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“TBI-Dx”: Traumatic Brain Injury Point-of-Care Multiplex in vitro Diagnostic Device

English title “TBI-Dx”: Traumatic Brain Injury Point-of-Care Multiplex in vitro Diagnostic Device
Applicant Sanchez Jean-Charles
Number 181013
Funding scheme Bridge - Discovery
Research institution Département de Science des Protéines Humaines Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Other disciplines of Engineering Sciences
Start/End 01.04.2019 - 31.03.2023
Approved amount 1'635'940.00
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All Disciplines (2)

Discipline
Other disciplines of Engineering Sciences
Neurophysiology and Brain Research

Keywords (6)

traumatic brain injury; Biomarker; microfluidics; proteomics; biosensor; poct

Lay Summary (French)

Lead
“TBI-Dx”: Traumatic Brain Injury Point-of-Care Multiplex in vitro Diagnostic Device
Lay summary

De nos jours, la prise de décisions thérapeutique par le médecin est basée en partie sur la mesure de molécules chimiques ou biologiques dans des fluides comme le sang. La détection et la quantification de ces paramètres se font principalement dans des laboratoires centraux sur des automates complexes. Un nombre limité de molécules est actuellement mesuré au lit du patient, dans le cabinet du médecin de famille ou en pharmacie et ceci malgré des développements importants dans la miniaturisation de dispositifs et les nouvelles possibilités de connectivité. La mesure de paramètres multiples et simultanée dans petit dispositif portable est une façon de réduire les coûts et permettre un diagnostic approprié, particulièrement dans les cas où un paramètre seul manque de performance. Le présent projet propose l’utilisation de la spectroscopie d'impédance électrochimique (EIS) afin de détecter et quantifier plusieurs paramètres biologiques à partir d’une goutte de sang et ceci en moins de 10 minutes.

Plus spécifiquement les buts sont :

  1. Concevoir et développer un prototype du dispositif capable de mesurer cinq protéines différentes avec une limite de quantification inférieures à 100 pg/mL. Le système comprendra une cartouche jetable et sera conçu afin de permettre des coûts de fabrication peu coûteux.
  2. Évaluer la performance du dispositif sur des échantillons cliniques dans le contexte du traumatisme cérébral léger (TCL). En Europe, plus de 2.5 millions de personnes subissent un TCL chaque année. Afin de détecter une potentielle lésion cérébrale le médecin doit effectuer un scanner crânien. Cependant, cette approche est nuisible pour les patients (irradiations), coûteuse et seulement quelques patients auront en réalité une lésion cérébrale (5 % à 8 %). Le développement d’un test permettant d’éviter les scans serait d’un apport crucial pour notre système de santé. Le prototype que nous proposons sera conçu pour permettre l'analyse dans une goutte de sang des cinq meilleurs marqueurs décrits dans la littérature.
Direct link to Lay Summary Last update: 23.12.2018

Responsible applicant and co-applicants

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Abstract

Nowadays therapeutic decision making by the physician is based to a major extent (~70%) on biomarker testing in body fluids such as blood. Detection and quantification of chemical and biological parameters occurs mainly in central laboratories on complex and expensive high-throughput in vitro diagnostics (IVD) systems. Only a limited number of analytes are currently measured at the point-of-care (POC), e.g. in a family doctor’s cabinet or pharmacy. Although powered by advances in device miniaturization and new connectivity as well as communication possibilities, the number of new, commercially successful POC diagnostic instruments capable of meeting clinical utility and cost-effectiveness requirements, is limited. On the other hand, the POC diagnostic market is among the most rapidly growing markets of IVD and decentralized testing has clearly a significant added value to the conventional centralized IVD.. Measuring multiple parameters simultaneously is a way to reduce costs per analysis and allows proper diagnosis of the human disease state, especially in many cases where one single parameter lacks adequate clinical sensitivity and specificity. Electrochemical impedance spectroscopy (EIS) is a label-free detection method that has experienced a lot of technological progress in recent years to reach the readiness level of a technology validated in the laboratory. It is thought to have matured to a level allowing its transition towards becoming a central component of a POC diagnostic system. Electrodes can be individually, chemically functionalized with specific capture molecules such as antibodies to enable simultaneous immobilization and quantification of analyte molecules. Faradaic and non-Faradaic EIS with properly surface-engineered electrodes was shown to be very sensitive with good linear relationships as a function of target molecule concentration. As opposed to standard IVD assays that employ reagents labelled e.g. with fluorescence- or chemiluminescence-tags, EIS measurements necessitate no (or very few) reagent additions and consists of fewer processing steps. There is no need for sophisticated light sources and/or detection methods which makes EIS an ideal candidate for a compact, portable and cost-effective measurement device for POC applications compatible with usability needs of non-specialized staff and general practitioner (GP) settings. The main objective of the TBI-Dx project is to bring this technology to the next readiness level, namely to validate it in a relevant environment and to initiate its demonstration. More specifically the goals are:1.To design and develop a prototype “sample-in-result-out” multi-channel biosensor device capable of measuring five different proteins in solution with nano-to picomolar lower quantification limits (LLOQ), adequate dynamic ranges and precision. The demonstrator system shall comprise cartridge disposables for sample preparation and metering, however, the core part of the project is the smart conception and implementation of a functionalized electrode biochip-based read-out platform for rapid multi-analyte measurement with time-to-results of less than 10 minutes. The prototype system will be designed with low manufacturability costs in mind and use of inexpensive materials. The ligand-modified electrode arrays will be designed in such a way to enable optimal analytical performance characteristics. The molecular ligands and and immobilization chemistry will be carefully selected to support appropriate shelf-life (structural and functional stability), binding kinetics, reproducibility, analytical sensitivity and specificity. To assess the performance of the biosensor system with clinical samples in the context of Traumatic Brain Injury (TBI). Mild traumatic brain injury (mTBI) is common worldwide, with an annual incidence estimated to be above 600/100,000 individuals. In Europe, 2.5 million people suffer a TBI each year. The incidence in elderly patients is increasing. In younger patients road traffic accidents are the most frequent cause of injury; in older patients falls. Sports, army and kids are vulnerable collectives. Clinicians diagnose and distinguish mTBI patients at risk of intracranial lesions using the Glasgow coma scale (GCS) and clinical symptoms such as headache, nausea, vomiting, loss of consciousness and amnesia. The GCS is used to estimate the conscious state and patients scoring between 13 and 15 are classified as having mild TBI (mTBI); indeed the majority of mTBI cases have the GCS best response score of 15. Subsequently, CT scans are often performed to exclude or confirm the existence of brain lesions due to the trauma. However, CT scans are harmful to patients, costly and only a few patients will actually have a brain lesion (5%-8%). Developing decision rules for safely distinguishing between patients who will turn out to be CT-positive and CT-negative could help to avoid many unnecessary CT scans. In the last years, several blood proteins were extensively investigated as potential promising marker for mTBI. The TBI-Dx prototype instrument will be thus designed to permit the analysis of blood or plasma/serum (volume of ~ 50µL or smaller) to detect the five best markers from the most described mTBI biomarkers (H-FABP, S100b, GFAP, Tau, UCHL-1, NFL, amyloidß42, amyloidß40 and IL-10). The prototype sensor can be upgraded to include other biomarkers to be included for analysis. The Geneva University has protected through a patent filing the combination of these markers for mTBI patient screening and their use to avoid unnecessary CT-scans.
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