Metastases, particularly those to vital organs such as the brain, are the ultimate killers in cancer. Predicting how and where cancer will metastasize is pivotal to a fundamental understanding and treatment of cancer progression. Forces and flows can govern where circulating tumor cells deposit in vascular beds, but predicting the site of deposition has proven impossible to date. Computational fluid dynamics models have been developed to address this problem, but the models must be validated against physical vascular models of controlled geometry.
To answer this need, we bioprinted living models of human brain vasculature and compared the behavior of these controlled, interrogable, living analogs to computational fluid dynamics simulations of increasing complexity. Our resulting three-dimensional, flow-based, long term bioreactor mimics the blood brain barrier in vitro and was used to directly challenge, refine, and validate a computational model of brain cancer metastasis. We used the computational model and bioprinted analogs to decouple biological and physical aspects of circulating tumor cell attachment to the vascular endothelium, which represents the first step in metastatic colonization of a distant organ. This first ever bioprinted blood brain barrier has a range of applications, such as rapid drug discovery, personalized medicine, and counterterrorism. Our intersectional study using tumor biology, bioengineering, and computation represents a new approach to training computational models of biological processes and provides new access to the fundamental biology and biophysics of metastasis.
This work supported and leveraged Lawrence Livermore National Laboratory's core competencies in bioscience and bioengineering as well as high performance computing, simulation, and data science, and it directly supports the Laboratory's initiative on predictive biology through computation and experimentation. The research addresses the biosecurity mission of the Laboratory in the area of medical countermeasures for rapid mitigation of evolving threats, and it advances science, technology, and engineering competencies that are the foundation of the NNSA mission.
Hynes, W., et al. 2019. "Bioprinting the Blood-Brain Barrier Microenvironment for the Validation of a Computational Model for Cancer Metastasis." Tissue Engineering and Regenerative Medicine International Society, Orlando, FL, December 2019. LLNL-POST-797978.
Moya, M.L. and E. K. Wheeler, 2017. "3D Dynamic Blood Brain Barrier Model." Tissue Engineering and Regenerative Medicine International Society, Charlotte, NC, December 2017. LLNL-PRES-713825.
Moya, M., et al., 2017. "Bioprinting the Blood-Brain Barrier Microenvironment for the Validation of a Computational Model for Cancer Metastasis." Biomedical Engineering Society Conference, Phoenix, AZ, October 2017. LLNL-POST-732748.
——— . 2018. "Bringing Life to 3D Printing: Bioprinting Vascular Networks for Engineered Tissues." Bay Area Biomedical Device Conference, San Jose, CA, March 2018. LLNL-PRES-748634.
——— . 2018. "CNS and BBB Experimental Models with Enhanced Cellular Complexity and Architecture." World Preclinical Congress Blood Brain Barrier Conference, Boston, MA, June 2018. LLNL-PRES-753318.
——— . 2018. "3D Bioprinting Microenvironments for Cancer Metastasis." World Congress Tissue Engineering and Regenerative Medicine International Society, Kyoto, Japan, September 2018. LLNL-POST-757479.
——— . 2018. "3D Models to Understand Neurotoxicity." Superfund Research Program Conference, Sacramento, CA, November 2018. LLNL-POST-763022.
——— . 2019. "Bioprinted Blood-Brain Barrier Mimic for Modeling Cancer Metastasis." Poster Rock Stars of Regenerative Engineering, San Francisco, CA, January 2019. LLNL-POST-765066.
——— . 2019. "3D Models to Understand Complex Neural Networks and Neurotoxicity." World Preclinical Congress Blood Brain Barrier Conference, Boston, MA, June 2019. LLNL-PRES-765368.
——— . 2019. "3D Bio-Printed Microenvironment for Studying Cancer Metastasis." Gordon Biomaterials and Tissue Engineering Conference, Castelldefels, Spain, August 2019. LNL-POST-782137.
——— . 2019. "Engineered 3D BioPrinted Model for Studying Cancer Metastasis." Biomedical Engineering Society Conference, Philadelphia, PA, October 2019. LLNL-POST-793358.
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