Instrument for Intracerebral Microinjections and Electrophysiology

描述(申请人提供)：最具破坏性的疾病之一是中枢神经系统(CNS)的疾病。他们给个人、他们的家庭和社会造成严重的残疾和慢性疾病，在情感、身体和经济上造成严重破坏。在家庭照顾者联盟(www.care giver.org)2000年的报告中，仅在美国就有110万例最常见的10种脑部疾病的新病例被诊断出来。1600多万患者正在接受这些疾病的持续护理，其中许多人仍可能受益于更有效的治疗方式。最有希望的干预措施之一是“恢复性神经外科”。传统上，神经外科手术包括切除病变组织。然而，在恢复性神经外科手术中，治疗剂或组织是使用微创立体定向手术程序在中枢神经系统的不同区域内引入的。恢复性疗法包括营养因子、基因治疗载体、化学疗法、治疗性细胞(神经移植)或其他神经活性化合物。优化恢复性治疗的益处将取决于神经外科医生以精致的准确性提供这些药物的能力，并将对功能正常组织的损害降至最低。立体定向手术允许对大脑深处的结构进行手术，减少但不能忽略对目标结构上方和周围组织的损害。例如，立体定向注射治疗性细胞有望成为重建细胞群体、补充局部产生的大脑化学物质水平和重建神经电路的一种方法。最初的SBIR赠款申请的一个重点是解决用于神经移植的方法和仪器方面的缺陷。尽管取得了一些成功，但到目前为止，脑细胞注射后的功能恢复是温和的，而且变数很大。患者的边缘恢复与植入细胞的低存活率直接相关；增加神经细胞植入的成功率将大大促进这一潜在强大的治疗方法的应用。动物研究表明，当用于将细胞输送到脑内的注射器较小、注射量减少时，移植细胞的存活率会提高。通过最终直径约为70微米的拉式玻璃微吸管输送的“微体积”细胞(0.25~25L)的存活率比通过0.5 mm直径的套管注射的大体积细胞(5-20.5L)高250%或更高。人体外科常用的注射器直径为0.5-1 mm，移植物体积通常为10-205L。SBIR的资助使一种脑内微量注射仪(IMI)的开发成为可能，这种仪器允许将精确的微量治疗剂立体地放置在人脑内的三维阵列中，方法是通过一根“引导”插管对覆盖的组织进行一次穿透。IMI的输液套管非常小，直径从20微米到200微米不等。它能够在提供治疗药物之前、期间和之后进行电生理记录，从而实现精致的靶向精度。除了神经移植，IMI特别适合直接输送各种药物，包括那些用于化疗的药物。事实上，多形性胶质母细胞瘤的神经外科治疗可能是IMI的主要适应症。这项提议是为了改进这一仪器，使其为用于人类中枢神经系统疾病的神经外科方法做好准备，并为FDA对该技术的市场批准获得资金。公共卫生相关性：脑部疾病神经外科治疗的一个新兴领域涉及将化疗药物、细胞、抗氧化剂或其他治疗剂直接注入大脑，以绕过血/脑屏障，并在大脑的精确解剖位置实现集中。本文提出的脑内微量注射仪提高了进行这种注射的能力，对大脑的损害最小，对异物的大脑排斥机制的激活也最小。

DESCRIPTION (provided by applicant): Among the most devastating diseases are those of the central nervous system (CNS). Profoundly disabling and chronic, they wreak emotional, physical, and economic havoc upon individuals, their families, and society. In the 2000 report by the Family Caregiver Alliance (www.caregiver.org), 1.1 million new cases of the 10 most common brain diseases were diagnosed in the U.S. alone. More than 16 million patients receive ongoing care for these diseases, many of whom might still benefit from more effective therapeutic modalities. Among the most promising interventions is "restorative neurosurgery." Traditionally, neurosurgical intervention has involved removal of pathological tissues. In restorative neurosurgery, however, therapeutic agents or tissues are introduced within distinct regions of the CNS using a minimally-invasive stereotactic surgical procedure. Restorative therapeutics include trophic factors, gene therapy vectors, chemo-therapeutics, therapeutic cells (neural transplantation), or other neuroactive compounds. Optimizing the benefits of restorative therapeutics will depend on a neurosurgeon's ability to deliver these medicines with exquisite accuracy and minimal damage to functionally normal tissue. Stereotactic surgery allows procedures to be performed on structures deep within the brain with reduced, but not negligible, damage to tissue above and surrounding the target structure. Stereotactic injection of therapeutic cells, for example, holds promise as a method for reconstituting cell populations, supplementing levels of locally produced brain chemicals, and re-establishing neural circuitry. One focus of the original SBIR grant application was to address the shortcomings in the methodology and instrumentation used for neural transplantation. Despite some successes, functional recovery following brain cell injections has been modest and highly variable to date. Marginal patient recovery has been directly associated with the implanted cells' poor survival rate; increasing the success of neural cell engraftment would substantially advance the utility of this potentially powerful therapeutic approach. Animal studies have demonstrated that transplanted cell survival rates increase when the injection instrument used to deliver cells into the brain is smaller and the injection volume reduced. "Microvolumes" of cells (0.25 2 5L) delivered through a pulled glass micropipette with a final diameter of approximately 70 microns have a survival rate 250% or greater higher than larger cell volumes (5-20 5L) injected through a 0.5 mm-diameter cannula. Commonly used injectors for human surgery are 0.5-1 mm in diameter, and graft volume is typically 10-20 5L. SBIR funding has enabled the development of an Intracerebral Microinjection Instrument (IMI) that permits precise micro-volumes of therapeutic agent to be stereotacticly placed in a three-dimensional array within the human brain using a single penetration of overlying tissue by a "guide" cannula. The IMI delivery cannula is extremely small, ranging from 20 to 200 micrometers in diameter. It is capable of electrophysiological recording before, during, and after delivery of the therapeutic, permitting exquisite targeting precision. In addition to neural transplantation, the IMI is particularly well-suited for direct delivery of a variety of agents, including those used for chemotherapy. Indeed, neurosurgical treatment for glioblastoma multiforme, an aggressively malignant and deadly carcinoma, may be a primary indication for the IMI. This proposal is for improvements to this instrument, preparing it for use in neurosurgical approaches for human diseases of the CNS, and to obtain funding for the FDA market clearance of the technology. PUBLIC HEALTH RELEVANCE: An emerging area of neurosurgical treatment of brain disease involves inserting chemotherapeutics, cells, antioxidants, or other therapeutic agents directly into brain in order to bypass the blood/brain barrier, and in order to achieve concentration at a precise anatomical site in brain. The Intracerebral Microinjection Instrument proposed herein improves the ability to make such injections with minimal damage to the brain, and with minimal activation of the brains rejection mechanisms for foreign material.