Novel Bioreactors for Mechanistic Studies of Engineered Heart Valves

Beyond the identification of the most appropriate cells and scaffold materials, translation of cardiovascular tissue engineering structures requires optimization of construct biological and mechanical properties in order to permit their long-term functionality in the native hemodynamic environment. Unfortunately, rudimentary tissue growth technologies such as plate or rotisserie culture do not lead to the generation of functional tissues, thereby limiting their usefulness. Dynamic culture systems or bioreactors with true construct mechanical conditioning capabilities thus form an essential part of the research and development pathway in cardiovascular regenerative medicine. This is because engineered tissues cultured under specific bioreactor mechanical environments enhance their biological properties such as functional stem cell differentiation to complex tissue phenotypes and also augment construct structural properties as a result of accelerated tissue formation. In the heart valve tissue engineering arena, based on at least a decade of scientific results, there is now general acceptance that bioreactor usage is a critical preclinical step. In this book chapter, we describe important considerations in bioreactor design as well as focus on the critical scientific findings in the development of de novo valvular tissues, including our own experience in this area. We subsequently detail scaffold and cell sources that have been used in conjunction with these devices and finally conclude by addressing the key challenges that still remain.

[1]  Frederick J. Schoen,et al.  Early In Vivo Experience With Tissue-Engineered Trileaflet Heart Valves , 2000, Circulation.

[2]  Michael S. Sacks,et al.  A novel bioreactor for the dynamic flexural stimulation of tissue engineered heart valve biomaterials. , 2003 .

[3]  Richard W. Bianco,et al.  Implantation of a Tissue-engineered Heart Valve from Human Fibroblasts Exhibiting Short Term Function in the Sheep Pulmonary Artery , 2011 .

[4]  Sharan Ramaswamy,et al.  Differentiation and Distribution of Marrow Stem Cells in Flex-Flow Environments Demonstrate Support of the Valvular Phenotype , 2015, PloS one.

[5]  J. Gardin,et al.  Burden of valvular heart diseases: a population-based study , 2006, The Lancet.

[6]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[7]  V. Tkachuk,et al.  Regulation of Immunity via Multipotent Mesenchymal Stromal Cells , 2012, Acta naturae.

[8]  U. Stock,et al.  Percutaneous tissue-engineered pulmonary valved stent implantation. , 2010, The Annals of thoracic surgery.

[9]  J. Rysä,et al.  Characterization of the Regulatory Mechanisms of Activating Transcription Factor 3 by Hypertrophic Stimuli in Rat Cardiomyocytes , 2014, PloS one.

[10]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[11]  Jiang Chang,et al.  Crosslinking effect of Nordihydroguaiaretic acid (NDGA) on decellularized heart valve scaffold for tissue engineering , 2010, Journal of materials science. Materials in medicine.

[12]  Gino Gerosa,et al.  Cells, scaffolds and bioreactors for tissue-engineered heart valves: a journey from basic concepts to contemporary developmental innovations. , 2011, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[13]  A. Lichtenberg,et al.  Detergent decellularization of heart valves for tissue engineering: toxicological effects of residual detergents on human endothelial cells. , 2010, Artificial organs.

[14]  Robert M Nerem,et al.  Valvular endothelial cells regulate the phenotype of interstitial cells in co-culture: effects of steady shear stress. , 2006, Tissue engineering.

[15]  Zhaoming He,et al.  Effects of Constant Static Pressure on the Biological Properties of Porcine Aortic Valve Leaflets , 2004, Annals of Biomedical Engineering.

[16]  G. Hardiman,et al.  The Long Non-Coding HOTAIR Is Modulated by Cyclic Stretch and WNT/β-CATENIN in Human Aortic Valve Cells and Is a Novel Repressor of Calcification Genes , 2014, PloS one.

[17]  M. Kaufman,et al.  Establishment in culture of pluripotential cells from mouse embryos , 1981, Nature.

[18]  J M Anderson,et al.  In vivo biocompatibility and biostability of modified polyurethanes. , 1997, Journal of biomedical materials research.

[19]  S. Hoerstrup,et al.  Cryopreserved amniotic fluid-derived cells: a lifelong autologous fetal stem cell source for heart valve tissue engineering. , 2008, The Journal of heart valve disease.

[20]  Robert M. Nerem,et al.  Dynamic Mechanical Conditioning of Collagen-Gel Blood Vessel Constructs Induces Remodeling In Vitro , 2000, Annals of Biomedical Engineering.

[21]  Patrick Thayer,et al.  The Effects of Combined Cyclic Stretch and Pressure on the Aortic Valve Interstitial Cell Phenotype , 2011, Annals of Biomedical Engineering.

[22]  Farshid Guilak,et al.  Advanced tools for tissue engineering: scaffolds, bioreactors, and signaling. , 2006, Tissue engineering.

[23]  F J Schoen,et al.  Functional Living Trileaflet Heart Valves Grown In Vitro , 2000, Circulation.

[24]  Gretchen J. Mahler,et al.  Effects of shear stress pattern and magnitude on mesenchymal transformation and invasion of aortic valve endothelial cells , 2014, Biotechnology and bioengineering.

[25]  Magdi H. Yacoub,et al.  Collagen synthesis by mesenchymal stem cells and aortic valve interstitial cells in response to mechanical stretch. , 2006, Cardiovascular research.

[26]  Benedikt Weber,et al.  Injectable living marrow stromal cell-based autologous tissue engineered heart valves: first experiences with a one-step intervention in primates. , 2011, European heart journal.

[27]  E Wolner,et al.  Early failure of the tissue engineered porcine heart valve SYNERGRAFT in pediatric patients. , 2003, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[28]  P. Hu,et al.  Fabrication of a novel hybrid scaffold for tissue engineered heart valve , 2009, Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban.

[29]  M. Gerdisch,et al.  Clinical experience with CorMatrix extracellular matrix in the surgical treatment of mitral valve disease. , 2014, The Journal of thoracic and cardiovascular surgery.

[30]  N Ohshima,et al.  Packed-bed type reactor to attain high density culture of hepatocytes for use as a bioartificial liver. , 2008, Artificial organs.

[31]  Magdi H. Yacoub,et al.  The cardiac valve interstitial cell. , 2003, The international journal of biochemistry & cell biology.

[32]  Anthony Atala,et al.  Bioreactors for Development of Tissue Engineered Heart Valves , 2010, Annals of Biomedical Engineering.

[33]  Thomas Schmitz-Rode,et al.  In vivo remodeling and structural characterization of fibrin-based tissue-engineered heart valves in the adult sheep model. , 2009, Tissue engineering. Part A.

[34]  Fotis Sotiropoulos,et al.  A novel bioreactor for mechanobiological studies of engineered heart valve tissue formation under pulmonary arterial physiological flow conditions. , 2014, Journal of biomechanical engineering.

[35]  W. Konertz,et al.  In-vivo repopularization of a tissue-engineered heart valve in a human subject. , 2007, The Journal of heart valve disease.

[36]  Michael S Sacks,et al.  Cyclic flexure and laminar flow synergistically accelerate mesenchymal stem cell-mediated engineered tissue formation: Implications for engineered heart valve tissues. , 2006, Biomaterials.

[37]  Arnold I. Caplan,et al.  Mesenchymal Stem Cells , 1991, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[38]  Bart Meuris,et al.  Design of a new pulsatile bioreactor for tissue engineered aortic heart valve formation. , 2002, Artificial organs.

[39]  Thomas Schmitz-Rode,et al.  Tissue-engineered heart valve with a tubular leaflet design for minimally invasive transcatheter implantation. , 2014, Tissue engineering. Part C, Methods.

[40]  S. Ramaswamy,et al.  Periodontal ligament cells cultured under steady-flow environments demonstrate potential for use in heart valve tissue engineering. , 2013, Tissue engineering. Part A.

[41]  Michael S Sacks,et al.  The independent role of cyclic flexure in the early in vitro development of an engineered heart valve tissue. , 2005, Biomaterials.

[42]  Michael S Sacks,et al.  Effects of cyclic flexural fatigue on porcine bioprosthetic heart valve heterograft biomaterials. , 2010, Journal of biomedical materials research. Part A.

[43]  C K Breuer,et al.  Tissue engineering heart valves: valve leaflet replacement study in a lamb model. , 1995, The Annals of thoracic surgery.

[44]  Gaetano Burriesci,et al.  The anti-calcification potential of a silsesquioxane nanocomposite polymer under in vitro conditions: potential material for synthetic leaflet heart valve. , 2010, Acta biomaterialia.

[45]  K. Rogers,et al.  Vascular smooth muscle cells as a valvular interstitial cell surrogate in heart valve tissue engineering. , 2009, Tissue engineering. Part A.

[46]  G. Lofland,et al.  Transesophageal Echocardiography in Healthy Young Adult Male Baboons (Papio hamadryas anubis): Normal Cardiac Anatomy and Function in Subhuman Primates Compared to Humans. , 2013, Progress in pediatric cardiology.

[47]  Richard A Hopkins,et al.  Design and efficacy of a single-use bioreactor for heart valve tissue engineering. , 2017, Journal of biomedical materials research. Part B, Applied biomaterials.

[48]  Stefan Dhein,et al.  Mechanical control of cell biology. Effects of cyclic mechanical stretch on cardiomyocyte cellular organization. , 2014, Progress in biophysics and molecular biology.

[49]  D. Wendt,et al.  The role of bioreactors in tissue engineering. , 2004, Trends in biotechnology.

[50]  W. Eaglstein,et al.  Tissue engineering and the development of Apligraf, a human skin equivalent. , 1997, Cutis.

[51]  M. Loebe,et al.  Magnetically Guided Recellularization of Decellularized Stented Porcine Pericardium-Derived Aortic Valve for TAVI , 2014, ASAIO journal.

[52]  Robert T. Tranquillo,et al.  Controlled cyclic stretch bioreactor for tissue-engineered heart valves. , 2009, Biomaterials.

[53]  J. Krieger,et al.  Short-term mechanical stretch fails to differentiate human adipose-derived stem cells into cardiovascular cell phenotypes , 2014, Biomedical engineering online.

[54]  K Schindhelm,et al.  Polydimethylsiloxane/polyether-mixed macrodiol-based polyurethane elastomers: biostability. , 2000, Biomaterials.

[55]  Artur Lichtenberg,et al.  Clinical Application of Tissue Engineered Human Heart Valves Using Autologous Progenitor Cells , 2006, Circulation.

[56]  Thomas Schmitz-Rode,et al.  TexMi: development of tissue-engineered textile-reinforced mitral valve prosthesis. , 2014, Tissue engineering. Part C, Methods.

[57]  Simon P. Hoerstrup,et al.  Cardiovascular tissue engineering: a new laminar flow chamber for in vitro improvement of mechanical tissue properties. , 2000 .