The new study cultured the liver, heart, bones and skin and connected by vascular flow for 4 weeks. These tissues can be generated from individual human-induced pluripotent stem cells to generate patient-specific chips, an excellent model for individualized studies of human disease and drug testing. Image credit: Keith Jaeger/Columbia University, Department of Engineering
Tissue cultured in a multi-organ chip (skin, heart, bone, liver, and endothelial barrier from left to right) in the left panel maintains its tissue-specific structure and function after being connected by a vascular flow. The new multi-organ chip on the right has the size of a glass microscope slide that can culture up to four types of human engineering tissue, the position and number of which can be adjusted depending on the question being asked. These tissues are connected by vascular flow, but the presence of a selectively infiltrated endothelial barrier maintains their tissue-specific ecological niches.
Image credit: Kathy Ronaldson-Borchad/Columbia University, Department of Engineering
【Today's Perspective】
A team of researchers from Columbia University's Department of Engineering and Medical Center in the United States report that they have developed a human physiological model in the form of a multi-organ chip that consists of engineered human hearts, bones, livers and skin that circulate blood vessels that circulate immune cells to reproduce interdependent organ function.
The researchers created this plug-and-play multi-organ chip, comparable in size to a microscope slide, that can be customized for patients. Since disease progression and response to treatment vary from person to person, this chip will eventually provide personalized treatment for each patient. The study was published in the April 27 issue of the journal Nature Biomedical Engineering.
Inspired by the human body
Engineering tissue has become a key component in disease modeling and testing drug efficacy and safety in human environments. A major challenge for researchers is how to use a variety of engineered tissues that can communicate physiologically to mimic bodily function and systemic disease, just as they do in the body. However, each engineered tissue must be provided with its own environment so that a particular tissue phenotype can be maintained for weeks to months, meeting the requirements of biological and biomedical research. Compounding the challenge is the need to connect tissue modules together to facilitate their physiological communication, which is necessary for modeling systems involving multiple organs.
Drawing inspiration from how the human body works, the research team built a human tissue-on-a-chip system in which they connected mature heart, liver, bone, and skin tissue modules through circulating vascular flow, allowing interdependent organs to behave like they would be in the human body. The researchers chose these tissues because they have distinctly different embryonic origins, structural and functional properties, and are influenced by cancer treatment drugs.
"Providing communication between tissues while maintaining their individual phenotypes has been a major challenge," said Kathy Ronaldson-Borchad, lead author of the study and associate research scientist at Columbia University's Stem Cell and Tissue Engineering Laboratory, "Because we focus on using tissue models derived from patients, we have to mature each tissue individually so that it works in a way that mimics the response in patients, and we don't want to sacrifice this advanced capability when connecting multiple tissues." In the body, each organ maintains its own environment while interacting with other organs through the flow of blood vessels carrying circulating cells and bioactive factors. Therefore, we chose to connect tissues through vascular circulation while retaining each individual tissue niche necessary to maintain its biofidelity, mimicking the way our organs are connected in the body. ”
The organization module can be maintained for more than one month
The research team created tissue modules, each in an optimized environment and separated from the common vascular flow through a selectively infiltrated endothelial barrier. The individual tissue environment is able to cross the endothelial barrier and communicate through the vascular circulation. The researchers also introduced macrophage-producing monocytes into the vascular circulation because they play an important role in directing tissue responses to injury, disease efficacy.
All tissues were derived from the same line of human induced pluripotent stem cells, obtained from a small number of blood samples to demonstrate the ability of individualized, patient-specific studies. And, to demonstrate that the model could be used for long-term studies, the team maintained tissue that had grown and matured for 4 to 6 weeks for another 4 weeks after being connected by vascular perfusion.
The researchers also demonstrated how the model can be used to study important diseases in the human environment and examine the side effects of anti-cancer drugs. They studied the effects of doxorubicin, a widely used anti-cancer drug, on the heart, liver, bones, skin and vasculature. They showed that the test effect summarized the effects of clinical studies using the same drugs for cancer treatment.
Use this model to study anti-cancer drugs
The team also developed a new multi-organ chip computational model for mathematical simulations of drug absorption, distribution, metabolism, and secretion. The model correctly predicted that doxorubicin was metabolized into doxorubicinol and diffused into the chip. In future pharmacokinetics and pharmacodynamic studies of other drugs, the combination of multi-organ chips and computational methods provides a basis for improvement in preclinical to clinical extrapolation, while improving the drug development process.
The researchers say the new technology can identify some of the early molecular markers of cardiotoxicity, which are major factors limiting the widespread use of drugs. Most notably, multi-organ chips accurately predict cardiotoxicity and cardiomyopathy, which often require clinicians to reduce the therapeutic dose of doxorubicin or even stop treatment.
The research team is currently conducting studies using variants of this chip, all in individualized, patient-specific settings. Such as breast cancer metastasis, prostate cancer metastasis, leukemia, the effect of radiation on human tissues, the impact of the new crown virus on multiple organs, the impact of ischemia on the heart and brain, and the safety and efficacy of drugs. The research team is also developing a user-friendly standardized chip for academic and clinical laboratories to help harness its potential to advance biological and medical research.
"We are excited about the potential of this approach," the researchers said. It is designed specifically for the study of systemic diseases associated with injury or disease and will allow us to maintain the biological properties of engineered human tissue and its communication. One patient at a time, from inflammation to cancer. (Reporter Zhang Mengran)
Source: Science and Technology Daily