Loss of vascular endothelial growth factor a activity in murine epidermal keratinocytes delays wound healing and inhibits tumor formation

The angiogenic cytokine vascular endothelial growth factor (VEGF)-A plays a central role in both wound healing and tumor growth. In the skin, epidermal keratinocytes are a major source of this growth factor. To study the contribution of keratinocyte-derived VEGF-A to these angiogenesis-dependent processes, we generated mice in which this cytokine was inactivated specifically in keratin 5-expressing tissues. The mutant mice were macroscopically normal, and the skin capillary system was well established, demonstrating that keratinocyte-derived VEGF-A is not essential for angiogenesis in the skin during embryonic development. However, healing of full-thickness wounds in adult animals was appreciably delayed compared with controls, with retarded crust shedding and the appearance of a blood vessel-free zone underneath the newly formed epidermis. When 9,12-dimethyl 1,2-benzanthracene was applied as both tumor initiator and promoter, a total of 143 papillomas developed in 20 of 23 (87%) of control mice. In contrast, only three papillomas arose in 2 of 17 (12%) of the mutant mice, whereas the rest merely displayed epidermal thickening and parakeratosis. Mutant mice also developed only 2 squamous cell carcinomas, whereas 11 carcinomas were found in seven of the control animals. These data demonstrate that whereas keratinocyte-derived VEGF-A is dispensable for skin vascularization under physiological conditions, it plays an important albeit nonessential role during epidermal wound healing and is crucial for the development of 9,12-dimethyl 1,2-benzanthracene-induced epithelial skin tumors.     

The effect of recombinant human growth hormone on wound healing in normal individuals

Growth hormone therapy has been suggested to speed wound healing in postoperative patients and in patients with severe burns. This study was undertaken to determine the effect of recombinant human growth hormone on the rate of wound healing in normal individuals. Twenty-three healthy males were evaluated in a randomized, double-blind placebo-controlled study. Each subject received a split-thickness wound (Davol-Keratome) on one buttock and a full-thickness wound (3-mm punch biopsy) on the other. The full-thickness wound healed significantly more slowly in the recombinant human growth hormone-treated group as compared with the placebo control group (t-test, P = .001). No statistically significant difference was noted in the healing of the split-thickness wounds. It is concluded that recombinant human growth hormone may impede healing in normal patients with full-thickness wounds as compared with treatment with placebo. We cannot rule out, however, that the recombinant human growth hormone affected the quality of the scab in full-thickness wounds and thereby only appeared to alter the wound-healing process.     

Improvement of the breaking strength of wound by combined treatment with recombinant human G-CSF, recombinant human M-CSF, and a TGF-beta1 receptor kinase inhibitor in rat skin

Effective doses of ionizing radiation during preoperative radiotherapy occasionally cause wound complications after subsequent surgery. The authors attempted to accelerate radiation-impaired wound healing in animal models. Recombinant human granulocyte colony-stimulating factor (rhG-CSF), recombinant human macrophage colony-stimulating factor (rhM-CSF), and an inhibitor of transforming growth factor (TGF)-β1 receptor kinase, SB431542, were injected s.c. into a full-thickness incisional wound site in the dorsal skin of rats after local irradiation of X-ray (30 Gy). Wound healing of irradiated skin was assessed using the breaking strength of the wound and histological analyses. The impaired wound healing in irradiated skin was found to be associated with impaired mobilization of bone marrow-derived cells and enhanced expression of TGF-β1 mRNA. The breaking strength of the wound in the irradiated skin was approximately one-eighth of that in the non-irradiated skin; however, following combined treatment with the above three compounds the breaking strength increased to approximately one-half of that in the non-irradiated skin. Histological analysis of the wounded skin revealed an increase in formation of collagen fibers and the panniculus carnosus following the combined treatment. Moreover, the increased breaking strength was associated with an increase in a subpopulation of fibrocytes (collagen I/ED1 double positive cells). These findings suggested that a combined treatment with rhG-CSF, rhM-CSF, and SB431542 is promising as a means of improving radiation-impaired wound healing. ( Cancer Sci 2008; 99: 1021–1028)     

Nasal cartilage fenestration in the application of full-thickness skin grafts

A technique is described that enables the application of full-thickness skin grafts to bare cartilage exposed in surgical wounds on the nose. By fenestrating the cartilage so that the lining on the inner side is exposed, the graft is able to receive a blood supply adequate for its survival.     

The effect of 13-cis-retinoic acid on wound healing in dogs

13-cis-retinoic acid is currently accepted as a valuable treatment for patients with severe nodulocystic acne. Many of these individuals express interest in surgical scar-correcting procedures. To ascertain the effect of 13-cis-retinoic acid on wound healing, sequential biopsies were examined from partial and full-thickness wounds in dogs following a 2-month course of retinoids. No significant difference was histologically observed from the control animal.     

Neu differentiation factor/heregulin induction by hepatocyte and keratinocyte growth factors

Hepatocyte growth-factor (HGF) is a potent, widely produced, pleiotropic mediator of mesenchymal-epithelial interaction. In a study of changes in gene expression initiated by HGF in Balb/MK keratinocytes, we observed the induction of Neu-differentiation factor (NDF) mRNA (also known as heregulin, or HRG). Further characterization of the regulation of NDF expression in Balb/MK keratinocytes revealed potent induction by keratinocyte growth factor (KGF) and epidermal growth factor (EGF), but not by HGF/NK2, an alternative HGF isoform with motogenic but not mitogenic or morphogenic activities. Sustained treatment (8 h) of Balb/MK cells with KGF stimulated secretion of mature NDF protein into the culture medium, and Balb/ MK cells treated with purified recombinant NDF protein showed increased DNA synthesis. We also found evidence of NDF induction in two models of tissue repair in mice: in full-thickness skin wounds, following locally increased KGF production, and in kidney after partial hepatectomy, following elevation of circulating HGF levels. These results reveal that mesenchymally-derived HGF and KGF can activate autocrine NDF signaling in their epithelial targets, and suggest that this mechanism contributes to the coordination of stages of wound repair, and possibly development, where these growth factors act in concert to direct epithelial proliferation, morphogenesis and differentiation.     

Epidermal cell outgrowth from CO2 laser- and scalpel-cut explants: implications for wound healing

We set out to determine if the slow healing of CO2 laser-incised skin wounds compared with that of scalpel-incised wounds is the result of an inhibitory effect of the CO2 laser energy on the rate of epithelialization. We compared the rate of epidermal outgrowth from laser- and scalpel-cut explants in vitro. The onset of epidermal cell outgrowth (epiboly) from CO2 laser-incised skin was delayed, but there was no difference in the rate of epidermal cell outgrowth. These studies suggest that a delay in onset of epidermal migration, not a decreased rate of epidermal migration, contributes to the slower epithelialization of CO2 laser-incised skin wounds.     

Epithelial stem cells, wound healing and cancer

It is well established that tissue repair depends on stem cells and that chronic wounds predispose to tumour formation. However, the association between stem cells, wound healing and cancer is poorly understood. Lineage tracing has now shown how stem cells are mobilized to repair skin wounds and how they contribute to skin tumour development. The signalling pathways, including WNT and Hedgehog, that control stem cell behaviour during wound healing are also implicated in tumour formation. Furthermore, tumorigenesis and wound repair both depend on communication between epithelial cells, mesenchymal cells and bone marrow-derived cells. These studies suggest ways to harness stem cells for wound repair while minimizing cancer risk.     

Exploratory analysis of the bacteriological status of post-irradiation wounds and its relationship to healing

AimsTo investigate the bacteriological status of post-irradiation wounds and its relationship to wound healing in patients with nasopharyngeal cancer.Materials and methodsOne hundred and forty-six nasopharyngeal cancer patients with post-irradiation wounds on one or both sides of the neck were studied prospectively. Swabs were taken from the wounds at the initial study visit for bacteriological examination. A further swab for culture was taken when possible signs of infection developed. Wound healing was assessed on alternate days with respect to wound condition, the presence of clinical infection and healing time.ResultsThe results showed that most of the post-irradiation wounds were colonised with bacteria. This was not associated with clinical signs of infection in any instance. There was no association between wound healing time and the presence of organisms, the identity of organisms, the number of species of organisms, or the use of antibiotics.ConclusionsThe presence of bacteria in post-irradiation wounds, in the absence of clinical signs of wound infection, is not a barrier to wound healing. Oncology practitioners should recognise the unique features of radiation-induced wounds and skin reactions with confidence and provide appropriate treatment as needed.     

ERBB3 is required for tumor promotion in a mouse model of?skin carcinogenesis

The epidermal growth factor receptor (EGFR) plays a key role in skin inflammation, wound healing, and carcinogenesis. Less is known about the functions of the structurally related receptor ERBB3 (HER3) in the skin. We assessed the requirement of ERBB3 for skin homeostasis, wound healing, and tumorigenesis by crossing mice carrying a conditional Erbb3 allele with animals expressing cre under the control of the keratin 5 promoter. Erbb3del mice, lacking ERBB3 specifically in keratinocytes, showed no obvious abnormalities. The EGFR was upregulated in Erbb3del skin, possibly compensating the loss of ERBB3. Nonetheless, healing of full‐thickness excisional wounds was negatively affected by ERBB3 deficiency. To analyze the function of ERBB3 during tumorigenesis, we employed the established DMBA/TPA multi‐stage chemical carcinogenesis protocol. Erbb3del mice remained free of papillomas for a longer time and had significantly reduced tumor burden compared to control littermates. Tumor cell proliferation was considerably reduced in Erbb3del mice, and loss of ERBB3 also impaired keratinocyte proliferation after a single application of TPA. In human skin tumor samples, upregulated ERBB3 expression was observed in squamous cell carcinoma, condyloma, and malignant melanoma. Thus, we conclude that ERBB3, while dispensable for the development and the homeostasis of the epidermis and its appendages, is required for proper wound healing and for the progression of skin tumors during multi‐stage chemical carcinogenesis in mice. ERBB3 may also be important for human skin cancer progression. The latter effects most probably reflect a key role for ERBB3 in increasing cell proliferation after stimuli as wounding or carcinogenesis.     

The effects of occlusive dressings on the recruitment of mononuclear cells by endothelial binding into acute wounds.

Mononuclear cell infiltration is a characteristic feature of wounds and may play an important role in the healing process. We have previously shown that the recruitment of peripheral blood mononuclear cells into wounded skin is an active, dynamic, and regulated process mediated at least in part by specific interactions between mononuclear leukocytes and specialized dermal microvascular endothelial cells in the wounded skin. The purpose of this study was to investigate the capacity of dermal microvascular endothelial cells in wounds exposed to air or covered with occlusive dressings to promote the adhesion of monocytes and lymphocytes. The results showed that dermal microvascular endothelial cells in both air-exposed and occluded wounds were capable of supporting peripheral blood mononuclear cell and monocyte adherence. However, in comparison with air exposed wounds, the level of peripheral blood mononuclear cell binding was significantly higher in occluded biopsies obtained at 0 to 9, 12, 15, and 21 days after wounding. In addition, monocyte and peripheral blood mononuclear cells binding to occluded wounds peaked earlier than peripheral blood mononuclear cell binding to air exposed wounds. These studies provide evidence that differences in the kinetics and magnitude of mononuclear cell adherence may account at least in part for the beneficial effects of occlusive dressing on wound healing.     

Cultured allogenic keratinocyte grafts in the management of wound healing: prognostic factors

Cultured allografts derived from neonatal foreskin provide a potent stimulus to wound healing in a wide variety of wounds. Their application is a simple outpatient procedure involving no discomfort for the patient. In contrast to autografting, no biopsy is necessary, and growth of newborn keratinocytes in cultures is more rapid than that of adult cells. Use of cultured allogeneic cells offers immediate graft availability and the possibility of stockpiling and preserving the graft for future use. Cultured epidermal allografts may be valuable in accelerating healing by second intention in surgical wounds, as well as being a helpful addition to chronic ulcer management. In venous disease, the outcome is at least comparable to other forms of skin grafting. Ulcers due to connective tissue disorders fared less well and deep chronic ulcers (down to fascia or tendon) were not significantly improved by cultured allograft application. Surprisingly, patient age did not influence outcome.     

改良型富血小板纤维蛋白在面部皮肤癌术后软组织缺损修复中的应用

目的探讨A PRF联合腹部全厚皮片移植修复面部恶性非黑色素瘤皮肤癌术后软组织缺损中的可行性及疗效。方法选择于2020年1月至2022年6月徐州医科大学附属淮安医院收治的面部皮肤癌术后需行全厚皮片移植患者80例,并根据随机数字表法将患者分为对照组（行皮片移植,外加多层无菌辅料,n=40）和研究组（将A PRF凝胶覆盖创面后,行皮片移植,外加多层无菌敷料包扎,n=40）,比较两组患者术后创面愈合情况,手术后 1月及 3 个月时患者的瘢痕评估（POSAS）得分,两组患者住院期间的平均换药次数、住院时间以及术后至出院前并发症发生率。结果研究组患者术后7 d的皮片存活率高于对照组（P＜0.05）, 研究组患者术后15 d及21 d的创面愈合情况优于对照组（P＜0.05）,研究组的创面完全愈合时间低于对照组（P＜0.05）;两组患者术后1个月和3个月的POSAS评分比较,差异具有统计学意义（P＜0.05）;研究组的平均换药次数、住院时间以及并发症发生率均低于对照组（P＜0.05）。结论A PRF联合腹部全厚皮片移植能够有效地修复面部恶性非黑色素瘤皮肤癌术后软组织缺损,且减少并发症的发生,减短患者的住院时间,值得临床推广应用。     

Surgical repair of atresia of nasal passages

Surgical correction of nasal atresia following healing of smallpox lesions in a 15-year-old girl is presented. The surgical technique used was complete excision of the scars and resurfacing of the resulting wound with grafts of full-thickness retroauricular skin. Particular attention was paid to prevention of postoperative contracture.     

New primary basal cell carcinomas arising in skin flaps following Mohs micrographic surgery for primary and recurrent basal cell carcinoma

Two patients developed new primary basal cell carcinomas (BCCs) in skin flaps used to reconstruct wounds that followed an earlier primary BCC and a recurrent BCC treated by Mohs micrographic surgery. Criteria for distinguishing a new primary BCC arising in a skin flap or full-thickness skin graft at a previous treatment site for BCC from a truly recurrent BCC are presented. The distinction between a new primary BCC and true tumor recurrence is important for accurate clinical assessment and may have a dramatic impact on the type of subsequent treatment. In addition, there may be less medicolegal liability in the case of a new primary BCC arising at the site of a previously treated BCC than for a BCC that is determined to be recurrent.     

A regional approach to reconstruction of the upper lip

Treatment of upper lip wounds by second intention, full-thickness skin grafts, and local flaps is discussed. The location, size, depth, and type of closure for each defect in 200 cases involving defects of the upper lip are reviewed. The percentages of wounds treated by each modality were 20, 6, 74% for second intention, grafts, and local flaps, respectively. Of wound treatment by local flaps, 80% used advancement flaps, 10% used transposition flaps, and 10% used island-pedicle flaps. Advancement flaps, island-pedicle flaps, possible complications, and post-operative care are reviewed.     

面部皮肤恶性黑色素瘤整复治疗的临床观察

目的 探讨治疗面部皮肤恶性黑色素瘤切除后皮肤缺损的手术方法 ,并评价其临床疗效。方法 2007年2月至2014年3月本科收治9例面部皮肤恶性黑色素瘤,均采用手术扩大切除病灶;术中常规冰冻切片监测手术切缘,病灶切除后皮肤软组织缺损,分别采用游离皮片移植2例,邻近任意皮瓣6例,游离皮瓣1例,术后常规辅以免疫治疗。结果 9例皮片及皮瓣均成活,伤口Ⅰ期愈合。局部形态较好,术区平整,瘢痕不明显。9例患者获随访3个月~7年,死亡2例,其中1例因其他疾病术后2年死亡;其余病例外形良好,未见局部复发。结论 面部皮肤恶性黑色素瘤手术治疗联合术后辅助免疫治疗疗效肯定,皮瓣修复可取得较为理想的局部外形,术中常规冰冻切片是保证肿瘤根治的一项重要手段。     

Celecoxib can prevent tumor growth and distant metastasis in postoperative setting

Much evidence suggests that an inflammatory condition provides a microenvironment favorable for tumor growth. One of the main components in the healing wound is the induction of cyclooxygenase-2 (COX-2) and prostaglandins, and many solid tumors have been known to overexpress COX-2. The present study investigated the relationship between surgical wounds and tumor growth and the roles of COX-2 and inflammatory reaction in this microenvironment. We created surgical wounds in syngeneic mice for the implantation of SCC VII murine cancer cell line. Accelerated tumor growth and increased angiogenesis by surgical wounds were clearly observed in C3H/HeJ mice with SCC VII tumor. The COX-2 expression of peritumoral tissues and leukocyte infiltration partly explained the accelerated tumor growth, especially in the early phase after surgical wounding. Celecoxib had a significantly suppressive effect on tumor growth, angiogenesis, and metastasis in tumor-implanted mice with surgical wounds. This tumor-suppressive action of celecoxib did not show any noticeable side effects on the late wound healing and on the gastrointestinal tracts. Prophylactic use of the drug can be advocated in many clinical situations, such as residual tumors or contamination of surgical fields by tumor cells.