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Scars are common and intractable consequences after scalded wound healing, while monotherapy of epidermal growth factors does not solve this problem. Maintaining the stability of epidermal growth factors and promoting scarless healing of wounds is paramount. In this study, engineering cellular nanovesicles overexpressing PD-L1 proteins, biomimetic nanocarriers with immunosuppressive efficacy, were successfully prepared to encapsulate epidermal growth factors for maintaining its bioactivity. Remarkably, PD-L1 cellular nanovesicles encapsulating epidermal growth factors (EGF@PDL1 NVs) exerted desired therapeutic effect by attenuating the overactivation of T cell immune response and promoting skin cells migration and proliferation. Hence, EGF@PD-L1 NVs promoted wound healing and prevented scarring in deep second-degree scald treatment, demonstrating a better effect than using individual PD-L1 NVs or EGF. This research proved that EGF@PD-L1 NVs is considered an innovative and thorough therapy of deep second-degree scald.

Objective: The purpose of this meta-analysis was to assess the efficacy and safety of nano-silver dressing combined with recombinant human epidermal growth factor for deep second-degree burns., Methods: PubMed, Web of Science, EMBASE, Cochrane Library and other databases were searched to identify relevant randomised controlled trials., Results: Twelve studies that assessed nano-silver dressing combined with recombinant human epidermal growth factor were identified. Nano-silver dressing combined with recombinant human epidermal growth factor for deep second-degree burns could significantly reduce the duration of wound healing (mean difference -5.68, 95% CI -7.38 - -3.99, P<0.00001), the wound healing rate (risk ratio [RR] 0.34, 95% CI 0.23-0.48, P<0.00001), the rate of scar hyperplasia (RR 0.67, 95% CI 0.54-0.84, P=0.0004), the wound bacterial positive rate (RR 0.50, 95% CI 0.28-0.89, P=0.02), and the adverse reactions rate (RR 0.31, 95% CI 0.16-0.58, P=0.0003)., Conclusion: This comprehensive meta-analysis of the available evidence suggest that the use of nano-silver dressing combined with recombinant human epidermal growth factor results in shorter duration of wound healing, reduced wound bacterial positive rates and adverse reactions rate, and improved wound healing rates., (Copyright © 2020 Elsevier Ltd and ISBI. All rights reserved.)

In the present study chitosan based gel formulations containing Egg Yolk Oil (EYO) and Epidermal Growth Factor (EGF) were formulated successfully aiming at enhanced topical treatment of dermal burns the combination of traditional approaches with modern drug delivery systems. Physicochemical properties of the formulations were analyzed and efficacy of the formulations prepared were evaluated versus a commercial product; Silverdin (1% silver sulfadiazine) in vivo on Wistar rats. Burns were generated on the back of the rats and at predetermined time intervals tissue samples were collected and evaluated histologically. The analyses showed that chitosan based gel formulations containing Egg Yolk Oil (E1) and chitosan based gel formulations containing EYO and EGF (M1) formulations seem to be better alternatives for Silverdin with a significant difference (p < 0.05) considering healing ranks of tissue samples.

The effect of recombinant human epidermal growth factor (rhEGF) on innate immunity and cellular composition of the destruction focus in the third-degree (IIIA) burn (skin contact with an object heated to 100°C; 4% body surface) was studied in experiments on outbred albino rats. On days 7-28 after burn, blood count of phagocytes and their absorbing capacity and oxygen-dependent metabolism increased, which correlated with the increase in serum IL-1β level and neutrophil count in the destruction focus. Local application of rhEGF led to earlier (on day 14) normalization of the count and functional activity of blood phagocytes and decrease in serum IL-1β level and accelerated neutrophil and lymphocyte replacement with fibroblasts in the focus of injury.

We evaluated the laser induced burn wound healing efficacy of a recombinant low-molecular-weight protamine conjugated epidermal growth factor (rLMWP-EGF). rLMWP-EGF was prepared by genetically combining LMWP with the N-terminal sequence of EGF; we obtained a homogeneous modified EGF without reduced biological activity. Because of the protein transduction domain of LMWP, rLMWP-EGF showed enhanced drug penetration across artificial skin constructs and excised mouse skin layers versus EGF and showed significantly improved burn wound healing efficacy, with accelerated wound closure and minimized eschar and scar formation, compared with EGF or no treatment. Histological examination also revealed that rLMWP-EGF permeated through the intact skin around the wound and facilitated residual epithelial cell proliferation in an integrated manner to reform an intact epidermis. Radiofrequency microwound formation was effective for reducing large hypertrophic scars formed after severe laser burning by collagen remodeling but rLMWP-EGF did not show a meaningful synergistic effect in burn scar reduction. However, rLMWP-EGF was helpful for forming skin with a more normal appearance and texture. Thus, rLMWP-EGF demonstrated therapeutic potential as a novel topical burn wound healing drug with no obvious toxic effect., (© 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.)

This study aimed to investigate the efficacy of an artificial dermis composed of hyaluronic acid (HA) and collagen (Col) with or without epidermal growth factor (EGF), both in in vitro and in vivo. The cross-linked high molecular weight HA spongy sheet was prepared by freeze-drying. The spongy sheet was immersed in a mixed solution of high molecular weight HA, low molecular weight HA, and heat-denatured Col, and then lyophilized to obtain a two-layered spongy sheet. Cross-linking among Col molecules was induced by ultraviolet irradiation to prepare the artificial dermis (Type I). In a similar manner, a two-layered artificial dermis containing EGF (Type II) was prepared using a similar mixed solution containing EGF. The in vitro experiments demonstrated that EGF released from the Type II artificial dermis stimulates fibroblasts to produce increased amounts of vascular endothelial growth factor and hepatocyte growth factor. The therapeutic efficacy of artificial dermis was evaluated in animal tests using Sprague Dawley (SD) rats. The dorsal skin of the SD rat was shaved and then exposed to boiling water for 3 s to induce a deep dermal burn. The necrotic tissue was then excised 3 days later. Each artificial dermis was applied to the skin defect for 7 days and assessed for its ability to generate a wound bed. The in vivo experiments demonstrated that the Type II artificial dermis promotes angiogenesis to a greater extent at an early stage (within 3 days), and also suppresses the inflammatory reaction more successfully compared with the Type I artificial dermis. In further animal tests, an autologous skin graft was performed by excising a piece of skin from the abdominal region and then grafting it onto the wound bed prepared using each artificial dermis for 7 days. Although the Type II artificial dermis had the highest potential to promote angiogenesis, in this animal study, each artificial dermis induced excellent wound bed formation acceptable for autologous skin grafting.

Clinical efficacy of preparation REGEN-D 150 for local treatment of burns was analyzed. In accordance to the data obtained, the preparation application for the burns treatment have secured the local inflammatory reaction reduction in the affection zone, reparative processes optimization in the burn wound and saving the functional possibilities of phagocytic cells on optimal level.

Objective: To explore the therapeutic effect of recombinant human epidermal growth factor (rhEGF) for burn wounds of degree II in the elderly patients., Methods: From February 2003 to October 2008, 80 patients with burn wounds of degree II were treated and randomly divided into two groups (n=40). In treatment group, there were 24 males and 16 females with an average age of 70 years (60-86 years), including 20 cases of superficial II degree and 20 cases of deep II degree. Burn wounds were caused by flame in 23 cases, by hot liquid in 16 cases, and by electricity in 1 case. The mean time from injury to hospitalization was (2.87 +/- 2.57) hours. The wounds were treated with silver sulfadiazine (SD-Ag) and rhEGF. In control group, there were 18 males and 22 females with an average age of 69 years (61-83 years), including 19 cases of superficial II degree and 21 cases of deep II degree. Burn wounds were caused by flame in 23 cases, by hot liquid in 14 cases, by electricity in 2 cases, and by chemistry in 1 case. The mean time from injury to hospitalization was (3.39 +/- 3.33) hours. The wounds were treated with SD-Ag. The dressing was changed every day until wounds healing. There were no significant differences in general data between two groups (P > 0.05)., Results: Wound did not heal in 1 case (deep II degree) of treatment group and in 5 cases (deep II degree) of control group over 40 days and free skin graft was used to repair wound. One case (superficial II degree) in control group gave up treatment. One case (deep II degree) died of pulmonary infection in treatment group. These cases were excluded and 72 cases were analysed. No other side reactions were observed in treatment group except for flash stabbing pain (4 cases) and pruritus (2 cases). Wound infection occurred in 5 cases of the control group and in 3 cases of the treatment group, and wound healed after symptomatic treatment. The healing time of burn wound was (14.30 +/- 1.26) days (superficial II degree) and (26.11 +/- 2.97) days (deep II degree) in the treatment group, was (16.22 +/- 1.40) days (superficial II degree) and (29.13 +/- 4.99) days (deep II degree) in control group, showing significant difference between two groups (P < 0.05)., Conclusion: In combined treatment, rhEGF can promote the healing of burn wounds of degree II in the elderly patients.

Objective: To investigate the effect of topical external administration of recombinant human epidermal growth factor (rhEGF) when controlling blood sugar on expression of epidermal growth factor receptor (EGFR) and EGFR mRNA of wound in diabetes mellitus (DM) combined with scald., Methods: A total of 136 male Wistar rats weighing (188.57 +/- 6.59) g were randomly divided into 4 groups (groups A, B, C, and D, n=34). The rats was made DM model by intraperitoneal injected 60 mg/kg streptozocin in groups A, B, and C; rats were injected buffer alone in group D as control group. After 8 weeks, the rats of 4 groups were placed in 80 degrees C hot water for 6 seconds for preparation of the back deep II degree scald model. In group A, the blood sugar level was controlled at the level of group D 1 week before scald model; within 24 hours after models preparation, rhEGF was sprayed on wound at 150 U/cm2. In group B, the rats were given the same treatment as group A except not controlling blood sugar. In group C, the blood sugar was controlled as group A and wound was suture fixation with 1% silver sulfadiazine cream at 24 hours after the model. In group D, the same treatment as group A was given after injury. The healing rate of the wound was detected at 3, 7, 11, 15, and 21 days after injury; the EGFR mRNA expression was determined by mRNA hybridization in situ, and the EGFR protein expression was determined by immunohistochemistry and Western blot at 1, 3, 5, 7, 11, 15, and 21 days., Results: All the rats survived at the end of experiment. There was no significant difference in the healing rate of the wound among the 4 groups at 3 days (P > 0.05). The healing rate of the wound was significantly higher in groups A and D than in groups B and C (P < 0.05) at 7, 11, 15, and 21 days. The expression of EGFR mRNA in 4 groups was observed by hybridization in situ, which mainly distributed in the dermal fibroblasts, capillary endothelial cells and remnants of skin and wound edge epithelium of the subsidiary; the expressions reached the peak at 5 days in group A, at 7 days in groups B and C, and at 11 days in group D; and the peak level was significantly higher in groups A and D than in groups B and C (P < 0.05). Immunohistochemistry and Western blot showed that the expression of EGFR protein was observed in 4 groups and reached the peak level at 7 days in groups A and B, and at 11 days in groups C and D; showing significant difference between groups B, C and groups A, D (P < 0.05)., Conclusion: External application of rhEGF when controlling blood sugar can accelerate obviously the wound healing in DM combined with scald. After controlling blood sugar, external application of rhEGF can boost obviously the expressions of EGFR mRNA, EGFR, and the extending process of signal conduction.

It was aimed to develop liposome formulations containing epidermal growth factor (EGF) and to investigate the healing effects of these formulations on second-degree burn wounds in rats. Multilamellar type liposomes containing EGF were prepared by film formation method. In vitro releases of EGF from liposome formulations were determined using spectrofluorometer. Second-degree standard burn wounds were formed on rats and liposome formulations containing 10 microg/mL EGF (ELP group), EGF solution (ES group), liposome without containing EGF (LP group), and Silverdine ointment (SIL group) were applied daily. Untreated control groups [unburned (S) and untreated (Y) rats] were also evaluated. Biopsies were taken at the 3rd, 7th, and 14th day of the treatment from the wounds and histological observations were performed under transmission electron microscope. Bromodeoxyuridine (BrdU) staining technique was used for immunohistochemical analysis. After trichrome stainings, the thicknesses of the epidermis and the areas of the fibroblast nucleus were measured using a light microscope and Vision Screening Analysis Program. It was observed that the healing in the ELP group was the fastest among all groups (p < 0.05) at the 14th day of therapy. The healing effect in order from highest to lowest efficacy was found to be ELP>SIL>ES groups, respectively, at the 14th day. All results indicated that the EGF-liposome formulation is effective and can be used for the treatment of burn wounds., (Copyright 2007 Wiley Periodicals, Inc.)

Various studies have shown that chitosan is effective in promoting wound healing. In this study, we aimed to develop an effective chitosan gel formulation containing epidermal growth factor (EGF), and to determine the effect on healing of second-degree burn wounds in rats. Ten micrograms per millilitre EGF in 2% chitosan gel was prepared. In an in vitro study to investigate release of EGF from the formulations, the release rate was 97.3% after 24 h. In in vivo studies, animals were divided into six groups as follows: silver sulfadiazine [Silverdin cream (SIL)], chitosan gel with and without EGF (EJ, J), EGF solution (ES) and untreated control groups [unburned (S) and untreated (Y) rats] applied groups, respectively. A uniform deep second-degree burn of the backskin was performed with water heated to 94+/-1 degrees C during a 15-s exposure. The EGF formulations were repeatedly applied on the burned areas with a dose of 0.160 microg/cm2 for 14 days (one application per day). Healing of the wounds was evaluated immunohistochemically, histochemically and histologically on the tissue samples. When the results were evaluated immunohistochemically, there were significant increases in cell proliferation observed in the EGF containing gel applied group (p<0.001). The histochemical results showed that the epithelization rate in the EJ group was the highest compared to the ES group results (p<0.001). The histological results indicated and supported these findings. It can be concluded that a better and faster epithelization was observed in the EJ group compared to the other groups.

To better define the relationship between dermal regeneration and wound contraction and scar formation, the effects of epidermal growth factor (EGF) loaded in collagen sponge matrix on the fibroblast cell proliferation rate and the dermal mechanical strength were investigated. Collagen sponges with acid-soluble fraction of pig skin were prepared and incorporated with EGF at 0, 4, and 8 microg/1.7 cm2. Dermal fibroblasts were cultured to 80% confluence using DMEM, treated with the samples submerged, and the cell viability was estimated using MTT assay. A deep, 2nd degree- burn of diameter 1cm was prepared on the rabbit ear and the tested dressings were applied twice during the 15-day, post burn period. The processes of re-epithelialization and dermal regeneration were investigated until the complete wound closure day and histological analysis was performed with H-E staining. EGF increased the fibroblast cell proliferation rate. The histology showed well developed, weave-like collagen bundles and fibroblasts in EGF-treated wounds while open wounds showed irregular collagen bundles and impaired fibroblast growth. The breaking strength (944.1 +/- 35.6 vs. 411.5 +/- 57.0 Fmax, gmm(-2)) and skin resilience (11.3 +/- 1.4 vs. 6.5 +/- 0.6 mJ/mm2) were significantly increased with EGF-treated wounds as compared with open wounds, suggesting that EGF enhanced the dermal matrix formation and improved the wound mechanical strength. In conclusion, EGF-improved dermal matrix formation is related with a lower wound contraction rate. The impaired dermal regeneration observed in the open wounds could contribute to the formation of wound contraction and scar tissue development. An extraneous supply of EGF in the collagen dressing on deep, 2nd degree-burns enhanced the dermal matrix formation.

Objective: To review the current condition of growth factors and their application to clinical treatment of acute and chronic wounds., Methods: Data from the literature and Medline were analyzed according to their different uses in acute and chronic wounds. Their potential side-effects were studied., Results: All data showed that wound healing time in acute and chronic wounds was accelerated and wound healing quality was improved after treatment with growth factors. No side-effect was observed., Conclusion: The efficacy and safety of growth factors in improving wound healing were confirmed. However, some reconsideration about potential problems of growth factors must be made to apply them clinically in the future.

Objective: To study an early comprehensive prevention and treatment of sepsis in severely burned patients with delayed fluid resuscitation., Methods: From January 1990 to December 2001, 72 cases of patients with delayed fluid resuscitation were admitted to our burn department. Two different periods were divided and analyzed retrospectively. The first period was from January 1990 to December 2001 and the span of the second period was from January 1995 to December 2001., Results: (1)The mortality rate and incidence of sepsis in the second period (6.5 percent and 17.4 percent) were significantly lower than those of the first period (23.0 percent and 57.7 percent, P<0.05 and P<0.01). (2)The time of wound healing in the second period was (1.9+/-0.9) hours, it was lower than that of the first period (6.6+/-2.5) hours. (3)The serum contents of tumor necrosis factor (TNF) and blood lactic acid (BLA) were increased at all times in two periods and were markedly increased in the first period (all P<0.01)., Conclusion: Our data demonstrated that measures adopted in the second period for patients with delayed fluid resuscitation, including early excision, early rapid adequate resuscitation, early enteral feeding, increased immunity function, early applying antibactials, xenotransfusion of ultraviolet-irradiated blood, application of recombinant human-growth factor (rh-GH), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), are beneficial to the prevention and treatment of sepsis in severely burned patients with delayed fluid resuscitation.

Objective: To explore an optimal method of recombinant human epidermal growth factor(rhEGF) application on the burn wounds of superficial II degree and profound II degree for accelerating its healing., Methods: There were 180 burn wounds in 60 patients with the self-corresponding wound of the same degree as controls. The wounds of all patients were divided three regions(A, B, C). The wounds were treated once a day with 1% SD-Ag in region A as controls, with rhEGF(40 U/cm2) in region B, and with a combination of rhEGF(40 U/cm2) and Su Yu Ping (5 g) in region C. The wound healing time was recorded and compared., Results: In regions A, B and C, the healing time of superficial II degree wound was (13.20 +/- 2.40) days, (10.20 +/- 2.20) days and (8.72 +/- 2.31) days (P < 0.01); that of profound II degree wound was (20.10 +/- 3.40) days, (17.20 +/- 3.12) days and (15.10 +/- 3.81) days respectively (P < 0.01, P < 0.05). The healed wound of profound II degree was elastic and tough in regions B and C, while that was not elastic and tough, and congestive in region A., Conclusion: The above results indicate that rhEGF can enhance burn wound healing markedly and that a combination rhEGF and Su Yu Ping has more significant effect than rhEGF alone and is recommended for clinical application.

Objective: To evaluate the safety and long-term effect of recombinant human epithelial growth factor (rhEGF) on deep partial-thickness burn wounds., Methods: Thirty-seven burn patients were enrolled in this study and were observed by randomized, double-blinded and placebo-controlled protocol. An area of deep partial-thickness burn wounds from each patient was divided into control (C) and treatment (T) portions. The wound in C was treated with normal saline while that in T with rhEGF. The patients were followed-up for 1 and 4 years after wound healing. The healed wounds were evaluated by modified Vancouver scar scale in terms of scar index (SI)., Results: 1 year after wound healing, it was found that the SI in T group (7.19 +/- 1.67) was obviously lower than that in C group (8.92 +/- 1.78, P < 0.01). The SI in T group (6.12 +/- 1.54) was still evidently lower than that in C group (8.09 +/- 1.81, P < 0.01) four years after wound healing. There were no signs of development of tumor or cancer in all the tested burn wound areas., Conclusion: External application of rhEGF might be beneficial to the healing quality of deep partial-thickness burn wound with less scar formation and better long-term effects, and it is safe.

Major burns are associated with multiple internal organ damages, including necrosis of the gastrointestinal mucosa. Failure of the intestinal barrier is a serious complication in burned patients. Epidermal growth factor (EGF) is a mitogenic polypeptide that stimulates wound repair and affords protection to the gastric mucosa. We examined whether a single systemic intervention with EGF prevents organ systems damages, following full-thickness scalds (25-30%) in rodents. Animals were randomly assigned to receive an intraperitoneal injection of EGF (30 microg/kg in mice, 10 microg/kg in rats) or saline solution, 30 min prior thermal injury in mice or after the cutaneous injury in rats. General clinical condition and mortality during 24h were recorded. Animals were autopsied and histopathological and histomorphometric studies were conducted. Mice treated with EGF exhibited a milder clinical evolution and acute lethality was significantly reduced as compared to saline counterparts (P<0.01). Histopathological and morphometric analysis showed that EGF significantly reduced intestinal necrosis and contributed to preserve jejunoileal architecture in mice (P<0.05) and rats (P<0.01). The onset of renal hemorrhagic foci was significantly reduced in EGF-treated groups (P<0.01). Lung damages appeared attenuated in EGF-treated animals. These data indicate the salutary effects of EGF by attenuating internal complications associated to thermal injuries. Further studies are warranted to fully elucidate the usefulness of this therapy.

Objective: To investigate the efficiency of recombinant human epidermal growth factor (rhEGF) on burn wound healing and to explore the effective density of the ointments., Methods: A total of 120 cases of burn in superficial II degree and profound II degree were randomly divided into 2 groups. In the first group of 15 cases of superficial II degree, the wounds were treated by rhEGF ointments of different density, 0.5 microgram/g, 10 micrograms/g and 50 micrograms/g, to screen out the effective density. And in the other 105 cases of the second group, optimal density of the ointments based on the result of the first group were employed to treat the burn wound in superficial II degree and profound II degree, with the self-corresponding wounds of the same degree as control, to study the efficiency of rhEGF on wound healing, according to the wound healing time, and adverse reaction of the ointment., Results: In the first group, the average healing time of superficial II wound treated by ointments of 10 micrograms/g and 50 micrograms/g significantly shortened when compared with that treated by ointments of 0.5 microgram/g(P < 0.01), but there was no obvious difference between the cases treated by ointments of 10 micrograms/g and 50 micrograms/g. In the second group, the healing time of superficial II wound treated by ointments of 10 micrograms/g was (8.39 +/- 2.25) days, (9.52 +/- 2.56) days in the control (P < 0.01); and healing time of profound II burn treated by ointments of 10 micrograms/g was (16.80 +/- 2.99) days, (18.27 +/- 3.17) days in the control (P < 0.01). And healing rates of burn wound at different periods were higher than those of the control., Conclusion: The above results indicate that rhEGF ointments can enhance burn wound healing significantly, and the ointment of 10 micrograms/g is a good choice for clinical application.

Wound healing is a complex biologic process in which peptide growth factors play a very important role. The object of this research was to study the effects of recombinant human epidermal growth factors (rh-EGF) and acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF) and bovine brain extract (bBE) on porcine partial-thickness burn wound healing. The biopsies were taken for determination of DNA contents and cell DNA cycle with the aid of flow cytometry and histological observation. The results showed that more extensive reepithelization and greater thickness of epidermis exhibited in growth factor treated wounds, and DNA contents and percent of S phase of cell DNA cycle were also higher in those groups treated with growth factors. The results suggested that repeated topical application of rh-EGF, aFGF, bFGF and bBE accelerated epithelial healing of burn wounds, and it may be helpful in clinical practice.

The topical application of recombinant growth factors such as epidermal growth factor, platelet-derived growth factor-BB homodimer (rPDGF-BB), keratinocyte growth factor (rKGF), and neu differentiation factor has resulted in significant acceleration of healing in several animal models of wound repair. In this study, we established highly reproducible and quantifiable full and deep partial thickness porcine burn models in which burns were escharectomized 4 or 5 days postburn and covered with an occlusive dressing to replicate the standard treatment in human burn patients. We then applied these growth factors to assess their efficacy on several parameters of wound repair: extracellular matrix and granulation tissue production, percent reepithelialization, and new epithelial area. In full thickness burns, only rPDGF-BB and the combination of rPDGF-BB and rKGF induced significant changes in burn repair. rPDGF-BB induced marked extracellular matrix and granulation tissue production (P = 0.013) such that the burn defect was filled within several days of escharectomy, but had no effect on new epithelial area or reepithelialization. The combination of rPDGF-BB and rKGF in full thickness burns resulted in a highly significant increase in extracellular matrix and granulation tissue area (P = 0.0009) and a significant increase in new epithelial area (P = 0.007), but had no effect on reepithelialization. In deep partial thickness burns, rKGF induced the most consistent changes. Daily application of rKGF induced a highly significant increase in new epithelial area (P < 0.0001) but induced only a modest increase in reepithelialization (83.7% rKGF-treated versus 70.2% control; P = 0.016) 12 days postburn. rKGF also doubled the number of fully reepithelialized burns (P = 0.02) at 13 days postburn, at least partially because of marked stimulation of both epidermal and follicular proliferation as assessed by proliferating cell nuclear antigen expression. In situ hybridization for KGFR in porcine burns revealed strong expression of KGFR on hair follicles and basal epidermis, confirming direct rKGF action on follicular as well as epidermal keratinocytes. Although the epithelial proliferation induced by rKGF resulted in marked neoepidermal psoriasiform hyperplasia with exaggerated rete ridges and neoepidermal and follicular maturation as assessed by expression of cytokeratin 10, a marker of keratinocyte terminal differentiation was not delayed and appeared to be accelerated in some rKGF-treated burns. Recombinant epidermal growth factor induced a trend toward increased new epithelial area in deep partial thickness burns, but had no effect on reepithelialization. The recombinant neu differentiation factor-alpha 2 isoform had no significant biological effects in either full or deep partial thickness burns.(ABSTRACT TRUNCATED AT 250 WORDS)

When epidermal growth factor (EGF) ointment containing a protease inhibitor, nafamostat (NM), was applied to burn sites in rats, the superoxide dismutase (SOD) enzyme activity and protein content increased 45% and 60%, respectively, at these sites 1 d after the burns compared with the control ointment. Following treatment with EGF plus NM (EGF + NM) ointment, messenger RNA for SOD also increased, to about 1.6 times that of the control at 1 d after the burn, indicating that this ointment stimulates SOD synthesis at burn sites in vivo. In contrast, following treatment with EGF + NM ointment, the content of heat shock protein (HSP 70) in the burned tissue decreased to about 70% of the control value 1 d after the burn. These findings suggest that EGF + NM ointment alleviated tissue damage at burn sites at an early stage, and that this was related to the stimulation of SOD synthesis and reduced HSP 70 levels. We also examined the effects of SOD ointment on wound healing at burn sites. A dose-dependent increase in the dry weight of granulation tissue at wound sites 3 d after the burn was observed following the application of this ointment. These results suggest that SOD may play an important role in wound healing after burns.

The systemic effects of epidermal growth factor (EGF) ointment containing nafamostat (NM), gabexate, or gelatin was studied in rats with burns or open wounds. At 1 d after burn, plasma epinephrine, cortisol, and glutamic-oxalacetic transaminase (GOT) levels were elevated, but treatment with EGF plus NM (EGF+NM) ointment significantly suppressed the increase in these levels. Further, there was no loss of body weight in the open wound model following treatment with EGF+NM ointment, while loss of body weight occurred in animals in which EGF ointments without NM were applied. Increases in plasma epinephrine 1 d after open wound formation were also suppressed by the application of EGF+NM ointment. Treatment with EGF ointment containing gabexate (GX) or gelatin (GL) ameliorated changes in body weight that occurred after open wound formation, while loss of body weight in animals with open wounds occurred following the application of ointment base, EGF ointment, GX ointment, or GL ointment. The present study thus indicates that the topical application of EGF ointment containing a protease inhibitor has ameliorative systemic effects.

The healing effect of human epidermal growth factor (hEGF) on second degree burn was studied in rats. No improvement in wound healing was found on topical application of EGF alone to burn sites, but an ointment containing EGF and nafamostat mesilate (NM), a protease inhibitor, accelerated the healing rate of burns. The dry weight of the granulation tissue on the wound site in the group treated with EGF plus NM ointment did not change, although that in other groups decreased. After treatment with EGF ointment containing NM, the content of uronic acid, as an index of acid mucopolysaccharide, at 3 d after burn rapidly increased and had recovered to nearly normal levels at 7 d after burn. However, the uronic acid content in the other groups (control, EGF alone, and NM alone) showed a higher value at 7 d than at 3 d. When compared with the control values significant increases in hydroxyproline, as an index of collagen, in the wound site were observed at 7 d after treatment with EGF ointment containing NM. The degradation of [125I]EGF in burned tissue homogenate decreased significantly in a concentration-dependent manner in the presence of NM. Body weights did not change after treatment with EGF plus NM ointment, although the body weights of other treatment groups decreased after burn, suggesting that EGF ointment containing the protease inhibitor, NM, alleviated the effects of burn shock. These findings indicate that the stabilization of EGF at the wound site is an important factor for the expression of its healing effects.

The effects of the topical application and the intraperitoneal administration of epidermal growth factor (EGF) on the healing of epidermal wounds, and of partial-thickness scalds in rats and of corneal wounds in rabbits were evaluated. The parameters measured were the daily percentage body weight change, time to complete healing of the wounds, the evaporative water loss from the wound surface and the rate of new formation of epithelial cell layers on the epidermal and corneal wounds. Wounded animals treated with 0.9% NaCl were used as controls. After removal of the corneal epithelium the local application of EGF stimulated the regeneration process appreciably. No significant healing advantage from the treatment with EGF was observed, however, in epidermal wounds and partial-thickness scalds. The result does not warrant any clinical evaluation.

Epidermal regeneration depends on mitosis and migration of keratinocytes. Epidermal growth factor is known to stimulate growth of keratinocytes in vitro, thus it might be expected to promote wound healing. The results of this study show that topical application of biosynthetic human epidermal growth factor accelerates epidermal regeneration in split-thickness wounds and partial-thickness burns. The significant enhancement of epidermal regeneration suggests the potential for clinical use of epidermal growth factor for accelerating healing of burns, wounds from trauma, diabetic ulcers, skin graft donor sites, and others.