ISOPTWPO Today

S EPTEMBER 2015, N O 20

ISOPTWPO Today

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Editorial Dear Reader It is my pleasure to introduce the ISOPTWPO. ISOPTWPO(International Space Flight & Operations - Personnel Recruitment, Training, Welfare, Protocol Programs Office) is part of ISA, which support research on Human Space Flight and its complications.

The International Space Agency (ISA) was founded by Mr. Rick Dobson, Jr., a U.S. Navy Veteran, and established as a non-profit corporation for the purpose of advancing Man’s visionary quest to journey to other planets and the stars.

ISOPTWPO will research on NASA’S Human Research Roadmap. It will also research on long duration spaceflight and publish special issues on one year mission at ISS and twin study.

ISOPTWPO Today, September 2015, No.20

Mr. Martin Cabaniss

Director Mr. Martin Cabaniss ISOPTWPO – International Space Agency(ISA) http: // www. international-space-agency. us/ Email:martin.cabaniss@international-space-agency.us

IN THIS EDITION Risk of Intervertebral Disc Damage There is an increased incidence of back pain expressed by crewmembers in space. Additionally, herniated Intervertebral Discs (IVD) have been diagnosed in returning Skylab and Shuttle astronauts on landing day, and after varying periods of time in the postflight period. Such injuries in astronauts, however, may be related to their careers as aviators (either high performance jet pilots and/or helicopter pilots). However, the evidence of IVD injuries raises the concern that astronauts are at increased risk during loading scenarios experienced during exploration missions (for example, re-entry to a gravitational field, activities on planetary surfaces).

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Concern of Intervertebral Disc Damage upon and immediately after re-exposure to Gravity,NASA

Risk of Intervertebral Disc Damage

Risk of Intervertebral Disc Damage In a questionnaire survey of astronauts who had flown in space, 68 % of the population reported generalized back pain, with some astronauts rating the pain between severe to moderate. This discomfort is considered most painful early during the spaceflight but is attenuated as flight duration progresses. At face value, the cause of back pain in space may be associated to the elongation of the vertebral column by IVD expansion or to other causes. Lower back pain in humans, for example, is also associated with trunk muscle weakness suggesting that the reduced biomechanical forces from space-induced atrophy of lower back muscles may be a contributing factor. Alternatively, pain caused by IVD changes may be related to increased strain of proximal facet joint capsules , fractured innervated vertebral end-plates , disc degeneration, or herniation of annulus fibrosis.

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Irrespective of the exact cause of back pain, there may be an increased risk for IVD injury or damage when the swollen IVDs of crewmembers (under the weightlessness of transit) are subjected to excessive forces or torques while performing work on planetary surfaces. Exploration missions on planetary surfaces may introduce habitability issues that could induce excessive torsional stress, an established risk factor for herniation of annulus fibrosus. For instance, excessive axial rotation could occur while carrying large masses in the partial G environment by a crewmember with de-conditioned back muscles and may consequently subject IVDs to lateral shear forces. Regardless, there are minimal data (medical evaluations or research) that characterizes the biomechanical and biochemical changes in IVDs in crewmembers during or after flight to assess how such changes predisposes the IVDs to injury under re-loading.

However, herniated nucleus pulposus is known to occur in aviators exposed to high G environments and has occurred in astronauts after a mission. There were three separate occurrences of IVD injury on the day of landing as determined by chart reviews and personal communication with crewmembers and flight surgeons (medical chart reviews, personal communication). The relative risk rate of IVD injury in the astronaut population has only recently been evaluated (Johnston, manuscript in revision 2009).

There is no evidence, however, connecting the origin of an IVD injury with changes in IVDs as a result of spaceflight - that is, morphological and biochemical changes in IVD composition.

Biochemical changes in the IVDs of crewmembers after flight have not been identified. However, there is in vitro research with bovine cartilage explants to use magnetic resonance technology to correlate changes in IVD proteoglycan content with the Tlrho relaxation rates of protons . This biomarker will enable non-invasive monitoring of proteoglycan content as a method of assessing the biochemical impact of weightlessness.

Evidence-to-Date Spaceflight Evidence An early quantification of spine elongation during weightlessness was performed in a single astronaut during the 84-day Skylab 4 mission. Changes in height were monitored during weightlessness (to the 1/16 in.) which described an asymptotic increase in height during flight that appeared to plateau 29 days into the flight. The absolute height change was 1.5 inches at the end of the mission. The increase in spine elongation is presumed associated with the expansion of IVDs during axial unloading. There was also a reported case of spine pain on landing day which was associated with herniated IVD (personal medical communication).

Astronaut Chart Review The reports of several astronauts developing cervical or lumbar herniated nucleus pulposus (HNP) in the immediate period following landing on earth prompted a retrospective review by NASA flight surgeons to evaluate the incidence of IVD damage in the astronaut population (S. Johnston, manuscript in revision, 2009).

The review sought to clarify whether spaceflight increased the risk for IVD damage because of • The exposure to both low- and high G environments during a mission; • The extended periods in an abnormal posture; and/or • The changes to IVD structure due to its expansion in the absence of axial loading in space.

Although the postflight incidence of IVD damage in astronauts is apparent, it is unclear whether the spaceflightinduced changes predispose the IVDs to injury. In particular, evidence indicates that many of the injured astronauts had previous, multiple exposures to excessive G forces (between 6-20 G) as high performance jet pilots or to vibrating forces as helicopter pilots.

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Risk of Intervertebral Disc Damage

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Notably, the pathophysiology of IVD injury after spaceflight has not been clearly identified. The documented expansion of disc volume after spaceflight, together with the IVD injuries after reloading in Earth’s gravity, suggests that the adaptive changes of the IVD in weightlessness disrupts the balance between osmotic pressure of the nucleus pulposus and the resistive collagen structure of the annuli fibrosus, thereby reducing the ability of the IVD structure to withstand re-exposure to G forces. Repeated, previous exposures to excessive G forces in high performance jets, however, may have also weakened IVD structures, particularly in the cervical vertebrae, increasing the susceptibility of these IVDs to damage.

Ground-based Evidence IVD volume changes were quantified by magnetic resonance imaging in response to varying scenarios of axial unloading. The cross-sectional areas and the transverse proton relaxation constants (T2) of IVDs were indices used to monitor adaptive changes of the IVDs to overnight bed rest (over 5 weeks and 17 weeks) and after 8 days of spaceflight. The averaged expansion of IVDs with bed rest appeared to reach an equilibrium anywhere between 9 hours and 4 days of unloading with the expansion ranging between 10-40% of baseline, pre-bed rest values (mean=22%). There were mild increases in T2 relaxation times relative to increases in disc area.

Restoration of IVD volumes after unloading was not evaluated systematically but the Table (below) provides a relative comparison of the elapsed time in 1 G at which time the measured IVD volumes were no different from baseline measurements; the relative periods of recovery appear to lengthen as the period of IVD adaptation to unloading increases.

Table. Relative comparison of the elapsed time in 1 G Period of Unloading Relative Time before Recovery 8 days spaceflight < 24 hours 5 weeks bed rest

days

17 weeks bed rest

> 6 weeks

Disc degeneration Disc degeneration occurs in all age groups and populations. Numerous risk factors have been proposed to be associated with the development of disc degeneration, such as age progression, abnormal biomechanics, lifestyle/environmental factors, and genetics.

Disc degeneration has been traditionally assessed by T2-weighted magnetic resonance imaging (MRI), which essentially assesses the water content based on the "signal intensity". The intervertebral disc comprises two main regions: an inner gelatinous core (nucleus pulposus) and an outer layer (annulus fibrosus) . These structures 4

Risk of Intervertebral Disc Damage are rich in collagen and macromolecules, such as proteoglycans, and contain an abundance of water in normal states.

It has been believed that as the disc degenerates, it loses proteoglycan and water content. As such, a loss of water content by the disc would be noted as a loss of signal intensity on MRI, resulting in a "black disc." This "black disc" has been regarded throughout the past three decades since the advent of MRI as a disc that has "degenerated." In other words, the disc was at one time well hydrated and "normal," but because of a series of events, water content was lost and various macromolecules were broken down leading to morphologic and biochemical alterations of the disc that would lead to "degenerated" changes.

Such changes can cause the disc to develop fissures in its outer annulus fibrosus, whereby nerve fibers can migrate in the disc and become irritated by proinflammatory cytokines associated with the degenerative process or its adjacent end plate may alter causing irritation of the surrounding nerve fibers This degenerative process, in time, may lead to "secondary structural changes" of the disc, characterized as disc height loss, disc displacement (eg, bulging, protrusion, herniation, sequestration), and annular tears in the disc or the formation of high-intensity zones .

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Moreover, the degenerative process alters the stress/strain applied on the vertebral motion segment and modifies its kinematics, resulting in additional secondary structural changes such as osteophyte or bone spur formations and/ or adjacent level vertebral bone marrow changes (ie, Modic changes) (Figure, Left).

In fact, studies have also noted that disc degeneration on MRI may manifest as skipped level patterns (21% of multilevel disc degeneration cases) throughout the lumbar spine. In other words, it has been commonly thought that disc degeneration occurs at a single level, predominantly at the lower lumbar region, and any new discs that degenerate occur consecutively in the adjacent levels.

However, skipped patterns of disc degeneration, whereby healthy discs are located in between these degenerated discs, challenge the traditional dogma of how degenerative discs occur in the lumbar spine . In line with this, studies have also noted that "black discs" are common in adolescents, which contradicts the traditional notion of wear and tear of the disc brought upon by aging and subsequent processes .

Such findings in the young could in fact have been preexistent in the life-span. Furthermore, although mechanical injury may play a role ,this may not always be definitive.

Spinal elongation is anticipated during spaceflight, and warrants special consideration for spacewalkers who must fit into conformal Extravehicular Mobility Units (EMUs, or spacewalking space suits) during their missions. Typically 2.5 cm of additional torso height (shoulder-to-crotch length) is factored in to accommodate some but not all of this microgravity growth.

One of the authors (ret. Astronaut S. Parazynski) measured 5.1-5.7 cm of height gain on each of his five Shuttle missions. As such, when he donned his EMU for the first EVA of his missions, there was considerable pressure on his shoulders. Over the course of EVA preparations, typically lasting slightly over an hour, the pressure abated, presumably due to spinal compression and reduction in disc height. On subsequent EVAs during these same missions, this shoulder pressure sensation did not repeat, suggesting that the suited operations induced a lasting re-equilibration of disc pressures and disc height.

During long spaceflight missions, deconditioning of the intervertebral discs and spinal muscles poses a serious injury risk upon re-exposure to upright posture in a gravitational environment . During normal upright activity, gravity and back musculature generate high axial compressive loads on the spine, and cause diurnal fluctuations in body height . Axial loads reduce body height primarily by vertical height reduction of the intervertebral discs with a likely increase in disc diameter, and increasing lumbar lordosis.

For example, on Earth the body loses about 15-20 mm in height (1% of total body height) following normal upright daytime activity. The disc maintains height and flexible load bearing by swelling due to hydrophilic, negatively-charged proteoglycans (PGs) present within the disc nucleus. During loading on Earth, hydrostatic pressure due to weightbearing exceeds swelling pressure and nucleus fluid is driven from the disc into surrounding tissues, primarily across the vertebral endplate into the bone vasculature.

During unloading, PGs cause intra-discal swelling via fluid movement across the vertebral endplates and into the discs . Because the intervertebral discs are avascular, the diurnal loading cycle is an important physiological mechanism that maintains the mechanical and metabolic properties of the intervertebral discs.

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Microgravity eliminates or significantly reduces the diurnal loading cycle and dynamic spinal compression, potentially accelerating disc degeneration and increasing risk of disc prolapse or herniation upon return to a gravitational environment.

Three potential mechanisms underlie this process.

• Biomechanically, the excessively swollen intervertebral disc distributes compressive and bending stresses in a non-physiologic and adverse manner.

• Excessive expansion of the nucleus pulposus increases vertebral endplate and annular ligament stresses.

• Increased disc height will alter the anatomic relationships between adjacent vertebrae and may excessively stress the facet joints, thus possibly generating capsular strain and facet pain.

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A potential fourth pathway could be due to altered metabolic activity of disc cells secondary to changes in disc hydration, osmotic pressure, and pH. During his first flight aboard STS 41-D, Astronaut Mike Mullane, through a personal communication with the authors, reported severe back pain in five out of six orbiter crew members including himself.

Back pain could precede more debilitating conditions as in the case of a herniated nucleus pulposus (HNP) when spines are subjected to greater mechanical demands on return to Earth.

An analysis of epidemiological data regarding HNP incidence (NASA’s Longitudinal Study of Astronaut Health at Johnson Space Center) on a 321 astronaut population (from April 1959 to December 2006) compared to 983 matched controls not involved with spaceflight, suggests a 4.3 times higher HNP incidence in the astronaut population.

There is currently no formal consensus regarding the pathogenesis of HNP during spaceflight but lack of dynamic weight-bearing, excessive swelling, and poorer intradiscal cell nutrition during microgravity maybe important causative factors.

Body-length increases from 4 to 6 cm and the vertebral column loses its normal curvature and flexibility during early exposure to microgravity.

Anecdotally, one of the authors (ret. Astronaut S. Parazynski) experienced 6.35 cm of body-length growth representing an 8% growth during one of his Shuttle missions. By the time he returned to crew quarters all of his height gain was lost.

Increased spinal length is caused by greater disc height from elevation of intradiscal fluid volume and a reduction of thoracic and lumbar curvatures . Disc swelling is a recognised factor in back pain pathogenesis.

For example, spinal unloading during bed rest causes hydration to increase within discs, and decrease within paraspinal muscles. Morning back pain upon waking is a recognised clinical indicator of inflammatory low back pain. To relieve back pain during spaceflight, astronauts assume a knee-to-chest position. Other techniques reported to ease back pain includes stretching, taking acetaminophen or ibuprofen, treadmill exercise, and deliberate compression of the spine.

Biomechanical research demonstrates that spine flexion transfers the sagittal instantaneous axis of rotation (IAR) to the anterior discs and increases disc compression with redistribution of tissue stresses that change the contour of the posterior annulus and soft-tissue elements.

The aetiology of back pain on Earth is broadly classified as visceral, non-mechanical, and mechanical (attributed to lumbar discs) but the exact mechanism of back pain in microgravity is unknown. Relieving low back pain in space by posture alteration towards flexion implies a mechanical pathogenesis. Altered spinal configuration may relieve back pain by unknown mechanisms involving lumbar disc fluid hydrodynamics, cellular nutrition and/or annular deformation.

Spinal flexion may involve neurophysiological pain relief through an inhibitory effect of local opioids in the spinal cord facilitated by collagen stretch receptors in the posterior elements of the lumbar spine.

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Risk of Intervertebral Disc Damage Biophysics of the spine In bipeds, the spine balances mobility and stability via the anterior intervertebral discs and the posterior facets.

Spinal curvature may have evolved to counteract gravity in upright posture in bipedal man by the development of lordosis in the cervical and lumbar spines, and kyphosis in the thoracic spine .

For example, cervical lordosis develops when an infant raises its head to move around and the lumbar lordosis follows when the child starts upright walking . Primary thoracic kyphosis is retained as a compensatory mechanism so that erect posture is maintained in spite of cervical and lumbar lordoses.

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According to Borelli, this concept of sensible angulation means that the spine was specifically angulated to protect the spinal cord . In addition, curvature of the vertebral column may aid the spine’s resistance to axial compression. During ambulation the pliable spine is able to dampen the ground reaction forces evidenced by a sagittal- plane curvature cyclic increase and decrease of 1-2 degree amplitude per lumbar level during human locomotion. In effect, the three flexible curvatures of the normal human spine (cervical, thoracic, and lumbar spines) redistribute forces generated in response to gravitational load, as a bowstring, allowing more efficient force distribution. The unloaded spine on the other hand, is subjected to spinal lengthening with a loss of curvatures and increased disc height , which may increase risk for overload during upright stance .

The physiological loads on the spine include body weight, external loads, and muscle forces . However, spinal loading will also vary when body mass plus acceleration is factored in during spinal movement. The equivalent percentages of body weight (BW) loaded on the spine are approximately 8% BW exerted at the cervical spine, 50% BW at the lumbar spine, and 100% BW at the feet . These forces are supported by muscles, tendons, and ligaments that generate trunk moments while simultaneously providing compressive load and shear .

Paraspinal muscles not only act as force generators to establish mechanical equilibrium, but also act as selfstabilizing springs that support the spine without requiring neuromuscular control . Importantly, the spine with compressive loads due to muscle contraction and gravity increase bending stiffness by an order of magnitude.

Actual spinal load on the spine in vivo is difficult to quantify and at best, can only be measured indirectly through electomyography (EMG) studies using bipolar surface and needle electrodes, intradiscal pressures using small transducers intra-abdomial pressures using a pressure-sensitive radio transducer and mathematical models .

Since there is no gravitational compressive force or effect of momentum with dynamic motions of the spine in microgravity, the anti-gravity muscles used for posture and stability invariably are the ones that show the most atrophy and degeneration.

Mechanisms of intradiscal fluid hydrodynamics Biological tissues depend on the transport of nutrients from blood to cells and the transport of metabolic waste products from cells to blood via the interstitium and lymphatic vessels .

Fluid and solute influx and efflux between lumbar intervertebral discs and the vertebrae through the vertebral endplates occur by two main processes: convection and diffusion .

• Diffusion occurs by movement of fluids and nutrients from regions of high to low solute concentration by random thermal motion in the absence of external force fields. This process results in the tendency of a solute to reach uniform distribution in the presence of a concentration gradient.

• Convection is a more rapid transport especially for macromolecules and involves bulk flow through a porous medium such as the interstitium and intervertebral endplates due to hydrostatic pressure gradients and sufficiently large channels.

The interstitia of the annulus fibrosus and nucleus pulposus contain the ground substance of connective tissue comprising structural components (collagen fibrils and GAGs) and fluid components (water, proteins, ions, and other metabolic substrates and end-products). Disc hydrostatic pressure is significantly reduced concurrent with reduced load-bearing during sleep despite the compressive load contribution by paraspinal muscle tone.

When the spine is unloaded during sleep, the hydrophilic nature of the PGs in the nucleus pulposus causes influx of fluid and nutrients from the vertebral bodies through the vertebral endplates by either of diffusion or convection, depending on molecular size and charge. Spine unloading that facilitates fluid influx into the discs together with PG’s fluid imbibition via its macromolecular electronegativity.

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In this regard, fluid inflow is due to large negative fluid pressures resulting from repulsive forces within a matrix of high anionic charge density in the nucleus pulposus. Resumption of normal spinal load-bearing activities during wakeful periods cause re-imposition in varying degrees of external compression on the nucleus pulposus.

Cyclical or intermittent intradiscal pressure changes as a homoeostatic stressor depend on threedimensional spine position and the amount of load carried by the individual. Diurnal spinal loads increase intradiscal pressure that forces fluid out of the disc by the process of convection through the vertebral endplates. Hence, by the day’s end, disc volume and height diminish, thus reducing spine length by 2-3 cm .

In addition, concurrent spinal soft-tissue adaptation at the end of a day’s load-bearing activities increases spine curvatures which may contribute to the total reduction of spine length. The diurnal result of cumulative spinal stress is a reduction of stature with active awake hours and an increased spinal length following unloading with recumbency and sleep.

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Physiology of the spine The lumbar IVD is largely composed of fluid, proteoglycan (PG; consisting of a core protein and glycosaminoglycan, GAG, side chains), and collagen, and is sparsely populated by cartilage-like cells in the nucleus, and fibroblasts within the collagen fibres of the annulus.

The PG and collagen components are in varied types and proportions between the nucleus pulposus, the annulus fibrosus, and the adjacent cartilaginous endplates. PG has an extensive electronegative charge causing a high osmotic pressure that attracts and retains fluid perhaps by more positive charged solutes in the nucleus pulposus.Through this osmotic mechanism, the disc is able to resist compressive loading during weight bearing.

IVD chondrocytes can transform mechanical signals rapidly and differentially into metabolic effects (mechanotransduction) from the application of hydrostatic pressure.

Pressure also stimulates cells indirectly by compacting IVD matrix and changing the extracellular micro - environment. Matrix compaction decreases tissue permeability, water content, oxygen tension , pH and osmolarity . These changes alter proteoglycan and collagen synthesis via altered cell volume and cytoskeletal rearrangement.

Lumbar discs are the largest avascular tissues in the body. In general, discs do not have lymphatic return and their limited blood supply only supports the external surface of the annulus.

When intra-discal pressure increases with posture and exercise-related load bearing, intra-discal fluid is driven out by convection through the endplates into the blood circulation of the vertebral body. Intervertebral disc deformation on Earth with static load-bearing as well as in combination with dynamic spine activity promote fluid and nutrient transport essential for disc viability.

Fluid efflux and influx facilitate transport of nutrients, water, and waste products into and out of the nucleus pulposus. Cyclical and dynamic loading of the disc result in modified tension in the annular collagen fibre line of stress (Sharpey’s fibres) as well as the scattered chondrocyte-like cells embedded within the disc. Under normal physiological loads, the disc follows Wolff’s law (applied stress affects cellular activity and the disc remodels and strengthens to minimise stress).

Therefore, biomechanical stress or mechanical signals such as increased hydrostatic pressure , fluid movement , and stretch of discs raise GAG production and promote collagen strength to maintain disc health and cellular turnover. Thus, aside from genetic, hormonal, and nutritional factors, development of the human spine requires biomechanical stresses derived from active weight-bearing motion for disc maturation and continued health.

Animal models may provide insight into probable human disc component changes during microgravity exposure or simulated weightlessness. Studies show that histological and biomechanical changes occur resulting in less collagen orientation in rat lumbar intervertebral disc annuli fibrosus, significant reduction of annuli fibrosus growth rate, reduced GAG/collagen ratio, decreased amount of PG, and reduced muscle volume.

Although the spines of Skylab-4 crew members lengthen twice the terrestrial values about 4-6 cm during 83 day in space, magnetic resonance imaging (MRI) of the spine after 8 day of microgravity exposure after STS-47 showed no evidence of disc expansion and there was a slight but non-significant decrease in disc area postflight.The difference in these spine measurements is that Skylab crewmembers measured spine lengthening inflight whereas STS-47 crewmembers’ spines were measured post-flight with re-exposure to Earth’s gravity.

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W OULD HUMANS BORN AND RAISED IN A MICROGRAVITY OR HYPO - GRAVITY ENVIRONMENT DEVELOP A LUM BAR LORDOSIS ?

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The development and the correct forming of a baby’s spine is a complex process which lasts until a child becomes a teenager. Its initial stage begins in the baby’s first year of life and it consists in straightening or correct forming of the physiological curvatures: cervical lordosis, thoracic kyphosis, lumbar lordosis.

The spine of a newborn baby is in a stage of the complete kyphosis. It is a physiological curve resulting from a fetal position. The process of spinal straightening is evenly spread over time and adjusted to the natural developmental rhythm of a baby. Even if a baby can sit with the back straight or stand straight for a few minutes, during sleep the muscles relax and the back returns to its curved shape.

The first of the formed curvatures is cervical lordosis. The process of straightening of this part of spine begins between 4-8 week of life. At that time, a baby lying on the front begins to lift the head for about 3 seconds.

During the next three months, 7 cervical vertebrae go forward and upward. This process is finished when a baby can hold the head by him/herself (about 4 months old).

Thoracic kyphosis is formed as a second curvature. During this process, the next 12 vertebrae go backward and upward. This stage of spinal straightening falls on the time when a baby is learning how to sit. The span of this period is very individual; however, usually a 10 months old baby is able to sit with the back straight unaided.

Lumbar lordosis is the last stage of spinal straightening. 6 lumbar vertebrae straighten- they go forward and upward. This process is finished when a baby can stand up and takes the first steps. The spine is completely straightened, that is it takes on a typical for a human being S-shaped form, when a baby can walk unaided.

The human spine is kyphotic or C-curved in the womb and develops the cervical and lumbar lordoses in response to conforming to an upright posture against gravity. Perhaps, only the cervical spine would develop a lordosis in response to functional tasks. These are highly speculative scenarios considering that the musculoskeletal system develops and matures in response to defined biomechanical loading against gravity.

Reference:

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La Grone MO. Loss of lumbar lordosis. A complication of spinal fusion for scoliosis. Orthop Clin North Am. 1988 Apr;19(2):383-93.

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Ella Been, Leonid Kalichman, Lumbar lordosis, The Spine Journal, Volume 14, Issue 1, 1 January 2014, Pages 87-97, ISSN 1529-9430, http://dx.doi.org/10.1016/j.spinee.2013.07.464.

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Nationwide Children’s Hospital, Website:http://www.nationwidechildrens.org/lordosis

Risk of Intervertebral Disc Damage

During supine unloading on Earth, intervertebral disc pressure is lower compared to standing erect although IDP remains positive during all postures . The unloaded spine in horizontal supine posture may not entirely simulate spine unloading in microgravity conditions because spinal muscles may have more tone on Earth than in space. Thus, bed rest with 6 degrees headdown tilt (HDT) with spinal traction position is probably a better experimental model for simulating conditions that elicit back pain during early space flight .

Styf and associatesâ&#x20AC;&#x2122; results for six subjects exposed to simulated microgravity with balanced traction produced back pain and psychosomatic reactions similar to actual microgravity. Low back pain and lower abdominal pain as reported by subjects in HDT with balanced traction is similar in anatomic location to astronauts. The intensity of pain between these subjects is similar to that experienced by astronauts during spaceflight. Crewmembers report of maximum back pain from Day 1 to Day 6 of the mission and duration of pain correlates with mission duration while HDT test subjects typically report back pain for three days.

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The Russian space programme however, reports very low incidence of back pain with only three cosmonauts experiencing back pain in microgravity from 1975 to 1987. Lower incidence of back pain in the Russian space programme may be partly attributed to the penguin suit, a compression garment worn several hours per day while in microgravity.

Changes in intervertebral disc cross-sectional area with bed rest and space flight Overnight or longer bed rest causes expansion of the disc area, which reaches an equilibrium value of about 22% (range 10-40%) above baseline within 4 days. Increases in disc area were associated with modest increases in disc T2. During bed rest, disc height increased approximately 1 mm, about one-half of previous estimates based on body height measurements. After 5 weeks of bed rest, disc area returned to baseline within a few days of ambulation, whereas after 17 weeks, disc area remained above baseline 6 weeks after reambulation. After 8 days of weightlessness, T2, disc area, and lumbar length were not significantly different from baseline values 24 hours after landing.

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Risk of Intervertebral Disc Damage

Neurophysiology of the lumbar disc The sinuvertebral nerve [also known as the recurrent nerve or nerve of von Luschka] innervates the lumbar disc along its external surface and one third into the thickness of the annulus . The sinuvertebral nerve is a meningeal branch and also innervates the anterior dura, blood vessel walls, periosteum, and ligaments. This nerve is unmyelinated and mixed having sensory fibres for nociception and sympathetic motor fibres for the local blood vessels.

Terminal nerve endings of the sinuvertebral nerves contain nociceptive Type IV mechanoreceptors. Also known as free nerve endings, Type IV mechanoreceptors function as collagen deformity receptors present in the annulus of the intervertebral disc and the posterior longitudinal ligament (PLL). These nociceptive fibres have a high threshold for nerve impulse propagation and are facilitated by collagen fibre deformation beyond the normal physiological limit of approximately 3 - 4% length change. Aside fromstress beyond the plastic range of collagen deformation, other factors that can cause nociceptive nerve impulse propagation include an acidic environment with reduction of pH, inflammatory exudates, and changes in barometric pressure in cases of chronic inflammatory and lumbar degenerative joint disease.

Some key mediators of synaptic transmission for pain perception include bradykinin, serotonin, histamine, potassium, adenosine, protons, prostaglandins, leukotriences, and cytokines . It is the Type IV mechanoreceptors or free nerve endings surrounding the discs that give rise to the subjective perception of discomfort and pain. Pain from tissue damage can also lead to muscle spasm and adaptation in activation patterns in attempts to stabilise spinal segments and reduce noxious tissue stress . This can lead to muscle pain from contraction hyperactivity.

There are three other types of receptors found in collagen namely: (a) Type I (Rufinni corpuscles), (b) Type II (Pacinian corpuscles), and (c) Type III (Golgi Tendon Organ) mechanoreceptors. Collagen mechanoreceptors provide spatial orientation with facilitation through normal physiological collagen deformation when the spine moves with muscle contraction. Proprioception or joint position sense is brought about by activation of Types I and II mechanoreceptors in the ligaments and joint capsules as well as the muscle spindles .

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With active movement, these spatial position receptors provide a neurological feedback mechanism that directly mediates vertebral segment position sensibility and muscular reflex stabilisation . The neurophysiological effect of normal activation of Types I and II mechanoreceptors is explained by an interneuron effect centrally in the spinal cord producing an inhibition at the spinal cord level to any form of nociception or pain perception (from Type IV mechanoreceptors) through locally-mediated opioids such as enkephalins.

Hence, physiological loading and spine movement may produce naturally-occurring opioids such as endorphins and enkephalins essential for nervous system homoeostasis and counteracting low back pain. Because of reduced amplitudes of spinal motion in microgravity, there may be reduced natural opioid production as well.

The adjacent vertebral bodies and cartilaginous endplates are innervated via the basivertebral nerve, which is a recurrent branch of the sinuvertebral nerve and enters the vertebral body via the posterior basivertebral foramen.

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The density of endplate innervation is comparable to that of the peripheral annulus, suggesting that the endplate is an important source of discogenic pain. Endplate nerves are prototypical pain fibres that demonstrate nociceptor markers such as the neurotransmitter substance P and high affinity nerve growth factor receptor trk-A. The clinical significance of vertebral innervation in back pain patients is reinforced by reports of pain amelioration after basivertebral nerve disruption during vertebroplasty as well as pain provocation studies on human subjects.

Possible mechanism of back pain in microgravity When the spine lengthens in microgravity, the nucleus pulposus increases its volume. When the disc expands, stretching of annular collagen may surpass the normal 3-4% physiological collagen expansion and stimulation of Type IV mechanoreceptors (free nerve endings). Nerve impulse propagation may continue via the sinuvertebral nerves causing low back pain. Nerve impulse conduction is slower in unmyelinated versus myelinated nerves producing pain characterised as slow, dull, achy, gnawing, scalding or burning sensation and which may also be classified as neuropathic pain.

During spaceflight, astronauts complain of pain localised to the lower back and the nature of the pain is described as "dull" pain without any intense or incapacitating nature.

The most likely pain generator for back pain during spaceflight is the intervertebral disc as opposed to vertebral bodies and their endplates because nuclear swelling subjects the annulus to supraphysiologic axial strain.

Collagen fibres have two types of viscoelastic properties: â&#x20AC;˘ The fluid phase gives rise to the viscoelastic response when collagen of the annuli deform with greater magnitude by the application of prolonged but low grade physical stress. â&#x20AC;˘ The solid phase is the collagen response by disc stiffening with less annular deformation by the application of high intensity and short duration stress .

Fluid accumulation during spaceflight is slow and prolonged and thus causes more annular deformity by fluid phase viscoelastic property. This is evidenced by a longer spine length in microgravity coupled with likely disc expansion.

It is proposed that tensioning of intrathecal ligaments and nerve roots is a possible source of low back pain experienced by astronauts during spaceflight. It is unclear however, if intrathecal ligaments are innervated at all with nociceptive free-nerve endings that cause the magnitude and quality of low back pain reported by astronauts.

Biomechanically, sagittal flexion of the spine in knee to chest position separates and increases distance between the spinous processes. This functional motion of the vertebral segments will potentially stretch and deform these ligaments that tether the spinal cord to the posterior spinal arch. Because relief of back pain is by spine flexion, invoking these ligaments as pain generators is less likely to be a primary cause of back pain during spaceflight.

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E FFECT OF HIGH - HEELED SHOES

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Some women complain that the wearing of highheeled shoes causes them to have low back pain. Many doctors and therapists seem to think that the source of the pain is that the high-heeled shoes cause an increase of the lordotic curve of the lumbar spine and that the increased lumbar lordosis is the cause of the pain.

Most studies of the relationship of high-heeled shoes and lumbar lordosis have found either a decrease of the lumbar curve or no significant effect.

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Reference:

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Russell BS. The effect of high-heeled shoes on lumbar lordosis: a narrative review and discussion of the disconnect between Internet content and peer-reviewed literature. J Chiropr Med. 2010 Dec;9(4):166-73.

Risk of Intervertebral Disc Damage

Fetal Tuck Position

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It is reported by astronauts that a "fetal tuck position" described as knees to chest position relieves back pain. It is possible that the pathogenesis of back pain in microgravity is discogenic (or mechanical) associated with reduction of gravitational compressive loads in space .

The pain mechanism appears somatic (referred via sinuvertebral nerve impulse propagation) due to excessive expansion and annular deformation of the lumbar intervertebral discs (IVDs). The fetal tuck position may increase IVD hydrostatic pressure by flexion and transfer spinal compressive forces towards the anterior IVD, subsequently reducing IVD volume.

Pain relief with the fetal tuck position may be due to : â&#x20AC;˘ Reduced IVD volume, reduce annular deformation, and nerve impulse propagation of the sinuvertebral nerves via Type IV mechanoreceptor inhibition . â&#x20AC;˘ Elongated posterior soft tissues (apophyseal joint capsules and ligaments) which potentially stimulate Type I and II mechanoreceptors thus, neutralizing substance P in the spinal cord dorsal horn by increasing naturally occurring opioids such as enkephalins.

Effects of Simulated Microgravity on Intervertebral Disc Degeneration Intervertebral disc (IVD) degeneration is a major cause of low back pain. The development of disc degeneration is a complex process and has a number of poorly understood determinants that involves both environmental and genetic contributions . The degenerative process begins in the nucleus pulposus with loss of cellularity and proteoglycan breakdown leading to diminished water-binding capacity . IVD function is chiefly dependent upon the dynamic balance between matrix synthesis and catabolism. Once this balance is disturbed, the altered matrix composition and organization are unable to bear even physiologic loads, thus resulting in disc degeneration.

Meanwhile,the well organized lamellar architecture of the annulus fibrosus begins to deteriorate, and eventually internal fissures develop which spread around the periphery of the annulus. Whether the astronautâ&#x20AC;&#x2122;s low back pain is caused by a disturbed balance between IVD matrix synthesis and breakdown, and how the process is initiated are unknown.

NASA at the Johnson Space Center has developed a commercially available Rotatory Cell Culture System (RCCS TM ) with which to perform simulated microgravity in ground-based experiments. It has been used previously with numerous cell culture systems to simulate the effects of a microgravity environment . It is equipped with High Aspect Ratio Vessels (HARVs; Synthecon, Inc., Houston, TX). During simulated microgravity, the vessel wall and medium containing cells with carrier rotate at the same speed, producing a vector-averaged gravity comparable with that of near-earth free-fall orbit.

Using this system, authors demonstrate in the current study that microgravity induces disc degeneration by altering extracellular matrix components and stimulating apoptosis within the nucleus pulposus. This disc degeneration organ culture model also provides a foundation with which to test potential therapeutic targets for preventing and treating back pain during or after spaceflight.

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Lumbar disc tissues were separated from 24 10-week Balb/C mice. The animals were euthanized with CO2 . The University of Virginia Animal Care and Handle protocol was followed with all animal procedures. In brief, lumbar IVDs including the superior and inferior endplates, annulus fibrosus, and nucleus pulposus were dissected and cleaned from connective tissues under aseptic conditions. The discs were cultured in DMEM media supplemented with 2% penicillin/streptomycin .

After incubation with antibiotic, discs were transferred to 50 ml high aspect ratio vessels and either maintained statically as controls or rotated at 36 rpm in rotating bioreactors. DMEM/F-12 media with 20% fetal bovine serum (Invitrogen), 1% penicillin/streptomycin, insulin transferrin - selenium (10Âľg/ml insulin, 5.5 Âľ g/ml transferrin, and 0.5 ng/ml sodium selenium) (Sigma), and 1% ascorbate at 37 â&#x2014;Ś C was used for culture and media was changed every 3 days. Discs were harvested at varying time points.

Results Microgravity induced disc degeneration To simulate the space environment, the IVDs were maintained in organ culture either in a rotating or static bioreactor. Discs were harvested at 10, 20, and 30 days, and subjected to Safranin-O staining (proteoglycan in red). As shown in Fig. 2, compared with in static culture, the disc tissues of the rotating culture showed markedly decreased red staining in the annulus fibrosus region. These changes were observed in both horizontal (Fig. 2A) and vertical (Fig. 2B) disc sections and were shown as early as 10 days becoming worse with prolonged culture time up to 30 days. In contrast, in static conditions, the Safranin-O signal decreased slightly over time, but disc structure was unaffected.

These results suggest that simulated microgravity was one of contributing factors for disc degeneration and correlate greater degeneration with longer duration of exposure to the simulated microgravity.

Proteoglycan was decreased in discs in microgravity condition A major feature of disc degeneration is the progressive reduction in proteoglycan expression. To further confirm the changes of disc degeneration seen in the histology study, biochemical assays were performed. Amino sugars and Hypro, as indicators of GAG and collagen, respectively, were measured in the cultured discs.

As indicated in Fig. 3, when compared with static culture, rotating conditions demonstrated significantly decreased GAG content within the IVDs. This decrease was evident as early as 2 weeks and progressively decreased at 4, 6 and 8 weeks to 80%, 70%, 40% and approximately 30%, respectively, of that seen in corresponding static culture.

However, similar levels of Hypro were maintained in both static and rotating conditions. The DNA content (as a reflection of overall cell number) was significantly decreased in the rotating bioreactor group compared with static culture group (Fig. 3). In addition, the ratio of GAG to Hypro was found to progressively decrease in rotating conditions.

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Microgravity increased MMP3 expression but not collagen II in discs Studies have shown that the expression of matrix metalloproteinases (MMPs) increases in the degenerated disc, and elevated MMPs correlate with progressive disc degeneration.

Authors measured the expression of MMP3 in the discs in simulated microgravity conditions using immunofluorescence.

As shown in Fig. 4, the expression of MMP3 was significantly increased in both annulus fibrosus and nucleus pulposus areas of discs cultured in the rotating bioreactor at 30 days compared to that in static condition (p<0.05).

Bar graph showed the quantitation of the MMP-3 fluorescence (Green) intensity. In contrast, the expression of type II collagen did not change between rotating and static conditions up to the 30 day time point (Fig. 5). This data is consistent with the biochemical assay (Fig. 3) and SafraninO staining (Fig. 2), which showed decreased GAG content and stable Hypro content, and less red staining, respectively, in the discs cultured in the rotating bioreactor.

Microgravity induced apoptosis in IVDs The above results suggested that disc degeneration occurred in microgravity conditions. We further tested the hypothesis that this degeneration was induced by the apoptotic pathway. To address this question, the in situ cell deaths were measured with the TUNEL assay.

As shown in Fig. 6, more cells underwent apoptosis (green color) in rotating conditions at 30 days than in static conditions (p<0.05). The nucleus staining was shown in red color. Bar graph shows the quantitation of the apoptotic fluorescence intensity. In addition, the number of apoptotic cells increased as the culture time increased (data not shown) in rotating condition. These results suggest that apoptosis plays a role in microgravity induced disc degeneration.

Numerous groups have reported different animal models for investigation of disc degeneration. Although in vivo models are possible to a certain extent, understanding the effect of complex environment would be feasible to a greater extent in ex vivo using a whole organ system. Therefore, several intervertebral disc organ culture models have been established in recent years . The large animals have a similar disc structure to humans, but are limited by the long duration and high cost.

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In addition, the insufficient nutrient supply caused cell deaths. Discs cultured with intact endplates preserved their integrity and shape, but most of the cells were dead after 10 days in culture, To overcome the cell death, a bioreactor has been used to investigate the effects of limiting nutrition to the intervertebral discs under highfrequency loading, and found cells survived for a period of 21 days.

The extracellular matrix of the IVD is composed largely of proteoglycan and includes a high concentration of water. Proteoglycan plays an important role as a shock absorber within the IVD providing protection against various stresses.

The proportion of the extracellular matrix changes across the disc with the nucleus containing a higher concentration of aggrecan and a lower level of type II collagen than the annulus fibrosus .

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Risk of Intervertebral Disc Damage

With aging, the proportions of aggrecan and water in the nucleus decreased markedly, while the proportion of collagen rises; a similar change is seen in degenerate discs. The degenerative process starts with cellular loss, proteoglycan breakdown, and decreased proteoglycan/collagen ratio, leading to diminished water-binding capacity and disc dehydration.

In simulated microgravity condition, the cultured discs also undergo disc degeneration as observed by progressively decreased red color in Safranin-O staining and reduced GAG/Hypro ratio (Fig. 2 and 3). The collagen II contents did not significantly change in the rotating conditions compared with the static ones. (Fig. 5).

These data are consistent with previous findings which characterize intervertebral disc degeneration by progressive loss of proteoglycan and decreased proteoglycan/collagen ratio in rat IVD after a 12.5 days in space flight .

In another disc degeneration model: the needle puncture model, authors and others have also found that the GAG contents were significantly decreased while no appreciable collagen changes have been observed.

The reason for the unchanged level of collagen may due to that the current method was unable to detect the damaged collagen. Collagenase cleaves collagen molecules at a single site within their triple helical region, but because of the extensive cross-linking within the collagen fibrils, proteolysis does not necessarily result in collagen loss. Instead, the damaged collagen molecules persist in the fibril structure. Such damage increases with disc degeneration and becomes more extensive from the outer annulus fibrosus to the nucleus pulposus .

The accumulation of such damaged collagen is a reflection of the very slow turnover of the collagen fibrils and would be expected to eventually weaken the mechanical strength of the tissue and ultimately result in tissue loss, as occurs in the later stages of disc degeneration. All of this knowledge suggests that the amount and balance of extracellular matrix exhibit in a temporal and spatial manner. The change of GAG/Hypro may better represent the pathology of disc degeneration.

Using an in vitro simulated microgravity model, we have characterized the deleterious effects of microgravity on the mouse intervertebral disc. This model may be used for the development and testing of future therapeutic strategies of human disc degeneration. Additional studies are needed to determine the mechanisms by which microgravity induces disc degeneration, and what genes may compensate for the disease.

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E FFECTS OF M ICROGRAVITY ON SEATED HEIGHT (S PINAL E LONGATION )

Astronauts Rick Linnehan and Mike Foreman try out a prototype display and control system inside an Orion spacecraft mockup at Johnson Space Center during the first ascent and abort simulations for the program. Credit: NASA Many physiological factors, such as spinal elongation, fluid shifts, bone atrophy, and muscle loss, occur during an exposure to a microgravity environment. Spinal elongation is just one of the factors that can also affect the safety and performance of a crewmember while in space. Spinal elongation occurs due to the lack of gravity/compression on the spinal column. This allows for the straightening of the natural spinal curve. There is a possible fluid shift in the inter-vertebral disks that may also result in changes in height. This study aims at collecting the overall change in seated height for crewmembers exposed to a microgravity environment.

During previous Programs, Apollo-Soyuz Test Project (ASTP) and Skylab, spinal elongation data was collected from a small number of subjects in a standing posture but were limited in scope. Data from these studies indicated a quick increase in stature during the first few days of weightlessness, after which stature growth reached a plateau resulting in up to a 3% increase of the original measurement. However, this data was collected only for crewmembers in standing posture and not in a seated posture. Seated height may have a different effect than standing height due to a change in posture as well as due to a compounded effect of wearing restraints and a potential compression of the gluteal area.

Seated height was deemed as a critical measurement in the design of the Constellation Program’s (CxP) Crew Exploration Vehicle (CEV), called Orion which is now the point-of-departure vehicle for the Multi-Purpose Crew Vehicle (MPCV) Program; therefore a better understanding of the effects of microgravity on seated height is necessary.

Potential changes in seated height that may not have impacted crew accommodation in previous Programs will have significant effects on crew accommodation due to the layout of seats in the Orion.

The current and existing configuration is such that the four crewmembers are stacked two by two with the commander and pilot seats on the top and the two remaining seats underneath, thereby limiting the amount of clearance for the crewmembers seated in the bottom seat. The inner mold line of these types of vehicles are fixed due to other design constraints; therefore, it is essential that all seats incorporate additional clearance to account for adequate spinal growth thereby ensuring that the crew can safely ingress the seat and be strapped in prior to its return to earth.

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If there is not enough clearance to account for spinal growth deltas between seats then there is the potential that crewmembers will not be able to comfortably and safely fit into their seats. The crewmember in the bottom stacked seat may even have negative clearance with the seat above him or her which could lead to potential ingress/egress issues or potentially injury of the crewmember during landing. These impacts are specific to these types of vehicles with stacked seat configuration.

Without proper knowledge of the amount of spinal elongation, or growth, which occurs due to microgravity and space flight, the design of future vehicle(s) or suits may cause injury, discomfort, and limit crew accommodation and crew complements.

The experiment primarily aimed to collect seated height data for subjects exposed to microgravity environments, and feed new information regarding the effect of elongation of the spine forward into the design of the Orion. The data collected during the experiment included, two seated height measurement and two digital pictures of seated height pre-, in-, and post-flight.

In addition to seated height, crewmembers had an optional task of collecting stature , standing height. Seated height data was obtained from 29 crewmembers that included 8 ISS increment crew (2 females and 6 males) and 21 Shuttle crew (1 female, 20 males), and whose mean age was 48 years (± 4 years). This study utilized the last six Shuttle flights, STS-128 to STS-134.

The results show that participating crewmembers experienced growth up to 6% in seated height and up to 3% in stature. Based on the worst case statistical analysis of the subject data, the recommended seated height growth of 6% will be provided to the designers as the necessary seated height adjustment.

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Young, K. S., and S. Rajulu. "The effects of microgravity on seated height (Spinal Elongation)." NASA Human Research Program Investigators’ Workshop; NASA: Houston, TX, USA. 2012.

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Spinal Elongation and its Effects on Seated Height in a Microgravity Environment (Spinal Elongation),NASA. Website: http://www.nasa.gov/mission_pages/station/research/experiments/701.html

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Risk of Intervertebral Disc Damage

Disc herniations in astronauts

A recent publication from the National Aeronautics and Space Administration (NASA) showed an increased risk of intervertebral disc (IVD) herniations in US astronauts (Fig. 1). 10.0 % (32 of a total of 321) of all US astronauts were diagnosed with IVD herniation after spaceflight compared to 3.5 % (34 of a total of 983) in the control, Earth-bound, population. The incidence was highest immediately upon returning to Earth, with 7 herniations occurring within 1 week of return to Earth (19 % of all postflight herniations) and 14 herniations in total occurring within the first year.

IVD herniations occurred in both the cervical and lumbar regions, with the incidence markedly increased at the cervical spine (21.4 times higher incidence rate than in the control population versus 2.8 times higher at the lumbar spine).

The most probable mechanism, at least for the lumbar spine, is swelling of the IVD in the unloaded condition during spaceflight. The overhydrated disc is then vulnerable to an IVD herniation, especially when the pressures on the lumbar spine are increased under flexion during or immediately after spaceflight. This mechanism is supported by mechanical experiments on cadaveric and animal spines which have shown that severe loading in combined bending and compression can cause apparently normal lumbar IVDs to herniate , and that herniation is more likely when the IVDs are fully hydrated.

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Risk of Intervertebral Disc Damage

Increased IVD swelling during spaceflight has not been shown directly. However, IVD swelling in spaceflight can be inferred from increases in spine length and body height during spaceflight and from IVD swelling observed in vivo following bed rest (Fig. 2) for a few hours, overnight , and for a number of weeks . At the end of overnight bed-rest, lumbar intradiscal pressure is increased.

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Flattening of the lumbar lordosis could explain increases in spinal length despite swelling of the IVD, but flattening of the lumbar lordosis has not been consistently found in bed rest studies. At the end of prolonged bed rest, decreases , no change , and increases of the lumbar lordosis have been seen.

This physical mechanism (Fig. 3) could explain why astronauts are at increased risk of herniation either during spaceflight, and/or after return to Earth. The time course of recovery of IVD size (Fig. 4) and hydration after actual or simulated spaceflight is not clear.

The only published work to date after spaceflight showed no significant differences in sagittal plane disc area and lumbar spine length of four astronauts measured 24 h after 8 days spaceflight . Diurnal studies suggest that reductions of IVD size upon rising are normally a rapid process (on the order of hours). However, data from spaceflight simulation (bed rest) have shown IVD volume and/or height to be still increased at followup compared to before bed rest 7 days, 5 months and even up to 2 years after prolonged bed rest.

In line with this, in vitro data suggest that an unloaded disc becomes hyper-swollen disc and may lose fluid relatively slowly when loading is resumed.

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For the cervical spine little data on possible herniation mechanisms are available. There are no published data from astronauts on changes in the cervical IVDs during spaceflight and while spinal length does increase during spaceflight , it is not clear which spinal region contributes to this lengthening. Data from studies on Earth show that some degree of cervical spine lengthening occurs with recumbency . There are a number of differences between cervical and lumbar discs: in composition , anatomy and biomechanical characteristics .

However, these data do not help us understand why the risk of IVD herniation is much more elevated at the cervical spine than at the lumbar spine in astronauts. Overall, a mechanism of increased cervical IVD injury risk due to increased IVD size and hydration may be possible, but there are no published data available to substantiate this hypothesis. Basic research on the cervical IVDs is needed.

Data from studies of neck pain suggest that the deep cervical extensors and deep cervical flexors may be important for protecting the spine, yet muscle groups such as these have not been examined in astronauts in any detail. In prolonged bed rest, hypertrophy of most of the cervical muscles was seen , but as argued, prolonged bed rest might not be a good model for the effects of spaceflight on the cervical spine region.

There are some ergonomic issues specific to astronauts that likely impact IVD injury risk (Figs. 5, 6). Apollo-era and Shuttle astronauts had a higher incidence of IVD injury than International Space Station (ISS) and Mir astronauts. Shuttle astronauts landed in a sitting-type position similar to landing in a commercial aeroplane.

Apollo astronauts landed in a more horizontal position: the reader should imagine sitting in a very large baby car seat whilst being positioned in a reclining position.

Mir and ISS astronauts coming down with the Soyuz vehicle also land in a more horizontal position in a moulded seat liner that is designed specifically for each crew member. In the US astronaut program, no spinal injuries are definitively known to have occurred during reentry, however.

Post-flight, ISS astronauts do not stand up and walk around or perform risky (flexion) activities like earlier Shuttle and Apollo astronauts did. ISS astronauts also spend much longer time in lying or reclining post-flight than Shuttle astronauts (Figs. 5, 6).

So, ergonomic factors likely play a very important role in lumbar IVD herniation risk. Specifically, loading the spine - as in walking, and performing risky movements such as spinal flexion activities when the IVDs are most vulnerable - will most probably increase the risk for IVD herniations.

The increased IVD herniation incidence in astronauts could result from cumulative IVD injury occurring prior to the spaceflights. Johnston et al. observed an increased risk of IVD herniation upon entering the astronaut program. This could potentially be due to pre-existing conditions or the training program itself.

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Since a number of astronauts had previously been fighter pilots, Johnston et al. evaluated whether this prior history may be a predictive factor for IVD herniation, but they did not find any significant relationship. Performing high-G manoeuvres , pilot ejection , and helicopter vibration present risk factors for injury to the neck.

Potentially, the resulting highcompressive forces on the spine could result in end plate fractures, then leading to adjacent IVD degeneration . Alternatively, the IVD injuries could have occurred whilst astronauts were still fighter pilots and that the injuries were only picked up as part of medical management once they entered the astronaut program.

However, the longitudinal data available and meta-analysis of cross-sectional data suggest that the majority of degenerative changes in the IVDs of fighter pilots are due to normal ageing and not the fighter pilot occupation per se.

Furthermore, the astronaut selection process might "select" people at higher risk of IVD problems. For example, in the Finnish Air Force, one of the selection criteria for fighter pilots is peak power on a cycling ergometry test.

Experience (unpublished observations; R. Sovelius) has been that applicants who are weightlifters or ice-hockey players typically perform better on these tests. Weightlifters typically show more degenerative IVD changes . It could be that persons selected for astronaut training, due to their previous sporting pursuits, are at risk for IVD problems.

Spaceflights may have an effect on IVD physiology and, in the long run, possibly also have an impact on the rate of IVD degeneration. This may thereby have an influence on medium to long-term IVD injury risk. Animal models investigating the IVD in spaceflight , hindlimb suspension and tail vertebra immobilisation have typically , but not always , found losses in glycosaminoglycan content.

However, the extent to which animal models can be used as a model of human IVD changes in spaceflight remains an open question. It is also unclear to what extent such changes in IVD composition occur in humans in unloading, and further if and how any such changes affect the herniation risk. In vitro work has shown that both glycosaminoglycan synthesis rates fall and production of proteases is able to degrade the IVD increases with the decrease in osmolarity arising from IVD swelling. Such changes in cellular activity could be responsible for the loss of glycosaminoglycans seen in fast-metabolising small animal IVDs. However, in the much larger and relatively acellular human IVDs, the half-life of the proteoglycan aggrecan, a major component of the IVD matrix and responsible for regulating IVD swelling pressure , is around 12 years for normal IVDs and 8 years for degenerate IVDs. Hence, spaceflight appears too short for such changes in cellular activity to influence human IVD composition noticeably, at least during the period when susceptibility to herniation is increased.

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Risk of Intervertebral Disc Damage

Vertebral body bone loss in spaceflights may influence the IVD. A loss of lumbar spine bone mineral density has been demonstrated in astronauts after a spaceflight. Clinically, it is observed that people with lower bone density have larger IVDs (Fig. 7). Presumably the lower bone strength permits the deformation of the vertebral end plate and expansion of the IVDs. Also, anchoring of annulus fibrosus fibres into the vertebrae may be less strong when bone mass is lost: a significant fraction of herniations occurs as a result of failure at the end plate junction . These factors may play a role in the injury risk of the IVD. Essentially nothing is known about the adaptation of the spinal ligamentous system to weightlessness. IVD swelling increases tension in the intervertebral ligaments, so that they may provide greater resistance to spinal flexion . Increased ligament tension would increase IVD compression, especially when the spine is flexed, and this could increase the risk of IVD herniations due to spaceflight. The role of the spinal ligaments in bending moments or in proprioceptive function may be disturbed after spaceflight, but data to support this are lacking.

What can we do to reduce the incidence of IVD herniations in astronauts?

• In general: avoid spinal flexion and compression activities. This includes care with daily tasks, such as when putting ones socks on, and also use of devices to assist in activities to avoid such positions.

• Spend more time in lying in the days after flight.

• Consider some kind of orthosis or taping for the lumbar spine, and for the cervical spine a neck collar.

• After flight: walking around gently, but otherwise further research is required on what kinds of exercise protocols are better for loading the disc when it is hyper-hydrated.

• The duration for which such "care with spinal flexion activities" protocols should be implemented should last for a few weeks. However, further work is needed to better define this time frame.

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The Role of Bone Morphogenetic Proteins 2, 7, and 14 in Approaches for Intervertebral Disk Restoration

Bone morphogenetic proteins (BMPs) are a group of cytokines in the transforming growth factor beta superfamily. Transforming growth factor beta originally was described as a group of substances that have the ability to produce exostosis formation, but it was later discovered to have a wide range of chondroinductive and osteoinductive actions during embryogenesis and later in life.

Recombinant BMPs were successfully introduced into clinical practice for augmentation of bone fusion in spinal and orthopedic surgeries; however, BMPs are now gaining attention from researchers for their role in intervertebral disk (IVD) pathology.

Recombinant human BMP-2, a component of INFUSE bone graft (Medtronic, Minneapolis, Minnesota, USA), was the first clinically available BMP drug. INFUSE bone grafts are used to enhance bone formation in lumbar fusion procedures, decreasing the rate of nonunions compared with autologous iliac crest bone grafts.

It is also approved by the U.S. Food and Drug Administration for several other bone fusion procedures. Initial studies for BMP-2 in the IVD showed regenerative potential in the nucleus pulposus, where BMP-2 resulted in a mitogenic effect and stimulated proteoglycan synthesis without ossification; additionally, studies in explanted rabbit IVDs showed that the presence of BMP-2 favorably increased expression of collagen II and aggrecans, while decreasing expression of catabolic matrix metalloproteinases in the anulus fibrosus.

However, BMP-2 also decreased glycosaminoglycan content and increased type I collagen production in the nucleus pulposus as well as initiating ossification of the anulus fibrosus.

Furthermore, exogenous application of BMP-2 can accelerate osteophyte formation, typically seen clinically in late-stage degenerative disk disease as a compensatory mechanism for spinal instability. Endogenous BMP-2 in the IVD increases with age and in mechanically induced models of disk degeneration.

Recombinant human BMP-7, also known as osteogenic protein-I, is currently marketed as OP-1 (Stryker Biotech, Hopkinton,Massachusetts, USA), an aid for posterior spinal fusion and long bone nonunion. Similar to BMP-2, 27

Risk of Intervertebral Disc Damage BMP-7 is widely used for spinal fusions and in other orthopaedic surgeries.

Although BMP drugs are used off-label in most cases, scientific evidence for their application in posterolateral or anterolateral spinal fusions is still insufficient for these indications.In cartilage and IVDs, BMP-7 has strong anabolic and anticatabolic roles in tissue homeostasis.

When injected into the IVDs of small animals, BMP-7 showed potent increases in proteoglycan production.

Recently Ren et al. showed that nucleus pulposus cells transfected with a BMP-7 adenovirus increase synthesis of type II collagen in vivo; however, bolus injection of recombinant human BMP-7 in a spontaneously degenerated canine IVD showed intradiscal ossification and no regenerative effects.

Furthermore, endogenous BMP-7 increases in the anulus fibrosus and nucleus pulposus with age. Further studies are required to explore BMP-7-induced anabolic activity, while avoiding undesirable ectopic ossification (Figure 1).

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BMP-14, also known as growth and differentiation factor 5 and cartilage-derived morphogenetic protein-I, activates the Smad pathway leading to activation of target genes, including COL2 A1 and ACAN, which encode for type II collagen and aggrecan, respectively. BMP-14 is thought to play an essential role in organization of articular cartilage, regulation of joint morphogenesis, degradation of cartilage, and fusion of joints in the dominant negative mutation. BMP-14 enhances production of beneficial components of IVD extracellular matrix (aggrecan, proteoglycans, and type II collagen), while decreasing matrix metalloproteinase expression. Endogenously, BMP-14 has consistent expression across degeneration levels.

BMP-14 has displayed osteoinductive properties only at very high concentrations compared with other BMPs. BMP-14 seems uniquely capable of promoting beneficial effects on IVD cells and extracellular matrix without inducing ectopic ossification.

The group of cholesterol-lowering drugs known as statins can upregulate BMP15 and can provide a rapid translational avenue for BMP therapies. A more recent study demonstrated that intradiscal injection of lovastatin can prevent IVD degeneration caused by diskography in rats.

Further studies are necessary to examine the modulation of BMP by statins in this regenerative pathway. Also, it is necessary to determine if statin-induced regeneration is beneficial enough to overcome the degeneration induced by the needle puncture necessary for intradiscal drug delivery.

The use of BMPs for IVD regeneration has not been evaluated in humans. There is still much work to be done to assess the safety of intradiscal delivery, dose, and duration before these proteins should be used to treat IVD pathology; however, in vitro and preclinical studies have shown some advantages of BMPs that encourage further work. Also, recent advances in whole-organ culture of ex vivo IVDs18 may expedite the translation of BMP therapies to the clinic.

BMPs are promising therapeutic targets for IVD regeneration. In vivo animal and human cell culture studies have demonstrated various methods to enhance BMP signaling cascades, inducing strong anabolic and antidegenerative responses; however, these are often accompanied by ectopic ossification. For BMPs to become clinically relevant for IVD pathology, the beneficial and harmful effects of BMPs need to be segregated.

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J.P.H.J. Rutges, R.A. Duit, J.A. Kummer, J.E.J. Bekkers, F.C. Oner, R.M. Castelein, W.J.A. Dhert, L.B. Creemers, A validated new histological classification for intervertebral disc degeneration, Osteoarthritis and Cartilage, Volume 21, Issue 12, December 2013, Pages 2039-2047.

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Thomas H. Marshburn, Chris A. Hadfield, Ashot E. Sargsyan, Kathleen Garcia, Douglas Ebert, Scott A. Dulchavsky, New Heights in Ultrasound: First Report of Spinal Ultrasound from the International Space Station, The Journal of Emergency Medicine, Volume 46, Issue 1, January 2014, Pages 61-70.

Ad Astra ! To The Stars! In Peace For All Mankind !

Mr. Rick R. Dobson, Jr. (Veteran U.S Navy)

International Space Agency(ISA) ( Non足Profit Organization ) P.O. Box 541053 Omaha, Nebraska 68154 United States