Animal Models for Limbal Stem Cell Deficiency: A Critical Narrative Literature Review

Abstract

This literature review will provide a critical narrative overview of the highlights and potential pitfalls of the reported animal models for limbal stem cell deficiency (LSCD) and will identify the neglected aspects of this research area. There exists significant heterogeneity in the literature regarding the methodology used to create the model and the predefined duration after the insult when the model is supposedly fully fit for evaluations and/or for testing various therapeutic interventions. The literature is also replete with examples wherein the implementation of a specific model varies significantly across different studies. For example, the concentration of the chemical, as well as its duration and technique of exposure in a chemically induced LSCD model, has a great impact not only on the validity of the model but also on the severity of the complications. Furthermore, while some models induce a full-blown clinical picture of total LSCD, some are hindered by their ability to yield only partial LSCD. Another aspect to consider is the nature of the damage induced by a specific method. As thermal methods cause more stromal scarring, they may be better suited for assessing the anti-fibrotic properties of a particular treatment. On the other hand, since chemical burns cause more neovascularisation, they provide the opportunity to tap into the potential treatments for anti-neovascularisation. The animal species (i.e., rats, mice, rabbits, etc.) is also a crucial factor in the validity of the model and its potential for clinical translation, with each animal having its unique set of advantages and disadvantages. This review will also elaborate on other overlooked aspects, such as the anaesthetic(s) used during experiments, the gender of the animals, care after LSCD induction, and model validation. The review will conclude by providing future perspectives and suggestions for further developments in this rather important area of research.

Keywords: Alkali burns; Animal models; LSCD; Limbal stem cell deficiency; Limbal stem cell insufficiency; Thermal burns.

Fig. 1

A comparative pie-chart analysis of limbal stem cell deficiency (LSCD) induction methods and research objectives in studies involving rabbit (A), rat (B), and mouse (C) models. A detailed account of the methodology used to construct this figure along with an exhaustive list of publications is provided in the Supplementary Material. NaOH sodium hydroxide

Fig. 2

A figure showing application of filter paper on a rabbit’s eye (A). For chemical injury, a sodium hydroxide (NaOH)-soaked filter paper may be applied over the entirety of the corneal and limbal surface (B) or, alternatively, they may be crafted to achieve a doughnut shape (C) using punch trephines for application exclusively to the limbal circumference. The application show in the figure is on a rabbit’s eye

Fig. 3

A diagram showing general recommendations for animal selection and injury types based on the intended purpose of the limbal stem cell deficiency (LSCD) model. NaOH sodium hydroxide, NV neovascularisation, ID inner diameter, OD outer diameter