Biomedical Engineering Reference
In-Depth Information
The early recognition of the ability of BMPs to induce de novo bone, combined
with better realization of the importance of BMPs in fracture-healing have led to the
development of growth factor-based therapies that incorporate recombinant human
proteins. A biomaterial scaffold, that provides a three-dimensional space for bone
deposition and is intended to mimic an extracellular matrix, has been an indispens-
able part of these therapies. INFUSE™ uses recombinant human bone morphoge-
netic protein-2 (rhBMP-2) loaded in collagen sponges. It was first FDA approved for
spine and oral/maxillofacial applications (McKay et al.
2007
) and then for orthopae-
dic trauma (Govender et al.
2002
). When evaluated in surgery for tibial trauma,
patients receiving recombinant human BMP-2 (rhBMP-2) therapy had faster wound-
healing, reduced incidence of secondary intervention, as well as reduced infection
risk (Govender et al.
2002
). BMP-7 (OP-1) has been used in a similar fashion for the
treatment of tibial non-unions (Friedlaender et al.
2001
) with similar results. Patients
receiving rhOP-1 in bone-derived bovine collagen (i.e., demineralised bone matrix
from bovine bones) had success rates comparable to those receiving an autograft.
The concentration rhBMP-2 used for implantation was ~1.5 mg/cc (McKay et al.
2007
), while we estimate the concentration of rhOP-1 to be 0.9 mg/cc (Friedlaender
et al.
2001
). These are exceedingly high growth factor concentrations, considering
that the endogenous levels of the BMPs are at expected to be at ng/mL to µg/mL
levels. Despite the success of these protein-based therapies, the expense associated
with milligram quantities of protein greatly limits their wide-spread use (especially
in developing countries) and presents an opportunity for improvement for wider
application of these therapeutics. A recent study has also cast a shadow on the
expected benefits of BMP protein therapeutics (Cahill et al.
2009
). In this retrospec-
tive study, patients receiving BMPs for spinal fusion (anterior cervical fusion) were
associated with a higher rate of complication and higher inpatient hospital charges.
BMPs are arguably the most studied growth factor for bone regeneration, but
several other proteins have been investigated for similar clinical use. In particular,
growth factors that stimulate new blood vessel formation have shown great prom-
ise. Angiogenesis is tightly intertwined with bone regeneration, as a good blood
supply is imperative for growth of new bone tissue (Carano and Filvaroff
2003
).
BMPs alone can indirectly stimulate angiogenesis in the early stages of bone induc-
tion. Treatment of osteoblasts with BMPs causes them to produce the vascular
endothelial growth factor (VEGF; Deckers et al.
2002
). VEGF stimulates angiogen-
esis, and delivery of this growth factor alone is useful for bone healing, although
not as effectives as the BMPs as a stand alone therapeutics in animal models.
Regeneration is impaired in the absence of VEGF, and exogenous VEGF accelerates
the healing process (Street et al.
2002
). In addition to its role in cell proliferation
and migration, fibroblast growth factors (FGFs) are also involved in angiogenesis
(Montesano et al.
1986
). Basic FGF (bFGF) stimulates bone formation (Nakamura
et al.
1995
) and facilitates healing of bone defects (Hong et al.
2010
). Both VEGF
and bFGF are being pursued for bone regeneration, and pre-clinical studies have
demonstrated their synergistic effect in BMP-induced bone repair.
In addition to bioactive proteins, low intensity pulsed ultrasound (LIPUS) has
been employed for enhancing bone fracture healing, both in animals and in human
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