Experimental and computational models for tissue-engineered heart valves: a narrative review

doi:10.12336/biomatertransl.2021.04.009

Biomaterials Translational ›› 2021, Vol. 2 ›› Issue (4): 361-375.doi: 10.12336/biomatertransl.2021.04.009

• REVIEW • Previous Articles

Experimental and computational models for tissue-engineered heart valves: a narrative review

Ge Yan, Yuqi Liu, Minghui Xie, Jiawei Shi, Weihua Qiao^*(), Nianguo Dong^*()

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China

Received:2021-08-30 Revised:2021-11-26 Accepted:2021-12-03 Online:2021-12-28 Published:2021-12-28
Contact: Weihua Qiao,Nianguo Dong E-mail:weihua_qiao@hust.edu.cn;dongnianguo@hotmail.com
About author:Weihua Qiao, weihua_qiao@hust.edu.cn; Nianguo Dong, dongnianguo@hotmail.com.
First author contact:
# Author Equally.

Abstract

Abstract:

Valvular heart disease is currently a common problem which causes high morbidity and mortality worldwide. Prosthetic valve replacements are widely needed to correct narrowing or backflow through the valvular orifice. Compared to mechanical valves and biological valves, tissue-engineered heart valves can be an ideal substitute because they have a low risk of thromboembolism and calcification, and the potential for remodelling, regeneration, and growth. In order to test the performance of these heart valves, various animal models and other models are needed to optimise the structure and function of tissue-engineered heart valves, which may provide a potential mechanism responsible for substantial enhancement in tissue-engineered heart valves. Choosing the appropriate model for evaluating the performance of the tissue-engineered valve is important, as different models have their own advantages and disadvantages. In this review, we summarise the current state-of-the-art animal models, bioreactors, and computational simulation models with the aim of creating more strategies for better development of tissue-engineered heart valves. This review provides an overview of major factors that influence the selection and design of a model for tissue-engineered heart valve. Continued efforts in improving and testing models for valve regeneration remain crucial in basic science and translational researches. Future research should focus on finding the right animal model and developing better in vitro testing systems for tissue-engineered heart valve.

Key words: animal model, bioreactor, computational modelling, tissue-engineered heart valve

1.	Fioretta, E. S.; Motta, S. E.; Lintas, V.; Loerakker, S.; Parker, K. K.; Baaijens, F. P. T.; Falk, V.; Hoerstrup, S. P.; Emmert, M. Y. Next-generation tissue-engineered heart valves with repair, remodelling and regeneration capacity. Nat Rev Cardiol. 2021, 18, 92-116. doi: 10.1038/s41569-020-0422-8 URL
2.	Eoh, J. H.; Shen, N.; Burke, J. A.; Hinderer, S.; Xia, Z.; Schenke-Layland, K.; Gerecht, S. Enhanced elastin synthesis and maturation in human vascular smooth muscle tissue derived from induced-pluripotent stem cells. Acta Biomater. 2017, 52, 49-59. doi: 10.1016/j.actbio.2017.01.083 URL
3.	Henaine, R.; Roubertie, F.; Vergnat, M.; Ninet, J. Valve replacement in children: a challenge for a whole life. Arch Cardiovasc Dis. 2012, 105, 517-528. doi: 10.1016/j.acvd.2012.02.013 URL
4.	Kaneko, T.; Cohn, L. H.; Aranki, S. F. Tissue valve is the preferred option for patients aged 60 and older. Circulation. 2013, 128, 1365-1371. doi: 10.1161/CIRCULATIONAHA.113.002584 URL
5.	Emmert, M. Y.; Hoerstrup, S. P. Challenges in translating tissue engineered heart valves into clinical practice. Eur Heart J. 2017, 38, 619-621. doi: 10.1093/eurheartj/ehx075 URL
6.	Zhang, B. L.; Bianco, R. W.; Schoen, F. J. Preclinical assessment of cardiac valve substitutes: current status and considerations for engineered tissue heart valves. Front Cardiovasc Med. 2019, 6, 72. doi: 10.3389/fcvm.2019.00072 URL
7.	Chester, A. H.; Grande-Allen, K. J. Which biological properties of heart valves are relevant to tissue engineering? Front Cardiovasc Med. 2020, 7, 63. doi: 10.3389/fcvm.2020.00063 URL
8.	Quint, C.; Kondo, Y.; Manson, R. J.; Lawson, J. H.; Dardik, A.; Niklason, L. E. Decellularized tissue-engineered blood vessel as an arterial conduit. Proc Natl Acad Sci U S A. 2011, 108, 9214-9219. doi: 10.1073/pnas.1019506108 URL
9.	Dahl, S. L.; Kypson, A. P.; Lawson, J. H.; Blum, J. L.; Strader, J. T.; Li, Y.; Manson, R. J.; Tente, W. E.; DiBernardo, L.; Hensley, M. T.; Carter, R.; Williams, T. P.; Prichard, H. L.; Dey, M. S.; Begelman, K. G.; Niklason, L. E. Readily available tissue-engineered vascular grafts. Sci Transl Med. 2011, 3, 68ra69.
10.	Majid, Q. A.; Fricker, A. T. R.; Gregory, D. A.; Davidenko, N.; Hernandez Cruz, O.; Jabbour, R. J.; Owen, T. J.; Basnett, P.; Lukasiewicz, B.; Stevens, M.; Best, S.; Cameron, R.; Sinha, S.; Harding, S. E.; Roy, I. Natural biomaterials for cardiac tissue engineering: a highly biocompatible solution. Front Cardiovasc Med. 2020, 7, 554597. doi: 10.3389/fcvm.2020.554597 URL
11.	Xue, Y.; Sant, V.; Phillippi, J.; Sant, S. Biodegradable and biomimetic elastomeric scaffolds for tissue-engineered heart valves. Acta Biomater. 2017, 48, 2-19. doi: 10.1016/j.actbio.2016.10.032 URL
12.	Mirani, B.; Parvin Nejad, S.; Simmons, C. A. Recent progress toward clinical translation of tissue-engineered heart valves. Can J Cardiol. 2021, 37, 1064-1077. doi: 10.1016/j.cjca.2021.03.022 URL
13.	Hayashida, K.; Kanda, K.; Yaku, H.; Ando, J.; Nakayama, Y. Development of an in vivo tissue-engineered, autologous heart valve (the biovalve): preparation of a prototype model. J Thorac Cardiovasc Surg. 2007, 134, 152-159. doi: 10.1016/j.jtcvs.2007.01.087 URL
14.	Yamanami, M.; Yahata, Y.; Uechi, M.; Fujiwara, M.; Ishibashi-Ueda, H.; Kanda, K.; Watanabe, T.; Tajikawa, T.; Ohba, K.; Yaku, H.; Nakayama, Y. Development of a completely autologous valved conduit with the sinus of Valsalva using in-body tissue architecture technology: a pilot study in pulmonary valve replacement in a beagle model. Circulation. 2010, 122, S100-106.
15.	Motta, S. E.; Lintas, V.; Fioretta, E. S.; Dijkman, P. E.; Putti, M.; Caliskan, E.; Rodriguez Cetina Biefer, H.; Lipiski, M.; Sauer, M.; Cesarovic, N.; Hoerstrup, S. P.; Emmert, M. Y. Human cell-derived tissue-engineered heart valve with integrated Valsalva sinuses: towards native-like transcatheter pulmonary valve replacements. NPJ Regen Med. 2019, 4, 14. doi: 10.1038/s41536-019-0077-4 URL
16.	Schmitt, B.; Spriestersbach, H.; D, O. H. I.; Radtke, T.; Bartosch, M.; Peters, H.; Sigler, M.; Frese, L.; Dijkman, P. E.; Baaijens, F. P.; Hoerstrup, S. P.; Berger, F. Percutaneous pulmonary valve replacement using completely tissue-engineered off-the-shelf heart valves: six-month in vivo functionality and matrix remodelling in sheep. EuroIntervention. 2016, 12, 62-70. doi: 10.4244/EIJV12I1A12 URL
17.	Capulli, A. K.; Emmert, M. Y.; Pasqualini, F. S.; Kehl, D.; Caliskan, E.; Lind, J. U.; Sheehy, S. P.; Park, S. J.; Ahn, S.; Weber, B.; Goss, J. A.; Hoerstrup, S. P.; Parker, K. K. JetValve: Rapid manufacturing of biohybrid scaffolds for biomimetic heart valve replacement. Biomaterials. 2017, 133, 229-241. doi: 10.1016/j.biomaterials.2017.04.033 URL
18.	Guo, G.; Jin, L.; Wu, B.; He, H.; Yang, F.; Xu, L.; Lei, Y.; Wang, Y. A method for simultaneously crosslinking and functionalizing extracellular matrix-based biomaterials as bioprosthetic heart valves with enhanced endothelialization and reduced inflammation. Acta Biomater. 2021, 119, 89-100. doi: 10.1016/j.actbio.2020.10.029 URL
19.	Lovekamp, J. J.; Simionescu, D. T.; Mercuri, J. J.; Zubiate, B.; Sacks, M. S.; Vyavahare, N. R. Stability and function of glycosaminoglycans in porcine bioprosthetic heart valves. Biomaterials. 2006, 27, 1507-1518. doi: 10.1016/j.biomaterials.2005.08.003 URL
20.	Jana, S.; Franchi, F.; Lerman, A. Trilayered tissue structure with leaflet-like orientations developed through in vivo tissue engineering. Biomed Mater. 2019, 15, 015004. doi: 10.1088/1748-605X/ab52e2 URL
21.	Soares, A. L.; Oomens, C. W.; Baaijens, F. P. A computational model to describe the collagen orientation in statically cultured engineered tissues. Comput Methods Biomech Biomed Engin. 2014, 17, 251-262. doi: 10.1080/10255842.2012.680192 URL
22.	Emmert, M. Y.; Schmitt, B. A.; Loerakker, S.; Sanders, B.; Spriestersbach, H.; Fioretta, E. S.; Bruder, L.; Brakmann, K.; Motta, S. E.; Lintas, V.; Dijkman, P. E.; Frese, L.; Berger, F.; Baaijens, F. P. T.; Hoerstrup, S. P. Computational modeling guides tissue-engineered heart valve design for long-term in vivo performance in a translational sheep model. Sci Transl Med. 2018, 10, eaan4587.
23.	Flanagan, T. C.; Sachweh, J. S.; Frese, J.; Schnöring, H.; Gronloh, N.; Koch, S.; Tolba, R. H.; Schmitz-Rode, T.; Jockenhoevel, S. In vivo remodeling and structural characterization of fibrin-based tissue-engineered heart valves in the adult sheep model. Tissue Eng Part A. 2009, 15, 2965-2976. doi: 10.1089/ten.tea.2009.0018 URL
24.	Wu, H.; Xu, Z. W.; Liu, X. M.; Gong, D.; Wan, J. Y.; Xu, X. F.; Zhou, Z. F.; Li, W. B. An in vivo model of in situ implantation using pulmonary valved conduit in large animals under off-pump condition. Chin Med J (Engl). 2013, 126, 4540-4544.
25.	Zakko, J.; Blum, K. M.; Drews, J. D.; Wu, Y. L.; Hatoum, H.; Russell, M.; Gooden, S.; Heitkemper, M.; Conroy, O.; Kelly, J.; Carey, S.; Sacks, M.; Texter, K.; Ragsdale, E.; Strainic, J.; Bocks, M.; Wang, Y.; Dasi, L. P.; Armstrong, A. K.; Breuer, C. Development of tissue engineered heart valves for percutaneous transcatheter delivery in a fetal ovine model. JACC Basic Transl Sci. 2020, 5, 815-828.
26.	Coyan, G. N.; D’Amore, A.; Matsumura, Y.; Pedersen, D. D.; Luketich, S. K.; Shanov, V.; Katz, W. E.; David, T. E.; Wagner, W. R.; Badhwar, V. In vivo functional assessment of a novel degradable metal and elastomeric scaffold-based tissue engineered heart valve. J Thorac Cardiovasc Surg. 2019, 157, 1809-1816. doi: 10.1016/j.jtcvs.2018.09.128 URL
27.	Schlegel, F.; Salameh, A.; Oelmann, K.; Halling, M.; Dhein, S.; Mohr, F. W.; Dohmen, P. M. Injectable tissue engineered pulmonary heart valve implantation into the pig model: A feasibility study. Med Sci Monit Basic Res. 2015, 21, 135-140. doi: 10.12659/MSMBR.894838 URL
28.	Bianco, R. W.; St Cyr, J. A.; Schneider, J. R.; Rasmussen, T. M.; Clack, R. M.; Shim, H. S.; Sandstad, J.; Rysavy, J.; Foker, J. E. Canine model for long-term evaluation of prosthetic mitral valves. J Surg Res. 1986, 41, 134-140. doi: 10.1016/0022-4804(86)90018-1 URL
29.	Ye, X.; Bhushan, B.; Zhou, M.; Lei, W. The surface microstructure of cusps and leaflets in rabbit and mouse heart valves. Beilstein J Nanotechnol. 2014, 5, 622-629. doi: 10.3762/bjnano.5.73 URL
30.	Weber, B.; Dijkman, P. E.; Scherman, J.; Sanders, B.; Emmert, M. Y.; Grünenfelder, J.; Verbeek, R.; Bracher, M.; Black, M.; Franz, T.; Kortsmit, J.; Modregger, P.; Peter, S.; Stampanoni, M.; Robert, J.; Kehl, D.; van Doeselaar, M.; Schweiger, M.; Brokopp, C. E.; Wälchli, T.; Falk, V.; Zilla, P.; Driessen-Mol, A.; Baaijens, F. P.; Hoerstrup, S. P. Off-the-shelf human decellularized tissue-engineered heart valves in a non-human primate model. Biomaterials. 2013, 34, 7269-7280. doi: 10.1016/j.biomaterials.2013.04.059 URL
31.	Smith, M. R.; Wood, W. B., Jr. An experimental analysis of the curative action of penicillin in acute bacterial infections. III. The effect of suppuration upon the antibacterial action of the drug. J Exp Med. 1956, 103, 509-522. doi: 10.1084/jem.103.4.509 URL
32.	Kim, M. S.; Jeong, S.; Lim, H. G.; Kim, Y. J. Differences in xenoreactive immune response and patterns of calcification of porcine and bovine tissues in α-Gal knock-out and wild-type mouse implantation models. Eur J Cardiothorac Surg. 2015, 48, 392-399. doi: 10.1093/ejcts/ezu501 URL
33.	Christ, T.; Dohmen, P. M.; Holinski, S.; Schönau, M.; Heinze, G.; Konertz, W. Suitability of the rat subdermal model for tissue engineering of heart valves. Med Sci Monit Basic Res. 2014, 20, 194-199. doi: 10.12659/MSMBR.893088 URL
34.	Assmann, A.; Delfs, C.; Munakata, H.; Schiffer, F.; Horstkötter, K.; Huynh, K.; Barth, M.; Stoldt, V. R.; Kamiya, H.; Boeken, U.; Lichtenberg, A.; Akhyari, P. Acceleration of autologous in vivo recellularization of decellularized aortic conduits by fibronectin surface coating. Biomaterials. 2013, 34, 6015-6026. doi: 10.1016/j.biomaterials.2013.04.037 URL
35.	Rashid, S. T.; Salacinski, H. J.; Hamilton, G.; Seifalian, A. M. The use of animal models in developing the discipline of cardiovascular tissue engineering: a review. Biomaterials. 2004, 25, 1627-1637. doi: 10.1016/S0142-9612(03)00522-2 URL
36.	Driessen-Mol, A.; Emmert, M. Y.; Dijkman, P. E.; Frese, L.; Sanders, B.; Weber, B.; Cesarovic, N.; Sidler, M.; Leenders, J.; Jenni, R.; Grünenfelder, J.; Falk, V.; Baaijens, F. P. T.; Hoerstrup, S. P. Transcatheter implantation of homologous “off-the-shelf” tissue-engineered heart valves with self-repair capacity: long-term functionality and rapid in vivo remodeling in sheep. J Am Coll Cardiol. 2014, 63, 1320-1329. doi: 10.1016/j.jacc.2013.09.082 URL
37.	Shinoka, T.; Ma, P. X.; Shum-Tim, D.; Breuer, C. K.; Cusick, R. A.; Zund, G.; Langer, R.; Vacanti, J. P.; Mayer, J. E., Jr. Tissue-engineered heart valves. Autologous valve leaflet replacement study in a lamb model. Circulation. 1996, 94, II164-168.
38.	Schroeder, F.; Polzer, S.; Slažanský, M.; Man, V.; Skácel, P. Predictive capabilities of various constitutive models for arterial tissue. J Mech Behav Biomed Mater. 2018, 78, 369-380. doi: 10.1016/j.jmbbm.2017.11.035 URL
39.	Swindle, M. M.; Makin, A.; Herron, A. J.; Clubb, F. J., Jr.; Frazier, K. S. Swine as models in biomedical research and toxicology testing. Vet Pathol. 2012, 49, 344-356. doi: 10.1177/0300985811402846 URL
40.	Grehan, J. F.; Hilbert, S. L.; Ferrans, V. J.; Droel, J. S.; Salerno, C. T.; Bianco, R. W. Development and evaluation of a swine model to assess the preclinical safety of mechanical heart valves. J Heart Valve Dis. 2000, 9, 710-719; discussion 719-720.
41.	Canty, J. M., Jr.; Suzuki, G.; Banas, M. D.; Verheyen, F.; Borgers, M.; Fallavollita, J. A. Hibernating myocardium: chronically adapted to ischemia but vulnerable to sudden death. Circ Res. 2004, 94, 1142-1149. doi: 10.1161/01.RES.0000125628.57672.CF URL
42.	Gallo, M.; Poser, H.; Bottio, T.; Bonetti, A.; Franci, P.; Naso, F.; Buratto, E.; Zanella, F.; Perona, G.; Dal Lin, C.; Bianco, R.; Spina, M.; Busetto, R.; Marchini, M.; Ortolani, F.; Iop, L.; Gerosa, G. The Vietnamese pig as a translational animal model to evaluate tissue engineered heart valves: promising early experience. Int J Artif Organs. 2017, 40, 142-149. doi: 10.5301/ijao.5000568 URL
43.	Gallo, M.; Bianco, R.; Bottio, T.; Naso, F.; Franci, P.; Zanella, F.; Perona, G.; Busetto, R.; Spina, M.; Gandaglia, A.; Gerosa, G. Tissue-engineered heart valves: intra-operative protocol. J Cardiovasc Transl Res. 2013, 6, 660-661. doi: 10.1007/s12265-013-9480-1 URL
44.	Gallo, M.; Naso, F.; Poser, H.; Rossi, A.; Franci, P.; Bianco, R.; Micciolo, M.; Zanella, F.; Cucchini, U.; Aresu, L.; Buratto, E.; Busetto, R.; Spina, M.; Gandaglia, A.; Gerosa, G. Physiological performance of a detergent decellularized heart valve implanted for 15 months in Vietnamese pigs: surgical procedure, follow-up, and explant inspection. Artif Organs. 2012, 36, E138-150. doi: 10.1111/aor.2012.36.issue-6 URL
45.	Boudjemline, Y.; Agnoletti, G.; Bonnet, D.; Behr, L.; Borenstein, N.; Sidi, D.; Bonhoeffer, P. Steps toward the percutaneous replacement of atrioventricular valves an experimental study. J Am Coll Cardiol. 2005, 46, 360-365. doi: 10.1016/j.jacc.2005.01.063 URL
46.	Dewey, T. M.; Walther, T.; Doss, M.; Brown, D.; Ryan, W. H.; Svensson, L.; Mihaljevic, T.; Hambrecht, R.; Schuler, G.; Wimmer-Greinecker, G.; Mohr, F. W.; Mack, M. J. Transapical aortic valve implantation: an animal feasibility study. Ann Thorac Surg. 2006, 82, 110-116. doi: 10.1016/j.athoracsur.2006.02.035 URL
47.	Lutter, G.; Kuklinski, D.; Berg, G.; Von Samson, P.; Martin, J.; Handke, M.; Uhrmeister, P.; Beyersdorf, F. Percutaneous aortic valve replacement: an experimental study. I. Studies on implantation. J Thorac Cardiovasc Surg. 2002, 123, 768-776. doi: 10.1067/mtc.2002.121157 URL
48.	Walther, T.; Dewey, T.; Wimmer-Greinecker, G.; Doss, M.; Hambrecht, R.; Schuler, G.; Mohr, F. W.; Mack, M. Transapical approach for sutureless stent-fixed aortic valve implantation: experimental results. Eur J Cardiothorac Surg. 2006, 29, 703-708. doi: 10.1016/j.ejcts.2006.01.062 URL
49.	Kokozidou, M.; Katsargyris, A.; Verhoeven, E. L. G.; Schulze-Tanzil, G. Vascular access animal models used in research. Ann Anat. 2019, 225, 65-75. doi: 10.1016/j.aanat.2019.06.002 URL
50.	Camacho, P.; Fan, H.; Liu, Z.; He, J. Q. Large mammalian animal models of heart disease. J Cardiovasc Dev Dis. 2016, 3, 30.
51.	Iwai, S.; Torikai, K.; Coppin, C. M.; Sawa, Y. Minimally immunogenic decellularized porcine valve provides in situ recellularization as a stentless bioprosthetic valve. J Artif Organs. 2007, 10, 29-35. doi: 10.1007/s10047-006-0360-1 URL
52.	Yang, H.; Shao, N.; Holmström, A.; Zhao, X.; Chour, T.; Chen, H.; Itzhaki, I.; Wu, H.; Ameen, M.; Cunningham, N. J.; Tu, C.; Zhao, M. T.; Tarantal, A. F.; Abilez, O. J.; Wu, J. C. Transcriptome analysis of non human primate-induced pluripotent stem cell-derived cardiomyocytes in 2D monolayer culture vs. 3D engineered heart tissue. Cardiovasc Res. 2021, 117, 2125-2136. doi: 10.1093/cvr/cvaa281 URL
53.	Rahman, M. A.; Robert-Guroff, M. Accelerating HIV vaccine development using non-human primate models. Expert Rev Vaccines. 2019, 18, 61-73. doi: 10.1080/14760584.2019.1557521 URL
54.	Brok, H. P.; Bauer, J.; Jonker, M.; Blezer, E.; Amor, S.; Bontrop, R. E.; Laman, J. D.; t Hart, B. A. Non-human primate models of multiple sclerosis. Immunol Rev. 2001, 183, 173-185. doi: 10.1034/j.1600-065x.2001.1830114.x URL
55.	Lu, T.; Yang, B.; Wang, R.; Qin, C. Xenotransplantation: current status in preclinical research. Front Immunol. 2019, 10, 3060. doi: 10.3389/fimmu.2019.03060 URL
56.	Anderson, J. M.; Rodriguez, A.; Chang, D. T. Foreign body reaction to biomaterials. Semin Immunol. 2008, 20, 86-100. doi: 10.1016/j.smim.2007.11.004 URL
57.	Raasch, M.; Rennert, K.; Jahn, T.; Peters, S.; Henkel, T.; Huber, O.; Schulz, I.; Becker, H.; Lorkowski, S.; Funke, H.; Mosig, A. Microfluidically supported biochip design for culture of endothelial cell layers with improved perfusion conditions. Biofabrication. 2015, 7, 015013. doi: 10.1088/1758-5090/7/1/015013 URL
58.	Rath, S.; Salinas, M.; Villegas, A. G.; Ramaswamy, S. Differentiation and distribution of marrow stem cells in flex-flow environments demonstrate support of the valvular phenotype. PLoS One. 2015, 10, e0141802. doi: 10.1371/journal.pone.0141802 URL
59.	Flanagan, T. C.; Cornelissen, C.; Koch, S.; Tschoeke, B.; Sachweh, J. S.; Schmitz-Rode, T.; Jockenhoevel, S. The in vitro development of autologous fibrin-based tissue-engineered heart valves through optimised dynamic conditioning. Biomaterials. 2007, 28, 3388-3397. doi: 10.1016/j.biomaterials.2007.04.012 URL
60.	Deb, N.; Ali, M. S.; Mathews, A.; Chang, Y. W.; Lacerda, C. M. Shear type and magnitude affect aortic valve endothelial cell morphology, orientation, and differentiation. Exp Biol Med (Maywood). 2021, 246, 2278-2289. doi: 10.1177/15353702211023359 URL
61.	Li, A.; Tan, L.; Zhang, S.; Tao, J.; Wang, Z.; Wei, D. Low shear stress-induced endothelial mesenchymal transformation via the down-regulation of TET2. Biochem Biophys Res Commun. 2021, 545, 20-26. doi: 10.1016/j.bbrc.2021.01.062 URL
62.	Bazan, O.; Simbara, M. M. O.; Ortiz, J. P.; Malmonge, S. M.; Andrade, A.; Yanagihara, J. I. In vitro hydrodynamic evaluation of a scaffold for heart valve tissue engineering. Artif Organs. 2019, 43, 195-198. doi: 10.1111/aor.2019.43.issue-2 URL
63.	Tefft, B. J.; Choe, J. A.; Young, M. D.; Hennessy, R. S.; Morse, D. W.; Bouchard, J. A.; Hedberg, H. J.; Consiglio, J. F.; Dragomir-Daescu, D.; Simari, R. D.; Lerman, A. Cardiac valve bioreactor for physiological conditioning and hydrodynamic performance assessment. Cardiovasc Eng Technol. 2019, 10, 80-94. doi: 10.1007/s13239-018-00382-2 URL
64.	Kim, J.; Lee, Y.; Choi, S.; Ha, H. Pulsatile flow pump based on an iterative controlled piston pump actuator as an in-vitro cardiovascular flow model. Med Eng Phys. 2020, 77, 118-124. doi: 10.1016/j.medengphy.2019.10.020 URL
65.	Qian, T.; Gil, D. A.; Contreras Guzman, E.; Gastfriend, B. D.; Tweed, K. E.; Palecek, S. P.; Skala, M. C. Adaptable pulsatile flow generated from stem cell-derived cardiomyocytes using quantitative imaging-based signal transduction. Lab Chip. 2020, 20, 3744-3756. doi: 10.1039/D0LC00546K URL
66.	Posmantur, R.; Hayes, R. L.; Dixon, C. E.; Taft, W. C. Neurofilament 68 and neurofilament 200 protein levels decrease after traumatic brain injury. J Neurotrauma. 1994, 11, 533-545. doi: 10.1089/neu.1994.11.533 URL
67.	Hildebrand, D. K.; Wu, Z. J.; Mayer, J. E., Jr.; Sacks, M. S. Design and hydrodynamic evaluation of a novel pulsatile bioreactor for biologically active heart valves. Ann Biomed Eng. 2004, 32, 1039-1049. doi: 10.1114/B:ABME.0000036640.11387.4b URL
68.	Gandaglia, A.; Bagno, A.; Naso, F.; Spina, M.; Gerosa, G. Cells, scaffolds and bioreactors for tissue-engineered heart valves: a journey from basic concepts to contemporary developmental innovations. Eur J Cardiothorac Surg. 2011, 39, 523-531. doi: 10.1016/j.ejcts.2010.07.030 URL
69.	Ramaswamy, S.; Boronyak, S. M.; Le, T.; Holmes, A.; Sotiropoulos, F.; Sacks, M. S. A novel bioreactor for mechanobiological studies of engineered heart valve tissue formation under pulmonary arterial physiological flow conditions. J Biomech Eng. 2014, 136, 121009. doi: 10.1115/1.4028815 URL
70.	Nguemgo Kouam, P.; Bühler, H.; Hero, T.; Adamietz, I. A. The increased adhesion of tumor cells to endothelial cells after irradiation can be reduced by FAK-inhibition. Radiat Oncol. 2019, 14, 25. doi: 10.1186/s13014-019-1230-3 URL
71.	Hampel, U.; Garreis, F.; Burgemeister, F.; Eßel, N.; Paulsen, F. Effect of intermittent shear stress on corneal epithelial cells using an in vitro flow culture model. Ocul Surf. 2018, 16, 341-351. doi: 10.1016/j.jtos.2018.04.005 URL
72.	Helle, E.; Ampuja, M.; Antola, L.; Kivelä, R. Flow-induced transcriptomic remodeling of endothelial cells derived from human induced pluripotent stem cells. Front Physiol. 2020, 11, 591450. doi: 10.3389/fphys.2020.591450 URL
73.	Moon du, G.; Christ, G.; Stitzel, J. D.; Atala, A.; Yoo, J. J. Cyclic mechanical preconditioning improves engineered muscle contraction. Tissue Eng Part A. 2008, 14, 473-482. doi: 10.1089/tea.2007.0104 URL
74.	Sun, L.; Qu, L.; Zhu, R.; Li, H.; Xue, Y.; Liu, X.; Fan, J.; Fan, H. Effects of mechanical stretch on cell proliferation and matrix formation of mesenchymal stem cell and anterior cruciate ligament fibroblast. Stem Cells Int. 2016, 2016, 9842075.
75.	Ku, C. H.; Johnson, P. H.; Batten, P.; Sarathchandra, P.; Chambers, R. C.; Taylor, P. M.; Yacoub, M. H.; Chester, A. H. Collagen synthesis by mesenchymal stem cells and aortic valve interstitial cells in response to mechanical stretch. Cardiovasc Res. 2006, 71, 548-556. doi: 10.1016/j.cardiores.2006.03.022 URL
76.	Syedain, Z. H.; Tranquillo, R. T. Controlled cyclic stretch bioreactor for tissue-engineered heart valves. Biomaterials. 2009, 30, 4078-4084. doi: 10.1016/j.biomaterials.2009.04.027 URL
77.	Engelmayr, G. C., Jr.; Rabkin, E.; Sutherland, F. W.; Schoen, F. J.; Mayer, J. E., Jr.; Sacks, M. S. The independent role of cyclic flexure in the early in vitro development of an engineered heart valve tissue. Biomaterials. 2005, 26, 175-187. doi: 10.1016/j.biomaterials.2004.02.035 URL
78.	Engelmayr, G. C., Jr.; Hildebrand, D. K.; Sutherland, F. W.; Mayer, J. E., Jr.; Sacks, M. S. A novel bioreactor for the dynamic flexural stimulation of tissue engineered heart valve biomaterials. Biomaterials. 2003, 24, 2523-2532. doi: 10.1016/S0142-9612(03)00051-6 URL
79.	Kutikhin, A. G.; Sinitsky, M. Y.; Yuzhalin, A. E.; Velikanova, E. A. Shear stress: an essential driver of endothelial progenitor cells. J Mol Cell Cardiol. 2018, 118, 46-69. doi: 10.1016/j.yjmcc.2018.03.007 URL
80.	Yang, Z.; Xia, W. H.; Zhang, Y. Y.; Xu, S. Y.; Liu, X.; Zhang, X. Y.; Yu, B. B.; Qiu, Y. X.; Tao, J. Shear stress-induced activation of Tie2-dependent signaling pathway enhances reendothelialization capacity of early endothelial progenitor cells. J Mol Cell Cardiol. 2012, 52, 1155-1163. doi: 10.1016/j.yjmcc.2012.01.019 URL
81.	Campinho, P.; Vilfan, A.; Vermot, J. Blood flow forces in shaping the vascular system: a focus on endothelial cell behavior. Front Physiol. 2020, 11, 552. doi: 10.3389/fphys.2020.00552 URL
82.	da Silva, R. A.; Fernandes, C.; Feltran, G. D. S.; Gomes, A. M.; de Camargo Andrade, A. F.; Andia, D. C.; Peppelenbosch, M. P.; Zambuzzi, W. F. Laminar shear stress-provoked cytoskeletal changes are mediated by epigenetic reprogramming of TIMP1 in human primary smooth muscle cells. J Cell Physiol. 2019, 234, 6382-6396. doi: 10.1002/jcp.v234.5 URL
83.	Gonzalez, B. A.; Perez-Nevarez, M.; Mirza, A.; Perez, M. G.; Lin, Y. M.; Hsu, C. D.; Caobi, A.; Raymond, A.; Gomez Hernandez, M. E.; Fernandez-Lima, F.; George, F.; Ramaswamy, S. Physiologically relevant fluid-induced oscillatory shear stress stimulation of mesenchymal stem cells enhances the engineered valve matrix phenotype. Front Cardiovasc Med. 2020, 7, 69. doi: 10.3389/fcvm.2020.00069 URL
84.	Li, J.; He, Y.; Bu, H.; Wang, M.; Yu, J.; Li, L.; Li, H.; Zhang, X.; Cui, X.; Cheng, M. Oscillating shear stress mediates mesenchymal transdifferentiation of EPCs by the Kir2.1 channel. Heart Vessels. 2020, 35, 1473-1482. doi: 10.1007/s00380-020-01625-w URL
85.	Gao, Y.; Cui, X.; Wang, M.; Zhang, Y.; He, Y.; Li, L.; Li, H.; Zhang, X.; Cheng, M. Oscillatory shear stress induces the transition of EPCs into mesenchymal cells through ROS/PKCζ/p53 pathway. Life Sci. 2020, 253, 117728. doi: 10.1016/j.lfs.2020.117728 URL
86.	Converse, G. L.; Buse, E. E.; Neill, K. R.; McFall, C. R.; Lewis, H. N.; VeDepo, M. C.; Quinn, R. W.; Hopkins, R. A. Design and efficacy of a single-use bioreactor for heart valve tissue engineering. J Biomed Mater Res B Appl Biomater. 2017, 105, 249-259. doi: 10.1002/jbm.v105.2 URL
87.	Jockenhoevel, S.; Zund, G.; Hoerstrup, S. P.; Schnell, A.; Turina, M. Cardiovascular tissue engineering: a new laminar flow chamber for in vitro improvement of mechanical tissue properties. ASAIO J. 2002, 48, 8-11. doi: 10.1097/00002480-200201000-00003 URL
88.	Engelmayr, G. C., Jr.; Sales, V. L.; Mayer, J. E., Jr.; Sacks, M. S. Cyclic flexure and laminar flow synergistically accelerate mesenchymal stem cell-mediated engineered tissue formation: Implications for engineered heart valve tissues. Biomaterials. 2006, 27, 6083-6095. doi: 10.1016/j.biomaterials.2006.07.045 URL
89.	Ramaswamy, S.; Gottlieb, D.; Engelmayr, G. C., Jr.; Aikawa, E.; Schmidt, D. E.; Gaitan-Leon, D. M.; Sales, V. L.; Mayer, J. E., Jr.; Sacks, M. S. The role of organ level conditioning on the promotion of engineered heart valve tissue development in-vitro using mesenchymal stem cells. Biomaterials. 2010, 31, 1114-1125. doi: 10.1016/j.biomaterials.2009.10.019 URL
90.	Mongkoldhumrongkul, N.; Latif, N.; Yacoub, M. H.; Chester, A. H. Effect of side-specific valvular shear stress on the content of extracellular matrix in aortic valves. Cardiovasc Eng Technol. 2018, 9, 151-157. doi: 10.1007/s13239-016-0280-z URL
91.	Engelmayr, G. C., Jr.; Soletti, L.; Vigmostad, S. C.; Budilarto, S. G.; Federspiel, W. J.; Chandran, K. B.; Vorp, D. A.; Sacks, M. S. A novel flex-stretch-flow bioreactor for the study of engineered heart valve tissue mechanobiology. Ann Biomed Eng. 2008, 36, 700-712. doi: 10.1007/s10439-008-9447-6 URL
92.	Vozzi, F.; Bianchi, F.; Ahluwalia, A.; Domenici, C. Hydrostatic pressure and shear stress affect endothelin-1 and nitric oxide release by endothelial cells in bioreactors. Biotechnol J. 2014, 9, 146-154. doi: 10.1002/biot.v9.1 URL
93.	VeDepo, M. C.; Buse, E. E.; Paul, A.; Converse, G. L.; Hopkins, R. A. Non-physiologic bioreactor processing conditions for heart valve tissue engineering. Cardiovasc Eng Technol. 2019, 10, 628-637. doi: 10.1007/s13239-019-00438-x URL
94.	Hutmacher, D. W.; Singh, H. Computational fluid dynamics for improved bioreactor design and 3D culture. Trends Biotechnol. 2008, 26, 166-172. doi: 10.1016/j.tibtech.2007.11.012 URL
95.	Williams, A.; Nasim, S.; Salinas, M.; Moshkforoush, A.; Tsoukias, N.; Ramaswamy, S. A “sweet-spot” for fluid-induced oscillations in the conditioning of stem cell-based engineered heart valve tissues. J Biomech. 2017, 65, 40-48. doi: 10.1016/j.jbiomech.2017.09.035 URL
96.	Salinas, M.; Ramaswamy, S. Computational simulations predict a key role for oscillatory fluid shear stress in de novo valvular tissue formation. J Biomech. 2014, 47, 3517-3523. doi: 10.1016/j.jbiomech.2014.08.028 URL
97.	Lichtenberg, A.; Tudorache, I.; Cebotari, S.; Suprunov, M.; Tudorache, G.; Goerler, H.; Park, J. K.; Hilfiker-Kleiner, D.; Ringes-Lichtenberg, S.; Karck, M.; Brandes, G.; Hilfiker, A.; Haverich, A. Preclinical testing of tissue-engineered heart valves re-endothelialized under simulated physiological conditions. Circulation. 2006, 114, I559-565.
98.	Lichtenberg, A.; Tudorache, I.; Cebotari, S.; Ringes-Lichtenberg, S.; Sturz, G.; Hoeffler, K.; Hurscheler, C.; Brandes, G.; Hilfiker, A.; Haverich, A. In vitro re-endothelialization of detergent decellularized heart valves under simulated physiological dynamic conditions. Biomaterials. 2006, 27, 4221-4229. doi: 10.1016/j.biomaterials.2006.03.047 URL
99.	Santoro, R.; Venkateswaran, S.; Amadeo, F.; Zhang, R.; Brioschi, M.; Callanan, A.; Agrifoglio, M.; Banfi, C.; Bradley, M.; Pesce, M. Acrylate-based materials for heart valve scaffold engineering. Biomater Sci. 2017, 6, 154-167. doi: 10.1039/C7BM00854F URL
100.	Best, C. A.; Szafron, J. M.; Rocco, K. A.; Zbinden, J.; Dean, E. W.; Maxfield, M. W.; Kurobe, H.; Tara, S.; Bagi, P. S.; Udelsman, B. V.; Khosravi, R.; Yi, T.; Shinoka, T.; Humphrey, J. D.; Breuer, C. K. Differential outcomes of venous and arterial tissue engineered vascular grafts highlight the importance of coupling long-term implantation studies with computational modeling. Acta Biomater. 2019, 94, 183-194. doi: 10.1016/j.actbio.2019.05.063 URL
101.	Hsu, M. C.; Kamensky, D.; Xu, F.; Kiendl, J.; Wang, C.; Wu, M. C.; Mineroff, J.; Reali, A.; Bazilevs, Y.; Sacks, M. S. Dynamic and fluid-structure interaction simulations of bioprosthetic heart valves using parametric design with T-splines and Fung-type material models. Comput Mech. 2015, 55, 1211-1225. doi: 10.1007/s00466-015-1166-x URL
102.	Martin, C.; Sun, W. Simulation of long-term fatigue damage in bioprosthetic heart valves: effects of leaflet and stent elastic properties. Biomech Model Mechanobiol. 2014, 13, 759-770. doi: 10.1007/s10237-013-0532-x URL
103.	Szafron, J. M.; Ramachandra, A. B.; Breuer, C. K.; Marsden, A. L.; Humphrey, J. D. Optimization of tissue-engineered vascular graft design using computational modeling. Tissue Eng Part C Methods. 2019, 25, 561-570. doi: 10.1089/ten.tec.2019.0086 URL
104.	Sulejmani, F.; Caballero, A.; Martin, C.; Pham, T.; Sun, W. Evaluation of transcatheter heart valve biomaterials: Computational modeling using bovine and porcine pericardium. J Mech Behav Biomed Mater. 2019, 97, 159-170. doi: 10.1016/j.jmbbm.2019.05.020 URL
105.	Zakerzadeh, R.; Hsu, M. C.; Sacks, M. S. Computational methods for the aortic heart valve and its replacements. Expert Rev Med Devices. 2017, 14, 849-866. doi: 10.1080/17434440.2017.1389274 URL
106.	Abbasi, M.; Barakat, M. S.; Vahidkhah, K.; Azadani, A. N. Characterization of three-dimensional anisotropic heart valve tissue mechanical properties using inverse finite element analysis. J Mech Behav Biomed Mater. 2016, 62, 33-44. doi: 10.1016/j.jmbbm.2016.04.031 URL
107.	Fernández-Ruiz, I. Computer modelling to personalize bioengineered heart valves. Nat Rev Cardiol. 2018, 15, 440-441.
108.	Butcher, J. T. The root problem of heart valve engineering. Sci Transl Med. 2018, 10, eaat5850.
109.	Simmons, C. A. Taking bioengineered heart valves from faulty to functional. Nature. 2018, 559, 42-43. doi: 10.1038/d41586-018-05566-3 URL
110.	Loureiro-Ga, M.; Veiga, C.; Fdez-Manin, G.; Jimenez, V. A.; Calvo-Iglesias, F.; Iñiguez, A. A biomechanical model of the pathological aortic valve: simulation of aortic stenosis. Comput Methods Biomech Biomed Engin. 2020, 23, 303-311. doi: 10.1080/10255842.2020.1720001 URL
111.	Conti, C. A.; Della Corte, A.; Votta, E.; Del Viscovo, L.; Bancone, C.; De Santo, L. S.; Redaelli, A. Biomechanical implications of the congenital bicuspid aortic valve: a finite element study of aortic root function from in vivo data. J Thorac Cardiovasc Surg. 2010, 140, 890-896, 896.e1-2. doi: 10.1016/j.jtcvs.2010.01.016 URL
112.	Arzani, A.; Mofrad, M. R. K. A strain-based finite element model for calcification progression in aortic valves. J Biomech. 2017, 65, 216-220. doi: 10.1016/j.jbiomech.2017.10.014 URL
113.	Rassoli, A.; Fatouraee, N.; Guidoin, R.; Zhang, Z. Comparison of tensile properties of xenopericardium from three animal species and finite element analysis for bioprosthetic heart valve tissue. Artif Organs. 2020, 44, 278-287. doi: 10.1111/aor.v44.3 URL
114.	Vashistha, R.; Kumar, P.; Dangi, A. K.; Sharma, N.; Chhabra, D.; Shukla, P. Quest for cardiovascular interventions: precise modeling and 3D printing of heart valves. J Biol Eng. 2019, 13, 12. doi: 10.1186/s13036-018-0132-5 URL
115.	van der Valk, D. C.; van der Ven, C. F. T.; Blaser, M. C.; Grolman, J. M.; Wu, P. J.; Fenton, O. S.; Lee, L. H.; Tibbitt, M. W.; Andresen, J. L.; Wen, J. R.; Ha, A. H.; Buffolo, F.; van Mil, A.; Bouten, C. V. C.; Body, S. C.; Mooney, D. J.; Sluijter, J. P. G.; Aikawa, M.; Hjortnaes, J.; Langer, R.; Aikawa, E. Engineering a 3D-bioprinted model of human heart valve disease using nanoindentation-based biomechanics. Nanomaterials (Basel). 2018, 8, 296. doi: 10.3390/nano8050296 URL
116.	Labrosse, M. R.; Beller, C. J.; Robicsek, F.; Thubrikar, M. J. Geometric modeling of functional trileaflet aortic valves: development and clinical applications. J Biomech. 2006, 39, 2665-2672. doi: 10.1016/j.jbiomech.2005.08.012 URL
117.	Marom, G.; Haj-Ali, R.; Rosenfeld, M.; Schäfers, H. J.; Raanani, E. Aortic root numeric model: correlation between intraoperative effective height and diastolic coaptation. J Thorac Cardiovasc Surg. 2013, 145, 303-304. doi: 10.1016/j.jtcvs.2012.08.043 URL
118.	Zhang, W.; Rossini, G.; Kamensky, D.; Bui-Thanh, T.; Sacks, M. S. Isogeometric finite element-based simulation of the aortic heart valve: Integration of neural network structural material model and structural tensor fiber architecture representations. Int J Numer Method Biomed Eng. 2021, 37, e3438.
119.	Li, Q.; Wang, J.; Tao, H.; Zhou, Q.; Chen, J.; Fu, B.; Qin, W.; Li, D.; Hou, J.; Chen, J.; Zhang, W. H. The prediction model of warfarin individual maintenance dose for patients undergoing heart valve replacement, based on the back propagation neural network. Clin Drug Investig. 2020, 40, 41-53. doi: 10.1007/s40261-019-00850-0 URL
120.	Obbink-Huizer, C.; Oomens, C. W.; Loerakker, S.; Foolen, J.; Bouten, C. V.; Baaijens, F. P. Computational model predicts cell orientation in response to a range of mechanical stimuli. Biomech Model Mechanobiol. 2014, 13, 227-236. doi: 10.1007/s10237-013-0501-4 URL
121.	Loerakker, S.; Obbink-Huizer, C.; Baaijens, F. P. A physically motivated constitutive model for cell-mediated compaction and collagen remodeling in soft tissues. Biomech Model Mechanobiol. 2014, 13, 985-1001. doi: 10.1007/s10237-013-0549-1 URL
122.	Ristori, T.; Bouten, C. V. C.; Baaijens, F. P. T.; Loerakker, S. Predicting and understanding collagen remodeling in human native heart valves during early development. Acta Biomater. 2018, 80, 203-216. doi: 10.1016/j.actbio.2018.08.040 URL
123.	Loerakker, S.; Ristori, T.; Baaijens, F. P. T. A computational analysis of cell-mediated compaction and collagen remodeling in tissue-engineered heart valves. J Mech Behav Biomed Mater. 2016, 58, 173-187. doi: 10.1016/j.jmbbm.2015.10.001 URL
124.	Soares, J. S.; T, B. L.; Sotiropoulos, F.; M, S. S. Modeling the role of oscillator flow and dynamic mechanical conditioning on dense connective tissue formation in mesenchymal stem cell-derived heart valve tissue engineering. J Med Device. 2013, 7, 0409271-0409272.
125.	Soares, J. S.; Sacks, M. S. A triphasic constrained mixture model of engineered tissue formation under in vitro dynamic mechanical conditioning. Biomech Model Mechanobiol. 2016, 15, 293-316. doi: 10.1007/s10237-015-0687-8 URL
126.	Sanders, B.; Loerakker, S.; Fioretta, E. S.; Bax, D. J.; Driessen-Mol, A.; Hoerstrup, S. P.; Baaijens, F. P. Improved geometry of decellularized tissue engineered heart valves to prevent leaflet retraction. Ann Biomed Eng. 2016, 44, 1061-1071. doi: 10.1007/s10439-015-1386-4 URL
127.	Loerakker, S.; Argento, G.; Oomens, C. W.; Baaijens, F. P. Effects of valve geometry and tissue anisotropy on the radial stretch and coaptation area of tissue-engineered heart valves. J Biomech. 2013, 46, 1792-1800. doi: 10.1016/j.jbiomech.2013.05.015 URL
128.	Motta, S. E.; Fioretta, E. S.; Lintas, V.; Dijkman, P. E.; Hilbe, M.; Frese, L.; Cesarovic, N.; Loerakker, S.; Baaijens, F. P. T.; Falk, V.; Hoerstrup, S. P.; Emmert, M. Y. Geometry influences inflammatory host cell response and remodeling in tissue-engineered heart valves in-vivo. Sci Rep. 2020, 10, 19882. doi: 10.1038/s41598-020-76322-9 URL

Species	TEHV manufacture	Surgical method	Functionality assessment and post-mortem analysis	Reference
Small animal model
Mouse	Sulfonic polymer hybrid extracellular matrix	Subdermal	Histological and immunohistochemical analysis	18
Rat	Glut-fixed porcine aortic valve	Subdermal	Histological and quantitative analysis	19
	Electrospinning polycaprolactone scaffold	Subdermal	Scanning electron microscopic and histological analysis	20
	Allogeneic aortic conduit grafts	End-to-side anastomosis with infrarenal aorta	Histological and immunohistochemical analysis, quantitative real-time polymerase chain reaction	21
Rabbit	Poly urethane scaffold	Subdermal	Macroscopic and histological analysis	13
Large animal model
Adult sheep	Poly(glycolic acid) scaffold	Pulmonary valve replacement via transcatheter-based jugular	Intracardiac echocardiography, cardiac magnetic resonance imaging, computed tomography, histological and immunohistochemical analysis	22
Adult sheep	Polyvinylidene fluoride scaffold	Left anterolateral thoracotomy	Inspected for thrombotic deposits, light microscopic analysis, electron microscopic analysis or processed for extracellular matrix assay	23
Juvenile sheep (13–17 kg)	Tissue-engineered porcine pulmonary valved conduit	Off-pump cardiopulmonary bypass/left anterolateral thoracotomy	Transthoracic ultrasound echocardiography, mortality, operating time	24
Foetal ovine	PCL scaffold	Transcatheter pulmonary valve replacement	Ultrasound (pulmonary valve annulus), foetal outcome	25
Yorkshire pigs (80 kg)	AZ31 magnesium alloy biodegradable stent frame scaffold-based polycarbonate urethane urea TEHV	Cardiopulmonary bypass in the pulmonary position	Echocardiography, biaxial mechanical testing, scanning electron microscopy	26
Porcine	Decellularised porcine pulmonary heart valves	Median sternotomy or limited lateral thoracotomy, then injection of TEHV	Echocardiographic examination, invasive pressure, angiographic measurements	27
Vietnamese pigs	Decellularised porcine aortic valves conduit	Xypho‐jugular incision, followed by median longitudinal sternotomy	Echocardiography, macroscopic inspection, metabolic labelling	28
Canine	Decellularised porcine pulmonary heart valves	Left anterolateral thoracotomy	Echocardiography, histology (haematoxylin and eosin, Masson) and immunohistochemistry, transmission electron microscopy	29
Non-human primate (Chacma Baboon)	Poly(glycolic acid) scaffold	A mini-sternotomy using an antegrade transapical approach	Transesophageal echocardiography, epicardial echocardiography, Pulmonary artery pressure measurement, biochemical analysis	30

Species	TEHV manufacture	Surgical method	Functionality assessment and post-mortem analysis	Reference
Small animal model
Mouse	Sulfonic polymer hybrid extracellular matrix	Subdermal	Histological and immunohistochemical analysis	18
Rat	Glut-fixed porcine aortic valve	Subdermal	Histological and quantitative analysis	19
	Electrospinning polycaprolactone scaffold	Subdermal	Scanning electron microscopic and histological analysis	20
	Allogeneic aortic conduit grafts	End-to-side anastomosis with infrarenal aorta	Histological and immunohistochemical analysis, quantitative real-time polymerase chain reaction	21
Rabbit	Poly urethane scaffold	Subdermal	Macroscopic and histological analysis	13
Large animal model
Adult sheep	Poly(glycolic acid) scaffold	Pulmonary valve replacement via transcatheter-based jugular	Intracardiac echocardiography, cardiac magnetic resonance imaging, computed tomography, histological and immunohistochemical analysis	22
Adult sheep	Polyvinylidene fluoride scaffold	Left anterolateral thoracotomy	Inspected for thrombotic deposits, light microscopic analysis, electron microscopic analysis or processed for extracellular matrix assay	23
Juvenile sheep (13–17 kg)	Tissue-engineered porcine pulmonary valved conduit	Off-pump cardiopulmonary bypass/left anterolateral thoracotomy	Transthoracic ultrasound echocardiography, mortality, operating time	24
Foetal ovine	PCL scaffold	Transcatheter pulmonary valve replacement	Ultrasound (pulmonary valve annulus), foetal outcome	25
Yorkshire pigs (80 kg)	AZ31 magnesium alloy biodegradable stent frame scaffold-based polycarbonate urethane urea TEHV	Cardiopulmonary bypass in the pulmonary position	Echocardiography, biaxial mechanical testing, scanning electron microscopy	26
Porcine	Decellularised porcine pulmonary heart valves	Median sternotomy or limited lateral thoracotomy, then injection of TEHV	Echocardiographic examination, invasive pressure, angiographic measurements	27
Vietnamese pigs	Decellularised porcine aortic valves conduit	Xypho‐jugular incision, followed by median longitudinal sternotomy	Echocardiography, macroscopic inspection, metabolic labelling	28
Canine	Decellularised porcine pulmonary heart valves	Left anterolateral thoracotomy	Echocardiography, histology (haematoxylin and eosin, Masson) and immunohistochemistry, transmission electron microscopy	29
Non-human primate (Chacma Baboon)	Poly(glycolic acid) scaffold	A mini-sternotomy using an antegrade transapical approach	Transesophageal echocardiography, epicardial echocardiography, Pulmonary artery pressure measurement, biochemical analysis	30

Species & bioreactors	Advantages	Disadvantages
Small animal model
Mouse	Low cost of maintenance, ease of gene-editing and surgical manipulation, multiple types of antibodies	Not-suitable for in situ studies for small size and mismatched anatomy and physiology
Rat	Low cost of maintenance, ease of surgical approach, access for implantation into the systemic circulation	Not-suitable for in situ studies
Rabbit	Low cost of upkeep, larger size for larger graft implantation	Especially suitable for ectopic studies (subcutaneous implantation)
Large animal model
Sheep	The golden standard for translational studies, the similarity of body size to human, easy access for transcatheter replacement of tissue-engineered heart valves, suitable growing speed for growing model	Higher cost of purchase and upkeep, special facilities required for housing
Pig	Resemblance to humans in terms of cardiovascular anatomy and physiology, access to transgenic models	Higher cost of purchase and upkeep, special facilities required for housing, higher risk of post-operation infection, the possibility of chronic arterial occlusion and cardiac death after CPB, unsuitable growing speed compared with sheep
Dog	Docile character, thin skin for implantation of catheters and convenient imaging, lower risk of post-operative infection	Higher cost of purchase and upkeep, special facilities required for housing, difficulty in getting approval
Non-human primate	The best model for translational clinical research for anatomical, physiological, genetic, and immune similarity	The highest cost of purchase and upkeep, special facilities required for housing and social needs of primates, special equipment, and training required for surgical approach
Bioreactors
Pulse-flow bioreactors	The anatomy is more similar to the physiology	Generate complex and ill-defined mechanical conditioning, which cannot be readily controlled
Single mechanical stimulus bioreactor	The type and size of the mechanical stimulation can be finely adjusted	Only single stimulation can be made, a good cultural environment is needed and high cost
Multi-mechanical stimulus bioreactor	Know the synergistic effect of different combinations of mechanical stimuli on cells and tissues	May exist mutual interference that led to inconsistent results
Computer-regulated bioreactor	Predictable, easy to understand hydrodynamic parameters	Only mechanical simulations, not chemical and biological ones

Species & bioreactors	Advantages	Disadvantages
Small animal model
Mouse	Low cost of maintenance, ease of gene-editing and surgical manipulation, multiple types of antibodies	Not-suitable for in situ studies for small size and mismatched anatomy and physiology
Rat	Low cost of maintenance, ease of surgical approach, access for implantation into the systemic circulation	Not-suitable for in situ studies
Rabbit	Low cost of upkeep, larger size for larger graft implantation	Especially suitable for ectopic studies (subcutaneous implantation)
Large animal model
Sheep	The golden standard for translational studies, the similarity of body size to human, easy access for transcatheter replacement of tissue-engineered heart valves, suitable growing speed for growing model	Higher cost of purchase and upkeep, special facilities required for housing
Pig	Resemblance to humans in terms of cardiovascular anatomy and physiology, access to transgenic models	Higher cost of purchase and upkeep, special facilities required for housing, higher risk of post-operation infection, the possibility of chronic arterial occlusion and cardiac death after CPB, unsuitable growing speed compared with sheep
Dog	Docile character, thin skin for implantation of catheters and convenient imaging, lower risk of post-operative infection	Higher cost of purchase and upkeep, special facilities required for housing, difficulty in getting approval
Non-human primate	The best model for translational clinical research for anatomical, physiological, genetic, and immune similarity	The highest cost of purchase and upkeep, special facilities required for housing and social needs of primates, special equipment, and training required for surgical approach
Bioreactors
Pulse-flow bioreactors	The anatomy is more similar to the physiology	Generate complex and ill-defined mechanical conditioning, which cannot be readily controlled
Single mechanical stimulus bioreactor	The type and size of the mechanical stimulation can be finely adjusted	Only single stimulation can be made, a good cultural environment is needed and high cost
Multi-mechanical stimulus bioreactor	Know the synergistic effect of different combinations of mechanical stimuli on cells and tissues	May exist mutual interference that led to inconsistent results
Computer-regulated bioreactor	Predictable, easy to understand hydrodynamic parameters	Only mechanical simulations, not chemical and biological ones

Model	Application	Objective	Year	Reference
Computational modelling	Tissue-engineered heart valve	Guiding tissue-engineered heart valve design for long-term in vivo performance in a translational sheep model	2018	22
	Tissue-engineered vascular graft	Identifying optimal design parameters to save development time and costs while improving clinical outcomes	2019	103
	Bioprosthetic heart valve	Investigating the impacts of bovine and porcine pericardium tissues with different thicknesses and tissue mechanical properties in bioprosthetic heart valve applications	2019 2017 2016	104–106
	Tissue-engineered heart valve	Integrating computational simulation into tissue-engineering approaches can lead to more successful and predictable clinical outcomes	2018	107–109
Biomechanical model	Aortic stenosis	Providing the results of the numerical simulation of the valve function	2020	110
Finite element models	Congenital bicuspid aortic valve	Quantifying aortic valve and root biomechanical alterations associated with bicuspid geometry	2010	111
	Calcific aortic valve disease	Studying the calcification progression in aortic valves	2017	112
	Bioprosthetic heart valve	Comparing tensile properties of xenopericardium to choose tissue more appropriate for bioprosthetic heart valve tissue	2020	113
Three-dimensional bioprinting	Heart valve	Using computational fluid dynamics, digital image processing, artificial intelligence, and continuum mechanics during their optimisation and implementation to mimic the original and understand valvular problems	2019 2018	114, 115
Geometric model	Functional tri-leaflet aortic valves	Establishing a list of geometric guidelines to ensure safe operation of the valve during the cardiac cycle	2006	116
Numeric model	Aortic root	Studying the correlation between intraoperative effective height and diastolic coaptation	2013	117
Neural network material model	Simulation of the aortic heart valve	Providing an efficient computational analysis framework with increased physical and functional realism for the simulation of native and replacement tri-leaflet heart valves	2021 2020	118, 119

Experimental and computational models for tissue-engineered heart valves: a narrative review

RichHTML

PDF

Knowledge

share this article

Abstract

Cite this article

Figures/Tables 6

References 128

Related Articles 2

Recommended Articles

Metrics

Comments

Journal Info

For Authors

For Reviewers

Archives

[1]	Xirui Jing, Qiuyue Ding, Qinxue Wu, Weijie Su, Keda Yu, Yanlin Su, Bing Ye, Qing Gao, Tingfang Sun, Xiaodong Guo. Magnesium-based materials in orthopaedics: material properties and animal models [J]. Biomaterials Translational, 2021, 2(3): 197-213.
[2]	Yizhong Peng, Xiangcheng Qing, Hongyang Shu, Shuo Tian, Wenbo Yang, Songfeng Chen, Hui Lin, Xiao Lv, Lei Zhao, Xi Chen, Feifei Pu, Donghua Huang, Xu Cao, Zengwu Shao. Proper animal experimental designs for preclinical research of biomaterials for intervertebral disc regeneration [J]. Biomaterials Translational, 2021, 2(2): 91-142.