The effect of finger millet feeding on the early responses during the process of wound healing in diabetic rats

In the present study, the role of finger millet feeding on skin antioxidant status, nerve growth factor (NGF) production and wound healing parameters in healing impaired early diabetic rats is reported. Hyperglycemic rats received food containing 50 g/100 g finger millet (FM). Non-diabetic controls and diabetic controls received balanced nutritive diet. Full-thickness excision skin wounds were made after 2 weeks prior feeding of finger millet diet. The rate of wound contraction, and the levels of collagen, hexosamine and uronic acid in the granulation tissue were determined. The skin antioxidant status and lipid peroxide concentration were also monitored during the study. In hyperglycemic rats fed with finger millet diet, the healing process was hastened with an increased rate of wound contraction. Skin levels of glutathione (GSH), ascorbic acid and alpha-tocopherol in alloxan-induced diabetic rat were lower as compared to non-diabetics. Altered activities of superoxide dismutase (SOD) and catalase (CAT) were also recorded in diabetics. Interestingly, thiobarbituric acid reactive substances (TBARS) were elevated in the wound tissues of all the groups, when compared to normal (unwounded) skin tissues. However, in diabetic rats the TBARS levels of both normal and wounded skin tissues were significantly elevated (P < 0.001) when compared with control (non-diabetic) and diabetics fed with FM. Impaired production of NGF, determined by ELISA, in diabetic rats was improved upon FM feeding and further confirmed by immunocytochemical observations reflects the increased expression of NGF in hyperglycemic rats supplemented with FM-enriched diet. Histological and electron microscopical evaluations revealed the epithelialization, increased synthesis of collagen, activation of fibroblasts and mast cells in FM-fed animals. Thus, increased levels of oxidative stress markers accompanied by decreased levels of antioxidants play a vital role in delaying wound healing in diabetic rats. However, FM feeding to the diabetic animals, for 4 weeks, controlled the glucose levels and improved the antioxidant status, which hastened the dermal wound healing process.     

联合应用NGF 和胰岛素对糖尿病大鼠烫伤创面表皮干细胞的影响

目的:通过局部联合应用神经生长因子和胰岛素对糖尿病大鼠深II度烫伤创面表皮干细胞标记物β1整合素和角蛋白19(K19)表达的影响,探讨神经生长因子和胰岛素联合应用于糖尿病烫伤创面治疗后对创面愈合的影响。方法:雄性wistar大鼠腹腔注射链脲佐菌素(STZ)建立糖尿病模型60只,1月后在大鼠背部造成深II度烫伤。将大鼠随机分为糖尿病对照组(B)、胰岛素治疗组(C)、神经生长因子治疗组(D)、神经生长因子联合胰岛素治疗组(E),每组15只。另取15只正常雄性wistar大鼠作为正常对照组(A)。观察伤后3、7、11、15、21 d各组创面愈合情况,检测创面β1整合素和角蛋白19(K19)的表达并计算创面愈合率。结果:E组创面愈合率自第7天起较A、B、C、D组增加,为[(25.33±2.32)%,(P<0.05)];A、C、D组创面愈合率较B组增加分别为[(22.51±1.78)%,(16.68±1.95)%,(18.29±1.70)%,(P<0.05)]。E组整合素β1和角蛋白19(K19)表达自伤后第7至21天各时相点显著增加,(P<0.05)。结论:糖尿病大鼠深II度烫伤创面局部联合应用神经生长因子和胰岛素可促进表皮干细胞的增殖与分化从而加速创面的愈合。     

Curcumin improves wound healing by modulating collagen and decreasing reactive oxygen species

Wound healing consists of an orderly progression of events that re-establish the integrity of the damaged tissue. Several natural products have been shown to accelerate the healing process. The present investigation was undertaken to determine the role of curcumin on changes in collagen characteristics and antioxidant property during cutaneous wound healing in rats. Full-thickness excision wounds were made on the back of rat and curcumin was administered topically. The wound tissues removed on 4th, 8th and 12th day (post-wound) were used to analyse biochemical and pathological changes. Curcumin increased cellular proliferation and collagen synthesis at the wound site, as evidenced by increase in DNA, total protein and type III collagen content of wound tissues. Curcumin treated wounds were found to heal much faster as indicated by improved rates of epithelialisation, wound contraction and increased tensile strength which were also confirmed by histopathological examinations. Curcumin treatment was shown to decrease the levels of lipid peroxides (LPs), while the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), activities were significantly increased exhibiting the antioxidant properties of curcumin in accelerating wound healing. Better maturation and cross linking of collagen were observed in the curcumin treated rats, by increased stability of acid-soluble collagen, aldehyde content, shrinkage temperature and tensile strength. The results clearly substantiate the beneficial effects of the topical application of curcumin in the acceleration of wound healing and its antioxidant effect. Both the authors have contributed equally towards this paper.     

The effect of disodium cromoglycate on the skin wound healing and collagen content in the wounds of rats

The effect of disodium cromoglycate on skin wound healing and collagen formation in the wounds was studied. Disodium cromoglycate (a mast cell stabilizer) administered to the rats in a dose of 2 mg/animal was found to retard wound healing and markedly increased wound surface in all examined days (3rd, 5th, 7th, 10th, 14th day of healing). The mast cell stabilizer injected directly into wounds decreased collagen content, especially on 10th and 14th day of the healing process.     

Efficacy of l-proline administration on the early responses during cutaneous wound healing in rats

Proline (Pro) plays a versatile role in cell metabolism and physiology. Pro and hydroxypro are major imino acids present in collagen, an important connective tissue protein, essential for wound healing, which is a primary response to tissue injury. This study explains the role of l-pro on cutaneous wound healing in rats when administered both topically and orally. Open excision wounds were made on the back of rats, and 200 μl (200 mg) of pro was administered topically and orally once daily to the experimental rats until the wounds healed completely. The control wounds were left untreated. Granulation tissues formed were removed after day 4 and 8 of post excision wounding, and biochemical parameters such as total protein, collagen, hexosamine, and uronic acid were estimated. Levels of enzymatic and non-enzymatic antioxidants such as catalase, superoxide dismutase, glutathione peroxidase, ascorbic acid, and reduced glutathione were evaluated along with lipid peroxides in the granulation tissues. Tensile strength and period of epithelialization were also measured. It was observed that the treated wounds healed very fast as evidenced by augmented rates of epithelialization and wound contraction, which was also confirmed by histological examinations. The results strappingly authenticate the beneficial effects of the topical administration of l-proline in the acceleration of wound healing than the oral administration and control.     

Effect of Ocimum sanctum Linn. on normal and dexamethasone suppressed wound healing

Ethanolic extract of leaves of O. sanctum was investigated for normal wound healing and dexamethasone depressed healing using incision, excision and dead space wound models in albino rats. The extract of O. sanctum significantly increased the wound breaking strength in incision wound model. The extract treated wounds were found to epithelialize faster and the rate of wound contraction was significantly increased as compared to control wounds. Significant increase in wet and dry granulation tissue weight, granulation tissue breaking strength and hydroxyproline content in dead space wound model was observed. The extract significantly decreased the antihealing activities of dexamethasone in all the wound models. The results indicated that the leaf extract promotes wound healing significantly and able to overcome the wound healing suppressing action of dexamethasone. Histological examination of granulation tissue to determine the pattern of lay-down for collagen confirmed the results.     

Efficacy of Butea monosperma on dermal wound healing in rats

Wound healing occurs as a fundamental response to tissue injury. Several natural products have been shown to accelerate the healing process. The present investigation was undertaken to determine the efficacy of topical administration of an alcoholic bark extract of Butea monosperma (B. monosperma) on cutaneous wound healing in rats. Full-thickness excision wounds were made on the back of rat and B. monosperma extract was administered topically. The granulation tissue formed on days 4, 8, 12 and 16 (post-wound) was used to estimate total collagen, hexosamine, protein, DNA and uronic acid. The extract increased cellular proliferation and collagen synthesis at the wound site, as evidenced by increase in DNA, total protein and total collagen content of granulation tissues. The extract treated wounds were found to heal much faster as indicated by improved rates of epithelialization and wound contraction, also confirmed by histopathological examinations. Also, the tensile strength of drug-treated wounds was increased significantly. In addition, we show that B. monosperma possesses antioxidant properties, by its ability to reduce lipid peroxidation. The results clearly substantiate the beneficial effects of the topical application of B. monosperma in the acceleration of wound healing.     

In vivo effect of whole grain flour of finger millet (Eleusine coracana) and kodo millet (Paspalum scrobiculatum) on rat dermal wound healing

Influence of finger millet and kodo millet on rat dermal wound healing was assessed by making a 4 cm2 (2 x 2 cm) excision wound on the shaven back of rats under ether anesthesia. Finger millet or kodo millet flour (300 mg) as aqueous paste was applied topically once daily for 16 days. The granulation tissue formed on day 4, 8 and 12 was used to estimate some biochemical parameters like protein, DNA, collagen and lipid peroxides. There was significant increase in protein and collagen contents and decrease in lipid peroxides. Biophysical parameters like rate of contraction and number of days for epithelialization were also studied. Rate of contraction was 88-90% in kodo millet and finger millet treated rats in comparison to 75% in untreated rats. The number of days for complete closure of wounds was lower for finger millet (13 days) and kodo millet (14 days) treated rats in comparison to untreated (16 days) rats. The results implicate a possible therapeutical role for finger millet and kodo millet in accelerating the process of wound healing.     

Effects of Foeniculum vulgare essential oil compounds,fenchone and limonene,on experimental wound healing

We investigated the wound healing efficacy of the Foeniculum vulgare compounds, fenchone and limonene, using an excisional cutaneous wound model in rats. An excision wound was made on the back of the rat and fenchone and limonene were applied topically to the wounds once daily, separately or together, for 10 days. Tissue sections from the wounds were evaluated for histopathology. The healing potential was assessed by comparison to an untreated control group and an olive oil treated sham group. We scored wound healing based on epidermal regeneration, granulation tissue thickness and angiogenesis. After day 6, wound contraction with limonene was significantly better than for the control group. Ten days after treatment, a significant increase was observed in wound contraction and re-epithelialization in both fenchone and limonene oil treated groups compared to the sham group. Groups treated with fenchone and with fenchone + limonene scored significantly higher than the control group, but the difference was not statistically significant compared to the olive oil treated group. Our findings support the beneficial effects of fenchone and limonene for augmenting wound healing. The anti-inflammatory and antimicrobial activities of fenchone and limonene oil increased collagen synthesis and decreased the number of inflammatory cells during wound healing and may be useful for treating skin wounds.     

Effect of bis [benzyl N'-(indol-3-ylmethylene)-hydrazinecarbodithioato]-zinc(II) derivatives on wound healing in Sprague Dawley rats

Effects of topical application of Bis[benzyl N'-(indol-3-ylmethylene)-hydrazinecarbodithioato]-zinc(II) (BHCZ) on wound healing and histology of healed wound were assessed. Sprague Dawley rats were experimentally induced wound in the posterior neck area. Tween 20 (0.2 ml of 10%) was applied to rats in Group 1 (negative control). Intrasite gel (0.2 ml) was applied topically to rats in Group 2 as reference. BHCZ at the concentrations 0.2 ml of 25, 50 and 100 mg/ml were applied to Group 3, 4 and 5, respectively. Wound dressed with BHCZ significantly healed earlier than those treated with 10% Tween 20. Also wound dressed with 100 mg/ml BHCZ accelerated the rate of wound healing compared to those dressed with intrasite gel and, 25 mg/ml and 50 mg/ml BHCZ. Histological analysis of healed wound with BHCZ showed comparatively less scar width at wound enclosure and the healed wound contained less macrophages and large amount of collagen with angiogenesis compared to wounds dressed with 10% Tween 20. Results of this study showed that wounds dressed with 100 mg/ml of BHCZ significantly enhanced acceleration of the rate of wound healing enclosure, and histology of healed wounds showed comparatively less macrophages and more collagen with angiogenesis.     

Effect of sodium diphenylhydantoin on skin wound healing in rats

This study evaluated the effect of phenytoin (sodium diphenylhydantoin) on skin wound healing in a rat model. The study was divided into two parts. In part I, 20 mul of phenytoin (10 mg/ml) was subcutaneously injected into the 3-cm dorsal full-thickness incisional wounds of 14 rats on postoperative days 0, 3, and 6. Twelve rats that received saline injections were used as the controls. The skin samples were harvested and tested for tensile strength and histology. An additional 12 rats with the same incisional wounds were tested for chemokine gene expressions. In part II, 20 mul of phenytoin (10 mg/ml) was applied topically once a day on a 4 x 4 cm area of the open dorsal wounds of 10 rats. Saline was applied to the wounds of the 10 control group rats. The wounds were measured weekly. The results showed that the average tensile strength of the phenytoin-treated wound was 0.49 +/- 0.08 MPa compared with the control group at 0.02 +/- 0.01 MPa (p < 0.05). The density ratio of chemokine monocyte chemotactic protein (MCP-1) to beta-actin in the phenytoin-treated group was also significantly higher than in the control group (p < 0.05). Histologic analysis of the phenytoin group showed a large amount of fibroblast proliferation, collagen synthesis, and neovascularization. Phenytoin-treated wounds were also smaller at 1 to 6 weeks postoperatively than the control group wounds. The authors conclude that the administration of phenytoin can promote wound healing and significantly increase MCP-1 expression. Phenytoin-treated wounds showed significant increase in collagen deposition and neovascularization, which resulted in an increased wound tensile strength and accelerated healing of both open and closed wounds.     

Curcumin treatment enhances the repair and regeneration of wounds in mice exposed to hemibody gamma-irradiation

Hemibody irradiation in multiple fractionated doses is frequently used for the treatment of various neoplastic disorders. It produces both acute and late effects on the skin and subcutaneous tissues that have profound implications in the healing of surgical wounds. Because of the crucial practical importance of hemibody radiation exposure associated with skin wounds, it is imperative to investigate the efficacy of cost-effective herbal products in the reconstruction of irradiated wounds. Therefore, the effect of pretreatment of curcumin was studied on the healing of excision wound in mice exposed to 2, 4, 6, or 8 Gy of hemibody gamma-radiation. A full-thickness skin wound was created by removing the skin flap of the dorsum of 8- to 10-week-old Swiss albino mice partially (lower half, below the rib cage) exposed to 2, 4, 6, or 8 Gy of gamma-radiation. The progression of wound contraction was monitored periodically by capturing video images of the wound, where the first image of each wound from different groups was obtained 1 day after wounding and that day was considered as day 0. Eight animals were used in each group at each exposure dose for wound contraction studies. Furthermore, the effect of curcumin on mean healing time after exposure of mice to 2, 4, 6, or 8Gy of hemibody gamma-radiation was also evaluated, where eight animals were used in each group at each exposure dose. Collagen, hexosamine, DNA, nitric oxide, and histologic profiles were also evaluated during the course of healing of excision wounds at days 4, 8, and 12 after irradiation treated or not with curcumin before exposure to 0 or 6 Gy of gamma-radiation. Six animals were used in each group at each interval for each biochemical parameter studied, except for histologic evaluations, where four animals were used in each group at each interval. Exposure of mice to different doses of gamma-radiation resulted in a dose-dependent delay in contraction and wound-healing time of excision wound, whereas curcumin pretreatment caused a significant elevation in the rate of wound contraction and a decrease in the mean wound-healing time. Treatment with curcumin before irradiation enhanced the synthesis of collagen, hexosamine, DNA, nitrite, and nitrate, and histologic assessment of wound biopsy specimens revealed improved collagen deposition and an increase in fibroblast and vascular densities. The authors' study demonstrates that curcumin pretreatment has a conducive effect on the irradiated wound and could be a substantial therapeutic strategy for ameliorating radiation-induced delay in wound repair in cases of radiation-induced skin injuries.     

Topical application of plasma fibronectin in full-thickness skin wound healing in rats

Fibronectin (Fn) has been shown to play an important role in wound healing because it appears to be the stimulus for migration of fibroblasts and epidermal cells. The purpose of this study was to investigate whether topical application of plasma Fn (pFn) improves healing of full-thickness skin wounds in rats. A round section of full-thickness skin (diameter of approximately 15 mm) was resected in rats. Animals were then divided into two groups, and wounds were treated topically with a single application of human plasma albumin (control group) or human pFn (FN group). Wound closure rate, hydroxyproline concentration, and histologic features (immunohistochemical staining) were evaluated. The FN group had a significantly higher wound closure rate and hydroxyproline level in the skin than the control group. Histologic analysis of macrophage and fibroblast migration, collagen regeneration, and epithelialization were significantly increased in the FN group compared with the control group. A single topical application of pFn increased the migration of macrophages, myofibroblasts, and fibroblasts. Moreover, further release of transforming growth factor-beta1 from activated fibroblasts, keratinocytes, and epithelial cells may also contribute to the beneficial effect of pFn on wound healing.     

Application of platelet derived growth factor-BB and diabetic wound healing: the relationship with oxidative events

The reasons that cause delay in wound healing in diabetes are a decrease in the level of growth factors secretion, an increase in the destruction of growth factors and in oxidative stress. Platelet derived growth factor (PDGF) is one of the important growth factors that play a role in all phases of wound healing. This study investigates time-dependent effects of topically PDGF-BB administration on oxidative events on the healing of dorsolateral-excisional wounds in diabetic rats. Forty-two female Wistar-albino rats with streptozotocin-induced diabetes were divided into four groups: control group, untreated group, chitosan-treated group, chitosan?+?PDGF-BB-treated group. Two identical full-thickness excisional skin wounds were made under anaesthesia in all rats except for the control group. In the PDGF-BB-treated and chitosan-treated groups, the wounds were treated topically PDGF-BB (7?ng/mL, single daily dose) and blank chitosan gel (equal amount) after wounding, respectively. After these administrations, on day 3 and day 7 of wound healing, rats were sacrificed. Thiobarbituric acid reactive substances, glutathione, nitric oxide, ascorbic acid levels, and superoxide dismutase activity in wound tissues were spectrophotometrically measured. PDGF-BB administration significantly increased TBARS levels and non-enzymatic antioxidant levels in early phase of diabetic wound healing. PDGF-BB dramatically reduced NO_x levels on day 3 and sharply increased NO_x levels on day 7 of wound healing. Consequently, PDGF-BB administration can be effective on oxidative balance in the early phase of diabetic wound healing.     

Wound healing activity of Carica papaya L. in experimentally induced diabetic rats

The aqueous extract of C. papaya fruit (100 mg kg(-1) day(-1) for 10 days) was evaluated for its wound healing activity in streptozotocin-induced diabetic rats using excision and dead space wound models. Extract-treated animals exhibited 77% reduction in the wound area when compared to controls which was 59%. The extract treated wounds were found to epithelize faster as compared to controls. The wet and dry granulation tissue weight and hydroxyproline content increased significantly when compared to controls. The extract exhibited antimicrobial activity against the five organisms tested. Carica papaya promotes significant wound healing in diabetic rats and further evaluation of this activity in humans is suggested.     

Combination of Adrenomedullin with Its Binding Protein Accelerates Cutaneous Wound Healing

Cutaneous wound continues to cause significant morbidity and mortality in the setting of diseases such as diabetes and cardiovascular diseases. Despite advances in wound care management, there is still an unmet medical need exists for efficient therapy for cutaneous wound. Combined treatment of adrenomedullin (AM) and its binding protein-1 (AMBP-1) is protective in various disease conditions. To examine the effect of the combination treatment of AM and AMBP-1 on cutaneous wound healing, full-thickness 2.0-cm diameter circular excision wounds were surgically created on the dorsum of rats, saline (vehicle) or AM/AMBP-1 (96/320 μg kg BW) was topically applied to the wound daily and wound size measured. At days 3, 7, and 14, skin samples were collected from the wound sites. AM/AMBP-1 treated group had significantly smaller wound surface area than the vehicle group over the 14-day time course. At day 3, AM/AMBP-1 promoted neutrophil infiltration (MPO), increased cytokine levels (IL-6 and TNF-α), angiogenesis (CD31, VEGF and TGFβ-1) and cell proliferation (Ki67). By day 7 and 14, AM/AMBP-1 treatment decreased MPO, followed by a rapid resolution of inflammation characterized by a decrease in cytokines. At the matured stage, AM/AMBP-1 treatment increased the alpha smooth muscle actin expression (mature blood vessels) and Masson-Trichrome staining (collagen deposition) along the granulation area, and increased MMP-9 and decreased MMP-2 mRNA expressions. TGFβ-1 mRNA levels in AM/AMBP-1 group were 5.3 times lower than those in the vehicle group. AM/AMBP-1 accelerated wound healing by promoting angiogenesis, collagen deposition and remodeling. Treatment also shortened the days to reach plateau for wound closure. Thus, AM/AMBP-1 may be further developed as a therapeutic for cutaneous wound healing.     

A study of the effect of low-intensity laser radiation of the blue, green, and red spectral regions on the healing of experimental skin wounds in rats

The effect of low-intensity laser radiation of the blue (441.2 nm), green (532 nm), and red (632.8 nm) spectral regions on the healing of experimental skin wounds in rats has been studied. The effect of the traditionally applied laser radiation in the red region has been compared with the effect of laser radiation in the other spectral regions, assuming that, upon irradiation of wounds by lasers emitting in the blue and green regions, a similar effect can be achieved at lower doses. The following parameters characterizing the healing of experimental wounds were used: the functional activity of phagocytes of wound exudates, which was determined by luminol-dependent chemiluminescence, and their number; the antioxidant activity of wound exudates; and the rate of healing, which was determined as a change in the wound area. It was shown that irradiation with laser accelerated the healing of wounds in all cases. The exposure to laser radiations in the red (1.5 J/cm), blue, and green (0.75 J/cm2) spectral regions shortened the time of wound healing from 22 to 17 and 19 days, respectively. The functional activity of leukocytes after the exposure increased on day 5 after the infliction of the wound, whereas in the control it decreased. The superoxide dismutase activity increased in all experimental groups by day 5 after the operation. A maximum increase in the superoxide dismutase activity occurred after the exposure to laser radiation in the red region at a dose of 1.5 J/cm and in the blue and green spectral regions at a dose of 0.75 J/cm2.     

中医病证相符的糖尿病慢性皮肤溃疡大鼠造模方法初探

目的观察不同造模方法致糖尿病大鼠慢性皮肤溃疡创面形态及愈合时间的影响。方法 50只SD大鼠随机分为5组:皮肤缺损组(QS组:剪皮),糖尿病组(DM组:STZ+剪皮),糖尿病加金黄色葡萄球菌组(DMJJ组:STZ+剪皮+金葡菌),糖尿病加激素组(DMJS组:STZ+剪皮+激素注射),糖尿病加激素加异物组(DMYW组:STZ+剪皮+激素注射+异物埋置)。糖尿病模型稳定后每周测量血糖1次,每日称量体重、观察疮面情况、测量创面面积。12 d后处死,石蜡包埋肉芽组织观察其组织病理形态。结果 DMJJ组前5d愈合速度快于其余组(P0.01);DMYW组的愈合时间延长,DMYW组愈合率显著偏低,与其余组比较有统计学意义(P0.01)。造模12 d其余组愈合率无统计学差异,DMYW组愈合率显著低于其余组(P0.01)。结论注射激素大鼠表现出中医"阴证"证型特点,糖尿病加激素注射加异物埋置复合因素造模法能使大鼠创面表现出与临床相似的"阴证"证型特点。     

The effects of topical treatment with acidified nitrite on wound healing in normal and diabetic mice

The effects of the application of a nitric oxide generating acidified nitrite cream comprising sodium nitrite and citric acid, on the healing of incisional wounds in mice, has been investigated. The effects of acidified nitrite on wound healing were critically dependent on the time of application after wounding. Application of acidified nitrite starting on the day of wounding and on consecutive days thereafter significantly inhibited both half time to closure and extent of wound closure. Conversely, application starting on days 1-4 after wounding and on consecutive days thereafter significantly augmented the rate and extent of wound healing. Optimal effects on improving wound healing were observed with cream concentrations of 3.0% (w/v) sodium nitrite and 4.5% (w/v) citric acid. Starting application on day 5 after wounding had no effect on the rate or extent of wound healing. In diabetic Lepr db/db mice, starting treatment at day 2 after wounding, acidified nitrite at 3.0% (w/v) sodium nitrite and 4.5% (w/v) citric acid significantly increased the rate and extent of wound healing. This suggests that acidified nitrite is effective in improving wound healing against a diabetic background. The present data shows that acidified nitrite cream, a clinically effective means of topically delivering nitric oxide, augments the wound healing process and may be of clinical benefit.     

Impaired cutaneous wound healing after sensory denervation in developing rats: effects on cell proliferation and apoptosis

The role of sensory nociceptor nerves in cutaneous wound healing was investigated following full-thickness 4-mm diameter dorsal cutaneous excision wounding of rats on postnatal day 12. In rats with intact innervation, wounds at 3 days contained large numbers of TUNEL- and BRDU-labeled nuclei, consistent with inflammatory cell death and granulation cell proliferation. Wound area and volume decreased through 11 days in concert with a transient appearance of alpha-smooth muscle actin-immunoreactive myofibroblasts, declining rates of cell division, and increased occurrence of apoptotic cells. Sensory denervation by capsaicin injections on postnatal days 2 and 9 reduced calcitonin gene-related peptide-immunoreactive wound innervation persistently by up to 43%. This was associated with increased wound surface area and volume, and delays in scab loss and re-epithelialization. Relative to control wounds, granulation tissue showed increased myofibroblast content at 5-7 days. Capsaicin-treated rats had more BRDU-labeled cells, including myofibroblasts, through day 7. Numbers of TUNEL apoptotic cells per unit area of tissue section were reduced by denervation in both early and late stages of healing. We conclude that partial loss of sensory innervation impairs cutaneous wound healing in developing rats, as manifested by delayed re-epithelialization and failure of the wound area to decrease normally through at least 21 days. This is associated with an abnormally enlarged wound tissue volume resulting from increased granulation cell proliferation without proportionate increases in apoptosis. These findings suggest that nociceptor innervation plays a critical role in wound healing by regulating wound cellularity.