Smart Medical Instrumentation On Chips For Early Detection and Treatment of Brain Molecular Disorder

医学、药物发现和新疗法的重大进步可以极大地提高世界人口的生活质量。另一方面，新的疾病正在浮出水面，影响着65岁以上的人口。这些健康问题大多与神经退行性疾病有关，这些疾病主要与大脑中的神经递质(NT)浓度紊乱有关。阿尔茨海默氏症是一种神经退行性疾病，影响世界上最大比例的老年人口。蒙特利尔阿尔茨海默氏症协会估计，2025年全球患有这种疾病的患者将达到3400万人，到2031年，加拿大的患者总数将达到75万人。到目前为止，阿尔茨海默氏症还没有治疗方法，但有几种替代方法可以减少其影响和影响。我们的发现提案将通过控制大脑局部区域的神经递质(NTS)浓度，为患有这种疾病的患者带来希望，以便使用微型和可植入的微系统来阻止阿尔茨海默氏症引起的疾病。事实上，NT是大脑中最重要的信息载体之一。几乎所有的人类行为和身体功能都受到NTS的监测，由这些分子引起的任何疾病都会影响我们的生活质量和健康状况。 我们最近发表的结果表明，脑脊液(CSF)的电学性质受到NTS浓度的影响。我们已经确定了脑脊液阻抗、电导率和NTS浓度之间的关系。最后，我们用谷氨酸NT和γ-氨基丁酸(GABA)NT证明了脑脊液的阻抗和电导率受NTS浓度变化的影响。例如，根据我们之前的研究，阿尔茨海默病与乙酰胆碱NT的大量减少有关，乙酰胆碱NT会影响脑脊液的特性。此外，由于NTS的浓度可以在亚纳米升的范围内，我们需要一个精度为0.001 S/米和10欧姆的极高灵敏度的装置来分别测量脑脊液的电导率和电阻率。这项工作的一个创新贡献是为分析大脑神经元活动建立了一个新的视角，其中假设可以根据NTS(乙酰胆碱、多巴胺和GABA)的浓度、阻抗和/或电导率来区分它们。如果成功，这可能为目前治疗阿尔茨海默氏症等神经退行性疾病的患者提供一种重要的替代方案。 我们正在提出新一代大脑植入性设备，这种设备可以感知大脑的化学和分子活动，还可以实现神经递质的局部传递，以阻止大脑功能紊乱。 为了实现这一目标，我们提出了一种片上医疗仪器(MIOC)来检测和调节有限区域内的NT浓度。这一发现涵盖了Mioc设计的以下方面： 1-开发新的制造工艺来设计用于NTS传感和操纵的微电极以及基于碳纳米管的NTS生物传感技术。 2-检测NT浓度变化的高灵敏度微电子电路的设计与实现 3-开发一种新的通道内和气泡液体采样技术，以采样几纳米升的NT。这种技术不需要任何专门的微细加工工艺，必将为替代传统的微泵开辟新的途径。 建议的MIOC也可以推广到血液化学和分子疾病，如胆固醇、镰状细胞性贫血等，因为传感和液体操作体系结构相同，而生物界面从一个应用到另一个不同。

Major advances in medicine, drug discovery and new treatments can considerably improve the quality of life of the world population. On the other hand, new diseases are surfacing and affecting the 65 years and plus population. Most of these health problems are associated with neurodegenerative diseases, which are mainly related to a neurotransmitter (NT) concentration disorder in the brain. Alzheimer’s is one of neurodegenerative diseases that affect the largest portion of the world’s elderly population. The Alzheimer’s society of Montreal estimates that the number of patient suffering from this disease will be 34 million worldwide in 2025 and will reach a total of 750 000 patients in Canada in 2031. Up to now, there is no treatment for Alzheimer’s disease, but there are several alternatives to reduce its impact and effects. Our discovery proposal will offer hope for patients suffering from this disease by controlling the neurotransmitters (NTs) concentration in a local area of the brain in order to stop the disorder caused by Alzheimer’s using miniaturized and implantable microsystems. Indeed, NTs are among the most important information vehicles in the brain. Almost all human behavior and body functions are monitored by NTs and any disorder due to these molecules will affect our quality of life and health conditions. Our recently published results show that the electrical properties of cerebrospinal fluid (CSF) are affected by the NTs concentration. We have identified a relation between CSF impedance, conductivity and NTs concentration. Finally, we have proven with glutamate NT and gamma amino butyric acid (GABA) NT that the CSF impedance and conductivity are affected by the change of NTs concentration. As an example, Alzheimer’s disease is related to a considerable decrease of acetylcholine NT which affects CSF properties based on our previous research. Furthermore, as the concentration of NTs can be in the range of sub-nano liters, we need an extremely highly sensitive device with an accuracy of 0.001 S/m and 10 ohm to measure the conductivity and resistivity of the CSF, respectively. An innovative contribution of this work is the establishment of a new perspective for the analysis of brain neuronal activities where one assumes that NTs (acetylcholine, dopamine and GABA) can be differentiated based on their concentration, impedance and/or conductivity. If successful, this could provide an important alternative to the current treatment of patients with neurodegenerative diseases such as Alzheimer’s. We are proposing a new generation of brain implantable devices that are sensing the chemical and molecular brain activity and can also achieve neurotransmitter local delivery in order to stop brain disorder. In order to achieve this objective, we propose a medical instrumentation on-chip (MIOC) to sense and modulate NT concentration in limited area. This discovery covers the following aspects of MIOC design: 1- Development of a new fabrication process to design microelectrode for NTs sensing and manipulation and biosensing techniques for NTs based on carbon nanotubes. 2- Design and Implementation of highly sensitive microelectronics circuit to detect NT concentration change 3- Development of a new in-channel and air bubble liquid sampling technique to sample a few nano-liters of NT. Such a technique, will certainly open other alternatives to replace conventional micro pumps as it does not require any dedicated microfabrication process. The proposed MIOC can also be generalized for blood chemical and molecular disorders such as for cholesterol, sickle-cell anemia, etc. as the sensing and liquid manipulation architecture are the same while the bio-interface differs from one application to another.