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（由申请人提供）：耳蜗是现代社会临床病理学的常见部位。每年有成千上万的美国人受到内耳疾病的影响，如梅尼埃，突发性感觉神经性听力损失（SSNHL）和耳鸣。如果不及时正确治疗，这些疾病可能会对听力或平衡产生慢性影响，并显着降低他们的生活质量。不幸的是，耳蜗被身体中最硬的骨头之一包围，并且在解剖学上很难达到。一些目前可用的治疗这些疾病的方法是有限的，因为它们依赖于药物通过血流或通过从中耳的简单扩散到达内耳，而其他方法则需要在耳蜗骨中制造破坏性的孔并破坏鼓阶。因此，迄今为止，不存在提供有效的、精确剂量的内耳治疗剂递送而不存在对人的听力造成永久性损伤的风险的方法。为了绕过这一屏障，研究人员的目标是通过耳朵的自然圆窗膜（RWM）创建微穿孔，以进入内耳液体进行药物输送。首先将探索中耳和内耳之间边界的机械特性，以加深对RWM的科学理解。纳米压痕、激光干涉测量、数字显微镜、微型CT（µCT）和高保真有限元建模等技术将用于完整了解整个穿孔过程中局部和全局压力下的RWM特性。基于这些研究的结果，将使用各向同性蚀刻和低温工艺设计实心和空心硅微针的各种阵列。将首先测试这些缝针的屈曲或弯曲倾向，并优化缝针设计以确保RWM穿孔期间的安全性。随后将使用豚鼠作为适当的动物模型进行一系列体外然后体内研究。这些研究将评估通过植入空心针的临时固体微穿孔或微注射系统可靠地增加RWM渗透性的能力。还将评估这些针对RWM组织学的影响、RWM穿孔后愈合的能力以及针对豚鼠听力的影响。最后，将分析穿孔持续提供精确颅内药物浓度的能力。我们的动物研究之后将进行相同的体外研究，新鲜的人颞骨样本，最终目标是创造一种手动机械装置，在临床试验中提供微穿孔。一旦针对人类RWM的特定特性进行优化，这种装置就可以在临床上安全、快速、有效地穿孔到内耳中。通过使用空心针，该设备可以在必要时对内耳外淋巴液进行采样并注射介质，从而开辟了内耳诊断的新领域，同时为以前经常发生的特发性内耳病变提供了精确，个性化的治疗手段。