Engineering Tissue Microstructure as a Primary Factor of Cell Microenvironment
Engineering Tissue Microstructure as a Primary Factor of Cell Microenvironment
One of the most exciting discoveries in biotechnology and medicine over the past 20 years has been the realization that behaviors of cells not only depend on the cells’ internal factors, such as genes and protein levels, but also depend on the microenvironment the cells are experiencing. As a result, a happy marriage between drug screening and engineering efforts to create physiological cell culture environment has significantly transformed practices in pharmaceutical R&D. New technologies such as 3D cultures, tissue organoids, and organs-on-chips are increasingly popular to replace conventional petri dishes. Investment in new technologies of cell-based screening may significantly bring down the overall cost of drug development, for instance by reducing the number of animals sacrificed and duration of the animal testing.
A cell’s microenvironment encompasses many biological, chemical and physical aspects. Drug developers may want to choose a culture system that controls the factors most crucial to their specific applications. For instance, when the drug target involves directed cell migration, such as during cancer metastasis and angiogenesis; or involves integrin signaling, such as in acute wound healing, in tissue or nerve system regeneration; extracellular matrix (ECM) alignment may strongly regulate the drug response of cells.
For 3D cell cultures in fibrous ECM, such as collagen and fibronectin, it is possible to steer the ECM fibers by controlling the gelation process. Advanced Tissue Microsystem has developed MicroTissue, a device that robustly control the direction and coherence of ECM alignment in 3D cell cultures. Here the coherence quantify the relative level of alignment.
The microstructure of radially aligned collagen ECM created with MicroTissue device from the Advanced Tissue Microsystems Inc.
The microstructure of tangentially aligned collagen ECM created with MicroTissue device from the Advanced Tissue Microsystems Inc.
In a MicroTissue device, cell-embedding ECM is sandwiched between two large liquid reservoirs. Therefore, one can simultaneously control the chemical background such as by forming a drug concentration gradient, or by inducing chemotaxis of the cells. This chemical background and aligned ECM will jointly regulate cell behaviors.
The spectacular images in the above are examples of cell dynamics under joint regulation of mechanical and chemical cues. Just by imposing a chemotactic gradient on top of two distinct configurations of ECM microstructures , we can learn the decision making of breast cancer cells when navigating a complex environment -- just like inside of human body.