Pain mediators and wound healing-Establishing the connection

Pain accompanies every disruption of the skin surface in a normal sensate individual. The intensity and duration of the pain varies depending on the nature of trauma, the healing trajectory and various host factors. Pain mediator release is the mechanism for pain perception following peripheral stimulus and central interpretation. The various mediators may have promoting effects on wound healing in the short term, but it appears that protracted release of these mediators may well have detrimental effects on wound healing. The exaggerated release of pain mediators may result in nociceptor hypersensitization, hyperinflammatory cellular and extracellular matrix (ECM) changes, and in some cases, the potential for a fibrotic healing pattern. This relates to an imbalance between mediators with differing healing characteristics arising in certain pathological conditions. In this respect, it may be worth examining pain mediator agonists or antagonists, not only on compassionate grounds of pain control, but relating to the potential effects on overall wound healing.     

A review of the role of mechanical forces in cutaneous wound healing

Cutaneous wound healing is a complex process with many types of mechanical forces regulating the quality and speed of healing. The role of mechanical forces in regulating tissue growth, repair and remodelling was recognised more than a century ago. Such forces influence gene expression, the synthesis of growth factors and inflammatory mediators and cellular processes like proliferation of many load-sensitive cells. However, the exact mechanisms by which these forces interact with cells and ways to use them to stimulate tissues are still active research fronts. This article sets to review the literature on mechanical forces and their role in cutaneous wound healing.     

Bioengineered alternative tissues and hyperbaric oxygen in lower extremity wound healing

With the advent and clinical application of recombinant chemical and cellular mediators of wound healing and a better understanding of the importance of serial debridement, most foot wounds can be healed with little morbidity. Despite these advances, there remains the recalcitrant wound for which more heroic efforts seem warranted. For these patients, advanced wound healing technologies, orthobiologics, and bioengineered alternative tissues may tilt the scales in the direction of definitive wound closure.     

Normal Cutaneous Wound Healing: Clinical Correlation with Cellular and Molecular Events

BACKGROUND: Cutaneous wound healing is a normal physiologic function, observed and described for centuries by those afflicted with wounds and by those caring for them. Recently, tremendous progress has been made in discovering the cellular and molecular mechanisms responsible for wound healing. Counseling patients appropriately and planning future therapeutic interventions in delayed or abnormal wound healing may be improved by a thorough understanding of the relationship between clinical, cellular, and subcellular events occurring during the normal healing process. MATERIALS AND METHODS: A review of the wound healing literature from the past several decades, with a focus on the past 5 to 10 years in particular, along with illustrative case examples from our clinical practice over the past decade. RESULTS: Traditional clinical stages of wounding healing are still relevant, but more overlap between stages is likely a more accurate depiction of events. The role of cells such as platelets, macrophages, leukocytes, fibroblasts, endothelial cells, and keratinocytes is much better known, particularly during the inflammatory and proliferation stages of healing. Molecules such as interferon, integrins, proteoglycans and glycosaminoglycans, matrix metalloproteinases, and other regulatory cytokines play a critical role in the regulation of healing mechanisms. CONCLUSION: Cutaneous wound healing in normal hosts follows an orderly clinical process. The scientific underpinnings for healing are better understood than ever, although much remains to be discovered. Eventually, such improved understanding of cellular and subcellular physiology may lead to new or better forms of therapy for patients with acute, chronic, and surgical skin wounds.     

The role of mast cells in wound healing

Mast cells are predominantly found in the vicinity of connective tissue vessels of skin and mucosa. The main immunological functions of mast cells are in IgE‐mediated reactions and in helminth infestations. Mast cells respond to tissue injury by releasing inflammatory mediators and have been implicated in diseases of excessive fibrosis of the dermis such as scleroderma. Current evidence suggests that mast cells exert its role during inflammation and cellular proliferation. Animal models have shown that by stabilising mast cells at the early stages of wound healing, wound contraction is reduced. Mast cells are an ideal candidate to play a pivotal role in wound healing due to its location, substances released and clinical associations.     

Inflammation and wound healing: the role of bacteria in the immuno-regulation of wound healing

Wound healing is a sequence of complex events, an imbalance of which can result in a failure of the wound to heal, with significant implications for patients and health care services alike. Although the exact mechanism that underlies these events is not fully understood, inflammatory processes and the innate immune system play a vital role, not only in normal wound healing but also in the pathophysiology of delayed wound healing. These defense mechanisms are affected by underlying disease states and medical conditions, for example, diabetes, venous insufficiency, and the inflammation associated with acute trauma. Importantly, however, these processes are also modulated in health by bacteria within the wound. This article examines the role of the mediators of inflammation involved in the wound-healing process and discusses the function of these mediators when normal healing fails. The reaction of the wound to bacterial contamination and the effect of bacteria on wound healing are also discussed.     

An update on wound management

This article provides an update on wound management with wound diagnosis and treatment discussed in terms of the normal cellular events of the wound healing process. The role of growth factors as cell regulators, the importance of wound fluids to wound metabolism, and the deleterious effects of some wound cleansers, disinfectants, and modalities are reviewed. Treatment guidelines are suggested based on negative or positive cellular response to individual management techniques. Wound evaluation, diagnosis, and treatment are considered in terms of a new color concept that simplifies clinical decision making. An explanation of the relatively new microenvironmental dressings designed to maintain wound humidity and speed wound healing is provided. A more physiologic approach to managing the simple and complex wound may prove to speed the process of epithelialization, contraction, and collagen deposition while diminishing the problems associated with delayed or inadequate healing. The wound healing process is subject to manipulation and facilitation by the clinician, a concept that is certain to receive much attention in the next decade. The importance of a scientific approach to this aspect of our discipline cannot be overemphasized.     

Stimulated neovascularization, inflammation resolution and collagen maturation in healing rat cutaneous wounds by a heparan sulfate glycosaminoglycan mimetic, OTR4120

Heparan sulfate glycosaminoglycans (HS-GAGs) are not only the structural elements of tissue architecture but also regulate the bioavailability and transduction pathways of heparan sulfate-bound polypeptides released by cells or the extracellular matrix. Heparan sulfate-bound polypeptides include inflammatory mediators, chemokines, angiogenic factors, morphogens, and growth-promoting factors that induce cell migration, proliferation, and differentiation in wound healing. OTR4120, a polymer engineered to mimic the properties of HS-GAGs, is used to replace the natural HS-GAGs that are degraded during wound repair, and enhance the tissue regeneration by preserving the cellular microenvironment and the endogenous signals needed for tissue regeneration. We previously demonstrated that OTR4120 treatment had a long-term effect on increasing breaking strength and vasodilation in healing rat full-thickness excisional wounds. The present study investigates the underlying mechanisms of the effects of OTR4120 treatment in improving the quality of cutaneous wound repair. We found that OTR4120 treatment stimulated inflammation resolution and increased neovascularization. OTR4120 treatment also promoted epidermal migration and proliferation during reepithelialization. Moreover, the granulation tissue formation and collagen maturation were improved in OTR4120-treated wounds. Three months after wounding, the effects of OTR4120 treatment on vascularization and inflammation resolution were normalized, except for an improved neodermis. We conclude that OTR4120 is a potential matrix therapeutic agent that ensures the quality of normal cutaneous wound repair and may restore impaired wound healing characterized by deficient angiogenesis and prolonged inflammation.     

Effect of aging on wound healing: current concepts.

The population is aging, and advanced age is commonly identified as a risk factor for delayed wound healing. Therefore, it is important for WOC nurses to be knowledgeable about how aging affects the wound healing and repair process, and strategies they can use to promote healing in the elderly population. Impaired wound healing in the aged is due partly to comorbidities common among the elderly, but evidence also suggests that inherent differences in cellular structure and function may impair tissue repair and regeneration as well. This article will address the effect of aging on wound healing, with a particular focus on processes of cellular senescence and related factors hypothesized to result in slowed or impaired wound healing in the elderly.     

Effect of estrogen and progesterone on macrophage activation during wound healing

Age-related impaired wound healing leads to substantial morbidity and mortality along with a large financial burden to health services. There is accumulating evidence that the tissue damage associated with chronic wounds is initiated and propagated by an inappropriately excessive inflammatory response. Research on age-related impaired wound healing suggests that the decline in sex steroid hormones with age may have a substantial influence on the inflammatory response in vivo. Topical and systemic estrogen treatments have shown an increased rate of healing by reducing inflammation, however the underlying mechanisms are little understood. In vitro studies also suggest progesterone may play a role in modulating inflammation. Macrophages are essential mediators of inflammation and wound healing. Macrophages can be activated in a classical or alternative manner in parallel with the T_H1/T_H2 dichotomy, respectively. Using a murine incisional wound healing model this study was carried out to investigate the roles of estrogen and progesterone on macrophage activation during the wound healing response. Our findings suggest with a reduction of steroid hormones following ovariectomy, alternatively activated macrophage markers (Fizz1 and Ym1) were reduced, with this effect being reversed with the administration of estrogen or progesterone; suggesting that with the reduction of steroid hormones macrophages are activated in a classical manner, promoting inflammation, whereas estrogen or progesterone are contributing toward macrophage activation in an alternative manner, driving wound repair, angiogenesis, and remodeling.     

Interactions of cytokines, growth factors, and proteases in acute and chronic wounds

A healing wound represents a complex series of interactions between cells, soluble mediators, and extracellular matrix. Within this multifaceted environment, there are multiple regulatory points which control the ordered series of events that lead to normal tissue repair. An alteration in this physiologic network can lead to the development of a chronic wound. This article presents an update on the numerous mediators that exist within the wound environment in both acute normal healing and chronic nonhealing wounds. We also present a hypothesis which may provide a conceptual pathophysiologic mechanism with which to understand all chronic wounds.     

Cachexia – an intrinsic factor in wound healing

Systemic diseases are intrinsic factors that alter and may impair the wound healing process. Cachexia is a manifestation of systemic, often chronic, diseases and is characterised by systemic inflammation, appetite suppression and skeletal muscle wasting. Anorexia in cachectic states is commonly associated with malnutrition. Malnutrition may cause impaired healing. Therefore, it would follow that cachexia could influence wound healing because of reduced food intake. However, the lack of response to measures to reverse cachexia, such as supported nutrition, would suggest that a direct causal link between anorexia and weight loss in cachexia is too simple a model. To date, there is no published literature that examines the role of cachexia in human wound healing specifically. This article aims to demonstrate that cachexia is an intrinsic factor in wound healing. The role of the common mediators in wound healing and in cachexia are compared – specifically inflammation, including the nitric oxide synthase pathway, collagen deposition and reepithelialisation.     

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.     

Wound metabolism

The science of wound healing is vital to all aspects of plastic surgery. Knowledge of wound metabolism is essential to a complete understanding of wound healing. Through various laboratory models, we have isolated and studied many of the parameters involved in tissue repair and metabolism. Our findings suggest that biochemical aspects of wound healing are directed by the metabolism of the cellular infiltrate in the wound. These findings help to explain the independent nature of the wound during its healing process ("biological priority").     

Role of alpha(v) integrins and angiogenesis during wound repair.

Angiogenesis, the formation of new blood vessels from pre-existing blood vessels, is thought to be critical for wound repair. Yet few studies have critically examined dermal wound repair in a system in which angiogenesis was impaired. Since alpha(v)-containing integrins are critical for angiogenesis, we administered either an alpha(v) integrin blocking antibody or cyclic Arg-Gly-Asp peptide into a murine excisional wound model to restrict wound angiogenesis. Although both methods markedly decreased wound angiogenesis, decreased angiogenesis had no significant effect on wound epithelization, contraction, or ultimate wound closure. These results suggest that if other cellular components of wound healing are intact, moderate impairment of angiogenesis alone does not necessarily retard normal wound healing.     

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.     

Electric stimulation and wound healing

Interest in accelerating the process of wound healing has existed since the beginning of health care. Although significant advances have been made in our understanding of the stages of wound healing, the mediators of tissue repair and regeneration, as well as the efficacy of many treatments, have not been fully evaluated. This article will review electric stimulation as one means to promote wound healing.     

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.     

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.