Growth Factor and Cytokine Delivery Systems for Wound Healing

Abstract

Skin wound healing is a highly coordinated process involving multiple tissue-resident and recruited cell types. Cells within the wound microenvironment respond to key secreted factors such as pro-proliferative growth factors and immunomodulatory cytokines to repair the skin and promptly restore its essential barrier role. Therefore, recombinant growth factors and cytokines are promising therapeutics for skin wounds, in particular for large acute wounds such as burns, or wounds associated with underlying pathologies such as nonhealing chronic and diabetic wounds. However, translation of growth factors and cytokines into clinically effective treatments has been limited. Short half-life, poor stability, rapid diffusion, uncontrolled signaling, and systemic side effects are currently the key challenges to developing efficient growth factor- and cytokine-based therapies. To overcome these limitations, novel delivery systems have been developed to improve the regenerative potential of recombinant growth factors and cytokines. In this review, we discuss biomaterial and protein engineering strategies used to optimize the delivery of growth factor and cytokine therapeutics for skin wound treatment.

Figure 1.

Key principles to optimize the delivery of recombinant growth factors and cytokines to wounds. The translation of recombinant growth factors and cytokines into effective therapeutics for skin wounds is limited in the absence of suitable delivery systems. Poor delivery systems require high doses of recombinant protein, have minimal ability to control their release, lead to rapid degradation, do not maintain effective signaling, and ultimately leads to increased side effects and poor efficacy (top panel). Optimal delivery systems are able to minimize the required dose of recombinant protein by restricting their release within the wound environment, increasing their half-life, and maintaining an optimal signaling activity. This has demonstrated improved wound healing outcomes in animal models with minimal adverse effects (bottom panel).

Figure 2.

Examples of strategies to improve growth factor and cytokine delivery to wounds. (A) Commonly used biomaterial systems used to deliver growth factors and cytokines to skin wounds. (B) Functionalization strategies for biomaterials or endogenous extracellular matrix (ECM) to control growth factor and cytokine retention and release. (C) Protein engineering strategies to improve growth factor and cytokine stability. (D) Approaches to modulate growth factor and cytokine signaling.