Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation

Abstract

Formation of scars after wounding or trauma represents a significant health care burden costing the economy billions of dollars every year. Activation of focal adhesion kinase (FAK) has been shown to play a pivotal role in transducing mechanical signals to elicit fibrotic responses and scar formation during wound repair. We have previously shown that inhibition of FAK using local injections of a small molecule FAK inhibitor (FAKI) can attenuate scar development in a hypertrophic scar model. Clinical translation of FAKI therapy has been challenging, however, because of the lack of an effective drug delivery system for extensive burn injuries, blast injuries, and large excisional injuries. To address this issue, we have developed a pullulan collagen-based hydrogel to deliver FAKI to excisional and burn wounds in mice. Specifically, two distinct drug-laden hydrogels were developed for rapid or sustained release of FAKI for treatment of burn wounds and excisional wounds, respectively. Controlled delivery of FAKI via pullulan collagen hydrogels accelerated wound healing and reduced collagen deposition and activation of scar-forming myofibroblasts in both wound healing models. Our study highlights a biomaterial-based drug delivery approach for wound and scar management that has significant translational implications.

Nanoparticle-mediated local delivery of pioglitazone attenuates bleomycin-induced skin fibrosis

“…However, there are only a few studies on the treatment of dermal fibrosis with sustained-release drugs. For example, Ma et al recently demonstrated that controlled delivery of a focal adhesion kinase inhibitor via pullulan collagenbased hydrogels accelerated the wound healing of excisional and burn wounds and reduced scar formation [16]. The activation of PPAR-g by both natural and synthetic agonists can effectively inhibit pro-fibrotic tissue reactions, cell migration, and inflammation in many organs [17] and inhibit collagen synthesis in human keloid fibroblasts [18].…”

Inflammation as an orchestrator of cutaneous scar formation: a review of the literature

“…Another strategy to reduce scar formation by affecting mechanotransduction is to inhibit FAK signaling with a small molecule inhibitor. Several small animal studies have suggested that FAK inhibitors can reduce scarring [ 93 , 172 ] , and treatment with FAK inhibitors and genetic ablation of FAK in fibroblasts have been reported to reduce inflammatory mediator production and inflammatory cell recruitment [ 93 ] . Collectively, the data suggest that altering mechanical signaling pathways may reduce scar formation at least in part by influencing inflammation.…”

Advances in scarless foetal wound healing and prospects for scar reduction in adults

“…As demonstrated both in vivo and in vitro, inhibition of calpain constrains granulation tissue growth by reducing collagen synthesis 94 . Considering that inhibitors of focal adhesion kinase (FAK) can suppress scar formation, Kun et al developed a controlled drug release of FAK, which provides an innovative approach for clinical treatment 95 . Fibromodulin, a small molecule that can effectively inhibit scar formation, is activated in both embryonic and adult stages through the TGF‐β pathway 33,96 .…”