Mouse models of diabetes-related ulcers: a systematic review and network meta-analysis

Abstract

Background: Diabetic foot ulcers (DFUs) are a common complication of diabetes, associated with important morbidity. Appropriate animal models of DFUs may improve drug development, and subsequently the success rate of clinical trials. However, while many models have been proposed, they are extremely heterogeneous, and no standard has emerged. We thus propose a systematic review with a network meta-analysis (NMA) to gather direct and indirect evidence, and compare the different mouse models of diabetes-related ulcers.

Methods: The systematic search was performed in Pubmed and Embase. The main outcomes were wound size measurement at days 3, 7, 11 and 15 (±1 day). The risk of bias and methodological quality of all included studies was assessed by using the Systematic Review Center for Laboratory animal Experimentation (SYRCLE) risk of bias tool. Meta-regressions were done on prespecified variables, including mouse strain, type of ulcer, sex, age, and use of a splint.

Findings: We included 295 studies. Among all models, only db/db, ob/ob, streptozotocin (STZ), and STZ + high fat diet mice showed a significantly delayed wound healing, compared with controls, at each time point. Age, sex and ulcer type had influence on wound healing, although not at all time points.

Interpretation: In conclusion, the db/db model is associated with the largest delay in wound healing The STZ model also exhibits significantly decreased wound healing. STZ + high fat diet and ob/ob mice may also be relevant models of diabetes-related ulcers, although the results rely on a more limited number of studies.

Funding: This work was funded by the Agence Nationale de la Recherche (grant ANR-18-CE17-0017).

Keywords: Animal models; Diabetes; Diabetic foot ulcers; Network meta-analysis; Wound healing.

Fig. 1

Flow diagram.

Fig. 2

Networks of included models of diabetes at day 3, 7, 11 and 15 (±1 day). Node size is proportional to the number of arms using the model. Lines between the nodes indicate direct comparisons between two models. The thickness of the lines and the number on it indicate the number of direct comparisons. HFD: high fat diet; NON/NZ: NONcNZO10/LtJ; STZ: streptozotocin.

Fig. 3

Forest plots of ulcer size between each diabetes model and wild-type at day 3, 7, 11 and 15 (±1 day). Data are expressed as standardized mean differences (SMD) with their 95% confidence intervals (95% CI).

Fig. 4

Wound healing over time expressed as the standardized mean differences (with their 95% confidence intervals) of ulcer size between wild-type mice and the four main diabetic models. HFD: high fat diet; STZ: streptozotocin.

Fig. 5

Risk of bias assessment using the SYRCLE tool (A) and additional indicators (B).