Abstract
Tunable biomaterials that mimic selected features of the extracellular matrix (ECM) such as its stiffness, protein composition, and dimensionality are increasingly popular for studying how cells sense and respond to ECM cues. In the field, there exists a significant trade-off for how complex and how well these biomaterials represent the in vivo microenvironment versus how easy they are to make and how adaptable they are to automated fabrication techniques. To address this need to integrate more complex biomaterials design with high-throughput screening approaches, we present several methods to fabricate synthetic biomaterials in 96-well plates and demonstrate that they can be adapted to semiautomated liquid handling robotics. These platforms include (1) glass bottom plates with covalently attached ECM proteins and (2) hydrogels with tunable stiffness and protein composition with either cells seeded on the surface or (3) laden within the three-dimensional hydrogel matrix. This study includes proof-of-concept results demonstrating control over breast cancer cell line phenotypes via these ECM cues in a semiautomated fashion. We foresee the use of these methods as a mechanism to bridge the gap between high-throughput cell-matrix screening and engineered ECM-mimicking biomaterials.
Highlights
Synthetic biomaterials are valuable platforms for studying cell behavior in vitro because they capture some features of real tissue microenvironments
The dynamics of microenvironments have been captured in some 3D models by using photoinitiated polymerization to change the hydrogel modulus and ligand density[11] and by creating patterns within a hydrogel to control the spatial arrangement of biochemical cues within the matrix to direct cell phenotype.[12]
We have shown that tumor spheroids encapsulated into 3D hydrogels are drug resistant compared to tissue culture polystyrene (TCPS).[10]
Summary
Synthetic biomaterials are valuable platforms for studying cell behavior in vitro because they capture some features of real tissue microenvironments. Many have used engineered biomaterials to better understand biological processes such as organoid development,[1] stem cell differentiation,[2,3] tumor progression,[4,5] and drug response.[6,7] Bioengineers in the field have developed many different classes of biomaterial systems in which to study cell-extracellular matrix (ECM) interactions These can be protein or peptide-based systems, or made from synthetic polymer precursors.[8] We focus here on this latter class of materials because they are engineered from the groundup, and provide a plethora of tunable characteristics to direct cell function. While these systems capture fluid flow and spatial gradients, they are generally labor-intensive[18] and low-throughput,[17] which makes expansion to large-scale studies a significant challenge
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