COPYRIGHT 2008 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED

III
Cellular Strategies for
Enhancement of Fracture Repair
By Thomas E. Patterson, PhD, Ken Kumagai, MD, PhD, Linda Griffith, PhD, and George F. Muschler, MD
Tissue engineering seeks to translate scientific knowledge into tangible products to advance the repair, replace-
ment, or regeneration of organs and tissues. Current tissue engineering strategies have progressed recently
from a historical approach that is based primarily on biomaterials to a cell and tissue-based approach that in-
cludes understanding of cell-sourcing and bioactive stimuli. New options include methods for harvest and trans-
plantation of tissue-forming cells, bioactive matrix materials that act as tissue scaffolds, and delivery of
bioactive molecules within scaffolds. These strategies are already benefiting patients, and they place increasing
demands on orthopaedic surgeons to have a solid foundation in the contemporary concepts and principles of
cell-based tissue engineering.
Essentially all orthopaedic tissue engineering strategies can be distilled to a strategy or combination of strategies
that seek to increase the number or relative performance of bone-forming cells. The global term connective tissue
progenitors has been used to define the heterogeneous populations of stem and progenitor cells that are found in
native tissue and that are capable of differentiating into one or more connective tissue phenotypes. These stem or
progenitor populations are found in various tissue sources, with varying degrees of ability to differentiate along
connective tissue lineages. Available cell-based strategies include targeting local cells with use of scaffolds or bio-
active factors, or transplantation of autogenous connective tissue progenitor cells derived from bone marrow or
other tissues, with or without processing to change their concentration or prevalence. The future may include
means of homing circulating connective tissue progenitor cells with use of intrinsic chemokine systems, or modify-
ing the biological performance of connective tissue progenitor cells by means of genetic modifications.
Stem and Progenitor Cells
in Musculoskeletal Tissues
tem and progenitor cells are present in all adult tissues
and are critical to tissue health, maintenance, and re-
sponse to injury or disease throughout life. Stem cells
give rise to progenitor cells and are distinguished from them
by their capacity for self-renewal by a process of asymmetric
cell division. Progenitor cells, by definition, have finite limits
on their capacity for self-renewal and generally progress to
give rise to one or more differentiated phenotypes
1,2
.
Stem and progenitor cell populations are the upstream
components of continuous systems of cell renewal in virtually
all human tissues. This turnover is most evident in tissues that
remodel rapidly, such as the lining cells of the gastrointestinal
tract (replaced every three days) or dermis (replaced every two
weeks). In bone, turnover is much slower. Osteocytes or bone-
lining cells, the differentiated cells that define bone tissue, may
survive for twenty years in human cortical bone. However,
continuous remodeling requires the formation of many new
osteoblasts. Osteoblasts, in turn, are continuously derived
from a much smaller number of preosteoblasts and upstream
progenitor cells. The number of true stem cells needed to sup-
port this process may be very small (on the average, less than
one in 20,000 nucleated cells in native marrow). The activa-
tion of stem cells and the proliferation of progenitor cells to
form new osteoblasts are vastly accelerated as a result of
trauma, such as fractures
2
.
In the 1960s, Burwell showed that implantation of can-
cellous bone grafts induced bone formation, which could be
traced to the activity of primitive osteogenic cells in bone
marrow
3
. Friedenstein
4
showed that new bone was formed by
proliferating fibroblast-like marrow cells and that the number
S
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or
grants in excess of $10,000 from the National Institutes of Health (the National Institute of Arthritis and Musculoskeletal and Skin Diseases
[NIAMS] and the National Institute of General Medical Sciences [NIGMS]) and Therics, Inc. One or more of the authors, or a member of his or her
immediate family, received, in any one year, payments or other benefits or a commitment or agreement to provide such benefits from commercial
entities in excess of $10,000 (DePuy, Synthes, and Therics, Inc.) and less than $10,000 (Orthofix). No commercial entity paid or directed, or
agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization
with which the authors, or a member of their immediate families, are affiliated or associated.
J Bone Joint Surg Am. 2008;90(Suppl 1):111-9 doi:10.2106/JBJS.G.01572
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of these proliferating cells could be assayed by counting the
number of fibroblastic colony-forming units in vitro. An in-
triguing feature of many tissues, including musculoskeletal
tissues, is that upstream progenitor cells are often multipotent.
Stem cells derived from bone, bone marrow, and peritrabecu-
lar tissues in cancellous bone, periosteum, cartilage, muscle,
fat, and vascular pericytes are capable of differentiation into
multiple phenotypes, including bone, cartilage, tendon, liga-
ment, fat, muscle, and nerve
5-18
. This has important implica-
tions with regard to the design of tissue engineering strategies,
in that cells derived from one tissue might be useful in form-
ing other tissue types. Harvest of these tissues varies with re-
spect to the associated host morbidity
19-25
. Aspiration of bone
marrow is associated with the least morbidity and provides a
single-cell suspension that can be readily processed intraoper-
atively for immediate implantation
13
. Fat has also been pro-
posed as a low-morbidity tissue source, although it requires
greater processing
11,26
. Many names have been used to describe
the colony-forming cells found in bone marrow, periosteum,
or trabecular bone, in addition to fibroblastic colony-forming
units. These terms include mechanocytes, bone marrow stro-
mal cells, and mesenchymal stem cells, although the precise
definition and biological capabilities ascribed by these terms
are not entirely synonymous.
For purposes of describing experimental and clinical re-
sults with use of primary cells isolated from human tissue and
grown without culture expansion, we have defined the term
connective tissue progenitor as the entire heterogeneous po-
pulation of stem and progenitor cells that are capable of dif-
ferentiating into one or more connective tissue phenotypes,
including bone, fat, cartilage, blood, and fibrous tissues
1
. The
number of connective tissue progenitor cells in various tissues
is most often estimated with use of the colony-forming unit
assays, that is, cells that give rise to a colony of proliferating
progenitor cells in vitro under conditions that are selected to
promote activation and proliferation of one or more fractions
of the connective tissue progenitor population. In these assays,
each colony represents the progeny of a founding stem or pro-
genitor cell. Functional biological differences between the
colony-founding cells are revealed by differences in the prolif-
eration rate, the morphology, the migration, and the differen-
tiation of their progeny in each colony (Fig. 1).
The term connective tissue progenitor recognizes that
these tissue-derived cells are not a pure or uniform popula-
tion and may be derived from more than one pool of stem
cells and progenitor cells in native tissues. These cells may in-
clude true quiescent, multipotent stem cells that become acti-
vated after harvest and are capable of self-renewal. However,
colonies may also be formed by cells that are already prolifer-
ating in vivocells that lack self-renewal capabilities and
may exhibit intrinsic commitment to various stages of diverse
lineages
17,27,28
. This diversity can be a source of frustration for
those looking for homogeneous purified populations of cells,
but in practice this diversity should be expected, given the
multifunctional nature of the bone marrow environment.
Therefore, this diversity can also be viewed as a source of
valuable information that can be dissected experimentally to
understand the prevalence and kinetics of various connective
tissue stem-cell populations and to understand the ways in
which these populations change according to age, gender, dis-
ease states, pharmacological intervention, and tissue engi-
neering strategies
1,13,29
.
Another experimental and tissue engineering approach
to study stem and progenitor populations from bone marrow
or other tissue sources involves the in vitro expansion of cells
derived from connective tissue progenitor cells. Various names
have been given to culture-expanded populations of cells that
have been selected under different culture conditions, includ-
ing bone marrow stromal cells
15
, mesenchymal stem cells
30
,
and adult multipotential progenitor cells
31,32
. These terms are
not synonymous
1
, but they all denote that progenitor cells can
be isolated and expanded under appropriate conditions and
that these cells can retain the capacity to differentiate into a
variety of musculoskeletal phenotypes
15,17,30
. The term mesen-
chymal stem cell has acquired a particularly narrow definition
of bone marrow-derived, culture-expanded cells that are iso-
lated and expanded according to the methods pioneered by
Caplan
33
.
Culture-expanded cell populations differ dramatically
from the heterogeneous population of connective tissue pro-
genitor cells that are present in native tissue. Under in vitro
culture conditions, the heterogeneous population rapidly be-
comes more homogeneous. When cells are grown in vitro,
clones of cells that divide most rapidly and those that have the
greatest capacity for continued proliferation have a competi-
tive advantage. In vitro expansion therefore produces a strong
selective pressure favoring these traits.
All tissues vary substantially with respect to cellularity
and the prevalence of connective tissue progenitor cells. As-
pirated bone marrow is the best characterized source of
connective tissue progenitor cells, containing a mean of ap-
proximately forty million nucleated cells and approximately
2000 connective tissue progenitor cells per milliliter. How-
ever, the yield of connective tissue progenitor cells can vary
widely between individuals, aspiration sites, and even be-
tween individual aspirations
13,25,29
. In contrast, fat is far less
cellular (approximately six million cells per cubic centimeter
of tissue) and the prevalence of connective tissue progenitor
cells is greater (as high as one per 4000 cells), but fat-derived
connective tissue progenitor cells exhibit different patterns of
proliferation, migration, and differentiation than do bone
marrow-derived connective tissue progenitor cells.
Differences between connective tissue progenitor cells
harvested from different individuals and from various tissue
sources are likely a function of the health and histological
characteristics of the local tissues and reflect the underlying
kinetics of stem cell function in that tissue. These variables are
in turn influenced by age, gender, and both local and systemic
disease
1,13,29,34
. For example, bone marrow cellularity declines
with age. There is also an age-related decline in the prevalence
of connective tissue progenitor cells, at least in women
29
. How-
ever, age and gender account for only a small fraction of the
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variation in the concentration and prevalence of connective
tissue progenitor cells among patients
13,25,29
. As a result, osteo-
genic connective tissue progenitor cells can be harvested with
use of bone marrow aspiration in patients of all ages.
Differences in biological potential among connective
tissue progenitor cells derived from various tissues can have
important practical implications with regard to the selection
of cell sources for tissue engineering. Individual bone marrow-
derived connective tissue progenitor cells can be capable of
differentiating into a broad range of phenotypes, including
bone, fibrous tissue, fat, muscle, cartilage, and perhaps even
neural tissue, liver, and cardiac muscle
1,2,15,27,30,35,36
. Connective
tissue progenitor cells derived from muscle, fat, and cartilage
also have a broad repertoire of intrinsic differentia-
tion
11,12,20,21,24,37
. Some studies have suggested that fat-derived
and bone marrow-derived cells are similar
38
, but others have
demonstrated a decreased osteogenic potential in fat-derived
cells
39
and the absence of surface markers characteristic of os-
teoblastic progenitor cells
40
.
Potential Strategies for Use of
Autogenous Connective Tissue Progenitor
Cells in Therapeutic Applications
here are five major types of cell-based tissue engineering:
(1) local targeting of connective tissue progenitor cells
where new tissue is needed, (2) homing of connective tissue
progenitor cells into areas where they may not currently re-
side, (3) physically transplanting autogenous connective tissue
progenitor cells to augment the local population, (4) trans-
planting culture-expanded or modified connective tissue pro-
genitor cells, and (5) transplanting fully formed tissue.
Targeting Connective Tissue Progenitors in Situ
Local targeting strategies are designed to promote desired tis-
T
Fig. 1
Heterogeneity of connective tissue progenitor cells. The colonies shown in this image were cul-
tured from human bone marrow for nine days and then stained for alkaline phosphatase activity,
a marker of early bone formation. The image illustrates that colonies differ in size, cell density,
and the extent and distribution of alkaline phosphatase activity. These morphologic differences
are manifestations of intrinsic differences among connective tissue progenitor cells at the time
that they were harvested from bone marrow and placed into culture. (Reprinted from: Muschler
GF, Nakamoto C, Griffith LG. Current concepts review. Engineering principles of clinical cell-based
tissue engineering. J Bone Joint Surg Am. 2004;86:1541-58.)
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sue formation by stimulating the activation, migration, pro-
liferation, and/or differentiation of local connective tissue
progenitor cells. The strategy relies on a sufficient local popula-
tion of connective tissue progenitor cells. Tissue scaffolds pro-
vide a surface on which cells and connective tissue progenitor
cells can attach, proliferate, migrate, and differentiate. These
scaffolds also prevent the encroachment of adjacent tissues into
an area where new tissue is desired. Examples of targeting in-
clude implantation of acellular tissue scaffolds (e.g., allograft
bone); locally delivered growth factors (e.g., bone morphoge-
netic proteins); biophysical stimulation, such as mechanical
loading
41-43
, electromagnetic stimulation
44-46
, or ultrasound
47
;
and systemic pharmacological strategies (e.g., parathyroid hor-
mone for the treatment of osteoporosis
48-53
or systemic growth
hormones to increase muscle mass in the elderly
54,55
).
Homing of Connective Tissue Progenitor Cells
Homing generally refers to the recruitment of cells from the
systemic circulation. Homing and the underlying mechanisms
of homing are well established in hematopoietic connective
tissue progenitor cells. Several studies have suggested that os-
teogenic connective tissue progenitor cells may travel through
the systemic circulation
56
, although the extent to which circu-
lating osteogenic cells contribute to normal fracture repair is
only beginning to be characterized.
With use of a mouse parabiosis model, Kumagai et al.
have recently shown that circulating cells do home to the site
of a fibular fracture
57
. By two weeks after fracture, roughly 6%
to 12% of cells that express alkaline phosphatase in the frac-
ture sites (interpreted as osteoblasts) were found to be derived
from circulating cells
57
. These and other data suggest that stem
cell homing may be a normal biological process that may be-
come the target of new therapies to enhance the arrival of os-
teogenic connective tissue progenitor cells at sites of bone
repair.
Transplantation of Connective
Tissue Progenitor Cells
In many clinical wound-healing scenarios, new tissue forma-
tion may be hampered by a local deficiency or suboptimal lo-
cal population of connective tissue progenitor cells. This is
particularly true in regions of previous trauma, infection, irra-
diation, scar, or compromised vascularity. Many studies have
shown that transplantation of connective tissue progenitor
cells into a bone-healing site can improve the outcome of both
conductive and inductive grafts, even in sites that are sur-
rounded by nondiseased tissues
1,58
. This suggests that many
and perhaps all situations of normal tissue repair may be lim-
ited by the population of connective tissue progenitor cells in
local tissues.
Autogenous cancellous bone-grafting has long been the
most prevalent and effective example of cell transplantation.
Several clinical studies have suggested that transplantation of
connective tissue progenitor cells in aspirated bone marrow
has value in bone-healing applications
3,10,59-65
. Additionally,
concentration of bone marrow cells by centrifugation could
increase osteogenesis further. Many surgeons now use bone
marrow because of its biological value and low risk.
The aspiration technique is important. Muschler et al.
found that limiting the volume of the aspirate to 2 mL per
site reduces dilution with peripheral blood and increases the
concentration of marrow-derived connective tissue progenitor
cells
13
. Furthermore, the efficacy of a bone marrow graft can
be enhanced by the use of certain porous implantable materi-
als to selectively concentrate and select marrow-derived con-
nective tissue progenitor cells from bone marrow, a process
known as selective retention
58
. Selective retention of connective
tissue progenitor cells can be used to rapidly enrich the popu-
lation of marrow-derived connective tissue progenitor cells by
removing red blood cells, serum, and most other cells in mar-
row and contaminating cells from peripheral blood. Grafts en-
riched in this way have improved the results of bone-grafting
in a canine spinal-fusion model
58
. The use of a centrifuge to
concentrate low-density cells from bone marrow (buffy-coat
cells) for transplantation has also been described by both
Connolly
66,67
and Hernigou et al.
68
.
Transplantation of Culture-Expanded Cells
Culture-expanded cells from muscle, fat, and bone marrow
may be useful in regeneration of bone, cartilage, muscle, and
tendon tissue
6,35,69-75
. In vitro expansion can generate a large
number of progenitor cells; however, it also adds substantial
cost and some risks, such as contamination with bacteria or
viruses or depletion of proliferative capacity
76-78
. This strategy
is already applied clinically in the area of cartilage repair
79-81
. In
vitro selection of the most rapidly proliferating cells may also
select cells with mutations or epigenetic changes that might
confer a tumor-forming potential, although we are not aware
of any reports of human tumors formed by culture-expanded
cells and the risk of tumor formation appears to be very low.
Transplantation of Genetically
Modified Cells and Their Progeny
The intrinsic biological potential and performance of connec-
tive tissue progenitor cells and their progeny can be genetically
modified by either transiently or permanently altering the ex-
pression of one or more genes
82
. Advances in genetic engineer-
ing techniques facilitate the efficient engineering of cells that
secrete factors (e.g., bone morphogenetic protein-2) that ef-
fect a change in local tissue formation
83
. Although transplanta-
tion of genetically modified cells may not play a role in elective
clinical tissue engineering in the near future, it has substantial
potential value, particularly in the setting of inherited genetic
defects (e.g., osteogenesis imperfecta
84
) and for tissues (such as
cartilage) that consist of relatively homogeneous long-lived
cells and in which stable phenotypic expression may be a cur-
rent limitation in biological outcome
85,86
.
Mass Transport Limitations
and Metabolic Demand
n all cell-transplantation settings, access to substrate mole-
cules and clearance of metabolic products are critical to cell I
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survival. Due to high demand and slow diffusion rates for ox-
ygen, few cells tolerate diffusion distances in excess of 0.2 mm.
At a graft site in which the radius of the graft is approximately
5 mm, diffusion of oxygen is able to support only a limited
number of transplanted cells, resulting in central necrosis.
This limitation highlights the need to design bone grafts that
(1) limit the total number of cells and (2) increase the fraction
of transplanted cells that will contribute to tissue repair, either
by positive selection or by negative selection (removal of non-
contributing, inhibitory, or competing cells).
Design and Selection of Scaffolds
for Tissue Engineering
hree-dimensional porous scaffolds can be designed with
specific architectures at the nano, micro, and macro scale
(i.e., molecular, cellular, and tissue-length scales, respectively).
Desirable scaffold features include (1) preservation of a tis-
sue volume for the formation of new tissue; (2) nanoporos-
ity and microporosity that allows effective mass transport to
support transplanted cells; (3) a connected microporosity and
macroporosity that allows for contiguous tissue and vascular
ingrowth; (4) a surface chemistry and texture that enhances
the attachment, migration, proliferation, and differentiation
of osteogenic connective tissue progenitor cells; and (5) degra-
dation properties that are consistent with preservation of the
health of local tissues and effective ongoing remodeling. Cur-
rent scaffold options include tissue-derived materials, biologi-
cal polymers, ceramics or mineral-based matrices, and metals
as well as composites of two or more materials. The overall
mechanical properties of a scaffold (strength, modulus, and
toughness) are determined both by the material properties of
the bulk material and by its three-dimensional structure.
Matching the mechanical properties of a scaffold to the graft
environment is critically important so that progression of
tissue-healing is not limited by mechanical failure of the scaf-
fold prior to successful tissue regeneration. Rapidly evolving
three-dimensional fabrication methods (e.g., three-dimen-
sional printing and three-dimensional stereolithography) as
well as the development of new materials (e.g., polycarbo-
nates
87-89
and polypropylene fumarates
90-93
) provide highly
promising platforms for future development.
The surface chemistry defines much of the environ-
ment that cells will experience soon after implantation and
has a profound effect on the attachment and survival of cells
following implantation as well as on early proliferation,
migration, and differentiation. Implanted materials rapidly
become coated with proteins and lipids, which are the prin-
cipal mediators of the cellular response to most materials. It
has been speculated that hydroxyapatite and some other ce-
ramics may preferentially sequester bioactive molecules that
are important for bone regeneration. Indeed, hydroxyapa-
tite and tricalcium phosphate materials perform successfully
as depot delivery vehicles for bone morphogenetic proteins
both in animals
94
and humans
95,96
. Protein adsorption can,
however, induce a conformational change, which may hide
or expose sites that interact with cell-surface receptors. For
example, fibronectin is a more active adhesion molecule
on hydrophilic surfaces (e.g., glass) than on hydrophobic
surfaces (e.g., polytetrafluoroethylene [Teflon] or polyethyl-
ene)
97-100
. The attachment, survival, proliferation, and dif-
ferentiation of stem and progenitor cells can be modulated
in vitro if scaffold surfaces are precoated with selected bioac-
tive proteins, including bone morphogenetic protein-2 and
bone morphogenetic protein-7
101-105
.
Proteins and small bioactive peptides can also be selec-
tively concentrated and presented by covalently linking them
to a surface
96,106,107
. This provides more control over conforma-
tion, a slower rate of release from the surface, and longer re-
tention. Presentation of growth factors in a matrix-bound
fashion may better mimic the native physiology of many sol-
uble signaling molecules, including most proteins. Tethering
may not be appropriate, however, for signaling molecules
that need to be internalized (e.g., steroid hormones)
108-111
.
This strategy may also be particularly well suited for the de-
sign of matrices with selective affinity for specific cells or sets
of cells (e.g., connective tissue progenitor cells, endothelial
cells, and platelets).
The pharmacokinetics of delivery of bone morphoge-
netic proteins has been shown to be an important clinical
variable in a variety of materials, including degradable
polymers
112-119
, type-I collagen
120-122
, and calcium phosphate
ceramics
123,124
. The retention time of implanted bone morpho-
genetic protein correlates with biological efficacy, presumably
because the longer a bone morphogenetic protein is retained,
the higher the probability that it will act on an appropriate
target cell. Retention time has been related both to solubility
125
and to isoelectric point
94
.
Current clinical strategies for protein delivery are tech-
nically simple but require that the protein be delivered in a
high concentration in order to diffuse into adjacent tissues
and act on local connective tissue progenitor cells. The disad-
vantage of these strategies is that they provide relatively little
control over the rate of delivery, conformation, presentation,
clearance, or degradation of the delivered protein. Although
current strategies for delivery of bone morphogenetic proteins
can be effective, the vast majority of the massively supraphysi-
ological doses of bone morphogenetic proteins that are cur-
rently required are likely wasted, and only a small fraction
actually elicits a receptor-mediated signal that enhances new
bone formation. These methods, therefore, leave substantial
room for improvement in delivery kinetics and distribution of
bioactive proteins.
A scaffold designed to deliver viable cells must provide
an environment with physiologic pH and osmolarity. The de-
sign of scaffold bulk material must also consider the effects of
degradation products. The degradation of many polyester-
based matrices, such as polylactides and polyglycolides, pro-
duces acidic degradation products (lactic acid and glycolic
acid), and therefore those matrices are not ideal for cell trans-
plantation and tissue regeneration. Similarly, materials that
result in an early hyperosmolar environment, such as glycerol
(used to improve handling of many bone pastes) and calcium
T
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sulfate (both acidic and hyperosmolar), are likely not appro-
priate materials for use in a cell-transplantation environment.
Opportunities for Rational Design of
Future Materials, Devices, and Strategies
Optimizing combinations of cells, matrices, and locally and
systemically active stimuli will remain a complex process char-
acterized by a highly interdependent set of variables with an
almost infinite range of possible combinations. Future tissue
engineering strategies that are particularly rich in opportunity
include (1) improved methods for intraoperative harvest, con-
centration, and selection of stem and progenitor cells; (2) cell-
delivery systems that enhance cell survival by managing the
balance of mass transfer and metabolic demand; (3) three-
dimensional scaffolds with architectural and mechanical
features that are customized for specific clinical applications;
(4) chemically defined surfaces that present covalently teth-
ered, biologically active molecules; (5) defined microtextured
surfaces to elicit desired cell attachment, migration, differenti-
ation, and survival; (6) scaffold materials for which degrada-
tion delivers biologically inert or even bioactive molecules,
minimizing the toxicity associated with degradation prod-
ucts; and (7) delivery systems for soluble molecule (e.g., bone
morphogenetic proteins and other protein growth factors)
delivery systems that ensure both a biologically active con-
formation and provide a local concentration profile that is ap-
propriate for the target cell population, minimizing the total
dose of bioactive agent that is required and the attendant risk
of unwanted collateral effects.
These developments in cell-based approaches to im-
prove fracture repair must also be informed by a combination
of clinical experience, knowledge of basic biological princi-
ples, medical necessity, and commercial practicality. The re-
sponsibility for rational development is shared by the entire
orthopaedic community (developers, vendors, and physi-
cians) and must be focused as much as possible on objective
and systematic assessment and reporting. This challenge is
made particularly urgent by the recent rapid addition of many
new clinical options that often have narrow and nonoverlap-
ping regulatory approval but that also are rapidly applied in
off-label applications by clinicians earnestly seeking the best
possible care for their patients. Prospective, randomized pre-
clinical and clinical trials will continue to play a critical role in
the initial evaluation of new materials for specific indications.
In addition, prospective cohort studies will remain critical as a
means of demonstrating that controlled studies can be gener-
alized to the broader orthopaedic community. Prospective
registries related to trauma care will also play an important
role by objectively defining settings in which current practice
falls short of reported or desired outcomes. Such registries
could be applied directly to define opportunities for needed
prospective trial and identify settings in which randomization
is impractical due to insufficient power or unethical due to ex-
isting evidence of success or failure in specific settings.
Corresponding author:
George F. Muschler, MD
Departments of Orthopaedic Surgery and Biomedical Engineering (ND-
20), Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail
address: muschlg@ccf.org
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