Instrument for Intracerebral Microinjections and Electrophysiology

描述（由申请人提供）：最具破坏性的疾病之一是中枢神经系统（CNS）的疾病。严重致残和慢性，对个人、家庭和社会造成情感、身体和经济上的严重破坏。根据家庭照顾者联盟（www.caregiver.org） 2000年的报告，仅在美国就诊断出110万例最常见的10种脑部疾病的新病例。目前有1 600多万患者正在接受这些疾病的治疗，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是“恢复性神经外科手术”。传统上，神经外科干预包括切除病理组织。然而，在恢复性神经外科手术中，使用微创立体定向手术将治疗药物或组织引入中枢神经系统的不同区域。恢复性治疗包括营养因子、基因治疗载体、化学疗法、治疗细胞（神经移植）或其他神经活性化合物。恢复性治疗的最佳效益将取决于神经外科医生的能力，以精确的准确度和对功能正常组织的最小损伤来提供这些药物。立体定向手术允许对大脑深处的结构进行手术，减少但不可忽略的是，对目标结构上方和周围组织的损伤。例如，立体定向注射治疗细胞有望成为一种重建细胞群、补充局部产生的脑化学物质水平和重建神经回路的方法。最初的SBIR拨款申请的一个重点是解决用于神经移植的方法和仪器的缺点。尽管取得了一些成功，但迄今为止，脑细胞注射后的功能恢复一直是适度的，而且变化很大。患者的边际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推进这种潜在的强大治疗方法的实用性。动物研究表明，当用于向大脑输送细胞的注射仪器变小，注射量减少时，移植细胞的存活率会增加。通过最终直径约为70微米的拉式玻璃微移液管输送的“微体积”细胞（0.25 - 2.5 l）的存活率比通过直径0.5 mm的插管注射的大体积细胞（5-20 5L）的存活率高250%或更高。人体手术常用的注射器直径为0.5-1 mm，移植物体积一般为10- 205l。SBIR的资金支持了脑内显微注射仪器（IMI）的开发，该仪器允许通过“引导”套管单次穿透覆盖组织，将精确的微体积治疗剂立体定向地放置在人脑内的三维阵列中。IMI输送管非常小，直径在20到200微米之间。它能够在治疗之前，期间和之后进行电生理记录，允许精确的靶向。除了神经移植，IMI特别适合于直接输送各种药物，包括那些用于化疗的药物。事实上，神经外科治疗多形性胶质母细胞瘤，一种恶性和致命的癌，可能是IMI的主要指征。该提案是为了改进该仪器，准备将其用于人类中枢神经系统疾病的神经外科方法，并为该技术的FDA市场许可获得资金。公共卫生相关性：脑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插入大脑，以绕过血脑屏障，并在大脑的精确解剖部位达到浓度。本文提出的脑内显微注射仪提高了进行此类注射的能力，同时对大脑的损伤最小，并且最小程度地激活大脑对外来物质的排斥机制。

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.