143various synthesis techniques , delivery characteristics can be fi nely tuned, where:
(1) delivery increases with protein loading, (2) polymer degradation varies
inversely with microsphere size, and (3) release profi les can be controlled by
pore size [ 309 – 311 ]. Demonstrating the effect of protein loading on delivery
time, Cao et al. delivered NGF from PLGA, PCL, and blended PCL/ PLGA
microspheres and varied the amount of protein loaded, with PCL encapsulating
the greatest amount of protein and PLGA encapsulating the least [ 312 ]. They
report that at the longest, bioactive NGF was detectable at 91 days in the PCL
group, demonstrating how polymer characteristics can modulate delivery effi -
cacy [ 312 ]. Benoit et al. confi rmed these results in in vitro studies of NGF release
from PLA and PLGA microspheres [ 313 ]. Burdick et al. produced similar results
with CNTF, BDNF, and NT-3 loaded into PLGA microspheres, reporting neuro-
trophin burst release for the fi rst 1–2 days followed by up to 3 weeks of near-
linear release [ 314 ]. Further, microspheres loaded with neurotrophic or growth
factors are commonly used to modulate stem cell behavior in experimental set-
tings. For example, Kim et al. investigated both the in vitro and in vivo effects of
dibutyryl cyclic-AMP (dbcAMP)-loaded PLGA microspheres on exogenous neu-
ral progenitor/stem cells (NPSCs) in a murine full transection model of SCI
[ 315 ]. The authors recorded signifi cantly improved NPSC survival in vivo and
differentiation into neuronal lineages in dbcAMP-MP treated groups versus
untreated groups [ 315 ]. In an interesting experiment by Ashton et al., PLGA
microspheres were loaded with alginate lysase, and then administered to alginate
hydrogels culturing NPSCs [ 316 ]. Alginate hydrogels are commonly used as 3D
scaffolds for cell culture and transplantation, but can take months to resolve
within implantation sites as mammals do not produce endogenous alginases
[ 317 , 318 ]. By loading PLGA MPs with alginate lysase, the authors demonstrate
a controllable and tunable method for inducing enzymatic degradation of algi-
nate hydrogels in vivo [ 316 ]. Further, the authors reported signifi cantly aug-
mented rates of NPSC expansion in PLGA MP groups as compared to
non-degrading alginate hydrogels [ 316 ]. A more recent study demonstrated the
ability of growth factor-loaded microspheres to mediate cellular behavior. Nie
et al. demonstrated that transforming growth factor-beta1 (TGF-1β) loaded into
PLGA microspheres promoted chondrocyte adhesion and growth on hydrogel
scaffolds [ 311 ]. The authors also demonstrated tunable release profi les based on
PLGA-MP pore size [ 311 ].
Microspheres themselves have also been used as scaffolds for cellular trans-plantation , as encapsulation of cells provides a protective barrier against host
immune cell interactions after grafting. In two separate murine SCI model stud-
ies, Tobias et al. demonstrated that alginate-encapsulated BDNF-producing
fi broblasts survived for 1 month in culture, produced bioactive neurotrophins,
survived transplantation into the spinal cord of immunocompetent animals, and
provided a permissive environment for local host axon growth [ 319 ]. These data
build a case for use of microspheres as in vivo drug delivery vehicles, cellular
grafting materials, and modulators of endogenous repair after brain and spinal
cord injury.
7 Regenerative Strategies for the Central Nervous System