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NASA NTRS2010

Human and Robotic Exploration of Near-Earth Objects

A study in late 2006 was sponsored by the Advanced Projects Office within NASA's Constellation Program to examine the feasibility of sending the Orion Crew Exploration Vehicle to a near-Earth object (NEO). The ideal mission profile would involve two or three astronauts on a 90 to 180 day flight, which would include a 7 to 14 day stay for proximity operations at the target NEO. More recently U.S. President Obama stated on April 15, 2010 that the next goal for human spaceflight will be to send human beings to a near-Earth asteroid by 2025. Given this direction from the White House, NASA has been involved in studying various strategies for NEO exploration in order to follow U.S. space exploration policy. Prior to sending a human mission, a series of robotic spacecraft would be launched to reduce the risk to crew, and enhance the planning for the proximity and surface operations at the NEO. The human mission would ideally follow five or more years later. This mission would be the first human expedition to an interplanetary body beyond the Earth-Moon system and would prove useful for testing technologies required for human missions to Mars and other solar system destinations. Piloted missions to NEOs would undoubtedly provide a great deal of technical and engineering data on spacecraft operations for future human space exploration while conducting in-depth scientific investigations of these primitive objects. The main scientific advantage of sending piloted missions to NEOs would be the flexibility of the crew to perform tasks and to adapt to situations in real time. A crewed vehicle would be able to test several different sample collection techniques and target specific areas of interest via extra-vehicular activities (EVAs) more efficiently than robotic spacecraft. Such capabilities greatly enhance the scientific return from these missions to NEOs, destinations vital to understanding the evolution and thermal histories of primitive bodies during the formation of the early solar system. Data collected from these missions would help constrain the suite of materials possibly delivered to the early Earth, and would identify potential source regions from which NEOs originate. In addition, the resulting scientific investigations would refine designs for future extraterrestrial resource extraction and utilization, and assist in the development of hazard mitigation techniques for planetary defense.

Abell, Paul A.↗

NASA NTRSDate not supplied

Surviving and Thriving in Space and on Earth's Oceans, Human Logistics and Sustainability: Comparisons and Considerations

Ocean exploration sailing journeys from hundreds of years ago typically required large vessels and large crews (in comparison with today’s space capsules) to travel between the continents and around the world. Modern sailors of today are able to complete similar distant voyages, in small vessels, with a minimal crew, comparable in size to modern space travel crews. This paper uses a systems engineering approach (e.g. using the NASA Human Integration Design Handbook (HIDH), NASA-SP-2010-3407, 2010 and the “Advanced Life Support Baseline Values and Assumptions Document, (BVAD)” NASA-CR-2004-208941, 2004.), to examine and compare the logistics and sustainability aspects of a small crew traveling on Earth's oceans in sailing vessels versus humans traveling in space. The “Mālama Honua Worldwide Voyage” of the Hōkūleʻa, a replica of an ancient Hawaiian double hulled sailing canoe, will be used as a baseline minimalist case study. This is a good comparison case since the Polynesian exploration of the vast (and virtually empty) Pacific Ocean with limited resources is an analogue to human space travel. A modern sailboat is compared to the ancient Polynesian methods and then a space craft is assessed with similar functional decomposition methods. In 1992 during his second Space Shuttle mission (STS-52, Columbia) Astronaut Lacy Veach received a radio message from a student: "What are the similarities and differences between canoe and space travel?" Astronaut Charles Lacy Veach answered, "Both are voyages of exploration. Hōkūle‘a is in the past, Columbia is in the future." Navigator Nainoa Thompson added from the sailing canoe, "Columbia is the highest achievement of modern technology today, a voyaging canoe was the highest achievement of technology in its day." This paper is dedicated to the memory of two great Hawaiian astronauts: US Air Force Colonel Charles Lacy Veach and US Air Force Colonel Ellison Onizuka and to legendary waterman and Hōkūleʻa crew member Eddie Aikau who was lost at sea in 1978, at the beginning of a 30-day, 2,500-mile (4,000km) journey by the Hōkūleʻa to follow the ancient route of the Polynesian migration between the Hawaiian and Tahitian island chains.

Robert P Mueller↗

NASA NTRS2019

Using Machine Learning to Predict Core Sizes of High-Efficiency Turbofan Engines

With the rise in big data and analytics, machine learning is transforming many industries. It is being increasingly employed to solve a wide range of complex problems, producing autonomous systems that support human decision-making. For the aircraft engine industry, machine learning of historical and existing engine data could provide insights that help drive for better engine design. This work explored the application of machine learning to engine preliminary design. Engine core-size prediction was chosen for the first study because of its relative simplicity in terms of number of input variables required (only three). Specifically, machine-learning predictive tools were developed for turbofan engine core-size prediction, using publicly available data of two hundred manufactured engines and engines that were studied previously in NASA aeronautics projects. The prediction results of these models show that, by bringing together big data, robust machine-learning algorithms and automation, a machine learning-based predictive model can be an effective tool for turbofan engine core-size prediction. The promising results of this first study paves the way for further exploration of the use of machine learning for aircraft engine preliminary design.

Tong, Michael T.↗

NASA NTRS2019

Using Machine Learning to Predict Core Sizes of High-Efficiency Turbofan Engines

With the rise in big data and analytics, machine learning is transforming many industries. It is being increasingly employed to solve a wide range of complex problems, producing autonomous systems that support human decision-making. For the aircraft engine industry, machine learning of historical and existing engine data could provide insights that help drive for better engine design. This work explored the application of machine learning to engine preliminary design. Engine core-size prediction was chosen for the first study because of its relative simplicity in terms of number of input variables required (only three). Specifically, machine-learning predictive tools were developed for turbofan engine core-size prediction, using publicly available data of two hundred manufactured engines and engines that were studied previously in NASA aeronautics projects. The prediction results of these models show that, by bringing together big data, robust machine-learning algorithms and data science, a machine learning-based predictive model can be an effective tool for turbofan engine core-size prediction. The promising results of this first study paves the way for further exploration of the use of machine learning for aircraft engine preliminary design.

Core Size↗

NASA NTRS2001

Human Centered Autonomous and Assistant Systems Testbed for Exploration Operations

The Engineering and Mission Operations Directorates at NASA Johnson Space Center are combining laboratories and expertise to establish the Human Centered Autonomous and Assistant Systems Testbed for Exploration Operations. This is a testbed for human centered design, development and evaluation of intelligent autonomous and assistant systems that will be needed for human exploration and development of space. This project will improve human-centered analysis, design and evaluation methods for developing intelligent software. This software will support human-machine cognitive and collaborative activities in future interplanetary work environments where distributed computer and human agents cooperate. We are developing and evaluating prototype intelligent systems for distributed multi-agent mixed-initiative operations. The primary target domain is control of life support systems in a planetary base. Technical approaches will be evaluated for use during extended manned tests in the target domain, the Bioregenerative Advanced Life Support Systems Test Complex (BIO-Plex). A spinoff target domain is the International Space Station (ISS) Mission Control Center (MCC). Prodl}cts of this project include human-centered intelligent software technology, innovative human interface designs, and human-centered software development processes, methods and products. The testbed uses adjustable autonomy software and life support systems simulation models from the Adjustable Autonomy Testbed, to represent operations on the remote planet. Ground operations prototypes and concepts will be evaluated in the Exploration Planning and Operations Center (ExPOC) and Jupiter Facility.

Malin, Jane T.↗

NASA NTRSDate not supplied

Preliminary Findings of the Experimental Development Unit Cold Flow Test for a Generation Zero Nuclear Propulsion Engine

Nuclear thermal propulsion (NTP) technology will greatly benefit human travel to Mars by significantly shortening transit times, improving crew safety, and providing more mission flexibility than traditional chemical rockets. As part of DRACO follow-on work to develop, build, and fly a generation zero NTP engine, a full scale flight-like experimental design unit (EDU) reactor was constructed to collect sufficient on-ground performance data to characterize flow induced vibrations (FIV) of critical reactor structures/components, inform development of the engine and reactor control algorithm, and collect pressure drop and flow distribution data across the reactor. The fluid conditions for the test program were designed to achieve system responses equivalent to that of an operational engine through all phases of engine operation including reactor startup, mainstage operation, reactor shutdown, and reactor cooldown. Over 100 tests were executed, flowing either GN2 or GHe through the EDU at varying flow rates and pressures. This experiment provided early validation of flow behavior and vibration risks before nuclear testing, boosted critical subsystem TRLs, informed design iterations, and reduced future test costs. The steady-state flow parameters for the experiment were modeled in Ansys Thermal Desktop, allowing rapid tuning and experiment-informed updates to a flight-like test matrix. The EDU dynamic environment was characterized with accelerometers, strain gauges, and high-frequency pressure transducers all sampled at 20 kHz. While many narrow-band oscillations were identified, no significant FIV occurred; the reactor structural responses tend to be enveloped by typical launch vehicle ascent vibration environments (defined up to 2 kHz), although significant energy is also present at higher frequencies.

Flow Induced Vibration↗

NASA NTRS2006

Habitability and Human Factors: Lessons Learned in Long Duration Space Flight

This study documents the investigation of qualitative habitability and human factors feedback provided by scientists, engineers, and crewmembers on lessons learned from the ISS Program. A thorough review and understanding of this data is critical in charting NASA's future path in space exploration. NASA has been involved in ensuring that the needs of crewmembers to live and work safely and effectively in space have been met throughout the ISS Program. Human factors and habitability data has been collected from every U.S. crewmember that has resided on the ISS. The knowledge gained from both the developers and inhabitants of the ISS have provided a significant resource of information for NASA and will be used in future space exploration. The recurring issues have been tracked and documented; the top 5 most critical issues have been identified from this data. The top 5 identified problems were: excessive onsrbit stowage; environment; communication; procedures; and inadequate design of systems and equipment. Lessons learned from these issues will be used to aid in future improvements and developments to the space program. Full analysis of the habitability and human factors data has led to the following recommendations. It is critical for human factors to be involved early in the design of space vehicles and hardware. Human factors requirements need to be readdressed and redefined given the knowledge gained during previous ISS and long-duration space flight programs. These requirements must be integrated into vehicle and hardware technical documentation and consistently enforced. Lastly, space vehicles and hardware must be designed with primary focus on the user/operator to successfully complete missions and maintain a safe working environment. Implementation of these lessons learned will significantly improve NASA's likelihood of success in future space endeavors.

Baggerman, Susan D.↗

NASA NTRS2012

Human Missions to Near-Earth Asteroids: An Update on NASA's Current Status and Proposed Activities for Small Body Exploration

Introduction: Over the past several years, much attention has been focused on the human exploration of near-Earth asteroids (NEAs). Two independent NASA studies examined the feasibility of sending piloted missions to NEAs, and in 2009, the Augustine Commission identified NEAs as high profile destinations for human exploration missions beyond the Earth-Moon system as part of the Flexible Path. More recently the current U.S. presidential administration directed NASA to include NEAs as destinations for future human exploration with the goal of sending astronauts to a NEA in the mid to late 2020s. This directive became part of the official National Space Policy of the United States of America as of June 28, 2010. Dynamical Assessment: The current near-term NASA human spaceflight capability is in the process of being defined while the Multi-Purpose Crew Vehicle (MPCV) and Space Launch System (SLS) are still in development. Hence, those NEAs in more accessible heliocentric orbits relative to a minimal interplanetary exploration capability will be considered for the first missions. If total mission durations for the first voyages to NEAs are to be kept to less than one year, with minimal velocity changes, then NEA rendezvous missions ideally will take place within 0.1 AU of Earth (approx about 5 million km or 37 lunar distances). Human Exploration Considerations: These missions would be the first human expeditions to inter-planetary bodies beyond the Earth-Moon system and would prove useful for testing technologies required for human missions to Mars, Phobos and Deimos, and other Solar System destinations. Missions to NEAs would undoubtedly provide a great deal of technical and engineering data on spacecraft operations for future human space exploration while conducting detailed scientific investigations of these primitive objects. Current analyses of operational concepts suggest that stay times of 15 to 30 days may be possible at these destinations. In addition, the resulting scientific investigations would refine designs for future extraterrestrial In Situ Resource Utilization (ISRU), and assist in the development of hazard mitigation techniques for planetary defense. Conclusions: The scientific and hazard mitigation benefits, along with the programmatic and operational benefits of a human venture beyond the Earth-Moon system, make a piloted mission to a NEA using NASA's proposed human exploration systems a compelling endeavor

Abell, P. A.↗

NASA NTRS2013

Human Exploration of Near-Earth Asteroids and Sample Collection Considerations

In 2009 the Augustine Commission identified near-Earth asteroids (NEAs) as high profile destinations for human exploration missions beyond the Earth-Moon system as part of the Flexible Path. Subsequently, the U.S. presidential administration directed NASA on April 15, 2010 to include NEAs as destinations for future human exploration with the goal of sending astronauts to a NEA in the mid to late 2020s. This directive became part of the official National Space Policy of the United States of America as of June 28, 2010. Human Exploration Considerations: These missions would be the first human expeditions to interplanetary bodies beyond the Earth-Moon system and would prove useful for testing technologies required for human missions to Mars, Phobos and Deimos, and other Solar System destinations. Missions to NEAs would undoubtedly provide a great deal of technical and engineering data on spacecraft operations for future human space exploration while conducting in-depth scientific examinations of these primitive objects. However, prior to sending human explorers to NEAs, robotic investigations of these bodies would be required in order to maximize operational efficiency and reduce mission risk. These precursor missions to NEAs would fill crucial strategic knowledge gaps concerning their physical characteristics that are relevant for human exploration of these relatively unknown destinations. Sample Science Benefits: Information obtained from a human investigation of a NEA, together with ground-based observations and prior spacecraft investigations of asteroids and comets, will also provide a real measure of ground truth to data obtained from terrestrial meteorite collections. Major advances in the areas of geochemistry, impact history, thermal history, isotope analyses, mineralogy, space weathering, formation ages, thermal inertias, volatile content, source regions, solar system formation, etc. can be expected from human NEA missions. Samples directly returned from a primitive body would lead to the same kind of breakthroughs for understanding NEAs that the Apollo samples provided for understanding the Earth-Moon system and its formation history. International Participation: In addition, robotic precursor and human exploration missions to NEAs would allow the NASA and its international partners to gain operational experience in performing complex tasks (e.g., sample collection, deployment of payloads, retrieval of payloads, etc.) with crew, robots, and spacecraft under microgravity conditions at or near the surface of a small body. This would provide an important synergy between the worldwide Science and Exploration communities, which will be crucial for development of future international deep space exploration architectures and has potential benefits for future exploration of other destinations beyond low-Earth orbit.

Abell, Paul↗

NASA NTRS2009

Electroactive Polymer (EAP) Actuators for Future Humanlike Robots

Human-like robots are increasingly becoming an engineering reality thanks to recent technology advances. These robots, which are inspired greatly by science fiction, were originated from the desire to reproduce the human appearance, functions and intelligence and they may become our household appliance or even companion. The development of such robots is greatly supported by emerging biologically inspired technologies. Potentially, electroactive polymer (EAP) materials are offering actuation capabilities that allow emulating the action of our natural muscles for making such machines perform lifelike. There are many technical issues related to making such robots including the need for EAP materials that can operate as effective actuators. Beside the technology challenges these robots also raise concerns that need to be addressed prior to forming super capable robots. These include the need to prevent accidents, deliberate harm, or their use in crimes. In this paper, the potential EAP actuators and the challenges that these robots may pose will be reviewed.

biomimetics↗

NASA NTRS2017

The Challenges of Human-Autonomy Teaming

Machine intelligence is improving rapidly based on advances in big data analytics, deep learning algorithms, networked operations, and continuing exponential growth in computing power (Moores Law). This growth in the power and applicability of increasingly intelligent systems will change the roles humans, shifting them to tasks where adaptive problem solving, reasoning and decision-making is required. This talk will address the challenges involved in engineering autonomous systems that function effectively with humans in aeronautics domains.

artificial intelligence↗

NASA NTRS2017

The Challenges of Human-Autonomy Teaming

Human-Autonomy teaming↗

NASA NTRS2008

Guidance, Navigation and Control (GN&C): Best Practices for Human-Rated Spacecraft Systems

In 2007 the NESC completed an in-depth assessment to identify, define and document engineering considerations for the Design Development Test and Evaluation (DDT&E) of human-rated spacecraft systems. This study had been requested by the Astronaut Office at JSC to help them to better understand what is required to ensure safe, robust, and reliable human-rated spacecraft systems. The 22 GN&C engineering Best Practices described in this paper are a condensed version of what appears in the NESC Technical Report. These Best Practices cover a broad range from fundamental system architectural considerations to more specific aspects (e.g., stability margin recommendations) of GN&C system design and development. 15 of the Best Practices address the early phases of a GN&C System development project and the remaining 7 deal with the later phases. Some of these Best Practices will cross-over between both phases. We recognize that this set of GN&C Best Practices will not be universally applicable to all projects and mission applications.

Lebsock, Ken↗

NASA NTRS2006

Development of the J-2X Engine for the Ares I Crew Launch Vehicle and the Ares V Cargo Launch Vehicle: Building on the Apollo Program for Lunar Return Missions

The United States (U.S.) Vision for Space Exploration directs NASA to develop two new launch vehicles for sending humans to the Moon, Mars, and beyond. In January 2006, NASA streamlined its hardware development approach for replacing the Space Shuttle after it is retired in 2010. Benefits of this approach include reduced programmatic and technical risks and the potential to return to the Moon by 2020, by developing the Ares I Crew Launch Vehicle (CLV) propulsion elements now, with full extensibility to future Ares V Cargo Launch Vehicle (CaLV) lunar systems. This decision was reached after the Exploration Launch Projects Office performed a variety of risk analyses, commonality assessments, and trade studies. The Constellation Program selected the Pratt & Whitney Rocketdyne J-2X engine to power the Ares I Upper Stage Element and the Ares V Earth Departure Stage. This paper narrates the evolution of that decision; describes the performance capabilities expected of the J-2X design, including potential commonality challenges and opportunities between the Ares I and Ares V launch vehicles; and provides a current status of J-2X design, development, and hardware testing activities. This paper also explains how the J-2X engine effort mitigates risk by building on the Apollo Program and other lessons lived to deliver a human-rated engine that is on an aggressive development schedule, with its first demonstration flight in 2012.

Snoddy, Jim↗

DOE OSTI2025

Structural studies of the IFNλ4 receptor complex using cryoEM enabled by protein engineering

Abstract IFNλ4 has posed a conundrum in human immunology since its discovery in 2013, with its expression linked to complications with viral clearance. While genetic and cellular studies revealed the detrimental effects of IFNλ4 expression, extensive structural and functional characterization has been limited by the inability to express and purify the protein, complicating explanations of its paradoxical behavior. In this work, we report a method for robust production of IFNλ4. We then use yeast surface display to affinity-mature IL10Rβ and solve the 72 kilodalton structures of IFNλ4 (3.26 Å) and IFNλ3 (3.00 Å) in complex with their receptors IFNλR1 and IL10Rβ using cryogenic electron microscopy. Comparison of the structures highlights differences in receptor engagement and reveals a distinct 12-degree rotation in overall receptor geometry, providing a potential mechanistic explanation for differences in cell signaling, downstream gene induction, and antiviral activities. Further, we perform a structural analysis using molecular modeling and simulation to identify a unique region of IFNλ4 that, when replaced, enables secretion of the protein from cells. These findings provide a structural and functional understanding of the IFNλ4 protein and enable future comprehensive studies towards correcting IFNλ4 dysfunction in large populations of affected patients.

Science & Technology - Other Topics↗

NASA NTRS2012

Fast Paced, Low Cost Projects at MSFC

What does an orbiting microsatellite, a robotic lander and a ruggedized camera and telescope have in common? They are all fast paced, low cost projects managed by Marshall Space Flight Center (MSFC) teamed with successful industry partners. MSFC has long been synonymous with human space flight large propulsion programs, engineering acumen and risk intolerance. However, there is a growing portfolio/product line within MSFC that focuses on these smaller, fast paced projects. While launching anything into space is expensive, using a managed risk posture, holding to schedule and keeping costs low by stopping at egood enough f were key elements to their success. Risk is defined as the possibility of loss or failure per Merriam Webster. The National Aeronautics and Space Administration (NASA) defines risk using procedural requirement 8705.4 and establishes eclasses f to discern the acceptable risk per a project. It states a Class D risk has a medium to significant risk of not achieving mission success. MSFC, along with industry partners, has created a niche in Class D efforts. How did the big, cautious MSFC succeed on these projects that embodied the antithesis of its heritage in human space flight? A key factor toward these successful projects was innovative industry partners such as Dynetics Corporation, University of Alabama in Huntsville (UAHuntsville), Johns Hopkins Applied Physics Laboratory (JHU APL), Teledyne Brown Engineering (TBE), Von Braun Center for Science and Innovation (VCSI), SAIC, and Jacobs. Fast Affordable Satellite Technology (FastSat HSV01) is a low earth orbit microsatellite that houses six instruments with the primary scientific objective of earth observation and technology demonstration. The team was comprised of Dynetics, UAHuntsvile, SAIC, Goddard Space Flight Center (GSFC) and VCSI with the United States Air Force Space Test Program as the customer. The team completed design, development, manufacturing, environmental test and integration in one year. FastSat HSV01 also deployed a Poly Picosatellite Orbital Deployer (PPOD) for a separate nano ]satellite class spacecraft (Cubesat: Nano Sail Demonstration) in partnership with Ames Research Center. The Robotic lunar lander is a MSFC JHU APL partnership that led to the development of a flexible architecture for landers to support robotic missions to a wide range of lunar and asteroid destinations. The team started with the goal of meeting NASA agency directives that led to the creation of a test bed focusing on GN&C and software to demonstrate the descent and landing on any airless body for the final 30 to 60 meters. The team created a complex technology demonstration as well as Guidance Control and Navigation (GN&C) algorithms providing autonomous control of the lander. The team uses a green propellant of 90% hydrogen peroxide and has completed 18 successful test flights. The International Space Station (ISS) SERVIR Environmental Research and Visualization System (ISERV) is a technology demonstration payload to assist the SERVIR project with environmental monitoring for disaster relief and humanitarian efforts. The ISERV project was a partnership with TBE. The ISERV payload consists of a commercial off the shelf camera, telescope, and MSFC developed power distribution box and interfaces on ISS with the Window Observational Research Facility in the US Lab. MSFC has identified three key areas that enabled the low cost mission success to include culture, partnering, and cost/schedule control. This paper will briefly discuss these three Class D efforts, FastSat HSV-01, the Robotic Lunar Lander and the ISERV camera system, the lessons learned, their successes and challenges.

Watson-Morgan, Lisa↗

NASA NTRS2015

Software Innovation in a Mission Critical Environment

Operating in mission-critical environments requires trusted solutions, and the preference for "tried and true" approaches presents a potential barrier to infusing innovation into mission-critical systems. This presentation explores opportunities to overcome this barrier in the software domain. It outlines specific areas of innovation in software development achieved by the Johnson Space Center (JSC) Engineering Directorate in support of NASA's major human spaceflight programs, including International Space Station, Multi-Purpose Crew Vehicle (Orion), and Commercial Crew Programs. Software engineering teams at JSC work with hardware developers, mission planners, and system operators to integrate flight vehicles, habitats, robotics, and other spacecraft elements for genuinely mission critical applications. The innovations described, including the use of NASA Core Flight Software and its associated software tool chain, can lead to software that is more affordable, more reliable, better modelled, more flexible, more easily maintained, better tested, and enabling of automation.

Fredrickson, Steven↗

NASA NTRS2012

Paramyxovirus Infection Mimics In Vivo Cellular Dynamics in Three-Demensional Human Bronchio-Epithelial Tissue-Like Assemblies

Respiratory syncytial virus and parainfluenza virus cause severe respiratory disease, especially in infants, children and the elderly. An in vitro model that accurately mimics infection of the human respiratory epithelium (HRE) would facilitate vaccine development greatly. Monolayer cultures traditionally used to study these viruses do not accurately and precisely differentiate the replication efficiencies of wild type and attenuated viruses. Therefore, we engineered novel three-dimensional (3D) tissue-like assemblies (TLAs) of human broncho-epithelial (HBE) cells to produce a more physiologically relevant in vitro model of the HRE. TLAs resemble HRE structurally and by expression of differentiated epithelial cell markers. Most significantly, wild type viruses exhibited a clear growth advantage over attenuated strains in TLAs unlike monolayer cultures. In addition, the TLAs responded to virus infection by secreting pro-inflammatory mediators similar to the respiratory epithelia of infected children. These characteristics make the TLA model a valuable platform technology to develop and evaluate live, attenuated respiratory virus vaccine candidates for human use. Respiratory virus diseases, the most frequent and least preventable of all infectious diseases, range in severity from the common cold to severe bronchiolitis and pneumonia . Two paramyxoviruses, respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3), are responsible for a majority of the most severe respiratory diseases of infants and young children. RSV causes 70% of all bronchiolitis cases and is a major cause of morbidity and mortality worldwide, especially in infants. PIV3 causes 10-15% of bronchiolitis and pneumonia during infancy, second only to RSV, and 40% of croup in infants To date, licensed vaccines are not available to prevent these respiratory diseases. At present, traditional monkey kidney (Vero and LLC-MK2) and human (HEp-2) tissue culture cells and small animal models (mouse, cotton rat, guinea pig, ferret, and hamster) fail to accurately imitate viral replication and human disease states (8). Lacking an authentic model has impeded the development and evaluation of live, attenuated vaccine candidates. Development of a physiologically relevant in vitro tissue culture model that reproduces characteristics of the HRE, the primary target of RSV and PIV3, would aid in predicting clinical attenuation and safety of vaccine candidates. Successful tissue engineering of a 3D human intestinal model using novel NASA technology inspired the development of a tri-culture 3D model for the HRE. Sequential layering of primary mesenchymal cells (comprised of normal human fibroblasts and endothelial cells) followed by BEAS-2B epithelial cells derived from human bronchi and tracheae were recapitulated on Cultisphere and/or cytodex3 microcarriers in cylindrical vessels that rotate horizontally creating an organized epithelial structure. Horizontal rotation randomizes the gravity vector modeling aspects of microgravity. Mesenchymal and epithelial cells grown under these conditions reproduce the structural organization, multi-cellular complexity, and differentiation state of the HRE. The opportunity to study respiratory viruses in a nasal epithelium model is invaluable because the most promising respiratory virus vaccine candidates are live attenuated viruses for intranasal administration. Here we characterize the interactions of respiratory viruses and epithelial cells grown under modeled microgravity in comparison to gravity-ladened monolayers. 3D HBE TLAs and traditional monolayers (2D) are infected at 35 C, the upper temperature of the upper HRE, to simulate in vivo infection conditions. Growth kinetics of wild type (wt) RSV and PIV3 viruses were compared in 2D and 3D cells to that of strains attenuated in humans or rhesus macaques. This novel 3D HBE model also offers an opportunity to study whether the epithelial cell function, especially in host defenses recapitulated by mimicking the structural organization of the HRE. In vivo, airway epithelial cells play a significant and dynamic role in host defense by blocking paracellular permeability and modulating airway function through cellular interactions or tight junctions. As regulators of the innate immune response, epithelial cells constitutively express cytokines, chemokines, and colony stimulating factors including RANTES, IL-8, IL-6, GM-CSF, and G-CSF for proactive host defense. In response to viral infection, epithelial cells induce potent immuno-modulatory and pro-inflammatory cytokines that recruit phagocytic and inflammatory cells to clear the virus and enhance protection. Although disease pathogenesis is classically attributed to the cytopathic effects of the pathogen, severe disease states associated with RSV and PIV3 are attributed to the inflammatory response, especially in infants. RSV is a potent inducer of cytokines and pro-inflammatory mediators in epithelial cells in vivo. A differentiated human epithelial model independent of the complete functional immune system will help elucidate the role of epithelial cells in respiratory disease. We reported here, virus and host cell interactions in 3D HBE TLAs are similar to that in vivo. Because the epithelial cell organization of the TLAs impacts not only the expression of airway epithelial characteristics, but also cellular communication, the TLAs represent a more physiologically relevant model of the HRE than BEAS-2B or other non-tumour monolayer models of respiratory disease. As a result, wild type respiratory viruses have a clear growth advantage over attenuated viruses in TLAs unlike traditional monolayers. In addition, the TLAs respond to wild type virus infection by secreting pro-inflammatory mediators characteristic of infected HRE. TLAs expressing microbial defense mechanisms provide an excellent model to study the interactions of respiratory pathogens with their host and to identify the innate immunity mediators. Therefore, 3D HBE TLAs offer advantages for the study of respiratory viruses and the development of viral vaccine candidates.

Deatly, Anne M.↗