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A combined developmental cell biology and tissue engineering approach to repair the articular surface of synovial joints

Periodic Reporting for period 2 - ReSurface (A combined developmental cell biology and tissue engineering approach to repair the articular surface of synovial joints)

Reporting period: 2021-08-01 to 2022-07-31

Articular cartilage lines our joints, allowing for frictionless joint movement. If damaged, the resident cells, articular chondrocytes (ACs), are unable to repair. Instead, a progressive degradation of the cartilage begins, eventually developing into osteoarthritis which affects approximately 10-12% of the adult population and causing pain, stiffness, and inflammation and thus severely impacting quality of life. Early treatment of articular cartilage damage may correct disease progression; however suitable treatments remain inadequate, due to gaps in our knowledge of how this type of cartilage forms from stem cells prenatally, and how it is maintained postnatally. Therefore, the objective of ReSurface was to develop methods to generate and study articular cartilage in the lab, carefully observing how articular cartilage forms and challenge this process with different chemicals to tease out important factors responsible for maintenance of healthy cartilage, and finally design a minimally-invasive device capable of safely delivering therapy to damaged cartilage. Results from ReSurface have pushed the frontiers of human cartilage biology by developing an in vitro model of human articular cartilage development. Previously, cartilage biology was studied using animal models so for the first time, our model allows us to probe early human cartilage development which will have impact across developmental biology and also cartilage disease research. We have performed in-depth analysis of human stem cells as they become articular chondrocytes and continued to study cell behavior over long-term experiments focusing on maintenance of healthy cartilage. As well as generating new insights into human cartilage development, we have identified novel drug targets that could mitigate osteoarthritis progression and designed a minimally invasive delivery device that can carry cells or drugs to sites of cartilage damage. Taken together, ReSurface has formed the basis of series of new therapies that could halt progression of osteoarthritis and remove the need for joint replacement surgery in the near future.
We have developed a method to generate stable articular cartilage tissue in a dish using human pluripotent stem cells and have used this model to study cartilage development over time, gaining a deeper understanding of how the cells produce cartilage tissue and how they respond to injury or aging. We have shown that unlike adult articular chondrocytes which lose their ability to produce healthy articular cartilage when expanded, hPSC-derived articular chondrocytes can produce healthy articular cartilage again and again. They also maintain stable behaviors unlike adult bone marrow derived stem cells. Adult articular chondrocytes are used clinically to treat cartilage damage and adult stem cells are being used in >120 clinical trials for cartilage repair so the result from ReSurface show that the hPSC-derived articular chondrocytes are clinically translatable. The results are currently being prepared for submission to Science Advances. The hyaluronic hydrogel was optimized for delivery of hPSC-derived articular chondrocytes and similar gels have previously been developed within the Duffy lab that can slowly release drugs in vivo, therefore, the work completed during ReSurface is a starting point for the development of new cell and drug-based therapies for cartilage repair. The researcher presented this work was presented at Harvard Medical School, the University of Galway, the Orthopedic Research Society Meeting in 2019, International Society for Stem Cell Research Meeting in 2020, the Center for Skeletal Research Meeting in 2021, and the Gordon Research Conference in Cartilage Biology and Pathology in 2023.
Osteoarthritis affects 10-12% of the population, causing severe pain and immobility, thus affecting quality of life and ability to contribute socioeconomically. With an aging population, the incidence of osteoarthritis is only set to increase and this project is closely aligned with the EU Framework for Research and Innovation for personalizing healthcare by understanding mechanisms of development, improving our ability to manage disease, and to demonstrate new tools for disease management. ReSurface has pushed the frontiers of human cartilage development allowing the field to move beyond the current state-of-the-art therapies and use of animal models to study disease mechanisms. Through ReSurface, we are now able to closely study human joint development for the first time. Several recent systematic reviews have determined that current cell-based therapies for articular cartilage repair are inadequate. We have developed a reproducible protocol for deriving stable articular chondrocytes from hPSCs, cells which produce articular cartilage tissue that appears very similar to healthy native human cartilage. The cells themselves have potential as a treatment for articular cartilage defects caused by trauma, which may in turn inhibit the progression of osteoarthritis. Furthermore, we have also generated datasets capturing the cellular dynamics of developing cartilage. This work has identified new drug targets that could stimulate articular cartilage regeneration in situ, without the requirement of surgery. The successful treatment of articular cartilage defects would limit pain and suffering for patients which would subsequently have socioeconomic benefits by limiting loss of wages caused by time away from work and promote healthy and active aging.
Successful production or cartilage tissues from hPSCs