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Review
. 2019 Nov;24(11):2139-2151.
doi: 10.1016/j.drudis.2019.08.001. Epub 2019 Aug 11.

A human-on-a-chip approach to tackling rare diseases

Camilly P Pires de Mello  1 , John Rumsey  2 , Victoria Slaughter  1 , James J Hickman  3
Affiliations
Review

A human-on-a-chip approach to tackling rare diseases

Camilly P Pires de Mello et al. Drug Discov Today. 2019 Nov.

Abstract

Drug development for rare diseases, classified as diseases with a prevalence of < 200 000 patients, is limited by the high cost of research and low target population. Owing to a lack of representative disease models, research has been challenging for orphan drugs. Human-on-a-chip (HoaC) technology, which models human tissues in interconnected in vitro microfluidic devices, has the potential to lower the cost of preclinical studies and increase the rate of drug approval by introducing human phenotypic models early in the drug discovery process. Advances in HoaC technology can drive a new approach to rare disease research and orphan drug development.

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Figures

Figure 1.
Figure 1.
Multi-organ microphysiological system consisting of four different human organ modules (4-organ system): liver, heart, skeletal muscle and neurons. (a) Schematic for noninvasive technology to monitor cellular function in the 4-organ system, (b) shear stress distribution in each compartment of the system. Adapted, with permission, from [32,143].
Figure 2.
Figure 2.
Physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PD) mathematical modeling schematic. (a) Concept of PBPK model as a mathematical representation of the human body, (b) one-compartment model, (c) two-compartment model, (d) PBPK ‘whole-human’ model. Adapted, with permission, from [75,144].
Figure 3.
Figure 3.
Neuromuscular junction (NMJ) platform. A microtunnel-based system (a) allows the neurons and skeletal muscle to remain in distinct compartments while allowing axons to pass to the muscle side and innervate the myotubes; microfabricated bioMEMS enable direct electrical stimulation of motoneurons and direct measurement of myotube contraction (lower panel). (b) Phase contrast images of myotubes on cantilevers (upper left) and motoneurons on microelectrode array (MEA) electrodes (lower left), immunocytochemistry indicating axons (green) growing through tunnels and forming NMJs with myotubes (red) (right panels). (c) Effect of drugs on the NMJ can be tested in the system, producing a dose–response curve, in this case using BOTOX as the NMJ blocking toxin. As the concentration of BOTOX on the muscle-side increases the amplitude of the myotube contraction decreases. IC50 = 600 mU.
Figure 4.
Figure 4.
Key elements for a platform for determining cardiac physiology using human cardiomyocytes. Cardiac function was extrapolated from measurement of rhythm generation (frequency and amplitude), conduction velocity, action potential length (QT interval) and force generation of the heart (a) schematic of the system used to pattern SAMs on microelectrode arrays (MEAs) (top). Phase contrast micrograph of patterned human-derived cardiomyocytes on top of substrate-embedded extracellular electrodes. Immunostaining verified that human-derived cells differentiated to cardiomyocytes (middle) and exhibited cardiac rhythm generation as measured by the embedded electrodes (bottom). (b) Diagram of the cantilever-based force measurement system (top) cardiomyocytes integrated into the BioMEMs device and immunocytochemistry indicating cardiac alignment along the cantilever (middle). Example traces of deflection and torsional force with the device after myocyte contractions (bottom) [132].
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