H2020-MSCA-Elveflow - Startup-Technology - Innovation - NBIC Valley Review done thanks to the support of the DeLIVER H2020-MSCA-ITN-2017-Action”Innovative Training Networks”

Grant agreement number: 766181

Written by Alessandra Dellaquila, PhD candidate: alessandra.dellaquila@elvesys.com

 Alessandra-Dellaquila- organ-on-chip-in vitro-in vivo-drug testing-Microfluidics-Elveflow-Startup-Innovation-Technology

Comparison between organ-on-chip and standard in vitro and in vivo systems for drug testing

1. Introduction into in vitro and in vivo models

mouse-organ-on-chip-in vitro-in vivo-drug testing-Microfluidics-Elveflow-Startup-Innovation-TechnologyIn vitro and in vivo models are widely used to investigate human pathophysiology as well as in toxicology studies. The goal of this review is to highlight the main advantages and limitations of each model and to show how the use of organ-on-chip technology can address their drawbacks. The article has been written referring specifically to lung systems (i.e. capillary-alveolar interface) but it applies also to the other organs since the characteristics of common in vivo/ in vitro systems result to be related to the system itself rather than to the organ/ tissue studied.

For a description of the use of the alveolar-capillray barrier for the design of microfluidic lung-on-a-chip systems, you can have a look here.

If you want to learn more about the origin and design of lung-on-chip systems, you can continue reading here.

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2. Overview of in vitro and in vivo models

ANIMAL MODELS [1], [2]

mouse-organ-on-chip-in vitro-in vivo-drug testing-Microfluidics-Elveflow-Startup-Innovation-Technology

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  • Have helped to understand disease (asthma, cystic fibrosis, …) mechanisms
  • Rodent lung injury models can reproduce some aspects of human diseases

 -
  • Different lung anatomy, cells morphology and localization compared to human
  • Partial representation of disease features
  • Difficult to correlate results among labs/ species and to translate results to human clinical trials
  • Ethical, economical and time-related issues

EX VIVO CULTURES (e.g. biopsy samples) [3], [4]

lung-organ-on-chip-in vitro-in vivo-drug testing-Microfluidics-Elveflow-Startup-Innovation-Technology

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  • Retain the normal tissue architecture
  • Enables studies that cannot be performed in vivo

 -
  • Short term viability
  • Barrier properties compromised by external agents
  • Lack of reproducibility

2D cell cultures [3], [4]

cell culture-organ-on-chip-in vitro-in vivo-drug testing-Microfluidics-Elveflow-Startup-Innovation-Technology

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  • Simple system
  • Used clinically for diagnoses (example: tuberculosis assays)

 -
  • Static systems
  • Co-culture of different cell types is impeded
  • No mimicry of the lung airway interface (submerged models)

AIR-LIQUID INTERFACE LUNG MODEL [1], [5]

cell-organ-on-chip-in vitro-in vivo-drug testing-Microfluidics-Elveflow-Startup-Innovation-Technology

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  • Biomimetic stimuli and possibility of cocultures
  • Phenotypes more representative compared to 2D models

 -
  • Lack of 3D environment
  • Not dynamic environment

ORGANOIDS [6], [7]

organoid-organ-on-chip-in vitro-in vivo-drug testing-Microfluidics-Elveflow-Startup-Innovation-Technology

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  • 3D microenvironment
  • Used to study stem cells behaviour
  • Different cellular types are included
  • Can mimic organ development, early-stage disease mechanisms and tumorigenesis

 -
  • Lack of immune and vascular components
  • Lack of control of stem cells behavior and few reproducibility

TISSUE ENGINEERING (1)

Artificial constructs [8]–[10]

tissue culture-organ-on-chip-in vitro-in vivo-drug testing-Microfluidics-Elveflow-Startup-Innovation-Technology

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  • Reproducibility and wide range of fabrication techniques
  • Several materials can be used (natural/ synthetic polymers, nanofibers, …)

 -
  • Difficult to mimic structural/ mechanical forces
  • Non autonomous production of ECM components

TISSUE ENGINEERING (2)

Biological (decellularized) constructs [8]–[10]

lung-organ-on-chip-in vitro-in vivo-drug testing-Microfluidics-Elveflow-Startup-Innovation-Technology

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  • Ability to model ECM-cell interactions
  • Complex 3D architecture is preserved
  • Presence of vascular structure

 -
  • Difficult to seed cells and reconstruct the functionality
  • Decellularization method can affect/ damage the device
  • Variability among species

3. How Organ-on-Chip systems can overcome the limitations of traditional in vitro and in vivo models

Advantages resulting from the fabrication process

  • Modularity and variety of techniques/ materials for microfabrication
  • The chip design can be easily created and modified based on need
  • High reproducibility of fabrication protocols
  • Possibility to integrate sensors for high-throughput analyses
  • Possibility to create personalized models

Advantages resulting from a microscale flow

  • Mimic physiological/diseased mechanical cues at a cellular/ tissue level
  • Create a controlled and dynamic microenvironment
  • Recreate the air- liquid interface (specifically for lung)

Advantages for the cellular/ biological component

  • Create a complex tissue-like environment with several cell types
  • Create modular devices mimicking different organ areas (ex: bronchi, alveoli, …in the case of lung)
  • Reproducing physiological and pathological conditions

Advantages for time/ costs of research

  • Fast fabrication processes (soft lithography, rapid prototyping, …)
  • Possibility to rapidly test drugs/compounds and have high- throughput outcomes
  • Possibility to easily mimic diseases conditions without the need to prepared, maintain and use animal models.

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References

[1]          A. J. Miller and J. R. Spence, “In vitro models to study human lung development, disease and homeostasis,” Physiology, vol. 32, no. 3, pp. 246–260, 2017.

[2]          B. A. Hassell et al., “Human organ chip models recapitulate orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro,” Cell Rep., vol. 21, no. 2, pp. 508–516, 2017.

[3]          C. Blume and D. E. Davies, “In vitro and ex vivo models of human asthma,” Eur. J. Pharm. Biopharm. Off. J. Arbeitsgemeinschaft Pharm. Verfahrenstechnik EV, vol. 84, no. 2, pp. 394–400, Jun. 2013.

[4]          H. Behrsing et al., “Assessment of in vitro COPD models for tobacco regulatory science: Workshop proceedings, conclusions and paths forward for in vitro model use,” Altern Lab Anim, vol. 44, no. 2, pp. 129–166, 2016.

[5]          R. Bhowmick and H. Gappa-Fahlenkamp, “Cells and Culture Systems Used to Model the Small Airway Epithelium,” Lung, vol. 194, no. 3, pp. 419–428, Jun. 2016.

[6]          K. Gkatzis, S. Taghizadeh, D. Huh, D. Y. R. Stainier, and S. Bellusci, “Use of three-dimensional organoids and lung-on-a-chip methods to study lung development, regeneration and disease,” Eur. Respir. J., vol. 52, no. 5, Nov. 2018.

[7]          M. Huch, J. A. Knoblich, M. P. Lutolf, and A. Martinez-Arias, “The hope and the hype of organoid research,” Development, vol. 144, no. 6, pp. 938–941, Mar. 2017.

[8]          A. Doryab, G. Amoabediny, and A. Salehi-Najafabadi, “Advances in pulmonary therapy and drug development: Lung tissue engineering to lung-on-a-chip,” Biotechnol. Adv., vol. 34, no. 5, pp. 588–596, Sep. 2016.

[9]          R. Langer and J. Vacanti, “Advances in tissue engineering,” J. Pediatr. Surg., vol. 51, no. 1, pp. 8–12, Jan. 2016.

[10]        D. M. Hoganson, E. K. Bassett, and J. P. Vacanti, “Lung tissue engineering,” Front. Biosci. Landmark Ed., vol. 19, pp. 1227–1239, Jun. 2014.