title: Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing.
abstract: Although growth factors naturally exert their morphogenetic influences within the context of the extracellular matrix microenvironment, the interactions among growth factors, their receptors, and other extracellular matrix components are typically ignored in clinical delivery of growth factors. We present an approach for engineering the cellular microenvironment to greatly accentuate the effects of vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) for skin repair, and of bone morphogenetic protein-2 (BMP-2) and PDGF-BB for bone repair. A multifunctional recombinant fragment of fibronectin (FN) was engineered to comprise (i) a factor XIIIa substrate fibrin-binding sequence, (ii) the 9th to 10th type III FN repeat (FN III9-10) containing the major integrin-binding domain, and (iii) the 12th to 14th type III FN repeat (FN III12-14), which binds growth factors promiscuously, including VEGF-A165, PDGF-BB, and BMP-2. We show potent synergistic signaling and morphogenesis between α5β1 integrin and the growth factor receptors, but only when FN III9-10 and FN III12-14 are proximally presented in the same polypeptide chain (FN III9-10/12-14). The multifunctional FN III9-10/12-14 greatly enhanced the regenerative effects of the growth factors in vivo in a diabetic mouse model of chronic wounds (primarily through an angiogenic mechanism) and in a rat model of critical-size bone defects (through a mesenchymal stem cell recruitment mechanism) at doses where the growth factors delivered within fibrin only had no significant effects.
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Mikaël M
authors.initials: MM
authors.lastname: Martino
authors.forename: Federico
authors.initials: F
authors.lastname: Tortelli
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mochizuki
authors.forename: Stephanie
authors.initials: S
authors.lastname: Traub
authors.forename: Dror
authors.initials: D
authors.lastname: Ben-David
authors.forename: Gisela A
authors.initials: GA
authors.lastname: Kuhn
authors.forename: Ralph
authors.initials: R
authors.lastname: Müller
authors.forename: Erella
authors.initials: E
authors.lastname: Livne
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Eming
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
mesh_terms: D000818:Animals; D000077214:Becaplermin; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D001861:Bone Regeneration / Q000187:drug effects; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005353:Fibronectins / Q000494:pharmacology*; D039081:Integrin alpha5beta1 / Q000378:metabolism; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D051381:Rats; D044968:Regenerative Medicine / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D055396:Bone Morphogenetic Protein 2; D005353:Fibronectins; D039081:Integrin alpha5beta1; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin