Problematic wounds: therapy developments

Wound healing aims for a successful closure of a wound with an intact epithelial layer of keratinocytes. An acute surgical wound may be cited as an “uncomplicated” wound which will heal uneventfully on its own. A “problematic” or chronic wound may be defined as one which presents difficulty in obtaining closure. A problematic wound is typically defined as one that has not healed within four weeks. So, at what point in the healing cycle does the repair process become compromised, and when does a wound make the transition from “uncomplicated” to “problematic”? A healing wound, regardless of its origin, will go through a series of processes that are interlinked and sometimes overlapped such as inflammation, proliferation and remodelling. All these phases are dominated by a multitude of cellular and extracellular interactions that will, in the majority of cases, culminate with a healed wound. However, some stages may be prolonged, or the wound may become static and unable to progress to the next stage of healing, thereby becoming problematic/chronic. In order to effectively treat a chronic wound, the phases of wound healing and the main cells involved need to be understood and correlated with the knowledge that molecular imbalances, as well as certain local and systemic factors may hinder wound healing. These factors are varied and may include conditions such as infection, uncontrolled diabetes, peripheral arterial disease and trauma. Some examples of local and systemic factors that could interfere with wound healing are presented in Table 1, and Table 2 presents the main molecular differences between healing and non-healing/ chronic wounds.

Burns

Many acute wounds will heal by primary intent. The wound edges can be bought sufficiently close together that the wound healing cascade can be initiated naturally. Primary closure of a burn wound cannot be achieved because of the large areas of tissue loss. Instead, reepithlelialisation is promoted from viable elements within the wound itself, or migratory cells at the wound edges. However, this secondary intent approach is associated with potential problems due to an open wound which includes prolonged inflammation, excessive contracture and exposure to infection. One approach to accelerate closure of a wound which would heal by secondary means, albeit slowly, is to provide a surgical solution by bringing tissue from elsewhere, either in the form of an autologous graft or flap, or by introducing cells which have been cultured ex vivo. To provide permanent closure, autologous tissue or cells are required. The healing response can be accelerated using viable allogeneic tissue or cell, although they will not provide permanent closure. There remains much clinical investigation still to be undertaken to fully understand the role of cultured keratinocytes in treating major burns, but the approach is becoming more common as the evidence base is built, and the delivery technologies to make viable cells reliably available are optimised. A range of autologous and allogeneic cell-based therapies for burns and chronic wound patients are now being made available in the UK. Similar activity is being promoted for military applications, both in the US and Europe. One of the challenges of reviewing the efficacy of autologous keratinocyte cells in burns patients relates to patient-to-patient variability. Altrika carried out a post-hoc analysis of autologous keratinocyte treatments for burns patients with more than 60% total body surface area (TBSA) burns in order to define the number of cell-based dressings required for an “average” burns patient. The results are outlined below: