Ingestible hydrogel device

Abstract

Devices that interact with living organisms are typically made of metals, silicon, ceramics, and plastics. Implantation of such devices for long-term monitoring or treatment generally requires invasive procedures. Hydrogels offer new opportunities for human-machine interactions due to their superior mechanical compliance and biocompatibility. Additionally, oral administration, coupled with gastric residency, serves as a non-invasive alternative to implantation. Achieving gastric residency with hydrogels requires the hydrogels to swell very rapidly and to withstand gastric mechanical forces over time. However, high swelling ratio, high swelling speed, and long-term robustness do not coexist in existing hydrogels. Here, we introduce a hydrogel device that can be ingested as a standard-sized pill, swell rapidly into a large soft sphere, and maintain robustness under repeated mechanical loads in the stomach for up to one month. Large animal tests support the exceptional performance of the ingestible hydrogel device for long-term gastric retention and physiological monitoring.

Fig. 1

Design of the pufferfish-inspired ingestible hydrogel device. a A pufferfish inflates its body into a large ball by rapidly imbibing water. b Bulk hydrogels swell in water with a low swelling speed. c Porous hydrogels swell in water with a low swelling ratio. d The designed hydrogel device swells in water with both a high speed and a high ratio. e Schematic of the fabrication process and working principle of the designed hydrogel device. f Photographs of the fabrication process and working principle of the designed hydrogel device. Scale bars are 0.5 mm for the first image in (f) and 10 mm for the other images in (f)

Fig. 2

High-speed and high-ratio swelling of the ingestible hydrogel device. a Time-lapse images of the hydrogel device swelling in water (pH 7). b Volume changes of the hydrogel device (membrane modulus 3 kPa), air-dried hydrogel, and freeze-dried hydrogel of the same size as a function of swelling time in water. c Comparison of the swelling ratios and speeds in water between the hydrogel device in current work and previously reported hydrogels^,,,. d Volume changes of the hydrogel devices with various membrane moduli as functions of swelling time in water. e Volume changes of the hydrogel devices (membrane modulus 3 kPa) as functions of swelling time in porcine gastric fluid and SGF (pH 3). f Swelling ratios of the hydrogel devices with various membrane moduli in water, SGF (pH 3), and porcine gastric fluid. g Swelling speeds of the hydrogel devices with various membrane moduli in water, SGF (pH 3), and porcine gastric fluid. Scale bars are 10 mm in (a). Data represent the mean ± s.d. (N = 3)

Fig. 3

Mechanical robustness of the ingestible hydrogel device. a True stress–stretch curves of the polyvinyl alcohol hydrogel membranes with and without pores, which have been immersed in SGF (pH 3) at 37 °C for 12 h. b Tensile strength of the hydrogel membranes with (open) and without (filled) pores, which have been immersed in water or SGF (pH 3) at 37 °C for 0–15 days. c Fracture toughness of the hydrogel membranes, which have been immersed in water or SGF (pH 3) at 37 °C for 0–15 days. d Time-lapse images of an SGF (pH 3)-saturated hydrogel device (diameter ~3.6 cm at undeformed state) exposed to a maximum compressive force of 70 N and a strain of 90%. e Force–strain curves of the SGF (pH 3)-saturated hydrogel device exposed to a maximum compressive force of 70 N and a strain of 90% for two cycles. f Measured compressive forces applied to a hydrogel device (diameter ~4.8 cm at undeformed state) on day 14 (the hydrogel device was immersed in SGF (pH 3), and sustained 1920 cycles of 40% compressive strains for 8 h per day). g Measured mass of the hydrogel device after 1920 cycles of 40% compressive strain for 8 h per day over 14 days. Scale bars are 10 mm in (d). Data in (b, c, g) represent the mean ± s.d. (N = 3)

Fig. 4

Long-term gastric retention and physiological monitoring of the ingestible hydrogel device. a Working principle of the gastric-retentive hydrogel device, which enters through the esophagus into the stomach as an ingestible pill, resides in the stomach in its swollen state for a prolonged period of time, and exits through the pylorus as a shrunken capsule and small particles. b Comparison of Young’s moduli among recently reported ingestible devices^–,,– and the hydrogel device in current work. c Number of hydrogel devices and non-swellable devices (i.e., without any superabsorbent particles) being retained in the porcine stomach as a function of time (N = 3 for each group). d Endoscopic images depicting the swelling of the hydrogel device in the porcine stomach. e X-ray images of the hydrogel device residing in the porcine stomach before being emptied into distal parts of the GI tract (here shown for 29 days in stomach). f Continuous measurement of porcine gastric temperature by a sensor embedded in the hydrogel device. g Photos of ex vivo shrinkage of the hydrogel device triggered by the addition of 0.6 M calcium chloride solution. Scale bars are 10 mm in (d), 5 cm in (e) and (g)

Fig. 5

Analysis on the prolonged porcine gastric temperature profile measured. a The long-term measured gastric temperature in Fig. 4f are replotted on a daily basis. b On a single day (day 17), the temperature profile is divided into different phases with different ingestion activities based on the degree of fluctuations. c The heatmap of the temperature (T) measured by hydrogel device over 29 days. d The heatmap of the absolute temperature derivative (|dT/dt|) measured by hydrogel device over 29 days. e The time slots (1 h) with food intake (if any |dT/dt| > 1.75 during the time slot) are marked as events for different pigs. Data represent the mean ± s.d. N = 34 events for pig 1 in 9 days, N = 41 events for pig 2 in 13 days, and N = 88 events for pig 3 in 29 days