Automation of 3D Cell Culture Using Chemically Defined Hydrogels

Rimann, Markus; Angres, Brigitte; Patocchi-Tenzer, Isabel; Braum, Susanne; Graf‐Hausner, Ursula

doi:10.1177/2211068213508651

Cited by 21 publications

(19 citation statements)

References 15 publications

(21 reference statements)

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“…These advances are in the form of a multitude of approaches including microfluidics [83,84,85] and novel scaffold/hydrogel designs [86,87]. These models have the potential to reduce the cost of materials and allow integration of elements, such as perfusion, that are unable to be incorporated into other models.…”

Section: Towards More Complex Assays Suitable For Integration In Dmentioning

confidence: 99%

Advanced Cell Culture Techniques for Cancer Drug Discovery

Lovitt

Shelper

Avery

2014

Biology

222

218

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Human cancer cell lines are an integral part of drug discovery practices. However, modeling the complexity of cancer utilizing these cell lines on standard plastic substrata, does not accurately represent the tumor microenvironment. Research into developing advanced tumor cell culture models in a three-dimensional (3D) architecture that more prescisely characterizes the disease state have been undertaken by a number of laboratories around the world. These 3D cell culture models are particularly beneficial for investigating mechanistic processes and drug resistance in tumor cells. In addition, a range of molecular mechanisms deconstructed by studying cancer cells in 3D models suggest that tumor cells cultured in two-dimensional monolayer conditions do not respond to cancer therapeutics/compounds in a similar manner. Recent studies have demonstrated the potential of utilizing 3D cell culture models in drug discovery programs; however, it is evident that further research is required for the development of more complex models that incorporate the majority of the cellular and physical properties of a tumor.

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Section: Towards More Complex Assays Suitable For Integration In Dmentioning

confidence: 99%

Advanced Cell Culture Techniques for Cancer Drug Discovery

Lovitt

Shelper

Avery

2014

Biology

222

218

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“…Biological inert synthetic polymers have also been developed for achieving tunable gel stiffness with constant ligand density. 74,75 Polyacrylamide (PA) hydrogels may achieve a large range of ECM stiffness by simply altering the relative concentrations of monomer (acrylamide) and cross-linker (bisacrylamide). 76 However, it is not compatible with cell culture directly because of potential toxicities as well as the lack of cell adhesion capability.…”

Section: Ecm and Substrate Propertiesmentioning

confidence: 99%

Advances in Techniques for Probing Mechanoregulation of Tissue Morphogenesis

et al. 2015

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“…Hydrogels containing proteins and ECM components are used to encapsulate cancer cells in micro-porous scaffolds that mimic native ECM and enable cells to adhere, proliferate, spread and migrate in 3D [13, 15, 19, 20, 22, 23, 34, 36, 37]. However, natural gel matrices such as the widely used matrigel contain an ill-defined myriad of growth factors and endogenous components that may exhibit considerable batch to batch variability, and temperature shifts required for gelation can be challenging to automate.…”

Section: Introductionmentioning

confidence: 99%

“…Reproducible calibration of the mechanical and biochemical properties of naturally derived hydrogels can also be difficult. Some of these limitations may be overcome by the use of covalently modified synthetic hydrogels, often based on poly ethylene glycol (PEG) [36]. However, the variable Z-plane locations of 3D colonies, heterogeneity in the size and shape of 3D colonies, and the opacity of gels or matrices can present a challenge to HTS signal capture and/or analysis.…”

Section: Introductionmentioning

confidence: 99%

“…Hydrogels may also limit the penetration of compounds and detection reagents, and for some assay formats, the gels must be dispersed and the cells isolated for subsequent analysis, thereby losing the ability to capture any spatial information. Despite such limitations (Table 1), several groups have developed 3D tumor models in hydrogel scaffolds and used these cultures to assess the potency of small numbers of cancer drugs or for small pilot screens of ≤1,500 compounds [20, 22, 23, 34, 36]. …”

Section: Introductionmentioning

confidence: 99%

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The production of 3D tumor spheroids for cancer drug discovery

Sant

Johnston

2017

Drug Discovery Today: Technologies

311

284

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New cancer drug approval rates are ≤ 5% despite significant investments in cancer research, drug discovery and development. One strategy to improve the rate of success of new cancer drugs transitioning into the clinic would be to more closely align the cellular models used in the early lead discovery with pre-clinical animal models and patient tumors. For solid tumors, this would mandate the development and implementation of three dimensional (3D) in vitro tumor models that more accurately recapitulate human solid tumor architecture and biology. Recent advances in tissue engineering and regenerative medicine have provided new techniques for 3D spheroid generation and a variety of in vitro 3D cancer models are being explored for cancer drug discovery. Although homogeneous assay methods and high content imaging approaches to assess tumor spheroid morphology, growth and viability have been developed, the implementation of 3D models in HTS remains challenging due to reasons that we discuss in this review. Perhaps the biggest obstacle to achieve acceptable HTS assay performance metrics occurs in 3D tumor models that produce spheroids with highly variable morphologies and/or sizes. We highlight two methods that produce uniform size-controlled 3D multicellular tumor spheroids that are compatible with cancer drug research and HTS; tumor spheroids formed in ultra-low attachment microplates, or in polyethylene glycol dimethacrylate hydrogel microwell arrays.

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Automation of 3D Cell Culture Using Chemically Defined Hydrogels

Cited by 21 publications

References 15 publications

Advanced Cell Culture Techniques for Cancer Drug Discovery

Advanced Cell Culture Techniques for Cancer Drug Discovery

Advances in Techniques for Probing Mechanoregulation of Tissue Morphogenesis

The production of 3D tumor spheroids for cancer drug discovery

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