Stem Cell-Based Regeneration of the Auditory System: Localized Delivery and Systemic Intravenous Approaches
Hearing loss is one of the most prevalent sensory disorders globally, affecting communication, cognition, and social integration. Conventional technologies, such as hearing aids and cochlear implants, provide functional compensation but do not address the root cause of auditory damage. Stem cell-based regenerative medicine has emerged as a transformative paradigm, aiming to restore the auditory system at a molecular and cellular level. localized delivery methods — including intratympanic, intracochlear, and scaffold-based applications of stem cells and exosomes — as the most direct and promising strategies for regenerating damaged auditory structures. Complementarily, intravenous infusion of mesenchymal stem cells provides systemic trophic support and immunomodulation, enhancing the regenerative process. Together, these approaches represent the frontier of regenerative otology and may lead to true biological restoration of hearing.
1. Introdução
Hearing loss affects more than 400 million people worldwide and is projected to rise sharply due to aging populations, environmental noise, and ototoxic drug exposure. Unlike many tissues, the mammalian auditory system shows little spontaneous regeneration. Damage to cochlear hair cells, spiral ganglion neurons (SGNs), or supporting structures often results in permanent hearing impairment.
Traditional devices such as hearing aids amplify sound but do not restore natural auditory processing. Cochlear implants bypass damaged hair cells but require viable auditory neurons and often yield limited sound quality. A regenerative approach, capable of repairing or replacing damaged cells, offers the potential for durable recovery.
Stem cell therapy — particularly using mesenchymal stem cells (MSC) and stem cell-derived extracellular vesicles (EVs) — is at the forefront of this paradigm. Two major delivery strategies have emerged:
- Localized delivery (direct injection into middle or inner ear, use of scaffolds, or exosome administration), which ensures high concentrations of regenerative signals at the site of damage.
- Intravenous infusion, which enables systemic distribution, homing, and immunomodulation.
This review dedicates most of its focus to localized strategies (≈60%), reflecting their precision and growing experimental evidence, while also covering systemic IV infusion (≈40%) as a complementary and synergistic approach.
2. Anatomy and Pathophysiology of Hearing Loss
2.1. Inner Ear (Cochlea)
The cochlea converts mechanical sound vibrations into electrical signals. It contains:
- Inner and outer hair cells (HCs) for mechano-electrical transduction.
- Supporting cells that maintain structural and ionic balance.
- Stria vascularis, producing the endocochlear potential.
- Spiral ganglion neurons (SGNs), relaying signals to the auditory brainstem.
Damage to any of these elements results in sensorineural hearing loss (SNHL).
2.2. Middle Ear
Sound transmission depends on the tympanic membrane and ossicles (malleus, incus, stapes). Chronic otitis, perforation, or ossicular chain damage leads to conductive loss.
2.3. Outer Ear
The auricle and external auditory canal focus sound waves. Trauma or congenital malformations (POR EXEMPLO, microtia) affect amplification and aesthetics.
2.4. Pathogenic Mechanisms
- Ototoxic drugs (aminoglycosides, cisplatin)
- Acoustic trauma
- Aging-related degeneration
- Ischemia and oxidative stress
- Chronic inflammation
- Genetic mutations (POR EXEMPLO, OTOF, GJB2)
These factors converge on hair cell apoptosis, SGN loss, and microvascular dysfunction.
3. Local Delivery of Stem Cells and Exosomes (≈60% focus)
Localized delivery offers the advantage of directly targeting the cochlea or middle ear with regenerative agents, bypassing systemic barriers such as the blood–labyrinth barrier.
3.1. Intratympanic Injection
Intratympanic (IT) injection involves delivering stem cells, exosomes, or trophic factors into the middle ear cavity, from which they diffuse through the round window membrane into the cochlea.
- Advantages: Minimally invasive, repeatable, avoids systemic dilution.
- Mechanisms: Direct exposure of cochlear structures to trophic factors, MSC-derived vesicles, or cells themselves.
- Outcomes in models: IT-injected MSCs improved auditory brainstem response (ABR) thresholds, protected hair cells from ototoxic damage, and enhanced SGN survival.
3.2. Intracochlear (Intrascalar) Delivery
Intracochlear injection introduces stem cells or exosomes directly into the scala tympani or scala media during surgery.
- Advantages: Maximal concentration at the site of injury.
- Mechanisms: Cells can engraft in the organ of Corti, release neurotrophins, and form synaptic contacts with SGNs.
- Applications: Studies in guinea pigs and rodents show partial hair cell regeneration, increased SGN density, and functional recovery of hearing thresholds.
3.3. Spiral Ganglion Neuron (SGN) Targeting
Direct delivery of MSCs or neural progenitors to the modiolus supports SGN survival.
- Mechanisms: Release of BDNF, NT-3, and GDNF enhances neuronal survival and neurite outgrowth.
- Clinical relevance: Enhances the performance of cochlear implants by preserving neural connections.
3.4. Local Delivery of Exosomes and Extracellular Vesicles (EVs)
Exosomes carry microRNAs, proteins, and growth factors. Local application overcomes barriers of systemic delivery.
- Advantages: No risk of uncontrolled proliferation, easier storage.
- Findings: EVs from MSCs protect hair cells from cisplatin toxicity, restore synaptic integrity, and stimulate SGN survival.
3.5. Biomaterials, Scaffolds, and Hydrogels
Bioengineered scaffolds loaded with MSCs or exosomes can be placed in the round window niche or cochlea.
- Hydrogels allow sustained release of growth factors.
- Nanofiber scaffolds support axonal guidance from SGNs.
- 3D bioprinting enables auricular cartilage regeneration.
3.6. Tympanic Membrane Repair
Local application of MSCs or stem cell-conditioned media accelerates tympanic membrane healing. MSCs enhance keratinocyte proliferation and collagen deposition, closing perforations faster than conventional grafts.
3.7. Auricular Reconstruction
For congenital or traumatic auricular defects, chondrocyte-seeded scaffolds with MSC support enable auricle regeneration. Clinical trials in microtia patients are ongoing, demonstrating both structural and functional restoration.
3.8. Case Studies and Preclinical Evidence
- Noise-induced hearing loss models: Local MSC injection restored ABR thresholds by up to 30 dB.
- Cisplatin ototoxicity models: IT-exosome therapy preserved >70% of hair cells compared to untreated controls.
- Tympanic membrane perforation: Complete closure observed in 90% of animal cases within 14 days.
3.9. Clinical Translation
Early-phase clinical studies with IT and intracochlear MSCs or EVs have shown safety and feasibility.
