Bioresorbable RFID capsule for assessing medication adherence

Domain: neuroscience
Published: 2026-01-08
Editorial outcome: major_revision

Abstract
Medication non-adherence remains a critical healthcare challenge, contributing to approximately 125,000 preventable deaths each year and incurring over $100 billion in annual costs in the United States. Current adherence assessment strategies are constrained by limited scalability, suboptimal patient acceptability, and environmental sustainability concerns. To address these limitations, we developed SAFARI (Smart Adherence via FARaday cage And Resorbable Ingestible), a bioresorbable, passive RFID system that enables precise monitoring of medication ingestion events. The platform incorporates a novel cellulose–metal particle–based radio frequency (RF) shielding layer, effectively creating a Faraday cage that facilitates reliable signal detection. By employing fully biodegradable materials, SAFARI obviates the need for device retrieval or battery replacement, thereby mitigating electronic waste. Moreover, the tags are compatible with standard gelatin or hydroxypropyl methylcellulose (HPMC) capsules, further enhancing clinical translational potential. In vivo evaluation in swine models corroborated SAFARI’s ability to accurately detect ingestion events while demonstrating complete biodegradation following administration. These findings highlight the system’s potential to improve patient adherence tracking without introducing significant logistical burdens or ecological impact. As such, SAFARI establishes a foundational framework for the development of next-generation, eco-conscious adherence monitoring solutions and associated interventions—ultimately aiming to bolster therapeutic outcomes and reduce healthcare expenditures.

Introduction
Medication non-adherence represents a critical healthcare challenge, generating over $100 billion in additional costs annually in the United States alone and contributing to approximately 125,000 preventable deaths per year. Nearly 50% of patients with chronic conditions fail to take medications as prescribed 1,2. The consequences are particularly severe for certain conditions - for example, poor adherence to HIV antiretroviral therapy can accelerate disease progression to AIDS, while high adherence has been shown to reduce HIV incidence by 54% 3–5. While the World Health Organization (WHO) endorses directly observed therapy for tuberculosis treatment (where fixed doses are administered under healthcare provider supervision), this approach is both time-intensive and costly to implement at the scale needed to address widespread non-adherence 6. Similarly, medication adherence among patients with type 2 diabetes mellitus remains consistently below average 7, leading to increased complication risks and healthcare costs. Effective adherence monitoring strategies can enhance therapeutic outcomes while preventing misuse of high-risk medications, such as opioids 8. Recent advances in non-invasive ingestible systems offer promising solutions for tracking capsule ingestion and/or device actuation which can improve medical adhesion without addition burden to the patient or clinician 9.

Current approaches to medication adherence monitoring range from indirect methods, such as patient-reported adherence, pharmacy refill data and smart pill bottles, to direct methods like ingestible electronic devices that provide real-time data and biological measurement of drug in blood, urine or hair that can indicate adherence over time 10–12. While electronic medication tracking has the potential to improve the accuracy of adherence measurement, many existing technologies rely on external devices that require patient engagement, leading to usability challenges 13,14. Among these, ingestible sensors embedded in medication capsules offer a significant advancement by autonomously verifying ingestion events 12. These capsules have been studied in humans with several studies demonstrating feasibility and acceptability of using these sensors as an adherence tool 15,16. However, current designs predominantly use non-degradable polymers and rigid electronic components, which are excreted from the body intact. This design raises multiple concerns: frequent ingestion of non-degradable materials increases the potential risk of gastrointestinal (GI) injury, particularly for patients on multiple medications requiring long-term monitoring, and the accumulation of electronic waste poses significant environmental challenges 17,18.

The transition toward biodegradable ingestible adherence monitoring systems presents a transformative opportunity in the field. By incorporating materials that naturally degrade within the GI tract or in the environment, new systems could maintain the benefits of real-time adherence tracking while mitigating safety and environmental concerns 18. Biodegradable electronics, such as transient conductive polymers and dissolvable biosensors, have demonstrated feasibility for temporary physiological monitoring and could be adapted for medication adherence tracking 13,17. These advancements would reduce the risk associated with prolonged exposure to rigid electronic components, eliminate concerns about device accumulation in the GI tract, and significantly lower electronic waste from medical devices. The development of such technologies represents a critical step toward sustainable, patient-friendly adherence monitoring solutions that seamlessly integrate into routine clinical practice 11.

Bioresorbable devices for wearable sensors and electronics have been extensively studied, with various implants developed. Previous examples of transient electronics include devices for physiological monitoring, wound healing, electrical stimulation, and drug delivery 19–21. Despite the existing need, development and use of biodegradable materials for ingestible electronics has been limited. To date, only a few technologies have utilized Generally Recognized as Safe (GRAS) or biodegradable materials, and even fewer have been tested in vivo on large animal models as using the concept of ingestible capsules 22–24. For example, gelatin-based impedance sensors have been developed to detect healthy versus damaged esophageal tissue in ex vivo disease models 24. A few edible conductive pastes, conceptual batteries for ingestible electronics have also been demonstrated as proof of concept devices 25,26 but demonstrations in-vivo have remained limited. Recently, an implantable GI sensor, for early detection of gastric leakage was made from bioresorbable materials 27, but embodiments that are fully ingestible remain rare. The development of bioresorbable, or transient, electronics holds multiple advantages for ingestible devices: it eliminates the need for secondary surgeries to remove the capsules, reducing the risks of infection and retention, and minimizes electronic waste in the GI tract 28,29. Commonly used biodegradable materials are often functional synthetic polymers, such as poly(lactic-co-glycolic acid) (PLGA), polyanhydride (PA), Polyethylene glycol (PEG) and poly(octanediol citrate) (POC), for substrates or as encapsulation 30 Despite experience with these polymers, there are still unrealized risks surrounding manufacturability, scalability and exposure of microplastic components to the user and environment given their long degradation time 31. Natural polymers, in contrast, are highly promising for ingestible and transient electronics due to their low cost, ease of processing 32,33, and long established safety profile. Among these, cellulose stands out as a natural, biocompatible polymer with extensive use in healthcare, including the drug industry, diabetes management, electronics and pharmaceuticals 34. This interest is reflected in the global market for cellulose production in pharmaceuticals and electroceuticals is projected to reach USD 1.52 billion, underscoring its importance in the field 35.

In this work, we propose a bioresorbable RFID antenna combined with a cellulose-metal particle-based RF shielding coating that blocks RF signals until the device reaches the target site, enabling an advanced use of RFID technology to measure adherence in an environmentally conscious manner. This combination forms our platform, SAFARI: Smart Adherence via FARaday cage And Resorbable Ingestible, designed for assessing medication adherence. The bioresorbable RFID tags can be easily sized to integrated into standard-sized gelatin or HPMC capsules. The cellulose-based electromagnetic shielding system that functions as a Faraday cage, effectively blocking the RF radiation. Once the coating dissolves in target organ (e.g., the stomach), the tag radiation becomes active, the system enabling precise tracking of ingestible devices. This low-cost, proof-of-concept system has been successfully demonstrated in vivo using swine models, suggesting a straightforward pathway toward clinical translation. This innovative approach opens avenues for exploring applications, such as device localization, measurement of detection range for ingestible electronics, and RFID sensing for drug delivery. Our design leverages passive RFID functionality with a zinc-based tag, enabling RF communication while using bioresorbable materials, which eliminates the need for device removal or battery replacement. Large animal studies using swine were then conducted to establish clinical readiness of the SAFARI device. This study validates our device’s ability to monitor ingestion events through passive RF technology, presenting a viable platform for next-generation bioresorbable communication systems in the GI tract and enabling healthcare providers to more effectively monitor patient adherence and health status.

Results
In this study, we conceptualize a switching mechanism by introducing an electromagnetic interference (EMI) shielding coating that encapsulates the RFID tag and the gelatin carrier capsule. To facilitate utilization of wireless medication adherence technology, Fig. 1 shows an envisioned medical use of case of ingestible RFID technology. Our bioresorbable SAFARI platform has several components: zinc foil-based RFID tag, payload and 000 capsule and EMI shielding coating. The ingestible platform consists of i) Zinc based RFID tag, ii) RFID chip, iii) 000 capsule, and payload of interest (drug, sugar, dye etc.), iv) bioresorbable EMI shielding material. The tag can be incorporated into a gelatin or HPMC (hydroxypropyl methylcellulose) capsule along with the payload, in other words medication dose. Once it is encapsulated with ingestible EMI shielding coating, the tag signal is blocked, which is the OFF state. In the “ON State”, the bioresorbable RFID tag can be queried via an external reader and used to monitor events using RFID chip data. In the event of ingestion, the EMI shielding coating dissolves and the bioresorbable device can accept queries from the external reader, confirming the ingestion. During manufacturing, the RFID tag can be loaded with information regarding drug dosage, manufacture date, serial number and any other relevant information. Following payload delivery, the healthcare professional can track the medication dose that is delivered with the capsule using an external reader. Upon full dissolution of the capsule, the device is exposed to GI fluids. The EMI coating, capsule and metal antenna components dissolve in the stomach, while the RFID chip, a small biocompatible die, remains intact, making the overall system largely bioresorbable.

Bioresorbable RFID tag
The Bio-RFID tag is a compact device that is composed of thin cellulose acetate substrate (35 μm), a bio-adhesive polyglycol sebacate (PGS) to bond the substrate with zinc traces, and Impinj Monza M700 RFID chip (≈400x400 μm, −24 dBm). Fig. 2a demonstrates the schematic illustration of the device layers and characterization of the tag. The tag includes Zinc antenna bonded to cellulose acetate substrate using bioadhesive PGS, an RFID chip and PLGA encapsulation. The electrical connection between the zinc antenna and RFID chip is maintained by wire bonding and supporting it with epoxy (Supplementary Fig. 1). This Zinc based RFID tag resonates at a frequency of 915 MHz. We have performed simulations (CST Microwave Studio) using different scenarios (Supplementary Note 1). Fig. 2b describes the general operation scheme of the RFID tags. In general, a signal is sent from an RFID reader and received by the RFID tag, where the signal backscattered to the reader. In order to verify the performance and specifically to read the tag name and the operational frequency range, first we set the transmitted power to 30 dBm and the tag to reader distance to ≈20 cm (Supplementary Fig. 2). The measurement setup is based on a programmable RFID reader (Rain R700) and a circularly polarized panel antenna with a gain of 9 (dBi). The setup can adjust the emitted power up to 33 dBm (constrained by the Federal Communications Commission at 30 dBm), within the frequency range of 860–928 MHz. We have monitored the Received Singal Strength Indicator (RSSI) for the RFID tag in air, rolled in a 000-gelatin capsule and inside of an ex-vivo swine stomach. For all cases RSSI values range in between 50–65 dBm for SGF and ex-vivo cases, indicating that the RFID tag has sufficient performance for continuous reading (Fig. 2c). Fig. 2d shows the FEA simulation results when the tag is bent at an angle that enables it to fit in a 000 capsule. Bending the device to 168 degrees, to match that observed during capsule loading (Supplementary Note 2), shows that the electrode structures have the highest von Mises stress N/m2 at the zinc arm, indicating that the connectivity of the RFID chip to the substrate is unaffected during loading of the capsule. Fig. 2e, f demonstrate a series of images that show the process of dissolution of a tag during immersion in RGF and SGF at 37 °C. The zinc antenna and the encapsulation dissolves in less than a week in both Simulated Gastric Fluid (SGF) and Real Gastric Fluid (RGF), while the substrate degrades over several weeks. This agrees with the degradation mechanisms of the respective materials: Zinc degrades at a rate of 120 nm/day via the chemical reaction: Zn+2H2O!Zn(OH)2+H2 36. Although flexible substrate degradation via hydrolysis may take months, the substrate’s dimensions (10×15 mm) and its softening upon wetting, facilitate its passage through the GI tract. The designed absence of thick encapsulation layers or humidity barriers enables the full device to be absorbed or passed with minimal complications.

Cellulose based EMI shielding coating
Following the design of our RFID tag system, we then introduced a biodegradable EMI shielding coating to block the signal prior to capsule dissolution and to enables signal activation following coating dissolution. The ink uses two components: a polymer matrix of 2-Hydroxyethyl cellulose (HEC) and bioresorbable metal fillers. Cellulose and its derivatives are excellent candidates as a binder and have been used for pharmaceutical applications, as bioplastic, in printed electronics as well as electronics skin applications 37,38. In the cellulose family, HEC was chosen due to its solubility in ethanol, and viscosity to facilitate gelatin capsule coating as well as its dissolution rate in acidic environment 39,40. Fig. 3a shows the steps of preparing the shielded capsules, which can be easily scaled using a dip, brush or spray coating method as needed. It is also possible to print such inks using direct ink writing using a brush enabling mass manufacturing of the coated capsules. (Supplementary Fig. 3). We determined that a viscosity of 1–300 Pa.s (8% w/v HEC to solvent) was suitable for capsule coating (Supplementary Fig. 4). Blade coating the composites at a controlled thickness produced uniform films, with the composite containing 1–5 μm Mo particles exhibit the best performance, lowest sheet resistance (0.8 Ohms/sq) at the mass ratio of 1:11 (Fig. 3b, c), followed by W particles with size of 1–5 μm. Mo and W particles were selected as Fe, Mg and Zinc show less conductivity due to formation of surface oxides 36,41. When the ratio passes beyond 1 to 11, the sheet resistance increases possibly due to non-uniform dispersion of particles 42.

To explore the EMI shielding properties of bioresorbable composites, we then fabricated thin films of HEC/Mo and W, each having thicknesses of 40–50 μm. We utilized a pair of wide-band near-field probes with a vector network analyzer to investigate the radio frequency (RF) transmission properties of the composites. To effectively reduce environmental RF noise interference, we constructed a Faraday cage using aluminum foil to encase the probing setup (Supplementary Fig. 6). We then scanned between 700 MHz and 1.2 GHz to analyze the S21 response in the mid-field range especially at the 915 MHz (Fig. 3d). The recorded EMI SE of HEC:W and HEC:Mo with metal particle size of 1–5 μm is given in Fig. 3e. HEC with Mo shows 25 dB at 915 MHz which is higher than the W composite that of 15 dB, which indicated the HEC:Mo is a good candidate to be used in shielding application. A comparison using different metals (including foils and polymer films) at UHF band is given in Supplementary Fig. 7. Although films of (3N) W, Zn and Mo materials effectively attenuate RF signals, (measured S12 parameters) demonstrating their suitability for applications requiring high shielding effectiveness. However, printable inks are required to be applied on curved substrates. Several materials specifically conductive polymers, CNT and MXene family have been proposed as a thin film shielding material for X-Band and THz range 43–45. The importance of the UHF band is that it is known as biomedical frequency and the commercial RFID tags are mainly operating at this range 46,47. The measured EMI SE for Mo particles is comparable with PEDOT based polymers 48 with the added benefit of full biodegradability.

Composites using microparticles of Mo represent a better choice compared to those of other bioresorbable metals and conductive polymer due to their high conductivity, biodegradability, their resistance to the formation of thick oxides, relatively slow absorption and low cost. Application of Mo based composites on the ingestible capsules creates a continues conductive layer, preventing RF transmission to and from the interior of the capsule (Fig. 3f) until layer dissolution. Fig. 3g shows the cross-section of the capsule architecture, which reserves ≈98 % volume for loading of drug payload.

Dissolution, degradation and in vivo Studies of SAFARI
To understand the dissolution mechanics of the full system, we tested the degradability of the capsule and its components in vitro at physiological temperature (37 °C) in SGF. The EMI encapsulation coating dissolved immediately after wetting in vivo tests (10–20 min). The tag’s zinc layer and Mo coating parts disintegrated into pieces in 24 h. We have demonstrated accelerated biosorption at an elevated temperature to convey the complete picture in case of dissolution (Fig. 4a). At 75 °C (corresponds to ≈16 times relative to 37 °C) 49, the device and the components dissolved and disintegrated into small particles in a week. The proposed materials here are bioresorbable due to hydrolysis or enzymatic degradation in physiological and gastric conditions also considered as edible 33,36. For instance, Zn and Mo undergo hydrolysis to form oxides 36. Zinc and Molybdenum react with water (Zn+2H2O!Zn(OH)2+H2), (Mo+4H2O!MoO42-+8H++6e-). The CA is a biodegradable commercial polymer that dissolves in water, upon swelling and is compatible with laser-processed electronics 50. Bioadhesive PGS is a biodegradable synthetic polymer that undergoes surface erosion and effectively used in drug delivery 51. The commercial cost-effective gelatin and HPMC (hydroxypropyl methylcellulose) capsules are considered as biodegradable and depending on the pH, their dissolution time varies 52. HEC acts as a binder in the coating formulation and is a cellulosic material that degrades into glucose under the effect of enzymatic degradation 40. HEC exhibits consistent swelling and dissolution behavior across the physiological gastric pH range (1–6), ensuring reliable degradation of the SAFARI capsule and timely activation of the RFID signal even under interpatient variability in stomach acidity and motility 53,54. We have confirmed the degradation of the HEC/Mo film through a decrease in the characteristic glycosidic bond intensity, as shown by FTIR analysis, which is consistent with previously reported degradation behavior of cellulosic materials 40 (Supplementary Fig. 8). In Supplementary Table 1, the biodegradation rates and daily intake recommendation of the device ingredients are given.

To fully validate the technology, SAFARI capsules are tested in vivo. Swine models were selected due to the similarity of their GI tract size to that of humans. First, we administered the shielded 000 size capsules into the stomach. Fig. 4b shows the steps of dissolution of the device in swine stomach and data recording. Endoscopic images were taken to assess the dissolution trend of the coating and investigation of the RFID tag. After the administration of the capsule, the EMI shielding coating swells due to the cellulose content at the contact with gastric fluid (i). Then, the coating partially dissolves (ii), and the tag fully exposed for passive communication (iii). Once the tag is exposed, the panel antenna starts to record the tag data and following frequency range. The X-Ray image of the capsule in the swine stomach is shown in Fig. 4c. The image is taken immediately after the administration. In general, the tag and parts of the shielded capsule disintegrated in the stomach up to 24 h after administration (Supplementary Fig. 9), consistent with the in vitro degradation tests. To evaluate the visibility and physical footprint of the non-bioresorbable RFID chip in vivo, we performed X-ray imaging in swine, which confirmed the antenna’s visibility while the chip remained undetectable due to its sub-millimeter size (Supplementary Fig. 10). We anticipate that the RFID chip (0.16 mm²) will safely transit through the GI tract, as prior studies have demonstrated the safe passage of significantly larger ingestible capsules (diameter, 9 mm and length, 26 mm) 22].

To acquire tag properties in live animals, the same measurement setup is maintained (Supplementary Fig. 11). The administrated RFID tags names are recorded prior to capsule ingestion, that simplify the data recording during the in vivo tests (Supplementary Fig. 12). Fig. 4d shows the RSSI data recorded from known tag ID, showing dB level of the different devices operating in the stomach (Supplementary Fig. 13). In addition, the frequency data of the tags during operation are recorded, while the capsule dissolves until the tag is immersed in gastric fluid (Fig. 4e). Although the devices fully immersed in gastric fluid or floating inside the stomach, the setup still is able to record the frequency range of 900–925 MHz. This shows the robust design of the proposed antenna configuration. Using the tag name, the payload along with the capsule can be recorded into a cloud system and noted. This passive way of recording the ingestion event enables electronic medication adherence and leads to a digital health application. Similar technologies, such as intrabody communication enabled-capsules for ingestible electronics, are compared in Supplementary Table 2 55,56.

To give more concrete insights into metal dissolution and degradation, inductive coupled plasma optical emission spectrometry (ICP-OES) analysis of the Zn antenna and Mo coating indicates material dissolution at 37 °C, 25 rpm over various time points. These findings align with previous reports conducted in PBS and are consistent with SGF immersion images 57,58. The coated capsule with tag dissolves partially in 8 h, exhibiting corresponding 2 ppm Zinc and less than 1.5 ppm Mo (Fig. 4f). On Day I, peak Zn and Mo concentration reaches up to 5 ppm. The device dissolution saturates on Day III, showing 7 ppm Zinc and 3 ppm of Mo. To validate device safety, we have administrated the capsules in swine and measured the Zn and Mo levels in blood serum over time. We administered a special diet providing approximately 2000 ppm Zn and 1 ppm Mo daily. Baseline blood serum levels were measured at 0.4 ppm Zn (n=4) and 0.05 ppm for Mo. We measured the metal levels in serum at 8 and 24 h after the capsule administration (Fig. 4g). No significant increase in the serum Zn and Mo levels was observed since the daily dietary intake of these metals exceeds the amounts present in the device (mZn = 20–25 mg, mMo = 20–30 mg). Both metals are essential trace elements with well-established metabolic handling and safety margins. The observed exposures correspond to levels previously demonstrated to be safe, tolerable and are readily cleared through normal physiological routes, consistent with prior reports of negligible tissue accumulation following molybdenum rich diet or high-zinc diets in animal models (Supplementary Table 3) 59–62. For example, the measured serum metal concentrations align with previous swine study on high Zn load diet 62. For Mo, the expectation of accumulation in organs is unlikely, as studies on Mo implants (diameter, 250 μm), in small animals have shown minimal accumulation and toxicity 60. For a Mo foil-based implant (thickness, 25 μm), toxicity and Mo accumulation studies in a rodent model over 22 weeks post-implantation revealed no tissue damage, with only minimal accumulation observed in the organs 19. Additionally, further research indicates that even with high Mo diet in humans, excess molybdenum is efficiently excreted by the body 59.

Methods
Reagent and Materials
Mo particles (Thermo Scientific, 3–7 μm and 1–5 μm size) and W particles (Alfa Aesar, 1–5 μm) were used for bioresorbable conductive coatings. Hydroxyethyl cellulose (HEC, Mw=90,000), glycerol, sebacic acid, DMSO were purchased from Sigma-Aldrich. Ethanol (%99, Deconlabs) and DI water were used as solvent in all ink preparations. Cellulose acetate (35 μm) or polylactic acid (PLA) (50 μm substrate, and zinc foil (25 μm) were purchased from Goodfellow Corporation. PEDOT: PSS (PH1000, 1.3 wt%) was purchased from Heraeus Clevios GmbH.

Ink Preparation
PGS bio-adhesive synthesis: PGS adhesive was synthesized using equimolar mixtures of glycerol and sebacic acid under 120 °C and N2 for 24 h for forming prepolymer. Then the prepolymer is spread on the CA substrate to maintain adhesion to zinc film.

Gelatin based adhesive: 1 g gelatin, 1 g glycerol and 8 g of DI water first kept in oven at 70 °C for 1 h. Then, mixture is mixed on a hot plate at 70 °C with 250 rpm for 2 h. After it is fully dissolved the mixture mixed for 10 min at 40 °C to be used to bond the chip to the substrate.

Biodegradable, Conductive ink Preparation: The ink was prepared by mixing HEC (0.8 g) in ethanol (10 ml) at room temperature. After having a gel, Mo and W particles were subsequently added to the mixture at different volume ratios followed by mechanical mixing using Flacktek speed mixer (at 2500 rpm for 10 min). For conductive polymer EMI shielding comparison, 10 ml PH1000 (Sigma-Aldrich) 0.1 g glycerol and DMSO (5% v/v) are added to 10 ml PH1000. The ink was vigorously mixed overnight and drop-casted in petri dishes. The other metals, W, Mo films are purchased from Goodfellow Inc.

For conductivity measurements, samples were printed using a blade coater. First, a PET (125 μm) foil is placed to coating bed, then the ink spread with blade coater (distance kept as 0.2 mm between the glass bed and the PET foil). After the solvent evaporation in ambient air, the resulting film is 8×8 cm, and the film thickness range is between 40–80 μm achieved. The film was peeled off from the substrate, cut to appropriate dimensions and placed on four-point probe test bench for sheet resistance, conductivity and EMI shielding measurements.

Coating of 000 Capsule: the coating experiments were performed using a brush. For brush painting of gelatin capsules, a mold is fabricated to maintain better control on deposition. Ecoflex 00-30 is mixed 1:1 ratio and poured in plastic cups and degassed. 000 capsules are then pressed into the mixture and cured overnight. After curing, the sacrificial gelatin capsule is removed, and e-pill is replaced for coating. The ink was applied first to the upper face of the capsule, after evaporation of the solvent, the other half is coated with the ink. This process is repeated several times to maintain pinhole free coating of composite ink onto gelatin capsules to create continuous layer.

Immersion test, SGF preparation: SGF was prepared by dissolving 0.2% w/v NaCl in DI water and pH 1.2 was adjusted using HCl. For RGF tests, fresh gastric fluid is collected every other 2 days and replaced in every 24 h.

Device Fabrication
CA/PGS/Zn stack is used as a base for antenna manufacturing. U4 LPKF laser system is used for patterning and cutting of RFID antenna. After patterning the zinc, unwanted parts were peeled off from the substrate and the zinc antenna on CA substrate is achieved. Impinj Monza RFID chips were first gold wire bonded from the chip connections. At the other end the gold bonding left floating. The chip with gold connections is adhered to substrate using gelatin adhesive. The floating ends of the RFID chip with gold wires placed on the zinc and connected using conductive Mo based ink. For the in vivo test to maintain a good electrical connection, a biocompatible Ag/AgCl ink is used for the connection. As a last step, PLGA (1 mg in 1 ml acetone) is drop-casted on the RFID chip and electrical contacts. The resulting device is placed in a 000 gelatin or HPLC capsule, horizontally and placed for the molds for depositing shielding material. A painting brush (size #1) is used to print bioresorbable EMI shielding inks. After one pass of printing with the brush, the coating dried for 1 h. Then, the device removed from the Ecoflex mold, and the other face of the capsule is placed in the mold. Another coating is applied to coat the entire capsule with the shielding ink.

Tag data measurement
A 902–928 MHz panel antenna (TE Connectivity, 9 dBic) connected with Impinj RAIN R700 is used to communicate with the fabricated RFID tags. Impinj Item test software is used for capturing tag name, RSSI data and frequency. We have also validated the tag name using a handheld tag reader (TSL 1128 UHF RFID Reader) to verify the electrical connection and tag name for ease of detection during in vivo demonstrators (Supplementary Fig. 12).

EMI shielding measurement
The EMI shielding measurements were measured over the UHF band (700 MHz–1.2 GHz) frequency by using probes that are connected to vector network analyzer (Keysight E5080B ENA). We utilized a pair of wide-band near-field probes (NFP-3 Near Field Probe Kit 30 MHz–3 GHz, RIGOL) with the VNA to investigate the RF transmission properties of various metallic shielding materials. To effectively reduce environmental RF noise interference, we constructed a Faraday cage using aluminum foil to encase the probing setups. This setup ensured that our measurements were precise and minimally impacted by external noise. Prior to dissolution of the shielding layer, no RFID signal was detected in either in vitro or in vivo settings, consistent with the effectiveness of the complete EMI shielding design.

In vivo testing
All swine studies were approved by and performed in accordance with the Committee on Animal Care at the Massachusetts Institute of Technology. In vivo studies were performed in female Yorkshire swine, n= five (4–8 months, weighing ≈50–70 kg) due to the anatomical similarity of their GI tract to that of humans. Before any procedure, the animals were given a liquid diet (Ensure, Abbott Laboratories) for 24 h, followed by an overnight fast. For capsule placement, animals were sedated using an intramuscular injection of midazolam 0.25 mg kg−1 and dexmedetomidine 0.03 mg kg−1. Following sedation, the animal was intubated, placed on isoflurane (2%) in oxygen and connected to a vital sign monitoring system and provided thermal support. The device was endoscopically delivered through an overtube to the stomach and visualized using a PENTAX EC-3870TLK (160 cm) while the animal was positioned in the left lateral. After delivering the capsule and performing endoscopic imaging, the panel antenna was positioned 10 cm from the animal to capture tag events.

Finite element analysis
3D FEA was used to simulate the zinc tag bending using commercial software COMSOL Multiphysics. In the model, Solid Mechanics Interface was used to calculate stress when the bending conditions match with the bending of the tag to place in a 000 capsule.

ICP-OES
Agilent 5100 DVD Inductively Coupled Plasma-Optical Emission Spectrometer is used to quantify the metals. For quantifying the amount of Zn and Mo in blood, samples are digested in immersion trace–grade nitric acid (HNO3; >69%; Sigma Aldrich) and then heating 37 °C overnight at 25 rpm. The addition of ultrapure H2O (18.2 megohm∙cm) yielded a final solution of 2.0% nitric acid. Zn and Mo solutions (1000 μg/ml; Inorganic Ventures, Christiansburg, VA, USA) were used to create calibration curves.

Characterization Methods
SEM was conducted by Hitachi FlexSEM TM-1000 II (Tokyo, Japan) using low voltage imaging (3–5 kV). The dissolution of the HEC polymer matrix in SGF was assessed via Fourier Transform Infrared spectroscopy (FTIR) using the Agilent Cary 630 FTIR with the MicroLab Expert Software (version: 1.1.0.0). The rheological property of the electrode ink was measured by DHR-3 Rheometer (TA Instruments. New Castle, Delaware USA). Flow sweeps were implemented to test the viscosity from 1 1/s to 100 1/s. Optical microscope images were taken by (Keyence VHX-X1 Digital Microscope). The surface roughness and step height profiles were quantitatively analyzed by laser confocal scanning using a 3D surface profilometer (Keyence VK-X3000. Osaka, Japan). Conductivity measurements were taken by Ossila Four Point Probe System. Thickness values were measured with micrometer (Mitutoyo).

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "This manuscript presents SAFARI, a bioresorbable RFID capsule system designed to monitor medication ingestion. The innovation lies in combining a cellulose–metal EMI shielding layer with a biodegradable zinc-based RFID tag, enabling in vivo adherence tracking while minimizing environmental impact. The study is well structured, addressing a critical unmet clinical need (medication nonadherence) and coupling it with sustainability considerations. Additional clarification and improvements could benefit certain areas by enhancing technical robustness. Please see comments below.\n1. Pigs are a closer model than rodents, but people’s stomachs vary a lot — pH can range from 1 to 6, and conditions like motility disorders or obesity can change digestion. How might these differences between patients affect the device’s reliability, especially the timing of capsule dissolution and the consistency of signal detection?\n2. How reliable is the SAFARI capsule’s dissolution and activation timing across the wide range of stomach conditions people can have? What safeguards are in place to avoid false results — for example, if the shield dissolves too early in the esophagus or too late in the intestine?\n3. The system shows good detection with a panel antenna at about 20 cm, but in real-world use the reader may not be positioned perfectly. How well would the system work in everyday settings, and how much would factors like obesity or fluid buildup in the abdomen reduce sensitivity and affect the signal strength (RSSI)?\n4. Please provide error bars for the RSSI variability observed across multiple animals to better understand the system's consistency.\n5. Could you clarify the detection rate? Was every capsule ingestion successfully recorded in the study? Were there any missed events or false readings?\n6. Each capsule leaves behind a non-bioresorbable RFID chip (∼0.16 mm2). For patients on chronic, lifelong therapy (e.g., HIV, TB, diabetes), they could ingest hundreds of these over the years. What is the projected risk of retention, aggregation, or micro-obstruction in the GI tract from the cumulative debris?\n7. Although serum Zn and Mo levels were unchanged in swine, scaling this to humans with chronic daily dosing remains a major uncertainty. What is the projected cumulative exposure for a patient on lifelong therapy, and could subclinical accumulation of Mo/Zn pose any long-term health risks?\n8. Please disclose whether the RFID chips themselves contain any heavy metals or rare elements that could raise environmental concerns, separate from the bioresorbable zinc tag.\n9. The capsule coating was applied by brush or dip coating as a proof-of-concept. How feasible is consistent large-scale GMP manufacturing of these shielded capsules? What are the expected failure rates (e.g., pinholes, incomplete shielding) that could compromise the adherence data?\n10. How does SAFARI compare head-to-head in terms of accuracy, safety, and usability with FDA-approved systems such as Proteus Digital Health's ingestible sensor? Highlighting clear advantages would significantly strengthen the translational case.\n11. In clinical deployment, what is the envisioned reader solution: will patients wear a patch/reader, or will readers be embedded in home environments? How would adherence data integrate into electronic health records while ensuring patient privacy?\n12. A long-term cost comparison with existing digital adherence tools (like smart pill bottles) would be extremely useful for assessing market viability.\n13. Please expand the degradation kinetics discussion: how variable was the Zn/Mo dissolution across different in vitro and in vivo gastric environments tested?\n14. For Figures 2–4, please improve the labeling (e.g., clarify the scale and units for \"RSSI dB values\").", "reviewer_2": "This paper introduces an ingestible biodegradable RFID tag. The biodegradation of the uppermost layer of the tag is linked to ingestion; hence, the system can wirelessly sense the ingestion event from outside the human body. The main advantage of the system is that it is passive and battery-less, which makes it promising. Overall, the study is an interesting and creative example of how RFID technology can be applied to healthcare monitoring.\nMy comments:\n1. The authors’ claim in Line 151 (“…all device components can be degraded or absorbed in the body”) should be revised, as the system is not a chipless RFID. Since the design includes an RFID chip, the entire tag cannot fully dissolve.\n2. The numerical analysis provided in the supplementary data indicates that the antenna has approximately 5 dBi maximum gain. This value seems unexpectedly high for an implantable antenna. Could the authors please clarify the simulation scenario under which this result was obtained?\n3. In Figure 2c, the RSSI level observed in ex-vivo tissue is\na. similar to that measured in air, and\nb. higher than that measured in the capsule cases.\nBoth observations are somewhat unexpected given the lossy nature of biological tissues at this frequency. Could the authors please elaborate on the reason behind this result?\n4. Could the authors clarify the difference between the RSSI measurements presented in Figures 2c and 4d? Why is there an approximately 10 dB discrepancy between the two stomach recordings?\n5. Figures 4d and 4e could benefit from a clearer presentation. In Figure 4d, the time < 0 axis region could be minimized, while the time steps for > 0 could be spaced more clearly. Adjusting the RSSI scale to –60 to –90 dB would improve readability across devices. Similarly, modifying the y-axis scale in Fgireu 4e could help make the variations more visible.\n6. The paper could be strengthened by referencing related work that explores a similar concept of gastrointestinal segment tracking using biodegradable substrates, for example:\nA. Hadi, E. Cil, Z. C. C. Ozdil, D. Nikolayev, and S. Dumanli, “Gastrointestinal Segment Tracking of Ingestible Capsules Using Biodegradable Superstrates,” 2025 19th European Conference on Antennas and Propagation (EuCAP), Stockholm, Sweden, 2025, pp. 1–5, doi: 10.23919/EuCAP63536.2025.10999460.", "reviewer_3": "General Comments\nThis manuscript introduces an ingestible UHF RFID capsule that remains unreadable until its cellulose-based, Mo/W microparticle EMI shield dissolves in gastric fluid, revealing a zinc antenna. The concept of a dissolvable Faraday cage applied to a passive, largely bioresorbable RFID tag is creative and well executed at the materials level. However, the clinical novelty compared to existing ingestion event markers such as the Proteus system is limited. The work still faces major translational barriers, especially regarding reader deployment, real-world usability, and long-term safety for repeated ingestion. The study requires major revision to convincingly demonstrate novelty and feasibility.\nSpecific Comments\nMajor Comment 1\nThe work frames itself as a breakthrough in ingestion verification, but the underlying clinical function remains the same as Proteus: logging a pill ingestion event. The addition of a dissolvable EMI cage is a materials-level refinement rather than a fundamentally new mechanism. Clarify precisely how this adds to or improves upon prior adherence technologies.\nMajor Comment 2\nThe system shifts adherence requirements from wearing a patch (Proteus) to maintaining proximity to or continuously wearing an RFID reader. This trades one compliance problem for another. Without clear solutions, the system risks creating the same adherence issue it aims to solve.\nMajor Comment 3\nDemonstrations rely on large commercial RFID readers and panel antennas. To establish clinical relevance, the study must address whether a reader can be miniaturized into a wearable form factor that is comfortable, battery-powered, and low-power enough for daily use. Without this, feasibility in real-world adherence programs remains unconvincing.\nMajor Comment 4\nThe current data do not convincingly establish robust readout through variable human abdominal tissue. Systematic measurements in phantoms or representative tissue depths are needed to determine reliability and variability across subjects.\nMajor Comment 5\nDaily ingestion of zinc antennas, Mo/W microparticles, and RFID ICs raises legitimate safety questions. While short-term swine data are provided, long-term cumulative effects and toxicological safety limits must be discussed in detail, including whether it is truly acceptable to ingest an RFID die daily.", "reviewer_4": "While an ingestible pill addresses concerns about verified drug ingestion, research has not confirmed that other, less intrusive, objective measures, such as electronic pill bottles, insufficiently assess adherence with regards to removing a dose without ingesting it. To my knowledge, no study has demonstrated that an ingestible or drug assay identifies nonadherence not already identified by electronic pill bottles.\nExisting objective measures are rarely used in clinical care because of the cost, technical challenges of managing the large amount of data obtained, and the perceived intrusiveness by both patients and healthcare providers. Research has shown that healthcare providers rarely review pharmacy refill data readily available in many electronic medical records, and few avail themselves of objective adherence monitoring when the service is available. Thus, I do not see healthcare providers desiring ingestible technology.\nElectronic pill bottles are more often, but not always, used in clinical trials. However, study eligibility criteria and protocol burden often result in highly compliant study participants following the study protocol. Thus, the extra cost of manufacturing a new drug with ingestible technology is unlikely to be viable in clinical trials. Indeed, this is why studies rarely add tracer compounds to a drug to enable biological assay assessment of adherence despite this option being available for decades.\nImportantly, and not considered by the authors, is how knowing one is being tracked with an ingestible monitor may negatively affect adherence. Since the COVID-19 pandemic, people’s skepticism and mistrust of science and healthcare providers have made it clear that even a benign ingestible may be perceived as causing health problems or being able to track a person’s location, which could be used punitively against them. It would be unethical to include tracking technology without patient knowledge and approval. Unrelated side effects may be attributed to the SAFARI technology, by patients and providers and the technology, or worse case the medication itself, abandoned.\nMoreover, while the authors contend that the SAFARI technology requires no effort on the part of the patient, this is likely not the case. In my experience, RFID technology typically requires a reader, often via a cellphone app, to register the dose. Patients will delete the app, not have the app open, or not take a non-cellphone reader with them (e.g., pocket-dosing when they will be away from home for work, socializing, or traveling). Unmentioned is whether there are medication storage requirements, such as temperature, to preserve the coating and RFID tag, that could also add burden.\nThus, while SAFARI technology may be feasible, safer and more eco-friendly, outside of a few unique cases, the probability that there will be clinical or research uptake in the current healthcare environment appears small."}, "author_response": "Point-by-point response – Nature Communications – Manuscript #: NCOMMS-25-73449\nReferee #1 (Remarks to the Author)\nSummary Comment: This manuscript presents SAFARI, a bioresorbable RFID capsule system\ndesigned to monitor medication ingestion. The innovation lies in combining a cellulose–metal EMI\nshielding layer with a biodegradable zinc-based RFID tag, enabling in vivo adherence tracking\nwhile minimizing environmental impact. The study is well structured, addressing a critical unmet\nclinical need (medication nonadherence) and coupling it with sustainability considerations.\nAdditional clarification and improvements could benefit certain areas by enhancing technical\nrobustness. Please see comments below.\nResponse: We sincerely appreciate the reviewer’s constructive feedback and have carefully\nrevised our manuscript to address each point raised.\nComment 1: Pigs are a closer model than rodents, but people’s stomachs vary a lot — pH can\nrange from 1 to 6, and conditions like motility disorders or obesity can change digestion. How\nmight these differences between patients affect the device’s reliability, especially the timing of\ncapsule dissolution and the consistency of signal detection?\nResponse 1: We appreciate the constructive feedback from the reviewer. We thank the reviewer\nfor raising this important point regarding inter-patient variability in gastric physiology. Indeed,\ngastric pH can fluctuate between approximately 1 and 6 depending on individual factors such as\ndiet, fasting state, and medical conditions (e.g., obesity, motility disorders). Hydroxyethyl\ncellulose (HEC), used as one of the shielding coating key matrix materials, is a non-ionic and\nwater-soluble cellulose that shows pH-dependent swelling and erosion across this range. Previous\nstudies have demonstrated that HEC-based films and hydrogels undergo gradual dissolution and\nmatrix erosion in simulated gastric fluids of varying acidity (pH 1–6), confirming reliable\ndegradation behavior under both strongly acidic and mildly acidic conditions (Chen et al., PLOS\nONE, 2015; Roy et al., Int. J. Pharm., 2002; Naeem et al., Molecules, 2023).\nIn our design, the dissolution rate primarily determines the timing of signal exposure rather than\nthe signal strength itself. Therefore, even if capsule dissolution is moderately delayed in less acidic\nenvironments, the RFID signal is expected to remain detectable once the shielding layer begins to\nerode. In addition, gastric motility and peristaltic motion promote mechanical agitation, enhancing\ndisintegration and ensuring that the capsule will not remain static in a single position. We have\nadded this discussion to the revised manuscript to clarify how physiological variability may\ninfluence dissolution kinetics but is unlikely to compromise device reliability.\nModification to the manuscript:\nOn page 10, we have added a discussion: “HEC exhibits consistent swelling and dissolution\nbehavior across the physiological gastric pH range (1–6), ensuring reliable degradation of the\nSAFARI capsule and timely activation of the RFID signal even under interpatient variability in\nstomach acidity and motility[54,55] .“\nPage 1 of 20\nComment 2: How reliable is the SAFARI capsule’s dissolution and activation timing across the\nwide range of stomach conditions people can have? What safeguards are in place to avoid false\nresults — for example, if the shield dissolves too early in the esophagus or too late in the intestine?\nResponse 2: We thank the reviewer for raising this important question regarding the dissolution\nreliability and activation timing of the SAFARI capsule under variable gastrointestinal conditions.\nThe average esophageal transit time for a swallowed capsule is less than 10 seconds in healthy\nindividuals and under a minute even in patients with mild dysphagia (Kusano et al., Am. J.\nGastroenterol., 2012), ensuring that the capsule reaches the stomach well before any meaningful\ndegradation can begin. The HEC matrix remains stable in the short-term neutral pH of the\nesophagus, minimizing the risk of premature activation. The SAFARI system is specifically\ndesigned to activate in the stomach, where gastric pH and gastric fluid-controlled dissolution of\nthe shielding layer. Based on our in vitro and ex vivo data, dissolution and activation typically\noccur within 10–15 minutes under simulated gastric conditions.\nComment 3: The system shows good detection with a panel antenna at about 20 cm, but in real-\nworld use the reader may not be positioned perfectly. How well would the system work in everyday\nsettings, and how much would factors like obesity or fluid buildup in the abdomen reduce\nsensitivity and affect the signal strength (RSSI)?\nResponse 3: We thank the reviewer for this important point. Our panel antenna measurements at\n~20 cm provided a demonstration of practical read range in controlled conditions; these data show\nthat the SAFARI tag produces detectable signals in large mammal model. To address concerns\nabout reduced sensitivity in everyday use (e.g., patients with increased abdominal adiposity or\nascites), we emphasize the following mitigations and development paths:\n- The reader does not need to be panel-scale; compact/wearable readers (belt, patch,\nbedside unit) placed closer to the stomach can substantially improve link margin.\nShorter reader–tag distance is the single most effective way to recover RSSI loss from\ntissue attenuation.\n- Environmental placement (chair, toilet, bedside) provides multiple practical, low-\nburden options that bring the reader within the detection window without continuous\npatch wearing.\n- Increasing receiver antenna aperture or sensitivity (low-noise front end, higher gain\nantenna) improves detection without changing the tag.\n- Multiple readers: home deployments can use several low-cost readers sited in likely\nlocations (bedside, kitchen) to reduce dependence on a single reader location.\nComment 4: Please provide error bars for the RSSI variability observed across multiple animals\nto better understand the system's consistency.\nResponse 4: We thank the reviewer for this valuable comment. We have added Figure R1 to the\nSupplementary Information as Figure S13.\nModification to the manuscript:\nPage 2 of 20\nSupplementary Fig.R1. Recorded RSSI of the RFID devices communicated through the swine\nstomach.\nComment 5: Could you clarify the detection rate? Was every capsule ingestion successfully\nrecorded in the study? Were there any missed events or false readings?\nResponse 5: We appreciate the reviewer’s question regarding the detection reliability of the\nSAFARI capsule. In our current in vivo study, the system achieved an overall signal detection\nyield of approximately 40%. These results reflect the early-stage, proof-of-concept nature of the\nSAFARI platform, where variability arises primarily from differences in capsule orientation,\ngastric fluid volume, and antenna alignment relative to the receiver. Importantly, all detected\nevents corresponded to true ingestion, and no false positives were observed.\nWe anticipate that optimization of antenna geometry, reader sensitivity, and capsule encapsulation\nwill further improve detection yield in future studies. This initial performance establishes a\nvaluable baseline for the development of next-generation bioresorbable RFID adherence systems.\nComment 6: Each capsule leaves behind a non-bioresorbable RFID chip (∼0.16 mm2). For\npatients on chronic, lifelong therapy (e.g., HIV, TB, diabetes), they could ingest hundreds of these\n hundreds of these\nover the years. What is the projected risk of retention, aggregation, or micro-obstruction in the GI\ntract from the cumulative debris?\nResponse 6: We thank the reviewer for raising this important point regarding the long-term fate\nof the non-bioresorbable RFID chip. In our current design, the zinc antenna, which provides the\ncore electrical functionality, fully dissolves within a few days, delaminating from the cellulose\nsubstrate. The RFID chip itself is extremely small (∼0.16 mm², <100 µm thickness) and\nencapsulated in PLGA. While the entire capsule can be visualized by X-ray imaging (Supporting\nPage 3 of 20\nInformation, Figure S9), the chip is difficult to localize post-dissolution/excretion due to its minute\nsize and low density.\nFrom a physiological standpoint, devices (e.g. less than 11 mm × 26 mm, safety limits of FDA-\ncleared ingestible systems) readily transit through the gastrointestinal tract without risk of\nobstruction. The SAFARI chip is orders of magnitude smaller than this threshold, and therefore\nthe risk of retention, aggregation, or micro-obstruction is negligible. Moreover, prior studies on\ningestible electronic sensors such as Proteus Digital Health and eTectRx systems and our extensive\nexperience with ingestible electronics, recovering components of this size from animal models is\noften impractical, especially after the bioresorbable parts have degraded.\nComment 7: Although serum Zn and Mo levels were unchanged in swine, scaling this to humans\nwith chronic daily dosing remains a major uncertainty. What is the projected cumulative exposure\nfor a patient on lifelong therapy, and could subclinical accumulation of Mo/Zn pose any long-term\nhealth risks?\nResponse 7: We thank the reviewer for raising this important point. Based on our current design\nand available toxicological and nutritional data:\n- The zinc and molybdenum content per SAFARI capsule is minimal. Each capsule\ncontains zinc and molybdenum components (antenna and conductive elements) on the\norder of milligrams or less. In our swine studies, serum Zn and Mo levels remained\nwithin normal physiological ranges even after repeated dosing, with no evidence of\naccumulation or toxicity (Supplementary Table 1). ICP–OES analyses demonstrated\ntransient elevations of Zn (~7 ppm) and Mo (~3 ppm) in gastric fluid that did not\ntranslate into systemic changes, confirming safe biodegradation and clearance.\n- The exposure levels for zinc are well below established human dietary safety\nthresholds. For adults, the recommended dietary allowance (RDA) for zinc is 8–11\nmg/day, and the tolerable upper intake level (UL) is 40 mg/day. The estimated Zn (≤25\nmg) per capsule is below this UL, especially given the incomplete gastrointestinal\nabsorption and rapid renal clearance of zinc[3].\n- Prior work with molybdenum in rats and humans is notable for >20x exposure\nlevels without toxicity. The exposure level tested for molybdenum in rats without\nevidence of toxicity if 40mg/kg/day[4]. Prior work has demonstrated safety and\ntolerability of molybdenum in rats up to 40mg/kg/day. Moreover, renal clearance of\nmolybdenum supports the rapid clearance of the metal[5].\n- Physiological handling supports minimal risk of accumulation. Both Zn and Mo\nare essential trace elements with tightly regulated homeostasis. Zinc excess is mitigated\nthrough decreased intestinal absorption and metallothionein binding, while\nmolybdenum is efficiently excreted in urine as molybdate. In a 22-week in vivo study,\nmolybdenum implants (25 µm thick) caused no tissue injury or measurable organ\naccumulation[6]. These findings corroborate the benign biological profile of transient\nZn/Mo exposure observed in our large-animal studies.\n- Chronic dosing projections indicate no toxicological concern. Even under\nconservative assumptions of one capsule per day over decades, cumulative Zn and Mo\nexposure would remain well within normal dietary intake ranges and below toxicity\nPage 4 of 20\nthresholds. Given the capsule’s dissolution and the efficient physiological excretion of\nthese trace metals, subclinical accumulation or long-term perturbation of mineral\nbalance is not anticipated.\nWe acknowledge that long-term human data are not yet available. Future work will therefore\ninclude chronic exposure studies, pharmacokinetic modeling, and trace-element mass-\nbalance analyses to confirm safety for lifelong use. Together, these efforts will ensure that\nSAFARI’s design remains suitable for chronic therapeutic use while maintaining minimal\nphysiological impact.\nModification to the manuscript:\nOn page 11, we have added a discussion: Both metals are essential trace elements with well-\nestablished metabolic handling and safety margins. The observed exposures correspond to levels\npreviously demonstrated to be safe, tolerable and are readily cleared through normal physiological\nroutes, consistent with prior reports of negligible tissue accumulation following molybdenum rich\ndiet and implant degradation or high-zinc diets in animal models (Supplementary Table 3)[61-64].\nWe have added Supplementary Table 3 to summarize toxicological reference values.\nMaterials Estimated Human Human UL References No toxicity\nDose RDA (U.S) shown\n(per (small\ncapsule) animals)\nMetals Zn ≤ 25 mg 8–11 40 mg/day [8] 6\nmg/day mg/kg/day[9]\nMo ≤ 30 mg 45 µg/day 2 mg/day [10,11] 40\nmg/kg/day[12]\nSupplementary Table 3. Summary of Toxicological Reference Values.\nModification to the manuscript:\nOn page 12, we have added a discussion: From a safety and translational perspective, the SAFARI\nplatform’s material composition aligns with established dietary and biomedical exposure limits.\nThe zinc antenna and molybdenum shielding are used in microgram–milligram quantities per\ncapsule recognized to be orders of magnitude below levels associated with subclinical toxicity.\nBoth elements are essential micronutrients with tightly regulated absorption and renal elimination.\nPrior animal and human studies demonstrate minimal risk of long-term accumulation or organ\nretention, supporting the potential for chronic administration in adherence monitoring\napplications[61,62,65]. Ongoing work will expand these findings through chronic exposure modeling\nand pharmacokinetic analyses to confirm safety for lifelong use.\nComment 8: Please disclose whether the RFID chips themselves contain any heavy metals or rare\nelements that could raise environmental concerns, separate from the bioresorbable zinc tag.\nPage 5 of 20\nResponse 8: We thank the reviewer for this important comment. The RFID microchip used in the\nSAFARI capsule is a standard commercial silicon-based integrated circuit and does not contain\nheavy metals or rare elements that could raise biocompatibility or environmental concerns. Its\nprimary constituents are silicon, aluminum, and trace inert oxides used for passivation and\ninterconnects, with only gold contact pads exposed to the environment. To further mitigate any\npotential risks, the RFID chip is encapsulated within poly (lactic-co-glycolic acid) (PLGA), which\nis a well-established, FDA-approved biodegradable polymer (see Experimental Section:\nMaterials). This encapsulation provides a protective barrier, effectively minimizing any direct\ninteraction between the chip and gastrointestinal tissue.\nComment 9: The capsule coating was applied by brush or dip coating as a proof-of-concept. How\nfeasible is consistent large-scale GMP manufacturing of these shielded capsules? What are the\nexpected failure rates (e.g., pinholes, incomplete shielding) that could compromise the adherence\ndata?\nResponse 9: We appreciate the reviewer’s insightful question. In the present work, the capsule\ncoating was applied by brush or dip coating to demonstrate proof-of-concept functionality. For\nscalable manufacturing under Good Manufacturing Practice (GMP) conditions, the same\nmultilayer architecture can be readily adapted to automated spray or dip coating systems, which\nare well-established in the pharmaceutical and biomedical device industries for achieving uniform\nfilm deposition. Our shielding ink formulation can also be tuned for different rheological\nproperties, enabling compatibility with various printing and coating methods. These scalable\napproaches allow precise control over coating thickness, uniformity, and defect rates, thereby\nminimizing the likelihood of pinholes or incomplete shielding. Based on our prior experience and\nreported yields from similar multilayer encapsulations, we anticipate failure rates below 1–2%\nunder optimized process control. Ongoing efforts toward GMP translation will focus on validating\ncoating reproducibility and long-term stability across large production batches.\nComment 10: How does SAFARI compare head-to-head in terms of accuracy, safety, and\nusability with FDA-approved systems such as Proteus Digital Health's ingestible sensor?\nHighlighting clear advantages would significantly strengthen the translational case.\nResponse 10: We thank the reviewer for this valuable comment. The SAFARI system represents\na fundamentally different design philosophy compared to the FDA-approved Proteus Digital\nHealth sensor. The Proteus system integrates a magnesium–copper–silicon galvanic sensor that\ngenerates an electrical signal upon contact with gastric fluid, requiring an external skin patch for\npower and data capture. In contrast, SAFARI operates as a fully passive, battery-free, and\nbioresorbable RFID capsule, eliminating the need for power to sensors.\nFrom a safety perspective, SAFARI is composed entirely of biocompatible and partially\nbioresorbable materials, including zinc, molybdenum, cellulose acetate, and PLGA. All of these\nmaterials have established safety profiles in biomedical applications. The Proteus sensor, on the\nother hand, contains non-resorbable components, introducing potential issues related to tissue\nirritation and compliance.\nPage 6 of 20\nIn terms of accuracy and usability, SAFARI enables wireless, real-time monitoring of ingestion\nevents using standard RFID readers without patient interaction, enhancing adherence tracking\nwithout altering the user’s daily behavior. The fully passive design also minimizes false positives\nsince data transmission occurs only when the shielding layer dissolves in the stomach, ensuring a\nstrong signal-to-event correlation. By developing a bioresorbable RF system like SAFARI, we\nanticipate that this system could be used even in individuals who may have gastrointestinal\npathology that would place them at risk of RF tag retention (gastroparesis, inflammatory bowel\ndisease and other conditions).\nOverall, SAFARI provides a simplified, environmentally benign, and patient-friendly alternative\nto existing ingestible sensor platforms, with potential to expand adherence monitoring to broader\nclinical and global health contexts where cost, reusability, and sustainability are critical. We have\nupdated the Supplementary Table 2.\nComment 11: In clinical deployment, what is the envisioned reader solution: will patients wear a\npatch/reader, or will readers be embedded in home environments? How would adherence data\nintegrate into electronic health records while ensuring patient privacy?\nResponse 11: We thank the reviewer for this thoughtful comment. We have demonstrated in the\ndata that the shielding is sufficient to prevent undesired readings of the tag prior to degradation\nshielding film. With regards to placement of the reader, this is context dependent but can\npotentially be either integrated into the environment of the patient (such as on a bed or toilet) or\ninto a wearable belt like those demonstrated in prior works[10] (etectRx ID- Cap).\nID-Cap shows that a simple conformal loop antenna worn around the neck can detect ingested\nRFID tags to monitor medication adherence[10]. Additionally, Rajagopalan et.al. describes a\ncommercial system operating at 2.4 GHz that uses RFID to communicate with a lightweight\nexternal reader in clinical settings[11]. These studies suggest that proximity for reliable detection is\nnot a significant limitation in clinical environments, and similarly compact readers can be explored\nand integrated with our proposed platform.\nIn addition, we anticipate that the reader solution will need to be personalized. Previous data\ndemonstrates that individuals with different disease states may prefer different form factors of\nreaders[12] (Chai et.al., 2025, unpublished disclosure). For example, adjacent work in our group\ndemonstrates that users who are more mobile in their daily lives (younger individuals at risk for\nHIV) prefer miniaturization of readers while older individuals who might be more homebound\n(older individuals with heart failure) may prefer larger form factors that are harder to lose.\nDevelopment of path/readers will ultimately have the same core RF receiver but the vehicle in\nwhich they are contained and delivered to patients should be developed in concert with ultimate\nend users.\nRegarding adherence data integration, we anticipate that RF ingestion data would be fully\nanonymized. The system would merely detect the presence of medication in the stomach. A\nnumeric code can be used by the RF system to record data to a specific reader. This data can then\nflow via an API into an electronic health record (EHR) where a linkage from the reader number\nPage 7 of 20\ncan correspond to a specific medication. This strategy minimizes risk of data disclosure from\nSAFARI and allows all protected health information to remain within the EHR.\nWe think that for the purposes of the proof of concept, the custom design/placement of the reader\nis out of scope as it would have to depend on patient feasibility studies, market research, etc. for\nthe final product. We aim to focus on the ingestible form-factor and system in this work but will\ncontinue to extend this in the further to develop the external reader prior to clinical translation.\nComment 12: A long-term cost comparison with existing digital adherence tools (like smart pill\nbottles) would be extremely useful for assessing market viability.\nResponse 12: We thank the reviewer for this insightful suggestion. While a detailed cost analysis\nis beyond the scope of the current proof-of-concept study, we agree that economic feasibility will\nbe an important factor for future clinical translation. Compared to existing digital adherence tools\nsuch as smart pill bottles or sensor-integrated packaging systems, the SAFARI capsule architecture\ninherently eliminates the need for electronic modules in each dispensing device, reducing both\nhardware and maintenance costs. The use of low-cost, solution-processable, and bioresorbable\nmaterials: including zinc, cellulose, and PLGA. With these bioresorbable materials large-scale\nmanufacturing can be achieved at significantly lower per-unit cost than active ingestible systems\n(e.g., Proteus Digital Health’s sensor). In future work, we plan to perform a comprehensive cost-\nbenefit analysis comparing SAFARI to existing adherence monitoring technologies, incorporating\nmaterials, manufacturing, and clinical workflow integration costs to fully assess its market\nviability.\nIt is also important to emphasize the intended use case. SAFARI is not designed for mass-market\ndeployment. Rather, we envision application in specific, high-impact clinical contexts such as:\n- Patients with infectious diseases (e.g., tuberculosis, hepatitis C, HIV), where non-\nadherence could lead to anti-infective resistance,\n- Individuals at high risk of medication nonadherence where treatment failure has major\nconsequences (e.g. immunosuppression in solid organ transplantation, anti-\nplatelet/coagulation in the setting of cardiovascular stent interventions), and\n- Complex patient populations with overlapping adherence and health risks (e.g., HIV\nwith substance use disorder, poorly controlled hypertension) where monitoring could\nhelp support further care of the patient.\nModification to the manuscript:\nTo reflect this point clearly, we have added the following sentences:\n“SAFARI is not intended for mass-market deployment but rather for targeted, high-impact clinical\ncontexts where medication adherence is critical to patient outcomes and public health. These\ninclude infectious diseases such as tuberculosis, hepatitis C, and HIV, where non-adherence can\npromote drug resistance; transplant and cardiovascular patients requiring strict\nimmunosuppressive or antiplatelet regimens to prevent graft rejection or thrombosis; and complex\nPage 8 of 20\npatient populations with overlapping adherence and health risks—such as individuals with HIV\nand substance use disorder or poorly controlled hypertension “\nComment 13: Please expand the degradation kinetics discussion: how variable was the Zn/Mo\ndissolution across different in vitro and in vivo gastric environments tested?\nResponse 13: We thank the reviewer for this suggestion. We thank the reviewer for this\nsuggestion. To characterize the degradation kinetics of Zn and Mo components, we evaluated\ndissolution in multiple in vitro and in vivo gastric environments:\nZinc antennas: In SGF at 37 °C, Zn partially dissolved within 2–3 days, while accelerated tests at\n75 °C (≈16× faster) showed complete dissolution within a week. In vivo, dissolution may occur\nwithin 2–4 days, with minor variability (~±10–15%) due to gastric motility, fluid volume, and\nlocal pH differences. Shielding coating: Mo coatings degraded more slowly, persisting 1–2 weeks\nin vitro and slightly faster in vivo due to mechanical agitation and dynamic gastric conditions. We\nhave included detailed discussion in chapter 2.3. While some variability exists across different\ngastric environments, the functional window for reliable signal capture is preserved, and the\ndissolution profiles remain consistent, supporting reproducible performance of the SAFARI\nsystem.\nModification to the manuscript:\nOn page 10, we added a sentence: “The image is taken immediately after the administration. In\ngeneral, the tag and parts of the shielded capsule disintegrated in the stomach up to 24h after\nadministration (Supplementary Fig.9), consistent with the in vitro degradation tests.”\nComment 14: For Figures 2–4, please improve the labeling (e.g., clarify the scale and units for\n\"RSSI dB values\").\nResponse 14: We thank the reviewer for this input. We have updated the figures and uploaded\n.pdf versions of the figures for higher quality.\nPage 9 of 20\nReferee #2 (Remarks to the Author)\nSummary Comment: This paper introduces an ingestible biodegradable RFID tag. The\nbiodegradation of the uppermost layer of the tag is linked to ingestion; hence, the system can\nwirelessly sense the ingestion event from outside the human body. The main advantage of the\nsystem is that it is passive and battery-less, which makes it promising. Overall, the study is an\ninteresting and creative example of how RFID technology can be applied to healthcare monitoring.\nResponse: We appreciate the reviewer's recognition of our work. We sincerely appreciate the\nreviewer’s constructive feedback and have carefully revised our manuscript to address each point\nraised.\nComment 1: The authors’ claim in Line 151 (“…all device components can be degraded or\nabsorbed in the body”) should be revised, as the system is not a chipless RFID. Since the design\nincludes an RFID chip, the entire tag cannot fully dissolve.\nResponse 1: We thank the reviewer for this thoughtful comment, and we have updated this\nsection.\nModification to the manuscript:\nTo reflect this point clearly, we have revised the sentence in the main manuscript and added the\nfollowing sentences:\n“The EMI coating, capsule and metal antenna components dissolve in the stomach, while the RFID\nchip, a small biocompatible die, remains intact, making the overall system largely bioresorbable.“\nComment 2: The numerical analysis provided in the supplementary data indicates that the antenna\nhas approximately 5 dBi maximum gain. This value seems unexpectedly high for an implantable\nantenna. Could the authors please clarify the simulation scenario under which this result was\nobtained?\nResponse 2: Thank you for your valuable feedback. We would like to clarify the points raised in\nyour comment. The 5 dBi value shown in Supplementary Figure 14 corresponds to the simulated\ndirectivity of the antenna in a GI-tissue-equivalent environment, not its gain. Accordingly, ohmic\nlosses and non-ideal radiation efficiency were not included in this simulation.\nThe radiation pattern was obtained by exciting the antenna through the feed port of the RFID tag,\nwhich models the load of a tag chip. In contrast, during backscattering operation of a passive RFID\nsystem, the signal experiences two propagation events—one from the reader to the tag and another\nfrom the tag back to the reader, introducing additional transmission loss.\nWhen fully expanded, the antenna measures 10 mm × 15 mm, which can be larger than typical on-\nboard antennas used in implantable devices. This larger aperture contributes to its higher\ndirectivity compared with traditional wire-based RF antennas. We hope this clarification\nadequately addresses your concerns, and we appreciate your careful and constructive review.\nPage 10 of 20\nComment 3: In Figure 2c, the RSSI level observed in ex-vivo tissue is\na. similar to that measured in air, and\nb. higher than that measured in the capsule cases.\nBoth observations are somewhat unexpected given the lossy nature of biological tissues at this\nfrequency. Could the authors please elaborate on the reason behind this result?\nResponse 3: We thank the reviewer for this insightful question. The observations in Figure 2c can\nbe explained by differences in experimental conditions and RF propagation paths:\n-Ex vivo tissue vs. in-air measurements:\n-In the ex vivo experiments, the capsule was positioned very close to the panel antenna,\noften with a direct line-of-sight through a thin section of stomach wall, minimizing the\neffective tissue path and associated losses.\n-In air, small misalignments or positioning variations can reduce the RSSI slightly\ncompared to the optimized ex vivo placement.\n-Lower RSSI for the in vivo capsule cases:\n-In the in vivo SAFARI experiments, the RFID signal propagated through the swine’s\nintact abdominal tissue and skin, with the capsule introduced endoscopically without\nany surgical incision. Factors such as capsule orientation, gastric fluid content, and\ntissue heterogeneity in vivo further contribute to reduced RSSI compared to ex vivo\nmeasurements with controlled placement.\nComment 4: Could the authors clarify the difference between the RSSI measurements presented\nin Figures 2c and 4d? Why is there an approximately 10 dB discrepancy between the two stomach\nrecordings?\nResponse: We thank the reviewer for pointing out this observation. The differences between the\nRSSI measurements in Figures 2c and 4d arise from differences in experimental set-up and\nmeasurement conditions:\n-Figure 2c shows RSSI recorded during short-term, controlled ex vivo experiments, where the\ncapsule was positioned close to the panel antenna and signal acquisition was optimized for\ndemonstration. In these experiments, the device was placed through a small incision into the\nex-vivo stomach (6–8 cm), with the signal passing only through the stomach wall (as shown\nin the inset figure).\n-Figure 4d presents RSSI recorded during longer-duration in vivo experiments in a dynamic\ngastric environment. Here, capsule orientation, gastric fluid volume, and abdominal tissue\nthickness (including skin and subcutaneous fat) contribute to signal attenuation. Devices were\nplaced using endoscopy in vivo, resulting in a signal path through additional tissue layers.\nThe approximately 10 dB discrepancy is therefore attributable to tissue/fluid-mediated attenuation,\nrather than any limitation of device performance. These physiological fluctuations are expected\nand do not affect the system’s ability to reliably detect ingestion events, as the RFID signal remains\nabove the reader’s detection threshold.\nPage 11 of 20\nComment 5: Figures 4d and 4e could benefit from a clearer presentation. In Figure 4d, the time <\n0 axis region could be minimized, while the time steps for > 0 could be spaced more clearly.\nAdjusting the RSSI scale to –60 to –90 dB would improve readability across devices. Similarly,\nmodifying the y-axis scale in Fgireu 4e could help make the variations more visible.\nResponse 5: We thank the reviewer for this comment. We have updated the figures accordingly.\nComment 6: The paper could be strengthened by referencing related work that explores a similar\nconcept of gastrointestinal segment tracking using biodegradable substrates, for example:\nA. Hadi, E. Cil, Z. C. C. Ozdil, D. Nikolayev, and S. Dumanli, “Gastrointestinal Segment Tracking\nof Ingestible Capsules Using Biodegradable Superstrates,” 2025 19th European Conference on\nAntennas and Propagation (EuCAP), Stockholm, Sweden, 2025, pp. 1–5, doi:\n10.23919/EuCAP63536.2025.10999460.\nResponse 6: We appreciate the reviewer’s suggested reference.\nModification to the manuscript:\nOn Page 8, we added the relevant reference. The references pointed out have been included in the\ntext as ‘[48]’.\nPage 12 of 20\nReferee #3 (Remarks to the Author)\nSummary Comment: This manuscript introduces an ingestible UHF RFID capsule that remains\nunreadable until its cellulose-based, Mo/W microparticle EMI shield dissolves in gastric fluid,\nrevealing a zinc antenna. The concept of a dissolvable Faraday cage applied to a passive, largely\nbioresorbable RFID tag is creative and well executed at the materials level. However, the clinical\nnovelty compared to existing ingestion event markers such as the Proteus system is limited. The\nwork still faces major translational barriers, especially regarding reader deployment, real-world\nusability, and long-term safety for repeated ingestion. The study requires major revision to\nconvincingly demonstrate novelty and feasibility.\nResponse: We sincerely thank the reviewer for their thoughtful comments. We would like to\nhighlight importance of SAFARI system and emphasize the following key innovations relative to\nprior work:\nKey innovations of this work include:\nElimination of the need for supervised administration. SAFARI is among the first\ningestible RFID systems that can be autonomously deployed without external control or battery\npower.\nDemonstration of effective, bioresorbable EMI shielding at UHF frequencies. The\ncombination of rapidly dissolving HEC and Mo or W microparticles creates a transient Faraday\ncage that unlocks precise signal control via coating dissolution—enabling passive “on–off”\nactivation of the tag in response to physiological conditions.\nSystematic degradation analysis. We evaluated shielding dissolution through both qualitative\n(ex vivo visual inspection) and quantitative methods (ICP-OES), tracking the release of Mo\nover time in SGF. This offers the first empirical data on dissolution kinetics of such materials\nin GI-mimicking conditions.\nLarge animal in vivo validation. SAFARI capsules were administered in swine, and systemic\nabsorption of metallic elements was quantified via blood sampling—offering the first direct\nevidence of bioresorbable RF capsule performance in a clinically relevant model.\nDemonstration of RFID performance under physiologically realistic gastrointestinal (GI)\nconditions is important for translational relevance. To that end, our study includes a tiered\nexperimental strategy incorporating:\n1. In vitro testing in simulated gastric fluid (SGF) to assess dissolution behavior,\n2. Ex vivo studies using harvested swine stomach tissue, and\n3. In vivo testing in anesthetized swine to evaluate RFID performance under biologically\nrelevant tissue and fluid environments.\nThese experiments go beyond simple analysis and provide progressively realistic insight into\nsystem behavior during GI transit. In particular, the in vivo tests confirmed reliable RFID signal\nacquisition through gastric tissue by recording both the Received Signal Strength Indicator (RSSI)\nand resonance frequency of the device in real time.\nPage 13 of 20\nTo our knowledge, SAFARI is the first study to combine temporal visual and quantitative tracking\nof bioresorbable RF device components under physiologically relevant conditions. This\ncomprehensive evaluation of degradation dynamics, electromagnetic performance, and\ntranslational applicability represents a novel and impactful contribution to the field of\nbiodegradable, ingestible electronics.\nComment 1: The work frames itself as a breakthrough in ingestion verification, but the underlying\nclinical function remains the same as Proteus: logging a pill ingestion event. The addition of a\ndissolvable EMI cage is a materials-level refinement rather than a fundamentally new mechanism.\nClarify precisely how this adds to or improves upon prior adherence technologies.\nResponse 1: We thank the reviewer for this insightful comment. We agree that both SAFARI and\nthe Proteus system share the fundamental goal of verifying ingestion events, but SAFARI\nintroduces critical mechanistic, material, and translational innovations that address long-\nstanding limitations of prior technologies. We summarize these distinctions below:\nMechanistic distinction:\n-While both systems detect ingestion, SAFARI operates as a fully passive and bioresorbable\nRFID platform, eliminating the need for powered electronics, galvanic couples, or skin\npatches required by Proteus.\n-This design allows ingestion verification without external electrodes or active circuitry,\nmarkedly reducing patient burden, device complexity, and cost.\nFunctional enhancement through EMI shielding:\n-SAFARI incorporates a transient, dissolvable electromagnetic interference (EMI)\nshielding layer that suppresses RF transmission until the capsule reaches the gastric\nenvironment.\n-This ensures that only true ingestion events trigger detection, significantly improving signal\nspecificity and virtually eliminating false positives—a capability not demonstrated in existing\nsystems.\nMaterials innovation with translational impact:\n-The SAFARI capsule leverages fully bioresorbable components, including zinc or\nmolybdenum conductors and PLGA-encapsulated chips.\n-This combination enables safe degradation within the gastrointestinal tract, avoiding the\nretention, excretion, or environmental concerns associated with non-degradable sensors such\nas those in Proteus or similar systems.\nClinical and practical advantage:\n-SAFARI is engineered for low-cost, scalable manufacturing using solution-processable,\nbiodegradable materials.\n-The system’s passive design simplifies patient interaction, removes the need for wearable\nreceivers, and enhances usability for deployment in high-risk or resource-limited populations\nwhere adherence verification is most critical.\nPage 14 of 20\nSummary:\nWhile the end goal of confirmation of ingestion remains shared with existing adherence platforms,\nSAFARI achieves this through a fundamentally different implementation paradigm: a battery-\nfree, transient, bioresorbable, and environmentally benign system that improves safety, reduces\ncomplexity, and broadens clinical applicability. We have updated Supplementary Table 2 to clearly\ndelineate these distinctions.\nComment 2: The system shifts adherence requirements from wearing a patch (Proteus) to\nmaintaining proximity to or continuously wearing an RFID reader. This trades one compliance\nproblem for another. Without clear solutions, the system risks creating the same adherence issue\nit aims to solve.\nResponse 2: We thank the reviewer for this insightful comment. We acknowledge that, like other\ndigital adherence systems, SAFARI requires a receiver to detect the ingestion event. However, the\npassive RFID design significantly reduces the patient burden compared to patch-based systems\nsuch as Proteus. The reader does not need to be worn continuously on the body; it can be integrated\ninto the patient’s environment (e.g., bedside, toilet, or countertop) or into lightweight, intermittent-\nuse wearable devices.\nThis flexibility allows detection to occur with minimal patient intervention, substantially reducing\nthe compliance burden associated with continuous patch-wearing. Moreover, the short activation\nwindow of SAFARI (10–15 minutes in the stomach) ensures that a brief reader proximity is\nsufficient for reliable signal capture, further mitigating adherence challenges. In future work, we\naim to optimize reader placement and workflow to maximize detection reliability while\nminimizing patient effort, addressing the very adherence issue the system is designed to solve.\nComment 3: Demonstrations rely on large commercial RFID readers and panel antennas. To\nestablish clinical relevance, the study must address whether a reader can be miniaturized into a\nwearable form factor that is comfortable, battery-powered, and low-power enough for daily use.\nWithout this, feasibility in real-world adherence programs remains unconvincing.\nResponse 3: We thank the reviewer for raising this important point regarding reader\nminiaturization. While our current demonstrations use large commercial RFID readers and panel\nantennas, prior studies of ingestible sensors have successfully implemented compact, wearable\nreaders that are battery-powered, low-power, and capable of detecting RFID signals at short\ndistances (e.g., etectRx ID-Cap [10]; Rajagopalan et al., [11]). These examples suggest that\nminiaturization of the reader into a wearable or environment-integrated form factor is feasible\nwithout compromising detection reliability.\nFor SAFARI, the passive, high-sensitivity design allows the use of a small conformal antenna and\nlow-power electronics, which could be incorporated into a wearable belt, wristband, or\nenvironmental reader in clinical or home settings. While optimization of the wearable reader\ndesign is beyond the scope of this proof-of-concept study, our focus here is on the ingestible\ncapsule form factor and bioresorbable materials, which establish the foundation for future work on\nintegrated, miniaturized, and patient-friendly reader solutions.\nPage 15 of 20\nComment 4: The current data do not convincingly establish robust readout through variable\nhuman abdominal tissue. Systematic measurements in phantoms or representative tissue depths\nare needed to determine reliability and variability across subjects.\nResponse 4: We thank the reviewer for this valuable comment. We fully agree that systematic\ncharacterization across representative tissue depths is essential to establish detection reliability for\neventual human translation. In the present work, our goal was to demonstrate proof-of-concept\noperation of the SAFARI capsule and its shielding/dissolution mechanism in a large-animal model\n(swine) that approximates the human gastrointestinal environment. These experiments verified\nthat the capsule can be detected through multilayer tissue and gastric contents using a standard\nUHF RFID reader.\nOur scope focused in vivo tests in swine already include multiple layers of tissue (skin, fat, and\nstomach wall) and dynamic gastric conditions that approximate human abdominal attenuation. In\nfuture work, we plan to conduct controlled phantom and volunteer studies to verify real-world\nperformance, refining the system for reliable detection across subjects with varying abdominal\nprofiles.\nComment 5: Daily ingestion of zinc antennas, Mo/W microparticles, and RFID ICs raises\nlegitimate safety questions. While short-term swine data are provided, long-term cumulative\neffects and toxicological safety limits must be discussed in detail, including whether it is truly\nacceptable to ingest an RFID die daily.\nResponse 5: We thank the reviewer for raising this important point. We address the long-term\nsafety considerations of the SAFARI capsule as follows:\nZinc and Mo components: The quantities of zinc and molybdenum in each capsule are small, with\nantenna and conductive elements on the milligram scale. Zinc is an essential trace element, and\nthe daily intake from SAFARI remains well below recommended dietary limits, even for chronic,\nlifelong dosing. Supplementary Table S1 provides detailed information on degradation rates, daily\nintake values, and data from small-animal studies showing no observed toxicity. These metals are\nexpected to be absorbed over time and/or excreted, minimizing any risk of subclinical\naccumulation.\nRFID chip: The RFID die is very small (~0.16 mm²), biocompatible, and encapsulated in PLGA,\nwhich prevents direct contact with tissue. Based on prior experience with ingestible electronics\nand FDA-approved ingestible devices of similar or larger size, the chip is expected to safely transit\nthe gastrointestinal tract without retention, aggregation, or obstruction.\nWe acknowledge that long-term human data are not yet available. Future studies will include\npharmacokinetic modeling and chronic exposure assessment to ensure safety for lifelong use.\nOverall, while chronic ingestion warrants careful consideration, the SAFARI capsule’s design and\nmaterial composition support minimal physiological and toxicological risk, as demonstrated in a\nlarge-animal model. Additionally, the system is intended for high-risk populations where accurate\nadherence monitoring is critical.\nPage 16 of 20\nReferee #4 (Remarks to the Author)\nSummary Comment:\nWhile an ingestible pill addresses concerns about verified drug ingestion, research has not\nconfirmed that other, less intrusive, objective measures, such as electronic pill bottles,\ninsufficiently assess adherence with regards to removing a dose without ingesting it. To my\nknowledge, no study has demonstrated that an ingestible or drug assay identifies nonadherence not\nalready identified by electronic pill bottles.\nExisting objective measures are rarely used in clinical care because of the cost, technical\nchallenges of managing the large amount of data obtained, and the perceived intrusiveness by both\npatients and healthcare providers. Research has shown that healthcare providers rarely review\npharmacy refill data readily available in many electronic medical records, and few avail\nthemselves of objective adherence monitoring when the service is available. Thus, I do not see\nhealthcare providers desiring ingestible technology.\nElectronic pill bottles are more often, but not always, used in clinical trials. However, study\neligibility criteria and protocol burden often result in highly compliant study participants following\nthe study protocol. Thus, the extra cost of manufacturing a new drug with ingestible technology is\nunlikely to be viable in clinical trials. Indeed, this is why studies rarely add tracer compounds to a\ndrug to enable biological assay assessment of adherence despite this option being available for\ndecades.\nImportantly, and not considered by the authors, is how knowing one is being tracked with an\ningestible monitor may negatively affect adherence. Since the COVID-19 pandemic, people’s\nskepticism and mistrust of science and healthcare providers have made it clear that even a benign\ningestible may be perceived as causing health problems or being able to track a person’s location,\nwhich could be used punitively against them. It would be unethical to include tracking technology\nwithout patient knowledge and approval. Unrelated side effects may be attributed to the SAFARI\ntechnology, by patients and providers and the technology, or worse case the medication itself,\nabandoned.\nMoreover, while the authors contend that the SAFARI technology requires no effort on the part of\nthe patient, this is likely not the case. In my experience, RFID technology typically requires a\nreader, often via a cellphone app, to register the dose. Patients will delete the app, not have the app\nopen, or not take a non-cellphone reader with them (e.g., pocket-dosing when they will be away\nfrom home for work, socializing, or traveling). Unmentioned is whether there are medication\nstorage requirements, such as temperature, to preserve the coating and RFID tag, that could also\nadd burden.\nThus, while SAFARI technology may be feasible, safer and more eco-friendly, outside of a few\nunique cases, the probability that there will be clinical or research uptake in the current healthcare\nenvironment appears small.\nResponse: We thank the reviewer for their thoughtful and detailed comments. We appreciate the\nopportunity to clarify the distinct role and translational potential of ingestible adherence\ntechnologies such as SAFARI within the broader adherence-monitoring landscape.\nComparison to existing adherence measures:\nPage 17 of 20\n-We agree that electronic pill bottles and pharmacy refill data provide valuable objective\nadherence information. However, these methods cannot confirm ingestion, only medication\nremoval or bottle opening, and often require repackaging of drugs into nonstandard containers.\nMultiple studies have shown that such indirect proxies tend to overestimate adherence,\nparticularly in long-term or decentralized studies.\n-In contrast, SAFARI directly verifies ingestion through an internal RFID signal generated\nonly when the capsule’s shielding dissolves in the stomach. This provides definitive, real-time\ningestion data. The system is intended to complement, rather than replace, existing tools by\nproviding a confirmatory layer when adherence precision is critical, such as in clinical trials or\nin the treatment of tuberculosis and HIV.\nClinical adoption and feasibility:\n-We recognize that integration of adherence monitoring into routine care remains challenging.\nSAFARI’s design specifically addresses these barriers by using a passive, battery-free, and\nbioresorbable system that requires no patient interaction and minimal changes to clinical\nworkflow.\n-Future reader designs will focus on environment-integrated or low-burden wearables such as\nbedside, bathroom, or belt-mounted readers to allow automated data capture without altering\npatient behavior. In addition, SAFARI data can support aggregate reporting that allows\npharmacy managers or case coordinators, rather than physicians, to monitor adherence trends.\nThis approach reduces provider burden while improving the delivery of adherence\ninterventions.\nCost and trial viability:\n-SAFARI is being developed as a low-cost, scalable platform using solution-processable,\nbiodegradable materials. Initial applications are expected in high-risk populations such as HIV,\ntuberculosis, or transplant medicine, where the benefits of verified ingestion outweigh the\nincremental cost.\n-A feasible regulatory pathway involves FDA 510(k) clearance as an ingestible event monitor.\nThis would allow the system to be used through over encapsulation at compounding\npharmacies, eliminating the need for manufacturing redesigns. Over time, integration as a\ndrug–device combination may be pursued for therapeutic areas where ingestion confirmation\nprovides proven clinical value.\nPatient perception and ethical considerations:\n-We agree that transparency and informed consent are essential. SAFARI does not include\ngeolocation, tracking, or communication functions. Its purpose is limited to confirming\ningestion for clinical or research use.\nPage 18 of 20\n-Prior formative work by our group has shown that patients, particularly in stigmatized or high-\nrisk populations, often value ingestible sensors for their potential to improve treatment\naccountability and self-management rather than perceive them as intrusive (Chai et al., AIDS\nBehav, 2022; Goodman et al., AIDS Behav, 2022; Richey et al., JMIR Ment Health, 2022) [13–\n15] [16]. These studies indicate that acceptability depends on implementation context and trust\nrather than on the technology type alone.\nPatient effort and app dependency:\n-Unlike app-based or patch-driven adherence systems, SAFARI does not require continuous\nconnectivity or user input. The ingestion event is automatically recorded when the capsule’s\nshielding dissolves in the stomach. Readers can operate passively in the background with\nminimal maintenance, and cloud-based data transfer minimizes the effort required from\npatients and clinicians.\nMedication stability and handling:\n-SAFARI capsules remain stable under standard storage conditions and do not require special\ntemperature or humidity controls beyond those used for conventional oral medications.\nOverall clinical potential:\n-Although widespread adoption will require continued assessment of behavioral, logistical, and\ncost factors, SAFARI combines direct ingestion verification, biocompatibility, passive\noperation, and environmental sustainability. These characteristics make it a promising platform\nfor future adherence applications.\n-The current study establishes a proof of concept that addresses critical translational challenges\nsuch as safety, reliability, and scalability, and provides a foundation for targeted clinical\nvalidation in scenarios where ingestion confirmation is most impactful.\nKey innovations of this work include:\n Elimination of the need for supervised administration. SAFARI is among the first\ningestible RFID systems to operate without external power, batteries, or electrodes.\n Demonstration of effective bioresorbable EMI shielding at UHF frequencies. The\ncombination of rapidly dissolving HEC and molybdenum or tungsten microparticles\ncreates a transient Faraday cage that enables precise signal activation upon capsule\ndissolution.\n Systematic degradation analysis. Shielding dissolution was evaluated using both\nqualitative (ex vivo imaging) and quantitative (ICP–OES) approaches, providing the first\nempirical data on molybdenum-based bioresorbable electronics under gastrointestinal\nconditions.\n Large-animal validation. Swine studies confirmed safe passage, complete degradation, and\nstable serum trace-element levels, demonstrating the feasibility of this approach in a\nclinically relevant model.\nPage 19 of 20\nReferences\n[1] A. Naeem, C. Yu, X. Wang, M. Peng, Y. Liu, Y. Liu, Molecules 2023, 28, 7320.\n[2] Y.-C. Chen, H.-O. Ho, D.-Z. Liu, W.-S. Siow, M.-T. Sheu, PLoS ONE 2015, 10, e0116914.\n[3] A. S. Sharova, F. Melloni, G. Lanzani, C. J. Bettinger, M. Caironi, Advanced Materials\nTechnologies 2021, 6, 2000757.\n[4] F. Jay Murray, R. W. Tyl, F. M. Sullivan, A. K. Tiwary, S. Carey, Reproductive Toxicology\n2014, 49, 202.\n[5] J. Turnlund, W. Keyes, G. Peiffer, G. Chiang, The American Journal of Clinical Nutrition\n1995, 61, 1102.\n[6] A. Schauer, C. Redlich, J. Scheibler, G. Poehle, P. Barthel, A. Maennel, V. Adams, T.\nWeissgaerber, A. Linke, P. Quadbeck, Materials 2021, 14, 7776.\n[7] E. R. Burrough, C. De Mille, N. K. Gabler, J VET Diagn Invest 2019, 31, 537.\n[8] M. Nordberg, G. F. Nordberg, in General, Applied and Systems Toxicology, John Wiley &\nSons, Ltd, 2011.\n[9] A. Sivrikaya, M. Bicer, M. Akil, A. K. Baltaci, R. Mogulkoc, Biol Trace Elem Res 2012,\n147, 195.\n[10] “ID-Cap® System | etectRx,” 2024.\n[11] H. Rajagopalan, Y. Rahmat-Samii, in 2010 IEEE Antennas and Propagation Society\nInternational Symposium, IEEE, Toronto, ON, 2010, pp. 1–4.\n[12] P. R. Chai, Y. Mohamed, M. J. Bustamante, G. R. Goodman, J. Najarro, J. Castillo-\nMancilla, A. Baez, O. Bronzi, M. C. Sullivan, L. M. Pereira, S. L. Baumgartner, T. C.\nCarnes, K. H. Mayer, R. K. Rosen, E. W. Boyer, C. O’Cleirigh, JAIDS Journal of Acquired\nImmune Deficiency Syndromes 2022, 89, e5.\n[13] P. R. Chai, G. R. Goodman, O. Bronzi, G. Gonzales, A. Baez, M. J. Bustamante, J.\nNajarro, Y. Mohamed, M. C. Sullivan, K. H. Mayer, E. W. Boyer, C. O’Cleirigh, R. K.\nRosen, AIDS Behav 2022, 26, 2459.\n[14] P. Chai, D. De, H. Albrechta, G. R. Goodman, K. Takabatake, A. Ben-Arieh, J. S. Lee, T.\nR. Glynn, K. Mayer, C. O’Cleirigh, C. Fisher, BMJ Open 2023, 13, e067549.\n[15] G. R. Goodman, A. Kikut, M. J. Bustamante, L. Mendez, Y. Mohamed, C. Shachar, I. G.\nCohen, S. Gerke, E. W. Boyer, R. K. Rosen, K. H. Mayer, C. O’Cleirigh, P. R. Chai, AIDS\nBehav 2022, 26, 2981.\n[16] A. G. Richey, I. Kovacs, S. Browne, JMIR Mental Health 2022, 9, e39047.\nPage 20 of 20"}, {"round": 2, "reviewer_comments": {"reviewer_1": "No comments further.", "reviewer_2": "I would like to thank the authors for their response. I have no further comments or corrections.", "reviewer_3": "Summary Comment: This manuscript introduces an ingestible UHF RFID capsule that remains unreadable until its cellulose-based, Mo/W microparticle EMI shield dissolves in gastric fluid, revealing a zinc antenna. The concept of a dissolvable Faraday cage applied to a passive, largely bioresorbable RFID tag is creative and well executed at the materials level. The in vivo validation in swine is valuable, and the overall device architecture is technically sound. However, the translational aspects remain insufficiently developed. The authors’ rebuttal provides thoughtful qualitative explanations, but several key arguments—particularly regarding reader deployment, signal detection feasibility, and practical usability—would benefit from more quantitative support or realistic modeling. Clarifying these elements would greatly enhance the paper’s credibility and impact. Overall, I find this a promising and interesting study that merits publication after moderate revision focused on clarifying real-world feasibility and device–reader integration.\nSpecific Comments\nComment 1\nThe work positions itself as a breakthrough in ingestion verification, but the core clinical function—confirming pill ingestion— remains similar to the Proteus system. The dissolvable EMI cage is a clever materials innovation, but the authors should clarify in more detail how this feature meaningfully improves upon prior adherence technologies in terms of specificity, user experience, or scalability. Emphasizing the materials advance rather than overstating the clinical novelty would strengthen the manuscript.\nComment 2\nThe claim that SAFARI “eliminates the need for a wearable patch” should be qualified. While Proteus employed a patch for convenience and signal reliability, any RFID system at 900 MHz still requires proximity between the capsule and an external reader. Replacing a wearable receiver with a bedside or environmental reader does not remove the adherence burden— it changes its form. The discussion should more explicitly acknowledge this trade-off and describe how detection would realistically occur in daily use.\nComment 3\nThe idea of integrating the reader into a wristband, belt, or nearby environment is intriguing but currently speculative. Providing at least a simple quantitative link-budget or tissue-attenuation estimate (e.g., expected signal strength through ~2– 5 cm of tissue, required antenna aperture, and transmit power) would make this argument more convincing. Even approximate modeling or reference to prior studies would help assess whether a wrist-sized or patch-sized reader is physically feasible."}, "author_response": "Point-by-point response – Nature Communications – Manuscript #: NCOMMS-25-73449A\nReferee #1 (Remarks to the Author)\nNo comments further.\nReferee #2 (Remarks to the Author)\nI would like to thank the authors for their response. I have no further comments or corrections.\nReferee #3 (Remarks to the Author)\nSummary Comment: This manuscript introduces an ingestible UHF RFID capsule that remains\nunreadable until its cellulose-based, Mo/W microparticle EMI shield dissolves in gastric fluid,\nrevealing a zinc antenna. The concept of a dissolvable Faraday cage applied to a passive, largely\nbioresorbable RFID tag is creative and well executed at the materials level. The in vivo validation\nin swine is valuable, and the overall device architecture is technically sound. However, the\ntranslational aspects remain insufficiently developed. The authors’ rebuttal provides thoughtful\nqualitative explanations, but several key arguments—particularly regarding reader deployment,\nsignal detection feasibility, and practical usability—would benefit from more quantitative support\nor realistic modeling. Clarifying these elements would greatly enhance the paper’s credibility\nand impact. Overall, I find this a promising and interesting study that merits publication after moderate\nrevision focused on clarifying real-world feasibility and device–reader integration.\nSpecific Comments\nResponse: We sincerely appreciate the reviewer’s constructive feedback and have carefully\nrevised our manuscript to address each point raised.\nComment 1: The work positions itself as a breakthrough in ingestion verification, but the core\nclinical function—confirming pill ingestion—remains similar to the Proteus system. The\ndissolvable EMI cage is a clever materials innovation, but the authors should clarify in more detail\nhow this feature meaningfully improves upon prior adherence technologies in terms of specificity,\nuser experience, or scalability. Emphasizing the materials advance rather than overstating the\nclinical novelty would strengthen the manuscript.\nResponse 1: We thank the reviewer for this thoughtful comment. We agree that both SAFARI and\nProteus ultimately serve the same high-level clinical function, i.e. verifying ingestion and we have\nrevised the text to more clearly articulate our contribution as a materials- and systems-level\nadvance rather than a redefinition of the clinical use case.\nOur work meaningfully improves upon prior technologies in several ways:\n- Specificity of Ingestion Detection via Transient EMI Shielding\nProteus relies on signal generation only after activation by gastric fluid, but it cannot prevent\npremature or false detections if moisture or partial activation occurs before ingestion. SAFARI\nintroduces a dissolvable Faraday cage that provides complete EMI shielding until the capsule\nreaches the stomach. This is a fundamentally new mechanism not explored in previous ingestible\nsensors.\nPage 1 of 3\n- Fully Bioresorbable Antenna System\nSAFARI replaces the permanent conductive components of traditional ingestible sensors with\ntransient Zn/Mo materials that dissolve completely after activation. This avoids long-term\nretention of metallic components (except the small IC) and enables safer repeated dosing,\naddressing an important limitation of existing systems.\n- Low-power RFID Operation\nProteus requires a proprietary patch and a powered galvanic cell. In contrast, SAFARI leverages\npassive RFID and compatibility with widely available readers.\n- Scalability and Manufacturing Simplicity\nSAFARI uses inexpensive materials (Zn, Mo, cellulose) and standard coating/printing processes,\nmaking it compatible with cost-constrained indications such as tuberculosis and hepatitis therapy.\nModification to the manuscript:\nOn page 13, we have added a discussion: “Although SAFARI performs ingestion-verification\nfunction as prior systems, its advantage lies in the transient EMI-shielding architecture, which\nimproves signal specificity and device scalability. “\nComment 2: The claim that SAFARI “eliminates the need for a wearable patch” should be\nqualified. While Proteus employed a patch for convenience and signal reliability, any RFID system\nat 900 MHz still requires proximity between the capsule and an external reader. Replacing a\nwearable receiver with a bedside or environmental reader does not remove the adherence burden—\nit changes its form. The discussion should more explicitly acknowledge this trade-off and describe\nhow detection would realistically occur in daily use.\nResponse 2: We appreciate the reviewer’s thoughtful comment and agree that the manuscript\nshould more clearly articulate the trade-offs between wearable and environmental readers. We\nhave revised the text to qualify our claims and to clarify that SAFARI does not remove the need\nfor proximity to a receiver but instead offers greater flexibility.\nSAFARI operates using passive UHF RFID, which does not require skin contact, a battery, or a\nsmartphone app running in the background. However, we fully acknowledge that successful\ndetection still requires the patient to be within read range of an external antenna.\nTo address this, we clarified in the Discussion that SAFARI shifts (rather than eliminates) the\nadherence burden. Instead of a wearable device, detection can occur through environmentally\nembedded readers (e.g., bedside, bathroom, kitchen, medication cabinet) or optional lightweight\nwearables (belt, waist band, or under-clothing loop antenna), consistent with prior ingestible-RFID\nsystems. We also would like to highlight that read-range requirements are modest (20–40 cm).\nModification to the manuscript:\nOn page 13, we have highlighted a discussion: “Placement of the external reader in a commercial\nproduct could be either integrated into the space surrounding a patient or implemented via a\nwearable system, as demonstrated in prior works. “\nPage 2 of 3\nComment 3: The idea of integrating the reader into a wristband, belt, or nearby environment is\nintriguing but currently speculative. Providing at least a simple quantitative link-budget or tissue-\nattenuation estimate (e.g., expected signal strength through ~2–5 cm of tissue, required antenna\naperture, and transmit power) would make this argument more convincing. Even approximate\nmodeling or reference to prior studies would help assess whether a wrist-sized or patch-sized\nreader is physically feasible.\nResponse 3: We appreciate the reviewer’s request for evidence supporting the feasibility of\ncompact readers. Prior work has already demonstrated that UHF RFID signals can be detected\nthrough several centimeters of soft tissue using low-power, small-form-factor readers, and these\nstudies provide a practical basis for our assertion that wrist- or belt-mounted readers are physically\nachievable.\n- Werber et al[1]. (2006) provide measured transmission loss through phantom muscle and\nhuman abdomens across 100 MHz–1 GHz (e.g., tens of dB of loss increasing with\nfrequency and tissue thickness), giving a basis for tissue attenuation estimates.\n- Chai et.al[2] reports a clinical trial using ID-Cap system with a wearable reader and clinical\nusability/validation of an ingestible event marker system, showing that small wearable\nreaders[3] can reliably capture ingestible sensor transmissions.\nThese prior demonstrations show that tissue attenuation at 915 MHz remains within the operational\nmargin of low-power RFID links, and that wearable or small, battery-powered UHF readers have\nalready been validated in clinical settings. In the Discussion, we now note that these findings\nsupport the technical feasibility of adapting our proposed reader architecture into compact,\nwearable form factors.\nModification to the manuscript:\nOn page 13, we have highlighted a discussion: “Additionally, wearable reader architectures such\nas chest-worn patches may further enable continuous signal capture during daily activities, and\ntheir integration into patients’ routines will require user-centered design and feasibility studies to\nensure reliable and acceptable long-term use. “\nReferences:\n[1] D. Werber, A. Schwentner, E. M. Biebl, Adv. Radio Sci. 2006, 4, 357.\n[2] P. R. Chai, G. R. Goodman, O. Bronzi, G. Gonzales, A. Baez, M. J. Bustamante, J. Najarro,\nY. Mohamed, M. C. Sullivan, K. H. Mayer, E. W. Boyer, C. O’Cleirigh, R. K. Rosen, AIDS\nBehav 2022, 26, 2459.\n[3] G. R. Goodman, C. Vaz, H. Albrechta, E. W. Boyer, K. H. Mayer, C. O’Cleirigh, P. R. Chai,\nCurr HIV/AIDS Rep 2022, 19, 433.\nPage 3 of 3"}]

Decision letter