modeling bone remodeling - the influence of microcracks
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Modeling Bone-Remodeling
21.04.2015 1UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de21.04.2015
Modeling Bone-Remodeling
The Influence of Microcracks
Tom Theile
Modeling Bone-Remodeling
21.04.2015 2UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de21.04.2015 2
Bone RemodelingIntroduction – The Bone Remodeling Process
The human skeleton serves many functions:
For all these functions, the remodeling-process plays an important role
Remodeling repairs damages and microdamages and lets the bone adapt to changing loads
~10% turnaround every year in adults (Heaney et al. 1978)
Pathologic changes may lead to osteoporosis and fractures
Mechanical functions Chemical functions Biological functions
• Carry loads
• Protect the body
• Allow movements
• Store calcium and iron
• Produce blood cells
• Release hormons
21.04.2015 UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de 3
Bone Remodeling – How is it done?Introduction – The Bone Remodeling Process
Osteoclasts resorp mineralized bone
Osteoblasts synthesize mineralized bone
Osteocytes are former osteoblasts, build into the mineralized matrix.
Osteocytes
Image-source: york.ac.uk
21.04.2015 UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de 4
Bone Remodeling – How is it done?Introduction – The Bone Remodeling Process
Osteoclasts resorp mineralized bone
Osteoblasts synthesize mineralized bone
Osteocytes are former osteoblasts, build into the mineralized matrix.
Osteocytes
Image-source: york.ac.uk
Modeling Bone-Remodeling
21.04.2015 5UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Osteocytes
Osteocytes form a network to exchange
nutrients and waste (Aarden et al. 1994)
This Network may also be used for
intercellular communication
Osteocytes secrete RANKL
Osteocytes initiate bone remodeling events
Osteocytes control the bone remodeling
process (Nakashima et al. 2011)
Modeling Bone-Remodeling
21.04.2015 6UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Microcracks
• Microcracks are tiny fractures
• Microcracks arise after many cycles of high (but not too
high) loads
• Accumulation and growth of microcracks leads to material
failure
• Bone remodeling repairs microcracks
• First evidence for higher remodeling rates at locations with
more microcracks (Mori et. al)
Modeling Bone-Remodeling
21.04.2015 7UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Microcracks – Our Objective
(afaik) no direct evidence, that osteocytes can really sense mechanical
or electrical fields
Our hypothesis:
• Osteocytes can (only) sense microcracks
• Local bone remodeling is only steered by microcracks
• Adaption to changing loads only by excessive repair of
microcracks
Our model
• We build a model, that tests this hypothesis quantitatively
Modeling Bone-Remodeling
21.04.2015 8UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Methods – Microcrack Simulation
Spatio-temporal, agent-based Monte Carlo simulation
Input:
• Micro-computer comography data of bone microstructure ( Fazzalari 2012)
• Parameters from the literature
• Remodeling volume fraction per year (usually 10% in adults)
• Remodeling volume per event
• New cracks per volume per year (hard to obtain)
Model
Output
• Number of microcracks per volume
• Mean length of microcracks
• Length of the biggest microcrack
Modeling Bone-Remodeling
21.04.2015 9UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Methods – Microcrack Simulation –The Model
Cracks• Add microcracks to the microstructure
Signals
• Send out signals at the positions of microcracks
• Spread signals by diffusion simulation
Remodel
• Find a remodel position
• Remove all microcracks and signals around theposition
1 time step
x 100 years
Modeling Bone-Remodeling
21.04.2015 10UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Mineralized bone (trabecula)
Marrow tissue
Modeling Bone-Remodeling
21.04.2015 11UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Cracks• Add microcracks to the microstructure
Modeling Bone-Remodeling
21.04.2015 12UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Signals
• Send out signals at the positions of microcracks
• Spread signals by diffusion simulation
Modeling Bone-Remodeling
21.04.2015 13UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Remodel• Find a remodel position
Modeling Bone-Remodeling
21.04.2015 14UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Remodel
• Remove all microcracks and signals around the remodel position
Modeling Bone-Remodeling
21.04.2015 15UNIVERSITÄT ROSTOCK | Institut für Informatik | Systems Biology and Bioinformatics Rostock | www.sbi.uni-rostock.de
Remodel
• Remove all microcracks and signals around the remodel position
Modeling Bone-Remodeling
21.04.2015 16UNIVERSITÄT ROSTOCK | Institut für Informatik | Systems Biology and Bioinformatics Rostock | www.sbi.uni-rostock.de
repeat
Modeling Bone-Remodeling
21.04.2015 17UNIVERSITÄT ROSTOCK | Institut für Informatik | Systems Biology and Bioinformatics Rostock | www.sbi.uni-rostock.de
Methods – Microcrack Simulation – Variants
With osteocytes and signal-steered remodeling
Remodeling events with higher probability near
microcracks
Without osteocytes and signal-steered remodeling
Random positions of remodeling events
• Two different versions of the simulation – to be able to compare the results
Modeling Bone-Remodeling
21.04.2015 18UNIVERSITÄT ROSTOCK | Institut für Informatik | Systems Biology and Bioinformatics Rostock | www.sbi.uni-rostock.de
Results
Modeling Bone-Remodeling
21.04.2015 19UNIVERSITÄT ROSTOCK | Institut für Informatik | Systems Biology and Bioinformatics Rostock | www.sbi.uni-rostock.de
Results
Modeling Bone-Remodeling
1
10
100
1000
10000
100000
0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4
crac
klen
gth
su
m in
mm
/mm
^3
remodeling volume fraction per year
mean cracklength over remodeling volume fraction
Random
Steered
21.04.2015 20UNIVERSITÄT ROSTOCK | Institut für Informatik | Systems Biology and Bioinformatics Rostock | www.sbi.uni-rostock.de
Results
~3 times more remodeling events are necessary to keep the bone on the same health without directed remodeling
Modeling Bone-Remodeling
1
1001
2001
3001
4001
5001
6001
0 0.05 0.1 0.15 0.2 0.25 0.3 0.35
mea
n m
axim
um
cra
ckle
ng
th in
m
m/m
m^
3
remodeling volume fraction per year
mean maximum cracklength over remodeling volume fraction
Random
Steered
21.04.2015 21UNIVERSITÄT ROSTOCK | Institut für Informatik | Systems Biology and Bioinformatics Rostock | www.sbi.uni-rostock.de
Results
The effect is even more extreme on the maximum crack-length ~6 times more efficient
Modeling Bone-Remodeling
21.04.2015 23UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Discussion 1
1
10
100
1000
10000
100000
0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4
remodeling volume fraction per year
mean cracklength over remodeling volume fraction
Random
Steered
Strange artifact in the steered simulation:
Especially good bone health at remodeling rates
of 10% per year!
Why?
• Random result?
• No. Simulation was repeated often
• Error in simulation?
• …probably not
• Negative influence of remodeling events on signal distribution – 10% rate may be an
optimum value?
10%/year is assumed as the actual turnover rate in adult humans – but that is probably a
coincidence
Needs further investigation
Modeling Bone-Remodeling
21.04.2015 24UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Discussion 2 & Conclusion
We showed: Guided bone remodeling is much more efficient than random bone remodeling!
Widely believed: The role of osteocytes is to guide the remodelling process. Our simulation shows why guidance is
needed.
It remains unclear wether osteocytes can sense mechanical strain
We showed: Microcrack-sensing is a sufficient mechanism to steer the remodeling locations
Modeling Bone-Remodeling
21.04.2015 25UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Outlook – What to do next
Combine with FE-Analysis
• Do osteocytes sense mechanical strain?
• Will the remodeling be even more efficient
compared to microcrack-sensing?
Modeling Bone-Remodeling
21.04.2015 26UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Outlook
• Investigate strange behaviour at 10% turnover rate
• Include variable parameters over lifetime
• Compare results to FE-coupled modell
• Include spatial remodeling into the model
• Compare spatial structure to experimental data
Modeling Bone-Remodeling
21.04.2015 27UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de
Thank you
for your attention and useful ideas!
Bibliography
Aarden, E.M., Nijweide, P.J. & Burger, E.H., 1994. Function of osteocytes in bone. Journal of
cellular biochemistry, 55(3), pp.287–299.
Heaney, R.P., Recker, R. & Saville, P., 1978. Menopausal changes in bone remodeling. The
Journal of laboratory and clinical medicine, 92(6), pp.964–970.
Lanyon, L., 1993. Osteocytes, strain detection, bone modeling and remodeling. Calcified tissue
international, 53(1), pp.S102–S107.
Nakashima, T. et al., 2011. Evidence for osteocyte regulation of bone homeostasis through
RANKL expression. Nature medicine, 17(10), pp.1231–1234.
Verborgt, O., Gibson, G.J. & Schaffler, M.B., 2000. Loss of osteocyte integrity in association with
microdamage and bone remodeling after fatigue in vivo. Journal of Bone and Mineral Research,
15(1), pp.60–67.
Nicola L. Fazzalari 2012, , Brianna L. Martin, Murk J. Bottema, Tammy M. Cleek, Arash Badiei. A
model for the change of cancellous bone volume and structure over time. Mathematical
Biosciences. 240 132–140
21.04.2015 UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de 28
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