NIH SBIR Phase I: Development of a Novel Boron-doped Ultrananocrystalline Diamond

描述(由申请人提供)：非常需要开发一种新的化学微型传感器，这种传感器具有通用性、选择性、灵敏和可靠，能够研究行为和疾病症状的神经生物学机制。目前，在活体内实时监测神经递质的首选方法是快速扫描循环伏安法(FSCV)，首选微电极材料是碳纤维。我们在这里提出了新一代电极材料--掺硼超非晶金刚石(BD UNCD)，与碳纤维相比，它具有更高的灵敏度和特异度、快速的响应时间、低的本底电流、长期的稳定性和抗结垢能力。其目标是开发一种可长期植入的UNCD微型传感器，用于长期(即数月至数年)神经化学记录，特别是在人类兼容的情况下。该项目的具体目标是：(1)开发一种可靠的可扩展和可批量生产的钽(Ta)丝衬底上的UNCD薄膜沉积工艺；(2)利用循环伏安法和亚铁氰化钾溶液演示图案化UNCD-Ta微传感器的微电极电化学行为(即更高的信噪比)；(3)通过流动注射分析测定多巴胺以及麻醉大鼠脑中的多巴胺含量，展示UNCD微电极的独特优势。计划中的一些改进包括修改Ta表面制备工艺，以提高薄膜附着力，以及对绝缘体进行选择性图案化，以产生应允许一致微电极行为的BD UNCD的“窗口”。作为概念验证，这些电极将被用来测量多巴胺(最广泛研究的神经递质)，低至10 NM的生理浓度。该传感器有可能用于同时测量多巴胺和许多其他重要的神经递质。如果该项目成功，它将很容易实现NIH神经科学和基础行为科学部门的许多任务目标，特别是：1)对于“体内伏安法”--UNCD由于其表面化学和小的伪电容而具有高度的生物惰性和高度选择性；2)对于“生物兼容的生物材料”--UNCD/对苯钝化是新颖的，并且对于慢性神经化学传感是完全生物相容的；3)对于“纳米技术”--UCND和纳米厚绝缘体的应用极大地改进了探针的制造方法；以及4)对于“生物传感器”-UNCD可以通过光化学或电化学手段轻松地用抗体和寡核苷酸探针进行修饰。最近的一份报告显示，医疗传感市场将在2012年达到109亿美元。如果仅有0.1%(1,090万美元)的市场可通过联合国CD-CD微电极技术进入，这仍将是拟议工作的充分理由。此外，更好地了解该项目对神经递质的实时传感将使该技术的替代应用成为可能，包括：用于毒素、代谢物和疾病生物标记物的低成本、可移植、可植入的传感器。 与公共卫生相关：该项目将开发一种使用超纳米晶体钻石电极的微型传感器技术，以进一步推动神经科学领域(大脑功能和疾病症状)的发展。它的多功能性、灵敏度和可靠性非常适合多种神经化学物质的实时、慢性测量和脑活动图谱。

DESCRIPTION (provided by applicant): There is an enormous need for the development of a new class of chemical microsensors that are versatile, selective, sensitive and reliable to allow investigation of the neurobiological mechanisms of behavior and disease symptoms. Currently, the preferred method for monitoring neurotransmitters in vivo real time is fast- scan cyclic voltammetry (FSCV) and the preferred microelectrode material is carbon fiber. We propose here the next generation electrode material, boron-doped ultrananocrystalline diamond (BD UNCD) that offers superior sensitivity and specificity, fast response time, low background currents, long-term stability and resistance to fouling compared to carbon fibers. The goal is to develop a chronically implantable UNCD microsensor for long-term (i.e., months to years) neurochemical recording, especially if human compatible. The specific aims of this project are, (i) to develop a reliable UNCD film deposition process on a tantalum (Ta) wire substrate that is scalable and mass-producible, (ii) to demonstrate microelectrode electrochemical behavior (i.e. higher signal-to-noise ratio) of a patterned UNCD-Ta microsensor using cyclic voltammetry and potassium ferrocyanide solution and (iii) to demonstrate the unique advantages of UNCD microelectrodes by measuring dopamine with flow injection analysis and in the anesthetized rat brain. Some of the planned improvements include modifications to the Ta surface preparation process to increase film adhesion and selective patterning of insulators to produce "windows" of BD UNCD that should allow consistent microelectrode behavior. As a proof-of-concept, the electrodes will be used to measure dopamine (the most widely studied neurotransmitter) down to 10 nM physiological concentration. The proposed sensor could potentially be used for simultaneous measurement of dopamine and many other important neurotransmitters. If this project is successful, it will readily accomplish many NIH mission goals for the Division of Neuroscience and Basic Behavioral Science, specifically: 1) for "in vivo voltammetry" - the UNCD is bioinert and highly selective due to its surface chemistry and small pseudo capacitance; 2) for "biocompatible biomaterials" - UNCD/parylene passivation is novel and completely biocompatible for chronic neurochemical sensing; 3) for "nanotechnologies'" - application of UCND and nanometer thick insulators greatly advance the way in which probes are fabricated; and 4) for "biosensors"- UNCD can be easily modified with antibodies and oligonucleotide probes through photochemical or electrochemical means. A recent report suggests that the medical sensing market will reach $10.9 billion in 2012. If only 0.1% ($10.9 million) of that market is accessible by UNCD microelectrode technology, it would still be sufficient justification for the proposed work. Also, a greater understanding of real-time sensing of neurotransmitters from this project would enable alternative applications for the technology, including: low-cost, point-of-use, portable, implantable sensors for toxins, metabolites and disease biomarkers. PUBLIC HEALTH RELEVANCE: This project will develop a microsensor technology using Ultrananocrystalline diamond electrodes to further advance the neuroscience field (brain function and disease symptoms). Its versatility, sensitivity and reliability are ideally suited for real-time, chronic measurement of multiple neurochemicals and brain activity mapping.