Development of an Enzymatic Organic Electrochemical Transistor for Studying Cerebral Cholesterol Metabolism in Alzheimer's Pathology

开发用于研究阿尔茨海默病病理学中脑胆固醇代谢的酶有机电化学晶体管

• 批准号: 2408391
• 金额: --
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2408391
• 关键词: Development; Enzymatic; Organic; Electrochemical; Transistor

Alzheimer's disease (AD) affects more than 50 million people worldwide and is expected to affect three times more people by 2050. AD is the most common form of dementia and causes progressive decline of neurons in the brain, which leads to memory impairment, decline in language and problem-solving skills. Recent studies show that dysfunction in cerebral cholesterol metabolism is directly linked to AD pathogenesis. Moreover, there is a significant change in cholesterol metabolism in the cerebral spinal fluid (CSF) of AD's patients. However, the current laboratory methods used for analysis of CSF cholesterol impose limitations to experiments because they are complex, expensive, and time-consuming. Therefore, in this PhD project, a novel method for measuring cerebral cholesterol from CSF is proposed. Organic polymer electrochemical transistors (OECTs) will be used as point-of-care (POC) biosensors, which can outperform current clinical detection methods. This will offer a fast, easily accessible, and reliable in-vitro method to study whether cholesterol in CSF can act as an early biomarker of AD. The first aim of the project is to design and fabricate an in-vitro biosensor to investigate the role of cholesterol's metabolism in the spread of AD in the brain. This will be achieved through treating cell cultures and samples with different cerebral cholesterol concentrations and using high resolution imaging to investigate the effect of cholesterol metabolism on AD's biomarkers. The second aim of the project is to develop the OECT biosensor into a point-of-care device, which can perform reliable monitoring of the cerebral cholesterol's concentration from CSF sample at the time of the medical consultation to help patients recognise the risk of developing AD at the early stages. For this purpose, the fabricated organic electrochemical transistors will be biofunctionalised with redox enzymes that are specific for cerebral cholesterol and are safe and reliable for long-term use. In this project, OECTs with a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) channel will be fabricated by processes such as layer deposition, lithography, etching, and spin-coating. PEDOT:PSS is one of the most promising bioelectronics materials due to its combined ionic and electronic charge, leading to huge signal amplification, outperforming most transistors. Moreover, it is very stable in aqueous media, which makes it very suitable for detection of cholesterol in CSF. Techniques for biofunctionalising the gate with different cholesterol oxidases including nanoparticles and artificial mediators will be investigated for achieving optimum response time and high selectivity. Then the accuracy of the OECTs will be tested by using CSF samples. Finally, they will be applied in real-time experiments to investigate the correlation between AD's pathology and cerebral cholesterol. Thus, OECTs hold a great potential for POC, which can address the challenges imposed by the current complex and time-consuming clinical methods for quantifying CSF cholesterol. Thus, at the end of this project, a novel biosensor for measuring CSF cholesterol will be produced, aligning with the strategies of sensors and instrumentation to incorporate a new advanced device to provide a future with better healthcare and diagnosis. The implementation of the project will be based on knowledge and ideas from microelectronic device technology in healthcare since it incorporates a low-power design of the OECTs microelectronic devices by novel technologies and materials such as the PEDOT:PSS organic polymer and nanoparticles. The vision of this project aligns fully with the ideas from clinical technologies research area since it focuses on developing a novel POC device for diagnosis and monitoring of AD and thus improves health and care by proposing a novel, reliable and fast sensing technology.

阿尔茨海默病（AD）影响全球超过5000万人，预计到2050年将影响三倍以上的人。AD是最常见的痴呆症形式，会导致大脑神经元进行性衰退，从而导致记忆障碍、语言和解决问题能力下降。近年来的研究表明，脑胆固醇代谢障碍与AD的发病有直接关系。此外，AD患者的脑脊液（CSF）中胆固醇代谢存在显著变化。然而，目前用于分析CSF胆固醇的实验室方法对实验施加了限制，因为它们复杂、昂贵且耗时。因此，在本博士项目中，提出了一种从CSF中测量脑胆固醇的新方法。有机聚合物电化学晶体管（OECTs）将被用作床旁（POC）生物传感器，其性能优于目前的临床检测方法。这将提供一种快速，容易获得和可靠的体外方法来研究CSF中的胆固醇是否可以作为AD的早期生物标志物。本计画的第一个目的是设计并制作一个活体外生物感测器，以探讨胆固醇代谢在脑内AD传播中的作用。这将通过处理细胞培养物和具有不同脑胆固醇浓度的样品并使用高分辨率成像来研究胆固醇代谢对AD生物标志物的影响来实现。该项目的第二个目的是将OECT生物传感器开发成一种即时设备，可以在医疗咨询时从CSF样本中可靠地监测脑胆固醇浓度，以帮助患者在早期阶段识别发展AD的风险。为此，制造的有机电化学晶体管将用氧化还原酶进行生物功能化，氧化还原酶对脑胆固醇具有特异性，并且长期使用安全可靠。在这个项目中，OECTs与聚（3，4-乙撑二氧噻吩）聚苯乙烯磺酸（PEDOT：PSS）通道将被制造的工艺，如层沉积，光刻，蚀刻和旋涂。PEDOT：PSS是最有前途的生物电子材料之一，因为它结合了离子和电子电荷，导致巨大的信号放大，优于大多数晶体管。此外，它在水性介质中非常稳定，这使得它非常适合检测CSF中的胆固醇。将研究用不同的胆固醇氧化酶（包括纳米颗粒和人工介质）生物功能化门的技术，以实现最佳的响应时间和高选择性。然后将使用CSF样本检测OECT的准确度。最后，它们将被应用于实时实验，以研究AD的病理与脑胆固醇之间的相关性。因此，OECTs对POC具有巨大的潜力，可以解决目前复杂且耗时的临床CSF胆固醇定量方法所带来的挑战。 因此，在该项目结束时，将生产一种用于测量CSF胆固醇的新型生物传感器，与传感器和仪器的策略保持一致，以整合一种新的先进设备，为未来提供更好的医疗保健和诊断。该项目的实施将基于医疗保健微电子器件技术的知识和想法，因为它采用了新技术和材料（如PEDOT：PSS有机聚合物和纳米颗粒）对OECT微电子器件进行低功耗设计。该项目的愿景与临床技术研究领域的想法完全一致，因为它专注于开发一种用于诊断和监测AD的新型POC设备，从而通过提出一种新型，可靠和快速的传感技术来改善健康和护理。