Oral Wound Healing Research Articles

Accelerating Oral Wound Healing Using Bilayer Biomaterial Delivery of FTY720 Immunotherapy.

Orofacial clefts are the most common congenital craniofacial anomaly. Adverse healing following cleft palate repair can lead to oronasal fistula (ONF), a persistent connection between the oral and nasal cavities. Although human allograft tissues are currently the gold standard for ONF repair, these methods carry risks of infection and rejection, often requiring surgical revision. Immunoregenerative therapies present a novel alternative approach to harness the body's immune response and enhance the wound healing environment. An FDA-approved immunomodulatory drug, FTY720, is repurposed to reduce lymphocyte egress and induce immune cell fate switching toward pro-regenerative phenotypes. In this study, a bilayer biomaterial system is engineered using Tegaderm to secure and control the delivery of FTY720-nanofiber scaffolds (FTY720-NF). The release kinetics of the bilayer FTY720-NF is optimized to maintain drug release for up to 7 days, ensuring safe transdermal absorption and tissue biodistribution. The comprehensive immunophenotyping results demonstrate a regenerative state transition in hybrid immune cells recruited to the wound site. Further, histological evaluations reveal a significant ONF closure in mice by day 7 following bilayer FTY720-NF implantation. These findings demonstrate the utility of immunomodulatory strategies for oral wound healing, better positing the field to develop more efficacious treatment options in pediatric patients.

Oral Wound Healing in Aging Population

Background: Oral wound healing in the aging population is a multifaceted issue requiring a comprehensive approach, considering the physiological changes that come with aging and the frequent presence of comorbidities. Methods: This descriptive review summarizes the factors influencing oral wound healing in aging patients, including age-related physiological changes, hormonal modifications, multimorbidities, polypharmacy, oralome alterations, and nutritional status. Results: The aging population encounters numerous challenges in oral wound healing due to intrinsic factors, such as biological aging and hormonal changes, and extrinsic factors, such as medication use and lifestyle. Conclusion: Understanding these factors and their combined impact is essential for effective clinical management and improved outcomes in older adults.

The Efficacy of Low-Level Laser Therapy on the Healing of Oral Wounds: A Systematic Review

The Efficacy of Low-Level Laser Therapy on the Healing of Oral Wounds: A Systematic Review

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.

Bilayer cellulose-coated hyaluronic acid-based scaffold for accelerating oral wound healing

Bilayer cellulose-coated hyaluronic acid-based scaffold for accelerating oral wound healing

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

SPRR1B+ keratinocytes prime oral mucosa for rapid wound healing via STAT3 activation

Oral mucosal wounds exhibit accelerated healing with reduced scarring compared to cutaneous wounds, representing an optimal wound healing paradigm. However, the specific cellular subtypes orchestrating the efficient healing of mucosal tissues remain elusive. Through a comprehensive analysis integrating bulk-mRNA and single-cell sequencing data during the wound healing process in oral mucosa and skin, we have delineated a distinct set of genes markedly upregulated during tissue repair. This collection of wound healing-associated genesets was highly enriched in a specific keratinocyte subpopulation identified as STAT3-activated SPRR1B+ keratinocytes. Notably, despite the inherent rapidity of oral mucosal healing, the induction of SPRR1B+ keratinocytes is evident in both skin and mucosal wound healing processes in murine model. Intriguingly, these wound healing-promoting SPRR1B+ keratinocytes, which are induced via STAT3 activation, inherently abundant in unwounded normal mucosa but absent in normal skin. SPRR1B knockdown significantly inhibits mucosal keratinocyte migration, a critical attribute for effective wound healing. In summary, through analysis of human oral and skin wound healing processes at single-cell resolution, coupled with validation in murine model, suggests STAT3-activated SPRR1B+ keratinocytes are associated with the rapid mucosal repair process. This discovery underscores the potential application of SPRR1B+ keratinocytes in the therapeutic management of chronic or non-healing wounds.

Effectiveness of cold plasma application in oral wound healing process: A scoping review.

Cold atmospheric plasma (CAP) has shown an ability to promote wound healing by modulating biological processes without causing thermal damage. This scoping review aimed to evaluate the effectiveness of CAP application in the oral wound healing process. An electronic literature search was conducted using PubMed/Medline, Embase, Web of Science, Scopus, and grey literature (Google Scholar). The search included all articles published up to October 11, 2023. Only studies focusing on the different CAP types' effects on oral cavity wounds or cells were included in the review. This review analyzed 13 studies including seven cell culture studies, one animal study, and five human studies (three invivo and two exvivo). The findings from the reviewed articles suggest that CAP may have therapeutic potential. It can maintain cell viability and influence gene expression, accelerate wound healing, and modulate inflammation-related cytokines. DBD plasma exhibited time-sensitive effects on cellular behavior and microplasma irradiation positively impacted cell count, biochemical profiles, and cellular migration. The application of CAP has been shown to have a positive impact on the healing of oral wounds in cell culture, animal, and human studies.

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

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

Effect of diode laser on oral pigmentation, pain, and wound healing in patients with gingival hyperpigmentation: a meta-analysis.

Diode laser represent a practical clinical strategy for treating gingival hyperpigmentation. However, its effectiveness remains controversial. We conducted a meta-analysis evaluating the quantitative effects of diode laser therapy on gingival hyperpigmentation. Pubmed, Embase, Web Of Science, and Cochrane Library were systematically searched for the use of diode laser in gingival hyperpigmentation. The primary outcomes assessed were the Dummett-Gupta Oral Pigmentation Index (DOPI), Visual Analog Scale (VAS) pain scores, and the Wound Healing Index (WHI) for overall evaluation. I2 index was calculated to identify heterogeneity and sensitivity analyses sources of heterogeneity. Funnel plots and Egger's test were utilized to evaluate publication bias. Thirteen randomized controlled trials (RCTs) involving a total of 233 participants were included in this study. The analysis demonstrated that diode laser had a significant effect on DOPI (standard mean difference [SMD] = -0.245, 95% CI = -0.415 to -0.040, P =.019) and VAS (SMD = -0.089, 95% CI = -1.332 to -0.285, P =.002), with no significant effect on WHI (SMD = -0.224, 95% CI = -1.100 to 0.653, P =.617). Despite the significant heterogeneity in VAS and WHI indicated by the I2 index statistic, the sensitivity analyses' results demonstrated the main findings' reliability. While no significant publication bias was detected for DOPI and WHI, the VAS results exhibited notable publication bias. The study demonstrated that diode laser prolongs gingival repigmentation time and reduces pain compared to other treatments. However, the efficacy in wound healing did not significantly promote.

Use of High-Frequency Ultrasound for the Correlation of Epithelial Rete Peg Variation

ObjectiveRete pegs are projections of the oral epithelium into connective tissue. Their dimensions change during pathological conditions and may correlate with wound-healing status. Non-invasive, high-frequency ultrasound (US) may be able to capture these changes and aid in early detection of histopathological changes. The aim of this preclinical study is to correlate US images with histology and quantify epithelial layers at different tooth sites. MethodsSagittal B-mode images of mid-facial and interproximal oral soft tissue sites were recorded in a preclinical minipig model using a linear array in second harmonic mode (12/24 MHz). Histology samples from the same locations were stained (hematoxylin and eosin), digitized and registered with US images. Manual annotations were used to measure distances D1 (thickness of epithelium on histology vs. hyperechoic zone on US) and D2 (sum of epithelial thickness and length of rete pegs on histology vs. sum of hyperechoic and hypoechoic zone on US) to statistically analyze them. ResultsUltrasonic-derived dimensions yielded a mean bias of -0.64 (55% coefficient of variance [COV]: -180 to +180 µm) and -12 µm (39% COV: -260 to +240 µm) for D1 and D2, respectively. Individualized analysis of D1 and D2 by tooth type showed similar tends in the ability to differentiate between epithelium at different tooth locations, on both histology and US. ConclusionAssessing soft tissue dimensions on a sub-millimeter scale using clinical imaging hardware is still a developing area. Future research might open doors for diagnosis of oral pathologies and abnormal wound healing, and may limit false-positive indications for biopsies.

Effects of Chitosan Membrane on Osteogenesis and Oral Wound Healing: A Literature Review

Effects of Chitosan Membrane on Osteogenesis and Oral Wound Healing: A Literature Review

Contribution of initial lymphatics to oral wound healing after tooth extraction.

Lymphatics are involved in the resolution of inflammation and wound healing, but their role in the oral wound healing process after tooth extraction has never been investigated. We therefore sought to evaluate the healing process following the extraction of maxillary molars in two transgenic mouse models: K14-VEGFR3-Ig mice, which lack initial mucosal lymphatic vessels, and K14-VEGFC mice, which have hyperplastic mucosal lymphatics. Maxillary molars were extracted from both transgenic mouse types and their corresponding wild-type (WT) controls. Mucosal and alveolar bone healing were evaluated. A delayed epithelialization and bone regeneration were observed in K14-VEGFR3-Ig mice compared with their WT littermates. The hampered wound closure was accompanied by decreased levels of epidermal growth factor (EGF) and persistent inflammation, characterized by infiltrates of immune cells and elevated levels of pro-inflammatory markers in the wounds. Hyperplastic mucosal lymphatics did not enhance the healing process after tooth extraction in K14-VEGFC mice. The findings indicate that initial mucosal lymphatics play a major role in the initial phase of the oral wound healing process.

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.

Combinatorial effects of hydroxyapatite and Tualang honey on medication-related osteonecrosis of the jaw (MRONJ): An in vitro study

BackgroundMedication-related osteonecrosis of the jaw (MRONJ) is a severe complication associated with prolonged bisphosphonate therapy. Increasing evidence shows that mucosal damage plays an important role in the pathogenesis of MRONJ. This study investigates the combinatorial effects of hydroxyapatite with Tualang honey on cell viability and wound healing in MRONJ. Materials and methodsThe incorporation of Tualang honey into hydroxyapatite was assessed using Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and field emission scanning electron-energy dispersive X-ray analysis microscopy (FESEM-EDX). The effect of hydroxyapatite combined with Tualang honey on cell viability was determined by WST-1 assay and wound healing was assessed by scratch assay. ResultsThe incorporation of Tualang honey into hydroxyapatite altered the functional groups, structure, size, morphology, and components of the crystal as evidenced by FTIR, XRD and FESEM-EDX analysis. High concentrations of pamidronic acid inhibit oral fibroblast viability and wound healing. Low and high concentrations of hydroxyapatite demonstrate non-toxicity towards fibroblast cells. Furthermore, hydroxyapatite reversed the action of pamidronic acid on the cells; it increased fibroblast viability but did not close the wound. Tualang honey promotes fibroblast viability and wound closure. However, the addition of Tualang honey is unable to overcome the inhibitory effects of pamidronic acid on fibroblasts. The addition of Tualang honey and hydroxyapatite improved the cell viability and accelerated wound closure of fibroblast exposed to pamidronic acid. ConclusionThese findings demonstrated that the combination treatment protects oral fibroblasts by preventing bisphosphonate toxicity.

From Short Circuit to Completed Circuit: Conductive Hydrogel Facilitating Oral Wound Healing (Adv. Healthcare Mater. 15/2024)

From Short Circuit to Completed Circuit: Conductive Hydrogel Facilitating Oral Wound Healing (Adv. Healthcare Mater. 15/2024)

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.

Angiogenic potential in periodontal stem cells from upper and lower jaw: A pilot study.

Teeth and supporting oral tissues are attractive and accessible sources of stem cells. Periodontal ligament stem cells (PDLSC) are readily isolated from extracted third molars, and exhibit the ability to self-renew and differentiate into multiple mesodermal cell fates. Clinical experience suggests that the exact location of periodontal defects affects the oral bone remodeling and wound healing. Compared to the mandible, the maxilla heals quicker and more efficiently. Angiogenesis is key in tissue regeneration including dental tissues, yet few studies focus on the angiogenic potential of PDLSC, none of which considered the differences between upper and lower jaw PDLSC (u-PDLSC and l-PDLSC, respectively). Here we studied the angiogenic potential of u-PDLSC and l-PDLSC and compared the results to well-established mesenchymal stem cells (MSC). Cells were characterized in terms of surface markers, proliferation, and vascular endothelial growth factor (VEGF) secretion, and angiogenic assays were performed. Newly formed capillaries were stained with CD31, and their expression of platelet endothelial cell adhesion molecule (PECAM-1), angiopoietin 2 (ANGPT2), and vascular endothelial growth factor receptor 1 and 2 (VEGFR-1, VEGFR-2) were measured. Periodontal stem cells from the upper jaw showed a higher proliferation capacity, secreted more VEGF, and formed capillary networks faster and denser than l-PDLSC. Gene expression of angiogenesis-related genes was significantly higher in u-PDLSC than in l-PDLSC or MSC, given that culture conditions were suitable. The oral cavity is a valuable source of stem cells, particularly PDLSC, which are promising for oral tissue engineering due to their robust growth, lifelong accessibility, low immunogenicity, and strong differentiation potential. Notably, u-PDLSC exhibit higher VEGF secretion and accelerate capillary formation compared to l-PDLSC or MSC. This study suggests a potential molecular mechanism in capillary formation, emphasizing the significance of precise location isolation of PDLSC.

Oral ulcer treatment using human tonsil-derived mesenchymal stem cells encapsulated in trimethyl chitosan hydrogel: an animal model study

BackgroundOral ulcers are a common side effect of chemotherapy and affect patients’ quality of life. While stem cell transplantation is a potential treatment for oral ulcers, its efficacy is limited as the stem cells tend to remain in the affected area for a short time. This study aims to develop a treatment for oral ulcers by using trimethyl chitosan (TMC) hydrogel with human tonsil-derived stem cells (hTMSCs) to increase the therapeutic effect of stem cells and investigate their effectiveness.MethodsAnimals were divided into four experimental groups: Control, TMC hydrogel, hTMSCs, and hTMSCs loaded in TMC hydrogel (Hydrogel + hTMSCs) (each n = 8). Oral ulcers were chemically induced by anesthetizing the rats followed by injection of dilute acetic acid in the right buccal mucosa. After confirming the presence of oral ulcers in the animals, a single subcutaneous injection of 100 µL of each treatment was applied to the ulcer area. Histological analyses were performed to measure inflammatory cells, oral mucosal thickness, and fibrosis levels. The expression level of inflammatory cytokines was also measured using RT-PCR to gauge therapeutic the effect.ResultsThe ulcer size was significantly reduced in the TMC hydrogel + hTMSCs group compared to the control group. The stem cells in the tissue were only observed until Day 3 in the hTMSCs treated group, while the injected stem cells in the TMC Hydrogel + hTMSCs group were still present until day 7. Cytokine analysis related to the inflammatory response in the tissue confirmed that the TMC Hydrogel + hTMSCs treated group demonstrated superior wound healing compared to other experimental groups.ConclusionThis study has shown that the adhesion and viability of current stem cell therapies can be resolved by utilizing a hydrogel prepared with TMC and combining it with hTMSCs. The combined treatment can promote rapid healing of oral cavity wounds by enhancing anti-inflammatory effects and expediting wound healing. Therefore, hTMSC loaded in TMC hydrogel was the most effective wound-healing approach among all four treatment groups prolonging stem cell survival. However, further research is necessary to minimize the initial inflammatory response of biomaterials and assess the safety and long-term effects for potential clinical applications.