Cell‐demanded release of VEGF from synthetic, biointeractive cell‐ingrowth matrices for vascularized tissue growth

Abstract

Local, controlled induction of angiogenesis remains a challenge that limits tissue engineering approaches to replace or restore diseased tissues. We present a new class of bioactive synthetic hydrogel matrices based on poly(ethylene glycol) (PEG) and synthetic peptides that exploits the activity of vascular endothelial growth factor (VEGF) alongside the base matrix functionality for cellular ingrowth, that is, induction of cell adhesion by pendant RGD-containing peptides and provision of cell-mediated remodeling by cross-linking matrix metalloproteinase substrate peptides. By using a Michael-type addition reaction, we incorporated variants of VEGF121 and VEGF165 covalently within the matrix, available for cells as they invade and locally remodel the material. The functionality of the matrix-conjugated VEGF was preserved and was critical for in vitro endothelial cell survival and migration within the matrix environment. Consistent with a scheme of locally restricted availability of VEGF, grafting of these VEGF-modified hydrogel matrices atop the chick chorioallontoic membrane evoked strong new blood vessel formation precisely at the area of graft-membrane contact. When implanted subcutaneously in rats, these VEGF-containing matrices were completely remodeled into native, vascularized tissue. This type of synthetic, biointeractive matrix with integrated angiogenic growth factor activity, presented and released only upon local cellular demand, could become highly useful in a number of clinical healing applications of local therapeutic angiogenesis.

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

“…Prior studies have reported vascularizaton of tissue engineered constructs using both synthetic and naturally-derived constructs containing growth factors and/or cells (for examples see (Borges et al, 2003a;Borges et al, 2003b;Elcin and Elcin, 2006;Ganta et al, 2003;Kaigler et al, 2006;Murphy et al, 2004;Tanihara et al, 2001;Yao et al, 2004;Zisch et al, 2003)). However, the primary focus of these studies did not address the manner of directed vascular invasion into the matrix, but only upon the end extent of vacularization.…”

Biomimetic Delivery of Keratinocyte Growth Factor upon Cellular Demand for Accelerated Wound Healing in Vitro and in Vivo

“…Fusion proteins containing a growth factor with the peptide linked at the N-terminus have been successfully delivered from fibrin gels in a cell-controlled manner. 46,47,50 However, the activity of the fusion protein may also be affected if the binding site is localized near the N-or C-terminus, as is the case with interleukin-1␣ and IGF-II. 58,59 Therefore, the Figure 5.…”

“…46,47 In particular, it was recently demonstrated that bi-domain peptides could be used to covalently attach small cell adhesion peptides 48,49 or heparin-binding growth factors, such as nerve growth factor or brain-derived neurotrophic factor, into fibrin gels. 44 For the latter, one domain of the peptide was recognized by factor XIIIa and incorporated into fibrin during polymerization, while the heparin-binding domain immobilized heparin, which in turn interacted with the heparin-binding growth factor.…”

Cell colonization in degradable 3D porous matrices

“…Recently they have been used to deliver growth and differentiation factors within tissue scaffolds. 152 Matrix turnover significantly influences cellular phenotypic characters which in turn alters assembly of de novo synthesized matrix elements. Tissue remodeling in a variety of patho/physiological processes including embryogenesis, 153 normal tissue development, cancer 154 and wound healing 155,156 has been evaluated.…”