Advances in microfluidic biofabrication technology for bone metastasis modeling.

Studying bone metastasis in in vitro models is essential for understanding the mechanisms driving this process, developing effective therapeutic strategies, and evaluating potential treatments for metastatic cancer patients. To this end, traditional two-dimensional (2D) cell culture models fail to replicate the native three-dimensional (3D) tissue microenvironment, resulting in significant disparities in biologically relevant behaviors and drug responses. The shift from 2D to 3D cell culture techniques represents an important step toward creating more biomimetic bone metastasis models. These systems more effectively emulate and replicate the complex interactions between cancer cells and bone tissue, including essential cell-cell and cell-extracellular matrix interactions, as well as in vivo biomechanical cues. The development and application of microfluidic-based 3D cancer models, incorporating diverse shapes, architectures, and modular structures such as organ-on-chip platforms, enable comprehensive screening and exploration of cellular interplay, the dissection of signaling pathways, and the resolution of limitations associated with traditional models. This review highlights recent advancements in microfluidic-based 3D bone metastasis models and examines innovative applications of this technology. These include hydrogel-based spherical and filaments biofabrication approaches, 2D and 3D tumor on-a- chips, and drug screening techniques such as concentration gradient generator-based, microdroplet-based, and microarray-based chips, as well as tumor tissue chips. Additionally, we discuss the benefits and limitations of these approaches in treating bone metastases and propose future directions for advancing microfluidic platforms in drug discovery and this research field.