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

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 Nevertheless, underlying infections still commonly go undetected due the nature of existing diagnostics, which are outdated, slow, and imprecise.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diagnostic tools are also limited – either synovial fluid must be transported to a central laboratory for testing or outdated point-of-care (POC) diagnostic technology must still be employed that yields less accurate, binary results (‘infected’ or not).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.