Harnessing organs-on-a-chip to model tissue regeneration

Abstract

Tissue engineering has markedly matured since its early beginnings in the 1980s. In addition to the original goal to regenerate damaged organs, the field has started to explore modeling of human physiology "in a dish." Induced pluripotent stem cell (iPSC) technologies now enable studies of organ regeneration and disease modeling in a patient-specific context. We discuss the potential of "organ-on-a-chip" systems to study regenerative therapies with focus on three distinct organ systems: cardiac, respiratory, and hematopoietic. We propose that the combinatorial studies of human tissues at these two scales would help realize the translational potential of tissue engineering.

Keywords: bioengineering; organ-on-a-chip; pluripotent stem cells; precision medicine; regenerative medicine; tissue engineering.

Figure 1.. In vitro models.

A range of models, from 2D cell culture to organoids and human OOC systems, enable a number of applications for modeling drug toxicity, disease phenotypes, and organ function while balancing the inverse relationship between complexity and throughput. Key: high (checkmark), medium (dash), low (X) frequencies.

Figure 2.

A framework for using engineered human tissues for testing regenerative therapies.

Figure 3.. OOCs and related technologies for testing regenerative therapies in vitro.

(A, B) Growth of the field (NIH PubMed database). (C) Engineered cardiac models for studying engraftment of injected cardiomyocyte progenitors, testing timing of delivery and efficacy of different cell types on cardiac muscle function (Song et al., 2010); Copyright (2010) National Academy of Sciences. (D) Extracellular vesicles (EVs) for hypoxia-induced myocardial infarction repair (Yadid et al., 2020); Reproduced with permission, AAAS. (E) Lymphoid progenitor expansion in vitro can mimic testing cryogel scaffolds for hematopoietic reconstitution in vivo (Shah et al., 2019). (F) Testing efficacy of CRISPR/Cas9 vector systems in liver organoids (Velazquez et al., 2021); Reproduced with permission. (G) Validating cell-specific integration of adeno-associated viruses with OOC models (Li et al., 2019). (H) Elucidating the effects of specific miRNAs on cardiac muscle repair (Daly et al., 2021); Reproduced under the terms of the Creative Commons License.

Figure 4.. Engineered cardiac models for testing cardiac regeneration therapies.

Top: dotted lines demonstrate the envisioned pathway of using bioengineered tools to make mimetic models of cardiac muscle and use such models to inform new therapeutic developments. Bottom: representative examples of recent cardiac muscle models: (Mathur et al., 2015), Reproduced under the terms of the Creative Commons License; (Hinson et al., 2015), Copyright 2015, American Association for the Advancement of Science (AAAS). (MacQueen et al., 2018); (Ronaldson-Bouchard et al., 2018), Reproduced with permission; (Zhao et al., 2019a), Reproduced with permission; (Giacomelli et al., 2020), Reproduced under the terms of the Creative Commons License.

Figure 5.. Engineered alveolar models for testing novel therapies for macro-scale lung regeneration.

Top: Dotted lines demonstrate the envisioned pathway of using bioengineered tools to make mimetic models of the lung and use such models to inform new and refined therapeutic development. Bottom: Representative examples of lung tissue models: (Huh et al., 2010), Copyright 2010, AAAS; (Chen et al., 2017); (Lehmann et al., 2018), Reproduced under the terms of the Creative Commons License; (Yamamoto et al., 2017).

Figure 6.. Engineered models of the bone marrow for testing hematopoietic regeneration.

Top: Dotted lines demonstrate the envisioned pathway of using bioengineered tools to make mimetic models of the bone marrow and use such models to inform new and refined therapeutic development. Bottom: representative examples of hematopoietic models: (Torisawa et al., 2014); (Bourgine et al., 2018), Reproduced with permission, Copyright 2018, National Academy of Sciences; (Tavakol et al., 2019), Reproduced with Permission, Copyright 2019, Elsevier; (Chou et al., 2020); (Ma et al., 2020), Reproduced with permission, Copyright 2020, AAAS.