Precise Lesion of the Vestibular Organs Using Photodynamic Therapy for Vertigo Treatment

People feel vertigo and dizziness when the vestibular system is dysfunctional. Conventional treatments for persistent, severe vestibular vertigo include surgery (semicircular canal occlusion and vestibular neurectomy) and administration of ototoxic drugs (intratympanic injection of aminoglycoside gentamicin), both of which alleviate (or suppress) vertigo by vestibular lesion.

However, surgery is challenged due to its side effects on the cochlear components, and the ototoxic drug is criticized because of its non-specified injury on adjacent cochlea, which would lead to hearing loss. Thus, it is important to establish a novel approach that could precisely target the vestibular organs with minimal damage on hearing.

To this end, we utilized the mechanism of photodynamic therapy (PDT) to realize precise injury on the vestibular apparatus, because of its excellent spatial and temporal specificity and minimal invasion to the non-targeted tissues. Here, we designed biodegradable nanoparticles loading with photosensitizer Chlorin e6 as the “drug” that could be excited by 650 nm light for reactive oxygen species generation to damage biological tissues. The lesion was achieved in vitro on HEI-OC1 cells and cochlear explants, and in vivo on mouse vestibular organs without impeding hearing. Furthermore, within the vestibular organ, the lesion can be restricted in the semicircular canal by adjusting the PDT dosage, which is the common treatment location of benign paroxysmal positional vertigo (BPPV) in clinic. The functional effect of PDT in vivo was evaluated by two tests: vestibular-ocular-reflex test for the function of the semicircular canal and off-vertical-axis-rotation test for the function of the utricle. After the PDT damage,the eye movements of the mice significantly decreased in the vestibular functional tests. The results demonstrated the feasibility of PDT to injure single vestibular organ with controllable damage level and location precision. The PDT approach on mouse vestibular apparatus in this study provides technical foundation for potential clinical treatment of vertigo with PDT.

当前庭系统功能失调时人们会感到头晕目眩。治疗严重的持续性前庭眩晕的传统方法包括手术(半规管阻塞术和前庭神经切除术)和耳毒性药物的使用(鼓室内注射氨基糖苷类药物如庆大霉素)，两者都可以缓解(或抑制)前庭异常引起的眩晕。然而，外科手术由于其对耳蜗产生的的手术副作用而备受争议，耳毒性药物的使用则会导致邻近耳蜗毛细胞的非特异性损伤进而导致听力下降。因此，建立一种可以精确损伤前庭器官而几乎不会损伤听力的方法是十分重要的。

为此，我们利用光动力疗法(PDT)的机制来实现精确前庭器官损伤，这是由于其具有良好的时空特异性，以及对非目标组织的极小损害。我们设计了可生物降解的纳米颗粒--装载光敏剂Chlorin e6作为光动力的“药物”，在650 nm光激发下产生活性氧物质进而损伤生物组织。这种损伤成功地实现在HEI-OC1细胞和耳蜗外植体上，以及成功地在小鼠活体前庭器官上产生了损伤，并验证没有损伤其听力。此外，在前庭系统内，通过调整PDT造成的损伤程度，可将这种损伤缩小并局限在半规管，而半规管则是临床治疗良性阵发性眩晕(BPPV)的常见部位。体内的PDT前庭损伤作用是通过两项测试来进行评估:前庭-眼反射测试评估半规管功能，非垂直轴旋转测试评估椭圆囊的功能。在前庭功能测试中，当PDT损伤后小鼠眼球运动明显下降。此外，结果表明了PDT对单个前庭器官的损伤程度和定位是具有可控性的。本课题研究了PDT应用于小鼠前庭器官的功能抑制的操作路径，为临床应用PDT治疗眩晕提供了技术基础。

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