Mesenchymal stem cells: Paracrine signaling and differentiation during cutaneous wound repair

Cutaneous wounds persist as a health care crisis in spite of increased understanding of the cellular and molecular responses to injury. Contributing significantly to this crisis is the lack of reliable therapies for treatment of wounds that are slow to heal including chronic wounds and deep dermal wounds that develop hypertrophic scars. This article will review the growing evidence demonstrating the promise of multipotent mesenchymal stem/stromal (MSCs) for the treatment of impaired wound healing. MSCs are often referred to as mesenchymal stem cells despite concerns that these cells are not truly stem cells given the lack of evidence demonstrating self-renewal in vivo. Regardless, abundant evidence demonstrates the therapeutic potential of MSCs for repair and regeneration of damaged tissue due to injury or disease. To date, MSC treatment of acute and chronic wounds results in accelerated wound closure with increased epithelialization, granulation tissue formation and angiogenesis. Although there is evidence for MSC differentiation in the wound, most of the therapeutic effects are likely due to MSCs releasing soluble factors that regulate local cellular responses to cutaneous injury. Important challenges need to be overcome before MSCs can be used effectively to treat wounds that are slow to heal.     

Compromised Wound Healing in Ischemic Type 2 Diabetic Rats

Ischemia is one of the main epidemic factors and characteristics of diabetic chronic wounds, and exerts a profound effect on wound healing. To explore the mechanism of and the cure for diabetic impaired wound healing, we established a type 2 diabetic rat model. We used an 8weeks high fat diet (HFD) feeding regimen followed by multiple injections of streptozotocin (STZ) at a dose of 10mg/kg to induce Wister rat to develop type 2 diabetes. Metabolic characteristics were assessed at the 5th week after the STZ injections to confirm the establishment of diabetes mellitus on the rodent model. A bipedicle flap, with length to width ratio 1.5, was performed on the back of the rat to make the flap area ischemic. Closure of excisional wounds on this bipedicle flap and related physiological and pathological changes were studied using histological, immunohistochemical, real time PCR and protein immunoblot approaches. Our results demonstrated that a combination of HFD feeding and a low dose of STZ is capable of inducing the rats to develop type 2 diabetes with noticeable insulin resistance, persistent hyperglycemia, moderate degree of insulinemia, as well as high serum cholesterol and high triglyceride levels. The excision wounds on the ischemic double pedicle flap showed deteriorative healing features comparing with non-ischemic diabetic wounds, including: delayed healing, exorbitant wound inflammatory response, excessive and prolonged ROS production and excessive production of MMPs. Our study suggested that HFD feeding combined with STZ injection could induce type 2 diabetes in rat. Our ischemic diabetic wound model is suitable for the investigation of human diabetic related wound repair; especically for diabetic chronic wounds.     

Treatment of massive thoracolumbar wounds and vertebral osteomyelitis following scoliosis surgery

Closure of thoracolumbar wounds and vertebral osteomyelitis after scoliosis surgery often proves difficult due to tautness and lack of usable tissue, and the resulting dead space containing metallic fixation devices is predisposed to infections and complications. The authors present their experience with 33 patients in whom massive thoracolumbar wounds and vertebral osteomyelitis developed following scoliosis surgery. Postoperative infection, due to the lack of vascularized tissue and presence of metallic hardware near the wound, is common and extremely counterproductive; within these cavernous wounds lie infected vertebrae, metallic hardware, and bone graft. The use of a modified and extended latissimus dorsi myocutaneous flap to close and supply blood to wounds in the lower thoracic and thoracolumbar areas is described. This surgical approach, predicated on effective débridement along with reconstruction by transposition of vascularized tissue, allows the wound to close and drastically decreases the risk of postoperative infection. Furthermore, for wounds already infected, the procedure allows for closure and increased blood supply to the area, thus giving the wound a much greater ability to heal. For wounds involving the lumbosacral area, the authors combine this with a transposed gluteus maximus muscle flap to obtain coverage over the caudal extent of the wound. In this study, all flaps accomplished their intended purpose: to secure the healing of once-infected wounds and to allow preservation of orthopedic instrumentation and bone graft. Follow-up revealed no flap losses, pseudarthroses, or loss of orthopedic instrumentation in the study group.     

Wet wound healing

Wound treatment in a flexible transparent chamber attached to the perimeter of the wound and containing a liquid has been extensively tested in preclinical experiments in pigs and found to offer several advantages. It protects the wound; the liquid medium or saline in the chamber provides in vivo tissue culture-like conditions; and antibiotics, analgesics, and various molecules can be delivered to the wound through the chamber. The wound chamber causes no injury to the wound itself or to the surrounding intact skin. Topical delivery of, for instance, antibiotics can provide very high concentrations at the wound site and with a favorable direction of the concentration gradient. A series of 28 wounds in 20 patients were treated with a wound chamber containing saline and antibiotics. Most patients had significant comorbidity and had not responded to conservative or surgical management with débridement and delayed primary closure or skin grafts. Six wounds had foreign bodies present; four of these were joint prostheses. Seven patients were on corticosteroids for rheumatoid arthritis, lupus, or chronic obstructive pulmonary disease, and four patients had diabetes. Most patients were treated with the wound chamber in preparation for a delayed skin graft or flap procedure, but one was treated with a wound chamber until the wound healed. Twenty-five of the wounds (89 percent) healed, and five wounds (18 percent) required additional conservative management after the initial chamber treatment and grafting procedure. Of the three wounds that did not heal, one healed after additional chamber treatment, one had a skin graft that did not take, and one required reamputation at a higher level. Antibiotic delivery was less than one intravenous dose daily, which avoided the potential for systemic absorption to toxic levels. Antibiotics such as vancomycin and gentamicin could be used in concentrations of up to 10,000 times the minimal inhibitory concentration. Forty-eight hours after application, 20 percent or more of the original antibiotic concentration was present in the wound chamber fluid. In conclusion, the wound chamber provides a safe, powerful tool in the treatment of difficult infected wounds.     

Zinc, Copper, and Selenium Tissue Levels and Their Relation to Subcutaneous Abscess, Minor Surgery, and Wound Healing in Humans

Trace element involvement in wounds left to heal by secondary intention needs clarification. We have previously reported faster healing of wounds following acute surgery compared with elective excision of pilonidal sinus disease. The effect of topical zinc on the closure of the excisional wounds was mediocre compared with placebo. In contrast, parenteral zinc, copper, and selenium combined appear effective for wound healing in humans. We have investigated zinc, copper, and selenium with respect to (a) impact of acute versus chronic pilonidal sinus and (b) regional concentrations within granulating wounds treated topically with placebo or zinc in 42 (33 males) pilonidal disease patients. Baseline serum and skin concentrations of copper correlated (r _S?=?0.351, p?=?0.033, n?=?37), but not of zinc or selenium. Patients with abscesses had elevated serum C-reactive protein (CRP) and copper levels (+29 %; p?<?0.001) compared with the elective patients consistent with the strong correlation between serum copper and CRP (r _S?=?0.715, p?<?0.0005, n?=?41). Seven days after elective surgery, serum CRP and copper levels were elevated (p?=?0.010) versus preoperative values. The copper concentration in wound edges was higher than in periwound skin (p?<?0.0005) and wound base (p?=?0.010). Selenium levels were increased in wound edge compared to wound base (p?=?0.003). Topical zinc oxide treatment doubled (p?<?0.050) zinc concentrations in the three tissue localizations without concomitant significant changes of copper or selenium levels. In conclusion, copper and selenium are mobilized to injured sites possibly to enhance host defense and early wound healing mechanisms that are complementary to the necessity of zinc for matrix metalloproteinase activity.     

A Novel Model of Chronic Wounds: Importance of Redox Imbalance and Biofilm-Forming Bacteria for Establishment of Chronicity

Chronic wounds have a large impact on health, affecting ∼6.5 M people and costing ∼$25B/year in the US alone [1]. We previously discovered that a genetically modified mouse model displays impaired healing similar to problematic wounds in humans and that sometimes the wounds become chronic. Here we show how and why these impaired wounds become chronic, describe a way whereby we can drive impaired wounds to chronicity at will and propose that the same processes are involved in chronic wound development in humans. We hypothesize that exacerbated levels of oxidative stress are critical for initiation of chronicity. We show that, very early after injury, wounds with impaired healing contain elevated levels of reactive oxygen and nitrogen species and, much like in humans, these levels increase with age. Moreover, the activity of anti-oxidant enzymes is not elevated, leading to buildup of oxidative stress in the wound environment. To induce chronicity, we exacerbated the redox imbalance by further inhibiting the antioxidant enzymes and by infecting the wounds with biofilm-forming bacteria isolated from the chronic wounds that developed naturally in these mice. These wounds do not re-epithelialize, the granulation tissue lacks vascularization and interstitial collagen fibers, they contain an antibiotic-resistant mixed bioflora with biofilm-forming capacity, and they stay open for several weeks. These findings are highly significant because they show for the first time that chronic wounds can be generated in an animal model effectively and consistently. The availability of such a model will significantly propel the field forward because it can be used to develop strategies to regain redox balance that may result in inhibition of biofilm formation and result in restoration of healthy wound tissue. Furthermore, the model can lead to the understanding of other fundamental mechanisms of chronic wound development that can potentially lead to novel therapies.     

Comparison of the effect of bacterial inoculation in musculocutaneous and fasciocutaneous flaps

The skin fascial flap is now recognized as a reliable flap for use in reconstructive surgery. The fasciocutaneous flap has been advocated for coverage of chronic infected wounds after debridement as an alternative to the musculocutaneous flap. Previous experimental and clinical studies have demonstrated the superior resistance of the musculocutaneous flap as compared to the random-pattern flap to bacterial inoculation. A canine model is presented for comparison of the effect of bacterial inoculation in fasciocutaneous and musculocutaneous flaps of similar dimensions. The area of skin necrosis secondary to bacterial inoculation was similar in these two flap types despite greater blood flow and skin oxygen in the fasciocutaneous flap. In a study of closed wound spaces formed by the deep surface of these two flap types, a greater degree of inhibition and elimination of bacterial growth and more collagen deposition are observed in the musculocutaneous wound space than in the fasciocutaneous flap.     

Accelerated healing of full-thickness skin wounds in a wet environment

Full-thickness skin wounds are preferably allowed to heal under controlled hydration dressings such as hydrocolloids. It was hypothesized that a wet (liquid) environment rather than a dry or moist one would accelerate the wound healing process. We compared skin repair by secondary intention in full-thickness skin wounds in wet (saline), moist (hydrocolloid), and dry (gauze) conditions in an established porcine wound healing model. The study included three animals with a total of 70 wounds layered in a standardized fashion on the back of young Yorkshire pigs. Twelve days after wounding, 0 percent of dry, 20 percent of moist, and 86 percent of saline-treated wounds were completely reepithelialized (p values = 0.0046 and 0.027 for saline wounds compared with dry and moist wounds, respectively). The accelerated healing was caused at least in part by faster contraction in wet wounds (p value < 0.005 compared with that of other groups 9 and 12 days after wounding). Development of granulation tissue was faster in moist conditions than it was for dry and wet wounds. The thickness and number of cell layers of the newly formed epidermis were greater in dry and wet wounds than in moist ones. It was concluded that these full-thickness porcine skin wounds healed faster in a wet environment than in a moist one. Dry wounds healed more slowly than moist wounds. The basic mechanisms of skin wound repair were influenced by the treatment modality as demonstrated by the observed differences in granulation tissue formation, reepithelialization, and rate of wound contraction.     

Application of Electron Paramagnetic Resonance (EPR) Oximetry to Monitor Oxygen in Wounds in Diabetic Models

A lack of oxygen is classically described as a major cause of impaired wound healing in diabetic patients. Even if the role of oxygen in the wound healing process is well recognized, measurement of oxygen levels in a wound remains challenging. The purpose of the present study was to assess the value of electron paramagnetic resonance (EPR) oximetry to monitor pO₂ in wounds during the healing process in diabetic mouse models. Kinetics of wound closure were carried out in streptozotocin (STZ)-treated and db/db mice. The pO₂ was followed repeatedly during the healing process by 1 GHz EPR spectroscopy with lithium phthalocyanine (LiPc) crystals used as oxygen sensor in two different wound models: a full-thickness excisional skin wound and a pedicled skin flap. Wound closure kinetics were dramatically slower in 12-week-old db/db compared to control (db/+) mice, whereas kinetics were not statistically different in STZ-treated compared to control mice. At the center of excisional wounds, measurements were highly influenced by atmospheric oxygen early in the healing process. In pedicled flaps, hypoxia was observed early after wounding. While reoxygenation occurred over time in db/+ mice, hypoxia was prolonged in the diabetic db/db model. This observation was consistent with impaired healing and microangiopathies observed using intravital microscopy. In conclusion, EPR oximetry using LiPc crystals as the oxygen sensor is an appropriate technique to follow wound oxygenation in acute and chronic wounds, in normal and diabetic animals. Nevertheless, the technique is limited for measurements in pedicled skin flaps and cannot be applied to excisional wounds in which diffusion of atmospheric oxygen significantly affects the measurements.     

A simplified technique for producing an ischemic wound model

One major obstacle in current diabetic wound research is a lack of an ischemic wound model that can be safely used in diabetic animals. Drugs that work well in non-ischemic wounds may not work in human diabetic wounds because vasculopathy is one major factor that hinders healing of these wounds. We published an article in 2007 describing a rabbit ear ischemic wound model created by a minimally invasive surgical technique. Since then, we have further simplified the procedure for easier operation. On one ear, three small skin incisions were made on the vascular pedicles, 1-2 cm from the ear base. The central artery was ligated and cut along with the nerve. The whole cranial bundle was cut and ligated, leaving only the caudal branch intact. A circumferential subcutaneous tunnel was made through the incisions, to cut subcutaneous tissues, muscles, nerves, and small vessels. The other ear was used as a non-ischemic control. Four wounds were made on the ventral side of each ear. This technique produces 4 ischemic wounds and 4 non-ischemic wounds in one animal for paired comparisons. After surgery, the ischemic ear was cool and cyanotic, and showed reduced movement and a lack of pulse in the ear artery. Skin temperature of the ischemic ear was 1-10 °C lower than that on the normal ear and this difference was maintained for more than one month. Ear tissue high-energy phosphate contents were lower in the ischemic ear than the control ear. Wound healing times were longer in the ischemic ear than in the non-ischemic ear when the same treatment was used. The technique has now been used on more than 80 rabbits in which 23 were diabetic (diabetes time ranging from 2 weeks to 2 years). No single rabbit has developed any surgical complications such as bleeding, infection, or rupture in the skin incisions. The model has many advantages, such as little skin disruption, longer ischemic time, and higher success rate, when compared to many other models. It can be safely used in animals with reduced resistance, and can also be modified to meet different testing requirements.     

Clinical challenges of chronic wounds: searching for an optimal animal model to recapitulate their complexity

The efficient healing of a skin wound is something that most of us take for granted but is essential for surviving day-to-day knocks and cuts, and is absolutely relied on clinically whenever a patient receives surgical intervention. However, the management of a chronic wound – defined as a barrier defect that has not healed in 3 months – has become a major therapeutic challenge throughout the Western world, and it is a problem that will only escalate with the increasing incidence of conditions that impede wound healing, such as diabetes, obesity and vascular disorders. Despite being clinically and molecularly heterogeneous, all chronic wounds are generally assigned to one of three major clinical categories: leg ulcers, diabetic foot ulcers or pressure ulcers. Although we have gleaned much knowledge about the fundamental cellular and molecular mechanisms that underpin healthy, acute wound healing from various animal models, we have learned much less about chronic wound repair pathology from these models. This might largely be because the animal models being used in this field of research have failed to recapitulate the clinical features of chronic wounds. In this Clinical Puzzle article, we discuss the clinical complexity of chronic wounds and describe the best currently available models for investigating chronic wound pathology. We also assess how such models could be optimised to become more useful tools for uncovering pathological mechanisms and potential therapeutic treatments.KEY WORDS: Animal models, Chronic wounds, Diabetic foot ulcer, Ischemia, Pressure ulcer, Venous leg ulcer     

Promotion of wound healing using adipose-derived stem cells in radiation ulcer of a rat model

Background

Wound healing is a complex biologic process that involves the integration of inflammation, mitosis, angiogenesis, synthesis, and remodeling of the extracellular matrix. However, some wounds fail to heal properly and become chronic. Although some simulated chronic wound models have been established, an efficient approach to treat chronic wounds in animal models has not been determined. The aim of this study was to develop a modified rat model simulating the chronic wounds caused by clinical radiation ulcers and examine the treatment of chronic wounds with adipose-derived stem cells.

Results

Sprague–Dawley rats were irradiated with an electron beam, and wounds were created. The rats received treatment with adipose-derived stem cells (ASCs), and a wound-healing assay was performed. The wound sizes after ASC treatment for 3 weeks were significantly smaller compared with the control condition (p < 0.01). Histological observations of the wound edge and immunoblot analysis of the re-epithelialization region both indicated that the treatment with ASCs was associated with the development of new blood vessels. Cell-tracking experiments showed that ASCs were colocalized with endothelial cell markers in ulcerated tissues.

Conclusions

We established a modified rat model of radiation-induced wounds and demonstrated that ASCs accelerate wound-healing.     

Inflammatory microenvironment and tumor necrosis factor alpha as modulators of periostin and CCN2 expression in human non-healing skin wounds and dermal fibroblasts

Non-healing skin wounds remain a significant clinical burden, and in recent years, the regulatory role of matricellular proteins in skin healing has received significant attention. Periostin and CCN2 are both upregulated at day 3 post-wounding in murine skin, where they regulate aspects of the proliferative phase of repair including mesenchymal cell infiltration and myofibroblast differentiation. In this study, we examined 1) the wound phenotype and expression patterns of periostin and CCN2 in non-healing skin wounds in humans and 2) the regulation of their expression in wound fibroblasts by tumor necrosis factor α (TNFα) and transforming growth factor-β1 (TGF-β1). Chronic skin wounds had a pro-inflammatory phenotype, characterized by macrophage infiltration, TNFα immunoreactivity, and neutrophil infiltration. Periostin, but not CCN2, was significantly suppressed in non-healing wound edge tissue at the mRNA and protein level compared with non-involved skin. In vitro, human wound edge fibroblasts populations were still able to proliferate and contract collagen gels. Compared to cells from non-involved skin, periostin and α-SMA mRNA levels increased significantly in the presence of TGF-β1 in wound cells and were significantly decreased by TNFα, but not those of Col1A2 or CCN2. In the presence of both TGF-β1 and TNFα, periostin and α-SMA mRNA levels were significantly reduced compared to TGF-β1 treated wound cells. Effects of TGF-β1 and TNFα on gene expression were also more pronounced in wound edge cells compared to non-involved fibroblasts. We conclude that variations in the expression of periostin and CCN2, are related to an inflammatory microenvironment and the presence of TNFα in human chronic wounds.     

Connexins in wound healing; perspectives in diabetic patients

Skin lesions are common events and we have evolved to rapidly heal them in order to maintain homeostasis and prevent infection and sepsis. Most acute wounds heal without issue, but as we get older our bodies become compromised by poor blood circulation and conditions such as diabetes, leading to slower healing. This can result in stalled or hard-to-heal chronic wounds. Currently about 2% of the Western population develop a chronic wound and this figure will rise as the population ages and diabetes becomes more prevalent [1]. Patient morbidity and quality of life are profoundly altered by chronic wounds [2]. Unfortunately a significant proportion of these chronic wounds fail to respond to conventional treatment and can result in amputation of the lower limb. Life quality and expectancy following amputation is severely reduced. These hard to heal wounds also represent a growing economic burden on Western society with published estimates of costs to healthcare services in the region of $25B annually [3]. There exists a growing need for specific and effective therapeutic agents to improve healing in these wounds. In recent years the gap junction protein Cx43 has been shown to play a pivotal role early on in the acute wound healing process at a number of different levels [4-7]. Conversely, abnormal expression of Cx43 in wound edge keratinocytes was shown to underlie the poor rate of healing in diabetic rats, and targeting its expression with an antisense gel restored normal healing rates [8]. The presence of Cx43 in the wound edge keratinocytes of human chronic wounds has also been reported [9]. Abnormal Cx43 biology may underlie the poor healing of human chronic wounds and be amenable therapeutic intervention [7]. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.     

Scarless skin wound repair in the fetus.

The ability of a fetus to heal without scar formation depends on its gestational age at the time of injury and the size of the wound defect. In general, linear incisions heal without scar until late in gestation whereas excisional wounds heal with scar at an earlier gestational age. The profiles of fetal proteoglycans, collagens, and growth factors are different from those in adult wounds. The less-differentiated state of fetal skin is probably an important characteristic responsible for scarless repair. There is minimal inflammation in fetal wounds. Fetal wounds are characterized by high levels of hyaluronic acid and its stimulator(s) with more rapid, highly organized collagen deposition. The roles of peptide growth factors such as transforming growth factor-beta and basic fibroblast growth factor are less prominent in fetal than in adult wound healing. Platelet-derived growth factor has been detected in scarless fetal skin wounds, but its role is unknown. An understanding of scarless tissue repair has possible clinical application in the modulation of adult fibrotic diseases and abnormal scar-forming conditions.     

The effect of induced biphasic pulsed currents on re-epithelialization of a novel wound healing model

The coordinated migration of keratinocytes is crucial to cutaneous wound healing; failure of keratinocytes to migrate into a wound can lead to chronic non-healing wounds. Keratinocyte migration can be influenced by applied electrical fields. Our aim was to investigate whether keratinocyte migration could be accelerated by applying an induced biphasic pulsed electrical field. We developed two in vitro biological systems models for this purpose: a keratinocyte colony-forming model and a reconstituted skin wound healing model with biphasic pulsed currents. Our in vitro skin models were capable of generating trans-epithelial potentials (TEP) similar to in vivo mammalian skin. Histological examination of the wound healing model also indicated that re-epithelialization occurred in a similar manner to that seen in vivo, although no evidence of a reconstitution of a basement membrane was seen during the 14 days in vitro experimental period. We found that growth of keratinocyte colonies and keratinocyte migration in an in vitro wound bed were not significantly affected by induced short duration biphasic pulsed currents at a frequency of 0.5 Hz of 100 and 200 mV/mm.     

The microvascular pathophysiology of chronic venous insufficiency.

Severe chronic venous insufficiency (CVI) demonstrates as chronic, hard-to-heal wounds of the lower extremity. The wound is the result of poor skin perfusion due to a complex series of pathologic events, often initiated by a deep vein thrombosis (DVT). As years pass, the DVT causes venous valvular damage and incompetence. The calf muscle pump fails to augment venous return, and venous blood pressure is chronically elevated upon standing. Mechanisms that normally prevent the transmission of venous hypertension back upstream to the dermal microcirculation are lost. Early dermal microvascular responses include increased fluid filtration and edema. An inflammatory response induces white cell activation and adhesion. It is thought that activated white cells are trapped in dermal capillaries and increase microvascular permeability. Plasma proteins leak into the tissue space, increasing the edema. Ischemic damage to the epidermis leads to epithelial cell necrosis and ulceration. The ulcer is often slow to heal, due to inadequate perfusion and delivery of substrates required for proper wound healing. Current treatments aim to improve calf pump function, reduce edema, improve perfusion, and enhance wound healing.     

Nerve dependency in scarless fetal wound healing

The human fetus is capable of healing cutaneous wounds without scar up to the third trimester of development This process of tissue repair is more akin to newt limb regeneration than classic adult scar forming wound repair. Regeneration of the newt limb is dependent on neural input in its early stages. This study was an attempt to determine whether a similar dependence on neural input exists for mammalian fetal wounds to heal without scar. The left hind limb of six fetal lambs was denervated during the early second trimester of development (day 55; term = 145 days). Two weeks after denervation, the animals were again exposed to create bilateral incisional and 6-mm-diameter excisional wounds on their innervated right and denervated left lower extremities. Five days after creation of these defects, the wounds were examined for alterations in repair. Four fetal lambs survived, and three were suitable for evaluation. There were marked alterations in wound healing seen after denervation. Excisional wounds on the innervated side contracted and decreased their surface area by 14 percent. In contrast, the denervated wounds not only failed to contract, but increased in size by 60 percent. Changes in the incisional wounds were equally distinctive. Innervated incisional wounds healed completely without scar and had a wound breaking strength comparable to that of normal skin (Table I). In contrast, two of the three denervated incisional wounds dehisced and failed to heal, even in the regions where the skin was approximated by suture. The third denervated incisional wound did heal but with a significant amount of scar. Electron microscopy confirmed this finding by clearly demonstrating thickened and irregular collagen deposition in the extracellular matrix of all the denervated incisional specimens. In summary, like the regenerating newt limb, scarless fetal skin wound repair requires neural stimulation for tissue regeneration to occur. Therefore, in the mammal, the primary regulator for this unique type of tissue repair may have a central neural, rather than a local, tissue origin.     

Embryonic skin development and repair

Fetal cutaneous wounds have the unique ability to completely regenerate wounded skin and heal without scarring. However, adult cutaneous wounds heal via a fibroproliferative response which results in the formation of a scar. Understanding the mechanism(s) of scarless wound healing leads to enormous clinical potential in facilitating an environment conducive to scarless healing in adult cutaneous wounds. This article reviews the embryonic development of the skin and outlines the structural and functional differences in adult and fetal wound healing phenotypes. A review of current developments made towards applying this clinical knowledge to promote scarless healing in adult wounds is addressed.