Animal Models of Choroidal Neovascularization: A Systematic Review

Abstract

Purpose: Animal models of choroidal neovascularization (CNV) are extensively used to characterize the pathophysiology of chorioretinal diseases with CNV formation and to evaluate novel treatment strategies. This systematic review aims to give a detailed overview of contemporary animal models of CNV.

Methods: A systematic search was performed in PubMed and EMBASE from November 20, 2015, to November 20, 2020, for mammalian animal models of CNV. Following inclusion by two investigators, data from the articles were extracted according to a predefined protocol.

Results: A total of 380 full articles, representing 409 independent animal models, were included. Mice were by far the most utilized animal (76%) followed by rats and non-human primates. The median age of rodents was 8 weeks but with a wide range. Male animals were used in 44% of the studies, but 32% did not report the sex. CNV was laser induced in 89% of the studies, but only 44% of these reported sufficiently on standard laser parameters. Surprisingly, 28% of the studies did not report a sample size for quantitative CNV evaluation. Less than half of the studies performed quantitative in vivo evaluation, and 73% evaluated CNV quantitatively ex vivo. Both in vivo and ex vivo evaluations were conducted primarily at day 7 and/or day 14.

Conclusions: The laser-induced mouse model is the predominant model for experimental CNV. The widespread use of young, healthy male animals may complicate clinical translation, and inadequate reporting challenges reproducibility. Definition and implementation of standardized methodologic and reporting guidelines are attractive.

Figure 1.

(A) Flow diagram depicting the selection process of articles and animal models. (B) Flow diagram depicting the selection process of laser-induced mouse models of CNV reporting on laser parameters and with CNV quantification.

Figure 2.

Frequency distribution of days from CNV induction until CNV evaluation, where >28 represents all time points beyond day 28 from CNV induction. Red columns represent studies evaluating CNV in vivo by all methods, and orange columns represent studies evaluating CNV in vivo only by fluorescein angiography. Dark blue columns represent studies evaluating CNV ex vivo by all methods, and light blue columns represent studies evaluating CNV ex vivo only by RPE/choroidal flatmount with or without FITC-dextran.

Figure 3.

Outline of a CNV animal model flowchart/checklist. Items were chosen according to the ARRIVE guidelines and the main findings of the present review (in bold). Dark colors represent mandatory items that should be a requisite for conducting and reporting on research on animal models of CNV, and bright colors represent optional items that should be considered.