Development of an Oscillated Insertion tool to Eliminate Surgically Induced Neurodegeneration for Optical Neuroimaging of Cognitive Aging and Dementia

开发振荡插入工具以消除手术引起的神经变性，用于认知衰老和痴呆的光学神经成像

• 批准号: 10792064
• 负责人: Kyle William Gheres
• 金额: $ 40.63万
• 依托单位: ACTUATED MEDICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10792064
• 关键词: Academic skills; Acute; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease care; Alzheimer' s disease related dementia; Area; Award; Axon; Blood Vessels; Businesses; Cannulas; Central Nervous System; Certification; Chronic; Cicatrix; Cognitive aging; Computers; Coupled; Dementia; Demyelinations; Development; Device or Instrument Development; Devices; Diameter; Disease; Doctor of Philosophy; Electrodes; Emotional; Encapsulated; Family; Fiber; Fiber Optics; Financial Hardship; Freezing; Geometry; Glial Fibrillary Acidic Protein; Goals; Head; Histologic; Human; Image; Imaging Device; Immersion; Impaired cognition; Implant; Industrialization; Inflammation; Inflammatory; Investigation; Investments; Legal patent; Light; Marketing; Measures; Mechanics; Medical; Medical Device; Medical Research; Mentors; Methodology; Methods; Microscope; Monitor; Morphology; Motion; Motor; Needles; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Noise; Operative Surgical Procedures; Optics; Patient-Focused Outcomes; Patients; Penetration; Perforation; Peripheral; Phase; Photometry; Postdoctoral Fellow; Pre-Clinical Model; Public Health; Puncture procedure; Quality of life; Research; Research Personnel; Resources; Rodent; Rodent Model; Sales; Signal Transduction; Silicon; Small Business Innovation Research Grant; Speed; Surface; System; Technology; Testing; Thinness; Tissue Model; Tissues; Translating; Ultrasonic Transducer; Ultrasonics; United States National Institutes of Health; Vacuum; Work; age related; aspirate; attenuation; brain tissue; care costs; clinical translation; clinically relevant; commercialization; comparison control; density; design; experience; grasp; imaging system; implantable device; implantation; improved; improved outcome; in vivo; innovation; lens; light weight; multiphoton microscopy; neural; neural implant; neuroimaging; neuronal excitability; operation; optical fiber; optical imaging; pre-clinical; preclinical study; pressure; programs; research and development; safety testing; tool; verification and validation

This Phase I SBIR develops a system for gentle and accurate insertion of large optical neuroscience probes (e.g., GRIN lenses) to improve outcomes in aging research. Additionally, the project supports Qingguang Zhang. Ph.D. through the NIA Research and Entrepreneurial Development Immersion (REDI) program at a small business. Entrepreneurial development activities for his project will include project factors such as reaching Design Freeze in an ISO-13485 system, Verification and Validation, Patent Development, FDA- Regulatory interactions and MedTech business operations. Dr. Zhang will interact with AMI mentors that have experience in translating their academic skillsets to commercial and R&D activities at a small company. Public Health Problem: Aging and neurodegenerative disorders are associated with loss of dendritic complexity, demyelination of axons and reduced neuronal excitability. Optical imaging tools such as fiber photometry, and implantable GRIN lenses coupled to head mounted microscopes, can be used to image neuron morphology and activity beyond the depths accessible through multiphoton microscopy. However, tissue damage caused by their surgical implantation methods can result in similar changes in neural activity and morphology as seen in aging and cognitive decline, confounding experimental results. Previous studies of oscillated insertion of needles into the peripheral tissue and electrodes in the central nervous system have reduced insertion force and tissue damage. A tool is needed to reliably reduce tissue damage and strain associated with implantation of large diameter (>100µm) imaging lenses used in optical neuroscience to eliminate the experimental confound and improve studies of age-related changes in neuron morphology and function. Value Proposition: This project develops the Optical Neuroscience Insertion Tool (ONIT) to improve insertion dynamics of GRIN lenses and other optical neuroscience systems. Later work will expand ONIT to insert large devices, like DBS probes, with less tissue damage, for treatment of neurodegenerative diseases in humans. Aim 1- Optimize, build, and test lightweight ONIT system. (AMI: Months 1-9). Acceptance Criteria: Construction of a computer controlled ultrasonic actuator capable of 1) grasping and releasing fiber optic cannula and GRIN lenses with vacuum pressure, 2) Advancing the implant at speeds less than 100µm/sec, 3) reducing the puncture force of fiber optic cannula (200µm diameter) >60% in an ex vivo rodent brain tissue model, and 4) monitoring force applied to actuator during insertion. Aim 2 - Demonstrate improved signal to noise of in vivo measures of neural activity and histological markers of neuron complexity for six weeks following oscillated insertion of large diameter GRIN lenses in a rodent model. (Months 9-12; AMI/ PSU). Acceptance Criteria: Ability to insert large diameter GRIN lenses without the need for tissue aspiration, reduced attenuation (>50%) of baseline and evoked GCaMP7f signal intensity 6wks following implant. Reduced histological indicators of neurodegeneration (>50% greater neuron complexity using Sholl analysis) and scar formation (<50% compared to control GFAP+ area) within 500µm of GRIN lenses implanted with oscillated insertion. Commercialization & Marketing: Early sales via third party distributors will be reinvested to continue development towards a clinically relevant system to insert similarly large DBS electrodes, a market expected to reach $4.3B by 2030.

第一阶段 SBIR 开发了一种用于轻柔、准确地插入大型光学神经科学探针的系统 （例如 GRIN 镜片）以改善衰老研究的成果此外，该项目还支持青光。 张，通过 NIA 研究和创业发展浸入式 (REDI) 项目获得博士学位 他的项目的创业发展活动将包括以下项目因素： 在 ISO-13485 系统中达到设计冻结、验证和确认、专利开发、FDA- 张博士将与具有丰富经验的 AMI 导师进行互动。 在小公司将学术技能转化为商业和研发活动的经验。 公共卫生问题：衰老和神经退行性疾病与树突的丧失有关 复杂性、轴突脱髓鞘和神经兴奋性降低等光学成像工具（例如纤维）。 光度测定和与头戴式显微镜耦合的植入式 GRIN 透镜可用于成像 神经元的形态和活动超出了多光子显微镜所能达到的深度。 手术植入方法造成的组织损伤可能会导致神经活动发生类似的变化 衰老和认知能力下降中所见的形态学，混淆了先前的实验结果。 将针振荡插入周围组织和中枢神经系统中的电极 减少插入力和组织损伤。 需要一种工具来可靠地减少与大直径植入相关的组织损伤和应变 (>100μm) 成像镜头用于光学神经科学，消除实验混乱并改善 研究神经元形态和功能与年龄相关的变化。 价值主张：该项目开发光学神经科学插入工具（ONIT）以改善插入 GRIN 透镜和其他光学神经科学系统的动力学后续工作将扩展 ONIT 以插入大型图像。 用于治疗人类神经退行性疾病的设备，如 DBS 探针，组织损伤较小。 目标 1 - 优化、构建和测试轻量级 ONIT 系统（AMI：第 1-9 个月）。 验收标准：构建计算机控制的超声波执行器，能够 1) 抓取和 利用真空压力释放光纤插管和 GRIN 透镜，2) 以更低的速度推进植入物 低于 100μm/秒，3) 在体外降低光纤插管（200μm 直径）的穿刺力 >60% 啮齿动物脑组织模型，4) 监测插入过程中施加到执行器的力。 目标 2 - 展示神经活动和组织学体内测量的信噪比得到改善 大直径 GRIN 振荡插入后六周的神经元复杂性标记 啮齿动物模型中的镜片（9-12 个月；AMI/PSU）。 验收标准：能够插入大直径 GRIN 透镜，无需组织抽吸， 植入后 6 周，基线衰减减少（>50%）并诱发 GCaMP7f 信号强度。 神经退行性变的组织学指标减少（使用 Sholl 分析，神经元复杂性增加 >50%） 植入 GRIN 镜片 500 µm 范围内的疤痕形成（与对照 GFAP+ 区域相比 <50%） 振荡插入。 商业化和营销：通过第三方分销商的早期销售将被再投资以继续 开发临床相关系统以插入类似的大型 DBS 电极，该市场预计将 到 2030 年将达到 $4.3B。