Polymeric system for dual growth factor delivery

Abstract

The development of tissues and organs is typically driven by the action of a number of growth factors. However, efforts to regenerate tissues (e.g., bone, blood vessels) typically rely on the delivery of single factors, and this may partially explain the limited clinical utility of many current approaches. One constraint on delivering appropriate combinations of factors is a lack of delivery vehicles that allow for a localized and controlled delivery of more than a single factor. We report a new polymeric system that allows for the tissue-specific delivery of two or more growth factors, with controlled dose and rate of delivery. The utility of this system was investigated in the context of therapeutic angiogenesis. We now demonstrate that dual delivery of vascular endothelial growth factor (VEGF)-165 and platelet-derived growth factor (PDGF)-BB, each with distinct kinetics, from a single, structural polymer scaffold results in the rapid formation of a mature vascular network. This is the first report of a vehicle capable of delivery of multiple angiogenic factors with distinct kinetics, and these results clearly indicate the importance of multiple growth factor action in tissue regeneration and engineering.

Improved growth factor directed vascularization into fibrin constructs through inclusion of additional extracellular molecules

“…One possibility is the use of other angiogenic growth factors (Richardson et al, 2001;Wong et al, 2003). So, in addition to FGF-2, we individually tested platelet derived growth factor-BB (PDGF-BB), vascular endothelial growth factor (VEGF 165 ), and bone morphogenic protein-2 (BMP-2) at 1, 10, and 100 ng/mL, while keeping all other construct components constant.…”

Polymers to direct cell fate by controlling the microenvironment

“…Polymeric systems allow for independent regulation of the localization, duration, and availability of one or more soluble factors [28][29][30], while limiting the overall quantity of drug and minimizing the potential side effects of systemic dosing. Many techniques have been developed to regulate the kinetics and distribution of soluble factors, including multiple levels of encapsulation [31] as well as noncovalently bonding the bioactive factors to peptides with a range of dissociation constants mimicking ECM immobilization of growth factors [32]. With respect to the latter, phage display has been a powerful technique for identifying ligands that can tightly control the kinetics of factor release [32].…”

“…With respect to the latter, phage display has been a powerful technique for identifying ligands that can tightly control the kinetics of factor release [32]. Dual delivery of multiple growth factors and morphogens has been achieved in multiple systems including poly (lactide-co-glycolide) (PLG) [31], oligo(poly(ethylene glycol) fumarate) [33], and alginate [34] scaffolds. Multiple factors can be delivered sequentially, simultaneously, or both, and these techniques can be combined with DNA or RNAi delivery to enable long-standing protein expression [35] or abrogation of expression [36].…”

“…Multiple factors can be delivered sequentially, simultaneously, or both, and these techniques can be combined with DNA or RNAi delivery to enable long-standing protein expression [35] or abrogation of expression [36]. The physiologic relevance of control over factors availability in time and space has been demonstrated by differentiation of stem cells [37], regulation over the extent of vascular network maturation with time [31], enhanced delivery and integration of transplanted cells [38], and the simultaneous formation of vascular networks at distinct stages of maturation in distinct spatial compartments [28].…”

Dual release of proteins from porous polymeric scaffolds

“…Different attempts have been already made to release different proteins from a single release system, in the shape of rods [20], hydrogels [21], or gelatin layers [22]. Porous scaffolds as reservoir for multiple proteins were so far obtained only by assembly and fusion of microspheres [23,24] or by associating them with pre-existing porous structures [25]. It is therefore of 0168 interest to investigate new approaches to deliver multiple proteins.…”