Nao Hiwatashi

Basic fibroblast growth factor combined with atelocollagen for closing chronic tympanic membrane perforations in 87 patients.

Objective: To present the clinical results of closing chronic tympanic membrane (TM) perforations using basic fibroblast growth factor (bFGF) combined with an atelocollagen/silicone bilayer membrane patch. Study Design: Closure of TM perforations in 87 patients was attempted using bFGF, which is thought to promote the regeneration of TM tissues by facilitating the growth of fibroblasts and collagen fibers. Methods: Under an operating microscope, the margin of the perforation was trimmed, and a piece of an atelocollagen/silicone bilayer membrane was placed in the perforation with the silicon layer facing outward and then infiltrated with 0.1 ml of trafermin. Data obtained from patient records included patient age, perforation size, and duration of treatment, with a focus on hearing improvement and complete TM closure. Results: The mean perforation size before treatment was 14.4%. Complete closure of the TM perforation was achieved in 80 patients (92.0%), whereas pinholes remained in 5 patients (8.7%), and small perforations were observed in 2 patients (2.3%). In the patients with complete closure, the TM perforations closed after an average 1.8 treatments, and hearing improved by 13.6 dB. Conclusion: This study demonstrated that bFGF combined with atelocollagen is effective for the conservative treatment of TM perforation.

Multidimensional Analysis on the Effect of Vocal Function Exercises on Aged Vocal Fold Atrophy

OBJECTIVES Age-related voice change is characterized as weak, harsh, and breathy. These changes are caused by histologic alteration of the lamina propria of the vocal fold mucosa as well as atrophy of the thyroarytenoid muscle. Several therapeutic strategies involving laryngeal framework surgery and injection laryngoplasty have been tried, but effects have been limited. Vocal function exercises (VFE) have been used to treat age-related vocal fold atrophy although the effectiveness has been shown with limited analysis. The present study aims to determine the effectiveness of VFE for the treatment of aged atrophy using multidimensional analysis. STUDY DESIGN This is a retrospective study. METHODS Sixteen patients with vocal fold atrophy aged 65-81 years underwent voice therapy using VFE. Six patients with vocal fold atrophy aged 65-85 years were involved as a historical control group. The grade, roughness, breathiness, asthenia, strain (GRBAS) scale, stroboscopic examinations, aerodynamic assessment, acoustic analysis, and Voice Handicap Index-10 (VHI-10) were performed before and after VFE. Normalized mucosal wave amplitude (NMWA), normalized glottal gap (NGG), and bowing index (BI) were measured by image analysis during stroboscopic examinations. RESULTS After VFE, significant improvements were shown in GRBAS, maximum phonation time, jitter, NMWA, NGG, and VHI-10 although BI has not changed significantly. There were no significant improvements in the historical control. CONCLUSIONS The data suggest that VFE produces significant improvement in subjective, objective, and patient self-evaluation and deserves further attention as a treatment for aged atrophy of the vocal fold. It was also suggested that VFE does not improve the vocal fold bowing but may improve muscular function during voicing.

Adipose-derived stem cells versus bone marrow-derived stem cells for vocal fold regeneration.

Vocal fold scarring presents therapeutic challenges. Recently, cell therapy with mesenchymal stromal cells has become a promising approach. The aim of this study was to compare the therapeutic potential of adipose‐derived stem cells (ASC) with bone marrow‐derived stem cells (BMSC) for vocal fold regeneration.

Biocompatibility and efficacy of collagen/gelatin sponge scaffold with sustained release of basic fibroblast growth factor on vocal fold fibroblasts in 3-dimensional culture.

Objective: Treatment of vocal fold scarring remains challenging. We have previously reported the therapeutic effects of local injection of basic fibroblast growth factor (bFGF) in animal models and humans. A novel collagen/gelatin sponge (CGS) is capable of sustained release of bFGF, which compensates for its quick absorption in vivo, avoiding multiple injections. This study aimed to evaluate the biocompatibility and efficacy of the CGS in rat vocal fold fibroblasts prior to human trials. Methods: Fibroblasts extracted from Sprague-Dawley rat vocal folds were seeded onto a CGS and then cultivated with bFGF at concentrations of 0, 10, and 100 ng/mL. Vocal fold fibroblast morphology, adhesion, proliferation, and gene expression were measured under these 3-dimensional conditions. Results: Cells adhered to the CGS from day 1. Although no significant differences in cell morphology were detected, cell proliferation was accelerated by bFGF administration. Expression of endogenous bFGF and hepatocyte growth factor was significantly up-regulated at 10 ng/mL bFGF. The expression of procollagen I and procollagen III was significantly suppressed, whereas HAS-1 and HAS-2 were up-regulated at 10 and 100 ng/mL bFGF. Conclusion: The collagen/gelatin sponge is biocompatible with vocal fold fibroblasts and may be useful as a bFGF drug delivery system for the treatment of scarred vocal folds.

Mesenchymal stem cells have antifibrotic effects on transforming growth factor-β1-stimulated vocal fold fibroblasts.

Mesenchymal stem cells (MSCs) hold therapeutic promise for vocal fold scar, yet the precise mechanism(s) underlying tissue level changes remain unclear. We hypothesize that MSCs interact with native fibroblasts to favorably affect healing. Furthermore, we hypothesize that these interactions vary based on MSC source.

Comparison of ASCs and BMSCs combined with atelocollagen for vocal fold scar regeneration

Vocal fold scar remains a therapeutic challenge. Mesenchymal stromal cells (MSCs) are promising tools for regenerative medicine. Nevertheless, few in vivo studies have directly compared various sources of MSCs. The aim of this study was to investigate the therapeutic potential of adipose‐derived stromal cells (ASCs) in comparison with bone marrow–derived stromal cells (BMSCs) for vocal fold regeneration.

Effect of astaxanthin on vocal fold wound healing

Our previous study demonstrated that a large amount of reactive oxygen species (ROS) is produced during the early phase of vocal fold wound healing. In the current study, we investigated the effect of astaxanthin, which is a strong antioxidant, on the regulation of oxidative stress and scarring during vocal fold wound healing.

Comparison of vocal outcomes after angiolytic laser surgery and microflap surgery for vocal polyps

OBJECTIVE The microflap technique is a standard procedure for the treatment of vocal fold polyps. Angiolytic laser surgery carried out under topical anesthesia is an alternative method for vocal polyp removal. However, it is not clear whether angiolytic laser surgery has the same effects on vocal outcomes as the microflap technique because of a lack of studies comparing both procedures. In the current study, vocal outcomes after both procedures were compared to clarify the effects of angiolytic laser surgery for vocal polyp removal. METHODS Vocal outcomes were reviewed for patients who underwent angiolytic laser surgery (n=20, laser group) or microflap surgery (n=34, microflap group) for vocal polyp removal. The data analyzed included patient and lesion characteristics, number of surgeries required for complete resolution, and aerodynamic and acoustic examinations before and after surgery. RESULTS In the laser surgery group, complete resolution of the lesion was achieved with a single procedure in 17 cases (85%) and with two procedures in 3 cases (15%). Postoperative aerodynamic and acoustic parameters demonstrated significant improvement compared to preoperative parameters in both the laser surgery group and the microflap surgery group. There were no significant differences in any postoperative aerodynamic and acoustic parameters between the two groups. CONCLUSION The current retrospective study demonstrated that angiolytic laser surgery achieved complete resolution of vocal polyps within two procedures. Postoperative effects on aerodynamic and acoustic functions were similar to those after microflap surgery.

The efficacy of a novel collagen–gelatin scaffold with basic fibroblast growth factor for the treatment of vocal fold scar

Vocal fold scar remains a therapeutic challenge. Basic fibroblast growth factor (bFGF) was reported to have regenerative effects for vocal fold scar, although it has the disadvantage of rapid absorption in vivo. A collagen–gelatin sponge (CGS) can compensate for the disadvantage by providing a sustained release system. The current study evaluated the efficacy of CGS combined with bFGF on vocal fold scar, using rat fibroblasts for an in vitro model and a canine in vivo model. We prepared fibroblasts from scarred vocal folds (sVFs) in rats and showed that bFGF accelerated cell proliferation and suppressed expression levels of cleaved caspase 3 and α‐smooth muscle actin. Has 1, Has 3, Fgf2, Hgf and Vegfa mRNA levels were significantly upregulated, while Col1a1 and Col3a1 were dose‐dependently downregulated, with a maximum effect at 100 ng/ml bFGF. In an in vivo assay, 6 weeks after lamina propria stripping, beagles were divided into three groups: CGS alone (CGS group); CGS with bFGF (7 µg/cm2; CGS + bFGF group); or a sham‐treated group. Vibratory examination revealed that the glottal gap was significantly reduced in the bFGF group and the two implanted groups, whereas the CGS + bFGF group showed higher mucosal wave amplitude. Histological examination revealed significantly restored hyaluronic acid and elastin redistribution in the CGS + bFGF group and reductions in dense collagen deposition. These results provide evidence that CGS and bFGF combination therapy may have therapeutic potential and could be a promising tool for treating vocal fold scar. Copyright

Pharmacokinetics and safety of human recombinant hepatocyte growth factor administered to vocal folds

Previous animal studies demonstrated that hepatocyte growth factor (HGF) has the potential to regenerate scarred vocal folds. In addition, HGF is now produced under a good manufacturing practice (GMP) procedure. Therefore, human clinical trials of HGF are warranted in patients with vocal fold scarring. In the current study, we investigated the pharmacokinetics and the local tissue responses of HGF administered to rat vocal folds.