The candidate will apply his MEMs and biomedical engineering background to the study and treatment of deafness and auditory dysfunction.
He aims to become an engineering expert in vertebrate animal research, auditory system pathologies, and calibrated delivery of gene-based therapies. He intends to contribute a critical engineering perspective and approach to successful creation of effective deafness therapies that are clinically tested and ultimately approved for human clinical use. To achieve this goal, the candidate requires additional training and mentorship in the areas of auditory system function and pathology, vertebrate animal research, and gene based therapies. This will be accomplished through a combination of coursework, seminars, conferences, and close interaction with the mentor and his multidisciplinary research team. Advanced deafness therapies that restore normal auditory function will require carefully timed and dosed, site-directed delivery of several gene vectors and/or compounds over a period of time. The candidate intends to advance deafness therapy research in the genetically controlled mouse model system through three Specific Aims: (1) develop an optimized dosing profile that achieves effective expression of lacZ reporter gene throughout the cochlea in the adult mouse while preserving afferent and efferent cochlear function from 3-48 kHz; (2) develop and evaluate an implantable micropump platform consistent with the size limitations of the mouse ear which meets, the requirements of intra-cochlear drug agent delivery; and (3) determine the impact of repetitive cochlear infusions to act as a guide for more complex deafness therapies. Permanent sensorineural hearing loss and deafness impact over 10% of the population in modern societies and in excess of 50% of those age 65 and older. Gene therapy investigations of the inner ear have the potential to correct major chronic medical disorders such as age-related hearing loss, age-induced balance problems, and other forms of permanent hearing loss and deafness. The complexity of disease states suggests elaborate protocols will be needed to achieve full restoration of hearing in animal models, and for translational results in human clinical trials. The proposed research will provide information, tools, and new capabilities critical for the advancement of intra-cochlear gene-based therapy research. ? ? ?
| Johnson, Dean G; Borkholder, David A (2016) Towards an Implantable, Low Flow Micropump That Uses No Power in the Blocked-Flow State. Micromachines (Basel) 7: |
| Borkholder, David A; Zhu, Xiaoxia; Frisina, Robert D (2014) Round window membrane intracochlear drug delivery enhanced by induced advection. J Control Release 174:171-6 |
| Haghpanahi, Masoumeh; Gladstone, Miriam B; Zhu, Xiaoxia et al. (2013) Noninvasive technique for monitoring drug transport through the murine cochlea using micro-computed tomography. Ann Biomed Eng 41:2130-42 |
| Pararas, Erin E Leary; Borkholder, David A; Borenstein, Jeffrey T (2012) Microsystems technologies for drug delivery to the inner ear. Adv Drug Deliv Rev 64:1650-60 |
| Johnson, Dean G; Frisina, Robert D; Borkholder, David A (2011) In-plane biocompatible microfluidic interconnects for implantable microsystems. IEEE Trans Biomed Eng 58:943-8 |
| Johnson, D G; Waldron, M J; Frisina, R D et al. (2010) Implantable micropump technologies for murine intracochlear infusions. Conf Proc IEEE Eng Med Biol Soc 2010:6441-4 |
| Borkholder, David A; Zhu, Xiaoxia; Hyatt, Brad T et al. (2010) Murine intracochlear drug delivery: reducing concentration gradients within the cochlea. Hear Res 268:2-11 |
| Borkholder, David A (2008) State-of-the-art mechanisms of intracochlear drug delivery. Curr Opin Otolaryngol Head Neck Surg 16:472-7 |
| Johnson, Dean G; Zhu, Xiao Xia; Frisina, Robert D et al. (2007) Micro-molded cannulae for intracochlear infusions in small rodents. Conf Proc IEEE Eng Med Biol Soc 2007:6617-20 |
