基于微流控传感技术的药物监测与药物性肝病快速诊断复合系统的研究

Therapeutic drug monitoring (TDM) is essential for ensuring the rationality of medication and achieving individualized drug administration. Since the hierarchical diagnosis and treatment system has been implemented in China, the requirement for clinical pharmacy service is gradually increasing. However, the present pharmaceutical analysis techniques are mostly based on chromatography, spectroscopy, immunoassay, etc., which are not conducive to extensive application of clinical pharmaceutical work, consequently hindering the China's medical reform and development. On the other side, drug-induced liver disease (DILD) has been paid insufficient attention all over the world, along with lack of effective detection and evaluation strategy of DILD. Both of them pose the disease under high incidence rate. This application aims to construct a composite platform based on microfluidic sensing technology, which can simultaneously monitor blood concentration and hepatic function during drug treatment. This platform is expected to realize real-time TDM and achieve rapid alert and diagnosis of DILD. The key elements of the detection system include nano-materials and molecularly imprinted film modified electrochemical sensor chips and multiplex enzyme modified biosensor chips. Electrochemical techniques based on different assay principles are also integrated into the microfluidic chip system in order to make it widely applicable towards different drugs. After that, association analysis between the obtained pharmacokinetic data and hepatic function indexes will be carried out, and early warning of drug-induced liver injury will be established. Finally, the developed technique and platform will be put into use in clinical departments for testing its practicability and to improve effectiveness and safety of drug therapy.

治疗药物监测（TDM）对于保障合理性和个体化给药至关重要。我国分级诊疗制度实施之后，对临床药学服务的需求不断增大，而目前基于色谱、光谱、免疫的药物分析技术不利于该工作的广泛开展和普及。同时，目前国内外对于不合理用药引起的药物性肝病（DILD）普遍重视不足，并缺乏相关检测手段，使得DILD处于高发态势。本申请拟建立一套基于微流控传感技术的复合平台，可以同时监测患者药物治疗期间的血药浓度和肝功指标，实现TDM与DILD快速预警和诊断。检测的核心元件分别是纳米材料和分子印迹聚合物双重修饰的电化学传感芯片和多重酶修饰的生物传感芯片。在前期工作基础上，该传感系统中整合了基于多种检测原理的电化学分析技术，以达到检测体系普适性的目的。将得到的药动学数据与肝脏器指标进行关联分析，建立药物性肝损害预警机制，提高药物治疗的有效性及安全性。建立的技术和平台将最终在临床科室进行应用和推广。

药物治疗是疾病治疗的重要手段，一些治疗窗狭窄、长期服用导致疗效降低或毒性增加的药物以及抗肿瘤药物在使用中都需要开展治疗药物监测（TDM），其对于提高用药合理性、实现个体化用药、保证药物安全等至关重要。然而，药物的不合理使用还会导致肝脏等药物代谢排泄器官发生功能异常甚至损伤，进而引发药源性疾病。目前国内外药源性肝疾病（DILD）评价手段及评价指标也存在较为单一，不能满足目前医学中多指征综合检测进行疾病诊断的需求。本课题致力于建立一套基于微流控传感技术的复合平台，以同时检测患者药物治疗期间的血药浓度和肝功指标，实现TDM和DILD的快速预警和诊断。在研究过程中，主要结合了分子印迹技术、微流控技术、3D打印技术、以及生物材料、功能纳米材料等材料，实现了对不同类别待测物的特异性识别和检测，构建了用于TDM和药物代谢器官肝脏功能指标检测的传感器，方法验证学实验的各项指标合格，且检测速度快，重复性好。本研究为TDM和DILD快速诊断做出了开创性工作，建立了有效的药物性肝损害预警机制，提高了药物治疗的有效性和安全性。

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