Delivery of Neurotrophin-3 to the Cochlea using Alginate Beads

Noushi, Fanoosh; Richardson, Rachael T.; Hardman, Jennifer; Clark, Graeme M.; O’Leary, Stephen

doi:10.1097/01.mao.0000169780.84588.a5

Cited by 57 publications

(60 citation statements)

References 36 publications

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“…However, the present experiment demonstrates that the potential role of neurotrophins in cochlear implantation include hearing protection as well as protection of the auditory nerve. Delivery methods for neurotrophins of potential clinical significance include elution from a polymer coating the cochlear electrode ), round window delivery (Noushi et al 2005) or release from genetically modified cells (Pettingill et al 2008). Our results suggest that round window delivery will only be effective in improving higher frequencies that arise from the basal turns of the cochlea, so its utility may be limited to individuals with functional low-frequency hearing where BDNF could be applied in an attempt to improve high-frequency thresholds.…”

Section: Discussionmentioning

confidence: 99%

“…Such investigations will extend the current literature, which suggests that neurotrophins are likely to be safe in a deafened cochlea when delivered exogenously with polymeric gels (Noushi et al 2005;Havenith et al 2011) or miniature osmotic pumps (Miller et al 1997;Shepherd et al 2005). Functional studies in deafened animals treated with neurotrophins reveal that electrically evoked auditory brainstem response (ABR) thresholds are lowered (Shinohara et al 2002;Shepherd et al 2005;) and may be reduced below pretreatment levels.…”

Section: Introductionmentioning

confidence: 95%

“…For example, Agterberg et al (2008) reported substantial damage to both inner hair cells (25% remaining) and outer hair cells (42% remaining) at the lower basal turn of the cochlea after intrascalar infusion of BDNF in normal hearing guinea pigs. Polymers, particularly hydrogels that may be applied directly to the round window, were considered (Noushi et al 2005). However, most have a release profile that varies over time, so instead we chose to place a cannula attached to a mini-osmotic pump directly onto the round window.…”

Section: Introductionmentioning

confidence: 99%

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Brain-Derived Neurotrophic Factor Modulates Auditory Function in the Hearing Cochlea

Sly

Hampson

Minter

et al. 2011

JARO

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Neurotrophins prevent spiral ganglion neuron (SGN) degeneration in animal models of ototoxin-induced deafness and may be used in the future to improve the hearing of cochlear implant patients. It is increasingly common for patients with residual hearing to undergo cochlear implantation. However, the effect of neurotrophin treatment on acoustic hearing is not known. In this study, brain-derived neurotrophic factor (BDNF) was applied to the round window membrane of adult guinea pigs for 4 weeks using a cannula attached to a mini-osmotic pump. SGN survival was first assessed in ototoxically deafened guinea pigs to establish that the delivery method was effective. Increased survival of SGNs was observed in the basal and middle cochlear turns of deafened guinea pigs treated with BDNF, confirming that delivery to the cochlea was successful. The effects of BDNF treatment in animals with normal hearing were then assessed using distortion product otoacoustic emissions (DPOAEs), pure tone, and clickevoked auditory brainstem responses (ABRs). DPOAE assessment indicated a mild deficit of 5 dB SPL in treated and control groups at 1 and 4 weeks after cannula placement. In contrast, ABR evaluation showed that BDNF lowered thresholds at specific frequencies (8 and 16 kHz) after 1 and 4 weeks posttreatment when compared to the control cohort receiving Ringer's solution. Longer treatment for 4 weeks not only widened the range of frequencies ameliorated from 2 to 32 kHz but also lowered the threshold by at least 28 dB SPL at frequencies ≥16 kHz. BDNF treatment for 4 weeks also increased the amplitude of the ABR response when compared to either the control cohort or prior to treatment. We show that BDNF applied to the round window reduces auditory thresholds and could potentially be used clinically to protect residual hearing following cochlear implantation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Brain-Derived Neurotrophic Factor Modulates Auditory Function in the Hearing Cochlea

Sly

Hampson

Minter

et al. 2011

JARO

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“…Round window delivery methodsâThe round window membrane offers an alternative site for atraumatic delivery of pharmacological agents to the cochlea, based upon its permeability to a variety of substances [71][72][73][74][75]. The application of a neurotrophin-soaked alginate polymer bead to the round window membrane resulted in SGN protection throughout the cochlea [74].…”

Section: Delivery Techniques For Neurotrophin Administration In the Cmentioning

confidence: 99%

Neurotrophic Factors and Neural Prostheses: Potential Clinical Applications Based Upon Findings in the Auditory System

Pettingill

Richardson

Wise

et al. 2007

IEEE Trans. Biomed. Eng.

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Spiral ganglion neurons (SGNs) are the target cells of the cochlear implant, a neural prosthesis designed to provide important auditory cues to severely or profoundly deaf patients. The ongoing degeneration of SGNs that occurs following a sensorineural hearing loss is therefore considered a limiting factor in cochlear implant efficacy. We review neurobiological techniques aimed at preventing SGN degeneration using exogenous delivery of neurotrophic factors. Application of these proteins prevents SGN degeneration and can enhance neurite outgrowth. Furthermore, chronic electrical stimulation of SGNs increases neurotrophic factor-induced survival and is correlated with functional benefits. The application of neurotrophic factors has the potential to enhance the benefits that patients can derive from cochlear implants; moreover, these techniques may be relevant for use with neural prostheses in other neurological conditions.

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“…34 The application of a neurotrophin-soaked polymer or bead to the RWM resulted in preservation of SGCs throughout the cochlea, indicating the permeability of these molecules across the RWM. 35,36 Based on the results of the current study, it is likely that the amount of locally applied drug entering the cochlea across the RWM may depend on the drug formulation.…”

mentioning

confidence: 99%

Enhanced bioavailability of nerve growth factor with phytantriol lipid-based crystalline nanoparticles in cochlea

Tang

Wei

et al. 2015

IJN

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Purpose Supplementation of exogenous nerve growth factor (NGF) into the cochlea of deafened animals rescues spiral ganglion cells from degeneration. However, a safe and potent delivery of therapeutic proteins, such as NGF, to spiral ganglion cells remains one of the greatest challenges. This study presents the development of self-assembled cubic lipid-based crystalline nanoparticles to enhance inner ear bioavailability of bioactive NGF via a round window membrane route. Methods A novel nanocarrier-entrapped NGF was developed based on phytantriol by a liquid precursor dilution, with Pluronic ® F127 and propylene glycol as the surfactant and solubilizer, respectively. Upon dilution of the liquid lipid precursors, monodispersed submicron-sized particles with a slight negative charge formed spontaneously. Results Biological activity of entrapped NGF was assessed using pheochromocytoma cells with NGF-loaded reservoirs to induce significant neuronal outgrowth, similar to that seen in free NGF-treated controls. Finally, a 3.28-fold increase in inner ear bioavailability was observed after administration of phytantriol lipid-based crystalline nanoparticles as compared to free drug, contributing to an enhanced drug permeability of the round window membrane. Conclusion Data presented here demonstrate the potential of lipid-based crystalline nanoparticles to improve the outcomes of patients bearing cochlear implants.

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Delivery of Neurotrophin-3 to the Cochlea using Alginate Beads

Abstract: This study demonstrates alginate beads to be a safe, biodegradable and effective delivery system for NT-3 to the cochlea.

Cited by 57 publications

References 36 publications

Brain-Derived Neurotrophic Factor Modulates Auditory Function in the Hearing Cochlea

Brain-Derived Neurotrophic Factor Modulates Auditory Function in the Hearing Cochlea

Neurotrophic Factors and Neural Prostheses: Potential Clinical Applications Based Upon Findings in the Auditory System

Enhanced bioavailability of nerve growth factor with phytantriol lipid-based crystalline nanoparticles in cochlea

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