Cartilage tissue engineering - a multidisciplinary approach

Abstract

Degeneration of articular cartilage and associated osteoarthritic changes are the leading cause of compromised joint articulation worldwide. Early stages of osteoarthritis (OA) are characterised by partial thickness chondral defects that fail to heal spontaneously. It is crucial to repair these defects during the early stages of cartilage degeneration to prevent the progression of OA. Currently used clinical interventions however have been unable to completely restore/regenerate damaged articular cartilage to its native state. This has led to considerable interest in the development of effective cartilage tissue engineering strategies for the treatment of chondral defects in an increasing ageing population. The present study aims to address some of the hurdles in cartilage regeneration, in particular, (i) identification of an appropriate cell source, (ii) an understanding the effect of oxygen on cartilaginous matrix formation, and (iii) the application of a novel bioreactor design for the generation of neocartilage grafts. Human articular chondrocytes (HACs) demonstrated excellent cartilage formation in both scaffold-free pellet culture and culture using three-dimensional biomaterial scaffolds. Chondrogenic differentiation of STRO-1-immunoselected skeletal stem cells (STRO-1+ SSCs) was significantly improved by the utilisation of scaffolds with a highly interconnected porous architecture in comparison to scaffold-free pellet culture. The predeposition of SSCs for hypertrophic differentiation however indicated a need for further development of cell culture protocols that may otherwise limit their application in cartilage bioengineering strategies. A combined experimental-computational approach was utilised to infer the likely effects of oxygen tension on cartilaginous matrix synthesis by HACs in the 3-D pellet culture model, from which a threshold oxygen tension (pO2 ≈ 8% atmospheric pressure) that separated collagenous matrix formation from PG deposition was determined. This study has also demonstrated the first successful application of perfusion bioreactor technology in combination with ultrasound cell trapping for the generation of “scaffold-free” neocartilage grafts of HACs that were analogous to native hyaline cartilage. Furthermore, the neocartilage grafts were able to adhere to host articular cartilage and mediate repair of partial thickness chondral defects. The work presented in this thesis has demonstrated the successful application of a multidisciplinary approach, encompassing skeletal cell biology, bioengineering, mathematical modelling and acoustofluidics, for the generation of neocartilage grafts ex vivo that could be ultimately scaled-up and subsequently used in the clinic for resurfacingarticular cartilage defects.

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Identifiers

ORCID for Rahul Tare: orcid.org/0000-0001-8274-8837

ORCID for Bram Sengers: orcid.org/0000-0001-5859-6984

ORCID for Richard Oreffo: orcid.org/0000-0001-5995-6726

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