building vascular networks and Blood-Brain-Barriers through a Biomimetic manufacturing Technology for the fabrication of Human tissues and ORgans

Project Information

THOR

Grant agreement ID: 101099719

DOI

10.3030/101099719

EC signature date 22 December 2022

Start date 1 January 2023

End date 31 December 2026

Funded under

• The European Innovation Council (EIC)

Total cost

€ 3 994 150,00

EU contribution

€ 3 994 150,00

Coordinated by

UNIVERSIDAD POLITECNICA DE MADRID
Spain

Periodic Reporting for period 2 - THOR (building vascular networks and Blood-Brain-Barriers through a Biomimetic manufacturing Technology for the fabrication of Human tissues and ORgans)

Reporting period: 2024-01-01 to 2025-06-30

Summary of the context and overall objectives of the project

Tenths of millions of people with organ failures or suffering from degenerative diseases are waiting for a novel cellular therapy or for a transplant of a donor compatible organ and the immense majority of these patients will die before receiving the tissue or organ they need. Despite the significant advances in tissue engineering, not a single artificial tissue has been used to replace a part of an organ, with the exception of simple or avascular tissues like skin or cartilage.

THOR proposes the development of a revolutionary tissue engineering technology, capable of producing any type of human tissue for organ repair or replacement in case of illness, trauma or degenerative diseases. Patient-tailored tissues will be fabricated by pools of bioinspired mini-robots in fully automated production plants, using the breakthrough incremental technologies of the THOR project:

- self-assembling molecules inspired to the extracellular matrix;
- self-assembling solid and hollow polymeric fibers;
- materials functionalization using photoactivable crosslinkers;
- cutting-edge mini robots to wave 3D self-assembling structures with factors and cells with micrometric precision.

THOR tissue arises from high-resolution 3D spatial positioning of self-assembling structures, angiogenic factors and relevant cell lineages, reprogrammed and expanded in a dedicated bioreactor under controlled conditions.
The overall objective is the construction of a functional piece of hippocampal tissue, a structure that is one of the most plastic regions in the mammalian brain. We aim at creating a precise organization of both neural fibres and vessels, a functioning blood-brain-barrier (BBB) on the microfluidic system with unprecedented life-time expectation.

Our long-term vision encompasses (1) the establishment of a Tissue Engineering industry for personalized organ repair, producing any type of well vascularized and fully functioning tissues and (2) the maintenance of such tissues alive for long periods of time, for an easy transportation to hospitals and clinics, even far from the big cities. THOR will foster the rise of a new industry and of a new biomedical field, while cadaveric donors' transplants will not be necessary.

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 main tasks developed during period 1, as detailed in the Technical Period Report 1 were:

• Working spiderbot. Design and fabrication of a spiderbot with the capacity of creating a fibrillar tissue scaffold in combination with a cell reservoir.
• Availability of SAS. Self-assembled tubular structures were produced that allow connection with the vascular system of the patient. SAS were produced from self-assembling molecules (SAM).
• Reservoir and chip thermalization. A novel microfluidic system was developed that allows controlling the temperature and flow rate in cell cultures, even outside an incubation chamber.
• New generation flow rate sensor. A novel flow rate sensor was designed and constructed that outperforms present sensors in terms of resolution and accuracy.
• Vascular tissue characterization. The conditions for the culture of endothelial cells on SAS and fibrillar SAMs were established. The effect exerted by the presence of the fibrillar SAMs was assessed.
• Co-culture of Organ on a chip and endothelials. The conditions for the co-culture of ex-vivo cultures and endothelial cells were established. The interaction between both systems (ex vivo tissue) and cells were explored.

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)

In relation with the tasks described in the previous section, the main progresses beyond the state of the art are:

• Working spiderbot. The spiderbot is a system that allows creating 3D tissue scaffolds with a technology different to conventional 3D printing.
• Availability of SAS. Biocompatible tubular self-assembled structures (SAS) of controllable permeability can be produced
• Reservoir and chip thermalization. The developed system allows maintaining cell cultures and tissues under physiological conditions without being contained in an incubator.
• New generation flow rate sensor. The novel flow sensor allows measuring flow rates with unprecedented resolution and accuracy.
• Vascular tissue characterization. Endothelial cells were observed to organized in tubular-like structures in cell cultures that contained fibrillar SAMs.
• Co-culture of Organ on a chip and endothelials. It has been possible to co-culture brain tissue and endothelial cells.