Modelling Human Physiology on-Chip: Historical Perspectives and Future Directions

Abstract

For centuries, animal experiments have contributed much to our understanding of mechanisms of human disease, but their value in predicting the effectiveness of drug treatments in the clinic has remained controversial. Animal models, including genetically modified ones and experimentally induced pathologies, often do not accurately reflect disease in humans, and therefore do not predict with sufficient certainty what will happen in humans. Organ-on-chip (OOC) technology and bioengineered tissues have emerged as promising alternatives to traditional animal testing for a wide range of applications in biological defence, drug discovery and development, and precision medicine, offering a potential alternative. Recent technological breakthroughs in stem cell and organoid biology, OOC technology, and 3D bioprinting have all contributed to a tremendous progress in our ability to design, assemble and manufacture living organ biomimetic systems that more accurately reflect the structural and functional characteristics of human tissue in vitro, and enable improved predictions of human responses to drugs and environmental stimuli. Here, we provide a historical perspective on the evolution of the field of bioengineering, focusing on the most salient milestones that enabled control of internal and external cell microenvironment. We introduce the concepts of OOCs and Microphysiological systems (MPSs), review various chip designs and microfabrication methods used to construct OOCs, focusing on blood-brain barrier as an example, and discuss existing challenges and limitations. Finally, we provide an overview on emerging strategies for 3D bioprinting of MPSs and comment on the potential role of these devices in precision medicine.

Alternative Methods as Tools for Obesity Research: In Vitro and In Silico Approaches

“…In practice, these are devices fabricated from different materials containing living cells organized in 2D or 3D architectures and maintained in finely controlled conditions. Often, these devices have a microfluidic system containing perfused hollow microchannels combined with culturing chambers allowing the reconstitution of tissue interfaces and organs microenvironments and functions [ 133 ]. The MPS field is growing fast, and the area has focused mainly on cardiac, hepatic, neuronal, and oncology models, which are of great interest for drug development purposes.…”

Basic models to advanced systems: harnessing the power of organoids-based microphysiological models of the human brain

“…Another limitation of MPSs is the undefined or inadequate interstitium that lacks the relevant ECM proteins that support brain parenchymal and cerebrovascular basement membranes (BMs). While many MPSs attempt to incorporate the brain's interstitium through the use of ECM proteins, such as Collagen IV or Matrigel (laminin-rich gel) [98], the brain and cerebrovascular BMs in MPSs may not accurately recapitulate the in vivo brain and cerebrovascular BMs, and often lack one or more of the four major glycoprotein families (collagen IV isoforms, laminins, nidogen, and heparan sulfate proteoglycans) [99,100]. These are important in ECM remodeling and tissue patterning in both health and disease, and their presence in the correct isoforms and quantities are essential for modeling disease states and studying drug-toxicity because many cellular responses, such as inflammation and oxidative stress, depend on the ECM's composition and ability to metabolize and degrade waste or injurious agents.…”

Understanding conceptus–maternal interactions: what tools do we need to develop?

“…While the advances in cell culture models have been beneficial, they still do not mimic the physiological systemic flow under which all biological structures function. Advances in bioengineering have introduced intricate microfluidic models (Pun et al 2021), which allow a two-way exchange of relevant nutritional material and waste removal alongside sufficient gas exchange. These microfluidic approaches allow us to mimic physiological flow in in vitro cell culture systems.…”