Dysphonia as a result of vocal fold scar is caused by loss of mucosal pliability and inability to normally modulate the airflow that produces voice. An individual with vocal fold scar often must increase effort (high phonation threshold pressure) to overcome the stiffness, which leads to a strained voice and compensatory hyperfunction that may damage the vocal folds further. ^, In general, once the vibratory margin of the vocal fold has been scarred, it is often not possible to return vocal fold function to normal, but it often can be improved.

Following damage to vocal fold mucosa, fibroblast proliferation and collagen deposition occur below the epithelial layer and lead to wound contraction. In animal models, there is disorganization of collagen and elastin fibers, and thick-bundle collagen formation. There is also less hyaluronic acid and more collagen types 1 and 3 compared to controls. Kitamura et al. analyzed the histology of human vocal folds following varying degrees of injury. They noted that following subepithelial cordectomy, there was well-organized collagen in the lamina propria, elastin was well organized in the deeper portion, and decorin was present in all cases. Decorin is a small-chain proteoglycan that is normally present in the superficial lamina propria and acts to regulate the formation of collagen fibrils. ^, After subligamentous cordectomy, there was extensive, disorganized collagen and either complete loss or disorganization of elastin. In trans-muscular cordectomy, decorin was barely observed.

Despite much scholarship to combat the effects of vocal fold scar, there is no universally successful treatment. Various techniques have been studied in animal models including injection of adipose-derived stem cells, hepatocyte growth factor, ^, mitomycin C, selective cultured autologous mesenchymal stem cells, laser ablation with 445 nm blue light laser (BL), or potassium titanyl phosphate laser (KTP), homologous collagen matrix, and basic fibroblast growth factor. The literature is more limited on the treatment of vocal fold scar in humans. Björck et al. reported some improvement of vibratory capacity with the injection of collagen, although documented acoustic and perceptual changes were marginal. Mortensen et al. reported the use of pulsed dye laser for vocal fold scar to be safe and effective. Autologous fat injection and implantation are effective in the treatment of vocal fold scar and glottic insufficiency. Ban et al. recently reported that injection of fibroblast growth factor improved voice quality and may be an alternative treatment for mild, chronic vocal fold scarring. In-office, percutaneous steroid injections have also been reported to be safe and effective. ^,

Intracordal injections remain one of the most common outpatient practices for laryngeal diseases or trauma, regarded as low risk, convenient, and easy to implement. Currently, the well-supported history of intralesional steroid injection efficacy and safety throughout the body makes this the standard scarring therapeutic for intracordal injection. ^, Established for the treatment of dermatologic hypertrophic scar, the suppression of normal inflammatory and proliferative processes with steroids has allowed for versatile treatment of scarring processes throughout the body. Young et al. quantified the perceived voice benefit of these steroid injections with a reduction in the self-reported Voice Handicap Index-10 score and the observed histological changes of reduced vocal fold inflammation and collagen deposition. While case-dependent, the inconsistency of clinical efficacy has proven a challenge and prompts discovery for new therapeutics or additives to these injections.

Research on hypertrophic scar therapeutics suggests improved efficacy in decreasing scar when 5-FU is added to an intralesional steroid injection. Local injections of 5-FU have been increasingly reported, and safety is supported in cases of pterygium treated with subconjunctival injections. Garcia et al. in 2019 reported no adverse effects with local injection while arresting the recurrence of postoperative pterygium. In a 2022 animal study, Xu et al. reported inhibition of fibrotic scar formation by reduction of matrix metalloproteinase 9 expression following spinal cord injury intervention after 5-FU injection. A study by Zhou et al. in 2021 supports 5-FU injection with steroid in promoting miRNA activity, leading to the reduction of urethral stricture from fibroblast scarring processes.

As reviewed elsewhere, the drug 5-FU is a pyrimidine antimetabolite that has a broad spectrum of clinical applications. Its uses range from chemotherapy for head and neck cancer and breast cancer to the topical treatment of actinic keratosis and basal cell carcinoma of the skin (Efudex, Valeant Pharmaceuticals International, Inc., Laval, Quebec, Canada). Since the late 1980s, the drug has also been used internationally as an injection for hypertrophic scars and keloids. ^,

Once inside cells, 5-FU acts by a few different mechanisms. It can bind the enzyme thymidylate synthase, resulting in decreased production of thymidine that blocks DNA replication. The drug can integrate into DNA that is being replicated, acting as a mutagen that incorporates guanine into the wrong location in various genes. This can have dramatic downstream effects, including inhibited production of proteins and inhibition of apoptosis. 5-FU inhibits fibroblast proliferation and myoblast differentiation. In low doses, it inhibits proliferation, induces G2/M cycle arrest, and apoptosis.

Several studies looking to improve hypertrophic scar results suggest improved efficacy in decreasing scar when 5-FU is added to intralesional steroid injections. 5-FU combined with triamcinolone was reported to lead to complete inhibition of type 1 collagen production in hypertrophic scars and keloids which has also been implicated in the formation of vocal fold scar. 5-FU has shown success in animal models in the treatment of subglottic stenosis. Davison et al. showed that 5-FU used in conjunction with triamcinolone was superior to the use of triamcinolone alone in the treatment of keloids. Nanda et al. also investigated the efficacy of 5-FU in the treatment of keloids since 5-FU inhibits the fibroblast proliferation that leads to excess collagen deposition. They found a 50% reduction in most keloids with no treatment failures and no serious side effects. 5-FU safety and efficacy have also been supported by its use in reducing scar after spinal cord injury and reduction of urethral stricture scarring. ^,

Recent studies of the use of 5-FU have centered on topical administration of the drug.

Prior data on the effect of 5-FU on vocal fold scar are limited. One interesting study performed by Baptistella et al. compared both mitomycin-C and 5-FU to a control in pigs that had undergone CO ₂ laser partial excision of the vocal folds. In the two treatment groups, the left fold was used as a control, and the right fold had a pledget soaked with the respective drug applied for 3 minutes. The control group underwent surgery only, and both vocal folds were left untreated. When the animals were euthanized at 30 days, the mitomycin-C and 5-FU animals were found to have significantly less collagen deposition as compared to the control animals. Interestingly, there were no significant differences noted between the mitomycin-C and 5-FU groups, suggesting similar clinical efficacy after topical application.