Synergistic effects of fibrin-enriched adipose decellularized extracellular matrix (AdECM) and microfluidic model on vascularization

Abstract

Vasculature is essential for maintaining the cellular function and balance of organs and tumors. As a key component of the tumor microenvironment (TME), it significantly influences tumor characteristics. Angiogenesis, heavily influenced by the extracellular matrix (ECM), which acts as a structural scaffold and growth factor reservoir, is regulated by various factors. Notably, adipose tissues and adipose-derived stromal cells contribute angiogenic and anti-apoptotic factors that promote angiogenesis. Sustained vasculature is essential for tissue engineering and ex vivo disease modeling. Lack of shear stress from fluid flow leads to vascular instability and regression. Microfluidic models replicate three-dimensional (3D) cultures from original tissues, encapsulate microenvironmental factors, and maintain consistent fluid flow. In our study, we established decellularized adipose ECM (AdECM) derived from bovine sources and engineered a 3D-printed microfluidic device. We observed significant increases in both the length and diameter of vascular networks after coculturing HUVECs and HDFs in a fibrin gel containing 0.5% AdECM. Additionally, gene expression related to ECM remodeling and angiogenesis was significantly enhanced in vasculature cultivated in fibrin gel containing 0.5% AdECM compared to that in fibrin gel alone. The enhanced vasculogenesis was further amplified and sustained by the 3D microfluidic device placed on a rocker during extended cultivation, primarily through the activation of the PI3K and JAK-mediated pathways. Our ex vivo model with vascularized colon tumoroids revealed that integrating AdECM within a microfluidic device correlates with increased tumoroid growth. Therefore, our study underscores the synergistic impact of AdECM and microfluidic device in promoting and sustaining vasculature. This synergy may have significant implications for tissue regeneration and ex vivo disease modeling, facilitating drug testing and efficacy evaluation.