Pharmaceutical Prophylaxis of Scarring with Emphasis on Burns: A Review of Preclinical and Clinical Studies

Abstract

Significance: The worldwide estimate of burns requiring medical attention each year is 11 million. Each year in the United States, ∼486,000 burn injuries receive medical attention, including 40,000 hospitalizations. Scars resulting from burns can be disfiguring and impair functions. The development of prophylactic drugs for cutaneous scarring could improve the outcomes for burns, traumatic lacerations (>6 million/year treated in U.S. emergency rooms), and surgical incisions (∼250 million/year worldwide). Antiscar pharmaceuticals have been estimated to have a market of $12 billion. Recent Advances: Many small molecules, cells, proteins/polypeptides, and nucleic acids have mitigated scarring in animal studies and clinical trials, but none have received Food and Drug Administration (FDA) approval yet. Critical Issues: The development of antiscar pharmaceuticals involves the identification of the proper dose, frequency of application, and window of administration postwounding for the indicated wound. Risks of infection and impaired healing must be considered. Scar outcome needs to be evaluated after scars have matured. Future Directions: Once treatments have demonstrated safety and efficacy in rodent and/or rabbit and porcine wound models, human testing can begin, such as on artificially created wounds on healthy subjects and on bilateral-surgical wounds, comparing treatments versus vehicle controls on intrapatient-matched wounds, before testing on separate cohorts of patients. Given the progress made in the past 20 years, FDA-approved drugs for improving scar outcomes may be expected.

Keywords: biopharmaceuticals; burns; drugs; pharmaceuticals; scars; wounds.

Peter D'Arpa, PhD

Kai P. Leung, PhD

Figure 1.

Patents in the field of scar outpace patents in all fields. Patent applications and patents granted in all fields worldwide (solid and dashed black lines, respectively) are shown in millions (WIPO IP Statistics Data Center, Direct and PCT System, updated October 2019). Also shown are worldwide patent applications and patents granted in the field of scarring (solid and dashed red lines, respectively); that is, “scar” or “fibrosis” as title words and “skin,” “cutaneous,” or “dermis” as abstract words in a Google Patents search.

Figure 2.

Animal model studies of prophylactic treatments for scarring. PubMed was searched using Boolean terms (Supplementary Data) that resulted in >500 records (in English) from 2000 to 2020 that were manually curated to include studies of pharmaceutical or biopharmaceutical scar prophylactics (PMID numbers are shown in brackets). The R package easyPubMed was used to facilitate the literature survey. PMID, PubMed identifier.

Figure 3.

Porcine studies of scar prophylactic treatments showing efficacy: routes of administration, time courses, and scar outcomes for burns and other wounds. Wounds are pink, treatment times are dark blue, and the outcomes are salmon. The light blue rectangles indicate i.v. infusions. PMID numbers are shown in brackets. Days postwounding with wounding on day 1 are shown on a log10 scale. i.v., intravenous.

Figure 4.

Studies listed in ClinicalTrials.gov for the Condition “burns” and the Intervention “drug,” “biological,” or “combination product,” with the Outcome Measure (A) “scarring” or (B) “healing or “epithelialization.” ClinicalTrials.gov identifiers (NCT number) are shown in brackets. Masking of 0, 1, 2, 3, or 4, corresponds to open-label, and single-, double-, triple-, and quadruple-blinding. Numbers indicate the total patients enrolled in the trial.

Figure 5.

Studies listed in ClinicalTrials.gov for the Condition “scarring” or “burns,” the Outcome Measure “scarring,” and the Intervention “drug,” “biological,” or “combination product.” NCT numbers are shown in brackets. The number of study subjects in each trial is shown next to the symbol.

Figure 6.

Human skin scar prophylaxis clinical study summary. PubMed was searched for scar[Title/Abstract] AND (skin[Title/Abstract] OR dermis[Title/Abstract] OR cutaneous[Title/Abstract]) AND (“Clinical Study” OR “Clinical Trial” OR “Phase I” OR “Phase II” OR “Phase III” OR “Phase IV” OR subjects OR participants), which resulted in 940 records in English from 2000 to 2020 (April) that were manually curated. PMID numbers are shown in brackets.

Figure 7.

Human skin scar prophylaxis: time course and outcomes of pharmaceutical treatments that showed efficacy. Wounds are pink, treatment times are blue, and the outcomes are salmon colored. PMID numbers are shown in brackets. rhGH was administered to patients after hospital discharge (an average of 7.5 weeks after burn) until 12 months. Days postwounding (wounding on day 1) are shown on a log10 scale. rhGH, recombinant human growth hormone.