epidermal-growth-factor and Skin-Ulcer

The role ofepidermal growth factor (EGF) has been extensively investigated in normal and pathological wound healing. It is implicated in keratinocyte migration, fibroblast function and the formation of granulation tissue. Since the discovery of EGF, the first growth factor to be isolated, over 45 years ago, growth factor therapy has progressed into clinical practice in the treatment ofwounds. The investigation EGF in wound healing has progressed from the treatment of acute wounds, to its limited effect in chronic wounds. EGF is readily degraded in the chronic wound environment, but with the recent focus of research in new drug delivery systems that are able to protect and stabilise the protein, the potential healing effects of EGF are at the forefront of research. In this review, the history of EGF and wound healing research is considered, as are current and future therapeutic options.

Topics: Drug Delivery Systems; Epidermal Growth Factor; Humans; Skin Ulcer; Wound Healing

Wet treatment of wounds has been used as an "irrigation" method since the seventh century. We have developed the concept of an in vivo tissue culture that facilitates wound healing and allows tissue engineering. A transparent, flexible, round chamber provides the wet environment. This system heals clean wounds as fast or faster than any other method, with less scarring. It allows delivery of analgesics, antibiotics, growth factors, growth media, and cells into the chamber, becoming a platform for tissue engineering. Gene therapy of the wound can be done in the chamber with growth factor and other genes. A tetracycline switch allows precise timing and amounts of expression and provides the opportunity for sequential expression of genes delivered at the same time.

Topics: Epidermal Growth Factor; Gene Transfer Techniques; Humans; Keratinocytes; Occlusive Dressings; Skin Ulcer; Wound Healing; Wounds and Injuries

We evaluated the effect of topical epidermal growth factor treatment on healing of chronic wounds in a prospective, open-label, crossover trial. Five males and four females who ranged in age from 40 to 72 years (average 57 +/- 9 years) were enrolled. Four patients had adult-onset diabetes mellitus, two had rheumatoid arthritis, two had old burn scars, and one had a failed abdominal incision. The average duration of the ulcers prior to treatment with epidermal growth factor was 12 +/- 5 months (range 1 to 48 months). Following failure of the wounds to heal with conventional therapies, including debridement, skin graphs, and vascular reconstruction, wounds were treated twice daily with Silvadene alone for periods ranging from 3 weeks to 6 months. No evidence of healing was observed in any of the patients' wounds during Silvadene treatment, and patients were crossed over to twice a day treatment with Silvadene containing 10 micrograms epidermal growth factor per gram. Wounds of eight patients healed completely with epidermal growth factor-Silvadene treatment in an average of 34 +/- 26 days (mean +/- SD, range 12 to 92 days) and did not reoccur for periods ranging from 1 to 4 years. One patient failed therapy. These results suggest that topical treatment of chronic wounds with epidermal growth factor may stimulate healing.

Topics: Administration, Cutaneous; Adult; Aged; Arthritis, Rheumatoid; Burns; Chronic Disease; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Pilot Projects; Postoperative Complications; Prospective Studies; Silver Sulfadiazine; Skin Ulcer; Wound Healing

The etiology of non-healing ulcers depends on both systemic and local factors. The introduction of advanced dressing, negative wound therapy and compression therapy have undoubtedly improved clinical outcomes. The principal aim of study was to demonstrate the efficacy of dermal micrografts in the treatment of ulcers with different etiologies. The second aim was to investigate in vitro the action of micrografts in the regenerative process.. The dermal micro-grafts were obtained from mechanical disaggregation of small pieces of skin tissue through a medical device called Rigeneracons.. We observed in vivo the ability of dermal autologous micrografts to improve the healing of venous, diabetic, pressure and post-traumatic ulcers after few week of treatment accomplished in general with a better quality of life for the patients. In vitro results showed that these micrografts express mesenchymal stem cells (MSCS) marker such as CD34, CD73, CD90 and CD105, and are able to form a viable and proliferative biocomplex with collagen sponge. Finally, the site of ulcers displayed a different expression of epidermal growth factors, insulin-like growth factors, platelet-derived growth factors and their receptors and tumor necrosis factor-β with respect to healthy skin samples.. We reported a good outcome for the treatment of chronic ulcers using dermal autologous micrografts. Finally, we suggest that the positivity to MSCs markers and the ability to interact with a scaffold can play a key role in their regenerative properties.

Topics: 5'-Nucleotidase; Aged; Aged, 80 and over; Antigens, CD34; Autografts; Biomarkers; Chronic Disease; Dermis; Epidermal Growth Factor; ErbB Receptors; Gene Expression; Humans; Mesenchymal Stem Cells; Middle Aged; Platelet-Derived Growth Factor; Receptors, Platelet-Derived Growth Factor; Regeneration; Regenerative Medicine; Reverse Transcriptase Polymerase Chain Reaction; Skin Transplantation; Skin Ulcer; Treatment Outcome

Cutaneous wound healing is a significant health issue in the US, often requiring skin grafts. StrataGraft (Stratatech Corporation, Madison, WI), a second-generation living human skin substitute created from NIKS human keratinocyte progenitors, was recently found to be a promising skin graft in phase I/II safety and efficacy clinical trial. NIKS proliferation is optimal in the presence of epidermal growth factor (EGF). Our preliminary data suggested that Notch signaling also plays a role in NIKS keratinocyte proliferation. Therefore, we hypothesized that EGF might stimulate NIKS proliferation by regulating Notch1 signaling.. Notch1 messenger RNA (mRNA) levels from NIKS cells in monolayer culture were assessed by real-time polymerase chain reaction and Notch1 protein levels were detected by Western blot. To determine the role of EGF on Notch1 regulation, cells were incubated in basal media and then treated with EGF (10 ng/mL). A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to test NIKS cell proliferation. Cells were grown in basal media supplemented with EGF for 72 h in the presence or absence of N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) (0-30 μM), an inhibitor of Notch1 signaling.. Notch1 mRNA levels were cell confluence-dependent, being more abundant in a subconfluent cell monolayer. We detected a 2-fold decrease in Notch1 mRNA expression and a reduction in active Notch1 protein level in response to EGF. EGF treatment stimulated NIKS cellular proliferation. However, co-treatment with DAPT inhibited NIKS proliferation to basal levels. Blocking Notch1 activation by DAPT alone inhibited NIKS cellular proliferation (P < 0.01%).. Our results suggest that Notch1 is an essential downstream mediator of NIKS cellular proliferation via the EGF signaling pathway.

Topics: Amyloid Precursor Protein Secretases; Cell Line, Transformed; Cell Proliferation; Dipeptides; Epidermal Growth Factor; Humans; Keratinocytes; Primary Cell Culture; Receptor, Notch1; RNA, Messenger; Signal Transduction; Skin Ulcer; Wound Healing

To compare the platelet enrichment ratio of platelet-rich plasma (PRP) prepared by different centrifuge methods and to compare the concentration of growth factors released from autologous platelet-rich gel (APG) with the whole blood.. Thirteen diabetic patients with refractory skin lesions were enrolled in APG treatment. (1) Three kinds of centrifuge methods were selected for PRP by 11 diabetic patients: A (n = 6): 529 x g for 4 minutes in the first centrifuge and 854 x g for 6 minutes in the second centrifuge; B (n = 5): 313 x g for 4 minutes in the first centrifuge and 1,252 x g for 6 minutes in the second centrifuge; C (n = 5): 176 x g for 5 minutes in the first centrifuge and 1,252 x g for 5 minutes in the second centrifuge. Platelet counted on the whole blood and PRP was determined. The APG, produced by combining the PRP with thrombin and calcium gluconate (10:1) was used by patients. (2) PDGF-BB, TGF-beta1, VEGF, EGF, and IGF-1 were measured in the APG and the whole blood using the enzyme-linked immunosorbent assay method.. (1) The average platelet concentration was higher in group B [(1,363.80 +/- 919.74) x 10(9)/L] than in groups A [(779.67 +/- 352.39) x 10(9)/L)] and C [(765.00 +/- 278.78) x 10(9)/L] and the platelet recovery rate was 75.2% +/- 21.0% in group B. (2) The concentration of growth factors all increased with the increasing platelet number. On average, for the whole blood as compared with APG, the PDGF-BB concentration increased from (145.94 +/- 133.24) pg/mL to (503.81 +/- 197.86) pg/mL (P < 0.05); TGF-beta1 concentration increased from (3.31 +/- 2.27) ng/mL to (5.67 +/- 4.80) ng/mL (P < 0.05); IGF-1 concentration increased from (14.54 +/- 35.34) ng/mL to (110.56 +/- 84.36) ng/mL (P < 0.05); and EGF concentration increased from (160.73 +/- 71.10) pg/mL to (265.95 +/- 138.43) pg/mL (P < 0.05). No increase was found for VEGF (P > 0.05). (3) There was positive correlation between the platelet concentration and PDGF-BB and TGF-beta1 (r = 0.627, r = 0.437, P < 0.05). (4) Thirteen diabetic repractory dermal ulcers received APG treatment for 18 times, 9 ulcers (69.2%) and 10 sinuses (88.3%) were cured at the end of 12-week treatment.. The method of group B is the best centrifuge method. A variety of growth factors are detected and released from the platelets at significant levels in APG. There is positive correlation between the platelet concentration and PDGF-BB and TGF-beta1.

Topics: Adult; Aged; Diabetes Complications; Diabetic Foot; Epidermal Growth Factor; Female; Gels; Growth Substances; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Platelet Count; Platelet-Derived Growth Factor; Platelet-Rich Plasma; Plateletpheresis; Skin Ulcer; Treatment Outcome; Vascular Endothelial Growth Factor A; Wound Healing

To investigate the expression and location of epidermal growth factor (EGF) and its receptor (EGFR) in dermal chronic ulcers and normal skin in order to explore their influence on ulcer formation.. The expression intensity and distribution of EGF and EGFR were detected with pathological method and immunohistochemistry method in 8 cases of dermal ulcers, 8 cases of edge of ulcer and 8 cases of normal skin.. The Positive signals of EGF could be found in epidermal cells, endothelial cells and some fibroblasts; EGFR was principally located in the cytoplasm and cellular membrane of these cells mentioned above in normal skin. From normal skin, edge of ulcer to ulcerative tissues, the protein contents of EGF and EGFR were decreased progressively. In ulcerative tissues, EGF was mostly distributed in monocytes and macrophages while EGFR was chiefly sited in monocytes. When compared with normal skins, the protein expression of EGF and EGFR was notably reduced in ulcerative tissues (both P<0.01). The positive cellular ratios of two proteins were reduced to (7.1+/-5.2) % and (8.8+/-5.5) % of those in normal skin respectively (all P<0.01).. The formation of dermal chronic ulcers is closely associated with the reduction of EGF and EGFR protein expression which may lead to binding obstruction between EGF and its receptor.

Topics: Adult; Chronic Disease; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Immunohistochemistry; Male; Middle Aged; Skin; Skin Ulcer

To observe the effect of recombinant human epidermal growth factor (rhEGF) on healing of chronic ulcer wound.. From January 1999 to January 2001, twenty-six patients with chronic wounds were adopted in this study. Among them, there were 17 males and 9 females, aged from 12 to 61 years. The area of the chronic wound varied from 3 cm x 3 cm to 5 cm x 8 cm and the disease course was 7 to 16 days. These patients were treated with rhEGF in the way of sprinkling locally (400 U/10 cm2). Another 26 patients with chronic wounds were adopted as the control group and were treated with 0.9% saline in the same way. The healing time of wounds and the local and systemic reactions of patients were observed.. The healing time of chronic wounds was shorter obviously to about 7 days with rhEGF than that of the control group and there was significant difference between the two groups(P < 0.01).. rhEGF can obviously promote the healing of chronic ulcer wound.

Topics: Adolescent; Adult; Child; Chronic Disease; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Recombinant Proteins; Skin Ulcer

Topics: Epidermal Growth Factor; Epidermis; Humans; Skin Ulcer; Stem Cells

To explore the cell reversion and epithelial stem cell distribution in skins from different developed stages and regenerated epidermis treated with rhEGF.. Tissue biopsies from 8 regenerated ulcer skins treated with recombinant human epidermal growth factor (rhEGF) were used to evaluate the cell reversion and stem cell distribution in epidermis. The expression of beta1 integrin, keratin 19 (K19), keratin 14 (K14) and keratin 10 (K10) in skin was detected with Streptavidin/Peroxidase (SP) immunohistochemical methods. Another 15 biopsies including 7 cases from the regenerated epidermis treated with SD-Ag, 3 cases from fetus (24 weeks), 3 cases from children and 2 cases from adults were used as the controls.. Immunohistochemical stain from beta1 integrin and keratin 19 showed that there were some stem cell islands in epidermis treated with rhEGF. These cells were small and exhibiting positive expression with beta1 integrin and K19 stain. They were isolated, bearing no anatomic relation with the epithelial stem cells in the basal layer. The serial identification experiments indicated that there were no similar stem cell islands in skins from normal adult skin, fetus or child's skin and the regenerated epidermis treated with SD-Ag. All of these results supported that these beta1 integrin and K19 positive stain cells were the stem cells.. The results indicated that these stem cell islands were the specific and individual cell structures in rhEGF treated wounds. There is a possibility that these cells come from the cell reversion from differentiated cells to undifferentiated stem cells.

Topics: Epidermal Growth Factor; Epidermis; Humans; Skin Ulcer; Stem Cells; Wound Healing

Stromelysin-2 is a matrix metalloproteinase that degrades in vitro several protein components relevant to wound repair such as collagens III and IV, gelatin, nidogen, laminin-1, proteoglycans, and elastin. Furthermore, it can activate other matrix metalloproteinases, such as collagenase-1 (matrix metalloproteinase-1) and collagenase-2 (matrix metalloproteinase-8), as well as 92 kDa gelatinase. The aim of this study was to determine in a large variety of wounds (normally healing dermal and mucosal wounds, suction blisters, ex vivo cultures, diabetic, decubitus, rheumatic, and venous ulcers) and keratinocyte cultures, which factors contribute to stromelysin-2 expression and how it is induced in relation to other matrix metalloproteinases. Our results show that stromelysin-2 mRNA and protein are upregulated later (at 3 d) than matrix metalloproteinase-1 in normally healing wounds and ex vivo explants, in which stromelysin-2 is invariably expressed by keratinocytes migrating over dermal matrix. The number of keratinocytes expressing stromelysin-2 was greatest in chronic inflamed diabetic and venous ulcers compared with rheumatoid and decubitus ulcers, six of which had no signal. In keratinocyte cultures, tumor necrosis factor-alpha, epidermal growth factor, and transforming growth factor-beta1 induced stromelysin-2 expression as measured by quantitative reverse transcriptase-polymerase chain reaction, whereas different matrices did not upregulate the mRNA. Immunostaining demonstrated stromal transforming growth factor-beta1 in contact with the stromelysin-2-positive keratinocytes. Our results suggest that stromelysin-2 expression is important for the normal repair process and is upregulated by cytokines rather than cell-matrix interactions. Stromelysin-2 is most likely to participate in the remodeling of the newly formed basement membrane, and is not overexpressed in retarded wound healing.

Topics: Cell Adhesion Molecules; Cell Communication; Cell Movement; Cytokines; Epidermal Growth Factor; Epithelial Cells; Kalinin; Keratinocytes; Matrix Metalloproteinase 10; Metalloendopeptidases; Neutrophils; RNA, Messenger; Skin Ulcer; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Up-Regulation; Wound Healing

The roles of polypeptide growth factors in promoting wound healing and in directing the specificity and sequence of responses of different tissues in wounds are little understood. We investigated the influence of four growth factors on the rates of healing of a novel full thickness dermal ulcer placed on an avascular base in the rabbit ear. The wound model precludes significant wound contraction and requires new granulation tissue and epithelial cells for healing to originate centripetally. 5 micrograms (7-31 pmol/mm2) of platelet-derived growth factor-B chain (PDGF-BB), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) applied locally at the time of wounding resulted in a twofold increase in complete reepithelialization of treated wounds (PDGF-BB, P = 0.02 chi square analysis; bFGF, P = 0.04; EGF, P = 0.05); transforming growth factor (TGF)-beta 1 significantly inhibited reepithelialization (P = 0.05). Both PDGF-BB and TGF-beta 1 uniquely increased the depth and area of new granulation tissue (P less than 0.005), the influx of fibroblasts, and the deposition of new matrix into wounds. Explants from 7-d old PDGF-BB-treated wounds remained metabolically far more active than controls, incorporating 473% more [3H]thymidine into DNA (P = 0.05) and significantly more [3H]leucine and [3H]proline into collagenase-sensitive protein (P = 0.04). The results establish that polypeptide growth factors have significant and selective positive influences on healing of full thickness ulcers in the rabbit.

Topics: Animals; Epidermal Growth Factor; Fibroblast Growth Factors; Platelet-Derived Growth Factor; Rabbits; Skin Ulcer; Transforming Growth Factors; Wound Healing