Int J Stomatol

Int J Stomatol ›› 2026, Vol. 53 ›› Issue (5): 761-770.doi: 10.7518/gjkq.2026229

• Review • Previous Articles    

Research progress of drug-loaded hydrogels for the treatment of oral mucosal diseases

Qi Jiang1(),Fang Zhang2()   

  1. 1.Academy of Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
    2.School and Hospital of Stomato-logy, Shanxi Medical University, Shanxi Provincial Key Laboratory of Oral Disease Prevention and New Materials, Shanxi Provincial Clinical Medical Research Center for Oral Diseases, Taiyuan 030001, China
  • Received:2025-04-02 Revised:2025-11-10 Online:2026-09-01 Published:2026-08-28
  • Contact: Fang Zhang E-mail:1286138438@qq.com;zhangfangdoctor@sxmu.edu.cn
  • Supported by:
    National Natural Science Foundation of China(82301052);Shanxi Provincial Basic Research Program(202403021221153)

RichHTML

1

PDF (PC)

7

Abstract:

Oral mucosal diseases, which are complex and resistant to treatment, face key challenges such as low drug delivery efficiency and short local retention duration throughout treatment. Hydrogels, with their excellent physicochemical properties, have become ideal carriers for localized drug delivery systems in the oral mucosa. This article systematically reviews the latest progress in hydrogel drug delivery systems for the treatment of oral mucosal diseases, focusing on key characteristics, classification, drug delivery, and release mechanisms of hydrogels, as well as the current research status of hydrogel drug delivery systems loaded with functional components. By analyzing the technological advantages and limitations of current drug delivery systems, this paper further proposes the future development directions for hydrogel drug delivery systems, providing a theoretical reference for promoting the precise treatment of oral mucosal diseases.

Key words: hydrogel drug delivery system, oral mucosal disease, small molecule drugs, active ingredients of traditional Chinese medicine

CLC Number: 

  • R988.2

TrendMD: 

Fig 1

Drug-loaded hydrogels for the treatment of oral mucosal diseases"

Tab 1

The core characteristics of hydrogels"

名称优势应用举例
三维多孔网络结构能容纳药物分子，也提供了细胞支架功能魔芋葡甘露聚糖水凝胶，具有高载药量[9]
生物相容性对组织无不良反应一种化学改性透明质酸水凝胶，具有高度的生物相容性[10]
黏膜黏附性黏附在黏膜表面以甲基丙烯酸明胶-甲基丙烯酸透明质酸为基质的水凝胶，具有优异的黏膜黏附性[11]
缓释性延缓药物扩散，实现可控释放以壳聚糖、明胶、聚乙烯醇为基质的水凝胶可显著延长吉他霉素释放时间[12]
可注射性能够微创给药和填充不规则组织缺损自修复可注射水凝胶在组织再生领域具有广泛应用[13]
刺激响应性能响应环境变化发生结构转变热敏水凝胶可在特定温度下实现凝胶化[14]

Tab 2

The classification of hydrogels"

分类名称特点应用举例
基质不同天然基质生物相容性优异，可降解，机械强度较弱三甲基壳聚糖水凝胶封装干细胞，生物相容性良好[15]
合成基质结构明确，机械性能易调控，需评估生物相容性聚乙二醇衍生物-ε-聚赖氨酸水凝胶，机械强度优异[16]
刺激响应不同温度敏感型特定温度发生溶胶-凝胶相变37 ℃触发凝胶化，大鼠口腔溃疡模型治疗效果显著[17]
光敏感型特定波长光照诱导结构变化负载Cu2Se纳米片水凝胶，激光照射下发生溶胶-凝胶相转变[18]
pH敏感型响应环境pH变化；调节溶胀行为创伤pH刺激下持续释放藏红花酸，减轻伤口炎症[19]
交联不同物理非共价键连接，可逆性强，易降解12 h自愈效率94.7%，兼具自修复性能与机械强度[20]
化学共价键连接，机械强度高，长期稳定性好希夫碱键构建，兼具良好的热稳定性与黏弹性 [21]
电荷不同中性型不带电荷聚乙烯醇水凝胶[22]
阳离子型带正电荷含季氨基团的水凝胶[23]
阴离子型带负电荷含羧基的聚丙烯酸水凝胶[24]
两性离子型兼具正负电荷基团，可在特定pH条件下表现出不同电荷性质含有季氨基团与末端磺基的磺基甜菜碱水凝胶[25]

Tab 3

The drug-loading mechanism and influencing factors of hydrogels"

分类举例说明
载药机制物理作用药物通过范德华力、氢键或疏水作用吸附于水凝胶表面或孔隙
化学作用药物通过共价键结合、带电荷药物与凝胶网络中的离子基团静电作用结合、主客体相互作用结合
影响因素水凝胶材料本身的性质[28]

交联密度增加致孔隙缩小，限制大分子进入

亲水凝胶：氢键/静电作用载亲水药

疏水凝胶：疏水作用载脂溶药

离子型凝胶：静电吸附反电荷药、高溶胀度提升扩散效率

药物分子的性质[29]

小分子：易经扩散进入孔隙

亲水药：依赖溶胀度与孔隙

疏水药：疏水作用/主客体包合

阳离子药：适配阴离子凝胶

制备工艺的影响[10]

交联条件：影响网络均一性

冻干：有助于形成多孔结构

引入功能基团：提升载药效率

Tab 4

The drug release mechanism and influencing factors of hydrogels"

分类机制影响因素
扩散药物分子通过水凝胶网络的孔隙或通道向外扩散，通常符合Higuchi方程[30]

孔径与孔隙连通性：孔径需大于药物分子尺寸

交联密度：高交联度降低扩散系数

药物性质：小分子扩散快

溶胀水凝胶吸水溶胀导致网络扩张，孔隙增大，促进药物扩散[31]高溶胀比通常加速药物释放
降解水凝胶网络通过化学键断裂或生物酶解破坏，释放负载的药物[32]

化学键断裂：希夫碱键的水解速率受pH、温度调控

酶降解：如明胶水凝胶可被基质金属蛋白酶（matrix metalloproteinase，MMP）靶向降解

Tab 5

Research progress on hydrogel drug delivery systems loaded with different components for the treatment of oral mucosal diseases"

成分成分核心功能成分局限性水凝胶系统组成水凝胶主要优势实验模型
小分子药物曲昔匹特[29]抗炎碱性特征导致口腔黏膜摄取受阻甲基纤维素、卡波姆934纳米粒子复合设计，突破黏膜摄取屏障黄金仓鼠口腔黏膜炎
瑞巴派特[27]抗炎、抗菌口腔滞留时间短甲基纤维素、卡波姆、2-羟丙基-β环糊精黏膜黏附+环糊精增溶，双重提升生物利用度黄金仓鼠口腔黏膜炎
曲安奈德[36]抗炎口服生物利用度低壳聚糖、岩藻多糖贴片剂型+无感贴合，兼顾高载药率与依从性体外实验
醋酸地塞米松[14]抗炎几乎不溶于水泊洛沙姆407、羟丙基-β-环糊精、黄原胶、卡波姆、海藻酸钠热敏原位凝胶化，同步实现黏附性与溶解性提升体外实验
中药有效成分蜂胶提取物：CAPE[39]抗白色念珠菌CAPE溶液黏度低、口腔滞留短结冷胶增加局部黏附性、延长药物滞留；针对性抑制真菌生物膜体外实验
甘草提取物[42]抗炎、抗微生物口腔滞留时间短羟乙基纤维素促进胶原蛋白生成，同步减轻炎症Wistar大鼠口腔外伤性溃疡
人参提取物：皂苷Rg1[45]促血管再生、抗细胞凋亡半衰期短GelMA、LAP光敏原位成形，持续释放人参皂苷Rg1SD大鼠腭黏膜缺损
姜黄提取物：姜黄素[28,48]抗炎、抗氧化难溶、亲水性差、吸收率低、肝脏代谢快、半衰期短

柠檬酸、壳聚糖、明胶[28]；

羟丙基甲基纤维素、泊洛沙姆407、壳聚糖、脂质核心纳米胶囊[48]

高溶胀特性，100 min可控释药[28]；

热敏黏附设计，黏膜滞留长达8 h[48]

体外实验
绿茶提取物：茶多酚[51]抗炎、抗氧化、抗菌病灶部位滞留时间短泊洛沙姆68简易混合离心制备，兼具黏附性与抗菌性SD大鼠口腔溃疡
其他成分干细胞[15]具有再生潜能的治疗性细胞病灶部位滞留时间短三甲基壳聚糖细胞友好型基质，维持干细胞活性，强化局部驻留能力SD大鼠口腔溃疡
益生菌[53]抗菌、促组织修复口腔潮湿环境难以驻留海藻酸钙、岩藻多糖湿组织高黏附贴剂设计，同步实现缓释与抗菌协同SD大鼠口腔溃疡
光敏剂：石墨烯量子点[54]PDT核心介质，产生活性氧杀伤靶细胞传统光敏剂型作用时间短鸟苷自组装水凝胶网络，舌面适配黏附，持续光响应小鼠口腔白斑
纳米粒子：氧化铈[55]抗菌、抗氧化合成批次差异影响产品一致性GelMA可注射型基质，适配不规则创面，强化细胞迁移调控兔口腔黏膜炎
[1] 陈谦明. 口腔黏膜病学[M]. 5版. 北京: 人民卫生出版社, 2020: 11-30.
Chen QM. Oral medicine[M]. 5th ed. Beijing: People’s Medical Publishing House, 2020: 11-30.
[2] 李凌, 陈熹. 中医药在口腔黏膜病治疗中的研究进展[J]. 中医药管理杂志, 2023, 31(22): 187-189.
Li L, Chen X. Research progress of traditional Chinese medicine in the treatment of oral mucosal di-seases[J]. J Trad Chin Med Manag, 2023, 31(22): 187-189.
[3] 曾梓灏, 漆明. 口腔健康相关生活质量在口腔黏膜病诊疗中的应用与进展 [J]. 临床医药文献电子杂志, 2019, 6(59): 196-198.
Zeng ZH, Qi M. Application and progress of OH-RQoL in treatment of oral mucosal diseases[J]. Electr J Clin Med Liter, 2019, 6(59): 196-198.
[4] 潘晓娇. 促透剂对药物透过口腔粘膜吸收的影响[D]. 杭州: 浙江大学, 2008.
Pan XJ. The effect of penetration enhancers on the permeability of drugs through buccal mucosa[D]. Hangzhou: Zhejiang University, 2008.
[5] Kesharwani P, Alexander A, Shukla R, et al. Tissue regeneration properties of hydrogels derived from biological macromolecules: a review[J]. Int J Biol Macromol, 2024, 271(Pt 2): 132280.
[6] Brumberg V, Astrelina T, Malivanova T, et al. Mo-dern wound dressings: hydrogel dressings[J]. Biomedicines, 2021, 9(9): 1235.
[7] Webber MJ, Pashuck ET. (Macro)molecular self-assembly for hydrogel drug delivery[J]. Adv Drug Deliv Rev, 2021, 172: 275-295.
[8] Wu JP, Yun ZH, Song WL, et al. Highly oriented hydrogels for tissue regeneration: design strategies, cellular mechanisms, and biomedical applications[J]. Theranostics, 2024, 14(5): 1982-2035.
[9] Gu CY, Wang CR, Ma WJ, et al. Drug-loaded konjac glucomannan/metal-organic framework compo-site hydrogels as antibacterial and anti-inflammatory cell scaffolds[J]. ACS Appl Mater Interfaces, 2023, 15(35): 41287-41298.
[10] Munar-Bestard M, Vargas-Alfredo N, Ramis JM, et al. Mangostanin hyaluronic acid hydrogel as an effective biocompatible alternative to chlorhexidine[J]. Int J Biol Macromol, 2024, 279(Pt 1): 135187.
[11] Liu HJ, Li Q, Xu YY, et al. Dual-light defined in situ oral mucosal lesion therapy through a mode swit-chable anti-bacterial and anti-inflammatory mucoadhesive hydrogel[J]. Biomater Sci, 2023, 11(9): 3180-3196.
[12] Ma B, Liu P, Zhang YF, et al. Hydrogel for slow-release drug delivery in wound treatment[J]. J Polym Eng, 2024, 44(9): 637-650.
[13] Bertsch P, Diba M, Mooney DJ, et al. Self-hea-ling injectable hydrogels for tissue regeneration[J]. Chem Rev, 2023, 123(2): 834-873.
[14] Diaz-Salmeron R, Toussaint B, Huang N, et al. Mucoadhesive poloxamer-based hydrogels for the release of HP-β-CD-complexed dexamethasone in the treatment of buccal diseases[J]. Pharmaceutics, 2021, 13(1): 117.
[15] Ryu HS, Abueva C, Padalhin A, et al. Oral ulcer treatment using human tonsil-derived mesenchymal stem cells encapsulated in trimethyl chitosan hydrogel: an animal model study[J]. Stem Cell Res Ther, 2024, 15(1): 103.
[16] Yang Y, He G, Pan Z, et al. An injectable hydrogel with ultrahigh burst pressure and innate antibacte-rial activity for emergency hemostasis and wound repair[J]. Adv Mater, 2024, 36(33): e2404811.
[17] Padalhin A, Abueva C, Ryu HS, et al. Impact of thermo-responsive N-acetylcysteine hydrogel on dermal wound healing and oral ulcer regeneration[J]. Int J Mol Sci, 2024, 25(9): 4835.
[18] Zhong NP, Xing JH, He J, et al. Cu2Se-based injec-table hydrogels for synergistic photothermal/gas the-rapy of oral squamous cell carcinoma[J]. Mater Des, 2024, 237: 112535.
[19] Wang L, Ma XM, Pan YN, et al. pH-responsive calcium ions and crocetin releasing hydrogel for acce-lerating skin wound healing[J]. Chem Asian J, 2024, 19(10): e202400198.
[20] Li X, Yang Z, Hu GR, et al. Tri-network, physical cross-linked sodium alginate hydrogel with strongly self-healing capacity and highly tough, for wearable flexible devices[J]. Eur Polym J, 2024, 209: 112823.
[21] Wang Q, Yan SZ, Ning YJ, et al. Effect of sodium alginate block type on the physicochemical properties and curcumin release behavior of quaternized chitosan-oxidized sodium alginate Schiff base hydrogels[J]. Food Chem, 2024, 444: 138688.
[22] You XY, Xiao X, Zhao Y, et al. Highly swellable hydrogel from neutral hydroxyethyl cellulose for human weight control[J]. ACS Appl Polym Mater, 2023, 5(11): 9425-9432.
[23] Wang ZH, Cheng QL, Lu BZ, et al. Fabrication of antimicrobial cationic hydrogels driven by physically and chemically crosslinking for wound healing[J]. Int J Biol Macromol, 2024, 259(Pt 1): 129213.
[24] Aktaş DK, Öztekin F. pH-Sensitive poly (acrylic acid-co-acrylamide) anionic hydrogels for jejunum targeted drug delivery systems[J]. Polym Bull, 2023, 80(3): 2801-2813.
[25] Liu SH, Tang JY, Ji FQ, et al. Recent advances in zwitterionic hydrogels: preparation, property, and biomedical application[J]. Gels, 2022, 8(1): 46.
[26] Bhattarai N, Gunn J, Zhang MQ. Chitosan-based hydrogels for controlled, localized drug delivery[J]. Adv Drug Deliv Rev, 2010, 62(1): 83-99.
[27] Nagai N, Seiriki R, Deguchi S, et al. Hydrogel formulations incorporating drug nanocrystals enhance the therapeutic effect of rebamipide in a hamster model for oral mucositis[J]. Pharmaceutics, 2020, 12(6): 532.
[28] Yang J, Duan AB, Shen LP, et al. Preparation and application of curcumin loaded with citric acid crosslinked chitosan-gelatin hydrogels[J]. Int J Biol Macromol, 2024, 264(Pt 2): 130801.
[29] Kadowaki R, Ogata F, Nishida M, et al. Therapeutic effects of hydrogel formulations incorporating troxipide nanoparticles on oral mucositis in hamsters[J]. Drug Des Devel Ther, 2023, 17: 3349-3361.
[30] Zhang JQ, Zhang SW, Liu C, et al. Photopolyme-rized multifunctional sodium alginate-based hydrogel for antibacterial and coagulation dressings[J]. Int J Biol Macromol, 2024, 260(Pt 2): 129428.
[31] Arayesh S, Tanhaei B, Khoshkho SM, et al. Enhanced dual-drug loaded κ-carrageenan/agar hydrogel films for wound dressing: optimizing swelling and drug release[J]. Int J Biol Macromol, 2025, 306(Pt 1): 141295.
[32] Li W, Tao C, Wang JX, et al. MMP-responsive in situ forming hydrogel loaded with doxorubicin-encapsulated biodegradable micelles for local chemotherapy of oral squamous cell carcinoma[J]. RSC Adv, 2019, 9(54): 31264-31273.
[33] Kusugami K, Ina K, Hosokawa T, et al. Troxipide, a novel antiulcer compound, has inhibitory effects on human neutrophil migration and activation induced by various stimulants[J]. Dig Liver Dis, 2000, 32(4): 305-311.
[34] Chaitanya B, Pai KM, Yathiraj PH, et al. Rebami-pide gargle in preventive management of chemo-radiotherapy induced oral mucositis[J]. Oral Oncol, 2017, 72: 179-182.
[35] Qu XY, Guo XL, Zhu TT, et al. Microneedle pat-ches containing mesoporous polydopamine nanoparticles loaded with triamcinolone acetonide for the treatment of oral mucositis[J]. Front Bioeng Biotechnol, 2023, 11: 1203709.
[36] Zheng WP, Hao YP, Wang DY, et al. Preparation of triamcinolone acetonide-loaded chitosan/fucoidan hydrogel and its potential application as an oral mucosa patch[J]. Carbohydr Polym, 2021, 272: 118493.
[37] Shao B, Wang MX, Chen AR, et al. Protective effect of caffeic acid phenethyl ester against imidaclop-rid-induced hepatotoxicity by attenuating oxidative stress, endoplasmic reticulum stress, inflammation and apoptosis[J]. Pestic Biochem Physiol, 2020, 164: 122-129.
[38] Prades-Sagarra E, Laarakker F, Dissy J, et al. Caf-feic acid phenethyl ester (CAPE), a natural polyphenol to increase the therapeutic window for lung adenocarcinomas[J]. Radiother Oncol, 2024, 190: 110021.
[39] Yin WM, Zhang Z, Shuai XX, et al. Caffeic acid phenethyl ester (CAPE) inhibits cross-Kingdom biofilm formation of Streptococcus mutans and Candida albicans [J]. Microbiol Spectr, 2022, 10(5): e0157822.
[40] Garcia MT, Carmo PHFD, Figueiredo-Godoi LMA, et al. Gellan-based hydrogel as a drug delivery system for caffeic acid phenethyl ester in the treatment of oral Candida albicans infections[J]. Pharmaceutics, 2024, 16(3): 298.
[41] Ji X, Liu N, Huang S, et al. A comprehensive review of licorice: the preparation, chemical composition, bioactivities and its applications[J]. Am J Chin Med, 2024, 52(3): 667-716.
[42] Moussa SG, El Hoffy NM, Mouselhy YY, et al. Sustainable treatment of oral traumatic ulcers with licorice containing hydrogels: Integrating computational modeling, quality by design, green synthesis, and molecular biological evaluation[J]. Pharmaceutics, 2023, 15(12): 2734.
[43] Ratan ZA, Haidere MF, Hong YH, et al. Pharmacological potential of ginseng and its major component ginsenosides[J]. J Ginseng Res, 2021, 45(2): 199-210.
[44] Yin SY, Xia FY, Zou WJ, et al. Ginsenoside Rg1 regulates astrocytes to promote angiogenesis in spinal cord injury via the JAK2/STAT3 signaling pathway[J]. J Ethnopharmacol, 2024, 334: 118531.
[45] Xu J, Zhang ZH, Ren XF, et al. In situ photo-crosslinked hydrogel promotes oral mucosal wound hea-ling through sustained delivery of ginsenoside Rg1[J]. Front Bioeng Biotechnol, 2023, 11: 1252574.
[46] Fu YS, Chen TH, Weng LB, et al. Pharmacological properties and underlying mechanisms of curcumin and prospects in medicinal potential[J]. Biomedecine Pharmacother, 2021, 141: 111888.
[47] Lee HM, Patel V, Shyur LF, et al. Copper supplementation amplifies the anti-tumor effect of curcumin in oral cancer cells[J]. Phytomedicine, 2016, 23(12): 1535-1544.
[48] Ortega A, da Silva AB, da Costa LM, et al. Ther-mosensitive and mucoadhesive hydrogel containing curcumin-loaded lipid-core nanocapsules coated wi-th chitosan for the treatment of oral squamous cell carcinoma[J]. Drug Deliv Transl Res, 2023, 13(2): 642-657.
[49] Yan ZM, Zhong YZ, Duan YH, et al. Antioxidant mechanism of tea polyphenols and its impact on health benefits[J]. Anim Nutr, 2020, 6(2): 115-123.
[50] Hr R, Jagwani S, Shenoy PA, et al. Thermorever-sible gel of green tea extract: Formulation and eva-luation for the management of periodontitis[J]. J Drug Deliv Sci Technol, 2022, 76: 103765.
[51] Chen X, Zhang X, Yang S, et al. An adhesive hydrogel for the treatment of oral ulcers[J]. Chin Chemical Lett, 2025, 36(3): 110021.
[52] Ansari S, Pouraghaei Sevari S, Chen C, et al. RGD-modified alginate-GelMA hydrogel sheet containing gingival mesenchymal stem cells: a unique platform for wound healing and soft tissue regeneration[J]. ACS Biomater Sci Eng, 2021, 7(8): 3774-3782.
[53] Dou X, Li G, Wang S, et al. Probiotic-loaded cal-cium alginate/fucoidan hydrogels for promoting oral ulcer healing[J]. Int J Biol Macromol, 2023, 244: 125273.
[54] Lv ZZ, Xia X, Cao PS, et al. Overcoming the drug retention barrier with photosensitive hydrogel for sustained photodynamic therapy of oral leukoplakia[J]. Chin Chemical Lett, 2025: 111282.
[55] Yang F, He Y, Wang F, et al. Antibacterial and antioxidant GelMA/CeO2 hydrogel promotes oral mucosal healing[J]. J Dent Res, 2025, 104(9): 973-982.
[56] Yuniarsih N, Chaerunisaa AY, Elamin KM, et al. Po-lymeric nanohydrogel in topical drug delivery system[J]. Int J Nanomedicine, 2024, 19: 2733-2754.
[1] Song Tao, Wang Jiongke, Wen Jing, Chen Qianming, Zeng Xin. Analysis of the safety of thalidomide in the treatment of oral mucosal diseases [J]. Inter J Stomatol, 2016, 43(3): 366-370.
[2] Li Xiaoying. The clinical nursing work experience of tissue autofluorescence imaging used for screening potential malignant disease of oral mucosa [J]. Inter J Stomatol, 2014, 41(6): 738-739.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!