiation-free, is costly, time-intensive, and dependent on specialized infrastructure, limiting its scalability and routine use in clinical or preclinical settings (Rao et al., 2011). Moreover, these approaches primarily provide structural visualization rather than direct measurement of material degradation kinetics.

In contrast, indirect approaches infer dissolution and drug release through downstream systemic signals, such as metabolic byproducts or pharmacokinetic profiles. Breath analysis, for example, can detect isotopically labeled compounds (e.g., 13C-labeled substrates) or volatile drug metabolites, providing insight into systemic drug absorption (Modak, 2007; Timmins, 2016; Trefz et al., 2017). Similarly, dual-label microdosing strategies using isotopic tracers (e.g., 14C oral and 13C intravenous dosing) enable precise quantification of bioavailability (Boulton et al., 2013). However, these methods lack spatial resolution, are influenced by physiological variability, and provide only indirect, temporally delayed information, making them unsuitable for real-time, localized assessment of dissolution processes (Isin et al., 2012).

These limitations highlight the need for non-invasive, real-time, and spatially resolved sensing approaches capable of directly interrogating material behavior within the GI tract. In this context, electrical measurement-based techniques offer a promising alternative. Electrical and electrochemical sensing modalities are inherently sensitive to changes in polymer structure, hydration, and interfacial properties, enabling direct monitoring of coating degradation and dissolution processes (Chang et al., 2023; Gopalakrishnan et al., 2023a; Waimin et al., 2022, 2021). Importantly, these techniques are highly compatible with complementary metal-oxide-semiconductor (CMOS) technology, facilitating miniaturization, low-power operation, and wireless integration suitable for ingestible device platforms (Abdigazy et al., 2024; Gopalakrishnan et al., 2024).

Recent advances in ingestible electronics have led to the development of capsule-based systems capable of monitoring physiological parameters within the GI tract, including pH, temperature, pressure, motility, and microbial activity (Diaz Tartera et al., 2017; Gopalakrishnan et al., 2023; Kadian et al., 2024; Krishnakumar et al., 2025; Nejati et al., 2024, 2022, 2021; Sarnaik et al., 2025; Sharma et al., 2023; Waimin et al., 2020). Commercial devices such as Medtronic’s SmartPill™ have demonstrated the ability to characterize GI transit and motility profiles in both clinical and ambulatory settings. Additionally, emerging platforms have explored impedance-based sensing of tissue properties for assessing inflammation and barrier integrity (Holt et al., 2025).

However, despite these advancements, existing ingestible systems are primarily designed to monitor physiological conditions of the GI environment, rather than the behavior of administered material systems such as drug coatings and polymer formulations. As a result, there remains a significant gap in the availability of tools capable of directly evaluating formulation performance and dissolution kinetics in vivo. This gap is particularly critical for pharmaceutical development, where understanding how coatings behave under real physiological conditions is essential for optimizing drug delivery systems. A comparative summary of existing ingestible technologies and their functional limitations is provided in Table S1.

To address this unmet need, we introduce a miniaturized ingestible capsule termed MEDIC (Monitoring Enteric Coating Dissolution via Impedance Change), designed as a formulation-centric sensing platform for real-time, spatially resolved monitoring of polymer coating dissolution within the GI tract. The MEDIC capsule integrates interdigitated electrodes (IDEs) for impedance-based sensing of coating integrity and a potentiometric pH sensor for anatomical localization, leveraging the distinct pH gradients across GI segments. By directly tracking changes in the electrical properties of SRP coatings during dissolution, rather than relying on indirect imaging or systemic biomarkers, this platform enables in situ characterization of material degradation kinetics.

The sensing architecture is interfaced with ultra-low-power electronics and Bluetooth Low Energy (BLE) telemetry for real-time wireless data transmission. Systematic in vitro characterization was performed under simulated and extracted GI fluid conditions, followed by validation in a porcine model under controlled placement to establish the relationship between electrical signatures and coating dissolution behavior. As a proof of concept, the system was evaluated using well-established pH-responsive enteric coatings (Eudragit® EPO and L100), demonstrating the ability to track dissolution kinetics within physiologically relevant environments.

Overall, this work establishes a new class of ingestible, formulation-centric sensing platforms for direct, non-invasive, and spatially resolved monitoring of polymer dissolution dynamics in vivo. This capability provides a powerful tool for researchers and pharmaceutical developers to evaluate and optimize oral drug delivery systems, with potential implications for improving formulation design, enhancing translational success, and enabling future strategies in patient-specific and adaptive drug delivery.

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Praveen Srinivasan, Muhammad Masud Rana, Akshay Krishnakumar, Devendra Sarnaik, Yashwanth Ramesh, Robyn R. McCain, Rahim Rahimi, A Smart Ingestible Capsule for Real-Time Monitoring of Stimuli-Responsive Polymer Dissolution Kinetics and Oral Drug Release in the Gastrointestinal Tract, Biosensors and Bioelectronics, 2026, 118715, ISSN 0956-5663, https://doi.org/10.1016/j.bios.2026.118715.