Contributor contact details .................................. xvii
Preface ..................................................... xxiii
Part I Sources, properties, modification and processing
of natural-based polymers
1. Polysaccharides as carriers of bioactive agents for
medical applications ......................................... 3
R. Pawar, W. Jadhav, S. Bhusare and R. Borade,
Dnyanopasak College, India, S. Farber, D. Itzkowitz
and A. Domb, The Hebrew University, Jerusalem, Israel
1.1. Introduction ............................................ 3
1.2. Starch .................................................. 6
1.3. Cellulose ............................................... 7
1.4. Heparinoid (sulfated polysaccharides) ................... 8
1.5. Dextran ................................................ 10
1.6. Pectin ................................................. 12
1.7. Arabinogalactan ........................................ 13
1.8. Drug conjugated polysaccharides ........................ 15
1.9. Polysaccharide dextrans ................................ 19
1.10.Mannan ................................................. 22
1.11.Pullulan ............................................... 23
1.12.Polysaccharide macromolecule-protein conjugates ........ 24
1.13.Cationic polysaccharides for gene delivery ............. 25
1.14.Diethylaminoethyl-dextran .............................. 26
1.15.Polysaccharide-oligoamine based conjugates ............. 27
1.16.Chitosan ............................................... 27
1.17.Applications of polysaccharides as drug carriers ....... 31
1.18.Applications of dextran conjugates ..................... 33
1.19.Site-specific drug delivery ............................ 38
1.20.Pectin drug site-specific delivery ..................... 38
1.21.Liposomal drug delivery ................................ 40
1.22.References ............................................. 45
2. Purification of naturally occurring biomaterials ............ 54
M.N. Gupta, Indian Institute of Technology Delhi,
India
2.1. Introduction ........................................... 54
2.2. Classes of naturally occurring biomaterials ............ 55
2.3. Downstream processing of small molecular. weight
natural products ....................................... 57
2.4. Purification strategies for proteins ................... 60
2.5. Purification of lipids ................................. 67
2.6. Purification of polysaccharides ........................ 71
2.7. Purification of nucleic acids .......................... 72
2.8. Purification of complex biomaterials ................... 75
2.9. Future trends .......................................... 76
2.10.Acknowledgement ........................................ 77
2.11.Sources of further information ......................... 77
2.12.References ............................................. 78
3. Processing of starch-based blends for biomedical
applications ................................................ 85
R.A. Sousa, V.M. Correlo, S. Chung, N.M. Neves,
J.F. Mano and R.L. Reis, 3B's Research Group,
University of Minho, Portuga l.
3.1. Introduction ........................................... 85
3.2. Starch ................................................. 85
3.3. Starch-based blends .................................... 88
3.4. Conclusions ............................................ 98
3.5. References ............................................. 99
4. Controlling the degradation of natural polymers for
biomedical applications .................................... 106
H.S. Azevedo, Т.С. Santos and R.L. Reis, 3B's
Research Group, University of Minho, Portugal
4.1. Introduction .......................................... 106
4.2. The importance of biodegradability of natural
polymers in biomedical applications ................... 106
4.3. Degradation mechanisms of natural polymers and
metabolic pathways for their disposal in the body ..... 107
4.4. Assessing the in vitro and in vivo biodegradability
of natural polymers ................................... 111
4.5. Controlling the degradation rate of natural
polymers .............................................. 120
4.6. Concluding remarks .................................... 124
4.6. Acknowledgements ...................................... 125
4.6. References ............................................ 125
5. Smart systems based on polysaccharides ..................... 129
M.N. Gupta and S. Raghava, Indian Institute of
Technology Delhi, India
5.1. What are smart materials? ............................. 129
5.2. Chitin and chitosan ................................... 131
5.3. Alginates ............................................. 136
5.4. Carrageenans .......................................... 140
5.5. Other miscellaneous smart polysaccharides and their
applications .......................................... 145
5.6. Polysaccharide-based composite materials .............. 146
5.7. Future trends ......................................... 149
5.8. Acknowledgement ....................................... 152
5.9. Sources of further information ........................ 152
5.10.References ............................................ 154
6. Surface modification and biomimetic coatings Surface
modification for natural-based biomedical polymers ......... 165
I. Pashkuleva, P.M. Lopez-Perez and R.L. Reis,
3B's Research Group, University of Minho, Portugal
6.1. Introduction .......................................... 165
6.2. Some terms and classifications ........................ 165
6.3. Wet chemistry in surface modification ................. 167
6.4. Physical methods for surface alterations .............. 171
6.6. Grafting .............................................. 177
6.6. Bio-approaches: Mimicking the cell-cell
interactions .......................................... 179
6.7. Future trends ......................................... 186
6.8. Acknowledgements ...................................... 186
6.9. References ............................................ 186
7. New biomineralization strategies for the use of
natural-based polymeric materials in bone-tissue
engineering ................................................ 193
I.B. Leonor, S. Gomes, P.C. Bessa, J.F. Mano,
R.L. Reis, 3B's Research Group, University of Minho,
Portugal and M. Casal, CBMA - Molecular and
Environmental Biology Center, University of Minho,
Portugal
7.1. Introduction .......................................... 193
7.2. The structure, development and mineralization of
bone .................................................. 194
7.3. Bone morphogenetic proteins in tissue engineering ..... 201
7.4. Bio-inspired calcium-phosphate mineralization from
solution .............................................. 206
7.5. General remarks and future trends ..................... 216
7.6. Acknowledgments ....................................... 217
7.7. References ............................................ 217
8. Natural-based multilayer films for biomedical
applications ............................................... 231
C. Picart, Universite Montpellier, France
8.1. Introduction .......................................... 231
8.2. Physico-chemical properties ........................... 234
8.3. Different types of natural-based multilayer films
for different applications ............................ 240
8.4. Bioactivity, cell adhesion, and biodegradability
properties ............................................ 244
8.5. Modulation of film mechanical properties .............. 248
8.6. Future trends ......................................... 250
8.7. Sources of further information and advice ............. 251
8.8. References ............................................ 252
9. Peptide modification of polysaccharide scaffolds for
targeted cell signaling .................................... 260
S. Levesque, R. Wylie, Y. Aizawa and M. Shoichet,
University of Toronto, Canada
9.1. Introduction .......................................... 260
9.2. Polysaccharide scaffolds in tissue engineering ........ 265
9.3. Peptide immobilization ................................ 267
9.4. Measurement ........................................... 272
9.5. Challenges associated with peptide immobilization ..... 274
9.6. Tissue engineering approaches targeting cell
signaling ............................................. 275
9.7. References ............................................ 277
Part III Biodegradable scaffolds for tissue regeneration
10.Scaffolds based on hyaluronan derivatives in
biomedical applications .................................... 291
E. Tognana, Fidia Advanced Biopolymers s.r.l., Italy
10.1.Introduction .......................................... 291
10.2.Hyaluronan ............................................ 291
10.3.Hyaluronan-based scaffolds for biomedical
applications .......................................... 293
10.4.Clinical applications ................................. 298
10.5.Future trends ......................................... 308
10.6.Sources of further information and advice ............. 309
10.7.References ............................................ 310
11.Electrospun elastin and collagen nanofibers and their
application as biomaterials ................................ 315
R. Sallach and E. Chaikof, Emory University/Georgia
Institute of Technology, USA
11.1.Introduction .......................................... 315
11.2.Electrospinning as a biomedical fabrication
technology ............................................ 316
11.3.Generation of nanofibers with controlled structures
and morphology ....................................... 317
11.4.Generation of collagen and elastin small-diameter
fibers and fiber networks ............................ 318
11.5.Biological role of elastin ............................ 321
11.6.Generation of crosslinked fibers and fiber
networks .............................................. 328
11.7.Multicomponent electrospun assemblies ................. 329
11.8.Future trends ......................................... 331
11.9.References ............................................ 332
12.Starch-polycaprolactone based scaffolds in bone and
cartilage tissue engineering approaches .................... 337
M.E. Gomes, J.T. Oliveira, M.T. Rodrigues,
M.I. Santos, K. Tuzlakoglu, С.A. Viegas, I.R. Dias
and R.L. Reis, 3B's Research Group, University
of Minho, Portugal
12.1.Introduction .......................................... 337
12.2.Starch+ ε-polycaprolactone (SPCL) fiber meshes ........ 338
12.3.SPCL-based scaffold architecture, stem cell
proliferation and differentiation ..................... 339
12.4.In vivo functionality of SPCL fiber-mesh scaffolds .... 341
12.5.Cartilage tissue engineering using SPCL fiber-mesh
scaffolds ............................................. 342
12.6.Advanced approaches using SPCL scaffolds for bone
tissue engineering aiming at improved
vascularization ....................................... 346
12.7.Conclusions ........................................... 350
12.8.Acknowledgments ....................................... 351
12.9.References ............................................ 351
13.Chitosan-based scaffolds in orthopedic applications ........ 357
K. Tuzlakoglu and R.L. Reis, 3B's Research Group,
University of Minho, Portugal
13.1.Introduction: Chemical and physical structure
of chitosan and its derivatives ....................... 357
13.2.Production methods for scaffolds based on chitosan
and its composites or blends .......................... 358
13.3.Orthopedic applications ............................... 365
13.4.Conclusions and future trends ......................... 369
13.5.Acknowledgements ...................................... 369
13.6.References ............................................ 369
14.Elastin-like systems for tissue engineering ................ 374
J.Rodriguez-Cabello, A. Ribeiro, J. Reguera, A. Girotti and
A. Testera, Universidad de Valladolid, Spain
14.1.Introduction .......................................... 374
14.2.Genetic engineering of protein-based polymers ......... 375
14.3.Genetic strategies for synthesis of protein-based
polymers .............................................. 376
14.4.State-of-the-art in genetically-engineered protein-
based polymers (GEBPs) ................................ 377
14.5.Elastin-like polymers ................................. 377
14.6.Self-assembly behaviour of peptides and proteins ...... 379
14.7.Self-assembly of elastin-like polymers (ELPs) ......... 379
14.8.Biocompatibility of ELPs .............................. 381
14.9.Biomedical applications ............................... 382
14.10.ELPs for drug delivery ............................... 382
14.11.Tissue engineering ................................... 383
14.12.Self-assembling properties of ELPs for tissue
engineering ........................................... 388
14.13.Processability of ELPs for tissue engineering ........ 388
14.14.Future trends ........................................ 389
14.15.References ........................................... 391
15.Collagen-based scaffolds for tissue engineering ............ 396
G. Chen, N. Kawazoe and T. Tateishi, National Institute
for Materials Science, Japan
15.1.Introduction .......................................... 396
15.2.Structure and properties of collagen .................. 396
15.3.Collagen sponge ....................................... 397
15.4.Collagen gel .......................................... 400
15.5.Collagen-glycosoaminoglycan (GAG) scaffolds ........... 402
15.6.Acellularized scaffolds ............................... 404
15.7.Hybrid scaffolds ...................................... 405
15.8.Future trends ......................................... 409
15.9.References ............................................ 409
16.Polyhydroxyalkanoate and its potential for biomedical
applications ............................................... 416
P. Furrer and M. Zinn, Swiss Federal Laboratories for
Materials Testing and Research (Empa), Switzerland,
and S. Panke, Swiss Federal Institute of Technology
(ETH), Switzerland
16.1.Introduction .......................................... 416
16.2.Biosynthesis .......................................... 417
16.3.Chemical digestion of non-PHA.biomass ................. 425
16.4.Purification of PHA ................................... 431
16.5.Potential applications of PHA in medicine and
pharmacy .............................................. 434
16.6.Conclusions and future trends ......................... 437
16.7.References ............................................ 437
17.Electrospinning of natural proteins for tissue
engineering scaffolding .................................... 446
P.I. Lelkes, M. Li, A. Perets, L. Lin, J. Han and
D. Woerdeman, Drexel University, USA
17.1.Introduction .......................................... 446
17.2.The electrospinning process ........................... 448
17.3.Electrospinning natural animal polymers ............... 455
17.4.Electrospinning blends of synthetic and natural
polymers .............................................. 460
17.5.Electrospinning novel natural 'green' plant
polymers for tissue engineering ....................... 466
17.6.Cellular responses to electrospun scaffolds: Does
fiber diameter matter? ................................ 474
17.7.Conclusions and future trends ......................... 474
17.8.Sources of further information and advice ............. 475
17.9.References ............................................ 476
Part IV Naturally-derived hydrogels: Fundamentals,
challenges and applications in tissue engineering
and regenerative medicine
18.Hydrogels from polysaccharide-based materials:
Fundamentals and applications in regenerative
medicine ................................................... 485
J.T. Oliveira and R.L. Reis, 3B's Research Group,
University of Minho, Portugal
18.1.Introduction: Definitions and properties of
hydrogels ............................................. 485
18.2.Applications of hydrogels produced from different
polysaccharides in tissue engineering and
regenerative medicine ................................. 487
18.3.Agarose ............................................... 488
18.4.Alginate .............................................. 489
18.5.Carrageenan ........................................... 491
18.6.Cellulose ............................................. 492
18.7.Chitin/chitosan ....................................... 493
18.8.Chondroitin sulfate ................................... 495
18.9.Dextran ............................................... 496
18.10.Gellan ............................................... 497
18.11.Hyaluronic acid ...................................... 498
18.12.Starch ............................................... 500
18.13.Xanthan .............................................. 501
18.14.Conclusion ........................................... 502
18.15.References ........................................... 503
19.Alginate hydrogels as matrices for tissue engineering ...... 515
H. Park and K.-Y. Lee, Hanyang University, South Korea
19.1.Introduction .......................................... 515
19.2.Properties of alginate ................................ 516
19.3.Methods of gelling .................................... 520
19.4.Applications of alginate hydrogels in tissue
engineering ........................................... 523
19.5.Summary and future trends ............................. 528
19.6.References ............................................ 528
20.Fibrin matrices in tissue engineering ...................... 533
B. Tawil, H. Duong and B. Wu, University of California
Los Angeles, USA
20.1.Introduction .......................................... 533
20.2.Fibrin formation ...................................... 534
20.3.Fibrin use in surgery ................................. 535
20.4.Fibrin matrices to deliver bioactive molecules ........ 535
20.5.Fibrin - cell constructs .............................. 536
20.6.Mechanical characteristics of fibrin scaffold ......... 540
20.7.Future trends ......................................... 541
20.8.Conclusions ........................................... 542
20.9.References ............................................ 543
21.Natural-based polymers for encapsulation of living
cells: Fundamentals, applications and challenges ........... 549
P. De Vos, University Hospital of Groningen, The
Netherlands
21.1. Introduction ......................................... 549
21.2.Approaches of encapsulation: Materials and
biocompatibility issues ............................... 550
21.3.Physico-chemistry of microcapsules and
biocompatibility ...................................... 556
21.4.Immunological considerations .......................... 559
21.5.Conclusions and future trends ......................... 561
21.6.Sources of further information and advice ............. 563
21.7.References ............................................ 564
22.Hydrogels for spinal cord injury regeneration .............. 570
A.J. Salgado and N.Sousa, Life and Health Sciences
Research Institute (ICVS), University of Minho,
Portugal, and N.A. Silva, N.M. Neves and R.L. Reis,
3B's Research Group, University of Minho, Portugal
22.1.Introduction .......................................... 570
22.2.Brief insights on central nervous system biology ...... 571
22.3.Current approaches for SCI repair ..................... 576
22.4.Hydrogel-based systems in SCI regenerative medicine ... 578
22.5.Conclusions and future trends ......................... 587
22.6.Acknowledgements ...................................... 588
22.7.References ............................................ 588
Part V Systems for the sustained release of molecules
23.Particles for controlled drug delivery ..................... 597
E.Т. Вaran and R.L. Reis, 3B's Research Group,
University of Minho, Portugal
23.1.Introduction .......................................... 597
23.2.Novel particle processing methods ..................... 597
23.3.Hiding particles: The stealth principle ............... 602
23.4.Finding the target .................................... 604
23.5.Delivery of bioactive agents at the target site and
novel deliveries ...................................... 608
23.6.Viral delivery systems ................................ 611
23.7.Conclusions ........................................... 612
23.8.Acknowledgements ...................................... 613
23.9.References ............................................ 613
24.Thiolated chitosans in non-invasive drug delivery .......... 624
A. Bernkop-Schnürch, Leopold-Franzens University,
Austria
24.1.Introduction .......................................... 624
24.2.Thiolated chitosans ................................... 625
24.3.Properties of thiolated chitosans ..................... 625
24.4.Drug delivery systems ................................. 633
24.5.In vivo performance ................................... 634
24.6.Conclusion ............................................ 638
24.7.References ............................................ 639
25.Chitosan-polysaccharide blended nanoparticles for
controlled drug delivery ................................... 644
J.M. Alonso and F.M. Goycoolea, Universidad de
Santiago de Compostela, Spain, and I. Higuera-Ciapara,
Centro de Investigation en Alimentationу Desarrollo,
Mexico
25.1.Introduction .......................................... 644
25.2.Polysaccharides in nanoparticle formation ............. 645
25.3.Nanoparticles constituted by chitosan ................. 651
25.4.Drug delivery properties and biopharmaceutical
applications .......................................... 654
25.5.Hybrid nanoparticles consisting of chitosan and
other polysaccharides ................................. 656
25.6.Future trends ......................................... 668
25.7.Sources of further information and advice ............. 668
25.8.Acknowledgements ...................................... 671
25.9.References ............................................ 671
Part VI Biocompatibility of natural-based polymers
26.In vivo tissue responses to natural-origin biomaterials .... 683
Т.С. Santos, A.P. Marques and R.L. Reis, 3B's
Research Group, University of Minho, Portugal
26.1.Introduction .......................................... 683
26.2.Inflammation and foreign-body reactions to
biomaterials .......................................... 684
26.3.Role of host tissues in biomaterials implantation ..... 686
26.4.Assessing the in vivo tissue responses to natural-
origin biomaterials ................................... 690
26.5.Controlling the in vivo tissue reactions to
natural-origin biomaterials ........................... 693
26.6.Final remarks ......................................... 695
26.7.Acknowledgements ...................................... 695
26.8.References ............................................ 695
27.Immunological issues in tissue engineering ................. 699
N. Rotter, Ulm University, Germany
27.1.Introduction .......................................... 699
27.2.Immune reactions to biomaterials ...................... 699
27.3.Host reactions related to the implant site ............ 701
27.4.Immune reactions to different types of cells .......... 701
27.5.Immune reactions to in vitro engineered tissues ....... 704
27.6.Immune protection of engineered constructs ............ 705
27.7.Strategies directed towards reactions to
biomaterials .......................................... 706
27.8.Strategies directed towards reactions to implanted
cells ................................................. 707
27.9.Future trends ......................................... 709
27.10.References ........................................... 710
28.Biocompatibility of hyaluronic acid: From cell
recognition to therapeutic applications .................... 716
K. Ghosh, Children's Hospital and Harvard Medical
School, USA
28.1.Introduction .......................................... 716
28.2.Native hyaluronan ..................................... 717
28.3.Therapeutic implications of native hyaluronan ......... 721
28.4.Engineered hyaluronan ................................. 722
28.5.Implications for regenerative medicine ................ 727
28.6.Conclusion ............................................ 728
28.7.Future trends ......................................... 728
28.8.References ............................................ 728
29.Biocompatibility of starch-based polymers .................. 738
A.P. Marques, R.P. Pirraco and R.L. Reis, 3B's
Research Group, University of Minho, Portugal
29.1.Introduction .......................................... 738
29.2.Starch-based polymers in the biomedical field ......... 740
29.3.Cytocompatibility of starch-based polymers ............ 745
29.4.Immunocompatibility of starch-based polymers .......... 748
29.5.Conclusions ........................................... 752
29.6.Acknowledgements ...................................... 753
29.7.References ............................................ 753
30.Vascularization strategies in tissue engineering ........... 761
M.I. Santos, and R.L. Reis, 3B's Research Group,
University of Minho, Portugal
30.1.Introduction .......................................... 761
30.2.Biology of vascular networks - angiogenesis versus
vasculogenesis ........................................ 761
30.3.Vascularization: The hurdle of tissue engineering ..... 762
30.4.Neovascularization of engineered bone ................. 763
30.5.Strategies to enhance vascularization in engineered
grafts ................................................ 765
30.6.In vivo models to evaluate angiogenesis in tissue
engineered products ................................... 774
30.7.Future prospects ...................................... 776
30.8.Sources of further information and advice ............. 776
30.9.References ............................................ 776
Index ......................................................... 781
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