A polymer microstructure array for the formation, culturing, and high throughput drug screening of breast cancer spheroids

Markovitz-Bishitz, Yael; Tauber, Yishay; Afrimzon, Elena; Zurgil, Naomi; Sobolev, Maria; Shafran, Yana; Deutsch, Assaf; Howitz, S.; Deutsch, Mordechai

doi:10.1016/j.biomaterials.2010.07.050

Cited by 76 publications

(81 citation statements)

References 29 publications

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“…Although the detailed chemical structures and additives are not known, NOA shows a wide range of elastic modulus (6 MPa–2.5 GPa, available from the provider’s website). 116 As a cell culture scaffold, sub-100-nm NOA patterns have been used for culturing endothelial cells, 95 fibroblasts, 104 human embryonic stem cells, 111,112 and breast cancer cells 101 without significant adverse effects.…”

Section: Synthetic Polymers and Their Properties/uses In Patterning Mmentioning

confidence: 99%

Patterning Methods for Polymers in Cell and Tissue Engineering

et al. 2012

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Polymers provide a versatile platform for mimicking various aspects of physiological extracellular matrix properties such as chemical composition, rigidity, and topography for use in cell and tissue engineering applications. In this review, we provide a brief overview of patterning methods of various polymers with a particular focus on biocompatibility and processability. The materials highlighted here are widely used polymers including thermally curable polydimethyl siloxane, ultraviolet-curable polyurethane acrylate and polyethylene glycol, thermo-sensitive poly(N-isopropylacrylamide) and thermoplastic and conductive polymers. We also discuss how micro- and nanofabricated polymeric substrates of tunable elastic modulus can be used to engineer cell and tissue structure and function. Such synergistic effect of topography and rigidity of polymers may be able to contribute to constructing more physiologically relevant microenvironment.

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Section: Synthetic Polymers and Their Properties/uses In Patterning Mmentioning

confidence: 99%

Patterning Methods for Polymers in Cell and Tissue Engineering

et al. 2012

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“…Immersion of spheroids in a bath of media throughout culture eliminates media evaporation and resulting alterations in drug concentrations inherent to hanging drop-based approaches [8, 19, 20] . Adapting this approach to robotic liquid handling allows formation of consistent size spheroids in standard 96-well plates, each well containing a single spheroid, to allow biochemical assays of cell responses in situ using plate readers, which is essential for efficient high throughput screening applications in drug discovery and development [6, 20, 21] . Robotic media exchange and addition of drugs and reagents and biochemical analysis of spheroids viability using standard plate readers is convenient and straightforward.…”

Section: Discussionmentioning

confidence: 99%

High Throughput, Polymeric Aqueous Two‐Phase Printing of Tumor Spheroids

Atefi

Lemmo

Fyffe

et al. 2014

Adv Funct Materials

115

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This paper presents a new 3D culture microtechnology for high throughput production of tumor spheroids and validates its utility for screening anti-cancer drugs. We use two immiscible polymeric aqueous solutions and microprint a submicroliter drop of the “patterning” phase containing cells into a bath of the “immersion” phase. Selecting proper formulations of biphasic systems using a panel of biocompatible polymers results in the formation of a round drop that confines cells to facilitate spontaneous formation of a spheroid without any external stimuli. Adapting this approach to robotic tools enables straightforward generation and maintenance of spheroids of well-defined size in standard microwell plates and biochemical analysis of spheroids in situ, which is not possible with existing techniques for spheroid culture. To enable high throughput screening, we establish a phase diagram to identify minimum cell densities within specific volumes of the patterning drop to result in a single spheroid. Spheroids show normal growth over long-term incubation and dose-dependent decrease in cellular viability when treated with drug compounds, but present significant resistance compared to monolayer cultures. The unprecedented ease of implementing this microtechnology and its robust performance will benefit high throughput studies of drug screening against cancer cells with physiologically-relevant 3D tumor models.

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“…For example, primary hepatocytes and articular chondrocytes maintained their organ-specific functions when they were cultured as spheroids but not when grown in monolayer cultures [18]. Various spheroid fabrication techniques that employ nonadherent surfaces [19], spinner flasks [20], hanging drop methods [21], micropatterning of cell-adhesive/non-adhesive surfaces [22,23], and micromolding [24,25] have been reported. Microwells consisting of thermoresponsive hydrogel have been used not only to generate spheroids but also to subsequently release them via a temperature-induced change in the hydrogel [26].…”

Section: Formation and Collection Of Spheroidsmentioning

confidence: 98%

Cell Detachment for Engineering Three-Dimensional Tissues

Enomoto

Kakegawa

Osaki

et al. 2015

Hyper Bio Assembler for 3D Cellular Systems

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Dynamic control of the biointerface between adherent cells and materials may provide a promising approach for the detachment and manipulation of cells in vitro. Thermoresponsive, electroresponsive, photoresponsive, pH-responsive, and magnetic systems have been reported as mechanisms for such control. These systems have been utilized to detach specific cells in a spatially controlled manner and to assemble cellular building blocks such as cell sheets and spheroids to engineer three-dimensional tissues and organs. Because assembled and thicker tissues require vascular networks to supply oxygen and nutrients throughout the constructs, some of these systems have also been employed to fabricate vascular structures in engineered tissues. This chapter provides an overview of the current technological advancements in the dynamic control of the biointerface, with particular emphasis on tissue engineering applications. A major focus of this chapter is on the application of electrochemistry to cell detachment and to engineering vascular structures. Current challenges and future prospects of these systems have been discussed.

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A polymer microstructure array for the formation, culturing, and high throughput drug screening of breast cancer spheroids

Cited by 76 publications

References 29 publications

Patterning Methods for Polymers in Cell and Tissue Engineering

Patterning Methods for Polymers in Cell and Tissue Engineering

High Throughput, Polymeric Aqueous Two‐Phase Printing of Tumor Spheroids

Cell Detachment for Engineering Three-Dimensional Tissues

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