Clinical challenges of chronic wounds: searching for an optimal animal model to recapitulate their complexity

Abstract

The efficient healing of a skin wound is something that most of us take for granted but is essential for surviving day-to-day knocks and cuts, and is absolutely relied on clinically whenever a patient receives surgical intervention. However, the management of a chronic wound - defined as a barrier defect that has not healed in 3 months - has become a major therapeutic challenge throughout the Western world, and it is a problem that will only escalate with the increasing incidence of conditions that impede wound healing, such as diabetes, obesity and vascular disorders. Despite being clinically and molecularly heterogeneous, all chronic wounds are generally assigned to one of three major clinical categories: leg ulcers, diabetic foot ulcers or pressure ulcers. Although we have gleaned much knowledge about the fundamental cellular and molecular mechanisms that underpin healthy, acute wound healing from various animal models, we have learned much less about chronic wound repair pathology from these models. This might largely be because the animal models being used in this field of research have failed to recapitulate the clinical features of chronic wounds. In this Clinical Puzzle article, we discuss the clinical complexity of chronic wounds and describe the best currently available models for investigating chronic wound pathology. We also assess how such models could be optimised to become more useful tools for uncovering pathological mechanisms and potential therapeutic treatments.

Keywords: Animal models; Chronic wounds; Diabetic foot ulcer; Ischemia; Pressure ulcer; Venous leg ulcer.

Fig. 1.

Flow diagram of chronic wound management. Skin lesions identified as chronic wounds are first classified into three broad categories (grey boxes): venous leg ulcers (VLUs), diabetic foot ulcers (DFUs) or pressure ulcers (PUs). Chronic wounds are then refined into sub-categories based on their suspected aetiology (blue boxes). All wounds are initially assumed to be ‘easy’ to treat and receive the appropriate care such as ‘offloading’, antibiotics or surgery. Subsequently, if healing fails, wounds receive progressively more aggressive treatment, including debridement and biological intervention. If all other treatment fails, the final resort is to amputate the affected appendage or limb.

Fig. 2.

Three classes of chronic wound on a diabetic patient’s foot. This image shows a diabetic individual with three classes of chronic wound on the same foot: an ischemic third toe, a neuropathic/infected diabetic foot ulcer (DFU) on the big toe and a pressure ulcer (PU) on the heel from prolonged immobility.

Fig. 3.

The cellular and molecular differences between acute healing wounds and chronic non-healing wounds. The healing of acute wounds (left) initiates with a transient inflammatory response as granulation tissue is formed, which provides an environment suitable for the re-epithelialisation required to complete repair. Chronic non-healing wounds (right) are often infected and exhibit persistent inflammation. By definition, re-epithelialisation has stalled but is hyper-proliferative. Granulation tissue is sub-optimal with elevated matrix metalloproteinases (MMPs) present together with poor fibroblast and blood vessel infiltration. Fibrin cuffs can also be present that prevent the diffusion of oxygen through the wound, rendering it hypoxic.

Fig. 4.

Chronic-skin-wound animal models. (A–E) Examples of chronic-skin-wound animal models, their clinical relevance, benefits and drawbacks. (A) Rabbit ear ischemia model (profile view). (B) Pig flap ischemia model (dorsal view). This method is also applicable to rodents and rabbits. (C) Rat magnet ischemia-reperfusion model (profile view). This method is also applicable to mice. (D) Genetically induced type 2 diabetic mouse model (dorsal view). (E) Pig wound infection model (dorsal view). This method is also applicable to rodents and rabbits.