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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.jpeg

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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