Introduction
Cochlear implantation (CI) has long been a primary treatment option for patients with severe-to-profound sensorineural hearing loss (SNHL). However, its efficacy has often been limited by secondary degeneration of spiral ganglion neurons (SGNs) and the physical distance between SGNs and the CI electrode array. Numerous studies have demonstrated that neurotrophins promote the survival of SGNs and stimulate neurite outgrowth, thereby contributing to improved efficacy of CI. This review examines various strategies for delivering neurotrophins into the inner ear, specifically: 1) pump-based delivery systems, 2) delivery using biodegradable materials, 3) drug-eluting electrodes, 4) the use of neurotrophin-secreting cells, and 5) gene therapy approaches. Through this review, the potential for clinical translation of neurotrophin-based therapies is discussed.
Developmental Neurotrophin Expression in Inner Ear
In mammals, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) are encoded by the Ngf, Bdnf, Ntf3, and Ntf4 genes in rats; the Ngf, Bdnf, Ntf3, and Ntf5 genes in mice; and the NGF, BDNF, NTF3, and NTF4 genes in humans [1]. Among these neurotrophic factors, BDNF and NT-3 are the predominant neurotrophins in the inner ear [2,3]. They signal through Trk family receptor protein tyrosine kinases—TrkB for BDNF and TrkC for NT-3. Activation of these receptors enhances neuronal metabolism, promotes neuronal survival, stimulates neurite outgrowth, supports synaptogenesis, and strengthens synaptic responses [4,5].
There are clear differences in the expression patterns of NT-3 and BDNF during prenatal and postnatal inner ear development. During prenatal cochlear development in the rat, BDNF is expressed in both inner and outer hair cells, exhibiting a spatial gradient with the highest levels in the apical region and the lowest in the basal cochlea. However, BDNF expression in the organ of Corti is markedly reduced by postnatal day 4 [2]. BDNF expression then transiently increases in the rodent organ of Corti between postnatal days 4 and 9 [6,7], displaying a base-to-apex gradient [8]. In the adult organ of Corti, BDNF immunoreactivity has been detected, although its mRNA levels remain low [8,9]. In contrast, NT-3 is expressed predominantly in supporting cells rather than hair cells during cochlear development. NT-3 expression in inner hair cells persists throughout both prenatal and postnatal periods, following an apex-to-base gradient, whereas NT-3 expression in outer hair cells ceases after birth.
In summary, both NT-3 and BDNF are expressed in the developing cochlea with spatial gradients along the cochlear axis. NT-3 continues to be expressed postnatally in an apex-tobase gradient, albeit at lower levels than during prenatal development, whereas BDNF expression in the postnatal organ of Corti is comparatively low. In SGNs, both TrkB and TrkC receptors are expressed around birth and persist into the postnatal period [10].
The Role of Neurotrophins in SGN Survival and Neurite Outgrowth
When hair cells are destroyed by exposure to antibiotics such as aminoglycosides, SGNs undergo gradual degeneration, a phenomenon that has been reported in rats, guinea pigs [11,12], cats [13], and humans [14]. Numerous studies have shown that SGN loss can be significantly attenuated by intracochlear infusion of neurotrophins, delivery of viral vectors that drive neurotrophin expression, or transplantation of genetically engineered cells expressing neurotrophins [15-19]. Neurotrophins can also induce the overgrowth of SGN neurites: 1) Co-treatment of BDNF and ciliary neurotrophic factor (CNTF) significantly increased neurite outgrowth in cultured dissociated SGNs from neonatal rats [20]; 2) Treatment of cultured dissociated SGNs from neonatal rats with BDNF, NT-3, and Trk receptor agonist monoclonal antibody M3 promoted neurite outgrowth in SGN explants [21].
This neurotrophin-mediated preservation of SGNs has been shown to enhance outcomes of CI [22-24]. In deafened guinea pigs implanted with CI, intracochlear infusion of BDNF for four weeks resulted in approximately 1.9 times more SGNs compared to the non-infused ear, and the characteristics of evoked compound action potentials were nearly normal [22]. Furthermore, when BDNF and NT-3 were coadministered for more than four weeks, the number of SGNs in the basal and middle turns of the cochlea increased, their morphology appeared nearly normal, and the electrically evoked auditory brainstem response thresholds were reduced [23].
Neurotrophin-mediated neurite outgrowth is also thought to influence CI outcomes, as the outgrowing neurites may reduce the gap between CI electrodes and SGNs [25]. When a CI is inserted into the inner ear, the electrode typically lies near the lateral wall of the scala tympani or along the wall of the modiolus, creating a physical gap between the electrode and the SGNs, which in turn reduces the effectiveness of SGN stimulation by the electrodes. When the gap between the electrode and the SGNs increases, a single electrode can stimulate a broader population of SGNs. As a result, adjacent electrodes stimulate overlapping SGN populations, thereby diminishing the functional performance of the CI. If SGN neurites could be guided to grow toward the CI electrodes, thereby reducing the distance between them, SGNs could be stimulated more precisely than when they are located farther away. This is why neurotrophin-mediated neurite outgrowth is important.
Considerations Regarding Neurotrophin-Induced Neurite Outgrowth in CI
In SGN neurite regrowth, the direction of growth is critically important. The apical part of the cochlea is responsible for low-frequency sounds, while the basal part is responsible for high-frequency sounds. This tonotopic arrangement is preserved even in the temporal lobe of the brain. If neurite outgrowth becomes tangled or disorganized, this tonotopic specificity may be lost, potentially reducing the sound resolution of the CI. It has been reported that SGNs treated with exogenous neurotrophins often exhibit ectopic neurite growth [26-28]. However, an experiment conducted by Landry, et al. [29] in 2013 on deafened guinea pigs showed that this concern could be somewhat alleviated. In this study, when neurotrophin was continuously administered intracochlearly for one month, ectopic growth and lateral deviation of SGN neurites were observed, but the degree of deviation was not significant relative to the size of the electrode, and it did not affect the spread of neural activation in the inferior colliculus. The results of this study suggest that the negative impact of neurotrophin-induced neurite outgrowth on the spatial selectivity of CI may be smaller than expected. These results were obtained by administering 30 μg/mL of BDNF and NT-3 together for one month. However, it is still an open question whether similar results would be observed with neurotrophin treatment longer than one month. If neurotrophins were to be directly delivered into the inner ear in actual patients, depending on the concentration and duration of administration, ectopic neurite growth could occur, which might affect spatial selectivity.
Another point to consider in the application of neurotrophins is what happens when their administration is discontinued. Just as SGNs degenerate following hair cell loss, stopping neurotrophin treatment may lead to renewed loss of SGNs. Previous studies reported such outcomes. In deafened guinea pigs, cessation of BDNF treatment for 28 days led to an accelerated decline in auditory neuron survival [30]. Shepherd, et al. [31] were also able to reproduce the accelerated loss of SGNs that Gillespie, et al. [30] had observed in guinea pigs, but they additionally found that this rapid degeneration could be prevented when continuous electrical stimulation was applied.
Although Shepherd, et al. [31] demonstrated the effect of electrical stimulation on the rapid degeneration of SGNs, and several studies have reported ES-induced SGN rescue [32-35], it is also true that there have been reports in cats, guinea pigs, or humans indicating that electrical stimulation by itself has little effect on SGN survival [36-40]. Therefore, the effect of CI-induced electrical stimulation on the survival of SGNs remains unclear. However, this has little relevance for patients who inevitably require a CI. Therefore, the more critical issue is how long neurotrophins should be administered or how they should be delivered.
Drug Delivery Methods to the Inner Ear and the Potential Applications of Neurotrophins
As discussed above, previous studies have shown that combining neurotrophin therapy with CI preserves SGNs and improves hearing outcomes [22-24,41,42]. In this section, we review the intracochlear drug application and examine whether these approaches can be utilized for the delivery of neurotrophins.
Methods for delivering neurotrophins to the inner ear can be broadly divided into cell-based and non–cell-based approaches. Non–cell-based approaches can be further subdivided into direct delivery from outside the inner ear and placement either inside or adjacent to the cochlea. The former refers to the use of pumps or catheters, whereas the latter involves biodegradable materials or drug-eluting electrodes. Cell-based approaches can be categorized into cell therapy and gene therapy.
Non–Cell-Based Approaches
Osmotic pump and catheter
Animal studies have shown that directly delivering neurotrophin into the inner ear using an osmotic pump is the most effective method for increasing its concentration within the inner ear [16,18,43]. With technological advances such as the use of microfluidic devices [44], direct intracochlear delivery via a catheter in experimental animals is still used not only for neurotrophins but also for other drugs [45]. However, due to the risk of infection, it is not formally used in actual patients. For the direct intracochlear delivery of neurotrophins using pumps or catheters to be applied in patients, issues such as infection risk, surgical complications, and secondary inner-ear damage must first be solved.
Biodegradable drug carrier
CI electrode arrays are not bioinert, and a universal intracochlear foreign body response to CI has been widely documented [46-49]. A severe foreign body response can lead to increased impedance at the CI electrode–tissue interface, resulting in reduced hearing performance. To mitigate the foreign body response, the non-specific anti-inflammatory agent dexamethasone has been widely used in clinical practice, animal studies, and in vitro models. It has been delivered in various forms—locally (via cochlear injection, round-window niche or middle-ear application, and dexamethasone-eluting implants or electrodes) and systemically (oral or parenteral administration) [50,51]. Among these approaches, roundwindow delivery and dexamethasone-eluting electrodes are particularly noteworthy as reference strategies for intracochlear neurotrophin delivery.
In a 2017 paper, Plontke, et al. [45] reported cases in which dexamethasone was delivered inside the inner ear using Ozurdex. Ozurdex is a biodegradable drug carrier containing dexamethasone embedded in a polylactic-co-glycolic acid (PLGA) polymer matrix. The authors placed Ozurdex in the basal part of the cochlear scala tympani to administer dexamethasone and found that the continuous intracochlear application resulted in a stable concentration for several weeks with higher drug levels more apically along the scala tympani. In a 2014 paper, Plontke, et al. [52] placed Ozurdex in the patients’ round window niche, reporting improvements in the mean hearing threshold and complete recovery in two of the five patients. Relating these results to neurotrophins, several positive aspects for their clinical application can be noted: 1) Ozurdex can serve as a drug carrier suitable for use in patients; 2) since the cochlea must be opened for CI surgery anyway, delivering neurotrophins using Ozurdex would not be difficult; and 3) if direct intracochlear injection is technically challenging, an alternative approach worth considering is the placement of an Ozurdex implant in the round window niche for neurotrophin delivery. Although drug entry into the inner ear via the round window membrane has inherent limitations, this strategy offers the advantage of avoiding the use of osmotic pumps or catheters, as required in animal experiments.
Drug eluting electrode
CI equipped with dexamethasone-eluting electrodes can be said to have opened new possibilities for neurotrophin delivery. In 2025, a study by Prenzler, et al. [53] published in Hearing Research reported the the safety and efficacy of CI with dexamethasone-eluting electrodes in 10 patients treated at the Hannover Medical School in Germany using the CIDEXEL system from June 2020 to May 2022. CIDEXEL system has a set of dexamethasone-loaded silicone coating between electrode contacts 2 and 10. This coating is designed to release the drug directly within the scala tympani over an extended duration of several months. The significance of the dexamethasone-eluting electrode approach lies in the fact that it has been applied in actual patients, and the safety of its clinical application has been verified. If a CI with neurotrophin-eluting electrodes were actually developed and applied to the inner ear, it might avoid issues such as 1) uneven distribution of neurotrophins that may result from placing a neurotrophincontaining substance in a specific part of the inner ear, such as the basal region; and 2) the use of osmotic pumps or catheters that were required in animal experiments for neurotrophin delivery.
Cell-Based Approaches
Cell-based therapy
An alternative approach to circumvent the use of osmotic pumps or catheters is cell-based therapy, involving the transplantation of cells that continuously and physiologically secrete neurotrophins. Genetically modified cells such as fibroblasts [54], retinal epithelial cell line [55], and stem cells [56], capable of secreting neurotrophins, have been used in cellbased therapy, and it has become possible to maintain neurotrophin expression for more than six months [57]. Moreover, the cell encapsulation technology introduced in cell-based therapy has enhanced safety by suppressing immune responses and restricting cell migration [57]. Recently, a more advanced method for delivering neurotrophins to the inner ear has been developed, which involves attaching neurotrophinsecreting cells to the surface of the CI [56]. Cell-based therapy has also been attempted in many other neurodegenerative diseases, such as Parkinson disease and Alzheimer disease, and its efficacy and outcomes have been reported [58]. Considering that cell-based therapy has recently expanded its scope to autoimmune diseases [59], this approach appears to be quite promising for delivering neurotrophins into the inner ear. However, for actual application in patients, issues such as 1) which type of cells should be selected, 2) how long the cells can survive, and 3) to what extent the concentration needs to be increased within the inner ear must be resolved.
Gene therapy
A recently emerging approach is gene therapy, which broadly encompasses treatments aimed at altering gene expression or modifying the functions and biological characteristics of living cells. To achieve the objectives of gene therapy, genetic material must be delivered into target cells. The delivery systems most commonly used are classified into viral vectors and non-viral vectors, such as liposomes. In this section, these approaches are briefly discussed.
Gene therapy via viral vectors
There have been reports that gene therapy approaches using viral vectors to express various neurotrophin genes in animal models inhibited degeneration of SGNs and increased SGN survival [18,60-64]. Neurotrophin gene transfer is not limited to the inner ear; it has also been applied to the retina, spinal cord, and neurodegenerative diseases such as dementia and Parkinson’s disease. For example, adeno-associated virus (AAV)–mediated BDNF transfer to Müller cells protected photoreceptors from light-induced retinal degeneration [65], while AAV-mediated glial-derived neurotrophic factor (GDNF) delivery prevented photoreceptor loss for at least 45 days [66]. In addition, BDNF overexpression using AAV in a rat model with complete spinal cord transection enhanced locomotor performance on a treadmill [67]. Similarly, in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, therapies involving viral delivery of neurotrophin genes have continued to be reported in various animal studies [68-70] as well as in clinical trials in humans [71-74].
The most active area of gene therapy in the inner ear is the field of hereditary hearing loss. Successful research outcomes in this field have led to clinical trials. In 2024, preliminary results were reported for two young children treated with AAVOTOF [75], and around the same time, a case series of six patients treated with AAV1-hOTOF was published in The Lancet [76]. In the same year, gene therapy was also reported in five pediatric patients with DFNB9 [77]. Those reports greatly established and confirmed the safety and efficacy of virus-mediated gene therapy in the inner ear. This level of safety and efficacy is expected to be readily applicable to neurotrophinbased gene therapy as well. Moreover, given the stable and effective long-term outcomes of gene therapy observed in conditions such as inherited retinal dystrophy [78], hemophilia A [79], and Leber hereditary optic neuropathy [80], it is reasonable to expect that neurotrophin-based gene therapy in the inner ear could achieve similar results.
However, gene therapy is not a magic bullet. Achieving therapeutic stable neurotrophin expression and applying it into effective patient treatment should overcome numerous challenges. The primary concern lies in the safety issues related to viral vectors. Several studies have shown that delivering microliter volumes of AAV vectors into the cochlear perilymphatic compartment can lead to substantial off-target leakage of expression. For example, in a translational model aimed at restoring hearing and balance in an Usher syndrome 1C mouse, unilateral delivery of an Anc80L65 AAV–harmonin-b1 vector through the cochlear round window membrane led to recovery of sound transduction in the contralateral, untreated cochlea [81]. The virus might arrive at the contralateral ear via perilymph within the cochlear aqueduct, which communicates with the subarachnoid cerebrospinal fluid compartment. The harmful effects of off-target AAV movement from the cochlea into the central nervous system (CNS) were reported in another neonatal mouse study employing an AAV-5 vector expressing GDNF. This study showed that the AAV5-hGDNF vector spread from the cochlea to the CNS and spinal cord, presumably via the cochlear aqueduct. This dissemination was associated with marked neurological dysfunction, including widespread loss of cerebellar Purkinje neurons, centrally mediated hearing loss, and impaired growth, all of which correlated with the AAV5-hGDNF vector titer [82]. Minor adverse events can also occur following viral therapy. In six children who received AAV1-hOTOF gene therapy, hearing improvement was achieved without any serious side effects, but a total of 48 minor adverse events were reported. Most of them (96%) were grade 1–2, and about 4% were grade 3 events involving a decrease in neutrophil count [76]. These effects were not severe enough to preclude the use of viral gene therapy, but if neurotrophin gene therapy using viral vectors is to be implemented in practice, such side effects would certainly need to be taken into consideration. In addition, issues such as determining the optimal duration and dosage of treatment, avoiding immune responses, and selecting appropriate patients need to be resolved. However, answers to such questions can only be obtained when the therapy is applied to humans—and so far, no such results have been reported.
Non-viral vector gene therapy
Considering the side effects associated with virus-based gene therapy, it may be worth exploring gene-therapy approaches that do not rely on viral vectors. The major non-viral gene delivery methods include lipid-based nanoparticles, polymeric nanoparticles, inorganic nanoparticles, and electroporation [83].
Lipid-based nanoparticles have demonstrated their safety, having been used in FDA-approved patisiran [84] and in the manufacturing of mRNA COVID-19 vaccines [85]. In addition, cationic lipids such as Lipofectamine are widely used commercially available agents [86]. Despite this safety, they have certain limitations. Injection via the round window using gelfoam or via cochleostomy cannot guarantee uniform effects throughout the cochlea [87,88]. There is also a risk of infection associated with cochleostomy.
Polymeric nanoparticles fabricated from materials such as PLGA [89], polyhydroxyethyl aspartamide [90], and polyethyleneimine are capable of crossing the round window membrane [91], enabling delivery via gelfoam. Because these nanoparticles can be readily modified, they offer clear advantages for the loading and delivery of genetic material. However, their potential toxicity, as well as their absorption, distribution, metabolism, and excretion in vivo, remain poorly understood. Moreover, it is unclear what adverse effects may arise if these particles accumulate within confined spaces such as the inner ear. Collectively, these factors represent significant limitations to their practical application [92]. There are also nanoparticles made of materials such as gold and silica (inorganic nanoparticles) [93,94], but they also have some drawbacks, including the potential for cell damage and difficulties in precise targeting. Electroporation, which uses short, high-intensity electrical pulses to introduce genetic material into cells, has been reported in several studies [95,96], however, a major drawback is tissue damage caused by the high voltages used [97].
Studies reporting the expression of neurotrophins in the inner ear using non‑viral vector gene therapy are very limited. The following study is noteworthy, in which BDNF expression mitigated damage in guinea pigs with hearing loss induced by gentamicin. Miwa, et al. [98] encapsulated BDNF mRNA in an SS‑cleavable, proton‑activated lipid‑like material (ssPalm) and soaked it into a gelatin sponge that was placed at the round window niche. BDNF expression was observed in the organ of Corti, SGNs, and stria vascularis, and this expression was shown to help mitigate cochlear damage induced by gentamicin. The protective effect on the cochlea was greater when the interval between administration of LNPssPalm‑BDNF mRNA and gentamicin ototoxicity was shorter [98].
Concluding Remarks
The ultimate goal of CI applied to patients with SNHL is to achieve hearing restoration that approximates normal hearing. Although CI clearly provides significant benefits in improving auditory perception, it remains difficult to restore hearing to pre-hearing-loss levels even after successful CI surgery. In fact, approximately 35%–50% of CI users experience difficulty using the telephone [99], and about 13% reportedly achieve less than 10% accuracy in recognizing words within sentences even in quiet environments [100]. These limitations are thought to arise not merely from deficits in sound perception, but more fundamentally from the limited frequency resolution of CI. This is because electrical stimulation from adjacent electrodes overlaps, resulting in the perception of spatially indistinct signals. Such channel interaction is closely associated with the physical distance between the electrodes and SGNs. As discussed above, neurotrophins have been proposed as a means of reducing this spatial gap and thereby improving auditory outcomes with CI. To summarize the above discussion and facilitate reader comprehension, a schematic was provided to depict neurite outgrowth via gene therapy and the consequent decrease in physical distance (Fig. 1).
In this paper, possible approaches for delivering neurotrophins into the inner ear, including Ozurdex, drug-eluting electrodes, cell-based therapy, and gene therapy, were proposed. Because these methods are already being applied in patients, they support the feasibility of the clinical application of neurotrophins. Additional methods and studies on neurotrophin administration into the inner ear, classified according to the approaches described above, are summarized in Table 1. The existence of those approaches supports the feasibility of translating neurotrophin-based therapies into clinical practice. Nevertheless, several important questions remain unre-solved. For example, how long should neurotrophins be administered? When is the optimal timing for administration? Which delivery method is the safest? And can neurotrophin therapy be considered a cost-effective option? Answers to these questions can only be obtained through clinical studies involving human subjects.
Encouragingly, according to the Australia New Zealand Clinical Trials Registry (ANZCTR), a clinical trial investigat-ing neurotrophin-based gene therapy in conjunction with CI surgery is currently underway [101]. It is hoped that further clinical trials will be conducted by additional institutions and countries, ultimately contributing to improved auditory rehabilitation outcomes for CI recipients.
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