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
6. Most commonly used
biomaterials for cardio
Polymer scaffold
tissue engineering are:
Biodegradable Polymeric
scaffolds (polyglycolic acid -
PGA)
http://union.igic.bas.bg/content_images/fe47f119130b1ae60
0f5ad23b26813eb.jpg
Hydrogels (seeded with
collagen, fibrin, alginate)
Biodegradale scaffold
Decellularized tissue
(composed of natural
ECMproteins: collagen,
elastin, fibronectin, etc)
http://www.ibi-sa.com/site/images/stories/prodotti22/cells-scaffold-
2d.jpg
7. Scaffold provides
250-for-tridion_tcm18-95841.jpg
http://www.rsc.org/images/b706654f-
structure for cells / tissue
to grow and deliver
biomolecules (growth
factors, cytokines, etc.)
Properties [chemical,
mechanical, biological]
should be adjusted to
provide appropriate
performance
8. Appropriate mechanical
and physical properties
Proper degradation rate
No production of toxic
degradation products
Promotes cell adhesion
http://www.nature.com/nmat/journal/v4/n7/images/nmat1421-f6.jpg Integration into
surrounding tissue
Minimal inflammatory /
immune response
9. 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
10. 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
http://www.sigmaaldrich.com/etc/medialib/life-science/stem-cell-
Adipose (fat)
biology/mesenchymal-stem-cell.Par.0001.Image.457.gif
Using adult stem cells allows
autologous cell transplantation
11. Can differentiate into cells
from all three germ layers
of the body
Ectoderm
Endoderm
Mesoderm
Can self-renew http://www.openbiosystems.com/collateral/genomics/images/Cells%20and%20cell%20line
s/ES_cell_isolation.jpg
Capable of
undifferentiated
proliferation in culture for
extended time
13. 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
14. 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
15. 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
16. Valves have complex architecture
TEHVs require complex molds
Cellularize with myofibroblasts to obtain a
functional valve
http://www.sciencecodex.com/files/different%20ways%20in%20which%20tissue%20engineers%20believe%20that%20heart%20muscle.jpg
17. 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.
http://www.edoctoronline.com/medical-atlas.asp?c=4&id=22190
18. 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.
http://circ.ahajournals.org/content/123/4/e18.full.pdf
19. ardiotext/tissueengineering.html
http://www.chir.uzh.ch/cardio/c
• Limitations of Mechanical valves
• Infections
• Thromboembolism
• Cannot grow
• important for pediatric
ypes_of_heart_valves.png
http://www.pages.drexel.edu/~nag38/Images/t
patients Caged
• No self-repair capability
Tilting
disc
• Limitations of Tissue-Engineered
valves Single
• Calcification of tissue leaflet
Bi-
leaflet
20. 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 http://en.wikipedia.org/wiki/File:Apikal4D.gif
21. 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
http://www.sciencecodex.com/files/different%20ways%20in%20which%20tissue%20engineers%20believe%20that%20heart%20muscle.jpg
22. Overview – Veins & Arteries
•Arteries carry oxygenated blood from
the heart to the body (except the
pulmonary artery).
• Veins carry deoxygenated blood used
by the body back to the heart (except
the pulmonary vein)
• Arteries are larger, thicker, and more
elastic than veins.
• Blood in arteries is at pressure
• Veins contain valves to prevent
backflow of blood
http://1.bp.blogspot.com/_Obwvpc-KSC4/S8Ud-
y0xQyI/AAAAAAAAAa8/QTBY1SKf_Z0/s1600/arterial%20stru
cture%20vs%20venous.JPG
23. 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
http://healthguru.biz/wp-content/uploads/2011/02/Atherosclerosis.jpg
24. 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
http://www.sciencecodex.com/files/different%20ways%20in%20which%20tissue%20engineers%20believe%20that%20heart%20muscle.jpg
25. Overview – Myocardial Infarction (Heart Attack)
One or more regions of the
heart muscle experience a
severe and prolonged
decrease in oxygen supply
because of insufficient
coronary blood flow.
The affected muscle tissue
subsequently becomes
necrotic.
http://nursingcrib.com/nursing-notes-reviewer/myocardial-infarction/
26. • 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.
28. 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
http://www.sciencecodex.com/files/different%20ways%20in%20which%20tissue%20engineers%20believe%20that%20heart%20muscle.jpg
29.
30. $6.9 billion global market
forecast to exceed $30 billion by 2018
Source:
http://mediligence.com/blog/2010/10/02/cardiology-
and-cardiovascular-cell-therapy-and-tissue-
engineering/
31. 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
http://www.mediligence.com/rpt/rpt-s520.htm
32. 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
http://www.mediligence.com/rpt/rpt-s520.htm
33. 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
http://www.mediligence.com/rpt/rpt-s520.htm
34. Company Development Clinical Approved /
al/ Preclinical Marketed
Orthopedic, cardio
3DM Inc. scaffolds
Cardio: IMPACT-DCM, Phase II; Vascular:
Aastrom Bioscience Inc. RESTORE-CLI
Advanced Cell Technology, Myoblasts for heart failure, completed Phase I
Inc. human
AdvanSource Biomaterials CardioPass
Aldagen, Inc. Ischemic heart failure, 2013
Adult stem cells for CHF, acute, MI, macular
degeneration, and cord blood transplantation,
Angioblast Systems, Inc. 2012
Angiotech Pharmaceuticals, Working with Athersys to develop MultiStem Collagraft, Neugraft
Inc. for heart damage bone graft matrices
ACY001 and ALO212
Arteriocyte Medical Systems, for lower extremity
Inc. 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)
35. Company Developmental/ Preclinical Clinical Approved /
Marketed
BeFutur Cellular implants for the regeneration of
Biotechnologies damaged heart tissue
Omniflow II (biosynthetic
vascular prosthesis for
peripheral
Bio Nova revascularization and
International 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 patient's fat tissue, not Therapy (TGI 1200) for
Bioheart Inc. heart damage FDA evaluated yet, for research only) acute MI
California Stem
Cell 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 of
Capricor, Inc. myocardial infarction myocardial infarction and heart failure
Chrysalin (Rusalatide Acetate or TP508) for
angiogenesis, revascularization, vascular
Capstone endothelial dysfunction (AMI, chronic
Therapeutics myocardial ischemia)
Regenerative cardiac patch (pulsating, living
CellSeed, Inc. cardiomyocyte cardiac patch on the heart)
36. Company Developmental/ Preclinical Clinical Approved / Marketed
Cook Group Regenerative tissue scaffolds
CryoValve SG pulmonary heart
valve and the CryoPatch SG
pulmonary cardiac patch
CryoLife, Inc. (CryoPatch SG)
LifeLine TE blood vessel (TEBV), LifeJacket
Cytograft Tissue Stent Graft (AAA), LifeGuard soft tissue
Engineering reinforcement patch
Adipose-derived stem and
Cytori Therapeutics regenerative cells for AMI,
Inc. chronic myocardial ischemia
ES Cell Neural progenitor cells (w/ CellCure); Embryonic stem cell lines
International pancreatic progenitor cells (cardiomyocytes)
Cell therapy for scar
Garnet reduction, myocardial
BioTherapeutics infarction
Biopharm for
Genzyme 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 and
Humacyte orthopedic)
37. Company Developmental/ Preclinical Clinical Approved / Marketed
Collagen biomaterials for
Kensey 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 for
Mesoblast Limited cardiovascular regeneration
MG MAGIC trial (myoblast
Biotherapeutics, Autologous cell therapies for damaged autologous grafting in
LLC heart tissue ischemic cardiomyopathy)
Adult, autologous stem cell therapy for
Miltenyi Biotec myocardial regeneration
NellOne
Therapeutics, Inc. Therapeutics to treat heart damage
NovoGen 3-D bioprinter to create NovoGen 3-D bioprinter being
Organovo artificial arteries and tissue distributed to researchers
Osiris Therapeutics Prochymal for heart tissue repair after
Inc. heart attack
Pluristem PLX-PAD therapeutic for
Therapeutics, Inc. critical limb ischemia
38. Company Developmental/ Preclinical Clinical Approved / Marketed
ReN009 stem cell therapy for
peripheral artery disease
ReNeuron Ltd. (uses CTX stem cell line)
Stem Cell Therapy
International, Inc. /
Histostem Regenerative stem cell transplantation
MYDICAR enzyme
Targeted Genetics replacement therapy for
Corporation heart failure
Intracardiac defect closure, absorbable
Tepha Inc. cardiovascular stents
Creating stem cells from adult cells
(retrodifferentiation technology) for
TriStem cancer (leukemia), organ, neurology,
Corporation cardiology
source: http://mediligence.com/blog/2010/10/02/cardiology-and-cardiovascular-cell-therapy-and-tissue-engineering/
39.
40. 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
41. 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
http://www.pdb.org/pdb/images/1T44_bio_r_25
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
http://www.pdb.org/pdb/images/3kfd_bio_r_500.jp
g?bioNum=1
43. Manufacture PEG scaffolds
synthetically
Treat scaffold with Tβ4 and
TGF-β
http://technewslit.com/sciencebusiness/wp-
Seed it with MSCs
content/uploads/2011/05/HeartNanoscaffold_Frank-
Mullin_Brown-University.jpg
Implant : patient’s ischemic
myocardium
44. Angiogenesis. Wikipedia. http://en.wikipedia.org/wiki/Angiogenesis. 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.
