Complete Restoration of Hearing Loss and Cochlear Synaptopathy via Minimally Invasive, Single-Dose, and Controllable Middle Ear Delivery of Brain-Derived Neurotrophic Factor–Poly(dl-lactic acid-co-glycolic acid)-Loaded Hydrogel

噪声性听力损失 耳蜗 神经营养因子 中耳 听力损失 听力学 医学 解剖 噪声暴露 内科学 受体
作者
Qianru Yu,Shengnan Liu,Rui Guo,Kuntao Chen,Jing Wang,Dan Jiang,Shusheng Gong,Lan Yin,Ke Liu
出处
期刊:ACS Nano [American Chemical Society]
卷期号:18 (8): 6298-6313 被引量:1
标识
DOI:10.1021/acsnano.3c11049
摘要

Noise-induced hearing loss (NIHL) often accompanies cochlear synaptopathy, which can be potentially reversed to restore hearing. However, there has been little success in achieving complete recovery of sensorineural deafness using nearly noninvasive middle ear drug delivery before. Here, we present a study demonstrating the efficacy of a middle ear delivery system employing brain-derived neurotrophic factor (BDNF)–poly-(dl-lactic acid-co-glycolic acid) (PLGA)-loaded hydrogel in reversing synaptopathy and restoring hearing function in a mouse model with NIHL. The mouse model achieved using the single noise exposure (NE, 115 dBL, 4 h) exhibited an average 20 dBL elevation of hearing thresholds with intact cochlear hair cells but a loss of ribbon synapses as the primary cause of hearing impairment. We developed a BDNF-PLGA-loaded thermosensitive hydrogel, which was administered via a single controllable injection into the tympanic cavity of noise-exposed mice, allowing its presence in the middle ear for a duration of 2 weeks. This intervention resulted in complete restoration of NIHL at frequencies of click, 4, 8, 16, and 32 kHz. Moreover, the cochlear ribbon synapses exhibited significant recovery, whereas other cochlear components (hair cells and auditory nerves) remained unchanged. Additionally, the cochlea of NE treated mice revealed activation of tropomyosin receptor kinase B (TRKB) signaling upon exposure to BDNF. These findings demonstrate a controllable and minimally invasive therapeutic approach that utilizes a BDNF-PLGA-loaded hydrogel to restore NIHL by specifically repairing cochlear synaptopathy. This tailored middle ear delivery system holds great promise for achieving ideal clinical outcomes in the treatment of NIHL and cochlear synaptopathy.
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