In vitro models of tissues. Key industry players in 2021.

Clinical trials are the final step to demonstrate if a new drug is safe and works. Before testing on humans, drugs usually pass numerous preclinical studies. Sometimes a compound seems to be effective in its therapeutic function and non toxic in a preclinical model, but then it fails to perform equally in humans. Actually, it happens most of the time. Statistics from the year 2000 to 2015 [1] show that the average success rate for all drugs and vaccines is only 13.8%. Oncology has an astonishing low 3.4%. Companies spend a lot of money only to fail during clinical testing. And success in this case just means regulatory approval, not automatically that a drug works well, it may be because there aren’t any good alternatives. Trials fail for diverse reasons [2]. Most times failure can be associated with deceptive information from preclinical studies.

The collaboration between biologists and engineers, in academia and in industry, is blooming with new in vitro models of tissues and organs that can improve our understanding of disease and physiology [3-5]. These systems arise fundamentally from the availability of new protocols to produce induced pluripotent stem cells (iPSCs) and differentiate them into several cell types, and from a better understanding of cell culture in 3D microenvironments. They themselves provide new strategies to understand extracellular matrix (ECM) functions, cell-to-cell and cell-to-ECM interactions, matrix mechanical properties in each tissue or pathological condition, growth factor and other molecule-mediated mechanisms, that individually or together can lead to changes in cell phenotype and alterations in drug response.

Organoids and other in vitro models are showing that they can be excellent functional models of human disease and of normal non-pathological function. Research to produce humanised in vitro systems that more closely recapitulate native tissues has an immediate application in making drug discovery more efficient: it improves results of current in vitro methods to screen for drug candidates, allows testing high numbers of molecules, and generally avoids the use of animal models. A different application is personalised medicine and toxicology testing, where in vitro models of our own organs can be used to predict the effect of a particular drug on us, or identify which drug from a cocktail is causing an adverse event.

Recreating complex tissue functionality at microwell or chip scale still remains challenging, but there is a growing number of companies that develop and already offer advanced human in vitro models to support drug discovery and toxicology testing. This is a selection of market leaders and emerging stars (alphabetical order):

BioIVT (USA) – https://bioivt.com. Provider of biological samples including human and animal tissues, cell products, blood, and other biofluids. Services from target and biomarker validation, phenotypic assays to characterize novel therapeutics, to in vitro hepatic modeling solutions. Focus on  hepatic modeling solutions. Supplier of ADME-Tox model systems, including hepatocytes and subcellular fractions.

Biopredic International (France) – https://www.biopredic.com.  Initial focus on primary hepatocyte cryopreservation, now offers the isolation, production and distribution of fresh and frozen human and animal biological products, including tissues, primary cells, cell lines and reagents. Founded in 1993 from a technology transfer of INSERM.

Cellesce (UK) – https://cellesce.com. Bioprocessing technology for the expansion of human-derived cancer organoids. Founded in 2013 on expertise from the University of Bath and Cardiff University.

Crown Biosciences (USA / UK) – https://www.crownbio.com. Preclinical efficacy models, both in vitro and in vivo testing services, for drug discovery in oncology, inflammation, cardiovascular, and metabolic disease. Multinational company, part of JSR Life Sciences since 2018.

Cyprio (France) – https://www.cyprio.fr. Expertise in physicochemistry, liver biology and drug screening. With proprietary technology for the fabrication of spheroids. Created in 2017 at ESPCI Paris.

DefiniGENhttps://www.definigen.com. Human induced pluripotent stem cell (hiPSC) derived hepatocytes, intestinal organoids and pancreatic beta cells. Created in 2012 on results (OptiDIFF platform) from Ludovic Vallier lab at the Wellcome–MRC Cambridge Stem Cell Institute.

Emulate (USA) – https://www.emulatebio.com. Organ-on-a-chip technology for liver, kidney, intestine, brain, and lung. With multicellular configurations, primary cells, relevant ECM components, hardware and software apps. Created around 2013 as a spin-out of Donald E. Ingber lab at Wyss Institute / Harvard University.

Hubrecht Organoid Technology (Netherlands) – https://huborganoids.nl.  Organoids from epithelial tissue derived adult stem cells (ASCs) and related assay services, for applications in cystic fibrosis, cancer, immuno-oncology, toxicology, infectious diseases and other indications. Founded on results from Hans Clevers lab at the Hubrecht Institute for Developmental Biology and Stem Cell Research (KNAW).

Hµrel Corporation (USA) – https://hurelcorp.com. “Microlivers” from self-assembling co-cultures of primary cryopreserved hepatocytes with a non-parenchymal (stromal) cell line.

Kirkstall (UK) – https://www.kirkstall.com. Hardware platform to build organ-on-a-chip type of systems, based on interconnected cell culture flows. Established 2006 initially with technology from the University of Pisa.

Mimetas (Netherlands) – https://www.mimetas.com/en/home/. Microfluidic culture plates for organoids and spheroids. Related services and protocol for some in vitro models. Founded in 2013 in Leiden, the Netherlands. Now over 100 employees in four sites in the Netherlands, USA, and Japan.

STEMCELL Technologies (Canada) – https://www.stemcell.com/. Multinational biotech company with products and services for academic and industrial research, including reagents and culture media kits for the culture of organoids (kidney, intestinal, lung, forebrain) from human stem or primary cells. The intestinal organdie kit is developed with licences from Hubrecht Organoid Technology.

OcellO B.V.  (Netherlands) – https://ocello.nl. Cell line-derived spheroids and organoid models grown in matrix embedded 3D cultures. Patient derived xenografts, tumoroids, models, for oncology, immuno-oncology, inflammation and cystopathy indications. Drug discovery screening services. Created in 2011 on technology developed at Leiden University.

Qgel (Switzerland) – https://www.qgelbio.com. Patient derived organoids based on synthetic hydrogel technology. Cancer, colon, lung, breast, and pancreas applications. Founded in 2009 in Lausanne, Switzerland.

References:

[1] Chi Heem Wong, Kien Wei Siah, Andrew W Lo. “Estimation of clinical trial success rates and related parameters.” Biostatistics, Volume 20, Issue 2, April 2019, Pages 273–286. DOI: 10.1093/biostatistics/kxx069

[2] David B.Fogel. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemporary Clinical Trials Communications, Volume 11, September 2018, Pages 156-164. DOI: 10.1016/j.conctc.2018.08.001

[3] The promise of organoids and embryoids. Nat. Mater. 20, 121 (2021). DOI: https://doi.org/10.1038/s41563-021-00926-3

[4] Small. Special Issue: Advanced In Vitro Models for Replacement of Animal Experiments. Volume 17, Issue 15. April 2021

[5] Horejs, C. Organ chips, organoids and the animal testing conundrumNat Rev Mater(2021).