Korean J Physiol Pharmacol.  2020 Nov;24(6):441-452. 10.4196/kjpp.2020.24.6.441.

Trends in the development of human stem cell-based non-animal drug testing models

• Lee SJ
• Lee HA

• KMID: 2507727
• DOI: http://doi.org/10.4196/kjpp.2020.24.6.441

Abstract

In vivo animal models are limited in their ability to mimic the extremely complex systems of the human body, and there is increasing disquiet about the ethics of animal research. Many authorities in different geographical areas are considering implementing a ban on animal testing, including testing for cosmetics and pharmaceuticals. Therefore, there is a need for research into systems that can replicate the responses of laboratory animals and simulate environments similar to the human body in a laboratory. An in vitro two-dimensional cell culture model is widely used, because such a system is relatively inexpensive, easy to implement, and can gather considerable amounts of reference data. However, these models lack a real physiological extracellular environment. Recent advances in stem cell biology, tissue engineering, and microfabrication techniques have facilitated the development of various 3D cell culture models. These include multicellular spheroids, organoids, and organs-on-chips, each of which has its own advantages and limitations. Organoids are organ-specific cell clusters created by aggregating cells derived from pluripotent, adult, and cancer stem cells. Patient-derived organoids can be used as models of human disease in a culture dish. Biomimetic organ chips are models that replicate the physiological and mechanical functions of human organs. Many organoids and organ-on-a-chips have been developed for drug screening and testing, so competition for patents between countries is also intensifying. We analyzed the scientific and technological trends underlying these cutting-edge models, which are developed for use as non-animal models for testing safety and efficacy at the nonclinical stages of drug development.

Keyword

In vitro model; Non-clinical testing; Organ-on-a-chip; Organoid; Stem cell

Figure

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  Fig. 1 Types of organoids depending on the originated cells and their applications.

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  Fig. 2 Establishment of human disease modeling using organoids. The human disease organoids currently established from the pluripotent stem cells and tissues. References are indicated in brackets.

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  Fig. 3 Status of documents related to nonclinical testing using organoids by year. Global scientific trends in organoid research. A summary of the publications on organoids that are indexed in Scopus according to publication output by year from 2008 to 2019 (Searched date: December 13, 2019).

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  Fig. 4 Status of documents related to nonclinical testing using organoids by country. A summary of the publications on organoids that are indexed in Scopus according to the 12 most frequent affiliation countries of the authors from 2008 to 2019.

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  Fig. 5 Status of documents related to nonclinical testing using organoids by institution. A summary of the publications on organoids that are indexed in Scopus according to the 9 most frequent affiliation countries of the authors from 2008 to 2019. NL, the Netherlands; US, the United States of America; AU, Australia; UK, the United Kingdom.

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  Fig. 6 Number of patent applications by category and country of organoids for a drug screening. The effective patent classification resulted in a total of 335 patents related to a drug screening using organoids. They were divided tissue generation, 3D cell culture method, and tissue or 3D cell culture device/system, using organoids for drug screening, safety evaluation, and efficacy evaluation of drug candidates. The Republic of Korea (KR), the United States of America (US), Europe (EP), Japan (JP), and China (CN).

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  Fig. 7 Comparison of in vitro cell culture models. Summarization of advantages/disadvantages in various cell culture systems with 2D models, 3D models, and microfluidics models.

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  Fig. 8 Number of companies and schools developing organ-on-a-chips. Excerpted from the Organs-on-chips: From Technologies to Market, YOLE (April, 2017) and modified the graph format.

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  Fig. 9 Global technology trends of biomimetic organ-on-a-chip by organ. (A) Percentage of patents for biomimetic organ chips by type of organ from 2003 to 2017. (B) The annual trend of applications for effective biomimetic chip patents by organ types. The gray section represents the unpublished section of the patent.

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  Fig. 10 Patent applications trend by country and year. (A) Percentage of patents for biomimetic organ chips by country from 2003 to 2017. (B) The annual trend of applications for effective biomimetic chip patents by country. The gray section represents the unpublished section of the patent. CN, China; EP, Europe; JP, Japan; KR, Republic of Korea; PCT, Patent Cooperation Treaty; US, United States of America.

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  Fig. 11 Number of patent applications by institution. A summary of the patents on organ-related chip that are indexed in WIPS ON search site according to the 10 most frequent affiliation (13 institutions are reported due to a tie for tenth place). DE, Germany; AU, Australia; CN, China; KR, Republic of Korea; US, United States of America.

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