High Throughput Screening of Cell Mechanical Response Using a Stretchable 3D Cellular Microarray Platform

Abstract

Cells in vivo are constantly subjected to multiple microenvironmental mechanical stimuli that regulate cell function. Although 2D cell responses to the mechanical stimulation have been established, these methods lack relevance as physiological cell microenvironments are in 3D. Moreover, the existing platforms developed for studying the cell responses to mechanical cues in 3D either offer low‐throughput, involve complex fabrication, or do not allow combinatorial analysis of multiple cues. Considering this, a stretchable high‐throughput (HT) 3D cell microarray platform is presented that can apply dynamic mechanical strain to cells encapsulated in arrayed 3D microgels. The platform uses inkjet‐bioprinting technique for printing cell‐laden gelatin methacrylate (GelMA) microgel array on an elastic composite substrate that is periodically stretched. The developed platform is highly biocompatible and transfers the applied strain from the stretched substrate to the cells. The HT analysis is conducted to analyze cell mechano‐responses throughout the printed microgel array. Also, the combinatorial analysis of distinct cell behaviors is conducted for different GelMA microenvironmental stiffnesses in addition to the dynamic stretch. Considering its throughput and flexibility, the developed platform can readily be scaled up to introduce a wide range of microenvironmental cues and to screen the cell responses in a HT way.

Emulating Human Tissues and Organs: A Bioprinting Perspective Toward Personalized Medicine

“… 62 Using extrusion of cell-laden hydrogels into dumbbell-shaped constructs attached to two postholders, it was possible to create an array of tissue models with an anisotropic microstructure displaying aligned myofibrils and the ability to contract. 409 The application of mechanical stimuli to musculoskeletal tissue engineered constructs has been explored as a way to promote cell differentiation and tissue formation using cyclic compression, 410 , 411 tension, 412 or shear. 413 Besides providing a unique environment mimicking physiological forces in vitro, the use of dynamic cell culture systems has been employed as an alternative to medium supplementation with growth factors.…”

“…The application of a mechanical stimulus led to cell alignment along the stretching direction, which was dependent on hydrogel concentration and stiffness. 412 …”

Combinatorial screen of dynamic mechanical stimuli for predictive control of MSC mechano-responsiveness

“…To address this limitation, we and others have previously developed deformable membrane array platforms to study the mechanobiological responses of cells to combinations of environmental cues in two dimensions (23,24). The deformable membrane platforms that we developed and the stretchable substrate array platforms that others developed have also been adapted to enable three-dimensional (3D) mechanical stimulation of cell-seeded biomaterial constructs (25)(26)(27).…”

Designing Gelatin Methacryloyl (GelMA)‐Based Bioinks for Visible Light Stereolithographic 3D Biofabrication

“…Although there have been some studies to directly use an assembly of cells to build 3D constructs, [20] the most common way to build 3D tissues is to use hydrogels as scaffolding materials. [21][22][23][24] There are several advantages associated with the use of hydrogels as they provide a 3D supporting structure along with attachment sites for cells to grow in a 3D microenvironment. Hydrogels are among the most prominent bioinks for biofabrication and tissue regeneration applications.…”