Tissue Engineering: Focus on the Musculoskeletal System - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 203

cells can engraft into the marrow with over 90% efficiency [34]. The mecha-
nism for stem cell homing is highly complex and multi-factorial, and stro-
mal derived factor-1 (SDF-1) is a key player in this process. SDF-1 is part
of the chemokine family and is expressed by bone marrow stromal cells
and endothelial cells. Its receptor, CXCR4, is expressed on human stem and
progenitor cells [35]. Of particular interest to bone tissue engineering, para-
thyroid hormone treatment led to an increase in SDF-1 production at the
growth plate in mice and a decrease in the serum [36]. This suggests a SDF-1
gradient for the localization of stem cells to the growth front in mice. Aiuti
et al. demonstrated that human hematopoietic progenitor cells migrated in
vitro and in vivo towards a gradient of SDF-1 produced by bone marrow
stromal cells [37]. Schantz et al. used this to their advantage in a bone tis-
sue engineering model via the delivery of three separate proteins [38] in an
experiment designed to promote vascularization, stem cell recruitment, and
bone formation, respectively. A polycaprolactone scaffold was connected to
an external microneedle reservoir system that was programmed to sequen-
tially deliver VEGF, SDF-1, and BMP-6. In-vitro findings showed that MSCs
expressed CXCR4 and migrated in response to stimulation by SDF-1; in-vivo
results showed enhanced vascularization. This study is a good example of
delivering biological signals to guide stem cell homing for the purpose of
musculoskeletal tissue engineering.
Instructive Signals
Biological signals play an important role during normal tissue development
process and mediate the tissue remodeling during injury. Musculoskeletal
diseases such as osteoporosis and arthritis are often accompanied by a
change in local biochemical cues, which set off the degenerative process.
To improve endogenous regeneration, we can restore the local microenvi-
ronment by delivering the right signals. For bone tissue repair, active clini-
cal trials are going on to assess the efficacy of delivering recombinant bone
morphogenetic protein-2 (rhBMP-2) from 3D collagen sponge implants [39].
Signals coordinate physiological responses on different length scales; soluble
signals can act locally or systemically depending on their diffusion limit,
access to the circulatory system, and stability in the body. Among the factors
that play a role in this process, BMP-2 received premarket approval from the
Food and Drug Administration (FDA) for spinal fusion in the case of disk
generation from L4 to S1, acute tibial fractures, and sinus augmentations [40].
BMP-7 has received a Humanitarian Device Exemption (HDE) from the FDA
for spinal fusion and as an alternative bone autograft when other treatments
have failed [41]. Vaccaroet et al. performed a one-year study on the effect of
BMP-7 as an iliac crest autograft for non-instrumented posterolateral fusions