Chemically modified hyaluronic acid (HA)-gelatin hydrogels have been documented to support attachment, growth, and proliferation of fibroblasts in vitro and to facilitate repair and engineering of tissues in vivo. The objective of this study was to determine the optimal composition of a synthetic extracellular matrix (sECM) that would promote wound repair and induce tissue regeneration in a rabbit vocal fold wound healing model. The sECM was formed using a thiol-modified semisynthetic glycosaminoglycan (GAG) derived of HA (Carbylan-SX) mixed with a thiolated gelatin derivative, co-cross-linked with poly(ethylene glycol) diacrylate to form Carbylan-GSX. Forty rabbits underwent vocal fold biopsy bilaterally. Rabbits were treated with Carbylan-SX, which lacks gelatin, or with Carbylan-GSX with different gelatin concentrations (2.5%, 5%, 10%, and 20%) via unilateral injection of the vocal fold at the time of biopsy. Saline was injected in the contralateral vocal fold as a control. Three weeks after biopsy and injection, animals were euthanized and mRNA levels of procollagen type 1, fibronectin, transforming growth factor beta 1 (TGF-beta1), fibromodulin, HA synthase 2, hyaluronidase 2, and tissue biomechanics were evaluated. Hyaluronidase mRNA levels were found to be significantly elevated in for Carbylan-GSX 20% w/w gelatin compared to controls. Both Carbylan-SX and Carbylan-GSX significantly improved tissue elasticity and viscosity. Carbylan-GSX containing 5% w/w gelatin showed the most promise as a scaffold material for vocal fold tissue regeneration.
Scarring of the vocal folds leads to a deterioration of the highly complex micro-structure with consecutively impaired vibratory pattern and glottic insufficiency. The resulting dysphonia is predominantly characterized by a reduced vocal capacity. Despite the considerable progress in understanding of the underlying pathophysiology, the treatment of scarred vocal folds is still an unresolved chapter in laryngology and phonosurgery. Essential for a successful treatment is an individual, multi-dimensional concept that comprises the whole armamentarium of surgical and non-surgical (i.p. voice therapy) modalities. An ideal approach would be to soften the scar, because the reduced pliability and consequently the increased vibratory rigidity impede the easiness of vibration. The chosen phonosurgical method is determined by the main clinical feature: Medialization techniques for the treatment of glottic gap, or epithelium freeing techniques for improvement of vibration characteristics often combined with injection augmentation or implantation. In severe cases, buccal mucosa grafting can be an option. New developments, include treatment with anxiolytic lasers, laser technology with ultrafine excision/ablation properties avoiding coagulation (Picosecond infrared laser, PIRL), or techniques of tissue engineering. However, despite the promising results by in vitro experiments, animal studies and first clinical trials, the step into clinical routine application has yet to be taken.
The role of myofibroblasts in vocal fold scarring has not been extensively studied partly due to a lack of a robust in vitro model. The objective of this investigation was to develop and characterize a myofibroblast in vitro model that could be utilized to investigate the molecular mechanism of myofibroblast differentiation and function in injured vocal fold tissue. Differentiation of human primary vocal fold fibroblasts (hVFF) to myofibroblasts was stimulated using 5, 10, or 20 ng/ml of recombinant transforming growth factor beta-1 (TGF-β1). Cultures were analyzed using immunofluorescence and western blotting, with an anti-alpha smooth muscle actin (α-SMA) antibody as a myofibroblast marker. Normal rabbit vocal folds were treated with 10 ng/ml of TGF-β1 for 7 days for in vivo corroboration. The effects of interleukin-6 (IL-6) and hepatocyte growth factor (HGF) on myofibroblast differentiation were studied using western blots. hVFF demonstrated positive α-SMA labeling in 10 and 20 ng/ml TGF-β1 stimulated cells indicating that hVFFs were capable of differentiation to myofibroblasts. TGF- β1 induced the largest increase in α-SMA at 10-ng/ml on day 5 of treatment. HGF and IL6 suppressed the expression of TGF-β1 induced α–SMA. Our work characterizes a useful in vitro model of TGF-β1 mediated vocal fibroblast-myofibroblast differentiation. The extent of differentiation appears to be attenuated by HGF suggesting a potential mechanism to support prior work indicating that HGF plays a protective role from scar formation in vocal fold injuries. Paradoxically, IL-6 which has been shown to play a profibrotic role in dermal studies also attenuated the TGF-β1 response.
The present results show that margins considered positive after laser resection do not significantly impact carcinologic course, while still requiring close surveillance. The most generally recommended attitude is control endoscopy with biopsy at 10 weeks.
Aberrant laryngeal sensation was identified in patients with PVFM and chronic cough. This response, however, normalized following a limited course of respiratory retraining, corresponding with improved patient symptoms.
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