Cost-effective microfluidic electronic devices for optimal drug administration based on fractional pharmacokinetics for leukemia treatments

Project Information

MEDLEM

Grant agreement ID: 690876

DOI

10.3030/690876

Project closed

EC signature date 14 December 2015

Start date 1 January 2016

End date 31 December 2019

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 333 000,00

EU contribution

€ 283 500,00

Coordinated by

UNIVERZITET U NOVOM SADU
Serbia

Periodic Reporting for period 2 - MEDLEM (Cost-effective microfluidic electronic devices for optimal drug administration based on fractional pharmacokinetics for leukemia treatments)

Reporting period: 2018-01-01 to 2019-12-31

Summary of the context and overall objectives of the project

Worldwide, more than a quarter of a million people are diagnosed with leukaemia each year – including around 75 000 in Europe – accounting for 2.5 % of all cancers. Significantly, the disease accounts for 35 % of all cancers in children up to the age of 14.

Though leukaemia treatments have advanced rapidly in recent years, the development of new therapeutic strategies and innovative drug delivery devices is considered essential to increasing long-term survival rates and reducing the debilitating side effects of chemotherapy.

The EU-funded MEDLEM project is harnessing advances in nano- and microtechnologies to develop and test a multi-functional and patient-tailored dosing solution for leukaemia patients.

The solution involves microfluidic chips – tiny biomedical devices able to accurately control the flow of drugs into the body – and promises to transform treatments for many diseases that require frequent and carefully regulated doses of medication.

Building on the experience of each team member, the MEDLEM project aims were to bring new technologies together, to form a comprehensive, integrative, multi-functional and patient-tailored therapy, using cutting-edge techniques and real-time analysis of patients’ well-being and response to medications. The MEDLEM team were focused on two main tasks: firstly, capturing pathology and physiology data in computer models combined with specific data about the health and treatment responses of individual patients in order to test the dynamics of different drug administration procedures, and secondly, to use this data to define an optimal dosing solution implemented via a smart microfluidic device.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

"The following activities have been carried out and results achieved in the framework of the MEDLEM project:
• A completely new fractional pharmacokinetical approach in modelling leukaemia treatments was proposed and the corresponding optimal control problem was posed and solved;
• This model was based on the experimental data obtained on patients and experimental animals;
• Two microfluidic chips were designed and manufactured using 3D printing techniques;
• Five new technologies were developed (printed circuit board, xurography, PMDS, SAVA, and hybrid technology) and more than 10 different designs were manufactured;
• Around 10 designs of microfluidic devices were optimised;
• Electronic device for very precise control of drug delivery using different shape of the flow signal was developed;
• The methodology for the collection and storage of white Wistar rats’ blood and plasma as well as brain, urine and feces were developed and their usage as biological samples studied;
• Accuracy, precision, selectivity, recovery and stability of cytostatic drug Methotrexate (MTX) from biological matrices were analysed by a LC-MS method;
• Concentrations from biological samples obtained after MTX intravenous application by microfluidic device were analysed.

The overview of the results and their exploitation and dissemination can be illustrated by following numbers:
• 41 secondments were performed (12 intersectoral and 29 international);
• 2 Workshops, 2 Summer Schools and 1 Final project conference organized;
• 40 published papers in scientific journals;
• 2 book chapter published;
• 29 conference papers reported;
• 2 patent applications submitted;
• 2 PhD dissertations defended;
• 93 dissemination and communication event attended;
• 9 Project Management Board meetings organized;
• 5 follow-up project proposals submitted;
• 2 Researchers’ nights attended;
• 2 International Festivals of Science and Education attended;
• 3 promotional movies created;
• 2 Fairs ""Science for Industry attended."

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The aim of Work package 1 was to propose a fractional pharmacokinetic model suitable for the analysis of methotrexate (MTX) distribution within the human body during a chemotherapy session. This informed the proposal of criterion for optimising chemotherapy administration, providing isoperimetric and minimal toxicity constraints and the development of numerical procedures suitable for the optimal control problem posed. The key novelty of this project was solving the current problem of uncontrolled dosing regimens with an innovative fractional pharmacokinetic model capable of addressing theoretical and practical aspects of treatments simultaneously. Anomalous between-patient rates of perfusion of a specific drug are accounted for in a calculated, optimally individualised drug administration protocol, which is then implemented by the manufactured microfluidic electronic device.

The objective of Work package 2 was to develop and test innovative microfluidic devices for optimal drug delivery using a cost effective rapid prototyping 3D printing process. The MEDLEM team developed microfluidic chips using a 3D rapid prototyping process, but we also created chips in PDMS technology and using a xurographic technique as well as with hybrid processes combining these methods. The MEDLEM project provides modern, flexible microfluidic chips capable of optimally delivering drugs using personalized and tailored nano and micro technologies.

Among the wide variety of drugs that could be chosen to treat cancer, the MEDLEM project addressed the pharmacokinetics of methotrexate (MTX). Being the most commonly used antimetabolite in cancer therapy, MTX was chosen for its wide dose range and because it has an antidote (leucovorine) in clinical use. A special feature of this study was the recognition and monitoring of potential problems at the commencement of MTX administration. This will enable accurate, precise and concise medical measurements to improve therapy and reduce side effects, transforming patients’ experiences and long-term prognosis.

Impacts of the project: The MEDLEM project has a significant impact on solving societal challenge such as leukaemia treatment on a creative way through fabrication of cost-effective microfluidic chips for optimal MTX dosage. According to the Innovate Union, strengthening of scientific cooperation between Europe and third countries (in MEDLEM case, Australia and Thailand) will contribute to global approaches and solutions to societal challenges and to the establishment of a long-term partnership. MEDLEM team developed 10 different microfluidic chips capable of optimally delivering drugs using personalized and tailored nano and micro technologies as well as improving leukaemia treatment, providing significant benefit for European and worldwide society.

MEDLEM testemonial at RISE Coordinators day 2020

Textile-based microfludic chip - patented

3D printed microfluidic chip

Developed microfludic chips exposed on Researchers' night 2019