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ON HEART TISSUE REENGINEERING ?

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 ?

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  1. Stem cell therapy and CV innovationsWhat’s new ? ON HEART TISSUE REENGINEERING ? JC Chachques, MD PhD Georges Pompidou European Hospital Paris, France

  2. 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

  3. 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.

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

  5. 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

  6. STEM CELL THERAPY andBIOARTIFICIAL MYOCARDIUM

  7. CARDIAC BIO-ASSIST

  8. 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)

  9. BONE MARROW ASPIRATION

  10. DEVELOPMENT OF BIO-ARTIFICIAL MYOCARDIUM

  11. 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

  12. 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?

  13. 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 »

  14. Heart extracellular matrixCell niche + cell homing ml : muscular lacunae cl : capillary lacunae

  15. 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

  16. 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

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

  18. DEVELOPMENT OF ARTIFICIAL MYOCARDIUM • Collagen matrix (type I) • 3D and Biodegradable • Seeded with stem cells

  19. Collagen Matrix without cells seeded with cells

  20. Confocal Microscopy3D matrix + cells

  21. MATRIX GRAFTED ON EPICARDIUM MATRIX

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

  23. BIOARTIFICIAL MYOCARDIUM « MAGNUM » Clinical Trial M yocardial A ssistance by G rafting a N ew bioartificial U pgraded M yocardium

  24. Rationale Associate a procedure for myocardial and extracellular matrix regeneration, i.e. Cellular cardiomyoplasty + Collagen scaffold grafting

  25. Cellular CMP + Cell Seeded Matrix

  26. Clinical Collagen Matrix Implantation

  27. MAGNUM Clinical Trial RESULTS

  28. Functional Outcomes: 1 year follow-up NYHA Class p =0.005 Baseline End FU

  29. LV Ejection Fraction (%) p = 0.04 Echocardiographic Study

  30. LV End Diastolic Volume (mL) p = 0.03 Echocardiographic Study

  31. LV FILLING Doppler-derived mitral deceleration time (ms) p = 0.01 DIASTOLIC FUNCTION

  32. Scar Area Thickness (mm) p = 0.005 Echocardiographic Study

  33. Cellular CMP + MatrixRadioisotopic SPECT sestamibi studiesPreop 12 Months

  34. 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

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

  36. 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

  37. 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

  38. 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

  39. 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.

  40. 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

  41. A generic peptide scaffold network Peptide nanofibers = 10-20 nm Scaffold pore size = 50-200 nm

  42. RECATABI PROJECT - European Union

  43. RECATABI PROJECT - European Union

  44. CARMAT ( Carpentier - Matra )Artificial Heart

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