Organs-on-a-Chip: A Fast Track for Engineered Human Tissues in Drug Development

Abstract

Organs-on-a-chip (OOCs) are miniature tissues and organs grown in vitro that enable modeling of human physiology and disease. The technology has emerged from converging advances in tissue engineering, semiconductor fabrication, and human cell sourcing. Encompassing innovations in human stem cell technology, OOCs offer a promising approach to emulate human patho/physiology in vitro, and address limitations of current cell and animal models. Here, we review the design considerations for single and multi-organ OOCs, discuss remaining challenges, and highlight the potential impact of OOCs as a fast-track opportunity for tissue engineering to advance drug development and precision medicine.

Keywords: disease modeling; drug development; human physiology; human stem cells; microfluidics; precision medicine; preclinical studies; tissue engineering.

Figure 1. OOC Design

A–C) Design considerations for an OOC of heart muscle involve mimicking the A) in vivo functions of conduction and contractility by defining the minimal functional unit as a strip of cardiac tissue and using B) electromechanical stimulation in-vitro to achieve functionality. C) An example is the cardiac Biowire OOC, consisting of a strip of human cardiomyocytes in a hydrogel that can be electromechanically stimulated. Reproduced with permission (Nunes et al., 2013; Sun and Nunes, 2016). D–F) Design considerations for an OOC of lung alveolae involve mimicking the D) in-vivo functions of cyclic breathing by defining the minimal functional unit as a single lung alveolus and using E) cyclic mechanical stretch in vitro to achieve functionality. F) An example is the lung OOC, consisting of layers of epithelium and endothelium on two sides of a membrane that is mechanically stretched by the application of vacuum. Reproduced with permission (Huh et al., 2010). G–I) Design considerations for an OOC of a solid tumor involves mimicking the G) in-vivo tumor microenviroment, the load bearing bone niche for bone cancer, and using H) mechanical loading in vitro to achieve functionality. I) An example is the tumor OOC, consisting of Ewing sarcoma cancer cells embedded in a bone scaffold that can be cyclically compressed in a mechanically loaded bioreactor. Reproduced with permission (Marturano-Kruik et al., 2018).

Figure 2. Integrating multiple OOCs towards a body-on-a-chip

Methods to integrate multiple OOC systems include A) Static culture, B) Single-loop perfusion, or C) Recirculation of a common media capable of supporting all organ systems. D) The development of individual OOCs connected to a selective membrane barrier, such as an endothelial layer, would enable integration of OOCs with perfusion that connects all OOCs while preserving the tissue specific media composition for each OOC. The recirculating media can include more biomimetic components, such as circulating immune cells.

Figure 3. Potential of OOCs to disrupt drug development

The use of OOC can disrupt drug development at multiple points: mechanistic studies of drug action, preclinical trials of drug toxicity and efficacy, clinical studies using patient-specific OOCs for models of patient diversity and the development of a “clinical-trial-on-a-chip” to discover therapeutic options for rare diseases.