Tackling Current Biomedical Challenges With Frontier Biofabrication and Organ-On-A-Chip Technologies

Abstract

In the last decades, biomedical research has significantly boomed in the academia and industrial sectors, and it is expected to continue to grow at a rapid pace in the future. An in-depth analysis of such growth is not trivial, given the intrinsic multidisciplinary nature of biomedical research. Nevertheless, technological advances are among the main factors which have enabled such progress. In this review, we discuss the contribution of two state-of-the-art technologies-namely biofabrication and organ-on-a-chip-in a selection of biomedical research areas. We start by providing an overview of these technologies and their capacities in fabricating advanced in vitro tissue/organ models. We then analyze their impact on addressing a range of current biomedical challenges. Ultimately, we speculate about their future developments by integrating these technologies with other cutting-edge research fields such as artificial intelligence and big data analysis.

Keywords: 3D biofabrication; drug development; organ-on-a-chip; precision medicine; regenerative medicine; tissue engineering.

FIGURE 1

Tissue engineering evolution: (A) from Petri dishes to biofabrication and organ-on-a-chip. (B) Milestones in bioprinting in the 21^st century (Kwon et al., 2000; Landers et al., 2002; Wilson Jr and Boland, 2003; Dhariwala et al., 2004; Jakab et al., 2008; Norotte et al., 2009; Wu et al., 2011; Skardal et al., 2012; Nakayama, 2013; Hinton et al., 2015; Gao et al., 2015; Kang et al., 2016; Retting et al., 2016; D O’Connell et al., 2016; Gladman et al., 2016; Lee J. H. et al., 2017; Pyo et al., 2017, 2017; Bernal et al., 2019; Skylar-Scott et al., 2019; Grigoryan et al., 2019, 2021; Jodat et al., 2020; Chen et al., 2020; Urciuolo et al., 2020; Brassard et al., 2021; Maharjan et al., 2021; Markert et al., 2021; De Santis et al., 2021). (C) Milestones in Organ-on-Chip in the 21^st century (Huh et al., 2010; Nakao et al., 2011; Franco and Gerhardt, 2012; Jang et al., 2013; Nguyen et al., 2013; Wei-Xuan et al., 2013; Bersini et al., 2014; Rigat-Brugarolas et al., 2014; Torisawa et al., 2014; Choi et al., 2015; Park et al., 2015; Miller and Shuler, 2016; Rosa et al., 2016; Wufuer et al., 2016; Zhang et al., 2017a, 2021; Lind et al., 2017; Vernetti et al., 2017; Wikswo et al., 2017; Ingber et al., 2018; Lee et al., 2018; Marturano-Kruik et al., 2018; Achberger et al., 2019; Park et al., 2019; Chou et al., 2020; Marx and Ramme, 2020; Park et al., 2020; Varghese et al., 2020; Si et al., 2021).

FIGURE 2

Biofabrication vs organ-on-a-chip. Multi-feature comparisons between biofabrication and organ-on-a-chip technologies highlighting their advantages, limitations, and challenges. Features are classified using a 1–5 scale with 1 meaning very limited and 5 well-suitable (e.g., operator dependency: 1 highly operator dependent, 5 not operator dependent).

FIGURE 3

Biofabrication strategies. Schematic representation of the various biofabrication methods employed for scaffold manufacturing divided into bioprinting and bioassembly strategies.

FIGURE 4

Engineered tissue and organ models manufactured using biofabrication strategies. A selection of representative and advanced studies carried out with biofabrication systems: 3D printing of layered brain-like structures reproduced from ref. (Lozano et al., 2015), hybrid 3D bioprinting of retina reproduced from ref. (Shi et al., 2017), engineering in vitro air-blood barrier reproduced from ref. (Horváth et al., 2015), 3D printing of complex biological structures of the heart reproduced from ref. (Hinton et al., 2015), multi vascular networks and functional intravascular topologies reproduced from ref. (Grigoryan et al., 2019), bioprinting of multiscale hepatic lobules reproduced from ref. (Kang et al., 2020), bioprinting of 3D convoluted renal proximal tubules reproduced from ref. (Homan et al., 2016), microfluidic-enhanced 3D bioprinting of aligned myoblast-laden hydrogels reproduced from ref. (Costantini et al., 2017), 3D bioprinting using scaffold-free approach reproduced from ref. (Pourchet et al., 2017).

FIGURE 5

Organ-on-a-chip geometrical units. Different geometrical and structural organ-on-a-chip elements are grouped in three major categories: micro, macro, and dynamic units. While micro units provide stimuli or confined cells at a small cluster or single-cell level, macro and dynamic units are employed to recapitulate specific systemic functions. Such division has been proposed for the sake of presentation, however, organ-on-a-chip units can be designed to possess multiple elements belonging to different groups.

FIGURE 6

Engineered tissues and organs manufactured using the organ-on-a-chip technology. A selection of the representative and advanced studies carried out with organ-on-a-chip systems: blood-brain-barrier-on-a-chip reproduced from ref. (Vatine et al., 2019), retina-on-a-chip reproduced from ref. (Achberger et al., 2019), small airway-on-a-chip reproduced from ref. (Benam et al., 2016), liver-on-a-chip reproduced from ref. (Jang et al., 2019), vascularized and perfused organ-on-a-chip platform reproduced from ref. (Phan et al., 2017), tubuloids of human adult kidney-on-a-chip reproduced from ref. (Schutgens et al., 2019), heart-on-a-chip reproduced from ref. (Qian et al., 2017), skeletal muscle-on-a-chip reproduced from ref. (Agrawal et al., 2017), small intestine-on-a-chip reproduced from ref. (Kasendra et al., 2018), full-thickness human skin-on-a-chip reproduced from ref. (Sriram et al., 2018), on-chip recapitulation of clinical bone marrow reproduced from ref. (Chou et al., 2020).