8 Table 2 Commercial development of in vitro models and applications. Company 3D Biomatrix 3D Biotek Avanticell Science Ltd.

BD Biosciences BellBrook Labs Biocrystal Ltd. Biopredic International Capsant Cellasic Corp Cellendes Core technology

Z. Li, Z. Cui / Biotechnology Advances xxx (2013) xxxxxx

Application 3D spheroid culture, tumorsphere formation, and chemosensitivity testing 3D Perfused spheroid models for stem cell/tissue engineering and drug discovery 3D medium throughput screening and drug discovery 3D cell culture Enzyme screening, and 3D perfusion culture Cancer immunotherapy Parallel testing Liver drug toxicity testing Stem cell derived 3D human neuron tissue models for drug testing High throughput screening 3D cell culture and high-throughput screening In vitro BBB toxicity and permeability testing High throughput screening Suspension culture for hepatocyte and stem cells culture in vitro toxicity testing 3D hydrogel scaffolds for cell culture and toxicity testing

References www.3dbiomatrix.com www.3dbiotek.com www.avanticell.com www.bdbiosciences.com www.bell-brooklabs.com Ohio-based, USA www.biopredic.com www.capsant.com www.cellasic.com www.cellendes.com www.cellial.com www.drugmode.com www.bercellsystems.com www.glycosan.com www.hepregen.com www.hurelcorp.com www.insphero.com www.invitroskin.com www.invivosciences.com www.kirkstall.org www.kiyatec.com www.mattek.com www.microtissues.com www.organovo.com

Perfecta3D hanging drop spheroid model Microfabricated polystyrene 3D insert scaffold 3D cell-based assays physiologically relevant alternatives to animal testing for drug discovery PuraMatrix self-assembly peptide hydrogel Transcreener HTS assay and iuvoMicroconduit Array Plates OptiCell technology Suspension culture Liverbeads3D alginate-based liver model Hi-spot technology & airliquid interface culture system

3D microuidic tools for cell biology research 3-D Life Hydrogels, dextran-based biomimetic hydrogel scaffolds Cellial Central Nervous System (CNS) models DrugMode Microgravity bioreactor to form liver spheroids FiberCell Systems Inc. Hollow bre cell perfused bioreactor system Glycosan Biosystems Hepregen HUREL Corp. InSphero Invitroskin InvivoSciences LLC Kirkstall Ltd. KiYATEC MakTak Microtissues Inc. Organovo Extracel, Glycosil and HyStem are PEG-based hyaluronic enrich hydrogel Micro-patterned co-culture human hepatocyte Microuidic devices and cell culture technology

PRECOS Protista RegeneMed Inc. Reinnervate Ltd. Robio Systems Ltd. SCIVAX SkinEthic Laboratories Solidus Biosciences, Inc. Tissue Growth Technologies Transparent Inc. VistaGen Weikai Bioeng Ltd. Wyss Institute

Zyoxel Ltd.

High throughput screening Multi-tissue cell-based human assays for drug toxicity testing and screening GravityPLUS 3D hanging drop cell culture platform Liver microtissues for toxicology and tumour microtissues for oncology study Multilayer 3D EPISKIN skin model Research, safety and chemical toxicity testing Microuidic bioreactor system and 3D human tissue based Engineered tissue for grafting or implantation study and high-content analysis phenotypic screening. Quasi-vivo system, a perfused bioreactor & on-line monitoring Provide in-vivo-like conditions for cell growth system 3D cell culture perfused chamber and based on co-culture 3D cell culture, liver and breast cancer cell models for system drug discovery EpiDerm 3D human epithelial tissue equivalents Safety assessment, gene expression analysis and drug discovery 3D Petri dish-agarose-based microstructures technology Tissue models for high-throughput screening Drug discovery NovoGen MMX Bioprinter a novel hardware and software platform for 3D cell culture 3D co-culture cancer models that clinically relevant Cancer oncology study and drug discovery oncology Cryogel, 3D macroporous hydrogel. Platforms available for 3D biodegradable matrices for cell culture. cell-based 96-well plate assays. Human-based tissue models (co-culture) ADME/Toxicity high throughput evaluation Alvetex, a polystyrene scaffold for 3D tissue formation Stem cell and 3D neuron model for drug testing 10-Well IVM DEVICE, a microuidic embryo culture Long-term culture embryos and shipment of fresh and transport platform embryos and oocytes at cool conditions. 3D spheroids culture on nano-culture plate (NCP) Cancer model and liver model for drug testing 3D human skin and epithelial models Skin corrosion, slin, ocular and oral irritation, (e.g. corneal, oral, gingival and vaginal epithelial) pigmentation and phototoxicity Drug safety on a Chip (Meta-Chip and Data-Chip High-throughput toxicity screening technology) DynaGenmechanical stimulation bioreactor System Various bioreactors for cartilage, bone, skin and for 3D cell culture and tissue growth cardiac tissue formation and parallel drug testing Cell-able 3D insert technology 3D spheroid liver model for drug testing Human Clinical Trials in a Test Tube a stem Toxicity prediction cell biology platform 3D cell culture for drug testing, hepatocyte Liver tox, neural tox testing, cancer/diabetes and islet culture drug testing 3D perfused lung, intestine, kidney and bone Organ-on-a-chip, a multi-channel 3D microuidic cell marrow models are used for drug screening. culture chip that simulates the entire organs and organ systems. TissueFlex and LiverChip 3D perfused Human-based tissue 3D perfused cell culture, stem cell application models and drug toxicity & efcacy evaluation

www.precos.co.uk www.protista.se www.regenemed.com www.reinnervate.com www.robiosystems.com www.scivax.com www.skinethic.com www.solidusbiosciences.com www.tissuegrowth.com www.transparent.co.jp www.vistagen.com www.weikaibioeng.com Wyss.harvard.edu

www.zyoxel.com

5.1. 3D perfusion cell cultures for drug toxicity testing In vitro 3D cell culture systems that can mimic organ and tissue structure and function in vivo, will be of great benet for drug discovery and toxicity testing. Development of in vitro 3D human tissue/organ models is of particular important as rodents or other animals can metabolize and respond to drugs differently from humans (Olson et al.,

2000). The 3D human models could potentially replace some animal testing and provide more reliable and predictive data for the early screening of human drug toxicity in the preclinical phase of drug development (Khademhosseini et al., 2006; Kunz-Schughart et al., 2004; Langer and Tirrell, 2004). The earlier that in vitro toxicity testing is performed in the drug development process and the more predictive of the data, the more it can save in terms of time and cost associated

Please cite this article as: Li Z, Cui Z, Three-dimensional perfused cell culture, Biotechnol Adv (2013), http://dx.doi.org/10.1016/ j.biotechadv.2013.10.006