Enhanced epithelial gap closure and increased angiogenesis in wounds of diabetic mice treated with adult murine bone marrow stromal progenitor cells

The direct application of bone marrow (BM) can accelerate the healing of chronic wounds. We hypothesized that this effect is due to the presence of stromal progenitor cells (SPCs) found within whole BM preparations. To test this hypothesis, we isolated adult murine SPCs from whole BM and examined their ability to enhance impaired wound healing compared with ficoll separated BM cells in the diabetic (db/db) mouse model. SPCs significantly enhanced reepithelialization, granulation tissue formation, and neovascularization compared with control wounds treated with BM or PBS alone. Higher frequencies of donor SPC cells compared with donor BM cells were observed in treated wounds at 7 days. Transdifferentiation into GFP-positive mature endothelial cells was not observed. These observations suggest that SPCs improve wound healing through indirect mechanisms which lead to enhanced vascularization rather than through direct participation and incorporation into tissue. We conclude that topical application of BM-derived SPCs may represent an effective strategy for the treatment of chronic diabetic wounds.     

Alteration of Smad3 signaling in ischemic rabbit dermal ulcer wounds

Impaired reepithelialization is a hallmark of chronic, ischemic wounds; however, the pathogenesis of the delayed reepithelialization in these wounds remains poorly understood. Transforming growth factor beta is involved in both the normal and hypoxic wound-healing response and exogenous overexpression of Smad3, which has been known to accelerate reepithelialization. Recently, it was shown in the rabbit ear dermal ulcer model that Ad-Smad3 injection enhanced reepithelialization and granulation tissue formation suggesting a positive effect of Smad3 on wound healing. However, little is known about the role of Smad3 in the ischemic wound healing process. In this study, we examined the effect of Smad3 in an ischemic wound model. Ad-Smad3 or Ad-LacZ (10(8) pfu/wound) was injected into either ear of white New Zealand rabbits. Twenty-four hours later, these ears were rendered ischemic using an established model, and four 7 mm full-thickness punch wounds were made on each ear. Histological evaluation showed a significant increase in reepithelialization parameters in Ad-Smad3-transfected wounds (p<0.01). In contrast, granulation tissue parameters were not affected by Smad3 in ischemia. Smad4 and Smad7 mRNA-expression was not affected by Smad3 overexpression. Connective tissue growth factor protein was up-regulated under ischemic conditions but was unaffected by Smad3 transfection in both ischemic and nonischemic wounds. Our results suggest an enhancing effect of Smad3 on reepithelialization in an ischemic wound model that, in turn, might provide novel therapeutic options. Furthermore, the lack of alteration of Smad-dependent intermediates by Smad3 overexpression suggests the activation of Smad-independent pathways in ischemia.     

012Microvascular Endothelial Cell Migration in Scaffolds of Electrospun Collagen

Introduction:  Chronic, nonhealing wounds are often observed in tissues with poor oxygen supply. Impaired reepithelialization is a hallmark of these wounds; however, the pathogenesis of the retarded reepithelialization in chronic, ischemic wounds remains poorly understood. Transforming Growth Factor beta (TGF‐beta) is involved in both normal and hypoxic wound healing response and exogenous overexpression of Smad3, a TGF‐beta signaling intermediate, has been known to accelerate reepithelialization. In a recent study, Ad‐Smad3 injection in the rabbit ear dermal ulcer model showed enhanced reepithelialization and granulation tissue area suggesting a positive effect of Smad3 on wound healing. However, little is known about the role of Smad3 in the ischemic wound healing process. In this study we examined the effect of Smad3 in an ischemic wound model.
Methods:  Ad‐Smad3 or LacZ (10⁸ pfu/wound) empty vector was injected in either ear of White New Zealand Rabbits. Twenty‐four hours later, these ears were rendered ischemic using an established model and four 7‐mm full‐thickness punch wounds were made on each ear.
Results:  Histological evaluation showed a highly significant increase in reepithelialization, epithelial ingrowth and percentage of epithelialization in Ad‐Smad3 transfected wounds versus ischemic wounds transfected with LacZ‐empty vector (p < 0.01).
Conclusion:  Our data confirm the enhancing effect of Smad3 on reepithelialization in an ischemic wound model. The deficiency in reepithelialization, as evident in chronic ischemic wounds, could thus be ameliorated by excess Smad3. Therapeutic interventions using overexpressed Smad3 may improve wound healing through accelerated epithelialization in chronic wounds.     

Cell suspension cultures of allogenic keratinocytes are efficient carriers for ex vivo gene transfer and accelerate the healing of full-thickness skin wounds by overexpression of human epidermal growth factor

The concept of using growth factor therapy to induce wound repair has been endorsed in studies that show reduced growth factors in wound fluid from chronic and aged wounds. In this study, we used cell suspensions of allogenic keratinocytes as gene-delivery vehicles for human epidermal growth factor (hEGF) and analyzed their impact on wound repair in a porcine wound-healing model. Full-thickness wounds were created on the backs of six Yorkshire pigs and covered with a wound chamber to create a wet wound-healing environment. First, 5 x 10(5) allogenic, autogenic, or mixed keratinocytes were transplanted into wounds and healing parameters were analyzed. Second, we measured long-term reepithelialization and contraction rates from day 8 until day 35. In the third experiment, allogenic keratinocytes were transfected with an hEGF-expressing plasmid pCEP-hEGF and transplanted in full-thickness wounds to improve repair. Wounds treated with autogenic, allogenic, or mixed keratinocytes showed a significantly higher rate of reepithelialization relative to saline-treated control wounds. Repetitive biopsies indicated that the use of allogenic keratinocytes did not lead to long-term wound breakdown. Wounds treated with hEGF-expressing allogenic keratinocytes reepithelialized faster than wounds treated with allogenic keratinocytes or control wounds. With a peak hEGF expression of 920.8 pg/mL, hEGF was detectable until day 5 after transplantation compared with minimal hEGF expression in control wounds. This study shows that allogenic keratinocytes can serve as efficient gene transfer vehicles for ex vivo growth factor delivery to full-thickness wounds and overexpression of hEGF further improves reepithelialization rates.     

Recombinant adenoviral mediated gene transfer in ischemic impaired wound healing

Chronic nonhealing wounds represent a large clinical problem resulting in severe disabilities and large healthcare expenditures. Despite the scope of this problem, effective new therapies are lacking. The deficiency of growth factors in chronic wounds has brought attention to the topical application of growth factors, but initial clinical trials have resulted in only modest improvements in healing despite large, repetitive doses. The modest improvement in healing observed in these trials show that growth factors can improve chronic wound healing, but a better means of growth factor delivery is needed. We hypothesized that gene therapy using a recombinant adenoviral vector could be used to induce transgene production directly by cells in the wound. An adenovirus containing the beta-galactosidase reporter transgene (Ad-LacZ) was used in the ischemic rabbit ear model to test this hypothesis. Ad-LacZ resulted in efficient transgene delivery to cells participating in the wound healing response, with expression up to 2 weeks. However, wound reepithelialization was impaired in Ad-LacZ treated wounds compared to vehicle control wounds. Adenoviral mediated gene transfer is a promising efficient means of growth factor delivery to chronic wounds. However, selection of the proper transgene with appropriate biologic activity in wound healing may be essential to overcome the potential adverse effects of adenoviral infection.     

Collagenase-2 (MMP-8) and matrilysin-2 (MMP-26) expression in human wounds of different etiologies

Wound healing involves highly controlled events including reepithelialization, neoangiogenesis, and reformation of the stromal compartment. Matrix metalloproteinases (MMPs) are a family of neutral zinc-dependent endopeptidases known to be essential for the wound-healing process. MMP-8 (collagenase-2) is a neutrophil-derived highly effective type I collagenase, recently indicated to be important for acute wound healing. MMP-26 is a more recent and less well-studied member of the MMP family. Our aim was to study the expression of MMP-8 and MMP-26 in human cutaneous wound repair and chronic wounds using histological methods and cell culture. MMP-8 expression was associated with epithelial cells, neutrophils, and other inflammatory cells in chronic human wounds. MMP-26 was prominently expressed in the extracellular compartment of most chronic wounds in close vicinity to the basement membrane area. MMP-26 was also expressed in acute day 1 wounds with declining expression thereafter. In vitro wound experiments showed that both MMP-8 and MMP-26 were expressed by migrating human mucosal keratinocytes. Inhibiting MMP-26 resulted in aberrant keratinocyte migration and proliferation. We conclude that MMP-8 and MMP-26 are differentially expressed in acute and chronic wounds.     

Second-hand cigarette smoke inhibits wound healing of the cornea by stimulating inflammation that delays corneal reepithelialization

Corneal reepithelialization is a key process in preventing abnormal cornea healing and impaired vision. To gain insight into the mechanisms of cigarette smoke-induced corneal epithelial damage, we injured the cornea of mice and exposed the wounds during the healing process to cigarette smoke in a system that mimics second-hand cigarette smoking by humans. Immunolabeling studies showed that in the mice exposed to smoke, fibronectin, an extracellular matrix molecule critical for epithelial cell migration, is not present in the wounded area and that there is an accumulation of neutrophils in the stroma beneath the wound. Furthermore, inflammatory cytokines, such as interleukin-1α, increase after injury in the second-hand-smoke-exposed mice. Localized treatment of the wounds with dexamethasone, an anti-inflammatory agent, resulted in improved healing and infiltration of fewer neutrophils into the wounded area. Depletion of neutrophils with nitrogen mustard or treatment of the wounds with proteinase inhibitors have similar effects to those of dexamethasone. In conclusion, the work presented here shows that second-hand cigarette smoke delays corneal reepithelialization and healing by stimulating both neutrophil attraction to the wound site and degradation of extracellular matrix and adhesion molecules that are important for corneal epithelial cell adhesion and migration.     

Quantitative and reproducible murine model of excisional wound healing

The goal of animal wound healing models is to replicate human physiology and predict therapeutic outcomes. There is currently no model of wound healing in rodents that closely parallels human wound healing. Rodents are attractive candidates for wound healing studies because of their availability, low cost, and ease of handling. However, rodent models have been criticized because the major mechanism of wound closure is contraction, whereas in humans reepithelialization and granulation tissue formation are the major mechanisms involved. This article describes a novel model of wound healing in mice utilizing wound splinting that is accurate, reproducible, minimizes wound contraction, and allows wound healing to occur through the processes of granulation and reepithelialization. Our results show that splinted wounds have an increased amount of granulation tissue deposition as compared to controls, but the rate of reepithelialization is not affected. Thus, this model eliminates wound contraction and allows rodents' wounds to heal by epithelialization and granulation tissue formation. Given these analogies to human wound healing, we believe that this technique is a useful model for the study of wound healing mechanisms and for the evaluation of new therapeutic modalities.     

Molecular and mechanistic validation of delayed healing rat wounds as a model for human chronic wounds

The purpose of this study was to provide molecular and mechanistic evaluation of an ischemic wound model in rats to determine if it is a valid model for human chronic wounds. Compared to acute wounds, human chronic wounds contain markedly elevated levels of proinflammatory cytokines and matrix metalloproteinases, while matrix metalloproteinase inhibitors and growth factor activity are diminished. Accordingly, tissue from ischemic and normal rat wounds were analyzed for cytokine, proteases and growth factor levels. Dorsal full thickness punch wounds were created in rats using a reproducible template. The ischemic wound group (n = 10) had six uniformly placed wounds within a bipedicled dorsal flap. The control group (n = 10) had the same wounds created without elevation of a flap. On postwound days 3, 6 and 13 wounds were excised and analyzed. Protein levels for tumor necrosis factor-alpha were determined with a rat-specific enzyme-linked immunosorbent assay, while mRNA was determined by RNase protection assay. Matrix metalloproteinases and serine protease detection was done using gelatin and casein zymography, respectively. Significant delay in healing was achieved in the ischemic group: 50% healing for control wounds was at 7 days and 11 days for ischemic wounds (p < 0.001). No significant differences between wound groups were found for interleukin-1beta, and mRNA for tumor necrosis factor-alpha and interleukin-1beta. However, at day 13 ischemic wounds contained significantly more tumor necrosis factor-alpha than controls and normal skin (586 +/- 106 pg/biopsy vs. 79 +/- 7 pg/biopsy vs. 52 +/- 2 pg/biopsy; p < 0. 001). Zymography showed substantially greater quantities of matrix metalloproteinase-2, matrix metalloproteinase-9, and serine proteases in ischemic wounds. This model of delayed healing in rats shares many of the key biochemical, molecular and mechanistic characteristics found in human chronic wounds, namely elevated tumor necrosis factor-alpha and protease levels. As such, this model will likely prove to be useful in chronic wound research, particularly in developing novel therapeutics.     

Wound bed preparation: a systematic approach to wound management

The healing process in acute wounds has been extensively studied and the knowledge derived from these studies has often been extrapolated to the care of chronic wounds, on the assumption that nonhealing chronic wounds were simply aberrations of the normal tissue repair process. However, this approach is less than satisfactory, as the chronic wound healing process differs in many important respects from that seen in acute wounds. In chronic wounds, the orderly sequence of events seen in acute wounds becomes disrupted or “stuck” at one or more of the different stages of wound healing. For the normal repair process to resume, the barrier to healing must be identified and removed through application of the correct techniques. It is important, therefore, to understand the molecular events that are involved in the wound healing process in order to select the most appropriate intervention. Wound bed preparation is the management of a wound in order to accelerate endogenous healing or to facilitate the effectiveness of other therapeutic measures. Experts in wound management consider that wound bed preparation is an important concept with significant potential as an educational tool in wound management. This article was developed after a meeting of wound healing experts in June 2002 and is intended to provide an overview of the current status, role, and key elements of wound bed preparation. Readers will be able to examine the following issues; ? the current status of wound bed preparation; ? an analysis of the acute and chronic wound environments; ? how wound healing can take place in these environments; ? the role of wound bed preparation in the clinic; ? the clinical and cellular components of the wound bed preparation concept; ? a detailed analysis of the components of wound bed preparation. (WOUND REP REG 2003;11:1–28)     

Hyperbaric oxygen therapy promotes wound repair in ischemic and hyperglycemic conditions,increasing tissue perfusion and collagen deposition

The treatment of chronic wounds remains inconsistent and empirical. Hyperbaric oxygen therapy (HBOT) is a promising method to improve wound repair but there is still a lack of understanding of its mechanisms of action and its indications are not yet clearly defined. We studied the effects of HBOT in four different wound conditions by inflicting bilateral wounds on the dorsal aspect of the feet of nonischemic or ischemic limbs in normoglycemic or hyperglycemic rats. To create an ischemic condition, arterial resection was performed unilaterally. Forty‐four animals received HBOT five times a week until complete wound closure. Wound repair was compared with 44 rats receiving standard dressing only. HBOT increased blood flow and accelerated wound closure in ischemic and hyperglycemic wounds, most significantly when the two conditions were combined. Wound contraction and reepithelialization were similarly stimulated by HBOT. The acceleration of wound contraction was not associated with increased myofibroblasts expression, nor fibroblast recruitment or higher cell count in the granulation tissue. Of note, we observed a significant increase in collagen deposition in early time points in ischemic wounds receiving HBOT. This data emphasizes that an early application of HBOT might be crucial to its efficacy. We concluded that wounds where ischemia and hyperglycemia are combined, as it is often the case in diabetic patients, have the best chance to benefit from HBOT.     

Topical negative pressure therapy: mechanisms and indications

Topical negative pressure (TNP) therapy has emerged as a high-technology, microprocessor-controlled physical wound-healing modality. Complex effects at the wound-dressing interface following application of a controlled vacuum force have been documented. These include changes on a microscopic, molecular level and on a macroscopic, tissue level: interstitial fluid flow and exudate management, oedema reduction, effects on wound perfusion, protease profiles, growth factor and cytokine expression and cellular activity, all leading to enhanced granulation tissue formation and improved wound-healing parameters. Primary indications for clinical use have been documented and include traumatic wounds, open abdominal wounds, infected sternotomy wounds, wound bed preparation, complex diabetic wounds and skin-graft fixation. Whilst this therapy now forms an essential part of the wound healing armamentarium, extensive clinical trials are recommended to confirm efficacy and delineate its optimum use.     

Intravenous curcumin efficacy on healing and scar formation in rabbit ear wounds under nonischemic,ischemic, and ischemia–reperfusion conditions

Curcumin, a spice found in turmeric, is widely used in alternative medicine for its purported anti‐inflammatory and antioxidant activities. The goal of this study was to test the curcumin efficacy on rabbit ear wounds under nonischemic, ischemic, and ischemia–reperfusion conditions. Previously described models were utilized in 58 New Zealand White rabbits. Immediately before wounding, rabbits were given intravenous crude or pure curcumin (6 μg/kg, 30 μg/kg, or 60 μg/kg) dissolved in 1% ethanol. Specimens were collected at 7–8 days to evaluate the effects on wound healing and at 28 days to evaluate the effects on hypertrophic scarring. Student's t test was applied to screen difference between any treatment and control group, whereas analysis of variance was applied to further analyze for all treatment groups in aggregate in some specific experiments. Treatment with crude curcumin suggested accelerated wound healing that reached significance for reepithelialization in lower and medium doses and granulation tissue formation in lower dose. Purified curcumin became available and was used for all later experiments. Treatment with pure curcumin suggested accelerated wound healing that reached significance for reepithelialization in lower and medium doses and granulation tissue formation in lower dose. Treatment with pure curcumin significantly promoted nonischemic wound healing in a dose–response fashion compared with controls as judged by increased reepithelialization and granulation tissue formation. Improved wound healing was associated with significant decreases in pro‐inflammatory cytokines interleukin (IL)‐1 and IL‐6 as well as the chemokine IL‐8. Curcumin also significantly reduced hypertrophic scarring. The effects of curcumin were examined under conditions of impaired healing including ischemic and ischemia–reperfusion wound healing, and beneficial effects were also seen, although the dose response was less clear. Systemically administrated pure curcumin significantly promotes nonischemic wound healing and reduces hypertrophic scarring. Improvements in wound healing were associated with decreased inflammatory markers in wounds. Further study is needed to optimize dosing in ischemic and ischemia–reperfusion wound healing. In aggregate, the studies strongly support the systemic administration of curcumin to improve wound healing.     

Streptolysin O enhances keratinocyte migration and proliferation and promotes skin organ culture wound healing in vitro

ML-05, a modified form of the hemolytic and cytotoxic bacterial toxin, streptolysin O, is currently being investigated as a treatment for collagen-related disorders such as scleroderma and fibrosis. Furthermore, ML-05 may be effective in promoting wound healing and alleviating the formation of hypertrophic scars and keloids. To investigate the effects of ML-05 on wound-healing processes, in vitro wound-healing scratch assays (using human primary epidermal keratinocytes and dermal fibroblasts) and a human skin organ culture wound model were utilized. ML-05 markedly enhanced keratinocyte migration and proliferation in wound scratch assays. ML-05 did not affect either proliferation or migration of dermal fibroblasts, indicating that ML-05's effects on cell migration/proliferation may be keratinocyte-specific. ML-05 was tested in a dose-dependent manner in a skin organ culture wound model using two different application methods: Through the culture media (dermal exposure) or direct topical treatment of the wound surface. ML-05 was found to accelerate wound healing as measured by reepithelialization, particularly after topical application. Therefore, ML-05 may have potential as a wound-healing agent that promotes reepithelialization through stimulation of keratinocyte migration and proliferation.     

Transforming growth factor-β and its effect on reepithelialization of partial-thickness ear wounds in transgenic mice

Transforming growth factor-beta (TGF-beta) is known to affect nearly every aspect of wound repair. Many of the effects have been extensively investigated; however, the primary effect of endogenously derived TGF-beta on wound reepithelialization is still not completely understood. To examine this, two types of wounds were made on a transgenic mouse over-expressing TGF-beta1. Full-thickness back wounds were made to compare the wound healing process in the presence of compensatory healing mechanisms. Superficial partial-thickness ear wounds involving only the epidermis were made to determine the effect of TGF-beta on reepithelialization. In the partial-thickness ear wounds, at later time points, the transgenic group had smaller epithelial gaps than the wild-type mice. A greater number of actively proliferating cells, as determined by bromodeoxyuridine incorporation, was also found in the transgenic mice at post-injury day 8. These results show that TGF-beta1 stimulates the rate of reepithelialization at later time points in partial-thickness wounds. However, in the full-thickness back wounds, the transgenic animals exhibited a slower reepithelialization rate at all time points and the number of bromodeoxyuridine-positive cells was fewer. Our findings would suggest that the overexpression of TGF-beta1 speeds the rate of wound closure in partial-thickness wounds by promoting keratinocyte migration. In full-thickness wounds, however, the overexpression of TGF-beta1 slows the rate of wound reepithelialization.     

Acceleration of wound healing with topically applied deoxyribonucleosides.

HYPOTHESIS: We hypothesized that a topical mixture of purified deoxyribonucleosides would accelerate wound healing in an open wound model. DESIGN: Full-thickness 6-mm wounds were made on the ears of young adult rabbits. In some experiments, 2 of the 3 arteries in each ear were divided to induce wound ischemia. INTERVENTIONS: An equiweight mixture containing all 4 of the major deoxyribonucleosides (deoxyadenosine, deoxycytidine, deoxyguanosine, and thymidine), designated PN105, or other subgroups of deoxyribonucleosides, or vehicle (saline) was applied to wounds on 1 ear every 2 days, with the other ear serving as a control. MAIN OUTCOME MEASURES: Wound tissue was processed for histological examination 7 days after the initial wounding. Granulation tissue formation and epithelialization were measured in histological cross sections of wounds. RESULTS: Treatment of wounds with PN105 resulted in a 191% increase in total new granulation tissue (P<.05) and a higher incidence of complete wound reepithelialization (67% vs 37%; P<.05) when compared with controls, and a similar increase under ischemic conditions on day 7. Wound ischemia markedly impairs healing; PN 105 treatment resulted in a 242% increase in the amount of new granulation tissue formed by day 7 in ischemic wounds, relative to the appropriate controls (P<.05). All 4 of the major deoxyribonucleosides were required for optimum activity; mixtures with 3 or 2 were less active or inactive. CONCLUSIONS: Topically applied deoxyribonucleosides reproducibly accelerate wound healing in normal and ischemic wounds, and to a magnitude equivalent to that of recombinant growth factors such as platelet-derived growth factor, previously studied in this model. In view of their safety, availability, and efficacy, deoxyribonucleosides hold considerable promise for improving healing of chronic wounds.     

Normal Cutaneous Wound Healing: Clinical Correlation with Cellular and Molecular Events

BACKGROUND: Cutaneous wound healing is a normal physiologic function, observed and described for centuries by those afflicted with wounds and by those caring for them. Recently, tremendous progress has been made in discovering the cellular and molecular mechanisms responsible for wound healing. Counseling patients appropriately and planning future therapeutic interventions in delayed or abnormal wound healing may be improved by a thorough understanding of the relationship between clinical, cellular, and subcellular events occurring during the normal healing process. MATERIALS AND METHODS: A review of the wound healing literature from the past several decades, with a focus on the past 5 to 10 years in particular, along with illustrative case examples from our clinical practice over the past decade. RESULTS: Traditional clinical stages of wounding healing are still relevant, but more overlap between stages is likely a more accurate depiction of events. The role of cells such as platelets, macrophages, leukocytes, fibroblasts, endothelial cells, and keratinocytes is much better known, particularly during the inflammatory and proliferation stages of healing. Molecules such as interferon, integrins, proteoglycans and glycosaminoglycans, matrix metalloproteinases, and other regulatory cytokines play a critical role in the regulation of healing mechanisms. CONCLUSION: Cutaneous wound healing in normal hosts follows an orderly clinical process. The scientific underpinnings for healing are better understood than ever, although much remains to be discovered. Eventually, such improved understanding of cellular and subcellular physiology may lead to new or better forms of therapy for patients with acute, chronic, and surgical skin wounds.     

In vitro binding of matrix metalloproteinase-2 (MMP-2), MMP-9, and bacterial collagenase on collagenous wound dressings

Chronic wounds are characterized by failure in wound-healing response and a delay in healing or nonclosure of the wounds. This results in a high effort in clinical treatment and/or home care. A major difference between acute wounds and chronic wounds is the imbalance of proteinase inhibitors and proteinase activity that regulates the degradation and regeneration of the extracellular matrix proteins. Collagen and collagen/oxidized regenerated cellulose dressings act as a competitive substrate for matrix metalloproteinase-2, matrix metalloproteinase-9, and bacterial collagenase and influence this imbalance positively. Both wound dressings, approved for chronic wound treatment, the bovine collagen type I sponge and the oxidized regenerated cellulose collagen sponge, did not differ significantly in their sorption profiles for all enzymes. In general, binding was enhanced with a longer incubation time. The density of the device and the accessible surface, which can be controlled by the manufacturing process, are the crucial factors for the efficiency of the wound dressing.     

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.