Table1_Surgical procedure of intratympanic injection and inner ear pharmacokinetics simulation in domestic pigs.DOCX

Introduction: One major obstacle in validating drugs for the treatment or prevention of hearing loss is the limited data available on the distribution and concentration of drugs in the human inner ear. Although small animal models offer some insights into inner ear pharmacokinetics, their smaller organ size and different barrier (round window membrane) permeabilities compared to humans can complicate study interpretation. Therefore, developing a reliable large animal model for inner ear drug delivery is crucial. The inner and middle ear anatomy of domestic pigs closely resembles that of humans, making them promising candidates for studying inner ear pharmacokinetics. However, unlike humans, the anatomical orientation and tortuosity of the porcine external ear canal frustrates local drug delivery to the inner ear.
Methods: In this study, we developed a surgical technique to access the tympanic membrane of pigs. To assess hearing pre- and post-surgery, auditory brainstem responses to click and pure tones were measured. Additionally, we performed 3D segmentation of the porcine inner ear images and used this data to simulate the diffusion of dexamethasone within the inner ear through fluid simulation software (FluidSim).
Results: We have successfully delivered dexamethasone and dexamethasone sodium phosphate to the porcine inner ear via the intratympanic injection. The recorded auditory brainstem measurements revealed no adverse effects on hearing thresholds attributable to the surgery. We have also simulated the diffusion rates for dexamethasone and dexamethasone sodium phosphate into the porcine inner ear and confirmed the accuracy of the simulations using in-vivo data.
Discussion: We have developed and characterized a method for conducting pharmacokinetic studies of the inner ear using pigs. This animal model closely mirrors the size of the human cochlea and the thickness of its barriers. The diffusion time and drug concentrations we reported align closely with the limited data available from human studies. Therefore, we have demonstrated the potential of using pigs as a large animal model for studying inner ear pharmacokinetics.

引言：验证用于治疗或预防听力损失的药物时，面临的一大核心阻碍是人类内耳中药物分布与浓度的相关数据极度匮乏。尽管小型动物模型可为内耳药代动力学研究提供部分参考依据，但相较于人类，此类模型的器官体积更小，且圆窗膜等生物屏障的通透性存在显著差异，这会大幅增加研究结果解读的复杂度。因此，开发可靠的大型动物模型用于内耳药物递送研究至关重要。家猪的中耳与内耳解剖结构与人类高度相似，使其成为内耳药代动力学研究的极具潜力的候选对象。然而，与人类不同的是，猪的外耳道解剖走向与弯曲程度会阻碍药物向内耳的局部递送。
方法：本研究开发了一种可稳定暴露猪鼓膜的外科手术技术。为评估手术前后的听力状态，我们检测了听觉脑干诱发电位对短声及纯音的响应。此外，我们对猪内耳影像进行了三维分割，并借助流体模拟软件（FluidSim）模拟了地塞米松在内耳中的扩散过程。
结果：我们通过鼓室内注射成功将地塞米松与地塞米松磷酸钠递送至猪内耳。记录的听觉脑干诱发电位结果显示，手术未对听力阈值产生可归因于手术操作的不良影响。同时，我们模拟了地塞米松与地塞米松磷酸钠在猪内耳中的扩散速率，并通过体内实验数据验证了模拟结果的准确性。
讨论：我们开发并验证了一种利用猪开展内耳药代动力学研究的标准化方法。该动物模型的耳蜗尺寸与屏障厚度均与人类高度匹配。我们测得的扩散时间与药物浓度，与已公开的有限人类研究数据高度吻合。因此，本研究证实了猪作为大型动物模型用于内耳药代动力学研究的应用潜力。