Cardiovascular Tissue Engineering


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Cardiovascular Tissue Engineering

  1. 1. Raul Sotoh/images/cardiovascular%20system%20248px.jpg BME501 Tissue Engineering
  2. 2. Introduction Biomaterials Cells Biomolecules TE Product Requirements Heart Valves Blood Vessels Myocardium Companies Products & Therapies Proposed Product
  3. 3.  Cardiovascular diseases  Leading cause of death worldwide for both men and women. Treatment Limitations:  restricted intrinsic regeneration capacity of the heart  Cardiomyocytes (adult heart muscle cells) cannot divide to replace injured cells  lack of organs for transplantation. Main Targets for Tissue Engineering  Blood vessels  Heart muscle – myocardium  Heart valves
  4. 4.
  5. 5.  Most commonly used biomaterials for cardioPolymer scaffold tissue engineering are:  Biodegradable Polymeric scaffolds (polyglycolic acid - PGA) 0f5ad23b26813eb.jpg  Hydrogels (seeded with collagen, fibrin, alginate)Biodegradale scaffold  Decellularized tissue (composed of natural ECMproteins: collagen, elastin, fibronectin, etc) 2d.jpg
  6. 6.  Scaffold provides 250-for-tridion_tcm18-95841.jpg structure for cells / tissue to grow and deliver biomolecules (growth factors, cytokines, etc.) Properties [chemical, mechanical, biological] should be adjusted to provide appropriate performance
  7. 7.  Appropriate mechanical and physical properties  Proper degradation rate  No production of toxic degradation products  Promotes cell adhesion  Integration into surrounding tissue  Minimal inflammatory / immune response
  8. 8.  Cell types most commonly used for Cardiac Tissue Engineering [Smart 2008]:  Embryonic Stem Cells  Bone Marrow-Derived Mesenchymal Stem Cells  Skeletal Myoblasts  Induced Pluripotent Stem Cells  Multipotent Adult Germline Stem Cells  Endothelial Progenitor Stem Cells  Very Small Embryonic-like Stem Cells  Endogenous Cardiac Stem Cells
  9. 9.  Found in many tissues and organs  Multipotent  Extensive proliferation potential  Bone marrow-derived adult stem cells can be differentiated to many cell types :  Cartilage  Bone  Adipose (fat)biology/mesenchymal-stem-cell.Par.0001.Image.457.gif  Using adult stem cells allows autologous cell transplantation
  10. 10.  Can differentiate into cells from all three germ layers of the body  Ectoderm  Endoderm  Mesoderm Can self-renew s/ES_cell_isolation.jpg Capable of undifferentiated proliferation in culture for extended time
  11. 11.  Angiogenic factors Vasculogenic factors Growth factors Differentiation factors
  12. 12.  FGF :  promotes proliferation and differentiation of endothelial cells, smooth muscle cells, fibroblasts Ang1, Ang2  Stabilize blood vessels PDGF and PDGFR  Recruit smooth muscle cells TGF-β, endoglin and TGF-β receptors  Produce ECM VE-cadherin, CD31  Promote endothelial junctions Eprin  Formation of veins or arteries Plasminogen activator inhibitor – 1  Stabilize nearby vessels
  13. 13.  Biocompatibility:  Minimize inflammatory and immunological responses  Should have growth and healing capabilities similar to native tissue  Tissue strength, stiffness, cellularity, composition should be similar to native tissue Functionality:  Appropriate mechanical and hemodynamic functionality  Must be durable
  14. 14.  Blood Vessels:  Must be able to withstand high-pressure fluid dynamics, turbulence Valves  Must be able to operate in a very dynamic and severe environment.  Open and close at 1 Hz, exposed to mechanical stresses, high- pressure fluid dynamics, turbulence, etc. Myocardium Patch  High vascularity is critical  Mechanical and electrical anisotropy
  15. 15.  Valves have complex architecture  TEHVs require complex molds  Cellularize with myofibroblasts to obtain a functional valve
  16. 16.  Overview The heart consists of four chambers • Two atria (upper chambers) • Two ventricles (lower chambers). Valves are flaps that located on each end of the two ventricles (lower chambers of the heart). Valves prevent the backward flow of blood. As the heart muscle contracts and relaxes, the valves open and shut, letting blood flow into the ventricles and atria at alternate times.
  17. 17. American Heart Association • Approximately 90,000 heart valve Heart Disease and Stroke Statistics 2011 replacements per year in the United States Valvular Heart Disease ICD-9 424; ICD-10 I34 to I38. • Approximately 275,000 per year Mortality 23,313 worldwide Any-mention mortality 44,149 Hospital discharges 98,000 • In the pediatric population, 15–25% of the congenital heart defects (>36,000/ year) are associated with the pulmonary position, requiring repair or replacement of the pulmonary valve.
  18. 18. ardiotext/tissueengineering.html• Limitations of Mechanical valves • Infections • Thromboembolism • Cannot grow • important for pediatric ypes_of_heart_valves.png patients Caged • No self-repair capability Tilting disc• Limitations of Tissue-Engineeredvalves Single • Calcification of tissue leaflet Bi- leaflet
  19. 19.  3 main approaches [Nerem, 2004]:  Cell seeding of biodegradable valve matrices  Cell seeding of decellularized allograft or xenograft valves  Promote repopulation and adaptive remodeling of decellularized allograft valves
  20. 20.  Graft fabrication requires design of a suitable mold  Walls are cellularized with smooth muscle cells  Lumen is cellularized with endothelial cells  Typical use is for coronary bypass surgery
  21. 21.  Overview – Veins & Arteries•Arteries carry oxygenated blood fromthe heart to the body (except thepulmonary artery).• Veins carry deoxygenated blood usedby the body back to the heart (exceptthe pulmonary vein)• Arteries are larger, thicker, and moreelastic than veins.• Blood in arteries is at pressure• Veins contain valves to preventbackflow of blood y0xQyI/AAAAAAAAAa8/QTBY1SKf_Z0/s1600/arterial%20stru cture%20vs%20venous.JPG
  22. 22.  Atherosclerosis: approximately 515,000 coronary artery bypass graft surgeries performed in the USA per year Due to age or state of health, many patients cannot provide an appropriate vessel for a graft
  23. 23.  x  Integrate primary contractile-phenotype cells with biomaterials  Tissue-engineered cardiac patches can be used to treat acute myocardial infarction  Augment contractile function  Promote revascularization of ischemic tissue
  24. 24.  Overview – Myocardial Infarction (Heart Attack)One or more regions of theheart muscle experience asevere and prolongeddecrease in oxygen supplybecause of insufficientcoronary blood flow.The affected muscle tissuesubsequently becomesnecrotic.
  25. 25. • 425,000 deaths in the United States in 2006 (about one of every six deaths)• 1,255,000 new and recurrent attacks per year.• About 34 percent of people who experience a coronary attack in a given year die from it.• 17,600,000 victims of angina (chest pain due to coronary heart disease), heart attack and other forms of coronary heart disease are still living.
  26. 26. [Curtis, 2009]
  27. 27.  Hollow structure with cardiac cells  Wall surface : Cardiac myocytes  Lumen: Endothelial cells  Can generate intramural pressure when electrically stimulated  Can contract in sync with host heart  Proposed for chronic heart failure
  28. 28.  $6.9 billion global market forecast to exceed $30 billion by 2018 Source:  and-cardiovascular-cell-therapy-and-tissue- engineering/
  29. 29.  AorTech International (UK/Australia)  Use of polymer Elast-Eon for heart valves Autogenics (USA)  Autologous tissue cardiac valves CryoLife (USA/UK)  Preserving human heart valves, veins, connective tissue for cardiac / vascular surgical reconstruction  75% cardiovascular procedures involving allograft tissue in USA use cryopreserved human heart valves from CryoLife TiGenix (Belgium)  Cell-based TE HVs Source: Tissue Engineering, Cell Therapy and Transplantation: Products, Technologies & Market Opportunities, Worldwide, 2009-2018 Published Feb 2010
  30. 30.  Vascular Biotech GmbH (Germany)  Patented TE aorto-coronary bypass graft in Clinical Trials  Consists of cryopreserved donor veins, lined with recipient-own endothelial cells Co.don (Germany)  Endothelialized vessels ,in Clinical Trials BioTissue Technologies (Germany)  Vessel prostheses coated with autologous cells, in Preclinical development AngioGenetics (Sweden)  Drug discovery in angiogenesis regeneration  Applicable in treatment of ischemic heart disease, chronic wounds Ark Therapeutics (Finland)  Vascular endothelial growth factor gene packed with adenoviral vector and biodegradable local drug delivery device Source: Tissue Engineering, Cell Therapy and Transplantation: Products, Technologies & Market Opportunities, Worldwide, 2009-2018 Published Feb 2010
  31. 31.  Genzyme Biosurgery (USA/ Europe)  Cardiac myoblast cell transplantation, in Clinical Trials  Autologous skeletal muscle cells from patient injected on scarred region of heart Diacrin (USA)  Treatment for ischemia damaged myocardium with autologous skeletal myoblasts. In Clinical Trials BioHeart (USA)  MyoCell: autologous cell-based product, in Clinical Trials  MyoCath: percutaneous needle injection to deliver cell therapy to myocardial tissue, in Clinical Trials  MyoCell VT: cell-based product for ventricular tachycardia, in PreClinical  BioPace: cell-based product for sinoatrial nodal dysfunction, in PreClinical Osiris Therapeutics (USA)  Differentiation of hMSC into specialized cell types, sells them to other companies Source: Tissue Engineering, Cell Therapy and Transplantation: Products, Technologies & Market Opportunities, Worldwide, 2009-2018 Published Feb 2010
  32. 32. Company Development Clinical Approved / al/ Preclinical Marketed Orthopedic, cardio3DM Inc. scaffolds Cardio: IMPACT-DCM, Phase II; Vascular:Aastrom Bioscience Inc. RESTORE-CLIAdvanced Cell Technology, Myoblasts for heart failure, completed Phase IInc. humanAdvanSource Biomaterials CardioPassAldagen, Inc. Ischemic heart failure, 2013 Adult stem cells for CHF, acute, MI, macular degeneration, and cord blood transplantation,Angioblast Systems, Inc. 2012Angiotech Pharmaceuticals, Working with Athersys to develop MultiStem Collagraft, NeugraftInc. for heart damage bone graft matrices ACY001 and ALO212Arteriocyte Medical Systems, for lower extremityInc. ischemia ACY001 for chronic cardiac ischemia (Phase I)Athersys, Inc. MultiStem AMI Isolex stem cell therapy for chronic myocardial ischemia and critical limb ischemia; ACT34- CMI (adult autologous cellular therapy CD34+ stem cells for chronic myocardial ischemia); ACT34-CLI (injection of autologous CD34+Baxter International Inc. positive cells for critical limb ischemia)
  33. 33. Company Developmental/ Preclinical Clinical Approved / MarketedBeFutur Cellular implants for the regeneration ofBiotechnologies damaged heart tissue Omniflow II (biosynthetic vascular prosthesis for peripheralBio Nova revascularization andInternational CABG graft arteriovenous access) MyoCell for heart failure (MARVEL, SEISMIC, MYOHEART, REGEN; ASC BioPace biological "pacemaker"; Allocell Treatment (generate adipose-derived Bioheart Acute Cell allogenic cell therapy for severe chronic stem cells from patients fat tissue, not Therapy (TGI 1200) forBioheart Inc. heart damage FDA evaluated yet, for research only) acute MICalifornia StemCell Inc. Therapeutics for coronary heart disease Autologous cardiac stem cells for direct Autologous cardiac stem cells for injection and matrix delivery treatment of catheter infusion treatment ofCapricor, Inc. myocardial infarction myocardial infarction and heart failure Chrysalin (Rusalatide Acetate or TP508) for angiogenesis, revascularization, vascularCapstone endothelial dysfunction (AMI, chronicTherapeutics myocardial ischemia) Regenerative cardiac patch (pulsating, livingCellSeed, Inc. cardiomyocyte cardiac patch on the heart)
  34. 34. Company Developmental/ Preclinical Clinical Approved / MarketedCook Group Regenerative tissue scaffolds CryoValve SG pulmonary heart valve and the CryoPatch SG pulmonary cardiac patchCryoLife, Inc. (CryoPatch SG) LifeLine TE blood vessel (TEBV), LifeJacketCytograft Tissue Stent Graft (AAA), LifeGuard soft tissueEngineering reinforcement patch Adipose-derived stem andCytori Therapeutics regenerative cells for AMI,Inc. chronic myocardial ischemiaES Cell Neural progenitor cells (w/ CellCure); Embryonic stem cell linesInternational pancreatic progenitor cells (cardiomyocytes) Cell therapy for scarGarnet reduction, myocardialBioTherapeutics infarction Biopharm forGenzyme cardiometabolic/renal Biopharm for genetic diseases,Corporation diseases cardiometabolic/renal diseases Regenerative medicine (glial cells, cardiomyocytes, islets, chondrocytes,Geron Corporation osteoblasts, hepatocytes) Proof of concept for a Vascular replacement (also R&D for products for cardiovascular, cosmetic, soft tissue reconstruction, neurosurgical andHumacyte orthopedic)
  35. 35. Company Developmental/ Preclinical Clinical Approved / Marketed Collagen biomaterials forKensey Nash regeneration of cardiac tissue Invested in cardiovascular research efforts at MG Biotherapeutics, REMEDI, Scill Cardio, ortho, neuro stem cell-Medtronic Technology (dental implant) based products Mesenchymal precursor cells forMesoblast Limited cardiovascular regenerationMG MAGIC trial (myoblastBiotherapeutics, Autologous cell therapies for damaged autologous grafting inLLC heart tissue ischemic cardiomyopathy) Adult, autologous stem cell therapy forMiltenyi Biotec myocardial regenerationNellOneTherapeutics, Inc. Therapeutics to treat heart damage NovoGen 3-D bioprinter to create NovoGen 3-D bioprinter beingOrganovo artificial arteries and tissue distributed to researchersOsiris Therapeutics Prochymal for heart tissue repair afterInc. heart attackPluristem PLX-PAD therapeutic forTherapeutics, Inc. critical limb ischemia
  36. 36. Company Developmental/ Preclinical Clinical Approved / Marketed ReN009 stem cell therapy for peripheral artery diseaseReNeuron Ltd. (uses CTX stem cell line)Stem Cell TherapyInternational, Inc. /Histostem Regenerative stem cell transplantation MYDICAR enzymeTargeted Genetics replacement therapy forCorporation heart failure Intracardiac defect closure, absorbableTepha Inc. cardiovascular stents Creating stem cells from adult cells (retrodifferentiation technology) forTriStem cancer (leukemia), organ, neurology,Corporation cardiology source:
  37. 37.  Composite Scaffold  Scaffold:  PEG (polyethylene) 3D MMP- responsive hydrogel  Mimics biochemical properties of collagen  Can direct differentiation of pluripotent cardio progenitor stem cells  Cells  Mesenchymal Progenitor Stem Cells
  38. 38.  Myocardial Patch – Composite Scaffold  Biomolecules  Tβ4: Thymosin β4  Enhances survival of vascular cells and cardiomyocytes in ischemic environments  Stimulates neovascularization after cardiac injury  Down-regulates expression of inflammatory cytokines 0.jpg?bioNum=1  TGF-β : Transforming growth factor beta  controls cell proliferation and differentiation  Vascular homeostasis  Angiogenesis  Vascular morphogenesis  Antiproliferative factor in normal epithelial cells
  39. 39. Tβ4, TGF-β Tissue Engineered Myocardial Patch MSC Hydrogel PEG mages/MToner_cellarray.jpg
  40. 40.  Manufacture PEG scaffolds synthetically  Treat scaffold with Tβ4 and TGF-β  Seed it with MSCscontent/uploads/2011/05/HeartNanoscaffold_Frank-Mullin_Brown-University.jpg  Implant : patient’s ischemic myocardium
  41. 41.  Angiogenesis. Wikipedia. Accessed 15 September 2011. Curtis, M and Russell, B. Cardiac Tissue Engineering. Journal of Cardiovascular Nursing. 2009; 24(2):87-92. Khait, L et al. Getting to the Heart of Tissue Engineering. J of CardiovascTrans Res. 2008; 1:71-84. Nerem, R and Ensley , A. The Tissue Engineering of Blood Vessels and the Heart. American Journal of Transplantation. 2004; 4:36-42. Roger, V et al. Heart Disease and Stroke Statistics - 2011 Update: A Report From the American Heart Association. Circulation. 2011; 123:e18-e209. Smart, N and Riley, P. The Stem Cell Movement. Circulation Research. 2008; 102:1155-1168.