First multi organ-on-a-chip made of engineered human tissues linked by vascular flow will improve modelling of systemic diseases.
Engineered tissues have become a critical component for modelling diseases and testing the efficacy and safety of drugs in a human context, but this organ-on-a-chip research comes with a significant challenge – how to ensure physiological communication between tissues while providing separate environments that maintain specific tissue phenotypes.
Longevity.Technology: Tissue modules need to be linked together to facilitate their physiological communication – this is required for modelling conditions that involve more than one organ system – but connected without sacrificing the individual engineered tissue environments that allow specific tissues to be maintained for weeks, or even months.
Now researchers from Columbia Engineering and Columbia University Irving Medical Center report in Nature Biomedical Engineering that they have developed a model of human physiology in the form of a novel multi organ-on-a-chip. The chip consists of engineered human heart, bone, liver, and skin that are linked by vascular flow with circulating immune cells and allows recapitulation of interdependent organ functions.
Plug-and-play longevity
The plug-and-play chip, which is the size of a microscope slide can be customised to the patient, a key part of its design; because disease progression and responses to treatment can vary greatly from one person to another, such a chip will eventually enable therapy that is personalised and optimised on an individual level, person-by-person.
“This is a huge achievement for us – we’ve spent ten years running hundreds of experiments, exploring innumerable great ideas, and building many prototypes, and now at last we’ve developed this platform that successfully captures the biology of organ interactions in the body,” said the project leader Professor Gordana Vunjak-Novakovic.
Taking inspiration from the human body
The research team built a human tissue organ-on-a-chip system in which they linked matured heart, liver, bone and skin tissue modules by recirculating vascular flow, allowing for interdependent organs to communicate just as they do in the human body. The tissues in the chip were selected, say the researchers, because they have distinctly different embryonic origins, structural and functional properties, and are adversely affected by cancer treatment drugs; this means they present a rigorous test of the proposed approach.
“Providing communication between tissues while preserving their individual phenotypes has been a major challenge,” said Kacey Ronaldson-Bouchard, the study’s lead author. “Because we focus on using patient-derived tissue models we must individually mature each tissue so that it functions in a way that mimics responses you would see in the patient, and we don’t want to sacrifice this advanced functionality when connecting multiple tissues. In the body, each organ maintains its own environment, while interacting with other organs by vascular flow carrying circulating cells and bioactive factors. So we chose to connect the tissues by vascular circulation, while preserving each individual tissue niche that is necessary to maintain its biological fidelity, mimicking the way that our organs are connected within the body. “
A modular approach
Tissue modules, each within its optimised environment, were created; they were separated from the common vascular flow by a selectively permeable endothelial barrier and the individual tissue environments were able to communicate across the endothelial barriers and via vascular circulation. Added into the mix were monocytes (which become macrophages) because they play an important role in directing tissue responses to injury, disease and therapeutic outcomes.
To demonstrate the ability for individualised, patient-specific studies, all tissues were derived from the same line of human induced pluripotent stem cells (iPSC) which had been obtained from a small sample of blood. To prove the model can be used for long-term studies, the team maintained the tissues, which had already been grown and matured for four to six weeks, for an additional four weeks, after they were linked by vascular perfusion.
Targeting cancer
In order to demonstrate the that the organ-on-a-chip model could be used for studies of an important systemic condition in a human context, the research team investigated the effects of doxorubicin, a broadly used anticancer drug, on heart, liver, bone, skin and vasculature and demonstrated that the measured effects recapitulated those reported from clinical studies of cancer therapy using the same drug.
In parallel, the researchers developed a novel computational model of the multi-organ chip for mathematical simulations of doxorubicin’s absorption, distribution, metabolism and secretion. This model correctly predicted the drug’s metabolism into doxorubicinol and its diffusion into the chip. The combined platform of multi-organ chip and computational methodology should provide an improved basis for preclinical to clinical extrapolation in future pharma research and lead to improvements in the drug development pipeline.
“While doing that, we were also able to identify some early molecular markers of cardiotoxicity, the main side-effect that limits the broad use of the drug. Most notably, the multi-organ chip predicted precisely the cardiotoxicity and cardiomyopathy that often require clinicians to decrease therapeutic dosages of doxorubicin or even to stop the therapy,” said Vunjak-Novakovic.
Other applications of organ-on-a-chip
The research team is currently using variations of this chip to study, in individualised patient-specific contexts, various cancers, leukaemia, radiation effects, COVID effects, ischemia and the safety and effectiveness of drugs. The group is also developing a user-friendly standardised chip for use in both academic and clinical laboratories, to help realise its full potential for advancing biological and medical studies.
Vunjak-Novakovic added: “After ten years of research on organs-on-chips, we still find it amazing that we can model a patient’s physiology by connecting millimeter sized tissues – the beating heart muscle, the metabolizing liver, and the functioning skin and bone that are grown from the patient’s cells. We are excited about the potential of this approach. It’s uniquely designed for studies of systemic conditions associated with injury or disease, and will enable us to maintain the biological properties of engineered human tissues along with their communication. One patient at a time, from inflammation to cancer!”
