Bryony A Nayagam

• PhD
• Principal Investigator at University of Melbourne

Article highlights Australian audiologists & their patients report a lack of awareness around current & emerging stem cell therapies for hearing loss Almost all patients surveyed in this study (92%) reported being unaware of any current or potential therapeutic use of stem cells for hearing loss, and only a third of participating audiologists note...

Aminoglycoside antibiotics are lifesaving medicines, crucial for the treatment of chronic or drug resistant infections. However, aminoglycosides are toxic to the sensory hair cells in the inner ear. As a result, aminoglycoside-treated individuals can develop permanent hearing loss and vestibular impairment. There is considerable evidence that react...

Sodium channel expression in inner ear afferents is essential for the transmission of vestibular and auditory information to the central nervous system. During development, however, there is also a transient expression of Na⁺ channels in vestibular and auditory hair cells. Using qPCR analysis, we describe the expression of four Na⁺ channel genes, S...

Objective. Infrared light can be used to modulate the activity of neuronal cells through thermally-evoked capacitive currents and thermosensitive ion channel modulation. The infrared power threshold for action potentials has previously been found to be far lower in the in vivo cochlea when compared with other neuronal targets, implicating spiral ga...

Objectives: Auditory neuropathy (AN) is the term used to describe a group of hearing disorders, in which the hearing impairment occurs as a result of abnormal auditory nerve function. While our understanding of this condition has advanced significantly over recent years, the ability to determine the site of lesion and the extent of dysfunction in...

Objective. To evaluate the electrochemical properties, biological response, and surface characterization of an electrodeposited Platinum-Iridium (Pt-Ir) electrode coating on cochlear implants subjected to chronic stimulation in vivo. Approach. Electrochemical impedance spectroscopy (EIS), charge storage capacity (CSC), charge injection limit (CIL),...

In infrared neural stimulation (INS), laser-evoked thermal transients are used to generate small depolarising currents in neurons. The laser exposure poses a moderate risk of thermal damage to the target neuron. Indeed, exogenous methods of neural stimulation often place the target neurons under stressful non-physiological conditions, which can hin...

Objective. Evaluate electrochemical properties, biological response, and surface characterization of a conductive hydrogel (CH) coating following chronic in vivo stimulation. Approach. Coated CH or uncoated smooth platinum (Pt) electrode arrays were implanted into the cochlea of rats and stimulated over a 5 week period with more than 57 million bip...

p38 mitogen-activated protein kinases (P38α and β) and c-Jun N-terminal kinases (JNK1, 2, and 3) are key mediators of the cellular stress response. However, prolonged P38 and JNK signalling is associated with damaging inflammatory responses, reactive oxygen species–induced cell death, and fibrosis in multiple tissues, such as the kidney, liver, cen...

Stem cells have been touted as a source of potential replacement neurons for inner ear degeneration for almost two decades now; yet to date, there are few studies describing the use of human pluripotent stem cells (hPSCs) for this purpose. If stem cell therapies are to be used clinically, it is critical to validate the usefulness of hPSC lines in v...

The inner ear is a complex organ containing highly specialised cell types and structures that are critical for sensing sound and movement. In vivo, the inner ear is difficult to study due to the osseous nature of the otic capsule and its encapsulation within an intricate bony labyrinth. As such, mammalian inner ear explants are an invaluable tool f...

Hair cells are specialized mechanosensitive cells responsible for mediating balance and hearing within the inner ear. In mammals, hair cells are limited in number and do not regenerate. Human pluripotent stem cells (hPSCs) provide a valuable source for deriving human hair cells to study their development and design therapies to treat and/or prevent...

Mechanotransduction of RCCS-derived organoids. HESC-derived organoid at 84 DIV is capable of uptake AM1-44 dye. Scale bar, 10 μm.

Expression profile of RCCS-derived organoids. (A–C) HESC-derived organoids show expression of dorsal hindbrain marker PAX7 (A) and neural marker PAX6 (B) at 21 DIV as well as supporting hair cell marker SOX2 (C) at 35 DIV, where white dash line delineates organoid boundary. (D) TUBβIII neural mass in hESC-derived organoid at 49 DIV with some proces...

Kinocilia length measurements. An example of procedure used for estimating kinocilium length in (A) organoid and (B) fetal tissue. Straight lines were drawn along the cilia (dash lines in red) to estimate the length. (C) Raw data of n = 6 kinocilium measurements each for an organoid and fetal tissue as plotted in Figure 2I. Scale bar, 1 μm.

Volume of components in each measurement by micro-computed tomography. The table shows the total number of components, as well as the mean, smallest and largest component volumes in each measurement, and the combined total volume of all components in a measurement. The two measurements (scans) of any single sample have not been pooled.

GMax, V½, and slope values of IV relationship of K+ and Na+ currents in organoid and human hair cells. Unless otherwise specified, all statistical analyses were independent sample t-tests. *p < 0.05, + Mann U Whitney statistical analysis.

Expression efficiency of ATOH1 in inner ear organoids. ATOH1 expression in organoids derived from hPSC lines (H3 hESC, H9 hESC and 007–5 iPSC lines) in n = 7 biological replicate experiments from 7 to 133 DIV. 58% of organoids showed ATOH1 expression.

Since its inception 30 years ago, diffusion-weighted magnetic resonance imaging (dMRI) has advanced to become a common component of routine clinical MRI examinations. Diffusion-weighted magnetic resonance offers a way to measure anisotropic diffusion in-vivo, which has led to the development of techniques capable of characterising the orientation o...

Objectives: To compare threshold and comfortable levels between a first and second cochlear implant (CI) for children, and to consider if the degree of difference between CIs was related to the age at bilateral implantation or the time between implants. A secondary objective was to examine the changes in levels over time for each CI . Design: Fi...

When studying white matter in baby brains with diffusion-weighted imaging, we face a range of challenges, including larger water-content, lower anisotropy, differentiated maturation and a (relatively) larger proportion of the brain being comprised of grey matter. We attempt to apply single-tissue, 2-tissue and 3-tissue constrained spherical deconvo...

Progress in aeronautics and spaceflight technologies requires in parallel further research on how microgravity may affect human tissue. To date, little is known about the effects of microgravity on human development. Here we used the rotary cell culture system (RCCS) to investigate whether microgravity supports the generation and maintenance of neu...

In this study, we explore the use of electrically active graphene foam as a scaffold for the culture of human-derived neurons. Human embryonic stem cell (hESC)-derived cortical neurons fated as either glutamatergic or GABAergic neuronal phenotypes were cultured on graphene foam. We show that graphene foam is biocompatible for the culture of human n...

The dorsal root ganglia (DRG) consist of a multitude of sensory neuronal subtypes that function to relay sensory stimuli, including temperature, pressure, pain and position to the central nervous system. Our knowledge of DRG sensory neurons have been predominantly driven by animal studies and considerably less is known about the human DRG. Human em...

In vitro cultures provide a valuable tool in studies examining the survival, morphology and function of cells in the auditory system. Primary cultures of primary auditory neurons have most notably provided critical insights into the role of neurotrophins in cell survival and morphology. Functional studies have also utilized in vitro models to study...

Optic neuropathies are characterised by a loss of retinal ganglion cells (RGCs) that lead to vision impairment. Development of cell therapy requires a better understanding of the signals that direct stem cells into RGCs. Human embryonic stem cells (hESCs) represent an unlimited cellular source for generation of human RGCs in vitro. In this study, w...

Induced pluripotent stem cells (iPSCs) may serve as an autologous source of replacement neurons in the injured cochlea, if they can be successfully differentiated and reconnected with residual elements in the damaged auditory system. Here, we explored the potential of hiPSC-derived neurons to innervate early postnatal hair cells, using established...

Hearing loss is an increasing problem for a substantial number of people and, with an aging population, the incidence and severity of hearing loss will become more significant over time. There are very few therapies currently available to treat hearing loss, and so the development of new therapeutic strategies for hearing impaired individuals is of...

Infrared stimulation offers an alternative to electrical stimulation of neuronal tissue, with potential for direct, non-contact activation at high spatial resolution. Conventional methods of infrared neural stimulation (INS) rely on transient heating due to the absorption of relatively intense laser beams by water in the tissue. However, the water...

Emerging therapies for sensorineural hearing loss include replacing damaged auditory neurons (ANs) using stem cells. Ultimately, it is important that these replacement cells can be patient-matched to avoid immunorejection. As human induced pluripotent stem cells (hiPSCs) can be obtained directly from the patient, they offer an opportunity to genera...

The degeneration of hair cells in the mammalian cochlea results in permanent sensorineural hearing loss. This study aimed to promote the regeneration of sensory hair cells in the mature cochlea and their reconnection with auditory neurons through the introduction of ATOH1, a transcription factor known to be necessary for hair cell development, and...

Friedreich ataxia (FRDA) is an autosomal recessive disease characterised by neurodegeneration and cardiomyopathy that is caused by an insufficiency of the mitochondrial protein, frataxin. Our previous studies described the generation of FRDA induced pluripotent stem cell lines (FA3 and FA4 iPS) that retained genetic characteristics of this disease....

Gene therapy has been investigated as a way to introduce a variety of genes to treat neurological disorders. An important clinical consideration is its long-term effectiveness. This research aims to study the long-term expression and effectiveness of gene therapy in promoting spiral ganglion neuron survival after deafness. Adenoviral vectors modifi...

Gene therapy has been investigated as a way to introduce a variety of genes to treat neurological disorders. An important clinical consideration is its long-term effectiveness. This research aims to study the long-term expression and effectiveness of gene therapy in promoting spiral ganglion neuron survival after deafness. Adenoviral vectors modifi...

Heterogeneous samples of spiral ganglion neuron primary cells were incubated with gold nanorods in order to investigate the photothermal processes induced by exposure to 780 nm laser light. Dark-field microspectroscopy was used to analyze the distribution and spectrum of nanorods in the neurons. The scattering data showed a typical gold nanorod spe...

In severe cases of sensorineural hearing loss where the numbers of auditory neurons are significantly depleted, stem cell-derived neurons may provide a potential source of replacement cells. The success of such a therapy relies upon producing a population of functional neurons from stem cells, to enable precise encoding of sound information to the...

It has been demonstrated in recent years that pulsed, infrared laser light can be used to elicit electrical responses in neural tissue, independent of any further modification of the target tissue. Infrared neural stimulation has been reported in a variety of peripheral and sensory neural tissue in vivo, with particular interest shown in stimulatio...

The cochlear implant provides auditory cues to profoundly deaf patients by electrically stimulating the residual spiral ganglion neurons. These neurons, however, undergo progressive degeneration after hearing loss, marked initially by peripheral fibre retraction and ultimately culminating in cell death. This research aims to use gene therapy techni...

Auditory neurons provide the critical link between a cochlear implant and the brain in deaf individuals, therefore their preservation and/or regeneration is important for optimal performance of this neural prosthesis. In cases where auditory neurons are significantly depleted, stem cells (SCs) may be used to replace the lost population of neurons,...

Stem cells have been touted as a potential source of replacement cells for the treatment of severe-to-profoundly deaf individuals, including possible combined therapy with a cochlear implant. The success of such a therapy is dependent on a number of factors, but of critical importance is the functional incorporation of transplanted cells into the p...

Introduction: In the auditory system, a specialized subset of sensory neurons are responsible for correctly relaying precise pitch and temporal cues to the brain. In individuals with severe-to-profound sensorineural hearing impairment these sensory auditory neurons can be directly stimulated by a cochlear implant, which restores sound input to the...

In mammals, the sensory hair cells and auditory neurons do not spontaneously regenerate and their loss results in permanent hearing impairment. Stem cell therapy is one emerging strategy that is being investigated to overcome the loss of sensory cells after hearing loss. In order to successfully replace auditory neurons, stem cell-derived neurons m...

Neurotrophins provide an effective tool for the rescue and regeneration of spiral ganglion neurons (SGNs) following sensorineural hearing loss. However, these nerve growth factors are also potent modulators of ion channel activity and expression, and in the peripheral auditory system brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3)...

According to 2010 estimates from The National Institute on Deafness and other Communication Disorders, approximately 17% (36 million) American adults have reported some degree of hearing loss. Currently, the only clinical treatment available for those with severe-to-profound hearing loss is a cochlear implant, which is designed to electrically stim...

The round window membrane (RWM) is an increasingly popular route for electrode insertion in cochlear implantation especially for hearing preservation. Limitations to this route include anatomical, physiological, and surgical aspects. The established soft-tissue cochleostomy route for electrode insertion is thought to place the basilar membrane and...

In mammals, the initial bridge between the physical world of sound and perception of that sound is established by neurons of the spiral ganglion. The cell bodies of these neurons give rise to peripheral processes that contact acoustic receptors in the organ of Corti, and the central processes collect together to form the auditory nerve that project...

Low numbers of primary auditory neurons (ANs) may compromise the clinical performance of a cochlear implant. The focus of this research is to determine whether stem cells can be used to replace the ANs lost following deafness. To successfully replace these neurons, stem cells must be capable of directed differentiation into a sensory neural lineage...

Green fluorescent protein (GFP) has been used extensively to label cells in vitro and to track them following their transplantation in vivo. During our studies using the mouse embryonic stem cell line R1 B5-EGFP, we observed variable levels of fluorescence intensity of the GFP within these transfected cells. The variable fluorescence of this protei...

Cochlear implants are dependent on functionally viable spiral ganglion neurons (SGNs) - the primary auditory neurons of the inner ear. Cell-based therapies are being used experimentally in an attempt to rescue SGNs from deafness-induced degeneration or to generate new neurons. The success of these therapies will be dependent on the development of s...

Sensory hair cells in the mammalian cochlea are sensitive to many insults including loud noise, ototoxic drugs, and ageing. Damage to these hair cells results in deafness and sets in place a number of irreversible changes that eventually result in the progressive degeneration of auditory neurons, the target cells of the cochlear implant. Techniques...

Auditory neurons, the target neurons of the cochlear implant, degenerate following a sensorineural hearing loss. The goal of this research is to direct the differentiation of embryonic stem cells (SCs) into bipolar auditory neurons that can be used to replace degenerating neurons in the deafened mammalian cochlea. Successful replacement of auditory...

Spiral ganglion neurons (SGNs), the primary afferent neurons of the cochlea, degenerate following a sensorineural hearing loss (SNHL) due to lack of trophic support normally received from hair cells. Cell transplantation is emerging as a potential strategy for inner ear rehabilitation, as injected cells may be able to replace damaged SGNs in the de...

The low regenerative capacity of the hair cells of the mammalian inner ear is a major obstacle for functional recovery following sensorineural hearing loss. A potential treatment is to replace damaged tissue by transplantation of stem cells. To test this approach, undifferentiated and partially differentiated mouse embryonic stem (ES) cells were de...