Patient on a chip
A "patient-on-a-chip" model can be created from the patient's own cells
Elena Kleshchenko, PCR.news
A diagram of organs on a chip: tissue cultures representing the liver, heart, bones and skin are connected by vascular blood flow. These tissues can be created from the patient's iPSC.
An organ on a chip is a device for growing human cell cultures that mimics the work of individual organs or organ systems. Such devices are used to simulate diseases, study the effectiveness and safety of medicines. They are cheap and provide qualitatively different information than studies on laboratory animals.
To simulate body functions, systemic diseases, drug metabolism, cells of various tissues must interact, just as in the body. Therefore, an organ on a chip usually consists of microcontainers with cells connected by microchannels. In addition, it is desirable that the tissues remain viable for a long time — weeks, preferably months.
This week, researchers from Columbia University (New York), together with colleagues from Harvard University, other research centers and companies, published an article in Nature Biomedical Engineering on the creation of a multi-organ chip whose tissues retained their molecular, structural and functional phenotypes for 4 weeks (. The biocompatible polymer plate contains samples of heart, bone, liver and skin tissues connected by vessels in which immune cells, as well as cytokines and extracellular vesicles circulate.
"Ensuring the connection between tissues while preserving their individual phenotypes was a serious task," says first author Casey Ronaldson-Bouchard, lead author of the study. — Since we focused on using tissue models obtained from patients, we had to individually carry out the maturation of each tissue so that when functioning it mimics the reactions that you could see in a patient (...) In the body, each organ maintains its own environment, while interacting with other organs through vessels that carry circulating cells and biologically active factors. Therefore, we decided to connect the tissues with vessels, while preserving the individual niches of each tissue."
Containers with tissue samples, each in its own optimized environment, are separated from the vascular bed by a barrier with selective permeability grown from endothelial cells. This barrier increases the plausibility of the model: tissues surrounded by endothelium are more similar to real organs. The developers placed monocytes in the vessels that give rise to macrophages — cells of the immune system that play an important role in controlling tissue responses to injuries, diseases and therapy.
All tissues were grown from the same line of induced human pluripotent stem cells (iPSCs) obtained from a small blood sample. This proves that it is possible to create such chips for specific people — in fact, to get a "patient on a chip".
The tissues presented on the chip are particularly susceptible to the adverse effects of anti-cancer drugs. The authors investigated the effect of doxorubicin, a widely used anticancer drug, on the heart, liver, bones, skin and blood vessels: the observed effects, including pharmacokinetics and pharmacodynamics, repeated those reported in clinical studies. In parallel, they developed a new computational model of drug absorption, distribution, metabolism and secretion. The model correctly predicted the features of the metabolic transformation of doxorubicin into doxorubicinol and its diffusion in the chip.
The authors also identified some microRNAs that can serve as early biomarkers of doxirubicin cardiotoxicity and cardiomyopathy caused by it: their appearance indicates the need to reduce the dose or discontinue therapy.
Among the limitations of the proposed approach, the researchers call the absence on the chip of samples of other organs important for metabolism: intestines, kidneys, fat. It is also possible that the polymer may absorb the drug and reduce its concentration; to prevent this, it may be necessary to modify the polymer surface.
Article by Ronaldson-Bouchard et al. A multi-organ chip with matured tissue niches linked by vascular flow is published in the journal Nature Biomedical Engineering.
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