Revisited and innovative perspectives of oral ulcer: from biological specificity to local treatment

Abstract

Mouth ulcers, a highly prevalent ailment affecting the oral mucosa, leading to pain and discomfort, significantly impacting the patient's daily life. The development of innovative approaches for oral ulcer treatment is of great importance. Moreover, a deeper and more comprehensive understanding of mouth ulcers will facilitate the development of innovative therapeutic strategies. The oral environment possesses distinct traits as it serves as the gateway to the digestive and respiratory systems. The permeability of various epithelial layers can influence drug absorption. Moreover, oral mucosal injuries exhibit distinct healing patterns compared to cutaneous lesions, influenced by various inherent and extrinsic factors. Furthermore, the moist and dynamic oral environment, influenced by saliva and daily physiological functions like chewing and speaking, presents additional challenges in local therapy. Also, suitable mucosal adhesion materials are crucial to alleviate pain and promote healing process. To this end, the review comprehensively examines the anatomical and structural aspects of the oral cavity, elucidates the healing mechanisms of oral ulcers, explores the factors contributing to scar-free healing in the oral mucosa, and investigates the application of mucosal adhesive materials as drug delivery systems. This endeavor seeks to offer novel insights and perspectives for the treatment of oral ulcers.

Keywords: bioadhesive polymers; local treatment; mucosa-inspired scarless healing; oral ulcer; ulcer-related factors.

FIGURE 1

The anatomy and histology structure of oral cavity.

FIGURE 2

Timeline of oral wound healing and oral mucosal remodeling. Following injury, the hemostatic cascade is initiated to prevent excessive bleeding at the wound site (2-1). In the days following injury, inflammation peaks through neutrophil debridement and macrophage-mediated secretion of inflammatory cytokines (2-2). Within a week, the proliferation phase promotes fibroblast migration, increases vascular networks by angiogenesis, and enhances macrophage migration (2–3). Following fibroblast migration, the tissue surrounding the defect begins to re-epithelialize and mature by aligned fibrillar and dense collagen networks (2–4). Copyright (2021) Elsevier.

FIGURE 3

Comparison between oral ulcer and skin injury.

FIGURE 4

Signaling pathways and potential functions of oral ulcer-related factors.

FIGURE 5

Summary of potential mechanisms of Smad7-mediated protection and healing of oral mucositis (from Han et al., Nature Medicine, 2013). (A) Radiation activates NF-κB, increases TGFβ1 and CtBP1. NF-κB and TGFβ1 induce inflammation. TGFβ1 induces apoptosis, growth arrest, and activates Smads which recruit CtBP1 to the Rac1 promoter to repress Rac1 transcription, leading to blunted re-epithelialization. (B) Smad7 blocks NF-κB and TGFβ1-induced inflammation and blocks TGFβ1-induced apoptosis and growth arrest. Smad7 activates Rac1 by either preventing TGFβ1-mediated Smad phosphorylation or competing with signaling Smads/CtBP1 transcriptional repression complex in the Rac1 promoter. Increased Rac1 induced by Smad7 contributes to keratinocyte migration during re-epithelialization. Copyright (2015) Springer.

FIGURE 6

Schematic illustration of the mucus distribution and structure. (A) Mucus is distributed in eyes, nasal cavity, lung, stomach, intestine, etc. (B) The network of mucus is composed of mucin fibers which contain glycosylation regions with negative charge and non-glycosylated hydrophobic regions rich in cysteine. Copyright (2021) Elsevier.

FIGURE 7

Classification of mucoadhesive mechanisms and polymers.

FIGURE 8

(A) Variation in the particle size of different PVA-DOPA-Mucin mixtures as a function of time. PVA: poly (vinyl alcohol), DOPA: 3,4-dihydroxy-D-phenylalanine. n = 3 independent samples per group; *p = 0.025; **p < 0.01; ***p < 0.001 vs. value at 0 h (B) Variation in the zeta potential of different PVA-DOPA-Mucin mixtures as a function of time. n = 3 independent samples per group; *p < 0.05; **p < 0.01; ***p < 0.001 vs. value at 0 h (C) UV-vis absorbance spectra of different PVA-DOPA-Mucin mixtures. (D) FTIR spectra of different PVA-DOPA before and after mixed with mucin. (E) SAXS spectra of different PVA-DOPA before and after mixed with mucin. (F) Schematic overview of the interactions between the PVA-DOPA film and mucus. NPs: nanoparticles, Dex: dexamethasone. All data are Mean ± S.D. Statistics was calculated by one-way ANOVA followed by Tukey’s post-test. Copyright (2021) Nature.