See the Light

Landmark literature: YH Jung et al., “3D Microstructured Scaffolds to Support Photoreceptor Polarization and Maturation”, Advanced Materials, 30 (2018). DOI: 201803550

Regenerative medicine is a promising and relatively new area of research inclusive of both gene therapy and cell-based approaches. There are many misconceptions regarding regenerative medicine approaches for retinal disorders; gene therapy should be thought of principally as a prevention scheme dependent on early intervention before significant cell loss. Gene therapy cannot produce visual improvement with the exception of the modest visual improvement observed with Luxturna (voretigene neparvovec-rzyl) for RPE 65 type of Leber Congenital Amarosis and RPE 65 subtype retinitis pigmentosa. On the other hand, cell-based therapies do have the potential to restore function. But intravitreal, subretinal stem cell or retinal progenitor cell injection cannot produce highly organized retinal architecture. Stem cells must be converted to RPE cells for geographic atrophy associated with AMD or to photoreceptors for inherited retinal disorders or possibly chronic retinal detachment treatment. The conversion process is complex, takes over 100 days, and has many potential pitfalls.

Blinding disorders of the outer retina involve dysfunction and degeneration of photoreceptors. One potential approach to treat these forms of blindness is to repopulate the outer retina via a simple bolus injection of donor photoreceptors. This approach may not be ideal due to the highly polarized organization of photoreceptors that include apical light sensing photopigments and basal axon terminals. In addition, bolus injections create uncertainty with regard to the area, density, and retention of donor cells. Jung, Phillips and colleagues recently published a highly cited paper on a revolutionary approach to photoreceptor replacement – my choice of landmark literature. The paper describes a novel and robust microfabrication process developed to create 3D, micron-sized complex structures in ultrathin and biocompatible elastomer films, such as non-biodegradable polydimethylsiloxane and biodegradable polyglycerol-sebacate that can serve as polarizable photoreceptor delivery scaffolds. The scaffolds consist of an array of cup-shaped photoreceptor capture wells that funnel into microchannels. This “wine glass” scaffold design promotes efficient capture of human pluripotent stem-cell-derived photoreceptor cell bodies and guidance of basal axon extensions, ultimately achieving a uniform level of organization and polarization that is not possible with bolus injections or previously described scaffolds.

In addition to future therapeutic applications, their scaffold design and materials provide a platform to generate reproducible and scalable in vitro models of photoreceptor-based diseases.