Regenerative Medicines: Bone and Joint Applications

Regenerative Medicines: Bone and Joint Applications

This BCC Research report focuses on the bone- and joint-related applications of and markets for the various categories of regenerative medicine products currently available and projected to be introduced during the five-year forecast period from 2015 through 2020.

Use this report to:
- Learn about leading bone and joint diseases and disorders applicable to regenerative technologies.
- Analyze the regenerative products used to treat bone and joint disorders.
- Receive information about the regulatory issues affecting regenerative medicine products.
- Review the profiles of leading and emerging companies in the bone and joint regenerative medicine markets.

Highlights
- The U.S. market for regenerative medicine products used in bone and joint applications is expected to grow at a compound annual growth rate (CAGR) of 6.8% from $2.9 billion in 2015 to nearly $4.1 billion in 2020.
- Bone replacement/grafting as a segment will grow from nearly $2.1 billion in 2015 to nearly $2.8 billion in 2020 at 5.9% CAGR for the period 2015-2020.
- Cell therapy/tissue engineering/cartilage as a segment will grow from $255 million in 2015 to $460 million by 2020, increasing at a CAGR of 12.5% for the period 2015-2020.

Introduction & Scope

INTRODUCTION
Regenerative medicine in orthopedic applications is a $2.9 billion per year niche sector in America’s $3.1 trillion per year healthcare system. However, it is a sector of
immense interest in terms of technical, medical and investment possibilities. The best analogy to the current state of regenerative therapies in the bone and joint healing
sector is the nascency of the microprocessors business back in 1971. At that time, microprocessors (namely Intel’s 4004), and related innovations, were just an infinitesimal segment of electronic component sales, but this innovation came to dominate the economy. The regenerative therapies sector, particularly areas such as cell therapy, genetic engineering and stem cell-derived products is in a comparable position today. A good example is Bluebird Bio, which received FDA designated breakthrough therapy status in February 2015 for one of the company’s gene therapies.

The regenerative medicine industry has been in existence for nearly 25 years. Actual product sales, along with research and development (R&D) expenditures, are projected
to amount to approximately $2.9 billion in economic activity in 2015, of which venture capital and R&D funding accounts for about $200 million. The rapid evolution of this
business is evidenced by the industry consolidation that has occurred since the first edition of this BCC Research report was published in 2003 and even since the most recent edition in 2013. Innumerable buyouts, consolidations, product abandonments, new firms and a few bankruptcies, too, have occurred in just the last several years. These changes are reflected in the Company Profiles section of this report. In addition, intensive R&D efforts at universities, the National Institutes of Health, the National Science Foundation and at FDA centers that focus on cutting-edge technology underscore the importance of this industry.

Regenerative therapies have the potential to improve medical outcomes, enhance quality of life and reduce overall healthcare costs. A key objective is the utilization of
living cells to repair or replace body tissue damaged by injury, disease or the aging process. The most successful products have drawn upon multidisciplinary fields such as
biology, medicine, engineering and, particularly, biomedical engineering. The principal focus in this report is on bone and joint applications; however, other regenerative
applications such as dental, neurologic, organ regeneration, cardiovascular, urologic, diabetes and wound care are important and are briefly covered to underscore the
larger importance of regenerative therapies. Stem-cell research is an important component of the sector as well. For example, the successful differentiation of embryonic stem cells into specific cell types is widely sought as a means to treat traumatic spinal-cord injury, as well as diseases such as diabetes, Duchene muscular dystrophy, heart disease, and vision and hearing loss.

OBJECTIVES AND GOALS OF STUDY
This report focuses on the bone- and joint-related applications of and markets for the various categories of regenerative medicine products currently available and projected
to be introduced during the five-year forecast period from 2015 through 2020. Market drivers discussed include the status of R&D and what is likely to issue from R&D in the
way of actual products and therapies. Other market drivers include the incidence, and rate of growth, of diseases and disorders that will benefit from these products, primarily arthritis, osteoporosis, and various types of bone and joint trauma (e.g., hip fractures, knee injuries); increasing use of nonautograft products by physicians; and
innovative devices that incorporate bone- and cartilage–growth-stimulating agents in a regenerative appliance. Products discussed include bone and cartilage grafting and
regenerative products derived from autologous, allogeneic and synthetic sources, as well as electrical stimulators for bone growth and regenerative cartilage products.
Profiles are provided of leading and emerging companies in the bone and joint regenerative medicine markets, along with analyses of the current and future positioning of their products and businesses in this active and rapidly changing market. Developmental and clinical stage companies are well covered.

INTENDED AUDIENCE
The aim of this report is to provide an overview of regenerative medicine products, both available and emerging, for the treatment of diseases and disorders of the bones
and joints. The information and analysis presented are important assets in decision making for managers involved in business development, marketing, market research,
product development, mergers and acquisitions, licensing, business management, investment banking and deal creation, as well as for consultants to the pharmaceutical
and biotechnology industries. The study provides a comprehensive analysis of the current markets for regenerative medicine products for bones and joints, relevant
applications, and the potential of products in development.

STUDY SCOPE AND FORMAT
The U.S. has been the main regenerative medicine market in terms of R&D innovation, patents and product sales often accounting for as much as half of the market
depending on the product niche; hence, the scope of the study is mainly the U.S., although worldwide developments are discussed and measurements provided where
relevant. The Overview section provides a background of the demographics underlying the market for bone and joint products, a definition of regenerative medicine and the
technologies involved, and a discussion of regenerative products in development for applications other than bones and joints. Various application sections describe the
leading bone and joint diseases and disorders applicable to regenerative technologies, including incidence and current methods of treatment.

The section on Products provides extensive descriptions and analyses (e.g., comparative analysis) of regenerative products used to treat bone and joint disorders,
as well as a discussion of products in development. The section on FDA clinical trials and newly approved products provides a discussion of regulatory issues affecting regenerative medicine products. An extensive Company Profiles section provides estimates for the revenues of the leading companies and a concise description of leading and emerging companies in the area of regenerative products for bones and joints, including product introductions, patents and overall business strategies.

METHODOLOGY
Both primary and secondary research methodologies were used to prepare this market research report. The base year for this study is 2014. Data for 2015 are estimated and
2020 is the forecast terminal year. Sales data are estimated in nominal current dollars, unadjusted for inflation. Information to prepare this study was derived from market
intelligence provided by leading companies involved in the regenerative medicine market. Data were accessed from government agencies such as the SEC and regulatory bodies (FDA, EMA) that monitor and/or regulate medical devices. Searches of secondary material such as company annual reports and 10Ks, medical journal articles, prospectus assessments, government resources and data from healthcare institutions were conducted. In addition, the study author attended the 2015 Third Annual Alliance for Regenerative Medicine Investor’s Conference in New York in order to conduct primary interviews with industry contacts.
TABLE OF CONTENTS
CHAPTER 1 INTRODUCTION 2
OBJECTIVES AND GOALS OF STUDY 2
INTENDED AUDIENCE 3
STUDY SCOPE AND FORMAT 3
METHODOLOGY 4
INFORMATION SOURCES 4
ANALYST'S CREDENTIALS 4
RELATED BCC REPORTS 4
BCC RESEARCH WEBSITE 5
DISCLAIMER 5
CHAPTER 2 SUMMARY 7
SUMMARY TABLE U.S. MARKET FOR REGENERATIVE MEDICINE PRODUCTS USED IN
BONE AND JOINT APPLICATIONS, THROUGH 2020 ($ MILLIONS) 8
SUMMARY FIGURE U.S. MARKET FOR REGENERATIVE MEDICINE PRODUCTS USED
IN BONE AND JOINT APPLICATIONS, 2014-2020 ($ MILLIONS) 8
CHAPTER 3 OVERVIEW AND OVERALL STATUS OF THE INDUSTRY 10
SCOPE OF REGENERATIVE MEDICINE MARKET 10
ESTIMATED NUMBER OF COMPANIES IN REGENERATIVE SECTOR 10
TABLE 1 FUNCTIONAL ACTIVITIES WITH REGENERATIVE MEDICINE SECTOR 11
TABLE 2 MOST PROMINENT COMPANIES IN THE REGENERATIVE MEDICINE
BUSINESS 12
SIZE OF ORTHOPEDIC SECTOR AND LEADING SUPPLIERS 13
TABLE 3 REVENUES FOR TOP SUPPLIERS OF ORTHOPEDIC PRODUCTS AND
MATERIALS, 2014 ($ BILLIONS) 13
HOW REGENERATIVE MEDICINE WORKS 14
TISSUES AND ORGANS ON DEMAND 15
ORGAN REPLACEMENT IS A $100 BILLION PER YEAR BUSINESS 15
EXAMPLES OF IMPACT ON EXISTING CONDITIONS AND DISEASES 16
BARRIERS TO REGENERATIVE MEDICINE 16
TABLE 4 NINE PRINCIPAL MARKET DRIVERS 18
CURRENT R&D PRIORITIES 18
TABLE 5 R &D FOCUSES FOR PRINCIPAL REGENERATIVE MEDICINE 18
TABLE 6 TWENTY-YEAR PLANNING HORIZON FOR REGENERATIVE MEDICINE
BUSINESS: LIKELY DEVELOPMENTS 20
NATIONAL SCIENCE FOUNDATION PRIORITIES 20
TABLE 7 NATIONAL SCIENCE FOUNDATION REGENERATIVE MEDICINE FUNDING
PRIORITIES, APRIL 1, 2015 ($) 21
TOTAL OUTPUT OF THE SECTOR 21
REGENERATIVE MEDICINE AND HEALTHCARE ECONOMICS 22
POPULATION TRENDS 23
MARKET TIMING 23
OVERSEAS INITIATIVES 23
CHAPTER 4 PRINCIPLE APPROACHES TO REGENERATIVE MEDICINE 25
HUMAN SUBSTANCES 26
CELLS AND TISSUES 26
TISSUE ENGINEERING 26
Importance of Scaffolding in Tissue Engineering 26
Plastic Scaffolding 27
Blood Vessel Scaffolding 28
Center for Integration of Medicine and Innovative Technology (CIMIT) 28
TABLE 8 PRINCIPLE RESEARCH PROJECTS OF CIMIT IN THE TISSUE-ENGINEERING
AND BIOMATERIALS FIELDS, 2008-2012 28
Massachusetts General Hospital 29
Duke University Stem Cell and Regenerative Medicine Program 30
University of Iowa 30
EMBRYONIC STEM CELLS 31
Therapeutic Cloning 31
ADULT STEM CELLS: JUST AS GOOD AS EMBRYONIC STEM CELLS 31
Genzyme 32
University of Minnesota Stem Cell Institute 32
STEM CELL RESEARCH PATENTS AND EFFECT ON STEM CELL MARKETERS 33
Stem Cells via Indirect Lineage Conversion (ILC) 33
COMPANIES INVOLVED IN BONE AND JOINT STEM CELL-BASED
THERAPEUTICS 34
TABLE 9 COMPANIES INVOLVED IN BONE AND JOINT STEM CELL-BASED
THERAPEUTICS 35
SETTING THE STAGE FOR REGENERATIVE MEDICINE TO TREAT BONE AND JOINT
DISORDERS 35
NOVEL MATERIALS 36
Nanoneedles 36
GENE THERAPY 36
Gene Therapy Trials Targeting Bone and Joint Diseases and Disorders 37
BIOREACTOR USE IN REGENERATIVE MEDICINE 38
TABLE 10 COMMERCIAL SUPPLIERS OF BIOREACTORS FOR USE IN REGENERATIVE
MEDICINE 38
THE IMPACT OF GENOMICS 38
CHAPTER 5 PRODUCTS AND TECHNOLOGIES: CATEGORIES OF REGENERATIVE
MEDICINE 41
GENE- AND PROTEIN-BASED APPROACHES 41
ANTIBODIES 41
The Importance of Antibody Drugs 42
Advantages of Monoclonal Antibody Drugs 43
Antibodies and Osteoarthritis 43
Denosumab 45
GROWTH FACTORS 45
HOW BMPS FUNCTION 46
TABLE 11 BONE MORPHOGENETIC PROTEINS 47
Clinical Uses 47
Companies 48
CELLS AND TISSUES 49
TISSUE ENGINEERING 49
ARTIFICIAL SKIN 50
CARTILAGE 51
Other Approaches to Cartilage 52
haMPC Therapy for Knee Osteoarthritis 53
Biosynthetic Composites for Cartilage Repair 53
3D Tissue Printing of Cartilage 53
3D Tissue Printing of Bone 54
Histogenics 54
Columbia University Work 55
The Market for Tissue-Engineered Cartilage Products 55
TABLE 12 U.S. MARKET FOR TISSUE-ENGINEERED AND CELL THERAPY-BASED
CARTILAGE PRODUCTS, THROUGH 2020 ($ MILLIONS) 55
OTHER PRODUCTS 56
CREATION OF ENTIRE ORGANS 56
EMBRYONIC STEM CELLS 57
NOVEL MATERIALS AND BIOMATERIALS 58
TABLE 13 WORLD'S LARGEST IMPLANTABLE BIOMATERIALS COMPANIES 59
CHAPTER 6 STEM CELL THERAPIES AND REGENERATIVE MEDICINE 62
STEM CELLS AS POTENTIAL REPLACEMENT CELLS 62
OVERALL MARKET AND PARTICIPANTS 63
STEM CELL MARKET RISKS 63
TECHNICAL IMPEDIMENTS 64
OVERVIEW OF FUNDING 64
TABLE 14 FEDERAL FUNDING FOR STEM CELL RESEARCH, THROUGH 2013 ($
MILLIONS) 65
STATE-LEVEL INITIATIVES FOR STEM CELL RESEARCH 65
TABLE 15 STATE LEVEL PROGRAMS FOCUSED ON STEM CELL RESEARCH 66
POTENTIAL APPLICATIONS: CURRENT STATUS 66
IN VIVO REPROGRAMMING 67
UMBILICAL CORD BLOOD STEM CELLS 67
Recent Research Developments 68
INDUCED PLURIPOTENT STEM CELLS 68
Recent Research Developments 68
Adult Multipotent Stem Cells 69
Embryonic Stem Cells 69
Adipose Stem Cells for Bone and Joint Applications 71
GERON AND THE FIRST HUMAN TRIALS 72
OTHER STEM CELL RESEARCH 74
STATUS OF OTHER CLINICAL TRIALS 74
STEM CELL THERAPY FOR ALS 75
STEM CELL THERAPY FOR DUCHENNE MUSCULAR DYSTROPHY 76
STEM CELL THERAPY AND BONE MARROW TRANSPLANTS 77
CHAPTER 7 REGENERATIVE PRODUCTS TO TREAT BONE DISEASES 79
REGENERATIVE PRODUCTS TO TREAT BONE DISEASES 79
OSTEOBIOLOGICS 79
BONE GRAFTS 80
PRINCIPAL USES OF BONE GRAFTS 80
TABLE 16 CHARACTERISTICS OF IDEAL BONE GRAFT MATERIAL 81
TABLE 17 U.S. BONE GRAFT PROCEDURE VOLUMES BY APPLICATION, THROUGH
2020 (NUMBER) 82
TABLE 18 U.S. BONE GRAFT PROCEDURE VOLUMES BY TYPE OF GRAFT, THROUGH
2020 (NUMBER) 82
TABLE 19 BONE GRAFT MATERIALS 83
TABLE 20 SUBSTITUTE BONE GRAFTS 84
AUTOGRAFTS 84
BIOSEED GRAFTS 85
ALLOGRAFTS 86
Demineralized Bone Matrix Products 88
TABLE 21 SELECTED DBM PRODUCTS AND PERCENTAGE OF DEMINERALIZED BONE
MATRIX 88
TABLE 22 U.S. MARKET FOR PRECISION-MACHINED ALLOGRAFTS, THROUGH 2020
($ MILLIONS) 92
BONE REPLACEMENT AND REPAIR PRODUCTS 92
CELL-BASED BONE GRAFT SUBSTITUTES 92
Factor-based Bone Graft Substitutes 93
BONE MORPHOGENIC PROTEINS 94
InductOs 95
InFUSE Bone Graft 95
OP-1 Implant 96
CERAMIC-BASED BONE GRAFT SUBSTITUTES 96
Bioactive Glasses 97
Types of Ceramics 97
POLYMER-BASED BONE GRAFT SUBSTITUTES 103
MARKET FOR BONE GRAFT PRODUCTS 105
TABLE 23 GLOBAL MARKET FOR BONE REPLACEMENT PRODUCTS, THROUGH 2020
($ MILLIONS) 105
TABLE 24 U.S. MARKET FOR BONE-REPLACEMENT AND GRAFTING PRODUCTS,
THROUGH 2020 ($ MILLIONS) 106
RESEARCH AND DEVELOPMENT OF OTHER REGENERATIVE MEDICINE
PRODUCTS FOR BONE APPLICATIONS 106
BIOLOGIC/SYNTHETIC GRAFTS 106
CHRYSALIN 107
NEW SCAFFOLDING TECHNIQUES 108
Honeycomb Implants 108
Electrospun Fiber Multiwell Plates 108
BIOCELLULAR GRAFTS 108
CHAPTER 8 REGENERATIVE APPLICATIONS FOR BONES AND JOINTS 111
MATERIALS FOR BONE TISSUE REPAIR 111
TABLE 25 EXAMPLES OF NANOSTRUCTURED BIOMATERIALS USEFUL IN BONE AND
JOINT REGENERATION 111
VANADIUM COMPOUNDS TO ACCELERATE BONE HEALING 112
BIONANOPARTICLES IN BONE HEALING 112
BIODEGRADABLE NANOSCALE FILAMENTS 113
SILK PROTEIN MICROFIBERS 114
INHERENT REGENERATION OF BONE 114
OVERALL SIZE OF BONE GRAFT BUSINESS 115
BONE GRAFT SUBSTITUTES 116
ALLOGRAFT TISSUE 117
OTHER OSTEOCONDUCTIVE BONE GRAFT SUBSTITUTES 118
HYDROGELS AND REGENERATION 118
UNIVERSITY OF ROCHESTER RESEARCH ON HYDROGELS 119
HYDROGEL SCAFFOLDING 120
HYDROGEL PATENTS 120
Bone Implant Materials Comprising Cross-Linked Bioactive Hydrogel
Matrices 121
Abstract 121
Hydrogel Bone Void Filler 121
Abstract 121
Amphiphilic Peptides and Hydrogel Matrices Thereof for Bone Repair 121
Abstract 122
Hydrogel Bioscaffold and Coating for Bone and Tooth Repair 122
Abstract 122
Antimicrobial Nanostructured Hydrogel Web Containing Silver 122
Abstract 122
Injectable Peptide Hydrogel That Kills Methicillin-Resistant
Staphylococcus Aureus 123
Abstract 123
Method to Repair a Damaged Intervertebral Disc Through the Use of
a Bioadhesive, Thermogelling Hydrogel 123
Abstract 123
Hydrogel Compositions 124
Abstract 124
Self-Assembling Protein Hydrogel With Bio-Active Protein 124
Abstract 124
Superporous Hydrogel with Cells Encapsulated Therein and Method
for Producing the Same 124
Abstract 125
Hydrogel Particles 125
Abstract 125
Composition and Method for Self-Assembly and Mineralization of
Peptide Amphiphiles 125
Abstract 125
Chondroitinase ABC I Polynucleotides 126
Abstract 126
Transdiscal Administration of Cycline Compounds 126
Abstract 127
Composition and Method for Preparing Biocompatible Surfaces 127
Abstract 127
Spinal Mobility Preservation Apparatus Having an Expandable
Membrane 127
Abstract 127
MAJOR DISEASES AND CONDITIONS AFFECTING BONES 128
OSTEOPOROSIS 128
Currently Available Products to Treat Osteoporosis 129
Bisphosphonates 130
Fosamax 130
Boniva 131
New Approaches 131
Sclerostin Antibody 131
Romosozumab 131
Probiotics 132
Stem Cell Treatments 132
TABLE 26 DRUGS USED TO TREAT OSTEOPOROSIS 133
Hormones 133
Evista 134
Forteo 134
Miacalcin 136
STEROIDS AND OSTEOPOROSIS 136
Glucocorticoids 136
MARKET FOR PRODUCTS TO TREAT OSTEOPOROSIS 137
TABLE 27 GLOBAL MARKET FOR DRUGS TO TREAT OSTEOPOROSIS BY CATEGORY,
THROUGH 2020 ($ MILLIONS) 138
PAGET'S DISEASE 138
DRUGS CURRENTLY AVAILABLE TO TREAT PAGET'S DISEASE 138
Actonel 139
Aredia 139
Skelid 139
Zometa 139
MARKET FOR PRODUCTS TO TREAT PAGET'S DISEASE 139
TABLE 28 GLOBAL MARKET FOR DRUGS TO TREAT PAGET'S DISEASE, THROUGH
2020 ($ MILLIONS) 140
INJURIES AND DEGENERATIVE CONDITIONS 140
HIP FRACTURES 141
TABLE 29 GLOBAL HIP FRACTURE VOLUMES, THROUGH 2020 (NUMBER) 141
TABLE 30 U.S. HIP FRACTURE VOLUMES, THROUGH 2020 (NUMBER/%) 142
TRADITIONAL TREATMENTS FOR BONE AND JOINT DISORDERS 142
TABLE 31 U.S. MARKET SHARES FOR MUSCULOSKELETAL PRODUCTS BY
CATEGORY, 2014 (%) 142
TABLE 32 U.S. MARKET SHARES FOR RECONSTRUCTIVE DEVICES BY CATEGORY,
2014 (%) 143
MARKET LEADERS 143
JOINT-REPLACEMENT SURGERY 143
TABLE 33 NUMBER OF U.S. HIP REPLACEMENT PROCEDURE VOLUMES, THROUGH
2020 143
TABLE 34 NUMBER OF HIP REPLACEMENT PROCEDURES IN SIX MAJOR STATES,
2001 144
TABLE 35 GLOBAL MARKET FOR HIP REPLACEMENTS, THROUGH 2020 ($ MILLIONS) 144
TABLE 36 U.S. MARKET FOR HIP REPLACEMENTS, THROUGH 2020 ($ MILLIONS) 144
KNEE REPLACEMENTS 145
VENDORS 145
TABLE 37 GLOBAL KNEE-REPLACEMENT PROCEDURE VOLUMES, THROUGH 2020
(NUMBER) 145
TABLE 38 U.S. KNEE REPLACEMENT PROCEDURES, THROUGH 2020 (NUMBER) 146
TABLE 39 GLOBAL MARKET FOR KNEE REPLACEMENTS, THROUGH 2020 ($
MILLIONS) 146
TABLE 40 U.S. MARKET FOR KNEE REPLACEMENTS, THROUGH 2020 ($ MILLIONS) 146
TABLE 41 U.S. MARKET FOR UNICONDYLAR KNEE REPLACEMENTS, THROUGH 2020
($ MILLIONS) 147
NATURAL THERAPEUTIC TREATMENTS FOR ARTHRITIS 147
IMAGING MARKETS AND REGENERATIVE THERAPIES 148
CHAPTER 9 ELECTRICAL BONE GROWTH STIMULATOR MARKET 151
OVERVIEW 151
SCIENTIFIC BASIS 152
ULTRASONIC OSTEOGENESIS STIMULATORS FOR BONE HEALING 153
MARKETERS OF INVASIVE AND NONINVASIVE ELECTRICAL BONE GROWTH
STIMULATORS 153
BIOMET 153
ORTHOFIX 155
DJO INC. 155
SMITH & NEPHEW (BIOVENTUS) 156
MARKET SIZE 156
TABLE 42 GLOBAL MARKET FOR NONINVASIVE BONE GROWTH STIMULATORS BY
APPLICATION, THROUGH 2020 ($ MILLIONS) 157
TABLE 43 U.S. MARKET FOR NONINVASIVE BONE GROWTH STIMULATORS BY
APPLICATION, THROUGH 2020 ($ MILLIONS) 157
R&D - FUTURE PRODUCT POSSIBILITIES 157
CHAPTER 10 ORTHOPEDICS - FDA CLEARANCES AND NEW PRODUCT DEVELOPMENT 160
SUPPLIERS OF REGENERATIVE BONE AND JOINT PRODUCTS 160
TABLE 44 RECENTLY APPROVED ORTHOPEDIC BONE AND JOINT DEVICES BY
PRODUCT, 2008-2015 161
CHAPTER 11 MARKET FOR TISSUE ENGINEERING PRODUCTS 181
COMPANY INVOLVEMENT 181
TISSUE ENGINEERING AND CELL THERAPY 181
RESEARCH INITIATIVES 182
NATIONAL INSTITUTES OF HEALTH (NIH) 184
DREXEL UNIVERSITY 185
BIO2 TECHNOLOGIES INC. 185
YESHIVA UNIVERSITY 186
CHAPTER 12 REGENERATIVE CONCEPTS AND PRODUCTS IN DENTISTRY 188
OVERVIEW 188
INDICATIONS AND HISTORY 188
CHARACTERISTICS AND MATERIALS 189
BARRIER MEMBRANES 189
Nonresorbable 189
Resorbable 189
COLLAGEN RESORBABLE MEMBRANES 190
SYNTHETIC RESORBABLE MEMBRANES 190
BIOENGINEERED HYBRID TEETH FROM AUTOLOGOUS GUM CELLS 190
STEM CELL STUDY RAISES HOPE FOR BONE REPAIR PASTES 191
DENTAL REGENERATIVE PRODUCT VENDORS 192
GEISTLICH PHARMA NORTH AMERICA INC. 192
ZIMMER 192
ORGANOGENESIS INC. 192
MATRICEL GMBH 193
COLLAGEN MATRIX INC. 193
CURASAN AG 193
CHAPTER 13 SKIN TECHNOLOGIES 195
TABLE 45 EXAMPLES OF FDA APPROVED HUMAN SKIN SUBSTITUTES 195
TABLE 46 GLOBAL MARKET FOR ENGINEERED SKIN GRAFTS AND REPLACEMENTS,
THROUGH 2020 ($ MILLIONS) 197
SKIN-LIKE TISSUE DEVELOPED FROM HUMAN EMBRYONIC STEM CELLS 197
SOLUBLE SYSTEMS 198
INVESTIGATIONAL SKIN AND SOFT TISSUE SUBSTITUTES 198
TABLE 47 INVESTIGATIONAL SKIN AND SOFT TISSUE SUBSTITUTES, MARCH 2015 198
CHAPTER 14 NEUROLOGICAL APPLICATIONS IN REGENERATIVE MEDICINE 201
OVERVIEW 201
NEURODEGENERATIVE DISEASES 201
BEST PROSPECTS FOR STEM CELLS IN THIS MARKET 201
STROKE 201
MULTIPLE SCLEROSIS 202
ALZHEIMER'S 202
CURRENT CONVENTIONAL THERAPIES FOR THE TREATMENT OF
NEURODEGENERATIVE DISEASE SYMPTOMS 203
SPINAL CORD INJURY, NEURODEGENERATIVE DISEASES AND REGENERATIVE
POTENTIAL 204
UNIVERSITY OF SOUTHERN CALIFORNIA (USC) 205
CHAPTER 15 REGENERATIVE MEDICINE AND APPLICATIONS IN CARDIAC CARE 207
OVERVIEW 207
ACTIVE COMPANIES 207
Aastrom 207
Amorcyte 207
Athersys Inc. 208
Capricor 208
Cytomedix 208
Cytori Therapeutics 208
Juventas Therapeutics 208
Mesoblast 208
VentriNova 209
GENETIC BASIS FOR REGENERATING CELLS AFTER HEART ATTACK 209
STEM CELLS FOR THE FUTURE TREATMENT OF HEART DISEASE 209
PARTICULAR R&D PRIORITIES 210
STEM CELLS AND BIOLOGICAL PACEMAKERS 212
HEART PROGENITOR CELLS DEVELOPED FROM EMBRYONIC STEM CELLS 212
OTHER CURRENT REGENERATIVE MEDICINE AS IT RELATES TO THE HEART 213
CHAPTER 16 REGENERATIVE MEDICINE AND DIABETES 215
BACKGROUND 215
POSSIBLE APPLICATIONS FOR REGENERATIVE MEDICINE 215
CLINICAL TRIALS 216
SERNOVA CORP 217
ATHERSYS INC. 217
MESOBLAST 217
VIACYTE 218
CHAPTER 17 FDA-APPROVED CLINICAL TRIALS INVOLVING REGENERATIVE MEDICINE 220
CURRENT STATUS OF THE REGENERATIVE MEDICINE BUSINESS 220
REGULATORY AND LEGAL ENVIRONMENT 220
STATUS OF RESEARCH AND CLINICAL TRIALS 222
ANALYSIS OF CLINICAL TRIALS 223
TABLE 48 REGENERATIVE MEDICINE CLINICAL TRIALS BY CATEGORY (NUMBER/%) 224
TABLE 49 CURRENT CLINICAL TRIALS IN THE FIELD OF REGENERATIVE MEDICINE,
STATUS, CONDITIONS AND SPONSOR, MARCH 30, 2015 224
CHAPTER 18 OVERSEAS ACTIVITIES 233
DOMESTIC VERSUS OVERSEAS REGENERATIVE MEDICINE COMPANIES 233
JAPAN 233
Japan's Regenerative Therapies Market Prospects 234
TABLE 50 JAPAN'S MARKET FOR REGENERATIVE AND TISSUE ENGINEERING, 2009
AND 2020 234
EUROPE 235
REMEDIC 235
Nanobiocom 236
Regenerating Bone Defects using New Biomedical Engineering
Approaches - (REBORNE) 236
Gene Activated Matrices for Bone and Cartilage Regeneration in
Arthritis - (GAMBA) 237
BIRAX 237
AUSTRALIA AND CHINA 237
CHAPTER 19 PATENT ANALYSIS 240
ANALYSIS 240
TISSUE ENGINEERING PATENTS 240
TABLE 51 TOP PATENT ASSIGNEES IN THE TISSUE ENGINEERING FIELD 241
GEOGRAPHIC DISTRIBUTION 241
TABLE 52 GLOBAL DISTRIBUTION OF REGENERATIVE MEDICINE PATENTS ISSUED
BY COUNTRY, 1985-2012 (%) 242
RECENT PATENTS 242
METHOD FOR OBTAINING PANCREATIC PROGENITOR CELL USING NEPH3 242
Abstract 242
SPONTANEOUSLY IMMORTALIZED MULTIPONENT MESENCHYMAL
CELL-LINE DERIVED FROM MOUSE SUBCUTANEOUS ADIPOSE TISSUE:
TOOL FOR REGENERATIVE MEDICINE AND BIOACTIVE MOLECULES AND/OR
DRUGS SCREENING
243
Abstract 243
METHODS OF MANUFACTURING BIOACTIVE GELS FROM EXTRACELLULAR
MATRIX MATERIAL 243
Abstract 243
ALIMENTARY PROTEIN-BASED SCAFFOLDS (APS) FOR WOUND HEALING,
REGENERATIVE MEDICINE AND DRUG DISCOVERY 244
Abstract 244
POLYMER CARRIER 244
Abstract 244
HERBAL COMPOSITION FOR THE TREATMENT OF WOUND HEALING, A
REGENERATIVE MEDICINE 244
Abstract 244
MAGNETIC CELL AND METHOD OF USING THE SAME 245
Abstract 245
THREE-DIMENSIONAL BIOPRINTING OF BIOSYNTHETIC CELLULOSE (BC)
IMPLANTS AND SCAFFOLDS FOR TISSUE ENGINEERING 245
Abstract 245
BIOMATERIAL BASED ON WHARTON'S JELLY FROM THE HUMAN UMBILICAL
CORD 246
Abstract 246
NONWOVEN FABRIC AND PROCESS FOR PRODUCING THE SAME 246
Abstract 246
THERAPEUTIC APPLICATIONS OF P53 ISOFORMS IN REGENERATIVE
MEDICINE, AGING AND CANCER 247
Abstract 247
DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC USES OF LONG
NON-CODING RNAS FOR CANCER AND REGENERATIVE MEDICINE 247
Abstract 247
NANO/MACROPOROUS BONE TISSUE SCAFFOLDS FOR REGENERATIVE
MEDICINE 248
Abstract 248
GUIDED DELIVERY OF CELL-, PARTICLE- AND DRUG-BASED THERAPIES 248
Abstract 248
TRANSGENIC NONHUMAN ANIMAL AND METHODS FOR STEM CELL
ENGRAFTMENT 249
Abstract 249
METHODS FOR MODULATING THE PROLIFERATION AND DIFFERENTIATION
POTENTIAL OF STEM CELLS AND PROGENITOR CELLS 249
Abstract 249
BIOPOLYMER PRODUCED BY FERMENTING THE EXTRACT OF SOYBEAN
WITH FOLIC ACID AND A COMPOSITION CONTAINING THEREOF 249
Abstract 250
SUBPOPULATIONS OF BONE MARROW-DERIVED ADHERENT STEM CELLS
AND METHODS OF USE THEREFOR 250
Abstract 250
METHOD FOR PREPARING BIOLOGICAL SCAFFOLD MATERIAL 250
Abstract 251
COMPOSITION FOR REGENERATIVE TREATMENT OF CARTILAGE DISEASE 251
Abstract 251
REGULATION OF STEM CELL GENE PRODUCTION WITH SPECIFIC AND
SELECTIVE ELECTRIC AND ELECTROMAGNETIC FIELDS 251
Abstract 251
COMPOSITIONS AND METHODS FOR BONE FORMATION AND REMODELING 252
Abstract 252
NEURAL CELL POPULATIONS FROM PRIMATE PLURIPOTENT STEM CELLS 252
Abstract 252
OSTEOINDUCTIVE BONE MATERIAL 253
Abstract 253
GENES WITH ES CELL-SPECIFIC EXPRESSION 253
Abstract 253
USE OF TGF BETA SUPERFAMILY ANTAGONISTS AND NEUROTROPHINS TO
MAKE NEURONS FROM EMBRYONIC STEM CELLS 254
Abstract 254
HYDROXYPHENYL CROSS-LINKED MACROMOLECULAR NETWORK AND
APPLICATIONS THEREOF 254
Abstract 254
MAGNETIC CELL AND METHOD OF USING THE SAME 255
Abstract 255
DIRECT DIFFERENTIATION METHOD FOR MAKING CARDIOMYOCYTES FROM
HUMAN EMBRYONIC STEM CELLS 255
Abstract 255
ISOLATION AND PRESERVATION OF FETAL HEMATOPOIETIC AND
MESENCYMAL SYSTEM CELLS FROM NONCONTROVERSIAL MATERIALS
AND/OR TISSUES RESULTING FROM MISCARRIAGES AND METHODS OF
THERAPEUTIC USE
256
Abstract 256
USE OF TGF BETA SUPERFAMILY ANTAGONISTS TO MAKE DOPAMINERGIC
NEURONS FROM EMBRYONIC STEM CELLS 256
Abstract 256
DIRECT DIFFERENTIATION METHOD FOR MAKING CARDIOMYOCYTES FROM
HUMAN EMBRYONIC STEM CELLS 257
Abstract 257
METHOD FOR PREPARING NOVEL TRANSCRIPTION FACTORS AND USE 257
Abstract 257
ENDODERM CELLS FROM HUMAN EMBRYONIC STEM CELLS 257
Abstract 258
GENES WITH ES CELL-SPECIFIC EXPRESSION 258
Abstract 258
MARKER SYSTEM FOR PREPARING AND CHARACTERIZING HIGH-QUALITY
HUMAN EMBRYONIC STEM CELLS 258
Abstract 258
CHAPTER 20 COMPANY PROFILES 261
TABLE 53 PUBLICLY TRADED COMPANIES IN THE REGENERATIVE MEDICINE
INDUSTRY, MARCH 6, 2015 ($/$ MILLIONS) 261
TABLE 54 COMPANIES ESTIMATED SALES ATTRIBUTABLE TO REGENERATIVE
THERAPIES (BONE AND JOINT), 2012 ($ MILLIONS) 262
OTHER ORGANIZATIONS INVOLVED IN REGENERATIVE MEDICINE R&D 322
ACADEMIC INSTITUTIONS 322
U.S. GOVERNMENT 323
OTHER SOCIETIES AND ORGANIZATIONS 323
CHAPTER 21 GLOSSARY OF KEY TERMS IN REGENERATIVE MEDICINE BUSINESS 325

LIST OF TABLES
SUMMARY TABLE U.S. MARKET FOR REGENERATIVE MEDICINE PRODUCTS USED IN
BONE AND JOINT APPLICATIONS, THROUGH 2020 ($ MILLIONS) 8
TABLE 1 FUNCTIONAL ACTIVITIES WITH REGENERATIVE MEDICINE SECTOR 11
TABLE 2 MOST PROMINENT COMPANIES IN THE REGENERATIVE MEDICINE BUSINESS 12
TABLE 3 REVENUES FOR TOP SUPPLIERS OF ORTHOPEDIC PRODUCTS AND
MATERIALS, 2014 ($ BILLIONS) 13
TABLE 4 NINE PRINCIPAL MARKET DRIVERS 18
TABLE 5 R &D FOCUSES FOR PRINCIPAL REGENERATIVE MEDICINE 18
TABLE 6 TWENTY-YEAR PLANNING HORIZON FOR REGENERATIVE MEDICINE
BUSINESS: LIKELY DEVELOPMENTS 20
TABLE 7 NATIONAL SCIENCE FOUNDATION REGENERATIVE MEDICINE FUNDING
PRIORITIES, APRIL 1, 2015 ($) 21
TABLE 8 PRINCIPLE RESEARCH PROJECTS OF CIMIT IN THE TISSUE-ENGINEERING
AND BIOMATERIALS FIELDS, 2008-2012 28
TABLE 9 COMPANIES INVOLVED IN BONE AND JOINT STEM CELL-BASED
THERAPEUTICS 35
TABLE 10 COMMERCIAL SUPPLIERS OF BIOREACTORS FOR USE IN REGENERATIVE
MEDICINE 38
TABLE 11 BONE MORPHOGENETIC PROTEINS 47
TABLE 12 U.S. MARKET FOR TISSUE-ENGINEERED AND CELL THERAPY-BASED
CARTILAGE PRODUCTS, THROUGH 2020 ($ MILLIONS) 55
TABLE 13 WORLD'S LARGEST IMPLANTABLE BIOMATERIALS COMPANIES 59
TABLE 14 FEDERAL FUNDING FOR STEM CELL RESEARCH, THROUGH 2013 ($
MILLIONS) 65
TABLE 15 STATE LEVEL PROGRAMS FOCUSED ON STEM CELL RESEARCH 66
TABLE 16 CHARACTERISTICS OF IDEAL BONE GRAFT MATERIAL 81
TABLE 17 U.S. BONE GRAFT PROCEDURE VOLUMES BY APPLICATION, THROUGH
2020 (NUMBER) 82
TABLE 18 U.S. BONE GRAFT PROCEDURE VOLUMES BY TYPE OF GRAFT, THROUGH
2020 (NUMBER) 82
TABLE 19 BONE GRAFT MATERIALS 83
TABLE 20 SUBSTITUTE BONE GRAFTS 84
TABLE 21 SELECTED DBM PRODUCTS AND PERCENTAGE OF DEMINERALIZED BONE
MATRIX 88
TABLE 22 U.S. MARKET FOR PRECISION-MACHINED ALLOGRAFTS, THROUGH 2020 ($
MILLIONS) 92
TABLE 23 GLOBAL MARKET FOR BONE REPLACEMENT PRODUCTS, THROUGH 2020
($ MILLIONS) 105
TABLE 24 U.S. MARKET FOR BONE-REPLACEMENT AND GRAFTING PRODUCTS,
THROUGH 2020 ($ MILLIONS) 106
TABLE 25 EXAMPLES OF NANOSTRUCTURED BIOMATERIALS USEFUL IN BONE AND
JOINT REGENERATION 111
TABLE 26 DRUGS USED TO TREAT OSTEOPOROSIS 133
TABLE 27 GLOBAL MARKET FOR DRUGS TO TREAT OSTEOPOROSIS BY CATEGORY,
THROUGH 2020 ($ MILLIONS) 138
TABLE 28 GLOBAL MARKET FOR DRUGS TO TREAT PAGET'S DISEASE, THROUGH
2020 ($ MILLIONS) 140
TABLE 29 GLOBAL HIP FRACTURE VOLUMES, THROUGH 2020 (NUMBER) 141
TABLE 30 U.S. HIP FRACTURE VOLUMES, THROUGH 2020 (NUMBER/%) 142
TABLE 31 U.S. MARKET SHARES FOR MUSCULOSKELETAL PRODUCTS BY CATEGORY,
2014 (%) 142
TABLE 32 U.S. MARKET SHARES FOR RECONSTRUCTIVE DEVICES BY CATEGORY,
2014 (%) 143
TABLE 33 NUMBER OF U.S. HIP REPLACEMENT PROCEDURE VOLUMES, THROUGH
2020 143
TABLE 34 NUMBER OF HIP REPLACEMENT PROCEDURES IN SIX MAJOR STATES, 2001 144
TABLE 35 GLOBAL MARKET FOR HIP REPLACEMENTS, THROUGH 2020 ($ MILLIONS) 144
TABLE 36 U.S. MARKET FOR HIP REPLACEMENTS, THROUGH 2020 ($ MILLIONS) 144
TABLE 37 GLOBAL KNEE-REPLACEMENT PROCEDURE VOLUMES, THROUGH 2020
(NUMBER) 145
TABLE 38 U.S. KNEE REPLACEMENT PROCEDURES, THROUGH 2020 (NUMBER) 146
TABLE 39 GLOBAL MARKET FOR KNEE REPLACEMENTS, THROUGH 2020 ($ MILLIONS) 146
TABLE 40 U.S. MARKET FOR KNEE REPLACEMENTS, THROUGH 2020 ($ MILLIONS) 146
TABLE 41 U.S. MARKET FOR UNICONDYLAR KNEE REPLACEMENTS, THROUGH 2020
($ MILLIONS) 147
TABLE 42 GLOBAL MARKET FOR NONINVASIVE BONE GROWTH STIMULATORS BY
APPLICATION, THROUGH 2020 ($ MILLIONS) 157
TABLE 43 U.S. MARKET FOR NONINVASIVE BONE GROWTH STIMULATORS BY
APPLICATION, THROUGH 2020 ($ MILLIONS) 157
TABLE 44 RECENTLY APPROVED ORTHOPEDIC BONE AND JOINT DEVICES BY
PRODUCT, 2008-2015 161
TABLE 45 EXAMPLES OF FDA APPROVED HUMAN SKIN SUBSTITUTES 195
TABLE 46 GLOBAL MARKET FOR ENGINEERED SKIN GRAFTS AND REPLACEMENTS,
THROUGH 2020 ($ MILLIONS) 197
TABLE 47 INVESTIGATIONAL SKIN AND SOFT TISSUE SUBSTITUTES, MARCH 2015 198
TABLE 48 REGENERATIVE MEDICINE CLINICAL TRIALS BY CATEGORY (NUMBER/%) 224
TABLE 49 CURRENT CLINICAL TRIALS IN THE FIELD OF REGENERATIVE MEDICINE,
STATUS, CONDITIONS AND SPONSOR, MARCH 30, 2015 224
TABLE 50 JAPAN'S MARKET FOR REGENERATIVE AND TISSUE ENGINEERING, 2009
AND 2020 234
TABLE 51 TOP PATENT ASSIGNEES IN THE TISSUE ENGINEERING FIELD 241
TABLE 52 GLOBAL DISTRIBUTION OF REGENERATIVE MEDICINE PATENTS ISSUED BY
COUNTRY, 1985-2012 (%) 242
TABLE 53 PUBLICLY TRADED COMPANIES IN THE REGENERATIVE MEDICINE
INDUSTRY, MARCH 6, 2015 ($/$ MILLIONS) 261
TABLE 54 COMPANIES ESTIMATED SALES ATTRIBUTABLE TO REGENERATIVE
THERAPIES (BONE AND JOINT), 2012 ($ MILLIONS) 262

LIST OF FIGURES
SUMMARY FIGURE U.S. MARKET FOR REGENERATIVE MEDICINE PRODUCTS USED IN
BONE AND JOINT APPLICATIONS, 2014-2020 ($ MILLIONS) 8