Innovations in gene and growth factor delivery systems for diabetic wound healing

Abstract

The rise in lower extremity amputations due to nonhealing of foot ulcers in diabetic patients calls for rapid improvement in effective treatment regimens. Administration of growth factors (GFs) are thought to offer an off-the-shelf treatment; however, the dose- and time-dependent efficacy of the GFs together with the hostile environment of diabetic wound beds impose a major hindrance in the selection of an ideal route for GF delivery. As an alternative, the delivery of therapeutic genes using viral and nonviral vectors, capable of transiently expressing the genes until the recovery of the wounded tissue offers promise. The development of implantable biomaterial dressings capable of modulating the release of either single or combinatorial GFs/genes may offer solutions to this overgrowing problem. This article reviews the state of the art on gene and protein delivery and the strategic optimization of clinically adopted delivery strategies for the healing of diabetic wounds.

Keywords: biomaterials; diabetic foot ulcer; gene; growth factors; wound healing.

Figure 1

A schematic depicting normal wound healing process. TIMPs = tissue inhibitors of metalloproteinases

Figure 2

Hyperglycaemia impairs angiogenesis and wound healing

Figure 3

The different formats of commonly adopted therapeutic dressings. (I) Electrospun nanofibres 1. Direct blending of GFs 2. Encapsulation of GFs in the core of a core‐shell construct 3. Incorporation of nanoparticles bound GFs 4. GFs conjugated on the surface of fibres 5. Encapsulation of GFs in the core of a core‐shell followed by surface‐conjugation of another GF. (II) Hydrogels and 3D scaffolds. (a) Entrapment of GFs within the hydrogel matrix; (b) entrapment of GFs within the porous scaffold; (c) micro/nanoparticles bound GFs embedded into hydrogel; (d) GFs chemically conjugated onto scaffolds; (e) incorporating micro/nanoparticles bound GFs into scaffold

Figure 4

Representative images of healing of foot ulcers following the treatment with GAM501 in phase 1/2 clinical trial (Mulder et al., 2009)