Point-of-Care-Testing in Acute Stroke Management: An Unmet Need Ripe for Technological Harvest

Abstract

Stroke, the second highest leading cause of death, is caused by an abrupt interruption of blood to the brain. Supply of blood needs to be promptly restored to salvage brain tissues from irreversible neuronal death. Existing assessment of stroke patients is based largely on detailed clinical evaluation that is complemented by neuroimaging methods. However, emerging data point to the potential use of blood-derived biomarkers in aiding clinical decision-making especially in the diagnosis of ischemic stroke, triaging patients for acute reperfusion therapies, and in informing stroke mechanisms and prognosis. The demand for newer techniques to deliver individualized information on-site for incorporation into a time-sensitive work-flow has become greater. In this review, we examine the roles of a portable and easy to use point-of-care-test (POCT) in shortening the time-to-treatment, classifying stroke subtypes and improving patient's outcome. We first examine the conventional stroke management workflow, then highlight situations where a bedside biomarker assessment might aid clinical decision-making. A novel stroke POCT approach is presented, which combines the use of quantitative and multiplex POCT platforms for the detection of specific stroke biomarkers, as well as data-mining tools to drive analytical processes. Further work is needed in the development of POCTs to fulfill an unmet need in acute stroke management.

Keywords: Biomarkers; Data-Mining; Diagnostics; Multiplex and Quantitative Detection; Point-of-Care-Test; Stroke; Time-Dependent Treatment.

Figure 1

Stroke Patient Conventional Prognostic Management vs. Improved Using point-of-care-tests (POCTs). (1) In case of medical emergency (stroke symptoms onset), there is contact to emergency medical services (EMS) dispatch (t = 0). (2) EMS follows ‘case entry protocol’ and evaluate the patient medical status by specific parameters. (3) Ambulance patient-transportation to the hospital (t ≤ 15 min). (4) Conventional stroke identification pathway: in the best scenario, the patients were already confirmed to be suffering from stroke by the EMS, so he is immediately transported to a stroke specialized unit. But in case he wasn’t, the patient will go through the Emergency Department (ED), like any other patient suffering from a range of medical problems (t ≤ 30 min). The suspected stroke patient will only then be evaluated by a neurologist (t ≤ 60 min). The most common neurologic examination used is NIHSS, and followed by a CT/MRI scan for initial stroke diagnosis (t ≤ 90 min). Subsequently, stroke subtype classification (t ≤ 120 min) is conducted by either Trial of Org 10172 in Acute Stroke Treatment (TOAST), National Institute of Neurological Disorders and Stroke (NINDS) or Oxford Community Stroke Project (OCSP) classification schemes. Admission of (tissue plasminogen activator (tPA) will be on average less than 3hr from stroke-symptoms-onset (t ≤ 180 min). (5) POCT based stroke identification pathway: available pre-hospital POCT devices can shorten the time from stroke-symptoms-onset to neurologist examination (t ≤ 20 min). In addition, with the use of in-hospital POCT, the time to CT/MRI scan can be reduced (t ≤ 45 min) and, most importantly, the time to tPA admission can be reduced as well (60 min ≤ t ≤ 90 min).

Figure 2

POCT vs. Conventional Technologies. The advantage of POCT vs. conventional technologies are: portability, a simple structure, easy to use, allows multiplex detection, gives results within min, and also does not require labelling. However, a POCT demonstrates lower sensitivity and gives less reliable and accurate results. Conventional technologies are usually characterized with a more sensitive and reliable detection, but the limitations deny its usage as an on-site diagnostic tool. The disadvantages of conventional technologies are: lab facility requirement, results take hours or even days and complicated usage that requires professional personnel which results in a time-consuming process.

Figure 3

Biosensor Structure. A Biosensor consists of three components: biospecific capture entity, chemical interface and transducer. A variety of biospecific capture entities are used for the bio-detection of the target analyte in biosensors, such as antibodies, enzymes, DNA and whole cells. The biosensor chemical interface can be based on either a covalent, entrapment, absorption, encapsulation or cross-linking binding. In addition, the transducer, which is used for the signal transmission and measurement, can be based on electrochemical signal (potentiometric or amperometric), optical signal (absorbance, luminescence or fluorescence) or acoustic signal (quartz crystal microbalance, surface acoustic wave or surface transverse wave).

Figure 4

Novel POCT Platforms. (A) Left: Schematic illustration of electro-lateral-flow-immunoassay (ELFI) prototype. This POCT consists of a sample pad, conjugation layer immobilized with specific immune-nanobeads, a transfer layer and a SPGE immobilized with second specific Antibody for the formation of sandwich bio-recognition. Right: ELFI test concept. In case the tested sample contains the target analyte, the formulated immune-nanobeads (AuNPs-Ab-Fc) bind to it and there is a sandwich immune-complex formation on the SPGE. The signal is then measured by electrochemical reaction. In case the tested sample does not contain the target analyte, there will not be a sandwich immune-complex formation on the screen-printed gold electrode (SPGE), which will change the electrochemical signal. (B) Schematic illustration of Stack-Pad prototype. This POCT consists of a sample pad, conjugation pad immobilized with specific HRP-conjugated antibodies, a separation pad, blocking pad immobilized with the target analyte and a substrate pad immobilized with HRP substrate, which later produce a measurable signal. In case the tested sample contains the target analyte, the HRP-conjugated antibodies will bind to it, and continue to flow through the stack, until reaching the last membrane and producing a measurable quantitative signal. In case the tested sample doesn’t contain the target analyte, the HRP-conjugated antibodies will bind to the analyte immobilized on the blocking pad, will not continue to flow through the stack and therefore will not produce a signal.