Delayed Onset of Physiological Loading Promotes Maturation of Avascular Meniscus Healing

We have recently reported an injectable bioactive glue that promotes healing of avascular meniscus tears by controlling the recruitment and differentiation of endogenous synovial mesenchymal stem/progenitor cells. Although our previous studies with bioactive glue have demonstrated the enhanced healing of avascular meniscus tears both ex vivo and in vivo, the functional properties of the healed menisci were still suboptimal compared to native tissues, likely associated with the immaturity of reconstructed tissue matrix. Thus, this study explored a mechanically regulated tissue maturation approach to enhance the functional properties of meniscus healing. To apply the complex physiological loading exerted on menisci, we designed a meniscus-specific bioreactor system for our well-established wedge-shaped meniscus explant injury healing model. A finite element model confirmed that the bioreactor exerts a combinational loading consisting of compression, tension, shear, and hoop forces, as reminiscent of physiological loading. In terms of timings of loading, we found that a delayed onset of dynamic physiological loading, initiated 5 weeks after bioactive glue application, was significantly more effective in maturing tissue integration than early loading onsets. The improved meniscal tissue integration was dependent on the magnitude of femoral compressive loading. In addition, the application of hoop strain with femoral compression significantly improved the maturation of multi-directional collagen fiber orientations, but applying 10% additional shear strain resulted in poor tissue integration. Together, our data suggests that the onset timing, magnitude, and mode of physiological stimulation play essential roles in the matured healing of avascular meniscus tears guided by our bioactive glue.