Inhibition of prolyl 4-hydroxylase reduces scar hypertrophy in a rabbit model of cutaneous scarring

Hypertrophic scars result from excessive collagen deposition at sights of healing dermal wounds and can be functionally and cosmetically problematic. Pharmacological regulation of collagen synthesis and deposition is a direct approach to the control of scar tissue formation. We tested the ability of the phenanthrolinone derivative FG-1648 (in 0.5% Carbopol 971 PNF gel, pH 6.5), a prolyl 4-hydroxylase inhibitor, to reduce hypertrophic scar formation in a rabbit ear hypertrophic scar model. New Zealand White rabbits were divided into two treatment groups (n = 12 wounds per group with an equal number of controls): low-dose group: 0.5% FG-1648; high-dose group: 1% FG-1648. Left ears were used for treatment and right ear for control. Four 7-mm dermal ulcer wounds were made on each ear. The inhibitor was topically applied to the wound at the time of wounding and once daily up to postoperative day 7. Wounds were harvested at postoperative day 28 and scar hypertrophy quantified by measurement of the scar elevation index. All wounds showed complete healing. Treatment of wounds with 1% prolyl 4-hydroxylase inhibitor decreased the scar elevation index by 26% compared to control wounds (p < 0.01). Wounds treated with 0.5% FG-1648 inhibitor showed no difference in scar elevation compared to control wounds. These results suggest that inhibition of prolyl 4-hydroxylase may be a suitable agent for topical treatment for the prevention of hypertrophic scar tissue.     

Topical platelet-derived growth factor enhances wound closure in the absence of wound contraction: an experimental and clinical study

The effects of platelet-derived growth factor (PDGF) on wound healing in animal and human models were investigated. Four 1-cm2 wounds were made on the dorsum of 3 rats. A 0.5-cm punch wound was made behind each ear of 4 patients. Half the wounds were treated daily with vehicle, controls, and the rest were treated with PDGF. Treated wounds closed faster than the controls (animals: 16 +/- 3.2 days vs. 17.8 +/- 2.17 days; p < 0.05) and (patients: 16 +/- 0.67 days vs. 19.5 +/- 0.33 days; p < 0.05). Biopsies were taken at day 20 for polarized light-Sirius red histological analysis. The granulation tissue of PDGF-treated wounds showed fine collagen fibers with weak birefringence, characteristic of immature granulation tissue, deposited throughout the healed wound site. Such a pattern indicates wound closure by reepithelialization and filling in with scar. Control wound biopsies showed a small area of immature granulation tissue surrounded by intact dermal thick collagen fibers with strong birefringence. Such a pattern indicates wound closure by wound contraction. This shows that PDGF enhances wound closure by reepithelialization and the prevention of wound contraction.     

Standardized qualitative evaluation of scar tissue properties in an animal wound healing model

There is a great need to establish reproducible methods for evaluative studies of wound treatment and wound healing. Validation of the healing process through optical techniques, as well as histologic and immunohistochemical methodologies, have been improved and to some extent have become well-established assays. Data relating to biomechanical properties, e.g., evaluation of the tensile strength of scar tissue that forms in experimental wound treatment strategies, are less widely available. We chose the domestic pig as an animal model in which to examine epidermal wound healing. We implanted specially made chambers that served to isolate the wounds and prevent epidermal migration from the edges. We performed histologic and immunohistochemical analyses as well as evaluation of biomechanical qualities of scar tissue using laser tensiometry. Pig skin is well suited for wound healing studies, and wound creation, implantation of the chambers, and the regular changing of dressings could all be carried out in the operating theater. In addition to established macroscopic evaluation and microscopic documentation, the need for objective biomechanical assessment of scar tissue by measuring tensile strength has been met using laser tensiometry. By optimizing methods for measuring tensile strength, it is possible to evaluate the biomechanical quality of scar tissue formed following different courses of wound treatment, as well as histologic assessment.     

硒化壳聚糖促创面愈合作用的体内研究

目的:研究硒化壳聚糖软膏促浅Ⅱ度烫伤小鼠创面愈合的作用。方法:147只昆明种小鼠随机分为硒化壳聚糖软膏治疗组、基质治疗组和京万红治疗组,每组49只,采用将脱毛区置于70℃恒温水浴中6s的方法制成10%体表面积浅Ⅱ度烫伤模型,伤情经病理切片证实。各组创面分别用硒化壳聚糖软膏纱布(1ml/cm2)、基质纱布(1ml/cm2)、京万红纱布(1ml/cm2)覆盖包扎固定后放回笼中饲养,换药1次/天,观察愈合时间,于伤后12h,第1、3、5、7和9天,分别处死各组小鼠7只,检测含水量、羟脯氨酸、TNF、NO、ALT,另取7只做为正常对照。结果:①创面愈合时间:硒化壳聚糖软膏组为(12.9±2.9)天、基质组为(16.3±2.1)天、京万红组为(11.8±2.4)天,硒化壳聚糖软膏组比基质组明显缩短(P<0.05);②创面含水量:伤后第1、3、5天硒化壳聚糖软膏组[(86.3±3.5)%、(77.8±3.9)%、(72.3±2.7)%]创面含水量显著低于基质组[(92.8±3.2)%、(84.9±4.2)%、(77.2±2.8)%,(P<0.05)],伤后7～9天,各组均基本恢复到正常水平;③创面TNF-α水平:伤后12h至1天达高峰,随后逐渐下降,至伤后第5天仍高于正常对照组(P<0.05);伤后12h、1天、3天、5天,硒化壳聚糖软膏组和京万红组TNF水平明显低于基质组(P<0.05);④创面组织NO含量:伤后12h各烫伤组NO含量达高峰,随后下降,至伤后第9天仍高于正常对照组(P<0.05);伤后12h、1天,硒化壳聚糖软膏组和京万红组NO含量明显低于基质组(P<0.05);⑤创面羟脯氨酸含量:伤后5、7、9天硒化壳聚糖软膏组羟脯氨酸含量显著高于基质组和京万红组(P<0.05)。结论:硒化壳聚糖软膏能有效减少烫伤后早期创面组织NO和TNF-α释放,减少渗出和水肿,晚期通过增强创面胶原合成来促进创面愈合。     

Skin substitute‐assisted repair shows reduced dermal fibrosis in acute human wounds validated simultaneously by histology and optical coherence tomography

Skin substitutes are heterogeneous biomaterials designed to accelerate wound healing through provision of replacement extracellular matrix. Despite growing evidence for their use in chronic wounds, the role of skin substitutes in acute wound management and their influence on fibrogenesis remains unclear. Skin substitute characteristics including biocompatibility, porosity, and elasticity strongly influence cellular behavior during wound healing. Thus, we hypothesize that structural and biomechanical variation between biomaterials may induce differential scar formation after cutaneous injury. The following human prospective cohort study was designed to investigate this premise. Four 5‐mm full thickness punch biopsies were harvested from 50 volunteers. In all cases, site 1 healed by secondary intention, site 2 was treated with collagen‐GAG scaffold (CG), and decellularised dermis (DCD) was applied to site 3 while tissue extracted from site 4 was replaced (autograft). Healing tissue was assessed weekly with optical coherence tomography (OCT), before being excised on days 7, 14, 21, or 28 depending on study group allocation for later histological and immunohistochemical evaluation. Extracted RNA was used in microarray analysis and polymerase chain reaction of highlighted genes. Autograft treatment resulted in minimal fibrosis confirmed immunohistochemically and with OCT through significantly lower collagen I levels (p = 0.047 and 0.03) and reduced mean grayscale values (p = 0.038 and 0.015), respectively. DCD developed intermediate scar formation with partial rete ridge reformation and reduced fasiculonodular fibrosis. It was uniquely associated with late up‐regulation of matrix metalloproteinases 1 and 3, oncostatin M, and interleukin‐10 (p = 0.007, 0.04, 0.019, 0.019). Regenerated dermis was significantly thicker in DCD and autografts 28 days post‐injury compared with control and CG samples (p = 0.003 and <0.0001). In conclusion, variable fibrotic outcomes were observed in skin substitute‐treated wounds with reduced scarring in autograft and DCD samples compared with controls. OCT enabled concurrent assessment of wound morphology and quantification of dermal fibrosis.     

A late defect in wound healing associated with recurrent spontaneous pneumothoraces: a presumptive role for abnormal collagenase activity

This case report concerns an individual with a defect in wound healing which resulted in recurring, bilateral pneumothoraces during the late postoperative period. This patient had no history of systemic disease or wound healing abnormalities before his recurrent wound disruption. Physical examination and routine biochemical studies failed to identify any causative agent for the multiple wound dehiscences in the patient. Histologic examination of scar tissue showed collagen fiber bundles with a diameter 50% less than that of normal fibrils. Elastic fibers were barely visible, and the scar tissue included a large number of inflammatory cells. A significant finding was an elevated and aberrant expression of collagenase by a fibroblast cell line established from a skin biopsy specimen. This enhanced level of collagenase expression could be inhibited by treatment of the cells with diphenylhydantoin, an inhibitor of collagenase biosynthesis. After initiation of diphenylhydantoin therapy, the patient's scar formation normalized with the recurrent pneumothoraces. These findings support the conclusion that an abnormal expression of collagenase resulted in enhanced degradation of collagen in the patient's wounds, thereby leading to wound dehiscence.     

The concurrent use of probiotic microorganism and collagen hydrogel/scaffold enhances burn wound healing: An in vivo evaluation

Treatment of burn wounds is technically demanding and several attempts have been taken to improve wound healing. Silver sulfadiazine antibiotic has been shown to have some beneficial effects on wound healing via reduction in infection. This study was designed to investigate the impact of collagen hydrogel-scaffold dressing with or without topical use of Saccharomyces cerevisiae on cutaneous burn wound healing in rat. Four circular 1 cm cutaneous wounds were created in the dorsum back of rats, 48 h post-burning. Thirty male rats were divided into the three major groups (1–3, n = 10), then the wounds in each group were equally divided into two subgroup treatments (6 treatments), (1) including (a) silver sulfadiazine (SSD) as positive control (PC) and (b) untreated wounds as negative control (NC) (2) including (c) S. cerevisiae and (S.C.) and (d) collagen scaffold (CS), (3) including (e) collagen hydrogel-scaffold (CH-S) and (f) S. cerevisiae with collagen hydrogel-scaffold (CH-S-S). In each group, the animals were euthanized at 12 and 22 days post-injury (DPI) and the skin samples were used for histopathological and biomechanical investigations. Collagen scaffold and hydrogel modulated the inflammation, especially when combined together. Moreover, they increased wound healing, epithelialization and biomechanical performance of wound area and also reduced the scar size. The best results gained when the combination of collagen scaffold and hydrogel were mixed with probiotic. The CH-S biological dressing along with probiotic microorganism (S.C.) significantly increased collagen content compared to the negative controls. Moreover, the CH-S-S treated lesions demonstrated greater ultimate load and stiffness compared to the untreated wounds. In conclusion, application of S. cerevisiae with a bi-phase biological dressing (CH-S) improved the morphological and biomechanical characteristics of the healing burned wounds in rats and the results were comparable to the positive control.     

Fetal wound healing. The ontogeny of scar formation in the non-human primate.

OBJECTIVE: This study determined how scar formation develops in a non-human primate model of fetal skin repair. SUMMARY BACKGROUND DATA: A transition from healing scarlessly to healing with scar formation characterizes skin repair in rat and sheep fetuses. New knowledge of the regulatory processes occurring in the fetal wound at the initial stages of scar formation may provide insights into the early mechanisms of scar formation. METHODS: Full-thickness wounds were made in fetal rhesus monkey lips from 75 through 114 days gestation (n = 6, term = 165 days). Wounds were harvested at 14 days postwounding and processed for histology (hematoxylin & eosin, Masson's trichrome) as well as immunohistochemistry (human type I or type III collagen). RESULTS: Wounds healed with complete restoration of normal tissue architecture in the 75-day gestation fetus. However in the 85-100 day gestation fetuses, wounds healed with an absence of hair follicles and sebaceous glands, but the dermal collagen pattern remained reticular and similar to that in unwounded dermis. At 107 days, a thin scar was present in the wound, thereby demonstrating a transition to scar formation between 100 and 107 days gestation (early 3rd trimester) in the non-human primate. CONCLUSIONS: In the non-human primate fetus, a transition from scarless repair to adult-type repair with scar formation occurs in the early third trimester. These data provide insight into the transition process; the ontogeny of scar formation is characterized initially by wounds healing without the presence of epidermal appendages but with a normal reticular dermal collagen pattern, which we term the "transition wound."     

Topical grape (Vitis vinifera) seed extract promotes repair of full thickness wound in rabbit

In recent years, oxidative stress and free radicals have been implicated in impaired wound healing. Grape (Vitis vinifera) seed extract (GSE) possesses anti-inflammatory and antioxidant properties. The present study was undertaken to assess the potential activity of grape seed hydroalcoholic extract in wound healing in rabbits. Rabbits of either sex were subjected to a 20 × 20 mm square excision made over the skin of the back. The animals were randomly divided into seven experimental groups, as negative and positive control, eucerin and treatments. Negative control group did not receive any treatment. Positive control and eucerin groups received phenytoin cream (1%) and topical eucerin, respectively, twice a day from the beginning of experiments to complete wound closure. Treatment groups were treated topically by cream of GSE (2, 5, 10 and 70% w/w) in eucerin base, twice daily. For evaluation of the percentage of wound healing, area of the wound was measured daily. Histological studies were performed on the 7th and 15th days of treatments. After complete healing, hydroxyproline content and tensile strength measurement of tissue samples were done. Results showed that there were statistically significant differences between GSE treatments groups and eucerin animals (P < 0·05) in most of the days. Rabbits treated with 2% GSE had best results (completed healing in 13 days, higher hydroxyproline content and higher tissue resistance). We concluded that the extract of 2% GSE administered topically has a good potential to promote wound healing in wound model of rabbits.     

bFGF治疗颌面颈部大面积软组织缺损

目的探讨重组牛碱性成纤维细胞生长因子（bFGF）在颌面颈部大面积软组织缺损患者治疗中对组织愈合及预防瘢痕形成的作用,为细胞因子在创伤修复的临床应用提供依据。方法通过对三例较典形病例使用重组牛碱性成纤维细胞生长因子（贝复济）治疗：一例为恶性肿瘤术后皮瓣坏死,一例为斜方肌皮瓣术区拆线后裂开,一例为严重狗咬伤伴感染的患者,创面均缺损面积较大、深度深。持续观察创面变化至创面完全愈合。结果三例患者创面均愈合良好,且无瘢痕增生及瘢痕疙瘩形成。结论重组牛碱性成纤维细胞生长因子（bFGF）对颌面颈部大面积软组织缺损,甚至是创面条件较差的情况下,也可起到良好的治疗作用,并且可有效的抑制瘢痕组织形成,细胞因子在创伤修复及预防瘢痕形成中有积极作用。     

Nitrosoglutathione triggers collagen deposition in cutaneous wound repair

The presence of nitric oxide (NO) is associated with enhanced wound fibroblast collagen synthesis; previous observations have focused on the effect of NO on wound collagen content. This article emphasizes the effect of nitrosothiols on wound collagen deposition and matrix-metalloproteinase activity, which is the primary breakdown pathway of collagen. We examined the effects of S-nitrosoglutathione (GSNO) and glutathione (GSH) on rat scar tissue. Hydroxyproline content, matrix metalloproteinase activity, total glutathione, and total nitrite of scar tissue were measured 3, 5, 7, and 10 days after wounding. It was observed that, at Day 5 and Day 10, wound collagen content was 52.0 percent and 47.5 percent higher, respectively, after GSNO administration than in controls (p<0.05). GSH administration decreased wound collagen deposition 76.5 percent by Day 5 (p<0.05). GSH lowered the matrix metalloproteinase activity 67 percent at Day 5 and 50 percent (p<0.05) at Day 10. Nitrite and nitrate levels were 55 percent higher in the GSNO treated rats than in the control group (p<0.05) at Day 3, whereas the GSH-treated groups showed no changes. GSNO increased systemic nitrite 53 percent 3 hours after intraperitoneal injection. Our findings suggest that collagen deposition increases in cutaneous wound healing after the administration of GSNO and that this nitrosothiol does not interfere with the collagenolytic pathway, thus maintaining the physiological conditions necessary for wound healing.     

Comparing the influence of two immunosuppressants (fingolimod,azathioprine) on wound healing in a rat model of primary and secondary intention wound closure

In this study, rat models of wound closure by first and second intention were developed to evaluate the influence that two immunosuppressants for treating multiple sclerosis (fingolimod, azathioprine) have on wound healing. Sixty‐three Sprague‐Dawley rats were daily treated with fingolimod (0.6 mg/kg), azathioprine (2.5 mg/kg), or placebo (saline). Following 6 weeks of treatment, a linear incision (1.5 cm) or a circular excisional defect (diameter 1.5 cm) was made on the dorsal skin. The treatments were uninterrupted and after 7 days (incisional) or 21 days (incisional, excisional), animals were euthanized (n = 7 per group and time‐point). Morphometric (wound closure), histological (stainings), and immunofluorescent studies (macrophages) were performed to evaluate the healing process. For both the incisional and excisional defects, animals treated with fingolimod exhibited a healing process equivalent to that of placebo in terms of collagenization, wound closure, and macrophage response. By comparison, groups treated with azathioprine displayed a delay in healing times which was especially evident in the excisional defect, where inflammatory reaction and collagen deposition in the repair tissue remained active by day 21. These results show that immunosuppressants with a selective mechanism of action (fingolimod) can have less impact on wound healing than their classical nonselective counterparts (azathioprine).     

Permissive environment in postnatal wounds induced by adenoviral-mediated overexpression of the anti-inflammatory cytokine interleukin-10 prevents scar formation

Wound healing in the mid-gestation fetus is scarless with minimal inflammation and a unique extracellular matrix. We have previously documented the relative lack of inflammatory cytokines in this environment. We demonstrate that interleukin (IL)-10 is highly expressed in mid-gestation human fetal skin but is absent in postnatal human skin. We hypothesize that overexpression of IL-10 in postnatal skin may replicate a permissive environment for scarless healing. To study the mechanism underlying this process we performed immunohistochemistry for IL-10 in human mid-gestation fetal and postnatal skin. We also determined if adenoviral-mediated overexpression of IL-10 could allow for scarless wound healing in a murine incisional wound model. Wounds were analyzed at 1–90 days postwounding for effects on scar formation, inflammatory response, and biomechanical properties. Ad-IL-10 reconstitutes a permissive environment for scarless healing as shown by reconstitution of a normal dermal reticular collagen pattern and distribution of dermal elements. Compared with controls, Ad-IL-10 treated wounds showed reduced inflammatory response and no difference in biomechanical parameters. Therefore, overexpression of IL-10 in postnatal wounds results in a permissive environment for scarless wound repair, possibly by replicating a fetal wound environment.     

Basic fibroblast growth factor (bFGF) alleviates the scar of the rabbit ear model in wound healing

Studies suggest a possible antiscarring effect of basic fibroblast growth factor (bFGF) during wound healing. However, little is known about the precise pathological mechanisms of bFGF. In particular, there is only limited information available about the mechanism of exogenous administration of bFGF to scar formation. To investigate the effect of bFGF on the hypertrophic scar in the rabbit ear model and to clarify the mechanisms of bFGF on treatment for scar in wound healing, the rabbit ear model of wound healing was created and treated topically with bFGF once daily for 3 months; then we examined the changes of macroscopic and histopathological characteristics of scars and the expression of collagen and collagenase-1 (matrix metalloproteinase-1). The results of macroscopic and histologic characteristics revealed a significant difference between scars treated with bFGF and control scars. The expression of collagen in the scars treated with bFGF was decreased, as compared with the scars treated with saline. Further study revealed that bFGF could remarkably enhance expression of matrix metalloproteinase-1. bFGF could improve the quality of wound healing and remarkably alleviate the scar in the rabbit ear model in wound healing, which suggests that bFGF exerted a net negative effecton scar formation in wound healing. The evidence should contribute to a better understanding of the biological activities of bFGF during hypertrophic scar formation.     

Stromal progenitor cell therapy corrects the wound-healing defect in the ischemic rabbit ear model of chronic wound repair

Chronic wounds create a formidable clinical problem resulting in considerable morbidity and healthcare expenditure. The etiology for wound healing impairment appears to be multifactorial; however, ischemia is a common factor in most types of chronic wounds. Ideal therapy for such wounds would be to correct deficiencies in growth factors and matrix components and provide cellular precursors required for timely wound closure. We hypothesized that stromal progenitor cell (SPC) therapy could correct the ischemic wound-healing defect through both direct and indirect mechanisms. To test this hypothesis, we used the ischemic rabbit ear model of chronic wound healing. We found that treatment of the wounds with SPCs was able to reverse the ischemic wound-healing impairment, with improved granulation tissue formation and reepithelialization compared with vehicle or bone marrow mononuclear cell controls. In vitro, SPCs were found to produce factors involved in angiogenesis and reepithelialization, and extracellular matrix components, providing evidence for both direct and indirect mechanisms for the observed correction of the healing impairment in these wounds. Treatment of ischemic wounds with SPCs can dramatically improve wound healing and provides a rationale for further studies focused on SPCs as a potential cellular therapy in impaired wound healing.     

金玉夫膏在整形术后伤口不愈合修复中的应用

目的 探究金玉夫膏在整形术后伤口不愈合修复中的应用效果。方法 选取2016年6月-2022年12月 我院门诊处理的18例整形术后伤口不愈合患者作为研究对象,均采用金玉夫膏进行局部换药,1次/d,直至愈合, 记录伤口愈合时间,观察愈合后的瘢痕增生、皮肤色泽和质地情况,统计患者满意度。结果 18例伤口全部愈 合,愈合时间5~15 d;随访6~12个月,所有伤口愈合良好,外观平整,不臃肿,局部无明显压痛和增生性瘢痕, 愈合皮肤柔软,有弹性,色素沉着不明显;瘢痕评价均为轻度;色泽分级显效16例,有效2例;质地分 级均为显效;患者满意17例,较满意1例,满意度为100.00%。结论 金玉夫膏局部换药在修复整形术后伤 口不愈合治疗中的效果确切,可缩短伤口愈合时间,且愈合过程中无明显不良反应,患者满意度较高。     

Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats

Bone marrow stem cells participate in tissue repair processes and may have a role in wound healing. Diabetes is characterised by delayed and poor wound healing. We investigated the potential of bone marrow-derived mesenchymal stromal cells (BMSCs) to promote healing of fascial wounds in diabetic rats. After manifestation of streptozotocin (STZ)-induced diabetic state for 5 weeks in male adult Sprague-Dawley rats, healing of fascial wounds was severely compromised. Compromised wound healing in diabetic rats was characterised by excessive polymorphonuclear cell infiltration, lack of granulation tissue formation, deficit of collagen and growth factor [transforming growth factor (TGF-beta), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor PDGF-BB and keratinocyte growth factor (KGF)] expression in the wound tissue and significant decrease in biomechanical strength of wounds. Treatment with BMSC systemically or locally at the wound site improved the wound-breaking strength (WBS) of fascial wounds. The improvement in WBS was associated with an immediate and significant increase in collagen levels (types I-V) in the wound bed. In addition, treatment with BMSCs increased the expression of growth factors critical to proper repair and regeneration of the damaged tissue moderately (TGF-beta, KGF) to markedly (EGF, VEGF, PDGF-BB). These data suggest that cell therapy with BMSCs has the potential to augment healing of the diabetic wounds.     

Effects of tretinoin on wound healing in aged skin

Aged and adult populations have differences in the structural, biological, and healing properties of skin. Comparative studies of healing under the influence of retinoids in both these populations are very important and, to the best of our knowledge, have not been performed to date. The purpose of this study was to compare the activities of topical tretinoin in aged and adult animal models of wound healing by secondary intention. Male aged rats (24 months old, n = 7) and adult rats (6 months old, n = 8) were used. The rats were assigned to the following groups according to the dates on which wound samples were excised (day 14 or 21 after model creation): treated group, control group, and naive group. Topical application of tretinoin cream was used only on the proximal wound and was applied daily for 7 days. Wound healing areas were measured using metal calipers, and morphological analysis was performed. Slides were stained with Hematoxylin and Eosin, Masson's trichrome, and periodic acid‐Schiff stains. Statistical analysis adopted a 5% coefficient for rejection of the null hypothesis. Although aged animals showed skin repair, complete reepithelialization was found on day 21 in some animals of both groups (treated and control). In aged rats, the wound area was significantly smaller in treated wounds than in untreated wounds, resulting in a larger scar area compared with the adult group. When treated wounds were compared, no differences were found between the wound areas in adult and aged rats. As expected, the collagen concentration was higher in normal skin from adult rats than in normal skin from aged animals, but there was no difference when aged skin was treated with tretinoin. These results indicate that tretinoin increases collagen synthesis in aged skin and returns the healing process to a normal state of skin healing.     

Exacerbated and prolonged inflammation impairs wound healing and increases scarring

Altered inflammation in the early stage has long been assumed to affect subsequent steps of the repair process that could influence proper wound healing and remodeling. However, the lack of explicit experimental data makes the connection between dysregulated wound inflammation and poor wound healing elusive. To bridge this gap, we used the established rabbit ear hypertrophic scar model for studying the causal effect of dysregulated inflammation. We induced an exacerbated and prolonged inflammatory state in these wounds with the combination of trauma‐related stimulators of pathogen‐associated molecular patterns from heat‐killed Pseudomonas aeruginosa and damage‐associated molecular patterns from a dermal homogenate. In stimulated wounds, a heightened and lengthened inflammation was observed based on quantitative measurements of IL‐6 expression, tissue polymorphonuclear leukocytes infiltration, and tissue myeloperoxidase activity. Along with the high level of inflammation, wound healing parameters (epithelial gap and others) at postoperative day 7 and 16 were significantly altered in stimulated wounds compared to unstimulated controls. By postoperative day 35, scar elevation of stimulated wounds was higher than that of control wounds (scar elevation index: 1.90 vs. 1.39, p < 0.01). Moreover, treatment of these inflamed wounds with Indomethacin (at concentrations of 0.01, 0.1, and 0.4%) reduced scar elevation but with adverse effects of delayed wound closure and increased cartilage hypertrophy. In summary, successful establishment of this inflamed wound model provides a platform to understand these detrimental aspects of unchecked inflammation and to further test agents that can modulate local inflammation to improve wound outcomes.