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Deep-space applications for point-of-care technologies
Journal Pre-proof Deep Space Applications for Point-of-Care Technologies Gary E. Strangman, PhD, Aenor Sawyer, MD, MS, Kristin M. Fabre, PhD, Emmanuel Urquieta, MD, MS, James Hury, III, Jimmy Wu, Andrew Peterman, BS, Jeff Hoffman, PhD, Dorit Donoviel, PhD PII:
S2468-4511(19)30034-0
DOI:
https://doi.org/10.1016/j.cobme.2019.08.014
Reference:
COBME 167
To appear in:
Current Opinion in Biomedical Engineering
Received Date: 15 July 2019 Accepted Date: 31 August 2019
Please cite this article as: G.E. Strangman, A. Sawyer, K.M. Fabre, E. Urquieta, J. Hury III., J. Wu, A. Peterman, J. Hoffman, D. Donoviel, Deep Space Applications for Point-of-Care Technologies, Current Opinion in Biomedical Engineering, https://doi.org/10.1016/j.cobme.2019.08.014. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Title:
Deep Space Applications for Point-of-Care Technologies Authors: Gary E. Strangman, PhD 1,2,3 ([email protected]) Aenor Sawyer, MD, MS 1,4 ([email protected]) Kristin M. Fabre, PhD 1,3 ([email protected]) Emmanuel Urquieta, MD, MS 1,3 ([email protected]) James Hury, III 1,3 ([email protected]) Jimmy Wu, 1,3 ([email protected]) Andrew Peterman, BS 1,3 ([email protected]) Jeff Hoffman, PhD 1,5 ([email protected]) Dorit Donoviel, PhD 1,3 ([email protected]) 1 Translational Research Institute for Space Health (TRISH), Houston, TX 2 Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston MA 3 Center for Space Medicine, Baylor College of Medicine, Houston, TX 4 Department of Orthopedic Surgery, University of California – San Francisco, San Francisco, CA 5 Department of Aeronautics and Astronautics, Massachusetts Institute of Technology, Cambridge, MA Corresponding Author: Gary Strangman Massachusetts General Hospital 149 13th St – Psychiatry Charlestown, MA 02129 (617) 724-0662 [email protected] Keywords: Space medicine Spaceflight medical risks Biomedical engineering Technology development Machine learning
Declarations of Interest: none
Highlights: • Key spaceflight medical concerns include altered gravity, radiation, and resupply • Spaceflight imposes many atypical design challenges on point-of-care systems • Non-invasive biomarker measures will be key to medical management in space • Small crews will require artificial intelligence and just-in-time training support
Abstract
Deep space missions—such as a crewed voyage to Mars—will require a comprehensive medical care system to treat and maintain astronaut health. This system must address many of the same medical conditions that occur on Earth, as well as several that are unique to spaceflight environments. Hardware constraints are numerous, including mass, volume, usability by nonspecialists, and minimal need for consumable supplies, all of which are also relevant to medical care in remote-, ambulatory- or home-care settings on Earth. This review describes the expected medical needs on deep space missions, outlines the current state-of-the-art of onboard medical capabilities, and highlights approaches and technologies that will likely be necessary to achieve autonomous healthcare for astronauts.
Graphical Abstract (optional)
1
Introduction When humanity set foot on the Moon decades ago, the feat drove key innovations in
numerous fields, and inspired many around the globe to become scientists, engineers, and mathematicians. For those of us that are motivated to understand human physiology, one of the most amazing discoveries of the Moon landing is that we are surprisingly adaptable and can function well in zero gravity and in a higher radiation environment. Since the late 1990’s, humans have been regularly living and working on the International Space Station (ISS) for 4-6 months at a time, and even up to a year, with no major adverse physiological effects on their overall health. A Mars trip—500-900 days [1]—will expose the crew to reduced gravity, deep space radiation, confinement, and isolation from Earth and access to friends and family. There will also be one-way communication delays of up to ~22 minutes, plus blackouts. For medical conditions that arise and require intervention, real-time guidance from Earth will thus not be available. While astronauts are highly intelligent, educated, trained, and motivated, only one of the crew is likely to be a trained physician. Perhaps this individual will be a generalist, a surgeon, or an emergency medicine doctor, but he or she will need to depend on point of care (POC) medical capabilities. The current minimal net habitable volume guidelines for a trip to Mars specify 25 cubic feet per person. For a crew of 4, that’s a mere 100 cubic feet [2]. The amount of space allotted to medical equipment and supplies will similarly be very limited. To ensure that the crew is equipped to handle health or medical events that require intervention, we must provide them with tools and knowledge to administer self-care in as small and lightweight a footprint as possible.
2 Point of Care for Health Monitoring and Treatments In any environment, humans exist in varying states of health, moving across a “health continuum” from wellness to illness and back again. To most effectively maintain wellness, deflections from a healthy state should be detected and corrected early before they progress into clinical or critical conditions (e.g., from asymptomatic under-hydration to dehydration with nausea/vomiting to renal failure). This requires the capability to monitor physiological, psychological and environmental conditions, and then translate such data into actionable insights [3]. Recent advances in sensor technology, genomics and data science are allowing for a needed shift in healthcare from merely responding to disease states to actually predicting and preventing clinical problems. These various capabilities, which will be discussed below, are extremely valuable in remote or extreme environments, and will support human survival on long duration deep space missions (Figure 1). 2.1 Medical needs specific to space Several health hazards exist for deep space missions that are unique or not commonly found on Earth. These include space radiation [4], cognitive, behavioral and psychiatric conditions derived from isolation and confinement [5], inadequate food and nutrition [6], reduced musculoskeletal loading [7], spaceflight associated neuro-ocular syndrome [8], and ineffective medications [9]. Besides these hazards, astronauts remain subject to normal Earth-relevant medical conditions, with perhaps a notable exception of reduced susceptibility to falls while in microgravity. From the vast array of possible conditions—and taking into account the nature of the typical deep space mission and astronaut screening procedures—NASA has developed a list of more than 100 medical conditions that are of particular concern during deep space missions
[10]. The conditions included in the list are broad and range from minor issues such as skin laceration and congestion [11], to urinary tract infections, dental problems, appendicitis, and life-threatening scenarios such as hypovolemic shock [10]. About a third of the 100 conditions could be diagnosed with specimens analyzed through POC devices that quantify cells, electrolytes, crystals, small molecules, and large biomolecules. These specimens could be obtained from bio-fluids such as blood, urine, saliva, skin swabs or even analyzing molecules in breath. Up to perhaps a dozen of the medical conditions could require surgery. Appendicitis and cholecystitis are the most common surgical emergencies on Earth and are also included in the medical conditions list [10]. To date, no case of appendicitis has been documented during space missions, however there is data suggesting at least one Russian cosmonaut has been evacuated due to appendicitis symptoms [12]. Evacuation, however, will not be available in deep space. Given the often-emergent nature of these as well as other surgical scenarios (trauma and non-trauma), easy-to-use POC devices will be key for diagnosis, mitigation and treatment on a deep-space mission. In addition, a number of medical conditions will require medications, and a mission to Mars requires a shelf life of up to five years—three years for the mission, plus up to two years for manifesting and packing. Most medications currently on the ISS cannot meet such requirements. Thus, technologies to support basic drug stability will be needed, as well as technologies to address the increased radiation, oxidation and high humidity which can cause some medications to lose their effectiveness or degrade into toxic byproducts [13].
2.2 Sensors and Spaceflight Constraints Because a spacecraft is by necessity a complete and stand-alone habitat, water, food, air, guidance and operations computers, space suits, exercise equipment, radiation protection, and redundant components are all essential. As a result, any tools and medical equipment that might be necessary for the mission are of secondary importance. This puts significant design pressure on the biomedical engineering teams developing healthcare components for deep space missions. The main constraints are summarized in Table 1 (see also [14]), along with rough or order-of-magnitude design guidelines for each. Briefly, the tremendous costs for launch mean device mass, volume, and consumable resupply are limited even onboard the ISS, much less in deep space. In addition, the distance and small crew restricts onboard technical expertise, while the unique environment leads to atypical device design requirements. Table 1: Spaceflight constraints and design guidelines for point-of-care medical devices
Reason Rough design guidelines * High cost to orbit, limited spacecraft < 500 grams, <1500 cm3 for a volumes. single device. Multi-use devices highly preferred. Resupply Distance from Earth, small Reusables instead of spacecraft volumes, and cost consumables Power All power onboard is self-generated < 5 Watts (<0.5 W preferred) Onboard technical Each astronaut can only be an Low-maintenance capacity expert in a fixed number of areas; components, minimize tools are limited moving parts Communication delays Distance from Earth and speed of Minimize repair, training, (up to 22 min one-way) light use and management needs Time to use Busy astronaut schedules < 10 min (ease of setup, use and cleaning, self-guidance, automated data management) Bulk fluid use In microgravity, the primary force Non-invasive devices, Spaceflight Constraint Mass & Volume
influencing fluids is surface tension Component degradation Off-gassing
Temperature, radiation, humidity, airborne particulates Sealed environments
Risk
Need to decrease current spaceflight risk posture
minimal fluid volumes, pretest in microgravity Parts should be robust to failure in space environment Use non-toxic materials and fluids; off-gas testing Remain aware of risks the device itself poses
Currently the ISS has sensors for vital signs (blood pressure, electrocardiography, heart rate, respiration rate, temperature, pulse oximetry), ocular tonometry, radiation dosimeters, CO2 monitors, and kits for analyzing volatile organics, formaldehyde, water microbiology and surface sampling [15]. Imaging ultrasound is a major piece of equipment available for noninvasive imaging [16]. For ophthalmological examinations, fundoscopy and optical coherence tomography (OCT) imaging is available [17]. There is also a centrifuge and an iSTAT system for basic blood analyses, plus limited DNA sequencing capabilities onboard [18]. Most of the sensors on ISS, however, are based on designs and technology that are over ten years old. Modernization and consolidation of the suite of sensors would help alleviate the spaceflight constraints described in Table 1. For example, hardware designs for vital signs, ultrasound, and blood analysis have over the past few years become smaller in volume and consume less power. For a deep space flight mission beyond low Earth orbit, optimization of spaceflight constraints will be critical to be able to provide all the sensor capability necessary to maintain crew health and performance.
2.3 Relevant Biomarkers Biomarkers must provide accurate and reproducible measurements to evaluate normal biological function, disease, environmental exposure or pharmacologic intervention, including efficacy and safety [19,20]. Biomarkers can be used for assessing disease development, testing various countermeasures, or better understanding underlying pathological mechanisms. They can be surrogates to clinical endpoints for diagnosing, monitoring, measuring therapeutic effects and staging diseases [19,20]. Furthermore, as healthcare and health management evolve to a more personalized approach, biological readouts will be a key feature. For deep space exploration, biomarkers can address several high priority risks for NASA Human Research Program [21], including radiation exposure, cerebrovascular, cardiovascular, immune response and infection. The ideal biomarker will be detected non-invasively and sensitive to pre-adverse events. Biomarkers already exist for a number of spaceflight risks. Readouts associated with radiation exposure and damage include DNA damage markers, chromosomal aberrations, mutation frequency, presence of persistent reactive oxygen species and telomere function [22]. Several of these biomarkers can also be indicative of chronic inflammation, which can impair immune function, gut health and neurocognitive function [23]. Cellular biomarkers that determine immune function could be used to determine neurological health. For example, aberrant microglia have been shown to play a pivotal role in neurodegenerative diseases [24] and malfunctioning immune response could impact behavior [25]. Such biomarkers can also to help assess countermeasure (i.e., therapy) efficacy.
New tools are also being developed to help identify and validate biomarkers such as human complex in vitro models [26-28]. But new tools that meet spaceflight constraints and are sensitive to numerous analytes are still needed.
2.4 Just-In-Time Training and End-To-End Care The skills and experience of those providing medical care often varies widely. Although astronauts have advanced degrees such as aeronautics, engineering, or science, they must also all be capable of performing mission-critical functions including provision of medical support. Even on missions with a physician crewmember, others will need to assist or even lead should the physician require care. Currently, real-time guidance from the ground is the default mode of operations onboard ISS. This approach, however, relies on near-synchronous two-way communication for interpretation of data (i.e., vital signs, ultrasound images, or photos of wound) and instruction from a remote medical expert. Such synchronous communications will be absent in deep space missions, and hence health care delivery—particularly for emergencies—will need to be far more autonomous than it is at present. Crewmembers will need not only appropriate POC equipment but also “augmented” knowhow and skills to deliver care when needed. Such augmentations are expected to involve: (i) basic ground training in health maintenance and medical management; (ii) in-mission knowledge reinforcement via onboard training modules (e.g. [29]); (iii) rapid refresher—or potentially de novo—instructions at time of need; and (iv) onboard “virtual” realtime guidance systems for diagnostics and treatments [30]. The inclusion of closed loop systems can also be an important goal. For example, in a major emergency, closed-loop
operation of (e.g.) a respirator would free up an astronaut to help with other medical needs. Other examples of such technologies being leveraged to extend or augment care capabilities on Earth include virtual-, augmented- or mixed-reality, AI-driven clinical decision support (CDS), “closed loop” smart POC diagnostics, and robotic-assisted procedures [30]. Finally, long-duration missions have a much greater need for end-to-end care. This spans pre-illness monitoring, to detection of a condition, to differential diagnosis, treatment, and either resolution or ongoing management of the condition. Few tools are currently available for this type of comprehensive patient management, particularly for remote settings.
2.5 Artificial Intelligence and Diagnostic Algorithms Given limitations in on-board medical expertise and real-time communications with Earth, artificial intelligence (AI) and machine learning (ML) approaches [31] will become increasingly important tools for generating diagnostic insights [32]. While AI and ML approaches are not currently used for medical applications in space, recent advances already enable decentralized statistical data analysis for consumer devices [33], eliminating the need for network connectivity and off-device computational resources. POC device manufacturers are beginning to use these same techniques to produce medical devices capable of running software algorithms that “learn” from real-world experience [34]. And new sensor systems may not even be necessary; for example, researchers recently showed superior diagnostic capabilities compared to specialized hardware when using standard smartphone hardware (microphone and speakers) and an on-device ML algorithm to diagnose ear infections [35].
While many techniques are applicable, a few ML approaches of relevance include federated learning (FL), reinforcement learning (RL) and recurrent neural networks (RNN). FL is commonly used in the consumer electronics industry and can leverage training data from multiple distributed sources yet minimize communication requirements [36,37]. Applying FL concepts to POC devices could allow for secure, large-scale aggregation of sensitive health data to improve models and help solve existing issues with POC data collection associated with suboptimal network reliability and data isolation. When combined with traditional deep-ML techniques, RL has solved decision making problems that can challenge—and often defeat— human players in games like Go [38]. Future POC devices could leverage “Deep RL” algorithms to combine device data with databases to develop treatment and dosing strategies based on analytics that account for measurements taken before and after treatment. Recent breakthroughs in RNN techniques have demonstrated hyper-accurate sequence transformation (i.e., prediction) models [39] that can dramatically reduce model size so they can be stored entirely on-device, eliminating the need for a network connection to evaluate a model [40]. The Food and Drug Administration has recognized the International Medical Device Regulators Forum designation of AI/ML software components as Software as a Medical Device. The FDA’s stated goal is to effectively regulate but not stifle these technologies, with multiple continuous-learning AI/ML devices having already obtained approval through the 510k process [34]. Acceleration of the development of AI/ML-enabled POC devices will be critical for deep space missions where physical space, computational hardware and software resources, and network connectivity will all be limited, and ease-of-use will be essential.
3 Astronaut perspective Current ISS medical operations—as with Space Shuttle missions—requires two “medically trained” individuals on-board, in case something happens to one of them. Crew composition typically includes either one MD plus one crew medical officer (CMO) trained as an emergency medical technician (EMT), or else two CMOs. Private medical conferences between the astronaut and their flight surgeon occur every 1-2 days, as well as real-time video links with ground physicians. In extreme emergencies, evacuation to Earth can be achieved in 6-10 hours. Due to distance, however, deep space missions will lack real-time conferences, video links or evacuation options. In addition, medical supplies will be limited. So, while non-urgent matters can still be handled via (lagged) communications with Earth, a major concern is the ability to diagnose and deal with acute medical problems where immediate action is required. Perhaps the biggest concern, however, is how to stay current—intensive CMO training is brief, with few refreshers, greatly increasing the chance of making a mistake 18 or 24 months into a long-duration mission during a medical emergency.
4 Conclusion Astronauts monitoring their own health and treating certain conditions in a spaceship far away from Earth is not unlike care models that are moving away from expensive emergency room or clinic visits and toward an ambulatory or in-home setting here on Earth. By providing actionable and continuous information at the point of care (POC), one can avoid deterioration via early diagnosis and intervention, plus cost savings. Importantly, any POC health capabilities to support deep space missions are thus also likely to help advance healthcare here on Earth.
5 Acknowledgements This paper was supported by the Translational Research Institute through NASA Cooperative Agreement NNX16AO69A. We wish to thank Rachel Dempsey for her assistance with manuscript figures.
6
Conflict of Interest
The authors declare no conflict of interest.
7
References
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Reference Highlights 3. Andreu-Perez J, Leff DR, Ip HM, Yang GZ: From Wearable Sensors to Smart Implants--Toward Pervasive and Personalized Healthcare. IEEE Trans Biomed Eng 2015, 62:2750-2762.
* This article describes the evolution of sensing technologies and the synergistic evolution of data science and computational capabilities which, in combination, are fueling an era of "smart" health management and provide the potential for autonomous real time medical care.
13. Blue RS, Bayuse TM, Daniels VR, Wotring VE, Suresh R, Mulcahy RA, Antonsen EL: Supplying a pharmacy for NASA exploration spaceflight: challenges and current understanding. Nature Microgravity (in press), 5. * This article summarizes decades of pharmacy applications for spaceflight and provides an overview of the challenges and opportunities on selecting an appropriate formulary for exploration class missions.
16. Law J, Macbeth PB: Ultrasound: from Earth to space. Mcgill J Med 2011, 13:59. ** This review summarizes the numerous applications of ultrasound during spaceflight. Some of these are atypical uses on Earth because ultrasound is currently the only medical imaging modality onboard the International Space Station.
18. Parra M, Jung J, Boone TD, Tran L, Blaber EA, Brown M, Chin M, Chinn T, Cohen J, Doebler R, et al.: Microgravity validation of a novel system for RNA isolation and multiplex
quantitative real time PCR analysis of gene expression on the International Space Station. PLoS One 2017, 12:e0183480. * NASA has worked to develop genetic analysis platform that could operate in microgravity where fluid flow and bubble formation is dramatically altered. This study describes the use of reverse transcriptase PCR , as well as gene expression from bacterial cells and mammalian tissue RNA samples.
21. Human Research Program: Human Research Roadmap: Risks. Edited by: NASA; 2019. vol 2019.] ** The NASA Human Research Roadmap lists the main spaceflight medical risks and gaps, and includes evidence reports detailing the current state of knowledge regarding each risk and gap. This represents a key resource for understanding NASA’s medical technology development needs.
30. Eckert M, Volmerg JS, Friedrich CM: Augmented Reality in Medicine: Systematic and Bibliographic Review. JMIR Mhealth Uhealth 2019, 7:e10967.
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35. Chan J, Raju S, Nandakumar R, Bly R, Gollakota S: Detecting middle ear fluid using smartphones. Sci Transl Med 2019, 11.
** On-device ML algorithms are being used to endow consumer electronic devices with adequate sensors and capabilities with POC device-like diagnostic capabilities. Consolidation of technical resources will be critical for deep space missions, where physical space, computational hardware and software resources, and network connectivity will all be limited, and ease-of-use will be essential
40. Alvarez R, Prabhavalkar R, Bakhtin A: On the efficient representation and execution of deep acoustic models. arXiv 2016:1607.04683.
* Techniques currently being developed to enable on-device model execution for consumer electronics use cases have shown that hyper-accuracy can be retained even with dramatic reductions in model size. These same techniques can be applied to addressed edge computing needs on POC devices, allowing for more robust diagnostic insight from even smaller devices and sensor systems.
Figures
Figure 1: Point of care medical needs for long-duration missions to deep space will require a comprehensive suite of tools, suitable for up to three-year missions, all contained within an exceptionally small and lightweight package.
S2468-4511(19)30034-0
DOI:
https://doi.org/10.1016/j.cobme.2019.08.014
Reference:
COBME 167
To appear in:
Current Opinion in Biomedical Engineering
Received Date: 15 July 2019 Accepted Date: 31 August 2019
Please cite this article as: G.E. Strangman, A. Sawyer, K.M. Fabre, E. Urquieta, J. Hury III., J. Wu, A. Peterman, J. Hoffman, D. Donoviel, Deep Space Applications for Point-of-Care Technologies, Current Opinion in Biomedical Engineering, https://doi.org/10.1016/j.cobme.2019.08.014. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Title:
Deep Space Applications for Point-of-Care Technologies Authors: Gary E. Strangman, PhD 1,2,3 ([email protected]) Aenor Sawyer, MD, MS 1,4 ([email protected]) Kristin M. Fabre, PhD 1,3 ([email protected]) Emmanuel Urquieta, MD, MS 1,3 ([email protected]) James Hury, III 1,3 ([email protected]) Jimmy Wu, 1,3 ([email protected]) Andrew Peterman, BS 1,3 ([email protected]) Jeff Hoffman, PhD 1,5 ([email protected]) Dorit Donoviel, PhD 1,3 ([email protected]) 1 Translational Research Institute for Space Health (TRISH), Houston, TX 2 Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston MA 3 Center for Space Medicine, Baylor College of Medicine, Houston, TX 4 Department of Orthopedic Surgery, University of California – San Francisco, San Francisco, CA 5 Department of Aeronautics and Astronautics, Massachusetts Institute of Technology, Cambridge, MA Corresponding Author: Gary Strangman Massachusetts General Hospital 149 13th St – Psychiatry Charlestown, MA 02129 (617) 724-0662 [email protected] Keywords: Space medicine Spaceflight medical risks Biomedical engineering Technology development Machine learning
Declarations of Interest: none
Highlights: • Key spaceflight medical concerns include altered gravity, radiation, and resupply • Spaceflight imposes many atypical design challenges on point-of-care systems • Non-invasive biomarker measures will be key to medical management in space • Small crews will require artificial intelligence and just-in-time training support
Abstract
Deep space missions—such as a crewed voyage to Mars—will require a comprehensive medical care system to treat and maintain astronaut health. This system must address many of the same medical conditions that occur on Earth, as well as several that are unique to spaceflight environments. Hardware constraints are numerous, including mass, volume, usability by nonspecialists, and minimal need for consumable supplies, all of which are also relevant to medical care in remote-, ambulatory- or home-care settings on Earth. This review describes the expected medical needs on deep space missions, outlines the current state-of-the-art of onboard medical capabilities, and highlights approaches and technologies that will likely be necessary to achieve autonomous healthcare for astronauts.
Graphical Abstract (optional)
1
Introduction When humanity set foot on the Moon decades ago, the feat drove key innovations in
numerous fields, and inspired many around the globe to become scientists, engineers, and mathematicians. For those of us that are motivated to understand human physiology, one of the most amazing discoveries of the Moon landing is that we are surprisingly adaptable and can function well in zero gravity and in a higher radiation environment. Since the late 1990’s, humans have been regularly living and working on the International Space Station (ISS) for 4-6 months at a time, and even up to a year, with no major adverse physiological effects on their overall health. A Mars trip—500-900 days [1]—will expose the crew to reduced gravity, deep space radiation, confinement, and isolation from Earth and access to friends and family. There will also be one-way communication delays of up to ~22 minutes, plus blackouts. For medical conditions that arise and require intervention, real-time guidance from Earth will thus not be available. While astronauts are highly intelligent, educated, trained, and motivated, only one of the crew is likely to be a trained physician. Perhaps this individual will be a generalist, a surgeon, or an emergency medicine doctor, but he or she will need to depend on point of care (POC) medical capabilities. The current minimal net habitable volume guidelines for a trip to Mars specify 25 cubic feet per person. For a crew of 4, that’s a mere 100 cubic feet [2]. The amount of space allotted to medical equipment and supplies will similarly be very limited. To ensure that the crew is equipped to handle health or medical events that require intervention, we must provide them with tools and knowledge to administer self-care in as small and lightweight a footprint as possible.
2 Point of Care for Health Monitoring and Treatments In any environment, humans exist in varying states of health, moving across a “health continuum” from wellness to illness and back again. To most effectively maintain wellness, deflections from a healthy state should be detected and corrected early before they progress into clinical or critical conditions (e.g., from asymptomatic under-hydration to dehydration with nausea/vomiting to renal failure). This requires the capability to monitor physiological, psychological and environmental conditions, and then translate such data into actionable insights [3]. Recent advances in sensor technology, genomics and data science are allowing for a needed shift in healthcare from merely responding to disease states to actually predicting and preventing clinical problems. These various capabilities, which will be discussed below, are extremely valuable in remote or extreme environments, and will support human survival on long duration deep space missions (Figure 1). 2.1 Medical needs specific to space Several health hazards exist for deep space missions that are unique or not commonly found on Earth. These include space radiation [4], cognitive, behavioral and psychiatric conditions derived from isolation and confinement [5], inadequate food and nutrition [6], reduced musculoskeletal loading [7], spaceflight associated neuro-ocular syndrome [8], and ineffective medications [9]. Besides these hazards, astronauts remain subject to normal Earth-relevant medical conditions, with perhaps a notable exception of reduced susceptibility to falls while in microgravity. From the vast array of possible conditions—and taking into account the nature of the typical deep space mission and astronaut screening procedures—NASA has developed a list of more than 100 medical conditions that are of particular concern during deep space missions
[10]. The conditions included in the list are broad and range from minor issues such as skin laceration and congestion [11], to urinary tract infections, dental problems, appendicitis, and life-threatening scenarios such as hypovolemic shock [10]. About a third of the 100 conditions could be diagnosed with specimens analyzed through POC devices that quantify cells, electrolytes, crystals, small molecules, and large biomolecules. These specimens could be obtained from bio-fluids such as blood, urine, saliva, skin swabs or even analyzing molecules in breath. Up to perhaps a dozen of the medical conditions could require surgery. Appendicitis and cholecystitis are the most common surgical emergencies on Earth and are also included in the medical conditions list [10]. To date, no case of appendicitis has been documented during space missions, however there is data suggesting at least one Russian cosmonaut has been evacuated due to appendicitis symptoms [12]. Evacuation, however, will not be available in deep space. Given the often-emergent nature of these as well as other surgical scenarios (trauma and non-trauma), easy-to-use POC devices will be key for diagnosis, mitigation and treatment on a deep-space mission. In addition, a number of medical conditions will require medications, and a mission to Mars requires a shelf life of up to five years—three years for the mission, plus up to two years for manifesting and packing. Most medications currently on the ISS cannot meet such requirements. Thus, technologies to support basic drug stability will be needed, as well as technologies to address the increased radiation, oxidation and high humidity which can cause some medications to lose their effectiveness or degrade into toxic byproducts [13].
2.2 Sensors and Spaceflight Constraints Because a spacecraft is by necessity a complete and stand-alone habitat, water, food, air, guidance and operations computers, space suits, exercise equipment, radiation protection, and redundant components are all essential. As a result, any tools and medical equipment that might be necessary for the mission are of secondary importance. This puts significant design pressure on the biomedical engineering teams developing healthcare components for deep space missions. The main constraints are summarized in Table 1 (see also [14]), along with rough or order-of-magnitude design guidelines for each. Briefly, the tremendous costs for launch mean device mass, volume, and consumable resupply are limited even onboard the ISS, much less in deep space. In addition, the distance and small crew restricts onboard technical expertise, while the unique environment leads to atypical device design requirements. Table 1: Spaceflight constraints and design guidelines for point-of-care medical devices
Reason Rough design guidelines * High cost to orbit, limited spacecraft < 500 grams, <1500 cm3 for a volumes. single device. Multi-use devices highly preferred. Resupply Distance from Earth, small Reusables instead of spacecraft volumes, and cost consumables Power All power onboard is self-generated < 5 Watts (<0.5 W preferred) Onboard technical Each astronaut can only be an Low-maintenance capacity expert in a fixed number of areas; components, minimize tools are limited moving parts Communication delays Distance from Earth and speed of Minimize repair, training, (up to 22 min one-way) light use and management needs Time to use Busy astronaut schedules < 10 min (ease of setup, use and cleaning, self-guidance, automated data management) Bulk fluid use In microgravity, the primary force Non-invasive devices, Spaceflight Constraint Mass & Volume
influencing fluids is surface tension Component degradation Off-gassing
Temperature, radiation, humidity, airborne particulates Sealed environments
Risk
Need to decrease current spaceflight risk posture
minimal fluid volumes, pretest in microgravity Parts should be robust to failure in space environment Use non-toxic materials and fluids; off-gas testing Remain aware of risks the device itself poses
Currently the ISS has sensors for vital signs (blood pressure, electrocardiography, heart rate, respiration rate, temperature, pulse oximetry), ocular tonometry, radiation dosimeters, CO2 monitors, and kits for analyzing volatile organics, formaldehyde, water microbiology and surface sampling [15]. Imaging ultrasound is a major piece of equipment available for noninvasive imaging [16]. For ophthalmological examinations, fundoscopy and optical coherence tomography (OCT) imaging is available [17]. There is also a centrifuge and an iSTAT system for basic blood analyses, plus limited DNA sequencing capabilities onboard [18]. Most of the sensors on ISS, however, are based on designs and technology that are over ten years old. Modernization and consolidation of the suite of sensors would help alleviate the spaceflight constraints described in Table 1. For example, hardware designs for vital signs, ultrasound, and blood analysis have over the past few years become smaller in volume and consume less power. For a deep space flight mission beyond low Earth orbit, optimization of spaceflight constraints will be critical to be able to provide all the sensor capability necessary to maintain crew health and performance.
2.3 Relevant Biomarkers Biomarkers must provide accurate and reproducible measurements to evaluate normal biological function, disease, environmental exposure or pharmacologic intervention, including efficacy and safety [19,20]. Biomarkers can be used for assessing disease development, testing various countermeasures, or better understanding underlying pathological mechanisms. They can be surrogates to clinical endpoints for diagnosing, monitoring, measuring therapeutic effects and staging diseases [19,20]. Furthermore, as healthcare and health management evolve to a more personalized approach, biological readouts will be a key feature. For deep space exploration, biomarkers can address several high priority risks for NASA Human Research Program [21], including radiation exposure, cerebrovascular, cardiovascular, immune response and infection. The ideal biomarker will be detected non-invasively and sensitive to pre-adverse events. Biomarkers already exist for a number of spaceflight risks. Readouts associated with radiation exposure and damage include DNA damage markers, chromosomal aberrations, mutation frequency, presence of persistent reactive oxygen species and telomere function [22]. Several of these biomarkers can also be indicative of chronic inflammation, which can impair immune function, gut health and neurocognitive function [23]. Cellular biomarkers that determine immune function could be used to determine neurological health. For example, aberrant microglia have been shown to play a pivotal role in neurodegenerative diseases [24] and malfunctioning immune response could impact behavior [25]. Such biomarkers can also to help assess countermeasure (i.e., therapy) efficacy.
New tools are also being developed to help identify and validate biomarkers such as human complex in vitro models [26-28]. But new tools that meet spaceflight constraints and are sensitive to numerous analytes are still needed.
2.4 Just-In-Time Training and End-To-End Care The skills and experience of those providing medical care often varies widely. Although astronauts have advanced degrees such as aeronautics, engineering, or science, they must also all be capable of performing mission-critical functions including provision of medical support. Even on missions with a physician crewmember, others will need to assist or even lead should the physician require care. Currently, real-time guidance from the ground is the default mode of operations onboard ISS. This approach, however, relies on near-synchronous two-way communication for interpretation of data (i.e., vital signs, ultrasound images, or photos of wound) and instruction from a remote medical expert. Such synchronous communications will be absent in deep space missions, and hence health care delivery—particularly for emergencies—will need to be far more autonomous than it is at present. Crewmembers will need not only appropriate POC equipment but also “augmented” knowhow and skills to deliver care when needed. Such augmentations are expected to involve: (i) basic ground training in health maintenance and medical management; (ii) in-mission knowledge reinforcement via onboard training modules (e.g. [29]); (iii) rapid refresher—or potentially de novo—instructions at time of need; and (iv) onboard “virtual” realtime guidance systems for diagnostics and treatments [30]. The inclusion of closed loop systems can also be an important goal. For example, in a major emergency, closed-loop
operation of (e.g.) a respirator would free up an astronaut to help with other medical needs. Other examples of such technologies being leveraged to extend or augment care capabilities on Earth include virtual-, augmented- or mixed-reality, AI-driven clinical decision support (CDS), “closed loop” smart POC diagnostics, and robotic-assisted procedures [30]. Finally, long-duration missions have a much greater need for end-to-end care. This spans pre-illness monitoring, to detection of a condition, to differential diagnosis, treatment, and either resolution or ongoing management of the condition. Few tools are currently available for this type of comprehensive patient management, particularly for remote settings.
2.5 Artificial Intelligence and Diagnostic Algorithms Given limitations in on-board medical expertise and real-time communications with Earth, artificial intelligence (AI) and machine learning (ML) approaches [31] will become increasingly important tools for generating diagnostic insights [32]. While AI and ML approaches are not currently used for medical applications in space, recent advances already enable decentralized statistical data analysis for consumer devices [33], eliminating the need for network connectivity and off-device computational resources. POC device manufacturers are beginning to use these same techniques to produce medical devices capable of running software algorithms that “learn” from real-world experience [34]. And new sensor systems may not even be necessary; for example, researchers recently showed superior diagnostic capabilities compared to specialized hardware when using standard smartphone hardware (microphone and speakers) and an on-device ML algorithm to diagnose ear infections [35].
While many techniques are applicable, a few ML approaches of relevance include federated learning (FL), reinforcement learning (RL) and recurrent neural networks (RNN). FL is commonly used in the consumer electronics industry and can leverage training data from multiple distributed sources yet minimize communication requirements [36,37]. Applying FL concepts to POC devices could allow for secure, large-scale aggregation of sensitive health data to improve models and help solve existing issues with POC data collection associated with suboptimal network reliability and data isolation. When combined with traditional deep-ML techniques, RL has solved decision making problems that can challenge—and often defeat— human players in games like Go [38]. Future POC devices could leverage “Deep RL” algorithms to combine device data with databases to develop treatment and dosing strategies based on analytics that account for measurements taken before and after treatment. Recent breakthroughs in RNN techniques have demonstrated hyper-accurate sequence transformation (i.e., prediction) models [39] that can dramatically reduce model size so they can be stored entirely on-device, eliminating the need for a network connection to evaluate a model [40]. The Food and Drug Administration has recognized the International Medical Device Regulators Forum designation of AI/ML software components as Software as a Medical Device. The FDA’s stated goal is to effectively regulate but not stifle these technologies, with multiple continuous-learning AI/ML devices having already obtained approval through the 510k process [34]. Acceleration of the development of AI/ML-enabled POC devices will be critical for deep space missions where physical space, computational hardware and software resources, and network connectivity will all be limited, and ease-of-use will be essential.
3 Astronaut perspective Current ISS medical operations—as with Space Shuttle missions—requires two “medically trained” individuals on-board, in case something happens to one of them. Crew composition typically includes either one MD plus one crew medical officer (CMO) trained as an emergency medical technician (EMT), or else two CMOs. Private medical conferences between the astronaut and their flight surgeon occur every 1-2 days, as well as real-time video links with ground physicians. In extreme emergencies, evacuation to Earth can be achieved in 6-10 hours. Due to distance, however, deep space missions will lack real-time conferences, video links or evacuation options. In addition, medical supplies will be limited. So, while non-urgent matters can still be handled via (lagged) communications with Earth, a major concern is the ability to diagnose and deal with acute medical problems where immediate action is required. Perhaps the biggest concern, however, is how to stay current—intensive CMO training is brief, with few refreshers, greatly increasing the chance of making a mistake 18 or 24 months into a long-duration mission during a medical emergency.
4 Conclusion Astronauts monitoring their own health and treating certain conditions in a spaceship far away from Earth is not unlike care models that are moving away from expensive emergency room or clinic visits and toward an ambulatory or in-home setting here on Earth. By providing actionable and continuous information at the point of care (POC), one can avoid deterioration via early diagnosis and intervention, plus cost savings. Importantly, any POC health capabilities to support deep space missions are thus also likely to help advance healthcare here on Earth.
5 Acknowledgements This paper was supported by the Translational Research Institute through NASA Cooperative Agreement NNX16AO69A. We wish to thank Rachel Dempsey for her assistance with manuscript figures.
6
Conflict of Interest
The authors declare no conflict of interest.
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Reference Highlights 3. Andreu-Perez J, Leff DR, Ip HM, Yang GZ: From Wearable Sensors to Smart Implants--Toward Pervasive and Personalized Healthcare. IEEE Trans Biomed Eng 2015, 62:2750-2762.
* This article describes the evolution of sensing technologies and the synergistic evolution of data science and computational capabilities which, in combination, are fueling an era of "smart" health management and provide the potential for autonomous real time medical care.
13. Blue RS, Bayuse TM, Daniels VR, Wotring VE, Suresh R, Mulcahy RA, Antonsen EL: Supplying a pharmacy for NASA exploration spaceflight: challenges and current understanding. Nature Microgravity (in press), 5. * This article summarizes decades of pharmacy applications for spaceflight and provides an overview of the challenges and opportunities on selecting an appropriate formulary for exploration class missions.
16. Law J, Macbeth PB: Ultrasound: from Earth to space. Mcgill J Med 2011, 13:59. ** This review summarizes the numerous applications of ultrasound during spaceflight. Some of these are atypical uses on Earth because ultrasound is currently the only medical imaging modality onboard the International Space Station.
18. Parra M, Jung J, Boone TD, Tran L, Blaber EA, Brown M, Chin M, Chinn T, Cohen J, Doebler R, et al.: Microgravity validation of a novel system for RNA isolation and multiplex
quantitative real time PCR analysis of gene expression on the International Space Station. PLoS One 2017, 12:e0183480. * NASA has worked to develop genetic analysis platform that could operate in microgravity where fluid flow and bubble formation is dramatically altered. This study describes the use of reverse transcriptase PCR , as well as gene expression from bacterial cells and mammalian tissue RNA samples.
21. Human Research Program: Human Research Roadmap: Risks. Edited by: NASA; 2019. vol 2019.] ** The NASA Human Research Roadmap lists the main spaceflight medical risks and gaps, and includes evidence reports detailing the current state of knowledge regarding each risk and gap. This represents a key resource for understanding NASA’s medical technology development needs.
30. Eckert M, Volmerg JS, Friedrich CM: Augmented Reality in Medicine: Systematic and Bibliographic Review. JMIR Mhealth Uhealth 2019, 7:e10967.
* This is a review of current published sources on the effectiveness of AR in healthcare provides needed clarity on terminology, highlights the promise for these advanced technologies in medical training and care delivery. There is also a clear need described for further research in this field for the technology to move from a novelty to an accepted and well-defined place in medical training and care delivery.
35. Chan J, Raju S, Nandakumar R, Bly R, Gollakota S: Detecting middle ear fluid using smartphones. Sci Transl Med 2019, 11.
** On-device ML algorithms are being used to endow consumer electronic devices with adequate sensors and capabilities with POC device-like diagnostic capabilities. Consolidation of technical resources will be critical for deep space missions, where physical space, computational hardware and software resources, and network connectivity will all be limited, and ease-of-use will be essential
40. Alvarez R, Prabhavalkar R, Bakhtin A: On the efficient representation and execution of deep acoustic models. arXiv 2016:1607.04683.
* Techniques currently being developed to enable on-device model execution for consumer electronics use cases have shown that hyper-accuracy can be retained even with dramatic reductions in model size. These same techniques can be applied to addressed edge computing needs on POC devices, allowing for more robust diagnostic insight from even smaller devices and sensor systems.
Figures
Figure 1: Point of care medical needs for long-duration missions to deep space will require a comprehensive suite of tools, suitable for up to three-year missions, all contained within an exceptionally small and lightweight package.