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      Outlook for Tissue Engineering of the Tympanic Membrane

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          Abstract

          Tympanic membrane perforation is a common problem leading to hearing loss. Despite the autoregenerative activity of the eardrum, chronic perforations require surgery using different materials, from autologous tissue - fascia, cartilage, fat or perichondrium - to paper patch. However, both, surgical procedures (myringoplasty or tympanoplasty) and the materials employed, have a number of limitations. Therefore, the advances in this field are incorporating the principles of tissue engineering, which includes the use of scaffolds, biomolecules and cells. This discipline allows the development of new biocompatible materials that reproduce the structure and mechanical properties of the native tympanic membrane, while it seeks to implement new therapeutic approaches that can be performed in an outpatient setting. Moreover, the creation of an artificial tympanic membrane commercially available would reduce the duration of the surgery and costs. The present review analyzes the current treatment of tympanic perforations and examines the techniques of tissue engineering, either to develop bioartificial constructs, or for tympanic regeneration by using different scaffold materials, bioactive molecules and cells. Finally, it considers the aspects regarding the design of scaffolds, release of biomolecules and use of cells that must be taken into account in the tissue engineering of the eardrum. The possibility of developing new biomaterials, as well as constructs commercially available, makes tissue engineering a discipline with great potential, capable of overcoming the drawbacks of current surgical procedures.

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          Most cited references77

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          Biomechanics of the tympanic membrane.

          The tympanic membrane is a key component of the human auditory apparatus which is a complex biomechanical system, devoted to sound reception and perception. Over the past 30 years, various bioengineering approaches have been applied to the ear modeling and particularly to the middle part. The tympanic membrane, included in the middle ear, transfers sound waves into mechanical vibration from the ear canal into the middle ear. Changes in structure and mechanical properties of the tympanic membrane due to middle ear diseases or damages can deteriorate sound transmission. An accurate model of the tympanic membrane, which simulates the acoustic-mechanical transmission, could improve clinical surgical intervention. In this paper a detailed survey of the biomechanics and the modeling of the tympanic membrane focusing on the finite element method is conduced. Eight selected models are evaluated and compared deducing the main features and most design parameters from published models, mainly focusing on geometric, constraint and material aspects. Non-specified parameters are replaced with the most commonly employed values. Our simulation results (in terms of modal frequencies and umbo displacement), compared with published numerical and experimental results, show a good agreement even if some scattering appears to indicate the need of further investigation and experimental validation. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Formation of the middle ear: recent progress on the developmental and molecular mechanisms.

            The middle ear allows animals to hear while moving in an aerial medium. It is composed of a cavity harbouring a chain of three ossicles that transmit vibrations produced by airborne sound in the tympanic membrane into the inner ear, where they are converted into neural impulses. The middle ear develops in the branchial arches, and this requires sequential interactions between the epithelia and the underlying mesenchyme. Gene-inactivation experiments have identified genes required for the formation of different middle ear components. Some encode for signalling molecules, including Endothelin1 and Fgf8, probable mediators of epithelial-mesenchymal interactions. Other genes, including Eya1, Prx1, Hoxa1, Hoxa2, Dlx1, Dlx2, Dlx5, and Gsc, are most likely involved in patterning and morphogenetic processes in the neural crest-derived mesenchyme. Mechanisms controlling formation of a functional tympanic membrane are also discussed. Basically, the tympanic ring, which serves as support for the tympanic membrane, directs invagination of the first pharyngeal cleft ectoderm to form the external acoustic meatus (EAM), which provides the outer layer of the membrane. Gsc and Prx1 are essential for tympanic ring development. While invaginating, the EAM controls skeletogenesis in the underlying mesenchyme to form the manubrium of the malleus, the link between the membrane and the middle ear ossicles.
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              Enhanced modulation of keratinocyte motility by transforming growth factor-alpha (TGF-alpha) relative to epidermal growth factor (EGF).

              Epidermal growth factor (EGF) and transforming growth factor (TGF)-alpha are high-affinity polypeptide ligands for the EGF receptor, which mediates their biologic activities. In this study, we directly compared the actions of both ligands in promoting keratinocyte motility. We found that normal and tumorigenic human keratinocytes responded to activation of the EGF receptor by either EGF or TGF-alpha; however, the two ligands did not elicit identical responses with regard to cell locomotion. TGF-alpha was more effective than EGF at promoting colony dispersion (cell scattering), in vitro wound closure, and single-cell migration as assessed by phagokinetic track analysis. In contrast, EGF and TGF-alpha evoked identical profiles for DNA synthesis with regard to concentration dependence and magnitude of response in normal keratinocytes and in a squamous cell carcinoma line. The overall pattern of tyrosine phosphorylation of intracellular substrates was similar when cells were stimulated with either growth factor; however, a limited number of differences in the kinetics or magnitude of protein phosphorylation were detected in subcellular fractions. These findings demonstrate that two growth factors implicated in promoting mitogenesis and locomotion may elicit divergent responses with regard to one biologic activity while retaining similar responses for other activities. This suggests that ligand-mediated mitogenic responses may not be tightly coupled to motogenic activity and further illustrates the multifunctional roles of polypeptide growth factors.
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                Author and article information

                Journal
                Audiol Res
                Audiol Res
                AUDIO
                Audiology Research
                PAGEPress Publications, Pavia, Italy
                2039-4330
                2039-4349
                23 January 2015
                21 January 2015
                : 5
                : 1
                : 117
                Affiliations
                Otology & Neurotology Croup CTS495, Centre for Genomics and Oncological Research (CENYO) - Pfizer, University of Granada , Andalusian Regional Government, Granada, Spain
                Author notes
                Otology & Neurotology Group CTS495, Centre for Genomics and Oncological Research (GENYO) - Pfizer, University of Granada, Andalusian Regional Government, Avda de la Ilustración 114, 18016 PTS Granada, Spain. +34.958.715.500.160. antonio.lopezescamez@ 123456genyo.es
                Article
                10.4081/audiores.2015.117
                4627121
                26557361
                87ed0be1-081c-40ce-9295-d1981b8a6fd4
                ©Copyright P. Prado-Gutierrez et al.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 03 September 2014
                : 23 December 2014
                : 23 December 2014
                Page count
                Figures: 1, Tables: 5, Equations: 0, References: 80, Pages: 11
                Categories
                Neurotology

                tympanic membrane perforation,myringoplasty,scaffold material,growth factors,cells,regenerative medicine

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