Contents
List of contributors xix
Preface xxvii
Acknowledgment xxix
Section 1 Properties and forms of biomaterials 1
1 Introduction to biomaterials for tissue/organ regeneration 3
Nihal Engin Vrana
1.1 Introduction 3
1.2 Many facets of new biomaterials: new naturally sourced biomaterials, new synthetic biomaterials, materiomics, metabiomaterials 4
1.3 Off-shoot technologies linked to biomaterials and tissue engineering: biorobotics, bioinks, and bioprinting 8
1.4 Biomaterial risk assessment 10
1.5 Conclusion 15
Acknowledgment 15
References 15
2 Physicochemical properties of biomaterials 19
Vincent Ball
2.1 Introduction 19
2.2 Bulk properties of biomaterials 20
2.2.1 Shape and size control 20
2.2.2 Mechanical properties 20
2.2.3 Corrosion and degradation in a given chemical environment 22
2.2.4 Control of porosity, pore size, and pore connectivity 22
2.3 Surface properties of biomaterials 23
2.3.1 Surface energy-hydrophilicity 23
2.3.2 Lack of toxicity, of unfavorable immunological response, hemocompatibility 25
2.3.3 Surface topography 25
2.3.4 Protein adsorption 25
2.3.5 Versatile modification of the biomaterials’ surface chemistry 26
2.3.6 Degradability of surface coatings 27
2.3.7 Antibacterial properties 27
2.3.8 Active biomaterials 28
2.4 Properties of biomimetic biomaterials 28
2.5 Real-time monitoring of an implanted biomaterial and personalized implants 29
2.6 Conclusion and perspectives 29
References 30
3 Polymer-based composites for musculoskeletal regenerative medicine 33
Patrina S.P. Poh, Maria A. Woodruff and Elena Garcı´a-Gareta
Abbreviations 33
3.1 Introduction 34
3.2 A brief history of composites 35
3.3 Polymer-based composites scaffold characteristics 36
3.3.1 Mechanical properties 36
3.3.2 Biodegradation properties 39
3.4 Polymer-based composite scaffolds for specific musculoskeletal
tissue regeneration 43
3.4.1 Bone 43
3.4.2 Cartilage and osteochondral regeneration 51
3.4.3 Tendon, ligament, and enthesis regeneration 54
3.4.4 Skeletal muscle regeneration 55
3.5 The necessity for nerve and vascular regeneration 57
3.5.1 Importance of vasculature and innervation for skeletal
muscle regeneration 57
3.5.2 Importance of vasculature and innervation for bone
regeneration 57
3.6 Nerve regeneration 58
3.6.1 Composite biomaterial approach for nerve regeneration 58
3.7 Vascular regeneration 65
3.7.1 Fabrication of polymer-based composite scaffolds that
incorporate a vascular network 65
3.7.2 Engineering of small diameter blood vessels (,6 mm)
with polymer-based composites 66
3.8 Conclusion and future prospects 67
Acknowledgments 68
References 68
4 Emerging biotechnological approaches with respect to tissue
regeneration: from improving biomaterial incorporation to
comprehensive omics monitoring 83
Rabah Gahoual, Yannis-Nicolas Franc¸ois,
Nathalie Mignet and Pascal Houze´
4.1 Introduction 83
4.2 Analytical methodologies for protein identification and monitoring 84
4.3 Mass spectrometry_based proteomic analysis 87
4.3.1 Sample preparation for proteomics experiments 88
4.3.2 Peptide mixture analysis by liquid chromatography
coupled to tandem mass spectrometry 90
4.3.3 Protein identification 92
4.3.4 Applications of proteomic analysis to the development
of biomaterials for tissue regeneration 94
4.4 Analytical methodologies adapted to protein structural
characterization 98
4.4.1 Sample preparation 100
4.4.2 Tandem mass spectrometry_based analysis
of posttranslational modifications 101
4.5 Conclusion 104
References 105
5 Use of nanoscale-delivery systems in tissue/organ regeneration 113
Milad Fathi-Achachelouei, Dilek Keskin and Aysen Tezcaner
5.1 Introduction 113
5.2 Properties and application areas of nanoscale-delivery systems in
biomedical field 114
5.2.1 Delivery systems for therapeutic purpose 114
5.2.2 Delivery systems for tissue and organ regeneration 114
5.3 Nanoscale-delivery systems for regeneration purposes 115
5.3.1 Morphological classification of nanoscale-delivery systems 116
5.4 Emerging delivery technologies in nanoparticle area 139
5.4.1 Microfluidic devices for production of nanoparticles 139
5.4.2 Recruiting 3D printing and nanoparticles for tissue
engineering applications 140
5.5 Conclusion and future perspectives 141
References 142
6 Surface functionalization of biomaterials for cell biology applications 163
E. Ada Cavalcanti-Adam and Wenqian Feng
6.1 Introduction 163
6.1.1 From artificial to bioinspired materials: challenges
at the cell_material interface 163
6.2 Engineering the cell_material interface 164
6.2.1 Surface mimics of the extracellular matrix 165
6.2.2 Chemical and spatial control of cell adhesion
to surface materials 166
6.3 Delivery strategies for growth factors at the cell_material interface 169
6.3.1 Biofunctionalization strategies for tailoring the
spatiotemporal delivery of growth factors 170
6.3.2 Guidance of cell responses by growth factors complexed with
surface materials 171
6.4 Conclusion and outlook 172
References 173
7 Stem cells: sources, properties, and cell types 177
Melis Asal and Sinan Gu¨ven
7.1 Introduction 177
7.2 Stem cell properties 177
7.2.1 Self-renewal 177
7.2.2 Potency 179
7.3 Cell types 180
7.3.1 Embryonic stem cells 180
7.3.2 Induced pluripotent stem cells 182
7.3.3 Adult stem cells 183
7.4 Applications of stem cells in tissue engineering 188
7.5 Conclusion 192
References 193
8 Immune cells: sources, properties, and cell types 197
S. Jung and Florent Meyer
Abbreviations 197
8.1 Introduction 198
8.2 Immune system consideration in the use of biomaterials
and tissue regeneration 199
8.2.1 Overall description of the immune system: innate versus
adaptive system (“know your basics”) 199
8.2.2 Tissue regeneration/wound healing
(“why immune system is so important”) 202
8.2.3 Immune response to biomaterials: when all goes
wrong, that is, the foreign body reaction 205
8.3 Immune cell description 209
8.3.1 Myeloid cells 209
8.3.2 Innate-like lymphocytes 213
8.3.3 Lymphocytes 216
8.4 Immune cell sourcing 220
8.5 In vivo testing 222
8.6 Conclusion 223
References 223
9 Cell signaling and strategies to modulate cell behavior 231
Claire Ehlinger, Dominique Vautier and Leyla Kocgozlu
9.1 Introduction 231
9.1.1 How to modulate cell adhesion, cell migration, and cell
extrusion? 232
9.1.2 Synthetic matrices to control cell programming and
reprogramming 235
9.1.3 Nuclear mechanics and mechanical memory 239
9.2 Conclusion 241
Acknowledgments 242
References 242
Section 2 Biomaterials use in organ specific applications 247
10 Cardiovascular tissue engineering 249
Richard A. O’Connor, Paul A. Cahill and Garrett B. McGuinness
10.1 Introduction 249
10.2 The cardiovascular system 250
10.2.1 Arterial tissue 250
10.2.2 Cardiac tissue 251
10.3 Cardiovascular disease 252
10.4 Coronary artery bypass grafting 253
10.4.1 Vascular grafts 254
10.4.2 Role of biomechanical compliance 255
10.5 Tissue-engineered blood vessels 257
10.5.1 Biomaterials for tissue-engineered blood vessels 261
10.5.2 Stem cells in tissue-engineered blood vessel applications 262
10.6 Electrospinning of tissue-engineered blood vessels 263
10.6.1 Fundamentals of electrospinning 264
10.6.2 Electrospinning parameters 264
10.6.3 Collector systems for creating electrospun vessels 264
10.6.4 Limitations of electrospun scaffolds 266
10.7 Future outlook for cardiovascular tissue engineering 266
Acknowledgments 267
References 267
11 Bioartificial gut—current state of small intestinal tissue engineering 273
Thomas D¨ aullary, Christina Fey, Constantin Berger,
Marco Metzger and Daniela Zdzieblo
11.1 Introduction 273
11.2 The small intestine—structural organization and function 273
11.3 Modeling the small intestine—biology meets engineering 278
11.3.1 Modeling the small intestine in vitro by two-dimensional
monolayer cell cultures 278
11.3.2 Small intestinal organoids—artificial mini organs
grown in vitro 280
11.4 Small intestinal tissue engineering in the Transwell—when cells
meet scaffolds 283
11.5 Next-generation models—integration of microenvironmental
factors 284
11.6 Outlook 288
References 289
12 From insulin replacement to bioengineered, encapsulated organoids 299
Elisa Maillard and Se´verine Sigrist
12.1 Introduction 299
12.2 Pancreas 299
12.3 Pancreatic islet 299
12.3.1 Composition of pancreatic islets 301
12.3.2 β-Cells role and insulin function 302
12.4 Diabetes 303
12.4.1 Type 1 diabetes 304
12.4.2 Type 2 diabetes 304
12.4.3 Gestational diabetes 305
12.4.4 Other diabetes 305
12.4.5 Poor glycemia regulation complications 305
12.5 Insulin replacement for type 1 diabetes 306
12.5.1 Glucose measurements 306
12.5.2 Exogenous insulin 307
12.5.3 Endogenous insulin production 309
12.6 Islet transplantation limits (Fig. 12.5) 311
12.6.1 Low isolation yield and high pancreas requirement 311
12.6.2 Extracellular matrix destruction 312
12.6.3 Hypoxia 312
12.6.4 Instant blood-mediated inflammatory reaction 312
12.6.5 Autoimmunity and alloimmunity 313
12.6.6 Immune suppressive regimen 313
12.7 Improvements in islet transplantation (Fig. 12.7) 313
12.8 Other sources of insulin-secreting cells 316
12.8.1 Cells of animal origin 316
12.8.2 Surrogate cells 318
12.9 The bioartificial pancreas 320
12.9.1 Definition 320
12.9.2 Microencapsulation 321
12.9.3 Macroencapsulation 322
12.10 Conclusion 325
References 325
13 Diabetic wound healing with engineered biomaterials 335
Laura E. Castellano, Jorge Delgado, Arturo Vega-Gonza´lez and
Birzabith Mendoza-Novelo
13.1 Introduction 335
13.2 Impaired wound healing under condition of diabetes 335
13.2.1 Diabetic foot ulcer complications 335
13.2.2 Cellular and molecular events in diabetic foot ulcer 336
13.2.3 Implication of advanced glycation end products
on cell function 337
13.2.4 Epigenetic changes related to diabetic foot ulcer 339
13.3 Physicochemical aspects and fabrication of biomaterials
in diabetic wound healing 340
13.3.1 Hydration 340
13.3.2 Oxygenation 340
13.3.3 Infection control 341
13.3.4 Nanoparticle synthesis and its bioactivity 341
13.3.5 Cross-linking of biopolymers 341
13.4 Biomaterials supporting the administration of bioactive agents 343
13.4.1 Therapy based on growth factors 344
13.4.2 Pharmacological treatment alternative to growth factors 345
13.4.3 Treatment with natural extracts 347
13.4.4 Gene therapy_based approaches 347
13.4.5 Cell therapy_based approaches 348
13.5 Biomaterials with prohealing activity 350
13.5.1 Natural extracellular matrix biomaterials 350
13.5.2 Peptide-based biomaterials 351
13.5.3 Inorganic agent_containing dressings 352
13.6 Final remarks 353
References 353
14 Bone morphogenetic protein_assisted bone regeneration
and applications in biofabrication 363
Naomi C. Paxton, Cynthia S. Wong, Mathilde R. Desselle,
Mark C. Allenby and Maria A. Woodruff
14.1 Background 363
14.2 Bone morphogenetic protein for bone regeneration 364
14.2.1 Bone morphogenetic protein delivery
via carrier materials 365
14.2.2 Clinical products 368
14.3 Bone morphogenetic protein limitations 370
14.3.1 On- and off-label use 370
14.3.2 Complications and risks 370
14.3.3 Implant considerations 371
14.4 Current strategies 372
14.4.1 Minimizing dose 373
14.4.2 Controlled release systems 374
14.4.3 Complex biomaterials and biofabrication systems 379
14.5 Conclusion 381
Acknowledgement 381
References 381
15 Adipose tissue engineering 393
Fiona Louis and Michiya Matsusaki
15.1 Introduction 393
15.2 The adipose cells for the reconstruction of in vitro models 393
15.2.1 Preadipocytes cell lines 394
15.2.2 Primary bone marrow mesenchymal stem cells 394
15.2.3 Primary adipose_derived stem cells 395
15.2.4 Primary mature adipocytes 395
15.2.5 The importance of the vascularization in adipose models 395
15.2.6 Human cells or other species? 395
15.3 Current existing in vitro adipose tissues models 396
15.3.1 Reconstruction of an in vitro adipose tissue without
scaffold 398
15.3.2 Use of synthetic scaffolds 399
15.3.3 Natural components in adipose tissue engineering 399
15.4 Medical applications of adipose tissues grafts 405
15.4.1 For cosmetic surgery 406
15.4.2 For reconstructive surgery 406
15.4.3 For wound healing 407
15.4.4 For bone healing 407
15.5 Further developments needed 407
15.5.1 Vascularized adipose tissues 407
15.5.2 Addition of other surrounding cells types 408
15.5.3 Reconstruction of the different types of adipose tissues 409
15.6 Conclusion 411
References 412
16 Blood_brain barrier tissue engineering 425
Agathe Figarol and Michiya Matsusaki
16.1 Introduction, specificities of the blood_brain barrier 425
16.1.1 A highly selective barrier 425
16.1.2 Endothelial cells, pericytes, and astrocytes 425
16.1.3 Extracellular matrix 426
16.1.4 First attempts in blood_brain barrier models 427
16.2 Spheroids 427
16.3 Templated vessels’ growth 428
16.3.1 Rigid channels 428
16.3.2 Extracellular matrix channels 428
16.4 Sprouts and guided capillaries growth 429
16.5 Capillaries self-organization 430
16.5.1 Capillaries self-organization on top of Matrigels 430
16.5.2 Capillary self-organization on microchips 431
16.5.3 Capillaries self-organization in device-free hydrogels 431
16.6 Current challenges in translational research 432
16.7 Implantation prospects 433
16.8 Conclusion 434
References 434
17 Tissue engineering in urology 441
Elif Vardar
17.1 Introduction 441
17.2 Biomaterials for urological tissues 444
17.2.1 Kidney tissue engineering 444
17.2.2 Bladder tissue engineering 447
17.3 Conclusion and future perspectives 450
Conflict of interest 451
References 451
Further reading 455
18 Respiratory tissue replacement and regeneration:
from larynx to bronchi 457
Lea Fath, Esteban Brenet, Dana M. Radu, Emmanuel Martinod
and Christian Debry
18.1 Introduction 457
18.2 Normal respiratory tissue 457
18.2.1 Embryology 457
18.2.2 Larynx 458
18.2.3 Lower airways: trachea, carina, bronchi, bronchioles 460
18.3 Airways diseases 463
18.3.1 Laryngeal diseases 463
18.3.2 Tracheobronchial diseases 464
18.4 Replacement and regeneration strategies 465
18.4.1 Laryngeal transplantation 465
18.4.2 Biomaterials 465
18.4.3 Tissue engineering 467
18.5 Transplant 470
18.5.1 Nonliving tissue transplants 470
18.5.2 Autografts 470
18.5.3 Allografts 471
18.6 Conclusion and outlook 472
References 472
19 Platelet-rich plasma in tissue engineering 477
Anne Lehn
19.1 Introduction 477
19.1.1 Blood composition 477
19.1.2 How does platelet-rich plasma work? 479
19.1.3 Preparation of platelet-rich plasma_based biomaterials 483
19.2 Tissue engineering 485
19.2.1 An autologous cell culture supplement 485
19.2.2 Platelet-rich plasma in tissue-engineered constructs 486
19.3 Platelet-rich plasma in regenerative medicine 488
19.4 Conclusion 492
References 492
Section 3 Emerging and enabling technologies
for biomaterials in tissue regeneration 497
20 Nanocomposite hydrogels for tissue engineering applications 499
Azadeh Mostafavi, Jacob Quint, Carina Russell and Ali Tamayol
20.1 Introduction 499
20.2 Conventional hydrogels and their limitations 500
20.2.1 Natural polymers 501
20.2.2 Synthetic polymers 505
20.3 Nanomaterials for engineering composite hydrogel systems 508
20.3.1 Methods for creating nanocomposite
hydrogel systems 508
20.3.2 Nanoparticles in tissue engineering 509
20.4 Properties of nanocomposite hydrogels 513
20.4.1 Tailored mechanical and structural properties 513
20.4.2 Enhanced electrical conductivity 515
20.4.3 Enhanced availability of biological factors and drugs 516
20.4.4 Cellular reprogramming 520
20.5 Conclusion and future directions 521
Acknowledgments 522
References 523
21 Functional carbon-based nanomaterials for engineered
tissues toward organ regeneration 529
Yasamin A. Jodat and Su Ryon Shin
21.1 Introduction 529
21.2 Characteristics of carbon-based materials used for tissue
engineering 530
21.2.1 Graphene 530
21.2.2 Carbon nanotubes 532
21.3 Function mimetic carbon-based engineered tissues 532
21.3.1 Skeletal muscle regeneration 533
21.3.2 Cardiac tissue regeneration 535
21.3.3 Neural tissue regeneration 537
21.4 Bone regeneration 539
21.5 Considerations for in vivo tissue regeneration 543
21.5.1 Toxicity 543
21.5.2 Biodegradability 543
21.6 Conclusion and future perspectives 544
References 545
22 Hyaluronic acid_based hydrogels for tissue engineering 551
N. Vijayakameswara Rao
22.1 Introduction 551
22.2 Chemical modifications of hyaluronic acid 552
22.2.1 Hyaluronic acid 552
22.3 Cross-linking chemistry of hyaluronic acid 555
22.3.1 Schiff-base cross-linking hydrogels 556
22.3.2 Diels_Alder click cross-linked hydrogel 560
22.3.3 Photo-cross-linking 561
22.3.4 The hyaluronic acid_disulfide cross-linking hydrogels 561
22.4 Hyaluronic acid as a biomaterial in tissue engineering 561
22.4.1 Hyaluronic acid_based scaffolds 561
22.5 Conclusion 563
Acknowledgement 563
References 563
23 Microfluidics in tissue engineering 567
Sudip Kumar Sinha and Arindam Bit
23.1 Introduction 567
23.2 Design considerations of microfluidics chips 567
23.2.1 Photolithography 568
23.2.2 Microcontact printing 570
23.2.3 Micropatterning of cells on microchannels 572
23.2.4 Cryopreservation techniques of cells for
tissue engineering 574
23.3 Biomaterials at microscale 576
23.3.1 Composite microparticles 576
23.3.2 Particulate biomaterials at the nanoscale 577
23.3.3 Fibrous biomaterials at micro- and nanoscale 578
23.3.4 Sheet biomaterials 579
23.4 Methods for cell patterning and cultivation 579
23.4.1 Cell-patterning techniques 581
23.4.2 Bioreactors 581
23.4.3 Microfluidic devices for cell manipulation 583
23.4.4 Microenvironment on cell integrity 584
23.5 Microfluidic cell culture models for tissue engineering 585
23.5.1 Basal lamina 585
23.5.2 Vascular tissue 585
23.5.3 Liver 588
23.5.4 Bone 589
23.6 Conclusion 590
References 591
Further reading 595
24 Biomechanical characterization of engineered tissues
and implants for tissue/organ replacement applications 599
Michael Gasik
24.1 Introduction 599
24.2 Biomechanics and mechanobiology 601
24.3 Mechanobiology and biomaterials functionality 603
24.4 Methods and challenges 608
24.5 Biomaterials evaluation: a practical example 611
24.6 Conclusion and outlook 618
References 619
25 In vitro disease and organ model 629
Emal Lesha, Sheyda Darouie, Amir Seyfoori,
Alireza Dolatshahi-Pirouz and Mohsen Akbari
25.1 Model development 629
25.1.1 Microengineered tissues 629
25.1.2 Microfluidic tissue models and microphysiological
systems 633
25.1.3 Emerging biofabrication technologies 636
25.1.4 Stem cell technology—biomaterial interface 638
25.1.5 Organoids 639
25.1.6 Rationale design of biomaterials for disease modeling 641
25.1.7 Biocompatibility 642
25.1.8 Biodegradability 644
25.1.9 Vascularity 644
25.1.10 Mechanical properties 647
25.1.11 Electrical conductivity 647
25.2 Emerging applications and clinical considerations 648
25.2.1 Inflammatory response and cancer modeling 648
25.2.2 Cardiovascular diseases 650
25.2.3 Skin diseases 651
25.2.4 Gastrointestinal diseases 652
25.2.5 Neurological disorders 653
25.3 Conclusion 654
References 655
26 Biomaterials for on-chip organ systems 669
Shabir Hassan, Marcel Heinrich, Berivan Cecen,
Jai Prakash and Yu Shrike Zhang
26.1 Introduction 669
26.2 Design and biomaterial considerations for the development
of specialized microphysiological systems 671
26.3 Selection parameters for biomedical applications 671
26.3.1 Lung 673
26.3.2 Brain 675
26.3.3 Heart 676
26.3.4 Kidney 677
26.3.5 Liver 678
26.3.6 Gut 679
26.3.7 Muscle 679
26.3.8 Bone 681
26.3.9 Multiorgan 682
26.4 Organ-on-chip platforms to mimic human pathophysiology 684
26.5 Applications beyond conventional research 686
26.5.1 Space 686
26.5.2 Military 687
26.6 Biomaterials for chip fabrication 688
26.6.1 Elastomers 688
26.7 Thermoplastics 689
26.8 Hydrogels 690
26.9 Biomaterials for tissue fabrication for organ-on-chip platforms 691
26.10 Challenges and outlook 695
References 696
Further reading 707
27 Bioreactors in tissue engineering: mimicking the microenvironment 709
Ece Bayir, Mert Sahinler, M. Mert Celtikoglu and Aylin Sendemir
27.1 The role of bioreactors in tissue engineering 709
27.2 Bioreactor configurations 711
27.2.1 Stirred bioreactors 711
27.2.2 Wave bioreactors 712
27.2.3 Parallel-plate bioreactors and parallel-plate flow chamber bioreactors 714
27.2.4 Rotating wall vessel (reduced gravity) bioreactors 715
27.2.5 Strain bioreactors 717
27.2.6 Perfusion bioreactors 722
27.2.7 Hollow-fiber bioreactors 725
27.2.8 Microfluidic bioreactors 727
27.2.9 Combined systems 729
27.3 Cell-seeding techniques for bioreactors 731
27.4 Design considerations and future outlook 733
27.5 Conclusion 739
References 739
Further reading 752
28 Simulation of organ-on-a-chip systems 753
Nenad Filipovic, Milica Nikolic and Tijana Sustersic
28.1 Introduction 753
28.1.1 General overview 754
28.1.2 Review of the lung and liver cell line models 757
28.2 Review of numerical solutions of developed models 760
28.2.1 Finite-difference method 760
28.2.2 Finite element modeling 762
28.3 Modeling of bioreactor for lung cells 763
28.4 Mathematical modeling of liver cells 773
28.5 Conclusion 784
Acknowledgments 786
References 786
Further reading 790
Index 791