ERISTO: European Research In Space and Terrestrial Osteoporosis

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1 ERISTO: European Research In Space and Terrestrial Osteoporosis Part of the European Space Agency - Microgravity Application Program. The project is focused on the effects of mechanical stress on bone remodeling, space environment providing access to unique "stress free" experimental conditions. ERISTO links medical research and the search for prevention of diseases related to bone fragility with the unique benefit of space, which provides an accelerated model of bone loss. Laurence VICO, INSERM U1059, St-Etienne University Hospital, France 1

2 ERISTO group European Research In Space and Terrestrial Osteoporosis Univ. Edinburgh D. Jones Danish Technological Institute N.Theilgaard Taastrup, Industrial partners Scanco Medical, Switzerland Octane Orthobiologics, Canada Cytoscience SA, Switzerland Amgen Inc., USA Servier, France Katholieke Univ. H Van Lenthe Leuven ESA-ESTEC Noordwijk. ESRF Grenoble F Peyrin Univ. Bochum M. Hofmann Univ. Basel I. Martin Univ. St-Etienne L. Vico Univ. Genova R. Cancedda Univ. Bari M Grano 2

3 Two main achievements 1 Bone imaging 2 In vitro bone trabecular bone cortical bone 3

4 X-ray bone measurement techniques Method Dual energy x-ray absorptiometry (DXA) Quantitative computed tomography (QCT) Peripheral QCT (pqct) High-Resolution pqct (HR-pQCT) Nominal resolution (µm) Effective radiation dose (µsv) Acquisition time (min) Regions and parameters assessed <1 Spine, hip, forearm, calcaneus, whole body, areal BMD and BMC <1 Spine, hip, forearm v olbmd, FEA ,5 Tibia, radius BMD v ol, cortical structure Tibia and radius distal end, BMD v ol, cortical and trabecular structure, FEA DEXA pqct 500 µm HR-pCT 100 µm µct 10 µm 4

5 The XtremeCT is an in vivo system for measurements on human extremities on the radius and the tibia Tibia Radius Tibia segmentation exploded view (Scanco Medical) Density Parameters Cortical Density Trabecular Density Structural Parameters Cortical Thickness Trabecular Separation Trabecular Number Volume Fraction 5

6 AT Six-month of Spaceflight and 1 Year Follow-Up Reveal Differential Responses of Cortical and Trabecular Bone Dependent on Bone Localization and Starting Bone Status launch landing 6-month 12-month L-60 and/or L-30 R+1 R+90 R+180 R+360d. At each time-point, HR-pQCT [and blood draw for bone markers] MISSIONS: Increments 15, 16, 17 ( ), 21 (2009), 29 ( ), 31 (2012), 33,34 ( ) BASELINE CHARACTERISTICS, n=13 Age, years /- 4.5 (from 35 to 54) Body mass index, g/cm / Previous missions [n, crew] 0 [n=8]; 1 [n=3]; 3 [n=2] 6

7 Summary: new findings Distal Tibia 6-month post-flight, cortical bone recovers 12-month post-flight, trabecular bone is as low as after landing Distal Radius Cortical porosity increases and remains increased over 12-m post-flight Even if other parameters are unaltered at immediate return, a progressive fragility develops, becoming significant at 12-m Ultimate load is compromised at both sites 1 year after reentry 7

8 Conclusion HR-pQCT Discordant patterns between bone envelopes Post flight long-term assessment of bone mass/structure is mandatory to evaluate : when or whether bone is able to recover duration of time required on Earth between 2 space missions Understanding underlying bone cellular mechanisms Performing HR-pQCT measurements on more crewmembers to increase statistical power HR-pQCT ~ 300 publications in PubMed: Documents age- and sex-related differences Provides advance to our understanding of bone quality and strength, and the effects of treatments with the ultimate goal of reducing fractures. Is capable of discriminating fracture status independent of DXA. 8

9 Two main achievements 1 Bone imaging 2 In vitro bone 9

10 In vitro bone Osteoclast Osteoblast Osteocyte The models were aimed at better understanding bone loss at the cellular level to better achieve bone generation. develop 3D multicell models mimicking bone marrow environment provide a complete model of bone remodeling in a very well controlled environment Migration from 2D to 3D cultures is a challenge! 10

11 In vitro bone 11

12 In vitro 3D bone culture model with perfused and mechanically IN VITRO 3D BONE CULTURE MODEL WITH PERFUSED AND MECAHNICALLY STRESSED CERAMIC stressed SCAFFOLD ceramic scaffold Cell culture in bioreactor Scaffold seeding Ceramic scaffold manufacturing CaP chemical synthesis Bouet G et al., Tissue Eng Part B Rev

13 In vitro bone 20 N signal Frequency Amplitude Cycle number Osteoblasts Alkaline phosphatase Collagen 1 Hydroxyapatite cristals Fibronectin extracellular matrix Bouet G et al., Eur Cell Mater Scaffold 13

14 In vitro bone Phase CT, ESRF Grenoble, Fr Bouet et al., Eur Cell Mater Tortelli et al., Tissue Eng, Ruggiu et al., J Tissue Eng Regen Med Part A, D display of a scaffold before seeding with OB and OC and subsequent in v itro culture. (yellow=v olumes with decreased density; blue=scaffold v olumes representing matrix deposition) Ruggiu et al., J Tissue Eng Regen Med

15 In vitro bone The model developed within the framework of this project will be an important in vitro tool for: space research: study effects of low gravity on bone cellular metabolism ground research: standardized reference 4D model tissue engineering: optimising the design and performance of engineered bone grafts drug testing: apply different chemical and mechanical factors and control and characterize the evolution of the coculture. test new anti-osteoporotic drugs decrease the number of candidate drugs and reduce the needs for animal testing 15