Tissue Engineering: Focus on the Musculoskeletal System - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 204

in 12 (6 female, 6 male) patients with degenerative spondylolisthesis [42]. The
Oswestry Disability Index (ODI) and dynamic radiographs showed solid bone
fusion. Clinical trials are also investigating parathyroid hormone-related
peptide (PTHrP), which is marketed as a treatment for osteoporotic fracture
[43]. The clinical uses of BMPs include spinal fusion, treatment of long-bone
defects and non-unions, and osteointegration with metallic implants [44].
Parathyoid hormone (PTH) is an anabolic agent whose recombinant human
(rhPTH (1-34)) form is approved by the FDA [45]. This 34-amino-acid frag-
ment of PTH is currently used by post-menopausal women with osteoporo-
sis and men with advanced osteoporosis. Antagonists such as sclerostin are
also being incorporated into clinical practices [46]. These clinical issues drive
scientist to continue to find solutions through tissue engineering strategies.
Synergistic delivery
Synergistic delivery has emerged as an effective approach for delivering ther-
apeutic growth factors and genes in a physiological relevant manner to mimic
the natural musculoskeletal tissue healing process [47]. The bone remodeling
process is characterized by an early upregulation of angiogenic growth fac-
tors such as VEGF, which is followed by expression of bone morphogenic
protein, insulin-like growth factor (IGF), and fibroblast growth factor (FGF).
Such a multi-phasic factor expression induces angiogenesis, which creates
highly vascular tissue optimal for bone regeneration later on [48]. Kumar et al.
reported that bone formation was enhanced in a mouse model of segmental
bone defect using genetically engineered mesenchymal stem cells (MSC)
that expressed osteogenic and angiogenic factors [47]. The MSCs were either
mock-transduced or transduced with recombinant adeno-associated virus 6
(rAAV)-BMP2:VEGF or rAAV-GFP. The groups that received dual delivery
of growth factors VEGF and BMP-2 resulted in prosperous bone growth
and consequently an increase in bone mineral density, as reported by the
DXA analysis. Micro-computed tomography (μCT) analysis also confirmed
enhanced tissue repair in the group receiving simultaneous release of both
growth factors. The control group that received VEGF alone did not exhibit
sufficient tibiae bone correction, compared to the dual-delivery group. After
16 weeks of physical therapy, the tibia from the dual-delivery treated groups
showed a substantial improvement in peak load, stiffness, and toughness
compared to the control. This study suggests the promise of using geneti-
cally modified stem cells to synergistically deliver multiple signals to pro-
mote musculoskeletal tissue repair. Biological signals such as growth factors
can also be controlled-released from a 3D depot in situ to achieve synergistic
delivery [49]. A dual growth factor-releasing scaffold consisting of VEGF 165
and BMP2 in PDLLA was developed to guide MSC differentiation and bone
repair in a murine femur defect model. The results showed that groups
receiving synergistic delivery of both angiogenic and osteogenic growth fac-
tors experience the strongest bone regenerative response. It is important to