Local Application of Statins Significantly Reduced Hypertrophic Scarring in a Rabbit Ear Model

Abstract

Background:We previously showed that intradermal injection of statins is a successful treatment for hypertrophic scarring. Topical application has many advantages over intradermal injection. In this study, we demonstrate the efficacy of topical statin treatment in reducing scar in our validated rabbit ear scar model.Methods:Twenty New Zealand White rabbits were divided into 2 study groups, with 6 rabbits receiving 10 μm pravastatin intradermally at postoperative days 15, 18, and 21, and 14 rabbits receiving 0.4%, 2%, and 10% simvastatin topical application at postoperative days 14–25. Four or 6 full-thickness circular dermal punches 7 mm in diameter were made on the ventral surface of the ear down to but not including the perichondrium. Specimens were collected at 28 days to evaluate the effects of statins on hypertrophic scarring.Results:Treatment with pravastatin intradermal administration significantly reduced scarring in terms of scar elevation index. Topical treatment with both medium- and high-dose simvastatin also significantly reduced scarring. High-dose simvastatin topical treatment showed a major effect in scar reduction but induced side effects of scaling, erythema, and epidermal hyperplasia, which were improved with coapplication of cholesterol. There is a dose response in scar reduction with low-, medium- and high-dose simvastatin topical treatment. High-dose simvastatin treatment significantly reduced the messenger ribonucleic acid (mRNA) expression of connective tissue growth factor, consistent with our previously published work on intradermally injected statins. More directly, high-dose simvastatin treatment also significantly reduced the mRNA expression of collagen 1A1.Conclusions:Topical simvastatin significantly reduces scar formation. The mechanism of efficacy for statin treatment through interference with connective tissue growth factor mRNA expression was confirmed.

Imiquimod‐induced skin inflammation is relieved by knockdown of sodium channel Nax

“…The thickness of stratum corneum and the density of hair follicles in the skin of the inner rabbit ear are more similar to that of human skin compared to rodent skin . Furthermore, we have extensive experience in establishing models in the rabbit ear including wound repair, hypertrophic scar, and atopic dermatitis models . Here, we demonstrated that, following repeated challenges of IMQ, dermatosis that parallels human psoriasis emerged in rabbit ear skin characterized by excessive keratinocyte proliferation (acanthosis), insufficient keratinocyte differentiation (parakeratosis) and infiltration of inflammatory cells, including neutrophils, macrophages, T cells and mast cells.…”

Liposome‐encapsulated statins reduce hypertrophic scarring through topical application

“…Thirteen New Zealand white rabbits at 3‐6 months age were purchased from Covance Research Products, Inc (Cumberland, VA), and acclimatized in the temperature‐controlled animal facility with a 12‐hour light/dark cycle for at least 1 week. The rabbit ear HTS model was created as previously described 12 . Briefly, under anesthesia with ketamine and xylazine, six paired, full‐thickness, 7‐mm diameter circular excisional wounds were created on the depilated ventral side of rabbit ears with biopsy punches and covered with Tegaderm (3M Health Care, St. Paul, Minnesota).…”

“…The HTS tissue was harvested on POD 28 for analysis of scar elevation index and gene expression. Topical application of statins to the skin has been demonstrated to cause symptoms of cutaneous scaling, 12 of which the severity and reversibility were observed after withdrawal of statin treatment on POD 25, until POD 42. All the animal procedures in this study were approved by Northwestern University Animal Care and Use Committee.…”

“…Noninvasive topical medication is an ideal medical arm with numerous advantages including convenience, painlessness, and fewer side effects due to local rather than systemic absorption. Through a micro‐emulsion delivery system composed of Transcutol as a surfactant and Capmul MCM EP as an oil base, we previously demonstrated that topical application of lipophilic simvastatin successfully reduced HTS formation 12 . However, with the same transdermal micro‐emulsion formula, hydrophilic pravastatin did not show notable efficacy on HTS formation in our unpublished preliminary study.…”

Statin treatment and hypertrophic scarring after cardiac surgery

“…Low doses of simvastatin, lovastatin, and pravastatin were associated with a significant reduction in SEI when compared to controls. A dose responsive effect has been observed in scar reduction at low, medium, or high doses of simvastatin for topical application 30,31 . High doses of simvastatin are associated with a significant reduction in the expression of the mRNA of CTGF 28,30 .…”