Covalently immobilized platelet-derived growth factor-BB promotes angiogenesis in biomimetic poly(ethylene glycol) hydrogels

Abstract

The field of tissue engineering is severely limited by a lack of microvascularization in tissue engineered constructs. Biomimetic poly(ethylene glycol) hydrogels containing covalently immobilized platelet-derived growth factor BB (PDGF-BB) were developed to promote angiogenesis. Poly(ethylene glycol) hydrogels resist protein absorption and subsequent nonspecific cell adhesion, thus providing a "blank slate", which can be modified through the incorporation of cell adhesive ligands and growth factors. PDGF-BB is a key angiogenic protein able to support neovessel stabilization by inducing functional anastomoses and recruiting pericytes. Due to the widespread effects of PDGF in the body and a half-life of only 30 min in circulating blood, immobilization of PDGF-BB may be necessary. In this work bioactive, covalently immobilized PDGF-BB was shown to induce tubulogenesis on two-dimensional modified surfaces, migration in three-dimensional (3D) degradable hydrogels and angiogenesis in a mouse cornea micro-pocket angiogenesis assay. Covalently immobilized PDGF-BB was also used in combination with covalently immobilized fibroblast growth factor-2, which led to significantly increased endothelial cell migration in 3D degradable hydrogels compared with the presentation of each factor alone. When a co-culture of endothelial cells and mouse pericyte precursor 10T1/2 cells was seeded onto modified surfaces tubule formation was independent of surface modifications with covalently immobilized growth factors. Furthermore, the combination of soluble PDGF-BB and immobilized PDGF-BB induced a more robust vascular response compared with soluble PDGF-BB alone when implanted into an in vivo mouse cornea micropocket angiogenesis assay. Based on these results, we believe bioactive hydrogels can be tailored to improve the formation of functional microvasculature for tissue engineering.

Comparison of Mesenchymal Stem Cell Source Differentiation Toward Human Pediatric Aortic Valve Interstitial Cells within 3D Engineered Matrices

“…Covalent bonding of growth factors to hydrogel matrix provides a more prolonged release profile, and the conjugated growth factors have more slowly degraded and internalized features. 48,49 Conjugation of bFGF to AC-RYL-PEG-SCM was confirmed via Western blot (Fig. 9A).…”

“…48 PEGylated growth factors were proved to maintain their biological activity after chemical coupling and to promote cell-cell contact formation. 49,51,75 The conjugated bFGF not only further promoted the fibroblastic differentiation of HAVIC and ADMSC but also significantly upregulated vimentin expression in BMMSC, which was not achieved by soluble bFGF. This indicated the importance to regulate both internal microenvironment and external environment to drive MSC differentiation toward the target fibroblastic phenotype.…”

Pericyte-targeting drug delivery and tissue engineering

“…51 Several cases have been noted in which PCs were incorporated into hydrogels and biomaterials with coculture of ECs in the areas of vascular grafts, cell sheets, and cell encapsulation. 17,[52][53][54][55][56] Mendes et al 55 showed that perivascularlike cells contributed to the stability of the vascular network of osteogenic tissue formed from cell sheet-based construction. The coculture combination of osteogenic, endothelial, and perivascular-like cells enhanced the vascularization of bone tissue engineering construction.…”

“…The application of perivascular-like cells to cell sheets is potentially promising in the induction of vascularization in three-dimensional construction. Fuoco et al 54 examined the three-dimensional polyethylene glycol-based hydrogel-encapsulated PCs for 56 studied polyethylene glycol-immobilized PDGF-BB hydrogel in order to stimulate PCs and to produce extracellular matrix proteins, fibronectin, collagen, and proteoglycans. Thus, angiogenesis stimulated by PCs in a tissueengineered microsystem formed the basement membrane of capillaries, although polyethylene glycol-immobilized PDGF-BB hydrogel may require clarification for multiple cellular responses, including release of matrix metalloproteinase-2 and -9 and PC stimulation.…”

Tissue Engineering

“…One strategy towards this goal is to develop prevascularized constructs for implantation [7], while other strategies focus on rapid vascular invasion and perfusion [8]. The most promising research has combined these techniques to develop of rapidly vascularized scaffolds that recreate vascular space-filling properties similar to those found in normal, functional tissues, to provide adequate perfusion of implanted constructs [9][10][11].…”