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Clinical REVIEW Current advances in modern

Under normal circumstances, are expected to heal within a reasonable period of time through a series of a regulated cascade of events. However, when the cascade becomes interrupted, wounds fail to heal in a timely manner, resulting in chronic non-healing wounds (ulcers). Over the years, a variety of measures have been attempted in the treatment of non-healing wounds, including a range of different products, drugs and devices. However, not all wounds respond to the above modalities of treatment and, consequently, non-healing, refractory wounds continue to be a significant burden in the hospital as well as the community.

Wai-Ping Linda Fan, Mamun Rashid, Stuart Enoch

discusses some of the aetiological chronic non-healing wounds (Lazarus KEY WORDS factors of non-healing wounds, the et al, 1994). A may be Complex wounds essential scientific aspects, the current defined as one that has not adequately Recent advances treatment options and the potential re-epithelialised within 6–8 weeks Novel therapies future advances in the management of (Enoch and Price, 2004). Although chronic wounds. a variety of measures have been Stem therapy attempted in the treatment of non- Gene therapy A systematic approach healing wounds, some wounds are refractory to all forms of treatment to research, a and result in chronic wounds. multiprofessional approach ecent advances in molecular to management and a Scientific enquiry into the many biology, nanotechnology and willingness to consider the aspects of chronic wound healing is far Rfunctional genomics, coupled patient’s perspective are from complete, and, consequently, the with an increased understanding of the some of the important knowledge base is continually being pathophysiology of chronic wounds enriched by input from clinicians and have resulted in the development changes that have paralleled researchers. A systematic approach to of novel therapies such as technological advances and research, a multiprofessional approach engineered substitutes and growth expertise, which, as ever, to management and a willingness to factors. In addition, promising have been the prime drivers consider the patient’s perspective are developments in the areas of stem of progress. some of the important changes that cells and gene therapy have given have paralleled technological advances rise to new hope in modulating and expertise, which, as ever, have non-healing wounds. This article Acute wound healing, triggered been the prime drivers of progress. In by tissue , comprises a addition to providing an overview of complex systemic cascade of the different types of common ulcers events that includes , and types of wounds healing, this neovascularisation, synthesis, article discusses some of the recent formation, developments in the management epithelialisation and wound of chronic wounds and the potential remodelling (Clark, 1996). Normally, future advances. wounds are expected to heal within a Wai-Ping Linda Fan is a Foundation Year 2 student, reasonable period of time that ranges Common types of chronic wounds Department of Accident and Emergency, Royal Preston Hospital; Mamun Rashid is Core Surgical Trainee, from about 7–14 days. However, Common types of chronic wounds Department of ENT , Tameside General Hospital, when the above cascade becomes arise from one of the following Manchester; Stuart Enoch is Speciality Registrar, and interrupted at any of the stages of the aetiologies: venous, arterial, , University Hospitals of South and healing process, the wounds will fail neuropathic or pressure. The other Central Manchester to heal in a timely manner, resulting in important causes include malignancy,

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regulated cascade of events, as Table 1 happens in acute wound healing, and Important characteristics of some common types of ulcers thus become recalcitrant or chronic wounds. In most chronic wounds, the healing process seems to be halted during the inflammatory or Type of ulcer Aetiology Site Salient features proliferative phases (Lazarus et al, 1994). Disturbance in the action Venous 8 Incompetent valves 8 Medial gaiter area 8 May be painful; particularly and balance between components in perforating veins of the leg if long-standing and such as growth factors, cellular and with atrophie blanche 8 Venous extracellular elements contribute hypertension 8 Usually shallow towards a non-healing wound (Table 8 May be 8 Irregular, sloping edges 4). Additionally, accumulation of secondary to DVT 8 Characterised by pigmentation in necrotic tissue or slough promotes and/or the surrounding skin colonisation of bacteria, which varicose veins prevents complete repair of the wound. Finally, condition-specific Arterial 8 Tissue and 8 Dorsum of foot, 8 Painful factors, such as peripheral oedema damage secondary to toes, heel and 8 Punched out appearance in sustained venous hypertension, arterial insufficiency bony prominences 8 The affected limb may be painful, ischaemia in peripheral vascular of foot 8 Atherosclerosis cool to touch and hairless or neuropathy in , as 8 The skin may be dusky, thin well as intake of certain drugs (e.g. and shiny non-steroidal anti-inflammatories and steroids), , poor 8 Nail(s) may be brittle or lost in dietary intake and malnutrition also the affected limb contribute to impaired healing (Table Neuropathic 8 Diabetes, spinal 8 Usually on 8 Painless 5) (Edmonds and Foster, 2006; Grey et al, 2006a). cord injury, plantar surface of 8 Surrounding calluses peripheral nerve the foot under 8 Warm limb; good peripheral injury the metatarsal Conventional management of pulses heads or toes difficult-to-heal wounds 8 Surrounding skin may be dry There are some established treatment and fissured due to decreased modalities in the treatment of difficult- sweating to-heal wounds (Humpherys et al, 2007). Some of the commonly used Pressure 8 Tissue compression 8 Most develop on 8 Painful or painless management options for such wounds between a bony the lower half of 8 Surrounding skin may appear are shown in Table 6. prominence and an the torso with inflamed or blistered external force heel ulceration 8 May go very deep extending Current advances/novel therapies becoming the to bone With great strides in technological most common innovations and increased under- standing of the pathophysiology of wound healing, various devices drug-induced ulcers and vasculitis. With great strides (physical modalities) have been Some of the salient features of the in technological developed to aid the management of common types of ulcers are shown in innovations and increased chronic wounds. Table 1. understanding of the Intermittent pneumatic compression (IPC) How do normal wounds heal? pathophysiology of wound Intermittent pneumatic compression Normal wounds heal by a systemic healing, various devices (IPC) is effective for managing cascade of events that includes four (physical modalities) have chronic venous ulcers with severe overlapping, but regulated phases been developed to aid oedema that are resistant to simple (Table 2). the management of compression therapy (Enoch et al, 2006a). A compression pressure of Types of wound healing chronic wounds. 20–120mmHg is provided at preset The salient features of the four intervals to improve venous and recognised types of wound healing are Why don’t some wounds heal? lymphatic flow. It is generally used summarised in Table 3. Some wounds fail to follow the two hours a day for up to six weeks.

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Hyperbaric Table 2 Hyperbaric oxygen may be a useful Phases of acute wound healing adjunct in the management of non- healing wounds. As most non-healing tissues are hypoxic, 100% oxygen given in a pressurised chamber may hasten Stages Time after injury Cell type Important features the healing process (Thackham et al, 2008). A systematic review (Wang et al, Haemostasis 8 Immediate 8 8 Loss of structural integrity 2003) on the use of hyperbaric oxygen cascade, triggers the coagulation cascade in wounds identified six controlled trials and inflammatory and constriction of the vessels, involving diabetic ulcers and chronic mediators which further limits loss non-healing wounds showing positive 8 Major initial stimulation results. However, its use is restricted for inflammation as special equipment and expertise is required. Inflammatory 8 24–72 hours 8 Neutrophils and 8 Neutrophils phagocytose phase bacteria and other foreign Biosurgery particles. Macrophages The use of sterile maggots, also known transformed from as biosurgery, has a selective technique appear to act as the of slough and necrotic tissue digestion key regular cell for repair from wounds without damaging the and stimulate division, surrounding healthy tissue (Kumar et collagen synthesis and al, 2004). Along with its effect, biosurgery is best suited for Neuropathic 8 3 days–2 weeks 8 8 Fibroblast migration, wounds with slough and . deposition, It is cost-effective and tolerance is formation of granulation tissue excellent (Wollina et al, 2002). Apart and epithelisation from the presence of fistulas and the proximity of the wound to major 8 / matrix will blood vessels or vital organs, there be replaced by the newly formed appear to be no contraindications. granulation tissue Limitations are the lack of aesthetic Remodelling 8 1 week– 8 Fibroblasts 8 Further development of appeal, short shelf-life of maggots and and several weeks 8 granulation tissue increased pain at the wound site which maturation is found in some patients. 8 Extracellular 8 Reorganisation of collagen matrix and 8 activity Others collagen Other non-surgical methods 8 Balance between include; laser therapy, hydrotherapy, MMP and TIMP electrotherapy, psoralen combined with profiles ultraviolet A (PUVA) therapy, radiant heat dressing and ultrasound therapy (Enoch et al, 2006a). However, to date, limited evidence is available to prove This method is ideal for patients with TNPT improves local dermal their effectiveness. limited mobility, and should be used , promotes angiogenesis, as an additional therapy to simple stimulates granulation tissue, decreases Drugs compression, not as a substitute interstitial fluid control, wound Some drug therapy has been proven (Enoch et al, 2006a). and bacterial load (Enoch et al, 2006a). to aid healing of chronic ulcers These effects have clinically translated (D’Hemecourt et al, 1998; Falanga Topical negative pressure therapy (TNPT) into faster healing rates of wounds et al, 1999). They are all based on The wound is compartmentalised by (Wong et al, 2010). Problems with the concept of increasing peripheral an airtight seal around it. Through a this method include pain, fluid loss, blood flow to the wound area through dressing interface the compartment especially in large wounds, and risk of . Drugs of this type include is connected to an external suction . It is contraindicated in patients calcium antagonists such as diltiazem apparatus creating a negative pressure with frail, thin or easily bruised skin, and and nifedipine, glyceryl trinitrate, to allow removal of excess fluid in those with forming part Iloprost and pentoxifylline (Falanga et (Kumar et al, 2004). of the wound floor (Hurd et al, 2010). al, 1999).

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Simple pain is treated with Table 3 appropriate analgesia based on the Types of wound healing World Health Organization (WHO) analgesic ladder (6. www.who.int/ cancer/palliative/painladder/en/). Neuropathic pain may need certain Type of wound healing Features tricyclic antidepressants such as amitriptyline, or antiepileptic drugs such Primary wound healing 8 Ideal, seen in wounds such as clean surgical incisions as gabapentin. 8 Wound edges closed directly by mechanical means such as sutures, glue, tapes or staples Natural products Natural products include honey, Delayed primary wound healing 8 Ideal in contaminated wounds such as animal and yoghurt, tea tree oil and potato peeling, human bites which have been used in various parts 8 Wound is left open for a few days and closed later of the world to treat chronic wounds (Enoch et al, 2006a). However, evidence Secondary wound healing 8 Preferred in large cavity wounds in difficult anatomical of success is lacking. positions where closure is not feasible, such as in grade 3 or 4 sacral pressure ulcers Tissue engineered skin substitutes 8 After appropriate debridement and control of infection, A variety of skin substitutes are now the wound is left open to heal by contraction available to treat non-healing wounds and burns (Bello and Phillips, 2000; Healing by epithelialisation 8 Found in wounds caused by split-thickness skin , Hrabchak et al, 2006). Some of the superficial burns and abrasions characteristics and indications for using 8 As only the superficial layer of skin is involved, the ‘new’ the recently developed products are skin will retain all the normal characteristics highlighted in Table 7. Despite the 8 Scarring is minimal availability of a fairly large range of products, randomised controlled trials (RCTs) are currently limited and there is little evidence to justify their use. Table 4 Furthermore, the cost-effectiveness of their usage has not been well Important molecular and cellular changes in chronic wounds established.

Growth factors Normal wound healing is dependent 1. Molecular changes on a range of growth factors and 8 Increased activity of (MMP — 1, 8 & 13), gelatinases A (MMP 2) and B (MMP 9), that interact with cells and stromelysins — MMP 3, 10 and 11, and serine (Cathepsin G, neutrophil elastase) the matrix at different stages (Brown 8 Decreased activity of TIMPs, a1- protease inhibitor and a2 – macroglobulin et al, 1991; Barrientos et al, 2008). Use of growth factors produced by 8 Increased degradation of fibronectin, vitronectin and tenascin recombinant DNA technology increase 2. Cellular changes the wound’s capacity to heal by causing cells to grow and attract new 8 Reduced mitotic activity cells to the wound (Barrientos et al, 8 Impaired migration 2008). Growth factors are designed to target the individual phases of wound 8 Altered fibroblast healing (Table 8). They should ideally 8 Decreased fibroblast proliferation and migration be resistant to rapid degradation 8 Decreased response of fibroblasts to growth factors from the proteolytic environment 8 Presence of increased proportion of senescent cells of the wounds and their release has to be sustained. derived -BB (PDGF-BB) is the only growth factor that has currently Medicated paste and bandages are agents, , phenytoin and vitamin been approved in the treatment of also available for the management of A (Enoch et al, 2006a), along with chronic ulcers (Barrientos et al, 2008), infected wounds. These include; iodine- systemic oral antibiotics depending on although others such as vascular based preparations, -releasing the extent of infection. endothelial growth factor (VEGF),

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Future advances Table 5 therapy Local and systemic factors that impede Stem cells have been identified wound healing in various tissues including bone Key points marrow, blood, muscle and cartilage. Although embryonic stem cells and 8 Tissue-engineered Local induced pluripotent stem cells are skin substitutes and theoretically highly beneficial, there other biological wound 8 Inadequate blood supply are considerable limitations to their manipulations are seldom 8 Poor venous drainage use. In addition to the strong ethical effective in sloughy and 8 Presence of foreign body and foreign disagreements, studies have shown that exudative wounds with body reactions they yield a low number of harvesting unhealthy wound beds. 8 Continued presence of microorganisms cells and bone marrow biopsies can 8 The novel treatment 8 Sustained wound infection (sub-acute) be painful (Mizuno, 2009). Therefore, stem cells from adults have been the modalities and biological- 8 Excess local mobility subject of targeted clinical research based therapies should 8 Underlying osteomyelitis (Charruyer, 2009). Adult stem cells are complement rather than 8 Malignant transformation (Marjolin’s ulcer) multipotent cells with the ability to replace the tenets of good, renew themselves and to differentiate basic wound care. Systemic into a diverse range of specialised cell types such as fibroblasts, endothelial 8 Cutaneous wound healing 8 General malnutrition cells and (Hanson et al, is a multi-step process 8 Deficiency of , vitamin (particularly 2010). Early reports from case series requiring the collaboration A and C) and/or trace elements such on the application of bone marrow- and coordination of many as zinc derived cells on the chronic wound different cell types 8 Peripheral vascular disease and vasculitis were promising (Badavias and Falanga, and molecules. 8 Venous oedema or lymphoedema 2003; Dash et al, 2009), but further research is necessary. Another study 8 Given the multiple 8 Neuropathy secondary to congenital or by Wu et al (2007) showed bone molecular mechanisms acquired spinal cord , marrow-derived mesenchymal stem involved, it is unlikely that leprosy (Hansen’s disease) cells to demonstrate the beneficial any one single mediator 8 Systemic such as diabetes mellitus, effect in cutaneous and or growth factor will be rheumatoid arthritis, wound healing in non-diabetic and successful in accelerating diseases and metabolic diseases diabetic mice through differentiation healing. 8 Systemic malignancy and terminal illness and paracrine effects. 8 8 Chemotherapy and whole body radiation Identification of the cellular Recent studies have looked at the and molecular dysfunction 8 Immunosuppressant drugs in individual wounds and and corticosteroids potential of skeletal muscle (Kumar et al, 2004; Jackson et al, 2010) and targeting or supplementing 8 Advancing age and immobility adipose-derived stem cells. They them is one of the goals for 8 Obesity are found to be capable of equally the future. 8 Anticoagulants differentiating into cells and tissues 8 Marfan’s syndrome of mesodermal origin compared to bone marrow-derived mesenchymal 8 Inherited neutrophil disorders such as stem cells. Since fat can be obtained leucocyte adhesion deficiency (harvested) relatively easily in most healing and exhibit antioxidant effects 8 Impaired activity people, adipose-derived stem cells have under various experimental conditions (malacoplakia) become the ideal large-scale source in (Kim, 2009). The wound-healing and practical regenerative medicine. They antioxidant effects are mainly regulated have an advantage over other stem cell by the activation of dermal fibroblasts sources, as they have neither ethical nor and keratinocytes via the paracrine basic (bFGF), immunoreactive considerations, as long mechanism. Administration of allogeneic and -macrophage colony- as they are of autologous tissue origin. adipose-derived stem cells may provide stimulating factor (GM-CSF) have Additionally, adipose tissue can be an alternative source for mesenchymal shown some promising initial results obtained under local anaesthetic with tissue regeneration and engineering. (Daniele et al, 1979; Greenhalgh minimal patient discomfort (Mizuno, and Rieman, 1994; Smiell et al, 1999; 2009). Adipose-derived stems cells Gene therapy Robson et al, 2000; Tsang et al, 2003). have been found to accelerate wound Gene therapy aims for the provision

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Table 6 Commonly used management options for difficult-to-heal wounds

Type of ulcer Conservative Indication for surgery Surgical procedure

Venous 8 Compression therapy 8 Pure superficial venous 8 Ligation and stripping of superficial veins or subfascial remains the mainstay. Examples incompetence either of the interruption of perforating veins include compression stockings, hosiery, long or short saphenous 8 Sclerotherapy system Unna’s boots, elastic wraps, medicated 8 Endovenous ligation bandages, orthotic compression devices 8 Skin grafting for large ulcers after treating the and pneumatic compression pumps underlying cause 8 Appropriate moisturising of surrounding skin, control of exudate and eczema, and treat infection

Arterial 8 Control of any underlying diabetes, 8 Non-healing ulcer(s), disabling 8 Revascularisation surgery such as bypass grafting or hypertension and hypercholesterolaemia claudication, rest pain stenting to restore blood supply to the affected limb 8 Smoking cessation and regular exercise and 8 Amputation of the affected digit or part of the limb (e.g. below knee) may be indicated in recalcitrant wounds +/- severe rest pain +/- ongoing local infection +/- sepsis

Diabetic 8 Good glycaemic (diabetic) control 8 Non-healing ulcers 8 Wound debridement 8 Appropriate foot wear and gangrene 8 Amputation of the affected digit or part of the limb 8 Assess vascular status regularly 8 Local or systemic infection (e.g. below knee) may be indicated in recalcitrant wounds +/- ongoing local infection +/- sepsis 8 Treat promptly

Pressure 8 Pressure relief 8 Non-healing ulcers 8 Wound debridement 8 Regular repositioning of patient and gangrene 8 Osteotomy/removal of affected bone 8 Support surfaces such as 8 Local or systemic infection 8 Reconstructive surgery (e.g. flap coverage) to provide air-fluidised mattresses tissue over affected bony prominence 8 Regular skin inspection 8 Optimise nutritional status

of specific genes to the target cell(s) delivered by different methods — the the wound environment in a selected to enhance, amend or negate the important ones being biological (viral population of cells that are then biological function of the cell(s) and its vectors), physical (e.g. microinjection), transplanted into the wound). Once inherent genetic coding (Branski et al, and chemical (e.g. cationic liposomes). in the wound environment, externally 2009). Genes, once incorporated in the applied substances may also control cell, affect the cell and its environment Another method for sustained the genes through specific mechanisms by changing the way their products (e.g. delivery of genes to the wound called genetic switches. ) are expressed. In the context environment called gene activated of wound healing, these are growth matrix (GAM) therapy is also being Genes may be employed to factors, receptors, adhesion molecules considered (Chandler et al, 2000). This augment an effect (e.g. promote and inhibitors of proteases (Branski et involves embedding genes onto a matrix, healing). These include genes for growth al, 2009). which remains in the wound increasing factors and their receptors. Alternatively, the length of exposure of target cells to they may be used to inhibit an effect Classical gene therapy involves the genes. Transfer could be established (e.g. suppress excessive scarring). These incorporating the gene into cells to in vivo (the gene being delivered to include genes for antibodies against directly influence the wound by its the cells in the wound directly), or in specific growth factors. Gene therapy product of expression. Genes can be vitro (gene transfer is achieved outside as applied to wound healing is currently

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Table 7 Tissue engineered substitutes in wound healing

Product Content and description Uses/advantages Disadvantages

Epicel® (Genzyme Cultured epidermal autograft (sheet) Permanent coverage for superficial and Two–three-week lag period between biopsy Biosurgery), partial-thickness burns and obtaining ; lacks (Laserskin * dermal component

Integra † Two-layered skin substitute comprising Immediate permanent coverage for Requires healthy and non-infected wound biodegradable matrix and bovine collagen, surgically excised full-thickness burns; base; in burns, autograft is needed after 3–4 and outer silicone layer reconstructive surgery weeks for epithelial cover

AlloDerm® † Processed human cadaver skin with a Intended to permanently cover full- In burns, may necessitate removal after 2–3 (LifeCell) cellular dermal matrix and intact thickness burns and deep ulcers; weeks; autograft is needed for epithelial reconstructive surgery cover; not suitable for infected wounds

Biobrane® † Porcine dermal collagen bonded to To cover extensive partial-thickness burns Temporary; not suitable for infected (LifeCell) semipermeable silicone membrane and donor sites wounds

TransCyte® ‡ Allogenic human fibroblasts cultured on nylon To cover surgically excised full-thickness Temporary (may need skin grafting after 2–3 (Smith and mesh coated with porcine collagen burns and non-excised partial- weeks); not suitable for infected wounds and Nephew and thickness burns patients allergic to porcine collagen Advanced Tissue Services)

Dermagraft® Allogenic human fibroblasts cultured on Non-healing diabetic foot ulcers and venous Not for infected wounds or ulcers with ‡ (Advanced bioabsorbable scaffold leg ulcers sinus tracts BioHealing)

Apligraf® § Allogenic cultured skin containing Non-healing diabetic foot ulcers and venous Not for infected wounds or patients allergic (Organogenesis) keratinocytes, fibroblasts, and bovine collagen leg ulcers to bovine collagen

OrCel® § (Forticell Allogenic cultured skin containing Acute and chronic deep dermal ulcers, Not for infected wounds or patients allergic Bioscience) keratinocytes, fibroblasts, and bovine collagen partial-thickness burns and donor to bovine collagen site wounds

* Epidermal; † Dermal, accellular; ‡ Dermal, cellular; § Composite. Adapted from Enoch et al, 2006

in its primitive stages (Charruyer and Conclusion Ghadially, 2009). Despite novel treatment Cutaneous wound healing is a modalities and the multi-step process requiring the A study using porcine has shown optimism anticipated collaboration and coordination accelerated dermal and epidermal from advances in gene of many different cell types and regeneration, as well as graft adhesion and stem cell research, molecules such as growth factors, rates by using liposomal PDGF- good basic wound care... cytokines and proteases. Thus, given complementary DNA (cDNA) gene the multiple molecular mechanisms transfer (Branski et al, 2010). should remain an integral involved, it is unlikely that any one component in treating single mediator, molecule or gene Currently, trials are also underway chronic wounds. will be successful in accelerating (Enoch et al, 2006b) exploring the use healing. However, identifying cellular of PDGF, VEGF and fibroblast growth concurrently (e.g. genes for growth and molecular dysfunction in factor (FGF) genes in diabetic foot and factors and their receptors), along with individual wounds and targeting or venous ulcers. Future developments genetic switches to fine-tune the supplementing them is certainly a may include using multiple genes gene expression. realistic option in selected wounds.

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Table 8 Growth factors involved in wound healing

Growth factor Major source Wound-healing related function

VEGF Plateles, Neutrophils 8 Stimulates angiogenesis in granulation tissue 8 Stimulates collateral formation in peripheral vascular disease

FGFs Fibroblasts, endothelial cells, cells and 8 Fibroblast and epithelial ; matrix deposition; wound macrophages; also brain and pituitary contraction; angiogenesis 8 Accelerates granulation tissue formation

KGFs Fibroblasts 8 Proliferation and migration of keratinocytes

EGF Platelets, macrophages, keratinocytes; also saliva, urine, 8 Keratinocyte differentiation, proliferation, migration and adhesion milk and plasma 8 Granulation tissue formation

PDGF Platelets, fibroblasts, macrophages, endothelial cells 8 Mitogenic for smooth muscle cells, endothelial cells and fibroblasts 8 Chemoattractant for neutrophils and fibroblasts 8 Fibroblast proliferation and collagen metabolism

G-CSF Monocytes, fibroblasts, lymphocytes 8 Stimulates production of neutrophils 8 Enhances neutrophil and function 8 Promotes keratinocyte proliferation

GM-CSF Keratinocytes, macrophages, lymphocytes, 8 Mediates epidermal cell proliferation and fibroblasts

TGF-a Activated macrophages, platelets, epithelial cells 8 Stimulates epithelial cell and fibroblast proliferation 8 Granulation tissue formation

TGF-ß Platelets, macrophages, fibroblasts, neutrophils, 8 Mitogenic for fibroblasts and smooth muscle cells keratinocytes 8 Chemotactic for macrophages 8 Stimulates angiogenesis (indirect) and collagen metabolism

IL-1 Macrophages, lymphocytes, many other tissues 8 Neutrophil and cells 8 Fibroblast proliferation

TNF Macrophages, mast cells, T-lymphocytes 8 Fibroblast proliferation

IGF-1 Fibroblasts, plasma, liver 8 Fibroblast proliferation 8 Stimulates synthesis of sulphated and collagen

HGF Fibroblasts, keratinocytes, endothelial cells, 8 Re-epithelialisation tumour cells 8 Neovascularisation 8 Granulation tissue formation

Abbreviations: VEGF, vascular endothelial growth factor; FGFs, fibroblast growth factors; EGF, ; KGFs, keratinocyte growth factors; TGF-a, transforming growth factor a; TGF-ß, transforming growth factor-ß; IL-1, interleukin-1; TNF, tumour factor; HGF, growth factor; IGF-1, insulin-like growth factor-1; G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte macrophage colony stimulating factor; PDGF, platelet-derived growth factor

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Despite novel treatment modalities factor (EGF) on the corneal treatment of challenging wounds. Int and the optimism anticipated from in humans. Graefes Arch Clin Exp Wound J 7(4): 305–11 Ophthalmol 210: 159–65 advances in gene and stem cell Jackson WM, Nesti LJ, Tuan RS (2010) research, good basic wound care Dash NR, Dash SN, Routray P, et al Potential therapeutic applications of consisting of adequate wound (2009) Targeting nonhealing ulcers muscle-derived mesenchymal stem and progenitor cells. debridement, exudate management, of lower extremity in human through Expert Opin Biol Ther autologous bone marrow-derived 10(4): 505–17 rest, skin care and control of infection mesenchymal stem cells. Rejuvenation Res Kim WS, Park BS, Sung JH (2009) The (along with specific modalities such 12(5): 359–66 wound-healing and antioxidant effects of as compression therapy for venous D’Hemecourt PA, Smiell JM, Karim MR adipose-derived stem cells. 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Gene Ther Apr 8 [Epub of basic fibroblast growth factor on the therapy to treat chronic wounds: A ahead of print] healing of partial-thickness donor sites: A prospective, randomized, double-blinded review. Wound Repair Regen 16(3): Brown GL, Curtsinger L, Jurkiewicz MJ, trial. Wound Rep Regen 2: 113–6 321–30 et al (1991) Stimulation of healing of Tsang MW, Wong WK, Hung CS, et al chronic wounds by epidermal growth Grey JE, Enoch S, Harding KG (2006a) (2003) Human epidermal growth factor factor. Plast Reconstr Surg 88: 189–94 Venous and arterial leg ulcers. Br Med J 332: 347–50 enhances healing of diabetic foot ulcers. Chandler LA, Go DL, Ma C, et al (2000) Diabetes Care 26: 1856–61 Matrix enabled gene — transfer for Grey JE, Enoch S, Harding KG (2006b) Wang C, Schwaitzberg S, Berliner E, et cutaneous wound repair. Wound Rep Pressure ulcers. Br Med J 332: 472–5 al (2003) Hyperbaric oxygen for treating Regen 8: 473 Hanson SE, Bentz ML, Hematti P (2010) wounds. 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