Research progress of multi-organ microfluidic chips, and prospects for its development trend

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/ 2019-05-07 / News

Microfluidic chip technology (MIcrofluidics) is also known as Lab-On-a-Chip (LOC), involving physics Multidisciplinary research fields such as chemistry, medicine, fluids, electronics, materials, and machinery. Through the micro-channel, reaction chamber and some other functional components, the fluid is precisely manipulated, and the basic operation unit is integrated and analyzed for sample preparation, reaction, separation and detection of biological, chemical and medical analysis processes, with liquid flow controllable and integrated. It has been widely used in research fields such as biomedicine and environmental science because of its advantages of low consumption, low throughput, and fast analysis. Human organs-on-chips based on microfluidic chip technology have developed rapidly in recent years, and have realized lung, kidney, intestine, liver, heart, blood vessels, skin, brain, bones, breast, spleen, and blood brain. The construction of chips such as barriers and blood-blood barriers, combined with methods of various disciplines such as cell biology, engineering and biomaterials, simulates a variety of living cells, tissue and organ microenvironments in vitro.Reflects the main structural and functional characteristics of human tissues and organs.

Toxic testing of different organs or entire systems of the human body is an important part of pharmacokinetic and pharmacodynamic studies, traditional two-dimensional cell culture models and animal experiments Many achievements have been made, but it is difficult to predict the human body's response to various drugs due to factors such as cycle, cost, precision, and ethics. Studies have shown that human organ chip technology can accurately control multiple system parameters, and it can reflect the real situation in human body compared with traditional toxicological animal experiments, and is more specific in the screening of new drugs. Therefore, the use of micro-machining technology to establish a biomimetic system closer to the human body has become a research hotspot in vitro physiological models.

However, with the development of organ chip technology, its application still has certain limitations. Most physiological pathways require continuous medium circulation and inter-organizational interaction. Single organ chips do not fully reflect the complexity, functional changes, and integrity of organ function. In order to adapt to the complexity of the human body structure,Future research will require the establishment of a more complex multi-organ microfluidic chip (Mul) system that combines several organ equivalents into a human-like metabolic environment. Laboratory microbial reactors for systemic toxicity testing and metabolic assessment.

This paper reviews the research progress of multi-organ microfluidic chips in recent years, and forecasts its development trend.

Design principle of multi-organ microfluidic chip

Multi-organ microfluidic chip will Cells from different organs and tissues are cultured on a chip and connected by microchannels to achieve multi-organ integration to examine their interactions or to establish a system for in vitro drug screening. The chip can integrate several specially designed micro-culture chambers, perfusion channels and simultaneously culture a variety of cells, using microfluidic technology to produce precise and controllable fluid shear forces, periodically varying mechanical forces and solute concentration gradients. Perfusion solution.Using these platform advantages, multi-organ microfluidic chips can be used to meticulously analyze tissue- and organ-specific stress responses, such as recruitment of circulating immune cells, responses to drugs, toxins, or other stimuli. In addition, a plurality of chips simulating different organs and tissues can be mimicked in vitro to mimic the physiology of different organs and tissues in vivo according to the relationship between the body and the vascular endothelium, blood cells or fluid medium. Role and drug distribution, etc.

Figure 1 shows the MOC system unit, Figure 1 (a) includes two polycarbonate covers, PDMS-glass chip for carrying the blood flow circuit (Pink) and drainage flow circuit (yellow); the numbers represent the four tissue culture compartments of the intestinal (1), liver (2), skin (3) and kidney (4) tissues, respectively. The top view of the multi-organ chip layout shows the position of the three measurement points (A, B and C) in the blood circuit and the two measurement points (D, E) in the drain circuit. The device uses a micropump device to control the clockwise and counterclockwise flow of the fluid, connected by microchannels,On the chip, a MOC system was constructed to accommodate the four organs of the intestine, liver, skin and kidney. The two drugs were used to simulate the absorption of the drug in the intestine, liver metabolism and renal excretion. Effectiveness assessment. The system was used to simulate the environment of glucose metabolism in human body. The results showed that the chip "oral" drugs, after absorption, through the simulated blood circulation, through the liver, then into the skin and kidneys, reached the kidney organ model metabolism and was discharged through the kidney urine. Further verified the metabolic pathway of glucose in the small intestine. In addition, there are related studies to co-culture neurospheres and hepatic spheroids, construct a nervous system-liver multi-organ microfluidic chip, and study its toxic and metabolic pathways with 2,5-hexanedione to determine glucose consumption. And lactic acid production as an indicator of metabolic activity in the MOC system. In the liver, n-hexane may be metabolized to hexanol by detoxification pathway or biological activation pathway, and the toxic effect is reached after the blood reaches the brain. The toxicity test results of two different concentrations of 2,5-hexanedione in the experiment indicate that it is induced. High apoptosis in neurospheres and liver micro-tissues.

Figure 1 Schematic diagram of multi-organ microfluidic chip design

Multi-organ microfluidic chip system research

Microcell culture analogues (μCCA) and PBPK models

Pharmacokinetic model PhARmacokinetics, PBPK) refers to a model that is more in line with the specific state of the drug's dynamic changes in the body and plays an important role in the development of new drugs.The PBPK model replaces the compartment (compartment model) in the classical model with the “physiology room”. According to the mass balance relationship, the velocity equation is established according to the model, the equations are solved, and the relationship between the concentration of the poison of each tissue or organ and time is obtained. It can basically determine the actual situation that the drug dynamically increases or decreases in the body. Because microfluidics can precisely control the flow and connection of multiple compartments, a regionalized microfluidic system can serve as an in vitro platform for the PBPK model.

A study of a multi-organ microfluidic chip system developed a high-throughput system for simulating human response to drugs A microfluidic chip-based microcell culture analog (μCCA) was used in combination with the PBPK model to establish a physical device (μCCA device) corresponding to the PBPK mathematical model. In the device, each organ represents a compartment, and chambers representing critical organs are fabricated on a silicon chip and interconnected by microchannels to simulate media recirculation in blood flow,The μCCAs reduction device can simulate near-physiological fluid flow conditions, body tissue size ratios, and multi-tissue organ interactions in vitro, supporting individual liver, bone marrow, and tumor cell line culture compartments by using external pumps and external common media recycling. interaction between. In the co-culture study of liver, bone marrow and tumor cell lines, the cell chamber and related parameters were set according to human tissue data. Different tissues or organs in the μCCA device were connected by separate compartments to simulate the action environment of multiple tissues and organs. The experimental results show that the μCCA device can capture the metabolism in the liver compartment, and the damage of tumor cells not observed in the conventional well plate assay can be observed.

The μCCA device combined with PBPK prediction can be matched with the drug treatment of human trials, not only to simulate dynamic multi-organ interactions, but also to simulate realistic physiological microscopy. The environment, the pharmacodynamics of the pharmacokinetics of the in vitro study drugs. The microenvironment of the μCCA device is based on a simplified PBPK mathematical model.It is of great significance in the study of pharmacokinetics, intercellular interactions between different organs, and hypothesis testing of toxicity and metabolic interactions. Insufficiently, when the cells are cultured in a fluidly connected manner, the medium may amplify the toxic effects of the unknown perfusate on the compartment cells while providing nutrients and removing cellular waste.

Multichannel three-dimensional microfluidic cell culture system (3D-μFCCS)

Because μCCA Insufficient device design, to design a highly conserved system in the body, it is important to cultivate a variety of cell types in a fluid-linked manner while maintaining isolation from each other, according to which a multi-channel 3D microfluidic cell culture system was developed ( 3D microfluidic Cell Culture System, 3D-μFCCS).

3D-μFCCS is composed of microfluidic channels and microarrays interconnected by multiple microchannels, using microarray technology for high-density physical fixation of multiple cell types for maximum cell-cell interaction. Micro-tissue and microfluidic techniques for multi-tissue experimental analysis, pre-formed spherical micro-tissues are loaded into micro-chambers and cultured under continuous perfusion, generated by gravity-driven flow through automated chip tilting, without the need for additional Pipeline and external pump. The rat liver and colorectal tumor MOC system constructed on the basis of 3D-μFCCS was cultured for 8 days in the presence of the prodrug cyclophosphamide, and tumor growth was observed only in co-cultures of different micro-tissue types on the chip. There was a significant effect, and the discontinuous transfer supernatant of the cyclophosphamide-treated static liver micro-tissue did not significantly affect tumor growth. The system verified that cyclophosphamide had a significant effect on tumor growth, but had no anti-tumor activity in vitro. Only works if the liver is activated by the creature.

In addition,Multi-channel 3D-μFCCS is also designed to simultaneously culture cell aggregates of different organs to mimic multiple organs in the body. Cultivate 4 different cell types to mimic four human organs: C3A (liver), A549 (lung), HK-2 (kidney) and HPA (fat), optimizing cells by supplementing common media and growth factors Features. In the process of cell culture, the specific release of TGF-β1 in A549 cells can enhance the function of A549 cells, while the functions of C3A, HK-2 and HPA cells are not affected, which is different from the function of simulating a single tissue. On the 3D-μFCCS device, the limited interaction between the cell culture compartments is similar to the situation in vivo.

One-way flow biometric system and other MOC systems

Compared to μCCA and 3D -μFCCS, a bioassay system built by Imura and colleagues is a relatively advanced version that will human the intestines,Liver and breast cancer cell line cultures [synthesis] A single linear channel that applies unidirectional flow without media recirculation. The microchip consists of a slide, a gas permeable membrane and a polydimethylsiloxane sheet containing microchannels made by photolithography. Caco-2 cloned colon adenocarcinoma cells were cultured on the membrane of microchips to mimic the intestinal transit of drugs: cyclophosphamide can penetrate the intestinal barrier and exhibit a high permeability coefficient. Cyclophosphamide cannot be absorbed by the intestinal wall. , showing a lower permeability coefficient. The results of the infiltration test were consistent with those obtained using the conventional method, and the consumption of the battery was reduced by 80%.

In recent years, based on the original organ chip system, the MOC system has been further developed. Loskill et al. used the μOrgano system to study multiple cardiac units, which can load different types of cells separately, control the time of differentiation and development, control the fluid connections of various tissues, and plug and play. Maschmeyer et al. designed an MOC device that accommodates two microbial fluid flow circuits.For the first time, the four organs tissues of the intestine, liver, skin and kidney were repeatedly cultured on a microfluidic chip for 28 days, and all tissues maintained high cell viability and discrete physiological tissue structure throughout the co-culture period, successfully demonstrating the intestine from a physiological point of view. The function of the road and the biological barrier of the kidney. In addition to the intestinal barrier and the renal barrier, the multi-organ microfluidic chip also successfully simulates multiple biological barriers in the human body. For example, using a Transwell device to culture cells on a filter suspended in a well to simulate blood-brain barrier for drug transport research and detection. The expression of a specific marker realizes a blood-staining barrier of co-culture of lung epithelial cells and vascular endothelial cells at a gas-liquid interface.

Design and new application of multi-organ microfluidic chip

Multi-organ microfluidic control Chip Design

The design of multi-organ microfluidic chips is based on the PBPK concept, which can be used to predict the body's response to drugs and the mechanism of action of drugs.The most commonly manufactured devices are microfluidic channels between 10 and 200 mm in size. The size of the compartments is correctly proportioned according to their function, and different organ functions have different scales depending on their mechanism. Microfluidic system materials typically use polydimethylsiloxane, which is optimized to use a more porous hydrogel that allows diffusion of molecules within the hydrogel scaffold. After the chip is fabricated, it is necessary to identify and measure the functional response of the cultured tissue when treated with drugs or engineering stimuli, and perform cell viability, mechanical force, electrical signal detection, and chemical analysis.

Currently, the design of the microfluidic chip system mainly uses the PBPK model and the PD model. In the PBPK model, methods of Pharmacokinetics (PK) modeling were used to design and manipulate to reproduce multiple organ interactions. PK modeling quantifies the amount of drug in different parts of the body. Simple terms can be used to describe the complex processes of absorption, distribution, metabolism, and elimination after drug administration, and to understand the dynamics of drug distribution. However, it is very difficult to build a physiologically accurate model.This limits the widespread use of PK modeling. Pharmacodynamics (PD) modeling pharmacological effects are considered as a function of drug concentration and a research model for the pharmacological effects of drugs in vivo. The PK model alone cannot clarify the time-effect relationship. The PD model alone cannot clarify the time-concentration relationship. Therefore, it is necessary to establish a PK-PD model in combination with the two to study the concentration-effect-time three-dimensional relationship of the target site of drug action. . In the PBPK-PD model, the PD model is coupled with the PK model, using a combined PK-PD model to predict or analyze the physiological effects of a given dose of drug, and the integrated PK-PD model can be evaluated at a specific dose. The time-dependent changes in the physiological outcome of the drug are relatively broadly applicable.

New application of multi-organ microfluidic chip

With multi-organ microfluidics The application of the chip in drug metabolism has also led to various new applications, such as the use of lung organ chips to study the toxicity and metabolism of nanomaterials.Harvard University explores the potential value of a pulmonary microarray system for environmental toxicology by studying a series of toxicities triggered by the transmission of fluorescent nanoparticles to lung epithelial cells, in vivo metabolism of environmental pollutants. Simulation research has opened up new horizons.

In the case of cancer related to atmospheric pollutants, fine particulate matter PM2.5 plays a vital role, PM2.5 can penetrate the human lung barrier and enter The blood system causes various diseases and even cancer. However, its metabolic pathways and carcinogenic mechanisms in the body are still unclear. The multi-organ microfluidic chip system currently applied for pharmacokinetics and pharmacodynamics provides new technical possibilities for this type of research. To study air pollution and disease, the currently developed on-chip system has been able to test the toxicity of particulates and substances in the air to monolayer or three-dimensional cell aggregates. Based on microfluidic technology to assess the impact of air quality on human health, using organ chips to simulate the function of healthy and morbid lungs, animal-free testing of the short- and long-term effects of airborne pollutant exposure on the respiratory system. Different from the metabolic pathway of oral drugs,There are two main metabolic pathways of particulate matter in the body: one is through the skin into the blood, through the heart into the lungs and then into the systemic circulation to the liver and kidney; the second is through the alveolar blood into the systemic circulation to the liver and kidney. However, the distribution and metabolism of unknown atmospheric particulate matter in the unknown concentration are difficult to monitor and the concentration cannot be determined. Therefore, there is no corresponding mathematical model for subsequent research and prediction. At present, fluorescent labeling is used. Artificial particles to simulate. Therefore, based on the lung chip-related toxicity research, a reasonable multi-organ microfluidic chip system for real-time reaction of particulate matter is designed, and a complete in vitro platform for simulating particulate matter metabolism, accurately determining the metabolic pathway of particulate matter, and formulating an accurate metabolic model are established. Further revealing the carcinogenic mechanism of particulate matter is an important scientific issue that needs further study.

In addition, microchip manufacturing through microelectromechanical systems (Microelect ROM) (MSMS) and chip labs and organ microflow Control chip system,MEMS allows the minimization of several tiny or nano-sensors, actuators, accelerometers, thermal controllers, microfluidic thrusters, microwave equipment, satellite communications, etc., for satellites Aerospace technology can also be used to monitor pollution sources such as sandstorms or volcanic activity.

Outlook

Microfluidic technology is a combination of micromachining technology and three-dimensional culture. The potential is higher in in vitro cell culture. The multi-organ microfluidic chip technology can precisely control the fluid at the micro-scale, simulate the human physiological environment, overcome the shortcomings of the traditional two-dimensional cell culture mode and animal experiments, and is highly biomimetic. The development of the MOC system combines the advantages of engineering techniques to adjust the fluid flow and controllable local tissue-to-fluid ratio in the microchannel. The MOC technology aims to establish an artificial biomimetic environment and simulate at the organ-tissue level to study the interactions between different organ cells, related physiological metabolic pathways, and physiological toxicity tests.

Human-on-a-chip is a micro-processing technology that uses multiple microfluidic chips to reflect the human body based on the MOC system. The simulation system of the overall system. Since the establishment of the NIH, FDA, and Department of Defense human body chips in 2011, the research boom of human body chips has been launched worldwide. Human-on-a-chip aims to restore the "human" system on the chip by dynamically controlling the various culture conditions of the cell microenvironment and simulating the main functions of multiple human organs on a microfluidic chip. Compared with single-organ chips, the human body chip can fully reflect the complexity, functional changes and integrity of the body's organ function, and is more applicable.

At present, based on the development and improvement of the MOC system, the environment for simulating heart, biological blood vessels, lung cancer cell metastasis, intestinal function and kidney biological barrier has been realized in vitro. . Although MOC overcomes many of the shortcomings of traditional two-dimensional cell and animal experiments,However, it also faces problems such as scaling of organs on the chip design, high-throughput analysis, on-chip detection and analysis, disease models, and cell sources. The long-term dynamic nutritional balance involved in the experiment, cell and tissue homeostasis, toxicity The integrity of the test, the specificity and sensitivity of the test method, the material of the chip, etc. are still urgently solved and perfected by the MOC system. In addition, MOC is widely used in biological research, medicine, toxicity testing, drug metabolism, etc., but there are few studies on pollutants such as particulate matter PM2.5 that affect the human body and metabolism in the body. It is believed that with the development of technology and the deepening of research, the MOC system will be widely used in the fields of medicine, pharmacy, life sciences, etc., and we are getting closer to the realization of ‘Human-on-a-chip’.

Keywords: Chip microfluidic
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