Spaceflight Associated Neuro-Ocular Syndrome: New Technologies to Advance Research in a Fast Moving Field

Abstract

Spaceflight is expected to boom in the next several decades. This will likely include an increase in deep space exploration and long-duration missions. It is well established that spaceflight has potentially hazardous effects on human health. One of the concerning conditions experienced by astronauts on long duration space missions is spaceflight associated neuro-ocular syndrome (SANS), which includes symptoms such as swelling around the optic disk, changes in ocular anatomy, and visual refractory errors. Multiple theories have been proposed to explain the pathophysiology of this syndrome. However, there are unique challenges faced with studying this syndrome and a clear etiology is not currently known. As more individuals venture into space for longer periods of time, it is important to assess the value new technologies could add to learning more about syndromes such as SANS and improving human health in space overall. New complex human in vitro models and other technological devices may allow researchers to investigate these issues and give greater insight into the pathophysiology of SANS, potentially leading to improved countermeasures and therapeutics.

INTRODUCTION

We live in an era where there is an ever-increasing interest in state-sponsored deep space exploration, as well as space travel by private citizens, often referred to as “space tourism.” Regardless of whether they are carefully selected astronauts or thrill seekers with significant means, several medical risks exist for all these explorers. This is especially true for those completing long-duration spaceflight missions, as they are exposed to environmental stressors, such as microgravity, for extended periods of time. One medical issue these individuals could potentially face is a group of anatomic changes to the eye and vision problems. This syndrome, previously called visual impairment intracranial pressure, is now known as spaceflight associated neuro-ocular syndrome (SANS). The risk of developing this syndrome appears directly related to mission duration. Therefore, the importance of understanding its etiology and creating effective preventative and therapeutic measures will increase in tune with the focus on deep space exploration, such as human missions to Mars.

From International Space Station (ISS) expeditions 1–52, the diagnostic criterion of SANS has been Frisen scale edema grade ≥1 as determined by analysis of fundoscopic images. Of the 68 U.S. crew members on these ISS missions, there were 10 cases of SANS based on this criterion.¹ However, many more astronauts have displayed related, but nondiagnostic, signs and symptoms, including cotton wool spots, choroidal folds, posterior globe flattening, and a hyperopic refractive error shift.² Because of the variety of signs and symptoms, the unclear etiology of the syndrome, and the lack of objectivity in classifying optic nerve edema through the Frisen scale, it is possible that the diagnostic criteria, and therefore the total number of cases, will be changed in the future.

Although knowledge of long-term effects of SANS is limited, current research shows that astronauts often report a subjective decrease in visual acuity after spaceflight. Many of these astronauts experience a hyperopic shift, ranging from +0.50 to +1.75 diopters, however, all had best corrected visual acuity of 20/20.³ Although best corrected visual acuity may not be affected, several signs of SANS, including the defining feature of optic disk edema, have persisted months to years in some individuals after returning from spaceflight.¹ This leads to concern about long-term effects of these changes, which have not been studied in the relatively small group of fairly young astronauts who have undergone long duration spaceflight.

As vastly more individuals plan to travel into space in the coming decades, understanding the long-term effects and discovering treatments related to SANS will become a priority for organizations and individuals involved in space exploration. Unfortunately, conducting research in the field of space medicine and SANS has unique challenges for investigators. These include, but are not limited to, a small sample size of affected subjects, lack of terrestrial analog syndrome, high cost of conducting research in microgravity environments, and limited availability of space medicine research opportunities on human subjects. Because of the difficulty of conducting research on subjects during spaceflight, several terrestrial analogues have been utilized in an attempt to simulate weightlessness. Studies utilizing a variety of analogues have been completed and others are currently under investigation. Several physiologic similarities have been recreated by using conditions such as head-down tilt bed rest, although with limitations.⁴ This article will not go into further detail about these environmental analogues, but instead will attempt to address the overall challenge of conducting space medicine research by examining emerging technologies and the role they could play in expanding research in this field.

DISCUSSION

Use of Innovative Technologies

Although several potential mechanisms have been identified, no single theory has definitively explained the signs and symptoms associated with SANS. As previously mentioned, one challenge in identifying the underlying mechanism includes the difficulty of carrying out SANS-related investigations. Much like emerging technologies, such as optical coherence tomography, may help physicians and researchers better identify and objectively measure the signs of this syndrome, there are several projects focused on innovations that could allow investigators to complete research promoting a better understanding of the SANS etiology.

One example of the of use of new technologies to conduct space medicine research is the use of microphysiologic systems (MPSs), also known as organs-on-chips (OoCs) or tissue chips, to study the effects of microgravity on functional engineered human cells and tissues in an in vitro environment.⁵ OoCs are small devices, typically about the size of an USB drive, engineered to resemble microenvironments of a specific region in human organ systems. Several different OoCs, including those designed after human kidneys, bone and cartilage, and the blood–brain barrier, have already been sent to the ISS through the “Tissue Chips in Space Program”.⁶ However, no MPS platforms have been developed specifically to study this unique eye–brain interface in an environment that mimics microgravity.

Although researchers have faced challenges in the past creating OoCs that mimic the structure and function of the eye, there have been several recent advancements in this area. One example is the development of a 3D “optic-nerve-on-a-chip” platform. This model uses induced pluripotent stem cells (iPSCs) to create a mass of human neurons and supportive neuronal cells. This spheroid-shaped tissue mass is then fixed in hydrogels and has been shown to experience outgrowth of 3D axon-like tissue, with lengths up to 4 mm. Histologic examination of this model revealed myelination and alignment of Schwann cells with this outgrowth of neuronal tissue. In addition, tests such as electrical stimulation have shown increased nerve conduction velocity compared with tissue chips with only iPSC neurons⁷ (Fig. 1). These results provide exciting evidence that utilizing in vitro models like this one could provide accessible and cost-effective ways of studying the effects of spaceflight on the human eye without utilizing human subjects.

Fig. 1.

Optic nerve-on-a-chip. (A) Phase image of nerve construct grown in 3D gel matrix displaying robust axonal outgrowth (∼4 mm). (B) Photo illustrates placement of the recording and stimulating electrodes used to measure CAPs. (C) Graph shows example of a CAP measured from the electrically stimulated nerve construct. CAP, compound action potential.

Another project with potential benefit to SANS-related research involves the use of a posterior cup of a postmortem human eye to evaluate the effects of various factors on tissue and cell structure. This model involves a donor eye, of which retina, choroid, and small portion of the optic nerve are harvested. The deceased cells are stripped, and the scaffolding is replaced with iPSCs resembling the cell tissue layers. Several pressure chambers are then applied around the tissues of the posterior cup, allowing for independent adjustments resembling changes in intraocular and intracranial pressures. This model could allow investigators to assess the effects of environmental stressors seen in spaceflight, such as physiologic pressure changes, ionizing radiation, and elevated CO₂ levels, on the eye and optic nerve. It may also provide therapeutic benefit through testing of pharmaceuticals without the need for affected human subjects⁸ (Fig. 2).

Fig. 2.

Translaminar autonomous system. A ground-based ex vivo human model analogue that can mimic aspects of SANS pathogenesis to identify pathways of pathogenesis and new therapies to overcome visual dysfunction observed in astronauts. Model depiction of the translaminar autonomous system with detailed description. Diagrammatic view of the (A) 6° tilt and (B) 10° tilt of the optic nerve to study the effects of the tilt on visual neuron degeneration. SANS, spaceflight associated neuro-ocular syndrome.

In addition to research focused on creating in vitro models to study pathophysiology, there are also projects working on the development of hardware to detect signs of SANS and enhance diagnostic and therapeutic capabilities in real time. These devices are designed to be compact, durable, user-friendly, and multifunctional, making them ideal for long duration spaceflight. A few examples include goggles for visual field assessment, a retinal imager that does not require pupillary dilation for visualization of the full retina, and an autorefractor for real-time refractive error adjustments as visual changes occur during spaceflight. This equipment could also provide societal benefits terrestrially, especially in less economically advantaged areas. Eventually, these technologies could be combined into a multipurpose device to allow space travelers to monitor their health and potentially apply countermeasures and therapeutics in real time. More information about this project is available at (https://webvisiontechnologies.net/vision-for-mars-project).

We believe the use of technologies such as those described in this article provides incredible opportunity to study the effects of microgravity on human tissues and begins to test countermeasures and therapeutics without the use of human subjects. Our hope is to spread knowledge of these projects with researchers and investigators engaged in work related to SANS and space medicine. In addition, eventually, we believe these technologies could also have important impacts beyond the field of space medicine and provide great benefit to the ophthalmic community globally.

Footnotes

ACKNOWLEDGMENTS

For providing information and images regarding their ongoing projects and research related to space medicine and SANS.

Bob Main

President and CEO of Vision for Mars Technologies and Web Vision Technologies

South Jordan, Utah

Wesley Anderson, PhD; Lowry Curley, PhD; Michael J. Moore, PhD; Anup Sharma, PhD

AxoSim, Inc

New Orleans, LA

Tasneem P Sharma, PhD

Assistant Professor Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Department of Pharmacology and Toxicology Indiana University School of Medicine Indianapolis, IN

AUTHOR DISCLOSURE STATEMENT

No competing financial interests exist.

FUNDING INFORMATION

No outside funding received.

References

Brunstetter

. Introduction to spaceflight associated neuro-ocular syndrome (SANS) and its risk to

NASA astronauts [PowerPoint slides]

, 2017. https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/20170009173.pdf (Last accessed March 24, 2021).

Brunstetter

. Spaceflight associated neuro-ocular syndrome (SANS): Current clinical insight & questions of interest [PowerPoint slides], 2018. https://media.bcm.edu/documents/2018/1c/brunstetter-sans-trish-red-risk-school-05apr18b-final.pdf (Last accessed May 12, 2021).

Mader

, Gibson

, Pass

, et al. Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight. Ophthalmology. 2011; 118(10):2058–2069.

Watenpaugh

. Analogs of microgravity: Head-down tilt and water immersion. J Appl Physiol. 2016; 120:904–914.

Dusang

. ‘Tissue chips' could reveal health risks of deep-space travel. [Blog post], 2019, May 3. https://blogs.bcm.edu/2019/05/03/tissue-chips-could-reveal-health-risks-of-deep-space-travel/ (Last accessed May 12, 2021).

NIH-funded tissue chips rocket to International Space

Station

, 2018, December 04. https://www.nih.gov/news-events/news-releases/nih-funded-tissue-chips-rocket-international-space-station (Last accessed April 1, 2019).

Sharma

, McCoy

, Jacobs

, et al. Engineering a 3D functional human peripheral nerve in vitro using the nerve-on-a-chip platform. Sci Rep, 2019; 9:8921.

Sharma

, Curry

, Lohawala

, et al. Translaminar autonomous system model for the modulation of intraocular and intracranial pressure in human donor posterior segments. J Visualized Exp. 2020; 24(158):e61006.