prospects for myocardial tissue engineering
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PROSPECTS FOR MYOCARDIAL TISSUE ENGINEERING Arjang Ruhparwar
Dublin, May 2015
Epidemiologie Herzinsuffizienz
Häufigste Todesursachen 2010
Todesursachenstatistik, Statistisches Bundesamt, Zweigstelle Bonn, 2011
Prostatea
Colon-CaHerzinsuffizienz
Myokardinfarkt
Blasencarcinom
Herzinsuffizienz
Jahre
Ku
mu
lati
ves
Üb
erl
eb
en
1.0
Brustkrebs
Myokardinfarkt
Colon-Ca
Bronchial-carcinom
Frauen
0.2
0.4
0.6
0.8
0
1 2 3 4 5
Bronchial-carcinom
1.0
0.2
0.4
0.6
0.8
0
1 2 3 4 5
Jahre
Männer
Mortalität der Herzinsuffizienz im Vergleich zu malignen Tumorerkrankungen
Stewart, S. et al., Eur J Heart Failure:3; 315-322
Ovarial-Ca
NUMBER OF HEART TRANSPLANTSBY YEAR AND LOCATION
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
19821983
19841985
19861987
19881989
19901991
19921993
19941995
19961997
19981999
20002001
20022003
20042005
20062007
20082009
2010
Num
ber o
f tra
nspl
ants
OtherEuropeNorth America
NOTE: This figure includes only the heart transplants that are reported to the ISHLT Transplant Registry. As such, the presented data may not mirror the changes in the number of heart transplants performed worldwide .ISHLT 2012
J Heart Lung Transplant. 2012 Oct; 31(10): 1045-1095
The HeartWare® Ventricular Assist System
• Implanted in the pericardial space
• Via median sternotomy or left thoracotomy
• Placed above the diaphragm next to the heart
• No surgical pump pocket
Challenges of continuous-flow VAD therapy
• Infections (driveline)
• Bleeding and thrombembolic complications including acquired v. Willebrand-syndrom
• Arteriovenous malformationen in the GI-tract
• Increasing aortic valve regurgitation
• RV-failure
Challenges of continuous-flow VAD therapy
INTERMACS-Report 2013
INTERMACS-Report 2013
Kirklin JK et al.: Fifth INTERMACS annual report: risk factor analysis from more than 6,000 mechanical circulatory support patients.
J Heart Lung Transplant. 2013 Feb;32(2):141-56. doi: 10.1016/j.healun.2012.12.004.
Are there alternatives to
heart transplantation ?
MECHANICAL ALTERNATIVES
• Assist devices
• Polymers
BIOLOGICAL ALTERNAIVES
• Cell therapy
•Tissue engineering
Soonpaa et al., Science 1994Soonpaa et al., Science 1994
First successful cell transplantation into the myocardiumFirst successful cell transplantation into the myocardium
Limitations of utilized cellsLimitations of utilized cells
1. Lack of adequate cell source (Fetal or neonatal cardiomyocytes)
2. Embryonic stem cell derived cardiomyocytes can form tumors
3. Difficult mass production of embryonic stem cell- or iPS-derived cardiomyocytes
1. Lack of adequate cell source (Fetal or neonatal cardiomyocytes)
2. Embryonic stem cell derived cardiomyocytes can form tumors
3. Difficult mass production of embryonic stem cell- or iPS-derived cardiomyocytes
Are there alternatives to
heart transplantation ?
MECHANICAL ALTERNATIVES
• Assist devices
• Polymers
BIOLOGICAL ALTERNAIVES
• Cell therapy
•Tissue engineering
Matrix-Cell Interaction
OrthopedicsOrthopedics
SkinSkin
CartilageCartilage
BoneBone
EyeEye
CorneaCornea
IrisIris
PancreasPancreas
Adominal SurgeryAdominal Surgery
LiverLiver
GutGut
Neuro SurgeryNeuro Surgery
Dopaminergic CellsDopaminergic Cells
Schwann‘s CellsSchwann‘s Cells
Spinal cordSpinal cordUrology/GynecologyUrology/Gynecology
UretherUrether
Urinary bladderUrinary bladder
UterusUterus
Cardiothoracic + Vasc. SurgeryCardiothoracic + Vasc. Surgery
ValvesValves
VesselsVessels
MyocardiumMyocardium
TracheaTrachea
Tissue EngineeringTissue Engineering
Limitations due to the Uniqueness of the HeartLimitations due to the Uniqueness of the Heart
1. Multidimensionality (pump function, time/rhythm)
1. Multidimensionality (pump function, time/rhythm)
2. Asymmetry2. Asymmetry
3. Anisotropy(different microstructure)
3. Anisotropy(different microstructure)
4. Stress Tolerance4. Stress Tolerance
5. Angiotropy (great amount of vessels)
5. Angiotropy (great amount of vessels)
6. Metabolism6. Metabolism
7. Healing and Engraftment are difficult
7. Healing and Engraftment are difficult
8. Disease model: acute vs.
chronic, limited
vs. global
8. Disease model: acute vs.
chronic, limited
vs. global
The heart: a complex helical structure with unique physical properties
The heart: a complex helical structure with unique physical properties
CWS = Pb/h × (1 – b2/2a2 – h/2b + h/8a2)
where: CWS is circumferential wall stress (in dyne/cm2 × 103),
P is left ventricular pressure (in dyne/cm2), a and b are major and minor semiaxes, respectively (in cm) and
h is left ventricular wall thickness (in cm).
CWS = Pb/h × (1 – b2/2a2 – h/2b + h/8a2)
where: CWS is circumferential wall stress (in dyne/cm2 × 103),
P is left ventricular pressure (in dyne/cm2), a and b are major and minor semiaxes, respectively (in cm) and
h is left ventricular wall thickness (in cm).
Engraftment of cardiomyocytes in a collagen matrixEngraftment of cardiomyocytes in a collagen matrix
Kofidis T et al., JHLT. 2001;20(2):188 Kofidis T et al., JHLT. 2001;20(2):188
Artificial myocardial tissue (fetal cardiomyocytes + Collagen)
Physiological features in vitroPhysiological features in vitro
Spontaneous contractilitySpontaneous contractility
Kofidis T et al. J Thorac Cardiovasc Surg. 2002 Jul;124(1):63-9.
Limitations of 3-D patchesLimitations of 3-D patches
1. Rigid or too soft2. Dissolves/hemorrhage3. Additional load to ventricle4. Suboptimal engraftment5. No innervation6. No vascularization
1. Rigid or too soft2. Dissolves/hemorrhage3. Additional load to ventricle4. Suboptimal engraftment5. No innervation6. No vascularization
Next StepNext StepNext StepNext Step
Vascularized 3-D Myocardial TissueVascularized 3-D Myocardial TissueVascularized 3-D Myocardial TissueVascularized 3-D Myocardial Tissue
Generation of vascularized full size heart muscle grafts in bioreactors
Generation of vascularized full size heart muscle grafts in bioreactors
Bioreactor improvescell viability
(3 x higher activity in FDG-PET Scan)
CM + collagen I + MatrigelCM + collagen I + Matrigel
Culture mediumCulture medium
Kofidis et al. Biomaterials. 2003;24(27):5009-14.
Engineered Heart Tissue
Zimmermann WH et al. Nature Med. 2006: 12: 452-457
BioVaM ApplicationsBioVaM Applications
myocardial patchmyocardial patch
PatencyPatency
Biological Vascularised Matrix: BioVaMBiological Vascularised Matrix: BioVaM
Endothelial cells
Cardiomyocytes
Ott HC et al.
Perfusion-decellularized
matrix: using nature's
platform to engineer a
Bioartificial heart.
Nat. Med. 2008
Ott HC et al.
Perfusion-decellularized
matrix: using nature's
platform to engineer a
Bioartificial heart.
Nat. Med. 2008
Ott HC et al. Perfusion-decellularizedmatrix: using nature's platform to engineer
A Bioartificial heart. Nat. Med. 2008; 14: 218-221
Are there alternatives to
heart transplantation ?
MECHANICAL ALTERNATIVES
• Assist devices
• Polymers
BIOLOGICAL ALTERNAIVES
• Cell therapy
•Tissue engineering
A
B
C
RESTORE FUNCTION,
NOT MORPHOLOGY!!!
Tissue Engineering Tissue Engineering
– – Role of Nano-Technology ?-Role of Nano-Technology ?-
Electroactive nanofibers
Electrically contractile nanofibers
Electrically contractile nanofibers
Normal circulation
Fontan circulation
Voss B, Sack FU, Saggau W, Hagl S, Lange R. Atrial Cardiomyoplasty in Fontancirculation. EJCTS 2002; 21: 780-786
Ruhparwar A, Piontek P, Ungerer M, Ghodsizad A, Partovi S, Foroughi J, Szabo G, Farag M, Karck M, Spinks GM, Kim SJ. Electrically Contractile Polymers Augment Right Ventricular Output in the Heart. Artif Organs 2014
Polymer Cardiomyoplasty
Ruhparwar A, Piontek P, Ungerer M, Ghodsizad A, Partovi S, Foroughi J, Szabo G, Farag M, Karck M, Spinks GM, Kim SJ. Electrically Contractile Polymers Augment Right Ventricular Output in the Heart. Artif Organs 2014
Polymer-Cardiomyoplasty: RV-pressure
Ruhparwar A, Piontek P, Ungerer M, Ghodsizad A, Partovi S, Foroughi J, Szabo G, Farag M, Karck M, Spinks GM, Kim SJ. Electrically Contractile Polymers Augment Right Ventricular Output in the Heart. Artif Organs 2014
Polymer-Cardiomyoplasty: RV-pressure
Polymer-Cardiomyoplasty: Area under the pressure-time curve
Fig 1.: Boxplot showing a direct comparison of median and data distribution before and after polymer contraction in group 2 (p<0.01).
Polymer-Cardiomyoplasty
Rat hearts with moderate pre-interventional AUC received the greatest benefit frompolymer contraction. Scatterplot comparing the AUC without polymer contraction with the relative increase in AUC following polymer contraction in group 2. The quadratic distribution (p<0.01) suggests that rat hearts with moderate pre-interventional AUC received the greatest benefit from polymer contraction.
New generation of electrically contractile polymers
Science 2014; 343: 868
New generation of electrically contractile polymers
Thank you
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