Regenerative Treatments in Sports and Orthopedic Medicine -

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Dedicated to all those who are still suffering; may you find a new road to recovery.
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Contents
Contributors ix
Preface xiii
Share Regenerative Treatments in Sports and Orthopedic Medicine

1. Current Concepts in the Pathophysiology of Orthopedic Conditions Affecting

Treatment 1
Christopher J. Visco and Wade Johnson
2. Understanding Regenerative Medicine Terminology 13
Jay Smith and Andre J. van Wijnen
3. Regulatory Issues Regarding the Clinical Use of Regenerative Treatments 27
Karl M. Nobert
4. Clinical and Administrative Considerations in Performing Regenerative
Procedures 35
Leah M. Kujawski, Michael A. Scarpone, and David C. Wang
5. Regenerative Medicine in the Canine: A Translational Model 43
Sherman O. Canapp, Jr. and Brittany Jean Carr
6. Principles of Platelet-Rich Plasma and Stem Cells: From Platelets to Cytokines 67
Ricardo E. Colberg and Ariane Maico
7. Scientific Evidence of Platelet-Rich Plasma for Orthopedic Conditions: Basic Science to
Clinical Research and Application 89
Peter I-Kung Wu, Robert Diaz, and Joanne Borg-Stein
8. Platelet-Rich Plasma to Enhance Orthopedic Procedures 121
Fadi Hassan, William D. Murrell, Suad Trebinjac, and Zaid Hashim
9. Amniotic and Umbilical Cord Products, Alpha-2 Macroglobulin, and Interleukin-1
Receptor Antagonist Protein 149
Sean Colio, Marko Bodor, and Ryan Dregalla
10. Setup and Procedures for Performing Platelet-Rich Plasma Injections 163
Robert W. Engelen and José A. Ramírez-Del Toro
11. Basic Science and Rationale for Using Stem Cells for Orthopedic Conditions 179
Christopher J. Williams, Walter I. Sussman, and Kenneth R. Mautner

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viii Contents

12. Harvesting Techniques of Bone Marrow and Adipose for Stem Cell Procedures 195
Jay E. Bowen, Raisa Bakshiyev, and Sony M. Issac
13. Techniques for Performing Regenerative Procedures for Orthopedic Conditions 221
Imran James Siddiqui, Timothy J. Mazzola, and Brian J. Shiple
14. Physical Therapy Considerations Following Regenerative Medicine Interventions 257
Angela T. Gordon and Kwang Han

Index 283
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Contributors

Raisa Bakshiyev, MD Brittany Jean Carr, DVM, CCRT

Department of Physical Medicine and Canine Sports Medicine and Rehabilitation
Rehabilitation Veterinarian
Northwell Health Sports Medicine and Rehabilitation
Manhasset, New York Veterinary Orthopedic and Sports
Medicine Group
Marko Bodor, MD Annapolis Junction, Maryland
Assistant Professor
Department of Physical Medicine and Ricardo E. Colberg, MD, RMSK
Rehabilitation Sports Medicine Physician
University of California at Davis Andrews Sports Medicine and Orthopedic
Sacramento,California; Center
Interventional Physiatrist American Sports Medicine Institute
Department of Spine and Sports Medicine Birmingham, Alabama
Bodor Clinic
Napa, California Sean Colio, MD
Clinical Assistant Professor
Joanne Borg-Stein, MD Department of Orthopedic Surgery
Associate Professor/Associate Chair Stanford University
Sports and Musculoskeletal Rehabilitation; Redwood City, California
Associate Director, Harvard/Spaulding Sports
Medicine Fellowship Robert Diaz, MD
Department of Physical Medicine and Resident Physician
Rehabilitation Department of Physical Medicine and
Harvard Medical School Rehabilitation
Wellesley, Massachusetts Spaulding Rehabilitation Hospital/Harvard
Medical School
Jay E. Bowen, DO Charlestown, Massachusetts
New Jersey Regenerative Institute, LLC
Cedar Knolls, New Jersey Ryan Dregalla, PhD
Regenerative Science Research and
Sherman O. Canapp, Jr., DVM, MS, CCRT, Development
DACVS, DACVSMR Dregalla Medical Technologies, LLC
Chief of Staff Scottsdale, Arizona
Orthopedic Surgery, Sports Medicine, and
Regenerative Medicine Robert W. Engelen, DO
Veterinary Orthopedic and Sports Medicine Sports Medicine Physician
Group; Department of Orthopedics
President and CEO Comprehensive Orthopedics and Sports
Orthobiologic Innovations Medicine/Physician Group of Utah
Annapolis Junction, Maryland Salt Lake City, Utah
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x Contributors

Angela T. Gordon, PT, DSc, MPT, COMT, OCS, Kenneth R. Mautner, MD

ATC, FMS Associate Professor
Co-Founder and Physical Therapist Departments of Physical Medicine and
Advanced Kinetics Physical Therapy and Sports Rehabilitation and Orthopedics
Performance Emory University;
Falls Church, Virginia Director, Primary Care Sports Medicine
Emory Sports Medicine Center
Kwang Han, PT, MPT Atlanta, Georgia
Co-Founder and Physical Therapist
Advanced Kinetics Physical Therapy and Sports Timothy J. Mazzola, MD
Performance Non-Operative Orthopedic and Regenerative
Falls Church, Virginia Medicine Specialist
Cornerstone Orthopedics and Sports Medicine
Zaid Hashim, MBBS, MRCS (Eng), PGCMedEd Louisville, Colorado;
Specialty Trainee in Trauma and Orthopedics Senior Clinical Instructor
Department of Trauma and Orthopedics Department of Family Medicine
York Teaching Hospitals University of Colorado School of Medicine
York, United Kingdom Aurora, Colorado

Fadi Hassan, MBBS, BSc (Hons) William D. Murrell, MD, MS

Junior Doctor Chief Science Officer
Good Hope Hospital Emirates Healthcare
Heart of England NHS Foundation Trust CEO and Consultant
Birmingham, United Kingdom Orthopedic Sports Medicine
Emirates-Integra Medical and Surgical Centre
Sony M. Issac, MD Dubai, UAE;
Resident Orthopedics, Rehabilitation, and Podiatry
Department of Physical Medicine and Department
Rehabilitation Fort Belvoir Community Hospital
Nassau University Medical Center Fort Belvoir, Virginia
East Meadow, New York
Karl M. Nobert, Esq.
Wade Johnson, DO FDA Regulatory Attorney
Department of Physical Medicine and Principal
Rehabilitation The Nobert Group, LLC
New York-Presbyterian Hospital Sterling, Virginia;
New York, New York President
ReCellerate Inc.
Leah M. Kujawski, RN, BSN Middleburg, Virginia
Clinical Operations Manager
Regenerative Orthopedics and Sports José A. Ramírez-Del Toro, MD
Medicine Director of Sports Medicine Fellowship
Washington, DC Department of Physical Medicine and
Rehabilitation
Ariane Maico, MD University of Pittsburgh Medical Center
Department of Physical Medicine and Pittsburgh, Pennsylvania;
Rehabilitation Director of Sports Medicine
University of Alabama School of Medicine California University of Pennsylvania
Birmingham, Alabama California, Pennsylvania
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Contributors xi

Michael A. Scarpone, DO Suad Trebinjac, MD, PhD

Medical Director Associate Professor
Sports Medicine Trinity Health System; Medical Director
Assistant Professor Dubai Physiotherapy and Rehabilitation Center
Drexel School of Medicine AGH Campus (DPRC);
Team Physician Pittsburgh Pirates Consultant
Steubenville, Ohio FIFA Medical Center of Excellence
Dubai, UAE
Brian J. Shiple, DO, CAQSM, RMSK
Founder Andre J. van Wijnen, PhD
The Center for Sports Medicine Professor
Glenn Mills, Pennsylvania; Department of Orthopedic Surgery
Assistant Clinical Professor of Family and Mayo Clinic
Community Medicine Rochester, Minnesota
Temple University School of Medicine
Philadelphia, Pennsylvania Christopher J. Visco, MD
Associate Professor
Imran James Siddiqui, MD, RMSK Department of Rehabilitation and Regenerative
Director of Clinical Care Medicine
Regenerative Orthopedics and Columbia University Medical Center
Sports Medicine New York, New York
Department of Physical Medicine and
Rehabilitation David C. Wang, DO, DABPMR
George Washington University Director of Education and Training
Washington, DC Regenerative Orthopedics and Sports
Jay Smith, MD Medicine
Washington, DC
Professor
Departments of Physical Medicine and
Christopher J. Williams, MD
Rehabilitation, Radiology, and Anatomy
Attending Physician
Mayo Clinic
Regenerative Orthopedics
Rochester, Minnesota
Centeno-Schultz Clinic
Walter I. Sussman, DO, RMSK Broomfield, Colorado
Sports Medicine Physician, CAQSM
Orthopedic Care Physician Network Peter I-Kung Wu, MD, PhD
North Easton, Massachusetts; Resident Physician
Assistant Professor Department of Physical Medicine and
Department of Physical Medicine and Rehabilitation
Rehabilitation Spaulding Rehabilitation Hospital/Harvard
Tufts University Medical School
Boston, Massachusetts Charlestown, Massachusetts
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Preface

The convergence of industry advancements and accelerating this process, a practitioner can ini-
medical research has resulted in an exponen- tiate and support a healing process that previ-
tial growth in the clinical use of regenerative ously was prescribed to surgical intervention.
medicine throughout the world. With its popu- Examples of this include meniscal and rotator
larity outpacing scientific data, the need for an cuff tears. Both common, and often resolving
authoritative text on the subject has become with a nonsurgical “watch and wait” principle,
essential. Modern-day research has tapped into many of these injuries currently progress to sur-
a deeper and more complex understanding of gical intervention. As meniscal and rotator cuff
cytokine- and cell-based regeneration theory surgeries have high failure rates, often reach-
that translates well into the clinical paradigm of ing up to 30%, they fail to provide a definitive
regenerative medicine. This textbook describes solution in many patients. In addition, these
the evolution of these research principles into an interventions invariably alter the joint environ-
effective and safe clinical practice. ment leading to further degenerative processes.
Today’s standard treatment options in ortho- This textbook presents nonsurgical treatment
pedics and sports medicine, many of which are options offering a new paradigm that enhances
outdated and ineffective, are being replaced by the natural healing of these injuries and degen-
regenerative medicine interventions. These inef- erative pathologies. So far, these interventions
fective and outdated treatment options include have been proven to be safe, simple, and effec-
the prolonged use of anti-inflammatory medi- tive, with potential economic benefits to our ail-
cations, the use of corticosteroid injections for ing modern health care system.
noninflammatory processes such as tendinop- Before beginning these regenerative treat-
athies, the use of arthroscopic partial menis- ments, baseline medical knowledge is required.
cectomy for degenerative meniscal tears, the First, the clinician has to be able to obtain a
repeated use of epidural injections with cortico- proper medical history. Next, the clinician has
steroids, and many of the spinal fusion surger- to be able to perform a comprehensive kinetic
ies being performed. It is clear that the current chain-based orthopedic physical examination,
American health care system needs improve- which includes a full understanding of the phys-
ments in the delivery of care to our patients. ical exam maneuvers and the strengths and
Medical care should include a more personal- weaknesses of these maneuvers in the gather-
ized approach, as well as an overall reduction in ing of information. This is then followed by the
the number of medication prescriptions and the ability to interpret imaging studies, including
number of surgical treatments, both of which x-rays and MRIs that are directly correlated to
have significant potential negative effects and the patient’s history and examination findings.
significant risks. Treatment should not be driven purely by what
The complexity of regenerative pathways has the images show, but rather needs to be based
long been described in the medical literature. upon the information that was gathered during
By distilling these studies, a more focused and the history and physical examination, as there
clinically relevant paradigm for regeneration is a plethora of information suggesting that
becomes apparent. The body has a remarkable abnormalities in images can frequently be seen
natural ability to heal itself. By facilitating or in asymptomatic populations.
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xiv Preface

Clinicians interested in developing a regener- modern-day regenerative medicine techniques

ative medicine practice must be aware that the are revolutionizing orthopedic and sports med-
office visit with patients takes time and requires a icine treatment. Our hope is that this book will
lengthy review of the findings and all the treatment inspire a deeper awareness of the issues sur-
options available to patients. This should include rounding such a revolution: from practice man-
the many nonsurgical and less invasive options agement to regulatory matters. We have been
such as diet/weight loss; vitamin supplements; fortunate to have chapter authors with great
orthotic, bracing, aggressive strengthening; hyal- knowledge, experience, and enthusiasm in the
uronic injections; and the like. Some patients with study and clinical use of various orthobiologic
biomechanical issues such as catching, locking, or treatments. We would like to thank them for
joint instability may be better served with surgical their hard work and diligence in providing the
treatment (perhaps enhanced with orthobiologic most up-to-date information on their topic
treatment). Clinicians need to keep up with the areas. We would also like to thank Beth Barry
current scientific evidence for these treatments from Demos for first approaching us regard-
and provide patients with as much information ing this project and her assistance in getting
as possible regarding the efficacy of these treat- it done.
ments that have been published in basic science, We hope the readers of this textbook will
animal, and human studies. The clinician must find it a useful reference that will facilitate a
take time with the patients to provide a personal- thoughtful introduction to this exciting new area
ized approach to their care. in orthopedic treatment, and we hope that most
Many practitioners of regenerative medicine will consider getting involved in data collection
believe in the effectiveness of these regenerative registries or other modes of research and facil-
medicine methods, but often struggle to provide itate further advancement to improve patient
a holistic and evidence-based rationale for this outcomes. Both our individual patients and the
approach. This textbook is intended as a working health care system would benefit greatly.
reference for these clinicians, offering a concise, Regenerative medicine is fundamentally a
evidence-based rationale for regenerative med- modern-day method of enhancing the human
icine in the world of sports medicine. Experts capabilities of healing. The principles of this
from a variety of renowned medical centers, book will provide the reader with a framework to
including Harvard and Mayo Clinic, expound this use this understanding to fulfill the calling of all
rationale to guide the reader through this para- practitioners: healing the patient.
digm shift.
From basic science to practical pearls, the Gerard A. Malanga, MD
authors provide a unique insight into how Victor Ibrahim, MD
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Regenerative Treatments in Sports and
Orthopedic Medicine
1

CHAPTER 1
CURRENT CONCEPTS IN
THE PATHOPHYSIOLOGY OF
ORTHOPEDIC CONDITIONS
AFFECTING TREATMENT
Christopher J. Visco and Wade Johnson

Conventional therapies for nonoperative ortho- et al. In the 1990s, PRP began gaining popular-
pedic conditions have long been targeted to ity in maxillofacial, periodontal, and cosmetic
reduce inflammation with the goal of decreasing surgery with reported significant improvements
pain. It is now well known that inflammation is in healing. In the early 2000s, the use of PRP
an important part of the healing process. Key cell expanded into orthopedic conditions and the
signaling responsible for repair make up a com- first published application of PRP for chronic
ponent of that inflammatory milieu. Therefore, tendinosis was published by Mishra and Pavelko
eliminating both inflammation and cell signaling in 2006 (1).
with medications including nonsteroidal anti- This chapter focuses on the science behind
inflammatory drugs (NSAIDs) and corticoste- chronic and degenerative processes involving
roids can be detrimental in the long run. As the cartilage and tendon, as well as how these pro-
pathophysiology of common musculoskeletal cesses influence current and future management
conditions has become better understood, it is strategies. The mechanisms by which regenera-
increasingly possible to target specific areas of tive therapies exert their effects is described in
the process to improve healing. detail in the later chapters.
Regenerative therapies, including platelet-
rich plasma (PRP) and mesenchymal stem cells
(MSCs), have been gaining popularity for ortho- COMMON MUSCULOSKELETAL
pedic pathology in recent years; however, their
DISORDERS IN ORTHOPEDICS
use dates back decades. PRP was first devel-
oped in the 1970s, and its first documented use The majority of musculoskeletal disorders are
was for cardiac surgery in Italy in 1987 by Ferrari managed nonoperatively in sports medicine and

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2 Regenerative Treatments in Sports and Orthopedic Medicine

orthopedics. Injuries to muscle, tendon, liga- the vascular, lymphatic, and nerve supply to the
ment, bone, and cartilage all have nonsurgical tendon. Paratenon is made up of type I and III
treatment options and are potential targets for collagen with the inner surface lined by syno-
regenerative therapies including PRP and MSCs. vial cells. Some tendons with a paratenon are
The pathophysiology behind both acute tears found in close approximation to a fat pad, which
and strains of muscles and ligament and chronic includes the triceps and patellar and Achilles
degenerative processes involving tendon and tendons (11,12).
cartilage, including fibrocartilage and hyaline The cellular component of tendons is made
cartilage, is well documented (2–10). up of tenoblasts and tenocytes arranged in par-
allel rows among collagen fibers running in the
long axis of the tendon. Tenoblasts are imma-
ture spindle-shaped cells with many cytoplas-
TENDINOPATHY mic organelles reflecting their high level of
metabolic activity. Tenoblasts become elon-
Normal Tendon Structure gated as they age, and transform into tenocytes.
To understand the pathophysiology of tendinopa- Tenocytes function to synthesize collagen and
thy, one must first understand the basic anatomy the other components of the ECM, and are also
of a tendon. Tendons consist of bundles of collagen very metabolically active. Together, tenoblasts
fibrils, which are formed from a three-polypeptide and tenocytes make up 90% to 95% of the cel-
chain triple helix. The collagen fibrils are held lular component of tendons. The remaining 5%
together by proteoglycans including aggrecan to 10% of the cellular component is made up of
and decorin, and line up in parallel and overlap- chondrocytes, present at the enthesis, synovial
ping fashion forming a collagen fiber. These fibers cells, located in the tendon sheath, and endothe-
are then bundled and enveloped in endotenon, lial cells of the arterioles supplying the tendon.
forming a primary fiber bundle, the subfascicle, There are two histologically distinct transition
which is further bundled to form a secondary fiber points in all tendons: the musculotendinous junc-
bundle, known as a fascicle (Figure 1.1). Fascicles tion and the point of insertion to bone known as
intercalate to form the tertiary structure recog- the “enthesis.” The musculotendinous junction is
nizable as tendon, which is then ensheathed in the rich in nerve receptors and is subject to significant
parietal layer by an epitenon. mechanical stress during muscle contraction.
The collagen portion of tendon is approxi- At this junction, collagen fibers from the tendon
mately 97% type I collagen, with small amounts are inserted into deep recesses within the mus-
of types II, III, IV, V, IX, and X collagen making cle formed by myocyte processes allowing the
up the various components of supportive tis- transmission of tension created by the muscle
sues. The extracellular matrix (ECM) is made up fibers to the collagen of the tendon. This architec-
of 65% to 80% collagen and provides strength. ture reduces tensile stress exerted on the tendon,
Elastin ensures flexibility and is present in small although the junction remains the weakest point
amounts. The remainder of ECM is known as of the muscle–tendon complex. The typical enthe-
“ground substance” and is made up primarily of sis displays a more gradual transition from tendon
water (accounting for 70% of tendon mass), with to cartilage and to lamellar bone and is made up
scant proteoglycans and glycoproteins. Few ten- of four zones: dense tendon zone, fibrocartilage,
dons, including the flexors and extensors of the mineralized fibrocartilage, and bone. This transi-
hand and wrist, have true synovial sheaths, while tion point helps to prevent collagen fiber dam-
others are surrounded by paratenon, with muco- age and failure during stress by dispersing forces
polysaccharides providing lubrication between (2). Tendons also insert onto bone in the form of
epitenon and paratenon (5). The epitenon is a myo-entheses, such as the distal iliacus. Myo-
fine, loose connective tissue sheath and contains entheses tend to develop degenerative pathology
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1 • Current Concepts in the Pathophysiology of Orthopedic Conditions Affecting Treatment 3

Pre-procollagen

Procollagen

Tropocollagen

Lysyl oxidase

Collagen fibril

Fibril Microfibril Tropocollagen

Fiber helix

FIGURE 1.1: Tendon structure.

Source: From Ref. (13). Caldwell M, Casey E, Powell B, Shultz SJ. Sex hormones. In: Casey E, Rho M, Press J, eds. Sex
Differences in Sports Medicine. New York, NY: Demos Medical Publishing LLC; 2016:11.

less frequently because of their superior blood

supply compared to cartilaginous entheses. It is
Tendon Blood Supply and Innervation
important to also note that muscle and tendon do Intrinsic blood supply to tendon is located at
not always insert onto bone, with muscle being the myotendinous and osteotendinous junc-
able to insert directly onto ligament (e.g., vastus tion points; extrinsic blood supply comes from
medialis inserting onto the medial patellofem- the paratenon and synovial sheath. Vessels
oral ligament), and ligament inserting onto ten- originating in muscle supply the myotendinous
don (e.g., vastus lateralis onto the iliotibial band junction and do not extend beyond the proximal
[ITB], the fibrous tract running along the lateral third of the tendon, while the blood supply at
thigh important in stabilization of an extended, to the enthesis is significantly limited and located
slightly flexed, knee), and tendon onto ligament only in the insertion zone near the periosteum.
(e.g., supraspinatus onto the cuff pulley). Ensheathed tendons have extrinsic blood supply