Description of the condition
Foot ulceration is a major problem in people with diabetes, and is often caused by a combination of factors such as neuropathy (nerve damage), foot deformity, external trauma or peripheral arterial disease (Boulton 2008; Falanga 2005; Quattrini 2008; Szabo 2009). A diabetic foot ulcer has been defined as a wound of full thickness (into the subcutaneous tissue, the innermost layer of the skin) below the ankle, or as a lesion of the foot penetrating through the dermis (the inner layer of the skin), in people with type 1 or type 2 diabetes (Apelqvist 1999; Schaper 2004).
Worldwide, almost 350 million people have been diagnosed with diabetes mellitus, and this number is still increasing (Danaei 2011). The annual incidence of development of a foot ulcer in people with diabetes is 1% to 4%, and the lifetime risk is approximately 12% to 25% (Abbot 2005; Singh 2005). These ulcers are a leading cause of hospitalisation and major amputations (above the ankle joint) (Levin 1998; Pham 2000). About 85% of amputations are preceded by ulceration (Boulton 2008). After amputation there is a high risk of re-amputation at a higher level on the same limb (Izumi 2009; Skoutas 2009). It is estimated that worldwide there is an amputation due to diabetes every 30 seconds (Game 2012).
Current treatment of foot ulcers in people with diabetes usually consists of pressure off-loading (keeping weight off the area) (Lewis 2013), debridement (removal of dead tissue) (Edwards 2010), infection control, the use of wound dressings or topical agents (Bergin 2006; Dumville 2013a; Dumville 2013b; Dumville 2013c; Dumville 2013d; Jull 2013), intensive regulation of blood glucose, and - in the case of ischaemia - vascular reconstruction (Falanga 2005). Additional treatments such as hyperbaric oxygen therapy (Kranke 2012; Stoekenbroek 2014), and granulocyte-colony stimulating factor (Cruciani 2013), may also be used in these people. Despite these multidisciplinary treatments, complete healing is not accomplished in 24% to 60% of ulcers (Hinchliffe 2012; Margolis 1999).
Diabetic foot ulceration has a great impact on quality of life and poses a significant burden to the healthcare budget (Nabuurs-Franssen 2005; Valensi 2005). The direct medical costs of each ulcer can frequently exceed USD 45,000 (Jeffcoate 2003; Jeffcoate 2004; Lw; Stockl 2004). The overall long-term costs attributable to diabetic foot ulceration were analysed over a period of three years (Apelqvist 1995). This showed that the costs, including inpatient care, outpatient care, home care and social services, ranged from USD 16,100 in a person with a healed ulcer without critical ischaemia to USD 63,100 in people who underwent a major amputation.
Description of the intervention
Skin grafts and tissue replacement can be used to treat foot ulcers in people with diabetes by reconstructing the skin defect. Skin substitutes need to be placed on a prepared wound bed to ensure contact between the wound bed and the graft and they take on the functions of the missing skin layer. Before the skin substitute is applied, ulcers are usually rinsed, and debrided to remove hyperkeratinised (abnormally horny or thickened skin) or necrotic tissue. The method of clinical application of the graft/tissue replacement and the frequency of application depends on the specific product used. Some skin substitutes are designed for temporary wounds coverage and some as a permanent replacement.
Different types of skin grafts and tissue replacements are currently available. These are generally divided into the following categories: autografts (taken from the patient), allografts (taken from one person, given to another) and xenografts (taken from animals), and bioengineered tissue or artificial skin. They are used in a number of ways.
Autografts: skin taken from the patient and placed directly in the bed of the target ulcer (e.g. split or full-thickness skin from pinch or mesh grafts).
Allografts and xenografts: skin taken from other humans or animals with a similar skin structure, placed directly in the bed of the target ulcer.
Bio-engineered or artificial skin: skin replacement products created in a laboratory from cultures of skin components and cells (e.g. fibroblasts or keratinocytes), before being placed in the bed of the target ulcer.
Grafting and tissue replacement of allogeneic skin is associated with some risk of transmission of infections such as hepatitis or the human immunodeficiency virus (HIV). Even with screening for these diseases in donors, this risk is not eliminated entirely (Falanga 1998).
How the intervention might work
Despite the current variety of strategies available for the treatment of foot ulcers in people with diabetes, not all ulcers achieve complete healing. Additional treatments with skin grafts and tissue replacement products have been developed and aim to promote complete wound closure by reconstructing the skin defect. It is believed that tissue replacements promote complete closure of the ulcer through the addition of extracellular matrices that induce growth factors and cytokine expression, although the exact mechanism underlying the process remains unclear.
Why it is important to do this review
The treatment of foot ulcers in people with diabetes is complex and challenging. Foot ulceration continues to be the leading risk factor for major amputation and is a significant burden to the healthcare system. Delayed ulcer healing is an example of the impaired process of wound healing (inflammation, tissue formation and tissue remodeling) characteristic of people with diabetes. Skin grafts and tissue replacements could function as a temporary cover for ulcers and aid normal wound healing alongside usual care that includes, for example, mechanical pressure relief and - in the case of ischaemia - vascular reconstruction.
There are some reviews on the use of skin replacement therapies for treating foot ulcers in people with diabetes (Blozik 2008; Langer 2009). One review suggests that tissue-engineered artifical skin products may be cost-effective in selected patients with chronic wounds (Langer 2009), however, there is no recent review that has included a rigorous quality assessment.
This systematic review will examine current evidence for skin grafts and tissue replacement for treating foot ulcers in people with diabetes to inform current practice about effectiveness, costs and safety. The review will help clinicians to make informed decisions about the use of grafting and tissue replacement alongside usual care.