Introduction

Abstract

In the past, the ability to understand the formation, function, and pathology of tissues/organs was mostly dependent on 2D cell culture [1, 2]. However, a drawback of 2D cell culture-based studies is that cells grown in 2D condition are substantially different in their morphology, and in cell–cell and cell–matrix interactions, from those grown in physiologically more relevant 3D environments [3]. This supports the fact that the 2D environment cannot be used to represent the 3D environment in understanding the situation taking place in our body. As an alternative, animal models have been used as a testing platform owing to their similarities with regard to morphology and cell–matrix interactions in 3D as well as bulky supplies. Although they offer plausible results demonstrating the importance of specific molecules and processes, there have still been discrepancies in gene ablation and chemogenomics [4]. Around 50% of drugs that pass preclinical tests turn out to be toxic for humans. As a representative example, researchers at a German pharmaceutical company firstly discovered that thalidomide could relieve morning sickness in pregnant women. After rigorous validation via animal experiments including dogs, cats, rats, hamsters, and chickens, this drug was marketed in 1957 [5]. However, thalidomide was found to cause deformity in children born to mothers who took the drug; the babies were born with missing or abnormal limbs, feet, or hands. It turned out to be toxic for humans and was withdrawn from the market. This incident is vividly remembered as a tragedy showing the inaccuracy and uncertainty of animal experiments, giving us a valuable lesson in drug development. However, this also means that some of the drugs may be nontoxic and effective for humans even if they fail in animal models [6]. This causes rejection of potentially important drugs even before they reach clinical trials. Moreover, animal models are often ineffective in reproducing features of human tumors and autoimmune diseases, which are related with physiological processes, due to the fundamental differences in the evolution of two complex systems. Furthermore, most scientific research involving the use of animals since 2013 has begun with an ethical focus, motivating researchers to find an appropriate substitute for more effective studies [7].