Post-traumatic Osteoarthritis (PTOA) has been linked to a prolonged pro-inflammatory response induced by tissue-trauma. Approximately 40% of patients suffering from joint trauma such as anterior crucial ligament rupture develop PTOA, and the number remains at 37% following reconstruction surgery. This suggest that the onset of PTOA is linked to the initial biological trauma, and not solely due to mechanical instability. We hypothesized that injury complexity and level as well as health status of the patient together play a role in PTOA onset. To investigate the early response to joint intervention, peripheral blood and synovial fluid was isolated prior, 24h- and 6 weeks post intervention. Cellular composition, matrix characterization and biomolecules was investigated employing a combination of flow cytometry, histology, immunohistochemistry and MALDI-imaging. The obtained samples were benchmarked against samples isolated from functional(regenerating) and dysfunctional(developing PTOA) pre-clinical joint injury models. Analysis of the early mechanism of healing in the clinical and pre-clinical models confirmed a corresponding trend between the intervention/trauma level and the immediate response in terms of immune-cell response, skeletal progenitor cell activation and matrix production. The obtained results confirmed that both the neutrophil activation status, availability of mature T-cells and trauma level significantly affects the healing response at an early phase of healing (p<0.5). Interestingly, scRNASeq from the affected joint environment confirmed a failed transition from the innate to the regenerative immune response when joint healing fails. To test whether the failed transition was the underlying cause for the failed tissue regeneration, an immunomodulatory cell treatment was developed based on joint-activated and pro-regenerative immune cells that was co-cultured with placenta derived progenitor cells. The treatment was injected intra-articularly one week post defect creation and evaluation in regards of treatment efficacy for PTOA resolution was investigated after 11 weeks. It was confirmed that the immunomodulatory cell treatment averted PTOA development in the pre-clinical model with a fully regenerated articular unit confirmed based on histology, OARSI scoring and IHC analysis for Collagen type 2 and Lubricin. These results confirm the integral role of the balanced activation of pro-inflammatory immune cells and pre-regenerative immune- and skeletal progenitor cells for functional tissue regeneration upon trauma or surgical intervention. The presented research suggests a mechanism of molecular, cellular, and matrix-based alterations preceding unresolved healing and thus the opportunity identify diagnostic and therapeutic targets for early clinical intervention.
Bolander et al. (Mon,) studied this question.