Activated tissue-resident macrophages contribute to hair cell insults in noise-induced hearing loss in mice.

Macrophages serve as the primary immune cell population and assume a pivotal role in the immune response within the damaged cochleae. Yet, the origin and role of macrophages in response to noise exposure remain controversial. Here, we take advantage of Ccr2RFP/+ Cx3cr1GFP/+ dual-reporter mice to identify the infiltrated and tissue-resident macrophages. After noise exposure, we reveal that activated resident macrophages change in morphology, increase in abundance, and migrate to the region of hair cells, leading to the loss of outer hair cells and the damage of ribbon synapses. Meanwhile, peripheral monocytes are not implicated in the noise-induced hair cell insults. These noise-induced activities of macrophages are abolished by inhibiting TLR4 signaling, resulting in alleviated insults of hair cells and partial recovery of hearing. Our findings indicate cochlear resident macrophages are pro-inflammatory and detrimental players in acoustic trauma and introduce a potential therapeutic target in noise-induced hearing loss.

Preparation, characterization, and in vitro/vivo evaluation of a multifunctional electrode coating for cochlear implants.

Cochlear implantation (CI) is the primary intervention for patients with sensorineural hearing loss to restore their hearing. However, approximately 90 % of CI recipients experience unexpected fibrosis around the inserted electrode arrays due to acute and chronic inflammation. This fibrosis leads to progressive residual hearing loss. Addressing this complication is crucial for enhancing CI outcomes, yet an effective treatment has not yet been found. In this study, we developed a multifunctional dexamethasone (DXM)-loaded polytrimethylene carbonate (PTMC) electrode coating to mitigate inflammatory reactions and fibrosis after CI. This thin and flexible coating could preserve the mechanical performance of the electrode and reduce the implantation resistance for CI. The in vitro release studies demonstrated the DXM-PTMC coating's efficient drug loading and sustained release capability over 90 days. DXM-PTMC also showed long-term stability, high biocompatibility, and effective anti-inflammatory effects in vitro and in vivo. Compared with the uncoated group, DXM-PTMC coating significantly inhibited the expression of inflammatory factors, such as NO, TNF-α, IL-1ß, and IL-6. DXM-PTMC coating suppressed fibrosis in rat implantation models for 3 weeks by reducing both acute and chronic inflammation. Our findings suggest that DXM-PTMC coating is a novel strategy to improve the outcomes of CI.

Electrical stimulation of cochlear implant promotes activation of macrophages and fibroblasts under inflammation.

Objectives: The implanted electrodes deliver electric signals to spiral ganglion neurons, conferring restored hearing of cochlear implantation (CI) recipients. Postimplantation intracochlear fibrosis, which is observed in most CI recipients, disturbs the electrical signals and impairs the long-term outcome of CI. The macrophages and fibroblasts activation is critical for the development of intracochlear fibrosis. However, the effect of electric stimulation of cochlear implant (ESCI) on the activity of macrophages and fibroblasts was unclear. In the present study, a human cochlear implant was modified to stimulate cultured macrophages and fibroblasts. Methods: By measuring cellular marker and the expression level of cytokine production, the polarization and activity of macrophages and fibroblasts were examined with or without ESCI. Results: Our data showed that ESCI had little effects on the morphology, density, and distribution of culturing macrophages and fibroblasts. Furthermore, ESCI alone did not affect the polarization of macrophages or the function of fibroblasts without the treatment of inflammatory factors. However, in the presence of LPS or IL-4, ESCI further promoted the polarization of macrophages, and increased the expression of pro-inflammatory or anti-inflammatory factors, respectively. For fibroblasts, ESCI further increased the collagen I synthesis induced by TGF-ß1 treatment. Nifedipine inhibited ESCI induced calcium influx, and hereby abolished the promoted polarization and activation of macrophages and fibroblasts. Conclusion: Our results suggest that acute inflammation should be well inhibited before the activation of cochlear implants to control the postoperative intracochlear fibrosis. The voltage-gated calcium channels could be considered as the targets for reducing postimplantation inflammation and fibrosis. Level of Evidence: NA.

Zwitterionic Polymer/Polydopamine Coating of Electrode Arrays Reduces Fibrosis and Residual Hearing Loss after Cochlear Implantation.

Since the first surgery 50 years ago, cochlear implantation (CI) is the major treatment for patients with severe sensorineural hearing loss. However, unexpected foreign body reactions (FBRs) after surgery are reported in 90% of CI recipients, resulting in the formation of fibrosis in the cochlea and progressive residual hearing loss. Zwitterion modification is universally used to reduce bio-fouling and suppress FBRs but never for CI. In the present study, a zwitterionic coating is developed, which is composed of poly sulfobetaine methacrylate (PSB) and polydopamine (PDA) for cochlear implants. The PSB-PDA coating shows a series of characters for an ideal anti-FBRs material, including super-hydrophilicity, low protein and cell adsorption, long-term stability, and high biocompatibility. Compared to the uncoated controls, PSB-PDA coating inhibits the activation of macrophages and reduces the release of inflammatory factors (TNF-α, IL-1ß, NO) and fibrosis-related factors (TGF-ß1, α-SMA, collagen I). PSB-PDA coated electrode arrays suppress fibrosis completely and preserve residual hearing significantly in rat CI models. These results suggest that PSB-PDA coating is a novel strategy for anti-fibrosis to improve the outcomes of CI.

Long-Term Release of Dexamethasone With a Polycaprolactone-Coated Electrode Alleviates Fibrosis in Cochlear Implantation.

Cochlear implantation (CI) is the major treatment for severe sensorineural hearing loss. However, the fibrotic tissue forming around the electrodes reduces the treatment effectiveness of CI. Dexamethasone (DEX) is usually applied routinely in perioperative treatment of cochlear implantation (CI), but its diffusion in the inner ear after systemic administration is limited. In the present study, an electrode coated with polycaprolactone (PCL) loaded with dexamethasone was developed with a simple preparation process to maintain the stability of the electrode itself. The DEX-loaded PCL coating has good biocompatibility and does not change the smoothness, flexibility, or compliance of the implant electrode. Stable and effective DEX concentrations were maintained for more than 9 months. Compared with the pristine electrode, decreasing intracochlear fibrosis, protection of hair cells and spiral ganglion cells, and better residual hearing were observed 5 weeks after PCL-DEX electrode implantation. The PCL-DEX electrode has great potential in preventing hearing loss and fibrosis by regulating macrophages and inhibiting the expression of the fibrosis-related factors IL-1ß, TNF-α, IL-4, and TGF-ß1. In conclusion, the PCL-DEX electrode coating shows promising application in CI surgery.

Preparation, characterization, and in vitro/vivo evaluation of dexamethasone/poly(ε-caprolactone)-based electrode coatings for cochlear implants.

With dexamethasone as the model drug and polycaprolactone (PCL) as the carrier material, a drug delivery coating for cochlear electrodes was prepared, to control cochlear fibrosis caused by cochlear implantation. A dexamethasone/poly (ε-caprolactone)-based electrode coating was prepared using the impregnation coating method. Preparation parameters were optimized, yielding 1 impregnation instance, impregnation time of 10 s, and PCL concentration of 10%. The coating was characterized in vitro using scanning electron microscopy, a universal machine, high-performance liquid chromatography, and CCK-8. The surface was porous and uniformly thick (average thickness, 48.67 µm)-with good flexibility, long-term slow drug release, and optimal drug concentration-and was biologically safe. The experimental results show that PCL is an ideal controlled-release material for dexamethasone as a drug carrier coating for cochlear implants.

Preparation, characterization and application research of a sustained dexamethasone releasing electrode coating for cochlear implantation.

Cochlear inflammatory response after cochlear implantation (CI) is an important mechanism for implantation trauma and hearing loss. The hearing loss was also caused by damage to auditory hair cells (HCs), whereas ion homeostasis within the cochlea can ensure survival of HCs. In our study, pure hyaluronic acid (HA) was crosslinked with 1, 4-butanediol diglycidyl ether (BDDE) and the successful preparation of the cross-linked hydrogel (CHA) was confirmed by rheological characteristics and FTIR spectra. Artificial perilymph (APL) was prepared to simulate the ion homeostasis microenvironment within scala tympani of human cochlear, and served as the major component of artificial perilymph soaked CHA (APL-CHA). The conductivity experiment indicated that APL-CHA is more suitable to the requirements of the electrical conductivity in scala tympani. The electrode coating process found that the extrusion coating method have advantages of controllable adhesive capacity of APL-CHA, uniform coating thickness and smooth surface as compared to common method. Due to CI surgery application requirement, optimization of coating process was selected as follows: extrusion coating method, degree of 3.6 vol%, pinhole diameter of 32G (110 µm), pressure of 200 ±â€¯15.81 Psi. Controlled dexamethasone 21-phosphate sodium salt (DSP) release of 20 days could be demonstrated using the hydrogel filled reservoir via a validated HPLC method. The morphological structure of CHA showed different sizes of porous structure among APL-CHA provided structural basis for drug delivery. L929 fibroblasts culture and Spiral Ganglion Neuron Explants culture results revealed that APL-CHA possesses fine biological compatibility. APL-CHA shows a promising application in CI surgery and has great potential in preventing hearing loss with well simulation of ion homeostasis within the cochlear, local DSP delivery for target anti-inflammatory, approximate conductivity within the scala tympani and optimization of electrode coating process.