Targeted Tissue Engineering: Enhancing Mesenchymal Stem Cell Localisation and Therapeutic Support for Cartilage Repair

Osteoarthritis, the most common form of arthritis, is a progressive degenerative disease of cartilage and the synovial joint. Since cartilage is an avascular tissue with a limited capacity for self-repair, mesenchymal stem cells (MSCs) are a potential therapeutic for cartilage regeneration. Local intra-articular delivery of MSCs has shown to slow the progression of cartilage degradation, however MSCs likely stimulated repair locally and not by direct engraftment to the cartilage. It is considered that insufficient numbers of cells are retained at the cartilage surface for effective repair and that increasing MSC localisation at the cartilage surface may in turn enhance the efficacy of engraftment and/or creation of a local MSC reparative environment. With an objective to increase cellular localisation at the diseased cartilage surface, methods of cellular targeting to the diseased cartilage surface were investigated. The adhesive 'Pullulan' was assessed for capacity to increase cell localisation in a non-specific manner. MSCs demonstrated biocompatibility and an upregulation of Dectin-2 receptor associated with an immunomodulatory response in the presence of the bioadhesive, with enhanced cell adhesion on pullulan coated degraded cartilage explants. Using a more specific approach, a dual-functioned construct, consisting of an arginine-glycine-aspartic acid (RGD) peptide to pre-coat MSCs and an anti-degraded collagen II antibody for degraded cartilage was developed to target cells, thereby increasing the numbers of cells localized. The peptide/antibody construct demonstrated enhanced MSC adhesion at the degraded cartilage surface; in addition, RGD alone showed comparable targeting efficiency in vitro and construct biocompatibility with MSCs was demonstrated. In conclusion, several methods of specific and non-specific viable cellular localisation where shown to have potential for enhancing localisation of MSCs at a degraded cartilage surface with additional beneficial MSC responses observed, such as enhanced proliferation, differential potential and potential immunomodulation.

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University of Galway Theses (PhD Theses)