It is estimated that more than 500,000 bone-grafting procedures
are performed annually in the United States, with approximately
half of these procedures related to spine fusion. These numbers
easily double on a global basis and indicate a shortage in the availability
of musculoskeletal donor tissue traditionally used in these reconstructions
(Fig. 1).
This reality has stimulated a proliferation of corporate interest
in supplying what is seen as a growing market in bone-substitute
materials (Fig. 2).
These graft alternatives are subjected to varying degrees of regulatory
scrutiny, and thus their true safety and effectiveness in patients
may not be known prior to their use by orthopaedic surgeons. It is
thus important to gain insight into this emerging class of bone-substitute
alternatives.
The biology of bone grafts and their substitutes is appreciated
from an understanding of the bone formation processes of osteogenesis,
osteoinduction, and osteoconduction.
Graft osteogenesis: The cellular elements within
a donor graft, which survive transplantation and synthesize new
bone at the recipient site.
Graft osteoinduction: New bone realized through
the active recruitment of host mesenchymal stem cells from the surrounding
tissue, which differentiate into bone-forming osteoblasts. This
process is facilitated by the presence of growth factors within
the graft, principally bone morphogenetic proteins (BMPs).
Graft osteoconduction: The facilitation of blood-vessel
incursion and new-bone formation into a defined passive trellis
structure.
All bone graft and bone-graft-substitute materials can be described
through these processes.
Fresh autogenous cancellous and, to a lesser degree, cortical
bone are benchmark graft materials that allograft and bone substitutes
attempt to match in in vivo performance. They incorporate
all of the above properties, are harvested at both primary and secondary
surgical sites, and have no associated risk of viral transmission.
Furthermore, they offer structural support to implanted devices
and, ultimately, become mechanically efficient structures as they are
incorporated into surrounding bone through creeping substitution.
The availability of autografts is, however, limited, and harvest
is often associated with donor-site morbidity.
The advantages of bone allograft harvested from cadaver sources
include its ready availability in various shapes and sizes, avoidance
of the need to sacrifice host structures, and no donor-site morbidity. Bone
allografts are distributed through regional tissue banks. Still,
the grafts are not without controversy, particularly regarding their
association with the transmission of infectious agents, a concern
virtually eliminated through tissue-processing and sterilization.
However, both freezing and irradiation modify the processes of graft
incorporation and affect structural strength. A comparison of the properties
of allograft and autograft bone is shown in Figure 3. Often, in
complex surgical reconstructions, these materials are used in tandem
with implants and fixation devices (Figs. 4-A through 4-D).
The ideal bone-graft substitute is biocompatible, bioresorbable,
osteoconductive, osteoinductive, structurally similar to bone, easy
to use, and cost-effective. Within these parameters, a growing number
of bone alternatives are commercially available for orthopaedic
applications, including reconstruction of cavitary bone deficiency
and augmentation in situations of segmental bone loss and interbody spine
fusion. They are variable in their composition, their mechanisms
of action, and the claims made about them. Figure 5 shows a sampling
of bone-graft-substitute materials. It is important to note that
they all are osteoconductive, offer minimal structural integrity,
and possess little, if any, ability to facilitate osteoinduction. Figs. 6-A, 6-B, 6-C,7-A, 7-B, 7-C,8-A, 8-B, and 8-C,
a series of case examples, demonstrate their mechanisms of action
through the healing process.
It is reasonable to assume that not all bone-substitute products
will perform analogously. Thus, a quandary of choice confronts the
orthopaedic surgeon. As a first principle, it is important to appreciate
that different healing environments (for example, a metaphyseal
defect, a long-bone fracture, an interbody spine fusion, or a posterolateral spine
fusion) have different levels of difficulty in forming new bone.
For example, a metaphyseal defect will permit the successful use
of many purely osteoconductive materials. In contrast, a posterolateral
spine fusion will not succeed if purely osteoconductive materials
are used as a stand-alone substitute. Thus, validation of any bone-graft
substitute in one clinical site may not necessarily predict its
performance in another location.
A second principle is to seek the highest burden of proof reported
from preclinical studies to justify the use of an osteoinductive
graft material or the choice of one brand over another. Whether
it is more difficult to make bone in humans than it is in cell-culture
or rodent models, with a progressive hierarchy of difficulty in
more complex species, has not been clearly determined. Only human
trials can determine the efficacy of bone-graft substitutes in humans
as well as their site-specific effectiveness.
A third principle requiring burden of proof specifically pertains
to products that are not subjected to high levels of regulatory
scrutiny, such as demineralized bone matrix or platelet gels containing "autologous
growth factors." Such products are considered to involve
minimal manipulation of cells or tissue and are thus regulated as
tissue rather than as devices. As a result, there is no standardized level
of proof of safety and effectiveness required before these products
are marketed and are used in patients. While these products may
satisfy the technical definition of "minimal manipulation," there
is a risk that they will not produce the expected results in humans
when there has been little or no testing in relevant animal models.
Ongoing human trials involving a number of BMP-derived growth
factors (particularly BMP-2 and OP-1) have demonstrated impressive
osteoinductive capacity in tibial fracture-healing and spine fusion.
Their methods of administration have included direct placement in
the surgical site, but results have been more promising when the
growth factors have been administered in combination with substrates
to facilitate timed-release delivery and/or to provide
a material scaffold for bone formation. Food and Drug Administration
regulatory imperatives will determine their availability, and they
are likely to be costly, which will influence specific clinical
use.
Further advances in tissue-engineering, "the integration
of the biological, physical, and engineering sciences," will
create new carrier constructs that regenerate and restore tissue
to its functional state. These constructs are likely to encompass
additional families of growth factors, evolving biological scaffolds,
and incorporation of mesenchymal stem cells. Ultimately, the development
of ex vivo bioreactors capable of bone manufacture
with the appropriate biomechanical cues will provide tissue-engineered
constructs for direct use in the skeletal system.
The increasing number of bone-grafting procedures performed annually
in the United States has created a shortage of cadaver allograft
material and a need to increase musculoskeletal tissue donation.
This has stimulated corporate interest in developing and supplying
a rapidly expanding number of bone substitutes, the makeup of which
includes natural, synthetic, human, and animal-derived materials.
Fresh autogenous cancellous and, to a lesser degree, cortical
bone are the benchmark graft materials that, ideally, both allograft
and bone substitutes should match in in vivo performance.
Their shortcomings include limited availability and donor-site morbidity.
The advantages of allograft bone include availability in various
sizes and shapes as wells as avoidance of host-structure sacrifice
and donor-site morbidity. Tissue-processing, however, modifies graft
incorporation as well as structural strength. Transmission of infection,
particularly the human immunodeficiency virus (HIV), has been virtually eliminated
as a concern.
The ideal bone-graft substitute is biocompatible, bioresorbable,
osteoconductive, osteoinductive, structurally similar to bone, easy
to use, and cost-effective. Currently marketed products are variable in
their composition, their mechanisms of action, and the claims made
about them.
It is reasonable that not all bone-substitute products will perform
the same. Tissue or cellular-derived products that satisfy the technical
definition of minimal manipulation with regard to processing and manufacture
are not subject to a high level of regulatory scrutiny. Their true
safety and effectiveness may not be known.
A quandary of choice confronts the orthopaedic surgeon. Caveat
emptor! Selection should be based on reasoned burdens of proof.
These include examination of the product claims and whether they
are supported by preclinical and human studies in site-specific
locations where they are to be utilized in surgery.