Sensitive and quantitative malaria diagnostic using nanoscale porous silicon.

摘要 最近的疟疾控制努力在减轻这种疾病的负担方面取得了重大进展。一个 据报道，2010-2016年间与疟疾相关的死亡人数减少了25%。尽管取得了这样的成功，疟疾仍然 这是一个令人震惊的全球负担，2018年有超过2亿人感染，导致超过 40万人死亡。此外，世界卫生组织最近收集的数据表明，没有额外的， 在过去几年中，在减少全球疟疾病例方面取得了重大进展。一项关键挑战 根除疟疾是诊断那些不太可能接受抗疟疾药物的无症状疟疾患者 尽管能够将疟疾寄生虫传播给其他人。同时，量化 表现出疟疾症状的人群中的疟疾寄生虫对于发现 患有脑型疟疾的风险很高，这往往是致命的，特别是在儿童中。因此，通过增加 由于存在杀虫剂和抗药性，迫切需要开发新的方法来广泛应用疟疾。 快速诊断测试(RDT)，在大动态范围内准确，识别无症状的 患者和那些有脑疟疾风险的人。目前的RDT不能满足这一需求。 该提议寻求在多孔硅光学器件的开发方面取得重要的里程碑 在一个易于使用和负担得起的平台上，能够满足上述关键需求的疟疾诊断。 我们将首先演示使用光学技术检测高度敏感和定量的疟疾生物标志物(PfHRP2) 在模型系统中读出多孔硅薄膜(目标1)，然后演示对疟疾的可靠检测 血液中的生物标志物(目标2)。这项工作利用了测量光学性质变化的简单性 多孔硅，与毛孔和大内表面中捕获的蛋白质数量直接相关 面积小的多孔硅面积，能够有效地捕获显著更多的疟疾 与目前的RDTs相比，每个手指刺血的生物标志物。关键的科学创新包括嫁接双功能 来自多孔硅的聚合物刷子，以实现高密度的疟疾生物标志物捕获探针和 防污性能，确保在检测血样时可以忽略不计的非特异性结合。 我们组建了一支在光学和纳米级多孔生物传感器(Weiss)、表面技术方面具有专业知识的研究团队。 化学和防污涂料(Laibinis)和低资源传染病诊断工具(ADAMS) 以满足为控制和消除疟疾而改进RDTs的需要。我们希望我们的多孔硅光学元件 诊断，使疟疾患者能够得到更广泛的知情治疗。预期的长期 影响包括改善对疟疾资源分配和消除疟疾的全球监测。

SUMMARY Recent malaria control efforts have yielded significant progress toward reducing the burden of this disease. A 25% reduction in malaria-related deaths was reported between 2010 – 2016. Despite this success, malaria still represents a staggering global burden with more than 200 million people infected in 2018, resulting in more than 400,000 deaths. Moreover, recent data collected by the World Health Organization suggest that no additional, significant progress has been made in reducing global malaria cases over the past few years. A key challenge to eradicating malaria is diagnosing asymptomatic malaria patients who are unlikely to receive anti-malaria drugs despite being able to cause transmission of the malaria parasite to others. At the same time, quantification of malaria parasites in people expressing malaria symptoms is also of critical importance to finding patients who are at high risk for cerebral malaria, which is often fatal, especially in children. Hence, compounded by increasing insecticide and drug resistance, there is a critical need to develop new approaches for widely deployable malaria rapid diagnostic tests (RDTs) that are accurate over a large dynamic range, identifying both asymptomatic patients and those at risk for cerebral malaria. Current RDTs cannot meet this need. This proposal seeks to achieve important milestones towards the development of a porous silicon optical diagnostic for malaria that can meet the aforementioned critical need in an easy-to-use and affordable platform. We will first demonstrate highly sensitive and quantitative malaria biomarker (PfHRP2) detection using optical readout of porous silicon films in a model system (Aim 1) and then demonstrate robust detection of the malaria biomarker in blood (Aim 2). This work leverages the simplicity in measuring changes in the optical properties of porous silicon that directly correlate to the quantity of protein captured in the pores, and the large internal surface area of porous silicon within a small areal footprint that enables the efficient capture of significantly more malaria biomarkers per finger-prick of blood than current RDTs. Key scientific innovations include grafting a bifunctional polymeric brush from porous silicon to realize both a high density of capture probes for malaria biomarkers and antifouling properties to ensure negligible non-specific binding when testing blood samples. We have assembled a research team with expertise in optics and nanoscale porous biosensors (Weiss), surface chemistry and antifouling coatings (Laibinis), and low resource diagnostic tools for infectious diseases (Adams) to address the need for improved RDTs for malaria control and elimination. We expect our porous silicon optical diagnostic to enable more informed treatment of malaria patients across a wide spectrum. Expected long-term impacts include improved global surveillance for malaria resource allocation and elimination of malaria.