An adhesive and resilient hydrogel for the sealing and treatment of gastric perforation

Abstract

Adhesive hydrogels have been recently proposed as a potential option to seal and treat gastric perforation (GP) which causes high mortality despite advancements in surgical treatments. However, to be effective, the hydrogels must have sufficient tissue adhesiveness, tough mechanical property, tunable biodegradability and ideally are easy to apply and form. Herein, we report an adhesive and resilient hydrogel for the sealing and treatment of gastric perforation. The hydrogel consists of a bioactive, transglutaminase (TG)-crosslinked gelatin network and a dynamic, borate-crosslinked poly-N-[Tris(hydroxymethyl)methyl]acrylamide (PTH) network. The hydrogel can be formed in situ, facilitating easy delivery to the GP and allowing for precise sealing of the defects. In vivo experiments, using a perforated stomach mouse model, shows that the adhesive hydrogel plug effectively seals GP defects and promotes gastric mucosa regeneration. Overall, this hydrogel represents a promising biomaterial for GP treatment.

Keywords: Adhesive hydrogel plug; Gastric perforation; Regeneration; Thermo-responsive.

Graphical abstract

Fig. 1

A) Scheme of an adhesive and resilient hydrogel for the sealing and treatment of gastric perforation. B) Hydrogels crosslinked by 30 U/mL TG with different solid contents of gelatin were examined by a time sweep. C) loss modulus (G′) and D) gelation time of hydrogels. E) In vitro degradation of 10% and 20% gelatin hydrogels crosslinked by 30 U/mL TG, in different concentrations of collagenase type II solution in PBS and 37 °C over time. F) 20% gelatin hydrogels crosslinked by different concentrations of TG were examined by a time sweep. G) loss modulus (G′) and H) gelation time of hydrogels. I) Shear strength of 20% gelatin hydrogels crosslinked by different concentrations of TG.

Fig. 2

A) Typical tensile stress-strain curves of the double network hydrogel: 20% gelatin hydrogel crosslinked by 20 U/mL TG as a first network and different contents of PTH crosslinked by 0.4 mM of borax as a secondary network under 37 °C. B) The GT20-PTH10 hydrogel was elongated to 13 times its initial length under 37 °C. C) Fracture energy of GT20-PTHy, y varied from 0 to 20 and D) corresponding compressive modulus of different hydrogels. E) The GT20-PTH10 hydrogel was compressed to 90% and recovered immediately. F) Tensile stress-strain curves of the GT20-PTH10 and GT20 hydrogels under 25 °C. G) Scheme of inter-network of GT20-PTHy hydrogels undergoing reverse temperature change.

Fig. 3

A) Typical shear stress curves of different hydrogels to a glass slide under 37 °C and B) corresponding shear strength (n = 3). C) Optical images of the GT20-PTH10 hydrogel sticking to the lid of cell culture dish and the adhesion interface when being lifted under 37 °C. D) Reversible adhesion property of GT20-PTH10 hydrogel under 37 °C and 25 °C. E) The GT20-PTH10 hydrogel adhered to various tissue surfaces including the stomach, liver, kidney, heart, and spleen.

Fig. 4

A) Representative LIVE/DEAD images from MSCs seeded on tissue culture well-plate and GT20-PTH10 hydrogel surface. (Green: live cells; Red: dead cells) B) Quantification of cell proliferation rate on GT20-PTH10 hydrogel surface compared to tissue culture well plate after 1, 2, and 3 days of culture. C) Representative LIVE/DEAD images of MSCs grown on tissue culture well plate and GT20-PTH10 hydrogel at 1, 2, and 3 days after scratching. D) Quantification of relative cell densities migrated to the scratched area on GT20-PTH10 hydrogels and control samples, at days 1, 2, and 3.

Fig. 5

A) (Top) Stress magnitude from unloaded to fully loaded state where displacement is applied to the inner surface until a final radial stretch of ${\lambda }_r=1.16$ is achieved, where ${\lambda }_r=1.02$ corresponds to an infusion volume of 0.1 mL (Middle) The sphere is in a biaxial stress state after deformation ($P_{xx}=P_{yy}$), with the adhesive plug aligning with the x-y plane. The stress interface between the native stomach and the adhesive material is displayed. (Bottom) The corresponding component of the deformation gradient ($F=I+\nabla u$). B) Representative images for creating a 5 mm hole on a rat stomach and blocking the hole with a GT20-PTH10 hydrogel plug. Representative images of a stomach C) treated with a GT20-PTH10 hydrogel plug (Left) and without any treatment (Right) before and after pressing with tweezers. D) H&E staining of GT20-PTH10 hydrogel plug sticking to a healthy mouse stomach surface after 10 days. E) Representative images of a perforated stomach before and after treatment of GT20-PTH10 hydrogel plug. Representative images of a perforated mouse stomach with treatment of a F) GT20-PTH10 hydrogel plug and G) suture after 10 days. H&E staining of H) GT20-PTH10 hydrogel plug and I) suture group after 10 days. Blue arrows point to the remaining hydrogels and the red ones point to the suture. Yellow arrows represent the mucosa thickness. J) Gastric mucosa thicknesses of GT20-PTH10 hydrogel and suture treatment groups. (n = 6 for the hydrogel group and n = 4 for the suture group).