Developing an ultrawide dynamic range analytical platform for biomarker panel analysis in serum

通过特异性生物亲和相互作用直接检测生物流体样品中的生物标志物种类是改善医疗保健的最有力工具之一。然而，对于许多疾病，越来越清楚的是，尽管正在寻求诊断的简单性和便携性，但每次测量仅关注一个目标物种是无法实现可靠的诊断的。相反，需要准确地比较一套或一组生物标志物，以便提供准确的疾病快照。特别具有挑战性的是，在血清这样复杂的环境中，同时对浓度范围从微摩尔（~10-6 M）到低于飞摩尔（<10-15 M）的多个生物分子靶标进行稳健和定量比较。该项目旨在解决这一测量挑战，利用光学仪器和数据分析设计的组合，以及纳米颗粒的制备和功能化以及用于样品输送和制备的集成3D打印微流体。这些将被应用于提供一个独特的多模态成像仪器平台，该平台能够快速和高通量地识别在靶分子存在下组装的个体和纳米颗粒以及其他物种，如细胞外囊泡。将使用与两种非常具有挑战性的健康状况相关的生物标志物来证明系统性能：（i）神经系统疾病和（ii）胰腺癌，关键目标是能够在相对较短的时间尺度内直接检测患者血清样本中多种物质的相对浓度。最终，能够稳健地进行此类测量也有可能适应多种其他疾病，并成为纳米颗粒设计和表征的基本工具，这两者都进一步增加了该项目的潜在影响和多样性。

The direct detection of biomarker species in biofluid samples via specific bioaffinity interactions is one of the most powerful tools for improving healthcare. However, for many diseases it is becoming increasingly clear that reliable diagnostics cannot be achieved by simply focusing on only one target species per measurement, despite the ongoing search for diagnostic simplicity and portability. Instead, a suite or panel of biomarkers needs to be accurately compared in order to provide an accurate disease snapshot. Particularly challenging is the robust and quantitative comparison of multiple biomolecular targets simultaneously at concentrations ranging from micromolar (~10-6 M) to below femtomolar (<10-15 M) in an environment as complex as blood serum. This project aims to address this measurement challenge utilising a combination of both optical instrumentation and data analysis design alongside the preparation and functionalisation of nanoparticles and integrated 3D-printed microfluidics for sample delivery and preparation. These will be applied to deliver a unique mutli-modal imaging instrument platform that enables rapid and high-throughput identification of both individual and nanoparticles assembled in the presence of a target molecule alongside the other species such as extracellular vesicles. The system performance will be demonstrated using biomarkers associated with two very challenging health conditions: (i) neurological disease, and (ii) pancreatic cancer, with a key objective being able to directly detect relative concentrations of multiple species in a patient serum sample within a relatively short timescale. Ultimately, being able to perform such measurements robustly also has the potential to be adapted to a large variety of other diseases as well as being a fundamental tool for nanoparticle design and characterisation, both of which further increase the potential impact and diversity of this project.