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104 Dinaki et al. | Journal of Clinical and Translational Research 2024; 10(2): 99-111
follow-up lasted for 2.5 years without any incidents of deformation muscular tissue of the vocal cords. Trauma, surgery, or long-term
being reported [52]. In 2018, a 7-year-old patient with arrhinia vocal misuse are the main causes of scar formation, leading to loss
underwent nasal reconstruction using a 3D-printed nasal stent to of pliability of the vocal folds. LP scarring causes stiffness and
prevent nasal cavity constriction. In this clinical research, a custom- reduces viscosity that changes the tissue biomechanics of the vocal
made silicone nasal stent was manufactured utilizing 3D printing fold [61]. As a result, the normal mucosa wave during phonation
technology. The muco-epithelial tissue successfully regenerated is disrupted, thereby affecting the vocals [62,63]. Nonetheless,
within 2 months following the stent placement. External nose damaged vocal folds can be regenerated through several methods,
shape, nasal passage structure, and respiratory functions were in including cell therapy, developing and implementing a scaffold,
good condition after 3 years following the stent removal without and using growth factors.
additional medical intervention [53].
The most prominent use of auricular cartilage was in 1997 when 5.2. Cell therapy
polyglycolic acid scaffolds were shaped into the 3D structure of a Fibroblasts and stem cells are extensively studied for vocal
human ear, seeded with bovine chondrocytes, and transplanted into fold regeneration. Fibroblasts produce a large proportion of the
the dorsal pockets of mice [54]. Thereafter, research was carried extracellular matrix (ECM) in the LP and further support the LP.
out in regenerative medicine with synthetic scaffolds and cultured Fibroblasts resemble MSCs because they possess the same cell
chondrocytes. Yanaga et al. injected a combination of autologous surface markers and differentiation capacity [63]. Chhetri et al.
serum and autologous chondrocytes from the outer ear cartilage were the first to study the use of autologous fibroblasts from the
into the ear, nose, and chin of 32 patients with craniofacial or buccal mucosa. In this study, fibroblasts were injected into the LP
nasal abnormalities [49]. A two-stage transplantation procedure of a canine model, subsequently improving the vocal fold mucosal
was performed for auricular and nasal/chin reconstructions, waves and acoustic characteristics. In addition, histological
respectively [55,56]. In the former, chondrocytes were first assessments revealed increased fibroblasts, collagen, and reticulin
extracted from the residual auricular cartilage of four children and decreased elastin [64]. Chhetri et al. also conducted a pilot
with microtia and cultivated respectively into a subcutaneous study where five individuals with damaged vocal folds were
pocket of fascia in the lower abdomen for 4 weeks. Subsequently, injected with autologous fibroblasts from the buccal mucosa [65].
the children did not report any adverse events during the 2- to Four out of five patients demonstrated subjective and objective
5-year follow-ups [55]. Similarly, 18 individuals were treated with improvements in the vocal quality and mucosal wave. In another
a comparable nasal/chin reconstructive technique [56].
study, Ma et al. examined the efficacy of fibroblasts in 15 patients
4.7. Salivary glands with vocal fold scarring or atrophy using postauricular skin-
derived autologous fibroblasts and reported improvements in the
The glands of the upper aerodigestive tract (i.e., parotid, mucosal wave without any side effects [66].
sublingual, and submandibular glands) and minor salivary Likewise, BM-MSCs have demonstrated positive indications
glands are known to produce saliva [57]. Hypofunctional can be in animal studies [67,68]. In 2020, a phase I/II human clinical trial
caused by radiation therapy for head and neck cancer, Sjogren’s was conducted with 16 patients to investigate the treatment of
syndrome (SS), and various medications. Possible oral problems vocal fold scarring with autologous BM-MSCs [69]. The patients
caused by hyposalivation include mucosal infections, dysphagia, were followed up for a year, and two-thirds of the participants
and aspiration pneumonia. In animal models, BM-MCSs have demonstrated improvements in vocal vibration and flexibility.
demonstrated the therapeutic capability to rebuild the salivary There was another phase I/IIA clinical trial that demonstrated
glands [58,59]. Xu et al. reported a successful restoration of the the efficacy and safety of adipose-derived regenerative cell-
secretory function of salivary glands in animal models and SS enriched fat grafting to repair glottal gaps following unilateral
patients using MSC therapy [58]. Adipose tissue-derived stem vocal fold paralysis [70].
cells (ASCs) have also been studied in clinical trials on irradiation-
induced hypofunctional salivary glands in patients [60]. The phase 5.3. Bioactive factors
I/II clinical trial evaluated the efficacy and safety of ASC-based
cell therapy, whereby the submandibular glands were injected with Hirano et al. studied the use of bFGF in treating atrophic human
autologous ASCs. In the ACS-treated group, the unstimulated total vocal fold. One week after the bFGF injection, the aerodynamic
salivary flow rate (assessed after 1 and 4 months) was significantly and acoustic parameters displayed improvements that lasted for
more than the baseline (pre-treatment). In contrast, the placebo 3 months [71]. In a recent study by Hirano et al., local injections
group reported a decrease in salivary flow rate after 1 month and a of bFGF were performed in 100 cases of vocal fold disease [72].
less prominent increase after 4 months. The findings of the study indicated that intracordal injection of
bFGF resulted in voice improvements without any significant
5. Applications in Laryngology adverse effects. Hirano et al. also reported that bFGF enhanced the
synthesis of HA in fibroblasts and decreased collagen deposition
5.1. Vocal folds
in the vocal folds of aged rats [73]. Subsequently, Hirano et al.
Lamina propria (LP) is a flexible, collagen- and elastin-rich conducted a clinical trial with 10 patients having aged vocal
vibratory connective tissue layer between the epithelium and the folds with scar tissue and sulcus vocalis [74]. The findings of the
DOI: https://doi.org/10.36922/jctr.22.00151