LABORATORY OF BIOLOGICAL STRUCTURE MECHANICS
www.labsmech.polimi.it
TECHNOLOGICAL INNOVATION FOR CORONARY STENTS
Francesco Migliavacca
Erice, 1 maggio 2015
International School of Cardiac Surgery
Introduction
Patent search
Heart valve
Stent
Francesco Migliavacca
Roma 26 Novembre 2009
Introduction
Francesco Migliavacca
Mechanical cardiac valves
Roma 26 Novembre 2009
Stent
Introduzione
Francesco Migliavacca
Roma 26 Novembre 2009
Mechanical heart valves
Introduction
Patent “heart valve” tot US+EP (1968-2000)
technological trend of mechanical heart valves (1968-2000)
450
400
350
# patents
300
250
SCIENTIFIC
RESEARCH
TECHNOLOGICAL
RESEARCH
technological trend
110
100
50
INDUSTRIAL
RESEARCH
200
150
100
1
50
0
Courtesy of : R. Pietrabissa
Francesco Migliavacca
1968
1970
1971
1975
1976
1980
Roma 26 Novembre 2009
1981
1985
1986
1990
1991
1995
1996 years
2000
Stent patents
Introduction
7F
5F
bare
self-ex
2F
?
DES …
Size unexpanded stent
absorbable
model
10000
# patents
8000
RISCIENTIFIC
RESEARCH
6000
TECHNOLOGICAL
RESEARCH
INDUSTRIAL
RESEARCH
?
4000
2000
0
Francesco Migliavacca
1992
1996
2000
2004
2008
2012 years
1995
1999
2003
2007
2011
2015
Roma 26 Novembre 2009
stent history
http://www.admedes.com/literature
Francesco Migliavacca
Roma 26 Novembre 2009
30 days after implant in porcine coronaries
Mg stent
SS stent
Waksman R. Adjunctive therapy: Biodegradable stents: They do
their job and disappear. J Invas Cardiol 2006; 18: 70)74.
Francesco Migliavacca
Roma 26 Novembre 2009
Stent requirements
Design requirements
Market issues
Drug
Price
adhesion
Clinical
requirements
Flexibility
Manufacturing technologies
Trackability
Radiopacity
Scaffolding
MR visibility
Biodegradability
Material properties
Francesco Migliavacca
Resistance to fracture
Roma 26 Novembre 2009
Drug eluting stents
Francesco Migliavacca
Roma 26 Novembre 2009
Drug eluting stents
↑
Drug
carrier
Polymer (biodegradable or
not biodegradable)
Stent
Drug
Francesco Migliavacca
Roma 26 Novembre 2009
↓
Inflammatory reaction
Drug eluting stents
van der Giessen, et al. Marked Inflammatory Sequelae to Implantation of
Biodegradable and Nonbiodegradable Polymers in Porcine Coronary Arteries
Circulation. 1996;94:1690-1697
Francesco Migliavacca
Roma 26 Novembre 2009
Drug eluting stents
Virmani, et al. Localized Hypersensitivity and Late Coronary Thrombosis Secondary
to a Sirolimus-Eluting Stent. Should We Be Cautious? Circulation. 2004;109:701-705
Francesco Migliavacca
Roma 26 Novembre 2009
Drug eluting stents
↑
↓
Drug
carrier
Polymer (biodegradable or
not biodegradable)
Inflammatory reaction
Stent
Regular “Spacing” between
struts
Uniform and controlled drug
release
Conformability (minimal
struts malapposition)
Drug
Francesco Migliavacca
Roma 26 Novembre 2009
More drug in the blood stream
than in the arterial wall
Drug eluting stents
OCT
Prati et al. European Heart Journal
doi:10.1093/eurheartj/ehs095
Francesco Migliavacca
Roma 26 Novembre 2009
Drug eluting stents
↑
↓
Drug
carrier
Polymer (biodegradable or
not biodegradable)
Inflammatory reaction
Stent
Regular “Spacing” between
struts
Uniform and controlled drug
release
Conformability (minimal
struts malapposition)
More drug in the blood stream
than in the arterial wall
Toxicity
Drug
Francesco Migliavacca
Uniform and controlled drug release
Roma 26 Novembre 2009
Drug eluting stents
LATE STENT THROMBOSIS
Francesco Migliavacca
Roma 26 Novembre 2009
Drug eluting stents
Dauerman H, The Magic of Disappearing Stents
J Am Coll Cardiol. 2011;58(15):1589-1591.
Francesco Migliavacca
Roma 26 Novembre 2009
Drug eluting stents
Strut thickness of only ≤ 50/60 μm
100% Polymer-Free Drug Delivery
Bio-resorbable Drug Matrix
Sirolimus - Matrix Excipient: Probucol
Source: www.bbraun.com
Francesco Migliavacca
Roma 26 Novembre 2009
bioresorbable stents
Muramatsu et al. Progress in Treatment
by Percutaneous Coronary Intervention:
The Stent of the Future. Rev Esp Cardiol.
2013;66:483-96.
Francesco Migliavacca
Roma 26 Novembre 2009
bioresorbable stents
Source: www.abbottvascular.com
Francesco Migliavacca
Roma 26 Novembre 2009
bioresorbable stents
Source: www.abbottvascular.com
Francesco Migliavacca
Roma 26 Novembre 2009
Biodegradable stents
BACKGROUND
Use of simulations for bioabsorbable stent
• to predict the mechanical behaviour of stent (recoil, radial strength, flexibility, …)
• to predict the degradation behaviour
• to optimise the design for a prolonged/shortened degradation resistance
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Biodegradable stents
DEGRADABLE MATERIALS FOR STENTING
Polymers:
Metals:
• PLLA
• polycarbonate
• PLGA/PCL-PGA
• salicyclic acid polymer
•
• Iron alloys
Magnesium alloys
Degradation mechanisms
Corrosion
Bulk vs surface degradation
Surface
Degradation
(lollipop)
undegraded
[Levesque et al 2008]
24
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Bulk
Degradation
(sponge)
Biodegradable stents
MAGNESIUM ALLOYS STENTS
Hansi et al, Cath Cardiovasc Interv, 73:488-496, 2009.
Bioresorbable Magnesium stent (BIOTRONIK, Berlin,
Germany) [Erbel et al 2007]
To improve corrosion resistance:
Degradation rate too fast!!!
TARGET:
Degradation rate has to be reduced to ensure mechanical
support to the vessel for a longer time
25
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• alloying
• mechanical/heat treatments
• surface modifications and coatings
Biodegradable stents
MECHANICAL PROPERTIES OF MATERIALS FOR STENTS
Material
Stiffness E [GPa]
yield stress σy [MP]
240
600
1100
Fe
210
150
210
SS 316L
200
190
490
WE43
44
150
210
PLLA
2
-
45
Stress
Co-Cr
Strain
26
ultimate stress
σu[MP]
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Biodegradable stents
MG - GEOMETRY
AMS (Biotronik, Germany): 4 struts with links
[Erbel et al 2007]
84476 elements C3D8R
27
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Biodegradable stents
MODEL OF STENTING PROCEDURE
• coronary vessel
3 hyperelastic layers:
=0.32 mm
media
s
=0.24 mm
intima
[Holzapfel et al 2005]
66000 C3D8R elements
Stress [MPa]
• stent material
Strain
28
=0.34 mm
adventitia
s
D =2.4 mm
int
D =4.2 mm
ext
s
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Biodegradable stents
RESULTS: DEGRADATION OF STENT STRUCTURE
Uniform Corrosion: 48 t
Stress Corrosion: 48 t
Stress
29
Combined Corrosion: 48 t
Damage
120 MPa
0.9
0 MPa
0
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Biodegradable stents
OPTIMISATION PROCEDURE
30
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Biodegradable stents
OPTIMISATION PROCEDURE
strain
original design
optimized design
Wu et al: ‘FE shape optimization for biodegradable magnesium alloy stents’ Ann Biomed Eng, 2010.
31
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Biodegradable stents
OPTIMISATION PROCEDURE
ZM21
original design
32
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optimized design
Biodegradable stents
OPTIMISATION PROCEDURE
33
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Biodegradable stents
OPTIMISATION PROCEDURE
strain
AMS
34
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optimized
Biodegradable stents
DEGRADATION RESULTS
0.6
1
AMS
magic
0.8
0.4
ott
optimized
Late recoil
ML/M
i
0.6
0.4
0.2
magic
ott
0.3
0.2
0.1
0
0
0
35
magic
optimized
ott
3080
AMS
0.5
10
40
20
30
50
40
Time
50
60
60
70
80
70
0
80
after 14 t corrosion
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10
20 Time
30
40
50
Biodegradable stents
Two FEA models of MAS in the simulation of degradation
Optimized design (OPT)
Patent design as control (CON)
The ratio of mass per length unit is 1.93 : 2.64
Ren et al., An Absorbable Implantation Stent of Magnesium Metal, Chinese patent, 2006
36
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Biodegradable stents
INTERACTION BETWEEN OPT MODEL AND VESSEL DURING DEGRADATION
When the stent degraded the vessel recoiled until then stent broke
37
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Biodegradable stents
RESULTS AFTER STENT IMPLANTATION
OPT
The distribution of residual stress
38
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CON
Biodegradable stents
UNIFORM AND STRESS CORROSION EVLUTION
Uniform corrosion
OPT
CON
Faster stress corrosion evolution
39
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Biodegradable stents
LASER CUTTING AND ELECTRO-POLISHING OF THE MAS SAMPLES
OPT
CON
Material: AZ31 tube
40
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Biodegradable stents
DEGRADATION EXPERIMENT OF THE TWO SAMPLES
• The two samples were crimped to 1.2 mm of outer diameter and expanded to 3.0 mm then
recoiled freely. The expanded CON sample is shown below.
• The two expanded samples were immersed in the D-Hank’s solution for 7 days, with pH
7.5 and and temperature 37°C.
• The two samples were observed with unaided eyes to check structural integrity when
immersed in solution. Then they were taken out for the observation with stereo or scanning
electron microscope (SEM) after 7 days of corrosion.
41
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Biodegradable stents
EXPERIMENTAL RESULTS: STRUCTURAL INTEGRITY
• After the first day of immersion, the CON sample had several broken points on the strut while
the OPT sample kept the structural integrity until the third day of immersion.
• After 7 days of corrosion, the CON sample has scattered into pieces, while the OPT has
not scattered even though it had several broken points. The result is compatible with
simulation that the OPT model has better property to resist corrosion.
OPT
42
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CON
Biodegradable stents
EXPERIMENTAL RESULTS: UNIFORM AND STRESS CORROSION
• The SEM observation shows that corrosion layers caused by uniform corrosion, which were
shedding from the stent matrix. The early broken points caused by stress corrosion can also be
observed and are compatible with the expected location in simulation.
43
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Biodegradable stents
CONCLUSIONS FROM MATHEMATICAL MODELLING
Both simulation and experiment indicated that the optimized MAS design

can yield better property to resist corrosion.
Both simulation and experiment showed that the degradation of MAS

consists of uniform and stress corrosion.
The experiment preliminarily verified that the proposed numerical

approach can be an effective tool for novel MAS design and property
comparisons.
44
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In progress
45
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Coronary bifurcation
Francesco Migliavacca
Roma 26 Novembre 2009
different stent applications
Francesco Migliavacca
Roma 26 Novembre 2009
stent patents
Introduction
10000
# patents
8000
SCIENTIFIC
RESEARCH
6000
TECHNOLOGICAL
RESEARCH
INDUSTRIAL
RESEARCH
?
4000
2000
0
1992
1996
2000
2004
2008
2012 years
1995
1999
2003
2007
2011
2015
The optimal design, however, of scaffolds, polymers, antiproliferative drugs and their
degradation/release kinetics is still under investigation.
Francesco Migliavacca
Roma 26 Novembre 2009
Thank you
Computational models presented here
are carried out with the help of:
Wei Wu
[email protected]
LABORATORY OF BIOLOGICAL
STRUCTURE MECHANICS
Dario Gastaldi
Lorenza Petrini
www.labsmech.polimi.it
Francesco Migliavacca
Roma 26 Novembre 2009