Infection is a devastating complication after total joint replacement (TJR), with major consequences for patients, including a high 5-year mortality rate (>25%), and an immense societal burden. Concern for infection is the single most common reason for patients to present to the emergency department (ED) after TJR, likely because the consequences of a delayed diagnosis can prolong morbidity, reduce the chances for successful infection eradication, and sometimes even lead to sepsis. Diagnostic errors and unnecessary overtreatment can be just as damaging, given the multiple aggressive surgical interventions and long-term, potentially toxic antibiotic treatment required to manage an infected joint replacement, much akin to cancer therapy. Unfortunately, making a diagnosis of infection remains a challenging task for physicians. Clinical suspicion alone is ineffective for identifying the presence of infection, as outward clinical signs, such as erythema or swelling, are non-specific and cannot be differentiated from other forms of inflammation. Traditional culture, which is heavily relied upon by physicians, is slow and has limited sensitivity. Isolation of an infecting organism may take greater than 2 weeks for certain pathogens, and as many as 20-50% of active infections are `culture-negative', in that an organism does not appear in culture. Other traditional tests on synovial fluid have limited diagnostic accuracy and must be performed by a technician in a laboratory setting. In fact, there is no practical point-of-care (POC) test available that can allow physicians to quickly and reliably diagnose a joint infection in order to facilitate prompt clinical decisions in real-time. CLEU Diagnostics' goal is to develop the first POC test for infection diagnosis based on a novel electrochemical assay that measures the activity of leukocyte esterases (LE) in joint fluid. LE are antimicrobial proteases released by activated neutrophils recruited to sites of infection. The cellular expression of such antimicrobial peptides rises dramatically in response to acute infection; thus, these enzymes serve as ideal biomarkers for joint infection, with nearly optimal diagnostic accuracy. Our approach is driven by our proprietary biosensor technology, which allows for rapid, quantitative detection of LE using low-cost, disposable screen-printed electrodes, similar to glucose meter test strips. CLEU Diagnostics' novel electrochemical substrates have proven to be highly sensitive for detecting LE in-fluid samples with minimal interference. Ultimately, our novel biosensor will allow physicians in the office or ED to evaluate fluid aspirated from a persistently painful joint replacement with a high diagnostic accuracy in just minutes. Not only will this facilitate prompt intervention for those with an infection, but more commonly it will allow physicians to definitively rule out infection and prevent undue psychological distress, and even hospital observation, for those without a joint infection. CLEU Diagnostics' biosensor may also be highly effective for diagnosing infection in urine and other common biological fluids, including cerebrospinal, peritoneal, pleural, and amniotic fluid; thus, CLEU's technology could have wide ranging applications in medicine.

Public Health Relevance

Infection after joint replacement is a devastating complication with a high 5-year mortality rate (>25%) and treatment costs that are projected to exceed $1.6 billion by 2020. The challenge of making a prompt diagnosis with currently available diagnostic tools, which are severely limited, has exacerbated this growing problem and contributes significantly to the prolonged morbidity of this disease process. As the first-ever point-of-care diagnostic test, our novel biosensor will revolutionize the management of joint infection by allowing physicians to make highly reliable diagnoses in real-time to guide timely clinical decisions and significantly improve a patient's chances for a successful outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43AI142886-01
Application #
9680930
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Minnicozzi, Michael
Project Start
2019-04-15
Project End
2019-09-30
Budget Start
2019-04-15
Budget End
2019-09-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cleu Diagnostics, LLC
Department
Type
DUNS #
081083539
City
Philadelphia
State
PA
Country
United States
Zip Code
19107