Establish the Feasibility of Engineering a Human Optic-Nerve-On-A-Chip as an In Vitro Model for SANS Research

Focused Investigation Project

During space travel, astronauts have to deal with long term exposure to zero gravity, galactic cosmic rays, elevated CO2, etc. The adverse effects of these challenging conditions result in a baffling physiological disorder such as Spaceflight Associated Neuro-ocular Syndrome (SANS). To understand the progression of SANS, in vitro human cells-based 3D biomimetic models capable of mimicking some of these adverse ocular symptoms is highly desired.

Exploring outer space is important for the long-term survival of species that have evolved over millions of years in this ever-changing cosmos. The question of whether life in its current form can survive on other planets or whether other planets already have life in some form has intrigued people for centuries, and the meteoric advances in rocket technology in the last few decades have resulted in prospects of ambitious space travel projects such as interplanetary missions. However, advances in rocket technology have not matched with our understanding of how long-term space travel affects human biology. Once in space, whether in the International Space Station (ISS) or while travel on possible future Mars missions, astronauts likely have to deal with long term exposure to zero gravity, ionizing cosmic rays, hypoxia, inflammation, etc. The adverse effects of these extremely challenging conditions on the physiological functions of the human body are largely unknown. Controlled ISS based experiments have revealed that long term space travel causes an alteration in specific genes, which impacts several important processes in the human body, including mitochondrial stress, genetic processes, connective tissue processes, and immune activity. Furthermore, it has been shown that microgravity can affect many aspects of nervous system physiology, such as vestibular and neuromuscular function, sympathetic tone and reflexes, vision, and even central processing and memory. One interesting and quite baffling physiological disorder that has been carefully documented by NASA in astronauts during and after long term spaceflights is spaceflight-associated neuro-ocular syndrome (SANS). This pathology causes unilateral and bilateral optic disc edema, globe flattening, choroidal and retinal folds, hyperopic refractive error shifts, nerve fiber layer infarcts, and thickening. The mechanism of SANS is currently a topic of great interest, and a single unifying mechanism has not yet been postulated. A possibility of multifactorial pathogenesis exists, and to study the progression, in vitro models capable of mimicking some of these adverse ocular symptoms is highly desired. The first step towards this is the development of a healthy 3D biomimetic ocular system, which mimics the development of both retinae as well as the optic nerve. In order to recreate SANS related pathophysiology in vitro, it was important to create a microphysiological system which not only begins to generate the complexity of the retina but is also capable of mimicking the optic nerve tract. Previously, we had successfully been able to create motor and sensory nerves in vitro using induced pluripotent stem cells (iPSC)-derived motor and sensory neurons using commercially available cell sources. However, currently, there is no commercially available source of retinal organoids and retinal ganglion cells. To create optic nerve-on-a-chip (NoaC), we took advantage of already published protocols. They were evaluated to determine the most effective protocol to differentiate iPSCs into retinal ganglion cells (RGCs), and perhaps more importantly, generated differentiated retinal organoids capable of dense 3D axonal outgrowth critical to the creation of a benchtop model of optic-nerve-on-a-chip. In the future, this optic NoaC model can be used for modeling diseases such as SANS and glaucoma.

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