Table 1.

Advantages and disadvantages of neovascular models.

Models	Advantages	Disadvantages
In Vitro
Cell Lines	Reduced donor-to-donor variability. Defined models with structured experimental conditions and good reproducibility.	A single cell type will not reproduce systemic defects. Does not reproduce the complexity of interactions in a living model. Cells grow unnaturally fast and gene and protein expression are often vastly different than in vivo.
PrimaryRPE cells	Human cells with natural differentiation. Mimic perfectly human pathology.	Can be used for only a few passages. Need to have access to this type of sample and the related authorizations
ARPE-19 cells	Immortalized, rapid cell growth. Exhibits similar morphology and genetic makeup to primary RPE cells.	Incomplete polarization of the cells compared to primary RPEs.
IPSC-RPE	Exhibits similar morphology and genetic makeup to primary RPE cells. Patient derived iPSC-RPE cells could be used in autologous cell replacement therapy.	Differentiation of the cells is time consuming and requires growth factors.
Cocultures	Enables cell-to-cell interactions and cross-talks, and modulation of cytokine production. More cytokines are usually produced in cocultures.
2D models	Easier to put in place than 3D models, better for long-term cultures.	Lack of sophistication, cells grow in monolayers at the same speed. Drugs are up-taken more easily than they would in vivo which is less accurate.
3D models	Multi layered, the cells can self-organize. The most accurate in vitro representation of the choroid, Bruch’s membrane and RPE cells. Cells develop vascular networks and can migrate. More representative of drug exposure. Gene and protein levels closer to those in vivo. Better cell junctions.	More resource intensive, electrospun scaffolds require specialized equipment, in addition to more time and expertise. Can be difficult to replicate.
In Vivo
Murine Models	Most retinal degeneration genes in mice have a corresponding gene in humans, many human gene orthologs in the mice genome. They have short lifespans which enables us to see the ageing process. Protocols for genetic studies are well established.	Mice do not possess a macula. They do not produce drusen that are similar in location and composition to human drusen. Pathogenesis can differ. Late onset genetic models can lead to waiting over a year.
Laser induced CNV	Replicates the neovascularization in neovascular AMD, is low cost, and the CNV develops rapidly.	It is an acute injury rather than a chronic one, and thus has the inability to reproduce the complex events that lead to AMD. Risk of cataract and fibrosis if the procedure is not performed correctly.
Injection induced CNV	Simulates the exudative deposits and lesions in neovascular AMD.	Lower incidence of CNV than laser induced. Injections can cause tears in Bruch’s membrane.
Injection of adenovirus	Injection of vectors expressing VEGF have high incidence and long-term capability to induce CNV. These models work well on transgenic models.
Transgenic models	Increased sensitivity to laser induced CNV, some models develop CNV with age. They are more complex models than acute induced CNV.	Most transgenic models exhibit dry AMD symptoms, such as drusen formation and retinal degeneration, and therefore will need injection or laser induced CNV to simulate neovascular AMD, making the experiment more costly and time consuming.
Zebrafish Models	Common features in retinal vasculature, many human orthologs in the zebrafish genome. Cost effective. Accessibility of screening and study of vascular patterning. Easy to treat.	Fewer models that replicate AMD, as zebrafish are less used than murine models. Pathogenesis can differ.
Hypoxia induced	Non-invasive induction of angiogenesis, easily reproducible and low cost. Can be induced in transgenic fish.
Transgenic models	VHL knockout models exhibit high vascularization. These models are easy to work with as treatments are easy to deliver.

RPE = retinal pigment epithelium; AMD = age related macular degeneration; CNV = choroidal neovascularization.