Bio-inspired human in vitro outer retinal models: Bruch's membrane and its cellular interactions.

Retinal degenerative disorders, such as age-related macular degeneration (AMD), are one of the leading causes of blindness worldwide, however, treatments to completely stop the progression of these debilitating conditions are non-existent. Researchers require sophisticated models that can accurately represent the native structure of human retinal tissue to study these disorders. Current in vitro models used to study the retina are limited in their ability to fully recapitulate the structure and function of the retina, Bruch's membrane and the underlying choroid. Recent developments in the field of induced pluripotent stem cell technology has demonstrated the capability of retinal pigment epithelial cells to recapitulate AMD-like pathology. However, such studies utilise unsophisticated, bio-inert membranes to act as Bruch's membrane and support iPSC-derived retinal cells. This review presents a concise summary of the properties and function of the Bruch's membrane-retinal pigment epithelium complex, the initial pathogenic site of AMD as well as the current status for materials and fabrication approaches used to generate in vitro models of this complex tissue. Finally, this review explores required advances in the field of in vitro retinal modelling. STATEMENT OF SIGNIFICANCE: Retinal degenerative disorders such as age-related macular degeneration are worldwide leading causes of blindness. Previous attempts to model the Bruch's membrane-retinal pigment epithelial complex, the initial pathogenic site of age-related macular degeneration, have lacked the sophistication to elucidate valuable insights into disease mechanisms. Here we provide a detailed account of the morphological, physical and chemical properties of Bruch's membrane which may aid the fabrication of more sophisticated and physiologically accurate in vitro models of the retina, as well as various fabrication techniques to recreate this structure. This review also further highlights some recent advances in some additional challenging aspects of retinal tissue modelling including integrated fluid flow and photoreceptor alignment.