SPACEFLIGHT RESEARCH: THE POTENTIAL TO IMPROVE WOUND CARE IN OUR CLINICS

M. Mark Melin MD, FACS, RPVI, FACCWS M Health Fairview, Wound Healing Institute, South Campus Adjunct Associate Professor, Department of Surgery, University of Minnesota Minneapolis, MN

Heather Hettrick PT, PhD, CWS, AWCC, CLT-LANA, CLWT, CORE Professor, Nova Southeastern University, Ft. Lauderdale, Florida

Frank Aviles Jr, PT, CWS, FACCWS, CLT-LANA, ALM, AWCC, DAPWCA Wound Care Service Line Director, Natchitoches Regional Medical Center, Louisiana

The American Vein & Lymphatic Society (AVLS) meeting in Denver brings an “elevated” component to the conference as a distinguished Wound Care Faculty discusses benchtop to clinical care and terra firma to Low Earth Orbit (LEO) topics aboard the weightless laboratory of the International Space Station (ISS). The session begins with an up-to-date data review of venous leg ulcer management, an intriguing discussion of the microcirculatory component of wound resolution and a deep dive into the endothelial glycocalyx: the historical perspective, glycocalyx recognition, the paradigm-shifting revision of the Starling Forces, and glycocalyx contribution to systemic health.

The extensive and growing recognition of the functions of the glycocalyx, the revision and modification of the Starling principle forces, and paradigm shift in understanding that nearly 100% of interstitial fluid is returned to the central venous circulation by lymphatic pathways1 has contributed to a renaissance in lymphatic research and treatment options. The recognition that an intact glycocalyx imparts healthy microcirculatory function, while “thinning” and/or “shedding” of the glycocalyx is recognized as part of the disease process or aging, resulting in microcirculatory dysfunction. Shedding of the glycocalyx has been recognized in diabetes, arterial and venous hypertension, tobacco abuse, COVID-19 infection, pre-eclampsia, sepsis, and other states of acute and chronic inflammation(2,3,4,5,6,7,8,9).

Lymphatic contractility benchtop research will be reviewed, as will the lymphatic focus for improving wound care outcomes. Countermeasure management of venous and lymphatic dysfunction is highlighted by the impact of flavonoids, specifically hesperidin – diosmin, which has a long and bountiful history of benchtop and clinical trials in Europe.

Emerging technologies in wound care and potential venous interventions will be discussed, with the morning session finale promising a robust discussion of astronaut health, adaptability to long-duration spaceflight, and reports on how environment and genetics impact astronaut health. The wound care session is an up-to-date, “Show Me the Data” session from some of the nation’s leaders in their fields.

A unique evening event to capitalize upon the current interest in spaceflight and human physiology will be held at the Colorado Air and Space Port. The event will explore the data to date for venous and lymphatic alterations in function during the weightlessness of space travel. This area of research has a specific impact on astronauts during long-duration space missions, both in low-Earth orbit and planned missions to the moon and Mars.

Spaceflight research and countermeasure development carry a high potential for “spinoffs” to improve treatment for patients in our own clinics. As the privatization of the space industry expands, these fields of research, in both Earth-based analogs and orbiting laboratories, will continue to grow and develop as the efforts for assuring nominal human function in “microgravity” and the weightlessness of space continue. Looking forward, the improvement of care in the extreme environment of space will require the brightest in both benchtop and clinical research.

We are witnessing the dawn of a new era as private astronaut missions fly on sub-orbital trajectories, and private crews enter orbital flight and experience true astrodynamics. The first-ever private civilian four-person crew of Inspiration4, a SpaceX Dragon capsule, is led by experienced tactical jet pilot Jared Isaacman. His team includes a crew member who is thriving as a pediatric cancer survivor with a prosthetic bone. For three days, at an orbit higher than ISS, the crew will experience views of the cosmos that few can dream of, and only government-supported astronauts have experienced. They will also be exposed to the physiologic consequences of crossing the 100km high atmospheric-space boundary known as the Kármán line.

Well above the Kármán line, in the weightlessness of space travel, humans and spacecraft travel at 5 miles/second, witness 16 sunrises and sunsets every 24 hours, and normal human physiology adapts to the state of the constant free fall resulting in weightlessness while orbiting the Earth. In the absence of the normal “1G” hydrostatic gradient from head to chest, astronauts experience a dramatic redistribution of fluid from the legs to the torso, head and neck during the first 6-24 hours of spaceflight. Other physiologic changes include a reduction in plasma volume (10-17%), increased cardiac output and stroke volume (Doppler technique on ISS, 23-25% and 1921%, respectively), and a decreased systemic vascular resistance (14-39%). Additional spaceflight-related changes include the phenomenon of “neocytolysis,” resulting in the culling of young red blood cells (RBCs) and a relative decline in RBC total mass. Tissues undergo increased oxidative stresses, and increased inflammatory biomarkers reflect the potential to impact arterial function.

Many astronauts experience ocular changes identified as Spaceflight Associated Neuroocular Syndrome (SANS), one of the top priorities for ground-based and spaceflight research. SANS has been suggested to occur because of “multiple hits;” cephalic fluid shifts and increased neck and facial venous diameters and pressures, a possible relative increased intracranial pressure, genetic differences (single nucleotide polymorphisms) resulting in B vitamin metabolism alterations, and dysfunctional glymphatic pathways in both cerebral and ocular tissues. SANS countermeasure development may positively impact our patients with venous and lymphatic disease where environment and genetics impact healing rates and recidivism. Other cardiovascular and body system adaptations also occur, as astronauts exercise daily to battle these and bone and muscle deterioration(10,11,12,13,14,15).

Research on human adaptation to microgravity began with the first Mercury spaceflight in 1961 and continues on the ISS, a true weightless laboratory. The ISS has been continuously inhabited since 2000, currently supporting seven astronauts on 6-month expeditions. The ISS vehicle and its astronaut corps are supported by an extensive, diverse, international collaborative of women and men. While human research on ISS is expansive, with limited numbers of astronauts and constraints of research in microgravity, ground-based analogs are often utilized for simulating elements of space travel and human adaptation to flight. These analogs include 6° head-down tilt bed rest, dry immersion, undersea habitats, and aircraft, which can provide 20-30 second periods of weightlessness during parabolic flight(16). Each can provide access to specific elements related to human adaptation to space travel and microgravity exposure.

Human research in space has spanned the physiological systems of function: cardiovascular, neurovestibular, musculoskeletal, etc. One relatively new area of research is wound healing and closure in space, which will have greater importance given increasing crew autonomy of planned exploration class missions to the moon and Mars. This research carries the potential “spinoff” of improving how we treat patients in our 1G wound clinics.

WOUNDS IN WEIGHTLESSNESS

A wound in space will be a defining moment and event as newly developed methods, and checklists will be used for medical management. Prevention of medical events is goal number one outside of low Earth orbit, as rescue missions or return to Earth-based care may be virtually impossible. Telehealth and telecare from ground-based medical teams will be the best option, to whatever degree of communication delays on distant missions allow.

During spaceflight, some astronauts experience rashes, hypersensitivity and atopic dermatitis, dermal changes that are potentially related to immune system dysregulation(17). Cytokine expression and dysregulation have been researched in astronauts, demonstrating downregulation and altered growth factor release(22). A pattern of novel cytokine alterations identified in astronaut saliva samples has recently been published(19), demonstrating growth factors and cytokines associated with immune mobilization; significant increases in the plasma concentration of IL-3, IL-15, IL-12p40, IFN-a2, and IL-7, significant decreases in saliva GM-CSF, IL-12p70, IL-10 and IL-13, and increases in plasma TGFb1 and TGFb2 concentrations. This extensive new data adds to a complete characterization of space flight immune system dysregulation.

Overall, the findings confirmed an in-vivo hormonal dysregulation of immunity that appears pro-inflammatory and persists during long-duration orbital spaceflight(19). These types of chronic pro-inflammatory alterations and associated immune dysregulation may impact typical wound healing trajectory. Further research of cellular response to trauma, ischemia-reperfusion, and impact on wound healing will be needed in both groundbased simulations of weightlessness and true conditions of weightlessness in the space environment.

Increased radiation exposure during space travel may also be a factor in wound healing as astronaut exposure to solar particle events and galactic cosmic rays will increase(20) , necessitating improved shielding for spacecraft and spacesuits. Endothelial cell function, nitric oxide production, and modulation of inflammation are processes recognized to be altered in “microgravity”(21). Blood will float and form “domes” over wounds, impacting the normal pathways of hemostasis(22). CO2 levels are higher in spacecraft than on Earth due to the resource constraints and the technical limits of scrubbing it from the spacecraft’s atmosphere. A fractured bone of the lower extremity will be challenging to stabilize, not to mention that limb elevation in weightlessness is not possible to minimize edema in an astronaut experiencing fluid shifts. These environmental constraints in orbit and altered gravity environments of the Moon and Mars will add layers of complexity to wound and injury management.

What will the space environment demand of wound care management in the altered gravity fields of the moon or Mars or the weightlessness of spacecraft?

• Lightweight and small, given the mass and volume constraints of all spacecraft and associated costs to transport to orbit

• Long shelf life, durable, reliable, no conditioned storage requirements (e.g., refrigeration), easy-to-maintain packaging, not bulky for storage

• Does not break down with increased radiation exposure (i.e., Galactic Cosmic Radiation, which will be much higher in travel beyond low-Earth orbit and the van Allen Belt)

• Easy to use by astronauts who may not have extensive medical training • Use of manageable liquids • Unique Hydrogels, poloxamers

• Rapid tissue regenerative and restorative qualities with low recidivism rates

• Provides an extensive replicative milieu of the tissue proteosome and matrisome make-up within the extracellular matrix

• Antibacterial qualities

Diet and nutritional status are known factors that can either enhance or delay wound healing. Food will obviously be flown (and likely grown) on all future space missions. Care needs to be taken to ensure nutrition is consistently used to optimize crew health(23,24,25). High-quality nutrition, macro- and micronutrients, flavonoids, polyphenols, fiber, and clean replenishable fluids will be tantamount to systemic tissue and immune function to ensure maximizing wound healing. Food will serve as a source of both refreshment and physical/psychological replenishment in an environment likely to be otherwise devoid of the normal comforts of Earth.

The five main hazards of spaceflight and the space exposome are radiation, altered gravity fields, hostile and closed environments, and distance from Earth. Countermeasure research and development are now being conducted in analogs and on ISS26. In our wound clinics, we often discuss the environment, genetics and psychological barriers as either significant benefits or barriers to healing; the space environment will be the same as human physiology and adaptability are based on DNA. As single nucleotide polymorphisms (SNPs) become increasingly defined and understood within the genomic response to injury and pharmacogenomics, we will better understand how to decrease chronic states of inflammation (e.g., diabetes, vascular disease, metabolic syndrome, obesity) to improve response to chronic wounds and lymphedema and begin to deliver personalized, prescriptive, and precision care(27).

A new hope is on the horizon for vast improvements in care delivery through improved diagnostics and treatments as we enter 2022. Part of this hope will be derived from missions bringing the first woman and the first person of color to the lunar surface, from missions being contemplated to the red planet, and from missions closer to home with the privatization of the space industry. All of these will accelerate “spinoffs,” allowing all of us to join in these exciting national and international endeavors.

While we know not what the future will grace us with for better serving our patients, we know that a better state of the art is always on the horizon, a pursuit we must continue throughout our time upon the Earth. We are in the era of “data,” and we applaud the AVLS leadership with their focus on data acquisition and application through research, presentations, educational support, open and transparent discussions, accountability, and fellowship at meetings.

We would like to thank Dr. Scott M. Smith, Biomedical Research and Environmental Sciences Division, Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX, for his thoughtful and insightful review and contribution to this editorial’s overall writing, nutritional and food components, and spaceflight elements.

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Photos submitted by Scott Smith, Biomedical Research and Environmental Sciences Division, Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX