Healing from burn injuries is a substantial physical and psychological challenge, with the goal of recovery being restoration of both aesthetic form and function. At least 186,786 individuals were hospitalized for partial or full-thickness burns in the U.S. from 2006 to 2015 (ABA, 2018), and the U.S. Army Institute of Surgical Research Burn Center has cared for over 1,200 military burn casualties since 2003 (USAISR, 2019). Psychological effects from hypertrophic scarring–a notably raised scar that can occur after burn injury–can contribute to decreased quality of life and delayed reintegration into society (Finnerty et al., 2016).
Researchers from Stanford University School of Medicine have developed a drug therapy that hastened healing time and reduced molecular events associated with scarring in mice (Ma et al., 2018). In previous work, this group demonstrated that mechanical force is a key contributor to hypertrophic scarring (Aarabi et al., 2007) mediated through focal adhesion kinase, which transduces both physical and inflammatory signals (Wong et al., 2011). They also showed that local injections of a focal adhesion kinase inhibitor (FAKI) decreased hypertrophic scarring in a mouse model (Wong et al., 2011). For the present study, the researchers incorporated the FAKI into a topical wound dressing (a pullulan collagen hydrogel), which can be applied to large wound areas like burn injuries more easily than a series of injections.
The team developed two variations of the FAKI-laden hydrogel: a sustained-release gel for use on excisional wounds (surgical removal of tissue) that need infrequent dressing changes and a rapid-release gel for use on burn wounds requiring frequent dressing changes. The hydrogels were applied to mice with excisional wounds or full-thickness burn wounds, and mice were evaluated for wound closure (healing time) and profibrotic activity via levels of α-smooth muscle actin (α-SMA; a proxy for hypertrophic scarring in this model).
In the excisional wound model, mice treated with hydrogel+FAKI did not have a faster healing time than those treated with hydrogel alone. This means that topical application of FAKI did not affect the healing time of an excisional wound. However, mice treated with hydrogel+FAKI had significantly less α-SMA at the wound site than the hydrogel alone and untreated groups, indicating less fibrotic activity and a better scarring outcome with FAKI application. In the burn wound model, mice treated with hydrogel+FAKI healed significantly faster than hydrogel alone or untreated mice, suggesting that topical FAKI does contribute to faster healing from burn wounds. In addition, levels of α-SMA were significantly lower in hydrogel+FAKI mice than hydrogel alone or untreated mice, again demonstrating FAKI's effect on reducing fibrogenic activity in the wound environment and suggesting its ability to limit hypertrophic scarring. In summary, the hydrogel+FAKI shortened healing time after burn wounds and reduced molecular activity associated with hypertrophic scarring in both excisional and burn wounds.
In addition to the promising implications of these findings for improving aesthetic outcomes after burn injury, this research is also an intriguing example of drug repositioning. The FAKI used in this work, VS-6062, had demonstrated efficacy as a cancer therapy in clinical trials, but was not pursued because of potential drug-drug interactions and undesirable pharmacokinetics when administered orally. Topical administration of this drug may not have the same systemic toxicities. Given the long development timeline and high research costs for new drug candidates, drug repositioning and repurposing provide opportunities to bring new therapies to market faster and with less investment, and therefore more efficiently deliver medical solutions to wounded Service members recovering from blast injury.
Aarabi S, Bhatt KA, Shi Y, Paterno J, Chang EI, Loh SA, Holmes JW, Longaker MT, Yee H, Gurtner GC. Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis. The FASEB Journal. 2007;21(12):3250-61.
American Burn Association. 2018. National burn repository: Report of data from 2008–2017. Retrieved from http://ameriburn.org/wp-content/uploads/2019/02/2017_aba_nbr_annual_report.pdf.
Finnerty CC, Jeschke MG, Branski LK, Barret JP, Dziewulski P, Herndon DN. Hypertrophic scarring: the greatest unmet challenge after burn injury. The Lancet. 2016;388(10052):1427-36.
Ma K, Kwon SH, Padmanabhan J, et al. Controlled delivery of a focal adhesion kinase inhibitor results in accelerated wound closure with decreased scar formation. Journal of Investigative Dermatology. 2018;138: 2452–2460.
USAISR. 2019. Burn center [Website]. Retrieved from https://usaisr.amedd.army.mil/12_burncenter.html.
Wong VW, Rustad KC, Akaishi S, Sorkin M, Glotzbach JP, Januszyk M, Nelson ER, Levi K, Paterno J, Vial IN, Kuang AA. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nature Medicine. 2012;18(1):148.
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