prospects for myocardial tissue engineering

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




• Assist devices

• Polymers


• Cell therapy


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-decellularizedmatrix: using nature's platform to engineer

A Bioartificial heart. Nat. Med. 2008; 14: 218-221




• Assist devices

• Polymers


• Cell therapy


A

B

C

RESTORE FUNCTION,

NOT MORPHOLOGY!!!

Tissue Engineering Tissue Engineering

– – Role of Nano-Technology ?-Role of Nano-Technology ?-

Electroactive 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


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