Systematic review and meta-analysis of mouse models of diabetes-associated ulcers

Abstract

Mouse models are frequently used to study diabetes-associated ulcers, however, whether these models accurately simulate impaired wound healing has not been thoroughly investigated. This systematic review aimed to determine whether wound healing is impaired in mouse models of diabetes and assess the quality of the past research. A systematic literature search was performed of publicly available databases to identify original articles examining wound healing in mouse models of diabetes. A meta-analysis was performed to examine the effect of diabetes on wound healing rate using random effect models. A meta-regression was performed to examine the effect of diabetes duration on wound healing impairment. The quality of the included studies was also assessed using two newly developed tools. 77 studies using eight different models of diabetes within 678 non-diabetic and 720 diabetic mice were included. Meta-analysis showed that wound healing was impaired in all eight models. Meta-regression suggested that longer duration of diabetes prior to wound induction was correlated with greater degree of wound healing impairment. Pairwise comparisons suggested that non-obese diabetic mice exhibited more severe wound healing impairment compared with db/db mice, streptozotocin-induced diabetic mice or high-fat fed mice at an intermediate stage of wound healing (p<0.01). Quality assessment suggested that the prior research frequently lacked incorporation of key clinically relevant characteristics. This systematic review suggested that impaired wound healing can be simulated in many different mouse models of diabetes but these require further refinement to become more clinically relevant.

A review of diabetic wound models—Novel insights into diabetic foot ulcer

“…Hair follicle stem cells have been shown to play an indispensable role in wound healing as skin areas with denser hair tend to heal faster (Martinot et al, 1994;Zomer & Trentin, 2018). Because of these reasons, the reliability of the animal diabetic wound models has been questioned over decades due to the low translational relevance into clinical wound healing scenarios (Gordillo et al, 2013;Huynh et al, 2020).…”

“…Hence, this highlights the need for alternate experimental models that match the 3Rs (refinement, reduction, and replacement) approaches while improving the translational relevance (Díaz et al, 2020). Reviews regarding the use of diabetic animals in DFU research have been published elsewhere (Gao et al, 2017;Huynh et al, 2020;King, 2012;Sriram et al, 2018;Velander et al, 2008), hence it will not be covered in this review. Apart from animal models, human skin biopsies have also been employed as ex vivo models for therapeutic screening (Abd et al, 2016;Franz et al, 2009;Sidgwick et al, 2016), albeit their limited availability and inter-individual variations often restrain them from being widely established (Dumont et al, 2015).…”

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

“…This is supported by a recent systematic review that suggested the need for refinement of currently used mouse models of diabetes-associated ulcers in order to make them more clinically relevant. 25 Five different interventions were tested in the included studies and reported to successfully improve healing rate through mechanisms such as promoting angiogenesis, collagen deposition, re-epithelialization and increased expression levels of proliferative markers such as VEGF and increased anti-inflammatory cytokines such as interleukin-8 in addition to reduction of leukocyte infiltration and reduced expression levels of inflammatory cytokines such as TNF 15 16 18-20 (table 3). The risk of bias and reporting quality of three of these studies was considered high but none of the models used were considered to be highly clinically relevant.…”

“…This is supported by a recent systematic review that suggested the need for refinement of currently used mouse models of diabetes-associated ulcers in order to make them more clinically relevant. 25 …”

The Problem of Wound Healing in Diabetes—From Molecular Pathways to the Design of an Animal Model

“…In mice and rats, the skin is thin and fragile, whereas the subcutaneous layer consists of a special muscular striatum, panniculus carnosus (absent in humans), which causes more rapid contraction and facilitates wound healing [120]. Nevertheless, rodents are widely used in experimental models of diabetic wound healing and a number of them provided experience, which allows for further optimization of models in the aspects such as glycemic levels, the method of induction of DM, or duration of DM [121]. The advantages and disadvantages of different animal models used in the studies on diabetic wounds are given in Table 2 A study conducted by the authors of this review showed that the duration of hyperglycemia in rats might reflect the long-term uncompensated course of DM in humans [123].…”