Fig. 1

Innate and adaptive immune response against dECM scaffolds. (1) Decellularization strategies inevitably produce various amounts of damage-associated molecular patterns (DAMPs), which trigger pattern recognition receptors (PRRs) on innate immune cells. (2) Stimulation of PRRs in antigen-presenting cells provides prerequisites of T cell activation, including pro-inflammatory cytokine and major histocompatibility complex and co-stimulatory molecules, as well as triggering complement cascade to produce C3a, C3b, and C5a. T cell activation is the essential trigger for B cells, which mediate antibody production against remaining antigens within dECM scaffolds. Antigen-antibody interactions further trigger complement cascades and implement a vicious cycle. (3) C3a and C5a recruit immune cells and induce T helper type 1 (TH1) and TH17 polarization in helper CD4⁺ T cells, increasing the production of pro-inflammatory cytokines. (4) Elevation of pro-inflammatory cytokine content in the implantation site leads to further recruitment of immune cells and induces M1 polarization in naïve macrophages. (5) C3b complements enhance matrix metalloproteinases (MMP) production in M1 macrophages, accelerating the decellularized extracellular matrix (dECM) scaffold degradation and failure