A team of researchers from Columbia Engineering and Columbia University Irving Medical Center has developed a multi-organ chip consisting of engineered human heart, bone, liver, and skin that are linked by vascular flow with circulating immune cells, to allow recapitulation of interdependent organ functions. The plug-and-play multi-organ chip, which is the size of a microscope slide, represents a model of human physiology that the can be customized to the patient. Because disease progression and responses to treatment vary greatly from one person to another, the researchers hope that the chip technology could eventually help to optimize personalized therapies for each patient.

“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 project leader Gordana Vunjak-Novakovic, PhD, University Professor and the Mikati Foundation Professor of Biomedical Engineering, Medical Sciences, and Dental Medicine.

Vunjak-Novakovic and colleagues reported on development of the tissue-chip system in Nature Biomedical Engineering, in a paper titled “A multi-organ chip with matured tissue niches linked by vascular flow,” in which they concluded, “Vascularly linked and phenotypically stable matured human tissues may facilitate the clinical applicability of tissue chips.”

Drug safety and efficacy are typically assessed in animal models, but testing in animals frequently fails to predict clinical responses, the authors explained. Engineered tissues have therefore become a critical component for modeling diseases and testing the efficacy and safety of drugs in a human context. A major challenge for researchers has been how to model body functions and systemic diseases with multiple engineered tissues that can physiologically communicate—just like they do in the body. “ … to model whole-body physiology and systemic diseases, engineered tissues with preserved phenotypes need to physiologically communicate,” the team further noted.

However, it is essential to provide each engineered tissue with its own environment so that the specific tissue phenotypes can be maintained for weeks to months, as required for biological and biomedical studies. Making the challenge even more complex is the necessity of linking the tissue modules together to facilitate their physiological communication, which is required for modeling conditions that involve more than one organ system, without sacrificing the individual engineered tissue environments. “Although there is a clear need for microphysiological system designs that can model the complexity of human physiology, the functional integration of tissues has been an elusive goal due to the conflicting requirements for maintaining and connecting tissue-specific niches,” the investigators commented.

In our study, we cultured liver, heart, bone, and skin, connected by vascular flow for four weeks. These tissues can be generated from a single human induced pluripotent stem cell, generating a patient-specific chip, a great model for individualized studies of human disease and drug testing. [Keith Yeager/Columbia Engineering]
Taking inspiration from how the human body works, Vunjak-Novakovic and colleagues built a human tissue-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 researchers chose these tissues because they have distinctly different embryonic origins, structural and functional properties, and are adversely affected by cancer treatment drugs, presenting 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, PhD, study lead author and an associate research scientist in Vunjak-Novakovic’s Laboratory for Stem Cells and Tissue Engineering. “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.”

The group created tissue modules, each within its specialized environment, and separated them from the common vascular flow by a selectively permeable endothelial barrier. “The endothelial barrier provided each tissue to be cultured with its own optimized environment while enabling communication by cytokines, circulating cells and exosomes,” they noted. “The topology of each tissue was designed to replicate its morphology and location,” they further explained. “The heart tissue was suspended by vertical pillars, the skin tissue was cultured in the top section to maintain air–liquid interface, and the liver and bone tissues were cultured in the lower sections.”

The individual tissue environments were able to communicate across the endothelial barriers and via vascular circulation. The researchers also introduced into the vascular circulation the monocytes giving rise to macrophages, because of their important roles in directing tissue responses to injury, disease, and therapeutic outcomes.

The tissues cultured in the multi-organ chip (skin, heart, bone, liver, and endothelial barrier from left to right) maintained their tissue-specific structure and function after being linked by vascular flow. [Kacey Ronaldson-Bouchard/Columbia Engineering]
All tissues were derived from the same line of human induced pluripotent stem cells (iPSC), obtained from a small sample of blood, in order to demonstrate the ability for individualized, patient-specific studies.

 

“The tissues were engineered from human induced pluripotent stem cells (hiPSC) for biological specificity and combined with supporting stromal cells (primary or hiPSC) within a physiologically relevant extracellular matrix (ECM), matured individually for 4–6 weeks under conditions promoting their phenotype, transferred into the tissue chip and linked by vascular flow,” they explained. And, 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.

Looking to demonstrate how the Multi-organ chip could be used to study an important systemic condition in a human context, the team set up a system to examine the adverse effects of the broadly used anticancer drug doxorubicin on heart, liver, bone, skin, and vasculature. Their results using the Multi-organ chip confirmed that the measured effects recapitulated those reported from clinical studies of cancer therapy using the same drug.

The team developed in parallel a novel computational model of the Multi-organ chip for mathematical simulations of the drug’s absorption, distribution, metabolism, and secretion. This model correctly predicted doxorubicin’s metabolism into doxorubicinol and its diffusion into the chip. “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,” said Vunjak-Novakovic. “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.”

The combination of the multi-organ chip with computational methodology in future studies of pharmacokinetics and pharmacodynamics of other drugs could offer an improved basis for preclinical to clinical extrapolation, with improvements in the drug development pipeline. “We believe that further studies of the Multi-organ tissue chip may lead to patient-specific models of systemic pathologies for testing new therapies and early biomarkers of drug toxicity,’ the investigators stated. “This study suggests that the Multi-organ tissue chip can serve as a patient-specific model for developmental testing of new therapeutic regimens and biomarkers of drug toxicity, on the basis of its ability to maintain the biological fidelity of each tissue while also allowing their communication.”

The research team is currently using variations of the Multi-organ chip to study – in individualized patient-specific contexts – breast cancer, and prostate cancer metastases, leukemia, the effects of radiation on human tissues, the effects of SARS-CoV-2 on heart, lung, and vasculature, the effects of ischemia on the heart and brain, and the safety and effectiveness of drugs. The group is also developing a user-friendly standardized chip for both academic and clinical laboratories, to help fully utilize its 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!”

Development of the multi-organ chip began from a platform with the heart, liver, and vasculature, known as the HeLiVa platform. For their newly reported development, Vunjak-Novakovic collaborated with the collective talent of her laboratory, including Andrea Califano PhD and his systems biology team (Columbia University), Christopher S. Chen, PhD, (Boston University) and Karen K. Hirschi, PhD, (University of Virginia) with their expertise in vascular biology and engineering, Angela M. Christiano, PhD, and her skin research team (Columbia University), Rajesh K. Soni, PhD, of the Proteomics Core at Columbia University, and the computational modeling support of the team at CFD Research Corporation.