**6.3 Developing the stem cells as advanced medical products for COVID-19**

Currently, there are 82 clinical trials investigating the therapeutic potential of mesenchymal stem cells in COVID-19 patients that are registered on clinicaltrials. gov website; out of all these, 70 trials have (83%) the MSCs as therapeutic agent being tested. The allogeneic bone-marrow or umbilical cord-derived MSCs transplanted intravenously on three different occasions is involved in 21 studies (63%). Most of these trials are either recruiting patients or have not yet started the enrolment. MSCs have been investigated and reported in ARDS both in pre-clinical [201] and clinical settings [127]. Now that, a number of promising trials are currently underway, which could revolutionize the regenerative or MSC-based cellular treatment prospects for severe COVID- 19 patients.

Regardless of how urgent the development of MSC-based therapies for COVID-19 is, it is critically important that the manufacturing of MSCs is in compliance with good manufacturing practices (GMP) and follows strict regulations prior to being approved for the use in humans.

The current findings clearly show that there is a huge unmet need for globally coordinated approach to support to conduct multicentre clinical trials aiming to demonstrate safety and effectiveness of various types of stem cells to treat health complications of novel virus. Also, there is a need in biomedical research and development to establish the most effective stem cell types that are ideally suited for the treatment of the complications.

The development of the stem cell advanced medicinal products will also require: (a) GMP compliant technologies to enable massive stem cell production, and (b) testing platforms that mimic human pathophysiology as much as possible, such as 3D bio-printed organoids, organon- chip, to allow targeted screening and rapid testing of stem cells safety and efficacy. EVs appears as an attractive alternative to cell–based therapy, recently. EVs have several advantages compared to the whole cell therapy including lower risk of oncogenic effects, lower susceptibility to harm by hostile disease tissues and for longer-term storage. The long-term storage is fundamental to make the treatment accessible globally and it surrounds the requirement to have expensive GMP cell manufacturing facilities. The production of EVs must follow the same strict guidelines that apply to stem cells and any EV-based therapy needs to be approved by the health authorities after being tested in clinical trials to demonstrate and confirm the safety and efficacy.
