OM represents a spectrum of middle ear inflammatory diseases which can be classified into acute otitis media (AOM), otitis media with effusion (OME, also known as glue ear), and chronic suppurative otitis media (CSOM), which is one of the most severe middle ear diseases. The common symptoms for AOM and OME include earache, hearing loss, swelling and bulging of the TM, and the accumulation of fluid behind the TM. Meanwhile, CSOM is characterized by chronic inflammation and recurrent purulent discharge through a perforated TM (Leach et al., 2021).

OM is one of the leading causes of permanent hearing loss in children and a significant disease burden in developing countries and several OM-prone populations such as Australian Aboriginals (Li et al., 2015; DeAntonio et al., 2016; DeLacy et al., 2020). Children and adolescents are particularly susceptible to OM, and two of the most accepted theories are an immature Eustachian tube (structural and functional) that is prone to blockage; and underdeveloped innate and adaptive immune systems (Bluestone, 2008; Pichichero, 2020).

Bacterial pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Pseudomonas aeruginosa are the most common cause of OM, but it can also be caused by Influenza viruses or fungal species such as Aspergillus (Mittal et al., 2015; Bhutta et al., 2017; Rowe et al., 2019). There is increasing evidence that biofilm, a microhabitat of microorganisms entrapped in self-produced extracellular proteins, contributes to the pathogenesis of OM. Biofilms are difficult to eradicate as they are resistant to antibiotics and firmly adhered to the middle ear epithelium, ossicles and tympanostomy tube (Mittal et al., 2015; Mittal et al., 2018; Silva and Sillankorva, 2019).

Perforations can occur due to OM or trauma to the TM, such as the piercing of the TM by a sharp object or a sudden change in pressure (barotrauma) (Spandow et al., 1996; Wang et al., 2014a). Most traumatic or acute TM perforations heal spontaneously within 1–2 weeks, but those that fail to heal within 3 months are considered chronic TM perforations which require surgical intervention (Tan et al., 2016). The mechanism that underlies the development of chronic TM perforation is unknown, but studies have identified risk factors that are linked to delayed healing of TM perforations, including perforation size and location (Lou et al., 2011; Tan et al., 2016), Eustachian tube dysfunction (Varsak and Santa Maria, 2016; Paltura et al., 2017) and long-term tympanostomy tube usage (Kay et al., 2001; Alrwisan et al., 2016; Knutsson et al., 2018).

Cholesteatoma is described as an inflammatory, non-malignant (and pearl-like) epithelial lesion in the middle ear cavity that can lead to conductive hearing loss, erosion of the ossicles, and other intracranial complications. Congenital cholesteatoma is rare and contributes to 1%–5% of all cholesteatoma cases; and is often detected within the first decade of life (Mansour et al., 2018; Jenks et al., 2022). The development of congenital cholesteatoma is thought to be due to the entrapment of epithelial remnants during embryogenesis, but the actual mechanism that drives this process remains under debate (Gilberto et al., 2020). Meanwhile, the more common acquired cholesteatoma is categorized into either primary acquired, which is caused by a retraction pocket in the TM; or secondary acquired, which is thought to be caused by an abnormal growth of the TM epithelial layer in the middle ear through a perforation (Cho et al., 2016; Clark et al., 2016). The pathogenesis of acquired cholesteatoma can be grouped into four theories: retraction pocket or invagination theory; epithelial invasion theory; squamous metaplasia theory and basal cell hyperplasia theory (Kuo et al., 2015; Hamed et al., 2016). More recently, the dysregulation of cell signaling and immunological pathways such as EGF; IL-6/JAK/STAT3, MicroRNA-21, Notch and TNF signaling have been identified as additional potential contributors (Hilton et al., 2011; Liu et al., 2014; Chen et al., 2016; Xie et al., 2016; Fukuda et al., 2021).

Hereditary SNHL is caused by the inheritance of one or more gene mutations from biological parents that carry defective alleles, and affects about 1 per 1,000 newborns with profound deafness (Gettelfinger and Dahl, 2018). Mutations cause the translation of malfunctional proteins that can no longer fulfil their native function and cohesively work with other components of the auditory system. Most hereditary-related deafness is monogenic, with approximately 80% of cases being autosomal recessive, although other modes of transmission such as autosomal dominant and X-linked can also occur (Schrujver, 2004). There have been 124 deafness-associated genes identified to date and some of the most prevalent include MYO7A and USH2A which are associated with Usher syndrome, PAX3 and SOX10 which are associated with Waardenburg syndrome, and PDS which is associated with Pendred syndrome (Nishio et al., 2015; Van Camp and Smith, 2023).

Noise-induced hearing loss (NIHL) is caused by progressive over-exposure to noise. NIHL affects all ages, however there is an increasing prevalence of NIHL occurring in younger populations from recreational noise exposure, for example from listening to music using headphones for prolonged periods, with over 50% of those aged 12–35 being estimated to risk developing NIHL (Chadha et al., 2021). Occupational NIHL from jobs involving prolonged exposure to loud noise, including from power tools, automotive, gunfire and music, has been attributed to 16% of worldwide severe hearing loss, with men shown to be more susceptible than women (Nelson et al., 2005). Long-term noise exposure can risk damage to the auditory structures which deteriorates cochlear hair cells and spiral ganglion nerves. Moreover, certain genetic variants have been identified clinically and experimentally to increase susceptibility to NIHL (Beaulac et al., 2021; Jiang et al., 2021). The early signs of NIHL are the loss of high frequency hearing and decreased ability to distinguish speech over background noises, and is often accompanied by tinnitus (Le et al., 2017).

Age-related hearing loss (ARHL), or presbycusis, affects the elderly as they gradually lose hearing in both ears and over 65% of adults over 60 years of age have been shown to be affected (Cunningham and Tucci, 2017; Chadha et al., 2021). ARHL usually has a complex etiology which encompasses lifestyle aspects such as noise, but does have some other defined risk factors such as smoking, ototoxic drug use and hypertension (Gates and Mills, 2005; Bowl and Dawson, 2019). Moreover, ARHL has been shown to cluster in families with prevalent cases (Gates et al., 1999). In terms of pathological features, four classifications of ARHL have been proposed from post-mortem human tissue examination, including ARHL from progressive hair cell loss, sensory and neural degeneration, loss of stria vascularis integrity and stiffening of the basilar membrane (Schuknecht, 1964; Schuknecht and Gacek, 1993). Additional etiologies have been proposed based on post-mortem human tissue analyses and animal models, involving oxidative stress, chronic inflammation, and loss of lateral wall fibrocytes (Ohlemiller and Gagnon, 2004; Suzuki et al., 2006; Tawfik et al., 2020), but it is likely that the clinical presentation will involve more than one of these causes.

Drug-induced hearing loss occurs when patients take drugs that have ototoxic side effects. Aminoglycoside and macrolide antibiotics in particular, such as gentamicin and azithromycin, are commonly used in the treatment of Meniere’s disease and in developing countries for other diseases, however they are highly ototoxic (Rauch et al., 2011; Rybak et al., 2021). Aminoglycosides can permeate through the BLB or round/oval window (when administered intratympanically for Meniere’s disease) due to their small molecular size, and accumulate in the apical side of hair cells through mechanoelectrical transduction (MET) channels or by endocytosis (Nyberg et al., 2019). When MET channels are stimulated by sound, antibiotics can enter them and exert cytotoxicity on hair cells through a yet unclear mechanism (Alharazneh et al., 2011; Zimmerman and Lahav, 2013). For ototoxic chemotherapies, cisplatin is perhaps the most widely prescribed example (Greene et al., 2015; Frisina et al., 2016). Cisplatin increases the generation of reactive oxygen species by inhibiting peroxidase enzymes which progressively damages hair cells over time, leading to SNHL (Sheth et al., 2017). Other ototoxic drugs include the antimalarial drug quinine and loop diuretics such as furosemide and acetylsalicylic acid (Tange et al., 1997; Ding et al., 2016). Furthermore, ototoxicity can be exacerbated by interactions with certain drugs, genetic polymorphisms and cochlear inflammation (Barbieri et al., 2019; Coffin et al., 2021).

Sudden sensorineural hearing loss (SSNHL) is characterized by the presentation of patients with at least 30 dB hearing loss occurring within 72 h. The incidence in the United States was reported to be 5 to 20 per 100,000 people with the vast majority of cases being unilateral and having an unknown etiology, being termed idiopathic (Kuhn et al., 2011). Bilateral SSNHL is less prevalent, comprising an estimated 4.9% of SSNHL cases, however is not usually idiopathic and is secondary to other complications including cancer, vascular disorders and autoimmune disease (Sara et al., 2013). Idiopathic SSNHL does spontaneously resolve in 45%–65% of patients, however controversy remains on potential etiologies and best course of treatment (Conlin and Parnes, 2007; Kuhn et al., 2011).

Middle ear diseases such AOM and OME are most commonly managed with supportive care such as painkillers or oral antibiotics such as Amoxicillin, but vaccination against common middle ear pathogens such as S. pneunomiae and H. influenzae has become standard practice in some countries (Martinovich et al., 2021; Clark et al., 2022; Izurieta et al., 2022). The treatment of CSOM remains a clinical challenge and often requires the combination of oral antibiotics, eardrops, and surgery due to the presence of antibiotic-resistant bacteria and bacterial biofilm (Mittal et al., 2018; Leach et al., 2021). Moreover, recurrence of the infection can occur from the presence of persister cells, a phenotype of bacteria within biofilms that exhibit low metabolic activity (Tolker-Nielsen, 2014; Fisher et al., 2017). Persister cells have been shown to escape the initial course of antibiotics and resume growth and metabolism once the administration is halted (Khomtchouk et al., 2020; Santa Maria et al., 2021).

Acute or traumatic TM perforations are most often treated with supportive care as with OM, to minimize pain and prevent infection (Orji and Agu, 2008; Lieberthal et al., 2013). Surgery is only indicated for chronic TM perforations (over 3 months) and this procedure is called myringoplasty (or tympanoplasty if ossicles are involved), which involves the placement of an autologous graft (typically temporalis fascia or auricular cartilage) over or under the defect to encourage wound healing and restore hearing. The success rate for such surgery is approximately 87% (Tan et al., 2016), but the harvesting of autologous grafts is associated with donor site morbidity (infection and pain) and higher operation cost (Villar-Fernandez and Lopez-Escamez, 2015; Sainsbury et al., 2022).

For cholesteatoma, surgical excision remains the only curative approach and this is often performed in conjunction with reconstruction surgeries (e.g., mastoid wall reconstruction) to repair damage caused by the lesion and surgical procedure (Mansour et al., 2018). Unfortunately, the recurrence rate for cholesteatoma is high with 10%–40% of patients requiring repeated surgery (Britze et al., 2017; Angeli et al., 2020; Bächinger et al., 2021). The recurrence of cholesteatoma may be affected by the type of surgical procedure and is thought to vary between congenital and acquired disease (Edfeldt et al., 2012; Morita et al., 2017; van der Toom et al., 2021; Adriaansens et al., 2022).

Bacteriophage or viral-based treatment has emerged as an alternative strategy to counteract the increasing threat of antibiotic resistance (Gordillo Altamirano and Barr, 2019). Wright et al. (2009) conducted the first clinical trial on the safety of a bacteriophage preparation against P. aeruginosa in patients with chronic OM. Overall, the treatment did not cause any severe side effects, significantly lowered the bacteria count (CFU per gram) and improved the clinical scores of patients. In a later clinical trial, bacteriophage therapy was conducted in burns patients infected with P. aeruginosa (Jault et al., 2019). Unlike the previous trial, a daily topical application of a cocktail of 12 bacteriophages suspended in saline solution was compared to the standard of care (1% sulfadiazine silver emulsion cream) over 7 days. Overall, the treatment was well tolerated, but there was no significant clinical improvement or reduction in bacterial load when compared to standard of care. This study also highlighted a few challenges associated with bacteriophage treatment, including the stability and titer of bacteriophage after manufacturing and concerns about bacterial resistance to bacteriophages. Overall, bacteriophage-based treatment remains an exciting and promising therapeutic approach for the treatment of OM and warrants further investigation.

There has been an increased interest in the development of effective anti-biofilm technology as a preventative and treatment approach. One of the most promising treatment targets is Type IV pili (Tfp), a type of proteinous appendage on the surface of most bacterial species, which plays a critical role in mechanosensing, motility, and the formation of biofilm (Lee et al., 2018; Horna et al., 2019). Novotny and colleagues have successfully developed a transcutaneous immunization strategy against Tfp and showed both in vitro and in animal studies the efficacy of anti-Tfp antibodies in destabilization of H. Influenzae biofilm and the eradication of the pathogen (Novotny et al., 2013; Novotny et al., 2015; Novotny et al., 2016; Novotny et al., 2021). Anti-Tfp treatment has also been shown to be effective against other middle ear pathogens such as M. catarrhalis (Mokrzan et al., 2018). More importantly, the antibody-mediated release bacteria (from the biofilm) were found to be more susceptible to antibiotic killing as compared to their planktonic (free-living) counterparts (Mokrzan et al., 2018; Mokrzan et al., 2020). Other promising strategies to tackle problems associated with biofilm include antibody treatment against bacterial DNABII protein, a key structural component of the biofilm (Barron et al., 2020; Novotny et al., 2021). Dornase alfa, a recombinant human deoxyribonuclease that breaks down DNA, has also been shown to reduce the development of otorrhea in pediatric patients undergoing tympanostomy (Thornton et al., 2013; Chan et al., 2018).

For the repair of TM, much research has been focused on developing biocompatible scaffolds using natural or synthetic materials such as collagen, chitosan, decellularized tissue and polylactic acid (PLA) (Hussain and Pei, 2021; Sainsbury et al., 2022). Some of the current commercially available scaffolding materials indicated for myringoplasty are EpiFilm^® (Medtronic, Ireland), which is a hyaluronic acid-derived implantable device, and acellular dermal allografts such as Alloderm (Allergan, Ireland) (Vos et al., 2005; Sayin et al., 2013).

Otherwise, adjuvant therapies using topical application of biomolecules are becoming popular in addition to myringoplasty to enhance the healing of perforations. The most commonly used biomolecules are growth factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) (Hong et al., 2013; Sainsbury et al., 2022). The efficacy of EGF on the closure of TM perforations has been investigated predominantly in acute/traumatic perforations. (Lou et al., 2016; Lou and Lou, 2017; Lou and Lou, 2018b). Despite the positive outcomes, the benefits of EGF on the repair of chronic TM perforation remain unclear due to the lack of well-controlled clinical studies.

Multiple clinical trials have been conducted to study the effects of bFGF on both acute and chronic TM perforations. For acute TM perforations, topical drops administration is the most commonly used approach and is associated with improved healing outcomes when compared to untreated controls (Huang et al., 2020). For chronic perforations, the most widely used approach for bFGF therapy was developed by Kanemaru and colleagues in which a bFGF-impregnated scaffold (Gelfoam) is applied over the perforation, which is then sealed with fibrin glue (Kanemaru et al., 2011). Clinical trials conducted in Japan have reported closure rates of 62%–100% in chronic perforations treated with bFGF (Hakuba et al., 2003; Hakuba et al., 2010; Hakuba et al., 2013; Hakuba et al., 2015). In contrast, a recent Phase 2 clinical trial comparing chronic TM perforations treated with bFGF or placebo (water) reported no statistical difference in closure rates between the two treatment groups (Santos et al., 2020). Besides that, there have been concerns about the safety of bFGF as it was found to lead to other middle ear disorders such as myringitis and cholesteatoma (Hakuba et al., 2013; Lou and Lou, 2018a).

Platelet-rich-plasma (PRP), a type of blood product that is rich in platelets and bioactive molecules, has been shown to be a promising alternative treatment option for tissue repair and regeneration (Amable et al., 2013; Everts et al., 2020; Huang et al., 2021). PRP has also emerged as a promising treatment for chronic TM perforations with 8 clinical trials conducted in the past 10 years (El-Anwar et al., 2015; Fawzy et al., 2018; Fouad et al., 2018; Yadav et al., 2018; Mandour et al., 2019; Anwar et al., 2020; Ersözlü and Gultekin, 2020; Taneja, 2020). The closure rate ranged from 85.7% to 100% in the PRP treatment group while a 55%–92% closure rate was reported in the control group. It is noteworthy that PRP was used in conjunction with a scaffolding material including a fat graft, temporalis fascia, or conchal perichondrium. Therefore, the real therapeutic benefit of PRP as a stand-alone treatment remains unclear.

Overall, adjuvant therapy using biomolecules with or without myringoplasty remains an attractive avenue for the management of TM perforations with research expanded beyond the traditional growth factors (Shen et al., 2014; Araujo et al., 2016). More recently, a Phase 1 clinical trial investigating the effect of a recombinant heparin-binding epidermal growth factor-like growth factor (HB-EGF) (dubbed ASP0598 Otic Solution) on the healing of chronic TM perforations has started patient recruitment in multiple locations in the United States (NCT04305184, clinicaltrials.gov).

Auditory rehabilitation with hearing devices or cochlear implants remains the primary treatment approach for SNHL. These technologies can significantly aid in communication, yet they are still unable to mimic the quality of natural hearing and, more importantly, they do not treat the underlying cause of the hearing loss (Beck and Le Goff, 2018; Solheim et al., 2018).

Hearing aid technology has advanced greatly over the past decade, with innovations allowing customization of every device to fit the unique hearing needs of each patient. These devices are designed to amplify sounds and restore hearing, however no currently available devices can provide sound quality comparable to that of a healthy cochlea. Some hearing aids are capable of selectively reducing background noise while maintaining access to all distinct speech sounds, but this typically requires the user to select the voice they wish to focus on and are usually ineffective in group settings. Moreover, hearing aids still rely on functional hair cells for sound transduction (Geleoc and Holt, 2014).

In contrast, cochlear implants have proven to be a successful therapeutic approach for patients, even for those with abnormal hair cells and severe hearing impairment. There is clear evidence showing rapid development in oral communication and auditory skills in infants and children with SNHL with cochlear implants (Mok et al., 2010; Dettman et al., 2016; Hoff et al., 2019; Dettman et al., 2021). Moreover, adult patients with cochlear implants were shown to have improved speech outcomes and quality of life (Santa Maria et al., 2013; Völter et al., 2020). However, evidence in patients and animal models show the surgical installation procedure risks chronic cochlear inflammation or fibrosis, which reduces the effectiveness of the implant over time (Wilk et al., 2016; Foggia et al., 2019).

There is currently a wide spectrum of drug types undergoing clinical trials for different types of SNHL, which has been recently comprehensively summarized by Isherwood et al. (2022). In recent years, strategies aiming to manipulate hair cell differentiation pathways have garnered significant interest. For example, hair cell differentiation is shown to be accompanied by ATOH1 gene expression, crucial for progenitor cells residing in the organ of Corti to be directed to differentiate into a non-sensory or sensory lineage (Cai et al., 2013; Driver et al., 2013). Currently, the CGF166 adenoviral vector contains ATOH1 cDNA transcript to replace absent hair cells has completed Phase 2 investigation (NCT02132130, clinicaltrials.gov). However, most recently reported novel otoprotective, regenerative and gene replacement treatments remain too early in their stage of development to be applied clinically.

For cisplatin-induced hearing loss, sodium thiosulfate has recently been approved by the US Food and Drug Administration as an otoprotective drug. As mentioned, cisplatin is a highly ototoxic drug, with children and adolescents undergoing cisplatin treatment being particularly vulnerable to cisplatin-induced hearing loss (Orgel et al., 2022). Sodium thiosulfate has been demonstrated in animal models and clinical trials to abrogate cisplatin-induced ototoxicity, thought to occur by directly chelating cisplatin (Videhult et al., 2006; Brock et al., 2018). However, as sodium thiosulfate directly binds cisplatin and is currently intravenously injected, this may risk decreasing the efficacy of the chemotherapy on the cancer itself. Methods of locally administering sodium thiosulfate to the inner ear are currently being investigated to reduce this risk and will be discussed in later sections.

Another developing approach to treating inner ear disorders is the application of exosomes. Exosomes are a subset of extracellular vesicle derived from the budding of endosomes from the plasma membrane, incorporating transmembrane proteins and lipids, and range from ∼30 to 160 nm in diameter. The precise physiological role of exosomes is unclear, however they have been demonstrated to have pleiotropic roles in cell-cell communication, signaling, proliferation, angiogenesis, immune response and metabolism and have been shown to carry proteins, nucleic acids and metabolites (Kalluri and LeBleu, 2020; Warnecke et al., 2022). Exosomes have been recently identified, isolated and characterized from the perilymph of adult patients with various forms of SNHL or mixed hearing loss, with the study suggesting a hair cell origin of the exosomes by their expression of MYO7A (Zhuang et al., 2021). On the therapeutic side, a study from Athanasia Warnecke and colleagues demonstrated protective effects of bone marrow mesenchymal stromal cell-derived extracellular vesicles on a mouse model of NIHL, which additionally promoted neurite outgrowth in vitro (Warnecke et al., 2020). This was followed up by a study demonstrating the safety of implanted extracellular vesicles in a Meniere’s disease patient that had undergone cochlear implantation 24 months post-operation (Warnecke et al., 2021). Exosomes thus represent an interesting potential avenue of biological, yet cell-free treatment of inner ear disorders.

Hydrogel delivery systems allow for the controlled release of a variety of therapeutic compounds. They can be manipulated into virtually any shape or size to facilitate controlled drug release and delivery to various locations in the body (Li and Mooney, 2016; Rathnam et al., 2019). For hearing-based therapies, the most common form tested preclinically is direct application of a liquid in situ gelling hydrogel. The hydrogel is administered to the TM or round window niche via intratympanic injection, which solidifies upon contact with the RWM (Rathnam et al., 2019). This allows for the continual and controlled release of drugs which diffuse across the RWM to the inner ear, without a need for highly invasive surgery (Paulson et al., 2008; Hütten et al., 2014; Lajud et al., 2015; Chen et al., 2022d).

Most hydrogel systems are advantageous due to their biocompatibility. For example, gelatin methacryloyl (GelMA) is highly biocompatible and has been extensively studied in the laboratory as a substrate for three-dimensional mammalian cell culture due to its inert nature, tunability, and higher batch-to-batch reproducibility over other commonly used substrates (Zhu et al., 2019). In an interesting recent approach for clinical application, GelMA hydrospheres were conjugated with polydopamine (PDA) for cell adhesion. The delivery of ebselen via these GelMA hydrospheres recovered hearing loss at some frequencies in a mouse model of NIHL (Chen et al., 2022d). Another biocompatible hydrogel composed of modified polyethylene glycol (PEG) was used to deliver a hydrophilic form of dexamethasone to a guinea pig cochlear trauma model, resulting in sustained drug delivery over several weeks, causing the recovery of hearing loss and reduced fibrosis (Hütten et al., 2014).

Additional classes of hydrogel include poloxamers, with a recent approach using the commercially available Poloxamer 407 to deliver a small molecule inhibitor of the apoptosome, LPT99. This approach was shown to preserve cell viability and auditory function in cisplatin-treated rats (Murillo-Cuesta et al., 2021). Finally, polylactic-co-glycolic acid (PLGA) hydrogels have shown promise due to their biodegradable nature and have potential to deliver a wide variety of drugs, including large molecules such as proteins (Dai et al., 2018; Kim et al., 2021). However high doses of a PLGA-PEG-PLGA copolymer were observed to affect hearing in guinea pigs (Feng et al., 2014).

Otiprio^® is an FDA-approved ciprofloxacin solution suspended in a thermosensitive Poloxamer 407 gel and has been indicated primarily for the treatment of pediatric otitis externa and OME associated with tympanostomy tube placement (Edmunds, 2017). Otiprio^® is thought to be superior to conventional ciprofloxacin eardrops (which usually requires three drops thrice a day) as it has been shown to reduce the occurrence of OM after a single intratympanic injection (Renukananda et al., 2014; Dohar et al., 2018). While Otriprio^® is not currently approved for the treatment of CSOM, it is a promising “off-label” treatment due to the similarity of the two disease subtypes.

There are several hydrogel-based therapies for SNHL that are currently undergoing or have completed clinical trials. One of the earliest was developed by Otonomy termed “OTO-104”, a poloxamer gel injected intratympanically to deliver dexamethasone across the RWM to the inner ear (Piu et al., 2011). This therapy underwent Phase 2 and 3 clinical trials for vertigo in cisplatin-induced hearing loss and Meniere’s disease respectively, however both were terminated once no significant difference was observed compared to placebo for the former trial. This has been postulated to be due to accelerated clearance of the drug, as dexamethasone can readily cross the BLB and may be eliminated prior to affecting the more apical regions of the cochlea (Salt and Plontke, 2018). More recent developments include DB-020 and FX-322 from Decibel Therapeutics and Frequency Therapeutics respectively. DB-020 is a hyaluronic acid-based gel containing sodium thiosulfate for the inactivation of cisplatin, an ototoxic chemotherapy. Phase 1 clinical trials showed DB-020 was well tolerated and that 13 of 17 patients treated displayed partial or complete otoprotection (Viglietta et al., 2020). The progression and further studies of DB-020 will be useful to determine if the hydrogel confers additional otoprotection or higher tolerability in patients than the intravenously injected formulation recently approved by the U.S. Food and Drug Administration (Brock et al., 2018). FX-322 is a poloxamer-based gel containing the glycogen synthase kinase inhibitor, CHIR99021 and the histone deacetylase inhibitor, valproic acid. Both have been shown to promote the differentiation of stem cells into an otic lineage (Koehler et al., 2017). FX-322 showed a significant improvement in patients with chronic SNHL compared to the placebo in Phase 1b clinical trials (McLean et al., 2021). Unfortunately, Frequency Therapeutics reported that FX-322 showed no statistically significant difference from placebo at day 90 of a Phase 2b trial in February 2023 and development of the drug was halted.

Hydrogels have great potential to facilitate controlled delivery of a wide variety of drugs, including nanoparticles which will be discussed in the next section, and are an appealing avenue based on their ever-expanding tunability and composition. Despite these advantages, some precluding factors remain in their progression to more prevalent clinical usage. Namely, sterilization and storage could be challenging given their hydrated nature (Li and Mooney, 2016). Nevertheless, the degree of controlled release afforded by hydrogel drug delivery remains a promising factor in their applicability to treat hearing loss.

Due to their small size and theoretically endless possibilities for customization, nanoparticles have become an attractive option for drug delivery (Table 1). The ability to customize nanoparticles is advantageous as size, charge, lipid solubility and membrane thickness strictly govern molecular passage across the RWM and these properties cannot be readily modified in most drugs (Goycoolea and Lundman, 1997; Valente et al., 2017; Xu et al., 2021a; Xu et al., 2021b). Nanoparticles of sizes between 10 and 640 nm have been demonstrated to diffuse across the RWM, however most studies concur that sizes below 200 nm display the greatest permeation (Valente et al., 2017; Xu et al., 2021a; Chester et al., 2021).

Regarding charge, positively-charged nanoparticles display higher diffusion and greater distribution in the apical region of the cochlea, which is likely due to the ability of more positively charged nanoparticles to cross the lipid membranes and plasma membranes into cells (Liu et al., 2013; Yang et al., 2018a). A study using nanoparticles coated with a positively-charged arginine 8 peptide shell exploited this to deliver connexin 26 siRNA and plasmids containing green fluorescent protein or brain-derived neurotrophic factor (BDNF), along with dexamethasone, which induced nuclear pore opening (Yoon et al., 2016). Another study demonstrated greater distribution of cationic lipid nanoparticles in an in vitro RWM model, over neutrally charged or anionic nanoparticles of the same type. This nanoparticle also mitigated against an induced inflammatory reaction in vivo (Yang et al., 2018b).

Moreover, like hydrogels, nanoparticles can provide a means of controlled drug release in the middle and inner ear. This could decrease the need for surgical intervention for routine application of therapeutics and decrease potential systemic toxicity. Thus, nanotechnology has become of great recent interest in drug delivery to the inner ear.

Homing peptides are widely used to deliver therapeutic payloads to tumors, diseased blood vessels and to treat neurological disorders. These peptides use “molecular zip codes” or cell/extracellular matrix recognition motifs to selectively identify cell surface markers and extracellular matrix, which permit accumulation of the peptide in not only specific tissues, but specific cells (Ruoslahti, 2022). Homing peptides additionally can be conjugated to a therapeutic cargo to guide the payload to the site of pathology (Mann et al., 2016; Yeow et al., 2019). They are commonly generated from ex vivo/in vivo phage display screening, where bacteriophages are incubated with cells from target tissue, generating a library of potential homing peptides on the phage surface. These peptides are generally small, usually up to 20–30 amino acids in length, which allows greater permeation across membranes than larger targeting moieties such as antibodies.

Recently, Allen Ryan’s group at the University of California, San Diego used this technique to identify homing peptides that could cross the TM. The ex vivo study used TM from rats with induced OM as the substrate for peptide identification, which produced candidate peptides which were able to transport the phage across the TM in vivo (Kurabi et al., 2018a). A follow up ex vivo study showed the homing peptides were able to cross human TM both as isolated peptides and connected to phage at the same rate (Kurabi et al., 2018b). The mechanism of transport was eventually implicated to be via transcytosis (Kurabi et al., 2022). Based on the relatively large size of bacteriophages (900 nm-1 µm in length), these would make homing peptides a highly promising approach for the delivery of larger drugs and nanoparticles to the middle and potentially inner ear.

Miniaturized perfusion systems have been trialed in animal models as a possible delivery device for drugs. Directed intracochlear delivery overcomes many limitations of intratympanic RWM administration. Larger and more unstable drugs such as RNA therapeutics or proteins can be continuously delivered and multiple doses can be accounted for with the continual delivery. However, introducing more fluid must be precise and delivered in small volumes to not risk increasing intracochlear pressure and damaging sensory tissue. Moreover, the design of the preclinical systems thus far suggests a direct translation of a wearable or implanted pump for human use. Such systems would necessitate the highest practical degree of miniaturization to avoid inconveniencing the patient and reduce any possible stigma if the device is visible, as those with hearing aids may experience (Wallhagen, 2009).

Jeffrey Borenstein’s group has been extensively involved in the design of micropumps for inner ear delivery. In 2015, they reported the design of a head-mounted micropump (using guinea pigs for demonstration), with infuse-withdraw capabilities. This functioned through the infusion-withdrawal of perilymph so as to not disturb intracochlear pressure and was used to deliver the glutamate receptor antagonist DNQX (Tandon et al., 2015). The group also created a device with a reciprocating pump and drug reservoir to ensure no net volume change in the cochlea (Kim et al., 2014). Another group was able to recently create an implantable micropump for mice (Forouzandeh et al., 2019).

Cochleostomy is a highly invasive process, which itself may risk affecting hearing. This procedure is usually employed to install cochlear implants and there is growing in vivo evidence in animal models and humans of a fibro-inflammatory response to implants (Wilk et al., 2016; Foggia et al., 2019). The resulting fibrosis interferes with the implant electrode array, and is thought to contribute to impedance, which hampers the effectiveness of the cochlear implant over time. To counteract the proliferation of fibrotic tissue, anti-inflammatory drugs, commonly dexamethasone, incorporated into the implant electrode array have shown effectiveness at preventing fibrosis and additionally trauma-induced hair cell and neural damage (Chang et al., 2009; Eastwood et al., 2010; Bas et al., 2016; Wilk et al., 2016; Plontke et al., 2017; Qnouch et al., 2021). Coating the surface of the implant with less adsorbing and immunogenic biomaterials has also shown benefit in inhibiting the inflammatory response (Chen et al., 2022a).

As discussed in previous sections however, certain drugs, especially dexamethasone and other glucocorticoids, risk being cleared prior to achieving sufficient bioavailability (Salt and Plontke, 2018). A study by Liebau et al. (2020) demonstrated this by implanting silicone dummy rods with different concentrations of dexamethasone, showing a dose-dependent relationship between drug loading amount and perilymph concentration over 7 weeks in guinea pigs. To ensure continual release of drugs, some compelling controlled release strategies have been developed. One study used Pluronic-coated gold nanoparticles to deliver dexamethasone in the round window niche after cochleostomy and demonstrated modest improvement in ABR threshold at 8 kHz, but no difference at other ranges (Blebea et al., 2022). Another study from Chen et al. (2022b) presented an interesting strategy using mesoporous silica nanoparticles containing siRNA against the pro-fibrotic cytokine, TGFβ, which were adsorbed onto the surface of the electrode array. In vivo results from animal studies from this group are highly anticipated.