One way to restore physiological blood flow to occluded arteries involves the deformation of plaque using an intravascular balloon and preventing elastic recoil using a stent. Angioplasty and stent implantation cause unphysiological loading of the arterial tissue, which may lead to tissue in-growth and reblockage; termed “restenosis.” In this paper, a computational methodology for predicting the time-course of restenosis is presented. Stress-induced damage, computed using a remaining life approach, stimulates inflammation (production of matrix degrading factors and growth stimuli). This, in turn, induces a change in smooth muscle cell phenotype from contractile (as exists in the quiescent tissue) to synthetic (as exists in the growing tissue). In this paper, smooth muscle cell activity (migration, proliferation, and differentiation) is simulated in a lattice using a stochastic approach to model individual cell activity. The inflammation equations are examined under simplified loading cases. The mechanobiological parameters of the model were estimated by calibrating the model response to the results of a balloon angioplasty study in humans. The simulation method was then used to simulate restenosis in a two dimensional model of a stented artery. Cell activity predictions were similar to those observed during neointimal hyperplasia, culminating in the growth of restenosis. Similar to experiment, the amount of neointima produced increased with the degree of expansion of the stent, and this relationship was found to be highly dependant on the prescribed inflammatory response. It was found that the duration of inflammation affected the amount of restenosis produced, and that this effect was most pronounced with large stent expansions. In conclusion, the paper shows that the arterial tissue response to mechanical stimulation can be predicted using a stochastic cell modeling approach, and that the simulation captures features of restenosis development observed with real stents. The modeling approach is proposed for application in three dimensional models of cardiovascular stenting procedures.

References

References
1.
Hoffmann
,
R.
,
Jansen
,
C.
,
Konig
,
A.
,
Haager
,
P. K.
,
Kerckhoff
,
G.
,
Vom Dahl
,
J.
,
Klauss
,
V.
,
Hanrath
,
P.
, and
Mudra
,
H.
, 2001, “
Stent Design Related Neointimal Tissue Proliferation in Human Coronary Arteries—An Intravascular Ultrasound Study
,”
Eur. Heart J.
,
22
, pp.
2007
2014
.
2.
Hoffmann
,
R.
,
Mintz
,
G. S.
,
Haager
,
P. K.
,
Bozoglu
,
T.
,
Grube
,
E.
,
Gross
,
M.
,
Beythien
,
C.
,
Mudra
,
H.
,
vom Dahl
,
J.
, and
Hanrath
,
P.
, 2002, “
Relation of Stent Design and Stent Surface Material to Subsequent In-Stent Intimal Hyperplasia in Coronary Arteries Determined by Intravascular Ultrasound
,”
Am. J. Cardiol.
,
89
, pp.
1360
1364
.
3.
Morton
,
A. C.
,
Crossman
,
D.
, and
Gunn
,
J.
, 2004, “
The Influence of Physical Stent Parameters Upon Restenosis
,”
Pathol. Biol.
,
52
, pp.
196
205
.
4.
Bennett
,
M. R.
, and
O’Sullivan
,
M.
, 2001, “
Mechanisms of Angioplasty and Stent Restenosis: Implications for Design of Rational Therapy
,”
Pharmacol. Ther.
,
91
, pp.
149
166
.
5.
Lally
,
C.
,
Kelly
,
D. J.
, and
Prendergast
,
P. J.
, 2006,
“Stents,”
In
Encyclopedia of Biomedical Engineering
,
Wiley
, pp.
3345
3355
.
6.
Gunn
,
J.
,
Arnold
,
N.
,
Chan
,
K. H.
,
Shepherd
,
L.
,
Cumberland
,
D. C.
, and
Crossman
,
D. C.
, 2002, “
Coronary Artery Stretch Versus Deep Injury in The Development of In-Stent Neointima
,”
Heart
,
88
, pp.
401
405
.
7.
Kornowski
,
R.
,
Hong
,
M. K.
,
Tio
,
F. O.
,
Bramwell
,
O.
,
Wu
,
H.
, and
Leon
,
M. B.
, 1998, “
In-stent Restenosis: Contributions of Inflammatory Responses and Arterial Injury to Neointimal Hyperplasia
,”
J. Am. Coll Cardiol.
,
31
, pp.
224
230
.
8.
Scott
,
N. A.
, 2006. “
Restenosis Following Implantation of Bare Metal Coronary Stents: Pathophysiology and Pathways Involved in the Vascular Response to Injury
,”
Adv. Drug Delivery Rev.
,
58
, pp.
358
376
.
9.
Welt
,
F. G.
, and
Rogers
,
C.
, 2002, “
Inflammation and Restenosis in the Stent Era
,”
Arterioscler., Thromb., Vasc. Biol.
,
22
, pp.
1769
1776
.
10.
Thyberg
,
J.
,
Hedin
,
U.
,
Sjolund
,
M.
,
Palmberg
,
L.
, and
Bottger
,
B. A.
, 1990, “
Regulation of Differentiated Properties and Proliferation of Arterial Smooth Muscle Cells
,”
Arteriosclerosis (Dallas)
,
10
, pp.
966
990
.
11.
Thyberg
,
J.
,
Blomgren
,
K.
,
Roy
,
J.
,
Tran
,
P. K.
, and
Hedin
,
U.
, 1997, “
Phenotypic Modulation of Smooth Muscle Cells After Arterial Injury is Associated With Changes in the Distribution of Laminin and Fibronectin
,”
J. Histochem. Cytochem.
,
45
, pp.
837
846
.
12.
Zempo
,
N.
,
Koyama
,
N.
,
Kenagy
,
R. D.
,
Lea
,
H. J.
, and
Clowes
,
A. W.
, 1996, “
Regulation of Vascular Smooth Muscle Cell Migration And Proliferation in Vitro and in Injured Rat Arteries by a Synthetic Matrix Metallopro-Teinase Inhibitor
,”
Arterioscler., Thromb., Vasc. Biol
,
16
(
1
), pp.
28
33
.
13.
Holzapfel
,
G. A.
,
Sommer
,
G.
,
Gasser
,
C. T.
, and
Regitnig
,
P.
, 2005, “
Determination of Layer-Specific Mechanical Properties of Human Coronary Arteries With Nonatherosclerotic Intimal Thickening and Related Constitutive Modeling
,”
Am. J. Physiol. Heart Circ. Physiol.
,
289
, pp.
2048
2058
.
14.
De Beule
,
M.
,
Mortier
,
P.
,
Carlier
,
S. G.
,
Verhegghe
,
B.
,
Van Impe
,
R.
, and
Verdonck
,
P.
, 2008, “
Realistic Finite Element-Based Stent Design: The Impact Of Balloon Folding
,”
J. Biomech.
,
41
(
2
), pp.
383
389
.
15.
Gervaso
,
F.
,
Capelli
,
C.
,
Petrini
,
L.
,
Lattanzio
,
S.
,
Di Virgilio
,
L.
, and
Migliavacca
,
F.
, 2008, “
On the Effects of Different Strategies in Modelling Balloon-Expandable Stenting by Means of Finite Element Method
,”
J. Biomech.
,
41
, pp.
1206
1212
.
16.
Gijsen
,
F.
,
Migliavacca
,
F.
,
Schievano
,
S.
,
Socci
,
L.
,
Petrini
,
L.
,
Thury
,
A.
,
Wentzel
,
J.
,
van der Steen
,
A.
,
Serruys
,
P.
, and
Dubini
,
G.
, 2008, “
Simulation of Stent Deployment in a Realistic Human Coronary Artery
,”
Biomed. Eng. online
,
7
(
1
), pp.
23
23
.
17.
Holzapfel
,
G. A.
,
Stadler
,
M.
, and
Schulze-Bauer
,
C. A. J.
, 2002, “
A Layer-Specific Three-Dimentional Model for the Simulation of Balloon Angio-Plasty Using Magnetic Resonance Imaging And Mechanical Testing
,”
Ann. Biomed. Eng.
,
30
, pp.
753
767
.
18.
Prendergast
,
P. J.
,
Lally
,
C.
,
Daly
,
S.
,
Reid
,
A. J.
,
Lee
,
T. C.
,
Quinn
,
D.
, and
Dolan
,
F.
, 2003, “
Analysis of Prolapse in Cardiovascular Stents: A Constitutive Equation for Vascular Tissue and Finite Element Modelling
,”
Trans. ASME
,
125
, pp.
692
699
.
19.
Lally
,
C.
,
Dolan
,
F.
, and
Prendergast
,
P. J.
, 2005, “
Cardiovascular Stent Design and Vessel Stresses: A Finite Element Analysis
,”
J. Biomech.
,
38
, pp.
1574
1581
.
20.
Migliavacca
,
F.
,
Petrini
,
L.
,
Massarotti
,
P.
,
Schievano
,
S.
,
Auricchio
,
F.
, and
Dubini
,
G.
, 2004, “
Stainless and Shape Memory Alloy Coronary Stents: A Computational Study on the Interaction With the Vascular Wall
,”
Biomech. Model. Mechanobiol.
,
2
, pp.
205
217
.
21.
Bedoya
,
J.
,
Meyer
,
C. A.
,
Timmins
,
L. H.
,
Moreno
,
M. R.
, and
Moore
,
J. E.
, 2006, “
Effects of Stent Design Parameters on Normal Artery Wall Mechanics
,”
J. Biomech. Eng.
,
128
, pp.
757
765
.
22.
Timmins
,
L. H.
,
Moreno
,
M. R.
,
Meyer
,
C. A.
,
Criscione
,
J. C.
,
Rachev
,
A.
, and
Moore
,
J. E.
, 2007, “
Stented Artery Biomechanics and Device Design Optimization
,”
Med. Biol. Eng. Comput.
,
45
, pp.
505
513
.
23.
Early
,
M.
, and
Kelly
,
D. J.
, 2010, “
The role of Vessel Geometry and Material Properties on the Mechanics of Stenting in the Coronary and Peripheral Arteries
,”
Proc. Inst. Mech. Eng., Part H: J. Eng. Med.
,
224
(
H3
), pp.
465
476
.
24.
Evans
,
D. J.
,
Lawford
,
P. V.
,
Gunn
,
J.
,
Walker
,
D.
,
Hose
,
D. R.
,
Smallwood
,
R. H.
,
Chopard
,
B.
,
Krafczyk
,
M.
,
Bernsdorf
,
J.
, and
Hoekstra
,
A.
, 2008, “
The Application of Multiscale Modelling to the Process of Development and Prevention of Stenosis in a Stented Coronary Artery
,”
Philos Trans. A
,
366
, pp.
3343
3360
.
25.
Garcia
,
J.
,
Doblare
,
M.
, and
Cegonino
,
J.
, 2002, “
Bone Remodelling Simulation: A Tool for Implant Design
,”
Comput. Mater. Sci.
,
25
(
1-2
), pp.
100
114
.
26.
Prendergast
,
P. J.
, 2009,
“Papers in Biomechanics and Bioengineering,”
ScD thesis, University of Dublin, Dublin, Ireland.
27.
Lally
,
C.
, and
Prendergast
,
P. J.
, 2006,
“Simulation of In-Stent Restenosis for the Design of Cardiovascular Stents,”
in
Mechanics of Biological Tissue
,
G. A.
Holzapfel
and
R. W.
Ogden
, eds.,
Springer
,
Berlin, Heidelberg
, pp.
255
267
.
28.
Rachev
,
A.
,
Manoach
,
E.
,
Berry
,
J.
, and
Moore
, Jr.,
J. E.
, 2000, “
A Model of Stress-Induced Geometrical Remodelling of Vessel Segments Adjacent of Stents and Artery/Graft Anastomoses
,”
J. Theor. Biol.
,
206
, pp.
429
443
.
29.
Peréz
,
M. A.
, and
Prendergast
,
P. J.
, 2007, “
Random-Walk Models of Cell Dispersal Included in Mechanobiological Simulations of Tissue Differentiation
,”
J. Biomech.
,
40
, pp.
2244
2253
.
30.
Boyle
,
C. J.
,
Lennon
,
A. B.
,
Early
,
M.
,
Kelly
,
D. J.
,
Lally
,
C.
, and
Prendergast
,
P. J.
, 2010, “
Computational Simulation Methodologies for Mechanobiological Modelling: A Cell-Centred Approach to Neointima Development in Stents
,”
Philos. Trans. R. Soc. London
,
368
, pp.
2919
2935
.
31.
Merks
,
R. M. H.
, and
Glazier
,
J. A.
, 2005, “
A Cell-Centered Approach to Developmental Biology
,”
Physica A
,
352
, pp.
113
130
.
32.
Schwartz
,
R. S.
,
Chu
,
A.
,
Edwards
,
W. D.
,
Srivatsa
,
S. S.
,
Simari
,
R. D.
,
Isner
,
J. M.
, and
Holmes
,
D. R.
, 1996, “
A Proliferation Analysis of Arterial Neointimal Hyperplasia: Lessons for Antiproliferative Restenosis Therapies
,”
Int. J. Cardiol.
,
53
, pp.
71
80
.
33.
Cipollone
,
F.
,
Marini
,
M.
,
Fazia
,
M.
,
Pini
,
B.
,
Iezzi
,
A.
,
Reale
,
M.
,
Paloscia
,
L.
,
Materazzo
,
G.
,
D’Annunzio
,
E.
,
Conti
,
P.
,
Chiarelli
,
F.
,
Cuccurullo
,
F.
, and
Mezzetti
,
A.
, 2001, “
Elevated Circulating Levels of Monocyte Chemoat-Tractant Protein-1 in Patients With Restenosis After Coronary Angioplasty
,”
Arterioscler. Thromb. Vasc. Biol.
,
21
(
3
), pp.
327
334
.
34.
Lee
,
Y. L.
, and
Pan
,
J. H. R. B. M.
, 2005,
Fatigue Testing and Analysis, Theory and Practice
,
Elsevier Butterworth-Heinmann
,
Burlington, MA and Oxford, UK
.
35.
Chopard
,
B.
, and
Droz
,
M.
, 1998,
Cellular Automata Modeling of Physical Systems
,
Cambridge University Press is in Cambridge University
,
Cambridge, UK
.
36.
Lennon
,
A. B.
,
Khayyeri
,
H.
,
Xue
,
F.
, and
Prendergast
,
P. J.
, 2011,
“Biomechanical Modelling of Cells in Mechanoregulation,”
In
Cellular and Biomolecular Mechanics and Mechanobiology
,
A.
Gefen
, ed.,
Springer
, pp.
295
329
.
37.
McLoughlin
,
R.
, 2008,
“Tensile Fatigue Behaviour of Porcine Coronary Arterial Tissue in the Longitudinal and Circumferential Directions,”
MSc thesis, University of Dublin, Dublin.
38.
DiMilla
,
P. A.
,
Stone
,
J. A.
,
Quinn
,
J. A.
,
Albelda
,
S. M.
, and
Lauffen burger
,
D. A.
, 1993, “
Maximal Migration of Human Smooth Muscle Cells on Fibronectin and Type IV Collagen Occurs at an Intermediate Attachment Strength
,”
J. Cell Biol
,
122
, pp.
729
737
.
39.
Tracy
,
R. E.
, 1997, “
Declining Density of Intimal Smooth Muscle Cells as a Precondition for Atheronecrosis in the Coronary Artery
,”
Virchows Archiv.
,
430
, pp.
155
162
.
40.
Farb
,
A.
,
Weber
,
D. K.
,
Kolodgie
,
F. D.
,
Burke
,
A. P.
, and
Virmani
,
R.
, 2002, “
Morphological Predictors of Restenosis After Coronary Stenting in Humans
,”
Circulation
,
105
, pp.
2974
2980
.
41.
Caiazzo
,
A.
,
Evans
,
D.
,
Falcone
,
J.-L.
,
Hegewald
,
J.
,
Lorenz
,
E.
,
Stahl
,
B.
,
Wang
,
D.
,
Bernsdorf
,
J.
,
Chopard
,
B.
,
Gunn
,
J.
,
Hose
,
R.
,
Krafczyk
,
M.
,
Lawford
,
P.
,
Smallwood
,
R.
,
Walker
,
D.
, and
Hoekstra
,
A. G.
, (2009),
“Towards a Complex Automata Multiscale Model of In-Stent Restenosis,”
in
Proceedings of the 9th International Conference on Computational Science: Part I
,
Springer-Verlag
, pp.
705
714
.
42.
Criscione
,
J.
, 2003, “
Rivlins Representation Formula is Ill-Conceived for the Determination of Response Functions via Biaxial Testing
,”
J. Elast.
,
70
(
19
), pp.
129
147
.
43.
Colombo
,
A.
,
Cahill
,
P.
, and
Lally
,
C.
, 2007, “
The Frequency of Cyclic Stretch Determines the Proliferative and Apoptotic Capacity of Vascular Smooth Muscle Cells In Vitro
,”
Arterioscler., Thromb. Vasc. Biol.
,
27
(
6
), pp.
E74
E74
.
44.
Bailon-Plaza
,
A.
, and
van der Meulen
,
M. C.
, 2001, “
A Mathematical Framework to Study The Effects of Growth Factor Influences on Fracture Healing
,”
J. Theor. Biol.
,
212
, pp.
191
209
.
45.
Murray
,
J. D.
, 2002,
Mathematical Biology
,
Springer
,
New York
.
46.
Khayyeri
,
H.
,
Checa
,
S.
,
Tgil
,
M.
,
Aspenberg
,
P.
, and
Prendergast
,
P. J.
, 2011, “
Variability Observed In Mechano-Regulated In Vivo Tissue Differentiation can be Explained by Variation in Cell Mechano-Sensitivity
,”
J. Biomech.
,
44
(
6
), pp.
1051
1058
.
47.
Reneman
,
R. S.
,
Arts
,
T.
, and
Hoeks
,
A. P.
, 2006, “
Wall Shear Stress—An Important Determinant of Endothelial Cell Function and Structure—In the Arterial System In Vivo Discrepancies With Theory
,”
J. Vasc. Res.
,
43
, pp.
251
269
.
48.
Prendergast
,
P. J.
,
Checa
,
S.
, and
Lacroix
,
D.
, 2010,
“Computational Models of Tissue Differentiation,”
in
Computational Modeling in Biomechanics
,
S.
De
,
F.
Guilak
, and
M.
Mofrad
,
R.
K.
, eds.,
Springer, Netherlands
, pp.
353
372
.
49.
Zahedmanesh
,
H.
, 2011,
“Finite Element and Mechanobiological Modelling of Vascular Devices,”
Ph.D thesis, Dublin City University.
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