Translational Regenerative Medicine

By Anthony Atala

Translational Regenerative Medicine is a reference book that outlines the life cycle for effective implementation of discoveries in the dynamic field of regenerative medicine. By addressing science, technology, development, regulatory, manufacturing, intellectual property, investment, financial, and clinical aspects of the field, this work takes a holistic look at the translation of science and disseminates knowledge for practical use of regenerative medicine tools, therapeutics, and diagnostics. Incorporating contributions from leaders in the fields of translational science across academia, industry, and government, this book establishes a more fluid transition for rapid translation of research to enhance human health and well-being.

• Provides formulaic coverage of the landscape, process development, manufacturing, challenges, evaluation, and regulatory aspects of the most promising regenerative medicine clinical applications
• Covers clinical aspects of regenerative medicine related to skin, cartilage, tendons, ligaments, joints, bone, fat, muscle, vascular system, hematopoietic /immune system, peripheral nerve, central nervous system, endocrine system, ophthalmic system, auditory system, oral system, respiratory system, cardiac system, renal system, hepatic system, gastrointestinal system, genitourinary system
• Identifies effective, proven tools and metrics to identify and pursue clinical and commercial regenerative medicine

• Language: English
• Publisher: Academic Press
• Release date: Dec 1, 2014
• ISBN: 9780124104570

Book preview

Translational Regenerative Medicine

Editors

Anthony Atala, MD

Julie G. Allickson, PhD

Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine Winston Salem, USA

Table of Contents

Cover image

Title page

Copyright

Dedication

Contributors

Chapter 1. The Landscape of Cell Tissues and Organs

I. The Regenerative Medicine Field

II. Conclusions

Disclaimer

Section I. Cell Banking

Chapter 2. Landscape of Cell Banking

I. Introduction: The Field of Cell Banking

II. Allogeneic and Autologous Cell Banking

III. Recruitment

IV. Regulations and Determination of Regulatory Guidance

V. Registration and Donor Eligibility Screening/Testing

VI. Current Good Tissue Practice (cGTP)

VII. Ethics (Personal Data, Health Information, Genetic Analysis, Privately Banked Cells)

VIII. Financial Aspects

IX. The Role of Banking in Regenerative Medicine

X. Conclusion

Chapter 3. Cell Banking: Process Development and Cell Preservation

I. Introduction

II. Product Characterization and Release Specifications

III. Standard Life Cycle of Banked Cell Therapy Product

IV. CT Facility

V. Cleaning and Disinfection

VI. Environmental Monitoring

VII. Equipment

VIII. Critical Reagents and Supplies Management

Chapter 4. Clinical Development of Placental Mesenchymal Stromal Cells

Conclusion

Chapter 5. Translation of Regenerative Medicine Products Into the Clinic in the United States: FDA Perspective

I. Introduction and Chapter Overview

II. Brief Legislative History of FDA

III. Roles of Laws, Regulations, and Guidance

IV. FDA Organizational Structure and Jurisdictional Processes

V. Approval Mechanisms and Clinical Studies

VI. Meetings with Industry, Professional Groups, and Sponsors

VII. Regulations and Guidance of Special Interest for Regenerative Medicine

VIII. Preclinical Development Plan

IX. Clinical Development Plan

X. Special Topic 1: Current Good Manufacturing Practices

XI. Special Topic 2: Regulation of Minimally Manipulated, Unrelated Allogeneic Cord Blood

XII. Special Topic 3: Animal Cell-Based Products for Veterinary Applications

XIII. Use of Standards in Regenerative Medicine

XIV. Advisory Committee Meetings

XV. FDA Regulatory Science Research Initiatives and Critical Path

XVI. Other Communication Efforts

XVII. Conclusion

Chapter 6. Newborn Stem Cell Banking Business Models

I. Introduction

II. Cell Biobanking History

III. Public NSC Biobanking

IV. Family NSC Biobanking

V. Operational Execution and Risk Management

VI. Unit Quality

VII. Unit Storage Maintenance

VIII. Risk Mitigation Strategies

IX. Market Potential

X. Competition

XI. Scalability

XII. Intrinsic Soundness of the Business Model

XIII. Hybrid NSC Biobanking Business Models

XIV. The Future of NSC Biobanking

Acronym

Section II. Stem Cells and Cell Therapy

Chapter 7. Cell Therapy Landscape: Autologous and Allogeneic Approaches

I. Introduction

II. Comparison of Commercial Potential between Autologous and Allogeneic Cell Therapy

III. Future Product Commercialization: Will Allogeneic or Autologous Cell Therapy Dominate?

IV. Conclusion

List of Abbreviations

Chapter 8. Stem Cells and Cell Therapy: Autologous Cell Manufacturing

I. Autologous Therapy

II. Bone Marrow Aspiration

III. Manufacturing

IV. Allogeneic Therapy

V. Manufacturing

VI. Summary

Chapter 9. Overview: Challenges of Process Development for Cellular Therapy

Chapter 10. Tissue Engineering: Propagation and Potency Evaluation

I. Introduction: The State of Stem Cell Potency Evaluation

II. Developing a Reliable Potency Assay with Clinical Relevance

III. The Future of Stem Cell Potency Enumeration

Section III. Biomaterials in Regenerative Medicine

Chapter 11. Biomaterials in Preclinical Approaches for Engineering Skeletal Tissues

I. Introduction to Skeletal Tissue Engineering (STE)

II. Biomaterials for Translational Regenerative Medicine

III. Could Bioreactors Be the Missing Link for Biomechanic Function?

IV. Scale-Up and Ready to Go Systems

V. Future Outcomes/Challenges

List of Acronyms and Abbreviations

Chapter 12. Biomaterials in Regenerative Medicine: Considerations in Early Process Development

I. Introduction

II. Assembling a Design Team

III. Identifying an Unmet Problem

IV. Biomaterial-Specific Considerations

V. Regulatory Challenges

VI. Conclusion

VII. Key Points

List of Acronyms and Abbreviations

Chapter 13. Biomaterials in Regenerative Medicine: Challenges in Technology Transfer from Science to Process Development

I. Introduction

II. Transfer of Biomaterials Technology from Laboratory to Commercial Production: Technical Considerations

III. Transfer of Technology from Science to Commercial Production: Current Challenges

IV. Options for Enabling Successful Transition of Technology from Science to Commercialization to Clinical Use

V. Additional Considerations for Process Development for Biomaterial-Based Products

VI. Summary

Further Reading

Chapter 14. Paracrine Regulation from Tissue Engineered Constructs

I. Introduction

II. The Development of Endothelial Cell–Based Paracrine Tissue Engineering Solutions

III. Designing Paracrine Tissue Engineering Constructs

IV. Implications of Paracrine Tissue Engineering in Clinical Study Design

V. Conclusion

Chapter 15. Creating Commercial Value from Biomaterials

I. Facing Reality: An Introduction to Translational Medicine and Commercialization

II. What Features Do You Really Need? Developing the Biomaterial

III. What Will You Sell? Choosing a Business Model

IV. Divide and Conquer: A Case Study in Licensing Focused Fields of Use

V. The Translational Imperative: Deliver Simplicity

Section IV. Tissue Engineering

Chapter 16. Manufacturing of Regenerative Medicine Products

I. Introduction

II. Manufacturing Process

III. Manufacturing Facilities and Process Equipment

IV. Cost of Goods

V. Good Manufacturing Practices, Good Tissue Practices, and Quality Systems

VI. Conclusions

Chapter 17. Regulatory Aspects

I. Introduction

II. Regulatory Path

III. Manufacturing Considerations

IV. Preclinical Considerations

V. Clinical Trial Design Considerations

VI. Developmental Challenges

VII. Conclusions

Chapter 18. Global Design for Clinical Trials

I. Tissue Engineering and Regenerative Medicine

II. Follow-Up Studies on Clinical Trials of Tissue Engineering

III. Topics on Scaffold

IV. Global Design for Clinical Trials of Tissue Engineering

Section V. Enabling Tools

Chapter 19. Biomarkers

I. Introduction

II. Disease- and Drug-Related Biomarkers

III. Biomarkers in Drug Development

IV. Biomarker Requirements

V. Biomarker Classification and Application

VI. Discovery of Molecular Biomarkers

VII. Surrogate End Points and Potential Disadvantages

VIII. Biomarker in Regenerative Medicine

XI. Quality Management

X. Personalized Medicine

Chapter 20. Translational Animal Models for Regenerative Medicine Research

I. Introduction

II. Brief History of Translational Animal Models for Regenerative Medicine Research with an Emphasis on Hematopoietic and Immune System Regeneration

III. Musculoskeletal Tissue Engineering

IV. Soft Tissue Regeneration

V. Ocular and Brain Repair and Regeneration

VI. Heart Muscle and Vascular Regeneration

VII. Lung Regeneration

VIII. Engineered Intestinal, Liver, and Pancreas Regeneration

IX. Urogenital Repair and Bladder Tissue Engineering

X. Future Approaches: Stem Cells, Reprogrammed Cells, and Immunodeficient and Humanized Mouse Models for Tissue Regeneration

XI. Pros and Cons of Translational Animal Models for Regenerative Medicine Research

Acronyms and Abbreviations

Chapter 21. Translational Imaging for Regenerative Medicine

I. Introduction

II. Contrast Agents

III. Ultrasound

IV. X-ray CT

V. Nuclear Imaging

VI. Magnetic Resonance Imaging

VII. Multimodal Imaging

VIII. Summary

Section VI. Clinical Aspects of Regenerative Medicine

Chapter 22. Skin and Skin Appendage Regeneration

I. Introduction

II. Epidermis

III. Hair Follicle and Sebaceous Gland

IV. Sweat Gland

V. Future Challenges in Skin Regeneration

Chapter 23. Clinical Aspects of Regenerative Medicine: Tendon, Ligament, and Joint

I. Introduction

II. Platelet-Rich Plasma

III. Bone Marrow Concentrate

IV. Discussion

V. Practical Considerations

VI. Summary

Chapter 24. Bone Regeneration

I. Clinical Importance of Bone Healing

II. Basic Biology of Bone Healing

III. Bone Regeneration

IV. Current and Future Repair Strategies

V. Conclusions

Chapter 25. Regenerative Medicine Therapies Using Adipose-Derived Stem Cells

I. Adipose-Derived Stem Cells for Therapy

II. Regulatory Process

III. Current Clinical Trials and Evolving Potential

IV. Methods of Lipoharvest

V. Methods of SVF Isolation: Automated versus Manual

VI. Flow Cytometry Analysis

VII. Concluding Remarks

List of Abbreviations

Chapter 26. Transplantation of Myogenic Cells in Duchenne Muscular Dystrophy Patients: Clinical Findings

I. Introduction

II. Cells with Myogenic Capacity: Candidates for Transplantation

III. Gene Complementation

IV. Neoformation of Myofibers

V. Generation of Donor-Derived Satellite Cells

VI. Control of Acute Rejection

VII. Potential Future Development in the Control of Acute Rejection

VIII. The Importance of the Method of Cell Injection

IX. Potential Future Developments in the Method of Cell Injection

X. Conclusions

Chapter 27. Regeneration of the Vascular System

I. Introduction

II. Tissue Neovascularization

III. Bioengineered Blood Vessels

IV. Summary

Chapter 28. Hematopoiesis in Regenerative Medicine

I. Introduction/Historical Perspective

II. HSC Transplantation for Hematologic Diseases/Disorders

III. Alternate Sources of HSC

IV. HSC Transplantation to Induce Immunological Tolerance and Treat Autoimmunity

V. HSC Transplantation for Diseases of Nonhematopoietic Organs/Tissues

VI. Summary

Chapter 29. The Application and Future of Neural Stem Cells in Regenerative Medicine

I. Establishment of Neural Stem Cells and Induction of Pluripotent Cells for Transplantation

II. Future Roles of Stem Cell Research

List of Abbreviations and Acronyms

Chapter 30. Central Nervous System

I. Introduction

II. Regenerative Strategies in the Injured CNS

III. The Current Landscape of Clinical Trials in the CNS

IV. Strategies to Address Clinical Challenges for Regenerative Medicine in the CNS

V. Conclusions and Outlook

Chapter 31. In situ Tissue Engineering Bone Regeneration in Jaw Reconstruction

I. The Biology of In situ Tissue Engineering

II. How the Three Components of the Tissue Engineering Triangle Work to Regenerate Bone

III. The Clinical Technique Required

IV. The Prepared In situ Tissue Engineered Bone Graft

V. Surgery to Place an In situ Tissue Engineered Graft

VI. Surgery for Mandibular Reconstruction

VII. Surgery for Maxillary Reconstruction

VIII. Biologic Activity within an ISTE

IX. Outcome Analysis: A Three-Cohort Study

X. Conclusion

List of Acronyms and Abbreviations

Chapter 32. Regenerative Medicine for Diseases of the Respiratory System

I. Introduction

II. Regenerative Medicine

III. Tissue Engineering

IV. Upper Airways: Nasopharynx Vocal Cords and Larynx

V. Trachea

VI. Lungs

VII. Cell Therapy

VIII. Clinical Translation and Its Barriers

IX. Mesenchymal Stromal Cells

X. Mononuclear Cells

XI. Endothelial Progenitor Cells

XII. ESCS and iPSCs

XIII. Other Cell Types

XIV. Pharmacological Intervention

XV. Conclusion

Chapter 33. Renal System

I. Introduction

II. Structure and Function of the Kidney

III. Acute and Chronic Kidney Disease

IV. Evidence of Normal Kidney Repair in Humans

V. Regenerative Strategies for Kidney Repair

VI. Cell Therapy for Renal Failure

VII. Tissue Engineering Approaches for Renal Failure

VIII. Conclusion

Chapter 34. Translational Regenerative Medicine–Hepatic Systems

I. Introduction: Hepatic Systems

II. Liver Diseases

III. Therapies for Liver Diseases

IV. Liver Transplantation

V. Cellular Therapies

VI. Gene Therapy Treatments for Liver Disease

VII. Liver Bioengineering

VIII. Liver Assist Devices

IX. Future Directions

X. Concluding Remarks

Chapter 35. Advances in Neo-Innervation of the Gut

I. Enteric Nervous System: Development and Functions

II. Enteric Nervous System Disorders: Descriptions and Clinical Treatments

III. Enteric Neural Cell Transplantation for Treatment of Aganglionic Disorders

IV. Utilizing Tissue Engineering to Improve Enteric Neural Cell Therapy

V. Conclusion

Chapter 36. Genitourinary System

I. Introduction

II. Genitourinary System Regeneration

III. Conclusions and Future Outlook

Chapter 37. Clinical Aspects of Regenerative Medicine: Immune System

I. Regenerating the Immune System by Entire or Partial Replacement

II. Engineering the Immune System with Specialized Component Therapies

III. Mesenchymal Stem Cells: Specialized Component Therapy Affecting Both Immune Responses and Regeneration

IV. Conclusions

Section VII. Translational Aspects of Regenerative Medicine

Chapter 38. Development of Appropriate Imaging Methods to Trace Cell Fate, Engraftment, and Cell Survival

I. Introduction

II. Imaging Approaches

III. Magnetic Resonance Imaging

IV. Positron Emission Tomography Imaging

V. Optical Imaging

VI. Emerging Approaches

VII. Selecting a Modality

VIII. Validation

IX. Conclusions

Chapter 39. Gap Analysis to Target Therapies

I. Introduction

II. The Pathway

III. Preclinical Data Packages

IV. Preclinical Expectations

V. Product Manufacturing

VI. Clinical Protocol

VII. Special Concerns for Cell and Gene Therapy Trials

Chapter 40. Funding for the Translation of Regenerative Medicines

I. Introduction

II. Investment Justification

III. Global Funding of Regenerative Medicine

IV. Private Funding of Regenerative Medicine

V. Stimulating Private Investment

VI. Creative Government Financing Mechanisms

VII. Conclusion

Index

Copyright

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Dedication

This textbook is dedicated to Katherine, Christopher, and Zachary.

Anthony Atala

This textbook is dedicated to Brandon and Jason.

Julie Allickson

Contributors

Mehran Abolbashari,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

Jaimo Ahn,     Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Salem Akel

St. Louis Cord Blood Bank & Cellular Therapy Laboratory, SSM Cardinal Glennon Children’s Medical Center, St. Louis, MO, USA

Department of Pediatric, Saint Louis University School of Medicine, St. Louis, MO, USA

Julie G. Allickson,     Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA

Graça Almeida-Porada,     Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Judith Arcidiacono,     Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

Anthony Atala,     Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA

Patrick Au,     Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

Danielle Aufiero

The Orthohealing Center and The Orthobiologic Institute (TOBI), Los Angeles, CA, USA

David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Orthohealing Center, Los Angeles, CA, USA

Western University of Health Sciences, Pomona, CA, USA

Touro University, Vallejo, CA, USA

Pedro M. Baptista

Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA

University of Zaragoza, Zaragoza, Spain

IIS Aragón, CIBERehd, Zaragoza, Spain

Aragon Health Sciences Institute (IACS), Zaragoza, Spain

Ronnda L. Bartel,     Aastrom Biosciences, Ann Arbor, MI

Amelia Bartholomew,     University of Illinois, Department of Surgery, Chicago, IL, USA

Elona Baum

Coherus BioSciences, Inc. Redwood City, California

formerly California Institute for Regenerative Medicine, San Francisco, California, USA

Angie Botto-van Bemden

Musculoskeletal Research International (MRI), Ft. Lauderdale, FL, USA

Clinical Research Experts (CRE), Ft. Lauderdale, FL, USA

Florida International University, Miami, FL, USA

Khalil N. Bitar

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Winston-Salem, NC, USA

Lynne Boxer,     Center for Veterinary Medicine, FDA, Rockville, MD, USA

Matthew P. Brown,     Founder Shama Consulting

Heather L. Brown,     Vice President Scientific Medical Affairs, Cord Blood Registry, San Bruno, CA, USA

Stephanie J. Bryant,     Department of Chemical and Biological Engineering, College of Engineering and Applied Science, University of Colorado, Boulder, CO, USA

Pedro P. Carvalho

3B’s Research Group, Department of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal

ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal

Prafulla Chandra,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

John R. Chapman,     President of Stem Cell Partners & Adjunct Professor of Biology, California State University Sacramento, USA

Shreyasi Das,     Sanford-Burnham Medical Research Institute, San Diego, CA, USA

Daniel B. Deegan,     Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA

Abritee Dhal,     Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA

Albert D. Donnenberg

University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

Matthew B. Durdy,     Cell Therapy Catapult, Guy’s Hospital, Great Maze Pond, London, UK

Charles N. Durfor,     Center for Devices and Radiological Health, FDA, Silver Spring, MD, USA

Elazer R. Edelman

Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA

Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

Donald Fink,     Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

Steven Fischkoff,     Celgene Cellular Therapeutics, Warren, NJ, USA

Joyce L. Frey-Vasconcells,     Frey-Vasconcells Consulting, LLC, Sykesville, MD, USA

Tobias Führmann,     Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada

Carmen Gacchina Johnson

Commissioner’s Fellowship Program, Office of the Commissioner, U.S. Food and Drug Administration, Silver Spring, MD, USA

Center for Devices and Radiological Health, FDA, Silver Spring, MD, USA

Or Gadish,     Harvard-MIT Program in Health Sciences and Technology, & Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA

Sanjiv S. Gambhir

Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, Stanford, CA, USA

Bioengineering, Materials Science & Engineering, Bio-X, Stanford University, Stanford, CA, USA

Adrian P. Gee,     Center for Cell & Gene Therapy, Baylor College of Medicine, Houston, Texas, USA

Manuela E. Gomes

3B’s Research Group, Department of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal

ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal

Kurt D. Hankenson,     Department of Small Animal Clinical Sciences College of Veterinary Medicine; and Department of Physiology, Colleges of Natural Sciences and Osteopathic Medicine

Robert J. Hariri,     Celgene Cellular Therapeutics, Warren, NJ, USA

Heather C. Hatcher,     Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA

Mohammad Heidaran,     Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

Ralf Huss

University of Munich, Munich, Germany

Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA

Apceth GmbH & Co. KG, Munich, Germany

Definiens AG, Munich, Germany

John Hyde,     Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

Yoshito Ikada,     Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

Deepak Jain,     Bioprocess Research & Development, Manufacturing and Technical Operations, Tengion, Inc., Winston-Salem, NC, USA

Paul A. Jain,     University of California-San Diego Medical Center, San Diego Veterans Affair Medical Center, San diego, CA, USA

Jesse V. Jokerst,     Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, Stanford, CA, USA

Philipp Jungebluth,     Department of Clinical Science, Intervention and Technology, Division of Ear, Nose and Throat, Advanced Center for Translational Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden

Eve Kandyba

Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA

Department of Pathology, University of Southern California, Los Angeles, CA, USA

David S. Kaplan,     Center for Devices and Radiological Health, FDA, Silver Spring, MD, USA

Safa Karandish,     Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

F. Kurtis Kasper,     Department of Bioengineering, Rice University, Houston, TX, USA

Sneha S. Kelkar

Wake Forest–Virginia Tech School of Biomedical Engineering and Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, USA

Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA

Norma Kenyon,     Diabetes Research Institute, Miami, FL, USA

Krzysztof Kobielak

Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA

Department of Pathology, University of Southern California, Los Angeles, CA, USA

Jesse Kramer,     Vice President Scientific Medical Affairs, Cord Blood Registry, San Bruno, CA, USA

Sang Jin Lee,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

Mark H. Lee,     Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

Yvonne Leung

Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA

Department of Pathology, University of Southern California, Los Angeles, CA, USA

Mei Ling Lim,     Department of Clinical Science, Intervention and Technology, Division of Ear, Nose and Throat, Advanced Center for Translational Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden

Neil J. Littman,     California Institute for Regenerative Medicine, San Francisco, California, USA

Paolo Macchiarini,     Department of Clinical Science, Intervention and Technology, Division of Ear, Nose and Throat, Advanced Center for Translational Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden

Nafees N. Malik

Cell Therapy Catapult, Guy’s Hospital, Great Maze Pond, London, UK

Asklepian Consulting, Birmingham, UK

Institute of Biotechnology, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK

Brenda K. Mann,     SentrX Animal Care, Salt Lake City, UT, USA

Kacey G. Marra

Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA

McGowan Institute of Regenerative Medicine, Pittsburgh, PA, USA

Robert E. Marx,     Chief Division of Oral and Maxillofacial Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

Lina Mastrangelo,     Sanford-Burnham Medical Research Institute, San Diego, CA, USA

Brent McCright,     Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

Richard McFarland,     Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

Michael Mendicino

Commissioner’s Fellowship Program, Office of the Commissioner, U.S. Food and Drug Administration, Silver Spring, MD, USA

Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

Antonios G. Mikos,     Department of Bioengineering, Rice University, Houston, TX, USA

Nikolaos Mitrousis,     Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada

Aaron M. Mohs

Wake Forest–Virginia Tech School of Biomedical Engineering and Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, USA

Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA

Department of Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, NC, USA

Thomas Moore,     Founder Shama Consulting

Emma C. Moran,     Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA

Walter Niles,     Sanford-Burnham Medical Research Institute, San Diego, CA, USA

Guoguang Niu,     Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston–Salem, NC, USA

Masashi Nomi,     Department of Urology, Suma-Ku, Kobe Children’s Hospital, Kobe, Japan

Tamara Nunez,     University of Illinois, Department of Surgery, Chicago, IL, USA

Robert Perry,     Athersys, Inc., Cleveland, Ohio, USA

Robert P. Pfotenhauer,     Vice President Scientific Medical Affairs, Cord Blood Registry, San Bruno, CA, USA

Christopher D. Porada,     Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Kavitha Premenand,     University of Illinois, Department of Surgery, Chicago, IL, USA

Glenn D. Prestwich,     Department of Medicinal Chemistry, The University of Utah, Salt Lake City, Utah, USA

Shreya Raghavan

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Winston-Salem, NC, USA

Mahendra Rao,     NIH Center for Regenerative Medicine, Bethesda, MD, USA

Anthony Ratcliffe,     Synthasome, Inc., San Diego, CA, USA

Stephen Rego,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

Rui L. Reis

3B’s Research Group, Department of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal

ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal

Ivan N. Rich,     HemoGenix, Inc, Colorado Springs, CO, USA

Márcia T. Rodrigues

3B’s Research Group, Department of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal

ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal

J. Peter Rubin

Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA

McGowan Institute of Regenerative Medicine, Pittsburgh, PA, USA

Steven Sampson

The Orthohealing Center and The Orthobiologic Institute (TOBI), Los Angeles, CA, USA

David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Orthohealing Center, Los Angeles, CA, USA

Western University of Health Sciences, Pomona, CA, USA

Touro University, Vallejo, CA, USA

Etai Sapoznik

Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston–Salem, NC, USA

Virginia Tech – Wake Forest University School of Biomedical Engineering and Sciences, Virginia Tech, Blacksburg, VA, USA

John G. Sharp,     Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE, USA

Molly S. Shoichet

Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada

Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada

Department of Chemistry, University of Toronto, Toronto, ON, Canada

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada

Daniel Skuk,     Neurosciences Division—Human Genetics, CHUQ Research Center—CHUL, Quebec, QC, Canada

Evan Y. Snyder,     Sanford-Burnham Medical Research Institute, San Diego, CA, USA

Shay Soker

Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston–Salem, NC, USA

Virginia Tech – Wake Forest University School of Biomedical Engineering and Sciences, Virginia Tech, Blacksburg, VA, USA

Sita Somara,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

Tom Spencer,     Process Development and Manufacturing, Tengion, Inc., Winston-Salem, NC, USA

Suzanne Stewart,     Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, USA

Premenand Sundivakkam,     University of Illinois, Department of Surgery, Chicago, IL, USA

Erszebet Szilagyi,     University of Illinois, Department of Surgery, Chicago, IL, USA

Alexander M. Tatara,     Department of Bioengineering, Rice University, Houston, TX, USA

Brian Tobe

Sanford-Burnham Medical Research Institute, San Diego, CA, USA

Department of Psychiatry, Veterans Administration Medical Center, San Diego, CA, USA

Jacques P. Tremblay,     Neurosciences Division—Human Genetics, CHUQ Research Center—CHUL, Quebec, QC, Canada

Alan O. Trounson,     Richie Centre, Monash University, Monash Medical Centre, Clayton, Victoria, Australia

Anup Tuladhar,     Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada

Lori Tull,     Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

Jolene E. Valentin,     Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA

Dipen Vyas,     Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA

Zhan Wang,     Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston–Salem, NC, USA

Alicia Winquist,     Sanford-Burnham Medical Research Institute, San Diego, CA, USA

Celia Witten,     Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, USA

Mark E.K. Wong,     Department of Oral and Maxillofacial Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA

James J. Yoo,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

Diana Yoon

Commissioner’s Fellowship Program, Office of the Commissioner, U.S. Food and Drug Administration, Silver Spring, MD, USA

Center for Devices and Radiological Health, FDA, Silver Spring, MD, USA

Elie Zakhem,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

Joao Paulo Zambon,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

Chapter 1

The Landscape of Cell Tissues and Organs

Mahendra Rao     NIH Center for Regenerative Medicine, Bethesda, MD, USA

Abstract

The regenerative medicine field is active and growing. It should not be considered as a unified field, but rather as a set of subfields that focus on different cells and different indications and are regulated by diverse regulatory pathways. The field remains united conceptually in that the players are all motivated to use cells, engineered cells, cells in combination with devices, and cell derivatives for treating disorders. As with any new field, several business models are being explored, and innovators are looking at different ways to offer services and to obtain returns on their investments. The regulatory authorities have had to scramble to keep up with these innovative breakthroughs, and academic investigators have developed ever more sophisticated ways to combine cells with biomaterials to generate complex three-dimensional structures to replace failing tissue. The field is dynamic, and new breakthroughs may change the field or accelerate existing trends.

Keywords

hematopoietic stem cells; mesenchymal stem cells; neural stem cells; regenerative medicine; Stem cell

Chapter Outline

I. The Regenerative Medicine Field 3

II. Conclusions 7

Disclaimer 8

References 8

I. The Regenerative Medicine Field

The dream of curing illness and injury by transplanting organs, bone, and other tissue is probably as old as the history of healing, with the first recorded attempts dating back to the Middle Ages [1–3] when tissue flaps were mobilized for wound repair. The term Regenerative Medicine is widely attributed to having first been coined by William Haseltine (founder of Human Genome Sciences), although the term was first found in a 1992 article on hospital administration by Leland Kaiser. Kaiser’s paper closes with a series of short paragraphs on future technologies that will have an impact on hospitals. One such paragraph had Regenerative Medicine as a bold print title and went on to state, A new branch of medicine will develop that attempts to change the course of chronic disease and in many instances will regenerate tired and failing organ systems. The regenerative medicine field as I see it is summarized in Figure 1. The field, as the National Institutes of Health (NIH) sees it, is summarized in a report [4] that states that regenerative medicine is the application of treatments developed to replace tissues damaged by injury or disease. These treatments may involve the use of biochemical techniques to induce tissue regeneration directly at the site of damage or the use of transplantation techniques using differentiated cells or stem cells, either alone or as part of a bioartificial tissue.

Successful transplantation of bone, skin, and corneas came first, with advances made between 1900 and 1920. The establishment of the U.S. Navy Tissue Bank in 1949 gave the nation its first bone and tissue processing and storage facility, and since then we have seen the birth of the bone marrow registries, cord blood and other tissue banks, and the Embryonic Stem Cells (ESC) and Induced Pluripotent Stem Cells (IPSC) banking initiatives. Table 1 provides an abbreviated timeline of some major milestones in tissue and organ transplants. Perhaps an important milestone is that by the 1990s, over half a million tissues had been transplanted and had benefitted hundreds of thousands of individuals. Equally important, the field has allowed us to standardize processes to collect, process, store, and distribute tissue and to understand the difficulties in solving the immune rejection phenomenon.

Other breakthroughs in immune suppression, such as cyclosporine treatment, allowed the development of bone marrow transplants [5]; this has led to treatment for a wide variety of disorders, and well over 25,000 bone marrow transplantations occur each year. The utility of bone marrow led to the search for other sources of blood cells, and two different findings have sculpted the field. One was the finding that mobilization simplifies the process of obtaining CD34-positive cells as compared to isolating bone marrow [6], and the other was that finding that cord and placenta contained a large number of engraftable marrow-like blood stem cells [7]. This observation has led to the birth of an entire industry dedicated to the collection and storage of cord blood and its use as an alternative source, supplement, or better substitute for marrow, particularly in children. A recent milestone reached was that the number of cord transplantations in children have exceeded those of bone marrow [8].

It was Friedenstein and coworkers, in a series of seminal studies in the 1960 and 1970s [9], who showed that the osteogenic potential, of BM cells, was associated with a minor subpopulation of cells in the bone marrow isolate. These cells were distinguishable from the majority of hematopoietic cells by their rapid adherence to tissue culture vessels and by the fibroblast-like appearance of their progeny in culture, pointing to their origin from the stromal compartment of BM. The currently popular albeit perhaps inaccurate term mesenchymal stem cells (MSCs) was first coined in 1991 by Dr Arnold Caplan (Paolo Bianco et al.). Work by Darwin Prockop and others (Phinney, Pittenger) further defined the cells and their multilineage capability. The ability to grow an autologous cell relatively easily and to obtain very large numbers of cells that appeared to be able to perform a wide variety of functions (Figure 2) has led to the birth of an entire subfield of regenerative medicine. More than 1000 trials have been run; more than 50 companies offering some variant of a mesenchymal cell are in existence; and commercial Food and Drug Administration (FDA)–approved products that use MSC are available to treat some diseases.

Figure 1   The overall field of regenerative medicine is broad and can be divided into several subfields based on whether cells, tissues or combination materials are used.

Figure 2   The multiple different ways mesenchymal stem cell like cells are used is summarized. Both autologous and allogeneic cells are available and can be used in most indications. The immune modulatory role of MSC in particular is being explored.

Table 1

Historical Highlights and Milestones

This table lists some milestones in using cells and tissue for transplants.

Modified from http://www.mtf.org/news_history_of_transplantation.html.

The ability to obtain HSC, cord blood–derived HSC, and MSC has allowed investigators to explore isolatable cells in other fields as well. Corneal Limbal cells found a niche use, and since the 1990s stem cells or progenitor cells or, perhaps more accurately, cells with a finite but impressive self-replicating potential, can be isolated from virtually all tissues. This has led to a further expansion of the regenerative medicine field (Figure 3).

Irrespective of how one defines the field or attributes the name, what is clear is that the field is growing by leaps and bounds due to the convergence of several different advances and recent breakthroughs (Figure 4). The Nobel Prize–winning work of Dr. Guerdon and Dr. Yamanaka [10,11] and the implementation of new methods of making human PSC [12] engineering pluripotent cells that further build on the Nobel prize-winning work of Dr. Capecchi and others [13,14] have further fueled the growth of this field. The past decade has seen an exponential increase in the products approved, the number of clinical trials initiated (www.cinicaltrials.gov), the number of biotechnology companies incorporated, and the number of papers published [15,16]. These developments have led to the treatment of hundreds of thousands of patients and the creation of entire new subfields fields such as that of induced pluripotence [17].

Making ESC from human cells and the demonstration that these cells are a unique population of cells that do not undergo senescence has meant that, in theory, every investigator had access to the same cell type and studies could be compared without the confounding influence of allelic variability, laboratory-to-laboratory variations, and other cell culture artifacts. The generation of iPSC in addition to forcing us to reevaluate our understanding of development in essence brought ESC technology to the masses, and for investigators working in the translation field suggested that the immune issue for transplantation could be solved in an elegant way.

Parallel advances in Next-GEN sequencing, which have exponentially reduced the cost and the number of cells required for analysis while increasing the variety of information that can be processed, have provided a depth of data that has allowed rapid analysis of single genomes and cell states [18,19]. Today it is very possible to sequence the entire genome, and to obtain an epigenome methylation and miRNA profile with as few as 10,000  cells at a cost that is well within the reach of an average laboratory. Such well-characterized pluripotent cell populations can then be readily grown and differentiated into multiple cell types using cost-saving bioreactor technology that has been optimized over the years for bioproduction and antibody generation, and that is now being adapted to primary cell culture. Perhaps equally important and, in my opinion a critical development, was our ability to preserve cells indefinitely by holding them frozen for years. Although we often take this for granted, one realizes how vital this is when it is not possible for us to do so. The entire skin therapy field has been shaped by the fact that cell sheets have to be shipped live and thus manufactured to demand, changing the entire cost structure of that industry. Success in storing hematopoietic stem cells, on the other hand, has shaped that industry differently.

Figure 3   The different kinds of cells being considered for therapy are listed.

Figure 4   The field of regenerative medicine is changing because of the many breakthroughs and advances in different scientific disciplines can be synergistically utilized.

Complementary advances in engineering cells, in particular homologous recombination and its variants using ZFNs [20], TALENS [21] or CAS9 systems [22], now allow us to take well-characterized pluripotent cells that have been comprehensively annotated and make single-gene (or multiple-gene) changes to model complex diseases or to repair cells for therapy. This level of unprecedented control over a system with high efficiency and high fidelity allows us to address problems that were simply intractable in the past.

Our ability to make cells jump through hoops has been complemented by advances in tissue engineering, biomimetic scaffolds, the development of thermoreversible gels that work at physiological temperatures, and three-dimensional tissue printing that allows us to mold structures using biological grade material, seed them with cells, and begin to develop two- and three-dimensional organized structures that can be used for therapy [23–25].

Table 2

Abbreviated List of Companies that Have a Market Cap of Greater than $20M

Note: Several of these companies are close to billion-dollar companies even though few have an approved product on the market. ALS, Alzheimer’s disease; CLI, critical limb ischemia; CNS, central nervous system; EMA, European Medicines Agency; ESC, embryonic stem cells; GVD, graft-versus-host disease; IBD, inflammatory bowel disease; MSC, mesenchymal stromal/stem cells; NA, Not Applicable.

The stem cell field has been shaped not just by technology and scientific breakthroughs but also by patents and regulations governing the delivery of cell-based therapy as well as by the enormous expectations that people have for this novel type of therapy [26–28]. Likewise, the field of regenerative medicine has been strongly influenced by regulatory authorities who have imposed different requirements in different countries [29–31]. The regulations have led to different foci of activity in different countries and, by extension, the players who implement these technologies. Overall, the field has shown some success, and there are several cell and tissue therapy products on the market, several companies have been set up, and more than 10 have a market capitalization of great than $20  million, with some being close to billion-dollar companies (Table 2). Several new discoveries have been made that have led to new spin-offs, and hundreds of patients have been treated. New business models for autologous therapy are being developed, and hundreds of clinical trials have been initiated.

II. Conclusions

The regenerative medicine field is active and growing. It should not be considered as a unified field but, rather, as a set of subfields that focus on different cells and different indications and that are regulated by diverse regulatory pathways. The field remains united conceptually in that the players are all motivated to use cells, engineered cells, cells combined with devices, and cell derivatives for treating disorders. As with any new field, several business models are being explored, and innovators are looking at different ways to offer services and to obtain returns on their investments. The regulatory authorities have had to scramble to keep up with these innovative breakthroughs, and have succeeded in reining in some of the excesses and hype in the field. Given the large number of companies and the ongoing investments and the recent approval of products in the United States and Korea, it is likely that the field will continue to grow.

I also remind investigators that the field is in a state of flux, and new discoveries have the possibility of changing the field yet again. As with any prediction, it is far more likely that I will be wrong than right, but nevertheless one can perhaps make some cautious predictions [32]. It seems to this writer that the gene engineering breakthroughs coupled with the ability to make differentiated cells of various kinds will allow functional cures. Perhaps the earliest success will come in the hematopoietic system or in the retina, where viral delivery of a missing gene product has already shown success. Using safe-harbor technologies and strategies to prevent silencing and regulating gene expression in immune-matched cells that are differentiated into a tissue or organ phenotype will allow controlled and regulated therapy. Another breakthrough that I believe will change the field is the ability to make more complex three-dimensional structures. Thus far we have been limited by our inability to construct a true vasculature that will allow nutrient delivery in synthetic constructs that are more than eight or 10 cell layers thick. Keeping organ structures alive while a vasculature develops has been difficult as well. Current work in angiogeneisis, the ability to print organs layer by layer, and the isolation of endothelial cells in large numbers suggest that we are close. A third breakthrough that builds on the work on iPSC is the idea of direct transdifferentiation using readily available sources of adult cells and directing their differentiation into a difficult-to-obtain cell type. Work by several investigators has suggested that this may be possible, and in some cases may be possible in vivo.

Disclaimer

The opinions expressed in this article are entirely my own and do not reflect the opinions or policy of the National Institutes of Health.

References

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Section I

Cell Banking

Outline

Chapter 2. Landscape of Cell Banking

Chapter 3. Cell Banking: Process Development and Cell Preservation

Chapter 4. Clinical Development of Placental Mesenchymal Stromal Cells

Chapter 5. Translation of Regenerative Medicine Products Into the Clinic in the United States: FDA Perspective

Chapter 6. Newborn Stem Cell Banking Business Models

Chapter 2

Landscape of Cell Banking

Heather C. Hatcher, Anthony Atala,  and Julie G. Allickson     Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA

Abstract

As the aging population grows in the United States and globally, regenerative medicine has become an important healthcare sustainability goal, as it has the potential to save billions of dollars in healthcare costs. One important aspect of regenerative medicine is cellular therapy, where the cellular component used in the construction of organs and tissue is extremely vital. Banking stem cells has generally been seen in the bone marrow and cord blood transplant fields for hematopoietic diseases; however, within the last decade regenerative medicine has expanded the use of banked stem cells to neurodegenerative, cardiac, and musculoskeletal diseases. The biobanking field for clinical use includes a public-unrelated/universal-donor model as well as an autologous-source model consisting of privately storing one's own cells. Banking cells for public use or to establish cell lines that could be used for multiple patients may be associated with financial savings, as the execution of federal regulations on one donor cell line would facilitate sourcing individual donors for each patient. With private banking or banking one's own cells, the threat of immune rejection is diminished; however, the time and cost required is a challenge compared to using cell lines or a universal donor. Taking into account the regulatory considerations, time constraints of patient treatment, and financial considerations, both public and private cell banking will play significant roles in the future of translational regenerative medicine.

Keywords

Clinical application; Public and private cord blood banks; Regenerative medicine; Translational medicine; Umbilical cord blood

Chapter Outline

I. Introduction: The Field of Cell Banking 13

II. Allogeneic and Autologous Cell Banking 13

III. Recruitment 14

IV. Regulations and Determination of Regulatory Guidance 14

V. Registration and Donor Eligibility Screening/Testing 15

VI. Current Good Tissue Practice (cGTP) 16

VII. Ethics (Personal Data, Health Information, Genetic Analysis, Privately Banked Cells) 16

VIII. Financial Aspects 17

IX. The Role of Banking in Regenerative Medicine 17

X. Conclusion 18

References 18

I. Introduction: The Field of Cell Banking

In recent years, cell banking activities have expanded worldwide. In 2010, nearly 17,000 products derived from bone marrow, peripheral blood stem cells (BSCs), and cord blood units (CBUs) were available worldwide for allogeneic transplantation to unrelated patients suffering oncologic, genetic, hematologic, and immunodeficiency disorders [1]. Human umbilical cord blood (UCB) has gained increasing importance as a source of BSCs and mesenchymal stem cells (MSCs) [2,3]. Clinical experience over the last two decades has shown that cord blood (CB) is a viable source for BSCs in the field of unrelated hematopoietic blood-stem-cell transplantation [4]. CB has significant advantages as a source of hematopoietic stem cells, including convenience to the donor, reduced risk of graft-versus-host disease, up to two human leukocyte antigen (HLA) mismatches, and almost immediate availability [5]. In 1989, the first CB transplantation was reported in a boy with Fanconi anemia, and the first series of CB transplantations from related and unrelated donors was reported in the mid-1990s (for review [6]). In the early 1990s, the first unrelated CB banking programs were started at the Eurocord/NetCord Bank in Düsseldorf and the New York Blood Center [7,8]. By 2010, the global inventory of CB available for transplantation was approximately 600,000 units, stored in more than 140 CB banks worldwide [1].

CB banking has risen to the forefront of cell banking through the establishment of standardized recruiting, collection, processing, storage, product release, and quality control. CB transplantation is successfully used to treat myeloid leukemia, lymphatic leukemia, lymphoma, myelodysplasia, aplastic anemia, hemoglobinopathies, thalassemia, metabolic storage diseases, immune deficiency, autoimmune diseases, and other diseases in pediatric and adult patients [9–13]. In addition, CB banks may be public (donated CBUs used for unrelated patients in need) or private (CBUs saved for the use of the donating family), which has led to a public health debate. In this chapter, the current state of cell banking for clinical use will be discussed, and also recent advances in the generation, characterization, and bioprocessing of stem cells sourced from tissues other than CB—human pluripotent stem cells and induced pluripotent stem cells—for cell banking and clinical applications.

II. Allogeneic and Autologous Cell Banking

Public banks store allogeneic CBUs that have been donated by parents to be made available to registered transplant centers to provide CBUs to unrelated individuals [5]. Some banks may have provisions that a sibling or close relative may access related units for families with a predisposition to a particular genetic disease [5]. These mixed banks offer separate storage for CBUs that can be accessed through public registries and for others that are stored for purely private use [14]. Public CB banks do not charge for the donation, have a limited geographic collection region, and may be supported by government funds, grants, or philanthropy [15]. In addition, a fee is charged to the transplant patient’s insurance when a CBU is accessed for transplant [15].

Private CB banks accept CB from families and store it on their behalf for possible autologous (for the donor only) or allogeneic (for a family member) transplantation; furthermore, the family is charged a fee for collection and processing (∼$1500–$2000 US) on acceptance of the units and an annual storage fee (∼$90–$200 US) that supports the operation of these private banks [15]. Consequently, these CBUs cannot be traced through the registries and are unavailable to the general public [16]. Based on the incidence of various pathologies, the possibility that a transplant will become necessary, and the probability of finding a compatible donor, it is estimated that the likelihood of privately stored CBUs being used for autologous purposes falls between 1:2500 (0.04%) and 1:20,000 (0.005%) [17,18]. The value of storing CBUs, therefore, may be realized by researchers who evaluate CB cells for pathologies other than hematological disorders such as heart disease, diabetes, stroke, traumatic brain and spinal cord injuries, and cancer [19–23]. Controversial issues in public CB banking include collection methods, processing techniques, and thawing methods [15]. CB can be collected in utero before delivery of the placenta by the delivering physician or midwife, or ex utero, which is a less invasive and more controlled technique, but is more expensive and requires additional trained personnel [15].

III. Recruitment

The legitimacy of public cell banking will depend on a number of factors. Public authorities are advised to take specific measures to ensure that sufficient donations are collected from different ethnic groups with different HLA patterns so that any patient needing a transplantation will be able to find an appropriate donor [24]. Moreover, a greater understanding of the impact of ethnicity on CB banking is required, as several recent studies have shown that ethnicity is associated with a higher risk of failing to meet banking criteria, lower CB volume, reduced total nucleated cell count, fewer CD34+ cells, and reduced colony-forming units [25]. Another important issue is that of informed consent for both allogeneic and autologous cell banking [26].

IV. Regulations and Determination of Regulatory Guidance

Regulatory oversight of therapeutics derived from biological sources has existed for some time. Due to the unique source of these products, assessment by traditional regulatory systems based on pharmaceutical quality-control parameters is difficult [27]. Growth within the field of regenerative medicine has led to increased use of novel transplantation therapies to repair or replace dysfunctional tissues and organs, which has led to increased public-health concerns. Consequently, established regulatory agencies throughout the world have developed new regulations for these products with the primary goal of minimizing infectious-disease risk. Regulators face challenges, as they must balance their roles as independent assessors with the needs of the overall public-health structure. Thus, regulators have recognized the need to assess life-saving therapies through systems that consider the risk–benefit ratios and include mechanisms for transparent and accountable release of products when full compliance with traditional manufacturing concepts is not possible [27].

In the United States, products composed of human cells, tissues, and cellular and tissue-based products (HCT/Ps) are regulated by two divisions within the US Food and Drug Administration (FDA), the Center for Devices and Radiological Health (CDRH) for medical devices, and the Center for Biologics Evaluation and Research (CBER) (Table 1). Title 21 of the Code of Federal Regulations (CFR) comprises FDA rules, and the most current version of CFR 21 can be accessed directly from the FDA’s Web site or from the website of the Government Printing Office [28,29]. According to the FDA Regulation of HCT/Ps Product List, CBER regulates HCT/Ps under 21 CFR 1271.3(d)(1) and Section 361 of the Public Health Service (PHS) Act; furthermore, these HCT/Ps are regulated solely as 361 products when they meet all of the criteria in 21 CFR 1271.10(a):

• Minimally manipulated;

• Intended for a homologous use only as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent;

• Not combined with another article, (except for water, crystalloids, or a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the HCT/P); and

• Either:

• Do not have a systemic effect and are not dependent upon the metabolic activity of living cells for their primary function; or

• Have a systemic effect or are dependent upon the metabolic activity of the other cells for their primary function, and:

• Are for autologous use;

• Are for allogeneic use in a first- or second-degree relative; or

• Are for reproductive use.

HCT/Ps not covered by this compliance program or for which only certain provisions apply are discussed further on the FDA Web site [28]. Human somatic cell therapy and gene therapy products are also regulated by CBER under Section 351 of the PHS Act and/or the Food, Drug, and Cosmetic (FD&C) Act. This grouping includes products that the FDA has determined do not meet all of the criteria in 21 CFR 1271.10(a) and are regulated as drugs and/or biological products, refer to Table 1. Devices composed of human tissues are regulated by CDRH under the FD&C Act and device regulations, refer to Table 1. A section is also included for combination products, refer to Table 1.

Table 1

FDA Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Product List http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues

21 CFR: Code of Federal Regulations Title 21; CBER: Center for Biologics Evaluation and Research; CDRH: Center for Devices and Radiological Health; FDA: US Food and Drug Administration; FD&C Act: Federal Food, Drug, and Cosmetic Act; HCT/Ps: Human Cells, Tissues, and Cellular and Tissue-Based Products; PHS Act: Public Health Service Act.

V. Registration and Donor Eligibility Screening/Testing

Within five days of engaging in the manufacture of an HCT/P, a facility must register with and submit to the FDA a list of each human-tissue product manufactured unless excepted by 21 CFR 1271.15. Manufacturing facilities must determine donor eligibility through appropriate screening and testing of HCT/P donors for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases; as well as communicable disease risks associated with xenotransplantation. These procedures must be designed to ensure compliance with the requirements of subpart C, 21 CFR part 1271. Title 21 CFR part 1270 applies only to certain human tissue intended for transplantation (musculoskeletal, skin, and ocular), recovered before May 25, 2005, and requires donor screening and testing for only certain diseases (HIV, hepatitis B, and hepatitis C). Title 21 CFR part 1271, subpart C, applies to donors of additional cells and tissues, recovered on or after May 25, 2005, and require screening and testing of these donors for additional relevant communicable diseases. For example, 21 CFR part 1271, subpart C, applies to donors of hematopoietic stem/progenitor cells derived from peripheral and UCB, reproductive cells and tissue, human dura mater, and human heart valves, in addition to donors of musculoskeletal, skin, and ocular tissue. Title 21 CFR part 1271 also applies to HCT/Ps regulated as drugs, devices, or biological products, whereas 21 CFR part 1270, does not [28,29].

VI. Current Good Tissue Practice (cGTP)

To prevent the introduction, transmission, or spread of communicable diseases by HCT/Ps, manufacturing facilities must follow current good tissue practice (cGTP) requirements, which are the requirements in 21 CFR part 1271, subparts C and D, that govern the methods used in, and the facilities and controls used for, the manufacture of HCT/Ps, including but not limited to all steps in recovery, donor screening, donor testing, processing, storage, labeling, packing, and distribution (21 CFR 1271.150(a)). The core cGTP requirements as referenced in 21 CFR 1271.150(b) include requirements relating to:

• Facilities (21 CFR 1271.190(a–b))

• Environmental controls (21 CFR 1271.195(a))

• Equipment (21 CFR 1271.200(a))

• Supplies and reagents (21 CFR 1271.210(a–b))

• Recovery (21 CFR 1271.215)

• Processing and process controls (21 CFR 1271.220)

• Labeling controls (21 CFR 1271.250(a–b))

• Storage (21 CFR 1271.260(a–d))

• Receipt, predistribution shipment, and distribution of an HCT/P (21 CFR 1271.265(a–d)).

• Donor eligibility determinations, donor screening, and donor testing (21 CFR 1271.50, 1271.75, 1271.80,