Migration in the surrounding microenvironment is the most essential step in the physical translocation of cancer cells from primary tumors to local and distant organs. Although cancer cells can move both randomly and directionally, most of the processes involved in the metastatic dissemination are more efficient when cellular movement is directed. Engineering tumor tissues with the capability to guide cancer cell migration will provide us a feasible in vitro platform to advance metastatic studies. This could be enabled via biomimicking the natural microenvironment of tumor tissues with high requirements of both the precise construction of physical structures and dynamic manipulations of extracellular chemical gradients in 3D cell-laden matrices, which remain critical challenges.
Chemotaxis is the most common mode of directed cell migration, which is demonstrated to be involved in each crucial step of tumor dissemination, such as invasion, angiogenesis, intravasation or extravasation. Therefore, we first manipulate chemical gradients surrounding 3D cultured tumor tissues and program migration pathways of cancer cells in this project. This is achieved by sequential 3D printing of cancer cell-laden natural hydrogels and multiplexed arrays of stimuli-responsive capsules within designed culture chambers. The former is constructed as tumor tissue, while the latter as programmably released chemotactic agents (i.e. growth factors and chemokines) which guide cancer cell migration. The capsules are comprised of an aqueous core with chemoattractant payloads, and a polymer shell functionalized with gold nanorods as photothermal reagents permitting selective photo-rupturing. They allow us to both spatially and temporally generate extracellular chemical cues, and provide a tool for post-printed modulation of cellular activities. Most critically, a fourth dimension (temporal control) will be added to 3D cultured tumor tissues, which has yet to be achieved.
Furthermore, by taking advantage of the manufacturing capabilities of 3D printing, we also integrate perfusable vessels within bioprinted architectures, as a tumor needs a dedicated nutrient supply and a hematogenous path. Aiming to present crucial steps of tumor dissemination, multiple cell types, including cancer cells, stromal cells, and endothelial cells, are incorporated. In addition to guided cancer cell migration, tumor angiogenesis is also dynamically mimicked, for in vitro models of both extravasation and intravasation. These 4D engineered models both physically and chemically reconstruct the surrounding microenvironments of living tumors, which provide a tool to: 1) lead 4D tissue engineering for dynamic mimicking of the in vivo natural microsystem, 2) further understand of the mechanism of metastatic dissemination, 3) test customized strategies of diagnosis and treatment, and 4) screen novel anti-cancer drugs.