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To heal or not to heal? Multiscale modelling of angiogenesis during bone regeneration Aurélie Carlier Best Doctoral Thesis Award European Society of Biomechanics

Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

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Page 1: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

To heal or not to heal? Multiscale modelling of angiogenesis

during bone regeneration

Aurélie Carlier

Best Doctoral Thesis Award European Society of Biomechanics

Page 2: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

The world is full of accidents…

7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award 2

Page 3: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Fracture healing

7/07/2015 3 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 4: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Fracture healing

7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award 4

Page 5: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Fracture healing

7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award 5

Page 6: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Fracture healing

7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award 6

Page 7: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Fracture healing

7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award 7

Page 8: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Treatment strategies

• USA: 6 million fractures/year

o 5-10 % delayed healing or non-union

• mechanical problem

o external/internal fixation

• biological problem

o bone grafting • autologous

• allogeneic

• synthetic

o tissue engineering

7/07/2015 8 Aurélie Carlier – ESB Best Doctoral Thesis Award

[TE, Van

Blitterswijk

et al.]

Page 9: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Objectives

• computational modelling is a useful tool

o study the complex interplay between factors

o observe emergent behavior (multiscale models)

o propose and test possible biological mechanisms

o design and test experimental strategies

7/07/2015 9

Objective 1: development of a novel multiscale bioregulatory

model including a detailed description of angiogenesis

Objective 2: development of a novel multiscale bioregulatory

model including a detailed description of oxygen

Objective 3: application of the novel multiscale model to

cases of impaired bone regeneration

Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 10: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Bone regeneration model

7/07/2015 10 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 11: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Bone regeneration model

7/07/2015 11 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 12: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Bone regeneration model

7/07/2015 12 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 13: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Hypothesis

7/07/2015 13

• bone is a highly vascularised tissue

• due to vessel rupture oxygen tension will decrease

o from 14 to 1.6% (after 10 days, sheep tibia) [Epari et al., Bone, 2008]

→ need for revascularisation

(angiogenesis) to heal the fracture

→ influence of oxygen on fracture healing

[Duvall et al.,

JBMR, 2007]

[Macdonald et al.,

Med. Biol. Eng. Comput., 2013]

Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 14: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Bone regeneration model

7/07/2015 14 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 15: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

The influence of oxygen

7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award 15

• Each process has its specific oxygen ‘working range’

• These ‘working ranges’ must be based on experimental

evidence!

0.1 0.8 2 7 4 5 6.5 8 12 1.5

oxygen tension (%)

Page 16: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Bone regeneration model

7/07/2015 16 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 17: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Sprouting angiogenesis

7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award 17

quiescent vessel

VEGF

sprouting

Page 18: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Sprouting angiogenesis

7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award 18

VE

GF

blood vessel integrity ?

Page 19: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Sprouting angiogenesis

Aurélie Carlier – ESB Best Doctoral Thesis Award 7/07/2015

VEGFR-2 Notch1 VEGF Dll4

TIP STALK STALK

VE

GF

D

V’ N’

D

V’ N’

D

V’ N’

Dll4-Notch signaling !

19

Page 20: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Bone regeneration model

7/07/2015 20 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 21: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Blood flow

7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award 21

[Carmeliet et al., Nature, 2010]

Page 22: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Bone regeneration model

7/07/2015 22 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 23: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Numerical methods

7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award 23

• compute new position of each tip cell

o speed

o direction

• anastomosis?

• update the intracellular level of every EC

• sprouting?

• calculate continuous variables

• continue loop until endtime

Page 24: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Computational model results

VEGF O2 tension

7/07/2015 24

days post fracture

low high

Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 25: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Computational model results

bone active blood vessels

7/07/2015 25

days post fracture

low high

Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 26: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Tissue fractions

26 7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 27: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Average oxygen concentration

27 7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 28: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Dll4 over- and underexpression

28

Dll4 standard

Dll4 over-

expression

Dll4 under-

expression

VEGFR-2 levels

7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 29: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Preliminary conclusions

• first multiscale model of fracture healing

• rigorous summary of the state-of-the-art literature on the

influence of oxygen on fracture healing

• first step towards a full implementation of blood flow

• captures many aspects of

o tip cell selection

• salt and pepper pattern

• increased tip cell density due to loss of Dll4 and in high VEGF

o bone regeneration

• emergent behavior

• interaction: angiogenesis ↔ osteogenesis

7/07/2015 29 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 30: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Towards clinical applications

30

computational

model

large segmental

defects

NF-1

patients

bone graft

healing

Aurélie Carlier – ESB Best Doctoral Thesis Award 7/07/2015

Page 31: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Normal versus critical size

7/07/2015 31

bone formation

5 mm 0.5 mm

90 days 35 days

low high

Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 32: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Normal versus critical size

7/07/2015 32

active blood vessels

5 mm 0.5 mm

90 days 35 days

Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 33: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Muscle damage is important!

damaged muscle

7/07/2015 33

healthy muscle

active blood vessels

active blood vessels

bone

bone

low

high

Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 34: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Optimal timing of treatment

7/07/2015 34 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 35: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Towards clinical applications

35

computational

model

large segmental

defects

NF-1

patients

bone graft

healing

Aurélie Carlier – ESB Best Doctoral Thesis Award 7/07/2015

Page 36: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

NF1 patients

7/07/2015 36 Aurélie Carlier – ESB Best Doctoral Thesis Award

[Pannier et al., OTSR, 2011]

[Schindeler et al., Bone, 2008]

Page 37: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

NF1 model results

bone normal patients bone NF1 patients

7/07/2015 37

days post fracture

low high

Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 38: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

NF1 model results

blood vessels normal patients blood vessels NF1 patients

7/07/2015 38

days post fracture

Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 39: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

NF1 model results

fibrous tissue normal patients fibrous tissue NF1 patients

7/07/2015 39

days post fracture

low high

Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 40: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Preliminary conclusions

• powerful framework to investigate the non-linear oxygen

dependent dynamics

• oxygen model captures the fundamental mechanisms of

bone regeneration

o large bone defects

o bone graft healing

o NF1 patients

• important role of the host environment

7/07/2015 40 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 41: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Conclusions

• Establishment of a novel computational framework of

bone regeneration including:

o a multiscale description of sprouting angiogenesis,

including the Dll4-Notch signalling pathway

o a first implementation of blood flow

o an accurate description of the influence of oxygen on

the behaviour of skeletal cells

41 Aurélie Carlier – ESB Best Doctoral Thesis Award

[LEGENDO, KU Leuven]

7/07/2015

Page 42: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Conclusions

• Application to three cases of impaired healing:

• large segmental defects: • mechanism of action

• design of a treatment strategy

• bone graft healing: • accurate prediction of the experimentally observed bone formation

patterns

• bone healing in NF1 patients: • first model to capture the effect of a NF1 mutation on bone healing

• captures the different degrees of severity of impaired bone healing

42 Aurélie Carlier – ESB Best Doctoral Thesis Award 7/07/2015

Page 43: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Conclusions

7/07/2015 43 Aurélie Carlier – ESB Best Doctoral Thesis Award

Page 44: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Outlook

• extensive quantitative characterization of the bone

regeneration process

o influence of the host environment

44 Aurélie Carlier – ESB Best Doctoral Thesis Award 7/07/2015

Page 45: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

Outlook

45

[Carlier et al., WIREs Syst Biol, 2015]

Aurélie Carlier – ESB Best Doctoral Thesis Award 7/07/2015

Page 46: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

References • Carlier, A., Brems, H., Ashbourn, J.M.A., Nica, I., Legius, E., Geris, L. (2015)

Capturing the wide variety of impaired fracture healing phenotypes in NF1 patients with eight key factors: a computational study. under review

• Carlier, A., Geris, L., Lammens, J., Van Oosterwyck, H. (2015). Bringing computational models of bone regeneration to the clinic. WIREs Syst Biol Med, doi:10.1002/wsbm.1299

• Carlier, A., van Gastel, N., Geris, L., Carmeliet, G., Van Oosterwyck, H. (2014). Size does matter: an integrative in vivo-in silico approach for the treatment of critical size bone defects. PLoS Comput Biol, 10(11), e1003888

• Carlier, A., Geris, L., van Gastel, N., Carmeliet, G., Van Oosterwyck, H. (2014). Oxygen as a critical determinant of bone fracture healing – a multiscale model. J Theor Biol, 365, 247-264

• Carlier, A., Geris, L., Bentley, K., Carmeliet, G., Carmeliet, P., Van Oosterwyck, H. (2012). MOSAIC: A Multiscale Model of Osteogenesis and Sprouting Angiogenesis with Lateral Inhibition of Endothelial Cells. PLoS Comput Biol, 8(10), e1002724,

• Chai, Y.C., Carlier, A., Bolander, J., Roberts, S.J., Geris, L., Schrooten, J., Van Oosterwyck, H., Luyten, F.P. (2012). Current views on calcium phosphate osteogenicity and the translation into effective bone regeneration strategies. Acta Biomaterialia, 8(12), 3876-3887

• Carlier, A., Chai, Y., Moesen, M., Theys, T., Schrooten, J., Van Oosterwyck, H., Geris, L. (2011). Designing optimal calcium phosphate scaffold-cell combinations using an integrative model based approach. Acta Biomaterialia, 7, 3573-3585

46 Aurélie Carlier – ESB Best Doctoral Thesis Award 7/07/2015

Page 48: Multiscale modelling of angiogenesis during bone regeneration...Best Doctoral Thesis Award European Society of Biomechanics The world is full of accidents… 7/07/2015 Aurélie Carlier

48 7/07/2015 Aurélie Carlier – ESB Best Doctoral Thesis Award

Questions?