Corsi   Regenerative medicine in orthopaedic surgery   2007
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Corsi Regenerative medicine in orthopaedic surgery 2007

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Regenerative Medicine in Orthopaedic Surgery
Karin A. Corsi,1,2,3 Edward M. Schwarz,4 David J. Mooney,5 Johnny Huard1,2,3,6
1Stem Cell Research Center, Children\u2019s Hospital of Pittsburgh, 4100 Rangos Research Center, 3460 Fifth Avenue,
Pittsburgh, Pennsylvania 15213
2Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
3Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania
4Center for Musculoskeletal Research, University of Rochester, Rochester, New York
5Division of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts
6Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania
Received 28 November 2006; accepted 27 March 2007
Published online 12 June 2007 in Wiley InterScience ( DOI 10.1002/jor.20432
ABSTRACT: Regenerative medicine holds great promise for orthopaedic surgery. As surgeons
continue to face challenges regarding the healing of diseased or injured musculoskeletal tissues,
regenerative medicine aims to develop novel therapies that will replace, repair, or promote tissue
regeneration. This review article will provide an overview of the different research areas involved in
regenerative medicine, such as stem cells, bioinductive factors, and scaffolds. The potential use of
stem cells for orthopaedic tissue engineering will be addressed by presenting the current progress
with skeletal muscle\u2013derived stem cells. As well, the development of a revascularized massive
allograft will be described and will serve as a prototypic model of orthopaedic tissue engineering.
Lastly, we will describe current approaches used to design cell instructive materials and how they
can be used to promote and regulate the formation of bony tissue. \ufffd 2007 Orthopaedic Research
Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:1261\u20131268, 2007
Keywords: orthopaedic surgery; gene therapy; stem cell; allograft; polymer; tissue
The field of orthopaedics has developed signifi-
cantly in the last century with the emergence of
new products and surgical techniques. Despite
these numerous advances, disease and injury to
the musculoskeletal system continue to occur and
risk increasing with the aging population. To
address such issues, regenerative medicine has
emerged as an important area of research and is
paving the way for new developments in ortho-
paedic surgery. To do so, regenerative medicine
focuses on therapies that will replace, repair, or
promote the regeneration of diseased or damaged
tissue. Research areas that have received parti-
cular attention are those employing stem cells,
scaffolds, and growth factors.
The use of stem cells in regenerative medicine is
a particularly appealing area of research that has
received a great deal of interest in recent years.
This is due, no doubt, to the uncommitted state of
stem cells, which provides them with the ability to
differentiate toward various lineages. Human
embryonic stem cells (hESCs) have been shown to
differentiate toward bone and cartilage lineages.1\u20133
However, scientific challenges, immunologic issues,
and ethical concerns motivate the examination of
reservoirs of stem cells from postnatal tissues.
These include, but are not limited to, cells isolated
from the bone marrow,4,5 the circulation or blood
vessels,6,7 adipose tissue,8\u201310 human placenta,11
human umbilical cord,12,13 human amniotic fluid,14
and skeletal muscle.15,16 As a means of demonstrat-
ing the potential of adult stem cell therapy for
regenerative medicine in orthopaedic surgery, the
first part of this review will detail current levels of
progress being made in research utilizing stem cells
isolated from adult skeletal muscle.
Regenerative medicine in orthopaedic surgery
will likely also require the use of scaffolds to
repair large defects. Acellular scaffolds, such as
demineralized bone matrix that have osteoinduc-
tive properties, may be used to promote tissue
regeneration. However, scaffolds may also be
Correspondence to: Johnny Huard (Telephone: 412-692-
7807; Fax: 412-692-7095; E-mail: jhuardþ
\ufffd 2007 Orthopaedic Research Society. Published by Wiley Periodicals,
designed to incorporate cells and growth factors, or
cells genetically modified to secrete the growth
factors of interest. Hence, scaffold design is another
important area of regenerative medicine. Although
the field of tissue engineering has steadily pro-
gressed over the last two decades, success of these
products, as measured by approval from the U.S.
Food and Drug Administration, has, unfortu-
nately, been limited. In the musculoskeletal field,
this is largely due to the technical difficulties in
generating highly efficacious engineered tissues,
but it is also due to a lack of outcome measures to
rigorously evaluate a novel construct in animals,
and the lack of a favorable patient population for a
cost-effective clinical trial. Tissue engineering of
articular and meniscal cartilage provides an excel-
lent example of these limitations for the following
reasons: (1) little is known about what factors, if
any, can truly restore damaged tissue to its native
form; (2) large animals (i.e., goats, sheep) appear to
be the only rigorous models; (3) while enormous,
the patient population is young and healthy, and
thus the risk:benefit assessment of a clinical trial is
very unfavorable for highly innovative technolo-
gies (i.e., genetically modified stem cells, viral gene
therapy); and (4) there are no quantitative out-
come measures to scientifically prove that tissue-
engineered cartilage restores defects to their native
form in humans. In contrast, tissue engineering of
bone has many advantages including the following:
(1) a wealth of available knowledge17; (2) the ability
to utilize acellular constructs that can remodel into
live tissue in vivo; (3) a potential patient population
with a favorable risk:benefit assessment (meta-
static cancer patients undergoing limb-sparing
surgery); and (4) definitive quantitative outcome
measures in animals and humans. Thus, as a
prototypic model of orthopaedic tissue engineering,
and, as a means of demonstrating the importance
of using scaffolds for bone healing, we will also
describe the current progress being made toward
the development of a revascularized massive
The delivery of osteogenic and angiogenic sig-
nals will also be of utmost importance for bone
tissue engineering. While systemic or local delivery
of these potent actors via injection of an aqueous
solution is the simplest approach, the short half-
lives of most of these factors require the adminis-
tration of large doses, which increases the cost of
such therapies. Furthermore, the utility of this
approach is seriously limited due to the inherent
broad tissue exposure, and to the potential of
growth factors to drive undesirable responses
at other sites in the body.18 To overcome such
limitations, gene therapy can be used to modify
cells for injection, so that they can produce the
desired growth factors in vivo. This is more cost
effective than direct administration of growth
factors, but may have limitations in terms of the
duration of expression, and the amount of growth
factor secreted. As another alternative to direct
administration of inductive factors, a variety of
external signals or cues may be exploited to direct
cells, including the presentation of immobilized
ligands that engage cellular adhesion receptors. As
well, growth factors can be incorporated into
polymeric scaffolds and be released in a controlled
manner. Hence, in the last section of this review, we
will describe how materials can provide a useful
platform to regulate the presentation of cues for
cells and to instruct