NANOFIBER BASED SCAFFOLD FABRICATION, CHARACTERIZATION …
Transcript of NANOFIBER BASED SCAFFOLD FABRICATION, CHARACTERIZATION …
NANOFIBER BASED SCAFFOLD FABRICATION, CHARACTERIZATION
AND OPTIMIZATION FOR TISSUE ENGINEERING AORTIC HEART VALVE
EHSAN FALLAHI AREZOUDAR
A thesis submitted in fulfilment o f the
requirements for the award o f the degree o f
Doctor o f Philosophy (Mechanical Engineering)
Faculty o f Mechanical Engineering
Universiti Teknologi Malaysia
FEBRUARY 2017
lll
To my beloved family
lv
ACKNOWLEDGEMENT
First and above all, I praise God, the almighty for providing me this
opportunity and granting me the capability to proceed with this research successfully.
Further, there are no proper words to convey my deep gratitude and respect for my
thesis and research advisor, Professor Dr. Noordin Mohd Yusof. He has inspired me
to become an independent researcher and helped me realize the power of critical
reasoning. He also demonstrated what a brilliant and hard-working scientist can
accomplish.
My sincere thanks must also go to co-advisory, Professor Dr. Ani Idris for the
trust, the insightful discussion, offering valuable advice, for her support during the
whole period of the study, and especially for her patience and guidance during the
writing process. She generously gave her time to offer me valuable comments toward
improving my work.
Besides, I would like to thank the authority of Universiti Teknologi Malaysia
(UTM) for providing me with a good environment and facilities. I also greatly
appreciate the excellent assistance and spiritual supports of my family and my friends
during my PhD study.
v
ABSTRACT
The four valves in a mammalian heart provide a unidirectional, unobstructed blood flow pathway as a result of synchronic movement of valves’ leaflets during cardiac cycle. When one of the valves malfunctions, the medical choice is to replace the original valve with an artificial one. However, the inability to grow or to remodel an artificial valve leads to the innovation of tissue engineering heart valve (TEHV). The previously tissue engineered heart valve tends to be rigid, have low degradation rate and adverse structure which leads to TEHV failure. This study presents the design and fabrication of an aortic heart valve (AOHV) based on tissue engineering (TE) principle via electrospinning method. In TE, a three-dimensional (3D) scaffold with proper design, structure, and mechanical properties that resembles the original tissue is required as an initial template for tissue regeneration. For this purpose, materials’ ratio tuning and process optimization as well as the 3D scaffold design were considered. Initially, five different ratios of poly-L-lactic acid (PLLA)/thermoplastic polyurethane (TPU) blends containing 1% (w/v) maghemite (y-Fe2O3) nanoparticles were electrospun and characterized in terms of morphology, degradation rate, biological compatibility and mechanical properties. The existence of three components in the mats was confirmed by Fourier transform infrared and energy-dispersive X-ray spectroscopy. Scanning electron microscopy images illustrated well fabricated nanofibers with smaller diameter distribution for PLLA. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay using human skin fibroblast cell indicates desired proliferation on the samples. Blood biocompatibility results in terms of clotting time, fibrin formation, and hemolysis were almost in the normal range. Samples’ degradation rate was investigated over 24 weeks where the PLLA shows 47.15% loss in mass versus 6.7% loss for TPU. High tensile strength and an extremely low elongation-at-break were determined from the stress-strain curve for PLLA, while TPU exhibits high elasticity. Overall, 50:50% of (1% y-Fe2O3) loaded PLLA/TPU mats are the most appropriate. Next, a two-level Taguchi (L8) experimental design followed by the response surface methodology (RSM) were used to optimize the fabrication process where the elastic modulus is the response while the factors investigated were A-flow rate (2-3 ml/h), B-voltage (20-30 kV), C- maghemite% (1-3% w/v), D-solution concentration (10-15 wt.%) and E-collector rotating speed (1000-2000 rpm). From the signal-to-noise ratio values, the influences of the factors were ranked as: D>B>C>E>A. The empirical quadratic model obtained consists of the voltage-B and second order effect of flow rate-(A)2, voltage-(B)2, maghemite %-(C)2 and concentration-(D)2. The optimum elastic modulus of the scaffold was found to be 35.24±0.64 MPa. Finally, an AOHV template was designed and installed as the electrospinning collector to fabricate the 3D scaffold based on the optimum ratio and settings. Later, the human aortic smooth muscles cell migration and proliferation, as well as the elastic modulus loss percent of the optimum 3D scaffold after cell seeding were checked during 34 days of incubation. Overall, the structural, biological and mechanical specifications of the fabricated TEHV have successfully proved that it can be a potential alternative in AOHV replacement surgery.
vi
ABSTRAK
Empat injap yang terdapat di dalam hati mamalia menyediakan laluan aliran darah yang searah, tidak terhalang disebabkan pergerakan daun injab yang diselarikan semasa kitaran jantung. Apabila salah satu daripada injap rosak, pilihan perubatan adalah menggantikan injap asal dengan injap tiruan. Walaubagaimanapun, injap tiruan tidak mempunyai kemampuan untuk tumbuh atau dimodel semula. Ini telah membawa kepada inovasi injap jantung kejuruteraan tisu (TEHV). Injap jantung kejuruteraan tisu sebelum ini adalah tegar, mempunyai kadar penurunan yang rendah dan struktur yang tidak sesuai yang membawa kepada kegagalan TEHV. Kajian ini membentangkan reka bentuk dan fabrikasi injap jantung aortik menggunakan prinsip kejuruteraan tisu (TE) melalui kaedah elektropintal. Dalam TE, perancah tiga dimensi (3D) dengan reka bentuk yang sesuai, struktur dan sifat-sifat mekanik yang boleh menyerupai tisu asal akan digunakan sebagai pencontoh permulaan untuk pertumbuhan semula tisu. Untuk tujuan ini, penalaan nisbah bahan-bahan utama yang digunakan dan pengoptimuman proses serta reka bentuk perancah 3D dipertimbangkan. Buat permulaan, lima nisbah berbeza poli-L-laktik asid (PLLA)/poliuretana termoplastik (TPU) dicampurkan dengan 1% (w/v) maghemite (y-Fe2O3) nanopartikel. Campuran ini telah melalui proses elektropintal dan pencirian dibuat dari segi morfologi, kadar penurunan, keserasian biologi dan sifat-sifat mekanik. Kewujudan tiga komponen dalam lapisan serat nano telah disahkan oleh jelmaan inframerah Fourier dan serakan-tenaga X-ray spektroskopi. Imej imbasan mikroskopi elektron menunjukkan bahawa serat nano yang baik terhasil dengan garis pusat yang lebih kecil untuk PLLA. Kajian MTT menggunakan sel fibroblas kulit manusia dan ia menunjukkan percambahan yang baik ke atas sampel. Keputusan bio-keserasian darah dari segi masa pembekuan, pembentukan fibrin, dan hemolisis hampir dalam julat normal. Kadar penurunan sampel telah diselidiki selama 24 minggu yang mana PLLA menunjukkan penurunan jisim sebanyak 47.15% berbanding dengan penurunan 6.7% bagi TPU. Kekuatan tegangan yang tinggi dan kadar pemanjangan sebelum putus yang amat rendah ditentukan dari lengkung tegasan-terikan untuk PLLA, manakala TPU mempamerkan keanjalan yang tinggi. Secara keseluruhan, lapisan serat nano PLLA/TPU yang mengandungi 50:50% daripada 1% (y-Fe2O3) adalah yang paling sesuai. Seterusnya, reka bentuk eksperimen dua aras Taguchi (L8) diikuti dengan kaedah gerak balas permukaan (RSM) telah digunakan untuk mengoptimumkan proses di mana modulus elastik merupakan sambutan manakala faktor yang dikaji ialah A- kadar alir (2-3 ml/h), B- voltan (20-30 kV), C-maghemite % (1-3% w/v), D-kepekatan larutan (10-15wt.%), dan E- kelajuan puteran pengumpul (1000-2000 rpm). Dari nilai nisbah isyarat-kepada-hingar (S/N), pengaruh faktor adalah: D>B>C>E>A. Model kuadratik empirikal yang diperolehi terdiri dari voltan-B dan kesan peringkat kedua kadar alir-(A)2, voltan-(B)2, maghemite %-(C)2 dan kepekatan-(D)2. Modulus elastik optimum perancah yang diperolehi adalah 35.24±0.64 MPa. Akhir sekali, AOHV telah direka dan dipasang sebagai pemungut kepada elektropintal untuk menghasilkan perancah 3D berdasarkan kepada nisbah optimum dan tetapan. Kemudian, penghijrahan dan perkembangan aortik sel-sel otot licin manusia serta peratusan kehilangan keanjalan modulus daripada perancah 3D optimum selepas pembenihan sel diperiksa semasa 34 hari pengeraman. Secara keseluruhan, spesifikasi struktur, biologi dan mekanikal bagi TEHV yang telah difabrikasi berjaya membuktikan yang ia boleh menjadi alternatif yang berpotensi untuk pembedahan penggantian AOHV.
vii
TABLE OF CONTENTS
CHAPTER TITLE PAGE
DECLARATION ii
DEDICATION iii
ACKNOWLEDGEMENT iv
ABSTRACT v
ABSTRAK vi
TABLE OF CONTENTS vii
LIST OF TABLES xii
LIST OF FIGURES xiv
LIST OF ABBREVIATIONS xix
LIST OF SYMBOLS xxii
LIST OF APPENDICES xxv
1 INTRODUCTION 1
1.1 Overview of the Research 1
1.2 Research Problem Statement 8
1.3 Research Questions 10
1.4 Research Hypothesis 11
1.5 Research Aim and Objectives 11
1.6 Research Scopes 12
1.7 Significance of Research 14
1.8 Organization of Thesis 14
2 LITERATURE REVIEW
2.1 Introduction
15
15
2.2 Overview of Heart Valves 15
2.3 Aortic Heart Valve 18
2.3.1 Microstructure and Function of Normal Aortic
Valve 18
2.3.2 Mechanical Properties of the Aortic Heart Valve 22
2.3.2.1 Uniaxial and Biaxial Mechanical
Properties 23
2.3.2.2 Flexural Mechanical Properties 28
2.3.3 Aortic Valves Pathology 29
2.4 Tissue Engineering Heart Valve (TEHV) 31
2.4.1 Three-dimensional Heart Valves Scaffold 32
2.4.1.1 Polymeric and Biological Materials 32
2.4.1.2 Scaffolds Fabrication Techniques 42
2.4.1.3 Synthetic Scaffolds Mechanical
Properties 47
2.4.2 Cells Sources and Cultivation Methods 48
2.4.2.1 Adipose-derived Cells 50
2.4.2.2 Valve Interstitial Cells 50
2.4.2.3 Bone Marrow Stem Cells 51
2.4.3 Development Condition 52
2.5 Summary 53
3 RESEARCH METHODOLOGY 55
3.1 Introduction 55
3.2 Research Framework 55
3.3 Materials Requirement 59
3.4 Solution Preparation 61
3.4.1 Synthesizing Maghemite (y-Fe2O3) 61
3.4.2 Poly-L-lactic Acid (PLLA) and
Thermoplastic Polyurethane (TPU) 61
3.5 Electrospinning Setup to Fabricate PLLA/TPU-(y-Fe2O3)
Nanofiber Mats 62
3.5.1 Chemically Characterization of Electrospun Mats 64
viii
3.6 Materials Ratio Tuning Process 64
3.6.1 Morphology and Porosity 65
3.6.2 Hydrophilicity and Surface Roughness 66
3.6.3 Degradation Rate of Electrospun Mats 67
3.6.3.1 Changes in Morphology 67
3.6.3.2 Mass Change of Electrospun Mats 68
3.6.3.3 Porosity (%) Change 68
3.6.4 Cell Biological Compatibility Tests 68
3.6.4.1 Fibroblast Cell Thawing, Plating and
Sub-culturing 69
3.6.4.2 Cell Cytotoxicity Assay and Cell
Viability (MTT Assay) 70
3.6.4.3 Cells Attachment 74
3.6.5 Blood Hemocompatibility 74
3.6.5.1 Blood Clotting Time (PT & TT Assay) 75
3.6.5.2 Fibrin Formation 76
3.6.5.3 Hemolysis Test 76
3.6.6 Mechanical Properties of Electrospun Mats 77
3.7 Fabrication Process (Electrospinning) Optimization 79
3.7.1 Two-level Taguchi Experimental Design 79
3.7.1.1 Test for Significance of the Regression
Model 83
3.7.1.2 Test for Significance on Individual
Model Terms 83
3.7.1.3 Test for Lack-of-fit 84
3.7.2 Steepest Ascent Method 85
3.7.3 Response Surface Methodology (RSM) 87
3.8 Design the 3D Semilunar Heart Valve Template 88
3.9 Characterizations of 3D Heart Valve Scaffold 91
3.9.1 Morphology, Hydrophilicity and Porosity
Characterization 91
3.9.2 Human Aortic Smooth Muscle Cell Viability
Evaluation 92
ix
3.9.3 Mechanical Evaluation of Seeded Scaffold 94
3.10 Statistical Data Analysis 96
4 RESULTS AND DISCUSSION 97
4.1 Introduction 97
4.2 Maghemite (y-Fe2O3) Nanoparticles Characterization 97
4.3 Chemically Characterization of Electrospun
Nanofiber Mats 99
4.4 Materials Ratio Tuning Process 103
4.4.1 Nanofibers Morphology, Diameter Distribution
and Porosity 103
4.4.2 Hydrophilicity and Surface Roughness 107
4.4.3 Degradation Rate of Electrospun Mats 111
4.4.3.1 Changes in Morphology 111
4.4.3.2 Mass Changes of Electrospun Mats 115
4.4.3.3 Porosity (%) Change 117
4.4.4 Cells Biocompatibility 119
4.4.4.1 Cytotoxicity Assay and Cell Viability
(MTT Assay) 119
4.4.4.2 Cell Attachment 122
4.4.5 Blood Hemocompatibility 126
4.4.5.1 Blood Clotting Time (PT & TT Assay) 126
4.4.5.2 Fibrin Formation and Hemolysis
Percent (HP %) 127
4.4.6 Mechanical Properties 129
4.4.7 Conclusion on Materials Ratio Tuning
Properties 132
4.5 Fabrication Process Optimization 132
4.5.1 Two-level Taguchi Experimental Design 132
4.5.1.1 Confirmation of Taguchi Design 136
4.5.1.2 ANOVA Analysis 137
4.5.1.3 Linear Regression Model 139
4.5.2 Steepest Ascent Pathway 144
x
4.5.3 Response Surface Methodology (RSM) 146
4.5.4 Confirmation Test 152
4.6 Three-dimensional Semilunar Heart Valve
Scaffold Fabrication 154
4.7 Characterization of 3D Heart Valve Scaffold 155
4.7.1 Morphology, Hydrophilicity and Porosity
(%) of 3D Scaffold 156
4.7.2 Human Aortic Smooth Muscle Cells Migration
and Proliferation 158
4.7.3 Blood Hemocompatibility Tests 160
4.7.4 Evaluate the Mechanical Properties of Seeded
Scaffold 163
4.8 Summary 166
5 CONCLUSION AND FUTURE DIRECTION 168
5.1 Introduction 168
5.2 Conclusions 168
5.3 Recommendations and Future Direction 171
xi
REFERENCES
Appendix A
173
202
LIST OF TABLES
TABLE NO. TITLE PAGE
2.1 Uniaxial mechanical properties of human and animal aortic valve 25
2.2 Summary of reported studies of biopolymers in TEHV 37
2.3 Techniques used to process biomaterials in TEHV 45
3.1 List of materials used in the research 60
3.2 Factors and levels for Taguchi experimental design 80
3.3 Layout of Taguchi experimental design orthogonal array 81
3.4 Normal human aortic valve dimensions (mm) at 80 mmHg pressure 89
4.1 Porosity measurement for different ratios of PLLA/TPU-(Y-Fe2O3) 106
4.2 Mean±SD results of water contact angles measurements in 60 sec 108
4.3 Mass change of PLLA/TPU-(y-Fe2O3) samples after immersion (mg) 116
4.4 Mechanical properties results of electrospun mats 131
4.5 Taguchi experimental results in terms of elastic modulus (MPa) 133
4.6 Taguchi design (L8) analysis for controllable factors and factors’ ranking 133
4.7 S/N ratio responses for controllable factors 136
4.8 List of aliased factors and interaction with intercept of ABC and ADE 137
4.9 ANOVA table (partial sum of square) for response surface model (response: elastic modulus) 138
4.10 ANOVA table (partial sum of square) for response surface after adding center points 140
4.11 ANOVA table (partial sum of square) for response surface after model reduction 141
4.12 Steepest ascent pathway design in terms of coded and actual variable 145
4.13 Responses of tensile strength, tensile strain and elastic modulus 146
4.14 Factors and levels for CCD design 147
4.15 Small fraction of CCD layout and responses of elastic modulus (MPa) 147
4.16 ANOVA table for quadratic model after model reduction 149
4.17 Confirmation experiments design and responses for elastic modulus 152
4.18 Water contact angle measurement for 3D optimum scaffold 157
4.19 Macro-indentation test result for 3D optimum scaffold after cell seeding 164
xiv
FIGURE NO.
1.1
1.2
1.3
1.4
2.1
2.2
2.3
2.4
2.5
2.6
2.7
3.1
3.2
LIST OF FIGURES
TITLE
Schematic of (a) heart anatomy (b) valve position (c) single valve leaflet and its ECM structure
Artificial heart valves (a) mechanical (b) biological (c) TEHV
Concept of tissue engineering heart valves (TEHV)
Schematic diagram o f electrospinning setup
Pathway o f blood flow through the heart and lungs. Oxygenated blood flow (red colour) transfer from the lungs to the left ventricles and deoxygenated blood (blue colour) returns from the body to the right ventricle
Structures o f atrioventricular valve (mitral and tricuspid) include the leaflets, annulus, chordae tendineae, and papillary muscles
Schematic semilunar valves (a) top view o f lateral section o f outflow vessel during diastole to show the close valve,(b) by cutting longitudinally the vessel between two leaflets
Schematic diagram of aortic valve leaflet layers and components
Biaxial mechanical behaviour of aortic heart valve leaflets radially and circumferentially
Biological, mechanical and physiochemical properties of commonly studied biodegradable natural and synthetic polymer
Chemical structure formula of (a) poly-L-lactic acid (b) thermoplastic polyurethane
Research framework in (a) summary form (b) detailed form
Electrospinning setup to fabricate PLLA/TPU-(y-Fe2O3) nanofibers
PAGE
2
3
4
7
16
17
18
22
27
37
39
56
63
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.10
3.11
3.12
3.13
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
4.10
Image of hemocytometer gridlines for under microscope cells counting
Layout of samples loading in 24-well plate
MTT assay procedure
Stress versus strain uniaxial tensile test
Linear graph for Taguchi L8 design
First order response surface and path of steepest ascent
Two-dimensional central composite design experiments with level (a)
Human aortic heart valve geometrical parameters
Design of aluminium based template to be used as collector
3D printed based design of aortic heart valve template
Schematic diagram of macro-indentation test
Characterization of (y-Fe2O3) nanoparticles (a) XRD pattern (b) TEM images (c) reference of maghemite XRD pattern
FTIR spectra of (a) TPU, PLLA, PLLA/TPU and PLLA/TPU-(y-Fe2O3) (b) references of PLLA and TPU polymers
EDX graphs of elements presented in PLLA/TPU and PLLA/TPU-(y-Fe2O3)
DSC heating curve of PLLA/TPU and PLLA/TPU-(y- Fe2O3)
FE-SEM images of nanostructure and diameter distribution of (a) 100:0% (b) 75:25% (c) 50:50% (d) 25:75% and (e) 0:100% PLLA/TPU-(y-Fe2 O3) scaffold
TEM image of 50:50% PLLA/TPU-(y-Fe2 O3)
Porosity (%) of different ratios of PLLA/TPU-(y-Fe2O3) electrospun mats
Water contact angle measurement of (a) 100:0% (b) 75:25% (c) 50:50% (d) 25:75% and (e) 0:100% PLLA/TPU-(y-Fe2O3) nanofibers
AFM results of surface roughness, 3D micrograph and region profile for (a) 100:0% (b) 75:25% (c) 50:50% (d) 25:75% and (e) 0:100% of PLLA/TPU-(y-Fe2 O3) scaffold
Correlation between porosity, hydrophilicity and surface roughness
71
72
73
78
80
86
87
88
90
91
95
98
100
101
102
104
105
106
107
109
110
xv
xvi
4.11
4.12
4.13
4.14
4.15
4.16
4.17
4.18
4.19
4.20
4.21
4.22
4.23
4.24
4.25
4.26
FE-SEM images of degradation rate of different ratios of PLLA/TPU-(y-Fe2O3) scaffolds in weeks 1, 4, 6, 12 and 24 of immersion 113
Change of mass (mg) as a function of degradation time 116
EDX graph of 50:50% PLLA/TPU-(y-Fe2O3) after 4 weeks of immersion in SBF 117
Change in porosity (%) as a function of degradation time 118
The well plate analysis of (a) cytotoxicity assay (b) MTT assay of different ratios of PLLA/TPU-(y-Fe2O3) scaffold during 1, 3, 5 and 7 days of incubation 119
Cytotoxicity result during 72 h of incubation 120
Results of relative cell viability versus the incubation time (days). Each value is the mean±SD of three independent experiments. (*,p<0.05) Indicates significant differences compared to the control analyzed by one-way ANOVA 121
Results of relative cell viability for (50:50%) neat PLLA/TPU and PLLA/TPU-(y-Fe2O3) electrospun mats.(*) Significant difference compared to the control analyzedby unpaired t-test (p<0.05). (**) Indicates Significantdifferent compare to the PLLA/TPU-(y-Fe2O3) 122
FE-SEM images of HSF-1184 fibroblast cells attachmentresults on PLLA/TPU-(y-Fe2O3) electrospun mats 124
Results of (a) thrombin time (b) pro-thrombin clotting time for different ratios of PLLA/TPU-(y-Fe2O3) and neat PLLA/TPU scaffolds. (*) Significant difference compared to the control analyzed by unpaired t-test (p<0.05). (**)Indicates the significant difference between neatPLLA/TPU and PLLA/TPU containing maghemite(p<0.05) 127
Results of the first fibrin detection point by using Clot Sp. instrument in terms of (a) time (s) (b) concentration (g/L) 128
Hemo-lytic test records for different ratios of PLLA/TPU-(y-Fe2O3) electrospun mats. (*) Represents significantdifference compared to the negative control analyzed byunpaired t-test (p<0.05). (**) Indicates the significantdifference between neat PLLA/TPU and PLLA/TPUcontaining maghemite (p<0.05) 129
Mechanical stress vs. strain curve for uniaxial tensile testof different ratios of PLLA/TPU-(y-Fe2O3) electrospunmats 131
Main effect plots for mean S/N ratio of elastic modulus 134
Interaction plots data means for elastic modulus 135
Contribution percent of each parameter on elastic modulus 139
4.27
4.28
4.29
4.30
4.31
4.32
4.33
4.34
4.35
4.36
4.37
4.38
4.39
4.40
4.41
4.42
4.43
4.44
xvii
Plot of (a) normal probability (b) residual vs. predictedvalue 142
Plot of (a) 3D surface response (b) counter plot of elastic modulus 143
Pathway of steepest ascent method 144
Trend of steepest ascent steps responses of elastic modulus 146
Plot of (a) normal probability (b) residual vs. predictedvalue for CCD 150
Plot of (a) 3D surface response (b) counter plot ofquadratic model for elastic modulus 151
Plot of trend between the predicted and actual elasticmodulus 153
Exterior and interior images of 3D scaffold (aluminiumbased design) 154
Images of fabrication procedure of 3D scaffold of aorticheart valve 155
Images of (a) FE-SEM (b) diameter distribution of 156optimum 3D scaffold leaflet
Water contact angle for optimum scaffold 157
Procedure of porosity measurement using liquiddisplacement method 158
FE-SEM and CLSM images of valve’s leaflet and root in 15, 20 and 34 days of incubation. The different colours represented the live cells (Green), dead cells (Red) and scaffold (Dark) area 159
Results of 3D scaffold relative cell viability versus theincubation time (days). Each value is the mean ± SD of allthe experiments 160
Blood clotting time in terms of PT and TT assay 161
Results of the first fibrin detection for optimum scaffold in terms of concentration (g/L) and time (sec). (*) Significant difference compared to the control analyzed by unpaired t- test (p<0.05) 162
Hemo-lytic test records for PLLA/TPU containing 3.80% and 1% of (y-Fe2O3) scaffold. (*) Represents significant difference compared to the negative control analyzed by unpaired t-test (p<0.05) 163
Load vs. extension curve for optimum scaffold after 15, 20and 34 days of cell seeding 165
xviii
4.45 Elastic modulus loss as a function of incubation time (days). (*) Represents significant difference compared to the day zero (for dry scaffold) and day 15 (for wet scaffold) analyzed by unpaired t-test (p<0.05).
xix
2D - Two-dimensional
3D - Three-dimensional
Adj-R - Adjusted R-Square
ADSCs - Adipose derived stem cells
AFM - Atomic force microscopy
ANOVA - Analysis of variance
AOHV - Aortic heart valve
AV - Atrioventricular valve
BMSCs - Bone marrow stem cells
C - Carbon
CAD - Computer aided design
CCD - Central composite design
CLSM - Confocal laser scanning microscopy
CT - Computed tomography
DCM - Dichloromethane
DMF - Dimethylformamide
DMEM - Dulbecco’s modified Eagle’s medium
DMSO - Dimethyl sulfoxide
DOE - Design of experiments
DSC - Differential scanning calorimetry
ECM - Extracellular matrix
EDX - Energy dispersive X-ray
EGFP - Enhanced green fluorescent protein
LIST OF ABBREVIATIONS
xx
FBS - Fetal bovine serum
FDA - Food and drug administration
Fe - Iron
FE-SEM - Field-emission scanning electron microscopy
FeCl2 - Ferric (Iron (II) chloride)
FeCl3 - Ferrous (Iron (III) chloride)
FTIR - Fourier transform infrared spectroscopy
GAG - Glycosaminoglycan
HASMCs - Human aortic smooth muscles cells
HBSS - Hank's buffered salt solution
HCl - Hydrochloric acid
HNO3 - Nitric acid
HRBCs - Human red blood cells
HSF-1184 - Human skin fibroblast
HA - Hydroxyl apatite
LV - Left ventricles
MRI - Magnetic resonance image
MTT - 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
NH 3 - Ammonia solution
O - Oxygen
P4HB - Poly-4-hydroxybutyrate
PAN - Polyacrylonitrile
PBS - Phosphate buffer saline
PCL - Polycaprolactone
PF - Polyfumaroles
PGA - Polyglycolic acid
PGS - Polyglycerol sebacate
PLA - Polylactid acid
PLGA - Poly (lactic-co-glycolic) acid
xxi
PLLA - Poly-L-lactic acid
PDLLA - Poly-DL-lactide
Pred-R - Predicted R-Squares
PT - Pro-thrombin time
PTT - Partial thrombin time
PVA - Polyvinyl alcohol
RSM - Response surface methodology
SBF - simulated body fluid
SD. - Standard deviation
SFF - Solid free form fabrication
S/N - Signal to noise
SV - Semilunar valve
TCP - Thricalcium phosphate
TE - Tissue engineering
TEHV - Tissue engineering heart valve
TEM - Transmission electron microscopy
TPU - Thermoplastic polyurethane
Tris - Tris hydroxymethyl amino methane
TT - Thrombin time
UTM - Universal testing machine
VICs - Valve interstitial cells
XRD - X-ray diffraction spectroscopy
Y-Fe2O3 - Maghemite
xxii
LIST OF SYMBOLS
A - Flow rate — First factor
B - Voltage — Second factor
C - Maghemite content — Third factor
D - Solution concentration — Fourth factor
E - Collector rotating speed — Fifth factor
El - Stiffness index
F - Force
H - Valve height
HP - Hemolysis percent
K - Number of factors
L - Gap length between grids
Ms - Mean of squares
S - Square area
SS - Sum of squares
T - Thickness
v/v - Volume/Volume
w/v - Weight/Volume
% - Percent
°C - Degree Celsius
Y - Gamma
Xc - Crystallinity
AHm - Melting enthalpy
W f - Weight fraction of reference polymer
xxiii
AH°m - Melting enthalpy of the reference polymer
a(E) - Tensile stress
8 - Tensile strain
P - Regression coefficient
S - Depth of indentation
5max - Maximum depth
p - Density
AL - Change in length
AX - Step size
Y - Regression response
R2 - R-square
A 0 - Cross section area
Cd - Commissure diameter
Ch - Commissure height
d f - Degree of freedom
Db - Base diameter
Dc - Absorbance value of control
DNegC - Absorbance value of negative control
DposC - Absorbance value of positive control
Ds - Absorbance value of sample
Dt - Top diameter
Ee - Elastic modulus
Er - Relative elastic modulus
L0 - Origin length
Lf - Leaflet free-edge
Lh - Leaflet height
M1 - Average of counted cells via hemocytometer
M2 - Number of cells to be seeded
Pr - Porosity
xxiv
Ra - Surface roughness average
Re - Contact surface area between ball probe and sample
Rpv - Peak to valley
Rq - Root-mean square of surface roughness
Rz - Five lowest valley and five highest peak averages
Tg - Glass transition temperature
Vc - Required volume of cell suspension
Vt - Total required solution
Vi - Known volume
V2 - Total of new volume after immersion of sample
Vs - Total of new volume after sample removal
Vf - Poisson’s ratio
Wd - Dry weight
W0 - Original weight of sample
Wt - Mass change
Ww - Wet weight
2 - Predicted response
xxv
APPENDIX
A
LIST OF APPENDICES
TITLE PAGE
List of publications 202
CHAPTER 1
INTRODUCTION
1.1 Overview of the Research
The four valves represented in the mammalian hearts are responsible to
maintain unidirectional, non-hinder blood flow from heart to the other parts of body.
The heart valves synchronically open and close approximately 40 million times a
year and more than 3 billion times during the life (75 years average life expectancy)
(Aagaard, 2004; Rabkin-Aikawa et al., 2005). The four valves are namely; (I):
Aortic, (II): Pulmonary, (III): Mitral (bicuspid) and (IV): Tricuspid. The aortic and
pulmonary valves are in the arteries leaving the heart and known as semilunar valves
(SV), the mitral and tricuspid are between the atria and ventricles which known as
atrioventricular valves (AV) (Gallyamov et al., 2014; Saito et al., 2016). Valvular
heart dysfunction is a significant cause of morbidity and mortality around the world.
The prevalence of heart disease in adult US population in the early of 21st century
has been estimated at more than 5 million (Schoen, 1997; Basso et al., 2013). In the
meantime; heart valves (especially aortic and mitral) dysfunction is a significant part
of heart disease, which leads to death of approximately 20,000 people around the
world annually. Approximately more than 290,000 heart valve surgeries is required
around the world each year and according to the increase in average age of the
population, it is estimated to reach 850,000 by the year 2050 (Yacoub and
Takkenberg, 2005; Sewell-Loftin et al., 2011). A heart valve consists of two or three
semicircular shape moving flaps which are called leaflets and comes together in the
center of the valves to close it. These leaflets are attached to the walls of a cylindrical
conduit which is called the valve root. The histology of the valve leaflets (cusps)
2
exhibits an extracellular matrix (ECM) structure of three distinct layers: fibrosa,
spongiosa and ventricularis. The fibrosa, the surface away from the blood flow,
compose of parallel, dense collagen which is associated with the mechanical
properties such as stiffness and strength of the leaflets. The spongiosa, the middle
surface, compose of proteoglycans and lower abundance of collagen which facilitate
the movement, and finally, the ventricularis, the adjacent surface, compose of aligned
fiber of elastin interspersed and short collagen fiber, which provides the elasticity
properties of leaflets. The aortic valves leaflets comprise of 45% collagen (types, I
(74%), III (24%) and V (2%)), 20% elastin in dry weight and 35% of glycosamino
acid (Gross and Kugel, 1931; Garcia-Martinez et al., 1991; Cox, 2009; Falk et al.,
2011; Gallyamov et al., 2014; Roberts et al., 2015) Figure 1.1 illustrates the
anatomy/position of the four valves and the structure of ECM of leaflets.
Pulmonary Valve
(b)
(c)
Figure 1.1: Schematic of (a) heart anatomy (b) valve position (c) single valve leaflet
and its ECM structure (Schoen, 1997)
3
Heart valve dysfunctions may arise due to development regulation,
mechanical properties shortage (such as leakage and overlaps of the leaflets),
absence or abnormality of tissue in congenital cases and even calcification causes by
the deposition of mineralized calcium and genetic defect in the matrix protein
structure (Nasuti et al., 2004; Ng et al., 2004). When one of the valves malfunctions,
the end stage of medical choice may be to replace the original valves with an
artificial one. Generally, the cardiac surgeries to replace the heart valves are common
around the world and improve the life expectancy. Currently, the mechanical valves
and the biological (glutaraldehyde xeno-grafts or cryopreserved homo-grafts) are
used clinically as the state-of-the-art of artificial valves, despite the occurrence of
prosthesis side effects such as the need to anticoagulation treatment and durability of
valves (Iung et al., 2003; Nkomo et al., 2006; Thom et al., 2006). In order to resolve
the drawbacks of prostheses, the tissue engineering concept is introduced (Tanaka et
al., 2005; Jain et al., 2010; Lueders et al., 2014; Cheung et al., 2015). Figure 1.2
depicts the artificial heart valves.
(a) (b) (c)
Figure 1.2: Artificial heart valves (a) mechanical (b) biological (c) tissue
engineering heart valve (Fallahiarezoudar et al., 2015c)
Tissue engineering (TE) is an integrated science between the engineering
principle and life science to overcome the limitation of prostheses. The principle of
TE is to provide a three-dimensional (3D) scaffold (that resembles the original tissue
properties) for a specific tissue to develop the neotissue from their cellular
components. The scaffold provides an initial environment for cell attachment and
tissue growth. The cell can be either seeded onto the scaffold matrix in vitro (pre
implementation) or in vivo (post-implementation) to develop a neotissue for
replacement or repair the damaged tissue. The fabrication of a neotissue from cellular
4
combination (which depicts most of the characteristics of the original tissue such as
non-inflammation and non-immunogenic reaction, adequate mechanical properties
and durability) is the ultimate goal of TE. The concept of tissue engineering heart
valve (TEHV) was introduced by Shinoka et al. (1995). The TEHV principle can be
summarized in three main phases: (I) 3D biocompatible scaffold fabrication, (II) cell
cultivation and seeding over the scaffold, and (III) development conditions of the
TEHV before implantation (Sheridan et al., 2000; Teebken et al., 2000). Figure 1.3
illustrates the concept of TEHV.
Figure 1.3: Concept of tissue engineering heart valve (TEHV) (Fallahiarezoudar et
al., 2015c)
In order to design and fabricate a proper 3D heart valve scaffold, the initial
and probably one of the most important phases of TEHV concept is to investigate the
valve structure and function. Each layer (fibrosa, spongiosa and ventricularis) which
has a particular property, forms the valves structure. In the scaffold fabrication phase,
the appropriate materials selection and fabrication techniques are debatable. The
scaffold architecture (matrix) is very important as it is the basis of TEHV concept. In
order to ensure a successful scaffold: (I) The utilized materials should be biologically
5
compatible, biodegradable and cover the requirements for mechanical properties, (II)
the structure should provide a hierarchical extensive network of interconnecting
pores to facilitate the cells attachment and provides the oxygen and nutrients to those
cells which are far away from the surface (usually more than 1 mm) and (III) the
shape and the size of the scaffold should resemble the native tissue (Aikawa et al.,
2006; Baaijens et al., 2010).
The usable materials for scaffolds fabrication purpose can generally be
classified into two groups: the polymer based and the natural based materials. The
basic of scaffold mechanical properties and hemocompatibility with in vivo are
highly dependent on the materials selection. The required properties for TEHV
scaffold can be translated into biocompatibility, biodegradability, thermo-plasticity,
elasticity and stiffness characteristics (Argento et al., 2012; Chen et al., 2013; Alves
et al., 2014). The main advantages of a synthetic polymer-based scaffold are the fact
that biomechanics and degradation properties can be chemically controlled according
to the requirements. Against the cytotoxicity, low degradation rate and inflammation
are the main drawbacks of the synthetic polymeric scaffold. Although no
biodegradable polymeric materials have been proven to be a desirable substitute for
the native valves, work continues to be promising (Zhai et al., 2010; Eckert et al.,
2013; Masoumi et al., 2013a). Furthermore, the utilization of the natural materials
such as collagen has also been reported as the raw material for scaffold fabrication.
Collagen is the main extracellular matrix protein of the origin heart valves. The
fibrosa is considered to be the main load carrying structure and is primarily
composed of circumferentially arranged densely packed bundles of collagen fibres
and a micro-fibrillar network of elastin. The use of collagen regarding to low
antigenicity and less immunogenicity can be the advantages of collagen based
scaffold. However, poor handling, low mechanical properties, and less controlled
biodegradability are the defects of collagen based scaffold (Chevallay and Herbage,
2000; Levy et al., 2004; Balguid et al., 2007; Chen et al., 2013).
Poly-L-lactic acid (PLLA) is one of the preferred biomaterials that are widely
used in different fields of TE. PLLA due to high tensile strength, good compatibility
in vivo and biodegradability is considered to be used in this research. However, the
6
rigidity and non-flexible matrix of PLLA limited the development of soft tissue by
this polymer (Kang et al., 2009; Sakai et al., 2013; Qiao et al., 2016). The PLLA
scaffold was fabricated through electrospinning technique for bone tissue
engineering purpose that indicated elastic modulus value of 35 MPa in such a way
that the tensile strain was around 5-10% (Luu et al., 2003). Application of pure
PLLA scaffold (fabricated by different techniques) was mostly reported as a template
for bone tissue engineering purpose. The biocompatibility and tissue formation using
nanofiber based PLLA scaffold was confirmed in vivo. PLLA scaffold was well
colonized with cells after implantation, but only showed marginal ossification
(Schofer et al., 2011). Besides, bio-grade thermoplastic polyurethane (TPU) exhibits
superb elasticity (more than 220% of strain) with non-inflammation behaviour in
vivo (Chen et al., 2010; Jing et al., 2016). The fabricated electrospun scaffold using
pure TPU exhibited the samples were deformed easily in a low stress value which
may not be appropriate in this case (Chen et al., 2009a; Jing et al., 2016). Fabricated
TPU electrospun nanofibers indicated super hydrophobicity that made difficulties for
cell culturing (Wang et al., 2011). Therefore, the mixture of these two polymers can
lead to a composite with desired tensile strength, elasticity and biocompatibility for
soft TE purpose (Mi et al., 2013; Jing et al., 2014; Marycz et al., 2016).
Maghemite (y-Fe2O3) nanoparticle, which is a novel biocompatible material,
has recently been used in biomedical applications such as magnetic cell seeding, cell
expansion and drug delivery and the results are quite promising. The outstanding bio
behaviours (mechanical and biological) of maghemite have been reported in previous
researches (Tartaj et al., 2003; Wei et al., 2011; Ngadiman et al., 2015). Maghemite
nanoparticles filled nanofibers such as polyvinyl alcohol (PVA) were used
previously for composite reinforcement purpose (Fallahiarezoudar et al., 2015b).
Furthermore, maghemite filled polyvinyl alcohol was reported as a potential
materials for bone tissue engineering purpose which resulted in higher tensile
strength and better cell proliferation (Ngadiman et al., 2017).
Scaffold fabrication can be classified into two main techniques. Conventional
techniques such as solvent casting in combination with particulate leaching and
phase separation in combination with freeze drying, and fashionable techniques such
7
as electrospinning and solid-free-form (3D printing) fabrication. The ECM structure
and subsequently the mechanical properties and biological compatibility are highly
dependent upon the parameters which can be modified in fashionable fabrication
methods. The microstructure parameters such as the fiber diameter, interconnectivity,
porosity properties and stiffness, which ultimately shape the macrostructure
properties of the scaffold, should be investigated. In perspective of scaffold
manufacturing, each technique has its own pros and cons (Hutmacher and Cool,
2007; Hoque et al., 2012).
Electrospinning is a versatile and straightforward technique for
cardiovascular scaffold fabrication. In the electrospinning setup, a high electric field
is responsible for transforming the emerging solution supplied via syringe pump into the
fibers. Figure 1.4 depicts a schematic diagram of the electrospinning setup. High
surface area to volume ratio and high porosity are the advantages of electrospinning
process. In fashionable fabrication techniques such as electrospinning the
microstructure can be modified according to the requirements by varying the
parameters involved such as types of polymers and solvents, flow rate, voltage,
needle-collector distance and others. The fibrous scaffold matrix prepares an
auspicious layout for the cell attachment, migrant and growth. However, the lack of
mechanical properties, time consuming and problems with residual solvent which
may stimulate the possibility of toxicity are the drawbacks (Ahmadipourroudposht et
al., 2015; Fallahiarezoudar et al., 2015a).
Figure 1.4: Schematic diagram of the electrospinning setup
8
The second phase in tissue engineering concept is the cell cultivation and
seeding over the scaffold. The successful cell seeding process is highly related to the
scaffold architecture and biocompatibility of materials that were used for the 3D
scaffold fabrication. The inter-related, hierarchical scaffold structure will stimulate
the cell proliferation/migration and subsequently shape the ECM. Three types of
cells are reported to be useful in TEHV: (i) The vascular smooth muscles cells
(Colazzo et al., 2011), (ii) the valves interstitial cells (Masoumi et al., 2013b) and
(iii) the bone marrow stem cells (Hadju et al., 2011). Two methods of cell seeding
are proposed as dynamic and static. In dynamic method the scaffold is in constant
motion during cell seeding in the incubator an opposed to the static environment.
Various types of cell adhesion molecules such as integrin have been used to coat the
scaffold matrix prior to cell seeding. Interaction between the integrins on the cell
membrane and the receptors on ECM are largely responsible for cell attachment. The
integrin consist of a and fi chains (18 subunits for a and 8 subunits for fi) which have
the responsibility for cell attachment to ECM and signal translation from the ECM to
the cells (Lam et al., 2002; Taylor et al., 2006).
Once the fabricated scaffold was seeded, the neo-tissue starts to develop. The
environment in which the scaffold grows is one of the criteria for successful TEHV.
The scaffold development environment will influence the formation of the ECM.
Two perspectives have been proposed by the researchers: (I) the black box approach
where the scaffold is implanted in vivo shortly after cell seeding and used as cell
delivery to the native tissue (Vacanti et al., 1988; Fong et al., 2006), (II) bioreactor
approach such as pulse duplicator which provides the physiological pressure and
flow to the developed TEHV and promotes both cell function and mechanical
properties (Sodian et al., 2001; Engelmayr et al., 2003; Mol et al., 2005).
1.2 Research Problem Statement
Currently the usable clinical prostheses of heart valves (mechanical or
biological) have a non-viable structure and have no capacity to grow, remodel or
9
repair. As a result, almost 50-60% of patients experienced problems with artificial
valves and require reoperation (Chevallay and Herbage, 2000; Aagaard, 2004; De
Heer et al., 2013; Grzymala-Lubanski et al., 2016). Mechanical valves as a foreign
material may cause inflammation, infection and thromboembolic complication due to
high shear stresses of blood flow which requires an anti-coagulation medication such
as a vitamin K antagonist (e.g. warfarin) along the life. Although warfarin could be
efficacious to alleviate coagulation, it has the risk of hemorrhagic and also the
embryo toxicity in fertile women (Lip et al., 2015; Roberts et al., 2016). On the other
hand, despite the lower thrombotic risk of biological valves compared to the
mechanical one (0.87% to 1.4% per annum, respectively) and no need to undergo
anti-coagulation treatment for the biological valves, the durability of these prostheses
are approximately 10-15 years due to the progressive tissue deterioration and this is
almost half the lifetime of the mechanical valves (20-30 years) (Potter et al., 2004;
Pibarot and Dumesnil, 2009; Tillquist and Maddox, 2011). These limitations forced
scientists to further investigate of other possible methods of creating a neo-tissue
similar to the original tissue that can fully solve the drawbacks of the artificial
valves. However, TEHV principle is introduced as a possible method of resolving
these limitations (Tanaka et al., 2005; Jain et al., 2010; Lueders et al., 2014; Cheung
et al., 2015). A biodegradable and biocompatible 3D scaffold with adequate
characteristics is fabricated, seeded with the appropriate cells source and developed
in vitro in a bioreactor to create a biomimetic tissue which resembles the original
tissue characteristics (Argento et al., 2012; Cui et al., 2016).
Previous researches on TEHV were performed using poly lactic acid (PLA)
(Armentano et al., 2013; Sakai et al., 2013), polyglycerol sebacate (PGS) (Masoumi
et al., 2013a; Sanz-Garcia et al., 2015), polyglycolic acid (PGA) (Matsumura et al.,
2003; Frese et al., 2016), polycaprolactone (PCL) (Vaz et al., 2005; Marei et al.,
2016) to fabricate the scaffold. Most of these researches result in a non-viable
structure or toxicity due to the use of inorganic solvent. In addition, the degradation
rate and mechanical properties of polymers also plays a critical role in TE concept.
Fabrication of scaffold using PLA indicated a desirable biocompatibility and
biodegradability (around 6 months), but much thicker and less flexible (roughly 1
2% tensile strain) which was in conflict with dynamic mechanism of original tissue
10
(Armentano et al., 2013; Sakai et al., 2013). Despite good mechanical properties of
PCL (3.7 MPa tensile stress and 90% tensile strain), low degradation rate (more than
2 years) causes the failure of TE concept (Vaz et al., 2005; Yao et al., 2016). Also
the fabricated PGS-based heart valve scaffold exhibited very fast degradation rate (2
3 weeks) with 0.5 MPa of elastic modulus but it could not provide the required
elastic modulus for heart valves (Masoumi et al., 2013a; Lin et al., 2015). On the
other hand, the scaffold adverse structure (that can be the result of inappropriate
fabrication method) may result in the aggregation of seeded cells just over the
scaffolds surface. As reported by Taylor et al. (2002) an extremely low expansion of
valvular interstitial cells was observed on micromould injection PLGA scaffold.
Colazzo et al. (2011) reported that the fabricated PLA scaffold using freeze drying
technique resulted in cell adhesion only on the surface that can be attributed to
disconnected pores. Furthermore, scaffold overgrowth, leakage and rupture before
implementation (Van Lieshout et al., 2006; Muylaert et al., 2014) or inflammation
due to low degradation rate after implementation (Choi and Park, 2002; Loger et al.,
2016) can happen due to the improper selection of polymeric materials source. Thus,
the selection of a proper source of polymeric based biomaterials in terms of
biocompatibility, biodegradability and mechanical properties as well as an applicable
fabrication technique that can satisfy the heart valve characteristics is the major
concern.
1.3 Research Questions
(i) What is the optimum ratio of polymer solutions blend according to the
required characteristics of an aortic heart valve?
(ii) What is the biological and mechanical effect of maghemite
nanoparticles presence in nanofibers matrix?
(iii) What are the biomechanical and structural characteristics of native
aortic heart valve leaflets?
(iv) What are the required specifications to design and fabricate a three
dimensional scaffold that can resemble the origin tissue characteristics?
11
(v) How to perform the cell seeding procedure and evaluate the mechanical
performance after cell seeding?
1.4 Research Hypothesis
Design of complex structures such as heart valves need to be simplified prior
to fabrication and modelling. It this case some assumptions are applied to the design
procedure to make it tractable.
First, it is assumed that the valves cusps have identical characteristics in
dimensions and mechanical properties. Since the access to the human heart valve
information and dimension is difficult, in this research the specifications are
extracted from other previous works (Swanson and Clark, 1974; Labrosse et al.,
2006). Second, the leaflets lie at 120° from each other in the 3D circle plate. Third, it
is assumed that the top and bottom of the cylinder with the valve inside of it (aortic
root) are parallel. The final and noticeable hypothesis in designing the valve is to
consider that the valves component’s dimensions are not changed significantly
during the cardiac cycle.
1.5 Research Aim and Objectives
The aim of this research is to fabricate, characterize and optimize a nanofiber-
based scaffold of aortic heart valve with the extracellular matrix (ECM) structure and
appropriate biological and mechanical characteristics to assist the aortic smooth
muscles cell adhesion, migration and proliferation.
Objectives of this research are:
12
(i) To characterize different ratios of poly-L-lactic acid/thermoplastic
polyurethane polymers to tune the ratio that proposes the best
performance for tissue engineering heart valve.
(ii) To investigate the effect of maghemite nanoparticles on chemical,
biological and mechanical properties of electrospun mat.
(iii) To optimize the fabrication process (electrospinning) in terms of elastic
modulus that tailors the scaffold structure and mechanical properties.
(iv) To design and fabricate a three-dimensional nanofiber-based aortic
heart valve scaffold.
(v) To evaluate the migration and proliferation of aortic smooth muscles
cell over the scaffold and dwindle of mechanical properties as a
function of incubation time.
1.6 Research Scopes
The left heart typically achieves a peak pressure about six times of the right
over the cardiac cycle. So, the two valves on the left side of the heart are subjected to
much higher loads than those on the right heart (Hasan et al., 2014). Since the
majority of valve diseases involve the valves of the left heart, therefore, the scope in
this research is limited to investigating the anatomy and design microstructure of the
tissue engineering aortic heart valves. The heart valve tissue engineering concept can
be split into three main steps: (i) Fabrication of 3D scaffold with proper design and
properties, (ii) cell seeding over the 3D scaffold, and (iii) development of neo-tissue
in bioreactor prior to implementation. In this research the scope is limited to the
characterization of the novel mixture of poly-l-lactic acid (PLLA), thermoplastic
polyurethane (TPU) and maghemite (y-Fe2O3) nanoparticles as the potential
biocompatible and biodegradable materials for heart valve scaffold fabrication. A 3D
template associated to the semilunar heart valves was designed to fabricate a 3D
scaffold and the biological and mechanical properties of the fabricated scaffold are
characterized as well.
13
In order to fabricate a biomimetic scaffold of aortic heart valve with adequate
properties that can resemble the original tissue, two parameters of usable materials
and fabrication techniques are among the available options considered.
(i) The utilized materials are PLLA, TPU and (y-Fe2O3) nanoparticles
which are categorized in the synthetic, polymeric materials group and
their optimum proportions were determined.
(ii) The fabrication method was limited to the electrospinning technique.
(iii) The controllable parameters involved (which may have significant
effect on the microstructure) such as flow rate, voltage, maghemite %,
solution concentration and rotating speed, as well as noise parameters
were selected as the variables to optimize the microstructure
properties.
(iv) The characterization of electrospun mats in terms of morphology,
porous properties, surface roughness, hydrophilicity, cytotoxicity
assay, degradation rate, blood hemocompatibility, mechanical
behaviour, cells attachment, migration and proliferation over the
samples were investigated during this research.
(v) The characteristics mentioned with emphasis on the mechanical
properties (tensile stress, tensile strain and elastic modulus) of the
aortic heart valve leaflets were the major scope.
(vi) The optimization of scaffold fabrication technique was performed
(based on uniaxial tensile properties) in terms of elastic modulus
using Taguchi experimental design and response surface
methodology.
(vii) The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) assay using human aortic smooth muscles cells (HASMCs)
were used to verify the cell viability.
(viii) Blood hemocompatibility in terms of clotting time, fibrin formation
and hemolysis were investigated.
(ix) The biomechanics behaviours of seeded scaffold as a function of
incubation time were characterized using macro-indentation
bending/flexural tests.
14
1.7 Significance of Research
A novel combination of material PLLA/TPU containing maghemite is useful
in the design and fabrication of a synthetic biodegradable scaffold. The unique
material developed has both the extracellular matrix structure of the aortic heart
valve with interconnected networks (to provide the oxygen and nutrients to the cells
which are far away from the surface) and the required mechanical properties such as
tensile strength and flexural to resist against the blood pressure. In addition, the
material has the stiffness and elastic characteristics that can be useful on biomaterials
for scaffold development. Information on the electrospinning process parameters that
produces nanofibers with optimum fiber diameter distribution and porosity with
excellent mechanical properties and structure were also disclosed for the unique
material. The findings of the research can also increase the life expectancy of
patients experiencing valvular heart dysfunction. The developed synthetic bio
polymeric TEHV has the possibility of reducing the number of times a patient needs
to undergo valve replacement surgery and this can reduce the complications after
surgery and also cost.
1.8 Organization of Thesis
In the first Chapter of this thesis, general information of the research,
objectives and scope are provided. In Chapter 2, the literature review on tissue
engineering and particularly tissue engineering heart valves is described including
the previous investigation on the microstructure, function and mechanical properties
of the origin porcine and/or human tissue. Chapter 3 presents the research framework
and detailed explanation of each phase to show the methods of experiments
conducted and initial finding is provided. Chapter 4 provides the results and a
detailed discussion on the findings of this research. This chapter is divided into three
main sections; materials ratio tuning, electrospinning process optimization using
Taguchi experimental design and 3D scaffold fabrication/characterization. In Chapter
5, the conclusion was made according to the assumptions made and the results
obtained.
REFERENCES
A a g a a r d , J . ( 2 0 0 4 ) . T h e c a r b o m e d i c s a o r t i c h e a r t v a l v e p r o s t h e s i s : a r e v i e w . Journal
o f Cardiovascular Surgery, 4 5 ( 6 ) , 5 3 1 - 5 3 4 .
A h m a d i p o u r r o u d p o s h t , M . , F a l l a h i a r e z o u d a r , E . , Y u s o f , N . M . , a n d I d r i s , A . ( 2 0 1 5 ) .
A p p l i c a t i o n o f r e s p o n s e s u r f a c e m e t h o d o l o g y i n o p t i m i z a t i o n o f
e l e c t r o s p i n n i n g p r o c e s s t o f a b r i c a t e ( f e r r o f l u i d / p o l y v i n y l a l c o h o l ) m a g n e t i c
n a n o f i b e r s . Materials Science and Engineering: C, 50, 2 3 4 - 2 4 1 .
A i k a w a , E . , W h i t t a k e r , P . , F a r b e r , M . , M e n d e l s o n , K . , P a d e r a , R . F . , A i k a w a , M . , e t
a l . ( 2 0 0 6 ) . H u m a n s e m i l u n a r c a r d i a c v a l v e r e m o d e l i n g b y a c t i v a t e d c e l l s
f r o m f e t u s t o a d u l t i m p l i c a t i o n s f o r p o s t n a t a l a d a p t a t i o n , p a t h o l o g y , a n d
t i s s u e e n g i n e e r i n g . Circulation, 1 1 3 ( 1 0 ) , 1 3 4 4 - 1 3 5 2 .
A l b e r t s , B . ( 1 9 9 4 ) . E x c e r p t f r o m t h e b o o k “ Molecular Biology o f the Cell ( 3 r d . e d . )
U n i t e d s t a t e : G a r l a n d P u b l i s h i n g .
A l e s s a n d r i , M . , C a l z a , L . , C o l o m b o , V . , D o l c i , L . , F i o r a n i , A . , F o c a r e t e , M . , e t a l .
( 2 0 1 3 ) . A t m o s p h e r i c p l a s m a s u r f a c e m o d i f i c a t i o n o f e l e c t r o s p u n p o l y ( L -
l a c t i c a c i d ) : E f f e c t o n m a t p r o p e r t i e s a n d c e l l c u l t u r i n g . Plasma Science
(ICOPS) IEEE International Conference, 1 6 th J u n e 2 0 1 3 , C a l i f o r n i a U S A , 1 .
A l - N b a h e e n , M . , A l i , D . , B o u s l i m i , A . , A l - J a s s i r , F . , M e g g e s , M . , P r i g i o n e , A . , e t a l .
( 2 0 1 3 ) . H u m a n s t r o m a l ( m e s e n c h y m a l ) s t e m c e l l s f r o m b o n e m a r r o w ,
a d i p o s e t i s s u e a n d s k i n e x h i b i t d i f f e r e n c e s i n m o l e c u l a r p h e n o t y p e a n d
d i f f e r e n t i a t i o n p o t e n t i a l . Stem Cell Reviews and Reports, 9 ( 1 ) , 3 2 - 4 3 .
A l v e s , P . , C a r d o s o , R . , C o r r e i a , T . , A n t u n e s , B . , C o r r e i a , I . , a n d F e r r e i r a , P . ( 2 0 1 4 ) .
S u r f a c e m o d i f i c a t i o n o f p o l y u r e t h a n e f i l m s b y p l a s m a a n d u l t r a v i o l e t l i g h t t o
i m p r o v e h a e m o c o m p a t i b i l i t y f o r a r t i f i c i a l h e a r t v a l v e s . Colloids and Surfaces
B: Biointerfaces, 113, 2 5 - 3 2 .
A n d e r s o n , R . H . ( 2 0 0 0 ) . C l i n i c a l a n a t o m y o f t h e a o r t i c r o o t . Heart, 8 4 ( 6 ) , 6 7 0 - 6 7 3 .
174
A n s s a r i - B e n a m , A . , B a d e r , D . L . , a n d S c r e e n , H . R . ( 2 0 1 1 ) . A c o m b i n e d
e x p e r i m e n t a l a n d m o d e l l i n g a p p r o a c h t o a o r t i c v a l v e v i s c o e l a s t i c i t y i n t e n s i l e
d e f o r m a t i o n . Journal o f Materials Science: Materials in Medicine, 2 2 ( 2 ) ,
2 5 3 - 2 6 2 .
A r g e n t o , G . , S i m o n e t , M . , O o m e n s , C . , a n d B a a i j e n s , F . ( 2 0 1 2 ) . M u l t i - s c a l e
m e c h a n i c a l c h a r a c t e r i z a t i o n o f s c a f f o l d s f o r h e a r t v a l v e t i s s u e e n g i n e e r i n g .
Journal o f Biomechanics, 4 5 ( 1 6 ) , 2 8 9 3 - 2 8 9 8 .
A r m e n t a n o , I . , B i t i n i s , N . , F o r t u n a t i , E . , M a t t i o l i , S . , R e s c i g n a n o , N . , V e r d e j o , R . , e t
a l . ( 2 0 1 3 ) . M u l t i f u n c t i o n a l n a n o s t r u c t u r e d P L A m a t e r i a l s f o r p a c k a g i n g a n d
t i s s u e e n g i n e e r i n g . Progress in Polymer Science, 3 8 ( 1 0 ) , 1 7 2 0 - 1 7 4 7 .
A u g u s t y n , C . , A l l s t o n , T . , H a i l s t o n e , R . , a n d R e e d , K . ( 2 0 1 4 ) . O n e - V e s s e l s y n t h e s i s
o f i r o n o x i d e n a n o p a r t i c l e s p r e p a r e d i n n o n - p o l a r s o l v e n t . RSC Advances,
4 ( 1 0 ) , 5 2 2 8 - 5 2 3 5 .
B a a i j e n s , F . , B o u t e n , C . , a n d D r i e s s e n , N . ( 2 0 1 0 ) . M o d e l i n g c o l l a g e n r e m o d e l i n g .
Journal o f Biomechanics, 4 3 ( 1 ) , 1 6 6 - 1 7 5 .
B a j i , A . , M a i , Y . - W . , W o n g , S . - C . , A b t a h i , M . , a n d C h e n , P . ( 2 0 1 0 ) . E l e c t r o s p i n n i n g
o f p o l y m e r n a n o f i b e r s : e f f e c t s o n o r i e n t e d m o r p h o l o g y , s t r u c t u r e s a n d t e n s i l e
p r o p e r t i e s . Composites Science and Technology, 7 0 ( 5 ) , 7 0 3 - 7 1 8 .
B a l g u i d , A . , R u b b e n s , M . P . , M o l , A . , B a n k , R . A . , B o g e r s , A . J . , V a n K a t s , J . P . , e t
a l . ( 2 0 0 7 ) . T h e r o l e o f c o l l a g e n c r o s s - l i n k s i n b i o m e c h a n i c a l b e h a v i o r o f
h u m a n a o r t i c h e a r t v a l v e l e a f l e t s - r e l e v a n c e f o r t i s s u e e n g i n e e r i n g . Tissue
Engineering, 13( 7 ) , 1 5 0 1 - 1 5 1 1 .
B a n e r j e e , R . , a n d C h e n , H . ( 1 9 9 5 ) . F u n c t i o n a l p r o p e r t i e s o f e d i b l e f i l m s u s i n g w h e y
p r o t e i n c o n c e n t r a t e . Journal o f Dairy Science, 7 8 ( 8 ) , 1 6 7 3 - 1 6 8 3 .
B a s s o , C . , M u r a r u , D . , B a d a n o , L . P . , a n d T h i e n e , G . ( 2 0 1 3 ) . A n a t o m y a n d
p a t h o l o g y o f r i g h t - s i d e d a t r i o v e n t r i c u l a r a n d s e m i l u n a r v a l v e s . I n Cardiac
Valvular Medicine ( p p . 2 1 1 - 2 2 1 ) L o n d o n : S p r i n g e r .
B e a c h , J . M . , M i h a l j e v i c , T . , S v e n s s o n , L . G . , R a j e s w a r a n , J . , M a r w i c k , T . , G r i f f i n ,
B . , e t a l . ( 2 0 1 3 ) . C o r o n a r y a r t e r y d i s e a s e a n d o u t c o m e s o f a o r t i c v a l v e
r e p l a c e m e n t f o r s e v e r e a o r t i c s t e n o s i s . Journal o f the American College o f
Cardiology, 6 1 ( 8 ) , 8 3 7 - 8 4 8 .
B e e , A . , M a s s a r t , R . , a n d N e v e u , S . ( 1 9 9 5 ) . S y n t h e s i s o f v e r y f i n e m a g h e m i t e
p a r t i c l e s . Journal o f Magnetism and Magnetic Materials, 1 4 9 ( 1 ) , 6 - 9 .
175
B e r n e , R . , a n d L e v y , M . ( 1 9 9 8 ) . S p e c i a l c i r c u l a t i o n s . Physiology. ( 4 th e d . ) St. Louis:
Mosby, 4 7 8 - 5 0 1 .
B i a n c o , P . , a n d R o b e y , P . G . ( 2 0 0 1 ) . S t e m c e l l s i n t i s s u e e n g i n e e r i n g . Nature,
4 1 4 ( 6 8 5 9 ) , 1 1 8 - 1 2 1 .
B i l l i a r , K . L . , a n d S a c k s , M . S . ( 2 0 0 0 ) . B i a x i a l m e c h a n i c a l p r o p e r t i e s o f t h e n a t i v e
a n d g l u t a r a l d e h y d e - t r e a t e d a o r t i c v a l v e c u s p : p a r t I I — a s t r u c t u r a l c o n s t i t u t i v e
m o d e l . Journal o f Biomechanical Engineering, 1 2 2 ( 4 ) , 3 2 7 - 3 3 5 .
B i s s e l l , M . M . , H e s s , A . T . , B i a s i o l l i , L . , G l a z e , S . J . , L o u d o n , M . , P i t c h e r , A . , e t a l .
( 2 0 1 3 ) . A o r t i c d i l a t i o n i n b i c u s p i d a o r t i c v a l v e d i s e a s e f l o w p a t t e r n i s a m a j o r
c o n t r i b u t o r a n d d i f f e r s w i t h v a l v e f u s i o n t y p e . Circulation: Cardiovascular
Imaging, 6( 4 ) , 4 9 9 - 5 0 7 .
C a r a b e l l o , B . A . ( 2 0 0 7 ) . A o r t i c v a l v e d i s e a s e . I n Cardiovascular Medicine, p p . 3 8 1
3 9 2 , L o n d o n : S p r i n g e r .
C h a n , K . C . , Y i n , M . C . , a n d C h a o , W . J . ( 2 0 0 7 ) . E f f e c t o f d i a l l y l t r i s u l f i d e - r i c h
g a r l i c o i l o n b l o o d c o a g u l a t i o n a n d p l a s m a a c t i v i t y o f a n t i c o a g u l a t i o n f a c t o r s
i n r a t s . Food and Chemical Toxicology, 4 5 ( 3 ) , 5 0 2 - 5 0 7 .
C h a v a r r i a , F . , a n d P a u l , D . ( 2 0 0 6 ) . M o r p h o l o g y a n d p r o p e r t i e s o f t h e r m o p l a s t i c
p o l y u r e t h a n e n a n o c o m p o s i t e s : E f f e c t o f o r g a n o c l a y s t r u c t u r e . Polymer,
4 7 ( 2 2 ) , 7 7 6 0 - 7 7 7 3 .
C h e n , R . , H u a n g , C . , K e , Q . , H e , C . , W a n g , H . , a n d M o , X . ( 2 0 1 0 ) . P r e p a r a t i o n a n d
c h a r a c t e r i z a t i o n o f c o a x i a l e l e c t r o s p u n t h e r m o p l a s t i c p o l y u r e t h a n e / c o l l a g e n
c o m p o u n d n a n o f i b e r s f o r t i s s u e e n g i n e e r i n g a p p l i c a t i o n s . Colloids and
Surfaces B: Biointerfaces, 7 9 ( 2 ) , 3 1 5 - 3 2 5 .
C h e n , R . , M o r s i , Y . , P a t e l , S . , K e , Q . - f . , a n d M o , X . - m . ( 2 0 0 9 a ) . A n o v e l a p p r o a c h
v i a c o m b i n a t i o n o f e l e c t r o s p i n n i n g a n d F D M f o r t r i - l e a f l e t h e a r t v a l v e
s c a f f o l d f a b r i c a t i o n . Frontiers o f Materials Science in China, 3 ( 4 ) , 3 5 9 - 3 6 6 .
C h e n , S . , H o u , H . , H u , P . , W e n d o r f f , J . H . , G r e i n e r , A . , a n d A g a r w a l , S . ( 2 0 0 9 b ) .
P o l y m e r i c n a n o s p r i n g s b y b i c o m p o n e n t e l e c t r o s p i n n i n g . Macromolecular
Materials and Engineering, 2 9 4 ( 4 ) , 2 6 5 - 2 7 1 .
C h e n , Q . , B r u y n e e l , A . , C a r r , C . , a n d C z e r n u s z k a , J . ( 2 0 1 3 ) . B i o - m e c h a n i c a l
p r o p e r t i e s o f n o v e l b i - l a y e r c o l l a g e n - e l a s t i n s c a f f o l d s f o r h e a r t v a l v e t i s s u e
e n g i n e e r i n g . Procedia Engineering, 59, 2 4 7 - 2 5 4 .
176
C h e n g , A . , H u m a y u n , A . , C o h e n , D . J . , B o y a n , B . D . , a n d S c h w a r t z , Z . ( 2 0 1 4 ) .
A d d i t i v e l y m a n u f a c t u r e d 3 D p o r o u s T i - 6 A l - 4 V c o n s t r u c t s m i m i c t r a b e c u l a r
b o n e s t r u c t u r e a n d r e g u l a t e o s t e o b l a s t p r o l i f e r a t i o n , d i f f e r e n t i a t i o n a n d l o c a l
f a c t o r p r o d u c t i o n i n a p o r o s i t y a n d s u r f a c e r o u g h n e s s d e p e n d e n t m a n n e r .
Biofabrication, 6 ( 4 ) , 5 0 0 7 - 5 0 1 2 .
C h e r a g h i p o u r , E . , T a m a d d o n , A . , J a v a d p o u r , S . , a n d B r u c e , I . ( 2 0 1 3 ) . P E G
c o n j u g a t e d c i t r a t e - c a p p e d m a g n e t i t e n a n o p a r t i c l e s f o r b i o m e d i c a l
a p p l i c a t i o n s . Journal o f Magnetism and Magnetic Materials, 328, 9 1 - 9 5 .
C h e u n g , D . Y . , D u a n , B . , a n d B u t c h e r , J . T . ( 2 0 1 5 ) . C u r r e n t p r o g r e s s i n t i s s u e
e n g i n e e r i n g o f h e a r t v a l v e s : m u l t i s c a l e p r o b l e m s , m u l t i s c a l e s o l u t i o n s . Expert
Opinion on Biological Therapy, 1 5 ( 8 ) , 1 1 5 5 - 1 1 7 2 .
C h e v a l l a y , B . , a n d H e r b a g e , D . ( 2 0 0 0 ) . C o l l a g e n - b a s e d b i o m a t e r i a l s a s 3 D s c a f f o l d
f o r c e l l c u l t u r e s : a p p l i c a t i o n s f o r t i s s u e e n g i n e e r i n g a n d g e n e t h e r a p y .
Medical and Biological Engineering and Computing, 3 8 ( 2 ) , 2 1 1 - 2 1 8 .
C h i o n o , V . , M o z e t i c , P . , B o f f i t o , M . , S a r t o r i , S . , G i o f f r e d i , E . , S i l v e s t r i , A . , e t a l .
( 2 0 1 4 ) . P o l y u r e t h a n e - b a s e d s c a f f o l d s f o r m y o c a r d i a l t i s s u e e n g i n e e r i n g .
Interface Focus, 4 ( 1 ) , 4 5 - 5 3 .
C h i r i t a , M . , G r o z e s c u , I . , T a u b e r t , L . , R a d u l e s c u , H . , P r i n c z , E . , S t e f a n o v i t s - B a n y a i ,
E . , e t a l . ( 2 0 0 9 ) . F e 2 O 3 - n a n o p a r t i c l e s , p h y s i c a l p r o p e r t i e s a n d t h e i r
p h o t o c h e m i c a l a n d p h o t o e l e c t r o c h e m i c a l a p p l i c a t i o n s . Chemical Bulletin, 54,
1 - 8 .
C h o i , S . H . , a n d P a r k , T . G . ( 2 0 0 2 ) . S y n t h e s i s a n d c h a r a c t e r i z a t i o n o f e l a s t i c
P L G A / P C L / P L G A t r i - b l o c k c o p o l y m e r s . Journal o f Biomaterials Science,
Polymer Edition, 1 3 ( 1 0 ) , 1 1 6 3 - 1 1 7 3 .
C h o u d h a r y , A . , a n d C h a u h a n , S . R . ( 2 0 1 3 ) . A p p l i c a t i o n o f r e s p o n s e s u r f a c e
m e t h o d o l o g y t o e v a l u a t e t h e e f f e c t o f c u t t i n g t o o l i n s e r t s o n m a c h i n i n g o f
a l u m i n i u m 7 0 7 5 a l l o y o n C N C t u r n i n g c e n t r e . International Journal o f
Machining andMachinability o f Materials, 1 3 ( 1 ) , 1 7 - 3 3 .
C h r i s t i e , G . ( 1 9 9 2 ) . A n a t o m y o f a o r t i c h e a r t v a l v e l e a f l e t s : t h e i n f l u e n c e o f
g l u t a r a l d e h y d e f i x a t i o n o n f u n c t i o n . European Journal o f Cardio-thoracic
Surgery, 6, 2 5 - 3 3 .
C h r i s t i e , G . W . , a n d B a r r a t t - B o y e s , B . G . ( 1 9 9 5 ) . M e c h a n i c a l p r o p e r t i e s o f p o r c i n e
p u l m o n a r y v a l v e l e a f l e t s : h o w d o t h e y d i f f e r f r o m a o r t i c l e a f l e t s ? The Annals
o f Thoracic Surgery, 60, 1 9 5 - 1 9 9 .
177
C h u , T . - M . G . , O r t o n , D . G . , H o l l i s t e r , S . J . , F e i n b e r g , S . E . , a n d H a l l o r a n , J . W .
( 2 0 0 2 ) . M e c h a n i c a l a n d i n v i v o p e r f o r m a n c e o f h y d r o x y a p a t i t e i m p l a n t s w i t h
c o n t r o l l e d a r c h i t e c t u r e s . Biomaterials, 2 3 ( 5 ) , 1 2 8 3 - 1 2 9 3 .
C i r k a , H . A . , K u r a l , M . H . , a n d B i l l i a r , K . L . ( 2 0 1 5 ) . M e c h a n o r e g u l a t i o n o f a o r t i c
v a l v u l a r i n t e r s t i t i a l c e l l l i f e a n d d e a t h . Journal o f Long-term Effects o f
Medical Implants, 25, 1 - 2 .
C l a r k , R . ( 1 9 7 3 ) . S t r e s s - s t r a i n c h a r a c t e r i s t i c s o f f r e s h a n d f r o z e n h u m a n a o r t i c a n d
m i t r a l l e a f l e t s a n d c h o r d a e t e n d i n e a e . I m p l i c a t i o n s f o r c l i n i c a l u s e . The
Journal o f Thoracic and Cardiovascular Surgery, 66( 2 ) , 2 0 2 - 2 0 8 .
C o l a z z o , F . , S a r a t h c h a n d r a , P . , S m o l e n s k i , R . T . , C h e s t e r , A . H . , T s e n g , Y . - T . ,
C z e r n u s z k a , J . T . , e t a l . ( 2 0 1 1 ) . E x t r a c e l l u l a r m a t r i x p r o d u c t i o n b y a d i p o s e -
d e r i v e d s t e m c e l l s : i m p l i c a t i o n s f o r h e a r t v a l v e t i s s u e e n g i n e e r i n g .
Biomaterials, 3 2 ( 1 ) , 1 1 9 - 1 2 7 .
C o x , M . ( 2 0 0 9 ) . Local mechanical properties o f tissue engineered heart valves.
D o c t o r P h i l o s o p h y , T e c h n i s c h e U n i v e r s i t e i t E i n d h o v e n , E i n d h o v e n .
C u i , W . , L i , X . , Z h o u , S . , a n d W e n g , J . ( 2 0 0 7 ) . I n v e s t i g a t i o n o n p r o c e s s p a r a m e t e r s
o f e l e c t r o s p i n n i n g s y s t e m t h r o u g h o r t h o g o n a l e x p e r i m e n t a l d e s i g n . Journal o f
Applied Polymer Science, 1 0 3 ( 5 ) , 3 1 0 5 - 3 1 1 2 .
C u i , W . , Z h o u , Y . , a n d C h a n g , J . ( 2 0 1 6 ) . E l e c t r o s p u n n a n o f i b r o u s m a t e r i a l s f o r t i s s u e
e n g i n e e r i n g a n d d r u g d e l i v e r y . Science and Technology o f Advanced
Materials, 1 1 ( 1 ) , 3 0 - 4 1
C z i t r o m , V . ( 1 9 9 9 ) . O n e - f a c t o r - a t - a - t i m e v e r s u s d e s i g n e d e x p e r i m e n t s . The
American Statistician, 5 3 ( 2 ) , 1 2 6 - 1 3 1 .
D a n i l e v i c i u s , P . , G e o r g i a d i , L . , P a t e m a n , C . J . , C l a e y s s e n s , F . , C h a t z i n i k o l a i d o u , M . ,
a n d F a r s a r i , M . ( 2 0 1 5 ) . T h e e f f e c t o f p o r o s i t y o n c e l l i n g r o w t h i n t o a c c u r a t e l y
d e f i n e d , l a s e r - m a d e , p o l y l a c t i d e - b a s e d 3 D s c a f f o l d s . Applied Surface Science,
336, 2 - 1 0 .
D a s i , L . P . , S i m o n , H . A . , S u c o s k y , P . , a n d Y o g a n a t h a n , A . P . ( 2 0 0 9 ) . F l u i d
m e c h a n i c s o f a r t i f i c i a l h e a r t v a l v e s . Clinical and Experimental Pharmacology
and Physiology, 3 6 ( 2 ) , 2 2 5 - 2 3 7 .
D a v i d , H . , B o u g h n e r , D . R . , V e s e l y , I . , a n d G e r o s a , G . ( 1 9 9 4 ) . T h e p u l m o n a r y v a l v e :
I s i t m e c h a n i c a l l y s u i t a b l e f o r u s e a s a n a o r t i c v a l v e r e p l a c e m e n t ? ASAIO
Journal, 4 0 ( 2 ) , 2 0 6 - 2 1 2 .
178
D e b , A . , W a n g , S . H . , S k e l d i n g , K . , M i l l e r , D . , S i m p e r , D . , a n d C a p l i c e , N . ( 2 0 0 5 ) .
B o n e m a r r o w - d e r i v e d m y o f i b r o b l a s t s a r e p r e s e n t i n a d u l t h u m a n h e a r t v a l v e s .
The Journal o f Heart Valve Disease, 1 4 ( 5 ) , 6 7 4 - 6 7 8 .
D e H e e r , L . M . , H a b e t s , J . , K l u i n , J . , S t e l l a , P . R . , W i l l e m , P . T . M . , v a n H e r w e r d e n ,
L . A . , e t a l . ( 2 0 1 3 ) . A s s e s s m e n t o f a t r a n s c a t h e t e r h e a r t v a l v e p r o s t h e s i s w i t h
m u l t i d e t e c t o r c o m p u t e d t o m o g r a p h y : i n v i t r o a n d i n v i v o i m a g i n g
c h a r a c t e r i s t i c s . The International Journal o f Cardiovascular Imaging, 2 9 ( 3 ) ,
6 5 9 - 6 6 8 .
D e n g , Y . , L i u , X . , X u , A . , W a n g , L . , L u o , Z . , Z h e n g , Y . , e t a l . ( 2 0 1 5 ) . e f f e c t o f
s u r f a c e r o u g h n e s s o n o s t e o g e n e s i s i n v i t r o a n d o s s e o i n t e g r a t i o n i n v i v o o f
c a r b o n f i b e r - r e i n f o r c e d p o l y e t h e r e t h e r k e t o n e - n a n o h y d r o x y a p a t i t e c o m p o s i t e .
International Journal o f Nanomedicine, 10, 1 4 2 5 - 1 4 4 7 .
D h a n d a y u t h a p a n i , B . , Y o s h i d a , Y . , M a e k a w a , T . , a n d K u m a r , D . S . ( 2 0 1 1 ) .
P o l y m e r i c s c a f f o l d s i n t i s s u e e n g i n e e r i n g a p p l i c a t i o n : A - r e v i e w .
International Journal o f Polymer Science, 2011, 1 - 1 9 .
D r i e s s e n , N . J . , M o l , A . , B o u t e n , C . V . , a n d B a a i j e n s , F . P . ( 2 0 0 7 ) . M o d e l i n g t h e
m e c h a n i c s o f t i s s u e - e n g i n e e r e d h u m a n h e a r t v a l v e l e a f l e t s . Journal o f
Biomechanics, 4 0 ( 2 ) , 3 2 5 - 3 3 4 .
D u a n , B . , K a p e t a n o v i c , E . , H o c k a d a y , L . , a n d B u t c h e r , J . ( 2 0 1 4 ) . T h r e e - d i m e n s i o n a l
p r i n t e d t r i l e a f l e t v a l v e c o n d u i t s u s i n g b i o l o g i c a l h y d r o g e l s a n d h u m a n v a l v e
i n t e r s t i t i a l c e l l s . Acta Biomaterialia, 1 0 ( 5 ) , 1 8 3 6 - 1 8 4 6 .
D u n k l e , T . , D e s c h a m p s , J . , a n d D a m , C . ( 2 0 1 5 ) . Design and development o f two
component hydrogel ejector for three-dimensional cell growth. H o n o r s
S c h o l a r P h D . T h e s i s . U n i v e r s i t y o f C o n n e c t i c u t , M a n s f i e l d .
E a g l e , K . A . , a n d B a l i g a , R . R . ( 2 0 0 8 ) . Practical cardiology: evaluation and
treatment o f common cardiovascular disorders. ( 2 n d e d . ) . U n i t e d s t a t e :
L i p p i n c o t t W i l l i a m s & W i l k i n s .
E c k e r t , C . E . , F a n , R . , M i k u l i s , B . , B a r r o n , M . , C a r r u t h e r s , C . A . , F r i e b e , V . M . , e t a l .
( 2 0 1 3 ) . O n t h e b i o m e c h a n i c a l r o l e o f g l y c o s a m i n o g l y c a n s i n t h e a o r t i c h e a r t
v a l v e l e a f l e t . Acta Biomaterialia, 9 ( 1 ) , 4 6 5 3 - 4 6 6 0 .
179
E m m e r t , M . Y . , W e b e r , B . , B e h r , L . , S a m m u t , S . , F r a u e n f e l d e r , T . , W o l i n t , P . , e t a l .
( 2 0 1 3 ) . T r a n s c a t h e t e r a o r t i c v a l v e i m p l a n t a t i o n u s i n g a n a t o m i c a l l y o r i e n t e d ,
m a r r o w s t r o m a l c e l l - b a s e d , s t e n t e d , t i s s u e - e n g i n e e r e d h e a r t v a l v e s : t e c h n i c a l
c o n s i d e r a t i o n s a n d i m p l i c a t i o n s f o r t r a n s l a t i o n a l c e l l - b a s e d h e a r t v a l v e
c o n c e p t s . European Journal o f Cardio-Thoracic Surgery, 4 5 ( 1 ) , 6 1 - 6 8 .
E n g e l m a y r , G . C . , H i l d e b r a n d , D . K . , S u t h e r l a n d , F . W . , M a y e r , J . E . , a n d S a c k s , M .
S . ( 2 0 0 3 ) . A n o v e l b i o r e a c t o r f o r t h e d y n a m i c f l e x u r a l s t i m u l a t i o n o f t i s s u e
e n g i n e e r e d h e a r t v a l v e b i o m a t e r i a l s . Biomaterials, 2 4 ( 1 4 ) , 2 5 2 3 - 2 5 3 2 .
E n g e l m a y r , G . C . , R a b k i n , E . , S u t h e r l a n d , F . W . , S c h o e n , F . J . , M a y e r , J . E . , a n d
S a c k s , M . S . ( 2 0 0 5 ) . T h e i n d e p e n d e n t r o l e o f c y c l i c f l e x u r e i n t h e e a r l y i n
v i t r o d e v e l o p m e n t o f a n e n g i n e e r e d h e a r t v a l v e t i s s u e . Biomaterials, 26( 2 ) ,
1 7 5 - 1 8 7 .
E r b e t t a , C . D . A . C . , A l v e s , R . J . , R e s e n d e , J . M . , d e S o u z a F r e i t a s , R . F . , a n d d e
S o u s a , R . G . ( 2 0 1 2 ) . S y n t h e s i s a n d c h a r a c t e r i z a t i o n o f p o l y ( D , L - l a c t i d e - c o -
g l y c o l i d e ) c o p o l y m e r . Journal o f Biomaterials and Nanobiotechnology,
3 ( 0 2 ) , 2 0 8 - 2 1 5 .
E y k e n s , L . , D e S i t t e r , K . , D o t r e m o n t , C . , P i n o y , L . , a n d V a n d e r B r u g g e n , B . ( 2 0 1 6 ) .
C h a r a c t e r i z a t i o n a n d p e r f o r m a n c e e v a l u a t i o n o f c o m m e r c i a l l y a v a i l a b l e
h y d r o p h o b i c m e m b r a n e s f o r d i r e c t c o n t a c t m e m b r a n e d i s t i l l a t i o n .
Desalination, 392, 6 3 - 7 3 .
F a l k , V . , W a l t h e r , T . , S c h w a m m e n t h a l , E . , S t r a u c h , J . , A i c h e r , D . , W a h l e r s , T . , e t a l .
( 2 0 1 1 ) . T r a n s a p i c a l a o r t i c v a l v e i m p l a n t a t i o n w i t h a s e l f - e x p a n d i n g
a n a t o m i c a l l y o r i e n t e d v a l v e . European Heart Journal, 32( 7 ) , 8 7 8 - 8 8 7 .
F a l l a h i a r e z o u d a r , E . , A h m a d i p o u r r o u d p o s h t , M . , Y u s o f , N . M . , a n d I d r i s , A . ( 2 0 1 5 a ) .
F a b r i c a t i o n ( f e r r o f l u i d / p o l y v i n y l a l c o h o l ) m a g n e t i c n a n o f i b e r s v i a c o - a x i a l
e l e c t r o s p i n n i n g . Journal o f Dispersion Science and Technology, 3 6 ( 1 ) , 2 8 - 3 1 .
F a l l a h i a r e z o u d a r , E . , A h m a d i p o u r r o u d p o s h t , M . , Y u s o f , N . M . , a n d I d r i s , A . ( 2 0 1 5 b ) .
I n f l u e n c e o f p r o c e s s f a c t o r s o n d i a m e t e r o f c o r e ( y - F e 2 O 3 ) / s h e l l ( p o l y v i n y l
a l c o h o l ) s t r u c t u r e m a g n e t i c n a n o f i b e r s d u r i n g c o - a x i a l e l e c t r o s p i n n i n g .
International Journal o f Polymeric Materials and Polymeric Biomaterials,
6 4 ( 1 ) , 1 5 - 2 4 .
F a l l a h i a r e z o u d a r , E . , A h m a d i p o u r r o u d p o s h t , M . , I d r i s , A . , a n d Y u s o f , N . M . ( 2 0 1 5 c ) .
A r e v i e w o f : A p p l i c a t i o n o f s y n t h e t i c s c a f f o l d i n t i s s u e e n g i n e e r i n g h e a r t
v a l v e s . Materials Science and Engineering: C, 48 , 5 5 6 - 5 6 5 .
180
F a r i a s - M a n c i l l a , R . , E l i z a l d e - G a l i n d o , J . T . , V i g u e r a s - S a n t i a g o , E . , H e r n a n d e z -
E s c o b a r , C . A . , V e g a - R i o s , A . , a n d Z a r a g o z a - C o n t r e r a s , E . A . ( 2 0 1 6 ) .
S y n t h e s i s a n d c h a r a c t e r i z a t i o n o f p o l y a n i l i n e / m a g n e t i t e n a n o c o m p o s i t e .
International Journal o f Theoretical and Applied Nanotechnology, 4, 2 0 1
2 1 3 .
F i r o u z i , A . , D e l G a u d i o , C . , M o n t e s p e r e l l i , G . , a n d B i a n c o , A . ( 2 0 1 5 ) . E l e c t r o s p u n
p o l y m e r i c c o a t i n g s o n a l u m i n u m a l l o y a s a s t r a i g h t f o r w a r d a p p r o a c h f o r
c o r r o s i o n p r o t e c t i o n . Journal o f Applied Polymer Science, 1 3 2 ( 2 ) , 1 - 1 0 .
F i s c h e r - C r i p p s , A . C . ( 2 0 0 0 ) . Factors affecting nanoindentation test data.
Nanoindentation, p p . 6 1 - 8 2 , N e w Y o r k : S p r i n g e r .
F o n g , P . , S h i n ' o k a , T . , L o p e z - S o l e r , R . I . , a n d B r e u e r , C . ( 2 0 0 6 ) . T h e u s e o f p o l y m e r
b a s e d s c a f f o l d s i n t i s s u e - e n g i n e e r e d h e a r t v a l v e s . Progress in Pediatric
Cardiology, 2 1 ( 2 ) , 1 9 3 - 1 9 9 .
F r e e d , L . E . , G u i l a k , F . , G u o , X . E . , G r a y , M . L . , T r a n q u i l l o , R . , H o l m e s , J . W . , e t a l .
( 2 0 0 6 ) . A d v a n c e d t o o l s f o r t i s s u e e n g i n e e r i n g : s c a f f o l d s , b i o r e a c t o r s , a n d
s i g n a l i n g . Tissue Engineering, 1 2 ( 1 2 ) , 3 2 8 5 - 3 3 0 5 .
F r e n k e l , J . , a n d D o r f m a n , J . ( 1 9 3 0 ) . S p o n t a n e o u s a n d i n d u c e d m a g n e t i s a t i o n i n
f e r r o m a g n e t i c b o d i e s . Nature, 1 2 6 ( 3 1 7 3 ) , 2 7 4 - 2 7 5 .
F r e s e , L . , S a s s e , T . , S a n d e r s , B . , B a a i j e n s , F . , B e e r , G . M . , a n d H o e r s t r u p , S . P .
( 2 0 1 6 ) . A r e a d i p o s e - d e r i v e d s t e m c e l l s c u l t i v a t e d i n h u m a n p l a t e l e t l y s a t e
s u i t a b l e f o r h e a r t v a l v e t i s s u e e n g i n e e r i n g ? Journal o f Tissue Engineering
and Regenerative Medicine. D O I : 1 0 . 1 0 0 2 / t e r m . 2 1 1 8 .
F r e s h n e y , R . ( 2 0 0 0 ) . Culture o f animal cells: a manual o f basic techniques. (6th ed).
ISBN, 471348899, U n i t e d k i n g d o m : W i l e y O n l i n e L i b r a r y .
F r i e d , A . , a n d R i c h t e r , D . ( 2 0 0 6 ) . Infrared absorption spectroscopy. O x f o r d U K :
B l a c k w e l l P u b l i s h i n g .
G a l l y a m o v , M . O . , C h a s c h i n , I . S . , K h o k h l o v a , M . A . , G r i g o r e v , T . E . , B a k u l e v a , N .
P . , L y u t o v a , I . G . , e t a l . ( 2 0 1 4 ) . C o l l a g e n t i s s u e t r e a t e d w i t h c h i t o s a n
s o l u t i o n s i n c a r b o n i c a c i d f o r i m p r o v e d b i o l o g i c a l p r o s t h e t i c h e a r t v a l v e s .
Materials Science and Engineering: C, 37, 1 2 7 - 1 4 0 .
G a r c i a - M a r t i n e z , V . , S a n c h e z - Q u i n t a n a , D . , a n d H u r l e , J . ( 1 9 9 1 ) . H i s t o c h e m i c a l a n d
u l t r a s t r u c t u r a l c h a n g e s i n t h e e x t r a c e l l u l a r m a t r i x o f t h e d e v e l o p i n g c h i c k
s e m i l u n a r h e a r t v a l v e s . Cells Tissues Organs, 1 4 2 ( 1 ) , 8 7 - 9 6 .
181
Ginns, J., Ammash, N., and Bernier, P. L. (2014). The tricuspid valve in adult
congenital heart disease. Heart Failure Clinics, 10(1), 131-153.
Gloeckner, D. G., Bihir, K. L., and Sacks, M. S. (1999). Effects of mechanical
fatigue on the bending properties of the porcine bioprosthetic heart valve.
ASAIO Journal, 45(1), 59-63.
Goel, M., Agrawal, A., Kumar, P., Dwivedi, R., and Yadav, B. (2016). To determine
the pattern and severity of cardiac valves involvement in children with
rheumatic heart disease. Indian Journal o f Child Health, 3(2), 98-101.
Grashow, J. S., Sacks, M. S., Liao, J., and Yoganathan, A. P. (2006). Planar biaxial
creep and stress relaxation of the mitral valve anterior leaflet. Annals o f
Biomedical Engineering, 34(10), 1509-1518.
Gross, L., and Kugel, M. (1931). Topographic anatomy and histology of the valves in
the human heart. The American Journal o f Pathology, 7(5), 445-474.
Grzymala-Lubanski, B., Svensson, P. J., Renlund, H., Jeppsson, A., and Sjalander,
A. (2016). Warfarin treatment quality and prognosis in patients with
mechanical heart valve prosthesis. Heart, DOI: heartjnl-2016-309585.
Guo, C., Xiang, M., and Dong, Y. (2015). Surface modification of poly (lactic acid)
with an improved alkali-acid hydrolysis method. Materials Letters, 140, 144
147.
Gupta, A. K., and Gupta, M. (2005). Synthesis and surface engineering of iron oxide
nanoparticles for biomedical applications. Biomaterials, 26(18), 3995-4021.
Hajdu, Z., Romeo, S. J., Fleming, P. A., Markwald, R. R., Visconti, R. P., and Drake,
C. J. (2011). Recruitment of bone marrow-derived valve interstitial cells is a
normal homeostatic process. Journal o f Molecular and Cellular Cardiology,
51(6), 955-965.
Hanson, S. R., and Ratner, B. (2004). Evaluation of blood-materials interactions.
Biomaterials Science: An Introduction to Materials in Medicine. San Diego,
64, 367-378.
Harini, S., Venkatesh, M., Radhakrishnan, S., Fazil, M. H., Goh, E. T., Rui, S., et al.
(2016). Antifungal properties of lecithin-and terbinafine-loaded electrospun
poly (s-caprolactone) nanofibres. RSCAdvances, 6(47), 41130-41141.
Hasan, A., Ragaert, K., Swieszkowski, W., Selimovic, S., Paul, A., Camci-Unal, G.,
et al. (2014). Biomechanical properties of native and tissue engineered heart
valve constructs. Journal o f Biomechanics, 47(9), 1949-1963.
182
H a u g h , M . G . , M u r p h y , C . M . , a n d O ' B r i e n , F . J . ( 2 0 0 9 ) . N o v e l f r e e z e - d r y i n g
m e t h o d s t o p r o d u c e a r a n g e o f c o l l a g e n - g l y c o s a m i n o g l y c a n s c a f f o l d s w i t h
t a i l o r e d m e a n p o r e s i z e s . Tissue Engineering Part C: Methods, 16( 5 ) , 8 8 7
8 9 4 .
H e , L . , a n d T j o n g , S . C . ( 2 0 1 6 ) . P r e p a r a t i o n o f n a n o c o m p o s i t e s . I n Nanocomposite
Materials: Synthesis, Properties and Applications ( p p . 1 4 7 - 1 7 2 ) : C R C P r e s s ,
N e w Y o r k .
H i n t o n , R . B . , L i n c o l n , J . , D e u t s c h , G . H . , O s i n s k a , H . , M a n n i n g , P . B . , B e n s o n , D .
W . , e t a l . ( 2 0 0 6 ) . E x t r a c e l l u l a r m a t r i x r e m o d e l i n g a n d o r g a n i z a t i o n i n
d e v e l o p i n g a n d d i s e a s e d a o r t i c v a l v e s . Circulation Research, 9 8 ( 1 1 ) , 1 4 3 1
1 4 3 8 .
H l a v k a , E . J . , M o l l , F . H . , Y o u n g e , R . G . , a n d W a l l a c e , D . T . ( 2 0 1 5 ) . S y s t e m a n d
m e t h o d f o r d e n a t u r i n g a n d f i x i n g c o l l a g e n o u s t i s s u e . U S 2 0 0 6 0 0 5 7 5 6 0 A 1 .
G o o g l e P a t e n t s .
H o b s o n , C . M . , A m o r o s o , N . J . , A m i n i , R . , U n g c h u s r i , E . , H o n g , Y . , D ' A m o r e , A . , e t
a l . ( 2 0 1 5 ) . F a b r i c a t i o n o f e l a s t o m e r i c s c a f f o l d s w i t h c u r v i l i n e a r f i b r o u s
s t r u c t u r e s f o r h e a r t v a l v e l e a f l e t e n g i n e e r i n g . Journal o f Biomedical
Materials Research Part A, 103( 9 ) , 3 1 0 1 - 3 1 0 6 .
H o c k a d a y , L . , K a n g , K . , C o l a n g e l o , N . , C h e u n g , P . , D u a n , B . , M a l o n e , E . , e t a l .
( 2 0 1 2 ) . R a p i d 3 D p r i n t i n g o f a n a t o m i c a l l y a c c u r a t e a n d m e c h a n i c a l l y
h e t e r o g e n e o u s a o r t i c v a l v e h y d r o g e l s c a f f o l d s . Biofabrication, 4 ( 3 ) , 5 0 0 5
5 0 1 0 .
H o n g , B . J . , C h i p r e , A . J . , a n d N g u y e n , S . T . ( 2 0 1 3 ) . A c i d - d e g r a d a b l e p o l y m e r - c a g e d
l i p o p l e x ( P C L ) p l a t f o r m f o r s i R N A d e l i v e r y : f a c i l e c e l l u l a r t r i g g e r e d r e l e a s e
o f s i R N A . Journal o f the American Chemical Society, 1 3 5 ( 4 7 ) , 1 7 6 5 5 - 1 7 6 5 8 .
H o q u e , M . E . , C h u a n , Y . L . , a n d P a s h b y , I . ( 2 0 1 2 ) . E x t r u s i o n b a s e d r a p i d
p r o t o t y p i n g t e c h n i q u e : a n a d v a n c e d p l a t f o r m f o r t i s s u e e n g i n e e r i n g s c a f f o l d
f a b r i c a t i o n . Biopolymers, 9 7 ( 2 ) , 8 3 - 9 3 .
H s u , Y . Y . , G r e s s e r , J . D . , T r a n t o l o , D . J . , L y o n s , C . M . , G a n g a d h a r a m , P . R . , a n d
W i s e , D . L . ( 1 9 9 7 ) . E f f e c t o f p o l y m e r f o a m m o r p h o l o g y a n d d e n s i t y o n
k i n e t i c s o f i n v i t r o c o n t r o l l e d r e l e a s e o f i s o n i a z i d f r o m c o m p r e s s e d f o a m
m a t r i c e s . Journal o f Biomedical Materials Research, 3 5 ( 1 ) , 1 0 7 - 1 1 6 .
183
H u a n g , C . , C h e n , R . , K e , Q . , M o r s i , Y . , Z h a n g , K . , a n d M o , X . ( 2 0 1 1 ) . E l e c t r o s p u n
c o l l a g e n - c h i t o s a n - T P U n a n o f i b r o u s s c a f f o l d s f o r t i s s u e e n g i n e e r e d t u b u l a r
g r a f t s . Colloids and Surfaces B: Biointerfaces, 8 2 ( 2 ) , 3 0 7 - 3 1 5 .
H u t m a c h e r , D . , a n d C o o l , S . ( 2 0 0 7 ) . C o n c e p t s o f s c a f f o l d - b a s e d t i s s u e e n g i n e e r i n g
t h e r a t i o n a l e t o u s e s o l i d f r e e - f o r m f a b r i c a t i o n t e c h n i q u e s . Journal o f Cellular
and Molecular Medicine, 1 1 ( 4 ) , 6 5 4 - 6 6 9 .
H u t m a c h e r , D . W . , S i t t i n g e r , M . , a n d R i s b u d , M . V . ( 2 0 0 4 ) . S c a f f o l d - b a s e d t i s s u e
e n g i n e e r i n g : R a t i o n a l e f o r c o m p u t e r - a i d e d d e s i g n a n d s o l i d f r e e - f o r m
f a b r i c a t i o n s y s t e m s . TRENDS in Biotechnology, 2 2 ( 7 ) , 3 5 4 - 3 6 2 .
I d r i s , A . , M i s r a n , E . , H a s s a n , N . , J a l i l , A . A . , a n d S e n g , C . E . ( 2 0 1 2 ) . M o d i f i e d P V A -
a l g i n a t e e n c a p s u l a t e d p h o t o c a t a l y s t f e r r o p h o t o g e l s f o r C r ( V I ) r e d u c t i o n .
Journal o f Hazardous Materials, 227, 3 0 9 - 3 1 6 .
I n d i r a , T . , a n d L a k s h m i , P . ( 2 0 1 0 ) . M a g n e t i c n a n o p a r t i c l e s — A r e v i e w . International
Journal o f Pharmecutical Science andNanotechnoly, 3 ( 3 ) , 1 0 3 5 - 1 0 4 2 .
I n z a n a , J . A . , O l v e r a , D . , F u l l e r , S . M . , K e l l y , J . P . , G r a e v e , O . A . , S c h w a r z , E . M . , e t
a l . ( 2 0 1 4 ) . 3 D p r i n t i n g o f c o m p o s i t e c a l c i u m p h o s p h a t e a n d c o l l a g e n
s c a f f o l d s f o r b o n e r e g e n e r a t i o n . Biomaterials, 3 5 ( 1 3 ) , 4 0 2 6 - 4 0 3 4 .
I u n g , B . , B a r o n , G . , B u t c h a r t , E . G . , D e l a h a y e , F . , G o h l k e - B a r w o l f , C . , L e v a n g , O .
W . , e t a l . ( 2 0 0 3 ) . A p r o s p e c t i v e s u r v e y o f p a t i e n t s w i t h v a l v u l a r h e a r t d i s e a s e
i n E u r o p e : T h e E u r o H e a r t S u r v e y o n V a l v u l a r H e a r t D i s e a s e . European
Heart Journal, 2 4 ( 1 3 ) , 1 2 3 1 - 1 2 4 3 .
J a i n , R . , R e n t s c h l e r , S . , a n d E p s t e i n , J . A . ( 2 0 1 0 ) . N o t c h a n d c a r d i a c o u t f l o w t r a c t
d e v e l o p m e n t . Annals o f the New York Academy o f Sciences, 1 1 8 8 ( 1 ) , 1 8 4
1 9 0 .
J a n a , S . , L e r m a n , A . , a n d S i m a r i , R . D . ( 2 0 1 5 ) . I n v i t r o m o d e l o f a f i b r o s a l a y e r o f a
h e a r t v a l v e . ACS Applied Materials & Interfaces, 7 ( 3 6 ) , 2 0 0 1 2 - 2 0 0 2 0 .
J i n g , X . , M i , H . - Y . , H u a n g , H . - X . , a n d T u r n g , L . - S . ( 2 0 1 6 ) . S h a p e m e m o r y
t h e r m o p l a s t i c p o l y u r e t h a n e ( T P U ) / p o l y ( s - c a p r o l a c t o n e ) ( P C L ) b l e n d s a s s e l f -
k n o t t i n g s u t u r e s . Journal o f the Mechanical Behavior o f Biomedical
Materials, 64, 9 4 - 1 0 3 .
184
J i n g , X . , M i , H . - Y . , S a l i c k , M . R . , C o r d i e , T . , C r o n e , W . C . , P e n g , X . - F . , e t a l .
( 2 0 1 4 ) . M o r p h o l o g y , m e c h a n i c a l p r o p e r t i e s , a n d s h a p e m e m o r y e f f e c t s o f
p o l y ( l a c t i c a c i d ) / t h e r m o p l a s t i c p o l y u r e t h a n e b l e n d s c a f f o l d s p r e p a r e d b y
t h e r m a l l y i n d u c e d p h a s e s e p a r a t i o n . Journal o f Cellular Plastics, 5 0 ( 4 ) , 3 6 1
3 7 9 .
J o c k e n h o e v e l , S . , Z u n d , G . , H o e r s t r u p , S . P . , S c h n e l l , A . , a n d T u r i n a , M . ( 2 0 0 2 ) .
C a r d i o v a s c u l a r t i s s u e e n g i n e e r i n g : a n e w l a m i n a r f l o w c h a m b e r f o r i n v i t r o
i m p r o v e m e n t o f m e c h a n i c a l t i s s u e p r o p e r t i e s . ASAIO Journal, 4 8 ( 1 ) , 8 - 1 1 .
K a n g , Y . , Y a o , Y . , Y i n , G . , H u a n g , Z . , L i a o , X . , X u , X . , e t a l . ( 2 0 0 9 ) . A s t u d y o n t h e
i n v i t r o d e g r a d a t i o n p r o p e r t i e s o f p o l y ( l - l a c t i c a c i d ) / p - t r i c a l c u i m p h o s p h a t e
( P L L A / p - T C P ) s c a f f o l d u n d e r d y n a m i c l o a d i n g . Medical Engineering &
Physics, 31( 5 ) , 5 8 9 - 5 9 4 .
K e m p e n , D . H . , L u , L . , K i m , C . , Z h u , X . , D h e r t , W . J . , C u r r i e r , B . L . , e t a l . ( 2 0 0 6 ) .
C o n t r o l l e d d r u g r e l e a s e f r o m a n o v e l i n j e c t a b l e b i o d e g r a d a b l e
m i c r o s p h e r e / s c a f f o l d c o m p o s i t e b a s e d o n p o l y ( p r o p y l e n e f u m a r a t e ) . Journal
o f Biomedical Materials Research Part A, 7 7 ( 1 ) , 1 0 3 - 1 1 1 .
K e m p p a i n e n , J . M . , a n d H o l l i s t e r , S . J . ( 2 0 1 0 ) . T a i l o r i n g t h e m e c h a n i c a l p r o p e r t i e s
o f 3 D - d e s i g n e d p o l y ( g l y c e r o l s e b a c a t e ) s c a f f o l d s f o r c a r t i l a g e a p p l i c a t i o n s .
Journal o f Biomedical Materials Research Part A, 9 4 ( 1 ) , 9 - 1 8 .
K h a l i l , S . , N a m , J . , a n d S u n , W . ( 2 0 0 5 ) . M u l t i - n o z z l e d e p o s i t i o n f o r c o n s t r u c t i o n o f
3 D b i o p o l y m e r t i s s u e s c a f f o l d s . Rapid Prototyping Journal, 1 1 ( 1 ) , 9 - 1 7 .
K i k u c h i , M . , I k o m a , T . , I t o h , S . , M a t s u m o t o , H . N . , K o y a m a , Y . , T a k a k u d a , K . , e t a l .
( 2 0 0 4 ) . B i o m i m e t i c s y n t h e s i s o f b o n e - l i k e n a n o c o m p o s i t e s u s i n g t h e s e l f
o r g a n i z a t i o n m e c h a n i s m o f h y d r o x y a p a t i t e a n d c o l l a g e n . Composites Science
and Technology, 6 4 ( 6 ) , 8 1 9 - 8 2 5 .
K i m , S . Y . , H w a n g , J . - Y . , S e o , J . - W . , a n d S h i n , U . S . ( 2 0 1 5 ) . P r o d u c t i o n o f C N T -
t a x o l - e m b e d d e d P C L m i c r o s p h e r e s u s i n g a n a m m o n i u m - b a s e d r o o m
t e m p e r a t u r e i o n i c l i q u i d : A s a s u s t a i n e d d r u g d e l i v e r y s y s t e m . Journal o f
Colloid and Interface Science, 442, 1 4 7 - 1 5 3 .
K o l e s n i c h e n k o , V . , G o l o v e r d a , G . , K u c h e r y a v y , P . , a n d S p i n u , L . ( 2 0 1 6 ) . I r o n o x i d e
n a n o p a r t i c l e s w i t h a v a r i a b l e s i z e a n d a n i r o n o x i d a t i o n s t a t e f o r i m a g i n g
a p p l i c a t i o n s . Nanotechnology in Medicine: From Molecules to Humans, 12,
1 2 2 - 1 2 7 .
185
L a b r o s s e , M . R . , B e l l e r , C . J . , R o b i c s e k , F . , a n d T h u b r i k a r , M . J . ( 2 0 0 6 ) . G e o m e t r i c
m o d e l i n g o f f u n c t i o n a l t r i l e a f l e t a o r t i c v a l v e s : d e v e l o p m e n t a n d c l i n i c a l
a p p l i c a t i o n s . Journal o f Biomechanics, 3 9 ( 1 4 ) , 2 6 6 5 - 2 6 7 2 .
L a m , C . X . F . , M o , X . , T e o h , S . - H . , a n d H u t m a c h e r , D . ( 2 0 0 2 ) . S c a f f o l d
d e v e l o p m e n t u s i n g 3 D p r i n t i n g w i t h a s t a r c h - b a s e d p o l y m e r . Materials
Science and Engineering: C, 2 0 ( 1 ) , 4 9 - 5 6 .
L a n c e l l o t t i , P . , M o u r a , L . , P i e r a r d , L . A . , P o p e s c u , B . A . , T r i b o u i l l o y , C . ,
H a g e n d o r f f , A . , e t a l . ( 2 0 1 0 ) . E u r o p e a n a s s o c i a t i o n o f e c h o c a r d i o g r a p h y
r e c o m m e n d a t i o n s f o r t h e a s s e s s m e n t o f v a l v u l a r r e g u r g i t a t i o n . P a r t 2 : m i t r a l
a n d t r i c u s p i d r e g u r g i t a t i o n ( n a t i v e v a l v e d i s e a s e ) . European Heart Journal-
Cardiovascular Imaging, 1 1 ( 4 ) , 3 0 7 - 3 3 2 .
L e e , J . M . , C o u r t m a n , D . W . , a n d B o u g h n e r , D . R . ( 1 9 8 4 ) . T h e g l u t a r a l d e h y d e -
s t a b i l i z e d p o r c i n e a o r t i c v a l v e x e n o g r a f t . I . T e n s i l e v i s c o e l a s t i c p r o p e r t i e s o f
t h e f r e s h l e a f l e t m a t e r i a l . Journal o f Biomedical Materials Research, 1 8 ( 1 ) ,
6 1 - 7 7 .
L e v y , I . , P a l d i , T . , a n d S h o s e y o v , O . ( 2 0 0 4 ) . E n g i n e e r i n g a b i f u n c t i o n a l s t a r c h -
c e l l u l o s e c r o s s - b r i d g e p r o t e i n . Biomaterials, 2 5 ( 1 0 ) , 1 8 4 1 - 1 8 4 9 .
L e w i s , T . ( 2 0 1 5 ) . H u m a n h e a r t : A n a t o m y , f u n c t i o n & f a c t s . LiveScience.
com.[Online] Available at: www.livescience.com/34655 humanheart.html
[Accessed 31 August 2016].
L ' H e u r e u x , N . , D u s s e r r e , N . , K o n i g , G . , V i c t o r , B . , K e i r e , P . , W i g h t , T . N . , e t a l .
( 2 0 0 6 ) . H u m a n t i s s u e - e n g i n e e r e d b l o o d v e s s e l s f o r a d u l t a r t e r i a l
r e v a s c u l a r i z a t i o n . Nature Medicine, 1 2 ( 3 ) , 3 6 1 - 3 6 5 .
L i , L . , T u , M . , M o u , S . , a n d Z h o u , C . ( 2 0 0 1 ) . P r e p a r a t i o n a n d b l o o d c o m p a t i b i l i t y o f
p o l y s i l o x a n e / l i q u i d - c r y s t a l c o m p o s i t e m e m b r a n e s . Biomaterials, 2 2 ( 1 9 ) ,
2 5 9 5 - 2 5 9 9 .
L i , W . J . , L a u r e n c i n , C . T . , C a t e r s o n , E . J . , T u a n , R . S . , a n d K o , F . K . ( 2 0 0 2 ) .
E l e c t r o s p u n n a n o f i b r o u s s t r u c t u r e : a n o v e l s c a f f o l d f o r t i s s u e e n g i n e e r i n g .
Journal o f Biomedical Materials Research, 6 0 ( 4 ) , 6 1 3 - 6 2 1 .
L i , X . , L i u , Y . , P e n g , H . , M a , X . , a n d F o n g , H . ( 2 0 1 6 ) . E f f e c t s o f h o t a i r f l o w o n
m a c r o m o l e c u l a r o r i e n t a t i o n a n d c r y s t a l l i n i t y o f m e l t e l e c t r o s p u n p o l y ( L -
l a c t i c a c i d ) f i b e r s . Materials Letters, 176, 1 9 4 - 1 9 8 .
186
L i , Y . , L i u , T . , Z h e n g , J . , a n d X u , X . ( 2 0 1 3 ) . G l u t a r a l d e h y d e - c r o s s l i n k e d
c h i t o s a n / h y d r o x y a p a t i t e b o n e r e p a i r s c a f f o l d a n d i t s a p p l i c a t i o n a s d r u g
c a r r i e r f o r i c a r i i n . Journal o f Applied Polymer Science, 1 3 0 ( 3 ) , 1 5 3 9 - 1 5 4 7 .
L i n , D . , Y a n g , K . , T a n g , W . , L i u , Y . , Y u a n , Y . , a n d L i u , C . ( 2 0 1 5 ) . A p o l y ( g l y c e r o l
s e b a c a t e ) - c o a t e d m e s o p o r o u s b i o a c t i v e g l a s s s c a f f o l d w i t h a d j u s t a b l e
m e c h a n i c a l s t r e n g t h , d e g r a d a t i o n r a t e , c o n t r o l l e d - r e l e a s e a n d c e l l b e h a v i o r f o r
b o n e t i s s u e e n g i n e e r i n g . Colloids and Surfaces B: Biointerfaces, 131, 1 - 1 1 .
L i p , G . Y . , M e r i n o , J . , E z e k o w i t z , M . , E l l e n b o g e n , K . , Z a m o r y a k h i n , D . , L a n z , H . , e t
a l . ( 2 0 1 5 ) . A p r o s p e c t i v e e v a l u a t i o n o f e d o x a b a n c o m p a r e d t o w a r f a r i n i n
s u b j e c t s u n d e r g o i n g c a r d i o v e r s i o n o f a t r i a l f i b r i l l a t i o n : t h e E d o x a b a N v s .
w a r f a r i n i n s u b j e c t S U n d e R g o i n g c a r d i o v E r s i o n o f A t r i a l F i b r i l l a t i o n
( E N S U R E - A F ) s t u d y . American Heart Journal, 1 6 9 ( 5 ) , 5 9 7 - 6 0 4 .
L i u , C . , X i a , Z . , a n d C z e r n u s z k a , J . ( 2 0 0 7 ) . D e s i g n a n d d e v e l o p m e n t o f t h r e e
d i m e n s i o n a l s c a f f o l d s f o r t i s s u e e n g i n e e r i n g . Chemical Engineering Research
and Design, 8 5 ( 7 ) , 1 0 5 1 - 1 0 6 4 .
L i u , Y . , C a i , D . , Y a n g , J . , W a n g , Y . , Z h a n g , X . , a n d Y i n , S . ( 2 0 1 4 a ) . I n v i t r o
h e m o c o m p a t i b i l i t y e v a l u a t i o n o f p o l y ( 4 - h y d r o x y b u t y r a t e ) s c a f f o l d .
International Journal o f Clinical and Experimental Medicine, 7 ( 5 ) , 1 2 3 3
1 2 4 3 .
L i u , Y . , H u a n g , Q . , K i e n z l e , A . , M u l l e r , W . , a n d F e n g , Q . ( 2 0 1 4 b ) . I n v i t r o
d e g r a d a t i o n o f p o r o u s P L L A / p e a r l p o w d e r c o m p o s i t e s c a f f o l d s . Materials
Science and Engineering: C, 38, 2 2 7 - 2 3 4 .
L o g e r , K . , E n g e l , A . , H a u p t , J . , d e M i r a n d a , R . L . , L u t t e r , G . , a n d Q u a n d t , E . ( 2 0 1 6 ) .
M i c r o s t r u c t u r e d N i c k e l - T i t a n i u m T h i n F i l m L e a f l e t s f o r H y b r i d T i s s u e
E n g i n e e r e d H e a r t V a l v e s F a b r i c a t e d b y M a g n e t r o n S p u t t e r D e p o s i t i o n .
Cardiovascular engineering and technology, 7 ( 1 ) , 6 9 - 7 7 .
L o v e k a m p , J . , a n d V y a v a h a r e , N . ( 2 0 0 1 ) . P e r i o d a t e - m e d i a t e d g l y c o s a m i n o g l y c a n
s t a b i l i z a t i o n i n b i o p r o s t h e t i c h e a r t v a l v e s . Journal o f Biomedical Materials
Research, 56( 4 ) , 4 7 8 - 4 8 6 .
L o w e r y , J . L . , D a t t a , N . , a n d R u t l e d g e , G . C . ( 2 0 1 0 ) . E f f e c t o f f i b e r d i a m e t e r , p o r e
s i z e a n d s e e d i n g m e t h o d o n g r o w t h o f h u m a n d e r m a l f i b r o b l a s t s i n
e l e c t r o s p u n p o l y ( e - c a p r o l a c t o n e ) f i b r o u s m a t s . Biomaterials, 3 1 ( 3 ) , 4 9 1 - 5 0 4 .
187
L u e d e r s , C . , J a s t r a m , B . , H e t z e r , R . , a n d S c h w a n d t , H . ( 2 0 1 4 ) . R a p i d m a n u f a c t u r i n g
t e c h n i q u e s f o r t h e t i s s u e e n g i n e e r i n g o f h u m a n h e a r t v a l v e s . European
Journal o f Cardio-Thoracic Surgery, 510, 1 2 - 2 4 .
L u u , Y . , K i m , K . , H s i a o , B . , C h u , B . , a n d H a d j i a r g y r o u , M . ( 2 0 0 3 ) . D e v e l o p m e n t o f
a n a n o s t r u c t u r e d D N A d e l i v e r y s c a f f o l d v i a e l e c t r o s p i n n i n g o f P L G A a n d
P L A - P E G b l o c k c o p o l y m e r s . Journal o f Controlled Release, 8 9 ( 2 ) , 3 4 1 - 3 5 3 .
M a n d a l , B . B . , a n d K u n d u , S . C . ( 2 0 0 9 ) . C e l l p r o l i f e r a t i o n a n d m i g r a t i o n i n s i l k
f i b r o i n 3 D s c a f f o l d s . Biomaterials, 3 0 ( 1 5 ) , 2 9 5 6 - 2 9 6 5 .
M a n j i , R . A . , L e e , W . , a n d C o o p e r , D . K . ( 2 0 1 5 ) . X e n o g r a f t b i o p r o s t h e t i c h e a r t
v a l v e s : P a s t , p r e s e n t a n d f u t u r e . International Journal o f Surgery, 23, 2 8 0
2 8 4 .
M a r e i , I . , C a r u b e l l i , I . , R e e d , D . M . , L a t i f , N . , Y a c o u b , M . H . , M i t c h e l l , J . A . , e t a l .
( 2 0 1 6 ) . S t u d i e s i n t h e u s e o f b l o o d o u t g r o w t h e n d o t h e l i a l c e l l s t o p o p u l a t e
p o l y c a p r o l a c t o n e s c a f f o l d s f o r t h e r a p i e s i n h u m a n h e a r t v a l v e d i s e a s e . Paper
presented at the Qatar Foundation Annual Research Conference
Proceedings, HBPP2474.
M a r y c z , K . , M a r ^ d z i a k , M . , G r z e s i a k , J . , L i s , A . , a n d S m i e s z e k , A . ( 2 0 1 6 ) . B i p h a s i c
p o l y u r e t h a n e / p o l y l a c t i d e s p o n g e s d o p e d w i t h n a n o - h y d r o x y a p a t i t e ( n h a p )
c o m b i n e d w i t h h u m a n a d i p o s e - d e r i v e d m e s e n c h y m a l s t r o m a l s t e m c e l l s f o r
r e g e n e r a t i v e m e d i c i n e a p p l i c a t i o n s . Polymers, 8 ( 1 0 ) , 3 3 9 .
M a s o u m i , N . , J e a n , A . , Z u g a t e s , J . T . , J o h n s o n , K . L . , a n d E n g e l m a y r , G . C . ( 2 0 1 3 a ) .
L a s e r m i c r o f a b r i c a t e d p o l y ( g l y c e r o l s e b a c a t e ) s c a f f o l d s f o r h e a r t v a l v e t i s s u e
e n g i n e e r i n g . Journal o f Biomedical Materials Research Part A, 1 0 1 ( 1 ) , 1 0 4
1 1 4 .
M a s o u m i , N . , J o h n s o n , K . L . , H o w e l l , M . C . , a n d E n g e l m a y r , G . C . ( 2 0 1 3 b ) .
V a l v u l a r i n t e r s t i t i a l c e l l s e e d e d p o l y ( g l y c e r o l s e b a c a t e ) s c a f f o l d s : t o w a r d a
b i o m i m e t i c i n v i t r o m o d e l f o r h e a r t v a l v e t i s s u e e n g i n e e r i n g . Acta
Biomaterialia, 9( 4 ) , 5 9 7 4 - 5 9 8 8 .
M a s s a r t , R . ( 1 9 8 1 ) . P r e p a r a t i o n o f a q u e o u s f e r r o f l u i d s w i t h o u t u s i n g s u r f a c t a n t -
b e h a v i o r a s a f u n c t i o n o f t h e p H a n d t h e c o u n t e r i o n s . Comptes Rendus
Hebdomadaires des Seances de l Academie des Sciences Serie C, 2 9 1 ( 1 ) , 1 - 3 .
M a s t e r s , K . S . , S h a h , D . N . , L e i n w a n d , L . A . , a n d A n s e t h , K . S . ( 2 0 0 5 ) . C r o s s l i n k e d
h y a l u r o n a n s c a f f o l d s a s a b i o l o g i c a l l y a c t i v e c a r r i e r f o r v a l v u l a r i n t e r s t i t i a l
c e l l s . Biomaterials, 2 6 ( 1 5 ) , 2 5 1 7 - 2 5 2 5 .
188
Matheny, R., Hutchison, M., Dryden, P., Hiles, M., and Shaar, C. (2000). Porcine
small intestine submucosa as a pulmonary valve leaflet substitute. The
Journal o f Heart Valve Disease, 9(6), 769-774.
Matsumura, G., Hibino, N., Ikada, Y., Kurosawa, H., and Shin’oka, T. (2003).
Successful application of tissue engineered vascular autografts: clinical
experience. Biomaterials, 24(13), 2303-2308.
Mavrilas, D., and Missirlis, Y. (1991). An approach to the optimization of
preparation of bioprosthetic heart valves. Journal o f Biomechanics, 24(5),
331-339.
Merryman, W. D., Huang, H.-Y. S., Schoen, F. J., and Sacks, M. S. (2006). The
effects of cellular contraction on aortic valve leaflet flexural stiffness. Journal
o f Biomechanics, 39(1), 88-96.
Mi, H.-Y., Salick, M. R., Jing, X., Jacques, B. R., Crone, W. C., Peng, X.-F., et al.
(2013). Characterization of thermoplastic polyurethane/polylactic acid
(TPU/PLA) tissue engineering scaffolds fabricated by microcellular injection
molding. Materials Science and Engineering: C, 33(8), 4767-4776.
Mikos, A. G., Sarakinos, G., Leite, S. M., Vacant, J. P., and Langer, R. (1993).
Laminated three-dimensional biodegradable foams for use in tissue
engineering. Biomaterials, 14(5), 323-330.
Millar, B. C., and Moore, J. E. (2004). Emerging issues in infective endocarditis.
Emerging Infectious Diseases, 10(6), 1110-1116.
Mirnajafi, A., Raymer, J., Scott, M. J., and Sacks, M. S. (2005). The effects of
collagen fiber orientation on the flexural properties of pericardial heterograft
biomaterials. Biomaterials, 26(7), 795-804.
Miwa, M., Nakajima, A., Fujishima, A., Hashimoto, K., and Watanabe, T. (2000).
Effects of the surface roughness on sliding angles of water droplets on
superhydrophobic surfaces. Langmuir, 16(13), 5754-5760.
Mol, A., Driessen, N. J., Rutten, M. C., Hoerstrup, S. P., Bouten, C. V., and Baaijens,
F. P. (2005). Tissue engineering of human heart valve leaflets: a novel
bioreactor for a strain-based conditioning approach. Annals o f Biomedical
Engineering, 33(12), 1778-1788.
Montgomery, D. C. (2007). Introduction to Statistical Quality Control. (7th ed.)
Jefferson City: John Wiley & Sons.
189
M o n t g o m e r y , D . C . ( 2 0 0 8 ) . Design and Analysis o f Experiments. J e f f e r s o n C i t y :
J o h n W i l e y & S o n s .
M o n t g o m e r y , D . C . ( 2 0 0 9 ) . Statistical Quality Control ( 7 th e d . ) N e w Y o r k : W i l e y .
M o o r a d i a n , D . ( 2 0 1 6 ) . A l l o g r a f t s a n d x e n o g r a f t s i n s o f t t i s s u e r e p a i r : c u r r e n t u s e a n d
f u t u r e t r e n d s . I n Extracellular Matrix-derived Implants in Clinical Medicine,
41, 2 2 - 2 9 .
M u y l a e r t , D . E . , F l e d d e r u s , J . O . , B o u t e n , C . V . , D a n k e r s , P . Y . , a n d V e r h a a r , M . C .
( 2 0 1 4 ) . C o m b i n i n g t i s s u e r e p a i r a n d t i s s u e e n g i n e e r i n g ; b i o a c t i v a t i n g
i m p l a n t a b l e c e l l - f r e e v a s c u l a r s c a f f o l d s . Heart, 1 0 0 ( 2 3 ) , 1 8 2 5 - 1 8 3 0 .
M y e r s , R . H . , M o n t g o m e r y , D . C . , a n d A n d e r s o n - C o o k , C . M . ( 2 0 1 6 ) . Response
surface methodology: Process and product optimization using designed
experiments. ( 4 th e d . ) H o b o k e n , N e w J e r s e y : J o h n W i l e y & S o n s .
N a k a n i s h i , K . ( 1 9 6 2 ) . Infrared absorption spectroscopy, practical. U n i t e d s t a t e :
H o l d e n - d a y
N a n d y , S . , a n d T a r b e l l , J . ( 1 9 8 6 ) . F l u s h m o u n t e d h o t f i l m a n e m o m e t e r m e a s u r e m e n t
o f w a l l s h e a r s t r e s s d i s t a l t o a t r i - l e a f l e t v a l v e f o r N e w t o n i a n a n d n o n -
N e w t o n i a n b l o o d a n a l o g f l u i d s . Biorheology, 2 4 ( 5 ) , 4 8 3 - 5 0 0 .
N a r i n e , K . , I n g , E . C . , C o r n e l i s s e n , M . , D e s o m e r , F . , B e e l e , H . , V a n l a n g e n h o v e , L . ,
e t a l . ( 2 0 0 6 ) . R e a d i l y a v a i l a b l e p o r c i n e a o r t i c v a l v e m a t r i c e s f o r u s e i n t i s s u e
v a l v e e n g i n e e r i n g . I s c r y o p r e s e r v a t i o n a n o p t i o n ? Cryobiology, 5 3 ( 2 ) , 1 6 9
1 8 1 .
N a s o u r i , K . , B a h r a m b e y g i , H . , R a b b i , A . , S h o u s h t a r i , A . M . , a n d K a f l o u , A . ( 2 0 1 2 ) .
M o d e l i n g a n d o p t i m i z a t i o n o f e l e c t r o s p u n P A N n a n o f i b e r d i a m e t e r u s i n g
r e s p o n s e s u r f a c e m e t h o d o l o g y a n d a r t i f i c i a l n e u r a l n e t w o r k s . Journal o f
Applied Polymer Science, 1 2 6 ( 1 ) , 1 2 7 - 1 3 5 .
N a s s e r i , B . A . , P o m e r a n t s e v a , I . , K a a z e m p u r - M o f r a d , M . R . , S u t h e r l a n d , F . W . ,
P e r r y , T . , O c h o a , E . , e t a l . ( 2 0 0 3 ) . D y n a m i c r o t a t i o n a l s e e d i n g a n d c e l l
c u l t u r e s y s t e m f o r v a s c u l a r t u b e f o r m a t i o n . Tissue Engineering, 9 ( 2 ) , 2 9 1 - 2 9 9
N a s u t i , J . F . , Z h a n g , P . J . , F e l d m a n , M . D . , P a s h a , T . , K h u r a n a , J . S . , G o r m a n , J . H . ,
e t a l . ( 2 0 0 4 ) . F i b r i l l i n a n d o t h e r m a t r i x p r o t e i n s i n m i t r a l v a l v e p r o l a p s e
s y n d r o m e . The Annals o f Thoracic Surgery, 77( 2 ) , 5 3 2 - 5 3 6 .
190
N e k k a n t i , V . , M u n i y a p p a n , T . , K a r a t g i , P . , H a r i , M . S . , M a r e l l a , S . , a n d P i l l a i , R .
( 2 0 0 9 ) . S p r a y - d r y i n g p r o c e s s o p t i m i z a t i o n f o r m a n u f a c t u r e o f d r u g -
c y c l o d e x t r i n c o m p l e x p o w d e r u s i n g d e s i g n o f e x p e r i m e n t s . Drug
Development and Industrial Pharmacy, 3 5 ( 1 0 ) , 1 2 1 9 - 1 2 2 9 .
N e t t e r , F . H . , a n d C o l a c i n o , S . ( 1 9 8 9 ) . Atlas o f Human Anatomy ( 1 1 th e d . )
N e w J e r s e y : C i b a - G e i g y S u m m i t .
N e u e n s c h w a n d e r , S . , a n d H o e r s t r u p , S . P . ( 2 0 0 4 ) . H e a r t v a l v e t i s s u e e n g i n e e r i n g .
Transplant Immunology, 12( 3 ) , 3 5 9 - 3 6 5 .
N g , C . M . , C h e n g , A . , M y e r s , L . A . , M a r t i n e z - M u r i l l o , F . , J i e , C . , B e d j a , D . , e t a l .
( 2 0 0 4 ) . T G F - P - d e p e n d e n t p a t h o g e n e s i s o f m i t r a l v a l v e p r o l a p s e i n a m o u s e
m o d e l o f M a r f a n s y n d r o m e . The Journal o f Clinical Investigation, 1 1 4 ( 1 1 ) ,
1 5 8 6 - 1 5 9 2 .
N g a d i m a n , N . H . A . , I d r i s , A . , I r f a n , M . , K u r n i a w a n , D . , Y u s o f , N . M . , a n d N a s i r i , R .
( 2 0 1 5 ) . y - F e 2 O 3 n a n o p a r t i c l e s f i l l e d p o l y v i n y l a l c o h o l a s p o t e n t i a l b i o m a t e r i a l
f o r t i s s u e e n g i n e e r i n g s c a f f o l d . Journal o f the Mechanical Behavior o f
Biomedical Materials, 49, 9 0 - 1 0 4 .
N g a d i m a n , N . H . A . , Y u s o f , N . M . , I d r i s , A . , M i s r a n , E . , a n d K u r n i a w a n , D . ( 2 0 1 7 ) .
D e v e l o p m e n t o f h i g h l y p o r o u s b i o d e g r a d a b l e y - F e 2 O 3 / p o l y v i n y l a l c o h o l
n a n o f i b e r m a t s u s i n g e l e c t r o s p i n n i n g p r o c e s s f o r b i o m e d i c a l a p p l i c a t i o n .
Materials Science and Engineering: C, 70, 5 2 0 - 5 3 4 .
N i s h i m u r a , R . A . ( 2 0 0 2 ) . A o r t i c v a l v e d i s e a s e . Circulation, 1 0 6 ( 7 ) , 7 7 0 - 7 7 2 .
N o r , F . M . , K u r n i a w a n , D . , S e o , Y . - K . , P a r k , J . - K . , L e e , H . Y . , a n d L i m , J . Y .
( 2 0 1 2 ) . P o l y c a p r o l a c t o n e - s t a r c h b l e n d s w i t h c o r n - b a s e d c o u p l i n g a g e n t :
p h y s i c a l p r o p e r t i e s a n d i n v i t r o a n a l y s i s . Proceedings o f the Institution o f
Mechanical Engineers, Part H: Journal o f Engineering in Medicine, 226 ( 9 ) ,
6 9 3 - 6 9 8 .
N k o m o , V . T . , G a r d i n , J . M . , S k e l t o n , T . N . , G o t t d i e n e r , J . S . , S c o t t , C . G . , a n d
E n r i q u e z - S a r a n o , M . ( 2 0 0 6 ) . B u r d e n o f v a l v u l a r h e a r t d i s e a s e s : a p o p u l a t i o n -
b a s e d s t u d y . The Lancet, 3 6 8 ( 9 5 4 0 ) , 1 0 0 5 - 1 0 1 1 .
N o o r d i n , M . Y . , V e n k a t e s h , V . C . , S h a r i f , S . , E l t i n g , S . , a n d A b d u l l a h , A . ( 2 0 0 4 ) .
A p p l i c a t i o n o f r e s p o n s e s u r f a c e m e t h o d o l o g y i n d e s c r i b i n g t h e p e r f o r m a n c e
o f c o a t e d c a r b i d e t o o l s w h e n t u r n i n g A I S I 1 0 4 5 s t e e l . Journal o f Materials
Processing Technology, 1 4 5 ( 1 ) , 4 6 - 5 8 .
191
Olivier, C. (2000). Rheumatic fever-is it still a problem? Journal o f Antimicrobial
Chemotherapy, 45(1), 13-21.
Otto, C. M. (2001). Evaluation and management of chronic mitral regurgitation. New
England Journal o f Medicine, 345(10), 740-746.
Ouyang, H. W., Goh, J. C., Thambyah, A., Teoh, S. H., and Lee, E. H. (2003).
Knitted poly-lactide-co-glycolide scaffold loaded with bone marrow stromal
cells in repair and regeneration of rabbit Achilles tendon. Tissue Engineering,
9(3), 431-439.
Pankhurst, Q. A., Connolly, J., Jones, S., and Dobson, J. (2003). Applications of
magnetic nanoparticles in biomedicine. Journal o f Physics D: Applied
Physics, 36(13), 167-183.
Passmore, M., Nataatmadja, M., Fung, Y. L., Pearse, B., Gabriel, S., Tesar, P., et al.
(2015). Osteopontin alters endothelial and valvular interstitial cell behaviour
in calcific aortic valve stenosis through HMGB1 regulation. European
Journal o f Cardio-thoracic Surgery, 48(3), 20-29.
Pelech, A. N., and Neish, S. R. (2004). Sudden death in congenital heart disease.
Pediatric Clinics o f North America, 51(5), 1257-1271.
Perloff, J. K., and Roberts, W. C. (1972). The mitral apparatus functional anatomy of
mitral regurgitation. Circulation, 46(2), 227-239.
Perry, T., Kaushal, S., Nasseri, B., Sutherland, F., Wang, J., Guleserian, K., et al.
(2001). Peripheral blood as a cell source for tissue engineering heart valves.
Circulation, 45(4), 433-433.
Piazza, N., de Jaegere, P., Schultz, C., Becker, A. E., Serruys, P. W., and Anderson,
R. H. (2008). Anatomy of the aortic valvar complex and its implications for
transcatheter implantation of the aortic valve. Circulation: Cardiovascular
Interventions, 1(1), 74-81.
Pibarot, P., and Dumesnil, J. G. (2009). Prosthetic heart valves selection of the
optimal prosthesis and long-term management. Circulation, 119(7), 1034
1048.
Poncin-Epaillard, F., Shavdina, O., and Debarnot, D. (2013). Elaboration and surface
modification of structured poly (L-lactic acid) thin film on various substrates.
Materials Science and Engineering: C, 33(5), 2526-2533.
192
P o n s o n n e t , L . , R e y b i e r , K . , J a f f r e z i c , N . , C o m t e , V . , L a g n e a u , C . , L i s s a c , M . , e t a l .
( 2 0 0 3 ) . R e l a t i o n s h i p b e t w e e n s u r f a c e p r o p e r t i e s ( r o u g h n e s s , w e t t a b i l i t y ) o f
t i t a n i u m a n d t i t a n i u m a l l o y s a n d c e l l b e h a v i o u r . Materials Science and
Engineering: C, 23( 4 ) , 5 5 1 - 5 6 0 .
P o t t e r , D . D . , S u n d t , T . M . , Z e h r , K . J . , D e a r a n i , J . A . , D a l y , R . C . , M u l l a n y , C . J . , e t
a l . ( 2 0 0 4 ) . R i s k o f r e p e a t m i t r a l v a l v e r e p l a c e m e n t f o r f a i l e d m i t r a l v a l v e
p r o s t h e s e s . The Annals o f Thoracic Surgery, 7 8 ( 1 ) , 6 7 - 7 2 .
Q i a o , T . , S o n g , P . , G u o , H . , S o n g , X . , Z h a n g , B . , a n d C h e n , X . ( 2 0 1 6 ) . R e i n f o r c e d
e l e c t r o s p u n P L L A f i b e r m e m b r a n e v i a c h e m i c a l c r o s s l i n k i n g . European
Polymer Journal, 74, 1 0 1 - 1 0 8 .
R a b k i n - A i k a w a , E . , M a y e r J r , J . E . , a n d S c h o e n , F . J . ( 2 0 0 5 ) . H e a r t v a l v e
r e g e n e r a t i o n . I n Regenerative Medicine II ( p p . 1 4 1 - 1 7 9 ) . B e r l i n : S p r i n g e r .
R a g a e r t , K . , D e S o m e r , F . , S o m e r s , P . , D e B a e r e , I . , C a r d o n , L . , a n d D e g r i e c k , J .
( 2 0 1 2 ) . F l e x u r a l m e c h a n i c a l p r o p e r t i e s o f p o r c i n e a o r t i c h e a r t v a l v e l e a f l e t s .
Journal o f the Mechanical Behavior o f Biomedical Materials, 13, 7 8 - 8 4 .
R e i m h u l t , E . , a n d A m s t a d , E . ( 2 0 1 4 ) . S t a b i l i z a t i o n a n d c h a r a c t e r i z a t i o n o f i r o n o x i d e
s u p e r p a r a m a g n e t i c c o r e - s h e l l n a n o p a r t i c l e s f o r b i o m e d i c a l a p p l i c a t i o n s . I n
Handbook o f Nanomaterials Properties ( p p . 3 5 5 - 3 8 7 ) , L o n d o n : S p r i n g e r .
R i b e i r o , C . , S e n c a d a s , V . , C o s t a , C . M . , R i b e l l e s , J . L . G . , a n d L a n c e r o s - M e n d e z , S .
( 2 0 1 6 ) . T a i l o r i n g t h e m o r p h o l o g y a n d c r y s t a l l i n i t y o f p o l y ( L - l a c t i d e a c i d )
e l e c t r o s p u n m e m b r a n e s . Science and Technology o f Advanced Materials.
1 2 ( 1 ) , 1 1 - 2 4 .
R o b e r t s , G . , R a z o o q i , R . , a n d Q u i n n , S . ( 2 0 1 6 ) . C o m p a r i n g u s u a l c a r e w i t h a
w a r f a r i n i n i t i a t i o n p r o t o c o l a f t e r m e c h a n i c a l h e a r t v a l v e r e p l a c e m e n t . Annals
o f Pharmacotherapy, D O I : 1 0 6 0 0 2 8 0 1 6 6 7 6 8 3 0 .
R o b e r t s , N . , M o r t i c e l l i , L . , J i n , Z . , I n g h a m , E . , a n d K o r o s s i s , S . ( 2 0 1 5 ) . R e g i o n a l
b i o m e c h a n i c a l a n d h i s t o l o g i c a l c h a r a c t e r i z a t i o n o f t h e m i t r a l v a l v e a p p a r a t u s :
I m p l i c a t i o n s f o r m i t r a l r e p a i r s t r a t e g i e s . Journal o f Biomechanics. 4 9 ( 1 2 ) ,
2 4 9 1 - 2 5 0 1 .
R o b e r t s , W . C . ( 1 9 8 1 ) . A o r t i c d i s s e c t i o n : a n a t o m y , c o n s e q u e n c e s , a n d c a u s e s .
American Heart Journal, 1 0 1 ( 2 ) , 1 9 5 - 2 1 4 .
R o d r i g u e s , C . , S e r r i c e l l a , P . , L i n h a r e s , A . , G u e r d e s , R . , B o r o j e v i c , R . , R o s s i , M . , e t
a l . ( 2 0 0 3 ) . C h a r a c t e r i z a t i o n o f a b o v i n e c o l l a g e n - h y d r o x y a p a t i t e c o m p o s i t e
s c a f f o l d f o r b o n e t i s s u e e n g i n e e r i n g . Biomaterials, 24( 2 7 ) , 4 9 8 7 - 4 9 9 7 .
193
R o d r i g u e z , F . , L a n g e r , F . , H a r r i n g t o n , K . B . , T i b a y a n , F . A . , Z a s i o , M . K . , C h e n g ,
A . , e t a l . ( 2 0 0 4 ) . I m p o r t a n c e o f m i t r a l v a l v e s e c o n d - o r d e r c h o r d a e f o r l e f t
v e n t r i c u l a r g e o m e t r y , w a l l t h i c k e n i n g m e c h a n i c s , a n d g l o b a l s y s t o l i c
f u n c t i o n . Circulation, 1 1 0 ( 1 1 ) , 1 1 5 - 1 2 2 .
R o u s s e a u , E . , S a u r e n , A . , V a n H o u t , M . , a n d V a n S t e e n h o v e n , A . ( 1 9 8 3 ) . E l a s t i c a n d
v i s c o e l a s t i c m a t e r i a l b e h a v i o u r o f f r e s h a n d g l u t a r a l d e h y d e - t r e a t e d p o r c i n e
a o r t i c v a l v e t i s s u e . Journal o f Biomechanics, 1 6 ( 5 ) , 3 3 9 - 3 4 8 .
S a c h l o s , E . , R e i s , N . , A i n s l e y , C . , D e r b y , B . , a n d C z e r n u s z k a , J . T . ( 2 0 0 2 ) . A p r o c e s s
t o m a k e c o l l a g e n s c a f f o l d s w i t h a n a r t i f i c i a l c i r c u l a t o r y s y s t e m u s i n g r a p i d
p r o t o t y p i n g . Paper presented at the MRS Proceedings, 758, 1 6 - 2 5 .
S a c k s , M . S . , a n d Y o g a n a t h a n , A . P . ( 2 0 0 7 ) . H e a r t v a l v e f u n c t i o n : a b i o m e c h a n i c a l
p e r s p e c t i v e . Philosophical Transactions o f the Royal Society o f London B:
Biological Sciences, 3 6 2 ( 1 4 8 4 ) , 1 3 6 9 - 1 3 9 1 .
S a c k s , M . S . , M e r r y m a n , W . D . , a n d S c h m i d t , D . E . ( 2 0 0 9 ) . O n t h e b i o m e c h a n i c s o f
h e a r t v a l v e f u n c t i o n . Journal o f Biomechanics, 4 2 ( 1 2 ) , 1 8 0 4 - 1 8 2 4 .
S a i t o , T . , W a s s i l e w , K . , G o r o d e t s k i , B . , S t e i n , J . , F a l k , V . , K r a b a t s c h , T . , e t a l .
( 2 0 1 6 ) . A o r t i c v a l v e p a t h o l o g y i n p a t i e n t s s u p p o r t e d b y c o n t i n u o u s - f l o w l e f t
v e n t r i c u l a r a s s i s t d e v i c e . Circulation Journal, 8 0 ( 6 ) , 1 3 7 1 - 1 3 7 7 .
S a k a i , R . , J o h n , B . , O k a m o t o , M . , S e p p a l a , J . V . , V a i t h i l i n g a m , J . , H u s s e i n , H . , e t a l .
( 2 0 1 3 ) . F a b r i c a t i o n o f p o l y l a c t i d e - b a s e d b i o d e g r a d a b l e t h e r m o s e t s c a f f o l d s
f o r t i s s u e e n g i n e e r i n g a p p l i c a t i o n s . Macromolecular Materials and
Engineering, 2 9 8 ( 1 ) , 4 5 - 5 2 .
S a n t o r o , M . , S h a h , S . R . , W a l k e r , J . L . , a n d M i k o s , A . G . ( 2 0 1 6 ) . P o l y ( l a c t i c a c i d )
n a n o f i b r o u s s c a f f o l d s f o r t i s s u e e n g i n e e r i n g . Advanced Drug Delivery
Reviews. 107, 2 0 6 - 2 1 2 .
S a n z - G a r c i a , A . , O l i v e r - D e - L a - C r u z , J . , M i r a b e t , V . , G a n d i a , C . , V i l l a g r a s a , A . ,
S o d u p e , E . , e t a l . ( 2 0 1 5 ) . H e a r t v a l v e t i s s u e e n g i n e e r i n g : h o w f a r i s t h e
b e d s i d e f r o m t h e b e n c h ? Expert Reviews in Molecular Medicine, 17, 1 6 - 2 2 .
S c h a e f e r , A . , C o n r a d i , L . , S e i f f e r t , M . , L u b o s , E . , B l a n k e n b e r g , S . , R e i c h e n s p u r n e r ,
H . , e t a l . ( 2 0 1 5 ) . V a l v e - i n - v a l v e p r o c e d u r e s i n f a i l i n g b i o l o g i c a l x e n o g r a f t s
u s i n g a n o v e l b a l l o o n - e x p a n d a b l e d e v i c e : e x p e r i e n c e i n a o r t i c , m i t r a l , a n d
t r i c u s p i d p o s i t i o n s . The Thoracic and cardiovascular surgeon, 6 4 ( 5 ) , 3 6 6
3 7 3 .
194
S c h i m a n k e , G . , a n d M a r t i n , M . ( 2 0 0 0 ) . I n s i t u X R D s t u d y o f t h e p h a s e t r a n s i t i o n o f
n a n o c r y s t a l l i n e m a g h e m i t e ( y - F e 2 O 3 ) t o h e m a t i t e ( a - F e 2 O 3 ) . Solid State
Ionics, 136, 1 2 3 5 - 1 2 4 0 .
S c h o e n , F . ( 1 9 9 7 ) . A o r t i c v a l v e s t r u c t u r e - f u n c t i o n c o r r e l a t i o n s : r o l e o f e l a s t i c f i b e r s
n o l o n g e r a s t r e t c h o f t h e i m a g i n a t i o n . The Journal o f Heart Valve Disease,
6 ( 1 ) , 1 - 6 .
S c h o e n , F . J . , a n d L e v y , R . J . ( 1 9 9 9 ) . T i s s u e h e a r t v a l v e s : c u r r e n t c h a l l e n g e s a n d
f u t u r e r e s e a r c h p e r s p e c t i v e s . Journal o f Biomedical Materials Research,
4 7 ( 4 ) , 4 3 9 - 4 6 5 .
S c h o f e r , M . D . , R o e s s l e r , P . P . , S c h a e f e r , J . , T h e i s e n , C . , S c h l i m m e , S . , H e v e r h a g e n ,
J . T . , e t a l . ( 2 0 1 1 ) . E l e c t r o s p u n P L L A n a n o f i b e r s c a f f o l d s a n d t h e i r u s e i n
c o m b i n a t i o n w i t h B M P - 2 f o r r e c o n s t r u c t i o n o f b o n e d e f e c t s . PLoS One, 6 ( 9 ) ,
2 5 4 6 2 - 6 8 .
S e w e l l - L o f t i n , M . , C h u n , Y . W . , K h a d e m h o s s e i n i , A . , a n d M e r r y m a n , W . D . ( 2 0 1 1 ) .
E M T - i n d u c i n g b i o m a t e r i a l s f o r h e a r t v a l v e e n g i n e e r i n g : t a k i n g c u e s f r o m
d e v e l o p m e n t a l b i o l o g y . Journal o f Cardiovascular Translational Research,
4 ( 5 ) , 6 5 8 - 6 7 1 .
S h e i k h , F . A . , M a c o s s a y , J . , C a n t u , T . , Z h a n g , X . , H a s s a n , M . S . , S a l i n a s , M . E . , e t
a l . ( 2 0 1 5 ) . I m a g i n g , s p e c t r o s c o p y , m e c h a n i c a l , a l i g n m e n t a n d
b i o c o m p a t i b i l i t y s t u d i e s o f e l e c t r o s p u n m e d i c a l g r a d e p o l y u r e t h a n e
( C a r b o t h a n e ™ 3 5 7 5 A ) n a n o f i b e r s a n d c o m p o s i t e n a n o f i b e r s c o n t a i n i n g
m u l t i w a l l e d c a r b o n n a n o t u b e s . Journal o f the Mechanical Behavior o f
Biomedical Materials, 41, 1 8 9 - 1 9 8 .
S h e r i d a n , M . , S h e a , L . , P e t e r s , M . , a n d M o o n e y , D . ( 2 0 0 0 ) . B i o a b s o r b a b l e p o l y m e r
s c a f f o l d s f o r t i s s u e e n g i n e e r i n g c a p a b l e o f s u s t a i n e d g r o w t h f a c t o r d e l i v e r y .
Journal o f Controlled Release, 6 4 ( 1 ) , 9 1 - 1 0 2 .
S h i n o k a , T . , B r e u e r , C . K . , T a n e l , R . E . , Z u n d , G . , M i u r a , T . , M a , P . X . , e t a l . ( 1 9 9 5 ) .
T i s s u e e n g i n e e r i n g h e a r t v a l v e s : v a l v e l e a f l e t r e p l a c e m e n t s t u d y i n a l a m b
m o d e l . The Annals o f Thoracic Surgery, 60, 5 1 3 - 5 1 6 .
S i m o n , P . , K a s i m i r , M . , S e e b a c h e r , G . , W e i g e l , G . , U l l r i c h , R . , S a l z e r - M u h a r , U . , e t
a l . ( 2 0 0 3 ) . E a r l y f a i l u r e o f t h e t i s s u e e n g i n e e r e d p o r c i n e h e a r t v a l v e
S Y N E R G R A F T ® i n p e d i a t r i c p a t i e n t s . European Journal o f Cardio-thoracic
Surgery, 2 3 ( 6 ) , 1 0 0 2 - 1 0 0 6 .
195
S i n g h , B . , a n d N a n d a , B . ( 2 0 1 2 ) . S l i p d a m p i n g m e c h a n i s m i n w e l d e d s t r u c t u r e s
u s i n g r e s p o n s e s u r f a c e m e t h o d o l o g y . Experimental Mechanics, 5 2 ( 7 ) , 7 7 1
7 9 1 .
S o d i a n , R . , H o e r s t r u p , S . P . , S p e r l i n g , J . S . , D a e b r i t z , S . , M a r t i n , D . P . , M o r a n , A .
M . , e t a l . ( 2 0 0 0 ) . E a r l y i n v i v o e x p e r i e n c e w i t h t i s s u e - e n g i n e e r e d t r i l e a f l e t
h e a r t v a l v e s . Circulation, 1 0 2 ( 3 ) , 2 2 - 2 9 .
S o d i a n , R . , L e m k e , T . , L o e b e , M . , H o e r s t r u p , S . P . , P o t a p o v , E . V . , H a u s m a n n , H . , e t
a l . ( 2 0 0 1 ) . N e w p u l s a t i l e b i o r e a c t o r f o r f a b r i c a t i o n o f t i s s u e - e n g i n e e r e d
p a t c h e s . Journal o f Biomedical Materials Research, 5 8 ( 4 ) , 4 0 1 - 4 0 5 .
S o m b a t m a n k h o n g , K . , S a n c h a v a n a k i t , N . , P a v a s a n t , P . , a n d S u p a p h o l , P . ( 2 0 0 7 ) .
B o n e s c a f f o l d s f r o m e l e c t r o s p u n f i b e r m a t s o f p o l y ( 3 - h y d r o x y b u t y r a t e ) , p o l y
( 3 - h y d r o x y b u t y r a t e - c o - 3 - h y d r o x y v a l e r a t e ) a n d t h e i r b l e n d . Polymer, 4 8 ( 5 ) ,
1 4 1 9 - 1 4 2 7 .
S o o d , A . , A r o r a , V . , S h a h , J . , K o t n a l a , R . , a n d J a i n , T . K . ( 2 0 1 6 ) . A s c o r b i c a c i d -
m e d i a t e d s y n t h e s i s a n d c h a r a c t e r i s a t i o n o f i r o n o x i d e / g o l d c o r e - s h e l l
n a n o p a r t i c l e s . Journal o f Experimental Nanoscience, 1 1 ( 5 ) , 3 7 0 - 3 8 2 .
S t e l l a , J . A . , L i a o , J . , a n d S a c k s , M . S . ( 2 0 0 7 ) . T i m e - d e p e n d e n t b i a x i a l m e c h a n i c a l
b e h a v i o r o f t h e a o r t i c h e a r t v a l v e l e a f l e t . Journal o f Biomechanics, 4 0 ( 1 4 ) ,
3 1 6 9 - 3 1 7 7 .
S t e l l a , J . A . , a n d S a c k s , M . S . ( 2 0 0 7 ) . O n t h e b i a x i a l m e c h a n i c a l p r o p e r t i e s o f t h e
l a y e r s o f t h e a o r t i c v a l v e l e a f l e t . Journal o f Biomechanical Engineering,
129( 5 ) , 7 5 7 - 7 6 6 .
S t o u t , K . K . , a n d V e r r i e r , E . D . ( 2 0 0 9 ) . A c u t e v a l v u l a r r e g u r g i t a t i o n . Circulation,
1 1 9 ( 2 5 ) , 3 2 3 2 - 3 2 4 1 .
S t r a d i n s , P . , L a c i s , R . , O z o l a n t a , I . , P u r i n a , B . , O s e , V . , F e l d m a n e , L . , e t a l . ( 2 0 0 4 ) .
C o m p a r i s o n o f b i o m e c h a n i c a l a n d s t r u c t u r a l p r o p e r t i e s b e t w e e n h u m a n a o r t i c
a n d p u l m o n a r y v a l v e . European Journal o f Cardio-thoracic Surgery, 2 6 ( 3 ) ,
6 3 4 - 6 3 9 .
S u l t a n a , N . a n d M . W a n g , ( 2 0 1 2 ) . P H B V / P L L A - b a s e d c o m p o s i t e s c a f f o l d s
f a b r i c a t e d u s i n g a n e m u l s i o n f r e e z i n g / f r e e z e - d r y i n g t e c h n i q u e f o r b o n e t i s s u e
e n g i n e e r i n g : s u r f a c e m o d i f i c a t i o n a n d i n v i t r o b i o l o g i c a l e v a l u a t i o n .
Biofabrication, 2 0 1 2 . 4 ( 1 ) , 0 1 5 0 0 3 .
196
S u n g , Y . K . , A h n , B . W . , a n d K a n g , T . J . ( 2 0 1 2 ) . M a g n e t i c n a n o f i b e r s w i t h c o r e
( F e 3 O 4 n a n o p a r t i c l e s u s p e n s i o n ) / s h e a t h ( p o l y e t h y l e n e t e r e p h t h a l a t e ) s t r u c t u r e
f a b r i c a t e d b y c o a x i a l e l e c t r o s p i n n i n g . Journal o f Magnetism and Magnetic
Materials, 3 2 4 ( 6 ) , 9 1 6 - 9 2 2 .
S w a n s o n , W . M . , a n d C l a r k , R . E . ( 1 9 7 4 ) . D i m e n s i o n s a n d g e o m e t r i c r e l a t i o n s h i p s o f
t h e h u m a n a o r t i c v a l u e a s a f u n c t i o n o f p r e s s u r e . Circulation Research, 35( 6 ) ,
8 7 1 - 8 8 2 .
T a h e r k h a n i , S . , a n d M o z t a r z a d e h , F . ( 2 0 1 6 ) . F a b r i c a t i o n o f a p o l y ( e -
c a p r o l a c t o n e ) / s t a r c h n a n o c o m p o s i t e s c a f f o l d w i t h a s o l v e n t - c a s t i n g / s a l t -
l e a c h i n g t e c h n i q u e f o r b o n e t i s s u e e n g i n e e r i n g a p p l i c a t i o n s . Journal o f
AppliedPolymer Science, D O I : 1 0 . 1 0 0 2 / a p p . 4 3 5 2 3 .
T a l m a n , E . , a n d B o u g h n e r , D . ( 1 9 9 6 ) . I n t e r n a l s h e a r p r o p e r t i e s o f f r e s h p o r c i n e
a o r t i c v a l v e c u s p s : i m p l i c a t i o n s f o r n o r m a l v a l v e f u n c t i o n . The Journal o f
Heart Valve Disease, 5 ( 2 ) , 1 5 2 - 1 5 9 .
T a n , A . , a n d H o l t , D . ( 1 9 7 6 ) . T h e e f f e c t s o f s t e r i l i z a t i o n a n d s t o r a g e t r e a t m e n t s o n
t h e s t r e s s - s t r a i n b e h a v i o r o f a o r t i c v a l v e l e a f l e t s . The Annals o f Thoracic
Surgery, 2 2 ( 2 ) , 1 8 8 - 1 9 4 .
T a n a k a , K . , S a t a , M . , F u k u d a , D . , S u e m a t s u , Y . , M o t o m u r a , N . , T a k a m o t o , S . , e t a l .
( 2 0 0 5 ) . A g e - a s s o c i a t e d a o r t i c s t e n o s i s i n a p o l i p o p r o t e i n E - d e f i c i e n t m i c e .
Journal o f the American College o f Cardiology, 4 6 ( 1 ) , 1 3 4 - 1 4 1 .
T a r a n , M . , a n d A g h a i e , E . ( 2 0 1 5 ) . D e s i g n i n g a n d o p t i m i z a t i o n o f s e p a r a t i o n p r o c e s s
o f i r o n i m p u r i t i e s f r o m k a o l i n b y o x a l i c a c i d i n b e n c h - s c a l e s t i r r e d - t a n k
r e a c t o r . Applied Clay Science, 107, 1 0 9 - 1 1 6 .
T a r t a j , P . , d e l P u e r t o M o r a l e s , M . , V e i n t e m i l l a s - V e r d a g u e r , S . , G o n z a l e z - C a r r e n o ,
T . , a n d S e r n a , C . J . ( 2 0 0 3 ) . T h e p r e p a r a t i o n o f m a g n e t i c n a n o p a r t i c l e s f o r
a p p l i c a t i o n s i n b i o m e d i c i n e . Journal o f Physics D: Applied Physics, 36( 1 3 ) ,
1 8 2 - 1 9 7 .
T a y l o r , P . , A l l e n , S . , D r e g e r , S . , a n d Y a c o u b , M . ( 2 0 0 2 ) . H u m a n c a r d i a c v a l v e
i n t e r s t i t i a l c e l l s i n c o l l a g e n s p o n g e : a b i o l o g i c a l t h r e e - d i m e n s i o n a l m a t r i x f o r
t i s s u e e n g i n e e r i n g . The Journal o f Heart Valve Disease, 1 1 ( 3 ) , 2 9 8 - 3 0 6 .
T a y l o r , P . M . , C a s s , A . E . , a n d Y a c o u b , M . H . ( 2 0 0 6 ) . E x t r a c e l l u l a r m a t r i x s c a f f o l d s
f o r t i s s u e e n g i n e e r i n g h e a r t v a l v e s . Progress in Pediatric Cardiology, 2 1 ( 2 ) ,
2 1 9 - 2 2 5 .
197
T e e b k e n , O . , B a d e r , A . , S t e i n h o f f , G . , a n d H a v e r i c h , A . ( 2 0 0 0 ) . T i s s u e e n g i n e e r i n g
o f v a s c u l a r g r a f t s : h u m a n c e l l s e e d i n g o f d e c e l l u l a r i s e d p o r c i n e m a t r i x .
European Journal o f Vascular and Endovascular Surgery, 1 9 ( 4 ) , 3 8 1 - 3 8 6 .
T e o , W . , a n d R a m a k r i s h n a , S . ( 2 0 0 6 ) . A r e v i e w o n e l e c t r o s p i n n i n g d e s i g n a n d
n a n o f i b r e a s s e m b l i e s . Nanotechnology, 1 7 ( 1 4 ) , 8 9 - 9 3 .
T h a d a v i r u l , N . , P a v a s a n t , P . , a n d S u p a p h o l , P . ( 2 0 1 4 ) . D e v e l o p m e n t o f
p o l y c a p r o l a c t o n e p o r o u s s c a f f o l d s b y c o m b i n i n g s o l v e n t c a s t i n g , p a r t i c u l a t e
l e a c h i n g , a n d p o l y m e r l e a c h i n g t e c h n i q u e s f o r b o n e t i s s u e e n g i n e e r i n g .
Journal o f Biomedical Materials Research Part A, 1 0 2 ( 1 0 ) , 3 3 7 9 - 3 3 9 2 .
T h o m , T . , H a a s e , N . , R o s a m o n d , W . , H o w a r d , V . J . , R u m s f e l d , J . , M a n o l i o , T . , e t a l .
( 2 0 0 6 ) . H e a r t d i s e a s e a n d s t r o k e s t a t i s t i c s - 2 0 0 6 u p d a t e a r e p o r t f r o m t h e
A m e r i c a n H e a r t A s s o c i a t i o n S t a t i s t i c s C o m m i t t e e a n d S t r o k e S t a t i s t i c s
S u b c o m m i t t e e . Circulation, 1 1 3 ( 6 ) , 8 5 - 1 5 1 .
T h u b r i k a r , M . , P i e p g r a s s , W . C . , D e c k , J . D . , a n d N o l a n , S . P . ( 1 9 8 0 ) . S t r e s s e s o f
n a t u r a l v e r s u s p r o s t h e t i c a o r t i c v a l v e l e a f l e t s i n v i v o . The Annals o f Thoracic
Surgery, 3 0 ( 3 ) , 2 3 0 - 2 3 9 .
T h u b r i k a r , M . J . ( 1 9 8 9 ) . The aortic valve: C R C p r e s s , N e w Y o r k : U n i t e d s t a t e .
T h u b r i k a r , M . J . , N o l a n , S . P . , A o u a d , J . , a n d D e c k , J . D . ( 1 9 8 6 ) . S t r e s s s h a r i n g
b e t w e e n t h e s i n u s a n d l e a f l e t s o f c a n i n e a o r t i c v a l v e . The Annals o f Thoracic
Surgery, 42( 4 ) , 4 3 4 - 4 4 0 .
T i l l q u i s t , M . N . , a n d M a d d o x , T . M . ( 2 0 1 1 ) . C a r d i a c c r o s s r o a d s : d e c i d i n g b e t w e e n
m e c h a n i c a l o r b i o p r o s t h e t i c h e a r t v a l v e r e p l a c e m e n t . Patient Prefer
Adherence, 5, 9 1 - 9 9 .
T o r r i c e l l i , P . , G i o f f r e , M . , F i o r a n i , A . , P a n z a v o l t a , S . , G u a l a n d i , C . , F i n i , M . , e t a l .
( 2 0 1 4 ) . C o - e l e c t r o s p u n g e l a t i n - p o l y ( L - l a c t i c a c i d ) s c a f f o l d s : m o d u l a t i o n o f
m e c h a n i c a l p r o p e r t i e s a n d c h o n d r o c y t e r e s p o n s e a s a f u n c t i o n o f
c o m p o s i t i o n . Materials Science and Engineering: C, 36, 1 3 0 - 1 3 8 .
T o r t o r a , G . , a n d G r a b o w s k i , S . ( 2 0 0 0 ) . Measuring blood pressure. Principles o f
Anatomy and Physiology, ( 9 th e d . ) N e w Y o r k : J o h n W i l e y & S o n s C o .
T s e n g , Y . T . , C h a p r o n , J . , T h o m p s o n , R . , D o n y i a , M . , S o h i e r , J . , A g i u b , H . , e t a l .
( 2 0 1 6 ) . The U s e o f c t a n d r a p i d p r o t o t y p i n g t o p r o d u c e a n e x a c t r e p l i c a o f t h e
n o r m a l h u m a n a o r t i c r o o t f o r t i s s u e e n g i n e e r i n g . Paper presented at the
Qatar Foundation Annual Research Conference Proceedings, HBOP3286.
198
T u l e t a , I . , A l G h a d d i o u i , A . K . , B a u r i e d e l , G . , W e r n e r t , N . , P r e u s s e , C . J . , W e l z , A . ,
e t a l . ( 2 0 1 3 ) . T h e i m b a l a n c e b e t w e e n p r o l i f e r a t i o n a n d a p o p t o s i s c o n t r i b u t e s
t o d e g e n e r a t i o n o f a o r t i c v a l v e s a n d b i o p r o s t h e s e s . Cardiology Journal,
2 0 ( 3 ) , 2 6 8 - 2 7 6 .
V a c a n t i , J . P . , M o r s e , M . A . , S a l t z m a n , W . M . , D o m b , A . J . , P e r e z - A t a y d e , A . , a n d
L a n g e r , R . ( 1 9 8 8 ) . S e l e c t i v e c e l l t r a n s p l a n t a t i o n u s i n g b i o a b s o r b a b l e a r t i f i c i a l
p o l y m e r s a s m a t r i c e s . Journal o f Pediatric Surgery, 2 3 ( 1 ) , 3 - 9 .
V a n D o o r n , C . ( 2 0 0 2 ) . T h e u n n a t u r a l h i s t o r y o f t e t r a l o g y o f F a l l o t : s u r g i c a l r e p a i r i s
n o t a s d e f i n i t i v e a s p r e v i o u s l y t h o u g h t . Heart, 8 8 ( 5 ) , 4 4 7 - 4 4 8 .
V a n L i e s h o u t , M . , V a z , C . , R u t t e n , M . , P e t e r s , G . , a n d B a a i j e n s , F . ( 2 0 0 6 ) .
E l e c t r o s p i n n i n g v e r s u s k n i t t i n g : t w o s c a f f o l d s f o r t i s s u e e n g i n e e r i n g o f t h e
a o r t i c v a l v e . Journal o f Biomaterials Science, Polymer Edition, 1 7 ( 1 ) , 7 7 - 8 9 .
V a z , C . , V a n T u i j l , S . , B o u t e n , C . , a n d B a a i j e n s , F . ( 2 0 0 5 ) . D e s i g n o f s c a f f o l d s f o r
b l o o d v e s s e l t i s s u e e n g i n e e r i n g u s i n g a m u l t i - l a y e r i n g e l e c t r o s p i n n i n g
t e c h n i q u e . Acta Biomaterialia, 1( 5 ) , 5 7 5 - 5 8 2 .
V a z q u e z , M . , D e l g a d o , R . , a n d C a s t r o , A . J . ( 2 0 0 9 ) . M o d e l l i n g o f t h e e n z y m a t i c
h y d r o l y s i s o f p o t a t o ( S o l a n u m t u b e r o s u m ) u s i n g r e s p o n s e s u r f a c e
m e t h o d o l o g y . Starch-Starke, 6 1 ( 1 0 ) , 6 0 1 - 6 0 9 .
V e s e l y , I . , a n d B o u g h n e r , D . R . ( 1 9 8 5 ) . A m u l t i p u r p o s e t i s s u e b e n d i n g m a c h i n e .
Journal o f Biomechanics, 1 8 ( 7 ) , 5 1 1 - 5 1 3 .
V e s e l y , I . , a n d B o u g h n e r , D . ( 1 9 8 9 ) . A n a l y s i s o f t h e b e n d i n g b e h a v i o u r o f p o r c i n e
x e n o g r a f t l e a f l e t s a n d o f n a t u r a l a o r t i c v a l v e m a t e r i a l : b e n d i n g s t i f f n e s s ,
n e u t r a l a x i s a n d s h e a r m e a s u r e m e n t s . Journal o f Biomechanics, 22( 6 ) , 6 5 5
6 7 1 .
W a l l i n , R . F . , a n d A r s c o t t , E . ( 1 9 9 8 ) . A p r a c t i c a l g u i d e t o I S O 1 0 9 9 3 - 5 : C y t o t o x i c i t y .
Medical Device and Diagnostic Industry, 20, 9 6 - 9 8 .
W a n g , L . , Y a n g , S . , W a n g , J . , W a n g , C . , a n d C h e n , L . ( 2 0 1 1 ) . F a b r i c a t i o n o f
s u p e r h y d r o p h o b i c T P U f i l m f o r o i l - w a t e r s e p a r a t i o n b a s e d o n
e l e c t r o s p i n n i n g r o u t e . Materials Letters, 6 5 ( 5 ) , 8 6 9 - 8 7 2 .
W a n g , X . , L i , X . , a n d Y o s t , M . J . ( 2 0 0 5 ) . M i c r o t e n s i l e t e s t i n g o f c o l l a g e n f i b r i l f o r
c a r d i o v a s c u l a r t i s s u e e n g i n e e r i n g . Journal o f Biomedical Materials Research
Part A, 7 4 ( 2 ) , 2 6 3 - 2 6 8 .
W a n g , Y . , A m e e r , G . A . , S h e p p a r d , B . J . , a n d L a n g e r , R . ( 2 0 0 2 ) . A t o u g h
b i o d e g r a d a b l e e l a s t o m e r . Nature Biotechnology, 20( 6 ) , 6 0 2 - 6 0 6 .
199
W a n g , Z . , B i , H . , L i u , J . , S u n , T . , a n d W u , X . ( 2 0 0 8 ) . M a g n e t i c a n d m i c r o w a v e
a b s o r b i n g p r o p e r t i e s o f p o l y a n i l i n e / y - F e 2 O 3 n a n o c o m p o s i t e . Journal o f
Magnetism and Magnetic Materials, 3 2 0 ( 1 6 ) , 2 1 3 2 - 2 1 3 9 .
W e i , Y . , Z h a n g , X . , S o n g , Y . , H a n , B . , H u , X . , W a n g , X . , e t a l . ( 2 0 1 1 ) . M a g n e t i c
b i o d e g r a d a b l e F e 3 O 4 / C S / P V A n a n o f i b r o u s m e m b r a n e s f o r b o n e r e g e n e r a t i o n .
Biomedical Materials, 6 ( 5 ) , 8 - 2 3 .
W e i n b e r g , E . J . , a n d K a a z e m p u r - M o f r a d , M . R . ( 2 0 0 6 ) . A l a r g e - s t r a i n f i n i t e e l e m e n t
f o r m u l a t i o n f o r b i o l o g i c a l t i s s u e s w i t h a p p l i c a t i o n t o m i t r a l v a l v e l e a f l e t
t i s s u e m e c h a n i c s . Journal o f Biomechanics, 3 9 ( 8 ) , 1 5 5 7 - 1 5 6 1 .
W e i n h a u s , A . J . ( 2 0 1 5 ) . A n a t o m y o f t h e h u m a n h e a r t . I n Handbook o f Cardiac
Anatomy, Physiology, and Devices ( p p . 6 1 - 8 8 ) , N e w Y o r k : S p r i n g e r .
W e s t o n , M . W . , L a B o r d e , D . V . , a n d Y o g a n a t h a n , A . P . ( 1 9 9 9 ) . E s t i m a t i o n o f t h e
s h e a r s t r e s s o n t h e s u r f a c e o f a n a o r t i c v a l v e l e a f l e t . Annals o f Biomedical
Engineering, 2 7 ( 4 ) , 5 7 2 - 5 7 9 .
W o n g , S . - C . , B a j i , A . , a n d L e n g , S . ( 2 0 0 8 ) . E f f e c t o f f i b e r d i a m e t e r o n t e n s i l e
p r o p e r t i e s o f e l e c t r o s p u n p o l y ( e - c a p r o l a c t o n e ) . Polymer, 4 9 ( 2 1 ) , 4 7 1 3 - 4 7 2 2 .
W r i g h t , J . T . , E l l i o t t , D . P . , a n d W e l l s , F . C . ( 1 9 9 3 ) . M i t r a l a n d t r i c u s p i d
a n n u l o p l a s t y r i n g s : U S 5 2 0 1 8 8 0 A , G o o g l e P a t e n t s .
W u , W . , W u , Z . , Y u , T . , J i a n g , C . , a n d K i m , W . - S . ( 2 0 1 6 ) . R e c e n t p r o g r e s s o n
m a g n e t i c i r o n o x i d e n a n o p a r t i c l e s : s y n t h e s i s , s u r f a c e f u n c t i o n a l s t r a t e g i e s a n d
b i o m e d i c a l a p p l i c a t i o n s . Science and Technology o f Advanced Materials, 16,
2 0 - 3 2 .
X i a , Z . , Y u , X . , J i a n g , X . , B r o d y , H . D . , R o w e , D . W . , a n d W e i , M . ( 2 0 1 3 ) .
F a b r i c a t i o n a n d c h a r a c t e r i z a t i o n o f b i o m i m e t i c c o l l a g e n - a p a t i t e s c a f f o l d s
w i t h t u n a b l e s t r u c t u r e s f o r b o n e t i s s u e e n g i n e e r i n g . Acta Biomaterialia, 9( 7 ) ,
7 3 0 8 - 7 3 1 9 .
X i n g , C . , G u a n , J . , C h e n , Z . , Z h u , Y . , Z h a n g , B . , L i , Y . , e t a l . ( 2 0 1 5 ) . N o v e l
m u l t i f u n c t i o n a l n a n o f i b e r s b a s e d o n t h e r m o p l a s t i c p o l y u r e t h a n e a n d i o n i c
l i q u i d : t o w a r d s a n t i b a c t e r i a l , a n t i - e l e c t r o s t a t i c a n d h y d r o p h i l i c n o n w o v e n s b y
e l e c t r o s p i n n i n g . Nanotechnology, 26( 1 0 ) , 1 0 5 7 0 4 .
X i o n g , Z . , Y a n , Y . , W a n g , S . , Z h a n g , R . , a n d Z h a n g , C . ( 2 0 0 2 ) . F a b r i c a t i o n o f
p o r o u s s c a f f o l d s f o r b o n e t i s s u e e n g i n e e r i n g v i a l o w - t e m p e r a t u r e d e p o s i t i o n .
Scripta Materialia, 4 6 ( 1 1 ) , 7 7 1 - 7 7 6 .
200
Y a c o u b , M . , a n d T a k k e n b e r g , J . ( 2 0 0 5 ) . W i l l h e a r t v a l v e t i s s u e e n g i n e e r i n g c h a n g e
t h e w o r l d ? Nature Clinical Practice Cardiovascular Medicine, 2 ( 2 ) , 6 0 - 6 1 .
Y a m a d a , H . , ( 1 9 7 3 ) . T e n s i l e p r o p e r t i e s o f h u m a n c a r d i a c v a l v e s , I n E v a n s , G . F .
( E d . ) , Strength o f Biological Materials ( p p . 1 0 9 ) , N e w Y o r k : K r i e g e r .
Y a n g , F . , M u r u g a n , R . , W a n g , S . , a n d R a m a k r i s h n a , S . ( 2 0 0 5 ) . E l e c t r o s p i n n i n g o f
n a n o / m i c r o s c a l e p o l y ( L - l a c t i c a c i d ) a l i g n e d f i b e r s a n d t h e i r p o t e n t i a l i n
n e u r a l t i s s u e e n g i n e e r i n g . Biomaterials, 2 6 ( 1 5 ) , 2 6 0 3 - 2 6 1 0 .
Y a n g , J . , S h i , G . , B e i , J . , W a n g , S . , C a o , Y . , S h a n g , Q . , e t a l . ( 2 0 0 2 ) . F a b r i c a t i o n a n d
s u r f a c e m o d i f i c a t i o n o f m a c r o p o r o u s p o l y ( L - l a c t i c a c i d ) a n d p o l y ( L - l a c t i c -
c o - g l y c o l i c a c i d ) ( 7 0 : 3 0 ) c e l l s c a f f o l d s f o r h u m a n s k i n f i b r o b l a s t c e l l c u l t u r e .
Journal o f Biomedical Materials Research, 6 2 ( 3 ) , 4 3 8 - 4 4 6 .
Y a n g , W . , F o r t u n a t i , E . , D o m i n i c i , F . , K e n n y , J . , a n d P u g l i a , D . ( 2 0 1 5 ) . E f f e c t o f
p r o c e s s i n g c o n d i t i o n s a n d l i g n i n c o n t e n t o n t h e r m a l , m e c h a n i c a l a n d
d e g r a d a t i v e b e h a v i o r o f l i g n i n n a n o p a r t i c l e s / p o l y l a c t i c ( a c i d )
b i o n a n o c o m p o s i t e s p r e p a r e d b y m e l t e x t r u s i o n a n d s o l v e n t c a s t i n g . European
Polymer Journal, 71, 1 2 6 - 1 3 9 .
Y a o , R . , H e , J . , M e n g , G . , J i a n g , B . , a n d W u , F . ( 2 0 1 6 ) . E l e c t r o s p u n P C L / g e l a t i n
c o m p o s i t e f i b r o u s s c a f f o l d s : m e c h a n i c a l p r o p e r t i e s a n d c e l l u l a r r e s p o n s e s .
Journal o f Biomaterials Science, Polymer Edition, 2 7 ( 9 ) , 8 2 4 - 8 3 8 .
Y i l g o r , I . , Y i l g o r , E . , G u l e r , I . G . , W a r d , T . C . , a n d W i l k e s , G . L . ( 2 0 0 6 ) . F T I R
i n v e s t i g a t i o n o f t h e i n f l u e n c e o f d i i s o c y a n a t e s y m m e t r y o n t h e m o r p h o l o g y
d e v e l o p m e n t i n m o d e l s e g m e n t e d p o l y u r e t h a n e s . Polymer, 4 7 ( 1 1 ) , 4 1 0 5
4 1 1 4 .
Y o r d e m , O . , P a p i l a , M . , a n d M e n c e l o g l u , Y . Z . ( 2 0 0 8 ) . E f f e c t s o f e l e c t r o s p i n n i n g
p a r a m e t e r s o n p o l y a c r y l o n i t r i l e n a n o f i b e r d i a m e t e r : A n i n v e s t i g a t i o n b y
r e s p o n s e s u r f a c e m e t h o d o l o g y . Materials & Design, 2 9 ( 1 ) , 3 4 - 4 4 .
Y o s h i m i t s u , Z . , N a k a j i m a , A . , W a t a n a b e , T . , a n d H a s h i m o t o , K . ( 2 0 0 2 ) . E f f e c t s o f
s u r f a c e s t r u c t u r e o n t h e h y d r o p h o b i c i t y a n d s l i d i n g b e h a v i o r o f w a t e r
d r o p l e t s . Langmuir, 1 8 ( 1 5 ) , 5 8 1 8 - 5 8 2 2 .
Y u a n , Q . , Z h o u , T . , L i , L . , Z h a n g , J . , L i u , X . , K e , X . , e t a l . ( 2 0 1 5 ) . H y d r o g e n b o n d
b r e a k i n g o f T P U u p o n h e a t i n g : u n d e r s t a n d i n g f r o m t h e v i e w p o i n t s o f
m o l e c u l a r m o v e m e n t s a n d e n t h a l p y . RSCAdvances, 5 ( 3 9 ) , 3 1 1 5 3 - 3 1 1 6 5 .
201
Z h a i , W . , L u , X . , C h a n g , J . , Z h o u , Y . , a n d Z h a n g , H . ( 2 0 1 0 ) . Q u e r c e t i n - c r o s s l i n k e d
p o r c i n e h e a r t v a l v e m a t r i x : m e c h a n i c a l p r o p e r t i e s , s t a b i l i t y , a n t i c a l c i f i c a t i o n
a n d c y t o c o m p a t i b i l i t y . Acta Biomaterialia, 6 ( 2 ) , 3 8 9 - 3 9 5 .
Z h a n g , C . , Y u a n , X . , W u , L . , H a n , Y . , a n d S h e n g , J . ( 2 0 0 5 ) . S t u d y o n m o r p h o l o g y o f
e l e c t r o s p u n p o l y ( v i n y l a l c o h o l ) m a t s . European Polymer Journal, 4 1 ( 3 ) ,
4 2 3 - 4 3 2 .
Z h a n g , P . , T i a n , R . , L v , R . , N a , B . , a n d L i u , Q . ( 2 0 1 5 ) . W a t e r - p e r m e a b l e p o l y l a c t i d e
b l e n d m e m b r a n e s f o r h y d r o p h i l i c i t y - b a s e d s e p a r a t i o n . Chemical Engineering
Journal, 269, 1 8 0 - 1 8 5 .
Z h a n g , Y . S . , Y u e , K . , A l e m a n , J . , M o l l a z a d e h - M o g h a d d a m , K . , B a k h t , S . M . , Y a n g ,
J . , e t a l . ( 2 0 1 6 ) . 3 D b i o p r i n t i n g f o r t i s s u e a n d o r g a n f a b r i c a t i o n . Annals o f
Biomedical Engineering, 1 - 1 6 .
Z h a o , F . , Y i n , Y . , L u , W . W . , L e o n g , J . C . , Z h a n g , W . , Z h a n g , J . , e t a l . ( 2 0 0 2 ) .
P r e p a r a t i o n a n d h i s t o l o g i c a l e v a l u a t i o n o f b i o m i m e t i c t h r e e - d i m e n s i o n a l
h y d r o x y a p a t i t e / c h i t o s a n - g e l a t i n n e t w o r k c o m p o s i t e s c a f f o l d s . Biomaterials,
2 3 ( 1 5 ) , 3 2 2 7 - 3 2 3 4 .
Z h a o , G . , Z h a n g , X . , L u , T . J . , a n d X u , F . ( 2 0 1 5 ) . T i s s u e e n g i n e e r i n g : R e c e n t
a d v a n c e s i n e l e c t r o s p u n n a n o f i b r o u s s c a f f o l d s f o r c a r d i a c t i s s u e e n g i n e e r i n g .
Advanced Functional Materials, 2 5 ( 3 6 ) , 5 8 7 5 - 5 8 7 5 .
Z o r i o , E . , G i l a b e r t - E s t e l l e s , J . , E s p a n a , F . , R a m o n , L . A . , C o s i n , R . , a n d E s t e l l e s , A .
( 2 0 0 8 ) . F i b r i n o l y s i s : t h e k e y t o n e w p a t h o g e n e t i c m e c h a n i s m s . Current
Medicinal Chemistry, 1 5 ( 9 ) , 9 2 3 - 9 2 9 .