Oral Mucosal Wound Healing Research Articles

Healing of soft tissue lacerations in diabetic-induced rats.

Prevalence and incidence of diabetes are increasing and many dental trauma patients today have diabetes. The implications of delayed wound healing, associated with diabetes mellitus, on oral mucosal wound healing have not been investigated extensively. The aim of this study was to investigate the implications of diabetes mellitus on the cellular, vascular, and fibroblastic changes induced by laceration on the oral mucosa of Wistar rats. Sixteen female Wistar rats were randomly assigned into two groups: 1. Experimental Streptozotocin-induced diabetic group (8 rats). 2. Control group (8 rats). A standardized laceration injury was induced from the corner of the mouth to the mid-check penetrating through dermal and oral mucosal contaminated by saliva. Samples were taken from the rats after sacrificing them on days 1,3,7, and 10. Inflammation was evaluated both qualitatively and quantitatively. Two investigators evaluated samples in a blinded manner. Histology reports indicated delayed wound healing patterns in diabetic rats through days 1, 3, 7, and 10 when compared to controls. Inflammation was also noted to be consistently present more often in diabetic rats. Furthermore, polymorphonuclear cell count was consistently higher in diabetic rats. The results suggest that oral mucosa wound healing is delayed in diabetic Wistar rats compared to non-diabetic rats in terms of wound closure, angiogenesis, and polymorphonuclear cells number. Furthermore, it is also suggested that wound healing is impaired both in the early and late stages of soft tissue wound healing.

Autophagy activation is required for myofibroblast differentiation during healing of oral mucosa.

It is known that periodontal tissues heal faster that skin, and gingiva in particular heal without scar formation. The mechanisms regulating this behaviour are still unclear. The aim of our work was to compare wound healing in oral mucosa and gingiva, investigating the role of α-smooth muscle actin (αSMA)-expressing myofibroblasts and autophagy. Biopsies were obtained from seven patients immediately before and 24hr after vertical releasing incision in oral mucosa and attached gingiva. Both whole biopsies and primary cultures of fibroblasts derived from the same tissues were subjected to immunofluorescence, Western blot and quantitative real-time PCR analyses. We demonstrated that in oral mucosa, characterized by partially fibrotic outcome during repair, the activation of autophagy determined an increase in αSMA and collagen 1a1 production. Conversely, wound healing did not stimulate autophagy in attached gingiva, and subsequently, no increase in myofibroblast differentiation and collagen deposition could be seen, thus justifying its scarless outcome. The elucidation of the differential regulation of autophagy in periodontal tissues and its correlation with myofibroblast differentiation and fibrotic outcome could allow the identification of new molecules involved in periodontal healing and the development of new surgical approaches for periodontal treatment that could improve the outcome of postoperative wounds.

Elevated CD26 Expression by Skin Fibroblasts Distinguishes a Profibrotic Phenotype Involved in Scar Formation Compared to Gingival Fibroblasts

Compared to skin, wound healing in oral mucosa is faster and produces less scarring, but the mechanisms involved are incompletely understood. Studies in mice have linked high expression of CD26 to a profibrotic fibroblast phenotype, but this has not been tested in models more relevant for humans. We hypothesized that CD26 is highly expressed by human skin fibroblasts (SFBLs), and this associates with a profibrotic phenotype distinct from gingival fibroblasts (GFBLs). We compared CD26 expression in human gingiva and skin and in gingival and hypertrophic-like scar-forming skin wound healing in a pig model, and used three-dimensional cultures of human GFBLs and SFBLs. In both humans and pigs, nonwounded skin contained abundantly CD26-positive fibroblasts, whereas in gingiva they were rare. During skin wound healing, CD26-positive cells accumulated over time and persisted in forming hypertrophic-like scars, whereas few CD26-positive cells were present in the regenerated gingival wounds. Cultured human SFBLs displayed significantly higher levels of CD26 than GFBLs. This was associated with an increased expression of profibrotic genes and transforming growth factor-β signaling in SFBLs. The profibrotic phenotype of SFBLs partially depended on expression of CD26, but was independent of its catalytic activity. Thus, a CD26-positive fibroblast population that is abundant in human skin but not in gingiva may drive the profibrotic response leading to excessive scarring.

Effect observation of honey and rb-bFGF in promoting the wound healing of oral mucosa

Objective To explore the efficacy of honey and recombinant bovine basic fibroblast growth factor (rb-bFGF) in promoting wound healing after the surgery of oral mucosa transplantation, and provide evidence for clinical nursing. Methods Eighty patients who underwent oral mucosa transplant surgery were selected and randomly divided into four groups by random number table method, with 20 cases in each group. Group A was the control group, the oral mucosa wounds were exposed to air and kept clean and dry; in group B, the oral mucosa wounds were treated with honey; in group C, the oral mucosa wounds were treated with rb-bFGF gel; and in Group D, the patients were treated with honey combined with rb-bFGF gel. The wound healing level, eating recovery time, and pain level of four groups were evaluated and compared. Results The comparison in wound healing degree among four groups seven days after surgery was statistically significant different (P<0.05) ; the wound healing level of group D was better than group B and C (P<0.05) ; the pain level of patients in four groups was significantly different (P<0.05) ; the pain level of group D was better than other three groups (P<0.05) ; the comparison of eating recovery time among four groups was significantly different (P<0.05) ; the eating recovery time of group D was better than group B and C (P<0.05) . Conclusions Both honey and rb-bFGFcan effectively promote the wound healing of oral mucosa. The combination of honey and rb-bFGF, can shorten the eating recovery time, relieve pain, and promote wound healing, so as to improve patients' quality of life. Key words: Honey; Recombinant bovine basic fibroblast growth factor; Oral mucosa; Wound healing

Benefits of Ethanolic Extract Paste of Noni (Morinda citrifolia L.) Leaves on Oral Mucosa Wound Healing by Examination of Fibroblast Cells

Wound healing is a biological response that occurred following trauma or pathologic condition of the oral mucosa. The wound itself needs proper management so it may heal faster and without complication. One of the indicators of wound healing in oral mucosa is fibroblast cells. In remodelling phase, fibroblast would decrease as they matured into fibrocyte and the collagen fibers has been synthesized. Noni (Morinda citrifolia L.) leaf is traditionally used to heal skin wound. The leaves has chemical compounds that may be useful in wound repair process. This experimental research was performed to examine the effect of Indonesian noni leaves ethanolic extract paste in oral mucosa wound healing by investigating visual wound closure and fibroblast cell count in Wistar rat. Rats were divided into 2 control groups and 4 treatment groups. The paste was formulated in 2.5%, 5%, 10% and 20% concentration, and each of it were applied on oral mucosa wound of treatment group rats. One control groups was given no medication and the other was applied ethanolic extract of noni leaves in 10% gel. The study showed that all paste-treated group has better wound closure (p<0.05) compared to control groups. However, fibroblast cell count did not show any significance among all groups (p=0.143) the cells in paste-treated group in all concentration were lower than control groups. It may be concluded that topical paste formula of noni leaves ethanolic extract promotes oral mucosa wound healing better than gel formula.

Repairmen of the rabbit's oral mucosa by tissue engineering technology

Objective:This experiment proposed to complicate BMMSCs and PLLA/SF scaffolds, to study its repairing ability for rabbit oral mucosa wound, and try to evaluate the most potential mixed proportion of PLLA and SF for tissue engineering. Method:Separating,cultivating and identifying BMMSCs. Observing cell phenotype of BMMSCs after cultivating BMMSCs in P70S30 PLLA/SF scaffold for one week.Observing the structure change of BMMSCs and P70S30PLLA/SF scaffold complexes after oral mucosa transplantation experiment for a week；Comparing the wound healing rate of composite of BMMSCs and PLLA/SF scafold，PLLA/SF scaffold and nature repair. Result:①There wasn't a significant effect of PLLA/SF scaffold on cell phenotype of BMMSCs.②The wounds fused well with the oral mucosa transplanted composite of BMMSCs and P70S30 PLLA/SF scaffold after a week.③The healing rate of composite of BMMSCs and P70S30 scaffold was the highest.The average healing rate of composite of BMMSCs and P70S30 scaffold was 94.8%,whose difference was statistically significant compared with natural healing and pure scaffold(P<0.01). Conclusion:①The complex composed of BMMSCs and PLLA/SF scaffolds has the potential as an ideal scaffold for tissue engineering oral mucosa.②The complex composed of BMMSCs and P70S30 PLLA/SF scaffolds is the most beneficial to wound healing of oral mucosa,and has the greatest potential for constructing tissue engineering oral mucosa.

IL-22 mediates the oral mucosal wound healing via STAT3 in keratinocytes

ObjectiveWounds are common in the oral cavity. During wound healing, several cytokines are released, which are probably helpful in providing wound debridement, removal of damaged tissues and microbes. Most of the target cells of IL-22 are epithelial cells, which play an important role in mucosa immunity. DesignThe function of IL-22 in oral diseases is not well understood. We investigated the expression level of IL-22, collagen I and p-stat3 (Tyr705) via a mice tongue wound model in vivo and detected the effect of IL-22 on the expression of MMP-1, type I collagen and p-stat3 in keratinocytes. ResultsIL-22 and p-stat3 were associated with wound healing, and STAT3 was activated when the keratinocytes or the tongue tissue were stimulated by IL-22. In addition, IL-22 could mediate gene expression involved in wounds involving keratinocytes, such as type I collagen and MMP-1, which may contribute to scarless healing. ConclusionOur study suggests that IL-22 mediates wound healing via STAT3 in keratinocytes. This study reveals a new role for IL-22 in mediating wound healing.

The effect of Tumor Necrosis Factor alpha inhibitor on wound healing of oral mucosa in induced diabetic rats

Background and objective: Impaired wound healing is a major complication of diabetes mellitus. This study was carried out to determine the healing process of oral mucosa in diabetic rats and the role of systemic tumor necrosis factor alpha inhibitor (infliximab). Methods: Thirty eight male rats were divided into two groups, the normoglycemic group (11 rats), and diabetic group (27 rats) that were rendered diabetic by alloxan injection. Two months later, wound was created in the lateral side of the tongue for both groups. The diabetic group was then subdivided into two subgroups, 14 rats received 5mg/kg infliximab subcutaneous injection at the day of wound creation while the other 13 rats received saline injection. After 7 days, biopsies of the tongue were collected and subjected to histological and histochemical procedure. Results: Histological examinations showed delayed healing in the diabetic group with persistence of epithelial discontinuity, large amount of granulation tissue and destruction of the underlying muscle fibers. In the subgroup injected with infliximab, reepitheliazation of the wound was demonstrated with well arranged underlying collagen fibers. Using PAS stain, diabetic group revealed a dramatically high amount of PAS positive precipitants in the lamina properia, especially in the wall of the blood vessels, while with infliximab injection, the PAS+ve precipitants were more prominent than normoglycemic group but less than diabetic group without infliximab. Conclusion: These findings suggest that infliximab accelerated mucosal wound healing in the diabetic rats with the formation of well organized connective tissue.

Effect of Topical Rambutan Honey Pharmaceutical Grade on Oral Mucosa Wound Healing Based on Tissue Wound Closure and Fibroblasts Proliferation in vivo

Effect of Topical Rambutan Honey Pharmaceutical Grade on Oral Mucosa Wound Healing Based on Tissue Wound Closure and Fibroblasts Proliferation in vivo

Ekstrak daun mangrove (A.marina)mempercepat kesembuhanulkus traumatikus (Extract of mangrove leaf (A.marina) accelerates the healing of traumatic ulcer)

Mangrove leaf (Avicennia marina) has a role in wound healing process, but its effect in wound healing in oral mucosa has not been researched yet. This study aimed to prove the effect of A.marina extract against traumatic ulcer and itseffective concentration in traumatic ulcer healing. The subjects of this research are 25 wistar rats that were randomized into 5 different groups; K0 control, K1 were given hyaluronic acid, P1 were given extract of A.marina10%, P2 were given extract of A.marina 20%, and P3 were given extract of A.marina 40%. After the subjects werewounded using amalgam stopper that has been heated before, they were given topical application once daily untilseven days. The ulcer diameter was measured at the second day and day 8 using caliper digital. The data, analyzedusing Kruskal-Wallis test showed that there’s difference in diameters between two groups (p&lt;0.05). The averagediameter differences of traumatic ulcer among rats are K0 = 0.5700 mm, K1 = 0.8380 mm, P1 = 0.7240 mm, P2 =0.8440 mm, and P3 = 0.9500 mm. It was concluded that A.marina extract of 10%, 20% and 40% concentrations haveeffect in the healing of traumatic ulcer, and 40% is the most effective concentration against traumatic ulcer.

Biochemical and biomechanical assessment of effects of L-carnitine on oral mucosal wounds.

The present study aimed to investigate the oral mucosal wound healing potential of L-carnitine in a rat model. Twenty-four Wistar-albino rats were divided into 4 groups: control group (group I), L-carnitine groups (100 and 200 mg/kg/day, intraperitoneally) (groups II and III), and vitamin E group (100 mg/kg/day, intraperitoneally) (group IV). A 1.5-cm linear incision was created on the buccal mucosa of each rat and was left to heal by secondary intention. On the tenth day, rats were anesthetized and sacrificed. The tensile strength of wound was measured with a tensiometer. Hydroxyproline (HYP) and malondialdehyde (MDA) levels in wound were assayed by spectrophotometry. Results were statistically analyzed using a one-way ANOVA analysis (p ≤ 0.001). In the analysis of tissue samples, there was a statistically significant decrease in MDA levels in group II (p < 0.01) and group IV (p < 0.001). Wound tension strength that was seen in groups II (57.88 %) and IV (48.71 %) was better than group III (33.39 %). Hydroxyproline levels in group II (46.98 ± 1.37) was higher than groups III (29.40 ± 1.64) and IV (38.83 ± 1.41). Although there was a tendency toward faster healing in the groups receiving L-carnitine, it may have a dose-related positive effect for wound healing. With the advantages of having positive effects on wound healing, being a natural substance in the body, being easy to procure, and having a practical usage, L-carnitine may be clinically feasible for human oral mucosal wounds.

21. Inflammation, wound healing, and periodontal disease

In separate past studies, higher inflammatory responses have been associated with the pathogenesis of periodontal disease (Periodontitis) and delayed wound healing in oral mucosa. The relationship between these factors is yet to be investigated. Using a standardized model of wound healing, this study objectively examined differences in oral mucosal healing rates and local tissue inflammation in response to wounding between individuals with Periodontitis and healthy controls. This study involved 20 systemically healthy, non-smoking, adult male participants (24–45 years); 10 individuals with untreated periodontitis and 10 healthy age-matched controls. Three excisional wounds were placed on the hard palate under local anesthesia, and were standardized for size, location, depth, and time of placement. Oral mucosal healing rates were determined using daily videographs. Tissue was biopsied at 0 h, 6 h and 24 h post-wounding and analyzed for inflammation using real-time PCR. It was found that wound healing in systemically healthy young men with periodontitis is the same as healing in men without periodontitis in an unaffected area of the mouth. Local tissue inflammation at baseline and after wounding (6 h and 24 h) also did not differ between groups. This suggests that periodontal disease and its associated inflammation, even when untreated, does not affect healing in unaffected oral tissues. These results have direct clinical implications on the timing and management of surgical procedures in patients with untreated Periodontitis.

Effectiveness of Noni (Morinda citrifolia L.) Leaves Extract Gel as Standardized Traditional Medicine to Accelerate Oral Mucosa Wound Healing on Wistar Rats

Effectiveness of Noni (Morinda citrifolia L.) Leaves Extract Gel as Standardized Traditional Medicine to Accelerate Oral Mucosa Wound Healing on Wistar Rats

Biology of soft tissue wound healing and regeneration – Consensus Report of Group 1 of the 10th European Workshop on Periodontology

The scope of this consensus was to review the biological processes of soft tissue wound healing in the oral cavity and to histologically evaluate soft tissue healing in clinical and pre-clinical models. To review the current knowledge regarding the biological processes of soft tissue wound healing at teeth, implants and on the edentulous ridge. Furthermore, to review soft tissue wound healing at these sites, when using barrier membranes, growth and differentiation factors and soft tissue substitutes. Searches of the literature with respect to recessions at teeth and soft tissue deficiencies at implants, augmentation of the area of keratinized tissue and soft tissue volume were conducted. The available evidence was collected, categorized and summarized. Oral mucosal and skin wound healing follow a similar pattern of the four phases of haemostasis, inflammation, proliferation and maturation/matrix remodelling. The soft connective tissue determines the characteristics of the overlaying oral epithelium. Within 7-14 days, epithelial healing of surgical wounds at teeth is completed. Soft tissue healing following surgery at implants requires 6-8 weeks for maturation. The resulting tissue resembles scar tissue. Well-designed pre-clinical studies providing histological data have been reported describing soft tissue wound healing, when using barrier membranes, growth and differentiation factors and soft tissue substitutes. Few controlled clinical studies with low numbers of patients are available for some of the treatments reviewed at teeth. Whereas, histological new attachment has been demonstrated in pre-clinical studies resulting from some of the treatments reviewed, human histological data commonly report a lack of new attachment but rather long junctional epithelial attachment and connective tissue adhesion. Regarding soft tissue healing at implants human data are very scarce. Oral soft tissue healing at teeth, implants and the edentulous ridge follows the same phases as skin wound healing. Histological studies in humans have not reported new attachment formation at teeth for the indications studied. Human histological data of soft tissue wound healing at implants are limited. The use of barriers membranes, growth and differentiation factors and soft tissue substitutes for the treatment of localized gingival/mucosal recessions, insufficient amount of keratinized tissue and insufficient soft tissue volume is at a developing stage.

Human Gingival Fibroblasts Display a Non-Fibrotic Phenotype Distinct from Skin Fibroblasts in Three-Dimensional Cultures

Scar formation following skin injury can be a major psychosocial and physiological problem. However, the mechanisms of scar formation are still not completely understood. Previous studies have shown that wound healing in oral mucosa is faster, associates with a reduced inflammatory response and results to significantly reduced scar formation compared with skin wounds. In the present study, we hypothesized that oral mucosal fibroblasts from human gingiva are inherently distinct from fibroblasts from breast and abdominal skin, two areas prone to excessive scar formation, which may contribute to the preferential wound healing outcome in gingiva. To this end, we compared the phenotype of human gingival and skin fibroblasts cultured in in vivo-like three-dimensional (3D) cultures that mimic the cells' natural extracellular matrix (ECM) niche. To establish 3D cultures, five parallel fibroblast lines from human gingiva (GFBLs) and breast skin (SFBLs) were seeded in high density, and cultured for up to 21 days in serum and ascorbic acid containing medium to induce expression of wound-healing transcriptome and ECM deposition. Cell proliferation, morphology, phenotype and expression of wound healing and scar related genes were analyzed by real-time RT-PCR, Western blotting and immunocytochemical methods. The expression of a set of genes was also studied in three parallel lines of human abdominal SFBLs. Findings showed that GFBLs displayed morphologically distinct organization of the 3D cultures and proliferated faster than SFBLs. GFBLs expressed elevated levels of molecules involved in regulation of inflammation and ECM remodeling (MMPs) while SFBLs showed significantly higher expression of TGF-β signaling, ECM and myofibroblast and cell contractility-related genes. Thus, GFBLs display an inherent phenotype conducive for fast resolution of inflammation and ECM remodeling, characteristic for scar-free wound healing, while SFBLs have a profibrotic, scar-prone phenotype.

Zoledronic acid impairs re-epithelialization through down-regulation of integrin αvβ6 and transforming growth factor beta signalling in a three-dimensional in vitro wound healing model

This study examined the negative effects of zoledronic acid on the re-epithelialization of oral mucosa in a three-dimensional in vitro oral mucosa wound healing model. A living oral mucosa equivalent was constructed by seeding a mixture of primary human oral keratinocytes and fibroblasts, at a cell density of 1.5×105cm2 each, onto human cadaver dermis. This was cultured in a submerged condition in 1.2mM Ca2+ EpiLife for 5 days, and then in an air–liquid interface for 14 days. The equivalent was wounded by excising a linear 2-mm-wide epithelial layer on day 8 and subsequently incubated with 10μM zoledronic acid for an additional 11 days. Histological and immunohistochemical observations revealed zoledronic acid to significantly suppress the epithelial thickness and Ki-67-labelling index. Zoledronic acid also abolished integrin αvβ6 expression, implying impaired keratinocyte migration. Zoledronic acid did not attenuate the total transforming growth factor beta 1 (TGF-β1) production into the supernatant, but down-regulated TGF-β receptor types I and II expression and Smad3 phosphorylation, as was also confirmed by immunofluorescence microscopy. This study therefore showed zoledronic acid to abrogate integrin αvβ6 expression, cause the down-regulation of TGF-β/Smad signalling in oral keratinocytes, and impair re-epithelialization, suggesting compromised oral mucosa homeostasis in patients receiving zoledronic acid.

Investigation of the effects of local glutathione and chitosan administration on incisional oral mucosal wound healing in rabbits

The aim of the present study was to investigate the effects of local glutathione (GSH) and chitosan applications on the oxidant events and histological changes that occur, during healing processes in rabbits with incisional intraoral mucosal wounds. For this purpose, discs containing glutathione and chitosan (1:1) were prepared and their physicochemical characteristics were evaluated. New Zealand white rabbits were used in in vivo studies. A standard incision was applied to the oral mucosa of rabbits. The rabbits were divided into four groups, being: an untreated incisional group (n=6), a group treated with discs containing GSH+chitosan (n=6), a group treated with discs containing solely chitosan (n=5) and a group treated with discs containing solely GSH (n=5). The levels of malondialdehyde (MDA), glutathione and nitric oxide (NOx) in the oral wound tissues were measured on the fifth day after the injury. Histological changes in the wound tissues were also investigated. The tissue MDA levels in the group treated with the disc containing GSH+chitosan were found to be lower than those in the other groups. There were no statistically significant differences in terms of tissue GSH and NOx levels between the group treated with the disc comprising GSH+chitosan and the control group that had untreated incision wounds. According to the histological findings, wound healing in the group treated with the disc containing solely chitosan was found to be better than in the other groups. The results of the experiments showed that the local application to the intraoral incision wounds of chitosan+GSH, and chitosan alone, can be effective in the wound healing processes of soft tissues and dental implants.

131. Oral mucosal wound healing: Sex differences and inflammation

Faster dermal wound healing has been reported in women compared to men. Conversely, our laboratory has repeatedly found an advantage in oral mucosal healing rates that favors men, implying that sex differences in healing rates are tissue dependent. Because mucosal tissue appears to heal optimally under conditions of reduced inflammation, this study compared inflammatory responses, following mucosal wounding, between men and women. These data were obtained from previously conducted studies. 404 healthy adults participated (18–35 or 50–88 years; 202 women). Two small excisional wounds were placed on the hard palate under local anesthesia. Healing rates were determined using daily videographs. To assess inflammation, gene expressions for IL-1β, IL-6, and TNF-alpha were determined in wounded tissue, at 6 h or 24 h post-wounding, using real-time PCR. Inflammatory gene expression was elevated in women compared to men at both 6 h (IL-6, TNF-α) and 24 h (IL-1β, IL-6) post-wounding, suggesting that women undergo higher and prolonged inflammation of the mucosa. In both men and women, higher tissue inflammation correlated with slower wound closure. High inflammation in oral mucosa has been associated with slower healing in past studies. Here, women exhibited both higher and prolonged inflammation in oral wounds, suggesting a putative mechanism through which women heal mucosal tissues more slowly than men. A better understanding of such mechanisms would aid in the identification of therapeutic targets to help optimize mucosal healing.

Detrimental dermal wound healing: What can we learn from the oral mucosa?

Wounds in adults are frequently accompanied by scar formation. This scar can become fibrotic due to an imbalance between extracellular matrix (ECM) synthesis and ECM degradation. Oral mucosal wounds, however, heal in an accelerated fashion, displaying minimal scar formation. The exact mechanisms of scarless oral healing are yet to be revealed. This review highlights possible mechanisms involved in the difference between scar-forming dermal vs. scarless oral mucosal wound healing. Differences were found in expression of ECM components, such as procollagen I and tenascin-C. Oral wounds contained fewer immune mediators, blood vessels, and profibrotic mediators but had more bone marrow-derived cells, a higher reepithelialization rate, and faster proliferation of fibroblasts compared with dermal wounds. These results form a basis for further research that should be focused on the relations among ECM, immune cells, growth factors, and fibroblast phenotypes, as understanding scarless oral mucosal healing may ultimately lead to novel therapeutic strategies to prevent fibrotic scars.

Platelet-Rich Fibrin Promotes Periodontal Regeneration and Enhances Alveolar Bone Augmentation

In the present study we have determined the suitability of platelet-rich fibrin (PRF) as a complex scaffold for periodontal tissue regeneration. Replacing PRF with its major component fibrin increased mineralization in alveolar bone progenitors when compared to periodontal progenitors, suggesting that fibrin played a substantial role in PRF-induced osteogenic lineage differentiation. Moreover, there was a 3.6-fold increase in the early osteoblast transcription factor RUNX2 and a 3.1-fold reduction of the mineralization inhibitor MGP as a result of PRF application in alveolar bone progenitors, a trend not observed in periodontal progenitors. Subcutaneous implantation studies revealed that PRF readily integrated with surrounding tissues and was partially replaced with collagen fibers 2 weeks after implantation. Finally, clinical pilot studies in human patients documented an approximately 5 mm elevation of alveolar bone height in tandem with oral mucosal wound healing. Together, these studies suggest that PRF enhances osteogenic lineage differentiation of alveolar bone progenitors more than of periodontal progenitors by augmenting osteoblast differentiation, RUNX2 expression, and mineralized nodule formation via its principal component fibrin. They also document that PRF functions as a complex regenerative scaffold promoting both tissue-specific alveolar bone augmentation and surrounding periodontal soft tissue regeneration via progenitor-specific mechanisms.