Physiologie und Pathophysiologie der Heilung von Defektwunden

Understanding wound healing involves more than simply stating that there are the three phases of inflammation, proliferation and maturation. Wound healing is a complex series of actions, reactions and interactions among cells and mediators in a sequential and simultaneously ongoing temporal process within a spatial frame. At first this article will attempt to provide a concise summary of the events, cellular components and main influential mediators of wound healing over time. Secondly, the pathophysiology of chronic non-healing wounds is described where an imbalance of stimulating and inhibiting factors causes failure of healing. The most relevant extrinsic and intrinsic determinants are described and related to the cellular and molecular level of disturbed wound healing. A basic understanding of wound healing is a prerequisite for any prophylactic or therapeutic maneuver to maintain or re-establish wound equilibrium to give a satisfactory healing trajectory.     

The science of wound bed preparation

The concept of wound bed preparation (WBP) heralded a new era in terms of how we treat wounds. It emphasized the difference between acute and chronic wounds, and it cemented the idea that the processes involved in the healing of acute wounds do not apply completely to the healing of chronic wounds. The arbitrary division of the normal healing process into the phases of hemostasis, inflammation, proliferation, and maturation addresses the events in acute wound healing. We have realized that the impediments to healing in chronic wounds lead to a failure to progress through these phases and are independent factors that make the chronic wound a much more complex condition. A major advance in resolving or addressing the chronic wound has been the concept of WBP. WBP allows us to address the problems of wound healing individually-the presence of necrotic tissue, hypoxia, high bacterial burden, corrupt matrix, and senescent cells within the wound bed. In WBP we can optimize our therapeutic agents to accelerate endogenous healing or to increase the effectiveness of advanced therapies.     

Integrated negative pressure wound therapy system with volumetric automated fluid instillation in wounds at risk for compromised healing

Nearly all wounds are at risk for compromised healing due to excessive exudation, oedema, contaminants and presence of inflammatory mediators. Compromised wounds have the potential to develop complications, such as infection, which may lead to delayed wound healing, prolonged hospitalisation and more frequent readmissions. It is generally believed that the wound advances from contamination to colonisation when the bacteria on the wound's surface begin to replicate and increase their metabolic activity. Heavy bacterial bioburden increases the metabolic requirements, stimulates a proinflammatory environment and encourages the in-migration of monocytes, macrophages and leukocytes - all of which can negatively impact wound healing. Bacteria also secrete harmful cytokines which can lead to vasoconstriction and decreased blood flow. Thus, controlling or preventing infections is essential for normal wound healing process to occur. While the mainstay of treating wound infection has historically included intravenous, oral and/or topical antimicrobials in addition to frequent gauze dressing changes, a shift towards wound management with advanced modalities, such as negative pressure wound therapy (NPWT), has occurred during the past decade. This review will provide expert opinion and scientific support for the use of NPWT with instillation (NPWTi; V.A.C. Instill? Wound Therapy and V.A.C. VeraFlo? Therapy, KCI USA, Inc., San Antonio, TX) for the treatment of at-risk and complicated wounds.     

基因治疗与皮肤创面愈合

皮肤创面愈合过程是一个多因素参与的复杂过程,慢性、难愈创面严重影响了人们的生活质量.重组生长因子已经在临床用于改善创面愈合,但由于半衰期短、生物利用度低等原因,使得其临床疗效欠佳.近年来,随着基因工程技术的不断发展,基因治疗已经成为改善创面愈合的一种新的治疗方法.本文就目前基因治疗方法的优缺点、治疗性基因选择和正在进行的临床试验等方面进行了综述.     

Epidermal growth factor therapy and wound healing--past, present and future perspectives

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.     

Wound chronicity and fibroblast senescence--implications for treatment

A proportion of chronic wounds fail to heal in response to standard therapy. For venous leg ulcers, a correlation exists between longer duration before treatment initiation and poor healing response to compression therapy. Differences identified between the healing wound microenvironment and that of the non healing chronic wound suggests that many potential mechanisms exist to impair healing. One contributory mechanism may be inhibition of fibroblast proliferation and induction of a stress-induced premature senescence phenotype by the continuing inflammation found in chronic wounds. Senescent fibroblasts exhibit an extracellular matrix degradative phenotype that contributes to wound chronicity. Accumulation of greater than 15% senescent fibroblasts has been described as a threshold beyond which wounds become hard to heal. The ratio of senescent : non senescent cells is therefore critical to determining response to treatment, and adjunctive therapies that modulate this ratio in favour of non senescent cells are likely to enhance therapeutic healing rates. A number of tissue-engineered dermal replacements contain non senescent fibroblasts and can donate cells to the wound environment additional to releasing growth factors and reversing the antiproliferative activity of chronic wound exudate. Recognition of the role of fibroblast senescence in wound chronicity may allow for identification of those wounds that will respond positively to these products.     

Wound bed preparation: a systematic approach to wound management

The healing process in acute wounds has been extensively studied and the knowledge derived from these studies has often been extrapolated to the care of chronic wounds, on the assumption that nonhealing chronic wounds were simply aberrations of the normal tissue repair process. However, this approach is less than satisfactory, as the chronic wound healing process differs in many important respects from that seen in acute wounds. In chronic wounds, the orderly sequence of events seen in acute wounds becomes disrupted or “stuck” at one or more of the different stages of wound healing. For the normal repair process to resume, the barrier to healing must be identified and removed through application of the correct techniques. It is important, therefore, to understand the molecular events that are involved in the wound healing process in order to select the most appropriate intervention. Wound bed preparation is the management of a wound in order to accelerate endogenous healing or to facilitate the effectiveness of other therapeutic measures. Experts in wound management consider that wound bed preparation is an important concept with significant potential as an educational tool in wound management. This article was developed after a meeting of wound healing experts in June 2002 and is intended to provide an overview of the current status, role, and key elements of wound bed preparation. Readers will be able to examine the following issues; ? the current status of wound bed preparation; ? an analysis of the acute and chronic wound environments; ? how wound healing can take place in these environments; ? the role of wound bed preparation in the clinic; ? the clinical and cellular components of the wound bed preparation concept; ? a detailed analysis of the components of wound bed preparation. (WOUND REP REG 2003;11:1–28)     

Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers

The cause of impaired healing in chronic leg ulcers is not known. However, recent attempts to modify the healing process have focused on adding growth factors to stimulate healing and have failed to produce dramatic improvements in healing. This study used a unique model of chronic wound healing in humans to obtain wound fluid samples from chronic venous leg ulcers that had changed from a nonhealing to a healing phase. These samples were used to assess cytokine and growth factor levels, and mitogenic activity in these nonhealing and healing chronic wounds. The pro-inflammatory cytokines interleukin-1, interleukin-6 and tumor necrosis factor-alphawere found to be present in significantly higher concentrations in wound fluid from nonhealing compared to healing leg ulcers. There were detectable levels but, no significant change in the levels of platelet derived growth factor, epidermal growth factor, basic fibroblast growth factor or transforming growth factor-betaas ulcers healed. Wound fluid was added to fibroblasts in vitro to assess mitogenic activity. There was a significantly greater proliferative response to healing wound fluid samples compared to nonhealing samples. These results suggest that healing may be impaired by inflammatory mediators rather than inhibited by a deficiency of growth factors in these chronic wounds.     

The role of endogenous and exogenous enzymes in chronic wounds: A focus on the implications of aberrant levels of both host and bacterial proteases in wound healing

Cutaneous wound healing is orchestrated by a number of physiological pathways that ultimately lead to reformation of skin integrity and the production of functional scar tissue. The remodeling of a wound is significantly affected by matrix metalloproteinases (MMPs), which act to control the degradation of the extracellular matrix (ECM). Regulation of MMPs is imperative for wound healing as excessive levels of MMPs can lead to disproportionate destruction of the wound ECM compared to ECM deposition. In addition to human MMPs, bacterial proteases have been found to be influential in tissue breakdown and, as such, have a role to play in the healing of infected wounds. For example, the zinc‐metalloproteinase, elastase, produced by Pseudomonas aeruginosa, induces degradation of fibroblast proteins and proteoglycans in chronic wounds and has also been shown to degrade host immune cell mediators. Microbial extracellular enzymes have also been shown to degrade human wound fluid and inhibit fibroblast cell growth. It is now being acknowledged that host and bacterial MMPs may act synergistically to cause tissue breakdown within the wound bed. Several studies have suggested that bacterial‐derived secreted proteases may act to up‐regulate the levels of MMPs produced by the host cells. Together, these findings indicate that bacterial phenotype in terms of protease producing potential of bacteria should be taken into consideration during diagnostic and clinical intervention of infected wound management. Furthermore, both host MMPs and those derived from infecting bacteria need to be targeted in order to increase the healing capacity of the injured tissue. The aim of this review is to investigate the evidence suggestive of a relationship between unregulated levels of both host and bacterial proteases and delayed wound healing.     

Wound bed preparation: a systematic approach to wound management

The healing process in acute wounds has been extensively studied and the knowledge derived from these studies has often been extrapolated to the care of chronic wounds, on the assumption that nonhealing chronic wounds were simply aberrations of the normal tissue repair process. However, this approach is less than satisfactory, as the chronic wound healing process differs in many important respects from that seen in acute wounds. In chronic wounds, the orderly sequence of events seen in acute wounds becomes disrupted or "stuck" at one or more of the different stages of wound healing. For the normal repair process to resume, the barrier to healing must be identified and removed through application of the correct techniques. It is important, therefore, to understand the molecular events that are involved in the wound healing process in order to select the most appropriate intervention. Wound bed preparation is the management of a wound in order to accelerate endogenous healing or to facilitate the effectiveness of other therapeutic measures. Experts in wound management consider that wound bed preparation is an important concept with significant potential as an educational tool in wound management.
This article was developed after a meeting of wound healing experts in June 2002 and is intended to provide an overview of the current status, role, and key elements of wound bed preparation. Readers will be able to examine the following issues;
• the current status of wound bed preparation;
• an analysis of the acute and chronic wound environments;
• how wound healing can take place in these environments;
• the role of wound bed preparation in the clinic;
• the clinical and cellular components of the wound bed preparation concept;
• a detailed analysis of the components of wound bed preparation.
(WOUND REP REG 2003;11:1–28)     

Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS‐modulating technologies for augmentation of the healing process

Reactive oxygen species (ROS) play a pivotal role in the orchestration of the normal wound‐healing response. They act as secondary messengers to many immunocytes and non‐lymphoid cells, which are involved in the repair process, and appear to be important in coordinating the recruitment of lymphoid cells to the wound site and effective tissue repair. ROS also possess the ability to regulate the formation of blood vessels (angiogenesis) at the wound site and the optimal perfusion of blood into the wound‐healing area. ROS act in the host's defence through phagocytes that induce an ROS burst onto the pathogens present in wounds, leading to their destruction, and during this period, excess ROS leakage into the surrounding environment has further bacteriostatic effects. In light of these important roles of ROS in wound healing and the continued quest for therapeutic strategies to treat wounds in general and chronic wounds, such as diabetic foot ulcers, venous and arterial leg ulcers and pressure ulcers in particular, the manipulation of ROS represents a promising avenue for improving wound‐healing responses when they are stalled. This article presents a review of the evidence supporting the critical role of ROS in wound healing and infection control at the wound site, and some of the new emerging concepts associated with ROS modulation and its potential in improving wound healing are discussed.     

Early healing events in a porcine model of contaminated wounds: effects of nanocrystalline silver on matrix metalloproteinases, cell apoptosis, and healing

A porcine model of wound healing was employed to examine the impact of nanocrystalline silver-coated dressings on specific wound healing events. Full-thickness wounds were created on the backs of pigs, contaminated with an experimental inoculum containing Pseudomonas aeruginosa, Fusobacterium sp., and coagulase-negative staphylococci, and covered with dressing products either containing silver or not. Nanocrystalline silver-coated dressings promoted rapid wound healing, particularly during the first several days post-injury. Healing was characterized by rapid development of well vascularized granulation tissue that supported tissue grafting 4 days post-injury, unlike control dressed wounds. The proteolytic environment of wounds treated with nanocrystalline silver was characterized by reduced levels of matrix metalloproteinases. Matrix metalloproteinases have been shown to be present in chronic ulcers at abnormally high levels, as compared with acute wounds, and may contribute to the nonhealing nature of these wounds. Cellular apoptosis occurred at a higher frequency in the nanocrystalline silver-treated wounds than in wounds dressed with other products. The results suggest that nanocrystalline silver may play a role in altering or compressing the inflammatory events in wounds and facilitating the early phases of wound healing. These benefits are associated with reduced local matrix metalloproteinase levels and enhanced cellular apoptosis.     

Topically applied rhGM-CSF for the wound healing: a systematic review

The process of wound healing involves a complex interplay of cells, mediators, growth factors and cytokines. GM-CSF has been shown to be involved in a number of processes essential in this event. Topically applied rhGM-CSF has been reported to successfully treat wounds with diverse etiology, including burns, chronic venous leg ulcers, pressure ulcers, and leprosy ulcers, both in animal experiments and clinical studies. To evaluate the effect of the rhGM-CSF on wound healing, 8 RCT studies and 23 clinical studies and case reports are collected for analysis of the evidence. The overall effects of rhGM-CSF on the healing of wound are diverse. Topically applied rhGM-CSF is beneficial for deep partial-thickness burn wounds, chronic leg ulcers, and leprosy ulcers. rhGM-CSF may have a positive effect on other type of chronic ulcers such as pressure ulcers and cancer related ulcers, but the evidence is not sufficient for generalised use at present. rhGM-CSF is suggested have no accelerating effect on the healing of healthy wounds or surgical incisions.     

Neutrophils extracellular traps and ferroptosis in diabetic wounds

Wound healing is an extremely complex process involving multiple levels of cells and tissues. It is mainly completed through four stages: haemostasis, inflammation, proliferation, and remodelling. When any one of these stages is impaired, it may lead to delayed healing or even transformation into chronic refractory wounds. Diabetes is a kind of common metabolic disease that affects approximately 500 million people worldwide, 25% of whom develop skin ulcers that break down repeatedly and are difficult to heal, making it a growing public health problem. Neutrophils extracellular traps and ferroptosis are new types of programmed cell death identified in recent years and have been found to interact with diabetic wounds. In this paper, the normal wound healing and interfering factors of the diabetic refractory wound were outlined. The mechanism of two kinds of programmed cell death was also described, and the interaction mechanism between different types of programmed cell death and diabetic refractory wounds was discussed.     

Enhanced epithelial gap closure and increased angiogenesis in wounds of diabetic mice treated with adult murine bone marrow stromal progenitor cells

The direct application of bone marrow (BM) can accelerate the healing of chronic wounds. We hypothesized that this effect is due to the presence of stromal progenitor cells (SPCs) found within whole BM preparations. To test this hypothesis, we isolated adult murine SPCs from whole BM and examined their ability to enhance impaired wound healing compared with ficoll separated BM cells in the diabetic (db/db) mouse model. SPCs significantly enhanced reepithelialization, granulation tissue formation, and neovascularization compared with control wounds treated with BM or PBS alone. Higher frequencies of donor SPC cells compared with donor BM cells were observed in treated wounds at 7 days. Transdifferentiation into GFP-positive mature endothelial cells was not observed. These observations suggest that SPCs improve wound healing through indirect mechanisms which lead to enhanced vascularization rather than through direct participation and incorporation into tissue. We conclude that topical application of BM-derived SPCs may represent an effective strategy for the treatment of chronic diabetic wounds.     

Human acellular dermal wound matrix: evidence and experience

A chronic wound fails to complete an orderly and timely reparative process and places patients at increased risk for wound complications that negatively impact quality of life and require greater health care expenditure. The role of extracellular matrix (ECM) is critical in normal and chronic wound repair. Not only is ECM the largest component of the dermal skin layer, but also ECM proteins provide structure and cell signalling that are necessary for successful tissue repair. Chronic wounds are characterised by their inflammatory and proteolytic environment, which degrades the ECM. Human acellular dermal matrices, which provide an ECM scaffold, therefore, are being used to treat chronic wounds. The ideal human acellular dermal wound matrix (HADWM) would support regenerative healing, providing a structure that could be repopulated by the body's cells. Experienced wound care investigators and clinicians discussed the function of ECM, the evidence related to a specific HADWM (Graftjacket^® regenerative tissue matrix, Wright Medical Technology, Inc., licensed by KCI USA, Inc., San Antonio, TX), and their clinical experience with this scaffold. This article distills these discussions into an evidence‐based and practical overview for treating chronic lower extremity wounds with this HADWM.     

Infected chronic wounds show different local and systemic arginine conversion compared with acute wounds

BACKGROUND: Several experimental studies have shown the importance of arginine in wound healing. However, little is known about its role in human wound healing. In this study, we investigated arginine metabolism in impaired wound healing. MATERIALS AND METHODS: Twenty patients with chronic wounds and 10 patients with acute wounds were included in a prospective study. Amino acids, nitrate/nitrite, and arginase concentrations were determined in plasma and wound fluid using high-performance liquid chromatography and enzyme-linked immunosorbent assay. Chronic wounds were divided into two groups: noninfected chronic wounds (n = 11) and infected chronic wounds (n = 9), based on quantitative bacterial analysis of wound fluid samples. RESULTS: Plasma arginine levels, next to total plasma amino acid levels, were significantly decreased in patients with infected chronic wounds compared with patients having acute or noninfected wounds. Citrulline and ornithine levels were significantly increased in infected chronic wounds and related to decreased nitrate/nitrite levels, whereas wound fluid arginine levels were similar in all groups. In addition, wound fluid arginase levels of infected chronic wounds were significantly enhanced. CONCLUSIONS: This study demonstrates that patients with infected chronic wounds have decreased plasma arginine levels and suggests enhanced arginine conversion in the wound. In contrast to noninfected chronic wounds, arginine seems to be mainly metabolized by arginase in infected chronic wounds. In conclusion, our hypothesis is that impaired wound healing is related to an altered arginine usage.     

Time course study of delayed wound healing in a biofilm‐challenged diabetic mouse model

Bacterial biofilm has been shown to play a role in delaying wound healing of chronic wounds, a major medical problem that results in significant health care burden. A reproducible animal model could be very valuable for studying the mechanism and management of chronic wounds. Our previous work showed that Pseudomonas aeruginosa (PAO1) biofilm challenge on wounds in diabetic (db/db) mice significantly delayed wound healing. In this wound time course study, we further characterize the bacterial burden, delayed wound healing, and certain aspects of the host inflammatory response in the PAO1 biofilm‐challenged db/db mouse model. PAO1 biofilms were transferred onto 2‐day‐old wounds created on the dorsal surface of db/db mice. Control wounds without biofilm challenge healed by 4 weeks, consistent with previous studies; none of the biofilm‐challenged wounds healed by 4 weeks. Of the biofilm‐challenged wounds, 64% healed by 6 weeks, and all of the biofilm‐challenged wounds healed by 8 weeks. During the wound‐healing process, P. aeruginosa was gradually cleared from the wounds while the presence of Staphylococcus aureus (part of the normal mouse skin flora) increased. Scabs from all unhealed wounds contained 10⁷ P. aeruginosa, which was 100‐fold higher than the counts isolated from wound beds (i.e., 99% of the P. aeruginosa was in the scab). Histology and genetic analysis showed proliferative epidermis, deficient vascularization, and increased inflammatory cytokines. Hypoxia inducible factor expression increased threefold in 4‐week wounds. In summary, our study shows that biofilm‐challenged wounds typically heal in approximately 6 weeks, at least 2 weeks longer than nonbiofilm‐challenged normal wounds. These data suggest that this delayed wound healing model enables the in vivo study of bacterial biofilm responses to host defenses and the effects of biofilms on host wound healing pathways. It may also be used to test antibiofilm strategies for treating chronic wounds.     

Wound duration and healing rates: Cause or effect?

Multiple factors affect the likelihood of a wound healing. One of these factors, wound duration, is well known to be related to healing rates, with numerous publications showing that older wounds are less likely to heal. However, disentangling the effect of this factor on wound healing rates is complex. Is this simply an observation of the obvious; wounds of longer duration will by definition be harder to heal? Or does time represent an independent factor, implying that should treatments be given earlier in the disease process, better outcomes may result? This review summarizes the available evidence of the effects of wound duration on healing rates and examines potential biological aberrations identified in chronic wounds, which may be significant in making chronic wounds difficult to heal. Wounds of longer duration are associated with excessive inflammation, fibroblast senescence, and alterations in wound bed flora, which appears to have a temporal relationship. Early and aggressive treatment of ulcers that fail to respond to standard care may well aid in reducing the burden of wounds that become chronic.