Infrapatellar fat-pad MSC-based osteochondral tissue engineering and chondrocyte niche engineering for osteoarthritis

Abstract

Osteoarthritis (OA) is the most prevalent joint disease which affects millions of individuals globally, OA is commonly found at loading bearing joints such as the knee of the elderly population or athletes, and significantly impacts an individual’s quality of life by causing joint pain, inflammation, and functional disability. Current treatment options remain undesirable with limited disease modifying options, conservative therapies centres around pain alleviation, whereas minimally invasive surgical options including microfracture or autologous chondrocyte implantation (ACI) regenerates unsatisfactory fibrocartilage. These undesirable treatment options often lead to severe OA progression and inevitability of the highly invasive total knee replacement (TKR) as a final resort.

Tissue engineering holds tremendous promise in providing an alternative approach in developing innovative OA therapeutic treatments, to directly restore, replace or regenerate the damaged OA joint tissue. Osteochondral tissue engineering specifically aims to fabricate autologous biphasic or multiphasic grafts that deliver correct recapitulation of the native zonal organization of the articular cartilage for improved functional outcome. In addition, the understanding of cartilage extracellular matrix (ECM) at the cellular level, and interactions between chondrocyte and its surrounding niche are also fundamental for such complex osteochondral tissues to be engineered. The interpretation of structural, biochemical and biomechanical factors within the chondrocyte niche that improves cartilaginous matrix secretion and maintenance provides valuable insights for improving existing osteochondral tissue engineering models and scaffold designs.

Chapter 2 focused on chondrocyte niche engineering, investigating chondrocyte cell behaviour at the cellular level with microenvironmental changes. With the use of multiphoton based microfabrication and micropatterning (MMM) technology, a library of single or combinatorial topological, biomechanical, and biochemical niches were successfully fabricated, and niche factors which promotes chondrogenic expression were elucidated. A multiplex triple-niche factor containing fibrinogen (FGN), epidermal growth factor (EGF) at an elastic modulus of 30kPa demonstrated excellent chondrocyte chondrogenic upregulation, maintenance, and morphology after a three-stage screening study.

Chapter 3 explored the possibility of infrapatellar fat-pad derived mesenchymal stem cells (IFP-MSCs) as an alternative MSC source for osteochondral tissue engineering. The differentiative potential of IFP-MSCs towards both chondrogenic and osteogenic lineages were examined and optimised via collagen microencapsulation platform. Large scale engineered cartilage tissue and osteochondral tissue (eOCT) were also fabricated and compared with tissues assembled using bone-marrow derived MSCs (BM-MSC). IFP-MSC derived eOCT demonstrated exceptional zonal recapitulation of articular cartilage, displaying a tri-layered construct consisting distinct cartilage, osteochondral interface, and bone layers.

Chapter 4 investigated towards the development of a post-traumatic OA animal model and examined the feasibility of anterior cruciate ligament transection (ACLT) at generating OA-like cartilage degeneration in rabbits, in preparation of downstream in vivo evaluations of hIFP-MSC derived engineered cartilage tissue and eOCT.

This work demonstrated IFP-MSC derived osteochondral tissue engineering is achievable with promising results. MMM technology is a robust platform for fabricating biomimetic niche and provides beneficial knowledge on niche factors capable of maintaining chondrogenic phenotype for subsequent eOCT implementation and improvements. The findings of this study paved the path for development of more advanced osteochondral tissues as a potential therapeutic option for OA in the future.