Artificial Gravity Bed rest study

Human spaceflight is currently entering the next phase of space exploration,
namely towards the Moon and Mars. Linked to such ambitious goals are - by
nature * physical, psychological and technological challenges which become
increasingly difficult to understand and overcome with longer-duration
missions: future exploration class missions may last up to several years,
exposing astronauts to extreme environmental conditions and physical stressors
that could cause major issues to both health and performance. Currently, some
of these issues are considered as showstoppers for long-duration exploration
missions with human crews. To safeguard astronauts* health, well-being and
working efficiency, a comprehensive strategy to mitigate various risks is
therefore required, including development of so-called countermeasures to
reduce adverse responses to stressors stemming from exposure to the space
environment. Over the past 50 years of human spaceflight experience, a palette
of countermeasures has been developed and tested, but they have had only
limited success. This may be explained by the fact that currently applied
countermeasures mitigate harmful responses of specific systems of the human
body. Future countermeasures, therefore, have to be approached in an
interdisciplinary manner. Because all physiological systems are challenged
through the application of artificial gravity (AG) by centrifugation, it has
been considered that AG has the unique feature of being a multi-system
countermeasure for mitigating the effects of weightlessness. The primary
objective of the AGBRESA bed rest study is to compare the protective effects of
one single daily bout (30 min) versus multiple daily bouts of AG (6 x 5 min) on
physiological functions that are affected by simulated weightlessness. A
secondary objective is to document the user*s point of view, such as subjective
rating of comfort/discomfort, perceived exhaustion, perceived benefits, and any
other psychological issues associated with the AG protocols. The research in
this bed rest study is proposed and will be performed by international
established research teams and characterizes changes in physiological and
psychological systems; systems of interest include, but are not limited to
musculoskeletal, sensorimotor, cardiovascular, cerebrovascular, ocular,
functional performance, cognition and behavioral health.

The primary objective for the measurements in the VieCuri in Venlo is to
measure the structure and bone density of the hip and lower leg and forearm;
for technical reasons, these measurements can not take place in Cologne:
3 (three) CT measurements (QCT) of the hip: 1 x before bed rest, 1 x after bed
rest and 1x 1 year after end of the bed rest
4 (four) HR-pQCT measurements of the Tibia and Radius: 1 x befor bed rest, 1x
after bed rest and 1, and 2 years after the end of the bed rest

Quantitative computed tomography (QCT) is a medical technique that measures
bone mineral density (BMD) using a standard X-ray Computed Tomography (CT)
scanner with a calibration standard to convert Hounsfield Units (HU) of the CT
image to bone mineral density values. QCT differs from DEXA in that QCT is a
truly 3D bone density exam; meaning QCT can measure the metabolically-active
trabecular interior bone separately from the dense cortical bone. Since
trabecular bone is affected earlier and to a greater degree than cortical bone,
QCT is able to detect changes in bone mass earlier in the proximal hip than
other bone mineral density exams. In the AGBRESA study, QCT scans are used to
evaluate bone mineral density of the proximal Femur.

The objective of the HR-pQCT measuzrements is to assess the efficacy of the AG
training to counteract the deterioration of trabecular and cortical
microstructure. DXA namely does not provide information about the bone
microstructure, which is an important determining factor for bone strength.
Recent developments in the field of imaging enable the evaluation of the bone
microstructure in vivo using high resolution peripheral quantitative computed
tomography (HR-pQCT). From this data, new image processing techniques can be
used to better characterize bone quality and strength.Measurement of dominant
forearm and lower left leg will be performed using the standard positioning
casts.

General research design
The bed rest study will be conducted in the: envihab facility of the Institute
of Aerospace Medicine at the German Aerospace Center, Cologne, Germany.
Nominally, each test person will stay in the Institute of Aerospace Medicine
for a total of 88 days, of which 60 days are continuously spend in bed. Prior
to and following bed rest, the subjects undergo a 14-day baseline data
collection phase and a 14-day in-house recovery phase in (14 + 60 + 14 = 88
days) respectively. In addition, 4 follow-up examinations are planned (28, 90,
360 and 720 days after the end of the bed rest).

During the study, the test subjects will bring a total of four visits to the
Vieçurie for the following bone Mineral density measurements:

during visits 1, 2 and 3 QCT measurements of the hip and HR-pQCT measurements
of the Tibia and Radius are performed

visit 1 --> 11 days before the start of bed rest
visit 2 --> 8 days after the end of the bed rest
visit 3 --> 360 days after the end of the bed rest

During visit 4, only HR-pQCT measurements of the Tibia and Radius are performed

visit 4 --> 720 days after the end of the bed rest

Prior to the bed rest phase, subjects will be randomly assigned to one of three
experimental groups (n=8 in each group).

* Group 1: 6° HDBR with no centrifugation (passive control).
* Group 2: 6° HDBR with supine centrifugation at +1Gz at the center of mass
for 30 minutes continuous per day.
* Group 3: 6° HDBR with supine centrifugation at +1Gz at the center of mass
for 6 bouts of 5 minutes per day (sessions 2-6 are separated by 5 minutes of
rest).

All subjects will be exposed to centrifugation at a reduced Gz level and
duration during the baseline phase to re-familiarize the subjects with the
centrifugation profile(s) in the study setting. Subjects already underwent the
centrifugation tolerance testing during the recruitment process.

With respect to the risks associated with the QCT and HR-pQCT measurement at
the VieCuri; irradiation involves all dangers known from the interaction of
ionizing radiation with tissue. When the radiation penetrates the human body
during an X-ray examination, some of the radiation is absorbed in the tissue
and can lead to biological changes in the cells due to chance. Depending on
intensity and duration of exposure to this radiation, metabolic disturbances
can be caused by changes in biologically important molecules (enzymes,
proteins, genetic material). Radiation exposure, thus, can in principle lead to
damage to the genome, as well as to the development of tumors. The probability
of occurrence of damage is proportional to the dose level. However, there is no
threshold of the dose for the occurrence of damage, i.e. the severity of
possible damage is independent of the dose. The body is, however, capable on
its own of rectifying this kind of damage to a certain degree with suitable
repair mechanisms. The danger of resulting damage depends not only on the
length and intensity of irradiation but also on the sensitivity to radiation of
the exposed material. Bone exhibits a lower sensitivity to radiation compared
with the stomach, lungs, colon or thyroid gland.

The cumulative radiation load for the measurements at the VieCuri is 4.32 mSv.
The total natural exposure to radiation in Germany, or the annual effective
dose to the public, is on average 2.1 millisievert. However, depending on the
place of residence, diet and lifestyle habits, it can range from 1 millisievert
to 10 millisieverts. The risk for the subject is therefore limited to
stochastic radiation effects, in which the causation of a radiation-induced
cancer plays the predominant role. Deterministic radiation effects can be
excluded with a radiation load <100 mSv. The "official" life-long risk of
radiation induction of fatal cancer was set at 5% / Sv by the International
Commission for Radiological Protection (ICRP) (1991).

We would like to refer to the complete research protocol for an overview of all
risks associated with the planned study, however, at this point it is worth
mentioning, that there is no increased fracture risk due to changes in bone
strength (not in the Radius and not in the Tibia) as a consequence of the 60
days of bed rest, since only bone-healthy subjects are included. A loss of up
to 20% of the bone in a healthy person has no consequences in practice. In the
study, maximum losses of up to 8% are expected in the Tibia.

In conclusion, the AGBRESA study is an international collaboration of three
main space Agencies and many institutions world-wide and, to our knowledge, the
first study to investigate long-term bed rest with artificial gravity (AG) as a
countermeasure. In contrast to other countermeasures tested in the past, AG
generated by centrifugation has the potential to alleviate all physiological
deconditioning caused by prolonged exposure to weightlessness. Because all
physiological systems are challenged through the application of AG, AG has
indeed the unique feature of being a multi-system countermeasure for mitigating
the effects of weightlessness. To test this hypothesis, this bed rest study is
performed under the most rigorous standardized conditions known in the field.
Bed rest immobilization has similar effects to a period of weightlessness, and
is, in this context, used as a strictly standardized spaceflight analogue. Many
of the implemented scientific methodologies are selected through peer-reviewed
processes and involve a broad suite of both gold-standard and innovative
monitoring technologies to provide a comprehensive understanding of the
etiology of the physiological changes seen with spaceflight. In accordance with
our science policy, the AGBRESA study (like the previous VaPER study) aims at
including 50 percent female volunteers. Maintenance of musculoskeletal strength
and function, cardiovascular integrity, but also eye sight, sleep quality and
cognitive skills are all vital for astronaut safety and wellbeing and
successful future long-duration spaceflight missions on board the international
space station ISS, to the Moon and eventually to Mars. In our opinion, the
scientific knowledge to be gained by this study justifies the extensive
measures and risks as described in detail in our reseactrh protocol.