REVIEW Delayed wound healing in diabetes: considering future treatments Thanh Dinh1, Sarah Elder1 & Aristidis Veves†1 Impaired wound healing and growth factors: ū The diabetic foot ulcer displays characteristics of a chronic wound with diminished expression of growth factors integral to healing, such as PDGF, FGF, VEGF, EGF, NGF and GM-CSF. Current therapies: ū The cornerstones of diabetic foot wound care include periodic debridement, adequate treatment of infection, treatment of ischemia, pressure off-loading and moist wound care. Practice Points Practice ū When standard wound care fails to heal the diabetic foot ulcer, adjunctive treatment with advanced therapies such as negative pressure wound therapy, topical growth factors, hyperbaric oxygen and living skin equivalents may be necessary. ū Adjuvant therapies have demonstrated equivocal effectiveness in scientific studies and judicious use of these modalities is encouraged, given their expense. Future therapies: ū Future therapies currently under investigation for the treatment of diabetic foot ulcers include platelet-rich plasma, stem cell therapy, extracorporeal shock-wave therapy, laser therapy and topical lactoferrin. SUMMARY Diabetic foot ulcers result from multiple risk factors including peripheral neuropathy, arterial insufficiency and foot deformities. Recent investigation has also revealed a chronic wound environment with diminished expression of growth factors and cytokines integral to the wound healing process. Current accepted standard of care for the treatment of diabetic foot ulcerations focuses on periodic debridement of the wound, appropriate topical wound therapy, pressure off-loading and treatment of infection. Owing to increased cost and equivocal effectiveness, topical growth factors, bioengineered living skin equivalents, hyperbaric oxygen therapy and negative pressure wound therapy are proposed as adjuncts to standard of care and may be added to the treatment regimen when healing of the wound has stalled. Other future therapies currently under investigation include stem cell therapy, platelet-rich plasma, extracorporeal shock-wave therapy and laser treatment. These modalities continue to be developed and tested, and may offer promise as effective therapies in the future for the chronic diabetic foot ulcer. 1Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA †Author for correspondence: [email protected] 10.2217/DMT.11.44 © 2011 Future Medicine Ltd Diabetes Manage. (2011) 1(5), 509–519 ISSN 1758-1907 509 REVIEW Dinh, Elder & Veves Diabetic foot ulcerations will affect approxi- Impaired wound healing & growth factors mately 15% of all patients with diabetes, are Over the last decade, it has been recognized the leading cause of hospitalization among all that diabetes is a disease based fundamentally patients with diabetes, and are the most com- on inflammation. Both Type 1 and 2 diabetes mon risk factor for lower extremity amputa- are characterized by a nonsequential release of tion [1,2]. The physical, psychological and eco- pro- and anti-inflammatory cytokines, result- nomic burden of diabetic foot ulcerations is of ing in an imbalance that leads to impaired tis- paramount concern to the patient, the patient’s sue repair and weakened cellular and humoral family and the healthcare system. As a result, immune defense mechanisms [8,9]. great attention has been focused on the cause, The normal cascade of wound healing treatment and prevention of diabetic foot ulcers involves an orderly transition through three in the last decade. well-defined phases: inflammation, prolifera- Diabetic foot ulcers are the result of various tion and remodeling. Normal wound healing etiological factors and are characterized by an involves a timely progression through these three inability to self-repair in a timely and orderly phases, ultimately resulting in wound epitheliali- manner [3]. Etiological factors can be categorized zation. However, in the chronic wound such as into intrinsic (i.e., neuropathy, peripheral vas- the diabetic foot ulcer, the progression of heal- cular disease and diabetes severity) and extrin- ing is stalled in the initial inflammation phase sic (i.e., wound infection, callus formation and and resists further progression. Central to their excessive pressure to the site) causes [4]. poor healing, diabetic foot ulcers demonstrate a Studies have found that the pathway to foot decreased immune cell infiltration, with persist- ulceration begins with the presence of three ence of neutrophils and macrophages [10]. This distinct conditions: peripheral neuropathy, foot diminishment in inflammatory cell recruitment deformities, and acute or chronic repetitive ultimately results in alterations in growth factor trauma. The presence of peripheral neuropa- expression (Table 1). thy results in an insensate foot with structural It is well established that growth factors play deformity vulnerable to trauma. This trauma an integral role in the normal wound healing may be presented in the form of chronic pres- cascade, and their addition to the chronic wound sures from everyday activity or sudden acute may serve as a catalyst to healing [11]. Growth trauma from the environment such as ill-fitting factors influence the wound healing process foot wear or stepping on a foreign object [5–7]. both through inhibitory and stimulatory effect In addition to the triad of risk factors on the local wound environment. A multitude of described, impaired wound healing, character- growth factors are present in wound healing with ized by a chronic wound environment, has been the most prominent growth factors consisting of: implicated as another reason for poor healing PDGF, FGF, VEGF, EGF, NGF and GM-CSF. exhibited in diabetic foot ulcers. Recent inves- PDGF plays a major role in wound healing, tigation into impaired wound healing in these acting as a mitogen on fibroblasts, vascular chronic wounds has highlighted impairments smooth muscle cells, endothelial cells, neurons at the microvascular level as well as abnormal and macrophages, and as a chemotactic agent expression of growth factors and other cytokines for neutrophils, macrophages and fibroblasts. involved in the healing process. PDGF also enhances proliferation of fibroblasts, Table 1. Growth factors and their roles in normal wound healing. PDGF Mitogenic on fibroblasts, vascular smooth muscle cells, endothelial cells, neurons and macrophages. Enhances proliferation of fibroblasts, stimulates the production of extracellular matrix by these cells and triggers fibroblasts to acquire a myofibroblast phenotype FGF Stimulate angiogenesis, cell proliferation, regulate migration and differentiation of cells of mesodermal, ectodermal and endodermal origin EGF Regulates re-epithelialization and granulation tissue formation VEGF Major regulator of both vasculogenesis and angiogenesis GM-CSF Involved in angiogenesis and is mitogenic for keratinocytes NGF Essential for the development and survival of certain sympathetic and sensory neurons in both the CNS and PNS 510 Diabetes Manage. (2011) 1(5) future science group Delayed wound healing in diabetes: considering future treatments REVIEW stimulates the production of extracellular matrix Wound debridement by these cells and triggers fibroblasts to acquire Debridement of the wound incorporates the a myofibroblast phenotype [12,13]. concept of wound bed preparation by control- FGFs typically stimulate cell proliferation, ling exudate and edema, decreasing bacterial regulate migration and differentiation of cells burden, promoting healthy granulation tis- of mesodermal, ectodermal and endodermal sue and removing necrotic tissue [19,20]. Over origin. FGFs are mitogenic for several cell types the last decade, the significance of wound bed present at the wound site, including fibroblasts preparation has evolved, given its multiple and keratinocytes [14]. Finally, both FGF1 and roles in wound healing. The role of wound bed FGF2 stimulate angiogenesis [15]. preparation has been described as a dynamic EGF plays an important role in re-epitheli- concept, involving a balance between aggres- alization and granulation tissue formation. It sive and repeated removal of all necrotic tis- has been shown to be mitogenic for fibroblasts sue followed by timely evaluation and tissue and keratinocytes. VEGF has been identified management [21]. as a major regulator of both vasculogenesis Wound bed preparation can be performed and angiogenesis, and its levels increase during through a variety of methods including sharp trauma and ischemia [16]. VEGF also serves to debridement, low-frequency ultrasound and stimulate wound angiogenesis in a paracrine enzymatic debriders. Sharp debridement is manner. NGF is essential for the development considered the gold standard as the operator and survival of certain sympathetic and sensory can visually identify the depth and extent of neurons in both the CNS and PNS. GM-CSF tissue that needs to be removed. It can be per- is involved in a ngiogenesis and is mitogenic formed in the office setting in an insensate foot for keratinocytes. with a variety of instruments, with the most The number of growth factors identified in c ommonly used being the scalpel blade. the normal wound healing process continues to However, when a sensate limb cannot tolerate be elucidated, offering further information on sharp debridement, other methods of wound how the chronic wound differs from a wound bed preparation must be explored. A novel that goes on to