Performance of nasal chondrocyte-based engineered tissues in osteoarthritis simulating environments

Abstract

Osteoarthritis (OA) is the most prevalent musculoskeletal disease in humans, characterized by a progressive degeneration of the articulation that causes pain and disability in a large percentage of the population. In this pathology, the joint environment becomes predominantly catabolic and concentrations of circulating pro-inflammatory factors significantly increase as compared to nonpathological conditions. Up to date, existing treatments can be effective in reduction of pain and improvement of mobility, but none of the available therapies is able to stop the progression of the disease. Non-degenerative cartilaginous lesions can be currently treated with cell-based approaches, consisting of the implantation of autologous chondrocytes into the defect site, those cells being isolated from presumable non-affected areas of articular cartilage. Differentially, OA is considered a contraindication for such treatments and, in the scarce cases they have been used for patients with degenerative traces, failure is reported as the more common long-term outcome. Possible causes of these results are the inferior chondrogenic capacity and phenotype stability demonstrated for articular chondrocytes (AC) harvested from affected joints, but also, the detrimental conditions of the OA environment, potentially compromising the performance of any implanted cell-based product. Nasal chondrocytes (NC) represent an alternative source for cell and tissue engineering approaches, since they can be obtained from a compartment that is not affected (i.e., the nasal septum), and show more reproducible capacity to generate functional cartilaginous tissues as well as similar responses to mechanical and inflammatory stimuli than AC. In fact, tissue engineered cartilage derived from nasal chondrocytes (N-TEC) have been already used in the clinic for the treatment of post-traumatic cartilage lesions, but not results are generated regarding their potential to additionally treat OA defects. In order to assess such potential, it is necessary to evaluate if N-TEC can survive and maintain their tissue-like properties in the pro-inflammatory and catabolic OA environment, to which cells from the different joint tissues (cartilage, synovial membrane and subchondral bone) contribute. The pillar of this thesis, my PhD dissertation, consists on the exploration of the suitability of NTEC for the treatment of OA lesions. Therefore, this manuscript summarizes methods and outcomes resulting from investigating the interactions between nasal chondrocytes and cells/tissues from OA-joints, as an approach to establish the possible compatibility of N-TEC within an OA cartilage defect. Results showed that N-TEC could maintain their cartilaginous properties, when exposed in vitro to inflammatory stimuli as those found in OA joints, and positively influence the inflammatory profile of cells from OA joints through secreted factors. Moreover, N-TEC were able to survive and engraft into OA compartments simulated in vivo, while preserving cartilaginous matrix properties and dampening inflammation, as observed in vitro. Acknowledging the positive and wide compatibility of N-TEC within OA environments that I demonstrated, the clinical application of autologous N-TEC was tested in two patients with advanced OA, who would have been otherwise considered for partial knee – prosthetic - replacement. After 14 months of implantation, patients have reported reduced pain as well as improved joint function and life quality; all findings indicating that N-TEC can be envisioned as a therapeutic approach for the repair of osteoarthritic knee cartilage defects. To assess efficacy of this procedure, a phase II trial would be required in a larger cohort of patients.