Clinical and Translational Research
Gene Therapy Approaches To
Bone And Musculoskeletal Disorders
Articular Cartilage Regeneration
Drs. Sherwin Ho,
Michael Terry, and
Bruce Reider have been intensively
investigating the biological processes in articular cartilage
regeneration and anterior cruciate ligament repair. Articular
cartilage has little intrinsic capacity to repair itself after
injury, prompting many researchers to explore new methods to
facilitate and augment cartilage regeneration. Currently, a
variety of approaches have been developed, including
chondroplasty, osteochondral transfer procedures (autologous and
allograft procedure), microfracture and autologous cultured
chondrocyte implant (ACCI). Each of these techniques is useful
when utilized in appropriate conditions; however, a significant
cohort of patients still fail to achieve good to excellent
results even when surgical, pharmacologic and physical therapy
are optimal by current standards. These clinical failures
suggest that new biologic strategies, including gene therapy,
may be a useful adjunct to current treatments to further improve
clinical outcome. Drs. Sherwin Ho, Michael Terry, and Bruce
Reider are investigating the possible use of Sox9 and/or other
biofactors to facilitate articular cartilage regeneration.
Previously, Drs. Dr. T.-C. He and Rex Haydon successfully
transduced intervertebral disc cells with Sox9, a transcription
factor necessary for chondrogenesis and Type II collagen
synthesis. They observed that human degenerative intervertebral
disc cells transfected with Sox9 genes led to chondrocyte
proliferation with increased production of Type II collagen.
Currently, Drs. Ho, Terry and Reider are investigating whether
ex vivo expression of Sox9 in articular cartilage cells or in
mesenchymal stem cells will augment articular cartilage repair
in a rabbit model. Dr. Ho has received the AOSSM Young
Investigator Award to carry out the Sox9 gene therapy for
articular cartilage repair. Dr. Ho and Dr. Terry are also
investigating the potential use of BMP-13 and/or other
biological factors in augmenting Anterior Cruciate Ligament
(ACL) repair in a rabbit model.
Gene Therapy in Flexor Tendon Healing
Dr. Mass, in
collaboration with Drs. T.-C. He,
Rex C. Haydon, and Hue H. Luu, is investigating
possible gene therapy approaches to enhancing tendon and
ligament healing using recombinant adenoviral vectors expressing
BMP-13 and/or other biological factors. In a recent study, which
was funded by the Orthopaedic Research and Education Foundation
(OREF), Dr. Mass and colleagues have demonstrated that BMP-13
can significantly improve the biomechanical properties of
lacerated flexor tendons in a rabbit model. More comprehensive
studies of gene therapy in flexor tendon healing are underway.
Gene Therapy in Spinal Fusion
Dr. Purnendu Gupta has
been investigating the different fixation techniques for
multilevel anterior cervical discectomy and fusion (ACDF). ACDF
is a common surgical procedure used to treat radiculopathy or
myelopathy in the cervical spine. However, there are multiple
fixation methods used to promote cervical fusion. Dr. Gupta has
examined static versus dynamic plating techniques for multilevel
ACDF and has presented his results at the North American Spine
Society Annual Meeting and American Academy of Orthopaedic
Surgeons Annual Meeting. In addition, Dr. Gupta has been
involved in collaborative investigations examining
percutaneously inserted pedicle screw-rod system following
anterior lumbar arthrodesis as well as functional impairment and
the prediction of spine loading.
The direction of spine research as the University of
Chicago has also included the application of gene therapy in
spinal fusion. In collaboration with Dr. Purnendu Gupta, Drs. T.-C. He, Rex C. Haydon,
and Hue H. Luu, have completed an animal study to
demonstrated an ex vivo gene therapy approach to
posterior-lateral spinal fusion using BMP-2, BMP-6, and BMP-9.
The findings were presented at the Annual Meetings of North
American Spine Society and Orthopaedic Research Society. These
studies have been supported by research grants from North
American Spine Society and the Musculoskeletal Transplant
Foundation.
Analysis Of Polyethylene Wear In Joint Replacements And The
Biology Of Osteolysis
As the director of The Orthopaedic
Biomedical Imaging Institute, Dr. John
Martell has completed an extensive evaluation of two-
and three-dimensional techniques for the analysis of
polyethylene wear in total hip replacements. Dr. Martell’s
research has been funded by research grants from NIH/NIAMS , and
DePuy/J & J. The Orthopaedic Biomedical Imaging Institute is
becoming known nationally and internationally as a resource for
the design and implementation of polyethylene wear studies and
has been involved in the analysis of cross-linked polyethylene
from Zimmer, DePuy/J & J, Stryker/Howmedica/Osteonics, and
Richards. Dr. Martell is now getting requests for visitors to
observe the techniques that are used in processing films and
analyzing films. Together with Dr.
David Manning, Dr. Martell intends to develop the
Orthopaedic Biomedical Imaging Institute into a world-class
resource for the analysis of polyethylene wear in total hip and
total knee arthroplasty.
Dr. Martell has recently
developed several important and innovative bio-medical imaging
tools. First, his mechanical analysis software allows
investigators to calculate the joint reaction force and stress
in normal and prosthetic hips. Using the joint stress as a
predictor variable in combination with patient activity
indicators (speed of walking,UCLA score or pedometer data) he
has developed a multiple logistic regression model that can
identify patients with total hips that will have high wear and
lysis in the long term. This model is now 87% accurate and has
no false negatives in a series of 300 hips with minimum 8 year
follow-up. Dr. Martell is investigating the potential of using
stress levels in native hips to identify patients who will
progress to hip arthritis. Second, Dr. Martell developed
pre-op templating software that allows the surgeon to see the
predicted stress on the hip joint, and identifies reconstructive
options that will put the patient at risk for high wear, while
planning surgery using digital templates. This software would
show the surgeon in real time the best combination of implant
size and position to minimize wear. Third, Dr. Martell is
working in collaboration with Dr. Maryellen Giger in the
Kurt Rossman Laboratory to develop radiographic texture analysis
techniques for the early detection of pelvic osteolysis in
patients with total hip replacements. Preliminary data shows
that texture analysis detects changes in peri-acetabular bone
two years prior to the development of clinically apparent
osteolysis on X-rays. Finally, Dr. Martell has upgraded
his Leg length discrepancy program for application in the
pediatric clinic by Dr. Christopher Sullivan.
Dr. Henry Finn continues his work in the development of
new prosthetic devices for both primary and revision total hip
replacement. The Vanguard Rx Condular Constrained Knee will be
available as a standard product line device in Spring 2005. In
addition, he has developed a new antiprotruseo cage for revision
acetabuli and is currently working on a femoral component
specific for minimal invasive hip surgery.
Biological Intervention of
Polyethylene Wear Particle-Induced Osteolysis
In
addition to the bioimaging analysis of polyethylene wear in
total hip and total knee arthroplasty,
Dr. David Manning is interested in developing more
effective therapeutic and/or preventive measures for the
clinical management of osteolysis. Osteolysis and resultant
aseptic loosening is the single most common complication of
total joint prostheses and is estimated to occur in over 25% of
implant recipients. Dr. Manning has recently completed an in
vivo wear comparison study of highly crosslinked and traditional
polyethylene in total hip arthroplasty. Current strategies to
combat osteolysis include modifications of the bearing surface
to decrease particle generation and biologic and/or
pharmaceutical treatments once osteolysis has occurred.
Alternate bearings, as of yet have not proven to be effective.
Pharmaceutical applications of bisphosphonates, fosamax, and
anti-inflammatories have, likewise, been unsuccessful. In
collaboration with Drs. T.-C. He and
Rex C. Haydon, Dr. Manning
and Hue H. Luu are investigating the potential use of several osteogenic BMPs,
such as BMP-2, BMP-6, and BMP-9, as a biologic treatment of
osteolysis related bone loss. Successful non-operative
treatment of osteolysis would improve implant survival, prevent
many revision arthroplasties, and simplify revision
reconstruction techniques. Recently, Dr. Manning has been
granted with the
Louis
Block Award and Maley Research
Award to study the treatment of wear particle-induced osteolysis with the osteogenic BMPs in
rodent models.
Flatfoot Deformity Contact
Characteristics
Dr.
Brian Toolan, in collaboration with
Dr. Draganich, has completed the
development of a cadaveric model on the effects of acquired
flatfoot deformity on tibiotalar contact characteristics and is
currently applying this model to investigate corrective
procedures with orthotics. As an extension of this
investigation, he has completed a study examining the effects of
UCBL orthotics on joint contact characteristics in our adult
acquired flatfoot deformity model. This manuscript has been
submitted to Foot and Ankle International for publication.
Similarly, Drs. Toolan and Draganich have begun a
parallel study to investigate the effects of orthotics on gait
and stair stepping in patients with flatfoot deformity.
In addition to his interests on flatfoot deformity, Dr.
Brian Toolan is interested developing a better understanding of
ruptured Achilles tendon healing process and potentially
developing new means in treating patients with this injury.
Achilles tendon ruptures are common injuries and both surgical
and non-surgical treatments have frequent complications such as
wound dehiscence and re-rupture. Therefore, Dr. Toolan, in
collaboration with Drs. He,
Haydon,and Hue H. Luu, is developing a rat model
to investigate the effects of BMP13 and other factors on
Achilles tendon healing. This study has been funded by a
research grant to Dr. Toolan from American Orthopaedic Foot &
Ankle Society.
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Last update:
January 11, 2008
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