3D bioprinting of in vitro brain metastasis model

Rivers twist and turn when viewed from above, and the grains of sand flow along the curves, settling in places where the currents slow. Similarly, recent research suggests that the winding paths of blood vessels might trigger the development of metastatic cancers, a topic gaining considerable attention in academia.

A collaborative team led by Professor Dong-Woo Cho and PhD candidate Wonbin Park from the Department of Mechanical Engineering at Pohang University of Science and Technology (POSTECH), along with Professor Byoung Soo Kim and PhD candidate Jae-Seong Lee from the School of Biomedical Convergence Engineering at Pusan National University, and Professor Ge Gao from the School of Medical Technology at Beijing Institute of Technology, utilized 3D bioprinting technology to reproduce in the laboratory intricate brain blood vessel structures. Their primary focus was on uncovering the impact of blood vessel curvature on the movement of tumor cells circulating within the brain. The groundbreaking research findings were published in Nature Communications, and were prominently featured as an Editors’ Highlight in the Biotechnology and Methods section.

Brain metastasis, often categorized as terminal due to its grim prognosis and the challenges in treatment, occurs when cancer cells, having detached from other tissues, navigate the intricate maze of blood vessels deep within the brain to initiate the disease. While several in vitro models have been developed to study its onset mechanisms, understanding the impact of physiological factors within brain blood vessels and their anatomical structures on metastatic cancer development has been a significant hurdle.

The team developed a specialized bioink tailored explicitly for creating brain blood vessels. The models 3D-printed using the conventional ink faced challenges in accurately replicating intricate cerebral vasculature, as they encountered difficulty in preserving the structure until complete solidification. To tackle this issue, the team created a hybrid brain-derived decellularized extracellular matrix (BdECM) by blending decellularized extracellular matrix sourced from the brain with alginate extracted from seaweed. This innovative hybrid BdECM, comprising collagen and some 2,000 other protein types, rapidly stabilizes after printing, enabling the precise replication of more intricate brain blood vessel structures than previously achievable.

The team utilized this advanced technology to engineer functional brain blood vessels comprising multiple cellular layers—endothelial, surrounding, and astrocyte/neuron layers—with varying curvatures. Their analysis of how circulating tumor cells responded to the cerebral vascular structure revealed a crucial finding: an increase in blood vessel curvature can correlate with a heightened adherence of cancer cells to the vessel walls. Furthermore, the team investigated the molecular-level mechanisms underlying metastatic cancer development through the interactions between cancer cells and brain vascular tissues.

Subsequently, the researchers employed computer simulations with the brain blood vessel model to examine factors like blood flow velocity and wall shear stress, and biophysically explored the correlation between cerebral vascular curvature and cancer cell extravasation.

Professor Dong-Woo Cho, who led the study, explained, “By examining the molecular and dynamic elements of cancer extravasation through bioprinted cerebrovascular models, we’ve delved into the disease’s onset mechanisms. We envision leveraging this technology for drug development aimed at treating brain metastasis.”

This study was conducted with the support from the Alchemist Project by the Ministry of Trade, Industry and Energy and the Korea Planning & Evaluation Institute of Industrial Technology, the cross-ministry Korea Fund for Regenerative Medicine, and the National Research Foundation of Korea grants, including the Young Researcher Program and the Medical Research Center Program.