On heart tissue reengineering
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Stem cell therapy and CV innovations What’s new ?. ON HEART TISSUE REENGINEERING ?. JC Chachques, MD PhD Georges Pompidou European Hospital Paris, France. Cardiac Bioassist - Cooperative Work Teams :. Olivier Schussler. Ottawa Heart Institut, Canada

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On heart tissue reengineering

Stem cell therapy and CV innovationsWhat’s new ?

ON HEART TISSUE REENGINEERING ?

JC Chachques, MD PhD

Georges Pompidou European Hospital

Paris, France


Cardiac bioassist cooperative work teams

Cardiac Bioassist - Cooperative WorkTeams :

  • Olivier Schussler. Ottawa Heart Institut, Canada

  • Carlos Semino. MIT + Barcelona Bioengineering Center

  • Jorge Genovese. Pittsburgh University, USA

  • Jorge Trainini. Avellaneda Hospital, Argentina


On heart tissue reengineering

HEART FAILURE IN EUROPE

  • Heart failure is the single biggest reason for acute hospital admission.

  • Around 30 million people in Europe have heart failure and its incidence is increasing.

  • More people are living to an old age, and more are surviving a heart attack but with damage to the heart.


Prevalence of heart failure in usa total population 305 millions

PREVALENCE of HEART FAILURE in USA (total population: 305 millions)


On heart tissue reengineering

Evidence for cardiomyocyte renewal in humansScience 2009; 324: 98-102 Frisen J. et al, Karolinska Institut, Stockholm, Sweden

  • Cardiomyocytes are generated also later in life ?

  • Carbon-14, generated by nuclear bomb tests during the Cold War, integrated into DNA allows to establish the age of cardiomyocytes in humans

  • Results: cardiomyocytes renew, with a gradual decrease from 1% turning over annually at age of 25, to 0.45% at age of 75

  • Fewer than 50% of cardiomyocytes are exchanged during a normal life span

  • Perspectives: development of therapeutic strategies aimed at stimulating this process in cardiac pathologies


Stem cell therapy and bioartificial myocardium

STEM CELL THERAPY andBIOARTIFICIAL MYOCARDIUM


Cardiac bio assist

CARDIAC BIO-ASSIST


On heart tissue reengineering

CELLS FOR MYOCARDIAL REGENERATION

  • Skeletal myoblasts

  • Bone marrow mononuclear cells

  • Bone marrow mesenchymal cells

  • Umbilical cord cells

  • Adipose tissue stroma cells

  • Mesothelial cells (from epiploon)

  • Menstrual blood endometrial cells

  • Stem cells from the testis

  • Embryonic cells (pluripotents)


On heart tissue reengineering

BONE MARROW ASPIRATION


On heart tissue reengineering

DEVELOPMENT OF

BIO-ARTIFICIAL MYOCARDIUM


On heart tissue reengineering

BACKGROUNDLimitations of Cellular Cardiomyoplasty

  • Cell bio-retention and engraftment within scar tissue is low

  • Mortality of implanted cells in ischemic myocardium is high

  • In ischemic heart disease the extracellular matrix is pathologically modified


Background 2 limitations of cellular cardiomyoplasty

BACKGROUND 2Limitations of Cellular Cardiomyoplasty

  • Implanted cells lack both mechanical synchronization and electrical integration, forming « islands of tissue »

    Questions and risks:

  • Excitation-contraction coupling?

  • Additional excitable cells?

  • Proarrhythmic?


Rationale for 3d cardiac tissue engineering

RATIONALE FOR 3D CARDIAC TISSUE ENGINEERING

  • The efficacy and arrhythmia occurrence of stem cell therapy depends on the surviving cell number as well as the delivery route of cells

  • A cell-seeded epicardial scaffolds should offert additional niches for cell homing without the risk of a proarrhythmogenic substrate

  • Allogeneic cells should be better tolerated in a matrix « niche environment »


On heart tissue reengineering

Heart extracellular matrixCell niche + cell homing

ml : muscular lacunae

cl : capillary lacunae


On heart tissue reengineering

COMPONENTS OF EXTRACELLULAR MATRIX IN HUMAN HEART

Collagen Type I (80%) : Ventricular chamber geometry, structural support

Collagen Type III (10%): Role in transduction of myocyte shortening during systole


On heart tissue reengineering

EXTRACELLULAR MATRIX IN ISCHEMIC HEART DISEASE

Collagen Type I :Decreases from 80% to 40%

Collagen Type III : Increases from 10% to 35%

RESULTS : Ventricular dilatation, systolic + diastolic dysfunctions


On heart tissue reengineering

COLLAGEN TYPE I MATRIX (Pangen 2, France)lyophilised, bovine collagen, 5 x 7 x 0.6 cm


On heart tissue reengineering

DEVELOPMENT OF ARTIFICIAL MYOCARDIUM

  • Collagen matrix (type I)

  • 3D and Biodegradable

  • Seeded with stem cells


On heart tissue reengineering

Collagen Matrix without cells seeded with cells


On heart tissue reengineering

Confocal Microscopy3D matrix + cells


On heart tissue reengineering

MATRIX GRAFTED ON EPICARDIUM

MATRIX


On heart tissue reengineering

PRECLINICAL STUDIESPublished in Tissue Engineering 2007; 13:2681-7Cell-seeded collagen matrix - 2 Mo Follow-up


On heart tissue reengineering

BIOARTIFICIAL MYOCARDIUM « MAGNUM » Clinical Trial

M yocardial

A ssistance by

G rafting a

N ew bioartificial

U pgraded

M yocardium


On heart tissue reengineering

Rationale

Associate a procedure for myocardial and extracellular matrix regeneration, i.e.

Cellular cardiomyoplasty

+

Collagen scaffold grafting


On heart tissue reengineering

Cellular CMP + Cell Seeded Matrix


On heart tissue reengineering

Clinical Collagen Matrix Implantation


On heart tissue reengineering

MAGNUM Clinical Trial

RESULTS


On heart tissue reengineering

Functional Outcomes: 1 year follow-up

NYHA Class

p =0.005

Baseline

End FU


On heart tissue reengineering

LV Ejection Fraction (%)

p = 0.04

Echocardiographic

Study


On heart tissue reengineering

LV End Diastolic Volume (mL)

p = 0.03

Echocardiographic

Study


On heart tissue reengineering

LV FILLING

Doppler-derived mitral deceleration time (ms)

p = 0.01

DIASTOLIC FUNCTION


On heart tissue reengineering

Scar Area Thickness (mm)

p = 0.005

Echocardiographic Study


On heart tissue reengineering

Cellular CMP + MatrixRadioisotopic SPECT sestamibi studiesPreop12 Months


On heart tissue reengineering

MAGNUM CLINICAL TRIALCONCLUSIONS

  • REDUCES THE SIZE AND FIBROSIS OF INFARCT SCARS

  • MINIMIZES GLOBAL VENTRICULAR DILATATION

  • IMPROVES DIASTOLIC FUNCTION

  • INCREASES MYOCARDIAL WALL THICKNESS

  • INDUCES MODULATION OF EXTRACELLULAR MATRIX


On heart tissue reengineering

MAGNUM CLINICAL TRIALCONCLUSIONS

  • The implanted matrix contributed to generate the “adequate niche” for native, transplanted and migrating stem cells


On heart tissue reengineering

FUTURE MATRIX IMPROVEMENTS

  • Crosslinking angiogenic growth factors

  • Prolong absorption delay by nanotechnologies and additional chemical - physical crosslinking

  • Stem cell preconditioning :

    hypoxic conditions (5%) during cultures

    in-vitro electrostimulation


Nature clin pract cardiovasc med 2009 6 240 9

Nature Clin Pract Cardiovasc Med 2009; 6: 240-9

Use of arginine-glycine-aspartic (RGD) acid adhesion peptides coupled with a new collagen scaffold to engineer a myocardium-like tissue graft

Schussler O, Coirault C, Louis-Tisserand M,

Chachques JC, Carpentier A, Lecarpentier Y


Frontiers in bioscience 2009 14 2996 3002

Frontiers in Bioscience. 2009; 14: 2996-3002

Cardiac pre-differentiation of human mesenchymal stem cells by electrostimulation

Genovese J, Spadaccio C, Schussler O,

Carpentier A, Chachques JC, Patel AN


Biomaterials 2009 30 1156 65

Biomaterials. 2009; 30: 1156-65

The effect of self-assembling peptide nanofiber scaffolds on mouse embryonic fibroblast implantation and proliferation

Degano IR, Quintana L, Semino C, et al.


On heart tissue reengineering

A prototypic synthetic extracellular matrix

  • Molecular designed material

  • Chemically defined

  • Synthetic process

  • Highly similarity to natural ECMs

  • structure: nano-scale fibers

  • self-assembling process

  • biologically permissive

  • non-competition with natural ECM

  • biodegradable

  • Mechanical properties for soft tissues

  • Modification control Building up properties

  • Transient scaffold

  • Injecting biological material


On heart tissue reengineering

A generic peptide scaffold network

Peptide nanofibers = 10-20 nm

Scaffold pore size = 50-200 nm


On heart tissue reengineering

RECATABI PROJECT - European Union


On heart tissue reengineering

RECATABI PROJECT - European Union


On heart tissue reengineering

CARMAT ( Carpentier - Matra )Artificial Heart


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