development of a novel sirolimus eluting pro-healing stent ... · in vivo tissue drug kinetics of...
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Development of a Novel Sirolimus Eluting Pro-Healing Stent: Early Animal Data on
Healing and Restenosis
Juan F Granada, MD.Medical Director, Skirball Center for Cardiovascular Research
The Cardiovascular Research FoundationColumbia University Medical Center
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Evolution of DES Technology
BiostableConformal Coating
High PolymerThick Coating
Sequestered Drug
BiodegradableCapped AbluminalModerate Polymer
Thick CoatingBinding Polymer
BiodegradableDirectional
Polymer Based
BiodegradableExclusively Abluminal
Low PolymerUltrathin
CypherTaxus
Biosensors
Conors
Labcoat
DES
DAS (Drug Application Stent) PolymerFree
Prohealing Strategies &Drug Elution
Putative Safety
Slide Modified and Courtesy of Art Rosenthal
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Directional Sirolimus Biodegradable Abluminal Coating and Anti-CD34
Surface Modification: Device Description
Abluminal Drug/Polymer Layer
Genous CD34 Ab
Stent Strut
Genous-DES Technology:• Rapamycin (5 µg/mm) applied in biodegradable SynBiosys polymer on the abluminal side.
Genous Technology:• Anti-CD34 surface to promote healing through rapid stent endothelialization.
Genous
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14-Day Porcine Coronary Artery SEM - Overlapping
Cyp
her +
Gen
ous
Cyp
her +
Cyp
her
Gen
ous
+ G
enou
s
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0
20
40
60
80
100
Endothelialization by SEM at 14 days Cypher + Cypher Genous + Cypher Genous + Genous
Above Struts Between Struts Above Between
Overlapping Non-Overlapping
* * * * * *
Cyp
her
Cyp
her
Gen
ous
Gen
ous
(%)
* p<0.05
35
75
90
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0
25
50
75
100
Endothelialization with CD31 (+) Cells at 14 Days
Above Struts Between Struts
2538 56 57 63 63
NS
NS
Non-overlapping site
Cypher + Cypher Genous + Cypher Genous + Genous
Cyp
her
Gen
ous
Overlapping site
Cyp
her
Gen
ous
Above Between
(%)
NS*
* p < 0.05
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1. Could anti-CD34 coating increase the potential for healing in current DES platforms?
2. It is abluminal coating really superior than circumferential coating?
3. How drug partitioning affects elution kinetics?4. Would partitioning drug elution have an effect
on device’s endothelialization?5. Can we prove these hypothesis in current
animal models?
EPC Capturing and Drug Elution: Relevant Research Questions
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• Objective: To characterize EPC capture technology applied to commercially available Cypher stents.• Test Devices:
– AntiCD34/Cypher Combination (n=4 / timepoint).– Cypher (n= 4 / timepoint)– Genous (n=4 / timepoint)
• Model: Porcine Coronary Injury Model (1.1:1 BAR).• Time-Points: 3 & 14 days.• Analysis:
– Endothelial Coverage by SEM – Endothelial Function by Confocal Microscopy.
Could Anti-CD34 Coating Increase Stent Coverage in Current DES Platforms?
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Stent Surface Coverage by SEM in Stented Arteries at 3 and 14 Days
3 Days 14 Days
GenousGenous
ComboCombo
CypherCypher3 Days 14 Days
0
25
50
75
100
Timepoint
% E
ndot
helia
lizat
ion
by S
EM
**
*
**
*=p<0.05; **=p<0.01; ***p<0.001
GenousComboCypher
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% Endothelialization by PECAM Expression in Confocal Microscopy in Stented Arteries: 3 and 14 Days
3 Days 14 Days0
25
50
75
100GenousComboCypher
Timepoint
% P
ECA
M E
xpre
ssio
n
9587
48
85
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1. Could anti-CD34 coating increase the potential for healing in current DES platforms?
2. It is abluminal coating really superior than circumferential coating?
3. How drug partitioning affects elution kinetics?4. Would partitioning drug elution have an effect
on device’s endothelialization?5. Can we prove these hypothesis in current
animal models?
EPC Capturing and Drug Elution: Relevant Research Questions
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It is Abluminal Coating Really Superior Than Circumferential Coating?
Background Data:• Anti-CD34 coating on the Cypher stent enhanced
endothelial cell coverage and functionality (PECAM expression) at 14 days.
Hypothesis:• By separating EPC capture from drug delivery using
the anti-CD34/DES Combo stents:– Minimize the amount of drug and polymer on the inner surface,
therefore, one could improve endothelial cell function, while maintaining inhibition of neointimal growth.
– Would partitioning of the drug increase the changes for device endothelialization?
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Abluminal Porcine Study:Biodegradable Abluminal Coating
• Objective: To compare the differences on strut coverage and functionality of 2 different coating techniques using the core technology anti-CD34 coating in the porcine injury model.
• Test Devices:– Anti-CD34 Stent + Sirolimus Abluminal Coating (n=18)– Anti-CD34 Stent + Sirolimus Uniform Coating (n=18)
• Analysis:– 3 Days: SEM & IMH (n = 6 in each group = 12)– 14 Days: SEM & IMH (n = 6 in each group = 12)– 28 Days: Light Microscopy (n = 6 in each group = 12)
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% Strut Endothelialization by SEM3 & 14 Days is High but Equivalent in Both Groups
Control AbC Control AbC0
25
50
75
100
% Endothelialization (SEM)
3 Days 14 Days
% E
ndot
helia
lizat
ion
AbluminalControl
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% PECAM Expression Above the Struts Higher Expression in Abluminal Combo
Control AbC Control AbC0
25
50
75
% of Endothelial Cells Expressing PECAM
(70.5)
(27.7)
3 Days 14 Days
% P
ECA
M
P= 0.07
Control
Abluminal
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28-Day Histology: Equivalent Reduction of Neointimal Thickness and Stenosis
Combo Control Abluminal Combo
NI Thickness (mm) 0.087 ±0.021 0.094 ±0.068
% Stenosis 17.19 ±4.35 18.57 ±6.43
Int. Inflammatory Score 0.94 ±1.14 0.56 ±0.62
Adv. Inflammatory Score 0.17 ±0.28 0.00 ±0.00
Fibrin Score 1.83 ±0.46 1.56 ±0.54
p=NS for all results
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1. Could anti-CD34 coating increase the potential for healing in current DES platforms?
2. It is abluminal coating really superior than circumferential coating?
3. How drug partitioning affects elution kinetics?4. Would partitioning drug elution have an effect
on device’s endothelialization?5. Can we prove these hypothesis in current
animal models?
EPC Capturing and Drug Elution: Relevant Research Questions
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In Vivo Tissue Drug Kinetics of the Rapa Combo DES System in a Porcine Model• Objective: To evaluate the local PK features of the Rapa Combo device up to 35 days in the porcine model.
• Test Devices:• Rapa Combo ¼ Dose (2.5 µg rapamycin/mm, n= 5). • Rapa Combo ½ Dose (5 µg rapamycin/mm, n= 5). • Cypher (10 µg rapamycin/mm, n= 4).
• Analysis:• Blood Collection: 15 minutes, 1, 3, 6 and 24 hours• PK analysis on stented arteries, myocardium, liver, kidney: 6 hours, 1, 3, 7, 14, 28 and 35 days
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In vivo Elution of Rapamycin Remaining Drug on Stent by HPLC
0
20
40
60
80
100
0 5 10 15 20 25 30 35
Time (days)
Am
ount
of d
rug
(%)
1/4 Dose
1/2 Dose
Cypher®
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Mean Distribution of Sirolimus in Porcine Heart Tissues
Cypher½ Dose¼ Dose
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1. Could anti-CD34 coating increase the potential for healing in current DES platforms?
2. It is abluminal coating really superior than circumferential coating?
3. How drug partitioning affects elution kinetics?4. Would partitioning drug elution have an effect
on device’s endothelialization?5. Can we prove these hypothesis in current
animal models?
EPC Capturing and Drug Elution: Relevant Research Questions
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Effect of Rapamycin Dose on Healing and Neointimal Proliferation in a Porcine Coronary Model at 14 and 28 Days
• Objective: To demonstrate the effect of dose on healing (anti-CD34 effect) and reduction of neointimal proliferation (rapamycin effect) utilizing imaging, and histology techniques.
• Test Devices:– Rapa Combo ¼ Dose (2.5 µg rapamycin/mm, n= 5) – Rapa Combo ½ Dose (5 µg rapamycin/mm, n= 5)– Cypher, Xience V, Genous.
• Endpoints:– 14 days:
• SEM & IMH (4 stents in each HD and LD)• In vivo OCT evaluation: (4 in each group)
– 28 days: OCT & LM (6 stents in Genous, HD and LD, 4 stents in DES controls).
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In vivo 14 Days OCT Analysis:Strut by Strut Coverage Analysis
1427 (100 %)374 (100 %)333 (100 %)359 (100 %)361 (100 %)Total Struts
1139 (79.82 %)337 (90.11 %)231 (69.37 %)270 (75.21 %)301 (83.38 %)Uncovered strut
288 (20.18 %)37 (9.89 %)102 (30.63 %)89 (24.79 %)60 (16.62 %)Covered strut
TotalXienceCypher¼ Dose½ DoseTotal Number
Covered Uncovered
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In vivo 14 Days OCT Analysis:Neointimal Thickness Covering the Strut
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14-Day Endothelialization Rates by SEM and PECAM-1 Expression
*
% Endothelialization at 14 Days (SEM)
½ Dose ¼ Dose Cypher Genous0
25
50
75
100
Device Type
% E
ndot
helia
l Cov
erag
e
% Expression of PECAM at 14 days
½ Dose ¼ Dose Cypher Genous0
25
50
75
100
Device Type
% E
xpre
ssio
n
P<0.001
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14-Day Histology Results
21.39±42.770.00±0.000.00±0.000.00±0.00Granuloma (%)
1.00±2.000.00±0.000.00±0.000.00±0.00Adv. Inflammatory Score
47.01±17.2237.94±7.2733.74±16.1550.51±17.02Giant Cells (%)
1.95±1.410.85±0.190.85±0.551.05±0.19Int. Inflammatory Score
1.50±0.121.55±0.341.65±0.682.04±0.64Fibrin Score
0.071±0.0620.031±0.0060.032±0.0110.035±0.007NI Thickness (mm)
12.31±6.269.99±2.159.75±2.6312.01±1.44Stenosis (%)
Xience¼ Dose½ DoseCypher
N=4/stent type; no statistically significant differences
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In vivo Evaluation of Neointimal Thickness by OCT at 28 Days
28-Day Neointimal Thickness (by OCT)
Cypher ¼ Dose ½ Dose Xience Genous0.0
0.1
0.2
0.3
0.4
0.5
NI T
hick
ness
(mm
)
P<0.001, compared to HD
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28-Day Histology Results
0.13±0.24
13.82±9.51
0.27±0.16
0.067±0.16
0.29±0.12
36.55±10.88
Genousn=6
0.13±0.120.52±0.590.24±0.540.20±0.20Adv. Inflam. Score
33.24±14.14**6.04±7.5510.06±7.1344.94±8.32Giant Cells (%)
0.67±0.830.24±0.330.28±0.231.20±0.20Int. Inflam. Score
0.53±0.421.32±0.500.60±0.752.00±0.72Fibrin Score
0.15±0.0490.18±0.0730.12±0.0500.21±0.019NI Thickness (mm)
22.22±6.2726.04±8.7419.92±5.6033.48±5.41*
Stenosis (%)
Xiencen=3
¼ Dosen=5
½ Dosen=5
Cyphern=3
*Cypher>Xience and HD; **Xience>Genous, HD and LD (p<0.0001)
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Conclusions (I)• In the present series of studies we demonstrated:
– The safety profile of current DES technologies could be enhanced by having the additive effect of EPC recruitment.
– Biological “compartmentalization” (abluminal coating) is possible and seems to be superior than circumferential coating.
– Therapeutic levels of rapamycin can be maintained despite the fact that the total effective dose is reduced by 50% to 75%.
• OCT and histological analyses demonstrate that at 14 days:– There was a statistically significantly lower neointimal
thickness by OCT in Rapa Combo ½ Dose compared to the other groups.
– PECAM expression was higher in Rapa Combo ½ Dose (81.3±19.9%) compared to Rapa Combo LD stents (62.7±22.6%).
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Conclusions (II)• At 28 days:
– Neointimal thickness and %AS were the lowest with Rapa Combo ½ Dose, and this correlated with statistically significantly lower neointimal thickness by OCT compared to the other groups.
• The nature of the animal model used in these studies (juvenile porcine) makes the evaluation of device endothelialization more challenging.
• These biological effects could potentially translate into a clinical advantage by improving vascular healing while maintaining effective control in neointimal proliferation.
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The Skirball Center for Cardiovascular Research
DirectorsJuan F. GranadaGreg L. KaluzaGenghua YiMartin B. LeonResearch AssociatesMichael AboodiKrzysztof MilewskiVeterinary SupportWilliam P. FeeneyJuan CarbonellAlyssa Flynn Diane OrdanesImaging Core LaboratoryYanping Cheng Shigenobu InamiGerard Conditt
Data Analysis/StatisticsDavid Wallace‐Bradley
Study ManagementJennifer McGregor
Pathology LaboratoryAnguo GuArmando Tellez
Administrative SupportGeorge LombardiKathy TroyanKim White
Facility ManagementDuane DennisFrancy Castro
GE Research SupportLaurence Gavit