Research progress on the application of thermosensitive hydrogel in gastrointestinal tract_West China Medical Journal

Authors：

GAO Yuan ¹ , WEN Pinghua ¹ , ZHAO Yajuan ² , ZHANG Yuyan ¹ , YAO Han ¹ , DU Jiang ¹ , PU Yuji ² ,  HU Bing ¹

1. Department of Gastroenterology and Hepatology, West China Hospital / Digestive Endoscopy Medical Engineering Research Laboratory, West China Hospital / Med-X Center for Materials, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan 610065, P. R. China;

Corresponding?author：

HU Bing, Email: hubing@wchscu.edu.cn

Keywords：

Thermosensitive hydrogel; gastrointestinal tract; drug delivery; submucosal injection

DOI：

10.7507/1002-0179.202502176

Video：

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Abstract Full text Figures/Tables Video References Cited by

Thermosensitive hydrogels are smart materials that undergo sol-gel phase transitions in response to body temperature, exhibiting excellent injectability and biocompatibility. This review systematically summarizes the research progress on their applications in the gastrointestinal tract, mainly focusing on drug delivery and endoscopic submucosal dissection (ESD) assistance. In terms of drug delivery, compared with conventional carriers such as nanoparticles and liposomes, thermosensitive hydrogels offer prolonged mucosal retention time, better stability, and more controllable drug release properties, and can be administered orally or locally for treating oral ulcers, gastric ulcers, inflammatory bowel disease, and gastrointestinal tumors. In ESD procedures, thermosensitive hydrogels serve as submucosal cushions to effectively elevate lesions and prevent thermal injury, while also facilitating postoperative wound closure, hemostasis, and healing promotion. This review also discusses optimization strategies and challenges in clinical translation for thermosensitive hydrogels, and provides perspectives on future development trends, aiming to provide references for their further application in gastrointestinal disease treatment.

Citation： GAO Yuan, WEN Pinghua, ZHAO Yajuan, ZHANG Yuyan, YAO Han, DU Jiang, PU Yuji, HU Bing. Research progress on the application of thermosensitive hydrogel in gastrointestinal tract. West China Medical Journal, 2025, 40(12): 2014-2022. doi: 10.7507/1002-0179.202502176 Copy

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2.	Fallingborg J. Intraluminal pH of the human gastrointestinal tract. Dan Med Bull, 1999, 46(3): 183-196.
3.	Hua S. Advances in oral drug delivery for regional targeting in the gastrointestinal tract - influence of physiological, pathophysiological and pharmaceutical factors. Front Pharmacol, 2020, 11: 524.
4.	Rashid MU, Alomari M, Afraz S, et al. EMR and ESD: indications, techniques and results. Surg Oncol, 2022, 43: 101742.
5.	Ni P, Li R, Ye S, et al. Lactobionic acid-modified chitosan thermosensitive hydrogels that lift lesions and promote repair in endoscopic submucosal dissection. Carbohydr Polym, 2021, 263: 118001.
6.	Ni P, Ye S, Li R, et al. Chitosan thermosensitive hydrogels based on lyophilizate powders demonstrate significant potential for clinical use in endoscopic submucosal dissection procedures. Int J Biol Macromol, 2021, 184: 593-603.
7.	Amiri N, Ajami S, Shahroodi A, et al. Teicoplanin-loaded chitosan-PEO nanofibers for local antibiotic delivery and wound healing. Int J Biol Macromol, 2020, 162: 645-656.
8.	Zhang K, Xue K, Loh XJ. Thermo-responsive hydrogels: from recent progress to biomedical applications. Gels, 2021, 7(3): 77.
9.	Hu X, Grinstaff MW. Advances in hydrogel adhesives for gastrointestinal wound closure and repair. Gels, 2023, 9(4): 282.
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11.	Ansari MJ, Rajendran RR, Mohanto S, et al. Poly(N-isopropylacrylamide)-based hydrogels for biomedical applications: a review of the state-of-the-art. Gels, 2022, 8(7): 454.
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28.	Mu?oz Taboada G, Dahis D, Dosta P, et al. Sprayable hydrogel sealant for gastrointestinal wound shielding. Adv Mater, 2024, 36(24): e2311798.
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1. Cheng LK, O’Grady G, Du P, et al. Gastrointestinal system. Wiley Interdiscip Rev Syst Biol Med, 2010, 2(1): 65-79.
2. Fallingborg J. Intraluminal pH of the human gastrointestinal tract. Dan Med Bull, 1999, 46(3): 183-196.
3. Hua S. Advances in oral drug delivery for regional targeting in the gastrointestinal tract - influence of physiological, pathophysiological and pharmaceutical factors. Front Pharmacol, 2020, 11: 524.
4. Rashid MU, Alomari M, Afraz S, et al. EMR and ESD: indications, techniques and results. Surg Oncol, 2022, 43: 101742.
5. Ni P, Li R, Ye S, et al. Lactobionic acid-modified chitosan thermosensitive hydrogels that lift lesions and promote repair in endoscopic submucosal dissection. Carbohydr Polym, 2021, 263: 118001.
6. Ni P, Ye S, Li R, et al. Chitosan thermosensitive hydrogels based on lyophilizate powders demonstrate significant potential for clinical use in endoscopic submucosal dissection procedures. Int J Biol Macromol, 2021, 184: 593-603.
7. Amiri N, Ajami S, Shahroodi A, et al. Teicoplanin-loaded chitosan-PEO nanofibers for local antibiotic delivery and wound healing. Int J Biol Macromol, 2020, 162: 645-656.
8. Zhang K, Xue K, Loh XJ. Thermo-responsive hydrogels: from recent progress to biomedical applications. Gels, 2021, 7(3): 77.
9. Hu X, Grinstaff MW. Advances in hydrogel adhesives for gastrointestinal wound closure and repair. Gels, 2023, 9(4): 282.
10. Rahmanian-Devin P, Baradaran Rahimi V, Askari VR. Thermosensitive chitosan-β-glycerophosphate hydrogels as targeted drug delivery systems: an overview on preparation and their applications. Adv Pharmacol Pharm Sci, 2021, 2021: 6649174.
11. Ansari MJ, Rajendran RR, Mohanto S, et al. Poly(N-isopropylacrylamide)-based hydrogels for biomedical applications: a review of the state-of-the-art. Gels, 2022, 8(7): 454.
12. Liu YY, Shao YH, Lü J. Preparation, properties and controlled release behaviors of pH-induced thermosensitive amphiphilic gels. Biomaterials, 2006, 27(21): 4016-4024.
13. Li S, Yang C, Li J, et al. Progress in pluronic F127 derivatives for application in wound healing and repair. Int J Nanomedicine, 2023, 18: 4485-4505.
14. Revdekar A, Shende P. Block copolymers in Alzheimer’s disease therapy: a perceptive to revolutionize biomaterials. J Control Release, 2021, 340: 271-281.
15. Sohail M, Mudassir, Minhas MU, et al. Natural and synthetic polymer-based smart biomaterials for management of ulcerative colitis: a review of recent developments and future prospects. Drug Deliv Transl Res, 2019, 9(2): 595-614.
16. Klouda L. Thermoresponsive hydrogels in biomedical applications: a seven-year update. Eur J Pharm Biopharm, 2015, 97(Pt B): 338-349.
17. Lei XX, Hu JJ, Zou CY, et al. Multifunctional two-component in-situ hydrogel for esophageal submucosal dissection for mucosa uplift, postoperative wound closure and rapid healing. Bioact Mater, 2023, 27: 461-473.
18. Li X, Zhao D, Shea KJ, et al. In situ formed thermogelable hydrogel photonic crystals assembled by thermosensitive IPNs. Mater Horiz, 2021, 8(3): 932-938.
19. Heine S, Aguilar-Pimentel A, Russkamp D, et al. Thermosensitive PLGA-PEG-PLGA hydrogel as depot matrix for allergen-specific immunotherapy. Pharmaceutics, 2022, 14(8): 1527.
20. Ruel-Gariépy E, Chenite A, Chaput C, et al. Characterization of thermosensitive chitosan gels for the sustained delivery of drugs. Int J Pharm, 2000, 203(1/2): 89-98.
21. Weng L, Chen X, Chen W. Rheological characterization of in situ crosslinkable hydrogels formulated from oxidized dextran and N-carboxyethyl chitosan. Biomacromolecules, 2007, 8(4): 1109-1115.
22. Kumano I, Ishihara M, Nakamura S, et al. Endoscopic submucosal dissection for pig esophagus by using photocrosslinkable chitosan hydrogel as submucosal fluid cushion. Gastrointest Endosc, 2012, 75(4): 841-848.
23. Eeckman F, Mo?s AJ, Amighi K. Poly(N-isopropylacrylamide) copolymers for constant temperature controlled drug delivery. Int J Pharm, 2004, 273(1/2): 109-119.
24. Fernández-Gutiérrez M, Fusco S, Mayol L, et al. Stimuli-responsive chitosan/poly (N-isopropylacrylamide) semi-interpenetrating polymer networks: effect of pH and temperature on their rheological and swelling properties. J Mater Sci Mater Med, 2016, 27(6): 109.
25. Zhang Z, Ni J, Chen L, et al. Biodegradable and thermoreversible PCLA-PEG-PCLA hydrogel as a barrier for prevention of post-operative adhesion. Biomaterials, 2011, 32(21): 4725-4736.
26. Ma H, He C, Cheng Y, et al. PLK1shRNA and doxorubicin co-loaded thermosensitive PLGA-PEG-PLGA hydrogels for osteosarcoma treatment. Biomaterials, 2014, 35(30): 8723-8734.
27. Gao B, Luo J, Liu Y, et al. Intratumoral administration of thermosensitive hydrogel co-loaded with norcantharidin nanoparticles and doxorubicin for the treatment of hepatocellular carcinoma. Int J Nanomedicine, 2021, 16: 4073-4085.
28. Mu?oz Taboada G, Dahis D, Dosta P, et al. Sprayable hydrogel sealant for gastrointestinal wound shielding. Adv Mater, 2024, 36(24): e2311798.
29. Zhu Y, Xu JX, Cheng J, et al. A novel injectable thermo-sensitive binary hydrogels system for facilitating endoscopic submucosal dissection procedure. United European Gastroenterol J, 2019, 7(6): 782-789.
30. Bhalani DV, Nutan B, Kumar A, et al. Bioavailability enhancement techniques for poorly aqueous soluble drugs and therapeutics. Biomedicines, 2022, 10(9): 2055.
31. Large DE, Abdelmessih RG, Fink EA, et al. Liposome composition in drug delivery design, synthesis, characterization, and clinical application. Adv Drug Deliv Rev, 2021, 176: 113851.
32. Ili?-Stojanovi? S, Nikoli? L, Nikoli? V, et al. Temperature-sensitive hydrogels as carriers for modulated delivery of acetaminophen. Gels, 2023, 9(9): 684.
33. Lee Y, Kamada N, Moon JJ. Oral nanomedicine for modulating immunity, intestinal barrier functions, and gut microbiome. Adv Drug Deliv Rev, 2021, 179: 114021.
34. Prasher P, Sharma M, Singh SK, et al. Targeting mucus barrier in respiratory diseases by chemically modified advanced delivery systems. Chem Biol Interact, 2022, 365: 110048.
35. Sun Z, Song C, Wang C, et al. Hydrogel-based controlled drug delivery for cancer treatment: a review. Mol Pharm, 2020, 17(2): 373-391.
36. Liu J, Sun J, Hu J, et al. Biomaterial-based drug delivery strategies for oral mucosa. Colloids Surf B Biointerfaces, 2025, 251: 114604.
37. He S, Liu Z, Xu D. Advance in oral delivery systems for therapeutic protein. J Drug Target, 2019, 27(3): 283-291.
38. Liu GW, Pickett MJ, Kuosmanen JLP, et al. Drinkable in situ-forming tough hydrogels for gastrointestinal therapeutics. Nat Mater, 2024, 23(9): 1292-1299.
39. Xiao Y, Gu Y, Qin L, et al. Injectable thermosensitive hydrogel-based drug delivery system for local cancer therapy. Colloids Surf B Biointerfaces, 2021, 200: 111581.
40. Wang Q, Qu Y, Zhang Z, et al. Injectable DNA hydrogel-based local drug delivery and immunotherapy. Gels, 2022, 8(7): 400.
41. Liu B, Chen K. Advances in hydrogel-based drug delivery systems. Gels, 2024, 10(4): 262.
42. Alqahtani MS, Kazi M, Alsenaidy MA, et al. Advances in oral drug delivery. Front Pharmacol, 2021, 12: 618411.
43. Scully C, Porter S. Oral mucosal disease: recurrent aphthous stomatitis. Br J Oral Maxillofac Surg, 2008, 46(3): 198-206.
44. Desai DD, Manikkath J, Lad H, et al. Nanotechnology-based mucoadhesive and mucus-penetrating drug-delivery systems for transbuccal drug delivery. Nanomedicine (Lond), 2023, 18(21): 1495-1514.
45. Luo Y, Tan J, Zhou Y, et al. From crosslinking strategies to biomedical applications of hyaluronic acid-based hydrogels: a review. Int J Biol Macromol, 2023, 231: 123308.
46. Xu X, Xia X, Zhang K, et al. Bioadhesive hydrogels demonstrating pH-independent and ultrafast gelation promote gastric ulcer healing in pigs. Sci Transl Med, 2020, 12(558): eaba8014.
47. Xiao Q, Li X, Li Y, et al. Biological drug and drug delivery-mediated immunotherapy. Acta Pharm Sin B, 2021, 11(4): 941-960.
48. Centurión F, Basit AW, Liu J, et al. Nanoencapsulation for probiotic delivery. ACS Nano, 2021, 15(12): 18653-18660.
49. Zhong D, Jin K, Wang R, et al. Microalgae-based hydrogel for inflammatory bowel disease and its associated anxiety and depression. Adv Mater, 2024, 36(24): e2312275.
50. Yang Z, Zhou X, Wang L, et al. Mn₃O₄ nanozyme loaded thermosensitive PDLLA-PEG-PDLLA hydrogels for the treatment of inflammatory bowel disease. ACS Appl Mater Interfaces, 2023, 15(28): 33273-33287.
51. Khaledi S, Jafari S, Hamidi S, et al. Preparation and characterization of PLGA-PEG-PLGA polymeric nanoparticles for co-delivery of 5-fluorouracil and Chrysin. J Biomater Sci Polym Ed, 2020, 31(9): 1107-1126.
52. Khan I, Panda S, Kumar S, et al. A composite hydrogel of porous gold nanorods and gelatin: nanoscale structure and rheomechanical properties. J Chem Phys, 2025, 162(1): 014904.
53. Ma N, Yan Z. Research progress of thermosensitive hydrogel in tumor therapeutic. Nanoscale Res Lett, 2021, 16(1): 42.
54. Pimentel-Nunes P, Libanio D, Bastiaansen BAJ, et al. Endoscopic submucosal dissection for superficial gastrointestinal lesions: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2022. Endoscopy, 2022, 54(6): 591-622.
55. Cao B, Lu J, Tan Y, et al. Efficacy and safety of submucosal tunneling endoscopic resection for gastric submucosal tumors: a systematic review and meta-analysis. Rev Esp Enferm Dig, 2021, 113(1): 52-59.
56. Duan C, Liu Z, Wang X, et al. New chapter in precision medicine: strategies for endoscopic resection of 10-20 mm non-pedunculated colorectal polyps. Therap Adv Gastroenterol, 2025, 18: 17562848251338672.
57. Libanio D, Pimentel-Nunes P, Bastiaansen B, et al. Endoscopic submucosal dissection techniques and technology: European Society of Gastrointestinal Endoscopy (ESGE) Technical Review. Endoscopy, 2023, 55(4): 361-389.
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West China Medical Journal

Research progress on the application of thermosensitive hydrogel in gastrointestinal tract

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