Extracellular Matrix-Inspired Growth Factor Delivery Systems for Skin Wound Healing

Abstract

Significance: Growth factors are very promising molecules for the treatment of skin wounds. However, their translation to clinical use has been seriously limited, facing issues related to safety and cost-effectiveness. These problems may derive from the fact that growth factors are used at vastly supraphysiological levels without optimized delivery systems. Recent Advances: The extracellular matrix (ECM) plays a fundamental role in coordinating growth factor signaling. Therefore, understanding the mechanisms by which the ECM modulates growth factor activity is key for designing efficient growth factor-based therapies. Recently, several growth factorbinding domains have been discovered within various ECM proteins, and growth factor delivery systems integrating these ECM growth factor-binding domains showed promising results in animal models of skin wound healing. Moreover, a novel strategy consisting of engineering growth factors to target endogenous ECM could substantially enhance their efficacy, even when used at low doses. Critical Issues: Optimal delivery of growth factors often requires complex engineered biomaterial matrices, which can face regulatory issues for clinical translation. To simplify delivery systems and render strategies more applicable, growth factors can be engineered to optimally function with clinically approved biomaterials or with endogenous ECM present at the delivery site. Future Directions: Further development and clinical trials will reveal whether growth factor-based therapies can be used as main therapeutic approaches for skin wound healing. The future impact of these therapies will depend on our capacity to deliver growth factors more precisely, to improve efficacy, safety, and cost-effectiveness.

Mechanotransduction and Growth Factor Signalling to Engineer Cellular Microenvironments

“…Fibronectin contains three kinds of domains which mediate interactions with other fibronectin molecules, other ECM molecules and cells (Figure 3b). [35] Sobel et al identified the heparin II binding region of fibronectin (FNIII [12][13][14] ) as a VEGF binding site. [36] They reported that fibronectin fragments including FNIII [9][10] (integrin binding region) and FNIII [12][13][14] endothelial cell migration, proliferation and signalling.…”

“…[35] Sobel et al identified the heparin II binding region of fibronectin (FNIII [12][13][14] ) as a VEGF binding site. [36] They reported that fibronectin fragments including FNIII [9][10] (integrin binding region) and FNIII [12][13][14] endothelial cell migration, proliferation and signalling. [36] Martino and Hubbell generalized this result to show that FNIII [12][13][14] not only bound VEGF but was actually a highly promiscuous region with affinity towards GFs from different families.…”

“…[36] They reported that fibronectin fragments including FNIII [9][10] (integrin binding region) and FNIII [12][13][14] endothelial cell migration, proliferation and signalling. [36] Martino and Hubbell generalized this result to show that FNIII [12][13][14] not only bound VEGF but was actually a highly promiscuous region with affinity towards GFs from different families. [37] Based on this ability of fibronectin to bind GFs, material systems that presented GFs by promoting the crosstalk between integrins and GF receptors have been engineered.…”

“…functionalized with two recombinant fragments of fibronectin joined together, FNIII [9][10] , to promote integrin binding and cell adhesion, [35] and FNIII [12][13][14] , to bind GFs. [37] They showed that the system enhanced the formation of tube-like structures in endothelial cells (with VEGF-A), sprouting of smooth muscle cells (with platelet-derived growth factor (PDGF)-BB) and differentiation of mesenchymal stem cells (MSC) (with BMP-2).…”

“…solid-phase presentation of GFs, resulted in higher efficiency compared to soluble release, improved biological functions and reduced concentration and dose. [13][14][15] Figure 2 shows a sketch of classical (soluble) vs. surface-bound presentation of GFs.…”