Harold Brem

Growth factors and cytokines in wound healing

Wound healing is an evolutionarily conserved, complex, multicellular process that, in skin, aims at barrier restoration. This process involves the coordinated efforts of several cell types including keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. The migration, infiltration, proliferation, and differentiation of these cells will culminate in an inflammatory response, the formation of new tissue and ultimately wound closure. This complex process is executed and regulated by an equally complex signaling network involving numerous growth factors, cytokines and chemokines. Of particular importance is the epidermal growth factor (EGF) family, transforming growth factor beta (TGF‐β) family, fibroblast growth factor (FGF) family, vascular endothelial growth factor (VEGF), granulocyte macrophage colony stimulating factor (GM‐CSF), platelet‐derived growth factor (PDGF), connective tissue growth factor (CTGF), interleukin (IL) family, and tumor nerosis factor‐α family. Currently, patients are treated by three growth factors: PDGF‐BB, bFGF, and GM‐CSF. Only PDGF‐BB has successfully completed randomized clinical trials in the Unites States. With gene therapy now in clinical trial and the discovery of biodegradable polymers, fibrin mesh, and human collagen serving as potential delivery systems other growth factors may soon be available to patients. This review will focus on the specific roles of these growth factors and cytokines during the wound healing process.

PERSPECTIVE ARTICLE: Growth factors and cytokines in wound healing

Wound healing is an evolutionarily conserved, complex, multicellular process that, in skin, aims at barrier restoration. This process involves the coordinated efforts of several cell types including keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. The migration, infiltration, proliferation, and differentiation of these cells will culminate in an inflammatory response, the formation of new tissue and ultimately wound closure. This complex process is executed and regulated by an equally complex signaling network involving numerous growth factors, cytokines and chemokines. Of particular importance is the epidermal growth factor (EGF) family, transforming growth factor beta (TGF‐β) family, fibroblast growth factor (FGF) family, vascular endothelial growth factor (VEGF), granulocyte macrophage colony stimulating factor (GM‐CSF), platelet‐derived growth factor (PDGF), connective tissue growth factor (CTGF), interleukin (IL) family, and tumor nerosis factor‐α family. Currently, patients are treated by three growth factors: PDGF‐BB, bFGF, and GM‐CSF. Only PDGF‐BB has successfully completed randomized clinical trials in the Unites States. With gene therapy now in clinical trial and the discovery of biodegradable polymers, fibrin mesh, and human collagen serving as potential delivery systems other growth factors may soon be available to patients. This review will focus on the specific roles of these growth factors and cytokines during the wound healing process.

Cellular and molecular basis of wound healing in diabetes

Diabetic foot ulcers (DFUs), a leading cause of amputations, affect 15% of people with diabetes. A series of multiple mechanisms, including decreased cell and growth factor response, lead to diminished peripheral blood flow and decreased local angiogenesis, all of which can contribute to lack of healing in persons with DFUs. In this issue of the JCI, Gallagher and colleagues demonstrate that in diabetic mice, hyperoxia enhances the mobilization of circulating endothelial progenitor cells (EPCs) from the bone marrow to the peripheral circulation (see the related article beginning on page 1249). Local injection of the chemokine stromal cell-derived factor-1alpha then recruits these EPCs to the cutaneous wound site, resulting in accelerated wound healing. Thus, Gallagher et al. have identified novel potential targets for therapeutic intervention in diabetic wound healing.

The Role of Vascular Endothelial Growth Factor in Wound Healing

BACKGROUND A chronic wound is tissue with an impaired ability to heal. This is often a consequence of one of the following etiologies: diabetes, venous reflux, arterial insufficiency sickle cell disease, steroids, and/or pressure. Healing requires granulation tissue depending on epithelialization and angiogenesis. Currently no growth factor is available to treat patients with impaired healing that stimulates both epithelialization and angiogenesis. The objective is to review is the multiple mechanisms of vascular endothelial growth factor (VEGF) in wound healing. MATERIALS AND METHODS The authors reviewed the literature on the structure and function of VEGF, including its use for therapeutic angiogenesis. Particular attention is given to the specific role of VEGF in the angiogenesis cascade, its relationship to other growth factors and cells in a healing wound. RESULTS VEGF is released by a variety of cells and stimulates multiple components of the angiogenic cascade. It is up-regulated during the early days of healing, when capillary growth is maximal. Studies have shown the efficacy of VEGF in peripheral and cardiac ischemic vascular disease with minimal adverse effects. Experimental data supports the hypothesis that VEGF stimulates epithelialization and collagen deposition in a wound. CONCLUSION VEGF stimulates wound healing through angiogenesis, but likely promotes collagen deposition and epithelialization as well. Further study of the molecule by utilizing the protein itself, or novel forms of delivery such as gene therapy, will increase its therapeutic possibilities to accelerate closure of a chronic wound.

Molecular Pathogenesis of Chronic Wounds : The Role of β-Catenin and c-myc in the Inhibition of Epithelialization and Wound Healing

Lack of understanding of the molecular mechanisms and pathogenesis of impaired healing in chronic ulcers is a serious health issue that contributes to excessive limb amputations and mortality. Here we show that beta-catenin and its downstream targets in keratinocytes, c-myc, and keratins K6 and K16, play important roles in the development of chronic wounds. In contrast to normal epidermis, we observed a significant nuclear presence of beta-catenin and elevated c-myc expression at the nonhealing wound edge of chronic ulcers from 10 patients. In vitro studies indicated that stabilization of nuclear beta-catenin inhibited wound healing and keratinocyte migration by blocking epidermal growth factor response, inducing c-myc and repressing the K6/K16 keratins (cytoskeletal components important for migration). The molecular mechanism of K6/K16 repression involved beta-catenin and arginine methyltransferase (CARM-1) acting as co-repressors of glucocorticoid receptor monomers. We conclude that activation of the beta-catenin/c-myc pathway(s) contributes to impaired healing by inhibiting keratinocyte migration and altering their differentiation. The presence of activated beta-catenin and c-myc in the epidermis of chronic wounds may serve as a molecular marker of impaired healing and may provide future targets for therapeutic intervention.

Evidence-based protocol for diabetic foot ulcers.

Background: Diabetic foot ulcers are the single biggest risk factor for nontraumatic foot amputations in persons with diabetes. Foot ulcers occur in 12 to 25 percent of persons with diabetes and precede 84 percent of all nontraumatic amputations in this growing population. Because of the high incidence of foot ulcers, amputations remain a source of morbidity and mortality in persons with diabetes. Strict adherence to evidence-based protocols as described herein will prevent the majority of these amputations. Methods: The collective experience of treating patients with neuropathic diabetic foot ulcers in four major diabetic foot programs in the United States and Europe was analyzed. Results: The following protocol was developed for patients with diabetic foot ulcers: (1) establishment of good communication among the patient, the wound healing team, and the primary medical doctor; (2) comprehensive, protocol-driven care of the entire patient, including hemoglobin A1c, microalbuminuria, and cholesterol as well as early treatment of retinopathy, nephropathy, and cardiac disease; (3) weekly objective measurement of the wound with digital photography, planimetry, and documentation of the wound-healing process using the Wound Electronic Medical Record, if available; (4) objective evaluation of blood flow in the lower extremities (e.g., noninvasive flow studies); (5) débridement of hyperkeratotic, infected, and nonviable tissue; (6) use of systemic antibiotics for deep infection, drainage, and cellulitis; (7) off-loading; (8) maintenance of a moist wound bed; (9) use of growth factor and/or cellular therapy if the wound is not healing after 3 weeks with this protocol; and (10) consideration of the use of vacuum-assisted therapy in complex wounds. Conclusions: In diabetic foot ulcers, availability of the above modalities, in combination with early recognition and comprehensive treatment, ensures rapid healing, minimizes morbidity and mortality rates, and eliminates toe and limb amputations in the absence of ischemia and osteomyelitis.

High Cost of Stage IV Pressure Ulcers

BACKGROUND The aim of this study was to calculate and analyze the cost of treatment for stage IV pressure ulcers. METHODS A retrospective chart analysis of patients with stage IV pressure ulcers was conducted. Hospital records and treatment outcomes of these patients were followed up for a maximum of 29 months and analyzed. Costs directly related to the treatment of pressure ulcers and their associated complications were calculated. RESULTS Nineteen patients with stage IV pressure ulcers (11 hospital-acquired and 8 community-acquired) were identified and their charts were reviewed. The average hospital treatment cost associated with stage IV pressure ulcers and related complications was

Protocol for treatment of diabetic foot ulcers.

129,248 for hospital-acquired ulcers during 1 admission, and

Clinical application of growth factors and cytokines in wound healing.

124,327 for community-acquired ulcers over an average of 4 admissions. CONCLUSIONS The costs incurred from stage IV pressure ulcers are much greater than previously estimated. Halting the progression of early stage pressure ulcers has the potential to eradicate enormous pain and suffering, save thousands of lives, and reduce health care expenditures by millions of dollars.

Novel Genomic Effects of Glucocorticoids in Epidermal Keratinocytes INHIBITION OF APOPTOSIS, INTERFERON-γ PATHWAY, AND WOUND HEALING ALONG WITH PROMOTION OF TERMINAL DIFFERENTIATION

Each year, 82,000 limb amputations are performed in patients with diabetes mellitus. The majority of these amputations could be avoided by following strict protocols. The collective experience treating patients with neuropathic diabetic foot ulcers of 4 major diabetic foot programs in the United States and Europe were analyzed. The following protocol has been developed for patients with diabetic foot ulcers: (1) measurement of the wound by planimetry; (2) optimal glucose control; (3) surgical debridement of all hyperkeratotic, infected, and nonviable tissue; (4) systemic antibiotics for deep infection, drainage, and cellulitis; (5) offloading; (6) moist-wound environment; and (7) treatment with growth factors and/or cellular therapy if the wound is not healing after 2 weeks with this protocol and a new epithelial layer is not forming. In addition, the pathogenesis of diabetic foot ulcers is discussed, as well as the associated costs and complications, including amputation. Debridement, wound-bed preparation, antibiotics, various types of dressings, biological therapies, growth factors, and offloading are described as treatment modalities for patients with diabetic foot ulcers. In diabetic foot ulcers, availability of the above modalities, in combination with early recognition and comprehensive treatment, ensure rapid healing and minimize morbidity, mortality, and costs, as well as eliminate amputation in the absence of ischemia and osteomyelitis.