Poor integration with target tissue significantly limits the effectiveness of nearly all neural prostheses. For example, cochlear implant (CI) recipients perform poorly with complex auditory tasks due to poor spatial and temporal resolution provided by the neural-electrode interface. Directing growth of spiral ganglion neuron (SGN) neurites into close proximity, or even contact, with the stimulating electrodes would likely improve spatial and temporal resolution and increase performance. To be useful, regrowth must be radial and directed towards the source of stimulation, recapitulating normal afferent cochlear innervation. To develop and understand technology designed to guide SGN neurite and Schwann cell (SC) growth, photopolymerization (PP), i.e. the formation of polymers using light, was used to create microchannels in biocompatible methacrylate polymers. These surface topographic features robustly guide SGN neurite and SGSC growth. We hypothesize that the ability of these physical cues to direct SGN neurite and SGSC alignment depends on specific surface topographic features and material properties and results from tuning of intracellular signals including RhoA and Rho associated kinase (ROCK). In response to BRG PA10-009, the work in this proposal is both design- and hypothesis-driven.
In aim 1 the excellent spatial reaction control afforded by PP will be leveraged to fabricate parallel line-space gratings with varied amplitude, periodicity, and surface nanoroughness. The extent to which these topographic features influence neurite and glial cell adhesion, survival and alignment to the pattern will then be determined. As cell-material interactions depend on substrate surface and mechanical properties in addition to surface topography, aim 2 determines the survival and morphological responses of neurons and glia to varied surface (e.g. polarity) and mechanical (e.g. stiffness) properties. Finally, aim 3 examines the contribution of RhoA/ROCK, key mediators of neurite guidance by chemorepulsive cues, to neurite and SC alignment to micropatterns. It also seeks to characterize second messenger systems including the cyclic nucleotides, cAMP and cGMP, that mediate neurite and SC alignment and RhoA/ROCK activity in response to surface topographies. The results of these studies will be among the first to define the basic mechanisms by which cells sense and respond to specific surface topographies and material properties. Furthermore, they will identify the topographic features and material properties necessary for future fabrication of scaffolds that can be used for in vivo neural regeneration models including the design of enhanced neuron:prosthesis interfaces.
Cochlear implants represent the most successful neuroprosthesis in clinical use. They provide direct electrical stimulation to the auditory nerve t restore hearing to deaf patients. However, cochlear implant recipients usually struggle to understand complex auditory signals such as music. These studies seek to develop and understand novel technologies designed to guide regeneration of auditory nerve fibers to directly interface with cochlear implant electrodes. This will greatly improve the ability of cochlear implants to represent complex auditory signals and thereby increase performance. The results will also inform efforts to improve the interface of other neural prostheses and nerve repair conduits with target tissue.
|Kopelovich, Jonathan C; Reiss, Lina A J; Etler, Christine P et al. (2015) Hearing Loss After Activation of Hearing Preservation Cochlear Implants Might Be Related to Afferent Cochlear Innervation Injury. Otol Neurotol 36:1035-44|
|Li, Shufeng; Tuft, Bradley W; Xu, Linjing et al. (2015) Microtopographical features generated by photopolymerization recruit RhoA/ROCK through TRPV1 to direct cell and neurite growth. Biomaterials 53:95-106|
|Tuft, Bradley W; Zhang, Lichun; Xu, Linjing et al. (2014) Material stiffness effects on neurite alignment to photopolymerized micropatterns. Biomacromolecules 15:3717-27|
|Tuft, Bradley W; Xu, Linjing; White, Scott P et al. (2014) Neural pathfinding on uni- and multidirectional photopolymerized micropatterns. ACS Appl Mater Interfaces 6:11265-76|
|Tuft, Bradley W; Li, Shufeng; Xu, Linjing et al. (2013) Photopolymerized microfeatures for directed spiral ganglion neurite and Schwann cell growth. Biomaterials 34:42-54|