Biomedical Engineering Reference
In-Depth Information
the migration of stem cells
in vivo
by conventional imaging techniques like MRI, without
significantly affecting cell viability or differentiation potential. However, additional studies
should be carried out to determine the fate of NPs in the transplanted cells.
Nanoparticles for Growth Factor Delivery to Stem Cells
Growth and differentiation factors play a key role in guiding the cell fate in regenerative
medicine [129-136]. The most common factors to regulate differentiation of stem cells are
bone morphogenetic proteins (BMP) for osteogenesis [137, 138], vascular endothelial growth
factor (VEGF) and basic fibroblast growth factor (FGF) for induction of vasculogenesis
[139-143], combination of BMP and VEGF for vascularized osteogenesis [144], transform-
ing growth factor-beta (TGF-β) for induction of chondrogenesis [145], brain-derived neuro-
trophic factors (BDNF) and nerve growth factor (NGF) for neurogenesis [146], epidermal
growth factor (EGF) for corneal epithelialization and gastrogenesis [147], hepatocyte growth
factor for hepatogenesis and tendon-bone healing [148-150], and platelet-derived growth
factor (PDGF) as a co-factor in regeneration of skeletal tissues and wound healing [151].
Direct addition of growth factors to tissue-engineered matrices severely limits the protein
efficacy and bioavailability, mainly due to diffusion of protein away from the regeneration
site, short half-life, and enzymatic degradation [152-155]. Furthermore, high concentra-
tions of these differentiation factors have adverse effects such as tissue overgrowth and
immune response [156]. Nanoparticles are very attractive as a carrier for growth factors to
regulate and control the lineage commitment and fate of stem cells [157-159]. However, the
activity of the immobilized proteins and aggregation depend on the interaction of protein
and other surface-active molecules with the NPs [160]. Protein-surfactant interaction can
lead to micelle formation in aqueous solution, whereas NP-protein interaction leads to the
aggregation of NPs [160]. In NP-protein-surfactant ternary systems, NP aggregates coexist
with protein-surfactant micellar structures [160]. Furthermore, proteins in the culture
medium and those in the tissue
in vivo
can interact with the NPs to form a corona that can
change protein release rate, cell-surface interaction, and cell uptake [161-164]. Barran-
Berdon
et al
. demonstrated that the protein corona on lipid NPs is composed mainly of
apolipoproteins, which can trigger a receptor-mediated endocytosis in cells [163]. Fleischer
et al
. observed that cellular binding to cationic NPs is enhanced in the presence of serum
proteins, while it is inhibited for anionic NPs [164]. Cell-culture medium can also affect
uptake and internalization of NPs when used with stem cells. Maiorano
et al
. reported that
protein-gold NP complexes formed in Roswell Park Memorial Institute medium are taken
up to a greater extent by the immortal HeLa cell line than in Dulbecco's modified Eagle's
medium medium, demonstrating that a thorough understanding of the effect of medium
and the NP's surface chemistry and structure is necessary for growth-factor delivery [165].
One approach is to encapsulate growth factors within biodegradable NPs for enzymatic
protection and sustained release over the implantation time. However, due to protein dena-
turation, encapsulation limits NP fabrication to those techniques that do not require organic
solvents, high temperatures or pressures. Double emulsion solvent evaporation in which the
growth factor is dissolved in aqueous solution and the coating polymer is dissolved in water-
immiscible organic solvent, like methylene chloride, is a viable encapsulation technique for
proteins [166-170] (Figure 9.3A). The glial-derived neurotrophic factor (GDNF) is effective
as a neuroprotective agent to reduce inflammation and improve axonal outgrowth in spinal
cord injury (SCI) [171, 172]. Wang
et al
. used double emulsion solvent evaporation to gen-
erate poly(lactic-co-glycolic acid) (PLGA) NPs as a carrier for transport and sustained
delivery of GDNF in the spinal cord [173]. In that approach, the water-in-oil emulsion of
