Table 2Commercial development of in vitromodels and applications.

Company Core technology Application References

3D Biomatrix Perfecta3D® hanging drop spheroid model 3D spheroid culture, tumorsphere formation, andchemosensitivity testing

www.3dbiomatrix.com

3D Biotek Microfabricated polystyrene 3D insert scaffold 3D Perfused spheroid models for stem cell/tissueengineering and drug discovery

www.3dbiotek.com

Avanticell ScienceLtd.

3D cell-based assays physiologically relevant alternativesto animal testing for drug discovery

3D medium throughput screening and drug discovery www.avanticell.com

BD Biosciences PuraMatrix™ self-assembly peptide hydrogel 3D cell culture www.bdbiosciences.comBellBrook Labs Transcreener® HTS assay and iuvo™Microconduit Array Plates Enzyme screening, and 3D perfusion culture www.bell-brooklabs.comBiocrystal Ltd. OptiCell technology Suspension culture Cancer immunotherapy Parallel testing Ohio-based, USABiopredicInternational

Liverbeads®3D alginate-based liver model Liver drug toxicity testing www.biopredic.com

Capsant Hi-spot technology & air–liquid interface culture system Stem cell derived 3D human neuron tissue modelsfor drug testing

www.capsant.com

Cellasic Corp 3D microfluidic tools for cell biology research High throughput screening www.cellasic.comCellendes 3-D Life Hydrogels, dextran-based biomimetic hydrogel

scaffolds3D cell culture and high-throughput screening www.cellendes.com

Cellial Central Nervous System (CNS) models In vitro BBB toxicity and permeability testing www.cellial.comDrugMode Microgravity bioreactor to form liver spheroids High throughput screening www.drugmode.comFiberCell Systems Inc. Hollow fibre cell perfused bioreactor system Suspension culture for hepatocyte and stem cells

culture in vitro toxicity testingwww.fibercellsystems.com

Glycosan Biosystems Extracel®, Glycosil and HyStem are PEG-based hyaluronicenrich hydrogel

3D hydrogel scaffolds for cell culture and toxicity testing www.glycosan.com

Hepregen Micro-patterned co-culture human hepatocyte High throughput screening www.hepregen.comHUREL Corp. Microfluidic devices and cell culture technology Multi-tissue cell-based human assays for drug toxicity

testing and screeningwww.hurelcorp.com

InSphero GravityPLUS™ 3D hanging drop cell culture platform Liver microtissues for toxicology and tumour microtissuesfor oncology study

www.insphero.com

Invitroskin Multilayer 3D EPISKIN™ skin model Research, safety and chemical toxicity testing www.invitroskin.comInvivoSciences LLC Microfluidic bioreactor system and 3D human tissue based

high-content analysisEngineered tissue for grafting or implantation study andphenotypic screening.

www.invivosciences.com

Kirkstall Ltd. Quasi-vivo system, a perfused bioreactor & on-line monitoringsystem

Provide ‘in-vivo-like’ conditions for cell growth www.kirkstall.org

KiYATEC 3D cell culture perfused chamber and based on co-culturesystem

3D cell culture, liver and breast cancer cell models fordrug discovery

www.kiyatec.com

MakTak EpiDerm™ 3D human epithelial tissue equivalents Safety assessment, gene expression analysis anddrug discovery

www.mattek.com

Microtissues Inc. 3D Petri dish-agarose-based microstructures technology Tissue models for high-throughput screening www.microtissues.comOrganovo NovoGen MMX Bioprinter™ a novel hardware and

softwareplatform for 3D cell culture

Drug discovery www.organovo.com

PRECOS 3D co-culture cancer models that clinically relevantoncology

Cancer oncology study and drug discovery www.precos.co.uk

Protista Cryogel®, 3D macroporous hydrogel. Platforms available forcell-based 96-well plate assays.

3D biodegradable matrices for cell culture. www.protista.se

RegeneMed Inc. Human-based tissue models (co-culture) ADME/Toxicity high throughput evaluation www.regenemed.comReinnervate Ltd. Alvetex, a polystyrene scaffold for 3D tissue formation Stem cell and 3D neuron model for drug testing www.reinnervate.comRobio Systems Ltd. 10-Well IVM DEVICE, a microfluidic embryo culture

and transport platformLong-term culture embryos and shipment of freshembryos and oocytes at cool conditions.

www.robiosystems.com

SCIVAX 3D spheroids culture on nano-culture plate (NCP) Cancer model and liver model for drug testing www.scivax.comSkinEthicLaboratories

3D human skin and epithelial models(e.g. corneal, oral, gingival and vaginal epithelial)

Skin corrosion, slin, ocular and oral irritation,pigmentation and phototoxicity

www.skinethic.com

Solidus Biosciences,Inc.

Drug safety on a Chip (Meta-Chip and Data-Chiptechnology)

High-throughput toxicity screening www.solidusbiosciences.com

Tissue GrowthTechnologies

DynaGen®mechanical stimulation bioreactor Systemfor 3D cell culture and tissue growth

Various bioreactors for cartilage, bone, skin andcardiac tissue formation and parallel drug testing

www.tissuegrowth.com

Transparent Inc. Cell-able™ 3D insert technology 3D spheroid liver model for drug testing www.transparent.co.jpVistaGen Human Clinical Trials in a Test Tube™ — a stem

cell biology platformToxicity prediction www.vistagen.com

Weikai Bioeng Ltd. 3D cell culture for drug testing, hepatocyteand islet culture

Liver tox, neural tox testing, cancer/diabetesdrug testing

www.weikaibioeng.com

Wyss Institute Organ-on-a-chip, a multi-channel 3D microfluidic cellculture chip that simulates the entire organs and organsystems.

3D perfused lung, intestine, kidney and bonemarrow models are used for drug screening.

Wyss.harvard.edu

Zyoxel Ltd. TissueFlex® and LiverChip 3D perfused Human-based tissuemodels

3D perfused cell culture, stem cell applicationand drug toxicity & efficacy evaluation

www.zyoxel.com

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

5.1. 3D perfusion cell cultures for drug toxicity testing

In vitro 3D cell culture systems that can mimic organ and tissuestructure and function in vivo, will be of great benefit for drug discoveryand toxicity testing. Development of in vitro 3D human tissue/organmodels is of particular important as rodents or other animals can me-tabolize and respond to drugs differently from humans (Olson et al.,

Please cite this article as: Li Z, Cui Z, Three-dimensional perfusedj.biotechadv.2013.10.006

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

cell culture, Biotechnol Adv (2013), http://dx.doi.org/10.1016/