RAPID ELECTROCHEMICAL BIOSENSOR FOR POINT-OF-CARE DIAGNOSIS OF JOINT INFECTION

用于关节感染护理点诊断的快速电化学生物传感器

• 批准号: 10570823
• 负责人: Andrew Neil Fleischman
• 金额: $ 47.08万
• 依托单位: CLEU DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570823
• 关键词: Accident and Emergency department; Altitude; Android; Ascorbic Acid; Bacterial Infections; Benchmarking; Biological Assay; Biosensor; Blood; Cells; Chemicals; Chemistry; Clinical; Clinical Research; Color; Complication; Consensus; Cytolysis; Dedications; Development; Devices; Diagnosis; Diagnostic; Diagnostic tests; Dryness; Dyes; Electrodes; Electromagnetics; Engineering; Erythema; Evaluation; Failure; Genus Mycobacterium; Goals; Hemoglobin; Hip Joint; Hospitalization; Humidity; Implant; Incidence; Incubated; Infection; Infectious Agent; Injections; International; Joints; Knee joint; Laboratories; Life; Liquid substance; Measurement; Mechanics; Meta-Analysis; Modification; Molds; Morbidity - disease rate; Multi-site clinical study; Multicenter Studies; Nature; Neutrophil Infiltration; Noise; Operative Surgical Procedures; Orthopedics; Outcome; Pain; Patients; Peptide Hydrolases; Performance; Periprosthetic joint infection; Persistent pain; Phase; Physicians; Predictive Value; Process; Production; Provider; Reaction; Reagent; Replacement Arthroplasty; Reporting; Reproducibility; Safety; Sampling; Signal Transduction; Site; Specific qualifier value; Specimen; Stress Tests; Surface; Suspensions; Swelling; Synovial Fluid; System; Temperature; Testing; Translating; Urinalysis; Validation; accurate diagnosis; antimicrobial; cost; design; diagnostic accuracy; diagnostic assay; diagnostic platform; diagnostic technologies; diagnostic tool; diagnostic value; esterase; graphical user interface; handheld equipment; high risk; improved; infection management; innovation; joint infection; leukocyte esterase; manufacture; manufacturing process; meetings; mobile application; mortality; operation; overtreatment; pathogen; point of care; point-of-care diagnosis; point-of-care diagnostics; printed circuit board; prototype; research clinical testing; safety testing; sensor; stability testing; standard of care

Periprosthetic joint infection (PJI) is a devastating complication following total joint replacement (TJR) often with major long-term consequences and morbidity. As many as 100,000 orthopedic infections are diagnosed each year in the US, a number that is expected to rise exponentially. However, the scope of the problem is much larger. Persistent pain is reported in up to 80% of patients after joint surgery, and all painful orthopedic implants require a complete evaluation to rule out the possibility of PJI. Concern for infection is also the single most common reason for patients to present to the emergency department after TJR. Unfortunately, making the diagnosis of infection remains a major challenge, especially since outward clinical signs, such as erythema and swelling, are not specific to PJI. Immediate and accurate diagnoses that also avoid unnecessary overtreatment are critical for favorable outcomes, especially given that PJI management often requires multiple operations and prolonged hospitalization. Nevertheless, underlying infections still commonly go undetected due the nature of existing diagnostics, which are outdated, slow, and imprecise. Problems include the inability to isolate infectious organism(s) in 20-50% of cases (‘culture-negative’), long incubation times required to isolate certain pathogens, and the relatively high incidence of false positives. Alternative diagnostic tools are also limited – either synovial fluid must be transported to a central laboratory for testing or outdated point-of-care (POC) diagnostic technology must still be employed that yields less accurate, binary results (‘infected’ or not). So how should physicians make timely and accurate diagnoses? Our team was the first to discover the diagnostic value of synovial fluid leukocyte esterase (LE), an antimicrobial protease released by activated neutrophils recruited to sites of bacterial infection. Since that discovery, the original LE ‘dipstick’ test (Roche Chemstrip®) has been used by physician to aid in PJI diagnosis with a high diagnostic accuracy of about 89% and a negative predictive value as high as 97%. Nevertheless, the test in its original form designed for urinalysis is impractical for widespread use in orthopedics. The ‘dipstick’ is a dry chemical reagent pad, in which a surface reagent reacts with esterase in the sample to produce a purple dye. The result is read by a clinician based on the degree of color change on the test pad. Unfortunately, lack of objectivity severely limits its clinical reliability. Joint fluid samples must also be centrifuged in an attempt to remove blood and debris that can distort results. Our breakthrough LE test is a POC diagnostic assay that provides a rapid quantitative LE measurement with just a tiny droplet of synovial fluid. Results are immediately available to providers via a mobile app in just 2 minutes to drive clinical decisions. In Phase I, we overcame significant challenges and delivered a highly stable production-ready prototype without signal drift or matrix interference, and designed a low-cost analyzer. Our Phase II goals are to prepare for scale manufacturing of production LE sensors and analyzers, perform master validation to establish product claims for FDA clearance, and conduct a multi-center study to determine real-world diagnostic accuracy of the device in the field.

假体周围关节感染（PJI）是全关节置换术（TJR）后的一种毁灭性并发症， 严重的长期后果和发病率。每例诊断出的骨科感染多达10万例 在美国，这一数字预计将呈指数级增长。然而，问题的范围很大， 更大。据报道，高达80%的患者在关节手术后会出现持续性疼痛，所有疼痛的骨科植入物 需要进行全面评估，以排除PJI的可能性。对感染的关注也是最重要的 TJR后患者到急诊室就诊的常见原因。不幸的是， 感染的诊断仍然是一个主要的挑战，特别是因为外部的临床症状，如红斑和 肿胀，不是PJI特有的。及时准确的诊断，避免不必要的过度治疗 对于有利的结果至关重要，特别是考虑到PJI管理通常需要多个操作， 延长住院时间。尽管如此，潜在的感染仍然普遍未被发现，由于性质， 现有的诊断方法过时、缓慢且不精确。问题包括无法隔离传染性 在20-50%的病例中存在微生物（“培养阴性”），分离某些病原体需要较长的孵育时间， 以及相对较高的误报率。替代诊断工具也有限-无论是滑膜 必须将液体运送到中心实验室进行检测或使用过时的床旁（POC）诊断技术 仍然必须使用产生不太准确的二进制结果（“感染”或未感染）的方法。那么医生应该如何 及时准确的诊断？我们的团队是第一个发现滑液白细胞的诊断价值 酯酶（LE），一种由激活的中性粒细胞释放的抗微生物蛋白酶，被招募到细菌感染部位。 自该发现以来，最初的LE“试纸”测试（Roche Chemstrip®）已被医生用于辅助PJI 诊断准确率约为89%，阴性预测值高达97%。 尽管如此，该测试在其最初的形式设计为尿液分析是不切实际的广泛使用骨科。 “试纸”是一种干化学试剂垫，其中表面试剂与样品中的酯酶反应， 产生紫色染料。临床医生根据测试垫上的颜色变化程度读取结果。 不幸的是，缺乏客观性严重限制了其临床可靠性。关节液样本也必须离心 试图去除可能扭曲结果的血液和碎片。我们的突破性LE测试是一种POC诊断 该检测仅用一小滴滑液即可提供快速定量LE测量。结果 提供者只需2分钟即可通过移动的应用程序立即获得这些信息，从而推动临床决策。在第一阶段，我们 克服了重大挑战，并交付了高度稳定的生产就绪原型，没有信号漂移， 基体干扰，并设计了一种低成本的分析仪。我们的第二阶段目标是为规模生产做准备 生产LE传感器和分析仪，执行主确认以确定FDA批准的产品声明， 并进行多中心研究，以确定该设备在现场的真实诊断准确性。