Oscillated Insertion Tool for Minimally Invasive, Low-Damage, Accurate Placement of Delivery Cannula to Improve Efficacy for DREADDS Therapy in Alcohol Addiction Treatment

这一阶段的SBIR开发并测试了一种用于颅内注射病毒结构物(OSII)的振荡注射器 对酒精成瘾的大脑神经回路进行化学遗传学研究。该项目的长期目标是 开发一种外科工具并将其商业化，以便能够可靠和安全地将病毒载体注射到 用于临床前研究的大脑，以及最终临床治疗方法。Actiated Medical，Inc.(AMI) 开发结合电子控制执行器技术的创新运动设备，以改进 患者的结果和先进的医学研究。这项工作是与K.Grant博士和V.Cuzon博士合作进行的 卡尔森在俄勒冈健康与科学大学(OHSU)工作。 公共卫生问题：据估计，酒精成瘾影响了2800万12岁以上的美国人 2020年--尽管有药物和心理社会疗法，但复发率仍高达40%-60%。 化学遗传工具具有巨大的潜力，可以在临床前研究中导致翻译发现，从而可以 阐明酒精、药理学和成瘾的潜在机制。然而，化学遗传学的效用， 例如由设计师药物(DREADD)独占激活的设计师受体，受到病毒效果的限制 构建物可以针对特定的大脑区域，以最大限度地精确控制设计者受体 表情。在最近一项将DREADD受体靶向伏核的临床前研究中， 表达DREADD受体的靶细胞比例为41%-87%。这种糟糕的投递准确率 显著影响随后的行为结果，并阻止了结论性研究假设检验。 解决方案：该项目将OSII商业化，以改善临床前研究中的靶向性和病毒表达， 初步检查酒精成瘾背后的神经回路。阿联酋将利用其振荡的神经 植入物插入技术，使探头和电极能够低力、低摩擦地插入到 大脑。OSII系统的目标是1)减少插入力，2)使使用更小和更灵活 病毒注射注射器，包括可能导致尖端钝化，3)减少组织损伤，4)降低病毒风险 沿注射器插入轨迹移动到其他组织，以及5)允许通过硬脑膜插入。 目的1演示25-36G微量注射导管在模拟脑深部靶点的准确定位 在有无完整硬脑膜的情况下使用振动。验收标准：&gt；插入力相比减少了70% 非振动插入，与目标路径偏差1 mm，插入深度为5厘米，使用25-36G 模型中的聚酰亚胺和金属套管。36G金属插管硬脑膜置入成功率100%。目标2 演示OSII改善了病毒载体向目标外传播和DREADD受体较少的目标的传递 在临床前模型中的表达。接受标准：改善的DREADD受体的平均百分比(&gt；55%) 通过OSII病毒注射，仅在目标组织中表达(与先前的研究相比)。

This Phase I SBIR develops and tests an Oscillated Syringe for Intracranial Injections (OSII) of viral constructs for chemogenetic studies of alcohol addiction neurocircuitry in the brain. The project’s long-term goal is to develop and commercialize a surgical tool to enable reliable and safe injections of viral constructs into the brain for preclinical studies, and eventually clinical therapeutic approaches. Actuated Medical, Inc. (AMI) develops innovative motion devices incorporating electronically-controlled actuator technologies to improve patient outcomes and advance medical research. This work is in collaboration with Drs. K. Grant and V. Cuzon Carlson at the Oregon Health and Science University (OHSU). Public Health Problem: Alcohol addiction is estimated to affect 28 million Americans over the age of 12 in 2020 – and is subject to relapse rates of 40-60% despite available pharmaceutical and psychosocial therapies. Chemogenetic tools have significant potential to lead to translational findings in preclinical research that can illuminate mechanisms underlying alcohol pharmacology and addiction. However, the utility of chemogenetics, such as designer receptors exclusively activated by designer drugs (DREADDs), is limited by how well the viral constructs can be targeted to specific brain regions, to maximize and precisely control designer receptor expression. In a recent preclinical study targeting DREADD receptors to the nucleus accumbens, the percent of targeted cells expressing the DREADD receptor ranged from 41-87%. This poor delivery accuracy significantly impacted subsequent behavioral outcomes and prevented conclusive study hypothesis testing. Solution: This project commercializes the OSII to improve targeting and viral expression in preclinical studies, initially examining the neural circuitry underlying alcohol addiction. AMI will leverage its oscillated neural implant insertion technology which enables low-force, low-friction insertion of probes and electrodes into the brain. The goals for the OSII system are 1) reduce insertion force, 2) enable use of smaller and more flexible viral injection syringes, including the potential for blunted tips, 3) reduce tissue damage, 4) reduce risk of virus migration to other tissues along the syringe insertion track, and 5) allow insertion through the dura. Aim 1 Demonstrate accurate placement of 25-36G micro-injection cannulas in simulated deep brain targets using vibration with and without intact dura. Acceptance Criteria: >70% reduction in insertion force compared to non-vibrated insertion, and <1 mm deviation from target path with 5 cm deep insertions using 25-36G polyimide and metal cannulas in models. 100% insertion success through dura with 36G metal cannula. Aim 2 Demonstrate OSII improves viral vector delivery to targets with less off-target spreading and DREADD receptor expression in preclinical model. Acceptance Criteria: Improved mean percentage (>55%) of DREADD receptor expression restricted to the target tissue with viral injection via OSII (as compared to previous study).