SLAS special issue editorial 2022: 3D cell culture approaches of microphysiologically relevant models

A 2 C Not long ago, researchers were skeptical of the value of culturing ells in a 3D environment. Today, 3D cell culture has become a routine ool that plays a vital role in drug discovery and life sciences research. D cell culture approaches are still relatively new despite their early mpact, and there is still ambiguity in the robustness of culturing techiques, the readiness of supply chain, and even the use of nomenclature epicting 3D morphology. The value of 3D cell cultures is defined by the ncreased dimensionality and access to contact between cells to generate phenotype predictive of in vivo biology but performed in vitro. Cellell interaction is fundamental, independent of whether 3D structures re called spheroids, organoids, organotypic, acinar structures, assemloids, or tumoroids, of course, a phenotype is agnostic to terminology. The fast pace of the 3D cell culture field has been fueled by the need or predictive in vitro outcomes, but it still faces many challenges. In toay’s world impacted by the Covid-19 pandemic, supply chain struggles ave hampered fast progress in the last two years with the inconsistent vailability of plastics, biologics, and reagents needed for 3D cell culure. New tools and protocols can function as catalyzers to make up for he lost productivity in these challenging times. A range of commercially vailable platforms has emerged to address practical and biological chalenges when culturing cells in 3D. This special issue is particularly timely, as it showcases results from ifferent enabling tools that help keep the pace and accelerate the adopion of in vitro 3D cell culture models beyond existing challenges. Reroducible protocols, standardization, miniaturization, scalability, and hroughput will push cell culture technologies across the chasm. The ighlighted enabling tools in this issue are magnetic 3D cell culture and ioprinting, matrix coated plates and inserts, spontaneous aggregation sing cell repellent surfaces with round-bottom microwells, microfludics, and artificial intelligence (AI) for image analysis of organoids. The first article, a review by Rodboona et al. [1] , gives a detailed verview of magnetic 3D bioprinting technology applied to generate acrimal gland organoid cultures for high-throughput analysis and drug iscovery. Following this work, the original research by Fernandez-Vega t al. [2] screened 150K compound library using magnetic 3D bioprintng and round bottom plates against primary pancreatic organoids; this s the first report of a high-throughput screening of this scale using linically relevant pancreatic tumor model generated from patient biopies. The next original research article, by Avelino et al. [3] , combines agnetic 3D cell culture and omics analysis by mass spectrometry to emonstrate adipocyte-derived spheroids can reproduce aspects of in ivo physiology that are not present in monolayer cultures. Stepping nto the artificial intelligence (AI) realm, Powel et al. [4] combine deep earning tools and brightfield images of patient-derived organoids to enerate a label-free and non-invasive method for monitoring organoid

Not long ago, researchers were skeptical of the value of culturing cells in a 3D environment. Today, 3D cell culture has become a routine tool that plays a vital role in drug discovery and life sciences research. 3D cell culture approaches are still relatively new despite their early impact, and there is still ambiguity in the robustness of culturing techniques, the readiness of supply chain, and even the use of nomenclature depicting 3D morphology. The value of 3D cell cultures is defined by the increased dimensionality and access to contact between cells to generate a phenotype predictive of in vivo biology but performed in vitro. Cellcell interaction is fundamental, independent of whether 3D structures are called spheroids, organoids, organotypic, acinar structures, assembloids, or tumoroids, of course, a phenotype is agnostic to terminology.
The fast pace of the 3D cell culture field has been fueled by the need for predictive in vitro outcomes, but it still faces many challenges. In today's world impacted by the Covid-19 pandemic, supply chain struggles have hampered fast progress in the last two years with the inconsistent availability of plastics, biologics, and reagents needed for 3D cell culture. New tools and protocols can function as catalyzers to make up for the lost productivity in these challenging times. A range of commercially available platforms has emerged to address practical and biological challenges when culturing cells in 3D.
This special issue is particularly timely, as it showcases results from different enabling tools that help keep the pace and accelerate the adoption of in vitro 3D cell culture models beyond existing challenges. Reproducible protocols, standardization, miniaturization, scalability, and throughput will push cell culture technologies across the chasm. The highlighted enabling tools in this issue are magnetic 3D cell culture and bioprinting, matrix coated plates and inserts, spontaneous aggregation using cell repellent surfaces with round-bottom microwells, microfluidics, and artificial intelligence (AI) for image analysis of organoids.
The first article, a review by Rodboona et al. [1] , gives a detailed overview of magnetic 3D bioprinting technology applied to generate lacrimal gland organoid cultures for high-throughput analysis and drug discovery. Following this work, the original research by Fernandez-Vega et al. [2] screened 150K compound library using magnetic 3D bioprinting and round bottom plates against primary pancreatic organoids; this is the first report of a high-throughput screening of this scale using clinically relevant pancreatic tumor model generated from patient biopsies. The next original research article, by Avelino et al. [3] , combines magnetic 3D cell culture and omics analysis by mass spectrometry to demonstrate adipocyte-derived spheroids can reproduce aspects of in vivo physiology that are not present in monolayer cultures. Stepping into the artificial intelligence (AI) realm, Powel et al. [4] combine deep learning tools and brightfield images of patient-derived organoids to generate a label-free and non-invasive method for monitoring organoid viability over time. Baarsma et al. [5] , in their original Research, give a unique perspective by studying the impact of pollutants in cell physiology using magnetic 3D bioprinting to probe air pollutant-induced lung pathology, as a tool for high-throughput screening and exploring molecular mechanisms. The technical note by Crownwell et al. [6] combines microfluidics and magnetic 3D bioprinting towards personalized medicine applications for profiling drug effects in patient-derived spheroids with the long-term goal of improving personalized treatments. The final article, a technical note by Stern et al. [7] , uses CellRaft® to generate clonal mouse hepatic and pancreatic organoids, where single organoids can be tracked over time using brightfield and fluorescent microscopy.
We thank the valuable contribution of the authors, the SLAS staff, and the editors who helped assemble this special collection, as well as the scientific reviewers for their valuable and thoughtful evaluations of the science. There is a critical need to continue an open dialogue regarding 3D cell culture and microphysiologically relevant models to improve research reproducibility, increase efficiency in drug discovery, and reach predictive outcomes to improve and save lives.

Declaration of Competing Interest
Glauco R. Souza reports a relationship with Greiner Bio-One, Inc., that includes employment. Timothy Spicer declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this issue.

Timothy Spicer
The Scripps Research Institute, Jupiter, FL, USA