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Woodhead Publishing Series in Biomaterials

HANDBOOK OF
BIOMATERIA LS
BIOCOMPATIBILITY
Edited by

MASOUD MOZAFARI

WP
WOODHEAD
PUBLISHING

ELSEVI ER An imprint of Elsevier

Woodhead Publishing is an imprint of Elsevier
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 Contents

List of contributors xi 3.4 The macrophages and the development of

Preface xvii immunomodulatory biomaterials 47
References 50
Acknowledgments xix
4. Dendritic cells responses to
biomaterials 53
I Sahil Inamdar and Abhinav P. Acharya
An introduction to biocompatibility 4.1 Introduction 53
4.2 Natural polymer biomaterials 55
1. Principles of biocompatibility 3 4.3 Gelatin 55
Masoud Mozafari 4.4 Alginate 57
4.5 Chitosan 59
1.1 Introduction 3
4.6 Synthetic polymer biomaterials 60
1.2 Conclusion 8
4.7 Poly(lactic-co-glycolic acid) 60
References 9
4.8 Polyethylene glycol 61
Further reading 9
4.9 Blends 62
4.10 Poly(lactic-co-glycolic acid)-chitosan 62
2. Bacterial cell biomaterials 4.11 Conclusion and future directions 64
interactions 11 References 64
Li-Chong Xu and Christopher A. Siedlecki
5. Impact of biomaterials’ physical
2.1 Introduction 11 properties on cellular and molecular
2.2 Theoretical theories of bacterial adhesion to responses 69
biomaterial surfaces 13
Jia He and Diane J. Burgess
2.3 Factors influencing bacterial adhesion to
biomaterial surfaces 14 Abbreviations 69
2.4 Bacterial interaction with antibacterial 5.1 Introduction 69
biomaterial surfaces 22 5.2 Cellular and molecular response following
2.5 Signaling molecules in the regulation of implantation 70
bacterial adhesion on biomaterial surfaces 28 5.3 Impact of physical properties on modulation
2.6 Summary and perspectives 31 of the host response 75
Acknowledgments 32 5.4 Conclusion 81
References 32 References 82

3. Macrophage response to biomaterials 43 6. Impact of biomaterial mechanics on

Judite Novais Barbosa and Daniela Pereira Vasconcelos cellular and molecular responses 85
Somasundaram Prasadh, Vaishnavi Ratheesh and Raymond Wong
3.1 The macrophage 43
3.2 Macrophage plasticity and polarization 44 6.1 Introduction 85
3.3 The macrophage response to biomaterials 45 6.2 Host response—biomaterial interplay 87

v
vi Contents

6.3 Other significant players of the foreign body 9.3 Comparison of proliferation tests 182
reaction 95 9.4 Special challenges and experimental design
6.4 Impact of biomaterial surface characteristics on considerations 186
the sequential phases of host response 96 9.5 Conclusion 189
6.5 Conclusion 102 References 189
Conflict of interest 103
References 103 10. In vivo models for biomaterials:
applications from cardiovascular tissue
7. Cell biomaterials interactions:
engineering 195
the role of growth factors 111
Joseph Boktor, Sara Abdollahi, Chin Siang Ong and
Alice Brion and Hassan Rammal Narutoshi Hibino

7.1 Introduction 111 Abbreviations 195

7.2 What are growth factors? 113 10.1 Introduction 196
7.3 Growth factors in bone tissue 10.2 Constructs and biomaterials used in cardiac
engineering 114 tissue engineering 196
7.4 Bone morphogenetic proteins 114 10.3 Constructs and biomaterials used in vascular
7.5 Transforming growth factor βs 117 tissue engineering 204
7.6 Platelet-derived growth factors 119 10.4 In vivo applications of constructs and
7.7 Fibroblast growth factors 121 biomaterials 209
7.8 Insulin-like growth factors 124 10.5 Conclusion 209
7.9 Bone growth factors clinical applications 126 References 210
7.10 Conclusion and perspectives 127
Acknowledgments 128
11. Clinical and surgical aspects of medical
Conflict of interest 128
References 129 materials’ biocompatibility 219
Selcuk Ozturk, Fatma Betül Ayanoğlu, Mahmut Parmaksiz,
8. Cell biomaterial interactions: Ayşe Eser Elçin and Yaşar Murat Elçin

the role of ligand functionalization 139 Author disclosure statement 219

Alice Zoso, Monica Boffito, Rossella Laurano, Irene Carmagnola Abbreviations 219
and Valeria Chiono
11.1 Introduction 220
8.1 Introduction 139 11.2 Orthopedic biomaterials 222
8.2 Ligand functionalization in the design of 11.3 General and reconstructive surgery
bioactive hydrogels 141 biomaterials 229
8.3 Ligand surface functionalization in the design of 11.4 Cardiovascular biomaterials 234
scaffolds and implants 153 11.5 Conclusion 241
8.4 Ligand functionalization of nanoparticles for References 242
cell targeting 158
8.5 General discussion and conclusion 162 12. Standardization and regulation of
Acknowledgment 167 biomaterials 251
References 167 Mehdi Ebrahimi

9. On the proliferation of cell proliferation 12.1 Introduction 251

tests 175 12.2 Biomaterials for therapeutic and regenerative
Nicholas G. Fischer and Conrado Aparicio medicine 252
12.3 Discussion 257
9.1 Introduction 175 12.4 Conclusion 262
9.2 Methods to measure cell proliferation 176 References 262
 Contents vii

II 16.1
16.2
Introduction 353
In vitro biocompatibility studies 354
Cellular Response to Biomaterials 16.3 In vivo biocompatibility studies 357
16.4 Biocompatibility study of other carbon
13. Cellular response to synthetic nanostructures 359
polymers 269 16.5 Approaches to reduce toxicity 363
16.6 Conclusion 364
Mihaela Baican, Elena Stoleru and Cornelia Vasile
References 364
Abbreviations 269
13.1 Introduction 271 17. Cellular response to calcium phosphate
13.2 Cellular response to synthetic nondegradable cements 369
polymers 273 Berivan Cecen, Ayse Kalemtas, Gulsum Topates and
13.3 Cellular response to biodegradable/resorbable Leyla Didem Kozaci
polymers 305
13.4 Conclusion and future trends 308 17.1 Introduction 369
Acknowledgments 309 17.2 General characteristics of calcium phosphate
References 309 cement 373
17.3 Chemistry and handling 375
14. Cellular responses to zirconia 321 17.4 Biological evaluation of calcium phosphate
Paolo Francesco Manicone, Antonio Ziranu, Andrea Perna and cements 378
Giulio Maccauro 17.5 Biodegradation of calcium phosphate
cements 378
14.1 Introduction 321 17.6 Bioactivity of calcium phosphate
14.2 “Aging” of zirconia 323 cements 379
14.3 Definitions of biocompatibility, 17.7 Osteoconductivity of calcium phosphate
osseointegration, osteoinductivity, and cements 380
osteoconductivity 324 17.8 Osteoinductivity of calcium phosphate
14.4 In vitro zirconia biocompatibility 325 cements 381
14.5 In vivo zirconia biocompatibility 328 17.9 Cellular response to calcium phosphate
14.6 Conclusion 329 cements 381
References 330 17.10 Clinical applications 382
References 387
15. Cellular response to alumina 335
Neda Alasvand, Sara Banijamali, Peiman Borouki Milan and 18. Cellular response to bioactive glasses
Masoud Mozafari
and glass ceramics 395
15.1 Introduction 335 Sara Banijamali, Mojgan Heydari and Masoud Mozafari
15.2 Physicochemical properties of alumina
surface 336 18.1 Introduction 395
15.3 Cellular responses and protein adsorption on 18.2 Biological responses to biomaterials 396
alumina surface 338 18.3 Bioactive glasses and glass ceramics: structure
15.4 Futures and conclusion 347 and their physicochemical properties 397
References 348 18.4 Innovative strategies for selective contribution
of bioactive glasses 403
16. Biocompatibility of graphene quantum 18.5 Commercialized bioactive glasses and
dots and related materials 353 glass ceramics 413
T.K. Henna and K. Pramod 18.6 Discussion 414
18.7 Conclusion 415
Abbreviations 353 References 415
viii Contents

19. Cell responses to titanium and 22.5 Hybrid or composite biomaterials 522
titanium alloys 423 22.6 Conclusion and future directions 536
Acknowledgments and financial support 537
Isha Mutreja, Zhou Ye and Conrado Aparicio
Conflicts of interest 537
19.1 Introduction 423 References 537
19.2 Surface modification of titanium alloys to
induce appropriate cell responses 424 23. Peripheral nervous system responses to
19.3 Antimicrobial coatings on titanium 434 biomaterials 555
19.4 Conclusion 441 R Murphy, A Faroni and A.J Reid
References 441
23.1 Introduction 555
20. Cellular response to metal 23.2 Allografts 559
implants 453 23.3 Xenografts 559
Ghazaleh Salehi, Aliasghar Behnamghader and Masoud Mozafari 23.4 Natural degradable nerve guidance
conduits 560
20.1 Introduction 453 23.5 Synthetic nerve guidance conduits 562
20.2 Metallic implants 454 23.6 Synthetic degradable nerve guidance
20.3 Corrosion and metal ion release 457 conduits 563
20.4 Cellular response to metal implants 458 23.7 Polymers 563
20.5 Modulation of host response to implants 464 23.8 Summary 565
20.6 Conclusion 465 References 565
References 466
24. Cardiac responses to biomaterials 573
21. Cellular response to
Joanne O’Dwyer, Robert Wylie, Sally Ann Cryan,
nanobiomaterials 473 Garry P. Duffy and Eimear B. Dolan
Robin Augustine and Anwarul Hasan
24.1 Biomaterials for cardiac applications 573
21.1 Introduction 473 24.2 Foreign body response 573
21.2 Factors affecting nanobiomaterial cell 24.3 Biocompatibility testing of biomaterials 575
interactions 474 24.4 Biomaterials 577
21.3 Various interactions between nanobiomaterials 24.5 State of the art approaches to reduce the
and cells 479 foreign body response 587
21.4 Conclusion 492 24.6 Potential uses of the foreign body
Acknowledgments 493 response 590
References 493 24.7 Conclusion 591
References 591
III 25. Vascular responses to
Tissue response to biomaterials biomaterials 601
Elisa A Liehn, Mihaela Rusu and Sauri Hernandez-Resendiz
22. Central nervous system responses to
biomaterials 507 25.1 Introduction 601
M. Tsintou, P.P. Wróbel and K. Dalamagkas 25.2 Biomaterials in vascular diseases 602
25.3 Vascular response to biomaterials 606
22.1 Introduction 507 25.4 Vascular response to biofunctionalization of
22.2 Polymers 510 biomaterials 610
22.3 Metals 519 25.5 Future perspectives 612
22.4 Ceramics 521 References 613
 Contents ix
26. Bone responses to biomaterials 617 29. Gastrointestinal response to
Cristina Sobacchi, Eleonora Palagano and Ciro Menale biomaterials 667
Amir Hossein Bahmanpour and Masoud Mozafari
Abbreviations 617
26.1 Introduction 618 29.1 Introduction 667
26.2 Skeletal cell response to biomaterials 620 29.2 Oral cavity and pharynx 668
26.3 Immune cell response to biomaterials 624 29.3 Oesophagus 669
26.4 Vascular cell response to biomaterials 628 29.4 Stomach 670
26.5 Conclusion 630 29.5 Small intestine 673
References 630 29.6 Large intestine 676
29.7 Conclusion 676
27. Tendon and muscle responses to References 677
biomaterials 637
30. Ocular responses to biomaterials 681
Wilson Wang, Bryan T.H. Koh and Chris Steffi
Maud Gorbet, Dana Toameh, Cameron Postnikoff and
Robert Pintwala
27.1 Introduction 637
27.2 Management of tendon/muscle injuries and 30.1 Introduction to biocompatibility in the
responses 640 eye 681
27.3 Regenerative strategies for tendon/muscle 30.2 Anatomy and physiology of the eye in relation
injuries 642 to biomaterial applications 682
27.4 Conclusion 648 30.3 Ocular response to biomaterials in the anterior
References 649 chamber 687
30.4 Ocular response to biomaterials in the
28. Pulmonary system responses to posterior segment 692
biomaterials 653 30.5 Conclusion 694
Amir Hossein Bahmanpour, Tina Navaei and Fereshteh Ahadi References 694

28.1 Introduction 653 31. Skin responses to biomaterials 701

28.2 Synthetic biomaterials and their applications Shiyu Liu, Haiyan Liu and Chenxi Zheng
in pulmonary administration 654
28.3 Synthetic biomaterials for drug delivery in 31.1 Introduction 701
lungs 656 31.2 General description of the skin tissue 702
28.4 Uses of synthetic biomaterials in lung tissue 31.3 Skin responses to biomaterials 704
engineering 657 31.4 The role of scaffolding materials in skin tissue
28.5 Natural biomaterials for pulmonary engineering 712
applications 659 31.5 Future perspectives 713
28.6 Conclusion 661 References 713
References 662 Index 719
 List of Contributors

Sara Abdollahi Department of Surgery, Judite Novais Barbosa i3S - Instituto de

Section of Cardiac Surgery, The University of Inovação e Investigação em Saúde,
Chicago, Chicago, IL, United States Universidade do Porto, Rua Alfredo Allen,
Abhinav P. Acharya Chemical Engineering, Porto, Portugal; INEB - Instituto de
School for the Engineering of Matter, Engenharia Biomédica, Rua Alfredo Allen,
Transport and Energy, Arizona State Porto, Portugal; ICBAS - Instituto de Ciências
University, Tempe, AZ, United States Biomédicas Abel Salazar, Universidade do
Porto, Rua de Jorge Viterbo Ferreira, Porto,
Fereshteh Ahadi Biomaterial Group, Faculty
Portugal
of Biomedical Engineering (Center of
Excellence), Amirkabir University of Aliasghar Behnamghader Nanotechnology &
Technology, Tehran, Iran Advanced Materials Department, Materials &
Energy Research Center (MERC), Tehran,
Neda Alasvand Bioengineering Research
Iran
Group, Department of Nanotechnology and
Advanced Materials, Materials and Energy Monica Boffito Department of Mechanical and
Research Center (MERC), Tehran, Iran Aerospace Engineering, Politecnico di Torino,
Turin, Italy
Conrado Aparicio MDRCBB-Minnesota Dental
Research Center for Biomaterials and Joseph Boktor Division of Cardiac Surgery,
Biomechanics, University of Minnesota, Johns Hopkins Hospital, Baltimore, MD,
Minneapolis, MN, United States United States
Robin Augustine Department of Mechanical Alice Brion Museum National d’Histoire
and Industrial Engineering, College of Naturelle, INSERM U1154, CNRS UMR 7196,
Engineering, Qatar University, Doha, Qatar; Sorbonne Universités, 43 rue Cuvier, Paris,
Biomedical Research Center (BRC), Qatar France
University, Doha, Qatar Diane J. Burgess Department of
Fatma Betül Ayanoğlu Tissue Engineering, Pharmaceutical Sciences, University of
Biomaterials and Nanobiotechnology Connecticut, Storrs, CT, United States
Laboratory, Ankara University Faculty of Irene Carmagnola Department of Mechanical
Science & Stem Cell Institute, Ankara, Turkey and Aerospace Engineering, Politecnico di
Amir Hossein Bahmanpour Biomaterial Torino, Turin, Italy
Group, Faculty of Biomedical Engineering Berivan Cecen Department of Biomechanics,
(Center of Excellence), Amirkabir University Dokuz Eylul University, Izmir, Turkey
of Technology, Tehran, Iran Valeria Chiono Department of Mechanical
Mihaela Baican Department of Pharmaceutical and Aerospace Engineering, Politecnico di
Physics, Faculty of Pharmacy, University of Torino, Turin, Italy
Medicine and Pharmacy “Grigore T. Popa”, Sally Ann Cryan Advanced Materials and
Iasi, Romania BioEngineering Research Centre (AMBER),
Sara Banijamali Engineering Ceramics Research Trinity College Dublin, Royal College of
Group, Ceramic Department, Materials and Surgeons in Ireland, & National University of
Energy Research Center (MERC), Tehran, Iran Ireland, Galway, Ireland; School of Pharmacy

xi
xii List of Contributors

and Biomolecular Sciences, Royal College of Nicholas G. Fischer MDRCBB—Minnesota

Surgeons in Ireland, Dublin, Ireland; Tissue Dental Research Center for Biomaterials and
Engineering Research Group, Royal College Biomechanics, University of Minnesota,
of Surgeons in Ireland, Dublin, Ireland Minneapolis, MN, United States
K. Dalamagkas UCL Division of Surgery & Maud Gorbet Department of Systems Design
Interventional Science, Center for Engineering, University of Waterloo, Waterloo,
Nanotechnology & Regenerative Medicine, ON, Canada; School of Optometry and Vision
University College London, London, United Science, University of Waterloo, Waterloo,
Kingdom; Department of Physical Medicine ON, Canada
and Rehabilitation, The University of Texas Anwarul Hasan Department of Mechanical
Health Science Center at Houston, and Industrial Engineering, College of
Houston, TX, United States; TIRR Memorial Engineering, Qatar University, Doha, Qatar;
Hermann Research Center, TIRR Memorial Biomedical Research Center (BRC), Qatar
Hermann Hospital, Houston, TX, United University, Doha, Qatar
States
Jia He Department of Pharmaceutical Sciences,
Eimear B. Dolan Biomedical Engineering, University of Connecticut, Storrs, CT, United
School of Engineering, College of Science and States
Engineering, National University of Ireland,
T.K. Henna College of Pharmaceutical Sciences,
Galway, Ireland
Govt. Medical College, Kozhikode, Kerala, India
Garry P. Duffy Anatomy, School of Medicine, Sauri Hernandez-Resendiz National Heart
College of Medicine Nursing and Health Research Institute Singapore, National Heart
Sciences, National University of Ireland, Centre, Singapore, Singapore; Duke-National
Galway, Ireland; Advanced Materials and University of Singapore Medical School,
BioEngineering Research Centre (AMBER), Singapore, Singapore
Trinity College Dublin, Royal College of
Surgeons in Ireland, & National University of Mojgan Heydari Nanomaterials Research
Ireland, Galway, Ireland Group, Nanotechnology and Advanced
Materials Department, Materials and Energy
Mehdi Ebrahimi Oral Rehabilitation, Prince Research Center (MERC), Tehran, Iran
Philip Dental Hospital, The University of
Narutoshi Hibino Department of Surgery,
Hong Kong, Hong Kong
Section of Cardiac Surgery, The University of
Ayşe Eser Elçin Tissue Engineering, Chicago, Chicago, IL, United States
Biomaterials and Nanobiotechnology
Sahil Inamdar Chemical Engineering, School
Laboratory, Ankara University Faculty of
for the Engineering of Matter, Transport and
Science & Stem Cell Institute, Ankara, Turkey
Energy, Arizona State University, Tempe,
Yaşar Murat Elçin Tissue Engineering, AZ, United States
Biomaterials and Nanobiotechnology
Ayse Kalemtas Department of Metallurgical
Laboratory, Ankara University Faculty of
and Materials Engineering, Bursa Technical
Science & Stem Cell Institute, Ankara,
University, Bursa, Turkey
Turkey; Biovalda Health Technologies, Inc.,
Ankara, Turkey Bryan T.H. Koh Department of Orthopaedic
Surgery, National University of Singapore,
A Faroni Blond McIndoe Laboratories,
Singapore, Singapore
Division of Cell Matrix Biology and
Regenerative Medicine, School of Biological Leyla Didem Kozaci Department of Medical
Sciences, Faculty of Biology, Medicine and Biochemistry, Ankara Yildirim Beyazit
Health, Manchester Academic Health Science University, Ankara, Turkey; Department of
Centre, The University of Manchester, Translational Medicine, Ankara Yildirim
Manchester, United Kingdom Beyazit University, Ankara, Turkey
 List of Contributors xiii
Rossella Laurano Department of Mechanical Peiman Borouki Milan Cellular and
and Aerospace Engineering, Politecnico di Molecular Research Center, Iran University
Torino, Turin, Italy of Medical Sciences (IUMS), Tehran, Iran;
Elisa A Liehn Institute for Molecular Department of Tissue Engineering &
Cardiovascular Research, University Hospital Regenerative Medicine, Iran University of
Aachen, Aachen, Germany; Department of Medical Sciences (IUMS), Tehran, Iran
Cardiology, Angiology and Intensive Care, Masoud Mozafari Department of Tissue
University Hospital Aachen, Aachen, Engineering & Regenerative Medicine, Faculty
Germany; Human Genetic Laboratory, of Advanced Technologies in Medicine, Iran
University for Medicine and Pharmacy, University of Medical Sciences (IUMS),
Craiova, Romania; National Heart Research Tehran, Iran; Lunenfeld-Tanenbaum Research
Institute Singapore, National Heart Centre, Institute, Mount Sinai Hospital, University of
Singapore, Singapore Toronto, Toronto, ON, Canada; Cellular and
Haiyan Liu State Key Laboratory of Military Molecular Research Center, Iran University
Stomatology & National Clinical Research of Medical Sciences (IUMS), Tehran, Iran
Center for Oral Diseases & Shaanxi R Murphy Blond McIndoe Laboratories,
International Joint Research Center for Oral Division of Cell Matrix Biology and
Diseases, Center for Tissue Engineering, Regenerative Medicine, School of Biological
School of Stomatology, The Fourth Military Sciences, Faculty of Biology, Medicine and
Medical University, Xi’an, P.R. China; Xi’an Health, Manchester Academic Health Science
Institute of Tissue Engineering and Centre, The University of Manchester,
Regenerative Medicine, Xi’an, P.R. China Manchester, United Kingdom; Department of
Plastic Surgery & Burns, Manchester
Shiyu Liu State Key Laboratory of Military
Academic Health Science Centre,
Stomatology & National Clinical Research
Wythenshawe Hospital, Manchester
Center for Oral Diseases & Shaanxi
University NHS Foundation Trust,
International Joint Research Center for
Manchester, United Kingdom
Oral Diseases, Center for Tissue
Engineering, School of Stomatology, The Isha Mutreja MDRCBB-Minnesota Dental
Fourth Military Medical University, Xi’an, Research Center for Biomaterials and
P.R. China Biomechanics, University of Minnesota,
Minneapolis, MN, United States
Giulio Maccauro Fondazione Policlinico
Universitario A. Gemelli IRCCS, Rome, Italy; Tina Navaei Department of Nanotechnology
Institute of Orthopedics, Catholic University & Advanced Materials, Material and Energy
of Sacred Heart, Rome, Italy Research Center (MERC), Tehran, Iran
Paolo Francesco Manicone Department of Joanne O’Dwyer Biomedical Engineering,
Head and Neck and Sensory Organs, School of Engineering, College of Science and
Division of Oral Surgery and Implantology, Engineering, National University of Ireland,
Institute of Clinical Dentistry, Catholic Galway, Ireland; Anatomy, School of
University of Sacred Heart, Rome, Italy; Medicine, College of Medicine Nursing and
Fondazione Policlinico Universitario A. Health Sciences, National University of
Gemelli IRCCS, Rome, Italy Ireland, Galway, Ireland
Chin Siang Ong Division of Cardiac Surgery,
Ciro Menale National Research Council,
Massachusetts General Hospital, Boston, MA,
Insititute of Genetics and Biomedical
United States
Research (CNR-IRGB), Milan Unit, Milan,
Italy; Humanitas Clinical and Research Selcuk Ozturk Tissue Engineering,
Center IRCCS, Rozzano, Italy Biomaterials and Nanobiotechnology
xiv List of Contributors

Laboratory, Ankara University Faculty of University of Manchester, Manchester, United

Science & Stem Cell Institute, Ankara, Turkey Kingdom; Department of Plastic Surgery &
Eleonora Palagano National Research Council, Burns, Manchester Academic Health Science
Insititute of Genetics and Biomedical Centre, Wythenshawe Hospital, Manchester
Research (CNR-IRGB), Milan Unit, Milan, University NHS Foundation Trust,
Italy; Humanitas Clinical and Research Manchester, United Kingdom
Center IRCCS, Rozzano, Italy Mihaela Rusu Institute for Molecular
Mahmut Parmaksiz Tissue Engineering, Cardiovascular Research, University Hospital
Biomaterials and Nanobiotechnology Aachen, Aachen, Germany
Laboratory, Ankara University Faculty of Ghazaleh Salehi Nanotechnology &
Science & Stem Cell Institute, Ankara, Turkey Advanced Materials Department, Materials &
Andrea Perna Fondazione Policlinico Energy Research Center (MERC), Tehran,
Universitario A. Gemelli IRCCS, Rome, Italy; Iran
Institute of Orthopedics, Catholic University Christopher A. Siedlecki Department of
of Sacred Heart, Rome, Italy Surgery, Biomedical Engineering Institute,
Robert Pintwala Department of Systems College of Medicine, The Pennsylvania State
Design Engineering, University of Waterloo, University, Hershey, PA, United States;
Waterloo, ON, Canada Department of Bioengineering, Biomedical
Engineering Institute, College of Medicine,
Cameron Postnikoff Department of Systems
The Pennsylvania State University, Hershey,
Design Engineering, University of Waterloo,
PA, United States
Waterloo, ON, Canada
Cristina Sobacchi National Research Council,
K. Pramod College of Pharmaceutical Sciences,
Insititute of Genetics and Biomedical
Govt. Medical College, Kozhikode, Kerala,
Research (CNR-IRGB), Milan Unit, Milan,
India
Italy; Humanitas Clinical and Research
Somasundaram Prasadh Discipline of Oral Center IRCCS, Rozzano, Italy
and Maxillofacial Surgery, National
Chris Steffi Department of Orthopaedic
University Centre for Oral Health/Faculty of
Surgery, National University of Singapore,
Dentistry, National University of Singapore,
Singapore, Singapore
Singapore
Elena Stoleru Physical Chemistry of Polymers
Hassan Rammal EFOR Healthcare Paris,
Department, “Petru Poni” Institute of
Biocompatibility Platform, Levallois-Perret,
Macromolecular Chemistry, Iasi, Romania;
France; Equipe de Recherche sur les
Faculty of Chemistry, “Alexandru Ioan
Relations Matrice Extracellulaire-Cellules
Cuza” University of Iasi, Carol I Blvd, Iasi,
(ERRMECe), Biomaterial for Health Research
Romania
Group, Institut des Matériaux, Maison
International de la Recherche, Université de Dana Toameh Department of Systems Design
Cergy-Pontoise, Neuville sur Oise, France Engineering, University of Waterloo,
Waterloo, ON, Canada
Vaishnavi Ratheesh Discipline of Oral and
Maxillofacial Surgery, National University Gulsum Topates Department of Metallurgical
Centre for Oral Health/Faculty of Dentistry, and Materials Engineering, Ankara Yildirm
National University of Singapore, Singapore Beyazit University, Ankara, Turkey
A.J Reid Blond McIndoe Laboratories, Division M. Tsintou Departments of Psychiatry and
of Cell Matrix Biology and Regenerative Neurology Services, Center for Neural Systems
Medicine, School of Biological Sciences, Faculty Investigations, Center for Morphometric
of Biology, Medicine and Health, Manchester Analysis, Athinoula A. Martinos Center for
Academic Health Science Centre, The Biomedical Imaging, Massachusetts General
 List of Contributors xv
Hospital, Harvard Medical School, Boston, MA, Robert Wylie Anatomy, School of Medicine,
United States; Department of Psychiatry, College of Medicine Nursing and Health
Psychiatry Neuroimaging Laboratory, Sciences, National University of Ireland,
Brigham and Women’s Hospital, Harvard Galway, Ireland
Medical School, Boston, MA, United States; Li-Chong Xu Department of Surgery,
UCL Division of Surgery & Interventional Biomedical Engineering Institute, College of
Science, Center for Nanotechnology & Medicine, The Pennsylvania State University,
Regenerative Medicine, University College Hershey, PA, United States
London, London, United Kingdom
Zhou Ye MDRCBB-Minnesota Dental Research
Daniela Pereira Vasconcelos INEB - Instituto Center for Biomaterials and Biomechanics,
de Engenharia Biomédica, Rua Alfredo Allen, University of Minnesota, Minneapolis, MN,
Porto, Portugal; ICBAS - Instituto de Ciências United States
Biomédicas Abel Salazar, Universidade do
Chenxi Zheng State Key Laboratory of
Porto, Rua de Jorge Viterbo Ferreira, Porto,
Military Stomatology & National Clinical
Portugal
Research Center for Oral Diseases & Shaanxi
Cornelia Vasile Physical Chemistry of International Joint Research Center for Oral
Polymers Department, “Petru Poni” Institute Diseases, Center for Tissue Engineering,
of Macromolecular Chemistry, Iasi, Romania School of Stomatology, The Fourth Military
Wilson Wang Department of Orthopaedic Medical University, Xi’an, P.R. China
Surgery, National University of Singapore, Antonio Ziranu Fondazione Policlinico
Singapore, Singapore Universitario A. Gemelli IRCCS, Rome, Italy;
Raymond Wong Discipline of Oral and Institute of Orthopedics, Catholic University
Maxillofacial Surgery, National University of Sacred Heart, Rome, Italy
Centre for Oral Health/Faculty of Dentistry, Alice Zoso Department of Mechanical and
National University of Singapore, Singapore Aerospace Engineering, Politecnico di Torino,
P.P. Wróbel Medical Faculty, Ludwig- Turin, Italy
Maxilmilians-Universität, Munich, Germany
 Preface

Over the past decade, I have been work- only by our knowledge about the interac-
ing on different classes of biomaterials for tion mechanisms. It is now the time to
applications ranging from advanced thera- strengthen the interdisciplinary collabora-
nostic devices, controlled delivery systems, tions between engineers, basic, and applied
to tissue engineering, etc. The key point in scientists in different fields. This extensive
almost all projects in the field is the set of chapters in this book depicts work by
response of the host tissue to the biomate- a variety of world-class researchers on
rial, known as biocompatibility. Although attempts to exploit the specific interactions
many groups are working on the cellular of biomaterials in the body. The book starts
and molecular interactions of biomaterials, with the basic and fundamental knowledge
there is still a lack of precise information about biocompatibility. Then, it explains
regarding the complex mechanisms of the cellular responses to different classes of
biocompatibility. These interactions may biomaterials. In the last part of the book, it
vary by the type of biomaterial and the deals with the tissue responses to biomater-
type of cell and microenvironment. These ials. Of course, problems and limitations
interactions could be even more compli- exist but the breadth of the collaborations
cated when we are dealing with submicron in this book indicate that the best is yet to
biomaterials in the nano range. I believe come.
that there are many opportunities when
Masoud Mozafari
playing with nanostructures and nanoparti-
cles in living systems which are still limited May 8, 2020

xvii
 Acknowledgments

I am grateful to all of those with whom such a creative and talented designer
we have had the pleasure to work during Catherin Aldana Ortiz who designed the
this project. I would like to thank the edito- book cover artwork. I would like to extend
rial team at Elsevier, Emily Joy Grace my special appreciation to the editorial
Thomson, Laura Overend, Kayla Dos assistant, Maryam Rahmati, for leading a
Santos, Sabrina Webber, Swapna Praveen, team who did most of the work and
Glyn Jones, and Jonathan Simpson, for their deserve the props. Without them, this does
help and support. I feel very fortunate that not happen.
I had the opportunity to collaborate with

xix
 C H A P T E R

1
Principles of biocompatibility
Masoud Mozafari
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto,
Toronto, ON, Canada

1.1 Introduction

There is a growing interest in the field of biomaterials science and engineering due to
its vital effects on human health [1]. There are many factors responsible for the efficacy of
biomaterials in contact with living tissues and organs [2]. The biomaterials should be able
to demonstrate the ability of implantation in the human body without producing an
unacceptable degree of harmful effect on the tissue. This is known by the general term
“biocompatibility” which is extensively used by biomaterials scientists. However, there is
still some hidden aspects about the mechanisms of biocompatibility [3]. The examinations
on the first generation of implantable biomaterials indicated that the most efficient bioma-
terials are those with the minimum chemical reaction in biological environments [4].
Among metallic biomaterials, the plain carbon and vanadium steels were first replaced
with stainless steels and further with titanium, platinum, and magnesium alloys, due to
their superior advantages in terms of biodegradability and biocompatibility [5]. For poly-
meric biomaterials, nylons and polyesters were replaced by polytetrafluoroethylene, poly
(methyl methacrylate), polyethylene, and silicone, since they are less degradable and toxic.
For ceramic-based biomaterials, a range of active glass-ceramics and bioactive glasses have
been introduced. This class of biomaterials has attracted great attention due to their ability
to incorporate therapeutic ions for the enhancement of biological reactions in the body [6].
In conclusion, biomaterials are usually selected and categorized on the basis that they
should not be toxic, immunogenic, thrombogenic, carcinogenic, irritant, and so on, direct-
ing us to the definition of biocompatibility [7]. There are a range of material characteristics
that greatly influence the host response and further affect the biocompatibility of biomater-
ials (see Table 1.1) [8]. These characteristics can be divided into two categories related to
the bulk and the surface.
Based on the type of biomaterial implanted in the body, a number of reactions can hap-
pen over time (see Table 1.2) [8]. In most cases, a sequence of events are involved within

Handbook of Biomaterials Biocompatibility

DOI: https://doi.org/10.1016/B978-0-08-102967-1.00001-3 3 © 2020 Elsevier Ltd. All rights reserved.
4 1. Principles of biocompatibility

TABLE 1.1 A number of important biomaterial characteristics that can potentially influence the host
response.

Bulk material composition

Micro- and nanostructure, morphology, porosity
Crystallinity and crystallography
Water content, hydrophobic hydrophilic balance
Corrosion parameters and ion release profile
Degradation profile and degradation by-products

Wear debris release profile

Mechanical properties (e.g., stiffness and elastic constants)
SSA
Textural characteristics
Surface chemical composition
Surface molecular mobility

Surface topography
Surface energy
Surface electrical characteristics
SSA, Specific surface area.
Reprinted with permission from Williams DF. On the mechanisms of biocompatibility. Biomaterials 2008;29(20):2941 53.

the interface of the biomaterials and tissues. The overall biocompatibility of biomaterials is
related to these interactions. The details of these sequential events have been previously
explained in the literature [9].
The definition of “biomaterial” has been officially introduced about half a century ago
as “a nonviable material used in a medical device, intended to interact with biological
systems” [10]. More specifically in 1986, a consensus conference on “definitions in
biomaterials: proceedings of a consensus conference of the European Society for
Biomaterials” was held in Chester, United Kingdom [11]. At that moment, a wide range
of biomaterials have been used in medical devices as inert materials. However, by that
time, the ability of biomaterials has been greatly changed to interact with living systems
in different ways [12].
The field has been further growing because of the need for emerging applications such
as applications in advanced delivery systems, imaging techniques, and regenerative medi-
cine. As a result of this transition shift the field needed to redefine the terms and defini-
tions in a more precise way. In a recent conference in Chengdu, China, 2018, a series of
biomaterials experts got together to redefine the most important principles of biomaterials
and biocompatibility [13]. According to this expert panel, the term “biomaterial” has been
defined as “a material designed to take a form that can direct, through interactions with
living systems, the course of any therapeutic or diagnostic procedure”.

Handbook of Biomaterials Biocompatibility

 1.1 Introduction 5
TABLE 1.2 The most important host characteristics responses to the implanted biomaterials.
Protein adsorption and desorption
Neutrophil activation
Macrophage activation, foreign body giant cell production, granulation tissue formation
Fibroblast behavior and fibrosis

Microvascular changes
Tissue/organ specific cell responses (e.g., osteoclasts and osteoblasts, endothelial proliferation)
Activation of clotting cascade
Platelet adhesion, activation, aggregation
Complement activation
Antibody production and immune cell responses

Acute hypersensitivity/anaphylaxis
Delayed hypersensitivity
Mutagenic responses, genotoxicity
Reproductive toxicity
Tumor formation
Reprinted with permission from Williams DF. On the mechanisms of biocompatibility. Biomaterials 2008;29(20):2941 53.

Among different basic characteristics defined for biomaterials, biocompatibility is of

great importance. Biocompatibility can be defined as the ability of a biomaterial with an
appropriate host response in a specific application [14 16]. According to this explanation,
a biomaterial can interact with biological systems with minimal risk of toxicity and rejec-
tion by the immune system.
In the context of host response to biomaterials, carcinogenicity is another important
characteristic of an implanted biomaterial, defined as the ability to initiate and/or stimu-
late the increase of cancerous cells [17].
When a biomaterial is implanted in the body, a series of interactions happen in biological
fluids. In most cases, a foreign body capsule is formed on the surface of the biomaterial.
This protein layer can greatly change the characteristics of the biomaterial which can further
act as a structural and biological barrier between the biomaterial and the tissue [18]. When a
biomaterial interacts with blood, a series of even more complex events can happen, where
the term hemocompatibility is defined as the compatibility of biomaterials with circulating
blood. This interaction should be sustainable without any adverse reactions [19 21].
According to expert opinions, hemocompatibility can be better explained as the ability of a
blood-contacting biomaterial to avoid the formation of a thrombus by minimal activation of
platelets and of blood coagulation, minimizing activation of the complement system and
minimizing hemolysis [13]. In some cases, the implanted biomaterial may also induce some
levels of thrombogenicity which is defined as the ability of the biomaterial to stimulate
and/or promote the formation of a thrombus in contact with blood [22].

Handbook of Biomaterials Biocompatibility

6 1. Principles of biocompatibility

TABLE 1.3 The International Standards Organization (ISO) series of guidance documents for biomaterials
and biocompatibility.

Number ISO number Title

1 ISO 10993-1:2018 Biological evaluation of medical devices—Part 1: Evaluation and testing within
a risk management process
2 ISO 10993-2:2006 Biological evaluation of medical devices—Part 2: Animal welfare requirements
3 ISO 10993-3:2014 Biological evaluation of medical devices—Part 3: Tests for genotoxicity,
carcinogenicity and reproductive toxicity
4 ISO 10993-4:2017 Biological evaluation of medical devices—Part 4: Selection of tests for
interactions with blood
5 ISO 10993-5:2009 Biological evaluation of medical devices—Part 5: Tests for in vitro cytotoxicity
6 ISO 10993-6:2016 Biological evaluation of medical devices—Part 6: Tests for local effects after
implantation
7 ISO 10993-7:2008 Biological evaluation of medical devices—Part 7: Ethylene oxide sterilization
residuals
8 ISO 10993-9:2009 Biological evaluation of medical devices—Part 9: Framework for identification
and quantification of potential degradation products
9 ISO 10993-10:2010 Biological evaluation of medical devices—Part 10: Tests for irritation and skin
sensitization
10 ISO 10993-11:2017 Biological evaluation of medical devices—Part 11: Tests for systemic toxicity
11 ISO 10993-12:2012 Biological evaluation of medical devices—Part 12: Sample preparation and
reference materials
12 ISO 10993-13:2010 Biological evaluation of medical devices—Part 13: Identification and
quantification of degradation products from polymeric medical devices
13 ISO 10993-14:2001 Biological evaluation of medical devices—Part 14: Identification and
quantification of degradation products from ceramics
14 ISO 10993-15:2000 Biological evaluation of medical devices—Part 15: Identification and
quantification of degradation products from metals and alloys
15 ISO 10993-16:2017 Biological evaluation of medical devices—Part 16: Toxicokinetic study design
for degradation products and leachables

16 ISO 10993-17:2002 Biological evaluation of medical devices—Part 17: Establishment of allowable

limits for leachable substances

17 ISO 10993-18:2005 Biological evaluation of medical devices—Part 18: Chemical characterization of

materials
18 ISO/TS 10993-19:2006 Biological evaluation of medical devices—Part 19: Physicochemical,
morphological, and topographical characterization of materials
19 ISO/TS 10993-20:2006 Biological evaluation of medical devices—Part 20: Principles and methods for
immunotoxicology testing of medical devices
20 ISO/TR 10993-22:2017 Biological evaluation of medical devices—Part 22: Guidance on nanomaterials
(Continued)

Handbook of Biomaterials Biocompatibility

 1.1 Introduction 7
TABLE 1.3 (Continued)
Number ISO number Title

21 ISO/CD 10993-23 Biological evaluation of medical devices—Part 23: Determination of skin

irritation of medical device extracts using reconstructed human Epidermis

22 ISO/TR 10993-33:2015 Biological evaluation of medical devices—Part 33: Guidance on tests to

evaluate genotoxicity—Supplement to ISO 10993-3
23 ISO/TR 15499:2016 Biological evaluation of medical devices—Guidance on the conduct of
biological evaluation within a risk management process
24 ISO/DTS 21726 Biological evaluation of medical devices—Application of the threshold of
toxicological concern for assessing biocompatibility of extractable substances
25 ISO 14155:2011 Clinical investigation of medical devices for human subjects—Good clinical
practice
26 ISO 22442-1:2015 Medical devices utilizing animal tissues and their derivatives—Part 1:
Application of risk management
27 ISO 22442-2:2015 Medical devices utilizing animal tissues and their derivatives—Part 2: Controls
on sourcing, collection and handling
28 ISO 22442-3:2007 Medical devices utilizing animal tissues and their derivatives—Part 3:
Validation of the elimination and/or inactivation of viruses and transmissible
spongiform encephalopathy (TSE) agents

29 ISO/TR 22442-4:2010 Medical devices utilizing animal tissues and their derivatives—Part 4:
Principles for elimination and/or inactivation of transmissible spongiform
encephalopathy (TSE) agents and validation assays for those processes
30 ISO 11737-1:2018 Sterilization of health care products—Microbiological methods—Part 1:
Determination of a population of microorganisms on products
31 ISO 11737-2:2009 Sterilization of medical devices—Microbiological methods—Part 2: Tests of
sterility performed in the definition, validation and maintenance of a
sterilization process
32 ISO 11135:2014 Sterilization of health-care products—Ethylene oxide—Requirements for the
development, validation and routine control of a sterilization process for
medical devices
33 ISO 7405:2008 Dentistry—Evaluation of biocompatibility of medical devices used in dentistry
34 ISO/TR 37137:2014 Cardiovascular biological evaluation of medical devices—Guidance for
absorbable implants
35 ISO 22794:2007 Dentistry—Implantable materials for bone filling and augmentation in oral and
maxillofacial surgery—Contents of a technical file
36 ISO 11979-5:2006 Ophthalmic implants—Intraocular lenses—Part 5: Biocompatibility
37 ISO 19227:2018 Implants for surgery—Cleanliness of orthopedic implants—General
requirements
38 ISO 5910:2018 Cardiovascular implants and extracorporeal systems—Cardiac valve repair
devices
(Continued)

Handbook of Biomaterials Biocompatibility

8 1. Principles of biocompatibility

TABLE 1.3 (Continued)

Number ISO number Title

39 ISO 15675:2016 Cardiovascular implants and artificial organs—Cardiopulmonary bypass

systems—Arterial blood line filters

40 ISO/TS 22911:2016 Dentistry—Preclinical evaluation of dental implant systems—Animal test

methods
41 ISO 14630:2012 Nonactive surgical implants—General requirements

42 ISO 17327-1:2018 Nonactive surgical implants—Implant coating—Part 1: General requirements

43 ISO 13175-3:2012 Implants for surgery—Calcium phosphates—Part 3: Hydroxyapatite and beta-
tricalcium phosphate bone substitutes

44 ISO/TR 37137:2014 Cardiovascular biological evaluation of medical devices—Guidance for

absorbable implants

45 ISO 3826-1:2013 Plastics collapsible containers for human blood and blood components—Part 1:
Conventional containers
46 ISO 3826-3 Plastics collapsible containers for human blood and blood components—Part 3:
Blood bag systems with integrated features
Reprinted with permission from Ghasemi-Mobarakeh L, Kolahreez D, Ramakrishna S, Williams D. Key terminology in biomaterials and
biocompatibility. Curr Opin Biomed Eng 2019;10 [23].

There have been always many attempts to systematically assess the biocompatibility of
biomaterials. In this regard, there are a range of proposed standard methods for investigat-
ing the biocompatibility of biomaterials by International Standards Organization (ISO).
Table 1.3 summarizes some of the most important standard methods for the investigation
of biomaterials and biocompatibility.

1.2 Conclusion

The understanding toward the exact mechanisms responsible for the cellular interactions at
the interface of biomaterials and tissues is not still quite clear. This is very important regard-
ing when a biomaterial should stay for a long-time in the body. More than five decades of
research experience in this field indicated that the most important requirement for the
biocompatibility of biomaterials is that the biomaterials should not be relatively harmful for
the target tissues. By the development of biomaterials for specific applications in tissue engi-
neering, regenerative medicine, niche engineering, immunoengineering, targeted delivery, and
critical biological applications, the need for specific interactions at the interface of biomaterials
and tissues becomes more essential. Although the knowledge behind the actual mechanisms
of biocompatibility on biomaterials surfaces is still in its infancy, this area of research is so
attractive that it has fascinated scientists. Undoubtedly, this topic needs further investigations
and a lot of critical questions have yet to be answered.

Handbook of Biomaterials Biocompatibility

 Further reading 9

References
[1] Mozafari M, Sefat F, Atala A, editors. Handbook of tissue engineering scaffolds: volume one. Woodhead
Publishing; 2019.
[2] Kargozar S, Ramakrishna S, Mozafari M. Chemistry of biomaterials: future prospects. Curr Opin Biomed
Eng 2019;10:181 90.
[3] Anderson JM. Biocompatibility and bioresponse to biomaterials. Principles of regenerative medicine.
Academic Press; 2019. p. 675 94.
[4] Mozafari M, Tariverdian T, Beynaghi A. Trends in biotechnology at the turn of the millennium. Recent Pat
Biotechnol 2019;14:78 82.
[5] Bordbar-Khiabani A, Yarmand B, Mozafari M. Emerging magnesium-based biomaterials for orthopedic
implantation. Emerg Mater Res 2019;8:305 19.
[6] Zhou Y, Wu C, Chang J. Bioceramics to regulate stem cells and their microenvironment for tissue regenera-
tion. Mater Today 2019;24:41 56.
[7] Kowalski PS, Bhattacharya C, Afewerki S, Langer R. Smart biomaterials: recent advances and future direc-
tions. ACS Biomater Sci Eng 2018;4(11):3809 17.
[8] Williams DF. On the mechanisms of biocompatibility. Biomaterials 2008;29(20):2941 53.
[9] Rahmati M, Mozafari M. Nano-immunoengineering: opportunities and challenges. Curr Opin Biomed Eng
2019;10:51 9.
[10] Williams DF. On the nature of biomaterials. Biomaterials 2009;30(30):5897 909.
[11] Williams DF. Definitions in biomaterials: proceedings of a consensus conference of the European Society for
Biomaterials, Chester, Engl., March 3 5, 1986. Elsevier; 1987.
[12] Stupp SI, Donners JJJM, Li L, Mata A. Expanding frontiers in biomaterials. MRS Bull 2005;30(11):864 73.
[13] Zhang X, Williams D, editors. Definitions of biomaterials for the twenty-first century. Elsevier; 2019.
[14] Rahmati M, Mozafari M. Biocompatibility of alumina-based biomaterials—a review. J Cell Physiol 2019;234
(4):3321 35.
[15] Rahmati M, Mozafari M. Biological response to carbon-family nanomaterials: interactions at the nano-bio
interface. Front Bioeng Biotechnol 2019;7. Available from: https://doi.org/10.3389/fbioe.2019.00004.
[16] Mozafari M, Rajadas J, Kaplan D, editors. Nanoengineered biomaterials for regenerative medicine. Elsevier;
2018.
[17] Klosterhalfen B, Klinge U, Schumpelick V. Carcinogenicity of implantable biomaterials. Abdominal wall her-
nias. New York: Springer; 2001. p. 235 6.
[18] Rahmati M, Mozafari M. Protein adsorption on polymers. Mater Today Commun 2018;17:527 40.
[19] Rosen Y, Elman N. Biomaterials science: an integrated clinical and engineering approach. Taylor & Francis;
2012.
[20] Wexler P, Anderson B, de Peyster A, Gad SC, Hakkinen PJB, Kamrin M, et al. Encyclopedia of toxicology.
3rd ed. Elsevier Science; 2014.
[21] Kabirian F, Milan PB, Zamanian A, Heying R, Mozafari M. Nitric oxide-releasing vascular grafts: a therapeu-
tic strategy to promote angiogenic activity and endothelium regeneration. Acta Biomater 2019;92:82 91.
[22] Braune S, Robert AL, Reinthaler M, Landmesser U, Lendlein A, Jung F. In vitro thrombogenicity testing of
biomaterials. Adv Healthc Mater 2019;8:1900527.
[23] Ghasemi-Mobarakeh L, Kolahreez D, Ramakrishna S, Williams D. Key terminology in biomaterials and
biocompatibility. Curr Opin Biomed Eng 2019;10:45 50.

Further reading
Ramakrishna S, Tian L, Wang C, Liao S, Teo WE. Medical devices: regulations, standards and practices. Elsevier;
2015.
Williams DF. Regulatory biocompatibility requirements for biomaterials used in regenerative medicine. J Mater
Sci Mater Med 2015;26:89.

Handbook of Biomaterials Biocompatibility

 C H A P T E R

2
Bacterial cell
biomaterials
interactions
Li-Chong Xu1 and Christopher A. Siedlecki1,2
1
Department of Surgery, Biomedical Engineering Institute, College of Medicine, The
Pennsylvania State University, Hershey, PA, United States 2Department of Bioengineering,
Biomedical Engineering Institute, College of Medicine, The Pennsylvania State University,
Hershey, PA, United States

2.1 Introduction

The use of biomedical implants, such as intravascular catheters, urinary catheters, stents,
valves, ventricular assist devices, and endoprosthetic joints, has been an important part of
modern healthcare system. Use of implants has revolutionized medicine and increased the
quality of life and in some instances, even on the patient survival rates. However, it can
also be associated with a variety of complications. One of the most frequent and severe
complications associated with the use of implants is biomaterial-associated infection [1,2].
For example, device-associated infections account for 25.6% of all healthcare-associated
infections (HAIs) in the United States [3], and the overall direct cost of HAIs to hospitals
ranges from $28 billion to $45 billion annually [4].
Biomaterial-associated infection is due to the pathogen bacterial adhesion and biofilm
formation on medical device surfaces. Bacterial cells adhere to the surface and produce
extracellular polymeric substances (EPS), proliferate, and colonize to form biofilms on bio-
material surfaces, resulting in microbial infection. The biomaterial-associated infections are
extremely difficult to treat using antibiotics alone. The minimal concentration of antibiotics
for eradication of mature biofilm can be up to 100
1000 times higher than for the plank-
tonic bacteria [5]. This is not only because the slime matrix they produce can be physical
barriers and protect bacteria from antimicrobial agents [6,7], but also the diverse physio-
logical states of biofilm organisms such as the creation of starved, stationary phase dor-
mant zone in biofilms [8], and the existence of persister cells [9] are the significant factors
in the resistance of biofilms to antimicrobials. In addition, biofilm formation may cause

Handbook of Biomaterials Biocompatibility

DOI: https://doi.org/10.1016/B978-0-08-102967-1.00002-5 11 © 2020 Elsevier Ltd. All rights reserved.
12 2. Bacterial cell
biomaterials interactions

the adverse effect on blood response. In the case of blood-contacting devices, a biofilm
may continuously release bacteria into the bloodstream and interact with platelets result-
ing in platelet activation [10] and thrombus formation [11]. All lead to severe clinical com-
plications often with lethal outcome. Further, a common problem with the long-term
treatment with potent antibiotics is the development and continuously expanding popula-
tion of bacteria resistant to common antibiotics [12
16]. As a result, surgical removal and
replacement of the implanted devices is often the only treatment, which naturally cause
significant morbidity and mortality, and increase the medical cost [17].
Microbial biofilms are complex consortia of adherent microorganisms embedded in a self-
produced polymer matrix of EPS that is composed of polysaccharides, proteins, and extracel-
lular DNA [18]. Development of biofilms is generally proposed as a four-stage model
beginning with the adherence of planktonic bacterial cells to surfaces, followed by accumula-
tion, maturation, and dispersal phases (Fig. 2.1) [19
22]. Biofilm formation on surfaces is
multifactorial, influenced by the particular strain, the growth environment, and the material
surface characteristics. It has been evidenced that capability to form a biofilm, biofilm slime
components and structure, and the regulatory biofilm network can be substantially different

FIGURE 2.1 The schematic representation of Staphylococcal bacterial adhesion and biofilm formation on bio-
material surface. The planctonic cells interact and anchor on biomaterial surface. Intercellular interactions medi-
ated by adhesins and cell wall proteins lead bacteria to cluster together and form microcolonies. The production
of EPS matrix composed of proteins, glycoproteins, glycolipids, polysaccharides, and eDNA facilities the forma-
tion of the biofilms. eDNA, Extracellular DNA; EPS, extracellular polymeric substances. Source: Reproduced and
modified from Arciola CR, Campoccia D, Montanaro L. Implant infections: adhesion, biofilm formation and immune evasion.
Nat Rev Microbiol. 2018;16(7):397
409 with permission from Nature Publishing Group.

I. An introduction to biocompatibility
 2.2 Theoretical theories of bacterial adhesion to biomaterial surfaces 13
between clinical isolates of the same species [23]. This biological variability has to be
addressed in the understanding of biofilm formation as well as the development of antibio-
film strategies [24]. The most common microorganisms diagnosed in the nosocomial infection
include Staphylococci, Enterococci, Pseudomonas, and Candida species [13,25]. Staphylococcus
aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Escherichia coli are mostly iso-
lated strains from IV catheters in catheter-related bloodstream infections [26
28]. Cluster-
forming Gram-positive S. aureus has received significant attention and has been intensively
studied in infection [29
32] because it is much more virulent and aggressive than others. It
synthesizes an array of toxins and other virulence factors, causing a range of acute and pyo-
genic infections. However, S. epidermidis ranks first among the causative agents of nosocomial
infections and represents the most common source of infections on indwelling medical
devices such as prosthetic heart valves and joint prostheses [33,34]. The main defined viru-
lence factor associated with S. epidermidis is its ability to colonize on biomaterials and form
biofilms which are recalcitrant to the deleterious action of antibiotics and impede the host
immune response [35].

2.2 Theoretical theories of bacterial adhesion to biomaterial surfaces

Bacterial adhesion to the device surface is the first and critical step in the pathogenesis
of implant-related infections, involving complex interactions between the pathogen and
the biomaterials. The planktonic bacteria in bulk fluid are freely suspended before attach-
ing to surface, and are transported to a substratum surface through flow of the fluid or
mass transport processes such as convection, diffusion, or sedimentation. Upon contacting
surface, bacterial attachment to implant surface can be divided into two phases, that is, the
initial instantaneous and unspecific reversible physical phase; and a specific irreversible
molecular and cellular attachment phase [36]. Initial attachment is rapid for a short period
of time on the order of B1 minute, and includes hydrodynamic and physicochemical
interactions [37,38]. Long range (Lifshitz
van der Waals and electrostatic forces) and short
range (Lewis acid
base) forces are generally involved in the initial attachment process.
The second phase of bacterial attachment is irreversible and can occur on a time scale of
several hours. Molecular and cellular molecular reactions between cell surface and sub-
stratum surface become predominant in this phase. A firmer adhesion of bacteria to a sur-
face is formed by the bridging function of bacterial surface polymeric structures including
capsules, fimbriae or pili, and slime [39]. Irreversible attachment is facilitated by the pro-
duction of EPS. The polysaccharide adhesins, clumping factors, and proteins are often
involved in this process [40,41].
Initial bacterial attachment is determined by the physical and chemical interactions,
depending upon the complex interplay of the physical and chemical properties of the bacte-
rial and substratum surfaces in aqueous. Various theoretical approaches have been made to
explain the mechanism of bacterial adhesion. The main theories include thermodynamic
approach, DLVO (named after Derjaguin, Landau, Verwey, Overbeek) theory and extended
DLVO (XDLVO) theory.
The thermodynamic theory is based on the measurements of interfacial energy between
two interfaces (liquid
solid, bacteria
liquid, and bacteria
solid) to calculate the Gibbs

I. An introduction to biocompatibility
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. L A D tcnídc"' r . LADRlLLADOjelfueloechodeladríÜoS, •q«e

en algunas partes fe vían rafpados , y liaicn labor con los azulejos
que Te les entremeten. Es pauimento frefco , 1í.tí\m"o', y alegre.
Ladrillazo, el golpe que Te da c«h el la drJUo. Lsdrlllejo, cierta burla
qlieíuelefl liazcr de noche los mo^os a las puertas, colgahdodcilas vh
barlUo.y dcfde lexos en "parte fccrcta le mehcan con vn cordel, V dá
golpes 3 la puerta , que hazedefpettar los de cafa Tv quahdb fe
iflbman a las ventanas no vecii a nadie : y con efto ios defaflofsíegah
gran parce de la rtoche. Burlas de mo^os , que a vczes fuelen coflar
caro ,fi ho fe toiiían eh donaire. Él edificio de ladrillo es ahtigüo
defde el tiempo del dllüuro, y mas perpetuo que otro ninguno, y
feVuro.VerasaPlIniolIb.35.c3p.i4.do refiérelas
tíbrasdéládrillosfáiiioras. L A O R 0 1^, del hoiiibre Latino htro. nís;
dlcuntiir lacrohes i raptotes , pradones , vlaruni obfcííores, qüí
vlatores auC vita, aiit pecunia fpollant.Hórat.lIb.i.epín. Vt iugiíhni
bom'mes , ftirgíint de nocle lat roñes. Diñifuntltaautore Fello.quod a
latere adorlantur vel á laterido , quod latehter Infidientur , vel a
nomine Grico /díírá/o/.otcüicus; vel a nomine /jmoj.clandcninus, por
venir oculta, y efcondldamente a lnirtar.s, y fe qu3)a,y pegaa los
lagrimales, ya las pcflañas. Dixofe lagaña , qi^aíi lagrlmaña a
lagrima; Lar. Íacryma,velqüali lipgaña , allpítúdíne.l;rciiei blo; Ojósa'y
quede lagañas fe enanioVan.Taies, y tan'diíerehres fon los gufto^de
los hombres. L AG Añoso, el qtie tlenelagañas,/ picaño
foquafipitíiicofo , el qüctleheel corrimicncoiie Ja pituita 3 las narízes.
Ambas enferiücdaües Von de viejos. ^
LAGAR,Jabalfadondeeftrujanl3vu3, V ¡a pifan, Lát. lacüs'jde donde
tomó nóbrcTaúiblcn fe dize LacunaTorcular.Ifai.cap.ój.nutíi.
j.Tiorcular calcAuijülm ,^ torquédo;porq tuercen c!
vlillodelavlgacyquandoháfaíldobuenmüíiü, \o q exprimen defpues
echándole ajgun poco de agoa , llaman torcedüras. También le
dlzcprxlum , ^ ptemendo ,, porque ie aprieta. Hazerfe lagarc ¡v»
lavuaque fe trae pira coirier , es quando vier,<. y="" eftrujada=""
:="" quando="" los="" mooon="" le="" apt-iebhenlospefcus=""/>
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Ú L Á A. J G L AGO^Iugar profundo, en el qual gy pci-pei

r:i3mente agua , que nacedelosmefínos ojos que cnncienee.nfj, y
dclfalenarrcyosjya vczes.ríos. Ca diferencia q ay de lago a laguna, es,
que la-Jar gima concrepe el agua, que baxa a eiU de losaion tes, y
lugares altos, y avezes en el Verano fe fecá: pero el lago como clcne
en fi los manantiales nun'C2 falca. Muchos lagos ay,q de vatabo a
otro fon nauegables-, comocl lago deGarda, y el lago de Coma , &c.
Divofelago , del nombre Latino La.cns á nomine Grjcco/áffoj , lacus,
fofla. Algunas vezes vale mazmorra , que es lugar profundo , y f¿co,
como el lago de los leones >5£Ci . . '• L AGOS , Ciudad antigua
cerca:del Cabo de Sanvíccnce, dicha Lacobriga, a.- « , : LAGARTO,
vn genero de fcrplenre bien conocido , vafe arrancando por laiiérra
con qiiacro píes a manera de bracos de hombr* : y por elTo fe llamó
lacercuszy en nueflro vulgar lagerto ,y de allí lagarto j con fola la
permutación de la c. tenue en la g, afpírada. Eftos lagartos de
ordinario tienen vn color verde.. Vlrgil.ealoií. 2. Nunc virides etiam
occíiltantfptneta lacertos, LAGARTljA , animal deíla cfpecle aunque
pequeño. Verás a Diofcorídeslib. 2. cap. 57.7 allí a Laguna.
LAGARTADO, vn cierto color verdcj que retira al color del lagarto.
LAGARTERO , el aoe , ó otro anlm? 1 que ca^a lagartos. LAGRIMA,
Lar; lacryma : del nombre Griego dacrtion^ inde dacryma , &
mutata d. In 1. lacryma ; y afsi los Antiguos dézlandacrumas, tefte
Fefto. Otros dizen fer nombre Lat.á laceran do, quafi lacérrimo;,
quoniá ex anlmi Jaceratlone Jacrim^ciráair. Llamamos lagrima cierto
humor que mana por los ojos del que llora ; algunas veaes las vierte
el que rie:yafslay lagrimas de conté to,y de dolor. Verás a At iliot. de
partibus anima, llb.i.cap.y.yenfus problemas fcftiün.5.nnm.l j. Se 3 5.
Alexand. Afrod.probJ.i,num.3i. LAGRIMA , llamamos cI vino que fe
dlflíla en el lagar antes que la vua fe pife, potq falc gota 3 gota, y
esdcfuOancia propia de la \ua; en Ciiego fe llama /'roíro/^o.f , vinum
quoci ína citanini fponte defluic , antequam vus-ca-lcenrur , ¿ctros,
^nxe,&c trepo, scTto. j .:.-.• c. 1 ■ vi ^ Lagrimas de Moyíen^ el
vuígo ha pticfro efte nombre a los guijarros, y picciras con quefepue
den defcalabrar;y no piecfo cuuo orre orI¿c mss, dequemandana
Dios apedreara losuDeccinttlá «íertos géneros de pecados , como era
lablasfeinla,el adulterio, ííc. de que ay if'ñrúzh', c^cp!o!5.■
Xeuicjcic3p.24.num.r5.^ i'6.
Hoif'/oqtvmalcdixeritDe9fuoportahrtpeccí>.tumfu»>n, cí?'
quibl^af^bemanerit nonftn Don>ini n?ortcr,;oriatur
,hprdíbasop^rimet éumomnii multitud^., f'tie Ule oums
€'mespertgrimisfiier:t,\>\\i% toii>oM-oyfen huuieffe de pronunciar
femejante^Ce'ñtencias , antes de darlas mouldo 3 con. pafsion
Lüraua;peroí¡iiíSU': '-. Seguada Parte, Sí Mt AA M ba'rgo
é.fiolaslagrlmjs fe conuertlnn crt plecií-as ftv3hda:-rk> «ecucar la
fentcncia. . ; \ i'sí ■¡ta^rimas de Datiid , es cierta yerua diera en
Griego ¡ithbfperírion , piedra (imlen re , herbí in eát'«mínlbusi:iu\ta
folia lapíllusquofdam , diu 1craiJapidea
iñbarbulisquIbuldamprxfcrens/iU'aii íapídeum femen. :; ■• L A GR LM
A L ,ci ángulo Inrcrírrdd ojo , pordondefcdíftílan las lagiimas. G;:£cé
ranthoSi • • ' ' . •• L A GVNA, fofa grande qi'p ha recogido crfi el
agua de las vertientes. Lar. Lacuna , videjiiüs. En las cofas que
auiendo de eltar llanas , é iguales tienen algunos hoyos, eflos íueicn
llairr.r •lagunas, Como en lOs libros inanufc! Intos qt'ando ay falta de
alg-unas palabras > y queda la ra2.cn manca llrman'lagunas. , .. L
AGVNAjDS , vocablo bárbaro q'aandtr cti vn campo ay muchos hoyos
con. agua j que no llegan a fer lagunas. LAICO, el que no pertenece
licuado EckfiaOico; es nombre Griego /.í/Vox , popuJaris, piO'fanus ,
qui facrisiriti;itiiS non eíl. Panes laicfis, lib.i.Regum cap. 2 i.num.4. fe
enrienden losqui; íe tenían para laprcuifion de la gente coir.un , a
diferécla de los psnes de la propoficipn. y afw' rtf pondió el
Sacerdote Ab>mc]ech a Daiíld, KcÉi babeo laicos panes ad manwa
,fedtantitín.pautm fan^um, &:c. -'-■.[- oi -•:■. íi.~.hn>l . LAMEDOR
, vide Lamer; ■ : LAMEGO, Ciudad en Portugal , dcJ nombre antiguo
Law^.Abralian, Oitel Lama Luliía•nli vrbstPtolonieojir Ventonlbui.
Gtrcslailaman Lamacum ,y Lameca. LAMENTAR , llorar, juntando al
lianro vozdclorofa >' del \erbo Latino Ijiucníor. aris. 5[ Lamentación ,
e¡ IK.nto con vozes , y quexaá. -En G. lego fe llama 21/r«:í?j , talos
fon Icsíhrcnos, ó lamentaciones dtl Profeta IercmÍ3s.*Sí dEa
mentabJe , loque es digno dellorarfeccn ^o-ze^, -y lamcnto^.-
^'Lamtnto, es lo mefmo qi £-hmi.ntacíon,y folo \fjdo-de losPo.ttas; ■
LAM£R,rec.ogtrcon la lengua el l>!;mor -¡e alguna cofa,
refregándola; y humedecfcrdola del verbo lambo. is. bi. iínguo,
lingua kniteraiiqíiki tango. LasoUejasiaiiicnla fai , los perros l;i landre
que hallan fobre la tierra. Algunas vC2Cs hm\s. fcrmaldicron
vfadaenla S.mta I fcrliiirajiliívi:^. Regum cap. 2 1 .nu. 1 ,9. Hiec didt
Dcnmiun ¿rJiító hoc,in qtiolifíxerunt cañes Jar.gincm Nabuth hmbent
quoqttejangti'metri itn-.m. VÍ3\i\\,6j,-tx\wxj^-Xí, Vt íntir.gatur pes
tinis in finguihc ¡h.gn¿r tmpim tuoruif! ex ¡nimitis abip/o.% Lamer
IcSpiacii^, is de uíuchachosgolofos. • ' LAME DOR , él .xaraue qUe
k^ii paYa">áíi5= ' jioco a poGb el enfermo lodc^te írdeslicnjUf»^:;
por la garganta: \i en eÜó difiere de la bebídatHc • iaraida , fuclen
dézír á la'tiU)gcr q cüánltiy aicíá■ lada.y eñá fajta caeíié.iiprctá
niugercíüiisdj'fvcr^onjadas i I bachilleras, q parece rd.^.mcH I :■?
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L A M naUbra"!, que v;;n díziciiclo: lo vriü, y lo orto ííg'

níhca. Relanurfe , pi.l.*rfc- , eítá roüíasJa la aluüon del y figura de
mugeres muy riciiiiofas arralan. 3 fi li-sníños,y los mancebos con
halagos:yvkímaniét;;loS maravan , y fe los comían. El nombrv es
Griego lam^apo t la'mos, gutur, por fu Ingltule, y rabia ■ de chupar
fangre humana , y dclcltarfe de que les •cayeflc dulcemente por
íusgargantas.Los que no tuuíeron noticia de la legua Griega
dizen.quc Umía fedixo quafi lanía ,á laníando,porque dcfpeda 5a los
hombres. Vide Albertinumde a^nofcendis alíert. CacholIcis,q.;4. Es
cofa vulgarmente recibida aueren África entre los demás monfinios,
que aquella región cria , vn animal con el rollro dedonzellamuy
hcrmofa, cabellos larr o'. , y rubios, el cuello , y pechos de tinta
pexfttion , que el pincel haría mucho en imitarlos, . y contrahazcrlos.
Eílosdefcubren con que atraen p9r:i fi los hombres, yquañdolos han
a lasmanos losdefpcdacá. Sobre aquellos dos lugares de Ifalas.e.l
vno cap. j4.n. 14. Ibi cubauít lamia,& inuenit requ¡e. YelotroThrenor.
cap,4. r.um.j. Sed,, & lamine dítdaueruKt maynma ,^la¿}aucrHM
catulosJMos, Podras ver lo q efcriucn los Santos, y ios 1 v ctcres
Expoíitores fobre eítos lugareíi JLo mas tíerio es fcr cierta efpecic de
monas. ■ ...: ' ' L A M I N A.Ia plancha dqalgviD mcol.oro, plata , y
los de(ná;sd§l.na>mbre Catiro lamina, metalli cuiufuis fruilruiH .ii)
laclcuíi.in^m dujftu!*), erafslus tamcn qiiam br-«»S cflfermedatl
conocida que naceenl3gafgant3)danledIuetfosnonibrcs,íiruma,
cheras, efctofulá,eíl hutnor in quoquar gian dulaí dura: orluntur In
cerulce i & alís, locmbranafualnc'.ufae. EAa enfermedad es ordinario
en los puercoi5,y afsltomó el nombre delloSjyen Caí rellano fe pudo
dezir latoparon efjvlehdor , porque la cutis del lamparon tiene vR
cierto rcfplandoralbicante , pof eñar can ertirado , y pcrfs corronoo.
LosReyes de Francia üizentcnerjj;racla de curar los latnparones , y el
ptfmcr Key Inglés que fue Edouardo toue lamífmagraciü, y de
algunos Otros particulares cambien fe44a lucho* LAMPAZO , la
pathon , planta muy conocida,tiene las hojas como las de la
cal3b39a,r üiayores , mas negras j y mas griieCas , y ctibiercas de
vello. Es nombre Gt\f:¿o lapatbos ,z\ tiho ¡ape.zo y euacuo , arque
etiam mol io , porque ^íbíarüatl vientre. Los Latinos le ILmafon
rumex , y por otro nombre fe dizearcium. Antes qnt ff.lnU)
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LA N L'AM P VG A , pez conocido i y tegilado;

LatrD.hippurus,Grxcé//'/'or¿;/ , crtc nombre le (dan algunos, no fe
con qiianca razon,cí; eníin híp|)iirus ex genere Jocuflaruui ,
qujhybeiúíbincníibns non caprcur.propccreaqnod id ccaipori^ . írígorls
impaciencia In caiicinas fjfe abuac.PilnJiü* p.cap.id.Sc
IIb.^2.c3p.vlrrni. LANA, es el vellón , y el pelo de la oue^ ja , y fu
cria;eít enim in fola one lana: nam cacer^vqiiadiüpedes, pilos, aut
fctashabenc. Dixofe Ja na a laniando,íkucIvellusa velendo.
AncÍL,uamé ce anees que haliaíTen clarcede efquiiar Jasouejas.les
arr3ncaiian,y pelauan la lana.Scinditur aii tem nunc lana,qux velll
folebat: vnde a vellendo vellusdicebacur: aucore Varronc. £1 nombre
lana es Griego /á«4,villus,c3pIl]iis.Y de aquí pudo nacer el
proverbioiQual mas, cual menos, toda la lana es peJos.Dízefe
quando nos tací^^inios en hazerdlftincionde vnacofa,y deocrA , y al
cabo viene a concurrir por lo menos en vn nombre genérico
:yeítasdifputas fon friuolas, c inucíles : y comodize elproverbio Latino
de lana caprina. Las lanas fon vnas mejores que otras, íegm el paf
codelasoucjas,y las aguas. Las de Tarcnro fueron antigúamete muy
loadas: cuyo ganado fe apa centaua en las riberas del rio Galcfo.Las
de Tiro leran de mucha eflima, porque las teñían con
purpura.EnErpañatouiercn fama las lanas del ganado de la ribera de
Betls, óGuadalquiuir. Ay vnas de fu propia color negras, y otras
pardas^que llaman color de fu me nte. Otras rubias de color
encendido,de dopudo nacer la fábula del vellocino dorado. Y por efto
, ó porque en los rios que licúan arenas de oro, poniendo en el fuelo
de las canallas eftos vcllonesjpaflaua el agua, y fe quedauá
incorporadas en ellas las laminicas de oro, proverbio: Ir por lana, y
bolver trcfquilado, quando vnopienfa que hade venir gananc'ofode
alguna jornada, y trato,y buelue con perdida. Licuarle han con vna
cuerda de lana , del que fin embarj;o de no moftrar voluntada vna
cofa la dt.fea,y condecicnde fácilmente có lo que fe le plde.^ Po
calaña, y tendida cn, y finalmente lanja.Pudofe dezir del verbo
¡;incar, que es arrojar con ímpetu alguna arma, a J^ncci por la
femejan(,3 de la balanza , quando car-a^lí de mayor pefo fe arroja a
lo piofundc. Fina) mente la I;)nc3csvnaarmaena!i¿<.ia fct=""
tiiucifjs="" formas="" de="" las="" lan="" losquehan="" devf:=""
ellas:="" porque="" los="" hombres="" armas="" dichos=""
eliradlotes="" tienen="" en="" cierta="" tcrnia="" con="" fu=""
j.i="" y="" acomertn="" al="" rilt="" hazititdc="" fuerza="" el=""
pecho.="" otrss="" fon="" largas="" aiyi="" ellas="" dos=""
hierros="" :="" otrascor="" h="" cuenco.="" efias="" traen=""
glnctes="" llaman="" janija="" ue="" gincra.="" otras=""
infanter="" quep="" losfoldadosdeapie="" ae="" janeas="" fe=""
toman="" muchas="" vezes="" por="" mifmos="" como="" dezir=""
tal="" cnel="" jornada="" trecientas="" lanqas="" enciende=""
crecientes="" armas.="" cuja="" janea="" riftrc="" t="" la=""
gente="" qiicbrac="" langas="" alufion="" vale="" empegar="" a=""
tratar="" alguri="" negocio="" romper="" dificultades.="" no=""
quedar="" enhlefta="" rendido="" todos="" eneui-gos.="" meter=""
hartad="" regaron="" apretar="" vno="" perfigulendole=""
ahincadamente="" eftacs="" vna="" buena="" tomado="" vn=""
remante="" vie="" diztfe="" iron="" alguno="" del="" qua=""
bofe="" citnc="" mutha="" ijri="" eoar="" declarada="" guerra=""
que="" va="" intimalla="" arroja="" lanca="" tierra=""
enemigojy="" quando="" han="" arremeter="" batalla="" o=""
capftan="" otro="" foldado="" n.="" i="" campo="" enemigo=""
punto="" le="" fivue="" toc:=""> el exercIto.Eflo quífo inl:nuar
Vírgík'ojlIb.,í».iu • blando de Turnciquedtfpues de aoer animaoó á los
fuyos feadelantó. Et iaculmniorqitensimittit ín auras i Pr'mcipmn
pugna i . _ , LAN5ADy\,tlg,6lpe,y heridadelá lan^a. A nioromueriro
gran ljn
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ne de tierra lo que vn buen braqo podrá acrausfar con i'DS

linca. AL ANCEÁRSÉvRosa otros > anclara las lanvidas.como fe li37e
en las fronceras.f Lan con,lancacorca,ygriieíra con hierro largo, y
an^ cao.Sfrvenclegiuraar la cafa.bs viñas,y losmelonare^ícc.f
^Lancera , que por otro nombre fe dízeaü;ilerüdcafta,esvn ertance
en que ponen laslancas.adornodelacafa de vn hidalgo en el |-,atIo,ó
foporcal con ahunos pauefes, arma defen fiuiEfpanola antigua.
LAN9AR,csarrojar,comofearroia lalan9a. lan9ardemon!OS,echarlos de
los cuerpos de los hombres con exorclfmos. Lan^arfe en cafa ,
recoserfe con diligencia, V prefteza. L ANCET A.fcalpelius.lapunta
con que el barbero abre la vena para fanj^rar. L ANj AOER A,el rayo
del texedor , dentro del qual va el cañuclllo de la cratna, ó la canilla,
tit.riá'.us.Grxcécercis^cerddos. LANCILLA . Y LANcVELA, fart93,de la
qual vfan los correos de a pie para de^ fenderfe,y para ayudarfe a
falcar los arroyos , y barrancos. , . , /> L A N C E, es la fuerce en
arrojar la red.o ert ía mar, ó eft el rio, Latiné laftus retís. Comprafe, y
vertdefc algunas vezes en la ribera a la ventura , y fuele no facar
ningún pefcado.y el que compro pierde fii dinero : otras fuele fallr
con inucha pefca , yafslesfuerte , y no cofa clert3. Comprar vna cofa
de lance , quando fe vende poc íitcnosde el ;ullo precio , con alguna
ocadon. -'tancc for9ofo , ocafion Ineuicable , que no fe pudo efcufar.
„ „, , LANCHA, piedra eñendida , y de poco groffor.Dixofc del nombre
Griego /.w/ , Japls , ó fea de orii;en vulgar por fer ancha ¡lanchazo ,
el ir o 'pe qi>e fe da de phno con ella. L AN DR E , es vna
enfermedad que da en las ingles , 6 debaxo de los fobacos. Eflá
corrompido el nombre de glande , porque es vnafeca, ó rumoren
forma de vna veüoca : yaffi fe llama en Latirá glándula. Suelen
cambien, y muy ordinariamente dar eftas fecas en las gargantas , y
ahogan al paciente conbreuedad, y es ¿enere [.le peüe.y mal
contagiofo , que fe pe'''LANDRBCILL A,es cierto nieriio vlfcofo que
cfla en medio del muslo del animal , que por otro nombre le llaman
la baba , tiene alguna «ordura.y en el carnero ferá de cantidad de
vna nuezpcqucña.ó vnaauellana, la qual landrecilla los ludios la facan
de la pierna del carnero, y no la comen, en memoria de aucrfelc
fecado a /acob . aqn;! nicruo , quando luchando con el Ángel U-
tocó en el, y quedo algo coxo , y tardoen el Inceflu , como fe
cuenta, Gcncf.cap. j 2. numer. 7 1 .& ? :; -v cerca del fin dlií.e ,
auiendo contado la luK.h'x'lt^p: verodandicabut pcík .quam oh
c.iujam mn comclunt mrmmjil'j IJ'racl, ^uja. emarcuit iq LAN femóte
Iacob,vJque adprafentem dietn,eo quod tetigerit nerumnfemofis
eius,'^ ohjlupuent . LANGAB.VTO llamamos al que es muy ako de
cuerpo ,y flaco dél,y de piernas. Es voca» blo bárbaro. LANGOST
A^anímalejoinfeao , y por mal nueüró conocido , fegun el daño que
haze en los frutos de la tierra, y cori tener vfías alUlas muy débiles
fueleh leuantarfe en el ayre n^Uchedumbre de langoflas qué cubren
el So), y donde fe afslentanlodexañ codoro
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LAR LAPISLAZVLL Efta piedra tiene ¿Rima^ cíen ; por

quanco dízeñ tener algunas vlrcudcs medicínales , en Latín fellama
Lapís cyancus, colorís ceriilei. Díxofe lazulí á lar.utío cyaneo colore ,
hallafc en las minas del oro,y placa, y ella faipícadade vnas gocas
doradas , CJtxcédícicur Knunon. LAPITAS, Latiné Lapíchas , vna
nación de gente valérofa en Tefaiia.Dízen auer íido los
prliiiciosqueenírenaion , y guarnecieron los cauai:üs pira fcruir fe
dellos en la guerra. YírgiJ. en el tercero de hs Georj^ícas. Fr¿enji
Felsthruny lapithíe ,¿yrosq;dedere. LARDO , logüfdodcl Cüziiiü.
Laciné lardum, ftu Lndum. LAivOAR , vntar loque fe afa con ellardo;
Martes lardero , el Marees de Carneltolcndas; poique las tozinaseitán
aquel día pingues, como cerca de los Romanos Its Kalendas de Lncró
Oiiíd.lib.6. Fafirnum. Finguia cítr jllis gnftantur larda Kalendis>
LARES, DiuicscIclaGcncíiidad , algunos creían fcr ios genios, iiuio . y
bueno que acompañan ai hombreen fu vida-, eran honrados en el
lugar de la cafa , adonde fe encetdia el luego ; y de aquí nació
Humar Jares los hierr*. sque eídnenel hogar ; de los qualcs cuelgan
los calderos pai a calentar el a¿ua,y guifar. ^ ¡¿en auer tomado cÜe
nombre de vna ninfa dicha Lara ; en la qiial Mercurio tuuo dos hijos ,
y ellos fe dixcron Lares.Cerca de los Latinos lares (ignifican las
niefm.s' cafas de nueílra niorada:y en Caítellanodezlmos/ Micafa , y
mí hogar :y en muchas ProuÍDciaSüiit-n Tantos ho¿ai es , 6 cancos
fuegos por tancas cafas. LARGO, Latine longus, comunmente cti
Caftcllano fe coma por vni-ípaciu muy eÚcndiJo, C'¡ino campo iar¿'0,
carrera larga ,y por coda cofa en eOa manera prolonga Ja, como la
lan^a larga , efpada larga .- y en el liombrefer lariiode cuerpo. Del
tiempo, largo tiempo. Largo fe coma á vezcsporei hombre h\ eral , y
gallador. Largo jugador , el que juega con mucho dinero , y libera
Jmence lo pierde , o lo gana. ^ Largo en razonar , el que tiene
muchas palabras. Cuento largo , en elqualay miitho t>iie dezir. Ir
muy a la larga, ir d£efpacío,y que durará mucho tiempo. Oponefe a
l.rgo ancho. Latine Jaricudo. Darfe tantas ch ancho como en largo,
deshonrarle de palabra v no a otro. Por largo, Ai~ 2en en algunas
parces largaria , y ancharía por lo ancho. Dar cinco de largo, p íTar
de la raya pucfta adonde ha de llegar la bo a,y no paííar de aíii.
Cinco de corro , quando no liega , 6 no palla de otra puefta atrás.
Vfamos denos dos termines quandoay exceflb, ó faltacn loque
hazemcs, y tratamos. LASAñA, cierra fruía de farté, vulgarmente
dicha orejaí-ie Abad. L;it. iaganum. ' ■ LASCIVIA , no es muy
vfadweílf círmii!''? LAS 85 en lengua Efpañola , vale lilxuria ,
ínconrinenci de animo, inelinai.íoo , y propenfioria lascofas venéreas,
blandas, y t(.galadas,alcgrcs , y chocarrefcas en elta materia.
Lafciuo, elqueelta afeftó de tal pafsion ;desincítaaiencodelia. Poeta
lafciuo, el que efcríue aaiores. L A ST AR,eshazer elgafíoen alguna
cofa con atíiino , y con derecho de rebocar lo de otro, á cuya cuenca
fe pone: quando yo Lelidoñador de vno , y me han hecho pa^ar por
él la deuda principal, y collas, fe me da carta de pago, y ¡ailo para
cobrar de la parce á quien fie ; y dizefé luto. Jas cofias que me han
Iiecho por él. Y lallar quaíi luLtar a verbo luo, luis, por pagar. '"•'''
LASTIMA^ I vale herir, ó maltratar vn6 á otro. Calieren le aya dicho
de el verbo laido. Ijídls. quaü Ixdimar. Puede vno lañimar afiide
palabra, como de obra, y el herido , o Injuriado dezimos quedar
laitímado; De aquí fe dixo laftima , y podría fcr Griego , quali
latímmade íyma. tos. vulnus , pert-ufio , y el articulo nueitro con
ínterpolicion de la s. ' LASTixH, laspiedrasquefonanchas, y de poco
canto, eita;» fueiwn falír en lafuperficie de IX cantera, que f(;n como
corcezone-s ,y afií los llaman lalirones, y fon inutiies para labrarlos :
pero' enibeucnlosen las aiuíallas , y ch la marina cargancun ellos ios
nauios en lo hondo de la
fencina.quandoháfacadolasmercaduriasquejlamaif iaÚre . y flechan
otra cofa en fu iu¿ar, dizcnqúe va por lallre, 3 faita de laitre echan
areno grueli'a,dixofclaftre , ó lallrou del nombrC Griego /4/, Japísry
afsi laftron como de piedra pediu'n. iLA T £ R A N O fue v n caualkro
en Roma quee'díficó vnosfum^ituofos palacios i mandóle macar
Nerón , y alitn' ine pcrfuacip qae wn toco'
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I A T loquees Efpañaavrla diferentes Icngiias ,

efpecíalm:;nte quahdo vinieren a cUa los ivomanos por auerla
fcáoreado diuerfas naciones ,y suczindadoíecn fus Proulncias , y que
dedos nos han quedado algunos vocablos haíta oy día , como fe
apuñea en fus lugares. Acudiendo 3 nucftroptopofito, digo , que
adiDicida la l«ngiia Latina ca Efpaña, fe habló como en Roma> y
hiiuo varones muy dodos en elia , que hablauan,y cfcrivíao con mas
policía que el vulgo ; pero entrando los Godos en Efpaña fe
corrompió notablememe , y la leof^ua que antes era pura Romana
fe conulrtíó en Romance , que vale tanto como deriuadade la lengua
de Roma, las leyes de los GodoSjydefpues las de las partidas nos
dan a entender como en aquel tiépo aun fe arrímauan a la lengua
Latina; pero agora cüá todo tan mudadoque parece otra lengua : y
efta es lacaufadequeígnorcmosmuchol vocablos que fon Latinos ;
pero la bachillcriadelos razonadores los han adelg39ado tanto quv no
fe conocen: y lo peor es , que eüos mefmos ion los prlmetos que
ignoran fu fuente , como lo conocerán, aunque les pefe ,
quandoeneAemi trabajo hallaren palabras que las traen cada dia
entre las manos, y lasdefconocen, digo las que traen origen del
Latln.queen las demás no es maraullla , fino ilen^ n noticia de las
lenguas. Al que fabia en aquellos tiempos la lengua Latina , le tenian
por hombre auifado , y difcreto -. y de allí nació llamar oy en día
Ladino , al hombre que tiene entendimiento, y difcurfo , auifado,
afluto, y cortefano. ^ Latinidad , el eftudlo , y facultad del Latin.
LÁTIGO , el a^ote , y correa ancha con que cafligan a los fieruos a
latltudlne , por fcr ancho, yl3Co. _ , ,v ", L A T I G A Z O , el golpe
que fe da con el; pero también fignifica látigo comunmente el aqo te
con que el carretero caftiga las mulas.^ Eñe haicn de cierto cordel ,
que llaman del látigo. LATÓN , vale lo mlfmo que arambrc , metal
conocido fufil: y algunos le llaman alaton Morifco. Vidc verbo Alaton.
Al artlculo-.aton es nombre corrompido del Italiano ottonc , que vale
lo mefmo. Dede metal ametalado fe hazen candeleros, lamparas,
aguamaniles, &c. ^ L A T R I A,lareuerenci3,elobfcquio, y
fervidumbre que fe deuc afolo Dios : es nombre Grieqo feruitus ,
obfequium , cultus diuinus a verbo latreo, coló, feruío. De allí
Idolatría, vide fupra. , , , LATRINA , el lugar donde expurgamos el
vientre. Lat. latrina , vel a latendo , por cHar en parte efcondida , v
arredrada en la cafa : ó fe d.xo latrina , quafi lauatrlna , fegun Mar.
Varron Iib. ■2. de Analogia^ó del nombre Gúe2,ollthron,
imm'undicl£s:y de allUitrina.y latrina el lugar donde fe echan las
inmundicias. Por otro nombre fe áhen fecrecas , porque eflán en lo
oías íecreto , y aparcado de la cafe. Crajce albodos , fscc-nusíi^ L A
V exonersndum vcntreni.Y neceffarlas por la neceffidadqueay
dellasiy aislen Roma aula efiaslatrinas,ó cloacas publicas, cerca de
los lugares de cpcurfo,y particulares en las cafas. LAVANCO, efpecíe
de añade , que comunmente anda en las lagunas, y por ^abulÜrfg
en el agua de ordinario, y lauaríe en ella tcraóeftenouíbre» LA
VAR,mundÍfic3r,y limpiar alguna cofa có agua. Lar. lauo.as. Lauar las
manos , cofa vfada para fentarfe a comer , y los luezes para dar á
entender la pureza con que fentencian,laua4]an fus manes ; de
donde quedó eJ proüetbio de elle negocio ; Yo lavo mis
manos.querlcndo fignificar no confentir en el hecho.Tambien fe vsó
en Efpaña vna coÜumbre incroducida(a lo que fe encicndejde los
Godos, que la mugeracufada deadulterio fe purgaua , lauahdofe las
manos con plomo derretido , como otras vezeslleuar el hierro
ardiendo tantos paílcs : io qualdefpues prohibieron los Sumos
Pcntiliceí conmuy jufiascaufas , fin embargo que nucÜfo Señor fue
férvido por eñe bárbaro medio.fal vara muchos inocentes, falfamtntc
acufadcs. Vee 1a palabra hierro.^ Ñola lauara con quanta agua lleua
Duero. DÍ2efe del que no puede purgarle de la culpa
manifiefla.Vicnefeá femar a la mefa con fus manos lavad? s.Dizefe
del que no ha trabajado como losdem;is,nicnfuciadofusm3nos,y a Ja
hora de comer fe viene con los dem^sa la n.efa, y come de
mogollón. Defic verbo fe dize lauar L la na,quando3 »noleefcudriúan
fu caufa halta facarla en limpio. O dizefe, lauar la lana qua ndo le ha
collado C3ro;porque de los muchos minilknos q ay en los lauadcros
de la iana,ts el mas trabaioío,y peligrofo el Jauaila,por auer de sndar
de ordinario metidos en el agua,vnas vczes fría , otr:.s caliente. ^
Salen defie verbo, lauandera, la muger que tiene por oficio lavar Ja
ropa- lauadero, donde felaua. Laua^aSjCl agua fuzla que file de la
ropa ove felaua: lauatorio ,elquefe haze por medicir;,'* Deslavado, la
cofa que no tiene luñre,y el que no tiene v erg uenca. L A V A j'o
S,ncn)brc de Itigaf . LAÚD, Lar. cefludo, inflrumcnto de
cuetdas.conocido.y muy vfadoen tfpaña , en Italia, y en África , y en
muchas otras naciones. Difiere de la vihuela, por quantOBo tiene el
vientre , ó cuerpo quadrado , fino rcdoiido,y gibofo , hcclio de
muchascoftiUas delgadas, fútilmente pegadas vnas con otras.
Algunos quieren fe aya dicl o a l3udandísHeroib¥s,porqueíc cantan a
éj Jos lomanccs^conuíeneafibcr .lashazsñasde los Reyes,y Principes;
yo pienfo fer non bre deriuado de el Griego, y que tila corre mpitiO
de lialiitr. quitárnosle la a.y di.xlmosltud ,y kiid: ydI^. fe afsi por la
forma que tlcr.c de h varquiUá de los pcfcadores,qiic es corta, y
venrrltrifa ; v efto DOS da a entender Akiato en vq jn bjti ;t . ...
^_^^
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L A V (\ue efcnue 3 M4xíinil*:4C0,Puquede Mílan.jque Hinc

cit/jaram,.} LemBiqn^forina h.il':stjca¡firt^iñ, Vjndicjt ,(¿N propri-am
Aíuja Latifhí/ibiy', ■•j-, . ; Y dixof£iialJcucíc3,lf§ai;or,' ^I Italiano le
Jiair,a iíiiro.D'c!?^ <.lc>í;d.r2e f?r Arabigo.Por modqde^iulian,)»
apod(>^íeliJ4^^^a,• laudlacorcoh3. V • :-,■'::.,■, [■ii[:.\i.(J i:: J^ A
V D £ , la piedra con *ítrcrípcí,B qp-e fe, pnr° fobre la f^puhura del
difímro , f^jríaftalauT; dmdo, porque en elb. fe cfculpcn íns Ci'cufos
..y fu"? looresj pero puede Tcr no.nbre Grk-^odelaáJ,: lipj's , y d; allí
hus,y laude. AduicrcalV .f}V!e ^i\e, Marino nombre mudado el
aceBEo , gensifíJ.yj'de-, clin-icíon vale el pueblo laos , .«jif^á
aluclK'ndoa, Ja fibula de Deuc.ilj'onjyPyrt'aftl.jndoajencender.'
ladorczade las G^nteSjdvfje acuella edad en ade lanrc.Eíla p'edra
laude fellama en Laci'n Cippus, y en Grie.'o/n

iumpjj:tm ' Vox canet rj- longus viftntC^pit olía: popas,

^^c. Entre otros priuiki;i->s quedjiO nattnilsr.. al laurel,es vno(fegun
la com.un opirdoo} que jarnos ha {ido tocado de! rayo pero yifc
haviilo locuntrar'o,fe2un cuenta el Doftor La, unj fobre. Piofc.
lib.i.cap.Sp.y entonces fe tuuo por maJ águejo en Roma ,aiio i5^9-
Vcrás; Plíniolil.!. 1 5.c¿p. ^o.quees el '/Itimo. . ..,■,„ o; jí'i,.í :f-j
,-..f'': €^ Del l."urcl ay algunos fimbolosanrj'.'iios,yYiío dernos;dos
troncos de laurel refregados vnocon otro, que echan defi
lJain,'is,fign;hc'3n el ^^raue peligro de la ruini de los d«ii¿sq:uando
fe confederan dos poderofos. Traele. Paridino en fus. fimbolos
heroicos, con el zkalpFIamefcit ella luef ma forma ensacados en el
collar de Ja Ojuien,del .Tufoneon los eslauones, y ej pedernal,, ■ ,
Muchas fuperf'iciones.ay cerca devfar de el laurel , en razón de
adiuinan^JS , porque algunos hahdíclio, que poniéndole debaxo de
Ja a^mb hada foñaran cofas verdaderas cerca de lo.que prc
tcnderifabcrJanief.nafijpüríikion ter)íJn,pchan¿o el laurel eo.ei tut¿o.
,.)'ri:AZE:RIiAí,ííe/»íigQr:y,alec3_n£0j.coín9,4eí-; pcdac?
niIericOj3:v,efb •íe.ljamo lacerado.BtcnesivVi'--. dad que en
eMen^^uagc antiguo deGaltilia laceria vale tiabsjo, quli es el
queíepad^pecn Ja guií-ra en diucrfasin3Dr?r3s.l.2..;ticL¡K2
i^paf.t.2.& J.io. titul.p.part.i.D.tfítonrraccionfeJIJanian lazdja,^' dos ,
V delie tcrmifto-yfatl Conde iji|canor ep fu hiftoria , y f ¡•'veyrüonr-
'ionfoeliiuenoen ej libro (|ue mando cfwpiíntf dicho Flores de filofor!,
fi4,qi)e dize 3Ísr:fc I Keyj^^^'r.nio el afXtol de Jpifj^,' que tif nti
gran fon bf a , y fuelgun Lfl-fo[dt^jfi^jL^¿ loscanfados, flacrs,y; h-
i^rzáo^, ..--^. j,f. }^:\..^ ,,, L A Z O, del r.ombr". LatítioJaqjif ivs^.
pÍ!,cc|.etraer origen del v€sbolj.tbrfola(:acJÍ/ , cápele;., porque con
el lazotom^aios la c¡i£Aí ,ootrc^'v.a) gji en tr.a.bajo. C
coinovailalJolcaJ ,y rambicn de jgpala igual , como amitjo leal , opr r-
fe. á h píU!»?? traydor. Prouerhio, No es la vida delle.iJ , jna's de
quanto quiere el cravdor ; cpnf¡dej;andoJ4, bond.id del vno , y
la.r\iajjcia del otru. pt kil^fci divo lealtad , fidelidad; La
muger.guarda ic.^Jpí.)^ 3 fn ¡narídoqu^ndoescalla, V honelia, y nc
jein-í centa hazer aleuofia , ni tray^ior. /, , ,.-,_ I^EdECJHE I viento
o.uelopJacaHrej^ünTcn*'
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^C L f. C te.y Nledío díi.Ta.nirld dúe fer noalbr J Arábigo. L

E B íl É L.vni carta de perros ^cncrofa qus fueleH cracr a Efpaús de
as Islas SecericríoniLs, fon de ayudj.y Jertcnden a fus amos. tiítibren
acó mecen las rieras, y las enibara^m dein2n;ra, que puede elí< El
lebrel caftizo conoce fu generofidad, y nobleza , y afsi yendo por la
calle,y falíendo quantos gozques ay a ladrarle.nl fe para , ni fe
defiende , ni lad^a , porque no eftlma oente can baxa. Refiere el
Padre Fray Luis de Granada , que eftando vn hermofo lebrel junta
alaplaya de lámar; llegófea él vft gozque, 7 c«niene«n-.i diIon.Y para
fignificar erta calidad fin^^ierco K>s Poetas auer la diofa Venus
embuelto a Adeorís defpues de muerto entce lechugas- Alciaco
eiiible-; mzjj. In guiña dente ferofujoj/iim Cypris Adon'mt
Laéiucitjolijs condidtt exammeni. Veras alli fus Comentadores el
Brocenfe , y Alinoes.En las cenas es muy ordinaria la lechuga» Ah
ti2;uamente fe fervía a la poftre,y defpues fe diü al
principIOjMarcial. Clctudere ,quie canas ladina folebat auorilr3!ij:i Dic
mibiyCurnoftras incboatjlla dapts, T La lechuga cozida ablanda el
vientre. £1 mifttio Marcial in Pboebum. ' .::f
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LE líi.: Eftcrecoí,y col lechuga ; Jos hortelanos en ri)

The text on this page is estimated to be only 10.18%
accurate

-^8 .1 £ G 'aQ feis mi],y ci«n infanccs.y fctcci'eñtüs y trtú.tl

ho.nbres lie armas ,que'lhman Infínccria , y
C3ralIcríjkDrxofede^lno.nbre Lacrn.lei^.io a dele¿lii imirtuin , rdíc
Varronc, ?;b.4.deiííi.",ua Latíüa , eo quod iég'iotiís milites víritim kgí
foleaor. LEGISTA.elqucprofe'íra la faculcad de leyes. *i<
LE&lTIMA,loc]uelecompeceal hijo por herencia de Jos bienes de fus
padres. LEGITIMO, vulgarmente entendemos el nacido de leglciino
matriinoniocen rigor, legitlmofs todo aquello qne fe hazc conforme f
la ley.Latin.legitlmus ,qyod eft iurtum , arquuiní conueniens > lege,
more , acqiie ínfticuto maiorüiu factmniMugcr legitima, la cafada con
fu marido leglcimamenre. Marcial haze vn juguete dé dos
amancebados , que los auian hecho cafac por fuerza conforme a la
ley lulia , líb. 5. epigr* JÓ, Ad Qníndluir!. Quíí iegis can/a nnpJH tibí
Ld'iA í¿¿ijn¿ie\ Vxorem potes hancdkcrc iegitimam. LEGITIMAR ,
hazcr leglrímo al que rio lo es, gracia que fuelenhazer los Reyes por
caufas que a ellos les parecen. Quales (can legítimos ^ d no vide
lurifconfultos. LEGO , el hombre que no pertenece al cftado
Eclefiaftíco ih'c, sutjiíbcndo, aut vetando á delcíti;. Psp."f,i;.ro
lürifconfulto la define deíla marera , I ex cf', ccmn-iuric praccpiuní ,
viroitm p_fuc!rr.trj m confultimi,deliiftoruin,c,i;a: fpf ntc , vcl i¿ nr rr.
ntla contrahuntur coercicio.l.i.D.de Jf jni.iií.Sm to Tomas
i.2»qüa;fi.po. arcic.i. la cífirc iras impíamente, comprelienditinio
redas }r,s- diur'rvciasdeleyes,y dizeafsí.í.fv elt regU!3,S.: i.V-cj) fura
aftuum agendorum,vcl omutendoriun.y q.?rv artic.
i.dÍ2eloniefm'o;Lex eií dfáamen ra'ci;. Desleal, deslealcad.
LEGISLADOR., el que con autoridad haze leyes, i^ Para la ejecución
d'. la Jcy r.inguna cofa hade fer eftonií^, ningíin reff'íedo lvi;ujno ha
de gozar de excepción. Selcuco , Leg-isK:d> r délos Lorcnfcs,
auitndo mandado por vna lí-, que le fueíTen facados lo?. o/';s a -
¡iiaiquicra q f;?^ f fe hallado en adulCw/Io : 3\iieí-;dt) fido hsHsdo
(.-rt el fu propio l)ijo , le condenó en la pena de laJf^-. y auícndofe
convocado todos losCiüdadanos,ir¡oi* uidosde compafsioii,
afuplicarle rcmitíel'e p^'t aquella vez tal cruel rigor, por lo que a tod
-s iúiportiua fu Principe', por lo menos permiciVnr;:i que folamentefe
le facaíf^ vn ojo; vencido ei Rey de los ruegos del Pueblo, pomo
defjgradarlosj, ni dcxar de cumplir con fu rigor Ja psna de la ley « fe
facó élfOaifmo vn ojo , y mando facar otro a fit hijo , como refiere
Valerio Máximo lib. 6. cap. 5 ¿ Aulendo Manlio Torquato Confuí
hecho acici do.que ninguno de fu c.^ercTto fe atreuielTe a faKr a
batalla fin licencia.peDadela vida? Tito Manlio fu hijo, como falicííe
contra vn Latino liamadoGcmínOjfin ferie defcnfa.aüerle vencido,
vaiut fido prouccado del , con palabras muy injui ioOií al Pueblo
Romano, fu mifmo padre mando tociír las trompetas en leñal que
todos fe juntafleh j y defpues de auerle dicho vn tazonamicrito ciuc),
aunque amorofo , mandó al Sargento le á¡cf\ muere» V como refiere
Tico I ñiío llb.S. de la t'c c«da j icagr^ .y ¿,X Marco Ponió Ce ton, en
v r*'i
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L E N oracíori que híztJiCxorcando ál Senadopara el cif tUo

de ciertos fculpad^s.eh la cor;uracIon de Ca cil*na , corüprobando
con cales excmp)os,que para la execüclon de la Jüíllclaj ningún
refpedo humano attía de fcrvir de eftorüo en conHrmacion de efla
verdad; RedéTrajanus Imperacor,Prit;fe cto Pretorio enfemtradens
dixíc : Accipchunc cnfem , & Ci bene ego Reípüblica: IniperauerOj
pro nje , fitt mirius contra me vcaris vtjlo.* ^ Ley
Sáícnj;ua({;nquehuuleíre otra) hafla dcfpucsJeel diKiuío, co.no iit
autem ierra Ub'j vniuí ^ fermonum fó'r/irz^iAíiPcio qutficndotn el
campo , v tierra de Scnaf hazer ifi f^beruio cdificio.diziendo vnos
aotros,eodemc3p.nurti.4. Venite fuciamus nobis Cinitatmi ,
^turrim,cuius culmehpertingat ad Ccelutn , ¿^ cekbremus mmen
noftrum , antequam diuidamur in vniuerfai térras. Enojado Dios de
fu fobciuia , enrre otras palabras del Sagrado Texto dize.ibidem
nuTñtT.-j.Venite igitur ,defiendamus , ó" confundj^mus ibi Unguatn
eoruf/i , vt non atidiat vmifqmf'. que vocemproximijui. Deíia
confufion rcfuicaron las fecenca y dos l'-ñgüas en que fe diuidíeró, y
fueocafion ,dequefiguicridocada vno la que le fue Infundid3,ó
confundida , fe diuidieroh a poblar díücrfas Provincias, yiio es de
marauiilar que en lenguas muy ertrañas fe hallen algunas pa labras
que ciren a las Hebreas : puesdeftajsndofedella,comodefumadre
lleualTen algún raílro de fu primer origen.^ Heber , dcfcendirnce del
primogénito de Noe,y los de fu familia quedaron con la lengua
antigua , que procedió de nucíhos primero? padres, y de fu nombre:
a diferencia de las demás fe llamó Hebrea: y afsl quando lacob, y fus
hijos fueron a E^ipro , los llamaron por efte nombre Hebreos, v el
tiempo que enuuiercn en lacautiuidad confervarort fu lengua,
Saliendo de Egipto, y comunicando con otras naciones la aicerarort .
y corrompieron de modo , que quando nueflro Redemptor vino al
Mundo , fe hablaua vulgarmente lajengua Siriaca mezclada, )í> folo
los libros de Moyfen,y los Profeta^conferüaronla Efcritura.y
lapurezadela lenuuaH embrea j fin embar¿o de que también van
mezcladas . algunas pa'abras Caldeas ; y afsi la Caldea como,. la
Syriaca.fe deriuaron de la lenguaHebrea ;y mu chos fon de opinión
que la lengua Arábiga trae origen deltas tres. Los Griegos cuuieron
por Barbaras a íasde- , mas naciones; peroellos vencidos délos
Romanos huuieron de admitir fu lengua Latina, partí- . cularmente
los hombres princip les , y que aulan de acudir con negocios al
Senado Romano, a donde no fe permitía hablarla lengua eftraña.
Sinctii-, bargode eílo fe introduxo ei aprender los Roma* nos la
lengua Griega , yira eliuJiarlaa Atenas : conlasdicIplinas,y artes
liberales, que efiauan efcrltas en la dicha lengua, y juntamente con
ello enriquecieron la lengua Latina , introduciendo infinitos vocablos
que craeil origen de laGriega; •■'■.•,:Qu; lengua fue la antigua que
hiblaroh los í B.om> nos, iio fe ha podido enteramente auerl-.i guar,
por lis muchas en que fe deuló de diuldlg ; la Provincia ; y porque
aquellos que en dlfe.-t;. rentes tiempos la dominaron Introducirían
kan,, guas propias. De las qquedaronmuchos vocablos fueron de la
lenguaHetrufca.y Hofca, y la coma deuia fer en los vlcimos tiempos
la deLacI< jdcfió de cotno el úoisbre de lengua Latina. ■-" '^' De
The text on this page is estimated to be only 10.14%
accurate

^^ M I. . H ' N it^ Decfendiéndo en parclcular i mthn leng-

J^ Eíp-irioU , dudafé qíuí aya fulo I.i propia que
lubhronancíf^uanrientc-.parecc verriünll auer (ido la quctrntoTiibal, y
.nuches fofpechan fcrU que aora Uimaaios Vsfcucnce ; pero de
canco tiempo acuauralidohierca el corromperfe. S^aeña,^ o fea otra
, ellafe vleneaGoní'uadír con la veníds dediuerfas nicír>nes a Efpañi :
como fueron Lydlos, Babilonios, Traces, diegos, Fenices» Frigios,
EgÍpcios,Focenfes, Mifios, yerras njuchasna Clones coinbidadas, y
acraidascon la ríqueíads las minas del oro , y placa , qu,' en elU
Prouincla defoubrúron los CarCigineofes. Y los Romanos vífli2f on en
compecencla vnos de otros, y la feñorearon , aiiniquealcibo ios
Romanos quedaron feíiores de coda Efpaáa.y como vencedores
incrodureron fu lengua Romana, y fehablava, y efcrlvla como en
Roma. Pero enerando ios Godos en ella la corrompieron , y
mezclaron vocablos fuyos , quedando juncamente con ellos algunas
de los de la ancigua len¿ua£fpaáola de do procedió vnlen^uage de
Lacin corrupto .qiuJcselde las leyes de los Godos, y de algunos ocros
libros, que en aquel clenapo fe ufcrivíeron» Vlcimamence , dsfpues
ds la perdida de Eípaííl , feñoreandola los Moros , incrodnxeronmu*
c.hos vocablos Árabes , que le mezclaron con la Icn'^ui
CafteÜana.ylos ludios también noscomu nicaron vocablos tlebreos , y
cenemos algunos otros que in nediacam-ncs vien .-n de la lengua
Griega: hanfe ayuntado algunos otros vocablos Italianos, Prancefss,
Aleinin2>',ydcotras naciones,aunque ellos fon pocos, y los mas han
venl.lo con las mercaderías, V cofas que fe Inn rraido a
Efpaña.conferuandoles fus propios no.nbres.De aqiii fe puede colegir
quan dificultofo fea el dar orIs;en a todos los vocablos Callellanos: y
cita ha fido U ciufa de que muelos que lo lun cmpr-endídr> ddíllen
muy defde los principios , contcncandofc con dar la eclmj logia
drqual, y qual vocablo. .„ * ,.- ., La lengua antigua Efpa ñola dcuiofer
dincil, y afpcra de'pronunciar a los foraÜeros ; y por efta razón fe
deue eftimar , fiendo lengua varonil. Marcial hablando della ,y de fus
vocablos groferos,dizelibro4.epl¿ramina 5 5.adLucIuin, Luei
¿hria,3iC.ib\: ,. , ■ ' ''' • Ridet nomina} ridsashcmt,' ; í;.-.'tjri-:
Hectam ru/iieadilicateííéhr; ■ Wniphlí ida el tiempo de el L^ey Don
Alonfo el Sabio f^hazian lasefcrituraspublicas en lengua Latiniiypor
fu mandado de al I i adelante fe hizieron en lengua Caltellana, con
fin deqt»í f; puKefle, y cnriqu^ecIeíTejComo fe ha hecho defde
aque? tiempo acá. j ' Eña lengua fe llama Roma rvCe í per deíiuarfc;
de Ial2n;/H3 Romana, y es nombre conuin a la l':n7ua vulgar leal
iana.a la Francef3,y a la CaílciiaT, ) j: lai codi? cce« :raen origen
dáia? )r cqjj lo dicho, plreceauerfe cumplick) con nucHra lengua
Caílellana, lo demás fe dirá en fus proeles Jugares; folo es de
adaertir,que los hctnbres doctos hablan, y efcriuen con mas
elegancia,y propíe dad que el vulgo , y a vezes con canta diferencia,
que parecen di verfas lenguas : y es lo que Quin tíliano dlxo de la
lengua Latina libro 1 2 .c pitido io.Namni|hi alíamquandam
vldeturhabere nacuram , fec/no vulgaris,ah'am vlrí eloquentls orado.
La noticia de muchas lenguas fe puede tener por gran felicidad en la
tierra , pues con ellas comunicad hombre diuerfas naciones , yfuele
fer demucho frucoelí tafos de necefsidad, refrer.aadocl furordel
cneinigo , que hablandole cu fu propia lengua fe reporra, y concibe
vnacícita a-., nnidadde parcntefco que leobiigaaferhuiv-ano, y
clemente, como lo dixoFilon de confuíion- i.n • guarum , tratando de
los d-rios,y mnertts íjue te han fegüido por no entender fe vnos a
ocros , con eílaspalabras ; Miiki abinfidiat.tribustx im¡-,rouí-fo , ob
impericlam linguarum op^rcfi íiint, ^ c. y mas adelante : Nonlcue
argii.iientuin Cocitcatisaftércns:loquell!m familiarem , vndc m^x
2ccedit ,fecnrícasapericu)n. Yenta.'jto qne \ftas'. naciones con otras
no vinieron a comunicar' fu lenguagc,no pudieron elhr en paz, ni en
amTilad, que como dixo Platón en el Tirneo : Proptcr h'oceíl
nobisdjtusferiDO.vt prefio íbrcnc.müuijE vo-.
luntatisinditia.DeMicridates.Rey del p
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