Heparin-binding domain of fibrin(ogen) binds growth factors and promotes tissue repair when incorporated within a synthetic matrix

Abstract

By binding growth factors (GFs), the ECM tightly regulates their activity. We recently reported that the heparin-binding domain II of fibronectin acts as a promiscuous high-affinity GF-binding domain. Here we hypothesized that fibrin, the provisional ECM during tissue repair, also could be highly promiscuous in its GF-binding capacity. Using multiple affinity-based assays, we found that fibrin(ogen) and its heparin-binding domain bind several GFs from the PDGF/VEGF and FGF families and some GFs from the TGF-β and neurotrophin families. Overall, we identified 15 unique binding interactions. The GF binding ability of fibrinogen caused prolonged retention of many of the identified GFs within fibrin. Thus, based on the promiscuous and high-affinity interactions in fibrin, GF binding may be one of fibrin’s main physiological functions, and these interactions may potentially play an important and ubiquitous role during tissue repair. To prove this role in a gain-of-function model, we incorporated the heparin-binding domain of fibrin into a synthetic fibrin-mimetic matrix. In vivo, the multifunctional synthetic matrix could fully mimic the effect of fibrin in a diabetic mouse model of impaired wound healing, demonstrating the benefits of generating a hybrid biomaterial consisting of a synthetic polymeric scaffold and recombinant bioactive ECM domains. The reproduction of GF–ECM interactions with a fibrin-mimetic matrix could be clinically useful, and has the significant benefit of a more straightforward regulatory path associated with chemical synthesis rather than human sourcing.

Reduction of relative centrifugal forces increases growth factor release within solid platelet-rich-fibrin (PRF)-based matrices: a proof of concept of LSCC (low speed centrifugation concept)

“…This information is reflected in the present results by showing significantly enhanced VEGF release on day 7 in the case of A-PRF+. By contrast, EGF is released in a high concentration level at the very early time point of 24 h. One explanation for this observation may be the low binding affinity of EGF to fibrin and fibrinogen [36]. Another factor may be the structure of the PRF-based matrices.…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…The heparin-binding domain of fibrin binds to a wide range of growth factors, including members of the PDGF, FGF, VEGF, and TGF families (57), that may activate reparative fibroblasts and vascular cells.…”

Fibrin structural and diffusional analysis suggests that fibers are permeable to solute transport

“…As discussed earlier, the fact that fibrin fibers can be permeable to solute transport may help in reducing mass transport limitations and promote cell survival. Further, fibrin is known for its ability to bind growth factors via its heparin-binding domains [56]. This, again in combination with the semi-permeability of fibrin fibers shown in this study, can prove to be a promising feature because it would allow the entrapment of growth factors within individual fibers and the formation of growth factor gradients by using hydrogel layers of different fiber densities in an ECM substitute.…”

“…Secondly, therapeutic agents could be designed to penetrate individual fibrin fibers to induce fibrinolysis. At the same time, due to the affinity of several growth factors for fibrin [56], the voids within the fibers could provide additional binding sites for growth factors by increasing the area to volume ratio of the protein. hydrogels with LL enzyme ratios exhibit the highest storage modulus, and those with HL ratios exhibit the lowest (Fig.…”