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A tissue-specific, injectable acellular gel for the treatment of chronic vocal fold scarring.

ABSTRACT: Gel-based injectable biomaterials have significant potential for treating vocal fold defects such as scarring. An ideal injectable for vocal fold lamina propria restoration should mimic the microenvironment of the lamina propria to induce scarless wound healing and functional tissue regeneration. Most current synthetic or natural injectable biomaterials do not possess the same level of complex, tissue-specific constituents as the natural vocal fold lamina propria. In this study we present a newly-developed injectable gel fabricated from decellularized bovine vocal fold lamina propria. Blyscan assay and mass spectrometry indicated that the vocal fold-specific gel contained a large amount of sulfated glycosaminoglycans and over 250 proteins. Gene Ontology overrepresentation analysis revealed that the proteins in the gel dominantly promote antifibrotic biological process. In vivo study using a rabbit vocal fold injury model showed that the injectable gel significantly reduced collagen density and decreased tissue contraction of the lamina propria in vocal folds with chronic scarring. Furthermore, this acellular gel only elicited minimal humoral immune response after injection. Our findings suggested that the tissue-specific, injectable extracellular matrix gel could be a promising biomaterial for treating vocal fold scarring, even after the formation of mature scar. STATEMENT OF SIGNIFICANCE: Vocal fold lamina propria scarring remains among the foremost therapeutic challenges in the management of patients with voice disorders. Surgical excision of scar may cause secondary scarring and yield inconsistent results. The present study reports an extracellular matrix-derived biomaterial that demonstrated antifibrotic effect on chronic scarring in vocal fold lamina propria. Its injectability minimizes the invasiveness of the delivery procedure and the degree of mucosal violation. In this work we also describe a new methodology which can more accurately identify proteins from the complex mixture of an acellular extracellular matrix gel by excluding interfering peptides produced during the enzymatic digestion in gel fabrication.

SUBMITTER: Xu CC

PROVIDER: S-EPMC6851489 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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A tissue-specific, injectable acellular gel for the treatment of chronic vocal fold scarring.

Xu Chet C CC Mau Ted T

Acta biomaterialia 20190816

Gel-based injectable biomaterials have significant potential for treating vocal fold defects such as scarring. An ideal injectable for vocal fold lamina propria restoration should mimic the microenvironment of the lamina propria to induce scarless wound healing and functional tissue regeneration. Most current synthetic or natural injectable biomaterials do not possess the same level of complex, tissue-specific constituents as the natural vocal fold lamina propria. In this study we present a newl ...[more]

PMID: 31425889

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Project description:BackgroundThere is growing interest to application of regenerative medicine approaches in otorhinolaryngological practice, especially in the framework of the therapy of vocal fold (VF) scar lesions. The used conservative and surgical methods, despite the achieved positive outcomes, are frequently unpredictable and do not result in the restoration of the VF's lamina propria's structure, which provides the mechanical properties necessary for vibration. In this connection, the aim of this study was to ascertain the safety and efficacy of a bioequivalent in the treatment of VF scars using a rabbit model of chronic damage.MethodsThe bioequivalent consisted of a hydrogel system based on a PEG-fibrin conjugate and human bone marrow-derived MSC. It was characterized and implanted heterotopically into rats and orthotopically into rabbits after VF scar excision.ResultsWe showed that the fabricated bioequivalent consisted of viable cells retaining their metabolic and proliferative activity. While being implanted heterotopically, it had induced the low inflammatory reaction in 7 days and was well tolerated. The orthotopic implantation showed that the gel application was characterized by a lower hemorrhage intensity (p = 0.03945). The intensity of stridor and respiratory rate between the groups in total and between separate groups had no statistically significant difference (p = 0.96 and p = 1; p = 0.9593 and p = 0.97…1, respectively). In 3 days post-implantation, MSC were detected only in the tissues closely surrounding the VF defect. The bioequivalent injection caused that the scar collagen fibers were packed looser and more frequently mutually parallel that is inherent in the native tissue (p = 0.018). In all experimental groups, the fibrous tissue's ingrowth in the adjacent exterior muscle tissue was observed; however, in Group 4 (PEG-Fibrin + MSC), it was much less pronounced than it was in Group 1 (normal saline) (p = 0.008). The difference between the thicknesses of the lamina propria in the control group and in Group 4 was not revealed to be statistically significant (p = 0.995). The Young's modulus of the VF after the bioequivalent implantation (1.15 ± 0.25 kPa) did not statistically significantly differ from the intact VF modulus (1.17 ± 0.45 kPa); therefore, the tissue properties in this group more closely resembled the intact VF.ConclusionsThe developed bioequivalent showed to be biocompatible and highly efficient in the restoration of VF's tissue.

Project description:The biomechanical function of the vocal folds (VFs) depends on their viscoelastic properties. Many conditions can lead to VF scarring that compromises voice function and quality. To identify candidate replacement materials, the structure, composition, and mechanical properties of native tissues need to be understood at phonation frequencies. Previously, the authors developed the torsional wave experiment (TWE), a stress-wave-based experiment to determine the linear viscoelastic shear properties of small, soft samples. Here, the viscoelastic properties of porcine and human VFs were measured over a frequency range of 10-200 Hz. The TWE utilizes resonance phenomena to determine viscoelastic properties; therefore, the specimen test frequency is determined by the sample size and material properties. Viscoelastic moduli are reported at resonance frequencies. Structure and composition of the tissues were determined by histology and immunochemistry. Porcine data from the TWE are separated into two groups: a young group, consisting of fetal and newborn pigs, and an adult group, consisting of 6-9-month olds and 2+-year olds. Adult tissues had an average storage modulus of 2309±1394 Pa and a loss tangent of 0.38±0.10 at frequencies of 36-200 Hz. The VFs of young pigs were significantly more compliant, with a storage modulus of 394±142 Pa and a loss tangent of 0.40±0.14 between 14 and 30 Hz. No gender dependence was observed. Histological staining showed that adult porcine tissues had a more organized, layered structure than the fetal tissues, with a thicker epithelium and a more structured lamina propria. Elastin fibers in fetal VF tissues were immature compared to those in adult tissues. Together, these structural changes in the tissues most likely contributed to the change in viscoelastic properties. Adult human VF tissues, recovered postmortem from adult patients with a history of smoking or disease, had an average storage modulus of 756±439 Pa and a loss tangent of 0.42±0.10. Contrary to the results of some other investigators, no significant frequency dependence was observed. This lack of observable frequency dependence may be due to the modest frequency range of the experiments and the wide range of stiffnesses observed within nominally similar sample types.

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A tissue-specific, injectable acellular gel for the treatment of chronic vocal fold scarring.

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A tissue-specific, injectable acellular gel for the treatment of chronic vocal fold scarring.

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