Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - MADIA (Magnetic DIagnostic Assay for neurodegenerative diseases)

Teaser

Early diagnosis of Alzheimer’s Disease (AD) and other Nuerodegenerative Diseases (NDDs) can delay further progression and lead to a better outcome for the patient. Among current diagnostics methods, molecular in-vitro diagnostic devices (IVD) are those with the highest...

Summary

Early diagnosis of Alzheimer’s Disease (AD) and other Nuerodegenerative Diseases (NDDs) can delay further progression and lead to a better outcome for the patient. Among current diagnostics methods, molecular in-vitro diagnostic devices (IVD) are those with the highest potential of an early diagnosis, which is related to the sensitivity, specificity and lower limit of detection (LOD) of the method.

Two approaches were demonstrated to be effective for early detection of AD: i) PET scan for in vivo detection of β-amyloid (Aβ) depositions, and ii) in-vitro analysis of levels of Aβ40, Aβ42, Total Tau (T-Tau), and Phosphorylated Tau (T-Tau) protein in the cerebrospinal fluid (CSF). High level of T-Tau and P-Tau, in combination with low level of Aβ40 or low Aβ42/Aβ40 ratio in CSF, is an indicator used for staging AD.
The invasiveness and high cost connected to the early diagnosis of NDDs hinders their use for primary screening, and highlights a knowledge, and market, gap for IVDs that enable clinicians to carry out their diagnosis in biological samples that are more readily available than CSF, such as blood and saliva, and that can abate the costs of the diagnosis.

The MADIA consortium is developing a highly sensitive device for the early diagnosis of NDDs, capable of recognizing target biomarkers existing at low concentration in treated CSF or blood samples. The device is initially conceived for the diagnosis of AD and Parkinson’s Disease (PD), and increases the threshold sensitivity for the detection of biomarkers towards femtograms/ml, three orders of magnitude greater than the state of the art.

Work performed

The first 18 months were dedicated to the developments of the individual components and solutions for the proposed IVD
The Consortium succeeded to:
- Develop and fabricate a range of aptamer and antibody functional layers as highly selective and robust binding shells for selected biomarkers
- Develop and fabricate two different classes oh high superparamagnetic quality of MNP – 10 nm sized MNP for small (amyloids) biomarkers and 100 nm sized MNP for large size biomarkers. This decision (in contrast with initial one, supposing that all the nanoparticles should be tested with all the biomarkers) allowed for the better organization of effort distribution.
- Identify Planar Hall Effect sensors as most suitable for this technology detectors and achieve already a field sensitivity (further improvable) corresponding to 1000 MNP. PHE as compared to TMR and GMR are more versatile and simpler for assembling with microfluidic channels. This selection was extremely beneficial and will significantly simplify the further assembling tasks.
- Design and assemble an aggregation chamber (prototype realized) for a magnetically guided complexation of MNP with biomarkers, achieving 66% of binding efficiency, lower than the planned 90% value, but sufficiently high for the accomplishment of the project objectives. The consortium identified ways to increase further the efficiency, unveiling that different concentrations of biomarkers require different geometries for aggregation
- Design and accomplish the integration of arrays of detecting sensors and corresponding circuitry in microfluidic channels able to accommodate the diffusion process and its monitoring. Importantly, the proposed technology based on diffusion cannot use microfluidic fluxes, but the whole analyzing process is assembled in microfluidic channels, uses microfluidic tools for inlet and outlet, that is use massively uses the microfluidic skills.
- Perform and extended theoretical modelling putting accurate quantitative basis under the recalculation of biomarker concentrations from diffusivity data and generally indicating technological possibilities going beyond the initial expectations for this technology. It was shown that both monodispersed and polydispersed (with known distribution) nanoparticles can be employed and that even 10% modification of the hydrodynamic radius can be detectable (doubling foreseen in the proposal)
- Last but not least, create a fully collaborative environment involving a broadest multidisciplinary team of physicists, chemists, biologists, engineers, doctors and companies personnel.

Final results

MADIA promotes a diagnostic technology based on size based variations of diffusivity of nano-objects in fluids. It is for the first time that this principle is advanced to the status of diagnostic technology. If successful, and the first 18 months premises are fully positive, the technology will represent opportunities not available yet in the diagnostic area. The technology will be demonstrated in application to neurodegenerative diseases, but is generally applicable to many other cases, where nano-scale biomarkers are well identified indicators of the patient problems.
MADIA plan to achieve ultrahigh sensitivity towards biomarker (and more generally - protein) detection, and indeed the achieved already detection limit of 1000 MNP corresponds to 10-100 femtograms , i.e. better than current technologies. Noteworthily, MADIA technology can also be successfully employed for high concentration of biomarkers (micro-nanograms) providing in this case a higher accuracy for the concentration monitoring. This last option appears compatible with simplest diagnostic tools employed in non-laboratory conditions, such as wearable sensing for monitoring the health on day-by-day mode or in extreme conditions. The two options promise high impact solutions on medium or medium-long terms and the consortium will move on the two strategies in parallel, approaching different stakeholders along these two radically different applications.
In addition, the magnetic aggregation tools may be used for a significand upgrade of the current diagnostic facilities. Indeed a highly efficient magnetic aggregation can be used to enhance the concentration of biomarkers from patient samples and bring those concentrations to values detectable by current equipment (ELISA or similar). This part option may represent the strongest impact line, and what is very plausible, this impact may move on a short or short-medium term.
The consortium plans to further enhance the sensitivity of Hall based magnetic sensors and bring them to qualities currently not available. This may have significant implications in different application areas, even beyond the biomedical field, being the magnetic sensors notoriously employed in various applications (from automotive to smart-home technologies).
Considering the societal implications, the further perfecting of diagnostic capability is of clear benefit for the whole human health system. Moreover, the early diagnostics may allow to develop therapies for diseases currently incurable, among which many neurodegenerative problems, which are often unveiled to late, causing tremendous troubles to patients and having enormous costs for the society.
Also, MADIA technology, expected so far to move on the level of SME companies, is predicted to generate new employment via the creation of new small companies, and hopefully stimulate also the near commercial areas.
The scientific potential of MADIA is mainly concentrated on the bio-functionalisation, where really innovative solutions are promoted, and on the sensing elements. On the other hand the developed diagnostic tool, may acquire an important role in research laboratories, for researches developing new, unavailable yet therapies.

Website & more info

More info: http://www.madia-project.eu/.