Silicon Nanowire Arrays for Viral Infection Markers

对血清等临床样本进行实验室分析是一种强大的诊断工具。它确定了特定生物分子的存在和浓度，该生物分子与特定疾病的风险或进展相关，或与疾病对给定治疗的易感性有关。对大量此类生物标志物的定期筛查将使预测性、预防性和个性化医学的大规模应用成为现实。从社会经济的角度来看，这种对医疗保健预防和个性化的强调是非常可取的，但所需的实验室测试数量的增加(在英国已经达到每年约10亿次)将是巨大的，不能满足目前使用的生化分析方法。这个大挑战项目的目标是开发硅纳米线阵列，这是唯一被证明能够通过电子而不是昂贵的光学检测来实现对蛋白质生物标记物的高度特异性和超灵敏分析的技术，成为一个强大的用户平台，用于同时分析同一临床样本中的大量生物标记物。我们将优化一种独特的方法，利用与微电子行业使用的类似于成本效益的大规模生产技术来制造大量的硅纳米线阵列。硅纳米线将被合并到先进的微流控基质中，这不仅允许样品体积非常小(通过简单的手指刺穿获得的血滴就足够了)，而且还将提供将纳米线阵列(可由多达1000条平行纳米线组成)划分为许多可单独寻址的纳米线组的方法。通过适当的官能化化学，每套纳米线可以识别和量化不同的生物标志物，使最大限度地从最少量的样本中提取信息。纳米线设备，包括用于处理样本的微流体，将被开发为单一的一次性芯片，适合大规模生产商业诊断试剂盒。我们的工业合作伙伴，一个制造商和两个不同的最终用户，将为纳米线平台的发展提供明显的商业前景。对于临床相关的商业化前原则证明，该项目将重点分析病毒感染和治疗的六种不同蛋白质标记物。该项目将以独特的方式获得临床样本--血清和诱导痰--这些样本来自南安普顿综合医院急性医疗部收治的急性哮喘加重患者。它还将获得哮喘志愿者的血清样本，这些志愿者正在进行使用吸入型β-干扰素进行I期临床试验的药物，这种药物正在开发用于治疗病毒引起的哮喘加重。硅纳米线技术将使常规和经济的高通量生物标记物分析能够在临床实验室之外进行，为向医疗保健系统过渡提供技术手段，在医疗保健系统中，定期筛查复杂疾病有助于预防和早期干预。在整个项目中，我们将探索在科学和技术发展期间实施的实际问题，而不是更常见的情况，即在科学和技术阶段完成后。为了实现这一目标，我们将与公众、医疗保健专业人员、医疗保健经理和政策制定者接触，探讨风险和监管的关键问题，并探索如何在既定的医疗工作和组织系统中有效使用这项技术。

Laboratory analysis of a clinical sample such as blood serum is a powerful diagnostic tool. It establishes the presence and concentration of a specific biomolecule that correlates with the risk or progression of a particular disease, or with the susceptibility of the disease to a given treatment. Regular screening for a large number of such biomarkers, the discovery of which is a major biomedical research activity, would make the large-scale application of predictive, preventive and personalized medicine a reality. This emphasis on prevention and individualization of healthcare is highly desirable from a socio-economical perspective, but the required increase in the number of laboratory tests (already about a billion per annum in the UK) will be huge and cannot be met with the biochemical analysis methods that are currently employed.The aim of this Grand Challenge project is to develop silicon nanowire arrays, the only technology that has been shown to enable highly specific and ultrasensitive analysis of protein biomarkers with electronic rather than costly optical detection, into a robust user platform for the simultaneous analysis of a large number of biomarkers in the same clinical sample. We will optimize a unique method to fabricate extensive arrays of silicon nanowires with a cost-effective mass-production technology that is similar to that used by the microelectronics industry. The silicon nanowires will be incorporated in an advanced microfluidic matrix that will not only allow the sample volume to be very small (a blood droplet obtained with a simple finger prick could be sufficient), but will also provide the means to divide the nanowire array, which can consist of up to a thousand parallel nanowires, into many individually addressable sets of nanowires. Through appropriate functionalization chemistry, each nanowire set can be made to recognize and quantify a different biomarker, enabling a maximum amount of information to be extracted from a minimal amount of sample.The nanowire devices, including the microfluidics for sample handling, will be developed as a single disposable chip, suitable for the mass production of commercial diagnostic kits. Our industrial partners, one manufacturer and two different end-users, will provide a pronounced commercial perspective to the development of the nanowire platform. For clinically relevant pre-commercialization proof of principle, the project will focus on the analysis of six different protein markers of viral infection and treatment. The project will have unique access to clinical samples -serum and induced sputum- obtained from patients admitted to the Acute Medical Unit at the Southampton General Hospital suffering from acute asthma exacerbations. It will also have access to serum samples from asthmatic volunteers undergoing Phase I clinical trials using inhaled beta-interferon which is being developed for treatment of virus-induced asthma exacerbations.The silicon nanowire technology will enable routine and economical high-throughput biomarker analysis outside the clinical laboratory, providing the technological means for a transition to a healthcare system in which regular screening for complex diseases facilitates prevention and early intervention. Throughout the project we will explore practical questions of implementation during scientific and technological development rather than, as is more commonly the case, after scientific and technological phases have been completed. To achieve this we will engage with the public, healthcare professionals, healthcare managers and policy makers to explore key questions of risk and regulation as well as exploring how this technology might be brought into effective use within established systems of healthcare work and organization.