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 supra-physiological 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 factor-binding 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.

Mikaël M. Martino, PhD

Jeffrey A. Hubbell, PhD

Figure 1.

Different ECM compositions in healthy skin and during wound healing. (Top) Locations of the different ECM present in the skin tissue. (Bottom) Schematic representations of the main ECM molecules composing the interstitial matrix (A) and the basal lamina (B) of healthy skin, and the fibrin clot (C) and the granulation tissue (D) during skin wound healing. Stars indicate ECM molecules that have been shown to have a strong affinity for several growth factors. ECM, extracellular matrix.

Figure 2.

Growth factor journey in healthy and impaired microenvironment. (A) After their secretion by cells, growth factors are sequestered in the ECM and interact with various ECM molecules before reaching their cell-surface receptors, which creates a tight spatio-temporal control of the growth factor delivery by the ECM. (B) Damage of the microenvironment in chronic wounds is a consequence of an increased level of proteases degrading both the ECM and the growth factors, which results in lower growth factor signaling and impaired healing.

Figure 3.

ECM-inspired growth factor delivery systems. (A) The choice of the appropriate biomaterial is central for designing a growth factor delivery system, depending on its ability to retain growth factors while being cell friendly. (B) Further engineering strategies can be implemented to specifically increase the biomaterial affinity for wild-type growth factors. (C) Other strategies are based on the engineering of the growth factors itself, to reduce the complexity of the delivery system.

Figure 4.

Engineering of the growth factor signaling microenvironment. Cosignaling of integrins and growth factor receptors has been shown to trigger a synergistic effect that increase and prolong growth factor signaling. The recruitment of common molecules from both signaling cascade induces an enhanced effect of growth factor. Exploiting this synergistic signaling permits to lower the effective dose of growth factors in wound healing therapies.

Figure 5.

Growth factors engineered for super-affinity to the ECM. (A) Fusing an ECM-binding domain on growth factors enhances their binding to endogenous matrices, which improves their retention and tissue healing effect in vivo. (B) Immunostaining of VEGF-A variants having different affinity for the ECM after their incubation on ear skin matrix. Super-affinity engineered VEGF-A shows a drastically increased retention in the matrix compared to wild-type VEGF-A. Scale bar=50 μm. VEGF-A, vascular endothelial growth factor-A.