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Jonathan Leor, MD, FACC
Sheba Medical Center
Tel Aviv UniversityTel-Hashomer, Israel
Injectable Biomaterials toRepair the Infarcted Heart
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Potential conflict
Bioline Innovations, Jerusalem
research grant
consultant
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Summary
Intracoronary delivery ofBL-1040is feasible, safe and effective inpreventing LV remodeling and
dysfunction after MI.
Our work enable catheter-based,acellular option to facilitate infarctstabilization, healing and repair.
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Heart failure after MI is often precipitated by early
and progressive extracellular matrix (ECM)
degradation and pathological remodeling of the
left ventricle.
The Problem
Jonathan Leor 2007
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Strategies thatinhibit postinfarct
remodeling
preserve left-
ventricular
geometry and
function and
prevent heartfailure
Whelan & al/ JCI 2007
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Cell therapy may be of limited benefit when the
extracellular matrix is absent or extensively
.damaged and cannot support cell engraftment
Extracellular matrix has a key role in
myocardial remodeling and repair
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Injection of abioresorbable scaffoldcan replace the
missing ECM andprovide a temporarystructural support and
signaling system fortissue repair.
HYPOTHESIS
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ESC 2007 Jonathan Leor
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Ease to produce
Off-the-shelfNon-immunogenic
BiodegradeableNot affected by age and disease
Potential Advantages of Injectable
Biomaterials
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Alginate ((Leor & Cohen 2005
Collagen ((Dai & al. 2005Fibrin or fibrin glue ((Christman & al. 2004
Self assembling peptide ((Davis & al. 2005
Injectable Biomaterials for
Treatment of Myocardial Infarct
http://circ.ahajournals.org/content/vol107/issue18/images/large/12FF2.jpeg8/14/2019 1200 2007 ISI Leor
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CRT 2007 Jonathan Leor
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Polysaccharide foundin brown seaweed.
Uronic acidcomposition is similar
to heparan-sulfate. Used extensively in the
food, pharmaceuticaland medical device
industries. Biocompatible. Bioresorbable.
Alginate Biomaterial
Patch
COO-
OH
OH
COO-
COO-
HO
COO-
HO
COO-
OH
OHOHOHO
O
O
OO
O O
O
O
O
OOH
OH
G(1C4) G(1C4) M(
4C1) M(4C1) G(
1C4) 1 ,4 1 ,4 1 ,4 1 ,4
G: Guluronate M: Mannuronate
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A liquid state at room temperature.
Forms a hydrogel as ECM, when it is
cross-linked by calcium ions.
Assuming gel state following depositionwithin infarcted tissue.
BL-1040: An Aqueous Solution of Calcium
Crosslinked Alginate
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Temporal tracking of biotin-labeled alginate
biomaterial in the scar
Temporal tracking of biotin-labeled alginate in the scar
0 10 20 30 40 500
10
20
30
40
50 p=0.0007
Days after injection
%
ofscararea
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Myofibroblasts replaced the injected
alginate-biomaterial
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Baseline 2 months0.00
0.05
0.10
0.15
0.20
Alginate (n=15)
Cells (n=14)
Control (n=13)
LV AWd
p
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Alginate biomaterial injection increases scar
thickness and reduces infarct expansion after MI
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Alginate biomaterial improves diastolic
function by Doppler echocardiography
E / A ratio linear regression
0.0
0.5
1.0
1.5
2.02.5
3.0 alginate (n=12)
control (n=6)
2m 4m7d
time after MI
p
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New approach:
Transcoronary delivery of alginate scaffold
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Catheter-based transcoronary delivery of
alginate biomaterial into the infarcted myocardium
Domestic pig Mid LAD occlusion - 90 min Transcoronary injection
3-4 d after MI 1,2 or 4 ml of alginate or saline Serial echo and MRI studies Follow-up 2 months Postmortem morphometry
and histology at 2 h or 2 m
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Mechanism and Pathway
ESC 2007 Jonathan Leor
Intracoronary injection
Deposition into infarcted tissue
Liquid to gel phase transition (polymerization)
upon contact with infarcted tissue
Liquid to gel phase transition at infarct area creates a resorbablebioprosthetic scaffold presumed to provide mechanical
support to damaged tissue
Alginate (BL-1040) mass is lost through ion exchange ofcalcium followed by dissolution of individual chains which are
excreted by the kidneys
Resorption occurs within 6 weeks
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Feasibility, safety and efficacy of intracoronary injection of
alginate biomaterial to prevent remodeling and dysfunction after
myocardial infarction
alginate biomaterial in infarct
((2h
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Transcoronary delivery of biotin-labeled alginate
biomaterial
scar
Border zone
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3 min 2m 3 min 2 m
0
1
2
3
1 ml (n=4)
2ml (n=4)
4 ml (n=3)saline (n=4)
flow
TIMIScore
blush
TIMI flow grade (TFG) and the TIMI myocardial
perfusion grade (TMPG) 3 min and 60 days after
BL1040 or saline delivery
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Transcoronary delivery of BL-1040 improves scar
thickness in pigs 2 months after MI
60 d postmortem morphometry
Scar thickness
Alginate(n=8) Control (n=4)0.0
0.5
1.0
1.5
2.0
2.53.0
3.5p
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Transcoronary delivery of BL-1040 prevents LV
dilatation in pigs 2 months after MI
Change in LVDA
Biomaterial (n=7) Control (n=4)0
20
40
p=0.0004
Change
%
Change in LVSA
Biomaterial (n=7) Control (n=4)-25
0
25
50
75
p
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Representative PV loops
Alginate & CellsAlginate
Saline- big MI
SV
EDV
ESV
Collagen
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Summary
Intracoronary delivery ofBL-1040is feasible, safe and effective inpreventing LV remodeling and
dysfunction after MI.
Our work enable catheter-based,
acellular option to facilitate infarctstabilization, healing and repair.
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Summary
Injectable biomaterials can serve as cell
implantation matrix that stabilaize the
infarct and enhance repair.
The concept of myocardial tissue
engineering will shift from replacement
and regeneration to healing and self-repair .
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Neufeld Cardiac Research Institute, Tel-hashomer, Israel Jonathan Leor Victor Guetta Micha S Feinberg Natali Landa David castel Udi Willenetz
University of Kaposvr, Kaposvr, Hungary Ivan Horvath Frenz Manzur
Zsolt Petrasi
University of Pcs, Pcs, Hungary Tamas Simor
Ben-Gurion Univ of the Negev, Beer-Sheva, Israel
Inbar Freeman Smadar Cohen
Bioline Rx, Jerusalem, Israel Shmuel Tuvia