Oral Mucosal Wound Healing Research Articles

Nutmeg (Myristica fragrans) Extracts Accelerate Oral Mucosal Wound Healing In Vivo

Background: Oral mucosal pain and sores are common concerns in dental care, often resulting from surgeries, infections, trauma, or autoimmune disorders. Conventional treatments like NSAIDs offer relief but carry adverse side effects. Nutmeg (Myristica fragrans) has been traditionally used for its analgesic, anti-inflammatory, and antimicrobial properties. However, its potential in oral mucosal wound healing remains underexplored. Methods: This study utilized male Wistar rats (Rattus norvegicus) to assess the wound healing effects of nutmeg extracts and fractions. Nutmeg was extracted using maceration, and the fractions were obtained through liquid-liquid extraction. Rats were divided into control and treatment groups, and topical nutmeg treatments were applied daily to incised gingival mucosa. Wound closure time was monitored daily, and healing rates were analyzed. Results: The ethyl acetate fraction of nutmeg exhibited the fastest wound healing, achieving an average healing rate of 88.79%, closely matching the positive control (94.65%). Other fractions also demonstrated efficacy, with the aqueous fraction achieving 82.46% and the ethanol fraction 75.54%. The hexane fraction showed the slowest healing at 63.67%. Statistical analysis revealed significant differences between the groups (p < 0.05). Conclusion: Nutmeg extracts, particularly the ethyl acetate fraction, significantly accelerated wound healing in the oral mucosa of Wistar rats, highlighting its potential as a natural wound-healing agent. Further research is needed to isolate the bioactive compounds responsible for these effects and to explore their clinical applications in dental care.

Promoting diabetic oral mucosa wound healing with a light-responsive hydrogel adaptive to the microenvironment

In diabetic patients, compromised angiogenesis due to endothelial dysfunction leads to delayed intraoral wound healing. However, the moist and dynamic environment of the oral cavity impedes the use of normal wound dressings. Sulfated chitosan (SCS) is a promising biomaterial that promoting angiogenesis. Here, a light-responsive hydrogel combined with SCS explored intraoral wound healing. We designed a SCS-modified hydrogel combined with alginate Methacryloyl (AlgMA) and acrylamide (AM) and demonstrated efficient wet adhesion and mechanical properties suitable for the wet and dynamic oral environment. In vitro, the SAA hydrogel improved the tube formation of human umbilical vein endothelial cells (HUVECs) under high-glucose conditions. Further investigations revealed that the SAA hydrogel can regulate HUVEC-macrophage interactions, leading to a shift in macrophage polarization from M1 to M2, thereby fostering an environment conducive to angiogenesis under high-glucose condition. The results demonstrated the substantial therapeutic impact of the SAA hydrogel on diabetic oral defect repair by effectively enhancing the local blood supply and angiogenesis.

An Integrated Dual-layer Heterogeneous PCL Scaffold Promotes Oral Mucosal Wound Healing through Inhibiting Bacterial Adhesion and Mediating HGF-1 Behaviour

An Integrated Dual-layer Heterogeneous PCL Scaffold Promotes Oral Mucosal Wound Healing through Inhibiting Bacterial Adhesion and Mediating HGF-1 Behaviour

The Impact of Oral Administration of Systemic Probiotics “Lactobacillus rhamnosus” on IL-1β and IL-10 Levels and Wound Healing of Oral Mucosa in Rabbits

The Impact of Oral Administration of Systemic Probiotics “Lactobacillus rhamnosus” on IL-1β and IL-10 Levels and Wound Healing of Oral Mucosa in Rabbits

P02-41 Toxicological aspects of in vitro oral mucosa wound healing models

P02-41 Toxicological aspects of in vitro oral mucosa wound healing models

Visible Light‐Responsive Polyphenolic Bio‐Glues for Oral Mucosal Wound Healing

AbstractAlthough bio‐adhesives have achieved many progresses, creating robust bio‐glues that could withstand the complex physiological microenvironment remains a significant challenge such as limited bioadhesion strength and stability, as well as slow adhesion speed caused by pH, enzymes, salt, and bacteria. Herein, a series of strong bio‐glues are successfully fabricated using a polyphenol–acrylamide–ruthenium crosslinking (PARC) reaction under visible light irradiation, involving acrylamides radical polymerization, polyphenols (extracts) coupling reaction, and ruthenium‐mediated photochemistry. The resulting bio‐glues underwent rapid sol–gel transition and exhibited adhesive properties within a short of time (≈5 s), which could quickly bond to various bio‐tissues. Moreover, these bioadhesives demonstrate high adhesion strength and stability with mucosal tissue in the oral environment, effectively promoting rat and pig oral mucosal wound healing. It is anticipated that this class of visible light‐responsive polyphenolic bio‐glues could serve as a robust tool for addressing oral mucosal defects in the clinic, offering a promising alternative to traditional treatments for oral mucosal disorders.

Immediate but Temporal Response: The Role of Distal Epithelial Cells in Wound Healing.

Efficient oral mucosal wound healing requires coordinated responses from epithelial progenitor cells, yet their spatiotemporal recruitment and activation remain unclear. Using a mouse model of palatal mucosal wound healing, we investigated the dynamics of epithelial cells during this process. Proliferation analysis revealed that, in addition to the expected proliferation center near the wound edge, distal cell populations rapidly activated post-injury by elevating their mitotic activity. These distal cells displayed predominant lateral expansion in the basal layer, suggesting roles beyond just tissue renewal. However, while proximal proliferation center cells sustained heightened proliferation until re-epithelialization was completed, distal cells restored basal turnover rates before wound closure, indicating temporally confined contributions. Lineage tracing of Wnt-responsive epithelial cells showed remarkable clone expansion in basal layers both proximally and distally after wounding, contrasting with gradual clone expansion in homeostasis. Although prioritizing tissue repair, epithelial progenitor cells maintained differentiation programs and barrier functions, with the exception of the leading edge. At the leading edge, we found accelerated cell turnover, but the differentiation program was suspended. In summary, our findings uncovered that oral wound re-epithelialization involves two phases: an initial widespread response with proliferation of proximal and distal cells, followed by proliferation confined to the wound proximal region. Uncovering these stage-specific healing mechanisms provides insights for developing targeted therapeutic strategies to improve wound care.

Identification of IGF2 promotes skin wound healing by co-expression analysis.

Oral mucosa is an ideal model for studying scarless wound healing. Researchers have shown that the key factors which promote scarless wound healing already exist in basal state of oral mucosa. Thus, to identify the other potential factors in basal state of oral mucosa will benefit to skin wound healing. In this study, we identified eight gene modules enriched in wound healing stages of human skin and oral mucosa through co-expression analysis, among which the module M8 was only module enriched in basal state of oral mucosa, indicating that the genes in module M8 may have key factors mediating scarless wound healing. Through bioinformatic analysis of genes in module M8, we found IGF2 may be the key factor mediating scarless wound healing of oral mucosa. Then, we purified IGF2 protein by prokaryotic expression, and we found that IGF2 could promote the proliferation and migration of HaCaT cells. Moreover, IGF2 promoted wound re-epithelialization and accelerated wound healing in a full-thickness skin wound model. Our findings identified IGF2 as a factor to promote skin wound healing which provide a potential target for wound healing therapy in clinic.

Ethanolic extract of Gracilaria spp. Attenuates the inflammatory stage of oral mucosa wound healing: An in vivo study.

Millions of bacteria present in the mouth cavity contribute to the challenging management of oral mucosa injury. On the other hand, Gracilaria spp. (red algae) is one of the widely cultivated algae that have a strong potential as a wound-healing agent for oral mucosa injury. This study aimed to investigate the wound-healing property of the red algae by observing its effect on polymorphonuclear (PMN), a neutrophil that is usually recruited during the initial wound healing. The extract was obtained through maceration and used as bioactive ingredient in gel preparation. Rattus norvegicus with incision wounds in the oral mucosa was used as the animal model. Our results revealed that rats treated with the red algae gel had significantly lower PMN on the injury site (P < 0.01) as observed on days 1, 3, and 5. Identification using gas chromatography-mass spectrometry showed that the extract was rich in hexadecenoic acid and glycerol. The brine shrimp lethality test suggested low cytotoxicity of this extract with LC50 = 10694.93 mg/mL. In conclusion, the extract could be potentially used as bioactive ingredient in gel formulation for topical management of oral mucosa wounds. Further, research to confirm these findings is warranted.

Retracted: Identification of the Potential Biomarkers Involved in the Human Oral Mucosal Wound Healing: A Bioinformatic Study.

[This retracts the article DOI: 10.1155/2021/6695245.].

The Effect of Orally Administered Lactobacillus rhamnosus as “Systemic Probiotics” on C-Reactive Protein Levels and Wound Healing of Oral Mucosa in Rabbits

The Effect of Orally Administered Lactobacillus rhamnosus as “Systemic Probiotics” on C-Reactive Protein Levels and Wound Healing of Oral Mucosa in Rabbits

The effect of resolvin D1n-3 DPA on primary oral epithelial cell migration in vitro.

Specialized pro-resolving lipid mediators (SPMs) are known for their anti-inflammatory and pro-resolving actions. The aim of the present study was to find new functions of the SPM resolvin D1n-3 DPA (RvD1n-3 DPA) on oral epithelial cells. As a starting point, we used a dataset obtained by RNA high-throughput sequencing of oral epithelial cells exposed to TNF-α and RvD1n-3 DPA versus TNF-α alone. GOrilla enrichment analysis showed that the actin cytoskeleton was significantly overrepresented after adjustment for multiple hypothesis testing. As actin, amongst others, is closely related to cell migration, we then explored whether RvD1n-3 DPA can modulate oral epithelial cell migration. To this end, we used an in vitro cell migration model, including TNF-α treatment, to mimic an inflammatory cell state. The analysis revealed that RvD1n-3 DPA increased oral epithelial cell migration in the presence but not in the absence of TNF-α. Addition of RvD1n-3 DPA also induced F actin accumulation around the cell nucleus, indicating that RvD1n-3 DPA potentially can mediate processes of intracellular transport. This indicates that this lipid mediator may be a promising therapeutic candidate in oral mucosal wound healing.

The Lamina Propria of the Oral Mucosa Harbors a Neural Crest-Like Stem Cell Population Resistant to Hyperglycemia Induced by Diabetes Type II

Oral mucosa stem cells (OMSC) are contained within niches in the lamina propria of the oral mucosa. In vitro, OMSC exhibit a primitive neural crest-stem cell phenotype and differentiate into neural crest-derived cell lineages. Clinical evidence indicate that wound healing of oral mucosa is scarless and negligibly affected by diabetes. Since stem cells play an important role in wound healing we hypothesized that in contrast to adult mesenchymal stem cells, OMSC are negligibly affected by diabetes type II hyperglycemia. The capacity of murine OMSC (mOMSC) obtained from diabetic db+/db+ mice (DmOMSC) to proliferate, express pluripotency-associated markers (PAM) (oct4, sox2, nanog) and neural crest stem cell markers (NCSM) (Klf4, c-Myc, twist, nestin), and differentiate along neural crest cell lineages was compared to that of OMSC derived from background WT C57BL/6 mice (WT-mOMSC) and to those of murine adipose tissue stem cells (mASC) derived from the same animals used for generating mOMSC. WT-mOMSC capacity to proliferate, express PAM and NCSM and differentiate was higher than that of WT-mASC. Diabetes reduced the proliferation rat of DmOMSC and db+/db+ derived mASC (DmASC) by 35% and 42%, respectively. Diabetes did not affect the expression of PAM and NSCSM in DmOMSC and nor their differentiation as compared to WT-mOMSC, but the diabetic state substantially reduced these parameters in DmASC as compared to WT-mASC and DmOMSC. We demonstrated that WT-mOMSC administration enhances wound healing in the db+/db+ diabetic wound skin model. To test the effect of diabetes on the therapeutic functionality of DmOMSC, the ability of these cells to enhance diabetic wound healing was assessed in this model. The results indicate that DmOMSC increased the rate of wound healing in db+/db+ mice as compared to placebo treated controls. The magnitude of this therapeutic effect is statistically equivalent to that of WT-mOMSC. Collectively, these data demonstrate that: i) diabetes decreased moderately DmOMSC proliferative ability; ii) in contrast to mASC, mOMSC withstand the detrimental effects of diabetes; and iii) the therapeutic properties of DmOMSC are mildly affected by long standing diabetes.

Oral administration of Bifidobacterium breve improves anti-angiogenic drugs-derived oral mucosal wound healing impairment via upregulation of interleukin-10

Recent studies have suggested that long-term application of anti-angiogenic drugs may impair oral mucosal wound healing. This study investigated the effect of sunitinib on oral mucosal healing impairment in mice and the therapeutic potential of Bifidobacterium breve (B. breve). A mouse hard palate mucosal defect model was used to investigate the influence of sunitinib and/or zoledronate on wound healing. The volume and density of the bone under the mucosal defect were assessed by micro-computed tomography (micro-CT). Inflammatory factors were detected by protein microarray analysis and enzyme-linked immunosorbent assay (ELISA). The senescence and biological functions were tested in oral mucosal stem cells (OMSCs) treated with sunitinib. Ligated loop experiments were used to investigate the effect of oral B. breve. Neutralizing antibody for interleukin-10 (IL-10) was used to prove the critical role of IL-10 in the pro-healing process derived from B. breve. Results showed that sunitinib caused oral mucosal wound healing impairment in mice. In vitro, sunitinib induced cellular senescence in OMSCs and affected biological functions such as proliferation, migration, and differentiation. Oral administration of B. breve reduced oral mucosal inflammation and promoted wound healing via intestinal dendritic cells (DCs)-derived IL-10. IL-10 reversed cellular senescence caused by sunitinib in OMSCs, and IL-10 neutralizing antibody blocked the ameliorative effect of B. breve on oral mucosal wound healing under sunitinib treatment conditions. In conclusion, sunitinib induces cellular senescence in OMSCs and causes oral mucosal wound healing impairment and oral administration of B. breve could improve wound healing impairment via intestinal DCs-derived IL-10.

In situ photo-crosslinked hydrogel promotes oral mucosal wound healing through sustained delivery of ginsenoside Rg1.

Oral mucosal wounds exhibit an increased susceptibility to inflammation as a consequence of their direct exposure to a diverse range of microorganisms. This causes pain, slow healing, and other complications that interfere with patients' daily activities like eating and speaking. Consequently, patients experience a significant decline in their overall quality of life. Therefore, the pursuit of novel treatment approaches is of great importance. In this study, ginsenoside Rg1, a natural active substance extracted from ginseng root, was chosen as a therapeutic agent. It was encapsulated in a screened photo-crosslinked hydrogel scaffold for the treatment of mucosal defects in the rat palate. The results demonstrated that Rg1-hydrogel possessed excellent physical and chemical properties, and that oral mucosa wounds treated with Rg1-hydrogel exhibited the greatest healing performance, as evidenced by more pronounced wound re-epithelialization, increased collagen deposition, and decreased inflammatory infiltration. Subsequent investigations in molecular biology confirmed that Rg1-hydrogel stimulated the secretion of repair-related factors and inhibited the secretion of inflammatory factors. This study demonstrated that the hydrogel containing ginsenoside Rg1 significantly promotes oral mucosal tissue healing in vivo. Based on the findings, it can be inferred that the Rg1-hydrogel has promising prospects for the therapeutic management of oral mucosal wounds.

Histological Assessment of the Effects of Derma + Flex®, versus Black Silk Suture on Oral Mucosal Primary Wound Healing in Rabbits

Histological Assessment of the Effects of Derma + Flex®, versus Black Silk Suture on Oral Mucosal Primary Wound Healing in Rabbits

Potential Effect of Red Algae Content on Fibroblasts and Collagen Type 3 in Oral Mucosa Wound Healing Diabetes-Induced Rattus Norvegicus

Potential Effect of Red Algae Content on Fibroblasts and Collagen Type 3 in Oral Mucosa Wound Healing Diabetes-Induced Rattus Norvegicus

Characteristics and cellular mechanism of the wound healing process in the oral mucosa

Abstract Wound healing involves four stages: haemostasis, inflammation, proliferation, and remodelling. Each wound should be considered separately because of the tissue’s different environment. The key to successful wound healing is cell signalling and synchronisation between cells and chemical transmitters, which gradient attracts immune cells and prevents pathogens from causing infection. Both skin and oral mucosa stages of the wound healing process are the same. Nonetheless, some differences affect the outcome of the healing. The most critical factors that impact the process are the time required for wound closure or immune response, the presence of saliva, the level of anti-inflammatory cytokines, and extracellular matrix (ECM) remodelling. Compared to the skin, wounds in the oral mucosa heal much faster and without scarring. Saliva plays a crucial role in healing the oral mucosa – because of higher levels of tissue factor, it reduces the clotting time. Furthermore, it is rich in many growth factors stimulating wound healing. Mesenchymal stem cells are yet another valid matter regarding wound healing in oral mucosa. Outstanding properties of these cells exhibit potential to be applied for therapeutical purposes. Additionally, immune cells’ participation and response to tissue damage are more substantial and faster in the oral mucosa than in the skin. Wound healing is a complex process influenced by many factors, including hyperglycaemia in diabetes, smoking, alcohol, and levels of sex hormones. Some of them, such as smoking, impair all stages of healing, while others only have some elements.

Promoting oral mucosal wound healing using a DCS-RuB2A2 hydrogel based on a photoreactive antibacterial and sustained release of BMSCs.

The high occurrence rate and difficulties in symptom control are listed as the major problems of oral mucosal disease by medical professionals. Following the development of oral mucosal lesions, the oral microenvironment changes, immunity declines, and continuous bacterial stimulation causes wound infection. Traditional antibacterial drugs are ineffective for oral mucosal lesions. To overcome this problem, a light-responsive antibacterial hydrogel containing sustained-release BMSCs was inspired by the trauma environment in the oral cavity, which is different from that on the body surface since it mostly remains under dark conditions. In the absence of light, the hydrogel seals the wound to form a barrier, exerts a natural bacteriostatic effect, and prevents invasion by foreign bacteria. Simultaneously, mesenchymal stem cells are presented, and the released growth factors and other substances have excellent anti-inflammatory and angiogenic effects, which result in rapid repair of the damaged site. Under light conditions, after photo-induced shedding of the hydrogel, RuB2A exerts an antibacterial effect accompanied by degradation of the hydrogel. Results in a rat oral mucosal repair model demonstrate that DCS-RuB2A2-BMSCs could rapidly repair the oral mucosa within 4 days. Sequencing data provide ideas for further analysis of the intrinsic molecular mechanisms and signaling pathways. Taken together, our results suggest that this light-responsive antibacterial hydrogel loaded with BMSCs can be used for rapid wound repair and may advance the development of therapeutic strategies for the treatment of clinical oral mucosal defects.

Effects of Platelet Lysate Gels Derived from Different Blood Sources on Oral Mucosal Wound Healing: An In Vitro Study.

The rapid healing of oral ulcers is important to prevent secondary infection, especially for chronic oral ulcers. Platelet lysate (PL) is rich in growth factors for cell growth and promotes tissue regeneration. Hence, this study was performed to compare the effects of PL originating from umbilical cord blood (CB) and peripheral blood (PB) on oral mucosal wound healing. The PLs were molded into gel form in the culture insert with the addition of calcium chloride and conditioned medium for sustained release of growth factors. The CB-PL and PB-PL gels were found to degrade slowly in culture and their degradation percentages by weight were 5.28 ± 0.72% and 9.55 ± 1.82% respectively. The results from the scratch assay and Alamar blue assay showed that the CB-PL and PB-PL gels increased the proliferation (148 ± 3% and 149 ± 3%) and wound closure (94.17 ± 1.77% and 92.75 ± 1.80%) of oral mucosal fibroblasts compared to the control with no statistical differences between the two gels, respectively. Quantitative RT-PCR showed that mRNA expressions of collagen-I, collagen-III, fibronectin, and elastin genes in cells treated with CB-PL (11-, 7-, 2-, and 7-fold) and PB-PL (17-, 14-, 3-, and 7-fold) decreased compared with the control, respectively. The concentration of platelet-derived growth factor of PB-PL gel (1303.10 ± 343.96 pg/mL) showed a higher trend than CB-PL gel did (905.48 ± 69.65 pg/mL) from ELISA measurement. In summary, CB-PL gel is as effective as PB-PL gel in supporting oral mucosal wound healing, making it a potential new source of PL for regenerative treatment.