**Author details**

formation, venous beading, capillary nonperfusion, and preretinal neovascularization [84]. Both VEGF injections and implants resulted in iris neovascularization [73, 85]. Despite their anatomical similarities to human eyes, DR development is highly variable and exceedingly

An alternate primate model is the marmoset. The marmoset has large eyeballs in respect to its body size with anatomical features closely resembling those of the human eye. The only study to date characterizing the development of retinal DR lesions in these animals reported the development of microaneurysms with increased acellular capillaries, pericyte loss, BM thickening, BRB breakdown, and macular edema in marmosets that were put on a 30% galactose-

Zebrafish (*Danio rerio*) uniquely offers the tractable genetics of rodent models and a retinal structure resembling that of the human eye. They have the distinctive five-layered human retinal structure, though they lack the subretinal plexi found in the inner and outer retina of human retinae [87, 88]. Despite lacking a macula, the density and number of cones in the

Researchers have developed high-glucose diabetic and angiogenic models to mimic DR. Hyperglycemia was induced by immersing zebrafish into glucose-added water [89, 90]. This resulted in reduced IPL and INL thickness [90] and increased diameter of hyaloid retinal vessels [33]. Zebrafish subjected to a hypoxia-induced retinopathy model developed neovascular features after 3 days [91]. One group developed an angiogenesis model using *vhl* (von Hippel-Lindau tumor suppressor gene) mutant fish. By inactivating the *vhl* tumor suppressor gene, hypoxia-inducible factor was upregulated, resulting in overproduction of VEGF. Extensive neovascularization and PDR features were observed in these *vhl* mutant zebrafish, but such a

The short lifespan, rapid development, and capability of zebrafish to breed in exceedingly large numbers allow for high-throughput screening [88], genetic screening, and significantly shorter experimental turnover times as compared with that of rodents. Techniques for developing transgenic lines and gene-targeting mutations have also been established. Although the presence of DR-like lesions and exact models ideal for the simulation of DR have not yet been well established, the zebrafish represents a promising short-term model for future DR drug screening.

The ideal animal model for DR would mimic the complete pathophysiological process of DR in humans, with initial development of NPDR features and gradual progression to PDR with

slow, making it an impractical model for DR studies.

60 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

*1.2.5.2. Marmoset models*

*1.2.6. Zebrafish models*

rich diet for two and a half years [86].

zebrafish are comparable to that of humans.

model is not commercially available.

**2. Next-generation DR models and conclusion**

Larissa H.C. Tang<sup>1</sup> , Ian Y.H. Wong<sup>1</sup> and Amy C.Y. Lo1,2\*

\*Address all correspondence to: amylo@hku.hk

1 Department of Ophthalmology, The University of Hong Kong, Hong Kong

2 Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong
