PROSPECTS FOR MYOCARDIAL TISSUE ENGINEERING
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PROSPECTS FOR MYOCARDIAL TISSUE ENGINEERING by Arjang Ruhparwar
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PROSPECTS FOR MYOCARDIAL TISSUE ENGINEERING
- 1. PROSPECTS FOR MYOCARDIAL TISSUE ENGINEERING Arjang Ruhparwar Dublin, May 2015
- 2. Epidemiologie Herzinsuffizienz Häufigste Todesursachen 2010 Todesursachenstatistik, Statistisches Bundesamt, Zweigstelle Bonn, 2011
- 3. Prostatea Colon-Ca Herzinsuffizienz Myokardinfarkt Blasencarcinom Herzinsuffizie nz Jahre KumulativesÜberleben 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
- 4. NUMBER OF HEART TRANSPLANTS BY YEAR AND LOCATION 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 19821983198419851986198719881989199019911992199319941995199619971998199920002001200220032004200520062007200820092010 Numberoftransplants Other Europe North 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
- 5. 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
- 6. 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
- 7. Challenges of continuous-flow VAD therapy
- 9. 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.
- 10. Are there alternatives to heart transplantation ? MECHANICAL ALTERNATIVES • Assist devices • Polymers BIOLOGICAL ALTERNAIVES • Cell therapy •Tissue engineering
- 11. Soonpaa et al., Science 1994 First successful cell transplantation into the myocardium
- 12. Limitations 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
- 13. Are there alternatives to heart transplantation ? MECHANICAL ALTERNATIVES • Assist devices • Polymers BIOLOGICAL ALTERNAIVES • Cell therapy •Tissue engineering
- 16. OrthopedicsOrthopedics Skin Cartilage Bone EyeEye Cornea Iris Pancreas Adominal SurgeryAdominal Surgery Liver Gut Neuro SurgeryNeuro Surgery Dopaminergic Cells Schwann‘s Cells Spinal cord Urology/GynecologyUrology/Gynecology Urether Urinary bladder Uterus Cardiothoracic + Vasc. SurgeryCardiothoracic + Vasc. Surgery Valves Vessels Myocardium Trachea Tissue Engineering
- 17. Limitations due to the Uniqueness of the Heart 1. Multidimensionality (pump function, time/rhythm) 2. Asymmetry 3. Anisotropy (different microstructure) 4. Stress Tolerance 5. Angiotropy (great amount of vessels) 6. Metabolism 7. Healing and Engraftment are difficult 8. Disease model: acute vs. chronic, limited vs. global
- 18. 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).
- 19. Engraftment of cardiomyocytes in a collagen matrix Kofidis T et al., JHLT. 2001;20(2):188
- 20. Artificial myocardial tissue (fetal cardiomyocytes + Collagen)
- 21. Physiological features in vitro Spontaneous contractility Kofidis T et al. J Thorac Cardiovasc Surg. 2002 Jul;124(1):63-9.
- 22. Limitations of 3-D patches 1. Rigid or too soft 2. Dissolves/hemorrhage 3. Additional load to ventricle 4. Suboptimal engraftment 5. No innervation 6. No vascularization Next StepNext StepNext StepNext Step Vascularized 3-D Myocardial TissueVascularized 3-D Myocardial TissueVascularized 3-D Myocardial TissueVascularized 3-D Myocardial Tissue
- 23. Generation of vascularized full size heart muscle grafts in bioreactors Bioreactor improves cell viability (3 x higher activity in FDG-PET Scan) CM + collagen I + Matrigel Culture medium Kofidis et al. Biomaterials. 2003;24(27):5009-14.
- 24. Engineered Heart Tissue Zimmermann WH et al. Nature Med. 2006: 12: 452-457
- 26. Biological Vascularised Matrix: BioVaM Endothelial cells Cardiomyocytes
- 28. Ott HC et al. Perfusion-decellularized matrix: using nature's platform to engineer a Bioartificial heart. Nat. Med. 2008
- 29. Ott HC et al. Perfusion-decellularized matrix: using nature's platform to engineer a Bioartificial heart. Nat. Med. 2008
- 30. Ott HC et al. Perfusion-decellularizedmatrix: using nature's platform to engineer A Bioartificial heart. Nat. Med. 2008; 14: 218-221
- 31. Are there alternatives to heart transplantation ? MECHANICAL ALTERNATIVES • Assist devices • Polymers BIOLOGICAL ALTERNAIVES • Cell therapy •Tissue engineering
- 32. A B C
- 34. Tissue EngineeringTissue Engineering –– Role of Nano-Technology ?-Role of Nano-Technology ?-
- 40. Voss B, Sack FU, Saggau W, Hagl S, Lange R. Atrial Cardiomyoplasty in Fontan circulation. EJCTS 2002; 21: 780-786
- 41. 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
- 42. 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
- 43. 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
- 45. 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).
- 46. Polymer-Cardiomyoplasty Rat hearts with moderate pre-interventional AUC received the greatest benefit from polymer 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.
- 47. New generation of electrically contractile polymers Science 2014; 343: 868
- 48. New generation of electrically contractile polymers
- 50. Thank you
Editor's Notes
- Despite of remarkable progress with solid matrices, every possible bioartificial tissue has some major limitations, the leading one being the lack of vessels to supply it. The next step in our lab was in conseqeunce to try to vascularize it, and eventually obtain thicker tissues, which would be good for the left ventricle.
- Tissue Engineering is the science that seeks to combine these three components, cells, scaffolds and biological signals, to generate human tissue equivalents at a large scale for restorative purposes.
- matrix cell interaction. These two biological procedures control cell migration, growth and differentiation during in vitro generation of functional bioartifical tissues.
- The achievements to the present time are truly remarkable…..And yet the heart is a very special organ to try to restore. Why is it so?
- Without trying to get into the hyperspace theory, let me share with you some thoughts about the uniqueness of the heart, compared to other, more static organs. The heart has more than the usual 3 dimensions, in which Tissue Engineering is perceived. The fourth dimension of the heart is its pump-function, which needs to be reproduced. Furthermore, the heart rhythm is another feature (dimension) we need to replicate.
- We proceeded to compose a bioartificial heart muscle from collagen components and neonatal cardiomyocytes. The result was a robust and spontaneously contracting tissue (the contractility started after 36 hours in culture medium). To the right you will appreciate the tight bonds cells form to each other and to the surrounding collagen fibers (for these studies we used neonatal rat cardiomyocytes).
- This is a sample of our tissue, which contracts spontaneously, without any electrical stimulation. On top of that, it displays natural physiological properties, such as those of the native heart muscle: the contractile force increasing under adrenalin and Calcium. The maximal force is achieved when this piece of tissue is passively stretched. This reminds us of the Frank Starling Law of the heart.
- Despite of remarkable progress with solid matrices, every possible bioartificial tissue has some major limitations, the leading one being the lack of vessels to supply it. The next step in our lab was in conseqeunce to try to vascularize it, and eventually obtain thicker tissues, which would be good for the left ventricle.
- This we did in a novel bioreactor system, where cells and collagen were poured into perfused chambers. The result were tissues as thick as 10mm with a 4 times higher viability and metabolism (as shown in the higher activity in the FDG-PET scan to the right and below).
- That‘s how this concepts looks like. Once again, the repopulated matrix is grafted to the right atrium, while the supporting vessels are anastomosed to aorta and right inferior vena cava.
- It seems there are no limits to natural resources for tissue replacement. In another experiment we used autologous bowel to replace the atria of the heart, for example in tumor patients. For this purpose, a piece of bowel with retained vessels was resected and decellularized and was then repopulated with endothelial cells and cardiomyocytes. The mesenteric vessels were anastomosed to the aorta and inferior vena cava, to provide blood supply. This autologous matrix was already implanted in two patients with cardiac tumors in our institution.