**1. Introduction**

It is quite well-known that classical 2D cell lines and *in vivo* models have been used near universally to investigate biological mechanisms and assess novel therapies across a large range of clinical problems [1]. Nevertheless, the results from these experiments are critically limited by a systemic lack of translational power for the response, efficacy, safety, and toxicity in humans despite its primary benefits in clinical research [2, 3]. Cell lines generically display insufficiency and inaccuracy in modeling the immune system, stromal components, and organ-specific functions after multiple passages [4]. Leaving aside animal welfare arguments, speciesspecific variations in organ development and pathogenesis are a long-standing bottleneck due to which animal models cannot mimic a given human disease that is polymorphic, to begin with [5]. Therefore, to define and treat disease pathology seamlessly, biologists exploited the critical features of stem-cell and came up with three-dimensional (3-D) or organotypic cultures or organoids from human samples that could successfully phenocopy cell-type composition, architecture, and to some extent, functionality (e.g., contraction, filtration, excretion, neural activity, etc.) of their natural counterparts [6–8].

Organoids, a term coined for referring to 'mini organs', [9] are best described as *in vitro* three dimensional (3D) cellular clusters exclusively derived from healthy cells – like primary tissue, embryonic stem cells, or induced pluripotent stem cells (iPSCs) [10] or even tumor cells [11]. Since these cells are capable of self-renewal

and self-organization, organoids portray outstanding similarity to organ functionality as the tissue of origin compared to other conventional routes [2, 12]. The sole purpose of developing organoids is to recreate and miniaturize the multicellular structure of organs while retaining the 3-dimensional construct indefinitely.

It can now be commented that the development of organoid technology has generated a robust new methodology to zoom into the physiological events *ex vivo*, and this fact can be explained. Firstly, scientists have a wider domain of cell types to choose from, some of which were historically hard-to-access; secondly, organoids contain multiple differentiated cell types; and thirdly, organoids are genetically stable [13]. The intrinsic nature of this innovative near-physiological technology has created a paradigm shift in our understanding of basic developmental biology or stem cell research directed to a host-pathogen relationship in infectious diseases, degenerative conditions, genetic disorders, oncology, genome engineering, biobanking, and regenerative and personalized medicine [14, 15]. Through a complete visualization of spatiotemporal cellular interactions, organoid modeling reflects the predominant structural and functional properties of essential organs like kidneys [16], lungs [17–20], gut [21], brain [22], prostate [23], heart [24] and retina [25].

Human organoids are intrinsically human-derived, rapid-to-set-up, robust in scaling up, and ideal for genetic manipulation and personalization [26]. In simple terms, the organoid is an attractive strategy for clinical applications and bridges the gap between basic research and clinical practice. Along these lines, biomedical and pharmaceutical investigations on particularly relevant, rigorously designed, well-characterized, and controlled organotypic models will travel a long way in redefining fundamental discoveries, testing novel hypotheses at the 3D level and for the validation of critical data without sacrificing the integrity of any living being in the name of science. It should also be kept in mind that this technology is still in its infancy; much of the current hype originates from its enormous potential rather than a finite number of real-life scientific advancements. Hence, COVID-19 researchers use bronchial, respiratory, liver, kidney, intestine, and brain organoids to study the pathogenesis of SARS-CoV-2 and virus-specific cellular reaction on various organ systems.

In this chapter, we aim to answer a plethora of scientific questions related to the situation around the SARS-CoV-2 battle in the light of organoid technology, emphasizing key findings in therapeutic interventions meant to prevent and cure the serious medical threats imposed by SARS-CoV-2. We will highlight the state-of-the-art tools and methodologies available for human organoid lines and deep-dive into the case studies of fantastic *in vitro* organ models that well-known research groups have employed for understanding the root cause of COVID-19 devastation.
