Animal models of ischemic limb ulcers: a systematic review and meta-analysis

The aims of this systematic review were to assess the clinical relevance and quality of previously published animal models of ischemic ulceration and examine the available evidence for interventions improving ulcer healing in these models. Publicly available databases were searched for original studies investigating the effect of limb ischemia on wound healing in animal models. The quality of studies was assessed using two tools based on the Animal research: Reporting of In Vivo Experiments (ARRIVE) guidelines and the clinical relevance of the models. A total of 640 wounds (ischemic=314; non-ischemic=326) were assessed in 252 animals (92 mice, 140 rats, 20 rabbits) from 7 studies. Meta-analyses showed that wound healing was consistently delayed by ischemia at all time-points examined (day-7 standard median difference (SMD) 5.36, 95% CI 3.67 to 7.05; day-14 SMD 4.50, 95% CI 2.90 to 6.10 and day-21 SMD 2.53, 95% CI 1.25 to 3.80). No significant difference in wound healing was observed between 32 diabetic and 32 non-diabetic animals with ischemic wounds. Many studies lacked methods to reduce bias, such as outcome assessors blinded to group allocation and sample size calculations and clinically relevant model characteristics, such as use of older animals and a peripheral location of the wound. Five different interventions were reported to improve wound healing in these models. The impaired wound healing associated with limb ischemia can be modeled in a variety of different animals. Improvements in study design could increase clinical relevance, reduce bias and aid the discovery of translatable therapies.