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Periodic Reporting for period 1 - BLOC (BENCHTOP NMR FOR LAB-ON-CHIP)

Reporting period: 2020-01-01 to 2020-12-31

Metabolic disorders severely affect the EU population, and prevalence is progressing rapidly because of population growth, aging, obesity, and sedentary lifestyles. The WHO estimates over 650 million people globally and more than 29 million Europeans have a chronic liver condition. However, there is limited understanding of liver metabolism changes in vivo that underpin disease progression, especially the transition to non-alcoholic steatohepatitis with the onset of inflammation and cirrhosis progression.
Similarly, diabetes affects about 347 million people and threatens their health. The progression towards type 2 diabetes is an example of a metabolic disease characterized by various organs’ failure, reflecting an evident interdependence between them that needs to be understood to cure this devastating worldwide disease.
However, the role of inter-organ metabolic communication is poorly understood. Studying the cross-talk between diverse cell populations in the liver and pancreas would broaden our understanding of complex systems contributing to metabolic diseases. The development of an in vitro device capable of recreating the physiological interaction among the different cell types in the tissues is an exciting future-changing strategy to unravel how cells and organs communicate.
In BLOC project, we will use Organ-on-a-chip (OOC) devices, which offer new approaches for metabolic disease modeling and drug discovery by providing biologically relevant tissues and organs in vitro integrated with sensing technology. Using these OOC devices, this project will address three unsolved problems:

1. Animal testing. Animal testing presents ethical and cross-species problems, among others. Organs-on-a-chip (OOC) represent a promising in vitro platform to mimic human physiology from cellular to multi-organ level complexity, with the potential to replace animal testing.

2. Personalised medicine. There is a clinical need for personalized treatment prescription to target the disease effectively. OOC can be set up with human cells, allowing for drug screening directly on the patient’s cells or specific population groups.

3. Early response detection. Evaluation of success or failure of a drug with conventional techniques usually requires waiting days to weeks. Conversely, the disruptive dissolution dynamic nuclear polarisation MR technique (DNP-MR) allows measuring immediate changes in metabolic reactions in vivo, increasing the Magnetic Resonance signal by a factor of up to 50,000.

In summary, OOC devices can revolutionize the pharmaceutical industry by enabling reliable and high predictive in vitro testing of drug candidates. The capability to miniaturize microfluidic systems and advanced tissue fabrication procedures have enabled researchers to create multiple tissues on a chip with a high degree of control over experimental variables for high-content screening applications.
This project’s overall objective is to develop a new technology based on magnetic resonance spectroscopy and imaging using dynamic nuclear polarisation (DNP-MR) integrated with OOC devices to monitor disease and evaluate drug response in OOC models.
During this first year of the project, our main results are:
1) We have shown that we can expect the scaffold to be shimmable to the level required to obtain NMR spectra for studying metabolism. As proof of concept, we have developed a protocol to shim the spectrometer with the scaffold in an NMR tube.
2) Regarding Chip design for DNP-MR applications, we have designed two radiofrequency coils, and we have optimized them with different fabrication methods.
3) We have proven the cryogelation allows the generation of a sponge-like scaffold with controllable structural properties and suitable properties for hyperpolarised MR. We have demonstrated that we could create and modulate a wide range of porosity that fits with primary pancreatic and hepatic ’islets’ size and shape.
4) Finally, one final objective was to compare metabolic traits in vivo with those observed in OOC using 13C hyperpolarization. So far, we have started the diet-induced protocol in mice in order to generate a model that presents characteristics of T2D, with the ultimate goal to perform conventional NMR in liver extracts, as well as islet- and liver-on-chips from control and obese mice. The metabolic phenotyping performed so far indicates that these mice gain weight and are glucose intolerant as expected. Moreover, we received the approval of submitted ethical reports to perform the protocol of DNP-NMR in vivo
BLOC Project aims to develop new metabolic imaging applications using next-generation DNP-MR technology that combines bioengineering and biochemical expertise, thus going beyond the State-of-the-art current technologies. While focusing on diabetes outcomes in the pancreatic islet and the liver, the study principles should be equally applicable to other diseases, organs, and metabolites in vitro and in vivo leading to many new avenues of metabolic study.
Our research on OOC is expected to enhance knowledge regarding tissue construction and shows a great promise to treat human diseases. As a cell culture, a tissue uses real human biology to grow together in a fabricated microenvironment in the form of thousands of human cells grown together. Like an animal, it has a functioning, interconnected tissue, with different cell types playing their unique roles in the model organism and mechanical engineering filling in for forces like blood flow and air exchange. In this way, our 3D engineered tissues can help reveal the system-wide effects of a compound without wandering too far from human drug response and toxicology. These tissues will be used in pharmaceutical assays and represent a step toward the ultimate goal of producing in vitro drug testing systems for medical and pharmaceutical industry applications.
BLOC is expected to enhance knowledge regarding tissue construction and shows a great promise to treat human diseases. Fortunately, the involvement of two large high-tech companies, such as OI and MW, will foster BLOC’s future engagement to industrial, clinical, and academic stakeholders to boost its impact. The social short and medium-term impact is to make new analytical tools available to the scientific community, which will strongly reduce the time required for drug development and include these Multi-OOC systems to monitor disease in the healthcare services. From an economic point of view, the BLOC project’s short-term impact is expected to develop suitable OOC platforms for drug development, which could reduce animal testing by a factor of 10. The medium-term economic impact of the established OOC-NMR platforms would be to increase the capability of MR in chemistry research.
So far, we have developed two disease models in vitro, one to study diabetes Type 2 (T2D) and the other to mimic non-alcoholic fatty liver disease (NAFLD). We have created the scaffolds with the necessary properties to embed the cell models and integrate them with the NMR chips, and now, we are ready to start with the intracellular metabolic measurements. We have also already designed and fabricated the chips with new micro coils integrated inside. These new prototypes will allow continuous measurements with an integrated microfluidic system for long term experiments.
NMR tube with the scaffold for cells
Shimming images showing artefact present in scaffold.