Fibrin-based biomaterials to deliver human growth factors

Abstract

SummaryFibrin-based biomaterial preparations can be used as provisional growth matrices for cells important in tissue repair during wound healing in vivo. Their efficacy can be enhanced by including bioactive agents that promote specific cellular responses. This study examined the controlled delivery of the angiogenic growth factors bFGF, VEGF165, and VEGF121 using biomatrix preparations prepared from Fibrin Sealant product components. The growth factors were added prior to formation of the Fibrin Sealant clots, and the release kinetics of the proteins from the clots measured. The results indicated that the proteins were released from the clots more slowly in the order bFGF << VEGF165 < VEGF121. The biologic activity of the growth factors delivered from Fibrin Sealant clots was established by assaying growth stimulation of human microvascular endothelial cells (HMVEC) and angiogenesis in the chicken embryo chorioallantoic membrane (CAM) model of neovascularization. In the latter assay, clots containing bFGF, VEGF165, or V EGF121 all displayed angiogenic activity. However, delivery of either bFGF, VEGF165, or VEGF121 alone resulted in a significant percentage of clots becoming filled with blood, indicating that the newly developing vessels invading the clots were leaky and immature. In contrast, this hemorrhaging behavior did not occur with delivery of combinations, e.g., (VEGF165 + VEGF121) or (VEGF165 + bFGF), indicating that the vessels were more mature than those produced in response to single growth factors. Thus, delivering a combination of growth factors constituted an improvement over the delivery of individual growth factors for enhancing neovascularization.Part of this research was presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society held in Munich, Germany.

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.…”

“…The chorioallantoic membrane (CAM) assay, used for more than half a century, has become a mainstay in the study of blood vessel development (Auerbach et al, 2003;Cruz et al, 2000;Cruz et al, 1997;DeFouw and DeFouw, 2000a;DeFouw and DeFouw, 2000b;Djonov et al, 2000a;Djonov et al, 2000b;McDonnell et al, 2005;Rizzo and DeFouw, 1996;Rizzo et al, 1995;Rizzo et al, 1993). The CAM assay has also proved useful for biological devices and in tissue engineering applications, particularly those concerning biocompatibility studies and angiogenic responses to tissue-engineered constructs (Borges et al, 2003a;Borges et al, 2003b;Nguyen et al, 1994;Ribatti et al, 2001;Rickert et al, 2003;Valdes et al, 2003;Valdes et al, 2002;Wong et al, 2003). In this work we extend the CAM assay in the development of a histological technique to specifically examine direct vascular invasion into fibrin-based constructs.…”

The past, present and future in scaffold-based tendon treatments

“…Collagen peptides have also been used, with preclinical data demonstrating increased collagen synthesis [129], maintenance of homeostasis [130] and improved healing, as judged by mean average diameter, distribution of fibrils and GAG composition [131]. The utilisation of fibrin has been advocated based on its high cytocompatibility, biodegradability, controllable cross-linking, carrier capacity and presence of several ECM proteins, such as fibronectin, that enhance cell adhesion and proliferation [132][133][134]. Preclinical analysis revealed that fibrin glue around the suture site enabled rabbit flexor tendon healing with smooth gliding surface and without formation of adhesions [119].…”

Sustained release and osteogenic potential of heparan sulfate-doped fibrin glue scaffolds within a rat cranial model

“…Fibrin glue enjoys widespread clinical application as a wound sealant, a reservoir to deliver growth factors and as an aid in the placement and securement of biological implants (Vasita et al 2006, Inman et al 2003, Pandit et al 2000, DeBlois et al 1994.…”

“…In the cellular environment, fibrin specifically binds to a variety of proteins, including fibronectin, albumin, FGF2, VEGF, and IL-1 (Fakhry et al 2005). These properties make it an interesting drug and cell delivery system for various applications in tissue engineering (Vasita et al 2006, Inman et al 2003, Pandit et al 2000, DeBlois et al 1994, Rai et al 2005. Previous studies have focused on capabilities with respect to tailoring the scaffold to generate release profiles of the growth factors over time.…”