Periodic Reporting for period 1 - BABHY-CART (Self-Healing Hydrogels for Material-Assisted Cell therapy in Osteoarthritis)
Reporting period: 2020-12-31 to 2022-12-30
Peripheral joint osteoarthritis (OA) is an incurable and painful disease. As the most common rheumatic disease, it affects approximately 65 % of the population over 65. OA results primarily in the inflammation and destruction of the cartilaginous tissue, and can further expand to all structures of the joint, including bone and synovial membrane. Treatment normally involves palliative measures to reduce pain and swelling, and total joint replacement is often inevitable at a later stage of the disease. Over 70 million Europeans are currently affected by OA – a number that is set to increase with aging population and prevalence of obesity. OA is expected to become the 4th leading cause of world-wide disability by 2020-2030, with an estimated burden to society as high as 817 billion euros/year for total costs in Europe. To date, no clinically-efficient therapy exists to treat this socioeconomically debilitating disease. In this context, innovative regenerative therapies for joints are a pressing medical challenge. The overall objective of the BABHY-CART project is to develop a novel hydrogel-assisted cell therapy for osteoarthritis treatment. To succeed, we envisioned to design an injectable hyaluronic acid (HA)-based hydrogel with long-lasting viscoelastic properties, mechanically suited for intra-articular injections, and that would enhance the immunomodulatory properties of encapsulated stem cells.
Overview of the results:
A series of injectable hydrogels was developed, using a newly-discovered boronate ester-based crosslinking strategy. We successfully demonstrated that optimal hydrogels are minimally- to non-swelling, stable long term (over months), tunable in terms of composition (e.g. polymer, peptide) and mechanical properties, and cytocompatible. We further characterized their viscoelastic and self-healing properties, highlighting their ability to be injected. In parallel, a series of covalent (non-viscoelastic) hydrogels was developed as controls for our investigations. Using these tunable hydrogels, we investigated the effect of the composition (e.g. polymer, peptides) and mechanical properties of the hydrogels on the secretion of encapsulated stem cells. We showed that hyaluronic acid (HA) in association with viscoelastic properties tend to increase the secretion of immunomodulatory factors by encapsulated stem cells. The investigation of subcutaneous injections of our hydrogels confirmed that the new viscoelastic hydrogels are stable for weeks in vivo, and do not trigger marked inflammatory response. Stem cells encapsulated in an optimal HA-based hydrogel were delivered in a rabbit model of OA. Our preliminary results suggest that delivering stem cells in an HA-based viscoelastic hydrogel reduces the variability in efficacy of intra-articularly delivered stem cells for the treatment of OA.
Exploitation and dissemination:
The newly-discovered crosslinking strategy has been patented (#EP 20 162 062.2). As a tunable hydrogel platform, the new hydrogels are are now being used in the context of several collaborations. These include a project dedicated to the improved delivery of neural progenitor cells, and one dedicated to the 3D culture of retinal organoids. Two new industrial collaborations are also been developed to use these gels, for tissue engineering applications and for the investigation of in vitro cell-material interactions in the context of aging, respectively.
A series of injectable hydrogels was developed, using a newly-discovered boronate ester-based crosslinking strategy. We successfully demonstrated that optimal hydrogels are minimally- to non-swelling, stable long term (over months), tunable in terms of composition (e.g. polymer, peptide) and mechanical properties, and cytocompatible. We further characterized their viscoelastic and self-healing properties, highlighting their ability to be injected. In parallel, a series of covalent (non-viscoelastic) hydrogels was developed as controls for our investigations. Using these tunable hydrogels, we investigated the effect of the composition (e.g. polymer, peptides) and mechanical properties of the hydrogels on the secretion of encapsulated stem cells. We showed that hyaluronic acid (HA) in association with viscoelastic properties tend to increase the secretion of immunomodulatory factors by encapsulated stem cells. The investigation of subcutaneous injections of our hydrogels confirmed that the new viscoelastic hydrogels are stable for weeks in vivo, and do not trigger marked inflammatory response. Stem cells encapsulated in an optimal HA-based hydrogel were delivered in a rabbit model of OA. Our preliminary results suggest that delivering stem cells in an HA-based viscoelastic hydrogel reduces the variability in efficacy of intra-articularly delivered stem cells for the treatment of OA.
Exploitation and dissemination:
The newly-discovered crosslinking strategy has been patented (#EP 20 162 062.2). As a tunable hydrogel platform, the new hydrogels are are now being used in the context of several collaborations. These include a project dedicated to the improved delivery of neural progenitor cells, and one dedicated to the 3D culture of retinal organoids. Two new industrial collaborations are also been developed to use these gels, for tissue engineering applications and for the investigation of in vitro cell-material interactions in the context of aging, respectively.
The patented hydrogels have shown promising results in a pre-clinical model of OA. As such, the project is now supported and co-funded by the French Institution for Technological Transfer Acceleration (SATT), and will allow us to soon test our hydrogel-assisted cell therapy in a big animal model, before a possible clinical transfer to humans in the coming years. In the long term, successfully improving the efficacy of stem cells for the treatment of OA could have a major impact on the lives of hundreds of millions of people wordlwide.