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

第一阶段SBIR开发了一种系统，用于轻柔而准确地插入大型光学神经科学探头 (e.g., GRIN镜片），以改善衰老研究的结果。此外，该项目还支持青光 张某博士通过NIA研究和创业发展沉浸（REDI）计划， 小生意。他的项目的创业发展活动将包括项目因素，如 在ISO-13485系统中达到设计冻结，验证和确认，专利开发，FDA- 监管互动和医疗技术业务运营。张博士将与AMI导师互动， 在一家小公司将他们的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状细胞的丢失有关 复杂性、轴突脱髓鞘和神经元兴奋性降低。光纤等光学成像工具 光度法和耦合到头戴式显微镜的可植入GRIN透镜可以用于成像 神经元的形态和活动超出了通过多光子显微镜可到达的深度。然而，在这方面， 由它们的外科植入方法引起的组织损伤可导致神经活动的类似变化 以及在衰老和认知衰退中所见的形态学，混淆了实验结果。以往的研究 将针振荡插入外周组织和将电极插入中枢神经系统 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物相关的组织损伤和应变。 （>100µm）成像透镜，用于光学神经科学，以消除实验混淆并提高 研究神经元形态和功能的年龄相关变化。 价值主张：该项目开发了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。以后的工作将扩大ONIT， DBS探头等设备，组织损伤较小，用于治疗人类神经退行性疾病。 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：能够1）抓取和 用真空压力释放光纤套管和GRIN透镜，2）以小于 小于100µm/sec，3）在离体条件下，光纤套管（直径200µm）的穿刺力降低>60% 啮齿动物脑组织模型，以及4）监测在插入期间施加到致动器的力。 目的2 -证明神经活动和组织学的体内测量的改善的信噪比 在振荡插入大直径GRIN后六周的神经元复杂性标志物 在啮齿类动物模型中的晶状体。（第9-12个月; AMI/ PSU）。 验收标准：无需组织抽吸即可插入大直径GRIN晶状体的能力， 植入后6周，基线衰减和诱发GCaMP 7 f信号强度降低（>50%）。 减少神经变性的组织学指标（使用Sholl分析，神经元复杂性增加>50%） 和植入的GRIN晶状体500µm内的瘢痕形成（与对照GFAP+面积相比<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重新投资以继续 开发临床相关系统以插入类似的大DBS电极，市场预期 到2030年达到43亿美元。

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.