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

描述（由申请人提供）：开发一种新型的化学微传感器是一个巨大的需求，这种传感器是通用的，选择性的，敏感的和可靠的，可以用来研究行为和疾病症状的神经生物学机制。目前，在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。我们在此提出了下一代电极材料，掺硼超晶金刚石（BD UNCD），与碳纤维相比，它具有卓越的灵敏度和特异性、快速的响应时间、低背景电流、长期稳定性和抗结垢性。目标是开发一种长期可植入的UNCD微传感器，用于长期（即数月至数年）的神经化学记录，特别是如果人类兼容。该项目的具体目标是：(i)在可扩展和可批量生产的钽（Ta）线衬底上开发可靠的UNCD薄膜沉积工艺；（ii）利用循环伏安法和亚铁氰化钾溶液，证明一种图案化的UNCD- ta微传感器的微电极电化学行为（即更高的信噪比）；（iii）通过流动注射分析和麻醉大鼠大脑中多巴胺的测量，证明UNCD微电极的独特优势。一些计划的改进包括修改Ta表面制备工艺，以增加薄膜的附着力和绝缘体的选择性图案，以产生BD UNCD的“窗口”，从而允许一致的微电极行为。作为概念验证，电极将用于测量多巴胺（研究最广泛的神经递质）至10纳米的生理浓度。提出的传感器可能用于同时测量多巴胺和许多其他重要的神经递质。如果这个项目成功，它将很容易完成许多NIH神经科学和基础行为科学部的任务目标，特别是：1)“体内伏安法”- UNCD具有生物惰性和高度选择性，因为它的表面化学和小的伪电容；2)“生物相容性生物材料”- UNCD/聚对二甲苯钝化是一种新型的、完全生物相容性的慢性神经化学传感材料；3)在“纳米技术”方面——UCND和纳米厚绝缘体的应用大大推进了探针的制造方式；4)“生物传感器”- UNCD可以很容易地通过光化学或电化学手段与抗体和寡核苷酸探针进行修饰。最近的一份报告显示，医疗传感市场在2012年将达到109亿美元。如果UNCD微电极技术仅占该市场的0.1%（1090万美元），这仍然足以证明所提议的工作是合理的。此外，该项目对神经递质的实时传感的更深入了解将使该技术的其他应用成为可能，包括：低成本、使用点、便携式、可植入的毒素、代谢物和疾病生物标志物传感器。

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.