OpenTox Virtual Conference 2021 Session 6
In vitro models of cellular barriers for safety assessment in drug development
Cuanalo-Contreras, Karina; Monteban, Vivian
Epithelial cells border most tissues, establishing a selective barrier that regulates the exchange of solutes, ions, and nutrients between different compartments. These cellular barriers play an important role in the field of toxicology.
Our aim is to raise awareness of the available in vitro cellular barrier models to assess drug safety and the challenges towards the use of these methods to:
- Improve the assessment of drugs
- Increase drug development success rates
- Advance human benefit
- Protect animal welfare
Tissue barriers (TB) serve filtration, secretion, absorption, and excretion functions. In vitro cellular models to study TB are pivotal for:
- Pharmacological research, allowing the study of drug transport across TB
- Integrity assessment of TB before, during, and after drug absorption
- Evaluation of drug toxicity
Current TB in vitro models mimic in vivo conditions. Nowadays it is possible to model the epithelium of the lung, intestine, skin, kidney, and blood-brain barrier, among others (Sakolish, 2016). In addition, techniques to measure barrier integrity and permeability, such as tracer diffusion and TEER, have shed light on the effect and safety of drugs.
TB in vitro models relies on the separation of two compartments to mimic the basolateral and apical sides. This setup provides an environment where cells can differentiate and polarize. The separation is achieved by a semi-permeable membrane used as support for cell growth. Epithelial layers grown in these conditions have in vivo-like transport and permeability qualities (Yeste, 2018), and cells can uptake and secrete drugs. In addition, it is possible to culture cells at the Air-Liquid-Interface (ALI), where cells are exposed to air through the upper compartment, meanwhile, the bottom chamber mimics the vascular side. New systems include the use of microchannels, microvessels, organs-on-a-chip, etc.
In vitro TB allows the use of human cells, eliminating cross-species variability providing human-relevant insights. Their scalability increases reproducibility and statistical power. Their regulatory acceptance is a current challenge, as animal testing has been the gold standard (Burden, 2021). Nevertheless, legislation changes have been a driving force towards the use of more human-relevant in vitro TB models for safety assessment in drug development.
Dr. Karina Cuanalo-Contreras works in the cell culture application division of SABEU GmbH. She did her Ph.D. and postdoctoral studies in Mexico, The University of Texas in Houston, and Northwestern University in Chicago, where she coordinated a multidisciplinary project to test the safety and efficacy of anti-aging drugs and participated in an initiative to generate human origin 3D brain organoids to model Alzheimer’s and Parkinson’s disease. Whereas part of her work was done using animal models, the fact that they don’t recapitulate all aspects of disease in humans, together with the many experimental and ethical concerns, made her transition to cell culture and in vitro assays. She is the recipient of prestigious fellowships and support from the Alzheimer's Association, the Institut Pasteur, and The Ellison Medical Foundation. She is currently focused to help develop higher-quality cell culture products for drug and cosmetic testing and to spread the voice regarding new in vitro technologies towards the 3Rs principle.