Disentangling the fibrous microenvironment: designer culture models for improved drug discovery

Standard high-throughput screening (HTS) assays rarely identify clinically viable 'hits', likely because cells do not experience physiologically realistic culture conditions. The biophysical nature of the extracellular matrix has emerged as a critical driver of cell function and response and recreating these factors could be critically important in streamlining the drug discovery pipeline.

The authors review recent design strategies to understand and manipulate biophysical features of three-dimensional fibrous tissues. The effects of architectural parameters of the extracellular matrix and their resulting mechanical behaviors are deconstructed; and their individual and combined impact on cell behavior is examined. The authors then illustrate the potential impact of these physical features on designing next-generation platforms to identify drugs effective against breast cancer.

Progression toward increased culture complexity must be balanced against the demanding technical requirements for high-throughput screening; and strategies to identify the minimal set of microenvironmental parameters needed to recreate disease-relevant responses must be specifically tailored to the disease stage and organ system being studied. Although challenging, this can be achieved through integrative and multidisciplinary technologies that span microfabrication, cell biology, and tissue engineering.