Growth Factor Delivery Systems for the Treatment of Cardiovascular Diseases - Biointerfaces: Where Material Meets Biology - page 92

improved cardiac function more eciently than each factor separately, in
animal models of MI. 112,123 More recently, Salimath et al. developed a PEG
based protease-degradable hydrogel combining VEGF with HGF. It was
demonstrated that dual factor release from a bioactive hydrogel was possible
and had the capacity to significantly improve cardiac function in an is-
chemia/reperfusion rat model. 124
Polymer microspheres fabricated from PLG containing pre-encapsulated
PDGF with lyophilized VEGF were incorporated together in a single struc-
tural polymer scaffold. This process allows for sustained protein delivery and
maintains the biological activity of incorporated and released growth factors.
They were implanted into the subcutaneous pockets on the dorsal side of
rats and histological analysis revealed a rapid formation of a mature vascular
network due to the dual delivery of both growth factors with different
kinetics. 93
Gelatin microspheres have also been used for multiple GF delivery in the
cardiac context. For instance, Cittadini et al. recently used gelatin micro-
spheres for VEGF and IGF administration in a rat model of MI. Animals
treated with microspheres containing both GFs showed remarkably better
effects on infarct size and left ventricular volume reductions, heart
function improvement, vascularization enhancement and apoptosis and
inflammation reduction when compared with single GF microsphere
administration. 125
In a mouse model of hind-limb ischemia sequential delivery of VEGF and
PDGF using an injectable, biodegradable alginate scaffold, resulted in stable
and sustained improvement in perfusion. 126 Collagen scaffolds with a
combination of FGF2 and VEGF displayed the highest density of blood
vessels and most mature blood vessels when implanted subcutaneously in
3-month-old Wistar rats. These results indicated that the enhancement of
early mature vasculature in an acellular construct could open prospects in
conditions as ischemic heart disease. 127
Kim et al. incorporated PDGF and FGF into self-assembling peptide
nanofiber scaffolds that mimicked extracellular matrix porosity and gross
structure and tested its ecacy in the rat model of MI. Animals treated with
the system containing both GFs almost recovered cardiac function. This
effect correlated with a decrease in cardiomyocyte apoptosis, capillary and
arterial density recovery, with stable vessel formation, higher reduction in
the infarction size and improvement in wall thickness. 128
Recently, our group examined whether the administration of MP con-
taining NRG1 and FGF1 in a rat model of MI promoted repair of heart tissue.
Three months after treatment, cardiac function improvement was observed
in rats treated with FGF1-MP, NRG1-MP or FGF1/NRG1-MP. A positive car-
diac remodeling with a lower degree of fibrosis, smaller infarct size, and
induction of tissue revascularization was also detected, together with car-
diomyocyte proliferation and progenitor cell recruitment. A consistent syn-
ergistic in vitro or in vivo effect was not observed with the combination
therapy involving the administration of both cytokines. 129 This important

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