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Shpichka, et al.
were successfully applied to test siRNA to treat showed that human recombinant ACE2 prevented
and prevent SARS-CoV infection . Moreover, the virus entry into cells that form blood vessel
[79]
transgenic mice expressing human ACE2 can and kidney organoids . Hoffmann et al. revealed
[8]
become a great option as ACE2 is one of the main that Camostat mesylate, a serine protease inhibitor,
SARS-CoV-2 targets . Nevertheless, almost all blocked SARS-CoV-2 infection in lung cell line
[7]
animal models are expensive and do not allow Calu-3 .
[86]
researchers to fully overcome species specificity These target enzymes, i.e., ACE2 and TMPR
for such host-specific virus as well as their use is SS2, are widely expressed by tissues in human
limited because of ethical issues. organisms. ACE2 is a monocarboxypeptidase
Cell-based models are a good alternative that regulates the peptide cleavage in the renin-
to animal models. Particularly, Vero cell line angiotensin system, and high levels of its expression
cultured in 2D conditions was used for anti- could be found in alveolar epithelial type II cells,
SARS-CoV-2 drug screening . However, the esophagus keratinocytes, small intestine, ileum
[80]
main limitation of such cell lines is the deficiency and rectum enterocytes, stomach epithelial cells,
of interferon, which is an important regulator colon colonocytes, liver cholangiocyte, arterial
of binding proteins involved in SARS-CoV-2 and venous endothelial cells, arterial smooth
infection . This requires the use of other cell muscle cells, myocardial cells, sustentacular cells
[81]
types and biofabrication methods that would of the olfactory epithelium, spermatogonia and
better recapitulate in vivo conditions, including Leydig and Sertoli cells, prostate epithelial cells,
3D environment, flows dynamics, and immune bladder urothelial cells, and kidney proximal
response. Moreover, blood vessel and human tubules cells [88-94] . TMPRSS2 regulating viral
kidney organoids are still the only 3D models used uptake by S protein priming is highly expressed
to study SARS-CoV-2 infection . by sustentacular cells of the olfactory epithelium,
[8]
small intestine enterocytes, bronchial transient
4.2 Specific targets secretory cells, prostate epithelial cells, nasal
Despite SARS-CoV-2 is a novel virus infecting goblet and ciliated cells, etc. [87,89,95-97] .
humans, understanding of its possible entry 4.3 Key points for the rational design
mechanisms was already pre-defined because
of earlier studies on other coronaviruses, for Our lack of knowledge in the COVID-19
example, SARS-CoV [82-85] . Therefore, after its pathogenesis and the absence of its adequate
appearance, most research teams have been and licensed therapy have led to the need to
[2]
focusing on SARS-CoV receptor ACE2 and other create novel in vitro platforms that mimic in vivo
related enzymes. Particularly, Hoffmann et al. conditions and are specifically tailored for the
[86]
proved that the entry of SARS-CoV-2 into a cell SARS-CoV-2 infection. There is no doubt that 3D
occurs due to binding of the viral surface spike tissue models are more suitable than 2D models
glycoprotein (S protein) to ACE2 and its priming to study any viral infections because they share
by the transmembrane protease serine protease the similarity to the native tissue, organ structure,
2 (TMPRSS2). Zang et al. also revealed that the and physiological functionality, and this is also
transmembrane protease serine protease 4 plays applicable to COVID-19.
a crucial role in virus entry using human small 3D tissue-like constructs can be fabricated by
intestinal enteroids as a model . a huge variety of methods that can be divided
[87]
Actually, the entry mechanisms are considered into two main groups: Scaffold-based and
the main targets for designing drugs treating and scaffold-free. However, scaffold-free techniques
preventing COVID-19. Hence, their inhibition such as bioprinting and cell self-organization
can block the infection that was proven to be true (spheroidogenesis and organoidogenesis) and
in several studies. For instance, Monteil et al. their combinations are considered to be the most

International Journal of Bioprinting (2020)–Volume 6, Issue 4 19