Automated Cellular Robot-Assisted Technologies for translation of discovery-led research in Osteoarthritis

Project Information

AutoCRAT

Grant agreement ID: 874671

DOI

10.3030/874671

Project closed

EC signature date 2 December 2019

Start date 1 January 2020

End date 30 June 2024

Funded under

• SOCIETAL CHALLENGES - Health, demographic change and well-being

Total cost

€ 7 452 770,00

EU contribution

€ 7 452 770,00

Coordinated by

UNIVERSITY OF GALWAY
Ireland

Periodic Reporting for period 3 - AutoCRAT (Automated Cellular Robot-Assisted Technologies for translation of discovery-led research in Osteoarthritis)

Reporting period: 2023-01-01 to 2024-06-30

Summary of the context and overall objectives of the project

Osteoarthritis (OA), a degenerative disease of joints, is a leading cause of disability worldwide and is associated with severe pain and loss of function. OA can profoundly impact the quality of life for those affected. Recent data indicates that over 651 million people globally suffer from knee OA alone (A. Cui, et al. 2020, doi: 10.1016/j.eclinm.2020.100587). Joint replacement surgery often fails to provide a long-term solution and carries significant risk and cost. Non-surgical options may involve the long-term use of non-steroidal anti-inflammatory drugs and/or opioids for pain management. These treatments aim to provide pain relief and control inflammation, but they do not cure or treat the causes of the condition. Novel stem cell-based therapeutics may deliver better and more efficient treatment options than the palliative options currently available.

Mesenchymal stromal cells (MSCs) have been studied for years as a treatment for OA, with early clinical trials showing promising results. The production of MSCs from tissues such as bone marrow, adipose tissue or umbilical cord obtained from healthy donors or patients means there is a limited, heterogeneous supply, and in the case of bone marrow and adipose tissue acquisition, an invasive procedure is required. Current manual processes to produce MSCs are labour-intensive and expensive and produce inconsistent results. The promise of MSC therapies dictates the need to produce cells at scale and in a consistent and affordable manner to ensure a sustainable supply of high-quality, therapeutic cells.

AutoCRAT aims to develop novel sustainable cell and cell-based therapies for OA. The project is using human-induced pluripotent stem cells (hiPSC) to generate articular chondrocytes for cartilage repair (hiCHO) and human-induced MSCs (hiMSC) for the prevention and treatment of established OA. In addition, the project will investigate the potential of the MSC cell secretome as a next-generation therapy, specifically exploring the therapeutic effect of extracellular vesicles (or EVs) secreted by cells. We aim to produce the therapeutics identified in the project using cost-effective, automated processes with incorporated product testing in a novel manufacturing system to expedite translation to patients.

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

AutoCRAT kicked off in January 2020 and concluded in June 2024. Throughout the project, we have successfully (i) delivered new cell-based therapies for OA and joint repair using a sustainable source of cells, and (ii) developed a closed, scalable, and regulatory-compliant automated system to facilitate the future production of therapeutic products.

We successfully generated and characterised human induced pluripotent stem cell (hiPSC)-derived mesenchymal stromal cells (hiMSCs) and chondrocytes (hiCHOs). These cells demonstrated strong potential for treating OA, as confirmed through extensive testing, including in human cartilage models. The hiMSCs showed significant benefits in promoting cartilage repair and exhibited anti-inflammatory properties.

The project also advanced the development of extracellular vesicle (EV)-based therapies derived from hiMSCs. These EVs were optimised and characterised, indicating their capacity to modulate inflammation and promote tissue regeneration in OA models. Their therapeutic potential was validated in preclinical studies, reinforcing their promise for clinical application.

In addition, a thermosensitive injectable hydrogel was developed and tested in preclinical OA models. This hydrogel proved to be an effective delivery system for hiMSCs and EVs, providing sustained release at the site of cartilage damage and enhancing therapeutic outcomes.

Results to date indicate improvements in cartilage regeneration in OA models, with enhanced therapeutic effects and prolonged retention of cells and EVs at the site when using a combination of hydrogel with cells or EVs. However, further studies are required to bring these results from the lab to the clinic.

We devised and validated scalable, automatable, and adaptive production processes for the cultivation and differentiation of hiPSCs into hiMSCs and hiCHOs, as well as the large-scale culture of these cells. These processes were rigorously tested to ensure they met the standards required for clinical use.

A prototype of ValitaCell’s MSC-specific ChemStress® characterisation tool was successfully manufactured, with ongoing testing yielding promising preliminary data indicating good plate quality.

The automated production systems developed during the project have been demonstrated to produce therapies of equivalent quality to those produced manually, with all processes documented in accordance with Good Manufacturing Practice (GMP) guidelines.

An economic evaluation of these automated processes confirmed their cost-effectiveness, highlighting their potential for broader clinical and commercial applications.

Throughout the project, ethical considerations were carefully managed, ensuring compliance with all relevant standards.

Finally, we have consistently disseminated our results and innovations to reach our target audiences. Further details are available on our website https://www.autocrat.eu and you can find us under 'AutoCRAT' on X, LinkedIn, and Zenodo.

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)

Delivery of new regenerative therapies to benefit patients with OA is AutoCRAT's overarching goal. The innovations we set out to achieve include:
1. Scalable, automated production of hiMSC as a treatment for moderate to severe OA, and to prevent development after joint injury.
2. Scalable, automated production of hiCHO for application as a treatment for cartilage repair.
3. Scalable, automated production of EV derived from hiMSC for treatment of OA and joint injury to prevent development of OA.
4. Assessment, development and production of cell-derived therapies.
5. A novel stem cell characterisation platform based on ChemStress® fingerprinting technology.
6. Novel methods for EV analysis.
7. The Automated Regenerative Medicine Factory (ARM-F).

We believe that AutoCRAT innovations can ultimately lead to:
• Benefits for patients, clinicians and healthcare systems - initially for people with OA, clinicians and the communities around them, but ultimately, we also hope to benefit people with other conditions, healthcare providers and healthcare systems.
• Innovation in the cell therapy industry - improving consistency and efficiency and reducing costs.
• Economic benefits - through reduced costs of cell therapy manufacturing and a reduction in the burden of OA disease.
• Technological impacts - through optimisation of existing technologies and the development of new innovations.
• Impacts on research, knowledge and science – advancing the state-of-the-art and researcher capacity.

We believe that AutoCRAT has laid the necessary foundations to address a significant healthcare challenge, enhance the accessibility of cell therapies, and improve patient outcomes.

AutoCRAT Project Logo

AutoCRAT Team members at plenary in Gothenburg June 2022