Scar management in burn injuries using drug delivery and molecular signaling: Current treatments and future directions

Abstract

In recent decades, there have been tremendous improvements in burn care that have allowed patients to survive severe burn injuries that were once fatal. However, a major limitation of burn care currently is the development of hypertrophic scars in approximately 70% of patients. This significantly decreases the quality of life for patients due to the physical and psychosocial symptoms associated with scarring. Current approaches to manage scarring include surgical techniques and non-surgical methods such as laser therapy, steroid injections, and compression therapy. These treatments are limited in their effectiveness and regularly fail to manage symptoms. As a result, the development of novel treatments that aim to improve outcomes and quality of life is imperative. Drug delivery that targets the molecular cascades of wound healing to attenuate or prevent hypertrophic scarring is a promising approach that has therapeutic potential. In this review, we discuss current treatments for scar management after burn injury, and how drug delivery targeting molecular signaling can lead to new therapeutic strategies.

Figure 1

A) Phases of wound healing during normal physioliogic skin healing. B) Hypertrophic scarring is characterized by a prolonged proliferation phase during wound healing which leads to excess ECM depiosition.

Figure 2

Schematic illustrating each phase of wound healing with important cell types and genes involved in regulating this well-orchestrated process.

Figure 3

In the absence of Wnt ligand, the transcriptional co-activator β-catenin is degraded by the cytoplasmic destruction complex composed of axin, glycogen synthase kinase (GSK) 3β, and adenomatous polyposis coli protein (APC). The binding of Wnts to frizzled (FZD) receptor transduces a signal across the plasma membrane activating Disheveled (DVL) protein. DVL inhibits the cytoplasmic destruction complex resulting accumulation of β-catenin in the cyotplasm. β-catenin then enters the nucleus and modulates gene transcription.

Figure 4

Transforming growth factor (TGF)-β is normally bound to latent TGF-β binding proteins. During wound healing, conformational changes caused by α_v integrins and mechanical strain release TGF-β allowing it to bind to serine/threonine kinase TGF-β receptor I and TGF-β-receptor II heterodimers. This causes the phosphorylation of Smads 2 and 3 and their translocation to the nucleus where they modulate gene expression along with other transcription cofactors.

Figure 5

Hypertrophic scarring is mainly caused by alterations in collagen synthesis, ECM degradation/remodeling, and fibroblast behavior during wound healing. Several target genes of the Wnt/β-catenin and TGF-β1 signaling pathways have been identified as directly involved in these processes.