Insulin and wound healing

Skin is a dynamic and complex organ that relies on the interaction of different cell types, biomacromolecules and signaling molecules. Injury triggers a cascade of events designed to quickly restore skin integrity. Depending on the size and severity of the wound, extensive physiological and metabolic changes can occur, resulting in impaired wound healing and increased morbidity resulting in higher rates of death. While wound dressings provide a temporary barrier, they are inherently incapable of significantly restoring metabolic upsets, post-burn insulin resistance, and impaired wound healing in patients with extensive burns. Exogenous insulin application has therefore been investigated as a potential therapeutic intervention for nearly a century to improve wound recovery. This review will highlight the important achievements that demonstrate insulin's ability to stimulate cellular migration and burn wound recovery, as well as providing a perspective on future therapeutic applications and research directions.     

烧伤创面愈合的信号转导机制

After 50 years of development in science of bums care in China, we have basically solved coverage of deep wounds of burn trauma, as well as role of multiple growth factors and stem cell in wound healing, making great contribution to improving the treatment of patients with large area of deep bums. Surgeons are paying close attention to problems of wound healing, especially in the fields of starless healing and rehabilitation. To solve these problems, we need to do further investigation on multiple growth factors as well as proliferation/differentiation of stem cells in regulation of cell growth and differentiation in wound healing. Therefore ,we are facing a even more serious challenge.     

The effect of a new wound dressing on wound healing: Biochemical and histopathological evaluation

Electrospinning process has gained importance in the production of wound dressings in recent years. The wound dressings prepared by electrospinning method provide many advantages over conventional wound dressings. The aim of this study was to assess the histological, biochemical, and immunohistochemical evaluation of collagen/doxycycline loaded nanofiber wound dressing in both acute and chronic wound healing. Full-thickness wound model was created on rats and rats were divided in two main groups: normoglycemic (acute) and hyperglycemic (chronic) groups. Each group was divided into three sub groups: not treated (control) group, treated with nanofiber wound dressing group and treated with commercial product group. Wound closure rates were measured. Oxidative events were investigated by biochemical analyses. In addition to histological studies, matrix metalloproteinase, tissue inhibitor of metalloproteinase, vascular endothelial growth factor, basic-fibroblast growth factor, and von Willebrand factor levels were investigated with immunohistochemical studies. According to the biochemical analyses, it was concluded that the nanofiber wound dressing helps to increase antioxidant capacity and decrease lipid peroxidation. Immunohistochemical studies showed that nanofiber wound dressing enhanced angiogenesis and shortened the inflammatory phase. It was concluded that an effective and safe prototype nanofiber wound dressing, which has similar wound healing effect to the commercial product, has been developed to be used in acute or chronic wound treatment.     

细胞免疫与烧伤创面愈合的实验研究

为探讨免疫低下对烧伤创面愈合的影响,设计了用低剂量钴源照射的方法建立的免疫抑制模型,并在该模型的基础上观察了免疫抑制大鼠Ⅱ度烧伤创面愈合的情况。结果表明:①大鼠接受2Gy~(60)Co 照射后20天内,Th/Ts 比值和 T 细胞肿瘤花环率持续下降。照射后皮肤组织 DNA 含量及细胞周期均无明显改变。②免疫抑制大鼠胶原修复能力下降,创面愈合百分率低于正常大鼠。由此证实了免疫功能低下对创面愈合的抑制作用。     

Implications of chlorhexidine use in burn units for wound healing

Chlorhexidine is known to be a potent antiseptic with evidence of a beneficial role in burn care. Nevertheless, several in vitro studies have reported cytotoxicity on cultured cells, while in vivo and clinical data seem to show more controversial results. In the frame of this work, we aimed to evaluate the use of chlorhexidine in burn units worldwide be sending a survey to professionals of the field. We associated survey results to those perspectives reported in the literature to update recommendations for the use of chlorhexidine in specific protocols for burn management. The survey results showed that there is no clear consensus on the use of chlorhexidine regarding the concentrations, the type of excipient and the cleansing after application. Literature searches showed evidence that the skin of premature infants appears to be more sensitive to chlorhexidine that adult skin, with more reported cases of adverse effects. It was also determined that aqueous formulations of chlorhexidine do not appear to be necessarily less efficient than with alcohol as an excipient, and that lower concentrations are as efficient as higher concentrations. In view of this study, we have adjusted our protocols for the use of aqueous formulations at low concentrations and investigated further the role of washing after application in order to standardize the indication of chlorhexidine and minimize the probability of adverse effects.     

烧伤创面愈合的理论探索与临床实践

The basic and clinical research in wound healing have made great progress in China in the past 50 years. The method of " intermingle skin transplantation" which was first advocated by surgeons of Ruijin Hospital in 1966 greatly reduced the amount of autologous donor skin, thus making the coverage of an extensive burn wound possible. This method is al so known as " Chinese therapy". In 1986,doctors of Jishuitan Hospital reported successful coverage of an extensive burn wound with mieroautografts and allogeneic skin. The basic research of wound healing has been carried out since 1992,a series of studies showed the characteristics of biological behaviours of cells in concern, extracellular matrix and growth factor, the mechanism underlying progressive injury in deep second burn wound, the effect of " skin island" and the local immune tolerance induced by it (which are the key factors of intermingle transplantation).The induction of local immune tolerance has now become the re search hot subject of skin transplantation immunology. Stem cell research in the field of wound healing has been extensively car ried out. The theory of " dermal template defection" has been proposed as one of the mechanisms of scar formation. On the other hand, great progress has been achieved in the treatment of bums on the basis of clinical researches. Doctors of PLA 304 hospital found that excision of eschar on patients with extensive deep burn injury at early shock stage greatly decreased the occurrence of complications and mortality. Doctors of Ruijin Hospital reported that healing of deep second burn wound could be improved by tangential excision of burn eschar within 24 hours after burn injury. Doctors of Xiang ya Hospital reported patients suffering from deep bums of the hands got satisfied functional restoration when treated with tangential excision of eschar while degraded dermal tissue could be retained with transplantation of autoskin grafts.     

Nerve growth factor and burn wound healing: Update of molecular interactions with skin cells

Burn wound healing is a very intricate and complex process that conventionally includes three interrelated and overlapping stages of hemostasis/inflammation, proliferation and remodeling. This review aims to explore the molecular interactions of NGF with the most prominent cell types in the skin and their respective secretory products during wound healing, particularly burn wound healing. Different types of cells such as, nerve cells, endothelial cells, mast cells, macrophages, neutrophils, keratinocytes and fibroblasts all come into play through a plethora of cytokines and growth factors including nerve growth factor (NGF). NGF is a pleiotropic molecule that exerts its effects on all the aforementioned cells using two types of receptors (TrkA and p75) and affects wound healing by decreasing healing time and improving the quality of the scar. Both receptors mediate cellular proliferation, survival and apoptosis through complex signaling molecules. During the inflammatory phase, macrophages and mast cells secrete ample cytokines and growth factors, including NGF, which participate in the inflammatory reaction and induction of other cells targeting a homeostatic state. The proliferative phase follows, and NGF promotes angiogenesis through VEGF and FGF expression in endothelial cells. NGF also stimulates keratinocyte proliferation and neurite extension through the TrkA-PI3K/Akt pathway. Other molecules such as TGF-β1, IL-1β and TNF-α increase NGF expression in fibroblasts through dynamic interactions with Smads and MAPK molecules. Stimulated fibroblasts induce new collagen production to form the granulation tissue. In the remodeling phase, NGF regulates fibroblasts and induces their differentiation into myofibroblasts ultimately leading to wound contracture. In addition, NGF stimulates melanocytes and enhances hair growth and pigmentation. Such data depict the mechanisms of action of NGF implicated in the various stages of the healing process and support its applicability as a new targeted therapeutic molecule effective in burn wound healing but with some limitations.     

Telemedicine in wound healing

Better care for patients and improved health care depends on the availability of good information which is accessible when and where it is needed. The development of technology, more specifically the Internet, has expanded the means whereby information can be acquired and transmitted over large distances enabling the concept of telemedicine to become a reality. Telemedicine, defined as the practise of medicine at a distance, encompasses diagnosis, education and treatment. It is a technology that many thought would expand rapidly and change the face of medicine. However, this has not happened and during the last decade although certain telemedicine applications, such as video-consulting and teleradiology, have matured to become essential health care services in some countries, others, such as telepathology, remain the subject of intensive research effort. Telemedicine can be used in almost any medical specialty although the specialties best suited are those with a high visual component. Wound healing and wound management is thus a prime candidate for telemedicine. Development of a suitable telemedical system in this field could have a significant effect on wound care in the community, tertiary referral patterns and hospital admission rates.     

Effect of silver on burn wound infection control and healing: review of the literature

Silver compounds have been exploited for their medicinal properties for centuries. At present, silver is reemerging as a viable treatment option for infections encountered in burns, open wounds, and chronic ulcers. The gold standard in topical burn treatment is silver sulfadiazine (Ag-SD), a useful antibacterial agent for burn wound treatment. Recent findings, however, indicate that the compound delays the wound-healing process and that silver may have serious cytotoxic activity on various host cells. The present review aims at examining all available evidence about effects, often contradictory, of silver on wound infection control and on wound healing trying to determine the practical therapeutic balance between antimicrobial activity and cellular toxicity. The ultimate goal remains the choice of a product with a superior profile of infection control over host cell cytotoxicity.     

影响碱性成纤维细胞生长因子促进烧伤创面愈合因素的探讨

采用大白鼠１５％Ⅲ度烧伤模型，探讨了影响碱性成纤维细胞生长因子（ｂＦＧＦ）促进烧伤创面愈合的因素。结果发现，烧伤创面早期切痂可保持ｂＦＧＦ的活性。４０天创面愈合率达８４．０％，而未切痂组愈合率仅９，Ｏ％。肝素可增强ｂＦＧＦ促进创面肉芽组织生长、毛细血管增生、纤维母细胞增殖及细胞ＤＮＡ合成。创面感染的控制有利于保护ｂＦＧＦ的活性。伤后１周开始使用ｂＦＧＦ为适宜时期。     

创面治疗中心建设的实践

The construction of wound healing or wound care center in China is necessary for patients and about 10 wound healing or care centers have already been established during the past years. In this paper, we summarize their experience and expect their development in the future.     

Stem cells in burn wound healing: A systematic review of the literature

IntroductionSevere burns are often associated with high morbidity and unsatisfactory functional and esthetic outcomes. Over the last two decades, stem cells have generated great hopes for the treatment of numerous conditions including burns. The aim of this systematic review is to evaluate the role of stem cell therapy as a means to promote burn wound healing.MethodsComprehensive searches in major databases were carried out in March 2017 for articles on stem cell therapy in burn wound healing. In total 2103 articles were identified and screened on the basis of pre-determined inclusion and exclusion criteria.ResultsFifteen experimental and two clinical studies were included in the review. The majority of studies reported significant improvement in macroscopic burn wound appearance as well as a trend toward improved microscopic appearance, after stem cell therapy. Other parameters evaluated, such as re-vascularization, collagen formation, level of pro- and anti-inflammatory mediators, apoptosis and cellular infiltrates, yielded heterogeneous results across studies.ConclusionStem cell therapy appears to exert a positive effect in burn wound healing. There is, therefore, justification for continued efforts to evaluate the use of stem cells as an adjunct to first-line therapies in burns.     

细胞免疫与烧伤创面愈合的实验研究

为探讨免疫低下对烧伤创面愈合的影响，设计了用低剂量钴源照射的方法建立的免疫抑制模型，并在该模型的基础上观察了免疫抑制大鼠Ⅱ度烧伤创面愈合的情况。结果表明：①大鼠接受２Ｇｙ６０Ｃｏ照射后２０天内，Ｔｈ／Ｔｓ比值和Ｔ细胞肿瘤花环率持续下降。照射后皮肤组织ＤＮＡ含量及细胞周期均无明显改变。②免疫抑制大鼠胶原修复能力下降，创面愈合百分率低于正常大鼠。由此证实了免疫功能低下对创面愈合的抑制作用。     

甲鱼油对大鼠浅Ⅱ度烫伤创面愈合过程中组织修复的影响

目的:探讨甲鱼油治疗大鼠浅Ⅱ度烫伤的效果及其对创面愈合过程中组织修复的影响。方法:108只Wistar大鼠随机分为单纯烫伤组、银锌霜治疗组和甲鱼油治疗组,每组36只。采用将脱毛区置于70℃恒温水浴中15s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。各组创面分别用生理盐水纱布(1ml/cm2)、银锌霜纱布(1ml/cm2)、甲鱼油(1ml/cm2)纱布覆盖包扎固定后放回笼中分笼饲养,换药1次/d。观察创面愈合率及愈合时间。各组动物分别于伤后1、3、5、10、14d取创面组织,常规苏木精-伊红染色,观察病理组织学变化;免疫组织化学链霉素-卵白素-生物素-过氧化物酶复合物法检测创面组织增殖细胞核抗原的表达。结果:①创面愈合时间:单纯烫伤组为(15.33±0.82)d、银锌霜治疗组(12.57±0.54)d,甲鱼油治疗组(11.33±0.67)d,甲鱼油治疗组比单纯烫伤组明显缩短(P<0.01)。②创面愈合率:3组大鼠伤后10和14d的创面愈合率与伤后7d相比差异均具有显著性(P<0.01),甲鱼油治疗组和银锌霜治疗组两组大鼠的创面愈合率比单纯烫伤组在伤后7、10及14d均明显升高(P<0.01)。③病理学观察:甲鱼油能减轻烫伤创面早期的炎症反应,组织学分析显示甲鱼油可促进创面的再上皮化和表皮各层的分化。④增殖细胞核抗原在创面组织标本中的表达量:甲鱼油治疗组比单纯烫伤组、银锌霜治疗组明显升高(P<0.01)。结论:甲鱼油能加速大鼠烫伤创面组织修复细胞的增殖,加快创面再上皮化,促进创面愈合。     

人创面愈合过程中同源异形框基因的表达及意义

目的 探讨人胎儿及成人皮肤创面愈合过程中，几种同源异形框基因的表达及在胎儿无瘢痕愈合中的作用。方法 采用原位杂交方法，对正常成人和胎儿皮肤及创面愈合过程中PRX—2、H0XBl3、H0X2．2和H0X2．3的表达进行观察。结果 (1)在正常胎儿和成人皮肤中可见PRX—2阳性表达，以前阳性程度为强。分布部位有所不同，在正常胎儿皮肤中，阳性表达主要见于真皮乳头层毛干部周围细胞，表皮中也可见阳性表达；而在正常成人皮肤中，表皮基底层细胞呈弱阳性表达，真皮组织中未见阳性表达。胎儿皮肤创伤后，接近切口的组织中阳性表达明显增强，而成人皮肤创伤后，阳性表达未见明显变化，仍局限于表皮基底层细胞；(2)在正常胎儿及成人皮肤均可见H0XBl3阳性表达，真皮部分主要集中在毛囊细胞，表皮部分主要集中在基底层细胞，创伤后其表达明显减弱，尤其是胎儿皮肤；(3)在正常胎儿皮肤中H0X2．2和H0X2．3阳性表达主要见于表皮全层，表皮基底层阳性表达比较强，真皮中可见弱阳性表达，创伤后近切口的组织中，表达增强。在正常成人皮肤及其创面，未见到阳性表达。结论 同源异形框基因作为与发育生物学密切相关的基因，在人胎儿及成人皮肤创面愈合过程中的表达有所不同，这可能是二创面愈合差异的根本原因。     

骨髓基质干细胞在IKVAV多肽纳米纤维凝胶表面增殖、黏附及向神经细胞诱导分化的研究

目的研究骨髓基质干细胞（BMSCs）与IKVAV多肽纳米纤维凝胶复合的细胞假体应用于脊髓损伤治疗的可行性。方法合成IKVAV多肽两亲性分子，进行自组装，用透射电镜检测。将IKVAV多肽纳米纤维凝胶与BMSCs复合培养，采用倒置显微镜下观察、Calcein—AM／PI染色、CCK-8法、免疫荧光双标法，检测IKVAV多肽对BMSCs增殖、黏附及向神经细胞方向诱导分化的影响。结果IKVAV多肽可成功自组装成纳米纤维凝胶，其与BMSCs复合培养细胞生长良好，活细胞数达90％以上，IKVAV多肽对BMSCs增殖没有影响，可促进BMSCs的黏附，并在诱导BMSCs向神经细胞分化过程中提高神经元分化比例。结论BMSCs在IKVAV多肽纳米纤维凝胶材料表面可良好的增殖及黏附，并可提高其向神经细胞分化过程中神经元的分化比例。     

不同来源的表皮干细胞促进皮肤创面愈合的研究

目的 观察表皮干细胞(ESCs)及去分化来源的表皮干细胞(DESCs)对皮肤创面愈合的促进作用及其异同.方法 由新鲜人包皮标本以贴壁法分离ESCs,随机分为3组,第1组作为原代ESCs:第2组传代培养至第6代时可见细胞成熟呈表皮细胞(ECs)形态,由原来的大克隆生长的小圆细胞形态变为较为肥大的不规则型细胞,无法形成克隆样增殖;其细胞表型也由β1整合素、CK19强阳性、CK10阴性变为β1整合素、CK19阴性,而CK10强阳性,予以100μg/L的碱性成纤维细胞生长因子(bFGF)培养48 h进行去分化诱导,48 h后ECs周边开始出现小圆细胞并呈克隆样生长,β1整合素、CK19、CK10等细胞表型也趋于与ESCs一致,即DESCs;第3组传代培养至第6代获得ECs.3组细胞皆以D-Hanks液重悬调其终质量浓度为2×106个/ml.将12只裸鼠每只背部左右各制备1个直径6 mm创面,共24个创面.将全部创面随机等分为4组,每组6个,分别以ESCs、DESCs、Ecs及生理盐水(NS)各0.2 ml进行创面注射.于术后0、3、7 d测量创面面积进行统计学分析,并于术后7 d行创面取材苏木素-伊红(HE)染色.结果 ESCs组与DESCs组在术后3 d时创面面积分别为(11.758±2.544)、(11.515±1.351)mm2,7 d时创面面积分别为(1.795±1.063)、(2.043±1.138)mm2,修复速度要明显快于ECs组与NS组[3 d时创面面积分别为(17.857±1.722)、(16.192±2.256)mm2,7 d时创面面积分别为(5.367±1.219)、(5.070±1.357)mm2,P＜0.01];而ESCs与DESCs组之间创面修复速度比较差异无统计学意义(P＞0.05);ECs组与NS组之间比较差异无统计学意义(P＞0.05).HE染色提示ESCs组与DESCs组的创面愈合质量优于ECs组与NS组,可见有皮肤附属腺的再生且纤维瘢痕组织较少.结论 ESCs与DESCs皆有促进创面愈合的作用,相互之间无明显差异.

Abstract：

Objective To investigate the enhancing effect of epithelial stem cells (ESCs) and dedifferentiation derived epithelial stem cells (DESCs) in the healing of epidermal wound. Methods ESCs were isolated from the fresh circumcised foreskins by using adherence method and randomly divided into three cohorts: ESCs cohort, DESCs cohort and epithelial cells (ECs) cohort. The final cell density was adjusted to 2 × 106/ml with D-Hanks in each group. The model of BALB/C mice full-thickness skin loss wounds was established. Two circular 6 mm-diameter skin loss wounds were cut on every BALB/C mouse back. Twenty-four wounds of 12 BALB/C mice were divided equally and randomly into 4 groups:DESCs, ESCs, ECs and NS. The cell suspensions of DESCs, ESCs and ECs were injected respectively into the wound edges with the density of 2 × 106/ml. And the volme was 0. 2 ml per treatment wound. The same volume of normal saline was injected in NS group. On the postoperative day 0, 3, 7, all of the wound areas were measured and analyzed statistically. On the postoperative 7 day, the sections were made and observed by using hematoxylin and eosin (HE) staining. Results The wound areas in DESCs group and ESCs group were ( 11. 758 ± 2. 544) and ( 11.515 ± 1.351 ) mm2 on the 3rd day postoperatively, and ( 1. 795 ±1. 063) and (2. 043 ± 1. 138) mm2 on the 7th day postoperatively, respectively. The wound areas in ECs group and NS group were ( 17. 857 ± 1. 722) and ( 16. 192 ±2. 256) mm2 on the 3rd day postoperatively,and ( 1. 795 ± 1. 063) and (2. 043 ± 1. 138) mm2 on the 7th day postoperatively, respectively. There was statistically significant difference in wound area between ESCs or DESCs group and ECs, NS groups on the 3rd, 7th day postoperatively ( P ＜ 0. 01 ), but there was no statistically significant difference between DESCs and ESCs groups ( P ＞ 0. 05 ). HE staining showed the repairing quality of treatment wounds was superior to that in the control wounds, and regenerating glands and less fibrous connective tissues were seen in ESCs and EDSCs groups. Conclusion Both ESCs and DESCs could promote the wound repair.     

骨桥蛋白促创面愈合的实验研究

目的　探讨骨桥蛋白 (OPN)在创面愈合中的作用和意义 ,为筛选促进伤口愈合的外用药物提供实验依据和理论基础。方法　建立创伤实验性模型 ,将其分为OPN组、血清组、EGF组。采用免疫组织化学染色 ,Westernblot分析等方法检测Ⅰ型胶原和羟脯氨酸含量。结果　 (1)形态学改变 :术后第 1天 ,OPN组创面可见有少量的渗出物。术后第 2～ 3天 ,血清组虽有肉芽组织增生 ,但没有充满伤口底层 ;而OPN组、EGF组的创面肉芽组织增生明显。术后第 4～ 7天 ,OPN组肉芽组织层明显较血清组、EGF组薄。 (2 )免疫组织化学染色显示 ,术后第 7天 ,在OPN处理的肉芽组织中Ⅰ型胶原含量略少于EGF组 ,但比血清组高 ,其Westernblot结果与免疫组织化学基本一致。 (3 )羟脯氨酸含量 :各实验组肉芽组织中羟脯氨酸含量差异无显著性 (P >0 .0 5 )。结论　OPN是一种促炎因子 ,具有诱导创伤早期炎症反应的和愈合后期抑制肉芽组织过度增生的功能。     

Effects of immunosuppressive therapy on wound healing

Immunosuppressive therapy is increasingly being used in clinical practice and has been shown to affect wound healing to varying degrees. This article looks at the effects of the newer immunosuppressive agents on wound healing. It is shown that wound healing is impaired via different mechanisms. Some of the animal and human studies are reviewed in more detail. It is shown that some of the newer agents affect wound healing to such an extent that reduction or avoidance of these drugs until complete wound healing is achieved is advocated. More research is required for these newer agents to determine the most appropriate time to introduce them.     

Cutaneous microcirculatory assessment of the burn wound is associated with depth of injury and predicts healing time

Rationale

Current trends for the treatment of deep partial thickness and full-thickness burns include early excision and skin grafting. In this study we retrospectively evaluated the ability of Laser Doppler Flowmetry (LDF), taken within 24 h of the burn to predict: (1) burn wound depth and (2) wounds which would heal in less than 21 days.

Method

The Laser Doppler Flowmeter (O2C, LEA Medizintechnik, Germany) was employed to non-invasively measure the cutaneous microcirculation of 173 selected areas on 28 patients who suffered burns.

Results

A distinct association between initial flow (<24 h after burn injury) and the clinical assessment of depth of burn wounds was observed. Wounds demonstrating an initial blood flow of >100 AU were, in 93.1% of cases, correctly (positively) predicted for spontaneous healing within 21 days. A blood flow of <100 AU (negatively) predicted in 88.2%, those wounds which would not go on to heal within 21 days. Sequential measurement analysis (<24 h, 3 days after injury and 6 days after injury) revealed no significant decrease in skin perfusion velocity or flow rate.

Conclusion

LDF can provide immediate results for early determination of burn wound depth and is useful in selecting patients for conservative treatment of their burn wounds.