Injectable Biomaterials to

Repair the Infarcted Heart

Jonathan Leor, MD, FACC

Sheba Medical Center
Tel Aviv University
Tel-Hashomer, Israel
 Potential conflict
• Bioline Innovations, Jerusalem
– research grant
– consultant
 Summary

 Intracoronary delivery of BL-1040

is feasible, safe and effective in
preventing LV remodeling and
dysfunction after MI.

• Our work enable catheter-based,

acellular option to facilitate infarct
stabilization, healing and repair.
 The Problem
Heart failure after MI is often precipitated by early
and progressive extracellular matrix (ECM)
degradation and pathological remodeling of the
.left ventricle

Jonathan Leor 2007

 Strategies that
inhibit postinfarct
remodeling
preserve left-
ventricular
geometry and
function and
prevent heart
failure
Whelan & al/ JCI 2007
 Extracellular matrix has a key role in
myocardial remodeling and repair

Cell therapy may be of limited benefit when the

extracellular matrix is absent or extensively
.damaged and cannot support cell engraftment
 HYPOTHESIS
Injection of a
bioresorbable scaffold
can replace the
missing ECM and
provide a temporary
structural support and
signaling system for
tissue repair.
ESC 2007 Jonathan Leor
Potential Advantages of Injectable
Biomaterials
•Ease to produce
•Off-the-shelf
•Non-immunogenic
•Biodegradeable
•Not affected by age and disease
 Injectable Biomaterials for
Treatment of Myocardial Infarct

Alginate ((Leor & Cohen 2005

Collagen ((Dai & al. 2005
Fibrin or fibrin glue ((Christman & al. 2004
Self assembling peptide ((Davis & al. 2005
CRT 2007 Jonathan Leor
 Alginate Biomaterial

• Polysaccharide found
in brown seaweed.
• Uronic acid
composition is similar
to heparan-sulfate.
• Used extensively in the
food, pharmaceutical
and medical device
industries.
• Biocompatible. Patch

• Bioresorbable. O
COO-

OH
OH

O
O
HO
COO-
OH
O HO
O O
O
COO-

OH
O OH O
OH
O COO- O

OH COO- OH

α 1 ,4 α 1 ,4 β 1 ,4 β 1 ,4
G(1C4) G(1C4) M(4C1) M(4C1) G(1C4)
G: Guluronate M: Mannuronate
 BL-1040: An Aqueous Solution of Calcium
Crosslinked Alginate
• A liquid state at room temperature.

• Forms a hydrogel as ECM, when it is

cross-linked by calcium ions.

• Assuming gel state following deposition

within infarcted tissue.
Temporal tracking of biotin-labeled alginate
biomaterial in the scar

Temporal tracking of biotin-labeled alginate in the scar

50 p=0.0007

% of scar area
40

30

20

10

0
0 10 20 30 40 50
Days after injection
Myofibroblasts replaced the injected
alginate-biomaterial
Alginate biomaterial injection reduce LV remodeling –
compare to fetal cardiomyocyte transplantation

p<0.01 LV AWs p<0.05

LV AWd
0.20
p<0.001 p<0.001
0.15 0.2
Alginate (n=15)
Cells (n=14)

cm

cm
0.10
Control (n=13)
0.1
0.05

0.00 0.0
Baseline 2 months Baseline 2 months

LVDD LVESD
p<0.01 p<0.01
p<0.01 1.0
p<0.05
1.0

cm
cm

0.5
0.5

0.0
Baseline 2 months
0.0
Baseline 2 months

1.0
1.0 LVDA p<0.01 LVSA
p<0.01 0.8 p<0.01
0.8
0.6 p<0.05
cm2

0.6
cm 2

0.4
0.4

0.2 0.2

0.0 0.0
Baseline 2 months Baseline 2 months
 Alginate biomaterial injection increases scar
thickness and reduces infarct expansion after MI
Alginate biomaterial improves diastolic
function by Doppler echocardiography

E / A ratio linear regression

3.0 alginate (n=12)

control (n=6)
2.5

2.0
E/A

1.5

1.0
p<0.00001
0.5

0.0
7d 2m 4m
time after MI
 New approach:
Transcoronary delivery of alginate scaffold
 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
 Mechanism and Pathway
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 resorbable

bioprosthetic scaffold presumed to provide mechanical
support to damaged tissue

Alginate (BL-1040) mass is lost through ion exchange of

calcium followed by dissolution of individual chains which are
excreted by the kidneys

Resorption occurs within 6 weeks

ESC 2007 Jonathan Leor
 Feasibility, safety and efficacy of intracoronary injection of
alginate biomaterial to prevent remodeling and dysfunction after
myocardial infarction

alginate biomaterial in infarct

((2h
 Transcoronary delivery of biotin-labeled alginate
biomaterial

Border zone

scar
 TIMI flow grade (TFG) and the TIMI myocardial
perfusion grade (TMPG) 3 min and 60 days after
BL1040 or saline delivery

1 ml (n=4)
2ml (n=4)
3
TIMI Score

4 ml (n=3)
saline (n=4)
2

0
3 min 2m 3 min 2m

flow blush
 Transcoronary delivery of BL-1040 improves scar
thickness in pigs 2 months after MI

60 d postmortem morphometry

Anterior wall thickness Scar thickness

10.0 3.5
p=0.01 p<0.01
3.0
7.5 2.5
2.0

mm
mm

5.0
1.5
1.0
2.5
0.5

0.0 0.0
Alginate (n=8) Control (n=4) Alginate(n=8) Control (n=4)
 Transcoronary delivery of BL-1040 prevents LV
dilatation in pigs 2 months after MI

Change in LVDA

40
Change %

p=0.0004 Change in LVSA

75
20

50

Change %
0 p<0.01
Biomaterial (n=7) Control (n=4) 25

-25 Biomaterial (n=7) Control (n=4)

 Transcoronary delivery of BL-1040 improves
anterior wall motion
in pigs 2 months after MI
Dyskinesis
Anterior wall motion score by MRI
3
Biomaterial
p<0.05 Control
Wall Motion Score

Normal 0
Baseline 60 d
ESC 2007 Jonathan Leor
 Representative PV loops
Alginate Alginate & Cells

SV

EDV
ESV

Collagen Saline- big MI

 Summary

 Intracoronary delivery of BL-1040

is feasible, safe and effective in
preventing LV remodeling and
dysfunction after MI.

• Our work enable catheter-based,

acellular option to facilitate infarct
stabilization, healing and repair.
 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” .
• Neufeld Cardiac Research Institute, Tel-hashomer, Israel
– Jonathan Leor
– Victor Guetta
– Micha S Feinberg
– Natali Landa
– David castel
– Udi Willenetz

• University of Kaposvár, Kaposvár, Hungary

– Ivan Horvath
– Frenz Manzur
– Zsolt Petrasi

• University of Pécs, Pécs, Hungary

– Tamas Simor

• Ben-Gurion Univ of the Negev, Beer-Sheva, Israel

– Inbar Freeman
– Smadar Cohen

• Bioline Rx, Jerusalem, Israel

– Shmuel Tuvia