The microgravity environment results in a multitude of physiological changes associated with aging and altered organ function. Deployment of microphysiological systems, also known as “tissue chips” to the International Space Station United States National Laboratory, will allow the study of these changes at the cellular/molecular level. The goal of these studies is to expand understanding of age‐related conditions to improve human health on earth.
Tissue Chips
In 2012, the National Center for Advancing Translational Sciences (NCATS) sponsored several projects to develop three‐dimensional (3D) microphysiological system (MPS) technologies to model human organ functions as a more representative alternative to two‐dimensional (2D) cell culture or animal testing for prediction of drug‐induced toxicities. The program was intended to address the high failure rate once drugs reach in‐human clinical trials; with failure rates in excess of 30% in phases I and III, and 15% in phase II due to safety issues.1 This high failure rate is a major factor in the cost of new drug development, with recent cost estimates in excess of US $2 billion.2
Our team at the University of Washington was selected to create a kidney MPS based on primary cells derived from pathologically normal surgical nephrectomy tissue remnants.3 Our proximal tubule MPS platform recapitulates the biochemical, synthetic, and physiological characteristics of the proximal tubule segment of the nephron, in particular the polarized epithelium.4 In addition, the kidney MPS has met the NCATS mandate of the Tissue Chips Program for predictive toxicity testing of drugs and xenobiotics in our laboratory.5, 6 The next phase of the Tissue Chips program has focused on disease modeling and efficacy testing, which includes the Tissue Chips in Space initiative. In partnership with the International Space Station United States National Laboratory (ISSNL), NCATS issued five awards in June 2017 to conduct MPS‐based research on board the ISSNL.
Tissue Chips in Space
The environment of microgravity exerts a unique range of stresses and pathophysiological perturbations on the human body resulting in muscle wasting, immunosuppression, cardiovascular deconditioning, and decreased bone density.7 Numerous studies over the 50+ years of manned space flights have been conducted to investigate these changes, including the recent National Aeronautics and Space Administration (NASA) Twins study of astronauts Mark and Scott Kelly. That study, as well as others conducted in Russian cosmonauts and crewmembers on the Space Shuttle missions, have been limited to analysis of easily accessible biosamples (blood or urine), precluding any examination of organs or tissue at the cellular or molecular level. As a surrogate, studies in mice have been conducted that included transcriptomic analysis on the effects in the liver and kidneys after 12 days in microgravity8 and biochemical/proteomic analysis of mouse retina following a 35‐day mission on the International Space Station.9 However, whether these findings translate to human health effects is unknown. The Tissue Chips in Space initiative was designed to bridge this gap in much the same manner that MPS technology has been used to elucidate mechanisms of disease progression and drug‐induced toxicity.
The Challenges
The MPS system at the University of Washington is based on the Nortis Bio (Woodinville, WA) microfluidic culture platform. Each chip contains three independently perfused channels (triplex) with identical structural dimensions as previous single channel versions.4 Our original proposal was to deploy 24 single‐channel MPS to the ISSNL for ~ 14 days of experimentation. In order to address interindividual variability and sexual dimorphism, we increased capacity to 24 triplex chips to allow testing of 72 independent kidney MPS tubules. This increase in capacity presented a significant challenge due to extreme physical space limitations on launch and installation in the ISSNL.
The footprint required to maintain chips in the conventional laboratory is significant, requiring four syringe pumps, two incubators, and > 30.5 m of tubing (Figure 1b) with a total volume of ~ 1,350 L. To meet spaceflight limitations, that had to be compressed into 55 L for launch in a powered locker on the SpaceX Dragon capsule, with a final installation volume on the ISSNL of 45 L (Figure 1c). This required a complete re‐engineering of the perfusion and environmental control system. The final platform design (Figure 2a) is composed of four modules, each containing six triplex MPS. These modules are completely self‐contained, housing motors to drive syringe pump pistons, temperature/CO2/humidity control, and cassettes containing cell media and Teflon‐coated effluent collection bags. The design eliminated all flexible tubing. The hands‐on involvement of crewmembers Anne McClain and Christina Koch (Figure 2b) was limited to replacing media and fixative cassettes at defined time points in the Life Sciences Glovebox (the ISSNL biosafety cabinet).
