, from now on your world more science~
Everyone · MASTERS of cutting-edge science and technology
Ding Xianting
Distinguished Professor of School of Biomedical Engineering, Shanghai Jiao Tong University, Deputy Director of the Office of International Cooperation and Exchange
As we all know, in the process of pre-marketing clinical trials, a large number of toxicity, kinetics and efficacy evaluations are traditionally mainly relied on animal models. Due to the problems of species differences, ethical issues and lengthy experimental cycles in animal models, the establishment of a rapid, high-throughput, automated, and novel drug screening platform that avoids species differences has become an urgent need for global drug development.
Recently, people have gradually realized that microfluidic organ-on-a-chip, especially microfluidic multi-organ-on-a-chip that integrates multiple organs to mimic human metabolic pathways, can supplement the value of animal experiments for medical research: from basic biological research to drug development and testing, microfluidic multi-organ-on-a-chip can supplement animal experiments by simulating the human microenvironment and combining cell culture technology to cultivate healthy or diseased human cells or tissues, verify the efficacy and toxicity, thereby shortening the long cycle of clinical trials.
What is a microfluidic chip? Microfluidic chips are one of the coolest technologies in science and engineering, and they play an important role in the development of cutting-edge technologies in the fields of biology, chemical engineering and medical testing.
At present, the mainstream form of microfluidic chip refers to the integration or basic integration of basic operating units such as sample preparation, reaction, separation, detection, cell culture, sorting, lysis and other basic operating units involved in the fields of chemistry and biology into a chip of a few square centimeters or even smaller, forming a network by microchannels, and running through the whole system with controllable fluids, so as to realize various functions of different laboratories such as conventional chemistry, biology, materials, optics, etc.
In 2017, the Ministry of Science and Technology positioned microfluidic chips as a "disruptive technology", and an important branch of microfluidic chips, organ-on-a-chip, was named one of the world's "top ten emerging technologies" in 2016 by the World Economic Forum.
Due to the advantages of lower cost, better performance, less resource occupation and stronger security, microfluidic chips are widely used in daily life: in the field of microelectronics, there are many tiny chips in mobile phones and computers; In the field of mechanical systems, whether it is an electric vehicle or a fuel vehicle, there are a lot of chips in it; In the field of biochemistry, chips are required for chemical detection and sensing of chemical substances; In the medical field, there are many chips such as artificial cochlear implants, pacemakers, etc.
The miniaturization of chips not only brings safer and greener benefits, but also leads to an integrated and systematic industrial revolution. In this industrial revolution, we inevitably have to mention its core technology, which we call the photoetching process, or lithography. Lithography is an important process for microscale etching.
The following article introduces the processing and fabrication of microfluidic chips, the advantages and challenges, and the application of microfluidic chips in real life and work.
Why do we have to encourage the processing and preparation of microfluidic chips to be smaller, more miniaturized, and more integrated? This is because miniaturized chips have many advantages, including lower cost, better performance, greater savings, safer and more environmentally friendly. In this context, the discipline of micromachining came into being, that is, the use of processes similar to integrated circuits and computer chips to gradually make large chips smaller, and some of the underlying technologies and principles used in this discipline are very similar to integrated circuits and computer chips, which are a process that gradually makes large chips smaller. A variety of physical, chemical, material, biological and other aspects of knowledge formed behind this process are integrated together to form a new interdisciplinary discipline, which we call micro-nano processing discipline.
Under the guidance of the discipline of micro-nano fabrication, more chips can be integrated at high density per unit area or unit space, making its system more intelligent, more integrated, and more functional, which may lead to the next generation of industrial revolution, that is, the new industrial revolution of integration and systematization.
In the process of system integration, a new term has emerged, that is, microelectromechanical systems (MEMS), or micromechanics, microsystems. It is to integrate a large number of chips with high density in a very small space, so that it has certain electrical properties and mechanical properties, so as to become a system with complex functions. MEMS is a comprehensive discipline with extremely obvious interdisciplinary phenomena, mainly involving micromachining technology, mechanics/solid acoustic wave theory, heat flow theory, electronics, biology and so on. The characteristic length of MEMS devices ranges from 1 mm to 1 micron (the diameter of a hair is approximately 50 microns).
How can such a small and highly integrated device be manufactured? The manufacture of MEMS draws extensively on processes such as lithography, etching, and coating in integrated circuits. Photolithography is the most technically difficult and critical technical step in the entire micromachining process. Lithography is a process that uses light to etch at a small scale. It involves light-sensitive materials, masks, and exposure systems.
Photoresist is a light-sensitive material, which can be etched after exposure, so it is also known as a photoresist, and its characteristics will change after being exposed to light, and it is one of the key materials for micro-pattern processing in microelectronic technology, mainly used in the electronics industry and the printing industry. Photoresist is divided into positive glue and negative glue: after the positive glue is exposed, the part that receives light becomes easy to dissolve, and is dissolved after development, leaving only the part that is not illuminated to form a pattern; On the contrary, after exposure, the illuminated part becomes less soluble, and after development, the illuminated part is left to form a pattern. There is a pattern on the mask plate, which is transferred to the photoresist after light is transmitted. Exposure systems are used to provide light of various intensities and wavelengths. The photolithography process is one of the more difficult technologies to overcome, including the photoresist process, the mask processing process and the exposure system process.
The lithography process gave rise to a concept that everyone often hears – Moore's Law. Moore's Law was proposed by Gordon Moore, one of the founders ·of Intel. Its content is: when the price remains the same, the number of components that can be accommodated on the integrated circuit will double every 18~24 months, and the performance will also be doubled. In other words, every dollar that can buy a computer performance will more than double every 18~24 months. This law reveals the speed at which information technology is advancing. Although this trend has been going on for more than half a century, Moore's Law is still considered an observation or speculation, not a physical or natural law. Moore's Law indicates the trend towards smaller and higher performance integrated systems. MEMS can be improved by photolithography.
Figure 1: The basic flow of lithography
As mentioned earlier, microchips have important applications in many fields, such as artificial insemination technology, microgear processing technology, etc. So we may ask, what can a chip do if it gets smaller? Here are a few typical MEMS applications.
1) Microtweezers: This is a classic application in the field of MEMS, which can be used to precisely manipulate cells and improve cell viability. In real life, we can improve sperm motility and improve the accuracy and success of the assisted reproduction process through artificial insemination technology.
2) Microgears: Micro gear processing technology makes mechanical parts smaller and lighter, thereby reducing energy consumption.
3) Micro robots: Microrobot drive technology controls the change of material shape through voltage, and micro mobile robots realize robot crawling and driving, and the application and innovation of these technologies have made important contributions to related fields.
4) Microneedling: Through microneedling technology, microneedle band-aids with fine needles can be made to avoid the pain of coarse needle injection. In addition, microneedling can also be used as a sensor to monitor physical performance indicators in real time, providing tips for hydration and rest, and the microneedling system has a wide range of applications in treatment and detection.
5) Biomimetic sensor: By imitating the dandelion system, it has great advantages in detecting atmospheric substances and performing gastrointestinal endoscopy. This small system can realize wireless transmission of signals and taking pictures, making human work more convenient and safer.
Advantages and Challenges of Microfluidic Chip Processing
Large-to-small scale changes deliver advantages in integrated performance, cost, and processing time, while also making the system more portable, consuming less power, and meeting volume production requirements. However, there are a variety of technical challenges in the processing of chips from large to small, including a series of differences in material optics, mechanical mechanics, chemistry, fluidics, temperature control, electricity, and magnetism. This difference in physical, chemical, and biological properties is only our intuition, and cannot be directly copied into this tiny world. Here we focus on the four aspects of mechanical mechanics, biology, physics and fluidics, from large to small processes.
Mechanical mechanics
When the world collapses to 1/10th of its original size, how does the attraction between two objects change? By analyzing the relationship between the law of gravitation and the size effect, it can be concluded that the attraction force will be proportional to the 4th power of the size effect. When the size is reduced by 1/10, the mutual attraction quickly becomes unimportant. Insects can lift objects that are ten times heavier than themselves, while humans cannot. These phenomena are all caused by the size effect, which shows that the size effect is very important. In the chip design process, macro experience is not applicable to the micro scale, and needs to be accumulated from scratch. The physical and chemical properties at different scales will change, and it is difficult to design with macroscopic intuition and common sense. By understanding the variation laws of volumetric, surface and linear forces, designers can be helped to separate and design in microchips. At the microscale, the surface force becomes the dominant force, while the effect of the volume force is negligible. Therefore, designers need to consider the storage effect and changes in relative importance to adapt to the design ideas and concepts.
biology
When the world collapses to 1/10 of its original size, how does the metabolic rate change? This involves the relationship between metabolic rate and size effect in biology. The rate of energy metabolism is related to the rate of heat loss, while the energy dissipation is related to the area, so the rate of metabolism is related to the 2nd power of the size effect, and the mass is related to the 3rd power of the size effect. Klieber's Law proves that the metabolic rate and mass of an organism are directly proportional. As a result, the metabolic rate increases with the size of the animal and decreases with the decrease in size.
physics
In physics, small objects are more affected by surface tension, while large objects are more likely to sink into water. Understanding the size effect can help us understand the phenomenon of water floating and the scaled world of Lilliputia.
Fluidics
Fluid mechanics is also an important branch of mechanics in daily life, involving fluid-related activities such as swimming and flying. The Reynolds number is an important physical quantity in fluid mechanics, which is composed of the density, velocity, size, and viscosity coefficient of a liquid. Fluid systems with Reynolds numbers greater than 4000 are called turbulent systems, while fluid systems with less than 2000 are called microscopic fluids or plane pops. Turbulent systems create eddy currents, and fluid mixing in microscopic fluids can become difficult. What kind of benefits will such a change in fluid dynamics from macro to micro bring us? The microfluidic chip uses the properties of laminar flow fluids to achieve accurate control and prediction of fluid direction. The screening experiment of drug combination through microfluidic chip can more conveniently and accurately evaluate the drug effect, improve the efficiency of cell utilization, and solve the troubles and limitations faced by traditional experiments.
Figure 2: Physical image of the microfluidic chip
Applications of microfluidic chips
Microfluidic chip is a chip system integrated by using microfluid characteristics, which is the main platform for the realization of microfluidic technology, also known as biochips and lab-on-a-chip. The device is characterized primarily by the effective structure (channels, reaction chambers, and certain other functional components) that houses the fluid, at least in one dimension, at the micron scale. Due to the micron-scale structure, in which the fluid displays and produces special properties that differ from the macroscopic scale, unique analytical properties are also developed:
It has the characteristics of controllable liquid flow, very few samples and reagents, and tens or hundreds of times faster analysis speed, which can analyze hundreds of samples at the same time in a few minutes or even less time, and can realize the whole process of sample pretreatment and analysis online.
Microfluidic technology is the key technology of microfluidic chips, which refers to the technology of precise manipulation of microfluids in micro-level microtubules, which can integrate the basic operations of biochemical experiments such as sample reaction, preparation, separation, and detection into a very small chip, with high sensitivity, high integration, high throughput, high efficiency and other advantages. From the perspective of the analytical performance of microfluidic chips, its future application fields will be very wide and still expanding, but the current focus is obviously in the biomedical field, which can be used in drug synthesis analysis, medical in vitro diagnosis, bionic skin tissues and organs, single-cell analysis, nucleic acid analysis, drug screening and delivery and other scenarios. In addition, high-throughput drug synthesis and screening, environmental monitoring, food hygiene, forensic science, and national defense will also become important application fields. Here are just three examples of the application of microfluidic chips in the biomedical field to illustrate the great potential of microfluidic chips.
Figure 3: Schematic diagram of a microfluidic chip for drug panel optimization and screening
Screening of combination drugs
Microfluidic chips can be used to mix and dilute drugs to form concentration gradients. By placing the patient's own cells in the microarray, effective drug combinations can be quickly screened. The results of the experiment can be judged by observing the survival of the cells, so as to determine the optimal drug ratio. This combination drug screening method is of great significance and provides a new idea for tumor treatment.
Circulating tumor cells
Microfluidic technology has the advantage of simplicity and accuracy in screening circulating tumor cells. Through traction and centrifugal forces in the microfluidic system, different types of cells can be separated, allowing for the enumeration of circulating tumor cells.
Human organ-on-a-chip
Microfluidic technology can also mimic the circulatory system of the human body, by integrating different types of cells to study organ function and drug action in a human chip. In 2010, Donal·d Ingber et al. of Harvard University published in the journal Science that the lung organ-on-a-chip is a representative organ-on-a-chip. Human organ-on-a-chip may free us from the ethical dilemma of animal experimentation.
Although there are still challenges in the effectiveness and function of organ-on-chips in replacing real organs, scholars at home and abroad are working hard. Human organs are complex, consisting of multiple cell types and three-dimensional structures, so mimicking real organs is a big challenge. The introduction of 3D microfluidic systems and printing technology may help to solve this problem. Although it is not yet possible to replace real organs, the future is full of confidence.
Conclusion
In general, a microfluidic chip is a microchip that uses microfluidic technology to achieve precise manipulation of tiny volume fluids. It has the characteristics of small size, low cost, short experimental cycle and easy operation, and can be widely used in biomedicine, environmental monitoring, food safety and other fields. For example, microfluidic chip technology can cultivate different types of cells in complex systems to form multicellular populations, which is expected to replace live animal experiments. By simulating personalized disease models in vitro, individualized drug screening can be carried out. With the development of technology, microfluidic chips will be increasingly used in various fields and achieve a higher level of integration and intelligence. However, it is undeniable that the challenges of physics, mechanical mechanics, fluidics, and biology in chip processing need to be overcome before chips can be used in clinical applications.
In the next ten or twenty years, microfluidic chips are destined to become a deeply industrialized science and technology, and the scientific research and industrial competition of microfluidic chips around the world will become increasingly fierce.
China is considered to be one of the countries with a high level of research in the field of microfluidic chips, but the domestic microfluidic chip industry is still in its infancy, and only a few microfluidic products have been launched, far behind developed countries such as Europe and the United States. Nevertheless, we are also pleased to find that in recent years, more and more microfluidic technology experts, market-oriented professionals, as well as scientific research institutions, enterprises and institutions, and investment institutions in China have begun to pay attention to and devote themselves to the industrialization of microfluidic chips. We have reason to believe that microfluidic chips will be successfully industrialized in China.
-This article is based on the author's report at the "Maritime Science Popularization Forum" hosted by the Shanghai Science and Technology Popularization Volunteer Association, and was published in the July 2024 ·issue of World Science Magazine.
END
World Science magazine edition is on sale Subscribe to it
The monthly magazine is priced at 15 yuan per issue
The annual subscription price is 180 yuan
Subscription method 1:
There is a discount for "Magazine Shop" subscription~
Subscription method 2:
Post offices across the country subscribe. Postal Code: 4-263
Subscription method 3:
For institutional subscriptions, please call
021-53300839；
021-53300838
Recommended Reading:
Liu Chenguang: Synthetic biology is playing the role of "creator". everyone
Tao Hu: Brain-computer interface, the disappearance of body boundaries | everyone
Blue ocean to green hydrogen, the future has come - everyone
Li Bo: Sensors in life|Everyone
Hu Jinbo on "Fluorine Chemistry": There is a big world in small elements - everyone