Intracochlear Delivery of Therapeutics Across RWM via Microneedle Array

通过微针阵列在 RWM 内进行治疗药物的耳蜗内输送

• 批准号: 9122335
• 负责人: Jeffrey W. Kysar
• 金额: $ 42.33万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-10 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122335
• 关键词: Affect; American; Anatomy; Animal Model; Animals; Aspirate substance; Auditory; Bacteria; Biomechanics; Biomedical Engineering; Blood Circulation; Cavia; Cell Membrane Permeability; Chronic; Clinic; Clinical Pathology; Clinical Trials; Cochlea; Development; Devices; Diagnosis; Diagnostic; Diffusion; Disease; Dose; Drug Delivery Systems; Ear; Effectiveness; Elements; Equilibrium; Experimental Designs; Gentamicins; Goals; Healed; Health; Hearing; Histology; Human; Implant; In Vitro; Injection of therapeutic agent; Interferometry; Intervention; Labyrinth; Lasers; Liquid substance; Manuals; Measures; Mechanics; Mediation; Membrane; Meniere' s Disease; Methods; Microinjections; Microscopy; Modeling; Molecular; Nature; Needles; Operative Surgical Procedures; Pathology; Patients; Perforation; Perilymph; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Prevention; Process; Property; Quality of life; Research; Research Personnel; Risk; Safety; Sampling; Scala Tympani; Sensorineural Hearing Loss; Series; Silicon; Site; Societies; Solid; Steroids; Structure; System; Techniques; Technology; Temporal bone structure; Testing; Therapeutic; Therapeutic Agents; Time; Tinnitus; Work; X-Ray Computed Tomography; base; biomaterial compatibility; bone; clinical application; cryogenics; design; digital; dosage; efficacy testing; healing; improved; in vivo; inner ear diseases; lithography; microCT; middle ear; multidisciplinary; nanoindentation; novel; personalized medicine; pressure; prevent; round window; therapy duration; tool

 DESCRIPTION (provided by applicant): The cochlea is a common site for clinical pathology in our modern society. Tens of thousands of Americans are affected every year by inner ear diseases such as Ménière's, sudden sensorineural hearing loss (SSNHL), and tinnitus. If not treated properly and in a timely manner, these illnesses can have a debilitating, chronic effect on one's hearing or balance, and significantly decrease their quality of life. Unfortunately the cochlea is surrounded by one of the hardest bones in the body, and is quite difficult to reach anatomically. Some currently available treatments for these diseases are limited by their reliance on the medications to reach the inner ear via the bloodstream or through simple diffusion from the middle ear, while others necessitate making destructive holes in the cochlear bone and breaching the scala tympani. Thus, to date no method exists to provide effective, precisely dosed delivery of inner ear therapeutics without risking permanent damage to one's hearing. To circumvent this barrier, the researchers aim to create micro- perforations through the ear's natural round window membrane (RWM) to access the inner ear fluid for drug delivery. The mechanical properties of this border between the middle and inner ears will first be explored to deepen the scientific understanding of the RWM. Techniques such as nanoindentation, laser interferometry, digital microscopy, micro CT (µCT), and high fidelity finit element modeling will be utilized for a complete picture of the RWM properties under both local and global pressures throughout the process of perforation. Based on the results of these studies, various arrays of both solid and hollow silicon microneedles will be designed using isotropic etching and cryogenic processes. These needles will first be tested for their propensity to buckle or bend, and needle design will be optimized for safety during RWM perforation. A series of in vitro then in vivo studies will follow, using guinea pigs as an appropriate animal model. These studies will assess the ability of temporary solid microperforations or microinjection systems through implanted hollow needles to reliably increase the permeability of the RWM. The effect of these needles on RWM histology, the ability of the RWM to heal post-perforation, and the impact of the needles on guinea pig hearing will also be assessed. Finally, the perforations will be analyzed for their ability to consistently provide precise intracochlear drug concentrations. Our animal studies will be followed by the same studies in in vitro, fresh human temporal bone samples, with the ultimate goal of creating a manual mechanical device to deliver microperforations in clinical trials. Once optimized for the specific properties of the human RWM, such a device could allow for safe, quick, effective perforations into the inner ear in the clinic. With the use of hollow needles, this device could both sample inner ear perilymph and inject mediations when necessary, opening up a new realm of inner-ear diagnostics while then providing a means of precise, personalized treatment of often previously idiopathic inner ear pathologies.

 描述（由适用提供）：耳蜗是我们现代社会中临床病理的常见地点。每年有成千上万的美国人受到内耳疾病的影响，例如梅尼尔（Ménière），突然的感觉听力损失（SSNHL）和耳鸣。如果不及时治疗，这些疾病可能会对自己的听力或平衡产生衰弱，慢性影响，并大大降低其生活质量。不幸的是，耳蜗被体内最坚硬的骨头之一包围，在解剖学上很难到达。这些疾病的一些目前可用的治疗方法受其疾病的限制，以通过血液或从中耳的简单扩散到达内耳，而另一些则必须在耳蜗骨骼中产生破坏性的孔，并违反Scala Tympani。迄今为止，尚无方法可以提供有效的，精确地给予内耳疗法的剂量，而不会冒着对听力的永久损害的风险。为了避开这一障碍，研究人员旨在通过耳朵的自然圆形膜膜（RWM）创建微型穿孔，以获取内耳流体以进行药物输送。首先将探索中间和内耳之间这种边界的机械性能，以加深对RWM的科学理解。在整个穿孔过程中，将利用纳米辅导，激光干扰，数字显微镜，微CT（µCT）和高富达有限元建模的技术。根据这些研究的结果，将使用各向同性蚀刻和低温过程设计固体和空心硅微针的各种阵列。这些针头将首先测试，以确保其弯曲或弯曲的承诺，并将针对RWM穿孔期间的安全性进行优化。然后，将使用豚鼠作为适当的动物模型进行一系列体外研究。这些研究将通过植入的空心针头评估临时固体微填料或微注射系统的能力，以可靠地提高RWM的渗透性。这些针对RWM组织学的影响，RWM治愈后续后期的能力以及针头对豚鼠听力的影响。最后，我们的动物研究将在体外进行相同的研究，并在临床试验中创建手动机械装置以提供微填料的最终目标。一旦对人RWM的特定特性进行了优化，这种设备就可以使诊所内耳的安全，快速，有效的穿孔。通过使用空心针，该装置可以在必要时采样内耳的围绕膜和注射介质，开辟了一个新的内耳诊断领域，然后提供一种精确的，个性化治疗的手段，对经常以前的特发性内耳病理。