TISSUE ENGINEERING OF THE INNER EAR

在过去的几年里，有三个关键的发现对听力系统的治疗有重要的影响。首先，成年动物的耳聋会导致外周听觉系统发生显著变化。第二，这些变化对耳聋后输入的重新引入产生了影响。第三，现在可以干预和影响与耳聋相关的变化，以允许对重新引入的输入进行最佳处理。这些干预措施可以被称为“组织工程学”，它们的基础发展和应用推动了我们拟议的研究。我们目前关于可能影响感觉神经存活和功能的干预措施的大量知识来自于对培养细胞和器官型制剂的体外研究。这项研究的目的是在活体内验证这些干预措施的有效性，并测试潜在干预措施的有效性和安全性，以在体内“设计”内耳组织。我们的第一个具体目标是测试与听神经存活有关的化学和活性因子在提高耳聋后螺旋神经节存活方面的效用和协同作用。我们假设，螺旋神经节细胞的维持自然涉及多种因素，这不仅提供了冗余(以增加保护)，而且具有协同效应，在多种因素的作用下可以实现最大限度的增强。我们的第二组研究神经营养因子和刺激诱导的活性不仅可以提高螺旋神经节细胞的存活率，还可以诱导听神经外周突起的再生，而听神经外周突起在内毛细胞丧失后退化。我们的最终目标是开发知识库和工具来干预和影响失聪的听觉系统，为重新引入听觉信息提供尽可能好的环境。希望这些体内研究将为将这项技术转移到人类应用中迈出关键的一步。所开发的干预措施将为未来重新连接再生的毛细胞提供必不可少的底物。目前应直接提高人工耳蜗术的效益。

Three critical findings have been made over the last several years with important implications to the treatment of the deafened auditory system. First, there are significant changes to the peripheral auditory system as a consequence of deafness in the adult animal. Second, these changes impact on the reintroduction of input after deafness. Third, it is now possible to intervene and influence deafness-related changes to permit optimal processing of re-introduced input. Such interventions can be termed "Tissue Engineering" and their basis development, and application drive our proposed studies. A great deal of our current knowledge regarding interventions that may effect the survival and function of the sensory nerves derives from in vitro studies of cells in culture and organotypic preparations. The goal of this investigation is to verify the validity of these interventions in vivo, and to test the efficacy and safety of potential interventions to "engineer" the tissues of the inner ear in vivo. Our first specific aim is to test the utility and synergy of chemical and activity factors involved in the survival of the auditory nerve for enhanced spiral ganglion survival after deafness. We hypothesize that there are naturally multiple factors involved in the maintenance of spiral ganglion cells, which not only provides redundancy (for increased protection) but also synergy in effect, and we can achieve maximal enhancement with multiple factors. Our second set of studies how neurotrophic factors and stimulation induced activity can not only enhance spiral ganglion cell survival but also induce regrowth of auditory nerve peripheral process, which regress after inner hair cell loss. Our ultimate goal is to develop the knowledge base and the tools to intervene in and influence the deafened auditory system to provide the best possible environment for re-introduction of auditory information. Hopefully, these in vivo studies will provide a critical step in the transfer of this technology to human application. The interventions that are developed will provide the substrate essential for reconnecting regenerated hair cells in the future. The should directly enhance the benefit of cochlear prostheses at present.