TISSUE ENGINEERING OF THE INNER EAR

在过去的几年里，有三个重要的发现对耳聋的听觉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重大变化。其次，这些变化影响耳聋后输入的重新引入。第三，现在有可能干预和影响耳聋相关的变化，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”，它们的基础发展和应用推动了我们提出的研究。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体外培养细胞和器官型制剂的研究。本研究的目的是验证这些干预措施在体内的有效性，并测试潜在干预措施在体内“工程”内耳组织的有效性和安全性。我们的第一个具体目标是测试化学和活性因子在耳聋后听觉神经存活中对增强螺旋神经节存活的效用和协同作用。我们假设自然有多种因素参与螺旋神经节细胞的维持，不仅提供冗余（以增加保护），而且还提供协同效应，我们可以通过多种因素实现最大的增强。我们的第二组研究神经营养因子和刺激诱导的活动不仅可以提高螺旋神经节细胞的存活率，还可以诱导内毛细胞丢失后退化的听神经外周突的再生。我们的最终目标是开发知识基础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最佳的环境。希望这些体内研究将为这项技术向人类应用的转移提供关键的一步。所开发的干预措施将为将来重新连接再生毛细胞提供必要的基质。目前应直接提高人工耳蜗的效益。

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.