Embryonic development consists of a complex series of cell signaling, cell migration and cell differentiation processes that are coordinated during morphogenesis. Collective cell sheet migration is an important process that sculpts the shape of an organism and its internal tissues during early development. Embryonic development and tissue self-assembly requires the integration of cell movements within multiple cell layers composed of different cell types. Considering the important role cell mechanics plays in tissue self-assembly it is surprising that little is known about the mechanical response of the multi-layer tissues to chemical cues. One of the reasons of this knowledge gap is the lack of the technologies to analyze the individual responses of epithelial and mesenchymal cell sheets in a multi cell layer tissue to mechanical cues. To investigate the processes that guide collective movements of multiple cell layers our group has focused on developing a novel microfluidic technique capable of producing complex patterns of laminar multicellular structures. We call this technique “3D tissue-etching” by analogy with the silicon micromachining techniques used to fabricate 3D structures in the MEMS field. We use tissue etching to shape a complex multi-layered embryonic tissue and explore the dynamic collective responses of epithelial and mesenchymal cells in a single tissue. We use a custom-designed microfluidic control system to deliver a range of tissue etching reagents over Animal Cap tissues of Xenopus laevis. Using etching, we produce free-edges of epithelial cells over mesenchymal cells and free-edges of mesenchymal cells. This allows us to study acute mechanical and behavioral response of intact epithelial and mesenchymal cell sheets to removal of neighboring or overlying tissues. The ability to control the multicellular tissues will have high impact in tissue engineering and regeneration applications in bioengineering and medicine.