A novel rat model of chronic subdural hematoma: Induction of inflammation and angiogenesis in the subdural space mimicking human-like features of progressively expanding hematoma.

Pathophysiological mechanisms of chronic subdural hematoma (CSDH) involve localized inflammation, angiogenesis, and dysregulated coagulation and fibrinolysis. The scarcity of reproducible and clinically relevant animal models of CSDH hinders further understanding the underlying pathophysiology and improving new treatment strategies. Here, we developed a novel rat model of CSDH using extracellular matrices (Matrigel) and brain microvascular endothelial cell line (bEnd.3 cells). One hundred-microliter of Matrigel-bEnd.3 cell (106 cells per milliliter) mixtures were injected into the virtual subdural space of elderly male Sprague-Dawley rats. This approach for the first time led to a spontaneous and expanding subdural hematoma, encapsulated by internal and external neomembranes, formed as early as 3 d, reached its peak at 7 d, and lasted for more than 14 d, mimicking the progressive hemorrhage observed in patients with CSDH. The external neomembrane and hematoma fluid involved numerous inflammatory cells, fibroblasts, and highly fragile neovessels. Furthermore, a localized pathophysiological process was validated as evidenced by the increased expressions of inflammatory and angiogenic mediators in external neomembrane and hematoma fluid rather than in peripheral blood. Notably, the specific expression profiles of these mediators were closely associated with the dynamic changes in hematoma volume and neurological outcome. In summary, the CSDH model described here replicated the characteristics of human CSDH, and might serve as an ideal translational platform for preclinical studies. Meanwhile, the crucial roles of angiogenesis and inflammation in CSDH formation were reaffirmed.