Xenogeneic native decellularized matrix carrying PPARγ activator RSG regulating macrophage polarization to promote ligament-to-bone regeneration.

Host immune response to tissue engineering tissues or organs directly determines the graft survival and the integration with host. Our and other previous studies have successfully regenerated the organs/tissues based on allogeneic native decellularized matrix (aNDM). But the very limited aNDM clinically hinders the artificial organs/tissues application to resolve the native organs/tissues loss with high incidence. However, the xenogeneic NDM will induce host immune rejection leading to the transplantation failure. This study constructed the xenogeneic (porcine) NDM (xNDM) which carried the immunoregulator Rosiglitazone (xNDM-RSG), a synthetic highly selective agonist of peroxisome proliferator-activated receptor-γ (PPARγ), evaluated xNDM's physical and chemical characterization, immunomodulatory properties, and its effect on the tissue regeneration. Results showed that the xNDM-RSG did not affect the proliferation and differentiation of odontogenic stem cells. In addition, the xNDM-RSG could also effectively decrease the expression of IL-1 and TNFα, and increase the expression of IL-10 and TGFβ to enable a favorable immunomodulation and promote the ligament-to-bone regeneration by PPARγ to induce the alternative activated macrophages (M2 macrophages) antagonizing classically activated macrophages (M1 macrophages). Meanwhile the xNDM-RSG obviously reduces the implants absorption and promotes the regenerated ligament-to-bone expressing the key proteins (ALP, OPN, DSP) which are relative to the native dental and bone. This study demonstrated that protein adsorption could aggravate the immune inflammatory reaction, whereas, xNDM-RSG could effectively control the host immune response to accelerate tissue reparation and regeneration by facilitating the macrophage polarization, which highlighted a new strategy for improving the transplantation survival of the artificial organ or tissue based on the xenogeneic decellularized biomaterials.