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SYNTHETIC EXTRACELLULAR MATRICES FOR PROMOTING ANGIOGENESIS

SYNTHETIC EXTRACELLULAR MATRICES FOR PROMOTING ANGIOGENESIS. Eduardo A. Silva Harvard University, Cambridge, MA, USA and Faculdade de Engenharia da Universidade do Porto, Porto, Portugal December 2004 Porto, Portugal. MOTIVATION. Cardiovascular Diseases:

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SYNTHETIC EXTRACELLULAR MATRICES FOR PROMOTING ANGIOGENESIS

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  1. SYNTHETIC EXTRACELLULAR MATRICES FOR PROMOTING ANGIOGENESIS Eduardo A. Silva Harvard University, Cambridge, MA, USA and Faculdade de Engenharia da Universidade do Porto, Porto, Portugal December 2004 Porto, Portugal

  2. MOTIVATION Cardiovascular Diseases: - Principal cause of mortality in western countries Current Approaches to treat Ischemic Heart Diseases: Pharmacologic InvasiveSurgical Therapeutic Angiogenesis

  3. Carmeliet & Jain Nature, 2000 ISCHEMIA Ischemia - isch- is restriction, hemia or haemia is blood

  4. ANGIOGENESIS Sprouting of new blood vessels from pre-existent vessels

  5. VASCULAR ENDOTHELIAL GROWTH FACTOR VEGF Is a key regulator of blood vessels formation and function Endothelial Cells are the primary target of VEGF 45 kDa homodimer Four isoforms obtained by alternative splicing: VEGF121, VEGF165, VEGF189, VEGF206 Muller et al., Structure, 5:1325-1338 (1997) Muller et al., Structure, 5:1325-1338 (1997) Fairbrother et al., Structure, 6:637-648 (1998)

  6. AIM I AIM I: Investigate VEGF signaling in cardiac cells under hypoxia.

  7. VEGF SECRETION UNDER HYPOXIA

  8. TISSUE ENGINEERING STRATEGY Localized, sustained delivery from bioactive polymeric systems Constant local concentration Protection from degradation Minimal side effects

  9. AIM II Development of an injectable polymeric system for controlled and defined delivery of angiogenic molecules VEGF incorporated in an injectable polymer

  10. OH OH O O HO O OH HO O OH O O O OH O OH O O OH OH G G M M G - - CO CO 2 2 - CO 2 - CO 2 - O C 2 POLYMERIC SYSTEM Alginate -L- Guluronic acid -D- Mannuronic acid Ca2+ Gelation process Hydrogel

  11. Bioactive molecules + + Polymeric system Microspheres MODEL SYSTEM Distinct approach used to incorporate VEGF Simple mixing VEGF and alginate Ca2+ + + Alginate Angiogenic molecules Pre-incorporation of VEGF in polymeric microspheres and immobilization in the alginate

  12.  Irradiation (5 Mrad) CHO CHO ALGINATE MODIFICATIONS Combination of binary molecular weight distribution and partial oxidation Oxidation with NaIO4

  13. Solution Properties

  14. Gel Properties

  15. VEGF RELEASE

  16. BIOACTIVITY OF VEGF RELEASED

  17. ANGIOGENESIS

  18. PDGF RELEASE

  19. VEGF/PDGF RELEASE

  20. In vivo evaluation of VEGF releasing materials Model: Ischemic hind limb of Apo E null (Apo E -/-) LDPI image

  21. In vivo evaluation of VEGF releasing materials Week 2 Week 4 Week 6 Blank VEGF VEGF&PDGF

  22. In vivo evaluation of VEGF releasing materials

  23. CONCLUSIONS Sustainable and controlled angiogenic molecules delivery can be achieved with binary alginate Blood vessel formation and perfusion can be significantly improved by using binary alginate as local dual delivery vehicle

  24. VEGF 121 + - µm VEGF 165 FUTURE WORK VEGF 121 AND VEGF 165 PLAY DISTINCT ROLES IN THE STIMULATION OF COLLATERAL VESSEL AND BLOOD FLOW RE-ESTABLISHMENT IN AN ISCHEMIC HEART

  25. ACKNOWLEDGMENTS Professor David J. Mooney Professor Mário Barbosa Department of Radiology Division of Cardiovascular Diseases Department of Internal Medicine University of Michigan Paul M. Grossman Sanjay Rajagopalan Qinghua Sun Mooney Lab 2nd PGDB FCT - Fundação para a Ciência e a Tecnologia IGC/FCG - Fundação Calouste Gulbenkian NIH - National Institutes of Health Harvard University/University of Michigan & Universidade do Porto

  26. Thinking about Curia 2005

  27. A - Alginate; B - New tissue; C - Blood Vessel; D - Inflammatory cells

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