Genetic and epigenetic events in diabetic wound healing

The prevalence of the chronic metabolic disorder, diabetes mellitus, is expected to increase in the coming years and worldwide pandemic levels are predicted. Inevitably, this will be accompanied by an increase in the prevalence of diabetic complications, including diabetic foot ulcers. At present, treatment options for diabetic foot ulcers are in many cases insufficient, and progression of the condition results in the requirement for limb amputation in a proportion of patients. To improve therapy, an increase in our understanding of the pathobiology of diabetic complications such as impaired wound healing is necessary. In this review, recent advances in molecular aspects of normal and impaired diabetic wound healing are discussed. Furthermore, investigations of the role of epigenetic processes in the pathogenesis of impaired diabetic wound healing are now emerging. Indeed, epigenetic changes have already been identified as key factors in diabetes and related complications and these are overviewed in this review.     

Inflammatory biomarkers,vascular procedures of lower limbs,and wound healing

Abnormal, persistent inflammation after bypass surgery could prevent healing of an ischaemic foot lesion. In 37 patients with peripheral arterial disease (PAD) (Rutherford Grade III Category 5) who underwent infrapopliteal vein graft and midfoot amputation, plasma levels of fibrinogen, C‐reactive protein (CRP), interleukin‐1 (IL‐1), interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α), and matrix metalloproteinase‐2 and ‐9 (MMP‐2 and MMP‐9) were determined preoperatively and during the follow up. Nine patients without clinical and Doppler evidence of arterial disease, who underwent post‐traumatic midfoot primary amputation, were included in the experiment group, and 15 age‐matched healthy volunteers served as control. In patients who had midfoot amputation for trauma, all wounds healed. Seven (19%) wounds in patients with an occluded graft healed, and five (13%) required major amputation because of a non‐healing wound. Time required for complete healing of the lesion was similar between trauma and PAD patients (8 ± 2 months vs 11 ± 6, respectively, P = NS). Univariate analysis demonstrated that, in PAD patients, the postoperative high levels of TNF‐α, IL‐6, and MMP‐2 and ‐9 were predictive for wound healing failure at 3, 6, and 9 months (P < 0.05), respectively. Furthermore, the subgroup of patients who experienced occlusion of the vein graft during follow up had a significant increase of MMP‐2, ‐9, IL‐6, and TNF‐α at 3, 6, and 9 months (P < 0.05), respectively. Monitoring inflammatory markers allows the determination of patients at risk of healing failure of midfoot amputation after distal revascularisation and might predict the fate of the vein graft.     

Increased calcium levels alter cellular and molecular events in wound healing

Surgical morbidity is dictated directly by wound healing. We have studied the effects of elevated calcium levels using cultured keratinocytes in vitro on two of the rate-limiting steps of wound healing, chemotaxis (directed migration) and adhesion. We found that the increased calcium (10 mmol/L) significantly inhibited both keratinocyte chemotaxis and adhesion (p less than 0.05). The calcium effect on adhesion could be partially reversed by pretreatment with the calcium channel blocker verapamil. Based on these data, an animal model was formulated in which topical calcium (5 mmol/L/day) was added to linear incision wounds. This resulted in significantly (p less than 0.05) delayed wound contraction characteristic of a chronic or impaired wound. Wound contraction depends on the presence of fibroblasts that synthesize collagen. The chronic wound was characterized by increased collagenase activity (p less than 0.05) but little alteration in collagen I synthesis. The addition of verapamil to these chronic wounds resulted in improved wound closure. These studies define the molecular and cellular events occurring as a result of the addition of elevated levels of calcium both in vitro and in vivo. Calcium may play a key role in the pathogenesis of chronic wounds.     

Chemotherapy and wound healing

This paper provides a review of common chemotherapeutic agents and the experimental evidence supporting their effects on wound healing. Correlation with clinical studies is used to establish relevance, and therapeutic guidelines are developed.     

Immunomodulators and wound healing

The synthetic immunomodulators muramyl dipeptide (MDP), thymopoietin pentapeptide (TP5), and CP-46,665 were examined for their effects on wound healing in mice. We found no differences in wound disruption strength between immunomodulator-treated animals and saline controls on days 11, 14, and 21. The only exception was with high-dose CP-46,665, which produced weakened wounds on day 14 (p less than 0.05) and 21 (p less than 0.01). CP-46,665 was further studied by injecting high and low doses 48 hours before or after wounding. No differences were seen for these groups compared to controls at 11 and 21 days. Finally, to simulate a common clinical situation, mice were subjected to a 10% total body surface area (TBSA) burn to the right paraspinal region. Twenty-four hours later, a left paraspinal incision was performed with simultaneous injection of saline, Corynebacterium parvum (C. parvum), or low-dose TP-5, MDP, or CP-46,665. At 11 days, no detriment in wound healing was found for burned control or any of the immunomodulator-treated animals except in the C. parvum-treated mice, with significantly weakened skin strips (p less than 0.001). While C. parvum may be detrimental to wound healing, the synthetic modulators tested appear to have little effect on wound healing.     

Nutrition and wound healing

Continued research and development in the field of wound healing holds the potential to affect both quality of life and incidence of mortality. For the health care provider to promote successful wound healing, an understanding of the function of nutrients in inflammation and tissue growth is helpful. The intent of this paper is to discuss the metabolic and cellular pathways crucial to wound healing and identify appropriate nutritional interventions and clinical applications.     

Capillaroscopy and wound healing

Capillaroscopy is a very simple examination which allows good evaluation of the superficial micro-circulation of the skin. The authors consider that this new examination constitute a method to evaluate the risks of skin necrosis after facelift and abdominoplasty and, may possibly change the strategy of operations.     

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.     

Radiotherapy and wound healing

This review article discusses basic radiation physics and effects of radiation on wounds. It examines various postulated hypothesis on the role of circulatory decrease and radiation-induced direct cellular damage. The new concept related to the radiation pathogenesis proposes that there is a cascade of cytokines initiated immediately after the radiation. Sustained activation of myofibroblasts in the wound accounts for its chronicity. Recent advances highlight that transforming growth factor beta1 is the master switch in pathogenesis of radiation fibrosis. This articles overviews its role and summarises the available evidences related to radiation damage. The goal of this article was to provide its modern understanding, as future research will concentrate on antagonising the effects of cytokines to promote wound healing.     

Colchicine and wound healing

Rats with incised and sutured wounds and having subcutaneously implanted polyvinyl alcohol sponges were treated with various doses of colchicine. Breaking strength of wound tissue and biochemical analysis of sponge-induced granuloma tissue were compared with similar measurements in pair-fed controls. Colchicine reduced breaking strength of wound scar tissue significantly while lysyl oxidase activity in sponge tissue was not affected. Synthesis of collagenous and noncollagenous protein was stimulated by colchicine but accelerated collagen synthesis did not result in increased deposition of collagen in sponge tissue. The increased urinary excretion of hydroxyproline in colchicine-treated rats was paralleled by loss of body weight. Colchicine-induced cytotoxicity was also identified in fibroblasts from sponge granuloma tissue examined by transmission electron microscopy. We conclude that some reduction of total collagen deposition and breaking strength of wound tissue in colchicine-treated animals may have been the result of general toxicity of the drug. A specific effect of colchicine on collagen metabolism cannot be ruled out.     

Nutrition and wound healing

The relationship between host nutrition and wound healing has been the subject of study and experimentation for centuries. Despite the many years of study and a substantial knowledge base of the specific processes and factors involved, wound healing remains enigmatic. There is still much to learn about the wound-specific nutritional interventions that are available to improve wound healing. Nutrition profoundly influences the process of wound healing. Nutritional depletion exerts an inhibitory effect, and nutritional supplementation with such positive effectors as arginine can stimulate wound healing. Within this paradigm, the physician should be able to recognize patients who may be expected to have wound healing difficulties and offer early intervention to avoid wound failure.     

Radiotherapy and wound healing

Radiotherapy is an invaluable weapon when treating cancer. However, the deleterious effects of radiation, both immediate and long-term, may have a significant effect on local tissues. Problematic wound healing in radiation-damaged tissue constitutes a major problem that is frequently overlooked during the management of patients who require radiotherapy, or have had radiotherapy in the past. Poor wound healing may lead to chronic ulceration, pain, secondary infection and psychological distress and compromise the outcome of general or reconstructive surgery. We discuss the pathophysiology of poor wound healing following radiotherapy, specific problems for radiation-damaged tissue and potential treatments to improve wound healing of irradiated tissues.     

Oxygen and wound healing

Surgeons have been aware of the detrimental effect of ischemia and hypoxia on healing tissues. In order to assist repair in such circumstances, a variety of modalities including revascularization, flaps, and hyperbaric O2 have been developed. Although these are apparently successful from a clinical standpoint, only recently has experimental evidence demonstrated conclusively that oxygen is a controlling factor in wound repair. Furthermore, it is now clear that traditional expectations of repair can often be exceeded by increasing the partial pressure at which oxygen is supplied to wounds.     

Disorders of wound healing

The healing wound offers a variety of potential end results. The surgeon's responsibility is to define what he wants and then arrange to get it. History has proved that technical improvements can eliminate disorders such as dehiscence and incisional hernias. Technical improvements should diminish the frequency of failed tendon repairs. When the author first became interested in wound healing and was asked to consult about a poorly healing wound, he could only offer the ideas that ascorbic acid might be given and that nutrition in some nonspecific way might be increased. Now, it is an unusual wound that cannot be made to heal in one way or another; wounds that cannot be made to heal are almost always a result of severe regional ischemia with or without osteoradionecrosis. Even moderately severe osteoradionecrosis can now be expected to heal by supplying the major deficiency consequent upon vascular damage by radiation, namely, oxygen (by hyperbaric administration). Perhaps most important to the surgeon is the knowledge that many kinds of disordered repair can be avoided. Liver disease can be treated, steroid hormone excess can be corrected or specifically treated with vitamin A, and nutritional defects can be anticipated and avoided. Familial tendencies to scar formation can be thwarted at an earlier rather than later, often hopeless, stage. Burn contractions in particularly susceptible joints can be anticipated and prevented by splinting and traction. In fact, we are coming very close to having effective treatment for most of the recognizable postsurgical reparative disorders. What we do not have is a prevention or cure for a vast variety of conditions of excessive repair, conditions that surgeons do not ordinarily recognize as complications. A vast amount of human misery is due to hypertrophic scar formation in arteries (arteriosclerosis), joints (arthritis), and ocular disease, especially those involving the scarring of the cornea. It is very likely that the surgeons will contribute to the prevention and cure of these disorders if they will accept the view that they can expect something close to perfection in any wound they make.     

Prognosis of wound healing

The knowledge of prognosis of wound healing ist important for the preparation of patients to the operation and for prophylaxis of wound infections. This study on 625 patients demonstrates a method for investigation an objective prognosis. The method allows the selection of patients with a high risk of wound infection.