Orthojournal V1issue1 04

Volume 1 Issue 1
ORTHOPAEDIC Journal
University Hospitals of
Cleveland
MetroHealth Medical
Center
Louis Stokes VA Medical
Center
CASE WESTERN RESERVE UNIVERSITY
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CONTENTS
RESIDENT STAFF
Jeffrey Roh, MD
Editor-in-Chief
Erika Mitchell, MD
Editor-in-Chief Elect
Robert Lowe, MD
Darin Friess, MD
Senior Editors
Mike Lee, MD
Adam Mirarchi, MD
Junior Editors, Advertising
Sam Akhavan, MD
Jerry Huang, MD
Junior Editors 2004-2005
FACULTY STAFF
Randall Marcus, MD
Victor Goldberg, MD
Henry Bohlman, MD
Jung Yoo, MD
George Thompson, MD
Heather Vallier, MD
Ed Greeneld, PhD
Ellen Greenberger
Secretary
LETTER FROM THE EDITOR-IN-CHIEF ................................................................ 1

CHARLES H. HERDON, M.D., 1915-1997 .......................................................... 2
YEAR IN REVIEW
CHAIRMANS REPORT, RANDALL E. MARCUS, M.D. ................................... 3
DIVISION OF PEDIATRIC ORTHOPAEDICS .................................................. 5
SPINE SURGERY PROGRAM ........................................................................ 6
RESEARCH SECTION .................................................................................. 8
BASIC SCIENCE FACULTY ......................................................................... 10
METRO ATTENDINGS .............................................................................. 11
UH ATTENDINGS ..................................................................................... 12
MANUSCRIPTS
TISSUE ENGINEERING OF A WHOLE BONE .............................................. 14
DISTAL FEMORAL LOCKING PLATES:
CALCULATION OF SCREW PLATE ANGLES ............................................... 17
TREATMENT FAILURE IN STABLE FEMORAL
NECK FRACTURES IN THE ELDERLY .......................................................... 21
CLINICAL OUTCOMES OF SURGICAL TREATMENT
OF THE SYMPTOMATIC ACCESSORY NAVICULAR .................................... 27
CLINICAL OUTCOME OF TIBIOTALAR ARTHRODESIS
UTILIZING THE CHEVRON TECHNIQUE ................................................... 30
THE EFFECT OF GAMMA RADIATION STERILIZATION ON
THE FATIGUE CRACK PROPAGATION RESISTANCE OF
HUMAN CORTICAL BONE........................................................................ 36
FIBRONECTIN PRETREATMENT OF HYALURONAN-BASED
SCAFFOLDS FOR THE TREATMENT OF OSTEOCHONDRAL DEFECTS ........ 39
IMPLANTED NEUROPROSTHESES FOR STANDING AND
TRANSFERS AFTER SPINAL CORD INJURY ................................................. 44
UNLOCKING THE SIGNALING MECHANISMS BEHIND
ASEPTIC LOOSENING .............................................................................. 51
MECHANOBIOLOGY OF CHONDROGENESIS........................................... 56
ASCORBATE IS ESSENTIAL FOR OSTEOCLASTOGENESIS........................... 59
REVIEW: REGULATION OF PKA SIGNALING BY PKI IN OSTEOBLASTS ....... 61
RECOMBINANT AGGRECAN AS A MODEL FOR ADAMTS-4/
AGGRECAN INTERACTIONS ..................................................................... 65
2004 CHIEF RESIDENTS FUTURE PLANS ......................................................... 70
INCOMING INTERNS CLASS OF 2009 ......................................................... 71
ALUMNI NOTES ............................................................................................. 72
FACULTY RESEARCH........................................................................................ 74
FACULTY GRANTS........................................................................................... 77
RESIDENT RESEARCH SYMPOSIUM ................................................................. 79
THE LITTLE ORTHOPAEDIC CLUB .................................................................... 80
TRAVELING FELLOWS ..................................................................................... 81
GRAND ROUNDS ........................................................................................... 82
CHARLES H. HERNDON SOCIETY.................................................................... 83
INSTRUCTIONS FOR AUTHORS ...................................................................... 84
04-803.SOM.OJ_final.indd 1
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LETTER FROM THE EDITOR-IN-CHIEF
am delighted to present the inaugural

edition of the Case Orthopaedic
Journal to you. As many of you know,
the Department of Orthopaedic
Surgery at Case has received the
distinct honor of being the top-ranked
orthopaedic department in the nation
in NIH research funding for ve of the
past six years. As the ofcial journal
for the Department, the COJ will help
to showcase the many scientic and
academic accomplishments of the Case
orthopaedic community.
Jeffrey S. Roh, M.D.
The specic purposes of the Case

Orthopaedic Journal are: 1) to promote
the exchange of scientic ideas and
ndings within the Case Orthopaedic
community, 2) to maintain an open
line of communication with Case
orthopaedic alumni and members of
the Charles Herndon Society, and 3)
to highlight the current activities and
achievements of the Department of
Orthopaedic Surgery at Case.
I would like to thank all of the
members of the Editorial Board for
their hard work and dedication to
the daunting task of making the Case
Orthopaedic Journal a reality. They

boldly accepted the challenge, and
effectively accomplished the goals set
before them. Special thanks to all of
the advertisers for their interest and
support of the journal.
This inaugural edition of the COJ
is proudly dedicated to Dr. Charles
Herndon. Although I regret not having
had the opportunity to meet Dr.
Herndon, his memory and tremendous
inuence on our Department and
in the eld of orthopaedic surgery
continue to live on. He was, and will
continue to be, a pioneer and visionary
in all of our eyes.
I hope you enjoy reading the Case
Orthopaedic Journal as much as I have
had in organizing it.
With highest regards,
Jeffrey S. Roh, M.D.

Editor-in-Chief
O R T H O PA E D I C JOURNAL | CASE WESTERN RESERVE UNIVERSITY | VOL.1, NO.1 | 2004 1
6/22/05 2:22:34 PM
CHARLES H. HERDON, M.D., 1915-1997
e dedicate the inaugural issue of the Case

Orthopaedic Journal to Dr. Charles H.
Herndon for his lasting inuence on orthopaedics
at Case Western Reserve University and to the
orthopaedic community at large.
Dr. Herndon was born in Dublin, Texas in 1915.
After graduating from the University of Texas (Phi
Beta Kappa), he received his medical degree from
Harvard University in 1940 (Alpha Omega Alpha).
After one year of surgical internship at University
Hospitals of Cleveland, Dr. Herndon volunteered
to serve at the American Hospital in Britain during
WWII and was subsequently inducted into the
U.S. Army in 1942. He was discharged as a Major
in 1946 and went on to complete his orthopaedic
residency at The Hospital for Special Surgery in
New York City.
In 1947, Dr. Herndon returned to University
Hospitals of Cleveland as the institutions rst fulltime orthopaedic surgeon. There he established the
Division of Orthopaedic Surgery in 1953 which
then became a full department in 1978. During
this time period, the Department of Orthopaedics
became recognized as one of the nest residency
programs in the country.
Besides his contributions to orthopaedics at Case
Western Reserve University, Dr. Herndon was an
internationally renowned surgeon and scientist.
He was a pioneer in
orthopaedic research,
primarily in the eld
of allograft bone
transplantation. He
served as a Trustee of
The Journal of Bone
and Joint Surgery from
1969 to 1974. He was a
founding member of the
Orthopaedic Research
Society, and served as
President in 1957. He also served as President of the
American Board of Orthopaedic Surgery from 1964
to 1966, of the American Academy of Orthopaedic
Surgeons from 1967 to 1968, and of the Council of
Medical Specialists Society in 1976.
In 1979, an endowed chair of Orthopaedics was
established in Dr. Herndons name in recognition
of his contributions to Case Western Reserve
University Medical School. He retired in 1982,
but has left his mark for all future generations of
orthopaedic surgeons at University Hospitals of
Cleveland. The orthopaedics department continues
to excel in research and residency training, building
on the foundation laid by Dr. Herndon. We present
the rst Case Orthopaedic Journal as a testament of
the continued academic excellence made possible by
the groundwork of Dr. Charles H. Herndon.
6/22/05 2:22:34 PM
YEAR IN REVIEW
CHAIRMANS REPORT
RANDALL E. MARCUS, M.D.
t is with great pleasure that I

introduce you to this new journal
designed to highlight the outstanding
achievements of the Department of
Orthopaedic Surgery at Case School
of Medicine, Case Western Reserve
University. The Department of
Orthopaedic Surgery at Case consists
of three medical centers: University
Hospitals of Cleveland, MetroHealth
Medical Center and the Stokes Veterans
Administration Medical Center. The
department continues to be ranked as
one of the top orthopaedic departments
in the United States, which makes me
extremely proud of the outstanding
achievements and excellent work
carried out during the last year by our
clinicians, scientists and staff.
I am pleased to report that the
department was notied by the
National Institutes of Health this
spring with the good news that we
were again ranked rst in the country
in NIH research awards to orthopaedic
departments. This marks the sixth time
in seven years that the Department
of Orthopaedic Surgery at Case has
received this distinct honor.
The department was further honored
in the selection, by the American
Orthopaedic Association, as one of the
twelve institutions to host the traveling
fellows from Asia. We were also
selected by the Insall (Knee Society)
to host traveling fellows for the third
consecutive year. The choice of our
department as a destination by surgeons
from Great Britain, Austria, New

Zealand, Germany, Switzerland, as well
as Asia, year after year, is something
that all of us are very proud of.
Our orthopaedic residency program
continues to be one of the more highly
sought-after post-doctoral training
programs in the country. This year, we
received 426 applications for our six
residency positions. The department
matched six of its top selections, and
we welcome our new residents:
Michael Chen, M.D.
Northwestern University School of
Medicine
Steven Fitzgerald, M.D.
Tulane University School of Medicine
Raymond Liu, M.D.
Johns Hopkins School of Medicine
Christopher McAndrew, M.D.
University of Tennessee School of
Medicine
Michael Paczas, M.D.
University of Michigan School of
Medicine
Ben Smucker, M.D.
Indiana University School of Medicine
The residency remains a ve-year clinical
and academic program for four of the
residents and a six-year program for two
of the residents who spend their PGY-2
year performing basic-science research in
one of our active research laboratories.
We continue to welcome new
Randall E. Marcus, M.D.
physicians and scientists to our

department here at Case to enhance
our clinical, educational and research
programs. In December, Dr. Douglas
G. Armstrong joined our department in
the Division of Pediatric Orthopaedic
Surgery. Dr. Armstrong, formerly at
the Pediatric Orthopaedic Hospital at
SUNY-University of Buffalo, is double
fellowship-trained in both spinal
surgery and pediatric orthopaedic
surgery. Dr. Shunichi Murakami joined
our faculty in molecular biology and
genetics. Dr. Murakami, formerly at
the University of Texas M.D. Anderson
Hospital, is an orthopaedic surgeon
who has gone on to obtain his Ph.D. in
molecular biology and is an expert in
collagen genetics.
6/22/05 2:22:35 PM
CHAIRMANS REPORT
The faculty of the Department of
Orthopaedic Surgery at Case is
second to none. Our physicians
represent us on editorial boards of
every major orthopaedic publication,
including The Journal of Bone and
Joint Surgery (Victor Goldberg, George
Thompson and Clare Rimnac),
Clinical Orthopaedics and Related
Research (Victor Goldberg and Randall
Marcus) and Spine (Henry Bohlman).
Our physicians participate in all of
the major orthopaedic organizations,
including the American Board of
Orthopaedic Surgery (Randall Marcus),
American Academy of Orthopaedic
Surgeons Board of Councilors (George
Thompson), Pediatric Orthopaedic
Society of North America (George
Thompson), American Orthopaedic
Rehabilitation Association (Byron
Marsolais), Orthopaedic Research
and Education Foundation (Victor
Goldberg) and the AO Foundation
North America (Jack Wilber).
This June, the department graduated

six chief residents, all of whom are
going on to fellowships in their
subspecialty areas of choice. We are
extremely proud of our chief residents
achievements over their residency
training time and look forward to
following their future careers:
R. Shay Bess, M.D.
Spine Fellowship Washington
University
St. Louis, Missouri
A. Michael Harris, M.D.
Trauma Fellowship Carolinas Medical
Center
Charlotte, North Carolina
Robert Lowe, M.D.
Spine Fellowship Rush Medical
Center
Chicago, Illinois
Joseph Smucker, M.D.

Spine Fellowship Emory University
Atlanta, Georgia
Andrea Young, M.D.
Sports Medicine Fellowship
U.C.L.A.Los Angeles, California
We are grateful for the ongoing
support of our departments alumni
and friends. Generous contributions
to the Herndon Fund and the
recently established Goldberg and
Bohlman Funds have provided us
with the long-term resources for an
outstanding educational program for
our residents and for the growth of
our internationally recognized research
programs. These contributions will
allow us to achieve breakthroughs in
musculoskeletal research and ultimately
improve the quality of life of our global
community.
Jeffrey Roh, M.D.

Spine Fellowship Hospital for Special
Surgery
New York, New York
PROM 2004
6/22/05 2:22:37 PM
YEAR IN REVIEW
DIVISION OF PEDIATRIC ORTHOPAEDICS

George H. Thompson, M.D.
Director, Division of Pediatric Orthopaedics
2003
was a busy year for the

Division of Pediatric
Orthopaedics. We had the addition
of two new faculty members: Dr.
Amanda Weiss-Kelly in Pediatric
Sports Medicine and Douglas G.
Armstrong, M.D. in Pediatric
Orthopaedics. Dr. Weiss-Kelly did
her residency in Pediatrics at Rainbow
Babies and Childrens Hospital
followed by a fellowship in Pediatric
Sports Medicine at UCLA Medical
Center. For the past two years she had
been at Childrens National Medical
Center in Washington D.C. before
returning home to Cleveland. She is
now developing our Pediatric Sports
Medicine Program. Dr. Armstrong
did his residency at the University of
Montreal followed by a fellowship
in adult spine surgery at University
of Ottawa, Ottawa, Ontario and his
pediatric orthopaedic fellowship at
Childrens Hospital of Buffalo, Buffalo,
New York. He had been on the faculty
at the Buffalo Childrens Hospital for
the past 12 years. We are very fortunate
to entice him to Rainbow Babies
and Childrens Hospital. His primary
responsibility will be in pediatric
spinal deformity. Our Division also
lost one faculty member. Dr. Lawrence
L. Haber, who was director of our
afliated program at Tod Childrens
Hospital in Youngstown, left to join the
faculty at the University of Mississippi
Medical Center in Jackson, Mississippi.
This places he and his wife closer to
their families. He will be missed.
Our other current faculty are George
H. Thompson, M.D, Director, Daniel
R. Cooperman, M.D., and Allison
Gilmore, M.D. All had productive

years professionally and academically.
Dr. Thompson was President of the
Pediatric Orthopaedic Society of
North America in 2002-2003 and was
named Deputy Editor of Pediatric
Orthopaedics for the Journal of Bone
and Joint Surgery. Dr. Cooperman
continues to direct our Pediatric
Neuromuscular Rehabilitation
Program. The Myelodysplasia
Program is the largest in Ohio. Dr.
Allison Gilmore is also involved in
the development of Pediatric Sports
Medicine. She does the majority of the
pediatric arthroscopy at Rainbow. Our
two Orthopaedic nurse practioners,
Connie Poe-Kochert, R.N. and
Suzanne Fortuna R.N., continue to
provide immensely appreciated care for
our pediatric spine and neuromuscular
patients. Although we typically
have a pediatric orthopaedic fellow,
unfortunately our position in 2003 was
not lled.
The highlight of each year is the annual
Rainbow Professorship Lectureship.
In 2003 the Rainbow Professor was
Dr. Richard Gross from the Medical
College of South Carolina. This was
held January 2 4, 2003. He gave
several excellent lectures including the
Cast Brace for Femoral Fractures in
Children, Spinal DeformityDo
We Know What we Are Doing?, and
Pediatric Orthopaedic Education.
We also had signicant academic
contributions both in presentations
and publications. Clinical research
continues to be a very active focus,
particularly in the area of spinal
deformity, neuromuscular disorders,
George H. Thompson, M.D.
and trauma. The particular interests

of the Division are the radiographic
analysis of the cervical spine in
children, the role of Amicar in
decreasing perioperative blood
loss in children and adolescents
undergoing spinal surgery, and the
use of submuscular growing rods
for the management of severe spinal
deformities in very young children.
Presentations on those studies are
presented in both the national and
international level in 2003. They will
continue to be the focus of research
for the next several years. Overall,
the Division had eight peer-reviewed
publications and nine chapters in
textbooks in 2003.
6/22/05 2:22:38 PM
SPINE SURGERY PROGRAM

Henry H. Bohlman, M.D., Professor of Orthopaedics
Case Western Reserve University School of Medicine
Director of The University Hospitals Spine Institute
he Department of Orthopaedic
Surgery has a long history
of treating various spine diseases,
deformities and injuries since the
1950s when Dr. Charles Herndon,
the Chairman of the department, had
a major interest in scoliosis and spinal
deformities. Dr. Les Nash was recruited
in the late 1960s, and subsequently
opened the Rainbow Youth Spine
Center. The recruitment of Dr.
Henry Bohlman in 1972 attracted
national and international patients
to Case Western Reserve University.
Since then, a number of full-time
staff orthopaedists have participated
in reconstructive spine surgery.
These included Drs. Victor Frankel,
Kingsbury Heiple, George Spencer,
John Makley and Byron Marsolais,
Peter Scoles, Geoffrey Wilber, Laurel
Blakemore, Gerg Carlson, Michael
Bolesta, and Sanford Emery. There are
currently seven full-time spine surgeons
on the academic staff participating at
three institutions.
University Hospital is the major
institution in the spine surgery
program. Dr. Bohlman continues in
academic practice of exclusively spine
surgery, with over 35% of his practice
from out of state complex referral cases.
He spends a signicant amount of time
teaching the residents and fellows. Dr.
George Thompson, Chief of Pediatric
Orthopaedics, carries out childrens
spinal deformity surgery at Rainbow
Babies and Childrens Hospital. Sadly,
after 15 years in Cleveland, in 2003
Dr. Sanford Emery left to become
Chairman of the Department of
Orthopedic Surgery at University

of West Virginia. Dr. Chris Furey
continues his academic practice of
spine surgery with expertise in adult
deformity and has the responsibility
for teaching fellows and residents.
Dr. Jung Yoo not only participates as
an attending spine surgeon, but also
serves as Director of Research for the
Department of Orthopaedics and runs
laboratory research on the mechanisms
of lumbar disc metabolism and
degeneration. In 2003, we recruited Dr.
Douglas Armstrong from University
of Buffalo, who has had fellowships in
both pediatric orthopaedics and spine,
to add to the childrens deformity staff.
There are three spine nurse clinicians in
the University Hospitals Orthopaedic
Department. Lynette Bennett, RN,
and Pamela Miller, RN, deal with the
adult spine patients. Connie Poe, RN,
is the spine nurse clinician for the
children deformity patients. All of the
nurse clinicians have aided in carrying
out clinical research studies on patient
follow-up and are all lecturers at the
various symposia and nursing courses
locally and nationally.
At the Veterans Administration Medical
Center, Dr. Chris Furey supervises
residents in the spine clinic, the general
orthopaedic oor, and the SCI Service.
Dr. Furey assumed this position in July
1999. Dr. John Shaffer is Director of
Orthopaedics at the VAMC and to
a certain extent supervises the spine
surgery teaching.
At the MetroHealth Medical Center,
Dr. John Davis is the primary spine
Henry H. Bohlman, M.D.
surgeon. He is Co-Director of the

Acute Spinal Cord Injury Unit and
supervises the rehabilitation on
the Spinal Cord Injury Service. He
participates in both traumatic and
reconstructive spine surgery as well
as the resident and fellow teaching
program. Dr. Michael Eppig also carries
out spinal surgery at MetroHealth
Medical Center, including surgery for
adult deformity.
On average 7000 patients are seen by
the spine surgeons. Notable patients
that Dr. Bohlman has operated upon
are Baltimore Orioles Cal Ripkin and
His Royal Highness, Prince Bandar
Bin Sultan, the Ambassador of Saudi
Arabia. The average annual number
of spine operations carried out by the
Orthopaedic Department at University
Hospital is 1200; at the Cleveland
6/22/05 2:22:39 PM
YEAR IN REVIEW
MetroHealth Medical Center, 350; and
at the VA, 60, making a grand total
of 1610 spinal operations at all of the
afliated institutions.
Clinical and basic science research has
always been a primary focus of the
Spine Surgery Program. Dr. Ralph
Horwitz, our Dean, is funding a new
orthopaedic clinical research center
in order to study outcomes of various
spine operations and treatment.
This will involve a full-time nurse,
statisticians, secretary and equipment.
We have created a computer database
of all the spine patients treated at
University Hospital as well as a
database at the VA Medical Center.
Our current projects involve an analysis
of 1800 patients surgically treated for
lumbar spinal stenosis with long-term
results. Dr. Thompson maintains

a separate database of nearly 1700
pediatric spinal deformity patients. In
addition, we are analyzing 365 anterior
cervical fusions in patients with cervical
spondylosis and radiculopathy or
myelopathy.
The fellowship program in spine
surgery here at CWRU continues to
be much sought after, and we select
three academic orthopaedic surgeons.
The spine fellows rotate four months
each at University Hospital, the VA
Medical Center, and MetroHealth
Medical Center. We continue to
educate academically based foreign
fellows also. The fellows are expected to
carry out clinical and research studies
and publish in peer-review journals.
The surgical experience for each fellow
includes approximately 340 spine

operations per year, either performing
or assisting. The purpose of our spine
fellowship program is to train full-time
academic spine surgeons who will be
productive in research, teaching and
patient care at other university training
programs, as well as our own, and in
other countries. From 1973 through
2003 we have trained 59 domestic
and 30 foreign fellows. Our Institute
and all the domestic fellows as of 2003
have produced 1737 publications.
The Foundation for Spine Research
and Education has been established to
create an endowment to support the
fellows, basic research, two PhDs, and a
chair for Dr. Bohlmans position.
RUBICON WINE & SPINE DINNER

Saturday, March 13, 2004
This dinner, organized by Dr. Henry Bohlman, is held yearly during the Annual Academy Meeting. As usual
there was a wonderful trifecta of food, wine and companionship.
Passed Hors doeuvres
Veuve Clicquot Ponsardin
Duck Cont with Orange Marmalade and Smoked Bacon
Chassagne Montrachet, 1997
Ramey Chardonnay, 2000
Roasted Wild Salmon with Shaved Fennel-Apple Salad and Curry Sauce & Filet of Beef with Onion-Potato
Gratin and Trufe Sauce
Chateau La Conseillante, 1996
Chateauneuf du Pape, 2001
Warm Apple Crisp
with Oat Streusel and Vanilla Bean Ice Cream
Chateau Raymond La Cor, 1990
6/22/05 2:22:39 PM
RESEARCH SECTION
OF THE DEPARTMENT OF ORTHOPAEDICS
AT CASE SCHOOL OF MEDICINE
Jung Yoo, M.D.
Research Section of the Department of Orthopaedics at Case School of Medicine
he mission of the research

program of the Department
of Orthopaedics at Case School of
Medicine is to advance and disseminate
basic, applied and clinical science
through excellence in investigation,
cooperation and education.
This new mission statement was
developed during the Research Retreat
of 2004. These words were chosen very
carefully to reect the emphasis and
direction of the Research Section of the
Department of Orthopaedics at Case
School of Medicine. The commitment
of those of us in research is that our
goal will not be limited to the success
of the individual research programs. We
are also committed to the greater goals
that will benet all those whom we
serve: the students, the clinicians, other
scientists, the institutions and, above
all, the patients. These goals will be
achieved through the development of
the best research programs and through
the excellent education of clinicians,
residents and graduate students in the
science of orthopaedics.
Without a doubt, this Department
has been one of the best orthopaedic
research programs in the country. This
success has not been an accident but
rather planned and cultivated by many
great Departmental leaders, past and
present. Their vision was aided by
the countless number of individuals
dedicated to the success of the research
mission, enhancing knowledge and
improving the quality of life through

the advancement of orthopaedic science.
For the past several decades, our
researchers have maintained many
highly successful research programs in
broad areas of orthopaedic research.
Currently, the Department is endowed
with world-class researchers working
on cartilage and bone-cell biology,
tissue engineering, biomechanics and
functional electrical stimulation. The
success of these endeavors is highlighted
by the fact that this Department has
been ranked #1 in funding by the
National Institutes of Health among all
orthopaedic departments for three of
the last four years. The total number of
our faculty presentations at the annual
Orthopaedic Research Society meetings
is one of the highest of any institution
in the country.
Recently, many individuals in this
Department have been awarded
recognition for their great achievements
in research. Dr. Hunter Peckham
who leads the functional electrical
stimulation group, was named
Engineer of the Year by Design News
Magazine. Dr. Goldberg has received
the Alfred Shands Award for lifetime
achievement in orthopaedic research.
Dr. Ed Greeneld received the Kappa
Delta Award from the Orthopaedic
Research Society. These individuals are
the nest examples of research
leadership not only in this Department
but also in the international
Jung Yoo, M.D.
orthopaedic community.
The future of musculoskeletal research
in our Department is even more
exciting. There has been an explosion
of interest in musculoskeletal biology at
Case Western Reserve University as well
as at the other institutions in Northeast
Ohio. At Case, the Department of
Biomedical Engineering is committed
to hiring four or ve additional faculty
members who have a strong interest
in musculoskeletal research, and the
Department of Radiology is currently
developing a $20-million small-animal
imaging center. Two other medical
centers in Northeast Ohio, the
Cleveland Clinic and the Northeastern
6/22/05 2:22:40 PM
YEAR IN REVIEW
Ohio Universities College of Medicine,
have also greatly expanded their
musculoskeletal research base. In the
spirit of new cooperation, monthly
combined research seminars are held
among these institutions. This has been
one of the most successful gatherings of
researchers dedicated to musculoskeletal
science and research. The attendance
regularly exceeds ninety people. This is
truly a staggering number of researchers
in one metropolis with a strong interest
in musculoskeletal research.
Specic to this Departments research
endeavors; new investments are being

made. The Case Research Institute,
the Case School of Medicine and the
University Hospitals of Cleveland have
committed several million dollars to
facilitate our research endeavors. These
funds will be used to recruit at least
three new top-rated basic scientists.
Half a million dollars has been
committed to upgrade the equipment
in the laboratory. Our existing
research space will increase by 50%.
Additionally, another $1.2 million has
been committed to develop a clinical
research center in the Department.

This is truly an exciting time for those
who are involved in musculoskeletal
research at Case Western Reserve
University. Much potential and hope
lies ahead of us. It is a privilege to be
part of this team of wonderful people
who are so dedicated to the mission
we have set into view. We invite all of
you who have dedicated your lives to
orthopaedics to be part of our large
family, by sharing your vision and
ideas with us, as we bring orthopaedic
science into the next century.
Left to right: Dr. Randall Marcus, Dr. John Carter, Dr. Jung Yoo
6/22/05 2:22:42 PM
UH ATTENDINGS
Douglas Armstrong
Henry Bohlman
Daniel Cooperman
Christopher Furey
Patrick Getty
Allison Gilmore
Victor Goldberg
Donald Goodfellow
Amanda Weiss Kelly
Matthew Kraay
Stephen Lacey
Randall Marcus
Thomas McLaughlin
William Petersilge
John Shaffer
George Thompson
Brian Victoroff
John Wilber
Roger Wilber
Jung Yoo
10
6/22/05 2:22:58 PM
YEAR IN REVIEW
METRO ATTENDINGS
Daniel Cooperman
John Chip Davis
Robert de Swart
Michael Eppig
Harry Hoyen
Michael Keith
Stephen Lacey
John Makley
Tim Moore
Clyde Nash
Brendan Patterson
Paul Saluan
John Sontich
Heather Vallier
John Wilber
Roger Wilber
6/22/05 2:23:11 PM
BASIC SCIENCE FACULTY
Dwight Davy
Edward Greeneld
Thomas Hering
Brian Johnstone
Shunichi Murakami
P Hunter Peckham
Clare Rimnac
Luis Solchaga
Ronald Triolo
12
6/22/05 2:23:22 PM
YEAR IN REVIEW
Football with the resident applicants after their interviews.

A tradition has begun
Paintball anyone?
6/22/05 2:23:26 PM
MANUSCRIPTS
TISSUE ENGINEERING OF A WHOLE BONE
Jung U. Yoo MD, Jerry I. Huang MD, Mahidhar M. Durbhakula MD, Peter Angele MD,
Brian Johnstone PhD
Department of Orthopaedics, Case Western Reserve University, Cleveland OH
INTRODUCTION
here has been a great interest in

using cell-based tissue engineering
strategies for repair of damaged skeletal
tissue.1-6 Much attention has been
directed at repairing damage portions
of a larger tissue. Example of this is
an osteochondral defect of knee joints
as might be seen in osteochondritis
desicans. However, it is likely that
same strategies of repairing a portion
of the bone can be used to create a
replacement of a whole bone. This
concept of whole bone generation has
not been tried in an animal model of
tissue engineering.
The whole bone regeneration strategy
is not only aimed at regeneration
of the bone itself, but rather of
bone, surrounding cartilage,
ligamentous attachments, and vascular
reconstitution into the bone. The
complexity of this process is certainly
much greater than the regeneration of
a small portion of the joint such as an
articular surface resurfacing or creation
of new bone to treat a segmental defect
of a long bone. However, there are
many orthopaedic conditions in which
truly the only adequate solution is
the creation of a whole bone. A good
example of this is the diseases and
injuries of the carpal bones. These are
small bones of wrist to which injuries
or diseases can cause loss of the normal
shape of the bone. This loss of shape
results in an abnormal anatomical
relationship between other surrounding

bones, leading to abnormal loading of
the joints. The arthritis of the carpus is
the nal endpoint of this process.
The causes that can lead to changes in
the shape of bone are numerous. These
include malunion of the fracture such
in scaphoid fracture or due to avascular
necrosis leading to the collapse of
the bone such as Kienbocks disease.
Therefore, the strategy of replacing a
whole bone may be applicable for the
diseases and injuries to foot and wrist
carpus, digits, and even patella.
In our laboratory we have been
working with various strategies of
tissue engineering. Most of this work
revolves around the use of bone marrow
derived progenitor cells to repair and
replace damaged tissue.1,7,8 We have
previously described ability to promote
chondrogenic differentiation of bone
marrow progenitor cells in vitro and
subsequently creation of a larger piece
of cartilage using a matrix/progenitor
cell based strategies.1,7,8 We have decided
to use our knowledge of cell, matrix,
and animal models of orthopaedic
conditions to design an experiment to
replace a carpal bone of rabbit wrist. We
believe that this is an ideal site to test
the concept of whole bone replacement
because of the clinical importance of
developing a useful replacement strategy
would be enormous.
MATERIALS AND METHODS

Cell Culture
Bone marrow aspirates were obtained

from New Zealand White rabbits and
then processed as previously described
to obtain broblast-like mesenchymal
stem cells (MSCs). The cells were
then passaged and culture-expanded.
The cells were then loaded on to a
biocompatible composite sponge of
hyaluronan and gelatin. The cells were
loaded at the nal concentration of 105
cells/l. Cell-loaded composites were
then cultured in a chemically dened
chondrogenic medium.7,8 Our previous
study demonstrates that well formed
cartilage tissue can be seen in this
MSC/matrix construct after 21 days of
culture.1
Surgical Implantation of
Matrix Constructs
The lunate was removed from the

forelimbs of the New Zealand White
rabbits by a dorsal capsulotomy. Each
animal received their own autologous
MSC/matrix implants. The rabbits
were allowed to weight-bear as
tolerated. Animals were sacriced at
6 and 12 weeks for radiographic and
histologic analysis.
Radiographic and Histologic Analysis
The carpometacarpal (CMC) index

was determined by measuring the
ratio between the length of the third
metacarpal and the carpal space. Rabbit
wrists were harvested and embedded in
polymethylmethacrylate. The sections
14
6/22/05 2:23:26 PM
MANUSCRIPTS
were then cut and toluidine blue
stained.
RESULTS
The tissue culture MSC/matrix

constructs produced cartilage matrix.
As compared to the pre-surgery wrist,
there was no signicant collapse of
the carpus as demonstrated by the
CMC index. Empty control group
demonstrated signicantly higher
collapse of the carpus. There was a
radiographic evidence of new bone
formation in the implant group. The
site of bone resection was lled with
signicant bone and cartilage, acting as
a biological spacer.
DISCUSSION
This paper describes a concept

of a whole bone replacement as a
strategy of biological reconstruction
of damaged whole bone. Because of
the current interest in our laboratory
in a cell -based tissue engineering,
these techniques are being used to
design a new alternative treatment
option. Mesenchymal stem cells
derived from bone marrow is a readily
available source of cells for cell based
tissue engineering.2,3,5,6,9 Bone and
cartilage tissue engineering strategies
using mesenchymal stem cells have
been explored in various preclinical
animal models.2.4-6 Several studies
have suggested that repair of fullthickness articular cartilage defects and
subchondral bone may be enhanced
by implantation of mesenchymal stem
cells.5,6
To our knowledge, there have not
been any previous studies examining
the possibility of reconstitution of a
complete bone with articular surfaces
using mesenchymal stem cells. There
are numerous orthopaedic conditions
where creation of the whole bone
would be the ideal solution. These
conditions are where the shape and
the size of the bone is critical to the
normal function and the disease

process essentially destroys the shape
of the bone and its relation to other
surrounding structures. The conditions
that this would include represent
mainly the conditions involving
relatively small bones of the body
such as lunate, scaphoid, and talus.
The purpose of our strategy for tissue
repair is to show that an osteochondral
construct can be tissue-engineered
from autologous mesenchymal stem
cells to create a biologic substitute that
is effective in carpal reconstruction.
Ideally, the success would mean the
maintenance of the normal relationship
to surrounding bone by creation of
normally shaped bone, cartilage, and
ligamentous attachments.
Carpal bones are small bones whose
accurate relationship to one another is
paramount to the normal functioning
wrist. Kienbocks disease represents
an ideal condition in which a creation
of a complete new bone would
serve as the ideal treatment options.
Currently available strategies for wrist
reconstruction for the treatment of
this disease are both invasive and
inadequate.10-15 This is because none
of these options really addresses the
optimal goal of normal anatomic
restoration with normal tissue.
Our strategy of in vitro cartilage
anlage creation, which is followed by
the normal process of endochondral
bone formation after implantation
results in a creation of a new bone in
the carpus. This would be very much
like development of carpus during
embryonic development and the
normal growth pattern of the carpus.
In this study, we demonstrated bone
and cartilage formation in the space
previously occupied by the resected
bone.
Despite the limitations of using
a small animal model to study
tissue engineering, the concepts

of tissue engineering such as cell
transformation, creation of matrix,
and re-establishment of normal
relationship to surrounding structures
remain the same. Using these concepts
of tissue engineering can show that a
whole bone creation is a possibility.
Therefore as part of tissue engineering
for the treatment of orthopaedic
diseases, a whole bone replacement
strategy should be explored as a
strategy especially, when normal shape
of whole bone is critical.
REFERENCES
1. Angele P, Kujat R, Nerlich M, Yoo J
Goldberg V, Johnstone B. Engineering
of osteochondral tissue with bone marrow
mesenchymal progenitor cells in a derivatized
hyaluronan-gelatin composite sponge. Tissue
Eng 1999; 5(6): 545-54.
2. Bruder SP, Kurth AA, Shea M, Hayes WC,
Jaiswal N, Kadiyala S. Bone regeneration by
implantation of puried, culture-expanded
human mesenchymal stem cells. J Orthop Res,
1998; 16(2): 155-62.
3. Caplan AI, Mosca JD. Orthopaedic gene
therapy. Stem cells for gene delivery. Clin
Orthop. 2000; (379 Suppl): S98-100.
4. Im GI, Kim DY, Shin, JH, Hyun CW, Cho
WH. Repair of cartilage defect in the rabbit
with cultured mesenchymal stem cells from
bone marrow. J Bone Joint Surg Br2001;83(2):
289-94.
5. Wakitani S, GotoT, Pineda SJ, Young RG,
Mansour JM, Caplan AI, Goldberg VM.
Mesenchymal cell-based repair of large, fullthickness defects of articular cartilage. J Bone
Joint Surg Am 1994; 76(4): 579-92.
6. Wakitani S, Imoto K, Yamamoto T, Saito
M, Murata N, Yoneda M. Human autologous
culture expanded bone marrow mesenchymal
cell transplantation for repair of cartilage
defects in osteoarthritic knees. Osteoarthritis
Cartilage 2002;10(3): 199-206.
7. Johnstone B, Hering TM, Caplan
AI, Goldberg VM, Yoo JU. In vitro
chondrogenesis of bone marrow-derived
mesenchymal progenitor cells. Exp Cell Res
1998; 238(1): 265-72.
8. Yoo JU, Barthel TS, Nishimura K, Solchaga
L, Caplan AI, Goldberg VM, Johnstone B.
The chondrogenic potential of human bonemarrow-derived mesenchymal progenitor cells.
J Bone Joint Surg Am 1998; 80(12): 1745-57.
6/22/05 2:23:27 PM
TISSUE ENGINEERING
9. Pittenger MF, Mackay AM, Beck SC, Jaiswal
RK, Douglas R, Mosca JD, Moorman
MA, Simonetti DW, Craig S, Marshak
DR. Multilineage potential of adult human
mesenchymal stem cells. Science 1999;
284(5411): 143-7.
10. Alexander AH, Turner MA, Alexander CE,
Lichtman DM. Lunate silicone replacement
arthroplasty in Kienbocks disease: a long-term
follow-up. J Hand Surg [Am] 1990; 15(3): 4017.
11. Begley BW, Engber WD. Proximal row
carpectomy in advanced Kienbocks disease. J
Hand Surg [Am] 1994; 19(6): 1016-8.
12. Eaton RG. Excision and fascial interposition

arthroplasty in the treatment of Kienbocks
disease. Hand Clin 1993; 9(3): 513-6.
13. Jebson PJ, Hayes EP, Engber WD. Proximal
row carpectomy: a minimum 10-year follow-up
study. J Hand Surg [Am] 2003; 28(4): 561-9.
14. Kato H, Usui M, Minami A. Long-term
results of Kienbocks disease treated by
excisional arthroplasty with a silicone implant
or coiled palmaris longus tendon. J Hand Surg
[Am] 1986; 11(5): 645-53.
15. Nakamura R, Horii E, Watanabe K, Nakao

E, Kato H, Tsunoda K. Proximal row
carpectomy versus limited wrist arthrodesis for
advanced Kienbocks disease. J Hand Surg [Br]
1998; 23(6): 741-5.
16. Takase K, Imakiire A. Lunate excision,
capitate osteotomy, and intercarpal arthrodesis
for advanced Kienbock disease. Long-term
follow-up. J Bone Joint Surg Am 2001; 83-A(2):
177-83.
Chief residents with Rainbow professor lecturer Dr. Richard Gross.
16
6/22/05 2:23:27 PM
MANUSCRIPTS
DISTAL FEMORAL LOCKING PLATES:

CALCULATION OF SCREW PLATE ANGLES
Adam J. Mirarchi MD, Brian W Fukushima MD, Daniel R. Cooperman MD
Department of Orthopaedic Surgery, Case Western Reserve University, Cleveland OH
ABSTRACT
ediatric femur distal femur fractures

commonly occur and can usually
be treated effectively non-operatively
or with the currently available
external xation or internal xation
devices. However, some of these
fractures, especially those with medial
comminution proximaly to the physis,
may require a specialized locked plating
construct. The goal of this project was
to determine the appropriate angles
and location for the locking screws in a
locking style plate that could be used in
the future to treat these fractures.
Twenty nine pediatric femora were
examined at the Hamann-Todd
Osteological Collection (Cleveland
Museum of Natural History, Cleveland,
OH). Templates size 3.5mm and 4.5
mm were made to conform to the distal
pediatric femora above the level of the
distal physis. Angles that would engage
the medial area above the physis for
locking style screw holes were measured
in the antero-postero and axial planes.
Additionally in the axial plane, medial
and lateral angles of the distal femora
themselves were also measured.
The AP and axial angles were made
for each of three screw holes for 3.5
mm and 4.5mm plates. Angles of the
medial and lateral condylar surfaces in
the axial plane were also measured. For
the antero-distal screw hole, in the AP
plane, the mean angle was 17.6 (+/3.5 ) on the right and 14.4 (+/- 2.9)
on the left. In the axial plane, 11.1
(+/- 2.9) on the right and 8.6 (+/2.7) on the left. For the postero-distal
screw, in the AP plane, 14.7 (+/- 3.5)

on the right and 12.1 (+/- 2.7) on the
left. In the axial plane, 9.9 (+/- 3.0)
on the right and 10.0 (+/-2.3) on
the left. For the proximal screw, in the
AP plane, 12.7 (+/- 2.8) on the right
and 12.3 (+/- 2.1) on the left. In the
axial plane, 9.6 (+/- 1.8) on the right
and 8.8 (+/- 2.5) on the left. The
medial condylar surface angle was 27.8
(+/- 4.5) on the and 28.5 (+/- 3.9)
on the left. The lateral condylar surface
angle was 12.8 (+/- 3.3). No statistic
difference was found between right
and left femoral, between 3.5 mm and
4.5mm plates, or between larger (older)
and smaller (younger) femora.
Growth disturbances of the pediatric
distal femur are not uncommon after
a high energy fracture. A new locking
plate that can be used to prevent medial
collapse of the femur above the level
of the physis and provide more stable
xation may help prevent this result.
The calculations of the necessary angles
in a locking-plate construct to engage
the medial fragments in these fractures
is the rst step in creating a device to
address this problem.
BACKGROUND
Fractures of the pediatric distal femur

are not uncommon injuries. Exact
numbers have not been determined
but injuries to the distal femoral physes
account for 1% to 6% of all physeal
injuries.1-3 The majority of these
fractures can be treated non-operatively.
Some, however, require reduction
and internal xation. This situation
occurs most commonly in polytrauma
pediatric patients and in children with
severe injuries.
Common mechanisms of injury
resulting in distal femur phsyeal
fractures include hyperextension and
varus-valgus forces. Most commonly
displacement occurs in the coronal
plane producing varus or valgus
deformity.4 These fractures can be
particularly problematic especially
when caused by high energy forces
associated with open wounds or bone
loss of the medial aspect of the distal
femur. (Figure 1)
These fractures typically require open
reduction and internal xation as part
of denitive treatment. However, due
Figure 1 A and B AP and lateral X-ray showing comminution above the physis
6/22/05 2:23:28 PM
DISTAL FEMORAL LOCKING PLATES

to medial bone loss these fractures often
develop a varus malalignment. Plating
with AO 4.5mm or 3.5mm plates
(Sythes Ltd., Paoli PA) along the lateral
cortex does not offer sufcient strength
or rigidity to allow stable xation and
early range of motion in may cases.
In adult distal femoral fractures with
extensive comminution the use of
locking screw-plate constructs, such
as the 4.5mm LCP Condylar Plate
(Synthes Ltd., Paoli PA) allow for more
stable xation.
Locking-plate systems have not yet
been adapted for use in pediatric
fractures. High energy peri-articular
fractures, such as distal femoral
fractures are well suited for these
systems but the anatomy of this
region is complex. This study seeks to
determine appropriate angles of the
locking screws in relation to the plate
to create a locking screw-plate construct
for use in the pediatric distal femur.
Twenty nine specimens including

13 bilateral and 3 unilateral femora
pediatric femora, ranging in age from
4-13 years were examined at the
Hamann-Todd Osteological Collection
(Cleveland Museum of Natural History,
Cleveland, OH). Templates were
constructed out of thin aluminum to
simulate AO 4.5mm and 3.5 mm plates.
The distal end of the templates had 3
screw holes: antero-distal, postero-distal,
and proximal. These holes were arranged
in an equilateral triangle conguration.
The plates were contoured to the lateral
distal femur. After this intitial contour,
the plates were not bent for each
individual specimen.
Each femur was clamped onto a
frame. A template was placed on the
lateral aspect of the femur, 5 mm
above the physis and taped tightly to
it. A Kirschner wire, size 0.062 inch,
was placed into each the holes of the
template to simulate a screw being

placed through the hole and into the
bone. Careful attention was made to
aim the K-wire in the antero-distal hole
medially and 5 mm above the distal
femoral physis. Similarly, the K-wire
in the postero-distal hole was directed
medially and 5 mm above the distal
femoral phsyis. The K-wire in the
proximal screw hole was aimed medial
and perpendicular to the long axis of
the femur. The K-wires were held in
place using a small ball of clay placed
in each hole of the template. (Figure
2). A computerized three dimensional
digitizer called a MicroScribe
(Immersion Corporation, San Jose, CA)
was then used to calculate of the angles
the K-wires in the anterior and axial
planes with respect to the plate fastened
to the femur. The mean and standard
deviation was calculated for each of the
3 different screwhole positions.
Additionally in the axial plane, medial
and lateral angles of the femora
themselves were measured. These angles
were based on the respective medial
or lateral slope of the distal femoral
condyle with respect to a 90 degree
reference line to the posterior femoral
condyles. Again, the mean and standard
deviation were calculated for each.
Figure 2A, B, C: Experimental setup of plate

construct and K-wires showing the two most
distal screw holes with K-wires placed in them
Figure 2A
Figure 2B
RESULTS
A 4.5 mm plate was used for 13

specimens and a 3.5 mm plate for 16
specimens. Generally, the larger plate
was used for specimens greater than 10
years of age due to the larger size of the
distal femur. Once the plate was initially
contoured, the plate did not need to
be recontoured for each individual
specimen. The average age of the right
specimens were 9.3 years old while those
of left femurs were 8.8 years of age.
For the antero-distal screw hole, in the
AP plane, the mean angle was 17.6 (+/3.5) on the right and 14.4 (+/- 2.9)
on the left. In the axial plane, the mean
Figure 2C
angle was 11.1 (+/- 2.9) on the right

and 8.6 (+/- 2.7) on the left. For the
postero-distal screw, in the AP plane, the
mean angle was 14.7 (+/- 3.5) on the
right and 12.1 (+/- 2.7) on the left.
In the axial plane, the mean angle was
9.9 (+/- 3.0) on the right and 10.0
(+/-2.3) on the left. For the proximal
screw, in the AP plane, the mean angle
was 12.7 (+/- 2.8) on the right and
12.3 (+/- 2.1) on the left. In the axial
plane, the mean angle was 9.6 (+/1.8) on the right and 8.8 (+/- 2.5) on
the left. The distance between the holes
18
6/22/05 2:23:29 PM
MANUSCRIPTS
on the plate surfaces was 13 mm on the
3.5 mm plate and 15 mm on the 4.5
mm plate. The holes were arranged in a
equilateral triangle conguration.
In the axial plane the angle formed
between the medial condylar surface
and the 90 reference line with respect
to the posterior femoral condyle was
27.8 (+/- 4.5) on the right and 28.5
(+/- 3.9) on the left. In the axial
plane, the angle formed between the
lateral condylar surface and the 90
degree reference line with respect to the
posterior femoral condyle was 12.8
(+/- 3.3). (Figure 3)
Figure 3B: Anterio-Posterior view showing

screw angles
Figure 3A: Axial measurements of the three

screw angles
No statistical difference existed between

left or right specimens for any of
the measured angles. No statistical
difference in angles existed between the
4.5 mm and 3.5 mm plates. Finally,
there was no statistical difference in
any angle measurement for specimens
9 years and older (generally larger in
size) and those 8 years and younger
(generally smaller in size).
DISCUSSION
The majority of pediatric distal femoral

fractures can be treated with nonoperatively or with open reduction and
internal xation with conventional
implants including screws, plates or
pins. However, distal femur fractures
caused by high-energy trauma resulting
in open wounds or signicant bone
loss and comminution may require
specialized implants to prevent
nonunion or malunion.
Growth disturbances after injury to
the distal femur are not uncommon.
Progressive angulation after separation
of the distal femoral epiphysis is
usually caused by asymmetric growth
inhibition.5 This may occur from
trauma at the time of initial physeal
injury or from bony bar formation
after healing.6 These angular growth
distrurbances often occur in the
coronal plane resulting in varus/valgus
Figure 3C: Axial view showing medial and lateral angles of distal femur
malunions. In cases of extensive medial

comminution or bone loss, varus
anglulation often results secondary to
failure of xation with conventional
plates and screws.
Biomechanical studies have shown
that plates, regardless of thickness or
rigiditiy, will undergo fatigue failure
and breakage with cyclical loading. If a
boney defect exists opposite a plate, the

bone is under bending load, and the
fulcrum will move closer and closer to
the plate until it falls within the plate.
At this point, with repetitive loading,
the plate will fail.7 The AO Foundation
(Davos, Switzerland) recommends early
bone grafting of this defect to create
an osseous bridge which acts as a load
sharing device to plate to reduce the
6/22/05 2:23:30 PM
likelihood of eventual fatigue failure

of a metal construct. The obvious
disadvantage of this recommendation,
particularly in the pediatric population,
is fusion across the physis. Thus
conventional plates and screws
placed on the lateral cortex may be
biomechanically inadequate to provide
stable internal xation when additional
load sharing of bone graft cannot be
applied.
In the adult population, xed angle
devices such as blade plates and
dynamic condylar screws have been
used with success. Schatzker reported
71% good to excellent results with a
95 degree blade plate.8 Gregory and
Sanders reported 83% good to excellent
results using the dynamic condylar
screw.9 However, these devices have
no application in the treatment of
pediatric distal femur fractures due
to the presence of the physis. Both
blade plates and dynamic condylar
screws cross the physis and would
likely disrupt the growth plate due
to the location of xation within the
metaphysis and epiphysis.
The distal femoral physis has been
described anatomically. The physis
undulates from medial to lateral and
from anterior to posterior. The distal
end of the metaphysis has a central
groove which runs from anterior to
posterior above the intercondylar notch.
Another groove runs from medial to
lateral. The combination of these two
grooves separate the distal femoral into
four protruding mamillary processes.
On the proximal end of the epiphysis,
there are four valleys which interdigitate
with the mamillary processes. The four
valleys are separated by an anterior to
posterior and a medial to lateral ridge.
As described, the physis adds to the
complexity of treating distal femur
fractures in children. With this in
mind, the ideal construct would be
placed on the lateral aspect of the distal

femur and above level of the physis.
The construct, including screws, would
not cross the physis and would engage
medial metaphyseal bone. Screws
should not protrude medially to avoid
soft tissue irritation and should not
protrude posteriorly due the risk of
injury to neurovascular structures.
This project identied appropriate
plate-screw angles for three positions:
antero-distal, postero-distal, and
proximal. These positions were created
to engage maximal medial metaphyseal
bone. When designing such a
construct, the screw must engage the
plate in a precise orientation, especially
in the AP and axial planes. Therefore, a
coordinate system to which references
the screw angles in the AP and axial
planes is a reproducible and familiar.
This coordinate system is important
since the anatomy of the pediatric
femur is complex. It is essential that all
screws must engage medial bone yet
also avoid the physis.
The largest angle was in the AP
plane for the anterior-distal most
screw. For all three screws, axial
plane measurements were tightly
clustered. The most proximal screw
demonstrated the tightest clustering
in the AP and axial planes, likely since
this region was at the metaphysealdiaphyseal junction and the anatomy
was much more predictable. For all
angle measurements, in the AP and
axial planes, standard deviations
were relatively small indicating tight
clustering of data points.
No signicant differences were noted in
angle values for left vs. right specimens,
age eight or less vs. age nine or older
(roughly correlating with size), or for
4.5 vs. 3.5 plate size. Additionally,
once the plates were pre-contoured,
they did not have to be reshaped for
each individual specimen. Therefore, a
complete set of hardware for pediatric

distal femur fractures should include
left and right 3.5 and 4.5 plates.
The Hamman-Todd Osteological
Collection is likely the largest of its
kind. The data collected is unique
since measurements were made directly
from these specimens. The templates
and bending patterns created are easily
reproducible as are the calculated
plate-screw angles. The next logical step
would be to create a prototype locking
plate-screw construct based on the
average angles as well as the extremes
of the standard deviations. These plates
would be placed on cast molds of the
pediatric femora from the collection.
Further evaluation of the appropriate
screw positions could then be made.
REFERENCES
1. Neer CS 2nd, Horwitz BS. Fractures of the
proximal humeral epiphyseal plate. Clin Orthop
1965; 41: 24-31.
2. Peterson HA, Madhok R, Benson JT, Ilstrup
DM, Melton LJ 3rd. Physeal fractures: part I:
epidemiology in Olmsted County, Minnesota,
1979-1988. J. Pediatric Orthop 1994; 12: 423430.
3. Mann DC, Rajmaira S. Distribution of
physeal and nonphyseal fractures in 2650 long
bone fractures in children age 0-16 years. J
Pediatric Orthop 1990; 10:713-716.
4. Sponseller PD, Beaty JH. Distal femoral
epiphyseal fractures. In: Rockwood CA Jr,
Wilkins KE, Beaty JH, eds. Fractures in
Children. 3th ed. Philadelphia, PA: LippincottRaven; 1996; 1233-1260.
5. Abbot et al. Valgus deformity of the knee
resulting from injury to the lower femoral
epiphysis. J Bone Joint Surg Am 1942; 24:97113.
6. Gomes LS, Volpon JB. Experimental
physeal fracture separations treated with rigid
internal xation. J Bone Joint Surg Am 1993
75(12):1756-1764
7. Schatzger J, Tile M. The rationale of operative
fracture care, Berlin: Springer Verlag; 1996
8. Schatzker J, Lambert DC. Supracondylar
fractures of the femur. Clin Orthop 1979;
138:77-83
9. Gregory P. The treatment of supracondylarintracondylar fractures of the femur using
the dynamic condylar screw. Techniques in
Orthopedics 1995; 9:195-202
20
6/22/05 2:23:31 PM
MANUSCRIPTS
TREATMENT FAILURE IN STABLE FEMORAL

NECK FRACTURES IN THE ELDERLY
Susan L. Stewart, MD1, Daniel R. Cooperman, MD2, Randall E. Marcus, MD2
1
Department of Orthopaedics, Harvard Medical School, Boston, MA
2
Department of Orthopaedics, Case Western Reserve University, Cleveland, OH
ABSTRACT
INTRODUCTION
ith the elderly population

living longer, the orthopaedic
surgeon can expect to treat more
femoral neck fractures in octogenarian
and nonagenarian patients. Younger
patients who sustain fractures of the
femoral neck that are non-displaced,
minimally displaced, and valgus
impacted have a good prognosis
when managed by internal xation
with multiple screws. We decided to
evaluate the success of this treatment
in elderly patients. We reviewed the
records of 25 consecutive octogenarian
and nonagenarian patients who, over
a 5-year period, underwent internal
xation with multiple-screw placement
for stable femoral neck fractures. Eight
patients (32%) had unsatisfactory
results and were considered treatment
failures: Five patients failed to heal
their fractures and three patients
fractures healed but developed late
avascular necrosis. Gender, type of
fracture conguration, and number
of xation screws failed to correlate
signicantly with the treatment result.
The only factor that revealed a possible
trend was the failure rate for patients
with postoperative complications
(p=0.061). We concluded from our
study that treatment with internal
xation in the elderly population for
non-displaced, minimally displaced, or
valgus impacted femoral neck fractures
may fail in approximately one-third of
patients.
The incidence of hip fractures increases

exponentially with age.1 With our
elderly population living longer, the
number of hip fractures in people 50
years and older is expected to climb
from 238,000 in 1986 to 512,000
by the year 2040,2 when the annual
cost of treating hip fractures may
approach $16 billion.2 Patients 80
years of age and older will likely
sustain an increasing percentage of
these hip fractures. An appreciation
of the age-related surgical risks,
complications, and outcomes will allow
the orthopaedic surgeon to give these
elderly patients the best care.
The orthopaedic surgeons in our

department treated 378 patients with
femoral neck fractures from January
1989 until January 1994. In reviewing
these cases, we identied 28 elderly
patients aged 80 years and older with
non-displaced, minimally displaced,
and valgus impacted femoral neck
fractures according to Garden.4
Twenty-ve of these 28 patients had
sufcient clinical data and complete
radiographic information to allow us
to retrospectively evaluate the course of
the fracture to a stage of healing or to
a stage of treatment failure because of
non-union or avascular necrosis.
Approximately half of all hip fractures

are located in the femoral neck.3 When
these fractures are non-displaced or
valgus impacted, they are typically
managed by internal xation in situ
utilizing multiple screws. These
fractures, once pinned, are stable,
with a good prognosis according to
Garden.4 Facing an increase in the
number of older elderly patients
sustaining hip fractures, we examined
the success of fracture treatment
utilizing multiple screw xation in nondisplaced, minimally displaced, and
valgus impacted femoral neck fractures
in octogenarian and nonagenarian
patients. A treatment failure was
dened as a patient who developed
avascular necrosis or non-union. These
patients are at risk for the morbidity of
dysfunction or a second operation, like
hemiarthroplasty.
For each patient, we noted age, gender,

preoperative health status, fracture
management including number of
xation screws, and postoperative
course including complications,
mortality, and healing. Using Fishers
exact test, we analyzed the effect of
gender, type of fracture, and postoperative complications with respect to
non-union or AVN. We compared our
rate of treatment failure with failure
rates noted by previous authors.
The 25 patients ranged in age from 82

to 95 years, with an average age of 86.8
years at the time of fracture. Nineteen
patients were female (76%) and six male
(24%). Preoperative radiographs revealed
that all 25 femoral neck fractures were
in acceptable alignment. Seventeen of
the 25 patients had valgus impacted
fractures, ve had nondisplaced
fractures, and three had minimally
6/22/05 2:23:31 PM
FEMORAL NECK FACTURES

displaced fractures (displacement of a
few millimeters or less).
Preexisting Medical Problems
From the clinical records, we noted

each patients presurgical medical
status. Twenty-four of the 25 patients
suffered from multiple preexisting
medical problems (see Table 1). All
patients had been preoperatively scored
by the anesthesiologist according to the
American Society of Anesthesiologists
(ASA) system, in which Grade I
indicates a healthy patient; Grade
II, mild systemic disease; Grade III,
severe systemic disease that is not
incapacitating; Grade IV, incapacitating
systemic disease that constantly
threatens life; and Grade V, a moribund

patient not expected to survive more
than 24 hours with or without an
operation.5 Four patients were assigned
an ASA rating of IV; thirteen, a rating
of III; and the remaining eight patients,
a rating of II.
Fracture Management
The average time between fracture and

surgery was 2.7 days (range, 1-4 days),
and the average hospital stay was 7.68
days (range, 3-10 days). Patients were
treated under conductive or general
anesthesia. The surgical procedure,
performed utilizing the fracture table
with uoroscopic C-arm imaging,
consisted of placing percutaneous,
parallel, cannulated screws into the

center of the femoral head to a depth
approximately 5 to 10 mm from the
articular surface. No attempt was made
to manipulate the fracture fragments, as
the alignment was considered acceptable.
Depending on the size of the patients
femoral neck, two to four cannulated
screws were utilized for fracture
xation. Although three or four screws
were considered ideal xation, ve
patients had only two screws placed.
These ve patients were all females
with small femoral neck diameters, and
according to the operative note a third
screw could not be safely placed into an
acceptable location.
TABLE 1. PATIENT MEDICAL HISTORY

Patient #
Age at Fx.
Sex
Preexisting Medical Problems
ASA*
(Yrs.)
1
95
Osteoarthritis, Pagets disease, mitral insufciency
III
2
3
4
5
6
7
8
9
10
11
12
85
95
84
88
89
88
82
83
83
82
93
F
F
F
F
F
F
M
F
M
F
F
III
III
III
II
III
III
III
II
III
IV
IV
13
91
14
15
16
17
18
19
20
21
22
23
24
25
92
89
82
84
85
87
89
86
87
84
83
83
F
M
F
F
M
F
F
M
F
F
F
F
Arthritis, breast CA, angina

Arthritis, HTN, asymptomatic CAD, fx + pinning contralateral hip
HTN, fx + hemi contralateral hip
Breast CA, DJD, fx + hemi contralateral hip, recurrent UTIs
Dementia, chronic venous stasis ulcers, colon CA, alcoholism
CAD, s/p CABG, unstable angina, HTN, syncope
COPD, duodenal ulcers, alcoholism
Hypercholesterolism
None
RA, dementia, HTN, hypothyroidism
Osteoarthritis, cystocoele, rectocoele, hypothyroidism, aortic stenosis, degenerative disc disease, midline C6
degeneration
CAD, TIAs, CVA, MI, DM, lung CA, bilateral femoral popliteal disease, COPD, stable angina, recurrent
syncope, ventricular arrhythmia
Arthritis, breast + colon CA, hemi of contralateral hip
Addisons disease, Parkinsons, chronic atrial brillations, hypothyroidism
Osteoarthritis, hypothyroidism, THA + revision of contralateral hip
HTN, CVA, DJD, h/o DVT, ORIF of foot
Osteoarthritis, aortic stenosis, mitral + tricuspid valve insufciency
Parkinsons disease, DJD
HTN, COPD, CVA, h/o multiple hernia repairs, shoulder arthroplasty
Parkinsons disease
Asthma, osteoarthritis, HTN, MI, dementia, hemi contralateral hip
HTN, anemia
HTN, laryngeal + breast + lung CA
HTN, endometrial CA, fx + hemi contralateral hip
IV
III
III
II
II
IV
II
II
III
III
II
III
II
*American Society of Anesthesiologists

CA = Cancer
HTN = Hypertension
CAD = Coronary artery disease
fx = Fracture
hemi = Hemiarthroplasty
DJD = Degenerative joint disease
UTI = Urinary tract infection

CABG= Coronary artery bypass graft
COPD = Chronic obstructive pulmonary disease
RA = Rheumatoid arthritis
TIA = Transient ischemic attack
CVA = Cerebrovascular accident
MI = Myocardial infarction
DM = Diabetes mellitus
DVT = Deep venous thrombosis
ORIF = Open reduction internal xation
22
6/22/05 2:23:31 PM
MANUSCRIPTS
Intraoperative and immediate
postoperative radiographs were
reviewed for adequacy of fracture
alignment and xation. All fractures
were in adequate alignment and no
apparent reduction or change in
alignment was noted from preoperative
to postoperative radiographs. Fixation
was noted to be acceptable with screw
tips located in the femoral head 5
to 10 mm from the articular surface
in all cases. Postoperatively, patients
were mobilized out of bed with
weightbearing as tolerated within 24
hours of the surgical procedure.
RESULTS
Complications
patients) expired within 2 years of their

surgery. Two patients died at 5 months
following fracture xation, two at 7
months, and four died between 13 and
24 months following fracture xation.
The remaining patients survived at least
2 years following their surgery.
Eight of the patients had postoperative

complications (Table 2, Table 3),
consisting of one wound hematoma,
one transient ischemic attack, one
pulmonary embolism, one urinary tract
infection, and one case of congestive
heart failure; four patients were noted
to have an enduring decline in mental
status postoperatively (Table 2).
Treatment Failure
Mortality
As would be predicted from the multiple

preexisting medical problems seen in
this patient population and reected
by the high ASA ratings, 32% (eight
Eight of our 25 patients (32%) who

underwent xation of their femoral neck
fracture had an unsatisfactory result:
Five had a non-union (Table 2), and
three additional patients with healed
fractures exhibited avascular necrosis of
the femoral head radiographically. Seven
of the eight treatment failures showed
TABLE 2. FRACTURE CLASSIFICATION, TREATMENT AND OUTCOME

Patient #
Type Fracture
Fixation
Screws
Postoperative Complications
Result
Valgus, impacted
None
Healed
Valgus, impacted
PE, decline in mental status
Asymptomatic AVN noted at 5 mos. after xation
Minimally displaced
None
Healed
Non-displaced
None
Healed
Valgus, impacted
UTI
AVN + collapse, revised 4.5 months after xation
Valgus, impacted
None
Healed
Valgus, impacted
None
Healed
Non-displaced
None
Healed
Non-displaced
None
10
Valgus, impacted
None
Asymptomatic AVN and pin protrusion noted 12 mos.

after xation
Healed
11
Valgus, impacted
Decline in mental status
Healing
12
Valgus, impacted
Wound hematoma
Failure of xation at 2 mos.; AVN
13
Minimally displaced
TIA
Healed
14
Non-displaced
None
Healed
15
Valgus, impacted
None
Healed
16
Valgus, impacted
None
17
Valgus, impacted
None
AVN + pin protrusion, revised to THA 6 mos. after

xation
Healed
18
Non-displaced
19
Valgus, impacted
Asymptomatic AVN, pin protrusion noted at 2.5 mos.

after xation
Healed
20
Valgus, impacted
CHF
Failure of xation, revised to hemi 1 mo. after xation
21
Valgus, impacted
None
Healed
22
Valgus, impacted
None
Non-union, revised to hemi 16 mos. after xation; AVN
23
Minimally displaced
None
Healed
24
Valgus, impacted
None
Healed
25
Valgus, impacted
None
PE = Pulmonary embolism
THA = Total hip arthroplasty
TIA = Transient ischemic attack

UTI = Urinary tract infection
Healed
hemi = Hemiarthroplasty
AVN = Avascular necrosis
CHF = Congestive heart failure
6/22/05 2:23:32 PM

avascular necrosis radiographically. One
failure occurred one month status-post
injury, and avascular necrosis could not
be diagnosed on x-ray.
Four of the ve patients with nonunions subsequently underwent revision:
one for pain (revised to hemiarthroplasty
16 months after fracture xation), and
three for loss of xation and collapse
of the femoral head (Figures 1-A, 1-B,
and 1-C; revised to hemi or total hip
arthroplasty between 1 and 16 months
after initial fracture surgery). The fth
patient (#12) with a non-union, 93
years old at the time of injury, was
noted to have failure of xation with
femoral head collapse at 2 months
postoperatively (Figure 2). The patients
family refused revision, however, due to
her age and medical risks. Although she
was not able to ambulate, she continued
to live comfortably in a nursing home
for 44 months postoperatively.
The remaining 20 patients were found
to have healed their fractures (Table
2). Three of these 20 patients (15%),
however, exhibited radiographic
Figure 1-A:
Postoperative AP radiograph of patient
#5, an 88-year-old female with a valgus,
impacted fracture.
evidence of avascular necrosis that

was asymptomatic at follow-up
examination: In one of these three
patients (#2), avascular necrosis with
segmental collapse was noted at 5
months after the time of xation,
but the patient had no complaints of
discomfort 1 year after surgery. In a
second patient (#9), avascular necrosis
with pin protrusion was evident 12
months after xation. This patient
remained asymptomatic 26 months
after xation. Late pin protrusion
following femoral head collapse was
also noted in the third patient (#18),
2.5 months after fracture xation, and
the patient reported no hip symptoms
during subsequent hospitalization for
cardiac problems 3 months following
his surgery.
Fracture Type and Treatment Failure.
Six of the valgus impacted type
fractures failed treatment compared
to two of the non-displaced fractures.
The failure rate for valgus impacted
fractures when compared by Fishers
exact test to minimally or nondisplaced fractures (p=0.657) reveals
insufcient evidence to suggest that the
type of fracture affects outcome in this
Figure 1-B:
Postoperative lateral radiograph of patient #5.
age group.
Gender and Treatment Failure. Seven
female patients and one male patient
were treatment failures. The failure
rate for the six male patients when
compared to the 19 females utilizing
Fishers exact test (p=0.624) shows
insufcient evidence to suggest that
gender inuences outcome.
Postoperative Complications and
Treatment Failure. Five of the
eight patients with postoperative
complications (Table 2, Table 3)
were fracture treatment failures even
though only one complication, wound
hematoma, was directly related to the
orthopaedic procedure. Three patients
without postoperative complications
failed treatment of their fracture.
Fishers exact test revealed a possible
trend (p=0.061) for patients with any
postoperative complication to fail
fracture treatment.
Number of Percutaneous Screws and
Treatment Failure. Of the ve nonunions (Table 2), two patients had
Figure 1-C:
Three-and-one-half-month postoperative AP
radiograph of patient #5 revealing avascular
change with collapse and non-union.
24
6/22/05 2:23:34 PM
MANUSCRIPTS
two screws for xation and three had
three-screw fracture xation. The three
healed fractures with avascular necrosis
had three-screw fracture xation.
Two of the ve patients (40%) with
only two screws for fracture xation
went on to non-union. Six of the 20
patients (30%) with three- or fourscrew xation, however, also went on
to treatment failure (Table 3). There
was no signicant difference (p=1.0) in
outcome when comparing the use of
two-screw xation (40% failure) with
our preferred xation method of three
or more screws (30% failure rate).
DISCUSSION
Non-displaced and valgus impacted

femoral neck fractures are typically
managed by internal xation. We
expect few to go on to non-union
or avascular necrosis.4,6,7,8 However,
eight of our 25 patients (32%) who
underwent screw xation of their
femoral neck fracture were treatment
failures. Five patients fractures (20%)
failed to heal (possibly because of early
avascular changes in a large portion of
the femoral head), and three additional
patients (12%) with healed fractures
exhibited avascular necrosis in a portion
of the femoral head.
We found a 20% non-union rate in
our patients 80 years and older, which
is much higher than rates reported for
patients in their sixties and seventies.6,9
Bentley found, in a study of 23
impacted femoral neck fractures, that
no patients (in a cohort of patients
with a mean age of 72) failed to unite
after xation.6 Barnes et al, in 1976,9
reported a failure rate of only about
1% after xation of valgus impacted
fractures in 236 patients of an average
age of 75.6 years for women and 69.4
years for men.
In 29 patients aged 80 or older with
minimally displaced or valgus impacted
femoral neck fractures, however,
TABLE 3. PATIENT OUTCOMES

Success
Failure
Valgus Impacted
11
Minimally Displaced
Non-Displaced
Fracture Type
p-value=0.657
Fixation Screws
2 screws
3+ screws
6
p-value=1.000
Postoperative Complications
Yes
No
3
p-value=0.061
Hui et al in 199410 found the rate of

failure of xation, dened as rate of
reoperation or readmission for local
complication, to be more than four
times greater than the rate of failure of
xation of the same kinds of fractures
in 28 patients aged 65 to 79 (31%
compared to 7%). Our results thus
concur with the ndings of Hui et al10
that xation of non-displaced and valgus
impacted fractures may fail about onethird of the time in octogenarian and
nonagenarian patients.
who were treatment failures exhibited

some degree of avascular necrosis
radiographically. Three of the 20
patients with healed fractures had partial
head or segmental avascular necrosis.
Their absence of symptoms may be
attributed to the decline in mental status
noted in two of these patients and the
lower degree of activity in this patient
population. Our nding that three
(15%) of the 20 patients with healed
fractures had notable late avascular
change is consistent with an 18% rate
Seven of the eight patients in our study
Figure 2-A:
Immediate postoperative AP radiograph of
patient #12.
Figure 2-B:
Five-month postoperative AP radiograph of
patient #12 revealing non-union and loss of
xation. These ndings were evident at two
months following surgery.
6/22/05 2:23:36 PM

of late avascular change observed by
Bentley.6 Barnes et al reported a similar
rate of late segmental collapse (16%)
after internal xation of valgus impacted
fractures in patients of average age 75.6
years.9 The rate of late avascular necrosis
following fracture healing in our series
therefore does not differ considerably
from the rates reported in patients in
their sixties and seventies.
In our study, gender, type of fracture,
or number of xation screws failed to
correlate signicantly with the treatment
result. The only factor that revealed a
trend was the failure rate for patients
with postoperative complications,
when compared to patients without
postoperative complication (p=0.061).
This trend probably reects the patients
overall health, adequacy of blood supply
to the femoral head, and local fracture
healing ability.
Although there is insufcient evidence
to suggest that the number of screws
affects outcome, we continue to prefer
three-screw xation of femoral neck
fractures. In some small, elderly female
patients, however, this is simply not
possible to achieve.
Internal xation for the treatment of
femoral neck fractures involves less
operative time and less blood loss than
primary arthroplasty. In addition, the
cost of internal xation is lower than
the cost of prosthetic replacement for
femoral neck fractures.11,12 If nonunion or avascular necrosis occurs,
however, revision to a hemi or total hip
arthroplasty is usually necessary. The
risks associated with internal xation
and possible subsequent revision to
arthroplasty need to be understood
by the patient and his or her family,
particularly in the octogenarian and
nonagenarian population, in view of
the relatively high probability of the
need for a second surgical procedure13
regardless of how innocent the
fracture may appear.

Our ndings suggest that this fracture
pattern does not necessarily represent
a benign fracture conguration in the
elderly patient and that the treatment
results will most likely correlate with
the patients health. Patients and their
families should be aware that in spite
of appropriately performed surgical
fracture xation, additional treatment
including prosthetic replacement may
be necessary to achieve a good result.
ACKNOWLEDGMENT
The authors would like to thank

Eduardo Gonzalez Hernandez, M.D.,
Nancy Obuchowski, Ph.D., and Valerie
Schmedlen for their help in preparing
the manuscript.
10. Hui ACW, Anderson GH, Choudhry

R, Boyle J, Gregg PJ. Internal xation or
hemiarthroplasty for undisplaced fractures of
the femoral neck in octogenarians. J. Bone Joint
Surg. Br. 1994; 76:891-894.
11. Soreide O, Alho A, Rietti D. Internal
xation versus endoprosthesis in the treatment
of femoral neck fractures in the elderly. A
prospective analysis of the comparative costs
and the consumption of hospital resources.
Acta. Orthop. Scand. 1980; 51:827-831.
12. Soreide O, Molster A, Raugstad TS. Internal
xation versus primary prosthetic replacement
in acute femoral neck fractures: a prospective,
randomized clinical study. Br. J. Surg. 1979;
66:56-60.
13. Cummings SR, Phillips SL, Wheat ME, et
al. Recovery of function after hip fracture.
The role of social supports. J. Am. Geriatr. Soc.
1988; 36:801-806.
REFERENCES
1. Gallagher JC, Melton LJ, Riggs BL,
Bergstrath E. Epidemiology of fractures of the
proximal femur in Rochester, Minnesota. Clin.
Orthop. 1980; 150:163-171.
2. Cummings SR, Rubin SM, Black D. The
future of hip fractures in the United States.
Numbers, costs, and potential effects of
postmenopausal estrogen. Clin. Orthop. 1990;
252:163-166.
3. Lu-Yao GL, Baron JA, Barrett JA, Fisher
ES. Treatment and survival among elderly
Americans with hip fractures: a populationbased study. Am. J. Public Health. 1994;
84:1287-1291.
4. Garden RS. Stability and union in subcapital
fractures of the femur. J. Bone Joint Surg. Br.
1964; 46:630-647.
5. Koval KJ, Zuckerman JD. Functional recovery
after fracture of the hip. J. Bone Joint Surg. Am.
1994; 76:751-758.
6. Bentley G. Impacted fractures of the neck of
the femur. J. Bone Joint Surg. Br. 1968; 50:551561.
7. Boyd HB, Salvatore JE. Acute fracture of the
femoral neck: internal xation or prosthesis? J.
Bone Joint Surg. Am. 1964; 46:1066-1068.
8. Coates RL, Armour P. Treatment of subcapital
femoral fractures by primary total hip
replacement. Injury. 1980; 11:132-135.
9. Barnes R, Brown JT, Garden RS, Nicoll EA.
Subcapital fractures of the femur. A prospective
review. J. Bone Joint Surg. Br. 1976; 58:2-24.
26
6/22/05 2:23:37 PM
MANUSCRIPTS
CLINICAL OUTCOMES OF SURGICAL

TREATMENT OF THE SYMPTOMATIC
ACCESSORY NAVICULAR
Franz Kopp MD, Randall Marcus MD
Dept. of Orthopaedics, Case Western Reserve University, Cleveland OH
Note: This article is published with permission from Foot and Ankle International (Foot Ankle Int., volume 25 (1), pgs. 2730, 2004).
ABSTRACT
hen conservative treatment

fails to provide relief for a
symptomatic accessory navicular,
surgical intervention may be necessary.
Numerous studies have been published,
reporting the results of the traditional
Kidner procedure and alternative
surgical techniques, all of which
produce mostly satisfactory clinical
outcomes. The purpose of this study
was to report the clinical results,
utilizing the AOFAS Midfoot Scale, of
surgical management for symptomatic
accessory navicular with simple excision
and anatomic repair of the tibialis
posterior tendon.
We retrospectively reviewed the results
of 13 consecutive patients (14 feet)
who underwent surgical treatment for
symptomatic accessory navicular. The
patients ranged in age from 16 to 64
years old (average 34.1 years) at the
time of surgery. All patients had a Type
II accessory navicular. The average
follow-up of the patients involved in
the study was 103.4 months (range
45-194 months). The AOFAS Midfoot
Scale was utilized to determine both
preoperative and postoperative clinical
status of the 14 feet included in the
study.
The average preoperative AOFAS score
was 48.2 (range 20 to 75). The average
postoperative AOFAS score was 94.5
(range 83 to 100). At last follow up, 13

of 14 feet were without any pain, no
patients had activity limitations, and
only two of fourteen feet required shoe
insert modication. Postoperatively,
no patients had a clinically notable
change in their preoperative midfoot
longitudinal arch alignment. All of the
patients in the study were satised with
the outcome of their surgery and would
undergo the same operation again
under similar circumstances.
When conservative measures fail to
relieve the symptoms of a painful
accessory navicular, simple excision of
the accessory navicular and anatomic
repair of the posterior tibialis tendon is
a successful intervention. Overall, the
procedure provides reliable pain relief
and patient satisfaction. In the current
study, the clinical status of each patient
improved signicantly postoperatively,
quantied utilizing the AOFAS
Midfoot Scale.
INTRODUCTION
When conservative treatment options

fail to provide adequate relief for a
symptomatic accessory navicular,
Numerous clinical studies have been
published, reporting the results of the
traditional Kidner procedure as well
as alternative surgical techniques, all
of which produce mostly satisfactory
clinical outcomes.1-12 Using MEDLINE
as a database reference, to our

knowledge, no publication has utilized
the AOFAS Midfoot Scale13 to report
the clinical outcomes in the surgical
management of the symptomatic
accessory navicular. The purpose of this
study was to report the clinical results,
utilizing the AOFAS rating system13,
of 13 patients (14 feet) that were
surgically managed for a symptomatic
accessory navicular with simple excision
of the accessory navicular and anatomic
repair of the tibialis posterior tendon.

of 14 consecutive patients (15 feet)
who underwent surgical treatment for
symptomatic accessory navicular. One
patient (one foot) was lost to followup, thus resulting in 13 patients (14
feet) for the nal analysis. All patients
had failed a course of conservative
management. Eight patients were
females and ve patients were males.
The patients ranged in age from 16 to
64 years old (average age 34.1 years) at
the time of surgery. Range of motion
of the ankle, subtalar, and transverse
tarsal joints was normal in all patients.
The procedure was performed on the
right side in six patients, on the left
side in six patients, and bilaterally in
one patient. All patients had a Type II
accessory navicular. Pain relief was the
primary goal of surgical treatment.
6/22/05 2:23:37 PM
SYMPTOMATIC ACCESSORY NAVICULAR

The average follow-up of the patients
involved in the study was 103.4
months (range 45-194 months). The
methods of evaluation included clinical
and radiographic examination, chart
review, and telephone interviews. The
AOFAS Midfoot Scale13 was utilized
to determine both preoperative and
postoperative clinical status of the 14
feet included in the study.
The Mann-Whitney Test was used to
compare preoperative and postoperative
AOFAS scores.
Operative Technique
A four-centimeter incision was made

in the skin crease directly over the
accessory navicular prominence.
Adequate hemostasis was obtained with
electrocautery and the posterior tibialis
tendon was identied at its insertion on
the navicular. The dorsal aspect of the
tendon was delicately elevated off of the
accessory navicular, which was usually
located along the posterior-medial
aspect of the navicular bone. Along the
dorsum of the posterior tibialis tendon
insertion, sharp dissection was used to
leave a thick periosteal or connective
tissue ap for closure following
removal of the accessory navicular.
Often, a periosteal elevator was used
to aid in delineating the attachment
of the accessory navicular to the main
navicular bone. The plantar aspect of
the posterior tibialis tendon was not
disturbed. Blunt and sharp dissection
was used to shell the accessory
navicular from its brous attachment to
the navicular bone and its attachment
to the posterior tibialis tendon. The
medial prominence of the navicular
bone was beveled using a rongeur and
power burr, making it ush with the
medial border of the medial cuneiform.
The dorsal tendinous insertion of the
posterior tibialis tendon was sutured
to the periosteal or connective tissue
ap with multiple interrupted sutures.
The skin and subcutaneous layers were
closed with absorbable suture and SteriStrips were applied to the skin. The leg
was placed into a posterior splint with
sugartong.
Postoperative Care
The patient was asked to remain

nonweightbearing. Forty-eight hours
post-operatively, the patient was placed
into a shortleg cast with the foot
plantigrade and with a well-molded
arch. The patient was asked to remain
nonweightbearing for three weeks, at
which time a shortleg walking cast was
applied for an additional three weeks.
At that time, all cast immobilization
was discontinued. Postoperative
radiographs were not routinely
obtained unless clinically indicated.
RESULTS
The fourteen feet (thirteen patients)

in the study were followed up for a
minimum of 45 months. The average
follow-up was 103.4 months (range
45-194 months). The preoperative and
postoperative AOFAS Midfoot Scale13
was calculated for each patient. The
maximum score is 100 points.
The average preoperative AOFAS
score was 48.2 (range 20 to 75).
The average postoperative AOFAS
score was 94.5 (range 83 to 100),
demonstrating a signicant (p < 0.001)
difference between preoperative and
postoperative AOFAS scores. Of the
subjective clinical factors measured by
the AOFAS grading system, all of the
patients stated that pain was the most
bothersome preoperative complaint. Six
patients rated their preoperative pain
as severe, and seven patients rated their
preoperative pain as moderate. At last
follow up, 13 of 14 feet were without
any pain (maximum 40 points), and
one foot had mild pain (30 points).
All of the patients had some degree of
preoperative activity limitation due to
their symptomatic accessory navicular.
Postoperatively, all patients stated that
they had no activity limitations and

used no ambulatory support (maximum
10 points). Eleven of fourteen feet were
managed with a preoperative shoe insert
or orthosis. Only two of fourteen feet
required shoe insert modication at
last follow-up evaluation. Clinically,
nine of fourteen feet were noted to
have pes planus both preoperatively
and postoperatively. The remaining
ve feet had a normally aligned
midfoot. Postoperatively, no patients
had a clinically notable change in their
preoperative midfoot longitudinal arch
alignment. Overall, all (13 of 13) of the
patients in the study were satised with
under similar circumstances. In the
current study, no apparent relationship
was noted between clinical result and
age at time of operative intervention or
duration of follow-up.
No acute postoperative complications
occurred in the study population.
One patient (one foot) required one
additional procedure. This patient,
who experienced initial relief of
symptoms, went on to develop
recurrence of medial-sided midfoot
pain several months postoperatively.
Postoperative radiographs revealed an
osseus spur along the underside on the
navicular bone. The etiology of this
spur formation was uncertain. Due
to refractory symptoms, this patient
underwent surgical exploration and
excision of this bony spur one year after
the index procedure. At last follow-up,
45 months after the second operative
procedure, this patients AOFAS
Midfoot Score13 was 93 with complete
pain relief.
DISCUSSION
The accessory navicular was rst

described by Bauhin in 1605.14
Since that time, this anatomic
structure has been referred to by such
names as tarsal navicular, accessory
28
6/22/05 2:23:38 PM
MANUSCRIPTS
scaphoid, prehallux, os tibiale, os
tibiale externum, and naviculare
secundarium.9,15 The accessory
navicular is reported to occur in
10% to 14% of normal feet.3,4 Most
cases of accessory navicular are
asymptomatic, and less than 1%
require surgical treatment.1,4 The
accessory navicular may exist as a
separate ossicle within the posterior
tibialis tendon (Type I), may form a
synchondrosis or brocartilaginous
bridge with the navicular (Type
II), or may fuse with the navicular
(cornuate navicular, or Type III).810,12,16
Of these variations, Type II is
most commonly associated with the
medial midfoot pain characteristic of a
symptomatic accessory navicular.17 The
association of exible atfoot deformity
with accessory navicular has been
described14, 18, but the exact relationship
between the two entities remains
controversial.1
Treatment of the symptomatic
accessory navicular begins with
nonoperative modalities such as
nonsteroidal anti-inammatory drugs,
immobilization, molded orthoses,
local injection, and physical therapy.
When these treatment options fail to
provide adequate symptomatic relief,
The Kidner procedure14, 18 consists
of excising the accessory navicular
and rerouting the tibialis posterior
tendon into a more plantar position.
Numerous clinical studies have been
published, reporting the results of the
traditional Kidner procedure as well
as alternative surgical techniques, all
of which produce mostly satisfactory
clinical outcomes in terms of relief
of pain and fatigue.1-12 Improvement
of the medial longitudinal arch and
correction of associated pes planus
deformity, if present, with the Kidner
procedure and its alternatives is less
predictable.8, 12
In the current study, the AOFAS

Midfoot Scale13 was used to report
the clinical outcomes of 13 patients
(14 feet) that were surgically managed
for symptomatic accessory navicular
with simple excision of the accessory
navicular and anatomic repair of the
tibialis posterior tendon. Pain relief was
the primary goal of surgical treatment.
The average AOFAS Midfoot Score13
improved from a preoperative score
of 48.2 to a postoperative score of
94.5 (p < 0.001). All 14 feet had an
improvement in pain, including 13
feet with no pain at all postoperatively.
This procedure did not notably change
the clinical midfoot alignment in any
patients; however, only two of fourteen
feet required postoperative shoe insert
modication. Overall, all (13 of 13) of
the patients in the study were satised
with the outcome of their surgery and
would undergo the same operation
again under similar circumstances.
Although patient satisfaction is a
nonobjective measure of treatment
outcome, it remains a valuable
parameter in assessing overall utility of
an intervention.
3. Geist ES. The accessory scaphoid bone. J Bone

Joint Surg 1925; 7:570-574
When conservative, nonoperative

measures fail to relieve the symptoms
of a painful accessory navicular, simple
excision of the accessory navicular and
anatomic repair of the posterior tibialis
tendon is a successful intervention.
Overall, the procedure provides reliable
pain relief and patient satisfaction. In
the current study, the clinical status
of each patient improved signicantly
postoperatively, quantied utilizing the
AOFAS Midfoot Scale.13
13. Kitaoka HB, Alexander IJ, Adelaar RS,

Nunley JA, Myerson MS, Sanders M. Clinical
Rating Systems for the Ankle-Hindfoot,
Midfoot, Hallux, and Lesser Toes. Foot Ankle.
15: 1994; 349-353
REFERENCES
17. Sullivan JA, Miller WA. The Relationship of

the Accessory Navicular to the Development of
the Flat Foot. Clin. Orthop. 1979; 144:233-237
1. Bennett GL, Weiner DS, Leighley B. Surgical

Treatment of Symptomatic Accessory Tarsal
Navicular. J Pediatr Orthop. 1990; 10:445-449
2. Clark GC. A Modied Kidner Procedure for
Symptomatic Flat Feet. Clin. Orthop. 1988;
228:258-260
4. Grogan D, Gasser S, Ogden J. The

Painful Accessory Navicular: A Clinical and
Histopathological Study. Foot Ankle 1989;
10:164-169
5. Leonard MH, Gonzalez, S, Breck LW, Basom
C, Palafox M, Kosicki ZW. Lateral Transfer of
the Posterior Tibial Tendon in Certain Selected
Cases of Pes Plano Valgus (Kidner Operation).
Clin. Orthop. 1965; 40:139-144
6. Macnicol JF, Voutsinas S. Surgical Treatment
of the Symptomatic Accessory Navicular, J.
Bone Joint Surg. 1984; 66B:218-226
7. Malicky ES, Levine DS, Sangeorzan BJ.
Modication of the Kidner Procedure with
Fusion of the Primary and Accessory Navicualr
Bones. Foot Ankle 1999; 20: 53-54
8. Prichasuk S, Sinphurmsukskul O. Kidner
Procedure for Symptomatic Accessory
Navicular and its Relation to Pes Planus. Foot
Ankle 1995; 16:500-503
9. Ray S, Goldberg VM. Surgical Treatment of
the Accessory Navicular. Clin. Orthop. 1983;
177:61-66
10. Sella EJ, Lawson JP, Ogden JA. The Accessory
Navicular Synchondrosis. Clin. Orthop. 1986;
209:280-285
11. Tan, SM, Chin TW, Mitra AK, Tan SK.
Surgical Treatment of Symptomatic Accessory
Navicular. Ann. Acad. Med. Singapore.
1995;24:379-381
12. Veitch JM. Evaluation of the Kidner Procedure
in Treatment of Symptomatic Accessory Tarsal
Scaphoid. Clin. Orthop. 1978; 131:210-213
14. Kidner FC. The Prehallux (Accessory

Scaphoid) in its Relation to Flat Foot. J. Bone
Joint Surg. 1929; 11:831-837
15. Chou LB. Miscellaneous Disorders of the
Foot. In Chapman MW (ed): Chapmans
Orthopaedic Surgery, 3rd ed, vol 3, pp 31373145, Philadelphia, Lippincott Williams &
Wilkins, 1993
16. Zadek I, Gold AM. The Accessory Tarsal
Scaphoid. J. Bone Joint Surg. 1948; 30A:957968
18. Kidner FC. The prehallux in relation to

atfoot. JAMA. 1933; 101:1539-1542
6/22/05 2:23:38 PM
CLINICAL OUTCOME OF TIBIOTALAR

ARTHRODESIS UTILIZING THE CHEVRON
TECHNIQUE
Franz Kopp MD, Randall Marcus MD
Note: This article is published with permission from Foot and Ankle International (Foot Ankle Int., volume 25 (4), pgs. 225230, 2004).
ABSTRACT
ibiotalar arthrodesis remains the

gold-standard reconstructive procedure for the treatment of disabling
ankle arthritis. The purpose of this
study was to review the clinical results
of tibiotalar arthrodesis utilizing the
chevron fusion technique.
We retrospectively reviewed the
results of 46 consecutive patients who
underwent ankle arthrodesis utilizing
the chevron technique. The etiology of
the tibiotalar arthritis was
post-traumatic in 29 of 46 patients.
Of the remaining 17 patients, seven
had osteoarthritis, ve had talar
osteonecrosis, two had rheumatoid
arthritis, one had hemophilic
arthropathy, one had gouty
arthropathy, and one had unrecognized
chronic osteomyelitis. Three patients
had prior hindfoot arthrodeses, and
two patients had bilateral ankle fusions
at last follow-up. All patients were
followed for a minimum of two years.
Of the 46 patients, 41 were available
for review, average follow-up 7.3
years (range 2.0 to 20.0 years). Twelve
patients had greater than ten-year
follow-up. The Mazur ankle score was
calculated for all 41 patients.
The average Mazur ankle score for the
41 patients available for review was
72.8, maximum possible score 90.
Eighteen patients had excellent results,
eleven patients had good results, ve

patients had fair results, and seven
patients had poor results. The most
common reasons for fair or poor results
were symptomatic subtalar arthritis
and multiple medical co-morbidities.
All patients with post-operative
symptomatic subtalar arthritis had
pre-operative radiographic evidence
of subtalar arthrosis. Of the twelve
patients with greater than ten year
follow-up, nine had excellent or good
results, average Mazur ankle score 76.6.
All patients with either prior hindfoot
arthrodeses or bilateral ankle fusions
had excellent or good results. Of the 41
arthrodeses included in the study, 38
(38/41, 93%) went on to clinical and
radiographic union.
The chevron technique provides a
predictable method to obtain fusion
of the tibiotalar joint. Most patients
can expect excellent or good results.
In the current study, ninety percent
(37/41) of patients were satised with
under similar circumstances.
INTRODUCTION
While short-term studies of total ankle

arthroplasty have provided encouraging
data, longer-term follow-up has shown
deterioration of clinical results1-10.
Tibiotalar arthrodesis remains the
gold-standard reconstructive procedure
for the treatment of disabling ankle

arthritis1,2, 11, 12, 13, 14, 15, 16. Prior analyses
have demonstrated that patients with
well-aligned ankle fusions, if wearing
shoes with appropriate modications,
can walk without a signicant limp,
with good velocity, and with a
rhythmic gait.13,17-21 Although tibiotalar
joint motion is eliminated with ankle
arthrodesis, tibiopedal motion remains
up to 40 percent of the preoperative
range18,19, 20, 22.
Since Charnley introduced the concept
of compression ankle arthrodesis23,
many effective techniques of ankle
fusion have been described in the
orthopaedic literature.12,14,22-35 These
techniques differ in terms of the
surgical approach, the type of xation,
the type of bone graft, or all of these
factors. Compression arthrodesis can
be achieved using internal, external,
or intramedullary xation.25 Each
method has its own advantages and
disadvantages. Although delayed union
and nonunion can occur, most current
ankle arthrodesis techniques achieve
successful fusion in 80% to 90% of
patients.25
At our institution, we have been
utilizing a technique of ankle
arthrodesis described as the chevron
technique29,36. In 1983, we reported
the preliminary results of the initial
thirteen patients who underwent
30
6/22/05 2:23:38 PM
MANUSCRIPTS
chevron arthrodesis of the ankle29.
This method resulted in few serious
complications, a high incidence of
fusion, and an excellent cosmetic result.
The purpose of this study was to review
the clinical results of ankle arthrodesis
utilizing the chevron technique in 41
patients.

of 46 consecutive patients (ages 17 to
82 years old, mean 42) who underwent
ankle arthrodesis utilizing the chevron
technique. All of the procedures
were performed between November
1974 and July 1999. All patients had
disabling ankle arthritis of variable
etiology. The chevron fusion technique
for ankle arthrodesis was used in all of
the surgical procedures. Patients with
Charcot neuropathic arthropathy were
excluded from the current study.
All patients included in the study
were followed for a minimum of
two years (average 7.3 years, range
2.0 to 20.0 years). The methods
of evaluation included clinical and
radiographic examination, chart
review, and telephone interviews. All
patients were followed with clinical
examination for at least two years
post-operatively. Once fusion was
documented radiographically, further
radiographs were obtained only if
clinically indicated. The Mazur ankle
score 20, a weighted point system for
grading ankle function, was calculated
for the 41 patients available for review.
The Mazur scoring system was used
because of its application in a prior
review of the chevron technique for
ankle arthrodesis29.
Operative Technique
The surgical approach was bimalleolar.

A lateral longitudinal incision was
made, extending from the tip of the
lateral malleolus proximally for six
centimeters. A subperiosteal dissection
(A)
(B)
Figure 1. The shaded areas represent the bone resected in the AP (A) and lateral (B)
projection.
(Used with permission. Marcus RE and Heiple KG, J. Bone Joint Surg. 65A:834, 1983.)
(A)
(B)
Figure 2. AP (A) and lateral (B) radiographs of an ankle arthrodesis demonstrating the
technique utilized in this series.
of the distal bula was performed,

taking care to protect the peroneal
tendons. The bula was obliquely
osteotomized four centimeters proximal
to its end and the bular fragment was
removed (Fig. 1).
The medial malleolus was exposed
with a longitudinal medial incision
beginning one centimeter distal to the
tip of the medial malleolus, extending
ten centimeters proximally. The
incision was placed just anterior to
the medial malleolus. A subperiosteal
dissection of the medial malleolus

and medial aspect of the tibia was
performed, taking care to protect
the medial neurovascular bundle and
tendons. Utilizing a sagittal saw, the
distal medial tibial are along with the
medial malleolus was removed in one
piece. This piece was used later in the
procedure as an onlay bone graft. With
sharp dissection, the remaining joint
capsule and ligaments were divided
anteriorly and posteriorly (Fig. 1).
The foot was dislocated laterally and a
6/22/05 2:23:39 PM
TIBIOTALAR ARTHRODESIS
resection of the distal articular surface
of the tibia was performed in a chevron
or pitched-roof conguration in the
sagittal plane. Resection was performed
to the level of subchondral cancellous
bone. The plane of the cuts was anteroposterior and the apex was superior.
The ankle was reduced and the foot
was brought to the desired alignment,
typically neutral plantarexiondorsiexion and slight valgus18, 37.
Using a marking pen or osteotome, the
corresponding apex and angles of the
chevron cuts on the dome of the talus
were marked. The articular surface of
the talus was prepared with saw cuts
matching those previously made on the
distal tibia. It was conrmed that the
concave tibial and convex talar surfaces
t snugly using manual apposition. The
cuts were augmented using a saw blade
or rasp as needed to achieve optimal
alignment and apposition (Fig. 1).
After proper alignment of the
osteotomy surfaces, with good quality
subchondral cancellous bone of the
tibia and talus in contact, a 5/32-inch
smooth Steinmann pin was inserted
axially through the heel and talus and
across the fusion site for temporary
stabilization in the desired position18,37.
The position was conrmed both
visually and radiographically. The
Steinmann pin maintained the position
of the ankle during the remainder of
the procedure. Next, two 7/8-inch bone
staples (Zimmer Inc., Warsaw, Indiana)
were placed laterally and one 7/8-inch
staple was placed anteromedially across
the ankle fusion into the talus and
tibia. The medial malleolar slab was
trimmed and used to bridge the fusion
medially, posterior to the medial staple.
The medial graft was secured with one
3.5mm cortical or 4.0mm cancellous
lag screw in the tibia and one in the
decorticated medial talus. The screw
heads were countersunk (Fig. 2).
The apposition of the tibial and talar
cuts and the xation were inspected

both visually and radiographically. If
any gaps remained, these were lled
using remaining cancellous bone
chips. The wounds were closed in
layers and a sterile dressing is applied.
The extremity was placed in a bulky
compressive dressing from toes to knee,
overlaid with a posterior splint and
plaster shell for 48 hours, followed by a
shortleg non-weightbearing cast.
Postoperative Care
The sutures and Steinmann pin were

removed in the outpatient setting at
two to three weeks. A shortleg nonweightbearing cast was continued
at this time. Four weeks later, a
shortleg walking cast was applied
and progressive weight bearing was
started. The cast was usually removed
at approximately three months postoperatively. If clinical and radiographic
examination revealed a solid union, the
patient resumed activity as tolerated.
An appropriately sized heel lift was
recommended for all patients.
RESULTS
In the current study, the etiology of the

tibiotalar arthritis was post-traumatic
in 29 of 46 patients. Of the remaining
17 patients, seven had osteoarthritis,
ve had talar osteonecrosis, two
had rheumatoid arthritis, one had
hemophilic arthropathy, one had gouty
arthropathy, and one had unrecognized
septic arthritis with chronic
osteomyelitis. Three patients had a
nonunion from previous attempted
ankle arthrodesis at other institutions.
Two of these patients underwent initial
fusion attempt for talar avascular
necrosis and one patient underwent
initial fusion attempt for posttraumatic arthritis. Three patients had
prior ipsilateral hindfoot arthrodeses,
two triple arthrodeses and one subtalar
arthrodesis. Two patients had bilateral
ankle fusions at the time of their last
follow-up. Each of these patients
contributed only one ankle arthrodesis

to the current study results. One of
these patients had the contralateral
fusion performed at a different
institution and the other patients
contralateral chevron arthrodesis was
excluded from the study due to less
than two-year follow-up.
Of the 46 patients, 41 (20 males,
22 females) ankles were available for
follow-up evaluation of two years or
greater, average 7.3 years (range 2.0 to
20.0 years). Three patients were lost to
follow-up, one patient died of unrelated
causes prior to two-year follow-up,
and one patient underwent below
knee amputation due to soft tissue
complications prior to two-year followup. The patient who underwent below
knee amputation did, in fact, have a
successful bony fusion; however, due to
amputation, an ankle score could not
be generated for this patient. Thus, a
Mazur ankle score could be generated
for 41 patients (41 arthrodeses). Twelve
of these patients had greater than tenyear follow-up. Of the 41 arthrodeses
included in the study, 38 (93%) went
on to clinical and radiographic union.
All patients that went on to both
clinical and radiographic fusion were
united at approximately 12 weeks
post-operatively. Three patients were
cigarette smokers, all of which went on
to successful fusion.
The Mazur ankle score20, a weighted
point system for grading ankle
function, was calculated for the 41
patients available for review. Because of
the lack of ankle motion, the maximum
score is 90. The average Mazur score
was 72.8 (SD 14.5, range 35 to 88).
Eighteen patients (18/41, 44%) had
excellent results (Mazur score 80-90),
eleven patients (11/41, 27%) had
good results (Mazur score 70-79),
ve patients (5/41, 12%) had fair
results (Mazur score 60-69), and seven
patients (7/41, 17%) had poor results
32
6/22/05 2:23:39 PM
MANUSCRIPTS
(Mazur score <60). Of the twelve
patients with greater than ten year
follow-up, nine had excellent or good
results, average Mazur ankle score 76.6
(SD 16.6, range 35 to 88). All three
patients with prior hindfoot arthrodeses
and both patients with bilateral ankle
fusions had either excellent or good
results in the studied ankle. The preoperative diagnoses of those patients
with either fair or poor results included
eight patients with post-traumatic
osteoarthritis (one of which had a
nonunion from a prior fusion attempt),
one patient with talar avascular necrosis
(also had a nonunion from a prior
fusion attempt), one patient with
rheumatoid arthritis, one patient with
osteoarthritis, and one patient with
chronic osteomyelitis.
Whereas 50 points for pain represents
none, or patient ignores it20, the
average pain points in the current
study was 44.1. Twenty-two patients
(22/41, 54%) reported no pain, seven
patients (7/41, 17%) reported slight
pain without limitation of activities of
daily living, and seven patients (7/41,
17%) reported pain only with stairs
and ambulating long distances. One
patient required intermittent narcotic
analgesia. The average functional score
in the study was 28.3. All patients
in the study lost points for running
ability. Of those patients who had
fair or poor results, ve patients had
symptomatic subtalar arthritis, ve
patients had multiple medical comorbidities such as severe cardiac and
respiratory disorders contributing
to lower functional scores, one had
unrecognized septic arthritis with
chronic osteomyelitis and a subsequent
nonunion, and one developed reex
sympathetic dystrophy. All patients
with symptomatic subtalar arthritis
post-operatively had pre-operative
radiographic evidence of subtalar
degenerative joint disease at the time of
their ankle arthrodesis. However, not

all patients (ten total) with radiographic
evidence of subtalar arthritis at last
follow-up were symptomatic. Although
the bula is discarded with this
procedure, no symptoms of peroneal
tendon pathology developed in the
study group. In the current series,
no apparent relationship was noted
between clinical result and age, etiology
of ankle arthritis, or duration of followup.
Overall, 90% (37/41) of the patients in
the study stated that they were satised
with the outcome of their surgery and
Six of twelve patients with fair or
poor Mazur scores stated that they
Although patient satisfaction is a
nonobjective measure of treatment
outcome, it remains a valuable
parameter in assessing overall utility of
an intervention.
Complications developed in eight
patients, seven of which are included
in the current study. Three patients
went on to nonunion at the fusion
site. One of these patients underwent
revision using iliac bone graft with
subsequent union and a good result.
The other two patients, both with
histories of signicant alcohol abuse
and one with unrecognized chronic
osteomyelitis, elected to undergo no
further treatment. Three patients had
postoperative wound infections, two
of which were treated uneventfully
with antibiotic therapy. Although the
relationship is uncertain, these two
patients also had histories of prior
irrigation and debridement for wound
infection with their initial ankle
fracture open reduction and internal
xation (ORIF) procedures. The
third patient, whose ankle fusion had
consolidated at three months post-
operatively, had rheumatoid arthritis

with severe eczema and venous stasis
disease. He was also a cigarette smoker.
He developed skin necrosis and deep
soft tissue infection, necessitating
below knee amputation eight months
after the initial procedure. An ankle
score could not be generated for this
patient. One patient was noted to have
a deep venous thrombosis six weeks
post-operatively. This resolved with
conservative treatment and without
sequelae. One patient with hemophilia
had a tibial insufciency fracture four
months after arthrodesis. He was
treated with a shortleg weightbearing
cast and healed uneventfully.
DISCUSSION
The chevron technique for ankle

fusion incorporates three principles
that provide a favorable milieu for
bone healing: surfaces of cancellous
bone in intimate contact, rigid
internal xation in compression,
and autogenous onlay bone grafting.
The bimalleolar exposure allows for
excellent visualization of the joint
surfaces. The chevron-type resection
possesses inherent mechanical stability
and minimizes the amount of bone
that must be resected, while providing
maximum bleeding cancellous bone
surface contact. Compression and
rigid internal xation utilizing staples
facilitate healing of the large cancellous
bone surfaces23, 38, 39. Failure of xation
did not occur in any of the patients
in the series. The use of the bone slab
from the distal tibia as autogenous
medial onlay graft40 provides additional
stability, a large cancellous surface with
osteogenic potential, and coapts well
to the osteotomy surface. The use of a
smooth Steinmann pin for temporary
xation does not appear to increase
the risk of future subtalar arthritis,
as this condition arises subsequent to
other ankle fusion techniques as well11.
The chevron technique is relatively
6/22/05 2:23:39 PM
TIBIOTALAR ARTHRODESIS
simple, using common orthopaedic
instruments, and can be performed
by either the general or specialized
orthopaedic surgeon.
The current study conrms many
known advantages of a successful
ankle arthrodesis. A solid ankle
arthrodesis provides predictable pain
relief and creates a stable, plantigrade
foot. Once solid fusion is achieved,
no functional limitations are placed
upon the patient. With proper shoe
modications, such as cushioned heels
or rocker-bottom soles, patients who
have undergone ankle fusion experience
minimal functional disability and can
perform most activities without pain.
Patients can ambulate with a normal or
nearly normal gait pattern. Although
limited in number, the current study
indicates that ankle arthrodesis can be
clinically successful in the presence of
prior contralateral ankle arthrodesis
or ipsilateral hindfoot fusions. Also,
clinical results did not appear to
deteriorate with longer-term follow-up
of greater than ten years.
Degenerative changes in the subtalar
joint following ankle fusion have
been documented radiographically
at long-term follow-up. In the
current study, as well as in prior
investigations15,22,30, however, there is
no consistent relationship between the
radiographic ndings and the severity
of symptoms. Patients, especially those
with pre-operative evidence of subtalar
arthritis, need to be educated with
respect to the possibility of subsequent
development of symptomatic subtalar
arthritis with possible further surgical
intervention. In those patients in
whom subtalar or midfoot arthrosis
becomes debilitating and refractory to
conservative management, arthrodesis
of these articulations may become
necessary. Due to the fact that the
lateral malleolus is sacriced with the
chevron technique, a conversion to
total ankle replacement using current

designs would not be possible. Patients
with ankle fusions need to be informed
pre-operatively that they will have
difculty running and with walking
on uneven surfaces. Although patients
with multiple medical problems often
have lower functional scores after
ankle fusion, most can expect an
improvement in pain.
While short-term studies of total
ankle arthroplasty have provided
encouraging data, longer-term
follow-up has shown deterioration of
clinical results. Notably, most longterm follow-up data represents older
prosthetic designs. Although modern
arthroplasty designs may eventually be
shown to provide improved long-term
results2,41, ankle arthrodesis currently
remains the standard reconstructive
procedure for the treatment of
disabling ankle arthritis of various
etiologies. Perhaps, in patients with
arthritis of adjacent articulations, such
as the subtalar of midfoot joints, or in
elderly, more sedentary patients, total
ankle arthroplasty will become a more
favorable option to arthrodesis once
long-term clinical outcomes of the
modern implants become available3,68,42
. In order for total ankle arthroplasty
to replace arthrodesis as the standard
treatment for disabling tibiotalar
arthritis, the procedure needs to
predictably result in a pain-free, stable
joint with few complications. Also,
ankle arthroplasty will need to provide
improved patient function without
activity restrictions. A prospective,
randomized clinical trial comparing the
long-term outcome of ankle arthrodesis
with that of ankle arthroplasty would
aid in dening the appropriate patient
population for each procedure.
Ankle arthrodesis utilizing the chevron
technique provides an excellent method
to obtain a fusion of the tibiotalar
joint. Most patients can expect
excellent or good results. The most

common reasons for fair or poor results
were symptomatic subtalar arthritis
and multiple medical co-morbidities.
Ninety percent (37/41) of patients
were satised with the outcome of
their surgery and would undergo the
same operation again under similar
circumstances. The chevron technique
for ankle fusion results in few serious
complications, a high incidence of
fusion, and an excellent cosmetic result
with a high level of patient satisfaction.
REFERENCES
1. Demottaz JD, Mazur JM, Thomas WH,
Sledge CB, Simon SR. Clinical Study of
Total Ankle Replacement with Gait Analysis:
A Preliminary Report. J Bone Joint Surg. 1979;
61A:976-988
2. Kile TA, and Alford DW. Arthritis and
Deformities of the Hindfoot and Ankle.
In Mizel MS, Miller RA, Scioli MW (eds):
Orthopaedic Knowledge Update: Foot and
Ankle, 2nd ed, pp 279-292, Rosemont, Illinois,
AAOS, 1998.
3. Kitaoka HB, Patzer GL. Clinical Results of
the Mayo Total Ankle Arthroplasty. J Bone Joint
Surg. 1996; 78A:1658-1664
4. Kitaoka, H.B., and Romness, D.W.
Arthrodesis for Failed Ankle Arthroplasty. J.
Arthroplasty, 7:277-284, 1992.
5. Kofoed, H. Cylindrical Cemented Ankle
Arthroplasty: A Prospective Series with LongTerm Follow-Up. Foot Ankle, 16: 474-479,
1995.
6. Neufeld SK, Lee TH. Total Ankle
Arthroplasty: Indications, Results, and
Biomechanical Rationale. Am. J. Orthop. 2000;
29:593-602
7. Pyevich MT, Saltzman CL, Callaghan JJ.
Total Ankle Arthroplasty: A Unique Design. J
Bone Joint Surg. 1998; 80A:1410-1420.
8. Saltzman CL. Total Ankle Arthroplasty:
State of the Art. AAOS Instructional Course
Lectures, 48:263-268, 1999.
9. Stauffer RN. Salvage of Painful Total Ankle
Arthroplasty. Clin. Orthop. 1982; 170:184-188.
10. Wynn AH, Wilde AH. Long-term Follow-up
of the Conaxial (Beck-Steffee) Total Ankle
Arthroplasty. Foot Ankle. 1992; 13:303-306.
11. Holt ES, Hansen ST, Mayo KA, Sangeorzan
BJ. Ankle Arthrodesis Using Internal Screw
Fixation. Clin. Orthop. 1991; 268:21-28
34
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MANUSCRIPTS
12. Kile, T.A.: Ankle Arthrodesis. In Morrey BF
(ed): Reconstructive Surgery of the Joints, 2nd
ed, vol. 2, pp 1771-1787, New York, Churchill
Livingstone, 1996.
13. Kile TA. Ankle Arthrodesis. In Morrey BF
(ed): Reconstructive Surgery of the Joints, 2nd
ed, vol. 2, pp 1771-1787, New York, Churchill
Livingstone, 1996.
28. Mann RA, Van Manen JW, Wapner K,

Martin J. Ankle Fusion. Clin. Orthop. 1991;
268:49-55.
29. Marcus RE, Balourdas GM, Heiple KG.
Ankle Arthrodesis by Chevron Fusion with
Internal Fixation and Bone Grafting. J. Bone
Joint Surg. 1983; 65A:833-838
14. Mann RA, Rongstad K. Arthrodesis of the

Ankle: A Critical Analysis. Foot Ankle. 1998;
19:3-9.
30. Moeckel BH, Patterson BM, Inglis AE,

Sculco TP. Ankle Arthrodesis: A Comparison
of Internal and External Fixation. Clin. Orthop.
1991; 268:78-83
15. Morrey BF, Wiedeman GP Jr. Complications

and Long-Term Results of Ankle Arthrodesis
Following Trauma. J. Bone Joint Surg. 1980;
62A:777-784
31. Myerson MS, Quill G. Ankle Arthrodesis: A

Comparison of an Arthroscopic and an Open
Method of Treatment. Clin. Orthop. 1991;
268:84-95
16. Stuart MJ, Morrey BF. Arthrodesis of the

Diabetic Neuropathic Ankle Joint. Clin.
Orthop. 1990; 253:209-211.
32. Paremain GP, Miller SD, Myerson MS. Ankle

Arthrodesis: Results After Miniarthrotomy
Technique. Foot Ankle. 1996; 17:247-252
17. Abdo RV, Wasilewski SA. Ankle Arthrodesis:

A Long-term Study. Foot Ankle. 1992; 13:307312.
33. Ratliff AH. Compression Arthrodesis of the

Ankle. J. Bone Joint Surg. 1959; 41B:524-534
18. Buck P, Morrey BF, Chao EY. The Optimum

Position of Arthrodesis of the Ankle. J. Bone
Joint Surg. 1987; 69A:1052-1062.
19. King HA, Watkins TB Jr, Samuelson KM.
Analysis of Foot Position in Ankle Arthrodesis
and its Inuence on Gait. Foot Ankle. 1980;
1:44-49.
20. Mazur JM, Schwarz E, Simon SR. Ankle
Arthrodesis: Long-Term Follow-up with Gait
Analysis. J. Bone Joint Surg. 1979; 61A:964975.
21. Scranton PE. An Overview of Ankle
Arthrodesis. Clin. Orthop. 1991; 268:96-101.
22. Morgan CD, Henke JA, Bailey RW,
Kaufer H. Long-Term Results of Tibiotalar
Arthrodesis. J. Bone Joint Surg. 1985; 67A:546550.
23. Charnley J. Compression Arthrodesis of the
Ankle and Shoulder. J. Bone Joint Surg. 1951;
33B:180-191.
24. Berman AT, Bosacco SJ, Yanicko DR Jr,
Raisis LW. Compression Arthrodesis of the
Ankle by Triangular External Fixation: An
Improved Technique. Orthopedics 1989;
12:1327-1330.
25. Christian CA, Donley BG. Arthrodesis of
the Ankle, Knee, and Hip. In Canale ST (ed):
Campbells Operative Orthopaedics, 9th ed, vol
1, pp 145-168, St. Louis, Mosby, 1998.
26. Glick JM, Morgan CD, Myerson MS,
Sampson TG, Mann JA. Ankle Arthrodesis
Using an Arthroscopic Method: Long-term
Follow-up of 34 Cases. Arthroscopy. 1996;
12:428-434.
27. Hansen ST. Posttraumatic and Degenerative
Problems in the Joints. In Functional
Reconstruction of the Foot and Ankle, pp 145186, Philadelphia, Lippincott Williams and
Wilkins, 2000.
34. Thordarson DB, Markolf K, Cracchiolo A.

3rd. Stability of an Ankle Arthrodesis Fixed by
Cancellous-Bone Screws Compared to That
Fixed by an External Fixator: A Biomechanical
Study. J. Bone Joint Surg. 1992; 74A:1050-1055
35. Thordarson DB, Markolf K, Cracchiolo A
3rd. Arthrodesis of the Ankle with CancellousBone Screws and Fibular Strut Graft:
Biomechanical Analysis. J. Bone Joint Surg.
1990; 72A:1359-1363.
36. Marcus RE, Heiple, KG. Arthrodesis of the
Ankle. In Chapman MW (ed): Operative
Orthopaedics, 2nd ed, vol 3, pp 2027-2036,
Philadelphia, J.B. Lippincott Company, 1993.
37. Mann RA. Surgical Implications of
Biomechanics of the Foot and Ankle. Clin.
Orthop. 1980; 146:111-118.
38. Bechtold JE, Meidt JD, Varecka TF, Bianco
PT. The Effect of Staple Size, Orientation,
and Number on Torsional Fracture Fixation
Stability. Clin. Orthop. 1993; 297:210-217
39. Weltmer JB, Cracchiolo A 3rd. The Use
of the Powered Metaphyseal Stapler for
Reconstructive Procedures in the Adult Foot.
Foot Ankle. 1990; 11:12-15
40. Herndon CH. Principles of Bone Graft Surgery
Different Methods of Operative Procedure
and Indications for Each. AAOS Instructional
Course Lectures, 17:149-164, 1960.
41. Jaakkola JI, Mann JA, Mann RA. Short-Term
Results With 50 Scandinavian Total Ankle
Replacements. Paper Presentation at American
Academy of Orthopaedic Surgeons annual
meeting, Dallas, TX, February, 2002.
42. McGuire MR, Kyle RF, Gustilo RB,
Premer RF. Comparative Analysis of Ankle
Arthroplasty Versus Ankle Arthrodesis. Clin.
Orthop. 1988; 22:174-181
6/22/05 2:23:40 PM
THE EFFECT OF GAMMA RADIATION

STERILIZATION ON THE FATIGUE CRACK
PROPAGATION RESISTANCE OF HUMAN
CORTICAL BONE
Erika Mitchell MD1, Allison Stawarz MS2, Clare Rimnac PhD1,2
1
Department of Orthopaedics, University Hospitals of Cleveland, OH;
2
Musculoskeletal Mechanics and Materials Laboratories, Department of Mechanical and
Aerospace Engineering, Case Western Reserve University, Cleveland OH
INTRODUCTION
arge cortical allografts have been

used for many years in the reconstruction of signicant bony defects
secondary to trauma, tumor resection
or revision joint arthroplasty. These
reconstructions are often performed in
active patients with the goal of restoring the patient to their prior functional
status. To minimize the risk of infection
in using allograft tissues, tissue banks
have come to use methods such as
antimicrobial washes, freeze-drying and
gamma irradiation.1 The latter method
is attractive because it is believed to be
more effective against viruses, and is
an inexpensive technique that provides
thorough tissue penetration. However,
risk of infection is not the only signicant concern in the use of allograft
tissue. The incidence of fracture in
allograft bone has been found to be
between 12-20%.2-5 Furthermore, the
method of sterilization may affect the
material properties of the allograft tissue.
Clinical evidence suggests that the rate
of fracture in allografts sterilized by
gamma radiation may be higher than
that in non-irradiated grafts.3 In this
regard, it has been shown that the postyield properties of bone are signicantly
affected by gamma radiation; that is the
yield stress, ultimate stress, ductility,
and toughness are decreased whereas

the elastic modulus (i.e., intrinsic
material stiffness) is largely unaffected.5-9
However, allograft fractures often
occur under normal, subcritical
repetitive loads during activities of
daily living which occur within the
elastic range. This suggests that the
cyclic properties (fatigue behavior) of
irradiated allograft may be diminished.
One important aspect of the fatigue
behavior of a material is its resistance to
fatigue crack propagation from a stress
concentration or defect. In this study,
we hypothesized that gamma radiation
signicantly reduces the fatigue crack
propagation resistance of human
cortical bone.
MATERIAL AND METHODS
Five pairs of fresh frozen human

femora were obtained to represent
different age and gender groups: one
younger male (18yr); one younger
female (15yr); two older males (60yr,
61yr); and one older female (75yr).
To simulate a stress concentration,
notched test specimens of compact
tension geometry10 were wet machined
from the diaphysis of each femur with
the crack plane longitudinal to the
osteonal orientation. Specimens were
assigned from the left or right femur to
an irradiated group or control group.
Each irradiated specimen had a control
specimen matched for position along

the longitudinal axis and circumference
of the diaphysis for each pair of femora.
Irradiated specimens received an
average dose of 31.7kGy (range 29.633.5kGy) of -radiation. Specimens
were cyclically loaded to failure in
tension using a servohydraulic testing
system. Crack growth was monitored
with a travelling microscope. Video
micrography was used to record
fatigue crack growth behavior in three
additional specimens.
The kinetics of fatigue crack growth
can be examined by evaluating the
relationship between the rate of fatigue
crack growth, da/dN (m/cycle) and
the cyclic driving force, or cyclic stress
intensity factor at the crack tip, K
(MPam1/2). The cyclic stress intensity
factor and the fatigue crack growth rate
were calculated for each specimen, and
the data was pooled for each individual.
Three to seven tests were conducted
in each group. For many materials,
including bone tissue, there is a log-log
linear relationship between da/dN and
K (i.e., da/dN=CKm, where C is a
coefcient and m is the slope of the
log-log linear relationship). C and m
were determined by linear regression
of log(da/dN) vs. log(K) for the
pooled data for each gender/treatment
group. Signicant differences in the
36
6/22/05 2:23:40 PM
MANUSCRIPTS
fatigue crack propagation resistance
between control and irradiated
specimens for each gender/treatment
group was determined by comparison
of the regression relationships using
the linear test method. In addition,
the magnitude of change in slope and
coefcient between irradiated and
control specimens for each gender/
treatment group was determined
from t-tests by examining the relative
magnitude of the T-values. Signicance
was taken at p < 0.05.
Portions of each specimen were used
to evaluate compositional features
of the bone tissue, including wet
density, dry density and ash content
of the bone to calculate water and
organic content. The region of crack
growth of each specimen was bulk
stained in basic fuchsin and thin
sections (approximately 100 microns)
were taken perpendicular to the
fracture plane were analyzed with
epi-uorescent microscopy to examine
microdamage at and near the plane of
crack growth.
RESULTS
The fatigue crack propagation

resistance of human cortical bone was
signicantly reduced by -radiation
in three of the four gender/treatment
groups. The greatest change in slope
and coefcient between control and
irradiated groups was seen in the
younger male specimens. By comparing
T-values, the loss in fatigue crack
propagation resistance between control
and irradiated specimens was greatest
in the younger male group, followed by
the younger female group and then the
older male group. Interestingly, there
was no signicant difference between
irradiated and control specimens from
the older female group.
Videomicrography documentation
of the manner in which the fatigue
cracks progressed demonstrated that
in non-irradiated specimens, the crack

would often bifurcate, slow or arrest
when it encountered a microstructural
barrier such as an osteon or vascular
channel. In irradiated specimens, the
crack would also slow or arrest upon
encountering a barrier, however, fewer
cycles were needed to break through
the barrier and for crack growth to
resume. Importantly, bifurcation of
the crack was never observed in the
irradiated specimens. In the younger
bone groups, both irradiated and
control, pores and vascular channels
were observed to blunt the crack tip
and slow progression of crack growth.
In the older bone groups, crack growth
into a pore or channel often led to
catastrophic failure.
Tissue characterization revealed
signicant differences in only two of
twenty comparisons between irradiated
and control groups. Dry density was
lower for irradiated specimens in
the younger female group. In older
males, the water content was lower in
irradiated specimens. No statistically
signicant differences were found for
all other comparisons.
Preliminary qualitative analysis of
microdamage around the crack
plane indicated less stain uptake
(i.e., microdamage) in the stable
crack growth region of the irradiated
specimens compared to controls. In
addition, the amount of microdamage
around the initial notch appeared
greater in control specimens than in
irradiated specimens.
DISCUSSION AND CONCLUSIONS
This is one of the rst studies to

examine how human cortical bone
tissue resists fatigue crack growth. It
was found that cracks can be grown
experimentally in human cortical bone
in a stable manner under cyclic loading
conditions. The kinetics of fatigue
crack growth and the manner in which
the cracks grow are both signicantly

affected by -radiation sterilization
and aging. The compositional tissue
characteristics we evaluated were
essentially unchanged following
irradiation; it is thus postulated
that the differences in fatigue crack
propagation resistance are more likely
due to structural changes caused by radiation rather than due to alterations
in mineral or organic content.
Interestingly, the effect of radiation on
fatigue crack propagation resistance
appeared to be inuenced by the age
and gender of the bone. The greatest
loss of fatigue crack propagation
resistance caused by radiation was
found in younger male bone whereas
there was no signicant difference in
fatigue crack propagation resistance in
older female bone.
Radiation is known to cause crosslinking and scission in the collagen
matrix. Alterations in collagen
cross-linking are also known to
occur with aging.11-13 These changes
in ultrastructure may inhibit the
formation of microdamage at the crack
tip, which may facilitate propagation
of a fatigue crack. It is believed that
microdamage at a crack tip leads
to energy dissipation and, thus, is
an effective crack growth resistance
mechanism in bone tissue.6 The
results of this study demonstrated no
signicant difference in fatigue crack
propagation resistance in older female
bone and irradiated bone. It is therefore
hypothesized that the ultrastructural
changes caused by aging or by gamma
radiation sterilization create comparable
losses in resistance to fatigue crack
growth.
Further studies are planned to
elucidate the ultrastructural changes
associated with irradiation. This
includes quantifying the amount and
type of microdamage along the crack
plane by examination of the stained
6/22/05 2:23:40 PM
GAMMA RADIATION STERILIZATION

sections obtained from the specimens
in this study. Raman spectroscopy may
also be utilized to more specically
determine the ultrastructural changes
in irradiated bone and compare these
to changes found in older bone. It
is also of interest to examine fatigue
crack growth in the plane transverse to
the osteonal orientation. Such in vitro
experiments are challenging due to
the propensity for transverse cracks in
bone tissue to deviate and grow along
a longitudinal direction. Interestingly,
in vivo fatigue fractures commonly
occur transversely to the longitudinal
axis of a long bone, and so it is of
clinical interest to pursue experimental
methodologies that reproduce
transverse fatigue crack growth.
Clinical implications of this
study include the need for greater
intraoperative precautions to reduce the
number of stress risers in the allograft
tissue to prevent the initiation of
cracks. This includes avoiding scratches
in the allograft bone or choosing
intramedullary xation where possible.
Alternatively, the surgeon may opt for
allograft bone sterilized by other means.
7. Currey JD, Foreman J, Laketic I, Mitchell

J, Pegg DE, Reilly GC. Effects of ionizing
Radiation on the Mechanical Properties of
Human Bone. J Ortho Res. 1997; 15: 111-117
8. Hamer AJ, Strachen JR, Black MM,
Ibbotson CJ, Stockley I, Elson RA.
Biomechanical Properties of Cortical Allograft
Bone Using a New Method of Bone Strength
Measurement: A Comparison of Fresh, FreshFrozen and Irradiated Bone. J Bone Joint Surg.
1996; 78(B): 363-368
9. Jinno T, Miric A, Feighan J, Kirk SK, Davy
DT, Stevenson S. The Effects of Processing and
Low Dose Irradiation on Cortical Bone Grafts.
Clin Orthop. 2000; 375: 275-285
10. ASTM E 647-95a Standard test method for
measurement of fatigue crack growth rates. In
Annual Book of ASTM Standards, pp. 565601. Edited by ASTM, 565-601, Philadelphia,
PA, 1996
11. Eyre DR, Dickson IR, VanNess K. Collagen
Cross-Linking in Human Bone and Articular
Cartilage. J Biochem 1988; 252: 495-500
12. Wang X, Bank RA, TeKoppele JM, Hubbard
GB, Athanasiou KA, Agrawal CM Effect
of collagen denaturation on the toughness of
bone. Clin Orthop. 2000; 371: 228-239
13. Zioupos P, Currey JD, Hamer AJ. The role of
collagen in the declining mechanical properties
of aging human cortical bone. J Biomed Mater
Res. 1999; 45: 108-116
A complete version of this manuscript has been
accepted for publication in JBJS.
REFERENCES
1. Friedlander GE. Bone Grafts: The Basici
Science Rationale for Clinical Applications. J
Bone Joint Surg. 1987; 69-A: 786-790
2. Berrey BH, Lord FL, Gebhardt MC, Mankin
HJ. Fractures of Allografts. J Bone Joint Surg.
1990; 72-A: 825-833
3. Leitman SA, Tomford WW, Gebhardt MC,
Springeld DS, Mankin HJ. Complications
of Irradiated Allografts in Orthopedic Tumor
Surgery. Clin Orthop. 2000; 375: 214-217
4. Mankin HJ, Doppelt S, Tomford W. Clinical
Experience with Allograft Implantation: The
First Ten Years. Clin Orthop. 1983; 174: 69-86
5. Pelker RR, Friedlander GE, Markham TC.
Biomechanical Properties of Bone Allografts.
Clin Orthop. 1983; 174: 54-56
6. Akkus O, Rimnac CM. Fracture Resistance
of Gamma Radiation Sterilized Cortical Bone
Allografts. J Ortho Res. 2001; 19: 927-934
38
6/22/05 2:23:41 PM
MANUSCRIPTS
FIBRONECTIN PRETREATMENT OF
HYALURONAN-BASED SCAFFOLDS FOR THE
TREATMENT OF OSTEOCHONDRAL DEFECTS
Luis A. Solchaga PhD1,2, Jizong Gao PhD2, James E. Dennis PhD2, Arnold I. Caplan PhD2, Victor
M. Goldberg MD1
1
2
Skeletal Research Center, Department of Biology, Case Western Reserve University, Cleveland
OH
ABSTRACT
he natural repair of osteochondral

defects can be enhanced with
scaffolds that provide structural support
and cuing for the reparative activity.
One such scaffold, named ACP, is
composed of cross-linked hyaluronan.
Osteochondral defects were created
on the medial femoral condyles of 27
4-month-old rabbits and treated with
ACP sponge, bronectin-coated
ACP sponge, bone marrow-loaded
ACP sponge or bronectin-coated,
bone marrow-loaded ACP sponge.
Rabbits were sacriced 4 and 12 weeks
after surgery, the condyles removed and
processed for histologic evaluation, and
the sections graded for repair on a 29point scale.
At identical time points, defects lled
with bronectin-coated ACP sponge
consistently showed greater amounts
of cartilage and bone within the
repair. The presence of bronectin as
a component of the implant appears
to accelerate the differentiation of
the repair cells within the defect that
results in improved regeneration of the
articular surface.
INTRODUCTION
The goal of any tissue engineering

strategy is the regeneration of a
specic tissue1, 2. The regeneration
process involves at least a partial
recapitulation of certain embryonic
events, wherein progenitor cells enter

a cascade of developmental events
culminating in cellular differentiation
and formation of new tissue3, 4. Our
working premise is that to recapitulate
selective embryonic events, a sufcient
quantity of progenitor cells must be
present in a repair site in a scaffold that
mimics the embryonic environment.
In this context, extracellular matrix
molecules are excellent candidates as
multifunctional scaffolds that could
serve as regulators of a regeneration
process5, 6.
The components of the embryonic
extracellular matrix provide the
structural7 and informational template
for future events. Hyaluronan and
bronectin are extracellular matrix
molecules that are abundant in the
embryonic mesenchyme, are important
mediators of skeletal development and
major structural components of adult
bone and cartilage8-12. In addition,
these macromolecules are useful
delivery vehicle components in ectopic
and orthotopic in vivo implantations
designed to promote osteogenic
or chondrogenic differentiation of
mesenchymal stem cells (MSCs)13.
Hyaluronan effects a number of events
in limb development. For example,
hyaluronan induces chondrogenic
differentiation of embryonic limb
MSCs14, 15. These observations support
the treatise of Toole and colleagues,

in which hyaluronan is prominent
during the morphogenetic phases of
development10, 11 Fibronectin serves
multiple roles during embryonic
development and repair of damaged
tissue in the post-natal organism.
With multiple binding sites for cell
receptors, collagen, heparin, and brin,
bronectin serves to organize and link
cellular and matrix components16.
In bone and cartilage, bronectin
is one of the earliest extracellular
matrix components expressed by the
progenitor cells17, 18.
We hypothesize that the optimal
scaffold for regeneration of skeletal
tissues should incorporate natural
extracellular matrix components
that contribute to the regenerative
process through structural support and
regulatory mechanisms.
METHODS
Cylinders (2 mm in idameter) of
cross-linked hyaluronan (ACP) were
used as scaffolds. Half of the implants
were pre-coated with bronectin13,
19
. Control uncoated implants were
hydrated in sterile saline solution prior
to implantation. Fresh autologous
bone marrow20 was combined with the
some of the ACP sponges. The knee
joint was exposed and a hand-driven
drill was used to create a full-thickness
defect (3 mm in diameter x 3 mm
6/22/05 2:23:41 PM
FIBRONECTIN PRETREATMENT
deep) on the center of the medial
femoral condyle, 1.5 mm above the
edge of the medial meniscus in 4month-old New Zealand White rabbits.
Implants were then press-tted into
the. Each rabbit received bronectincoated ACP sponge in one knee and
non-coated ACP sponge in the other
knee. Rabbits were euthanized 4 and
12 weeks after surgery by overdose of
sodium pentobarbital. Representative
Toluidine Blue- or Safranin O-stained
sections through the center of the
defects were scored blindly by four
investigators with a 29-point grading
scale13. The histologic scores were
compared with a Wilcoxon signed
rank test. P values less than 0.05 were
considered signicant.
RESULTS
The Histologic examination revealed

that bronectin pre-treatment has
a dramatic effect in the short-term
outcome of the repair. Four weeks
after implantation, defects treated with
bronectin-coated implants exhibited
bone lling and a well-integrated

supercial layer with the appearance
of hyaline cartilage (Figure 1A, B).
Defects treated with non-coated
sponges presented less bone, and the
repair tissue was recessed from the
surface of the adjacent cartilage (Figure
1C, D); most of these defects presented
brous or brocartilaginous tissue.
The effect of bronectin coating
was masked by the addition of bone
marrow. Four weeks after surgery,
defects treated with bone marrowloaded bronectin-coated scaffolds,
exhibited bone lling and a well
integrated supercial layer with
the appearance of hyaline cartilage
(Figure 2A, B). Defects treated with
uncoated bone marrow-loaded ACP
sponges presented less bone, and the
non-mineralized surface layer was less
mature (Figure 2C, D).
At the 12-week time point, the
maturation of the bone in the untreated
implants (Figure 3C, D) was inferior to
Figure 1. Light microscopy of osteochondral defects 4 weeks after surgery.

A, B: ACP-treated defect. C, D: Fibronectin-coated ACP-treated defect. Microphotographs
correspond to paired defects (left and right knee of the same rabbit). Panels B and D display
the interface between the repair and host tissues at higher magnication. Toluidine Blue
staining.
that of the bronectin-treated implants

and, as a result, the cartilaginous layer
was thicker in the defects that received
untreated implants (Figure 3A, B).
The overall histologic scores of
specimens treated with bronectincoated ACP sponges were higher than
those of uncoated ACP sponges at 4
weeks (Table I). The main contributors
to the differences are the amount of
bone lling and the thickness and
regularity of the cartilaginous layer.
No statistical differences were found
in the overall scores between defects
treated with bronectin-coated and
uncoated implants when bone marrow
was loaded into the scaffolds. However
at 12 weeks there are differences in
categories that reect the quality of the
cartilage.
DISCUSSION
Fibronectin pretreatment of the

implant materials had an effect in the
short-term outcome of defects treated
with ACP sponges. The differences
between coated and non-coated
implants diminish with the addition of
fresh bone marrow to the implants.
From observations reported here
and elsewhere21, 22, we suggest that
the empty scaffolds are ooded with
progenitor cells and that these cells
rapidly form cartilage within the
defects. This differentiation may be
enhanced by hyaluronan itself14, 15,
23, 24
. Between days 8 and 14, the
scaffolds break down contributes
to, or triggers bone formation and
facilitates integration of the newly
formed cartilage. Hyaluronan
oligomers released upon breakdown
of the scaffold induce invasion of
blood vessels25 with a resultant inux
of osteogenic cells that fabricate
woven bone. We speculate that the
cartilaginous layer is maintained
due to the inuence of the synovial
environment and mechanical stimuli.
40
6/22/05 2:23:43 PM
MANUSCRIPTS
Additionally, we hypothesize that
the hyaluronan oligomers facilitate
integration of the neo-cartilage with
host cartilage by displacing aggrecan
from the cartilaginous matrix
and promoting new synthesis of
proteoglycans26.

A, B: ACP plus bone marrow-treated defect. C, D: Fibronectin-coated ACP plus bone
marrow-treated defect. Microphotographs correspond to paired defects (left and right knee of
the same rabbit). Panels B and D display the interface between the repair and host tissues at
higher magnication. Toluidine Blue staining.

A, B: ACP plus bone marrow-treated defect. C, D: Fibronectin-coated ACP plus bone
marrow-treated defect. Microphotographs correspond to paired defects (left and right knee of
the same rabbit). Panels B and D display the interface between the repair and host tissues at
The main difference observed between

uncoated sponges and sponges coated
with bronectin is a delay in the bone
formation with uncoated sponges.
Because of this, we speculate that
one of the effects of bronectin is an
improvement of initial cell recruitment,
attachment, and retention13, 19.
This would imply that an increase
in the number of repair cells in the
defect early in the process translates
into better and faster restoration of
the tissue. However, the effect of
bronectin may be more than an
increase in the number of cells that
populate the implant. Fibronectin
is one of the ligands for integrins.
Integrins are key elements in cellmatrix interactions and have been
hypothesized to play important roles
in bone and cartilage differentiation9,
27, 28
. Fibronectin on the surface of the
implant may act as a cuing agent for
the reparative cells.
Fibronectin pretreatment of the materials
as used in the present study could be a
complication in a clinical setting since
the bronectin used in our protocol is
human extracted and not recombinant.
However, the potential benecial effect of
this treatment cannot be ignored. Future
efforts should be directed toward the
development of recombinant bronectin
or bronection substitutes. Pre-coating
with autologous serum or RGDcontaining peptides are two of a variety of
options that could be explored.
6/22/05 2:23:48 PM
FIBRONECTIN PRETREATMENT
Table I. Histologic scores (mean standard deviation). The shaded boxes identify the categories in which statistically signicant differences
were found.
4 weeks (n = 9)
Category
ACP
4 weeks (n = 9)
ACP +FN
ACP +BM
12 weeks (n = 9)
ACP +FN+BM
ACP +BM
ACP+FN+BM
% hyaline
cartilage
0.97 1.43
154 2.07
2.00 1.80
3.11 1.60
3.04 1.83
3.11 2.26
surface
regularity
0.79 0.69
1.20 1.05*
2.22 0.94
2.48 0.60
1.41 0.83
2.26 0.55#
degenerative
changes
0.72 0.54
1.00 0.68
1.41 0.32
1.59 0.32
1.22 0.33
1.59 0.36#
structural
integrity
0.72 0.37
0.72 0.36
1.33 0.50
1.37 0.35
1.37 0.39
1.74 0.15#
cartilage
thickness
0.42 0.60
0.89 0.73*
1.26 0.36
1.44 0.37
1.78 0.33
1.78 0.33
integration
1.72 1.63
2.40 0.94
3.15 1.33
3.19 1.00
3.15 1.30
2.93 1.05
bone
lling
0.24 0.31
1.33 0.87*
2.11 1.01
2.37 0.65
2.37 0.31
2.41 0.70
tidemark
reconstitution
0.13 0.24
0.00 0.00
0.00 0.00
0.04 .011
0.33 0.41
0.37 0.35
adjacent
cartilage
w2.72 0.24
2.78 0.26
3.00 0.34
1.96 0.11
2.74 0.36
2.89 0.17
Overall
Score
8.43 3.32
11.86 5.93*
16.30 3.32
17.41 2.63
17.41 2.63
19.07 2.61
FN: FIBRONECTIN; BM: BONE MARROW.

(Footnotes)
*
Different from ACP (p < 0.05).
#
Different from ACP+BM (p < 0.05).
ACKNOWLEDGMENTS
The authors thank Debbie Fein-Krantz

and Amad Awadallah for their excellent
technical assistance. We also thank
Fidia Advanced Biomaterials srl for
their generous support and supply of
the materials used in this study. This
work was supported by grants from
N.I.H.
REFERENCES
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instructive. bioessays. 1986;5(3):129-132.
6. Caplan AI. Tissue engineering designs for the
future: new logics, old molecules. Tissue Engin.
2000;6:1-8.
7. Fell HB. The histogenesis of cartilage and bone
in the limb bones of the embryonic fowl. J
Morphol Phys. 1925;40:417-459.
8. Entwistle J, Hall CL, Turley EA. HA
receptors: regulators of signalling to the
cytoskeleton. J. Cell. Biochem. 1996;61(4):569577.
1. Vacanti J, Langer R. Tissue engineering: the

design and fabrication of living replacement
devices for surgical re-construction and
transplantation. Lancet. 1999;354(Suppl. 1):
SI32-SI34.
9. Miyamoto S, Katz BZ, Lafrenie RM, Yamada

KM. Fibronectin and integrins in cell adhesion,
signaling, and morphogenesis. Annals Of The
New York Academy Of Sciences. 1998;857:119129.
2. Langer R, Vacanti JP. Tissue engineering.

Science. 1993;260(5110):920-926.
10. Toole BP. Hyaluronan in morphogenesis. J Int

Med. 1997;242(1):35-40.
3. Caplan AI, Elyaderani M, Mochizuki Y, et al.

Principles of cartilage repair and regeneration.
Clin Orthop. 1997;342:254-269.
11. Toole BP, Turner RE, Banerjee SD.

Hyaluronan-binding protein in chondrogenesis
and angiogenesis in the developing limb. Prog
Clin Biol Res. 1993;383B:437-444.
4. Caplan AI, Goldberg VM. Principles of tissue

engineered regeneration of skeletal tissues. Clin
Orthop. 1999(367 Suppl):S12-16.
12. Dessau W, Sasse J, Timpl R, von der Mark

K. Role of bronectin and collagen types I
and II in chondrocytic differentiation in vitro.
Annals Of The New York Academy Of Sciences.
1978;312:404-405.
13. Solchaga LA, Dennis JE, Goldberg VM,
Caplan AI. Hyaluronic acid-based polymers as
cell carriers for tissue-engineered repair of bone
and cartilage. J Orthop Res. 1999;17(2):205213.
14. Kujawa MJ, Carrino DA, Caplan AI.
Substrate-bonded hyaluronic acid exhibits a
size-dependent stimulation of chondrogenic
differentiation of stage 24 limb mesenchymal
cells in culture. Dev Biol (Orlando).
1986;114(2):519-528.
15. Kujawa MJ, Caplan AI. Hyaluronic acid
bonded to cell-culture surfaces stimulates
chondrogenesis in stage 24 limb mesenchyme
cell cultures. Dev Biol. (Orlando).
1986;114(2):504-518.
16. Humphries MJ, Akiyama SK, Komoriya
A, et al. Identication of an alternatively
spliced site in human plasma bronectin that
mediates cell type-specic adhesion. J Cell Biol.
1986;103(6 Pt 2):2637-2647.
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17. Moursi AM, Damsky CH, Lull J, et al.
Fibronectin regulates calvarial osteoblast
differentiation. J Cell Sci. 1996;109(Pt 6):13691380.
21. Shapiro F, Koide S, Glimcher MJ. Cell

origin and differentiation in the repair of fullthickness defects of articular cartilage. J Bone
Joint Surg. Am 1993;75(4):532-553.
25. West DC, Hampson IN, Arnold F, Kumar

S. Angiogenesis induced by degradation
products of hyaluronic acid. Science.
1985;228(4705):1324-1326.
18. Moursi AM, Globus RK, Damsky CH.

Interactions between integrin receptors and
bronectin are required for calvarial osteoblast
differentiation in vitro. J Cell Sci. 1997;110(Pt
18):2187-2196.
22. Huibregtse BA, Johnstone B, Caplan AI,

Goldberg VM. Natural repair of full-thickness
osteochondral defects in growing and mature
rabbits. Trans Orthop Res Soc. 1998;23:796.
26. Knudson W, Casey B, Nishida Y, et al.

Hyaluronan oligosaccharides perturb cartilage
matrix homeostasis and induce chondrocytic
chondrolysis. Arth Rheum. 2000;43(5):11651174.
19. Dennis JE, Caplan AI. Porous ceramic vehicles

for rat-marrow-derived (Rattus norvegicus)
osteogenic cell delivery: effects of pre-treatment
with bronectin or laminin. J Oral Implant.
1993;19(2):106-115; discussion 136-107.
20. Solchaga LA, Johnstone B, Yoo JU, et al.
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23. Feinberg RN, Beebe DC. Hyaluronate in

vasculogenesis. Science. 1983;220(4602):11771179.
24. Deed R, Rooney P, Kumar P, et al. Earlyresponse gene signalling is induced by
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Fibronectin gene expression during limb
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TROUT CLUB 2004
6/22/05 2:23:51 PM
IMPLANTED NEUROPROSTHESES FOR

STANDING AND TRANSFERS AFTER SPINAL
CORD INJURY
Ronald J. Triolo PhD, John A. Davis, Jr MD
Dept. of Orthopaedics, MetroHealth Medical Center, Cleveland OH
ABSTRACT
his paper describes a research

program focusing on functional
electrical stimulation (FES)
applications that allow persons with
spinal cord injuries (SCI) to exercise,
stand, transfer, and to reach objects
and places otherwise inaccessible from
their wheelchairs. The initial results
of a Phase II multicenter trial of a
surgically implanted neuroprosthesis
is establishing the technical and
clinical performance of an 8-channel
implantable receiver/stimulator. Longterm follow-up in 13 volunteers at
3 institutions who have received the
CWRU standing system is establishing
its safety and efcacy.
INTRODUCTION
There are between 219,000 and

279,000 people with spinal cord
injuries (SCI) of all types in the
United States today1,2,3 more than
half of whom need assistance with
activities of daily living, community
mobility or essential transfers4. Paralysis
compromises the ability to work,
engage in social or leisure activities or
participate in other behaviors associated
with an independent and productive
lifestyle. Complications resulting from
SCI can lead to recurrent and costly
hospitalization, and long periods of
immobility can cause degenerative
changes of almost every major organ
system including the bones, joints,
heart, lungs and skin.
If the lower motor neurons are intact
and excitable, and the neurological

injury is conned to the central
nervous system (i.e., the upper motor
neuron), then they can be excited
by a small electrical current. The
resulting action potentials generated
in the peripheral motor nerve, in turn,
cause contractions of the muscles they
innervate. Coordinating the actions of
numerous muscles about a joint can
produce useful, purposeful movements
of the otherwise paralyzed limb.
Functional electrical stimulation (FES)
refers to this method of interacting
with the nervous system for restoring or
facilitating function after SCI or other
neurological disorder.
FES can postpone or prevent these
medical complications and improve
the functional independence of
persons with SCI by providing
a means to exercise, stand, and
negotiate the physical barriers to life
opportunities. No existing options
other than FES, such as braces and
standing wheelchairs, are powered by
contractions of the otherwise paralyzed
lower extremity muscles. They
therefore have minimal impact on the
accelerating physical deterioration and
psychological decline that often result
from prolonged immobility. For all
these reasons, FES is a unique approach
to facilitating the intrinsic enablement
of this population.
Although the wheelchair offers a
means of efcient transportation over
unobstructed level surfaces, individuals
with SCI need options for negotiating

architectural barriers, completing
daily bed, shower or toilet transfers,
and gaining access to high cabinets,
cupboards or shelves that are difcult
or impossible to reach from a seated
position. FES directly addresses these
issues by providing a means to stand,
transfer, maneuver in the vicinity of
the wheelchair, and exert more control
over the environment without special
adaptations.
Functional electrical stimulation
can provide individuals paralyzed by
thoracic or low cervical spinal cord
injuries with the ability to exercise,
stand, transfer, and perform simple
mobility functions such as side
and back stepping5,6,7. Preliminary
clinical trials of lower extremity
neuroprostheses for standing clearly
indicate that continuous open-loop
stimulation of the trunk, hip and
knee extensors can allow people with
paraplegia to overcome physical
obstacles8, negotiate architectural
barriers9 and exert a greater control over
their environment by affording them
the ability to reach and manipulate
objects that are otherwise inaccessible
from the wheelchair10,11.
Standing with FES has been achieved
with relatively simple systems consisting
of two to six channels of continuous
open-loop surface stimulation12,13,14,15,
16,17
. Percutaneous approaches to most
muscles of the lower extremities have
been dened, allowing the generation
44
6/22/05 2:23:52 PM
MANUSCRIPTS
of more complex movements than with
surface stimulation alone18,19,20, and
16 or fewer channels of intramuscular
stimulation can provide users with
the ability to perform simple mobility
and one-handed reaching tasks
while standing21. More recently,
totally implanted pacemaker-like
neuroprostheses for standing after
SCI have undergone feasibility and
initial clinical testing. Exercise and
standing have been reported with a
cochlear implant modied to deliver
22-channels of stimulation22, and a
12-channel system for activation of the
L2-S2 motor roots has been applied to
a handful of volunteers23. Alternative
systems of distributed single-channel
micro-modular implants are also under
development24. For long-term clinical
application, implanted systems such
as these offer major advantages over
surface and percutaneous stimulation
including improved convenience,
cosmesis and reliability25.
In our laboratory, rst-generation
implanted standing neuroprostheses
delivering eight channels of stimulation
via epimysial26 or surgically implanted
intramuscular electrodes27 have been
undergoing successful clinical testing28.
Continuous open-loop stimulation
to the knee, hip and trunk extensor
musculature braces the body against
collapse while the hands are used
for balance, as shown in Figure 1.
Recipients of this neuroprosthesis have
been able to exercise, stand, complete
transfers to and from high surfaces,
retrieve objects out of reach from the
wheelchair, and perform swing-to
ambulation29. The preliminary results
of a small-scale Phase-II multicenter
clinical trial of this 8-channel standing
neuroprosthesis are summarized below.
The CWRU implanted standing

neuroprosthesis is depicted
schematically in Figure 2. The internal
Figure 1: Standing with continuous stimulation to the trunk, hip and knee extensors via the
8-channel implanted neuroprosthesis.
components of the system consist

of a single 8-channel implanted
receiver-stimulator (IRS-8), inline connectors, and epimysial and
surgically implanted intramuscular
electrodes30,31. For standing, the system
targets the hip (gluteus maximus
and semimembranosus or posterior
portion of adductor magnus), knee
(vastus lateralis), and trunk (lumbar
erector spinae) extensor muscles to
raise and support the body against
collapse. External components include
a rechargeable wearable external control
unit (ECU) with a command ring

and transmitting coil, and a clinical
programming station32,33. The ECU
powers and controls the implant,
weighs slightly less than a pound
and can operate for six hours on a
single charge. A molded ankle-footorthosis (AFO) protects the structures
of the ankle and midfoot during
weightbearing, pivot transfers and
swing-to gait. A clinical interface based
on a laptop PC allows clinicians to
quickly adjust stimulation parameters
and download usage information from
6/22/05 2:23:52 PM
IMPLANTED NEUROPROTHESES
Figure 2: Composite x-ray of the 8-channel standing neuroprosthesis (left) and schematic representation of the system and major
implanted and external components (right).
the external controller.

Users interact with the neuroprosthesis
through three command switches
mounted on the enclosure of the
ECU or worn on a ring around the
index nger. The command switches
allow users to navigate a menudriven interface to select, activate or
terminate patterns of pre-programmed
stimulation customized to the
stimulated responses of their individual
set of electrodes. With the transmitting
coil taped securely to the skin over
the IRS-8 and the ECU suspended
on a belt around the waist, implant
recipients select the STAND option

from their menu of choices. A single
depression of one of the command
switches activates the standing pattern,
which begins with an initial audio tone.
A three-second delay enables the user
to prepare to stand by repositioning
the body at the edge of the wheelchair
and placing the hands on an assistive
device. A second audio cue is issued
immediately prior to the delivery of
the stimulation. Activation of the knee
extensors is followed immediately
by activation of the hip and trunk
extensors. A nal audio tone signals
the end of the maneuver and cues the
subject that continuous stimulation

is being applied. A second depression
of the command switch reverses the
sequence and lowers the user back to
the seated position. A similar process
is performed to select and activate
prescribed patterns of stimulation for
exercise.
This design obviates many
impediments to spontaneous home
and community use. First, the system
is intimate, private and unobtrusive.
Since the stimulator, electrodes, leads
and connectors are internal to the
body, the system is cosmetic and does
46
6/22/05 2:23:53 PM
MANUSCRIPTS
not draw attention to itself. Second,
the design insures reliability. Because
the electrodes are secured permanently
to nerve entry points of the target
muscles, stimulated responses are
strong, isolated and repeatable from day
to day. External cables and connectors
that can tangle or foul in the wheelchair
are eliminated. Third, the system is
convenient and continuously available.
Donning and dofng of the ECU
is simple and can be accomplished
quickly and easily whenever the need
or desire to exercise or stand arises.
Finally, users are self-contained and
require no other specialized equipment
to be functional. System recipients with
strong upper extremities can utilize
any standard walker or mechanically
stable object in the environment to
maintain balance while standing with
the neuroprosthesis and do not need
to carry around customized assistive
devices, further facilitating spontaneous
use.
RESULTS
To date, a total of 13 subjects have

received the CWRU standing system,
including three at collaborating centers.
Implant recipients are uniformly
satised with the results and use the
neuroprostheses weekly for exercise and
function. The willingness of clinicians
at satellite centers to participate
in the trial at their own expense
and of participants to comply with
inconveniences such as travel, surgery
and the rigorous study protocol all
further indicate the value attached to
the technology.
Subjects were primarily male and
exhibited complete sensory and motor
decits. Mean height and weight were
59 and 175 lbs, and mean time post
injury and age at implant were 7 and
35 years, respectively. The rst two
volunteers in the series served as pilot
subjects for the development and
renement of system implementation
and follow-up assessment procedures.

Subject 4 voluntarily withdrew due to
clinical complications unrelated to the
system (persistent tibial fracture nonunion sustained during a conventional
car transfer, followed by a rotator cuff
tear requiring surgical repair) just prior
to completing rehabilitation and before
follow-up data could be collected.
Subject 12 withdrew before completing
the exercise phase due to a late onset
methicillin resistant staphylococcus
aureus (MRSA) infection two months
post-surgery that required explantation
of all internal components.
Table 1 summarizes the functional
milestones achieved by subjects in
the preliminary series. All implant
recipients were able to exercise
with the system, and all 12 subjects
completing the exercise program were
able to stand and transfer with the
neuroprosthesis. All nine subjects
with lower level (C7-T9) injuries who
completed rehabilitation were able to
stand independently in a walker using
the system. Eight of these individuals
were able to release a hand from the
walker to perform reaching tasks above
shoulder height while standing. Seven
implant recipients achieved swing-to
gait with a walker or crutches.
The outcomes achieved later in the
series are superior to those of the
rst two volunteers due primarily
to improvements in the selection
criteria and renements in the surgical
technique. Subject 1 exhibited hip
range of motion limitations and
heterotopic ossication (HO) that
prevented him from achieving an
erect posture and compromised
the moment generating capacity of
his quadriceps. Subject 2 was the
tallest and heaviest implant recipient
and exhibited some signs of diffuse
peripheral denervation. His stimulated
responses, particularly of the hip
extensors, were sufcient to complete
the sit-to-stand transition but fatigued

rapidly to levels inadequate to support
his body weight. The posterior portion
of adductor magnus was targeted for
implantation in both subjects because
of our early lack of condence in the
ability of vastus lateralis to counteract
the active knee exion produced by
the hamstrings while supporting the
body against collapse. Based on the
stimulated strength of vastus lateralis in
these subjects, semimembranosus was
preferentially targeted in subsequent
volunteers. This hamstring muscle
generates signicantly more hip
extension moment than posterior
adductor and leads to an improved
and sustainable upright posture. These
cases highlight the importance of preoperative joint and muscle status and
the interactions of body size and muscle
selection on system performance.
Implant recipients have employed
the system to return to work, transfer
and engage in recreational and social
activities. Rehabilitation includes
training in sit-to-stand, balance,
stand-to-reach, transfer and swing-to
activities with the neuroprosthesis in
the laboratory and simulated home
and community environments. Study
volunteers identify individual tasks of
personal importance that are addressed
during training, and home visits are
performed to resolve potential barriers
to use. After demonstrating mastery
of the skills for safe unsupervised use,
implant recipients incorporate the
system into their daily routines, such
as working under the hood of a car
or participating fully in other societal
roles.
Stimulated responses of the quadriceps
produced a statistically and clinically
signicant increase in ASIA Motor
Scores (p=0.002) averaging 20% across
all subjects. Maximal standing times
approaching or exceeding 20 minutes
were achieved by several individuals
6/22/05 2:23:53 PM
(Subjects 3, 5 and 6), and
the mean standing duration
across all subjects was greater
than 10 minutes. All implant
recipients who completed
rehabilitation were able to stand
for functionally relevant periods
of time sufcient to retrieve
objects from high shelves,
perform standing pivot transfers
or maneuver in the vicinity of
the wheelchair.
Functional
Milestone
SUBJECT
2
83
10 11 124 13
Exercise
Assisted Standing
1,3
Independent standing in
walker
Assisted transfer
Independent transfer
Release one hand
while standing
Retrieve item above
shoulder
Unlike their peers with lower
(C7-T12) level injuries, implant

Stand at counter
recipients with mid-cervical
tetraplegia (Subjects 1 and 8)

Swing-to gait with
lack the upper body strength

walker
to stand independently with a
1 Hip ROM limitations & HO
3 C5/C6 injury with UE weakness/impairment
walker and use the system to
2 Large body size
4 Implant removed; did not complete rehabilitation
exercise and facilitate transfers.
Table 1: Functional milestones achieved by recipients of the CWRU implanted standing
In these cases, elapsed standing
neuroprosthesis. None of these functions were possible without the neuroprosthesis.
time is irrelevant since a FESfacilitated standing pivot transfer
hand from the walker while standing
separate subpopulation of potential
maneuver takes only seconds to
to manipulate objects otherwise
users
of
the
neuroprosthesis
who
may
perform. Use of the neuroprosthesis
inaccessible from the wheelchair, and
benet differently than, but just as
signicantly reduces the effort and
78% (7/9) were able to achieve short
profoundly
as,
implant
recipients
with
assistance required to transfer relative
lower
level
injuries.
distance mobility with a swing-to gait.
to conventional techniques for
None of these functions were possible
these individuals by eliminating the
One key measure of standing
without the neuroprosthesis. Moreover,
heavy lifting and lowering otherwise
performance with the neuroprosthesis
the system successfully facilitated
demanded of the caregiver. In these
is the percentage of bodyweight placed
standing transfers for users with cervical
cases the neuroprosthesis facilitates
on the legs, which is assessed by
level injuries and their assistants.
transfers by employing the users own
standing on a force platform within a
stimulated muscle power to perform
set of instrumented parallel bars34,35. On Stimulated thresholds were stable over
the most difcult portions of the
time and across subjects. Approximately
average, subjects can stand with 85%
standing transfer maneuver (standing
90% of all epimysial electrodes were
of their bodyweight on their legs while
up and sitting down), while allowing
balance is maintained by light touch on operational at long-term follow-up.
the assistant to concentrate on the
Mechanical failures were observed only
the assistive device. Eight individuals
less demanding tasks of pivoting and
in the posterior muscle groups (gluteus
with lower level (C7-T9) injuries were
providing balance. This nding is
able to release one hand from a support
maximus and semimembranosus or
supported quantitatively by subjective
device and perform reaching tasks
posterior adductor). In no case did a
and objective measures of effort,
above shoulder height while standing.
single failure compromise standing
assistance and preference on the
performance.
Of the nine volunteers with lower level
parts of the caregiver and implant
injuries and good upper extremity
The neuroprosthesis reduces the
recipient alike who both benet from
strength who completed rehabilitation,
difculty and assistance required to
the intervention. The observation
100%
were
able
to
exercise,
stand
and
perform transfers, and users and their
highlights the possibility that
transfer independently with a walker,
assistants alike prefer employing the
individuals with mid-cervical (C5-6)
89% (8/9) were able to release one
system over conventional methods for
level lesions may constitute a distinctly
48
6/22/05 2:23:54 PM
MANUSCRIPTS
transfers to and from high surfaces.
Effects of exercise and standing on
tissue viability and other indicators
of health have been documented, and
implant recipients are satised with
the system and nd value in continued
use in the home and community. Data
collection on the possible effects of FES
on global health and quality of life is
ongoing. Rehabilitation and followup protocols have been successfully
transferred to collaborating centers,
illustrating the suitability of this
intervention for wider deployment.
DISCUSSION
These preliminary results clearly

indicate that the neuroprosthesis is
reliable and free from harmful effects
within the rst 18 months postimplant. There is also substantial
evidence that begins to establish the
efcacy of the system and delineate its
safety prole on the short-term. What
remain to be accomplished before a
clinical trial for market approval can
proceed are transfer of the surgical
technique for system installation at
satellite institutions, and collection
of longitudinal data to determine
the long-term clinical and technical
performance of the neuroprosthesis.
While these rst-generation FES
systems are sufcient for basic function,
they rely exclusively on continuous
stimulation and are therefore
unresponsive to internally generated
disturbances (e.g. arm movements) or
externally applied perturbations (e.g.,
bumps, pushes or changes in carried
loads). This necessitates a walker or
other assistive device to maintain
balance, precludes bimanual activities,
and ultimately restricts spontaneity of
use. Furthermore, all available stimulus
channels were assigned to the knee,
hip and lumbar trunk extensors to
support the body against collapse. The
system has no capacity for stimulating
the ankle plantar/dorsiexors or hip
ab/adductors to help stiffen the body

in the sagittal and coronal planes. Any
posture other than nominal upright
stance with the knees hips and trunk
fully extended and the ankles locked in
neutral by the AFOs requires implant
recipients to pull or push against
the walker or other object in the
environment to adjust their position.
Automatic control of standing balance
is the next major advancement that
will improve the functionality of
neuroprostheses now approaching
widespread clinical use. All standing
neuroprostheses, whether or not they are
implanted, still require assistive devices
such as crutches, walkers, or additional
bracing to provide supplemental
support or allow the upper extremities
to make the corrections necessary to
maintain a stable upright posture. The
magnitudes of these corrective forces
can be quite small on the order of
10 percent of bodyweight or less - and
can be produced routinely by a single
extremity without undue exertion,
freeing the other hand altogether
to perform reaching tasks or other
functional activities. However, relying
on an assistive device for balance
restricts the range of activities possible
with FES, and limits the environments
in which the neuroprosthesis can
be used. Bimanual activities are
prohibitively difcult or impossible with
continuous open-loop stimulation, and
system users must carry their walkers
with them at all times in order to
stand spontaneously, or nd working
environments containing a counter,
desk or other appropriately sturdy waisthigh support surface.
Existing FES systems can readily
generate the muscle forces and joint
moments required to rise from a
chair and assume an upright standing
posture with minimal assistance from
the upper extremities. Producing
the postural corrections necessary
to maintain balance in the presence

of intrinsic (voluntary motions) or
extrinsic (unanticipated environmental
perturbations) destabilizing
disturbances, however, remains a major
challenge to the designers of standing
neuroprostheses. Practical and robust
control systems to provide standing
balance (i.e., maintenance of posture),
even for the brief periods of time
required to complete simple reaching
activities, remain an elusive goal.
The system in its current conguration
appears to be most benecial to
shorter (< 6 ft.) and lighter (< 200 lbs.)
individuals. New implant technologies
providing additional channels of
stimulation to activate synergistic
or complementary muscles, or more
complete activation of the targeted
muscles via different nerve-based
electrode designs, would improve
system performance and make it
applicable to a wider user population.
CONCLUSIONS
The technical and clinical components

of the surgically implanted
neuroprosthesis for standing after
spinal cord injury appear to be safe,
effective and suitable for distribution to
other medical centers. Usage patterns,
interactions with body size, and other
issues remain to be determined in longterm clinical follow-up.
REFERENCES
1. Harvey C, Rothschild R, Asmann A,
Stripling T. New estimates of traumatic SCI
prevalence: a survey-based approach. Paraplegia,
1990; 28: 537-544.
2. Stover SL, Fine PR. Spinal Cord Injury: The
Facts and Figures, Birmingham: The University
of Alabama at Birmingham, 1986.
3. Stover SL, Fine PR. The epidemiology and
economics of spinal cord injury. Paraplegia,
1987; 28:225-228.
4. Berkowitz M, Harvey C, Greene C, Wilson
S. The Economic Consequences of Traumatic
Spinal Cord Injury. Demos Press, New York
NY, 1992.
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5. Jaeger RJ. Lower extremity applications of
functional neuromuscular stimulation. Assistive
Technol. 1992; 4(1): 19-30.
extremities. J Rehab R & D. 1986; 23(3): 1-8.
paralyzed muscle. IEEE Trans Biomed Eng.

34(7):499-508, 1987.
6. Marsolais EB, Kobetic R. Functional electrical

stimulation for walking in paraplegia. J Bone
Joint Surg. Am 1987, 69A: 728-733.
19. Scheiner A, Polando G, Marsolais EB: Design

and clinical application of a double helix
electrode for functional electrical stimulation.
IEEE Trans Biomed. Engr, 1994; 41(5): 42531.
31. Letechepia J, Peckham P, Gazdik M,

Smith B. In-line lead connector for use with
implanted neuroprostheses. IEEE Trans Biome Eng.
38(7):707-709, 1991.
7. Marsolais EB, Kobetic R, Chizeck HJ, Jacobs

JL. Orthoses and electrical stimulation for
walking in complete paraplegia. J Neuro Rehab.
1991; 5(1-2): 13-22.
20. Kobetic R, Marsolais EB. Synthesis of

paraplegic gait with multichannel functional
neuromuscular stimulation. IEEE Trans
Biomed Engr. 1994; 2(2): 66-67.
32. Buckett J, Triolo R, Ferencz D, Katorgi

M, Bieri C. A wearable controller for clinical
studies involving multi-implant FNS systems. J.
Spinal Cord Med 21(2):179, 1998.
8. Triolo RJ, Kobetic R, Betz R. Standing and

walking with FNS: technical and clinical
challenges. In: Human Motion Analysis, G.
Harris editor. IEEE Press, New York NY. 1996
(pp. 318-350).
21. Triolo RJ, Bieri C, Uhlir J, Kobetic R,

Scheiner A, Marsolais EB. Implanted FNS
systems for assisted standing and transfers for
individuals with cervical spinal cord injuries:
clinical case reports. Arch Phys Med & Rehab.
1996; 7(11): 1119-1128.
33. Vrabec T, Triolo R, Uhlir J, Lissy D,

Bier C. A clinical interface for control and
evaluation of FNS systems, Proceedings 2nd
National Meeting VA Rehabilitation Research
& Development Service, Washington DC,
February 2000, pp. 187.
22. Davis R, Eckhouse R, Patrick JF, Delehanty

A. Computer-controlled 22-channel stimulator
for limb movement. Acta Neurochirurgica,
Suppl. 1987; 39: 117-120.
34. Jin Z, Chizeck H. Instrumented parallel bars

for three-dimensional force measurement. J
Rehab Res Dev. 1992; 29(2): 31-38.
9. Moynahan M, Mullin C, Cohn J, Burns CA,

Halden EE, Triolo RJ, Betz, RR. Home use
of a FES system for standing and mobility in
adolescents with spinal cord injury. Arch Phys
Med & Rehab. 1996; 77(10): 1005-1013.
10. Triolo RJ, Reilley B, Freedman W, Betz R.
Development and standardization of a clinical
evaluation of standing function. IEEE Trans
Rehab Eng. 1993; 1(1): 18-25.
11. Triolo RJ, Eisenhower G, Stabinski T,
Wormser D. Inter-rater reliability of a clinical
test of standing function. J Spinal Cord Med.
1995; 18(1): 13-21.
12. Kralj A, and Bajd T. Functional Electrical
Stimulation: Standing and Walking After Spinal
Cord Injury. CRC Press, Boca Raton, FL, USA,
1989.
13. Jaeger RJ, Yarkony GM, Roth EJ.
Rehabilitation technology for standing and
walking after spinal cord injury. Am J Phys Med
Rehab.1989; 68(3): 128-133.
14. Yarcony GM, Rothe EJ, Cybulski GR, Jaeger
RJ. Neuromuscular stimulation in spinal cord
injury: I Restoration of functional movement
of the extremities. Arch. Phys. Med. & Rehab.
1992; 73: 78-86.
15. Jaeger RJ, Yarkony GM, Roth EJ. Standing
the spinal cord injured patient by electrical
stimulation: renement of a protocol for
clinical use. IEEE Trans Biomed Eng. 1989;
36(7): 720-728.
16. Yarcony GM, Jaeger RJ, Roth E, Kralj
A, Quintern J. Functional neuromuscular
stimulation for standing after spinal cord
injury. Arch Phys Med & Rehab. 1990; 71: 201206.
17. Graupe D, Kohn K. Functional Electrical
Stimulation for Ambulation by Paraplegics.
Krieger Publishing Co., Malabar, FL. 1994.
18. Marsolais EB, Kobetic R. Implantation
techniques and experience with percutaneous
intramuscular electrodes in the lower
23. Rushton DN, Perkins TA, Donaldson N,

Wood DE, Harper VJ, Tromans AM, Barr
FMD, Holder DS. LARSI: How to obtain
favourable muscle contractions. Proceedings of
the Second Annual IFESS Conference (IFESS
97) and Neural Prosthesis: Motor Systems 5
(NP 97), Burnaby, British Columbia, Canada,
16-21 Aug. 1997, pp.163-164.
35. Jin Z, Kobetic R. Rail supporting transducer

posts for 3-D force measurement. IEEE Trans
Rehab Eng. 1997; 5(4): 380-387.
24. Cameron T, Loeb GE, Peck RA.

Micromodular implants to provide electrical
stimulation of paralyzed muscles and limbs.
IEEE Trans Biomed Eng. 1997; 44: 781-790.
25. Kilgore KL, Peckham PH, Keith MW,
Thrope GB, Wuolle KS, Bryden AM,
Hart RL. An implanted upper extremity
neuroprosthesis: A ve patient follow-up, J
Bone Joint Surg Am, 1997; 79A: 533-541.
26. Akers JM, Peckham PH, Keith MW, Merritt
K. Tissue response to chronically stimulated
implanted epimysial and intramuscular
electrodes. IEEE Trans Rehab Eng. 1996; 5(2):
207-220.
27. Memberg WD, Peckham PH, Keith MW. A
surgically-implanted intramuscular electrode
for an implantable neuromuscular stimulation
system. IEEE Trans Biomed Eng. 1994; 2(2):
80-91.
28. Davis JA, Triolo RJ, Uhlir JP, Bieri C,
Rohde L, Lissy D. Preliminary performance
of a surgically implanted neuroprosthesis for
standing and transfers. J Rehab Res Dev. 2001;
38(6): 609-617.
29. Triolo RJ, Bogie K. Lower extremity
applications of functional neuromuscular
stimulation after spinal cord injury. Topics in
SCI Rehab, 1999; 5(1): 44-65.
30. Smith B, Peckham PH, Keith MW, Roscoe
DD. An externally powered, multichannel
implantable stimulator for versatile control of
50
6/22/05 2:23:54 PM
MANUSCRIPTS
UNLOCKING THE SIGNALING MECHANISMS

BEHIND ASEPTIC LOOSENING
Matthew V. Smith MD, Michelle A. Innocenti BS, Edward M. Greeneld PhD
INTRODUCTION
oint replacement surgery is a common and effective way to treat

patients with severe arthritis of large
joints. The goal is to allow patients
to resume normal pain-free activities. Unfortunately, the orthopaedic
implants used for joint replacements
fail over time because of loosening
from the bone. As the implants loosen,
they generate wear debris that induces the production of pro-inammatory cytokines such as IL-1, IL-6, and
TNF.1 These inammatory mediators
promote osteoclast differentiation and
further bone loss around the implants.
Bone loss and loosening occur more
rapidly in the presence of infection
often leading to immediate revision or
removal. However, loosening in the absence of clinical signs of infection, also
known as aseptic loosening, is also a
common cause of implant failure. The
nite period in which these implants
remain well xed in bone limits their
usefulness in patients.
The Role of Wear Debris in Aseptic
Loosening
Wear debris generated from implant

surfaces is postulated to provide the
inammatory stimulus that leads to
osteolysis in aseptic loosening. Particles
are produced at the femoral headacetabular cup interface, the implantbone interface, areas of impingement
like the femoral neck on the acetabular
cup, or the femoral head-femoral
neck interface. Efforts to decrease
wear particle generation include
developing crosslinked ultra-high

molecular weight
polyethylene,
optimizing surgical
techniques to
ensure proper
implant placement,
and development
of metal-on-metal
and ceramic-onceramic, femoral
head-acetabular
cup interfaces.
In addition to
improvements
in materials and
surgical techniques,
understanding
the cellular
mechanisms
leading to bone
loss in response
to wear particles
may provide new
pharmacological
approaches to
address this
problem.
Figure 1. Particles with adherent endotoxin become phagocytosed

by macrophages. Macrophages release the inammatory cytokines
IL-1, IL-6, and TNF(. TNF( acts directly on osteoclast precursors to
promote differentiation. IL-1 and IL-6 act through osteoblasts to
induce osteoclast differentiation.
Wear particles induce an inammatory

response by activating macrophages
that release the pro-inammatory
cytokines IL-1, IL-6, and TNF.
TNF acts to directly induce osteoclast
differentiation.2 IL-1 and IL-6 act
through osteoblasts to promote
osteoclast differentiation (Fig. 1).2 Our
lab examined the effect of adherent
endotoxin on particle phagocytosis
and cytokine production in mouse
macrophages. Endotoxin, also known

as lipopolysaccharride or LPS, is an
outer cell wall component of Gramnegative bacteria that mediates the
inammatory responses in Gramnegative infection and sepsis (Fig. 2).
Endotoxin on particles dramatically
increased cytokine production but
did not increase phagocytosis.3 This
suggests that phagocytosis alone is not
enough to initiate the inammatory
response. One hypothesis to explain
6/22/05 2:23:55 PM
SIGNALING MECHANISMS
Fig. 2. LPS is a component of the outer cell membrane of Gram-negative

bacteria.
this nding is that the particles

themselves do not account for the
induction of inammatory cytokines.
Rather, the biological activity of these
particles may be due to adherent
endotoxin. Thus, low levels of
adherent endotoxin may account for
the inammatory response that causes
aseptic loosening.
Does Endotoxin Contribute to Wear
Debris-Generated Osteolysis?
Evidence to support this theory starts

with studies in our lab showing sizeable
levels of endotoxin on commercially
available titanium particles that are
frequently used to study biological
responses to particles.4 We also found
a signicant amount of endotoxin on
titanium discs that were sterilized,
processed, and packaged by a major
orthopaedic implant manufacturer in
the same manner as their commercially
available joint replacement implants.4
Other studies have shown the presence
of bacteria on implants retrieved from
patients who have no clinical evidence
of infection.1 A study of 22,170 hip
replacements
by the Norway
Arthroplasty
Register
showed that
systemic
antibiotics and
antibiotics
in cement
signicantly
reduced the
incidence
of aseptic
loosening,
emphasizing
the clinical
relevance of
bacteria and
endotoxin on
implants.5
More specic
evidence for
the role of
endotoxin in wear particle induced
inammation comes from in vitro
studies using mouse macrophages.
In these cells, both soluble LPS
and titanium particles stimulate an
increase in TNF, IL-1, and IL-6.
However, removal of endotoxin from
the titanium particles results in a
near total reduction of TNF, IL-1,
IL-6 and osteoclast differentiation.
Adding back LPS to the endotoxinfree particles restores their ability to
induce the aforementioned cytokines.1
These factors suggest that endotoxin
plays a signicant role in the biological
response to wear debris.
Our lab has also demonstrated that
removing endotoxin from titanium
particles reduces their biological
effects in vivo, thus providing further
support that endotoxin is important
in the development of osteolysis
in aseptic loosening. Studies have
shown that endotoxin-free particles
implanted on mice calvaria for 7 days
resulted in signicantly less osteolysis
when compared to titanium with

adherent endotoxin.1 Moreover, recent
studies have shown that endotoxinfree titanium and polyethylene
particles placed on mouse calvaria
accumulate endotoxin in the rst 7
days after implantation.6 This evidence
suggests that the limited amount of
osteolysis seen with endotoxin-free
particles in the rst 7 days may be
due to accumulation of endogenous
endotoxin. Potential sources for this
circulating endotoxin include minor
infections, gut ora, and dental
procedures.7 This lends support to
the hypothesis that wear particles
can acquire endotoxin from systemic
sources and contribute to aseptic
loosening.
How Do Wear Particles with Adherent
Endotoxin Increase Osteolysis?
The mechanisms by which

macrophages induce cytokines in
response to titanium particles with
adherent endotoxin are poorly
understood. However, there is
substantial literature examining the
biological response to LPS. This data
indicates that mitogen-activated protein
kinases (MAPKs), phosphoinositol3 kinase (PI3K)/Akt, and the NFB
pathways mediate inammatory
cytokine production in macrophages.810
Based on our previous ndings that
endotoxin contributes to wear particleinduced osteolysis, we can postulate
that wear particles with adherent
endotoxin and LPS work through
similar pathways.
Role of Toll-like Receptor 4 (TLR-4) in
Macrophage Response to LPS
TLR-4 is a transmembrane receptor

protein that transmits external signals
across the cell membrane. LPS activates
the MAPK pathway, PI3K/Akt, and
NFB pathways through TLR-4.10-11
A mutation in the TLR-4 gene renders
C3H/HeJ mice hyporesponsive to LPS
and reduces MAPK phosphorylation
52
6/22/05 2:23:55 PM
MANUSCRIPTS
and NF-kB translocation in response
to LPS.11,12 Thus, TLR-4 is thought to
mediate the signaling response to LPS.
TLR-4 also mediates wear particleinduced inammation since the
TLR-4 mutation in C3H/HeJ decreases
cytokine production, osteoclast
differentiation, and osteolysis.1 Paterson
et al. showed that mice subjected to a
burn injury had a signicant increase
in TLR-2 and TLR-4 mediated
cytokine release from macrophages
and dendritic cells after stimulation
with systemic LPS.13 This effect began
within 24 hours and persisted for 7
days. It is possible that an insult like
total joint arthroplasty could increase
TLR-4 sensitivity in macrophages
thereby enhancing endotoxin-mediated
cytokine release. Thus, it is of interest
to investigate the role(s) of the MAPK
and PI3K/Akt pathways in wear
particle-induced osteolysis.
Fig. 3. The MAP kinase phosphorylation cascade sequentially activates upstream kinases,
MAPKs, transcription factors, and gene expression.
Fig. 4. Titanium with adherent endotoxin activates TLR-4, which then activates PI3K. PI3K
converts PIP2 to PIP3. PIP3 recruits Akt and PDK1 to the plasma membrane where PDK1
phosophorylates Akt at the Thr308 position. Akt is then phosphorylated at the Ser473 site by
a mechanism that has not been clearly identied.
MAPKs and Their Role in Particleinduced and LPS Signaling
The MAPK protein family regulates

many cellular processes in response
to various stimuli. There are four
known members of this family:
p38, extracellular signal-regulated
kinases-1/2 (ERK1/2), Jun aminoterminal kinase (JNK), and ERK5,
also referred to as big MAP kinase 1
(BMK1). Stressors such as osmotic
stress, ultraviolet light, cytokines, and
LPS activate p38 and JNK resulting
in cytokine release.14 Growth factors,
serum and LPS activate the ERK1/2
and ERK5 to regulate cell growth,
differentiation, and cytokine release.14
MAPKs are activated by
phosphorylation via upstream kinase
cascades (Fig. 3). Once activated,
each MAPK can activate a distinct set
of nuclear transcription factors that
enhance gene expression. Human
monocytes/macrophages treated with
titanium particles activate ERK1/2
resulting in increased production
6/22/05 2:23:55 PM
SIGNALING MECHANISMS
of vascular endothelial growth
factor (VEGF).15 In another study,
polymethylmethacrylate (PMMA)
particles induced p38, ERK1/2, and
JNK kinase activity in bone marrow
macrophages isolated from mice.16
However, the effects of adherent
endotoxin were not addressed in any of
these studies.
Despite their association with diverse
stimuli, the MAPK pathways converge
to produce TNF in response to
LPS.17 Results from our lab show that
titanium particles with and without
adherent endotoxin activate the p38,
ERK1/2 and JNK pathways. However,
titanium particles with adherent
endotoxin substantially potentiate the
activation of these pathways compared
to endotoxin-free titanium (data not
shown).
Is There a Role for the PI3K/Akt
Pathway in Aseptic Loosening?
PI3K and Akt are protein kinases

that regulate many cellular functions
including mitogenesis, insulin
signaling, respiratory burst in
neutrophils, cell motility, cell survival,
and inammation.18 We hypothesize
that TLR-4 activates PI3K in response
to particles with adherent endotoxin as
has been shown for soluble LPS (Fig.
4). Upon activation, PI3K converts
phosphatidylinositol (3,4) bisphosphate
(PIP2) to phosphatidylinositol (3,4,5)
triphosphate (PIP3). PIP3 recruits Akt
and PDK1 to the plasma membrane
where PDK1 phosphorylates Akt at
a threonine residue (Thr308) in the
catalytic loop. To be active, Akt also
requires phosphorylation at a serine site
(Ser473) in the regulatory domain. The
mechanism of Ser473 phosphorylation
remains controversial with evidence
supporting autophosphorylation,
a distinct serine kinase, or an
integrin-linked kinase.19 Despite
this controversy, inhibition of Akt
phosphorylation at either or both sites
results in disruption of this pathway.

Soluble LPS has recently been shown
to activate the PI3K/Akt pathway in
mouse macrophages.9,10 Inhibition
of PI3K with LY294002 blocks Akt
activation and TNF production in
response to LPS.9,10 Preliminary results
in our lab show that this pathway is
also activated in response to titanium
particles with adherent endotoxin.
Inhibition of the PI3K/Akt pathway in
response to these particles also decreases
TNF production. Our evidence
suggests that this pathway at least
partially mediates the inammatory
response to wear particles with adherent
endotoxin.
TNF produced in response to
wear debris may alter the balance
of bone loss and bone formation
through its effects on osteoclasts and
osteoblasts. TNF inhibits osteoclast
apoptosis through PI3K/Akt and
ERK activation.20 Recent evidence
also suggests that TNF inhibits
osteoclast apoptosis by up-regulating
Bcl-xL gene expression.21 Although
the mechanism of Bcl-xL activation in
osteoclasts is unclear, there is evidence
that the PI3K/Akt pathway may, in
part, regulate Bcl-xL activation in
other cell types.22 In addition to its
effects on osteoclasts, TNF appears
to promote osteoblast activation in
mice.23 However, high concentrations
of titanium particles inhibit osteogenic
precursors from differentiating into
osteoblasts.24 The presence of titanium
particles may counteract TNFs
ability to promote osteoblast formation
leading to an imbalance between the
number of osteoclasts and osteoblasts.
Further studies are needed to clarify
how titanium and TNF affect the
balance between osteoclasts and
osteoblasts in patients with aseptic
loosening.
CONCLUSIONS
Bone loss around orthopaedic implants

results from a complex interaction
of implant properties such as metal
stiffness, material manufacturing,
implant placement, bone integration
and biological responses to wear
debris. Endotoxin and endotoxin-like
molecules adherent to wear particles
augment their biologic effect in cell
culture and animal models. Potential
endotoxin sources include external
sources like inadequate removal
from the implant during processing,
accumulation of systemic endotoxin,
and the biolm around the implant
that contains mostly Gram-positive
bacteria. In addition, it is likely the
lipoteichoic acid or peptidoglycan from
Gram-positive bacteria also contributes
to the inammatory response.
Advances in surgical technique, metal
alloys, and polyethylene cross-linking
have reduced particle generation
and osteolysis. Finding potential
pharmacological targets to block
inammation and alter the imbalance
between osteoclast and osteoblast
activity offers a novel therapeutic
approach to this problem. Ongoing
studies in our lab are examining
the contribution of the MAPK and
the PI3K/Akt pathways in aseptic
loosening. As their roles become clearer,
therapeutics targeting these pathways
may provide another weapon in the
arsenal to increase the longevity of
orthopaedic implants.
ACKNOWLEDGMENTS:
Supported by NIH RO1 AR43769 to

EMG.
REFERENCES
1. Bi Y, Seabold JM, Kaar SG, Ragab AA,
Goldberg VM, Anderson JM, Greeneld
EM. Adherent endotoxin on orthopedic wear
particles stimulates cytokine production and
osteoclast differentiation. J Bone Miner Res.
2001; 16(11): 2082-91.
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6/22/05 2:23:56 PM
MANUSCRIPTS
2. Ragab AA, Nalepka JL, Bi Y, Greeneld EM.
Cytokines synergistically induce osteoclast
differentiation: support by immortalized or
normal calvarial cells. Am J Physiol Cell Physiol.
2002; 283: C679-687.
13. Paterson HM, Murphy TJ, Purcell EJ,

Shelley O, Kriynovich SJ, Lien E, Mannick
JA, Lederer JA. Injury primes the innate
immune system for enhanced Toll-like receptor
reactivity. J Immunol. 2003; 171(3): 1473-83.
3. Bi Y, Collier TO, Goldberg VM, Anderson

JM, Greeneld EM. Adherent endotoxin
mediates biological responses of titanium
particles without stimulating their
phagocytosis. J Orthop Res. 2002; 20(4):696703.
14. English J, Pearson G, Wilsbacher J, Swantek

J, Kaarandikar M, Shuichan X, Cobb MH.
New insights into the control of MAP kinase
pathways. Experimental Cell Research. 1999;
253: 255-270.
4. Ragab AA, Van De Motter R, Lavish SA,

Goldberg VM, Ninomiya JT, Carlin CR,
Greeneld EM. Measurement and removal of
adherent endotoxin from titanium particles and
implant surfaces. J Orthop Res. 1999; 17(6):
803-9.
5. Engester LB, Lie SAM, Espehaug B,
Furnes O, Vollset SE, Havelin LI. Antibiotic
prophylaxis in total hip arthroplasty: Effects of
antibiotic prophylaxis systemically and in bone
cement on the revision rate of 22,170 primary
hip replacements followed 0-14 years in the
Norwegian Arthroplasty Register. Acta Orthop
Scand. 2003; 74(6): 644-651.
6. Seabold JM, Taki M, Goldberg VM,
Greeneld EM. Endotoxin accumulation
during polyethylene (PE) induced osteolysis in
murine calvaria. Trans Orthop Res Soc. 2004;
29: 1515
7. Cooperstock MS, Tucker RP, Baublis JV.
Possible pathogenic role of endotoxin in Reyes
syndrome. Lancet. 1975; 1(7919): 1272-4.
8. Guha M, Mackman N. LPS induction of
gene expression in human monocytes. Cellular
Signalling. 2001; 13: 85-94.
9. Lim HK, Choi YA, Park W, Lee T, Ryu
SH, Kim SY, Kim JR, Kim JH, Baek
SH. Phosphatidic acid regulates systemic
inammatory responses by modulating the
Akt-mammalian target of rapamycin-p70 S6
kinase 1 pathway. J Biol Chem. 2003; 278(46):
45117-27.
10. Ojaniemi M, Glumoff V, Harju K, Liljeroos
M, Vuori K, Hallman M. Phosphatidylinositol
3-kinase is involved in Toll-like receptor
4-mediated cytokine expression in mouse
macrophages. Eur J Immunol. 2003; 33(3):597605.
11. Vogel S, Hirschfeld MJ, Perera, PY. Signal
integration in lipopolysaccharide (LPS)stimulated murine macrophages. J Endo Res.
2001. 7(3): 237-241.
12. Poltorak A, He X, Smirnova I, Liu M, Huffel
CV, Du X, Birdwell D, Alejos E, Silva M,
Galanos C, Freudenberg M, RicciardiCastagnoli P, Layton B, Beutler B. Detecting
LPS signaling in C3H/HeJ and C57BL/10ScCr
mice: mutations in TLR-4 gene. Science. 1998;
282: 2085-2088.
15. Miyanishi K, Trinadade M, Ma T, Goodman

SB, Schurman DJ, Smith RL. Periprosthetic
osteolysis: Induction of vascular endothelial
growth factor from human monocyte/
macrophage by orthopaedic biomaterials. J
Bone Min Res. 2003; 18: 1573-83.
16. Abbas S, Clohisy JC, Abu-Amer Y. Mitogenactivated protein (MAP) kinase mediate
PMMA-induction of osteoclasts. J Orthop Res.
2003; 21: 1041-48.
17. Zhu W, Downey JS, Gu J, Padova FD, Gram
H, Han J. Regulation of TNF expression by
multiple mitogen-activated protein kinase
pathway. Immunology. 2000; 164: 6349-6358.
18. Franke, TF. A difcult Akt to Follow. Neural
Notes. 1999; 2(2): 3-7.
19. Scheid MP, Woodgett JR. Unravelling the
activation mechanisms of protein kinase B/Akt.
FEBS Lett. 2003; 546(1): 108-12.
20. Lee SE, Chung WJ, Kwak HB, Chung
CH, Kwack KB, Lee ZH, Kim HH. Tumor
necrosis factor-alpha supports the survival of
osteoclasts through the activation of Akt and
ERK. J Biol Chem. 2001; 276(52): 49343-9.
21. Xing L, Zhang Q, Schwarz EM, Boyce BF.
TNF prevents bisphosphonate-induced
osteoclast apoptosis in vivo by stimulating BclxL expression. Trans Orthop Res Soc. 2004; 29:
166.
22. Hatano E, Brenner DA. Akt protects
mouse hepatocytes from TNF-alpha- and
Fas-mediated apoptosis through NK-kappa
B activation. Am J Physiol Gastrointest Liver
Physiol. 2001; 281(6): G1357-68.
23. Gerstenfeld LC, Cho TJ, Kon T, Aizawa T,
Cruceta J, Graves BD, Einhorn TA. Impaired
intramembranous bone formation during bone
repair in the absence of tumor necrosis factoralpha signaling. Cells Tissues Organs. 2001;
169(3): 285-94.
24. Wang ML, Nesti LJ, Tuli R, Lazatin J,
Danielson KG, Sharkey PF, Tuan RS.
Titanium particles suppress expression of
osteoblastic phenotype in human mesenchymal
stem cells. J Orthop Res. 2002; 20(6): 1175-84.
6/22/05 2:23:56 PM
MECHANOBIOLOGY OF CHONDROGENESIS
Parke Oldenburg MD, Peter Angele MD, Joseph Mansour PhD,
Jung Yoo MD, Brian Johnstone, PhD
Department of Orthopaedics, Case Western Reserve University, Cleveland, OH
INTRODUCTION
esenchymal progenitor cells

(MPCs) are pluripotent and
depending on the environment, are
capable of differentiating into a variety
of cell types including bone, adipose
tissue and cartilage. These cells represent a promising source of reparative
cells for musculoskeletal tissue and
considerable research has focused on
enumerating the biologic factors that
affect MPC differentiation. In 1998,
we rst described an in vitro model for
the induction of human bone marrow derived MPCs into chondrocytes
using a dened culture medium.1,2 The
system contains a specic chondrogenic
medium and allows for the study of
additional factors that may affect the
process of chondrogenesis. Since the
biomechanical loading of musculoskeletal tissues plays a role in their formation and ultimate structure, one area of
interest in our laboratory is the effect
of mechanical loading on MPCs. Until
recently, the mechanical parameters
affecting MPC differentiation have not
been extensively examined.
One potential therapeutic application
for MPCs is in articular cartilage
regeneration. Normal articular cartilage
continually responds to a variety
of mechanical stimuli, including
hydrostatic pressure, compressive
deformation and shear.3 Measurement
of hip contact pressures using an
instrumented endoprosthesis recorded
an average free walking pressure of
5.6 megapascals (MPa).4 A number
of studies suggest the normal stress
across human joints ranges from 3
to 10 MPa.4,5 Many investigators

have examined the response of
chondrocytes to mechanical loading
in vitro. Bushmann demonstrated that
chondrocytes embedded in agarose
decreased proteoglycan synthesis in
response to static compression, while
dynamic compression increased
proteoglycan synthesis.6 Kim further
characterized the effects of loading by
demonstrating that static compression
inhibited aggrecan and link protein
synthesis with little effect on
hyaluronan synthesis.7
Valhmu established an increase in
both aggrecan and link protein mRNA
transcription with short periods of low
compressive pressure but not during
longer periods of compression.8 Further
studies correlated increased aggrecan
synthesis in areas of increased uid
ow suggesting its role in increased
proteoglycan synthesis.9 Later work
has minimized the importance of uid
ow and emphasized the importance
of tissue shear deformation on
chondrocyte production of matrix
molecules.10 Subjecting chondrocytes to
cyclical hydrostatic pressure has similar
results to mechanical compression,
demonstrating increased type II
collagen and aggrecan expression.11,12
Mechanical stimulation can also affect
cellular differentiation. Finite element
models have been used to predict
the pattern of tissue differentiation
during fracture healing and distraction
osteogenesis.13,14 The models predicted
bone formation at locations of low
tensile strain and chondrogenesis in
areas of hydrostatic compressive stress.
Applying this theoretical model, many

investigators have studied the role of
mechanical loading on embryonic
limb bud cellular differentiation;
a diverse mixture of mesenchymal
progenitor cells and chondrocyte
precursor cells. Takahashi et al. showed
that static compression of embryonic
cells embedded in a collagen sponge
increases the expression of type II
collagen and aggrecan expression along
with Sox 9, a transcription factor
expressed during chondrogenesis.15
In contrast, Elder et al. demonstrated
that although cyclic compression
of limb bud cells increases the
proportion of chondrocyte nodules and
increases sulfate uptake (a marker for
glycosaminoglycan (GAG) synthesis)
static compression did not enhance
matrix production.16,17 Using an in vivo
loading device, Tgil and Aspenberg
demonstrated hydrostatic stress induced
healing tissue to form cartilage.18
Mesenchymal progenitor cells are
predominantly found within the
medullary cavity and periosteum where
hydrostatic pressures are low. Articular
cartilage injury in association with
subchondral fracture allow MPCs to
migrate from the marrow cavity to
the joint space where they experience
greater hydrostatic pressure. At the
location of cartilage injury, MPCs
differentiate and produce extracellular
matrix with predominantly type I
collagen. The forces that inuence MPC
differentiation and the mechanism
by which the cells respond to these
mechanical stimuli remain unclear.
56
6/22/05 2:23:56 PM
MANUSCRIPTS
Recently, our lab demonstrated that
cyclical hydrostatic pressure enhanced
the chondrogenic differentiation of
MPCs.19 Mesenchymal progenitor cells
were obtained from the bone marrow
of patients undergoing spine surgery.
After isolation and expansion in
culture, cells were pelleted in a dened
chondrogenic medium containing
TGF-1. Aggregates were loaded
into polypropylene tubes containing
medium and sealed with a exible
rubber cap before being placed into a
custom hydrostatic pressure chamber
(Fig 1). The loading device consists
of a computer controlled piston that
delivers pressure to a water lled
chamber. Preliminary studies using
pressure sensitive lm (Fuji prescale
low pressure lm, Fuji) conrmed that
the force produced by the piston was
accurately applied to the contents of
the chamber. It was also established
that placing the pressure sensitive lm
within the polypropylene tubes sealed
with the rubber stopper did not alter
pressure transmission. Aggregates
were loaded with hydrostatic pressure
ranging from 0.55 MPa to 5.03 MPa
at 1 Hz for four hours a day. Cells
were either loaded for a single time
point on either day one or day three
of culture, or for seven consecutive
days from days one through seven.
Aggregates were harvested for histology,
immunhistochemistry and quantitative
DNA and matrix macromolecule
analysis at days 14 and 28.
RESULTS
Upon histological analysis, the

aggregates loaded for seven consecutive
days were larger and demonstrated
a greater matrix/cell ratio (Fig 2).
The aggregates loaded for only one
day did not demonstrate increased
glycosaminoglycan content compared
to non-loaded controls, while
aggregates loaded for a week produced
signicantly more glycosaminoglycan
at both days 14 and 28

of culture. Similar results
were found for collagen
production .
SUMMARY
Mechanical forces alter

chondrocyte matrix
production; however, it
is unclear if loading alters
MPC differentiation. In
aggregate culture, type
II collagen, a marker for
chondrogenesis, can be
detected from day four
of culture onwards. In
our model, hydrostatic
loading was applied
for the rst seven days
and it is unknown if
the increased matrix
production was the
result of earlier cell
differentiation or if
the differentiated
chondrocytes produced
more matrix. DNA
content was measured
and did not increase
with loading, implying
that the increase in GAG
and collagen was not
the result of increased
cell proliferation. Future
studies will characterize
the temporal expression of
chondrogenic markers in
response to intermittent
hydrostatic loading,
examine the signal
transduction mechanisms,
and determine if hydrostatic
pressure in the absence
of growth factors such
as TGF- can induce
chondrogenesis.
Figure 1. Custom-build hydrostatic pressure chamber. A

computer controls an Enduratec machine which drives a
hydraulic piston which delivers hydrostatic pressure to the
chamber.
Figure 2. Sections of aggregates stained obtained from

culture on day 28 stained with toluidine blue (16 x
magnication). (A) Aggregate maintained in culture
without loading. (B) Aggregate loaded for 7 days.
It is clear that certain mechanical forces

can alter gene transcription and protein
expression to increase extracellular
matrix production of differentiating
mesenchymal cells. Further

investigation in this area of research
may lead us to the understanding
of how cells perceive mechanical
forces and how these forces affect
chondrogeneis.
6/22/05 2:23:57 PM
MECHANOBIOLOGY OF CHONDROGENESIS
REFERENCES:
1. Johnstone B, Hering T, Caplan A, Goldberg V,
Yoo J. In vitro chondrogenesis of bone marrowderived mesenchymal progenitor cells. Exp Cell
Res. 1998;238(1): 265-72.
2. Yoo JU, Barthel TS, Nishimura K, Solchaga
L, Caplan AI, Goldberg VM, Johnstone B.
The chondrogenic potential of human bonemarrow-derived mesenchymal progenitor cells.
J Bone Joint Surg Am. 1998; 80(12): 1745-57.
3. Grodzinsky A, Levenston M, Jin M, Frank E.
Cartilage tissue remodeling in response to
mechanical forces. Annu Rev Biomed Eng. 2000;
2: 691-713.
4. Tackson S, Krebs D, Harris B. Acetabular
pressures during hip arthritis exercises. Arthritis
Care Res. 1997; 10(5): 308-19.
5. Afoke N, Byers P, Hutton W. Contact pressures
in the human hip joint. J Bone Joint Surg Br
1987; 69(4): 536-41.
6. Buschmann M, Gluzband Y, Grodzinsky A,
Hunziker E. Mechanical compression
modulates matrix biosynthesis in chondrocyte/
agarose culture. J Cell Sci. 1995; 108 ( Pt 4):
1497-508.
7. Kim Y, Grodzinsky A, Plaas A. Compression
of cartilage results in differential effects on
biosynthetic pathways for aggrecan, link
protein, and hyaluronan. Arch Biochem Biophys.
1996; 328(2): 331-40.
8. Valhmu WB, Stazzone EJ, Bachrach NM,
Saed-Nejad F, Fischer SG, Mow VC, Ratcliffe
A. Load-controlled compression of articular
cartilage induces a transient stimulation of
aggrecan gene expression. Arch Biochem Biophys.
1998; 353(1): 29-36.
13. Carter D, Blenman P, Beaupre G. Correlations

between mechanical stress history and tissue
differentiation in initial fracture healing. J
Orthop Res. 1988; 6(5): 736-48.
14. Carter D, Beaupre G, Giori N, Helms J.
Mechanobiology of skeletal regeneration. Clin
Orthop. 1998; (355 Suppl): S41-55.
15. Takahashi I, Nuckolls GH, Takahashi K,
Tanaka O, Semba I, Dashner R, Shum L,
Slavkin HC. Compressive force promotes sox9,
type II collagen and aggrecan and inhibits IL1beta expression resulting in chondrogenesis in
mouse embryonic limb bud mesenchymal cells.
J Cell Sci. 1998; 111 ( Pt 14): 2067-76.
16. Elder S, Kimura J, Soslowsky L,
Lavagnino M, Goldstein S. Effect of
compressive loading on chondrocyte
differentiation in agarose cultures of chick
limb-bud cells. J Orthop Res. 2000; 18(1):
78-86.
17. Elder S, Goldstein S, Kimura J, Soslowsky L,
Spengler D. Chondrocyte differentiation is
modulated by frequency and duration of cyclic
compressive loading. Ann Biomed Eng. 2001;
29(6): 476-82.
18. Tagil M, Aspenberg P. Cartilage induction by
controlled mechanical stimulation in vivo. J
Orthop Res. 1999; 17(2): 200-4.
19. Angele P, Yoo JU, Smith C, Mansour J,
Jepsen KJ, Nerlich M, Johnstone B. Cyclic
hydrostatic pressure enhances the chondrogenic
phenotype of human mesenchymal progenitor
cells differentiated in vitro. J Orthop Res. 2003;
21(3): 451-7.
9. Buschmann M, Kim Y, Wong M, Frank E,

Hunziker E, Grodzinsky A. Stimulation of
aggrecan synthesis in cartilage explants by cyclic
loading is localized to regions of high interstitial
uid ow. Arch Biochem Biophys. 1999; 366(1):
1-7.
10. Jin M, Frank E, Quinn T, Hunziker E,
Grodzinsky A. Tissue shear deformation
stimulates proteoglycan and protein
biosynthesis in bovine cartilage explants. Arch
Biochem Biophys. 2001; 395(1): 41-8.
11. Ikenoue T, Trindade MC, Lee MS, Lin
EY, Schurman DJ, Goodman SB, Smith
RL. Mechanoregulation of human articular
chondrocyte aggrecan and type II collagen
expression by intermittent hydrostatic pressure
in vitro. J Orthop Res. 2003; 21(1): 110-6.
12. Smith RL, Rusk SF, Ellison BE, Wessells P,
Tsuchiya K, Carter DR, Caler WE, Sandell
LJ, Schurman DJ. In vitro stimulation of
articular chondrocyte mRNA and extracellular
matrix synthesis by hydrostatic pressure. J
Orthop Res. 1996; 14(1): 53-60.
58
6/22/05 2:23:57 PM
MANUSCRIPTS
ASCORBATE IS ESSENTIAL FOR

OSTEOCLASTOGENESIS
Renata M. Kadlcek BA, Ashraf A. Ragab MD, and Ed M.Greeneld PhD
INTRODUCTION
steoclasts and osteoblasts are

the cells responsible for bone
turnover and growth. Osteoclasts resorb
bone and osteoblasts in turn ll in gaps
created by osteoclasts and build new
bone. The delicate balance between
these two cell types is regulated by
systemic hormones and local factors,
such as cytokines and prostaglandins.
Should this balance be skewed in favor
of either osteoclasts or osteoblasts,
osteoporosis or osteopetrosis results,
respectively. Given that osteoporosis is
a major concern for post-menopausal
women and affects an estimated 28
million Americans, it is essential to
understand how the increase in the
number of osteoclasts initially creates
and sustains the imbalance that gives
rise to osteoporosis.
Ascorbate, also known as ascorbic
acid and Vitamin C, has been
shown to play a major role in
bone health. Although ascorbate
deciency impairs bone formation,
we have shown that ascorbate is
also necessary for osteoclastogenesis
and bone resorption in cell culture1.
The regulatory mechanisms of
ascorbate in osteoclastogenesis are
poorly understood and require
further characterization. Here we
propose several mechanisms by
which ascorbate may inuence
osteoclastogenesis (Figure) and discuss
our on-going efforts to test these
possibilities.
Extracellular Matrix Assembly
The best characterized action
FIGURE: Schematic overview of possible osteoclastogenic mechanisms induced by ascorbate.

Ascorbate may act directly on osteoclast precursors or indirectly through osteoblasts. possible
mechanisms include extracellular matrix (ECM) assembly, antioxidant effects, regulation of
gene expression, and protein ascorbylation.
of ascorbate is as a cofactor for

collagen crosslinking and subsequent
extracellular matrix (ECM) assembly.
This effect accounts for ascorbates
role in osteoblastic differentiation2
. Since a specc stage of osteoblast
differentiation is required to support
osteoclastogenesis3,4, ascorbate may
act by promoting this stage. In this
regard, ascorbate increases production
of RANKL5 , which is an osteoblastderived cytokine essential for
osteoclastogenesis6. Several isoforms
of RANKL have also been identied7
and it is possible that ascorbic acid
may induce each one of these isoforms
differently. However, our recent

experiments suggest that RANKL
cannot support osteoclastogenesis in
the absence of ascorbate.
Alternatively, the ECM itself may
contain molecules that support
osteoclastogenesis, either by directly
targeting the osteoclast precursors
or by acting indirectly by targeting
osteoblasts that then support
osteoclastogenesis. Consistent with
this hypothesis, we have shown that
provision of exogenous ECM allows
for osteoclastogenesis in the absence of
ascorbate.
6/22/05 2:23:57 PM
OSTEOCLASTOGENESIS
Antioxidant
The second most studied effect

of ascorbate is as an antioxidant.
Since other workers have shown
that various antioxidants inhibit
osteoclastogenesis8,9,10 and NF-kB
signaling11, which is a requirement
for osteoclastogenesis12, ascorbate
may not induce osteoclastogenesis
by this mechanism. However, we
have found that N-acetyl cysteine,
another antioxidant not involved
in collagen crosslinking, can induce
osteoclastogenesis, albeit at a lower
level than ascorbate. Therefore, we
are examining the effects and possible
mechanisms of these and other
antioxidants such as alpha-tocopherol
(vitamin E).
Gene Expression
Direct regulation of gene expression

may also account for the ascorbate
requirement during osteoclastogenesis.
Since ascorbate directly regulates
expression of certain genes in
chondrocytes13,14, it may also upregulate
genes required for osteoclastogenesis.
This mechanism could operate in the
osteoclast precursors by upregulating
expression of receptors for essential
cytokines (RANK, c-fms, etc.),
signaling molecules (TRAFs, MAPKs,
PI3K, Akt, etc.), transcription factors
(PU.1, MITF, fos, etc.) or other marker
genes (TRAP, CtRs, etc.). Alternatively,
ascorbate could upregulate osteoblast
genes required for support of
osteoclastogenesis, such as RANKL or
M-CSF.
Protein Ascorbylation
Ascorbylation of proteins15 is another

potential mechanism that may account
for the ascorbate requirement during
osteoclastogenesis. Ascorbylation results
from a series of degradative events
resulting in production of reactive
intermediates, such as L-erythrulose,
that glycate and crosslink proteins15.
Osteoclastogenesis may therefore
depend on ascorbates degradation

products rather than ascorbate itself. To
test this hypothesis, we are determining
whether specic degradation products
can substitute for ascorbate during
osteoclastogenesis.
SUMMARY
Ascorbate is required for

osteoclastogenesis. One mechanism
that likely contributes to this
requirement is collagen crosslinking leading to ECM assembly.
Molecules contained in the ECM
may support osteoclastogenesis either
by directly targeting the osteoclast
precursors or by acting indirectly
by targeting osteoblasts that then
support osteoclastogenesis. Alternative
mechanisms that may also contribute
to osteoclastogenesis include direct
gene expression, protein ascorbylation
and antioxidant effects.
ACKNOWLEDGEMENTS
These studies were supported by NIH

AR46803 awarded to EMG.
REFERENCES
1. Ragab A, Lavish S, Banks M, Goldberg
V, Greeneld E. Osteoclast Differentiation
Requires Ascorbic Acid. J of Bone Min Res
1998; 13(6):970-977.
2. Franceschi R. The role of ascorbic acid in
mesenchymal differentiation. Nutr Rev 1992;
50:65-70.
3. Suda T, Takahashi N, Martin TJ. Modulation
of osteoclast differentiation. Endocr Rev 1992;
13:66-80.
4. Udagawa N, Takahashi N, Akatsu T, Sasaki
T, Yamaguchi A, Kodama H, Martin TJ,
Suda T. The bone marrow-derived stromal
cell lines MC3T3-G2/PA6 and ST2 support
osteoclast-like cell differentiation in co-cultures
with mouse spleen cells. Endocrinology 1989;
125:1805-1813.
Tomoyasu A, Yano K, Goto M, Murakami

A, Tsuda E, Morinaga T, Higashio K,
Udagawa N, Takahashi N, Suda T.
Osteoclast differentiation factor is a ligand for
osteoprotegerin/osteoclastogenesis-inhibitory
factor and is identical to TRANCE/RANKL.
Proc Natl Acad Sci 1998; 95:3597-3602.
7. Ikeda T, Kasai M, Suzuki J, Kuroyama
H, Seki S, Utsuyama M, Hirokawa K.
Multimerization of the Receptor Activator of
Nuclear Factor-B Ligand (RANKL) Isoforms
and Regulation of Osteoclastogenesis. T J of
Biol Chem 2003; 278(47):47217-47222.
8. Suda N, Morita I, Kuroda T, Murota S.
Participation of oxidative stress in the process of
osteoclast differentiation. Biochim Biophys Acta
1993; 1157:318-323.
9. Garrett IR, Boyce BF, Oreffo RO,
Bonewald L, Poser J, Mundy GR Oxygenderived free radicals stimulate osteoclastic bone
resorption in rodent bone in vitro and in vivo. J
Clin Invest 1990; 85:632-639.
10. Lean J, Davies J, Fuller K, Jagger C,
Kirestein B, Partington G, Urry Z,
Chambers T. A crucial role for thiol
antioxidants in estrogen-deciency bone loss. J
Clin Invest 2003; 112(6):915-923.
11. Schreck R, Meier B, Mannel DN, Droge W,
Baeuerle PA. Dithiocarbamates as potent
inhibitors of nuclear factor kappa B activation
in intact cells. J Exp Med 1992; 175(5):11811194.
12. Takahashi N, Udagawa N, Suda T. A new
member of tumor necrosis factor ligand family,
ODF/OPGL/TRANCE/RANKL, regulates
osteoclast differentiation and function. Biochem
Biophys Res Commun 1999; 256(3):449-55.
13. Sullivan T, Uschmann B, Hough R, Leboy
P. Ascorbate Modulation of Chondrocyte
Gene Expression Is Independent of Its Role
in Collagen Secretion. J Biol Chem 1994;
269(36):22500-06.
14. Clark A, Rohrbaugh A, Otterness I, Kraus
V. The effects of ascorbic acid on cartilage
metabolism in guinea pig articular cartilage
explants. Matrix Biology 2002; 21:175-184.
15. Simpson G, Ortwerth B. The non-oxidative
degradation of ascorbic acid at physiological
conditions. Biochim Biophys Acta 2000;
1501:12-24.
5. Otsuka E, Kato Y, Hirose S, Hagiwara

H. Role of Ascorbic Acid in the Osteoclast
Formation: Induction of Osteoclast
Differentiation Factor with Formation of the
Extracellular Collagen Matrix. Endocrinology
2000; 141(8):3006-3011.
6. Yasuda H, Shima N, Nakagawa N,
Yamaguchi K, Kinosaki M, Mochizuki SI,
60
6/22/05 2:23:58 PM
MANUSCRIPTS
REVIEW:
REGULATION OF PKA SIGNALING BY PKI IN
OSTEOBLASTS
Erica Keenan BS, Xin Chen MD, PhD, and Edward M. Greeneld PhD
ABSTRACT
he balance between the anabolic

and catabolic effects of parathyroid
hormone (PTH) regulates bone
turnover and calcium homeostasis.
The effects of PTH in osteoblasts
occur via the cAMP-dependent protein
kinase (PKA) signaling pathway,
which leads to expression of genes
encoding regulatory proteins in an
immediate-early fashion. Our recent
studies indicate that, in osteoblasts,
the protein kinase inhibitor, PKI, is
responsible for termination of this
immediate-early response. In response
to PTH stimulation, PKI translocates
to the nucleus, where it inhibits PKAinduced gene expression and shuttles
PKA to the cytoplasm. Thus, PKI
could be a key regulator of the balance
between the catabolic and anabolic
effects generated by PTH. As such,
pharmacological modication of PKI
levels or activity may provide a useful
therapy for bone loss in conditions
such as osteoporosis and orthopaedic
implant loosening.
INTRODUCTION
PTH and parathyroid-related protein

(PTHrP) stimulate bone resorption but
can, when administered intermittently,
stimulate bone formation. The
catabolic and anabolic effects of
PTH and PTHrP are due to genes
encoding cytokines and transcription
factors1. Thus, an understanding of
the mechanisms underlying regulation
of these genes may have important
implications for treatment of diseases

involving increased bone turnover,
such as osteoporosis and loosening of
orthopaedic implants.
The effects of these hormones occur
in osteoblasts via the cAMP signaling
pathway, of which PKA is the key
component. The role of PKA in this
hormone-induced gene expression
has been extensively investigated. In
the absence of stimulation, PKA is
maintained in the cytosol as a tetramer
composed of two regulatory and
two catalytic subunits. Binding of
cAMP releases the catalytic subunits,
which are then able to phosphorylate
targets in both the cytosol and the
nucleus. Inhibition of this activity
occurs upon reassociation with the
regulatory subunits or, alternatively,
upon association with PKI. In vitro,
PKI binds PKA with high afnity2
and selectivity3. There is compelling
evidence that PKI can regulate both
the cellular localization and activity
of PKA4,5. However, these studies
have been performed using injected
or overexpressed PKI constructs.
The physiological role of this protein
remains unclear.
This review will focus on investigations
into regulation of PKA activity and
cellular localization by endogenous
PKI, specically as it occurs under
hormonal stimulation in osteoblasts.
In these cells, PKA induces cytokine
and transcription factor genes in an
immediate-early fashion in response
to PTH. PKI may bind to PKA in

the nucleus, inhibiting its activity
and shuttling it to the cytoplasm
essentially resetting the system for later
hormonal responses.
The Catabolic and Anabolic Effects of
PTH
PTH and PTHrP are major

regulators of bone turnover in
mammalian systems. Continual
release or administration of these
agents leads to bone resorption and
increased extracellular calcium levels,
in what is known as the catabolic
effect. Paradoxically, intermittent
administration of these agents produces
the opposite result: bone formation6.
PTH and PTHrP exert these diverse
effects by inuencing osteoblast
activity. When stimulated, osteoblasts
release cytokines and other molecules
that affect osteoclast differentiation and
activity. For example, PTH triggers the
osteoblastic expression of RANKL, a
cell surface molecule that stimulates
osteoclast differentiation, activity, and
survival7,8,9. Conversely, the anabolic
effects of PTH are mediated by factors
such as IGF-110 and c-fos11. The levels
and complex interplay of these factors
determines the balance between bone
formation and resorption. Therefore,
it is important to understand the
mechanisms by which expression of
these factors are regulated, with an eye
to developing potential treatments for
diseases related to bone turnover.
6/22/05 2:23:58 PM
REGULATION OF PKA SIGNALING

PKA Signaling in Response to PTH
Both PTH and PTHrP bind to the
type 1 PTH/PTHrP receptor, a G
protein-coupled receptor (GPCR), on
the osteoblast cell surface. As illustrated
in Figure 1, this event triggers a
cAMP signaling pathway, leading to
activation of PKA. Once activated, the
catalytic subunit of PKA translocates
to the nucleus, where it phosphoryates
transcription factors such as cAMP
response element binding protein
(CREB), thereby initiating gene
expression. Our lab showed that
PKA signaling is responsible for
IL-6 expression in osteoblasts12,13. As
evidence that cytokines such as IL-6
stimulate osteoclasts, we demonstrated
that adding exogenous IL-6 promotes
osteoclast activity in a manner
similar to that observed with PTH
stimulation11. Alternatively, blocking
the osteoclast IL-6 receptor with a
neutralizing antibody inhibits activity
of these cells in vitro. Complementing
the ndings of these in vitro studies,
Grey et al.15 showed that IL-6
deciency blocks the ability of PTH
to increase bone resorption in vivo.
Thus, the catabolic and anabolic effects
of PTH and PTHrP are achieved via
cytokine release by osteoblasts.
We have shown that PTH-stimulated
cytokine expression occurs in a rapid
and transient fashion12,16. Maximal
levels of IL-6 mRNA are achieved
within 30-60 minutes following PTH
treatment, with a return to baseline
after 4-6 hours. Furthermore, this
response is inhibited by blocking
transcription but superinduced by
protein synthesis inhibitors12. Levels
of c-fos mRNA, a key anabolic
factor induced by PTH 11, increase
in a similar fashion13. Together, this
evidence supports the assertion that
PTH induction of key regulatory genes
is characteristic of an immediate-early
gene response. The rapid nature of
this response can

be attributed to
rapid increases
in intracellular
cAMP levels,
activation of
PKA, and
phosphorylation
of key
transcription
factors in the
nucleus. However,
the mechanisms
responsible for
termination of
these effects have
not been fully
elucidated.
Termination of the
Immediate-Early
Response
Figure 1. Binding of PTH or PTHrP to the type 1 PTH/PTHrP receptor

on the osteoblast cell surface triggers a cAMP signaling pathway,
leading to activation of PKA, phosphorylation of CREB, and
subsequent gene expression.
Given the
effect of PTHstimulated cytokines on osteoclast
activity, we hypothesized that time
span of their expression would be
strongly controlled. Termination of
the immediate-early response likely
occurs at a certain step in the cAMP/
PKA signaling pathway. One such
step could be desensitization of the
PTH receptor by G protein-coupled
receptor kinase 2 (GRK2). GRK2 can
desensitize 2-adrenergic receptors via
phosporylation17. However, we have
shown that GRK2-directed antisense
oligonucleotides or transfection
with GRK2 antisense constructs
reduce GRK2 levels and receptor
desensitization but have little effect
on the time course of IL-6 and c-fos
expression following treatment with
PTH13.
Alternatively, degradation of intracellular cAMP by phosphodiesterases

could cause a return to basal levels of
cAMP and thereby end the immediateearly gene response. In support of such
a mechanism, phosphodiesterases are
rapidly activated by PTH treatment in

osteoblast-like cells18. However, we have
shown that treatment with forskolin
leads to sustained activation of adenyl
cyclase and elevated cAMP levels but
produces only transient gene expression. Additionally, treatment with
IBMX, an inhibitor of phosphodiesterase, blocks cAMP degradation but fails
to prolong gene expression13. Similar
results were demonstrated in two osteoblastic cell lines and in broblastic cells,
suggesting that this is a general mechanism of regulation13. Together, these
experiments suggest that the PKA-mediated gene response is terminated at a
point downstream of receptor desensitization and cAMP degradation.
Inhibitory transcription factors, such
as the cAMP early repressor (ICER)19,
or histone deacetylases (HDACs)20
are candidates for this downstream
inhibitory event. However, the
inhibitory activity of ICER or HDACs
cannot account for cessation of
PKA activity observed in our studies
62
6/22/05 2:23:58 PM
MANUSCRIPTS
Figure 2. PKI can bind to nuclear PKA, inhibiting its activity and returning it to the cytoplasm.
because it would occur downstream

of PKA-mediated transcription factor
phosphorylation. Thus, based on
the evidence obtained thus far, we
hypothesized that direct inhibition of
PKA ends expression of immediateearly genes and that PKI is responsible
for this inhibitory activity.
The Role of Endogenous PKI in
Osteoblasts
Various studies conducted in vitro

have suggested that PKI can regulate
the activity and cellular localization
of PKA. When injected into cells, the
catalytic subunit of PKA (C) can enter
and exit the nucleus freely, but a C-PKI
complex exhibits rapid export from the
nucleus and remains sequestered in the
cytoplasm4. These ndings suggest that,
in addition to being a stoichiometric
inhibitor of PKA, PKI can shuttle PKA
from the nucleus to the cytoplasm.
Consistent with this putative role, it
has been demonstrated that PKI bears
a highly conserved, leucine-rich nuclear
export signal22. As further evidence
of the dual activity of PKI, Wiley et
al.5 demonstrated that transfection
with PKI prevents accumulation of
the catalytic subunit in the nucleus
and inhibited gene expression. A PKI
lacking a NES fails to shuttle the

catalytic subunit out of the nucleus.
However, this mutant protein inhibits
gene expression similarly to that of the
wild-type protein, suggesting that its
nuclear export function is not crucial
for inhibition of PKA activity5.
A similar mechanism might be
responsible for inactivating PKA and
thereby ending immediate-early gene
expression in osteoblasts (Figure 2).
Three isoforms of PKI exist: PKI,
PKI, and PKI. We found that PKI
is strongly expressed in osteoblasts,
whereas PKI and PKI are very
weakly expressed22. Upon stimulation
with PTH, PKA moves into and
out of the nucleus, with maximum
nuclear levels observed 15-30 minutes
after initial exposure22. These kinetics
support a model in which PKA
associates with PKI in the nucleus and
is thereby shuttled to the cytoplasm.
PKI knock down experiments provide
further support for this model. We
were able to demonstrate that knock
down of endogenous PKI using
antisense transfection or siRNA
substantially extends nuclear PKA
activity and expression of c-fos and
IL-6 genes22. Furthermore, treatment

with leptomycin B, a NES inhibitor,
blocks nuclear export of both PKI and
PKA but does not alter the time course
of gene expression22. Taken together,
these results suggest that endogenous
PKI plays a major role in terminating
immediate-early gene expression,
most likely by inactivating PKA in the
nucleus. Inactivation of PKA likely
occurs via direct binding between the
two proteins, not via their nuclear
export. Further work is necessary to
demonstrate that such an association
occurs in osteoblasts and to elucidate
the regulatory mechanisms underlying
PKI activity in the context of PTH
stimulation.
CONCLUSION
Our recent studies have shown

that endogenous PKI is primarily
responsible for termination of
immediate-early gene expression
following stimulation by PTH. Thus,
pharmacological manipulation of PKI
levels or PKI activity may alter the
balance between the catabolic and
anabolic effects of this hormone. These
studies may therefore lead to useful
therapies for conditions characterized
by excessive bone loss, such as
osteoporosis and orthopaedic implant
loosening.
ACKNOWLEDGEMENTS
Supported by NIH DK64963 to EMG.
REFERENCES
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N, Partridge NC. Parathyroid hormonedependent signaling pathways regulating genes
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3. Scott JD, Fischer EH, Demaille JG, Krebs
EG. Identication of an inhibitory region of
the heat-stable protein inhibitor of the cAMP-
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REGULATION OF PKA SIGNALING
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U S A. 1985;82:4379-83.
4. Fantozzi DA, Harootunian AT, Wen W,
Taylor SS, Feramisco JR, Tsien RY, Meinkoth
JL. Thermostable inhibitor of cAMPdependent protein kinase enhances the rate of
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5. Wiley JC, Wailes LA, Idzerda RL, McKnight
GS. Role of regulatory subunits and protein
kinase inhibitor (PKI) in determining nuclear
localization and activity of the catalytic
subunit of protein kinase A. J Biol Chem.
1999;274:6381-7.
6. Tam CS, Heersche JN, Murray TM, Parsons
JA. Parathyroid hormone stimulates the bone
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action: differential effects of intermittent and
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7. Udagawa N, Takahashi N, Jimi E, Matsuzaki
K, Tsurukai T, Itoh K, Nakagawa N, Yasuda
H, Goto M, Tsuda E, Higashio K, Gillespie
MT, Martin TJ, Suda T. Osteoblasts/stromal
cells stimulate osteoclast activation through
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8. Lee SK, Lorenzo JA. Parathyroid
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expression in murine bone marrow cultures:
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9. Itoh K, Udagawa N, Matsuzaki K, Takami
M, Amano H, Shinki T, Ueno Y, Takahashi
N, Suda T. Importance of membrane- or
matrix-associated forms of M-CSF and
RANKL/ODF in osteoclastogenesis supported
by SaOS-4/3 cells expressing recombinant
PTH/PTHrP receptors. J Bone Miner Res.
2000;15:1766-75.
10. Bikle DD, Sakata T, Leary C, Elalieh
H, Ginzinger D, Rosen CJ, Beamer W,
Majumdar S, Halloran BP. Insulin-like growth
factor I is required for the anabolic actions of
parathyroid hormone on mouse bone. J Bone
Miner Res. 2002;17:1570-8.
expression after stimulation by parathyroid

hormone or isoproterenol. Am J Physiol Cell
Physiol. 2002;283:C1432-40.
14. Greeneld EM, Shaw SM, Gornik SA, Banks
MA. Adenyl cyclase and interleukin 6 are
downstream effectors of parathyroid hormone
resulting in stimulation of bone resorption. J
Clin Invest. 1995;96:1238-44.
15. Grey A, Mitnick MA, Masiukiewicz U,
Sun BH, Rudikoff S, Jilka RL, Manolagas
SC, Insogna K. A role for interleukin-6 in
parathyroid hormone-induced bone resorption
in vivo. Endocrinology. 1999;140:4683-90.
16. Greeneld EM, Gornik SA, Horowitz
MC, Donahue HJ, Shaw SM. Regulation
of cytokine expression in osteoblasts by
parathyroid hormone: rapid stimulation of
interleukin-6 and leukemia inhibitory factor
mRNA. J Bone Miner Res. 1993;8:1163-71.
17. Pitcher JA, Freedman NJ, Lefkowitz RJ. G
protein-coupled receptor kinases. Annu Rev
Biochem. 1998;67:653-692.
18. Ahlstrom M, Lamberg-Allardt C. Rapid
protein kinase A-mediated activation of cyclic
AMP-phosphodiesterase by parathyroid
hormone in UMR-106 osteoblast-like cells. J
Bone Miner Res. 1997;12:172-178.
19. Molina CA, Foulkes NS, Lalli E,
Sassone-Corsi P. Inducibility and negative
autoregulation of CREM: an alternative
promoter directs the expression of ICER, an
early response repressor. Cell. 1993;75:875-886.
20. Hassig CA, Tong JK, Fleischer TC, Owa T,
Grable PG, Ayer DE, Schreiber SL. A role
for histone deacetylase activity in HDAC1mediated transcriptional repression. Proc Natl
Acad Sci U S A. 1998;95:3519-24.
21. Wen W, Harootunian AT, Adams SR,
Feramisco J, Tsien RY, Meinkoth JL, Taylor
SS. Heat-stable inhibitors of cAMP-dependent
protein kinase carry a nuclear export signal. J
Biol Chem. 1994;51:32214-20.
22. Chen X, Dai JC, Orellana SA, Greeneld
EM. PKI knock down inhibits termination
of immediate-early gene expression induced
by PTH. J Bone Miner Res. 2003;18:S75.
(Abstract).
11. Demiralp B, Chen HL, Koh AJ, Keller ET,

McCauley LK. Anabolic actions of parathyroid
hormone during bone growth are dependent on
c-fos. Endocrinology. 2002;143:4038-47.
12. Greeneld EM, Horowitz MC, Lavish
SA. Stimulation by parathyroid hormone of
interleukin-6 and leukemia inhibitory factor
expression in osteoblasts is an immediateearly gene response induced by cAMP signal
transduction. J Biol Chem. 1996;271:10984-89.
13. Chen, X, Dai JC, Greeneld EM.
Termination of immediate-early gene
64
6/22/05 2:23:59 PM
MANUSCRIPTS
RECOMBINANT AGGRECAN AS A MODEL FOR

ADAMTS-4/AGGRECAN INTERACTIONS
Thomas M. Hering, PhD
INTRODUCTION
ggrecan, the large proteoglycan

of the cartilage extracellular
matrix, is critical to the functional
properties of the tissue. Aggrecan
contains sites susceptible to cleavage
by matrix metalloproteinases as well as
additional sites which can be cleaved
by proteinases jof the ADAMTS
class, referred to as aggrecanases.
There is evidence that N-linked or
O-linked glycosylation may inuence
the susceptibility of aggrecanase sites
to cleavage, and that glycosylation
patterns on aggrecan may vary with
age. Aggrecan turnover, therefore,
may be regulated by the glycosylation
patterns near the aggrecanase cleavage
sites. We have constructed a series
of aggrecan expression vectors
with specic mutations to analyze
aggrecanase-mediated aggrecan
catabolism such as normally occurs
during development, and maturation,
and which is accellerated during aging
and osteoarthritis.
Aggrecan: Core protein structure and
glycosylation
Aggrecan has a 220-250 kDa core

protein which is glycosylated with
chondroitin sulfate (CS) and keratan
sulfate (KS) glycosaminoglycan (GAG)
chains as well as N- and O-linked
oligosaccharides. Two globular regions
near the amino-terminal are referred to
as the G1 and G2 domains. They are
separated by an extended interglobular
domain (IGD). A third globular region
termed G3 is found at the carboxyl
terminal end of the core protein (Figure
1). The aggrecan G1 region has been

shown to bind hyaluronan (HA). The
link protein has sequence homology to
the G1 domain of aggrecan 1, and binds
to both the G1 domain of aggrecan and
hyaluronan, to stabilize the interaction
between aggrecan and HA. Between
the G2 region and the G3 region of
the molecule are found the KS and
CS attachment regions. This extended
region is contains closely spaced
keratan sulfate and chondroitin sulfate
GAG chains, with a concentration
of KS chains in the amino-terminal
portion of this extended region 2 .
Aggrecan degradation: Identication
of protease cleavage sites
Proteolytic cleavage of aggrecan

between the G1 and G2 domains is the
dening event which releases the GAGcontaining portion of the aggrecan
molecule from the extracellular
matrix of cartilage, culminating in
cartilage destruction. The interglobular
domain of aggrecan is susceptible
to cleavage by two major classes of
proteases. One site is susceptible to
cleavage by matrix metalloproteinases
(MMPs). Several different matrix
metalloproteinases, including MMP-1
(interstitial collagenase), MMP-2 (72
kDa gelatinase), MMP-3 (stromelysin),
MMP-7 (PUMP), MMP-8 (neutrophil
collagenase), MMP-9 (95 kDa
gelatinase) and MMP-13 (collagenase3), can cleave the Asn341-Phe342
site of the aggrecan core protein
3-8
. Fragments of aggrecan resulting
from cleavage at the MMP site have
been identied in normal as well as
osteoarthritic cartilage 3,9.

Sandy et al 10 found that in bovine
cartilage explants aggrecan degradation
involves proteolytic cleavage at a second
site within the IGD, resulting in the
separation of the G1 domain from
the remainder of the proteoglycan
monomer. Synovial uid samples
collected from patients with recent
knee injury, and from patients with
early or late stages of OA, were shown
to contain two major aggrecan core
protein fragments 90 kD and 150
kDa in size 11. The NH2-terminal
analysis of both populations gave the
sequence ARGSV, indicating that both
fragments were the products of cleavage
of the aggrecan core protein between
Glu373 and Ala374 corresponding
exactly to the site of cleavage previously
found in bovine articular cartilage
explant cultures. It became apparent
that additional aggrecan core protein
heterogeneity was occurring due to
proteolysis in vivo at sites which are
both within the interglobular domain
of aggrecan or in the CS attachment
regions of the molecule. Truncation
of aggrecan was observed to occur
from the C-terminal end, as only 3050% of G1-G2-CS bearing aggrecan
molecules had the G3 domain 3. The
CS-2 regions of aggrecan contain gap
or nodal sites with an absence of
Ser-Gly sequences for CS substitution
12
. Catabolism of bovine aggrecan in
the CS-2 region was shown to involve
cleavage within these nodal sites 13.
Identication of the enzyme responsible
for the observed aggrecanase activity
6/22/05 2:23:59 PM
RECOMBINANT AGGRECAN
domain (IGD) sequence, except for
residues surrounding the MMP and
aggrecanase sites. Among the conserved
sequences are glycosylation motifs,
which suggests a mechanism by which
the chondrocyte might regulate the rate
of aggrecan catabolism.
Figure 1. Structure of bovine aggrecan showing globular (G1, G2 and G3) domains,
interglobular domain (IGD), and the extended regions of the core protein to which are bound
keratan sulfate (KS) and chondroitin sulfate (CS) chains. Three CS-containing domains are
present in bovine aggrecan, designated CS-1, CS-2 and CS-3, on the basis of specic patterns
of repeated sequence in each region.
was accomplished using a direct

approach. Cartilage aggrecanase activity
was characterized with respect to assay
kinetics, pH and salt optima, heat
sensitivity and stability 14. Sensitivity to
different protease inhibitors indicated
that aggrecanase is a metalloproteinase.
It was shown that atrolysin C, a
snake venom metalloproteinase with
homology to the ADAM (a disintegrin
and metalloptoteinase domain) family
of proteins, could cleave aggrecan at
the aggrecanase (Glu373-Ala374) site 15.
These data suggested that aggrecanase
is a member of this proteinase family.
This was conrmed when aggrecanase1 was puried from IL-1 stimulated
bovine nasal cartilage chondrocytes,
and the human ortholog was cloned
and sequenced 16. Aggrecanase-1
was found to be a member of the
ADAMTS family of proteins, and
was designated ADAMTS-4 (a
disintegrin and metalloproteinase
with thrombospondin motifs-4). A
second aggrecanase (ADAMTS-5) was
subsequently identied 17. Another
ADAM family member, ADAMTS1 was also recently determined to be
aggrecanase 18.
Analysis of aggrecan degradation in
bovine articular cartilage explants
suggested that the cleavage of
aggrecan in the IGD by aggrecanase
is preceeded by or may require prior
proteolytic processing within the
CS-substituted region of the core

protein 19. It was demonstrated 20
using recombinant ADAMTS-4
that the protease cleaves at four sites
within the CS-rich region of aggrecan,
and that two of these cleavages in
the CS-2 domain appear to occur
more efciently than cleavage within
the IGD at the Glu373-Ala374
bond. (Figure 2). Cleavage of intact
aggrecan (Fig. 2; #1) rst occurs at
Glu1666-Gly1667, generating a large
G1 domain-containing fragment
(Fig. 2; fragment #2) and a large G3
domain-containing fragment (Fig. 2;
fragment #3). Fragment #2 is then
trimmed by cleavage at the Glu1480Gly1481 bond. Cleavage within the
IGD at the Glu373-Ala374 bond then
occurs to produce a fragment (Fig.
2; fragment #4) with the neoepitope
NITEGE at the C-terminus. Two
additional cleavages occur within the
G3 containing fragment produced by
the rst cleavage, at Glu1771-Ala1772
and between Glu 1871 and Leu 1872.
Age related aggrecan glycosylation
and aggrecanase cleavage
Conservation of protease cleavage

sites between species suggests a role
in regulated turnover of aggrecan 12.
Although the amino acid sequence of
the HA binding domains in the G1
region of aggrecan is highly conserved,
there is considerably less interspecies
conservation within the interglobular
Age-related differences is aggrecan

glycosylation have been demonstrated,
which may relate to differences in
turnover rates with age. Cartilage
isolated from calves and steers shows
glycosylation differences related to
maturation when cultured as explants
21
. In monolayer culture, newly
synthesized calf high buoyant density
fraction proteoglycans were found
to be larger, withlonger CS chains
and lower ratios of keratan sulfate
chains/chondroitin sulfate chains
than did steer high buoyant density
proteoglycans 22. These maturation
related differences were also found to
be present in proteoglycan isolated
from the extracellular matrix of
steer and calf cartilage. Age related
patterns of substitution with N-linked
oligosaccharides or N-linked KS at each
of the sites within the G1 region has
been characterized in bovine aggrecan
23
. Articular chondrocytes may have an
inherent program that results in the
biosynthesis of qualitatively different
aggrecan at different ages.
Pratta et al. 24 have demonstrated
that age-related changes in aggrecan
glycosylation affect cleavage by
aggrecanase. Deglycosylation of
aggrecan by enzymatic removal of GAG
chains results in diminished cleavage
at the aggrecanase site in the IGD.
MMP-3 cleavage at the site in the
IGD was not affected by glycosidase
treatment. Furthermore, it was shown
that removal of KS prevented cleavage
at the aggrecanase site, but removal of
CS did not.
66
6/22/05 2:24:00 PM
MANUSCRIPTS
Figure 2. Sequential degradation of aggrecan by ADAMTS-4, as described by Tortorella, et al. 24. Fragments 1-4 would be predicted to be
detectible by Western blot analysis using antisera raised against the G1 or G3 domains. An additional neoepitope (NITEGE) is produced by
ADAMTS-4-mediated cleavage within the interglobular domain.
Recombinant aggrecan: A model for

ADAMTS-4/aggrecan interactions
Our laboratory completed the

sequencing of the bovine aggrecan
core protein 12. Comparison of the
bovine aggrecan sequence with
other species revealed similarities
in regions that surrounded sites for
proteolytic cleavage. Regulated
catabolism of aggrecan by proteinases
is likely to be important for tissue
homeostasis, especially during
development and growth, and for
repair and maintenance of cartilage.
Differences in catabolism are likely
to be a component of cartilage
destruction in OA. To investigate
aggrecan degradation by proteinases,
we produced an expression plasmid
for the synthesis of recombinant

bovine aggrecan (rb-aggrecan) in
mammalian cells. The advantage
of this approach is that specically
mutated aggrecan can be produced in
this system, enabling targeted analysis
of individual cleavage sites.
Overlapping cDNA clones for bovine
aggrecan were joined to generate a
single full length aggrecan cDNA in
the vector pED (Wyeth Research).
This construct was used to transiently
transfect COS-7 cells. Aggrecan
from transfected COS-7 conditioned
media was puried by Sephadex G50
gel ltration and DEAE Sephacel
chromatography. The puried rbaggrecan was characterized using a
number of approaches. Hydrodynamic
size of rb-aggrecan monomers was

determined by Sepharose CL-2B
chromatography. GAG chain length
was determined by Sepharose CL-6B
chromatography of papain-digested rbaggrecan. Conditions were established
for digestion of recombinant aggrecan
with recombinant human ADAMTS4 (aggrecanase-1), Following
chondroitinase ABC, keratanase and
keratanase II digestion, core protein
fragments were analyzed by gradient
SDS-PAGE and Western blot analysis
using antisera to the G1 and G3
domains, and an antiserum to the Cterminal sequence (NITEGE) of the
fragment generated by cleavage within
the IGD.
Characterization of rb-aggrecan
6/22/05 2:24:00 PM
RECOMBINANT AGGRECAN
of the gel. Over two hours, there was
observed an incubation time-dependent
loss of the full sized core protein band
(band #1), and increase in a bands
reactive with the G3 antibody (band
#2) and G1 antibody (bands #3 and
#4). The lower molecular mass G1reactive band (#4) is also reactive
with the antibody directed toward
the aggrecanase-generated neoepitope
-NITEGE. It should be noted that
the C-terminus of fragment 2 and the
N-terminus of fragment 3 have not yet
been conrmed. Fragments labeled 1,
2, 3, and 4 may correspond to similarly
labeled fragments in Figure 2, or they
may have been generated by cleavage at
different CS-2 region sites.
Figure 3. Degradation of rb-aggrecan by recombinant ADAMTS-4. Samples were degraded by

rhADAMTS-4 for the indicated times, and were analyzed by SDS-PAGE and Western blotting,
immunodetected using antisera raised against (A) the G3 domain, (B) the G1 domain, and
(C) the NITEGE neoepitope. The position of molecular mass standards (kDa) are indicated
to the right of the gure. Bands likely to correspond to full sized core protein or fragments
diagrammed in Fig. 2 are indicated by the numbered arrows.
revealed some differences in the

glycosaminoglycan chains, likely due
to biosynthetic differences between
COS7 cells and chondrocytes.
Recombinant aggrecan has a smaller
hydrodynamic size compared with
steer articular cartilage aggrecan and
aggrecan puried from chondrocyte
cultures. The molecular weight of
glycosaminoglycan chains is higher
for rb-aggrecan than for bovine
chondrocyte aggrecan or articular
cartilage derived aggrecan. Core
protein reactivity with a specic
monoclonal antibody indicated
the presence of chondroitin sulfate
chains. Reactivity with a monoclonal
antibody specic for keratan sulfate
was signicantly lower for rb-
aggrecan than for cartilage-derived

aggrecan.
Time-course digestion of recombinant
aggrecan with rhADAMTS-4 was
performed with Western blot analysis
of proteolytic fragments generated
at discrete time intervals (Figure
3). An antibody raised against the
G3 domain was used to detect Cterminal fragments, and a G1 domain
antibody was used to detect N-terminal
fragments. The fragment generated
by ADAMTS-4 cleavage within the
IGD was detected with an antibody
to the new C-terminus generated with
cleavage (anti-NITEGE). Prior to
digestion, the full-sized core protein
was evident as a band near the top
Current efforts in our laboratory are

directed toward the testing of a number
of mutant forms of aggrecan using an
assay similar to that illustrated in Figure
3, to determine whether certain highly
conserved residues of the aggrecan core
protein are required for interactions
with aggrecanase. Some of these highly
conserved amino acids have been
shown to be glycosylated in an agedependent manner, having O-linked or
N-linked oligosaccharides, or keratan
sulfate GAG chains. Our preliminary
data indicates that these glycosylated
residues may play an important role
in regulating aggrecanase-aggrecan
interactions.
ACKNOWLEDGMENTS
Members of the laboratory who have

worked on this project include Tru
Huynh, Lori Duesler, John Kollar, Dr.
David Flory, Dr. Judith Varelas, Dr.
Najam Kazmi, and Hazuki Miwa. We
thank Dr. Thomas Gerken (Depts. of
Pediatrics and Biochemistry, CWRU)
for many helpful discussions. We
are grateful for antisera provided by
Dr. John Sandy (Shriners Hospital,
Tampa, FL), Dr. John Mort (Shriners
Hospital, Montreal, Quebec Canada),
and Dr. Kurt Doege (LSU Medical
68
6/22/05 2:24:01 PM
MANUSCRIPTS
Center, Shreveport, LA). We thank
Dr. Elisabeth Morris (Wyeth Research,
Cambridge, MA) for supplying us with
recombinant human ADAMTS-4.
Funding for this work was provided by
NIH grants NIH AG17303, AR47892
and AR07505.
9. Fosang AJ, Last K, Maciewicz RA. Aggrecan

is degraded by matrix metalloproteinases
in human arthritis. Evidence that matrix
metalloproteinase and aggrecanase activities can
be independent. J Clin Invest, 98(10): 2292-9,
1996.
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TE, Murphy G, Hamilton JA. The
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Ross OH, Abbaszade I, Burn T, Arner E. Sites
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EC. The interglobular domain of cartilage
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2. Arner EC, Pratta MA, Trzaskos JM,
Decicco CP, Tortorella MD. Generation and
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3. Barry FP, Rosenberg LC, Gaw JU, Baw JU,
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Murphy G, Hamilton JA. Cleavage of
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22. Thonar EJ-MA, Buckwalter JA, Kuettner
KE. Maturation-related differences in the
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23. Tortorella MD et al. Purication and cloning
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14. Hering TM, Kollar J, Huynh TD, Sandell

LJ. Bovine chondrocyte link protein cDNA
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17. Kuno K, Okada Y, Kawashima H, Nakamura
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human cartilage. Evidence for both matrix
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19. Pratta MA, Tortorella MD, Arner EC. Agerelated changes in aggrecan glycosylation affect
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20. Sandy JD, Flannery CR, Neame PJ,
Lohmander LS. The structure of aggrecan
fragments in human synovial uid. J. Clin.
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CR. Catabolism of aggrecan in cartilage
explants. Identication of a major cleavage site
within the interglobular domain. J Biol Chem,
6/22/05 2:24:01 PM
2004 CHIEF RESIDENTS FUTURE PLANS
R. Shay Bess
Spine
Washington University
A. Michael Harris
Trauma
Carolinas Medical Center
Robert Lowe
Spine
Rush University
Jeffrey Roh
Spine
Hospital for Special Surgery
Joseph Smucker
Spine
Emory University
Andrea Young
Sports Medicine
UCLA Medical Center
70
6/22/05 2:24:02 PM
INCOMING INTERNS CLASS OF 2009
Michael Chen
Northwestern University
Steven Fitzgerald
Tulane University
Raymond Liu
Johns Hopkins University
Christopher McAndrew
University of Tennessee
Michael Paczas
University of Michigan
Benjamin Smucker
Indiana University
6/22/05 2:24:04 PM
ALUMNI NOTES
1960 Linke, Thomas F.
Bay Village, OH
Retired 1/1/00. First wife died 1/7/96.
Complications of MS. Remarried 1/16/99.
1962
1974
Kan, Robert
1975
Malone, Bruce
1978
Henderson, Bruce
1984
Bos, Gary
1986
Figgie, Mark
Hanover, NH
Still serving as the Wm. N. & Bessie Allyn Chairman
of Surgery in Orthopaedics at Dartmouth. Practice
focus is hip and knee replacement and hip and knee
arthroscopy.
1987
Boyd Jr, Allen D.
Sammarco, G. James
1987
Dollinger, Beth
NY
3 daughters, 2 teenagers. Planning a trip to
Cambodia for Orthopaedics Overseas. Still married
to Alan Angell.
1990
Junglass, William
1991
Bouchard, Jacques
1992
Soldatis, Jeff
Matern, Donald I.
Peoria, AZ
Retired from practice in 1991 - Delighted with
retirement.
Pierce, Donald S.
Wellesley, MA
Now retired from surgery (2000, age 70); teaching to
age 73, maybe longer. Academic life at Harvard was a
wonderful life experience. I thank Dr. Herndon for
pointing me in the direction of an academic practice.
Currently healthy and active, skiing and sailing with
my grandchildren.
1967
Cohen, Lawrence
1971
Goldman, Sidney
Lutz, FL
Wife-Betty; 4 children; Have lived in Tampa since
leaving residency. Tampa VA Hospital.
Key West, FL
Retiring Sept. 04. Moving full time to Key West,
Florida with wife, Deborah who is an artist and with
Rosie who is a 2 year old black standard schnauzer.
Mayor, Michael B.
1972
1973
Cincinnati, OH
Clinical Orthopaedic Society, President 2003-2004.
American Orthopaedic Foot and Ankle Society
President 1996-1997. American Orthopaedic
Association. Adult Orthopaedic Foot and Ankle
Reconstructive Fellowship, Director. Editor of ten
books and journals, contributing author of 36
chapters in books, author of 65 full length published
scientic articles in juried journals.
Alanseth, Paul
Tampa, FL
Orthopaedic practice in Tampa, FL. Has had
opportunity to serve in USAF and Special Forces in
Baghdad, Iraq in May 04 in my capacity as
orthopaedic trauma consultant to USSOCOM
(Special Forces) HQ in Tampa.
Towson, MD
I am retired and am no longer doing any
orthopaedics. Ill be spending most of 2004 in
Europe and Australia.
Austin, TX
Currently in active practice with special interest in
joint replacement. The oldest living doc on the
trauma rotation - about to elect emeritus status.
Serving on the AMA delegation from Texas and a
member of the Board of Trustees of the 39,000
member TMA.
Bloomeld, MI
4 kids-3 boys, 1 girl. All married (3 grandchildren).
Expanded our practice May 03 - added Christopher
Tisdel, MD (also a Case graduate). Now the practice
is called Oakland Orthopaedic Partners.
Columbus, OH
Currently Professor and Chair, Ohio State University
Dept. of Orthopaedics.
New York, NY
5/2003, appointed Chief of Surgical Arthritis service
at Hospital for Special Surgery.
Rochester, NY
Associate Professor, Division Chief Adult
Reconstructive Surgery, University of Rochester.
Highland Hts, OH
5 children. Solo practice looking for a partner!
Calgary, CA
Chairman, University of Calgary Spine Program.
Program Director, University of Calgary Orthopaedic
Surgery. Chairman, Exam Committee Royal College
of Physicians and Surgeons of Canada. Married 22
years. 3 children (18, 16, 13).
Northampton, MA
New England Orthopaedic Surgeons. Kids: Erin, 8;
Sam, 5. Married, still, to Christy (she keeps me).
Hello to all other 92s.
72
6/22/05 2:24:04 PM
1993
Tisdel, Christopher
Birmingham, MI
Left academic practice at Cleveland Clinic after 7
years, joined private practice based out of St. Josephs
Mercy Hospital. Suburban Detroit, 3 man group,
one partner - Bruce Henderson - is also Case
Resident Alumnus.
1994
Ziran, Bruce
1995
Phillips, Frank
1996
Boardman, OH
Recent move from University of Pittsburgh to St.
Elizabeths / NEOUCOM. Director of Orthopaedic
Trauma. New book release on fractures due later this
year. Wife, Marcela. Music CD being released - Jazz/
Blues.
2000
Lexington,MA
Karan (son) 13yrs; Rohan (son) 6 yrs; Maya (girl,
born at CCF) 3 yrs. Sharmila (wife) completed
fellowship in Occupational and Environmental
Medicine at Harvard School of Public Health. Both
of us have clinical teaching positions at Harvard
Medical School.
2001
Married 10/9/1999 to Daniel Vickers. Private

practive Ohio Valley Orthopaedics since 1/97.
Birth of rst child 2/24/03, Sydney Anne Vickers.
Expecting second child 6/24/04!
1998
Davis Jr, William L.
1999
Elyaderani, Mehrun
Mahwah, NJ
In private practice with ve other orthopaedic
surgeons and two physiatrists with ofces in
Rockland and Orange Counties, NY. Son, Taylor,
just turned 4. Hoping for number two!
Hoang, Bang
Aliso Viejo, CA
Assistant Professor, UC Irvine, Orthopaedic
Oncology.
Stanford, Ralph
Sydney, Australia
Dept. of Orthopaedics, Prince of Wales Hospital.
Daughter, Imogen, 18 months old.
Hilibrand, Alan S.
Schiering Vickers, Lisa Cincinnati, OH
St. Louis, MO
Practice: Spine surgery, Midcounty Orthopaedics,
621 S. New Ballas Rd, St Louis, MO 63141. Births:
Alex 1998, John 2002.
Mudgal, Chai
Chicago, IL
Professor of Orthopaedic Surgery, Rush University
Medical Center.
Philadelphia, PA
Associate Professor fo Orthopaedic Surgery, Director
of Medical Education, Jefferson Medical College /
The Rothman Institute. Wife, Gittel Hilibrand
(same as during fellowship). Children, Miryl (DOB
8/5/98), Ari (DOB 12/27/00).
Curlyo, Lukasz
2002
Bosita, Ray
Plano, TX
My wife, Judy (Ob/Gyn), and I love being in Dallas,
Texas. I have a great job - there is light at the end of
the tunnel! Thank you to all of the UH residents
who helped me so much during the year back in
Cleveland. You have a wonderful program - be proud
of it! You have excellent teachers who have built a
strong department at Case.
Huang, Robert
Houston, TX
Married 8/31/2003 to Karen Elaine Hansen.
Westlake, OH
Married Melinda Peterson on July 26, 2003 and are
expecting their rst child in June 2004.
Kahlon, Randeep (Deep) Newark, DE

Serve as Associate Director, Orthopaedic Trauma
Service at Christiana Care Level I Trauma Center
and specializing in all disorders of the upper
extremity. Expecting our rst child in February 04.
2000
Archdeacon, Michael
Cincinnati, OH
In September 2003, I was promoted to Director,
Division of Orthopaedic Trauma, Department of
Orthopaedic Surgery, University of Cincinnati.
6/22/05 2:24:04 PM
FACULTY RESEARCH
Douglas G. Armstrong, M.D.
Journal Articles and Book Chapters
Brian Johnstone, PhD

Ferrick M, Armstrong DG. Pediatric Hip Disorders - a

review of 2002-03. Current Opinion in Orthopaedics 2003
14(6): 370-374.
Gilbert JG, Sturm PF, Hatch RS, Schwend RM, Robertson
WW, Armstrong DG. Extremity Injuries. (ch 88) in Ziegler
MM, Azizkhan RG, Weber TR, ed. Operative Pediatric
Surgery, McGraw Hill; New York, 2003
Yee AJ, Bae HW, Friess D, Robbin M, Johnstone B, Yoo JU.

Augmentation of rabbit posterolateral spondylodesis using
a novel demineralized bone matrix-hyaluronan putty. Spine.
2003; 28:2435-2440.
Johnstone B, Stewart M, Yoo J. Cell sources for cartilage
tissue engineering. In: Freshney I, Vunjak-Novakovic G,
editors. Culture of Cells for Tissue Engineering. Wiley, New
York (in press).
Johnstone B, Angele P, Yoo J, Goldberg VM. Tissue
engineering of meniscus. Orthopaedic Tissue Engineering: Basic
Science and Clinical Practice. Marcel Dekker, NY (in press).
Yoo J, Johnstone B. Tissue engineering of intervertebral disc.
Orthopaedic Tissue Engineering: Basic Science and Clinical
Practice. Marcel Dekker, NY (in press).
Johnstone B, Yoo J. Meniscus repair through tissue
engineering. In: Sandell L, Grodzinsky A, editors. Tissue
Engineering in Musculoskeletal Clinical Practice. American
Academy of Orthopaedic Surgeons Symposium, Park Ridge
(in press).
Abstracts and Presentations
Turning stem cells into chondrocytes - from basic science
to tissue engineering. July 3, 2003, SPUR Invited Lecture,
CWRU, Cleveland, OH.
Siesel G, Johnstone B, Bogie K. Electrical stimulation of
human dermal broblasts. August 1, 2003, SPUR Poster
Session, CWRU, Cleveland, OH.
Daniel R. Cooperman, M.D.

Ragab, AA, Steward, SL, Cooperman, DR: Implications of

subtalar joint anatomic variation in calcaneal lengthening
osteotomy. J. Peds. Ortho., 23:79-83, 2003.
Fractures in Children younger than age 1 year: Importance of
collaboration with child protention services. Banaszkiewicz,
PA., Scotland, TR, Myerscough, EJ: J. Pediatr. Orthop.
2002;22:740-744. Commnet in the Quarterly Child Abuse
Medical Update. Vol. X, No. 2, April, 2003.
Injuries when childrne reportedly fall from a bed or couch.
Hennrikus, WL, Shaw, BA, Gerardi, JA: Clin. Orthop.
2003; 407:148-151. Comment in the Quarterly Child Abuse
Medical Update. Vol. X No. 3, July 2003, pp. 26-27.
Allison Gilmore, M.D.
Gilmore, A and Thompson, GH: Common Childhood Foot

Deformities. Consultant for
Pediatrics, Vol 2:63-71, February 2003
Edward M. Greeneld, Ph.D.
Rubin J, Greeneld E. Osteoclast origin and differentiation.

In: Bronner F, Farach-Carson MC, Rubin J, editors. Bone
Resorption, Volume 2 in Topics in Bone Biology Series.
Springer-Verlag, London, in press.
PKI knock down inhibits termination of immediate-early
gene expression induced by PTH. Plenary Poster Session,
Annual Meeting of the American Society for Bone & Mineral
Research (presentation given by X. Chen). September 19 to
25, 2003, Minneapolis, MN.
Inhibition of PTH signaling by protein kinase inhibitor.
Midwest Connective Tissue Workshop. November 14 to 15,
2003, Chicago, IL.
P. Hunter Peckham, PhD

Kilgore KL, Peckham PH, Keith MW, Montague FW,

Hart RL, Gazdik MM, Bryden AM, Snyder SA, Stage TG.
The durability of implanted electrodes and leads in upper
extremity neuroprostheses. Journal of Rehabilitation Research
and Development. 2003; 40:457-468.
Wuolle KS, Bryden AM, Peckham PH, Murray PK,
Keith M. Satisfaction with upper-extremity surgery in
individuals with tetraplegia. Archives of Physical Medicine and
Rehabilitation. 2003; 84:1145-1149.
Bryden AM, Wuolle KS, Murray PK, Peckham PH.
Perceived outcomes and utilization of upper extremity
surgical reconstruction in individuals with tetraplegia at
model spinal cord injury systems. Spinal Cord. 2004; Feb 3
(e-pub ahead of publication).
74
6/22/05 2:24:04 PM
Re-engineering the paralyzed nervous system. Dedication

of Wallace H. Coulter School of Engineering, Clarkson
University. October 11, 2003, Potsdam, NY.
Restoring upper extremity function with neuroprostheses.
IGERT Seminar Series, Case Western Reserve University.
November 24, 2003, Cleveland, OH.
FDA and CMS approval for an implantable FNS system
from a researchers perspective. Thirty-Fourth Neural
Prosthesis Workshop, National Institutes of Health. October
21 to 23, 2003, Bethesda, MD.
Neuroprostheses for functional restoration: current status
and future directions. Featured Speaker, Ninth International
Symposium on Neural Regeneration. December 10 to 13,
2003, Pacic Grove, CA.
Clare M. Rimnac, PhD
Gencur SJ, Rimnac CM, Kurtz SM. Failure

micromechanisms during uniaxial tensile fracture of
conventional and highly crosslinked ultra-high molecular
weight polyethylene used in total joint replacements.
Biomaterials. 2003; 24:3947-3954.
Kurtz SM, Hozack W, Marcolongo M, Turner J, Rimnac
C, Edidin A. Degradation of mechanical properties
of UHMWPE acetabular liners following long-term
implantation. Journal of Arthroplasty. 2003; 18 (7 suppl
1):68-78.
Collier MB, Kraay MJ, Rimnac CM, Goldberg VM. Critical
evaluation of contemporary software methods for quantifying
polyethylene wear following total hip arthroplasty. Journal of
Bone and Joint Surgery Am. 2003; 85:2410-2418.
Bergstrm JS, Rimnac CM, Kurtz SM. An augmented
hybrid constitutive model for simulation of unloading
and cyclic loading behavior of conventional and highly
crosslinked UHMWPE. Biomaterials. 2004; 25:2171-2178.
Luis A. Solchaga, PhD
Dennis JE, Solchaga LA, Caplan AI. Human mesenchymal

stem cells for cartilage repair. In: Grisola S, Miana MD,
Bendala-Tufanisco E, editors. Mesenchymal Stem Cells: Biology
and Potential Clinical Uses. Madrid, Spain: Ministerio de
Sanidad y Consumo, 2003
Solchaga LA, Welter JF, Lennon DP, Caplan AI. Generation
of pluripotent stem cells and their differentiation to the
chondrocytic phenotype. In: Sabatini M, Pastoureau P,
DeCeuninck F, editors. Osteoarthritis: Methods and Protocols.
Totowa, NJ: The Humana Press, in press.
Welter JF, Solchaga LA, Stewart MC. High efciency non-
viral transfection of primary chondrocytes. In: Sabatini M,

Pastoureau P, DeCeuninck F, editors. Osteoarthritis: Methods
and Protocols. Totowa, NJ: The Humana Press, in press.
FGF-enhanced chondrogenesis. Skeletal Research Center
Seminar Series. October 2003, Cleveland, OH.
Solchaga L, Gao J, Goldberg VM, Caplan AI. Hyaluronanbased scaffolds for articular cartilage tissue engineering.
Hyaluronan 2003. October 2003, Cleveland, OH.
Solchaga L, Gao J, Temenoff, JS, Mikos AG, Caplan AI,
Goldberg VM. Hyaluronan- versus poly-ester-based scaffolds
in the repair of osteochondral defects. Hyaluronan 2003.
October 2003, Cleveland, OH.
Hedberg EL, Shih C, Solchaga L, Caplan AI, Mikos AG.
Controlled release of hyaluronic acid oligomers from
biodegradable polymeric microparticle. Annual Meeting
of the Biomedical Engineering Society. October 2003,
Nashville, TN.
George H. Thompson
Gilmore A, Thompson GH: Common childhood foot

deformities. Consultant for Pediatricians. Feb 2003 p. 63-71.
Grisoni N, Ballock RT, Thompson GH: Bilateral pedicle
fractures of the second cervical vertebrae versus synchondrosis
in a child. Clin. Orthop., 413:238-242,2003.
Huang RP, Bohlman HH, Thompson GH, Poe-Kochert
C: Predictive Value of Pelvic Incidence in Progression of
Spondylolisthesis/ Spine 28:2381-2385,2003.
Florentino-Pineda I, Thompson GH, Poe-Kochert C,
Blakemore LC, Haber LL, Huang RP: The effect of Amicar
in perioperative blood loss in idiopathic scoliosis. The results
of a prospective, randomized double-blind study. Spine 28,
2004(In Press).
Bess RS, Robbin M, Bohlman HH, Thompson GH: Spinal
exostoses: Analysis of twelve cases and review of the literature.
Spine 28, 2004(In Press).
Thompson, GH: Multiple hereditary exostoses. In: The
NORD Guide to Rare Diseases. Philadelphia. Lippincott,
Williams & Wilkens, 2003, p. 191.
Thompson, GH and Blakemore, LC: Pharmacologic agents
that minimize perioperative blood loss in spine surgery. In:
Spinal Deformities - The Comprehensive Text. Dewald,
R(ed). New York, Thieme, 2003, p. 2000-2005.
Huang, RP and Thompson, GH: Antibiotic therapy for
spine infections. In: Spinal Deformities - The Comprehensive
Text. DeWald, R(ed). New York, Thieme, 2003, p. 188-194.
Thompson, GH and Scoles PV. Orthopedic problems. Part
XXXI, Section 1, Chapters 662-673. In: Nelsons Textbook
of Pediatrics. 17th edition. Behrman RE, Kleigman RM and
6/22/05 2:24:04 PM
RESEARCH FACULTY
Jenson HB (eds)Philadelphia, W.B. Saunders Co., 2003, p.

2251-2297.
Huang, RP and Thompson GH: Capsulotomy, midfoot,
extensive (resistant clubfoot). In: Orthopaedic Pocket
Procedures: Pediatrics. Drennan JC and Blasier RD (eds).
McGraw-Hill. 2003, p. 326-331.
Huang, RP and Thompson, GH: Correction hammertoe In:
Orthopaedic Pocket Procedures: Pediatrics. Drennan JC and
Blasier RD (eds), McGraw-Hill, 2003, p. 332-333.
Thompson, GH: Gait disturbances. In: Practical Strategies in
Pediaric Diagnosis and Therapy. 2nd edition. Kliegman, RM,
Greenbaum, LA and Lye, PS(eds) Philadelphia, Harcourt
Health Sciences, 200r(In Press).
Ron Triolo, PhD
Agarwal S, Triolo RJ, Kobetic R, Miller M, Bieri C, Kukke

S, Rohde L, Davis JA Jr. Long-term user perceptions of an
implanted neuroprosthesis for exercise, standing and transfers
after spinal cord injury. Journal of Rehabilitation Research &
Development. 2003; 241-252.
Bogie K, Triolo RJ. The effects of regular use of
neuromuscular electrical stimulation on tissue health. Journal
of Rehabilitation Research & Development. 2003; 40:469-476.
Audu ML, Kirsch RF, Triolo RJ. A computational technique
for determining the ground reaction forces in human bipedal
stance. Journal of Applied Biomechanics. 2003; 19:361-371.
Chae J, Kilgore K, Creasey G, DiMarco A, Triolo R.
Neuromuscular electrical stimulation in spinal cord injury.
In: Kirschblum S, Campagnolo D, DeLisa J, editors. Spinal
Cord Medicine. Philadelpha PA: Lippincott Williams &
Wilkins, 2003, Chapter 25, p 360-388.
Kobetic R, Marsolais EB, Triolo R. The next step: restoring
walking after paralysis. In: Agramonte JR, editor. Human
Walking, 3rd edition. Philadelphia PA: Lippincott Williams &
Williams (in press).
Strategies to improve transfers and gait. American Society
of Neurorehabilitation Workshop: Scientic Basis of
Neurorehabilitation for Spinal Cord Injury and Stroke.
August 9, 2003, Cleveland, OH.
Standing, transfers and walking with FES after spinal cord
injury. American Society of Neurorehabilitation Workshop:
Scientic Basis of Neurorehabilitation for Spinal Cord Injury
and Stroke. August 9, 2003, Cleveland, OH.
Gait and human motion analysis. American Society
of Neurorehabilitation Workshop: Scientic Basis of
Neurorehabilitation for Spinal Cord Injury and Stroke.
August 9, 2003, Cleveland, OH.
Multicenter clinical evaluation of an implanted
neuroprosthesis for standing transfers. American Paraplegia

Society. September 2003, Las Vegas, NV.
Feasibility of controlling seated posture with functional
electrical stimulation. American Paraplegia Society.
September 2003, Las Vegas, NV.
Lower extremity FES treatment options in SCI. Case Western
Reserve University School of Medicine Physical Medicine
and Rehabilitation Resident Seminar, MetroHealth Medical
Center. December 4, 2003, Cleveland, OH.
Amanda Weiss-Kelly, M.D.
Weiss Kelly AK. The Pediatric Athlete. In: Sports Medicine:

Just the Facts. OConnor, Sallis
R, Wilder R, Patrick S (Eds). McGraw-Hill Professional, New
York In Press
Weiss Kelly AK. The Pediatric Athlete. In:Sports Medicine:
Board Review and Examination.
OConnor, Sallis R, Wilder R, Patrick S (Eds). McGraw-Hill
Professional, New York In Press
Jung U. Yoo, MD
Yee AJ, Bae HW, Friess D, Robbin M, Johnstone B, Yoo JU.

Augmentation of rabbit posterolateral spondylodesis using
a novel demineralized bone matrix-hyaluronan putty. Spine.
2003; 28:2435-2440.
Johnstone B, Stewart M, Yoo J. Cell sources for cartilage
tissue engineering. In: Freshney I, Vunjak-Novakovic G,
editors. Culture of Cells for Tissue Engineering. Wiley, New
York (in press).
Johnstone B, Angele P, Yoo J, Goldberg VM. Tissue
engineering of meniscus. Orthopaedic Tissue Engineering: Basic
Science and Clinical Practice. Marcel Dekker, NY (in press).
Yoo J, Johnstone B. Tissue engineering of intervertebral disc.
Orthopaedic Tissue Engineering: Basic Science and Clinical
Practice. Marcel Dekker, NY (in press).
Johnstone B, Yoo J. Meniscus repair through tissue
engineering. In: Sandell L, Grodzinsky A, editors. Tissue
Engineering in Musculoskeletal Clinical Practice. American
Academy of Orthopaedic Surgeons Symposium, Park Ridge
(in press).
76
6/22/05 2:24:05 PM
FACULTY GRANTS
RESEARCH GRANTS
Edward M. Greeneld, PhD

NIH
NIH
NIH
Cellular Mechanisms of Implant Loosening

Support of Osteoclast Differentiation by Mesenchymal Cells
Termination of PTH Responses in Osteoblasts
2000-2004
2002-2006
2003-2007
Transcriptional Control of Chondrogenic Differentiation

Regulation of Aggrecan Catabolism
In Vitro Chondrogenesis of Bone Marrow-Derived
Mesenchymal Cells (Brian Johnstone, PhD, Principal
Investigator)
1999-2004
2001-2006
2001-2005
Tissue-Engineered Meniscus Repair

Mesenchymal Cells
Transcriptional Control of Chondrogenic Differentiation
(Thomas M. Hering, PhD, Principal Investigator)
Posterolateral Lumbar Fusion Using a Strip Formulation of
DBM (Jung U. Yoo, MD, Principal Investigator)
Prevention of Cartilage Degradation by Green Tea (Tariq M.
Haqqi, PhD, Principal Investigator)
2002-2006
2001-2005
VA Functional Electrical Stimulation (FES) Center

Implantable FES for Control of the Extremities for Spinal
Cord Injury
Senior Research Career Scientist Award
Multichannel Implantable System for Neural Control
Magnuson Award
Integrated Engineering and Rehabilitation Training (Training
Grant; Patrick Crago, PhD, Principal Investigator)
Restoration of Hand and Arm Function by Functional
Neuromuscular Stimulation (Contract; Robert Kirsch, PhD,
Principal Investigator)
Development of Networked Implantable Neuroprostheses
(Biomedical Research Partnership)
Neurostimulation and Neuromodulation Partnership
Restoration of Hand-Arm Function with Neuroprostheses
2002-2006
2002-2004
Thomas M. Hering, PhD

NIH
NIH
NIH
Brian Johnstone, PhD

NIH
NIH
NIH
Musculo-skeletal
Transplant Foundation
NIH
1999-2004
2003-2004
2001-2006
P. Hunter Peckham, PhD

VA
VA
VA
NIH
VA
NIH
NIH
NIH
State of Ohio
FDA
2000-2007
1999-2004
2001-2003
1999-2004
2001-2005
2001-2004
2003-2006
2003-2006
6/22/05 2:24:05 PM
FACULTY GRANTS
Clare M. Rimnac, PhD

Musculo-skeletal
NIH
NIH
NIH
NIH
NIH
Luis A. Solchaga, PhD
Arthritis Foundation
NIH
Ronald J. Triolo, PhD
NIH
NIH
VA
VA
VA
VA
NIH
NIH
VA
Jung U. Yoo, MD
Musculo-skeletal
NIH
NIH
Effect of Radiation Sterilization and Mechanically Induced

Damage on the Fragility of Allograft Cortical Bone
Constitutive Model for Polyethylenes in Total Joint
Replacements
Mechanics and Performance of Traceable UHMWPE (Ultra
High Molecular Weight Polyethylene) Hip Implants (on
subcontract to Drexel)
Short and Long Fatigue Crack Growth in Bone
Non-Linear Stress-Strain Behavior of Cortical Bone (Dwight
T. Davy, PhD, Principal Investigator)
Strength and Resorption of Biodegradable Skull Implants
(David Dean, PhD, Principal Investigator)
2003
Chondrogenic Preconditioning of Cell/Scaffold Constructs

for the Repair of Large Cartilage Defects (Jean F. Welter,
MD, PhD, Principal Investigator)
2002-2005
Controlled Cartilage Repair (Victor M. Goldberg, MD,

2000-2005
Enhancing Neuroprosthesis Performance with Nerve Cuff

Electrodes
Realtime Interface for Implanted FNS Systems with
StimGym II
Facilitating Ambulation After Incomplete SCI (Spinal Cord
Injury) with FES
Standing and Transfers After SCI with Implanted
Neuroprostheses
Effects of Trunk Stimulation on Seated Wheelchair Function
After SCI
Pressure Sore Prevention Using Neuromuscular Electrical
Stimulation
Automatic Control of Standing Balance with FES
Implantable FNS Systems for Standing After SCI
2003-2006
Career Scientist Award
2002-2007
Posterolateral Lumbar Fusion Using a Strip Formulation of

DBM
Tissue-Engineered Meniscus Repair (Brian Johnstone, PhD,
2003-2004

Mesenchymal Cells (Brian Johnstone, PhD, Principal
Investigator)
2001-2005
2001-2004
2001-2004
2000-2004
2000-2005
2000-2004
2003-2004
2002-2005
2004-2007
2002-2004
2001-2004
2000-2004
1999-2004
2002-2006
78
6/22/05 2:24:06 PM
RESIDENT RESEARCH SYMPOSIUM

May 14-15, 2004
Visiting Professor
Robert H. Coeld, M.D.
Robert H. Coeld, M.D.
R. Shay Bess
Spinal Exostosis: Analysis of Twelve Cases and Review of the Literature
A. Michael Harris
Results and Outcomes after Operative Management of Tibial Plafond Fractures:Comparison of

Internal and External Fixation
Robert Lowe
A Morphologic and Functional Classication of Transitional Vertebrae and Associated Degenerative

Changes at the Lumbosacral Junction
Jeffrey Roh
Cervical Spinal Canal Stenosis: Anatomic and Radiographic Analyses of Sagittal Canal Dimensions
Joseph Smucker
Understanding the Bony Safety Zone in the Posterior Iliac Crest
Andrea Young
ACL Reconstruction in Patients Over the Age of Fifty
Darin Friess
Comparison of Locking Plate Fixation with Other Techniques for Displaced Fractures of the
Proximal Humerus
Ryan Grabow
Anthropometric Study of the Radial Shaft
Theresa Hennessey Pediatrics and the OITE

Joseph Janicki
Efcacy and Cost Effectiveness of the Oblique Views of the Cervical Spine Series in the Trauma
Setting
Erika Mitchell
A Biomechanical Comparison of Lateral Condylar Buttress Plating, Locked Condylar Plating and
Dual Plating in a Distal Femur Fracture Model
ChristopherVara
A Cadaveric Examination of Juvenile Cervical Pedical Morphology
R. Shay Bess
A. Michael Harris
Robert Lowe
Jeffrey Roh
Darin Friess
Ryan Grabow
Theresa Hennessey
Joseph Janicki
Erika Mitchell
Randall E. Marcus
6/22/05 2:24:09 PM
THE LITTLE ORTHOPAEDIC CLUB

46th Annual Meeting
September 24-27, 2003
Christopher Furey
1. Operative Treatment of Degenerative Scoliosis

2. Translumbar Interbody Fusion
Darin Friess
Mitogen Activated Protein Kinase Signaling During Chondrogenesis
Matthew Kraay
1. Measurement of Wear in Total Hip Replacement

2. Introduction to Minimally Invasive Total Joint Replacement
Roger Wilber
Post-Traumatic Acetabular Reconstruction
Erika Mitchell
The Effect of Gamma Radiation Sterilization on the Fatigue Crack Propagation Resistance of
Human Cortical Bone
Cheryl Petersilge
Radiologic Diagnosis of Piriformis Syndrome
George Thompson
1. The Role of Amicar in Decreasing Perioperative Blood Loss in Idiopathic Scoliosis Surgery
2. Submuscular Rods for the Treatment of Severe Scoliosis in Very Young Children
Heather Vallier
Fractures of the Talus
Charles Malmood
Future Directions in Osteoarthritis Research
Donald Goodfellow
Fulkerson Procedure for Patellar Malalignment
Allison Gilmore
Anterior Cruciate Injuries in the Skeletally Immature Patient
Ed Greeneld
Endotoxin and Aseptic Loosening of Total Joint Replacement
Thomas Chelimsky
The Gain in Pain is Mainly How You Train
Brian Johnstone
Tissue Engineering with Mesenchymal Stem Cells
William Petersilge
Unicompartmental Knee Replacement
Jung Yoo
Dysphagia Following Anterior Cervical Fusion
Henry Bohlman
Cervical Extension Osteotomy for the Correction of Kyphosis in Patients with Ankylosing Spondylitis
Patrick Getty
Outcomes of Osteoarticular Reconstruction of the Proximal Femur
Shay Bess
Evaluation fo the Pediatric Lateral Cervical Radiograph
80
6/22/05 2:24:10 PM
TRAVELING FELLOWS
March 3, 2003 - AOA Austria-Swiss-German
Traveling Fellows
Steffen Breusch, M.D.
Associate Professor, Department of Orthopaedics
Heidelberg University, Germany
Chris Hendrich, M.D.
Wurzburg University, Germany
Jaques Menetrey, M.D.
University of Geneva, Switzerland
Cornelius Wimmer, M.D.
Innsbruck University, Austria
June 1-2, 2004 - AOA ASEAN (Association of

South East Asian Nations)
Traveling Fellows
Dr. Heri Suroto
Department of Orthopaedic and Traumatology
Dr. Soetomo Hospital, Indonesia
Dr. Badrul Shah Badaruddin
Institute of Orthopaedic & Traumatology
Hospital Kuala Lumpur, Malaysia
Dr. Prarop Tiyapatanaputi
Nopparatrajathanee Hospital, Bangkok
Dr. S. S. Sathappan
Tan Tock Seng Hospital, Singapore
Dr. Albert Dy, Jr.
Associate Professor, University of Philippines
Philippines General Hospital
6/22/05 2:24:10 PM
GRAND ROUNDS
On March 3rd, 2004, the rst
Grand Rounds on Wednesday
instead of Saturday took place in the
newly opened Wolstein Auditorium.
Dr. Victor Goldberg gave the rst
lecture.
Dr. Randall Marcus introduces Dr. Victor Goldberg
A captivated audience in the new

auditorium.
Dr. Goldberg lectures on the most recent data in bone graft and
bone graft substitute research.
82
6/22/05 2:24:11 PM
CHARLES H. HERNDON SOCIETY
Faculty, residents and alumni

gather in San Francisco
during March 2004 for the
Charles H. Herndon Society
Dinner.
6/22/05 2:24:14 PM
INSTRUCTIONS FOR AUTHORS

1. Manuscript admissions will be accepted throughout
the year. An ofcial call for manuscripts will go out in
January with the last date for admission for the given
years publication in April.
2. Submissions will only be accepted in electronic format
via CD or e-mail.
2a. Figures
Figures and tables must be submitted separately from
text with a separate page for legends
Illustrations and photographs must be submitted in
TIFF, EPS or high resolution JPEG format in black
and white
3. Title
Include degree and institutional afliation with each
authors name
7. If a manuscript has previously been published in or has

been accepted to a peer-reviewed journal, permission
must be obtained from the journals editor for
publication in the Case Orthopaedic Journal. Proof of
permission must be submitted with the manuscript.
7a. Publication in the Case Orthopaedic Journal does not
prohibit publication in a peer-reviewed journal, however,
efforts should be made by the authors to submit an
abridged version to the Case Orthopaedic Journal if
submission to another journal is planned.
Paragraphs and Spaces

Do not indent paragraphs, place a return between
paragraphs, but do not use returns inside a paragraph.
Use a single space between sentences, not a double space.
4. Abstract
Limit to 325 words
5. The Body of the manuscript should include:
Introduction: a brief review of the literature
Materials and Methods
Results
Discussion
6. References
References should be numbered and superscripted in
the text and sequenced as they occur
Format should be as in the example below:
1. Wang X, Bank RA, Koppele JM, Hubbard GB,
Athanasiou KA, Agrawal CM. Effect of collagen
denaturation on the toughness of bone. Clin Orthop. 2000;
(329)228-39.
2. Dowling NE. Mechanical Behavior of Materials. Upper
Saddle River, NJ: Prentice Hall, 1999:488-524.
84
6/22/05 2:24:14 PM
We wish to thank
MetroHealth Medical Center
for their contribution
in the publication of
our inaugural edition of the
Orthopaedic Journal.
6/22/05 2:24:14 PM
6/22/05 2:28:48 PM
IMPLANT SELECTION
MADE EASY.
Weve combined our Summit and Pinnacle
technologies to form a comprehensive system
for total hip reconstruction. Together, these
systems provide exceptional function and
MARATHON POLYETHYLENE
flexibility. Consider all the Summit/Pinnacle

combination has to offer proven fixation,
multiple bearing options, advanced biomechanics,
ULTAMET METAL INSERT
simple instrumentation and youll easily

make it your implant selection.
ADVANCED BIOMECHANICS
6/22/05 2:28:52 PM
I t doesnt come from training. Or reading.

It was there at the very beginning of this journey.
If it hadnt been, youd have switched from pre-med to philosophy.
You count on it.

A certain sense, an ability youve always had to know what to do.
A simple condence that somehow, some way, youll nd the answer.
Its yours, this feeling. You own it.

And theres a person on the other side of the OR door who is glad you do.
The healing is about to begin. And its chosen your hands.
Zimmer, Inc.
www.zimmer.com
6/22/05 2:29:02 PM

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Volume 1 Issue 1

CASE WESTERN RESERVE UNIVERSITY

Hawaiis Volcanoes National

Dressing application illustration

Introducing the V.A.C.ATS

flaps and grafts

Advanced Care. Advanced Caring

Simplify stem insertion.

MAST SEXTANT 8_3125 x 10_875

A NEW ROAD TO RECOVERY.

MINIMAL ACCESS SPINAL TECHNOLOGIES

TECHNOLOGY THAT FOCUSES ON THE CUTTING EDGE.

SEE PACKAGE INSERT FOR LABELING LIMITATIONS.

LETTER FROM THE EDITOR-IN-CHIEF ................................................................ 1

LETTER FROM THE EDITOR-IN-CHIEF

am delighted to present the inaugural

Jeffrey S. Roh, M.D.

The specic purposes of the Case

Orthopaedic Journal a reality. They

With highest regards,

Jeffrey S. Roh, M.D.

O R T H O PA E D I C JOURNAL | CASE WESTERN RESERVE UNIVERSITY | VOL.1, NO.1 | 2004 1

CHARLES H. HERDON, M.D., 1915-1997

e dedicate the inaugural issue of the Case

t is with great pleasure that I

from Great Britain, Austria, New

Randall E. Marcus, M.D.

physicians and scientists to our

O R T H O PA E D I C JOURNAL | CASE WESTERN RESERVE UNIVERSITY | VOL.1, NO.1 | 2004 3

This June, the department graduated

Joseph Smucker, M.D.

Jeffrey Roh, M.D.

DIVISION OF PEDIATRIC ORTHOPAEDICS

was a busy year for the

Gilmore, M.D. All had productive

George H. Thompson, M.D.

and trauma. The particular interests

O R T H O PA E D I C JOURNAL | CASE WESTERN RESERVE UNIVERSITY | VOL.1, NO.1 | 2004 5

SPINE SURGERY PROGRAM

Orthopedic Surgery at University

Henry H. Bohlman, M.D.

surgeon. He is Co-Director of the

results. Dr. Thompson maintains

includes approximately 340 spine

RUBICON WINE & SPINE DINNER

O R T H O PA E D I C JOURNAL | CASE WESTERN RESERVE UNIVERSITY | VOL.1, NO.1 | 2004 7

he mission of the research

improving the quality of life through

Jung Yoo, M.D.

endeavors; new investments are being

research center in the Department.

O R T H O PA E D I C JOURNAL | CASE WESTERN RESERVE UNIVERSITY | VOL.1, NO.1 | 2004 9

Amanda Weiss Kelly

John Chip Davis

O R T H O PA E D I C JOURNAL | CASE WESTERN RESERVE UNIVERSITY | VOL.1, NO.1 | 2004 11

BASIC SCIENCE FACULTY

Football with the resident applicants after their interviews.

O R T H O PA E D I C JOURNAL | CASE WESTERN RESERVE UNIVERSITY | VOL.1, NO.1 | 2004 13

here has been a great interest in

relationship between other surrounding

MATERIALS AND METHODS

Bone marrow aspirates were obtained

The lunate was removed from the