Table Of ContentPreface
The textbook Principles of Regenerative Medicinehas been created to be the primary resource for
scientists,clinicians,teachers,students,and the public at large in the area ofregenerative medicine.I am hon-
ored to have had the opportunity to edit the first edition with our co-editors,Robert Lanza,Robert Nerem,
and Jamie Thompson.The contributions ofthe editors and editorial board cannot be overestimated.We are
indebted to their vision,and the strong foundation they have created,upon which the current text is built.
The specialty of regenerative medicine continues to grow and change rapidly. There have been major
areas ofadvances in just the last few years.The field now encompasses multiple areas ofscientific inquiry,each
complex,but together,a powerful combination of technologies such as stem cells,genetic reprogramming,
nuclear transfer,cloning,genomics,proteomics,nanotechnology,and tissue engineering.We are on the verge
ofan era oftranslation ofbenchside discoveries to clinical therapies.We hope that this book will enlighten all
ofthese areas,and supply guidance where it is needed most.
The textbook was organized in a manner which builds upon the basic science ofthe field,and goes for-
ward to possible clinical applications and clinical utility.The textbook is organized into seven major areas,
starting with an Introduction to Regenerative Medicine that encompasses some of the fundamentals of the
field.The Biologic and Molecular Basis ofRegenerative Medicine covers the molecular,mechanistic and pheno-
typic aspects of cells and cloning.The third section,Cells and Tissue Development,deals with the various
types of cells and determinants of tissue formation.A section is dedicated to the area of biomaterials,espe-
cially as it pertains to tissue engineering.The fifth and sixth sections cover the topics oftherapeutic applica-
tions, and deal with cell and tissue therapy, respectively. The last section of the book is dedicated to the
regulatory and ethical aspects of the field.This area is becoming increasingly more important as the nexus
between science,safety,and ethics is constantly changing.The authors have been tasked with enlightening the
reader with the scientific efforts that are likely to impact the future ofthe field.We are indebted to our authors
who graciously accepted their assignments,and who have infused the text with their energetic contributions.
We are especially indebted to our publisher,Academic Press,without whose trust and guidance this work
would not have begun;and our developmental editor,Melissa Turner,without whose hard work it would not
have been finished.
Anthony Atala,M.D.
For the Editors
xiii
List of Contributors
Jon D.Ahlstrom Stephen F.Badylak*
Department ofMolecular and Cellular Biology McGowan Institute for Regenerative Medicine
University ofCalifornia at Davis University ofPittsburgh
Taby Ahsan Ashok Batra
Parker H.Petit Institute for Bioengineering and Office ofCellular,Tissue and Gene Therapies
Bioscience Center for Biologics Evaluations and Research
Georgia Institute ofTechnology
M.Douglas Baumann
Julie Allickson* Chemical Engineering and Applied Chemistry
Vice President Laboratory Operations,Research & University ofToronto
Development
Ravi V.Bellamkonda*
Cryo-Cell International,Inc.
Professor ofBiomedical Engineering
Alejandro J.Almarza Neurological Biomaterials and Therapeutics
Research Assistant Professor Wallace H Coulter Department ofBiomedical
Musculoskeletal Research Center Engineering
Department ofBioengineering Georgia Institute ofTechnology/Emory University
University ofPittsburgh Atlanta
James M.Anderson* Nicole M.Bergman
Department ofPathology Department ofBioengineering
University Hospitals ofCleveland Rice University
Z.Beyhan
Peter Andrews*
Cellular Reprogramming Laboratory
Department ofBiomedical Science
Michigan State University
University ofSheffield
Western Bank
Mickie Bhatia*
Sheffield,Great Britain
Stem Cell and Cancer Research Institute (SCC-RI)
Michael G.DeGroote School ofMedicine,
Hadi Aslan
McMaster University
Hebrew University – Hadassah Medical Center
Canada
Hebrew University
Center for Converging Sciences & Technologies Sangeeta N.Bhatia
Skeletal Biotechnology Lab Division ofMedicine
Brigham & Women’s Hospital
Anthony Atala*
W.B.Boyce Professor and Director, Peter M.Black
Wake Forest Institute for Regenerative Medicine, Harvard Medical School
Wake Forest School ofMedicine,Winston-Salem, Department ofNeurosurgery and Physical
North Carolina,USA Medicine & Rehabilitation
xv
xvi LIST OF CONTRIBUTORS
Helen Blau* George J.Christ*
Donald E.and Delia B.Baxter Professor Professor ofRegenerative Medicine,
Director,Baxter Laboratory in Genetic Pharmacology Urology and Physiology & Member,
Stanford University School ofMedicine Molecular Medicine Program and Virginia
Department ofMicrobiology and Immunology Tech-Wake Forest University
Clinical Sciences Research Center School ofBiomedical Engineering and Sciences
CA,USA Head ofthe Cell,Tissue & Organ
Physiology Program
Scott D.Boden
Wake Forest Institute for Regenerative Medicine
Professor ofOrthopaedic
Wake Forest University Baptist Medical Center
Surgery Director,Emory Orthopaedics &
NC,USA
Spine Center
Seyung Chung
Eric M.Brey Childrens Hospital Los Angeles
Department ofResearch University ofSouthern California Keck School of
Hines V.A.Hospital Medicine
Ali H.Brivanlou* J.B.Cibelli*
Professor and Head ofthe Laboratory ofMolecular Cellular Reprogramming Laboratory
Vertebrate Embryology,Rockerfeller University Michigan State University
Massimo Cimini
Chris R.Brown
MaRS Center
The Emory Spine Center
Toronto Medical Discover Tower
Scott P.Bruder
Paolo De Coppi*
DePuy Spine,Inc.,a Johnson & Johnson Company
Department ofGeneral Paediatric Surgery
Great Ormond Street Hospital and Institute of
S.M.Chambers
Child Health
Center for Cell & Gene Therapy
Baylor College ofMedicine
Mahesh C.Dodla
Georgia Institute ofTechnology
Christopher S.Chen*
University ofPennsylvania Juan Dominguez-Bendala
Translational Research Labs University ofMiami Leonard M.Miller
School ofMedicine
LiHow Chen
Pancreatic Development & Stem Cell Laboratory
GTC Biotherapeutics
Diabetes Research Institute
Mike Chen*
AM Doyle
Department ofSurgery
Georgia Institute ofTechnology
University ofFlorida
Parker H.Petit Institute for Bioengineering and
Bioscience
Sulin Chen
Department ofBiomedical Engineering Charles N.Durfor
Johns Hopkins School ofMedicine Center for Devices and Radiological Health
N.Cheng Yann Echelard
UNC School ofMedicine GTC Biotherapeutics
List of Contributors xvii
Rita B.Effros* Andres Garcia*
Department ofPathology & Laboratory Medicine Associate Professor
David Geffen School ofMedicine at UCLA WoodruffFaculty Fellow
WoodruffSchool ofMechanical Engineering
Jennifer Elisseeff*
Petit Institute for Bioengineering and Bioscience
Department ofBiomedical Engineering
Georgia Institute ofTechnology
Johns Hopkins University
William Gavin
Ewa C.S.Ellis
GTC Biotherapeutics
Department ofPathology
University ofPittsburgh
Daniel Gazit*
Juliet A.Emamaullee Hebrew University – Hadassah Medical Center
University ofAlberta Hebrew University
Center for Converging Sciences & Technologies
Carol A.Erickson* Skeletal Biotechnology Lab
Department ofMolecular and Cellular Biology International Stem Cell Institute – Department of
University ofCalifornia at Davis Surgery
Cedars Sinai Medical Center
Roger De Filippo*
Los Angeles,CA
Childrens Hospital Los Angeles
Division ofUrology
Zulma Gazit
Hebrew University – Hadassah Medical Center
Donald Fink
Hebrew University
Office ofCellular,Tissue and Gene Therapies
Center for Converging Sciences & Technologies
Center for Biologics Evaluations and Research
Skeletal Biotechnology Lab
William H.Fissell
University ofMichigan Medical School, Christopher S.Gemmiti
Department ofInternal Medicine Georgia Institute ofTechnology
Gary E.Friedlaender
Jörg C.Gerlach*
Department ofOrthopaedic Surgery
McGowan Institute for Regenerative Medicine,
Yale University School ofMedicine
Bridgeside Point Boulevard
University ofPittsburgh
Mark E.Furth
Department ofUrology
Paul J.Gokhale
Wake Forest University
University ofSheffield
Institute for Animal Breeding (FAL)
Yossi Gafni
Hebrew University – Hadassah Medical Center
M.A.Goodell*
Hebrew University
Center for Cell & Gene Therapy
Center for Converging Sciences & Technologies
Baylor College ofMedicine
Skeletal Biotechnology Lab
Keneth Gage May Griffith
McGowan Institute for Regenerative Medicine, University ofOttawa Eye Institute
University ofPittsburgh Ottawa Hospital-General Campus
xviii LIST OF CONTRIBUTORS
Louis M.Guenin Chantal E.Holy*
Department ofMicrobiology and Molecular Director ofScientific Affairs DePuy Spine 325
Genetics Paramount Drive Raynham,MA,USA
Harvard Medical School
Mariah Hout
Stefano Giuliani McGowan Institute for Regenerative Medicine,
Division ofUrology,Childrens Hospital Los Angeles, University ofPittsburgh
Saban Research Institute,Keck School ofMedicine,
University ofSouthern California Jiang Hu
Department ofBiologic and Materials Sciences
Robert E.Guldberg*
University ofMichigan
Professor,Associate Director,Institute for
Bioengineering and Bioscience
George T.-J.Huang
School ofMechanical Engineering
Division ofEndodontics
Georgia Institute ofTechnology
Baltimore College ofDental Surgery
University ofMarlyand
M.C.Hacker
Rice University
Johnny Huard*
Laboratory ofBiomedical Engineering
The Growth and Development Lab,
Benjamin S.Harrison* Childrens Hospital ofPittsburgh
Wake Forest University School ofMedicine
Elliot E.Hui
Bernd Hartmann Harvard – M.I.T.Division ofHealth Sciences
Burn Center and Biology
Unfalkrankenhaus Electrical Engineering and Computer Science
Stephen H.Hilbert H.David Humes*
Center for Devices and Radiological Health University ofMichigan Medical School,
Department ofInternal Medicine
Alexander Hillel
Department ofOtolaryngology – Head &
Marcos Intaglietta
Neck Surgery
Department ofBioengineering
Johns Hopkins University School ofMedicine
University ofCalifornia San Diego
MD,USA
Junfeng Ji
Jason Hipp*
McMaster Cancer and Stem Cell Biology Research
Department ofUrology and Regenerative Medicine
Institute
Wake Forest University
McMaster University
Col.J.B.Holcomb
U.S.Army Institute ofSurgical Research Yueha Jiang
Stem Cell Institute
Jeffrey O.Hollinger* University ofMinnesota
Professor ofBiomedical Engineering and Biological
Sciences Christa Johnen
Director,Bone Tissue Engineering Center Charite-Campus Virchow
Carnegie Mellon University Humboldt University
List of Contributors xix
Josephine Johnston* Yash Kolambkar
Associate for Law and Bioethics Graduate Research Assistant
Director ofResearch Operations Department ofBiomedical Engineering
The Hastings Center,New York Georgia Tech/Emory Center for the Engineering of
Living Tissues
Akira Joraku
Department ofRegenerative Medicine, Chester J.Koh
Wake Forest University Health Sciences, Childrens Hospital Los Angeles
Winston Salem University ofSouthern California Keck School of
Medicine
David L.Kaplan*
Department ofBiomedical Engineering Makoto Komura
Tufts University The Department ofPediatric Surgery
Tokyo University Hospital
David S.Kaplan
Douglas Kondziolka
Center for Devices and Radiological Health
University ofPittsburgh
Gilson Khang Neurological Surgery
Department ofPolymer NanoScience and
Deniz Konya
Technology
Department ofNeurosurgery and Physical
Chonbuk National University
Medicine & Rehabilitation
Rehan N.Khanzada Harvard Medical School
Sr.Process Development Engineer
Wilfried A.Kues
Johnson & Johnson Regenerative Therapeutics,LLC
Department ofBiotechnology
Institute for Animal Breeding (FAL)
Soon Hee Kim
Department ofPolymer NanoScience and Technology
Francois Ng kee Kwong
Chonbuk National University
Tissue Engineering,VA Boston Healthcare System
Moon Suk Kim
Deepak Lamba
Nanobiomaterials Laboratory
Department ofBiological Structure,School
Korea Research Institutes ofChemical Technology
ofMedicine
University ofWashington
Nadav Kimelman
Hebrew University – Hadassah Medical Center
Hai Bang Lee*
Hebrew University
Nanobiomaterials Laboratory
Center for Converging Sciences & Technologies
Korea Research Institutes ofChemical Technology
Skeletal Biotechnology Lab
Hyukjin Lee
Irina Klimanskaya* Department ofBiological Sciences
Advanced Cell Technology Korea Advances Institute ofScience and
Biotech Five Technology
Jonathan A.Kluge Gary G.Leisk
Department ofBiomedical Engineering Department ofBiomedical Engineering
Tufts University Tufts University
xx LIST OF CONTRIBUTORS
Kam W.Leong* Peter X.Ma*
James B.Duke Professor ofBiomedical Professor,
Engineering,Director ofthe Bioengineering Fellow,American Institute for Medical and
Initiative,UK Biological Engineering
Department ofBiologic and Materials Sciences
Ariel J.Levine
Department ofBiomedical Engineering
Rockerfeller University
Macromolecular Science and Engineering Center
The University ofMichigan
Ren Ke Li*
MaRS Center
Ellen Maher
Toronto Medical Discover Tower
Office ofCellular,Tissue and Gene Therapies
Wan-Ju Li Center for Biologics Evaluations and Research
Cartilage Biology and Orthopaedics Branch
Manuela Martins-Green*
National Institute ofArthritis
Department ofCell Biology and Neuroscience
Grace J.Lim* University ofCalifornia
Medical Research Institute
Department ofMedical and Biological Engineering Randall E.McClelland*
Kyungpook National University School of University ofNorth Carolina School ofMedicine
Medicine,South Korea
Richard McFarland
Yan Lin
Office ofCellular,Tissue and Gene Therapies
The Forsyth Institute
Center for Biologics Evaluations and Research
William J.Lindblad*
Larry V.McIntire*
Department ofPharmaceutical Sciences
The Wallace H.Coulter Chair and Professor
Massachusetts College ofPharmacy & Health Sciences
Department ofBiomedical Engineering
Wendy F.Liu Georgia Tech
University ofPennsylvania
Translational Research Labs Harry Meade*
Senior Vice President
Xiaohua Liu Research and Development
Department ofBiologic and Materials Sciences GTC Biotherapeutics
University ofMichigan
David L.Melican
Andrea Lucas-Hahn
GTC Biotherapeutics
Department ofBiotechnology
Institute for Animal Breeding (FAL)
A.G.Mikos*
Rice University
Aernout Luttun
Laboratory ofBiomedical Engineering
Department ofMedicine
Stem Cell Institute
Fernando Ulloa Montoya
University ofMinnesota
Department ofMedicine
Samuel Lynch Stem Cell Institute
BioMimetic Therapeutics Inc. University ofMinnesota
List of Contributors xxi
Robert M.Nerem* Antonello Pileggi
Georgia Institute ofTechnology Research Assistant,Professor ofSurgery
Parker H.Petit Institute for Bioengineering and Cell Transplant Center & Clinical Islet
Bioscience Transplant Program
Diabetes Research Institute
Heiner Niemann*
Division ofCellular Transplantation
Department ofBiotechnology
DeWitt Daughtry Department ofSurgery
Institute for Animal Breeding (FAL)
University ofMiami Miller School ofMedicine
Aparna Nori
Jason H.Pomerantz
Department ofBiomedical Engineering
Baxter Laboratory in Genetic Pharmacology
Johns Hopkins School ofMedicine
Stanford University School ofMedicine
Patrea L.Pabst*
Blaise Porter
Pabst Patent Group LLP
Georgia Institute ofTechnology
Kook In Park
Milica Radisic
Department ofPediatrics and Brain
Assistant Professor
Korea 21 Project for Medical Science
Institute ofBiomaterials and Biomedical Engineering
Yonsie University College ofMedicine
Department ofChemical Engineering and Applied
Tae Gwan Park* Chemistry Heart & Stroke/Richard Lewar Centre of
Department ofBiological Sciences Excellence
Korea Advances Institute ofScience and Technology University ofToronto
David P.Patterson
Buddy D.Ratner*
Cartilage Biology and Orthopaedics Branch
Director,University ofWashington Engineered
National Institute ofArthritis
Biomaterials (UWEB)
Michael L.and Myrna Darland Endowed Chair in
Karen Pauwelyn
Technology Commercialization
Stem Cell Institute
Professor ofBioengineering and Chemical
Katholike Universiteit
Engineering
Leuven
University ofWashington
Gadi Pelled
A.Hari Reddi*
Hebrew University – Hadassah Medical Center
Professor and Lawrence J.Ellison Chair
Hebrew University
University ofCalifornia,Davis Sacramento,
Center for Converging Sciences & Technologies
CA,USA
Skeletal Biotechnology Lab
Laura Perin Thomas A.Reh*
Wake Forest Institute for Regenerative Medicine Professor ofBiological Structure
Wake Forest University School ofMedicine Health Sciences Center University ofWashington
Medical Center Boulevard School ofMedicine
Winston-Salem
Lola M.Reid*
M.Petreaca University ofNorth Carolina School ofMedicine
Department ofCell Biology and Neuroscience Cell and Molecular Physiology & Biomedical
University ofCalifornia Engineering
xxii LIST OF CONTRIBUTORS
Camillo Ricordi* Heather Sheardown*
Diabetes Research Institute (R-134) Associate Professor
Miller School ofMedicine Department ofChemical Engineering
University ofMiami McMaster University
JeffRoss Molly S.Shoichet*
Stem Cell Institute Professor,Chemical Engineering and Applied
University ofMinnesota Medical School Chemistry
Director,Undergraduate Collaborative
Alan J.Russell*
Bioengineering,
McGowan Institute for Regenerative Medicine
Canada Research Chair in Tissue Engineering
University ofPittsburgh
University ofToronto
Terrence Donnelly Centre for Cellular and
Filipe N.C.Santos
Biomolecular Research
Depts.OfNeurosurgery and Physical Medicine &
Rehabilitation Harvard Medical School
M.Minhaj Siddiqui
Massachusetts General Hospital
John P.Schmitz
San Pedro Facial Surgery Richard L.Sidman
Department ofNeurology
Gunter Schuch
Beth Israel-eaconess Medical Center
Wake Forest University School ofMedicine
Harvard Medical School
Institute for Regenerative Medicine
Ronald Silverman
Sargis Sedrakyan
Department ofBiomedical Engineering
Department ofUrology Children’s Hospital
Johns Hopkins University
Los Angeles
Keck School ofMedicine Daniel Skuk
University ofSouthern California Human Genetic Unit
Centre de Recherche du CHUL
Michael V.Sefton*
University Professor Evan Snyder*
Institute ofBiomaterials and Biomedical Engineering, The Burnham Institute
Michael E.Charles Professor,Department of
Shay Soker*
Chemical Engineering and Applied Chemistry
Associate Professor ofRegenerative Medicine and
University ofToronto
Surgical Sciences
Marta Serafini Head,Molecular and Cell Biology
Stem Cell Institute, Wake Forest Institute for Regenerative Medicine
Department ofMedicine Wake Forest University School ofMedicine
University ofMinnesota Medical School
Myron Spector*
Paulesh Shah Tissue Engineering,VA Boston Healthcare System
Department ofBiomedical Engineering
David L.Stocum*
Johns Hopkins University
Center for Regenerative Biolog and Medicine
A.M.James Shapiro Indiana University-Purdue University
University ofAlberta Indianapolis
List of Contributors xxiii
Stephen C.Strom* Deborah Vavoie
Department ofPathology Office ofCellular,Tissue and Gene Therapies
University ofPittsburgh Center for Biologics Evaluations and Research
Doris A.Taylor* Catherine Verfaillie*
Bakken Professor Professor ofMedicine
Director,Center for Cardiovascular Repair Director,Stamcelinstituut,K U Leuven
University ofMinnesota Onderwijs & Navorsing
1Herestraat 49,bus 80343000
Yang D.Teng* Leuven
Associate Professor,Harvard Medical School
Director,Lab ofSpinal Cord Injury & Neural Stem F.Jerry Volenec
Cell Biology DuPuy Spine
Neosurgery & PM&R,HMS/BWH/SRH
Sara Wargo
James Thomson McGowan Institute for Regenerative Medicine
Department ofAnatomy
Wisconsin Regional Primate Research Center Joseph W.Warnwath
Department ofBiotechnology
Robert T.Tranquillo*
Department ofBiomedical Engineering Lawrence Wechsler
University ofMinnesota University ofPittsburgh
Jacques P.Tremblay* Shen Wei
Human Genetic Unit The Growth and Development Lab,
Centre de Recherche du CHUL Childrens Hospital ofPittsburgh
Amy Tsai Richard D.Weisel
Department ofBioengineering MaRS Center
University ofCalifornia San Diego Toronto Medical Discover Tower
Rocky S.Tuan* Jennifer L.West*
Chief,Cartilage Biology and Orthopaedics Branch Rice University
National Institute ofArthritis,and Department ofBioengineering
Musculoskeletal & Skin Diseases
National Institute ofHealth Chrysanthi Williams
MD,USA Bose Corporation
ElectroForce Systems Group
Ross S.Tubo*
Senior Director, J.Koudy Williams
Stem Cell Biology,Genzyme Corp. Wake Forest University School ofMedicine
Institute for Regenerative Medicine
Mark Van Dyke*
The Wake Forest Institute for Regenerative Celia Witten*
Medicine Office ofCellular,Tissue and Gene Therapies
Wake Forest University School ofMedicine Center for Biologics Evaluations and Research
