Recent advances and emerging treatments

Abstract

Biological based treatments Cryopreserved human cadaver skin (used in the UK), and human amniotic membrane and frog skin (used in other parts of the world) have long been used to treat wounds, particularly burns. More recently, artificial “skin substitutes” and growth factors have been developed to help achieve healing in chronic, non-healing wounds of varying aetiologies. These treatments target different stages of the healing process and, in the case of skin substitutes, replace lost tissue. Artificial skin substitutes, products of tissue engineering, consist of a microengineered, biocompatible, polymer matrix in combination with cellular and/or extracellular elements such as collagen. Several growth factors (proteins involved in coordinating and regulating various interrelated processes during wound healing) produced by recombinant DNA technology have also been developed to aid healing of such wounds. This is the last in a series of 12 articles Products targeting inflammatory phase The production and activity of several proteases—including metalloproteinases, serine proteases, and neutrophil elastases, which are tightly regulated in acute wound healing—may be altered in chronic wounds. Raised levels of such proteases can be detrimental to wound healing, and products aimed at counteracting their effect have been developed. One such product is Promogran, which is designed to inactivate proteases and also protect the host's naturally produced growth factors. It may be useful in the treatment of chronic wounds refractory to conventional treatments, but it is not effective in infected wounds or those with unhealthy wound beds. Left: Chronic venous leg ulcer suitable for protease inhibitor dressing. Right: Infected diabetic foot ulcer, associated with Charcot's arthropathy, suitable for G-CSF treatment View this table: In this window In a new window Selected growth factors in wound healing* Products targeting proliferative phase Growth factors Fibroblasts, the key type of cell in the healing process, are attracted to the wound site by several growth factors, including platelet derived growth factor (PDGF) and TGF-β. They proliferate and produce the matrix proteins fibronectin, hyaluronan, and later, collagen and proteoglycans, all of which help to construct the new extracellular matrix. Topical application of recombinant platelet derived growth factor on a diabetic foot ulcer Growth factors, including granulocyte colony stimulating factor (G-CSF) and transforming growth factor-β (TGF-β), have also been used to target this phase of healing. G-CSF, an endogenous haemopoietic growth factor, induces terminal differentiation and release of neutrophils from the bone marrow, enhances neutrophil and macrophage function, and promotes keratinocyte proliferation. Recombinant human G-CSF, injected subcutaneously, has been shown to enhance healing in infected diabetic foot ulcers. TGF-β is chemotactic for macrophages, induces the production of collagen and fibronectin, and inhibits metalloproteinase activity. TGF-β1 has been shown to accelerate wound healing in animal models, and topical application of TGF-β2 has been shown to be effective in the healing of diabetic foot ulcers PDGF attracts keratinocytes and promotes the formation of granulation tissue. Recombinant PDGF was developed to expedite the proliferative phase. Becaplermin (as Regranex gel) is the only growth factor currently licensed for commercial use in the United Kingdom. A multicentre, double blind randomised controlled trial in patients with chronic diabetic foot ulcer showed topical PDGF to be superior to placebo in promoting healing. Its effectiveness was further enhanced when used in conjunction with debridement of the wound bed, emphasising the importance of good basic wound care. Venous leg ulcer suitable for use of dermal or composite skin substitute Fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) are active in this phase of repair. FGF promotes fibroblast proliferation and collagen accumulation and accelerates the formation of granulation tissue. VEGF plays a crucial role in angiogenesis. Partial thickness burn suitable for an epidermal skin substitute Cell and matrix based treatments Autologous fibroblasts (that is, from the patient's own dermis) seeded onto a matrix derived from hyaluronic acid have been shown to be useful in treating diabetic foot ulcers and venous leg ulcers. Similarly, acellular collagen based matrices designed to mimic the extracellular matrix have been successfully used to treat chronic ulcers of varying aetiologies. View larger version: In this window In a new window Wounds suitable for therapies aimed at the remodelling and epithelialisation phases of wound healing Loss of the dermal layer occurs frequently in deep ulcers and burns. Allogenic fibroblasts, obtained from neonatal human foreskin and cultured in vitro, have been used to provide the dermal replacement in such wounds. They are seeded either on a biologically absorbable scaffold (for example, Dermagraft) or on a nylon mesh (for example, TransCyte). The proliferating fibroblasts secrete collagen, matrix proteins, and growth factors and promote healing. They are designed to provide dermal replacement in a variety of wounds, though most evidence to date comes from the treatment of diabetic foot ulcers and burns. Left: Hypertrophic scar complicating healing of a sternotomy wound. Right: Keloid scarring of acne in an adolescent Processed human cadaver skin, in which the cells are removed to leave a non-antigenic dermal scaffold (for example, AlloDerm), was one of the first dermal replacement treatments. Composite skin substitutes comprising allogenic keratinocytes (epidermal equivalent) and fibroblasts (dermal equivalent) are also effective in treating diabetic foot ulcers and venous leg ulcers. Products targeting epithelialisation and remodelling Growth factors...